Lilly does not ﬁnance the development of the contents of the manual but its publication in all its formats, printed and electronic.

IOC 2nd Ed. (2024)

INSTRUCTIONS FOR PARTICIPATING AS AN AUTHOR 2ND INTERNATIONAL EDITION OF THE COMPEDIUM

The 2nd Edition will consist of 110 chapters. The next compendium will be communicated on our website www.ioncocare.org, and those interested can write to [email protected] where they will be given instructions on how to participate and be accepted as authors.

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All copyrights are reserved to iOncoCare (INTERNATIONAL GROUP FOR SUPPORTIVE CANCER CARE STUDY). Participation in this compendium in previous and present editions implies the cession of these rights by the authors or co-authors.

AUTHORSHIP POLICY

The authorship policy is decided by the First Author based on the contributions of each co-author and in consensus with the other co-authors.

In the event of disagreement, the Editorial Steering Committee constituted by iOncoCare (INTERNATIONAL GROUP FOR SUPPORTIVE CANCER CARE STUDY) will act as arbitration, to which the parties will address themselves to justify their position by writing to the following e-mail address:

Jose Garcia Project Manager: [email protected]

To the attention of the iOncoCare Editorial Steering Committee in the subject line: “Co-authorship Arbitration” followed by the chapter in question.

The decision of the Editorial Steering Committee will be sent in writing by e-mail to the co-authors involved and its decision will be final and not subject to appeal.

Copyright:

iOC – INTERNATIONAL GROUP FOR SUPPORTIVE CANCER CARE STUDY

National Register: 620487 NIF: ESG40650178

Project Manager: José Garcia

Editing and Printing: Rafael Diagüez – PUBLIPUNT

Adaptation of content and layout: Rafael Diagüez , Juan Fco. Moreno y Carlos Manuel Zamudio.

I.S.B.N: 9788409441525

AUTHORS

Adrián Pablo Huñis Alberto Albiol Colomer Alberto Alves Alejandro Bermejo

Alejandra Giménez-Ortiz Alexander Ariel Padrón González Alexandre Sarmento

Alice Pimentel Alicia Oliveira Alexandra Guedes Ana Barbosa

Ana Carolina Vasques Ana Carlota Caetano Ana Catarina Brás

Ana Filipa Coroado da Silva Ferreira Ana Isabel Paiva Santos

Ana Leonor Matos Ana María Comín Orce Ana Sofia Montez André Ferreira

André da Silva Ribeiro Andre Oliveira

Andreia do Carmo Lopes Ana Joaquim

Ana Teijo Quintans Andre Coutinho Andreia Silva Andrés Beltrán Giner André Pires

Beatriz Alonso de Castro Belén López Roldán Bárbara Castro

Bárbara Lima Bárbara Paracana Bernardo Santos Bruno Pereira

Bruno Moura Fernandes Candida Abreu

Carmen Salvador Coloma Carolina Carvalho Carolina Mazeda

Carlos Manuel Oliveira Soares da Costa Carolina Nunes Capucho Luzia Pereira Carlos Rabaça

Carlota Sofia Vieira Baptista Carolina Trabulo

Catarina Almeida Catarina Martins Silva Cecília Caramujo de Sá Clara Maria Dias Pinto Cláudia Sá

Cláudia Salgado Claudia Rosado Claudio Avila Andrade Claudia Matos

David Gomes Daniela Meireles Daniela Lira

Daniela Ribeiro Alves Delfim D. Duarte Diana Borges Duarte Diana Cardoso Simão Diana Correia

Diana Neto da Silva

Diana Pessoa Diogo Abreu

Diogo Augusto Ribeiro Soares* Diogo Lima Lopes

Duarte Vieira e Brito Pedro Duarte Domingues Ema da Silva Neto Fernanda Estevinho Filipa Ferreira

Filipa Pontes Flávia Fernandes

Francisco Garcia Navalón Gloria Ortega Pérez Grezia Siancas Gonzáles Gonçalo Durão Carvalho Guillermo Estrada Riolobos Henrique Costa

Helena Guedes Helena Sousa

Inês da Conceição Félix Pinto Inês Fernandes Santos

Inês Cunha

Inês Ferreira Gomes Ines Gois

Inês Leão Ines Pinheiro Inês Pintor

Inmaculada Soler-Ferrero Irene Rojo

Iria Parajó Vázquez Isa Peixoto

Isabel C. G. Fernandes

Isabel Domingues Isis Alonso

Jéssica Sobreiros Krowicki Jessica Archer Jiménez Joaquín Mosquera Martínez José García González Jose Mazarico

Joana Cruz Monteiro Joana Albuquerque Joana Marinho

Joana Duarte Albuquerque Joana Ferreira Mendes Joana Graça

Joana Liz Pimenta Joana Mendonça Joana Guimarães Joana Noronha Joana Providência João Boavida Ferreira João Barbosa Martins João Faia

Joao Faustino João Fonseca João Oliveira

Joao Paulo Gonçalves Vilas-Boas Jorge Moreira

Jorge Ricardo Sousa Rodrigues Jose Miguel Martins

José Pedro Leão Mendes

José Pedro Portela Cidade Silva João Pedro Lima

Juan Carlos Mellídez

Juan Carlos Samamé Pérez-Vargas Juan Pablo Fusco

Kiko Albiol

Lara Otero Plaza

Laura Martins Sobral Falcão Baptista Lúcia Borges

Lucrecia Ruiz Echevarría Luísa Leal da Costa Leonor Fernandes Leonor Naia

Luis Moreno Sánchez Mafalda Miranda Baleiras Mafalda Costa

Manuel Fernandez Bruno Marcos Dumont Bonfim Santos Mariana Malheiro Rodrigues Maria Menezes

Maria João Ramos Mariana Rebordão Pires Mariana Sardinha Maria Teresa Neves Marta Baptista Freitas Marta Riquito

Marta Teijo Quintáns

Martín-Igor Gómez-Randulfe Márcia Alves

Marcos Pantarotto

Margarida Batista Caldeira Massas Margarida Bettencourt

Maria del Castillo Maria Ribeiro Gomes María Rodríguez Plá

Maria Joao de Sousa Mariana Estevam Mariana Teixeira Marília Ferreira Marina Meri Abad

Marina Veloso Gonçalves Marisa Carvalho Couto Maria Madalena Machete Mário Lourenço

Martín Igor Gómez-Randulfe Rodríguez Michele Ghidini

Miguel Barbosa Mónica Mata Patricio Natacha Mourão

Nuno de Almeida Cordeiro Nuno Figueiredo

Oscar Alonso Casado

Paula Alexandra Sousa Mesquita Paulo Vilas-Boas

Paula Castilho

Patricia Cordeiro González Patricia Garrido

Patricia Chow Liu Pedro Bernardo Santos Pedro Marílio Cardoso

Pedro Miguel Antunes Meireles Pedro Simões

Rafael Matias

Raquel Barroso Varela Raquel Borrego

Raquel Margarida Gomes Martins Raquel Monteiro Vieira

Raquel Pereira Raquel Romao Rehab Ahmed Hamdy Ricardo Pinto

Rita Freitas

Rita Isabel Cebolais Bizarro Ricardo Godinho

Ricardo Roque Ricardo Prat Acín Rita Antunes Santos Rita Sousa

Ritu Dave

Rodrigo dos Santos Vicente Rosario Garcia Campelo Rui Dinis

Salvador Gámez Casado Salvador Tortajada Veler Sara Bravo

Sandra Custódio Sandra Silva

Santiago González Moreno Sara Couto Gonçalves Sara Cerejeira

Sara Gabriela Esteves Ferreira Sara Encinas

Sérgio Costa Monteiro Sergio Pascual Solaz Sara Marques Zorro Sofia Amorim

Sofia Durão Sofía Silva Díaz Sofia Pedrosa

Sofia Viamonte

Soraia Marques Carvalho Susana Sarandao

Tânia Duarte

Telma Amorim Santos Teresa Fraga

Teresa Padrão Teresa Puértolas Tiago Rabadão Tiago Valente Tomás Dinis Valter Duarte

Víctor Sacristán Santos

INDEX

Oncologic Pain
1. NEUROPATHIC PAIN. pgs.9
2. SOMATIC PAIN. pgs.13
3. VISCERAL PAIN. pgs.18
4. IRRUPTIVE PAIN. pgs.25
5. BONE PAIN. pgs.33
Emesis
1. CANCER-ASSOCIATED EMESIS. pgs. 36
2. IATROGENIC EMESIS. pgs. 39
Oncologic Emergencies
1. SPINAL COMPRESSION SYNDROME. pgs. 46
2. SUPERIOR VENA CAVA SYNDROM. pgs. 49
3. TUMOR HYPERCALCEMIA . pgs. 52
4. ENDOCRANIAL HYPERTENSION. pgs. 58
5. ACUTE BLEEDING. pgs. 64
6. INFUSION REACTIONS. pgs. 67
7. EMERGENCY KIT. pgs. 72
Immunotherapy-Associated Toxicity
IMMUNOTHERAPY-ASSOCIATED TOXICITY. pgs. 75
Neurological alterations
1. ENCEPHALOPATHIES. pgs. 88
2. WAKEFULNESS-SLEEP RHYTHM DISTURBANCES. pgs. 90
3. INSOMNIA. pgs. 92
4. MYELOPATHIES. pgs. 97
5. PERIPHERAL AND CRANIAL NERVE NEUROPATHY. pgs. 98
6. DELIRIUM IN CANCER PATIENT. pgs.105
Endocrinological alterations
1. HYPOPHYSITIS. pgs. 109
2. DIABETES. pgs. 113
3. THYROID ALTERATIONS. pgs. 117
4. ADRENAL ALTERATIONS. pgs. 124
5. CARCINOID SYNDROME. pgs. 127
Ophthalmologic disorders
1. ECTROPION – ENTROPION. pgs. 130
Constitutional
1. CANCER RELATED AND IATROGENIC ASTHENIA. pgs. 243
2. ANOREXIA CACHEXIA (FALTA CACHEXIA). pgs. 246
Nutrition in cancer patients
1. NUTRITIONAL RISK PATIENT. pgs. 249
2. MALNUTRITION IN CANCER PATIENT. pgs.254
Genito-urinary disorders
1. IATROGENIC MENOPAUSE. pgs. 260
2. ERECTILE DYSFUNCTION. pgs. 266
3. DYSPAREUNIA AND DECREASED FEMALE LUBRIFICATION.

pgs. 276

1. RADIATION THERAPY INDUCED CYSTITIS. pgs. 279

Hematological alterations
1. ANEMIA. pgs. 290
2. THROMBOCYTOPENIA. pgs. 295
3. LEUCOPENIA. pgs. 301
4. FEBRILE NEUTROPENIC SYNDROME. pgs. 306
5. BLOOD HYPER VISCOSITY. pgs. 308
Skin disorders
1. RADIATION THERAPY EPITELITIS. pgs. 313
2. ALOPECIA AND OTHER HAIR IATROGENIC DISORDERS. pgs.318
3. SKIN HYPERSENSITIVITY. pgs. 326
4. PHOTOSENSITIZATION. pgs. 336
5. HAND-FOOT ERYTRHODYSESTESIA. pgs. 339
6. UNGUAL ALTERATIONS. pgs. 346
7. SKIN TOXICITY INDUCED BY TARGETED THERAPIES. pgs. 348
Metabolic disorders
1. DEHYDRATION. pgs. 358
2. TUMOR LYSIS SYNDROME. pgs. 360
3. SODIUM METABOLISM. pgs. 365
4. POTASSIUM METABOLISM. pgs. 368
5. MAGNESIUM METABOLISM. pgs. 373
6. CALCIUM METABOLISM. pgs. 378
Kidney disorders
1. PROTEINURIA/NEPHROTIC SYNDROME. pgs.381
2. NEFROTOXICITY. pgs. 386
3. KERATITIS / KERATO-CONJUNCTIVITES SICCA . pgs. 131
4. CONJUNCTIVITIS. pgs. 133
Oropharyngeal disorders
1. OROPHARYNGEAL CANDIDIASIS. pgs. 135
2. STOMATITIS/MUCOSITIS. pgs. 137
3. XEROSTOMIA. pgs. 142
Gastrointestinal disorders
1. DIARRHEA. pgs. 145
2. INTESTINAL OCCLUSION. pgs. 149
3. CONSTIPATION. pgs. 154
4. COLITIS. pgs. 159
5. POST-RADIATION THERAPY PROCTITIS. pgs. 164
Hepato-Biliary disorders
1. LIVER FAILURE AND CHEMOTHERAPY. pgs. 167
2. HEPATIC ENCEFALOPATHY. pgs. 172
3. BILIARY OBSTRUCTION. pgs. 178
Cardiovascular disorders
1. HIGH BLOOD PRESSURE. pgs. 181
2. CONGESTIVE HEARTH FAILURE. pgs. 185
3. PERICARDIAL EFFUSION. pgs. 190
Respiratory disorders
1. PULMONARY FIBROSIS. pgs. 192
2. PNEUMONITIS. pgs. 197
3. PLEURAL EFFUSION. pgs. 201
4. BRONCHIAL HYPERSECRETION. pgs. 207
5. HEMOPTYSIS. pgs. 210
Rheumatological alterations
1. BONE DISORDERS. pgs. 216
2. CHEMOTHERAPYS AND HORMONTHERAPY ASSOCIATED RHEUMATIC COMPLICATIONS. pgs. 220
3. PARANEOPLASTIC RHEUMATIC MANIFESTATIONS. pgs. 224
4. MALIGNANT DISEASES WITH MUSCULOSKELETAL MANIFESTATIONS. pgs. 230
5. AUTOANTIBODIES ASSOCIATED TO RHEUMATIC DISEASE IN

CANCER PATIENTS. pgs. 234

1. IMMUNE CHECKPOINT INHIBITOR ASSOCIATED RHEUMATIC CONDITIONS. pgs. 235
2. RADIOTHERAPY TREATMENT ASSOCIATED RHEUMATIC

COMPLICATIONS. pgs. 241

1. Kidney Function Assessment. pgs. 390
2. KIDNEY DISORDERS: RENAL FUNCTION EVALUATION. pgs. 395

Clotting disorders
1. PULMONARY THROMBOEMBOLISM. pgs. 407
2. DEEP VEIN THROMBOSIS. pgs. 411
3. COAGULOPATHY. pgs.418
4. DISSEMINATED INTRAVASCULAR COAGULOPATHY. pgs. 424
5. BLEEDING IN CANCER PATIENT. pgs. 427
Sedation
1. SEDATION IN CANCER PANTIENT. pgs. 431
Prosthesis and endoprosthesis
1. MANAGEMENT OF OBSTRUCTIVE COLON CANCER. SELF-EXPANDING METALLIC STENT VERSUS EMERGENCY SURGERY. pgs. 435
Surgical Complications
1. SEROMAS, BRUISES. pgs. 440
2. LYMPHEDEMA. pgs. 442
3. FISTULA. pgs. 450
Exercice in cancer patients
1. EXERCISE IN CANCER PATIENT. pgs. 452
Other
1. FUNGAL INFECTIONS. pgs. 457
2. BONE METASTASIS. pgs. 473
3. PERSISTENT HICCUPS. pgs. 485
4. CANNABIS IN CANCER PATIENT. pgs. 487
5. CENTRAL VENOUS CATHETER. pgs. 494
6. VACCINATION IN CANCER PATIENT . pgs. 496
7. PATHOLOGIC BONE FRACTURES. pgs. 499
8. RISK OF SECOND IATROGENIC TUMORS (LONG SURVIVORS). pgs. 502
9. ARTIFICIAL INTELLIGENCE AND SYMPTOMS ASSOCIATED WITH CANCER AND ITS TREATMENTS. pgs. 506
10. COMMUNICATION WITH CANCER PATIENT AND FAMILY. pgs. 511
11. ADDRESSING MOURNING AT THE HEALTH CARE PROFESSIONAL. pgs. 514
12. COVID IN CANCER PATIENT. pgs. 517

Supportive care is an essential and inseparable part of the therapeutic approach to cancer patients.

A short, clear and practical decision-making compendium, accessible to all doctors and healthcare professionals who come into daily contact with cancer patients and need to understand and manage their symptoms, was missing from the literature.

INTERNATIONAL GROUP FOR SUPPORTIVE CANCER CARE STUDY publishes the “IOC 2022” as a guide to help professionals.

This compendium is intended to be the first updated review of most of the clinical situations that cancer patients may present. It identifies the clinical picture and the therapeutic orientation, with the degrees of recommendation and evidence, as well as the direct bibliographic reference for each statement.

We took a multidisciplinary approach, with the collaboration of 270 authors from 9 countries, 59 hospitals and 25 medical and non-medical specialties. This compendium (IOC 2022) is the result of the effort and innovative spirit of its authors, will be updated every two years.

The first international edition of cancer care support based on real world evidence (RWE) contains all the latest news in cancer care support treatment and assigns levels of evidence and grades of recommendation so that the reader can obtain

a quick impression and certainty of each of the treatments and strategies presented. The GRADE and OXFORD scales have been used for the levels of evidence.

GRADE SYSTEM (ADAPTED)

LEVEL OF EVIDENCE
Level 1	Evidence obtained from a Systematic Review or all Relevant Randomized Control Trials
Level 2a	Evidence obtained from at least one properly deigned Randomized Control Trial
Level 3a	Evidence obtained from well-designed Pseudo-Randomised Control Trials (alternative allocation or some other method)
Level 3b	Evidence obtained from Comparative Studies (including systematic review of such studies) with concurrent controls an allocation is nor tandomised Cohort Studies, Case Control Studies, Interrupted Time Series with a Control Group
Level 4	Evidence obtainded Case-Series-Either Post Test or Pre -Tests and Post Test
Level 5	Evidence obtained from Expert Opinion Without Critical Appraisal, or Based on Physiology, Based on Bench Resears Baed on Historically Based Clinic Principles

GRADE OF RECOMENDATION
QUALITY OF EVIDENCE	DEFINITION
High	Further research is very unlikely to change our confidence in the estimate off effect: Several high-quality studies with consistent results In special cases: one large, high quality multi center trial
Moderate	Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate One high-quality study Several studies with some limitations
Low	Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate One or more studies with severe limitations
Very Low	Any estimate of effect is very uncertain Expert opinion No direct research evidences One or more studies with very severe limitations

Oxford Center for Evidence-Based-Medicine Hierarchy (adapted)

Adapted from: “levels of Evidence (Oxford Centre for Evidence-based Medicine-March 2009)

The toxicity grades follow the CTCAE v5.0 classification.

We would like to thank all the authors for their work and dedication to this project. Without the effort of all of them it would not have been possible.

Level	Rec.	Therapy/Prevention, Etiology/Harm
1a	A	Systematic Review (with homogeneity) of randomized controlled trials
1b	A	Individual Randomized Controlled Trial (with narrow confidence interval)
1c	A	All or none
2a	B	Systematic Review (with homogeneity) of cohort studies
2b	B	Individual cohort study (including lox quality Randomized Controlled Trial
2c	B	“outcomes” research; Ecological studies
3a	B	Systematic Review (with homogeneity) of case control studies
3b	B	Individual case-control study
4	C	Case-series (and poor-quality cohort and case-control studies)
5	D	Expert opinion

Dr. Juan Carlos Mellídez – Coordinator

Cancer is part of our lives. Who has not had a relative, a friend or even experienced first-hand the consequences of suffering from a tumour pathology? Who has not, to a greater or lesser extent, talked about cancer in the last year? Who has not panicked because something has gone wrong in a medical test recently carried out on someone dear to them? While it is true that the prognosis for cancer has improved dramatically over the last few years, the word still has a negative quality to it. It is still, if you will pardon the expression, a word that no one likes to hear, for many people it is hopelessly associated with death. Nothing could be further from the truth. Most tumours can be cured with early diagnosis and timely treatment. We have improved diagnostic techniques, we have more and better treatments, mostly as a result of a better understanding of the molecular biology of cancer. Vast amounts of resources are devoted to cancer research. However, too often we forget the essence of what we do; our patients. We are getting better at treating cancer and worse at treating cancer patients.

That is why this compendium is so necessary. Because it addresses what patients care about. How they feel; what they may experience; the “famous” side effects. Symptoms related in one way or another to cancer and/or its treatments. Thanks to this group of experts (iOncoCare), we bring the needs of patients closer to clinical practice to help you treat not only cancer better, but above all the patients who suffer from it.

Javier Cortés

ONCOLOGIC PAIN

NEUROPATHIC PAIN

Authors: Adrián Pablo Huñis, Sara Zorro and José Pedro Cidade. . Evidence

Definition

Neuropathic or neurogenic pain (NP) is defined by the International Association for the Study of Pain (IASP) as pain initiated or caused by a lesion or dysfunction of the nervous system .
What differentiates NP from other types of pain is its poor response to cyclooxygenase-2 inhibitors and opioids. At any stage of life, NP is more common in women than in men . Approximately 70% of the patients have chronic NP .

Symptoms

Symptoms are very varied. Pain can be associated to sensory abnormalities (paraesthesia, allodynia, dysesthesia, hyperalgesia) and have different characteristics (burning, tingling, shooting, stabbing, cramping, electric shock-like pains, etc.) (Table 1)(Jensen et al. 2001).

Table1: Sensory abnormalities and characteristics of neuropathic pain

Level Grade PMID Nº

16827265

18439759

18003941

11698022

Dysesthesia

Unpleasant abnormal sensations:

Burning sensation
Sunburn-like
Skin tingles

Etiology

Paraesthesia

Abnormal sensations that are not unpleasant:

Pins and needles
Electric-like
Numb but achy
Like feet in ice water

Allodynia

Pain due to a stimulus that does not normally provoke pain.

Hyperalgesia

Increased pain from a stimulus that normally provokes pain.

Neuropathic pain is traditionally classified based on underlying disease. In the ICD11 classification, neuropathic pain is first organized into peripheral and central neuropathic pain based on the location of the lesion or disease in the peripheral fibres (Aβ, Aδ and C fibres or central somatosensory nervous system . It affects 7–10% of the general population .

A focal peripheral nerve injury can result in a range of peripheral and central nervous system events that contribute to the persistence of pain. The inflammation, the reparatory mechanisms of neural tissues in response to injury, and the reaction of adjacent tissues to injury lead to a state of hyperexcitability termed peripheral sensitization. Then, central neurons innervated by primary afferent nociceptors undergo dramatic functional changes including a state of hyperexcitability termed central sensitization. Normally, these sensitization mechanisms stop as the tissue heals and inflammation disappears. However, when primary afferent function is altered, the process persists .

Positive sensory phenomena (spontaneous pain, allodynia, and hyperalgesia) characteristic of NP has many underlying mechanisms, including ectopic generation of impulses as well as the expression of new neurotransmitters and their receptors and ion channels. In conclusion, the processes involved in the pathophysiology of NP are the following :

- Increased firing of stimuli by the primary afferent nociceptor as result of an abnormal amount of sodium channels in damaged peripheral nerves causing ectopic discharges.
- Decreased inhibition of neuronal activity in central structures due to loss of inhibitory neurons.
- Altered central processing (central sensitization) so that the input of sensory impulses is amplified and sustained.

NP can be caused by alcoholism, diabetes (risk factor for pharmacological neuropathic pain), metabolic disfunctions, central nervous system disorders (stroke, Parkinson’s disease, multiple sclerosis, etc.), complex regional pain syndrome, fibromyalgia, HIV infection or AIDS, postherpetic neuralgia, chemotherapy drugs (oxaliplatin, cisplatin, paclitaxel, vincristine, vinorelbine, thalidomide, bortezomib), radiation therapy, surgery, amputation (phantom pain), spinal nerve compression or inflammation, nerve compression or infiltration by tuomrs .

28205574

30586071

12707429

12620591

21356652

29056655

33671327

32584191

33858611

The diagnosis of NP is not always straightforward because symptoms are very varied. A thorough medical history that includes the patient´s symptoms, work environment, social habits, exposure to toxins, alcoholism history, risk of human immunodeficiency virus and other infections and family history of neurological diseases is essential. Diabetes, vitamin deficiencies, liver or kidney dysfunction, and abnormal immune system activity should be ruled out.

In the patient´s anamnesis and clinical examination, pain is assessed according to duration, site, distribution, intensity, associated sensory abnormalities (paraesthesia, allodynia) and qualities (burning, tingling, shooting, stabbing, cramping, electric shock-like pains, etc.) .

There are several tools based on pain descriptors to distinguish NP from non-NP (screening tools) and characterize multiple neuropathic phenotypes (assessment tools). The main advantage of screening tools is to identify potential patients with NP, particularly by non-specialists. However, these tools fail to identify 10–20% of patients with clinician diagnosed NP and cannot replace careful clinical evaluation. Pain quality assessment tools are useful to discriminate amongst various pain mechanisms associated with distinct NP experiences.

Diagnostic Studies

Screening Tools

- The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) contains ﬁve symptom items and two clinical examination items. It has also been validated as a self- report tool, the S-LANSS. Compared to clinical diagnosis, its sensitivity and speciﬁcity range 82–91% and 80–94%, respectively .
- The Neuropathic Pain Questionnaire (NPQ) contains 12. It demonstrated 66% sensitivity and 74% speciﬁcity, compared to clinical diagnosis in the validation sample.
- The Douleur Neuropathique in 4 questions (DN4) contains seven items related to symptoms and three related to clinical examination. A total score >=4 out of 10 suggests NP. It showed 83% sensitivity and 90% speciﬁcity when compared to clinical diagnosis in the development study.
- Pain DETECT was developed and validated in German and is available in several other languages. It is a self-report questionnaire with nine items. It correctly classiﬁes 83% of patients to their diagnostic group with 85% sensitivity and 80% speciﬁcity .

Assessment Questionnaires

- The Neuropathic Pain Symptom Inventory (NPSI) was originally validated in French and has been submitted to linguistic validation in 50 other languages. It is recommended to evaluate treatment e ects on neuropathic symptoms or their combination –.

Neurophysiology

- The trigeminal reﬂexes mediated by Aβ ﬁbres are useful in the diagnosis of trigeminal pain disorders. They are abnormal in patients with structural damage, in conditions such as trigeminal neuropathy (TN) and postherpetic neuropathy (PHN), and normal in patients with classic trigeminal neuralgia.
- Laser-evoked potentials are useful for assessing function of the Aδ ﬁbre pathways in patients with NP .

Skin Biopsy

- Small ﬁbres dysfunction.

Pain Scales

- Pain scales such as the Numerical Rating Scale (NRS), Verbal Rating Scale (VRS), or Visual Analogue Scale (VAS) are useful tools to assess the intensity of pain and treatment effect .

11698022

16091164

20298428

I High 11323136 15772908

20298428

20851519

I High 12966256 20298428

20851519

I High 15733628 20298428

20851519

I High 17022849 24200014

20298428

I High 15030944 31431674

20298428

I High 16401867 30860637

18721143 18716236

I High 20298428 23040705

28106318

I High 34335876 33802768

20642627

I High 20851519 22588748

21621130 29794282

First Line Treatment
- Multidisciplinary care in conjunction with gabapentinoids, tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), are the first-line agents for treating neuropathic pain. A four to six-week trial is recommended with at least two reviews to assess effectiveness .
Second Line Treatment
- Tramadol, a weak u-opioid agonist and inhibitor of serotonin and norepinephrine reuptake, is considered second-line treatment in most guidelines but first-line in cancer- related neuropathic pain.
- Tapentadol is a strong analgesic with a dual mechanism of action that combines μ-opioid receptor agonism (MOR) and norepinephrine reuptake inhibition (NRI). Experimental and clinical evidence indicates that its NRI component may become predominant in NP conditions. It proved to be effective in the treatment of diabetic peripheral neuropathy (DPN).
- Lidocaine 5% works by decreasing ectopic firing of peripheral nerves. It is recommended for the treatment of focal neuropathic pain such as PHN. Safety and tolerability are excellent.
- Capsaicin 8% patches acts through binding to the TRPV1 receptor located on the Aδ and C-nerve fibres. This results in release of substance P and depolarization of the nerve. Long-term exposure causes overstimulation, depletion of substance P, desensitization of the nerve, and reversible nerve degeneration. It is recommended for the treatment of PHN and HIV peripheral neuropathy .
Third Line Treatment
- Strong opioids (particularly oxycodone and morphine) have weak recommendations for use and are recommended as third line. Prescription of opioids should be strictly monitored particularly for patients requiring high dosages .
- Botulinum toxin (BoNT) is a potent neurotoxin produced by Clostridium botulinum, which blocks acetylcholine release at neuromuscular junctions causing muscle relaxation. The mechanism of action of BoNT in NP is related to the inhibition of the release of neurotransmitters and neuropeptides involved in pain mechanisms and inflammation (substance P, CGRP, glutamate). BoNT/A seems helpful in TN, PHN, painful diabetic neuropathy (PDN), occipital neuralgia, post-surgical pain and in SCI-related pain. However, ore studies are needed to confirm the efficacy, tolerability, and dose of BoNT.
- Oro mucosal cannabinoids are prepared from extracts of the plant cannabis sativa . Delta-9-tetrahydrocannabinol (THC), a partial agonist of cannabinoid type 1 (CB1) and type 2 (CB2) receptors, mimics the effects of endogenous cannabinoids. Activation of cannabinoid receptors by endogenous or extraneously administered cannabinoids has multiple analgesia-associated effects mediated by the peripheral and central nervous systems . The quantity and quality of evidence are such that cannabis-based medicines may be reasonably considered for chronic neuropathic pain . Patients must be kept under close clinical surveillance, mainly because of negative results, potential misuse, abuse, diversion, and long-term mental health risks.
Fourth Line Treatment
- For those patients with neuropathic pain who are unable to achieve an acceptable quality of life, neurostimulation is a treatment option .

20402746 31152178

20194146 25575710

25479151

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20402746

31152178

25479151

29737410

31190965

25575710

31152178

28530786

25575710

25479151

28837075

32104061

30074291

31152178

· GABAPENTINOIDS

Gabapentin:

Level Grade PMID Nº

31152178

· TOPICALS (FOCAL NEUROPATHIC PAIN)

5% lidocaine:

Level Grade PMID Nº

31152178

Dose: Slow titration up to 600mg 8h/8h, until max daily dose of 3600mg.
Cautions: Reduce dose for renal impairment.

Pregabalin:

Dose: Start at 150mg 12h/12h or 8h/8h, until max daily dose of 600mg.
Cautions: Reduce dose for renal impairment.

· ANTIDEPRESSANT AGENTS

Nortriptyline (TCA):

Dose: Start at 10–25mg before bed, until max daily dose of 150 mg.
Cautions: Autonomic neuropathy, urinary retention, glaucoma.

Amitriptyline (TCA):

I High 25575710

29737410

31152178

I High 29737410

I High 31152178

Most useful for postherpetic neuralgia. I
Dose: Available in cream or patch. Apply to site of pain 12 hours on, 12 hours off, until max of three patches at one time.
Cautions: Virtually has no systemic side effects.

8% capsaicin:

Most useful for postherpetic neuralgia (PHN). I
Dose: Apply for 60 minutes under supervision of a physician.
Cautions: Avoid in diabetic peripheral neuropathy. Is painful on initial application, and its efficacy depends on regular consistent use.

Low 20194146

25479151

20402746

25575710

31152178

High 20194146

25479151

20402746

25575710

- Dose: Start at 10–25mg before bed, until max daily dose of 150 mg. I
- Cautions: More likely to produce drowsiness and anticholinergic side effects.

Mod. 31152178

25575710

WEAK μ-OPIOID AGONISTS AND SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS

Taking SNRI, SSRI, MAOI, and/or tramadol.

Duloxetine (SNRI):

- In the management of chemotherapy-induced painful peripheral neuropathy I showed a significant reduction in pain intensity relative to placebo.
- Dose: Start at 30mg daily, until max daily dose of 60mg.
- Cautions: Renal or liver disease.

Venlafaxine (SNRI):

- Has shown efficacy in trials involving painful diabetic neuropathy and mixed I painful polyneuropathy.
- Dose: Start at 3mg daily, until max daily dose of 60 mg.
- Cautions: Renal or liver disease.

High 31152178

23549581

High 31152178

23549581

Tramadol:

- Most useful for postherpetic neuralgia. I
- Dose: Start at 50mg immediate release from two to four times a day, until max daily dose of 400mg.
- Cautions: Seizure disorder. Taking SNRI, SSRI, TCA, and/or MAOI. Reduce dose for renal impairment.

Tapentadol:

- Some efficacy in DPN. I
Dose: Start with 50mg every 12h, until max of 300–450 mg/day.
Cautions: Constipation.

31152178

Mode 20194146

rate 25479151

20402746

25575710

31152178

Low 20194146

21162697

25575710

31190965

· STRONG OPIOIDS

Morphine:

Level Grade PMID Nº

28530786

CANNABINOIDS

Tetrahydro-cannabinol/cannabidiol:

Level Grade PMID Nº

25575710

- Dose: Start with 15mg every 12h, until max of 120 mg every 12h.
- Cautions: Constipation requiring laxatives. Monitor for addiction.

Oxycodone:

- Dose: Start with 10 mg every 12h, until max of 20–60 mg every 12h.
- Cautions: Constipation requiring laxatives. Monitor for addiction.

I Mod. 21621130

23549581

28530786

I Mod. 21621130

23549581

Dose: Start with 0.25–0.5mg at night; increase weekly by 0.5 mg/day. I
Cautions: Causes positive urine drug testing for cannabinoids. Monitor application site (oral mucosa).

Nabilone:

Dose: Start with 1–2 sprays every 4h, max 4 sprays on day 1; titrate slowly. I
Cautions: Does not test positive for cannabinoids on routine urine drug testing.

Mod. 25479151

32104061

30074291

25575710

Mod. 25479151

32104061

30074291

SOMATIC PAIN

Authors: Helena Isabel Poças da Silva e Sousa and Margarida Bettencourt.

Definition1

Somatic pain is a type of nociceptive pain, typically described as well localized (distribution of the somatic enervation), as aching, stabbing, or pressure. It is defined as a pain resulting from the reduced irritability threshold in nociceptors located in superficial (cutaneous pain from skin cancer) or deep structures (muscles, bone marrow infiltration).

Symptoms2,3,4

Musculoskeletal pain – Pain caused by metastasis to the bone is the most common source of moderate and severe cancer pain
Referred pain
BTcP – transient pain exacerbation that can occur in patients with stable and adequately controlled background pain.

Etiology2

Pain syndromes are divided into those arising from

A direct effect of a neoplasm on nearby tissues and structures (85%) – invasion of the skin, connective tissue, bone, or joints
side effect of a treatment (17%) – mucositis resulting from radiation or chemotherapy, postsurgical incisional pain or spasm of muscle from tissue damage
pain due to disease progression (9%),
and pain from other causes not related to malignancy.

Studies5,6

Assess the components of the pain.

Causes, onset, type, site, absence/presence of radiating pain, duration, intensity, relief and temporal patterns of the pain, number of BTcPs, pain syndrome, inferred pathophysiology, pain at rest and/or moving.

The intensity of pain and the treatment outcomes should be assessed regularly and consistently using the VAS or NRS using the question: ‘What has been your worst pain in the last 24 hours?’ [V, D]

Observation of pain-related behaviours and discomfort is indicated in patients with cognitive impairment to assess the presence of pain [V, C]

Evidence

Level Grade PMID Nº

Description of the pain quality.

Aching, throbbing, pressure: often associated with somatic pain in in skin, muscle and bone. Aching, cramping, gnawing, sharp: often associated with visceral pain in organs or viscera. Shooting, sharp, stabbing, tingling, ringing: often associated with NP caused by nerve damage

Presence of trigger factors and signs and symptoms associated with the pain; Presence of relieving factors.
Use of analgesics and their efficacy and tolerability.
Impact in the patient daily life.

The assessment of all components of suffering, such as psychosocial distress, should be considered and evaluated [II, B]

Treatment7, 8, 9, 10, 11, 2

A comprehensive and holistic approach to the treatment of cancer pain is a standard of care. This would include pharmacologic as well as nonpharmacologic modalities. Many chronic pain syndromes are mixed, thus requiring a combination of treatment approaches and medications targeting a variety of nociceptor sites. The WHO proposes a strategy for cancer pain treatment based on a sequential three-step analgesic ladder, from non-opioids to weak opioids to strong opioids, according to pain intensity.

Treatment strategy

Step I – mild pain

Non-opioids

Evidence

Level Grade PMID Nº

30052758

- Paracetamol (acetaminophen): analgesic and antipyretic. It has hepatic and renal toxicity. It was insufficient evidence to support use of paracetamol in combination with step 3 opioids
- Nonsteroidal anti-inflammatory drugs [NSAIDs] – side effect profile problematic in high-risk groups – gastrointestinal bleeding, vascular risks and nephrotoxicity. There is no significant evidence to support or refute the use of NSAIDs alone or in combination with opioids for mild to moderate pain.

Asystematic review of the safety and efficacy of NSAIDs in cancer pain found NSAIDs to be approximately equivalent to 5 to 10mg intramuscular morphine.

- Adjuvant analgesics work at different levels to relieve pain.

Step II – moderate pain

“Weak” opioids“

For mild to moderate pain, weak opioids such as tramadol, dihydrocodeine and codeine can be given in combination with non-opioid analgesics.

- Tramadol – Up to 10% of patients are slow metabolizers and derive a weaker analgesic effect.

In the dose 100 mg causes similar analgesia to 10 mg of morphine when the drugs are given orally. Advertencies:

1. Side effects: dizziness, nausea, vomiting and constipation
2. Affects serotonin metabolism or availability, potentially leading to serotonin toxicity (particularly in the elderly), and can lower seizure thresholds
- Codeine – has no or little analgesic effect until metabolised to morphine, mainly via CYP2D6 (ineffective in poor metabolisers).

After oral administration, 60 mg DHC analgesic activity is similar to 10 mg of morphine. Prescribed as both an analgesic and an antitussive agent. Advertencies:

Side effects: nausea, vomiting and constipation.
Hypersensitivity, asthma, DPOC, respiratory depression.
Low metabolizers with 5 to 10% of patients having no clinical benefit.

Step III – severe pain

Low-dose formulations of strong opioids

There is no evidence of increase in adverse effects from the use of low-dose strong opioids instead of the standard step 2 approach with weak opioids

I C 30052758

I C 32119322 28220448

19117155 21448038

22126843 29432225

I C 30052758

21448038

I C 28326952 10388250

3 C 30052758

3 C 28220448 21448038

20935619 22300860

20946274

30052758

20946274

31166900

2 C 30052758

Level Grade PMID Nº

Morphine is the opioid of first choice for moderate to severe cancer pain. I

The average relative potency ratio of oral to i.v. morphine is between 1:2 and 1:3. 2

The average relative potency ratio of oral to s.c. morphine is between 1:2 and 1:3. 4

M6G is an active metabolite that contributes significantly to morphine’s analgesic effects, whereas M3G is inactive as an analgesic, but may cause paradoxical central neuroexcitatory effects.

Large presystemic elimination (in gut wall and liver). Advertencies:

1. adjustment of doses is required in renal dysfunction.Drug interactions: Ranitidine, rifampicin, valspodar. 2

Oxycodone – The analgesic effect seems to have less individual variability compared to codeine. There is a lack of good evidence to support the use of oxycodone over morphine. Compared with morphine showed less sedation, delirium, vomit and itching, and less constipation in the association with naloxone.

It is extensively metabolized to nor oxycodone, oxymorphone, and their glucuronides. Nor oxycodone is reported to be a considerably weaker analgesic than oxycodone.

Hydrocodone – some patients are slow or fast metabolizers causing problems of variability with analgesic efficacy and toxicity. Hydrocodone is commonly combined with paracetamol, limiting the maximum allowable dose that can be administered.
Hydromorphone – rapid onset and increased potency (high lipophilicity). Unlike other opioids, hepatic metabolism is independent of the CYP450 isoenzymes. The renally excreted metabolite hydromorphone-3-glucuronide can accumulate (excitatory neurotoxic effects including myoclonus and restlessness). It absorbed in colon.
Hydromorphone – rapid onset and increased potency (high lipophilicity). Unlike other opioids, hepatic metabolism is independent of the CYP450 isoenzymes. The renally excreted metabolite hydromorphone-3-glucuronide can accumulate (excitatory neurotoxic effects including myoclonus and restlessness). It absorbed in colon.

Very little data on potential interactions. 4

Without immunosuppressor effect. 2a

Fentanyl – much rapid onset and greater potency due to its lipophilicity (can be administered intravenous, subcutaneous, as well as intrathecally). Transdermal patch is frequently used when cannot be administered orally – The t.d. route is usually contraindicated during the titration phase, in opioid-naive patients or to control BTcP.

Safe to use in hepatic insufficiency. Advertencies:

1. Concomitant use with potent CYP P450 3A4 inhibitors (ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazodone) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression

Buprenorphine – In some trials, intramuscular buprenorphine is 25 times more potent than intramuscular morphine, and sublingual buprenorphine is 15 times more potent than intramuscular morphine.

Advertencies:

Risk of prolonged QT with doses >20mcg/h.
Precaution in respiratory disease, hypothyroidism, mixedeme, Addison Disease, central nervous system disease
Is not expected to cause significant alteration of other drugs’ metabolism because of the low plasma concentrations reached after transdermal application. Fentanyl TD and buprenorphine TD can be useful in patients with nausea, vomiting, problems with swallowing, constipation and poor compliance.

Fentanyl and buprenorphine (via the t.d. or i.v. route) are the safest opioids in patients with chronic kidney disease stages 4 or 5 (estimated glomerular filtration rate < 30 3

mL/min)

Tapentadol – it is a more potent mu-receptor agonist and a noradrenaline reuptake inhibitor, although a much weaker serotonin reuptake inhibitor – better adverse effect profile (because it has low plasma protein binding activity and is not metabolized by the CYP system). It proved non-inferior to standard opioids like morphine or oxycodone in the management of moderate-to-severe cancer pain.

Proved efficacy in nociceptive and neuropathic pain.

A 30052758

C 30052758

28220448 21448038

B 18503626

31166900

18503626

28220448 21448038

32302346

28220448 21448038

32302346

18503626

32302346 18503626

30052758

32302346

32302346 18503626

28220448 32909847

16010532 18503626

30052758 22300860

28220448

B 30052758

28220448 31190966

34471056

31166900

Advertencies:

1. Nausea, vomiting, somnolence, and dizziness
2. Should not be associated with buprenorphine, SSRI (associated with serotoninergic syndrome), cetoconazol or fluconazole (excretion inhibition of Tapentadol)
Methadone – treatment of complex pain associated with advanced cancer and neuropathic pain syndromes in which conventional opioids were no longer effective. Its big concern is the individual variability in metabolism and the difficulty in titrating the correct dose.

Adverse effects: myoclonus, sedation, confusion, nausea and vomiting.

A different opioid should be considered in the absence of adequate analgesia (despite opioid dose escalation) or in the presence of unacceptable opioid side effects. Step IV – interventional approaches: nerve blocks, neurolytic blocks and intrathecal drug delivery	3	C	30052758
Interventional techniques include nerve blocks, neurolytic blocks (including spinal neurolytic blocks and cordotomy) and intrathecal (i.t.) drug delivery (spinal or epidural).
Employed to provide an immediate pain control after surgical procedures and to alleviate refractory chronic oncologic pain when oral analgesics fail to provide a satisfactory pain			30320541
relief, or when is hindered by debilitating adverse effects of the medications.
These interventional strategies are not appropriate in patients with infections, coagulopathy or very short life expectancy.
Intrathecal drug delivery	2	B	30052758
Intraspinal techniques (both epidural and intrathecal routes) should be considered when patient experiences pain in head and neck, upper and lower extremities, and trunk,
although it is more likely to be useful for pain below the diaphragm.
This form of pain relief includes percutaneous catheters, tunnelled catheters, and implantable programmable pumps.
When compared with epidural, i.t. drug delivery presents fewer catheter problems, smaller drug dose requirement and fewer adverse effects.
Peripheral nerve blocks – when pain occurs in the field of one or more peripheral nerves, or if pain is caused by complications such as pathological fracture or vascular			28265859
occlusion.
Used together with systemic combined analgesia.
Neurolytic blockade – limited to patients with short life expectancy (produce a block lasting 3– 6months).
It can be used for the sympathetic system for visceral pain as well as for spinal neurolytic purposes for somatic pain. Spinal neurolytic blocks are used when pain is localised to a
few dermatomes.
Spinal neurolytic blocks: for focal somatic pain in a small number of dermatomes.
Side effects of this neuroablative technique includes numbness or dysesthesia.
Cordotomy (also called spinothalamic tractotomy) should be considered in patients with poorly controlled cancer-related pain.	5	C	30052758
It results in selective reduction of pain and temperature perception on the contralateral side, up to several segments below the level of the disruption – via percutaneous, open,			28265859

Level Grade PMID Nº

31166900

32874036 32599153

32564328

endoscopic, or trans discal approach.

The use of open cordotomy has diminished significantly in recent years because of the advent of other less invasive approaches.

Other therapies

For advanced cancer patients with pain not fully alleviated by opioid therapy, the additive effect of different cannabis-based therapies to the ongoing opioid treatment remains 2 D unclear.

30320541

30052758

28934780

Farmacotherapy Level GradeEvidence

PMID Nº

Step I

Paracetamol: 500-1000mg (PO or IV). 4000mg/24h. It can be combined with codeine or tramadol (step II) 2 B
Metamizol: 500-2000 mg (PO or IM) each 8h; rectal route 1g/6-12h. 8000mg/24h.
Ibuprofen: 200-600mg/per os/6-8h. 1200mg/24h. I A
Cetorolac: 10-30mg/PO/6h; 10mg/IM/single dose; 30mg/rectal route/single dose. 40mg/24h. 1b A Cetorolac 10mg/IM/single dose is as effective as cetorolac 30mg/IM/single dose.
If CV risk factors, should be prescribed naproxen (1 g/24 h) or low dose ibuprofen (<1200 mg/24 h). If high risk of upper GI complications, NSAIDs should be avoided; for those in whom it is essential, celecoxib (200 mg/24 h) plus a proton pump inhibitor has been recommended.

WHO step II

Codeine: 30mg/PO/4-6h. Maximum dose 240mg/24h PO (because of association with paracetamol). If > 360mg/24h, should be done rotation to a strong opioid (step III) 2a B
Tramadol: prolonged release, 400mg/24h PO. IV dose is about 50% of the oral dose.

WHO step III

Morphine: PO treatment should be started with immediate release 5mg (if opioid naïve) or 10mg (if opioid tolerant). In PO treatment manutention the modified-release are I A preferred: start with 10-30mg in 12/12h. If IV, IM or SC route used: 10-20mg/mL. 60mg/24h PO, 30mg/24h SC.

Starting a low-dose strong opioid (e.g., ≤30 mg/day oral morphine) has been shown to give better pain relief than using weak opioids such as codeine

The NCCN Guidelines (2015) recommend starting with immediate-release oral morphine or equivalents at 5 -15 mg. If pain does not diminish or increases, the dose should be 2 C increased by 50 -100%; if pain decreases, but remains severe, the same dose should be repeated, up to a maximum of three doses. If pain decreases, the same dose should be

maintained for 24 h, then changed to oral or transdermal administration.

If the pain improves, the dose should be calculated for 24 h and divided into 4-6 h intervals.

Oxycodone: 30-40mg/24h PO.
Hydromorphone: initial dose of 4mg/24h and increment of 4-8mg/24h.
Oxycodone or hydromorphone, in both immediate-release and modified-release formulations for oral administration.

There are no differences between morphine, oxycodone, and hydromorphone. Treatment typically starts with immediate-release doses every 4 h.

Fentanyl TD: 600mcg/24h = 25 mcg/h patch. Effective systemic analgesic concentrations reached in 3-24h (steady state plasma concentrations 36-48h). Similar absorption in thorax, abdomen, and thigh (rotation of the region in each application).
Buprenorphine TD – 600 mcg/24 h = 25 mcg/h patch. Analgesic effect in 30 minutes. Similar absorption in thorax, abdomen, and thigh (rotation of the region in each application).
Tapentadol: prolonged release, start with 50mg 12/12h.

Doses of Tapentadol may be increased at least up to 400-500 mg/day, which corresponds to the range of 60-150 mg/day of oral morphine equivalents.

Methadone is available as a liquid suspension (5mg/ml) and oral tablet (5mg, 10mg) which is administered by oral, buccal, sublingual routes and less preferred being rectal, intravenous, subcutaneous, and intrathecal routes.
A different opioid should be considered in the absence of adequate analgesia (despite opioid dose escalation) or in the presence of unacceptable opioid side effects.
if despite opioid titration the patient experiences pain scoring >4 on an 11-point numeric rating scale and adverse drug reactions occur, namely nausea for >1 week or sedation for more than 2 to 3 days. If refractory obstipation occurs, rotation to fentanyl or methadone is explicitly recommended.
The SC route is simple and effective for the administration of morphine, diamorphine and hydromorphone and it should be the first-choice alternative route for patients unable to 3 B receive opioids by oral or TD routes.

2196536

15654708

9620101 31800611

29436434

31166900	29436434
	29436434
29436434	30052758
	29436434
30052758	28326952
	29436434
	31166900
30052758	28326952
22300860	28220448
	29436434
29436434	31166900
	31166900
30052758	22300860
32874036	32599153
	32564328
	30052758
	29563006
	30052758

IV infusion should be considered when SC administration is contraindicated (peripheral oedema, coagulation disorders, poor peripheral circulation and need for high volumes and doses).
IV administration is an option for opioid titration when rapid pain control is needed.

Fourth step WHO ladder: nerve blocks, neurolytic blocks and intrathecal drug delivery

Intrathecal drug delivery

The exact dosage comparison of different opioid analgesic agents for intraspinal use is difficult. It is generally accepted that the dose of morphine sulphate for intrathecal route is one-tenth the dose for epidural route, which, in turn, is one-tenth the intravenous dose.

Evidence Level Grade PMID Nº

30052758 22300860

32799614 12516896

References

PMID: 31085106. Russo, M.M, Sundaramurthi, T. An Overview of Cancer Pain: Epidemiology and Pathophysiology. Semin Oncol Nurs, 2019. doi: 10.1016/j.soncn.2019.04.002.
PMID: 12703331. Burton AW. Acute, Chronic, and Cancer Pain: Clinical Management. Methods Mol Med. 2003. DOI: 10.1385/1-59259-379-8:267 3. PMID: 24799469
PMID: 30052758. Fallon M, Giusti R, Aielli F, Hoskin P, Rolke R, Sharma M, Ripamonti C.I. Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines. European Society for Medical Oncology, 2018. DOI: 10.1093/annonc/mdy152.
PMID: 31980005. Chapman, E.J., Edwards, Z., Boland, J.W., Maddocks, M., Fettes, L., Malia, C., Et al. Practice review: Evidence-based and effective management of pain in patients with advanced cancer. Palliat Med, 2020. doi: 10.1177/0269216319896955.
PMID: 21856077. Valente, M.A.F., Ribeiro, J.L.P., Jensen, M.P. Validity of four pain intensity rating scales. Pain, 2011. doi: 10.1016/j.pain.2011.07.005.
PMID: 28326952. Lara-Solares, Argelia; Olea, Marisol A.; Pinos, Amparito A.; et al. Latin-American guidelines for cancer pain management. Pain Manag. 2017. DOI: 10.2217/pmt-2017-0006.
PMID: 32119322. Anekar A, Cascella M. WHOAnalgesic Ladder. StatPearls, 2021.
PMID: 28265859. Candido, Kenneth; Kusperm Teresa M.; Knezevic, Nebojsa N. New Cancer Pain Treatment Options. Curr Pain Headache Rep. 2017. DOI: 10.1007/s11916-017-0613-0
PMID: 28220448. Liu, Weiyang C.; Zheng, Zhong X.; Tan, Kian H; Meredith, Gregory J. Multidimensional Treatment of Cancer Pain. Curr Oncol Rep. 2017. DOI: 10.1007/s11912-017-0570-0.
PMID: 7500538. Jadad AR, Browman GP. The WHO analgesic ladder for cancer pain management: Stepping up the quality of its evaluation. JAMA. 1995. Doi:10.1001/jama.1995.03530230056031

VISCERAL PAIN

Authors: Helena Isabel Poças da Silva e Sousa and Margarida Bettencourt. Evidence

Definition1, 2, 3

Visceral pain affects approximately 70% of patients with advanced cancer disease.
It is diffuse and poorly localized, often characterized by ill-defined deep, squeezing, or colicky sensations, includes the involvement of multiple luminal organs at once, with visceral differentiation often relying on the determination of associated pathology and changes in organ function.

Symptoms4, 5, 3

Visceral pain is often associated with dysautonomia including pallor, sweating, nausea or vomiting, and cardiovascular perturbations.
Acute pain syndromes – related directly to the cancer or to antineoplastic therapy, or to diagnostic or therapeutic interventions.
Breakthrough cancer pain (BTcP), defined as ‘a transitory flare of pain that occurs on a background of relatively well-controlled baseline pain’, requires careful assessment and appropriate management. Typical BTcP episodes are of moderate to severe intensity, rapid in onset (minutes) and of relatively short duration (median 30 minutes).

Level Grade PMID Nº

Etiology1, 3, 6, 7

Neoplasms generate visceral pain through numerous mechanisms including chemical release from cancer and immune cells, distension or obstruction of luminal organs, and direct nerve compression or infiltration.
Localization is challenging due to the low density of visceral sensory innervation and secondary hyperalgesia caused by referral to parietal somatic structures.
Mechanisms continue to be poorly understood but are generally thought to involve sensitization of primary sensory afferent innervating visceral organs, dysregulation of descending pathways that modulate spinal nociceptive transmission, and hyperexcitability of spinal ascending neurons that receive synaptic input from the viscera.

Studies 8, 9

Assess the components of the pain: Causes, onset, type, site, absence/presence of radiating pain, duration, intensity, relief and temporal patterns of the pain, number of BTcPs, pain syndrome, inferred pathophysiology, pain at rest and/or moving

The intensity of pain and the treatment outcomes should be assessed regularly and consistently using the VAS or NRS using the question: ‘What has been your worst pain in the last 24 hours?’ [V, D]
Observation of pain-related behaviours and discomfort is indicated in patients with cognitive impairment to assess the presence of pain [V, C]

Description of the pain quality:
- - Aching, throbbing, pressure: often associated with somatic pain in skin, muscle and bone
  - Aching, cramping, gnawing, sharp: often associated with visceral pain in organs or viscera
  - Shooting, sharp, stabbing, tingling, ringing: often associated with NP caused by nerve damage
Presence of trigger factors and signs and symptoms associated with the pain, Presence of relieving factors
Use of analgesics and their efficacy and tolerability
Impact in the patient daily life

The assessment of all components of suffering, such as psychosocial distress, should be considered and evaluated [II, B]

Evidence

Level Grade PMID Nº

1. Assess the components of the pain

Observation of pain-related behaviours and discomfort is indicated in patients with cognitive impairment to assess the presence of pain [V, C]

Evidence Level Grade PMID Nº

2. Description of the pain quality

Aching, throbbing, pressure: often associated with somatic pain in in skin, muscle, and bone.

Aching, cramping, gnawing, sharp: often associated with visceral pain in organs or viscera. Shooting, sharp, stabbing, tingling, ringing: often associated with NP caused by nerve damage

3. Presence of trigger factors and signs and symptoms associated with the pain; Presence of relieving factors

4. Use of analgesics and their efficacy and tolerability

5. Impact in the patient daily life

The assessment of all components of suffering, such as psychosocial distress, should be considered and evaluated [II, B]

Treatment 10, 11, 12, 13, 14, 15

A comprehensive and holistic approach to the treatment of cancer pain is a standard of care. This would include pharmacologic as well as nonpharmacologic modalities. Many chronic pain syndromes are mixed, thus requiring a combination of treatment approaches and medications targeting a variety of nociceptor sites. The WHO proposes a strategy for cancer pain treatment based on a sequential three-step analgesic ladder, from non-opioids to weak opioids to strong opioids, according to pain intensity.

Treatment strategy

Step I – mild pain

Non-opioids

Paracetamol (acetaminophen): analgesic and antipyretic. It has hepatic and renal toxicity. I There was insufficient evidence to support use of paracetamol in combination with step 3 opioids.
Nonsteroidal anti-inflammatory drugs [NSAIDs] – side effect profile problematic in high-risk groups – gastrointestinal bleeding, vascular risks and nephrotoxicity. There is no significant evidence to support or refute the use of NSAIDs alone or in combination with opioids for mild to moderate pain.

Asystematic review of the safety and efficacy of NSAIDs in cancer pain found NSAIDs to be approximately equivalent to 5 to 10mg intramuscular morphine. I

Adjuvant analgesics work at different levels to relieve pain.

30052758

C 30052758

32119322 28220448

19117155 21448038

22126843 29432225

C 30052758

21448038

28326952 10388250

Step II – moderate pain

Weak” opioids

Evidence

Level Grade PMID Nº

For mild to moderate pain, weak opioids such as tramadol, dihydrocodeine and codeine can be given in combination with non-opioid analgesics. 3

Tramadol – Up to 10% of patients are slow metabolizers and derive a weaker analgesic effect.

In the dose 100 mg causes similar analgesia to 10 mg of morphine when the drugs are given orally. Advertencies:

1. Side effects: dizziness, nausea, vomiting and constipation
2. Affects serotonin metabolism or availability, potentially leading to serotonin toxicity (particularly in the elderly) and can lower seizure thresholds.
Codeine – has no or little analgesic effect until metabolised to morphine, mainly via CYP2D6 (ineffective in poor metabolisers).

After oral administration, 60 mg DHC analgesic activity is like 10 mg of morphine. Prescribed as both an analgesic and an antitussive agent. Advertencies:

Side effects: nausea, vomiting and constipation.
Hypersensitivity, asthma, DPOC, respiratory depression.
Low metabolizers with 5 to 10% of patients having no clinical benefit.

Step III – severe pain

Low-dose formulations of strong opioids. 2

There is no evidence of increase in adverse effects from the use of low-dose strong opioids instead of the standard step 2 approach with weak opioids

Morphine is the opioid of first choice for moderate to severe cancer pain. I

The average relative potency ratio of oral to IV morphine is between 1:2 and 1:3. 2

The average relative potency ratio of oral to SC morphine is between 1:2 and 1:3. 4

M6G is an active metabolite that contributes significantly to morphine’s analgesic effects, whereas M3G is inactive as an analgesic, but may cause paradoxical central neuroexcitatory effects.

Large presystemic elimination (in gut wall and liver). Advertencies:

Adjustment of doses is required in renal dysfunction.

Drug interactions: Ranitidine, rifampicin, valspodar. 2

Oxycodone – The analgesic effect seems to have less individual variability compared to codeine. There is a lack of good evidence to support the use of oxycodone over morphine.

Compared with morphine showed less sedation, delirium, vomit and itching, and less constipation in the association with naloxone.

It is extensively metabolized to nor oxycodone, oxymorphone, and their glucuronides. Nor oxycodone is reported to be a considerably weaker analgesic than oxycodone.

Hydrocodone – some patients are slow or fast metabolizers causing problems of variability with analgesic efficacy and toxicity. Hydrocodone is commonly combined with paracetamol, limiting the maximum allowable dose that can be administered.
Hydromorphone – rapid onset and increased potency (high lipophilicity). Unlike other opioids, hepatic metabolism is independent of the CYP450 isoenzymes. The renally excreted metabolite hydromorphone-3-glucuronide can accumulate (excitatory neurotoxic effects including myoclonus and restlessness).

It is absorbed in the colon.Very little data on potential interactions. 4

Without immunosuppressor effect. 2a

Fentanyl – much rapid onset and greater potency due to its lipophilicity (can be administered intravenous, subcutaneous, as well as intrathecally). Transdermal patch is frequently used when cannot be administered orally – The TD route is usually contraindicated during the titration phase, in opioid-naive patients or to control BTcP.

Safe to use in hepatic insufficiency.

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Advertencies:

1. Concomitant use with potent CYP P450 3A4 inhibitors (ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazodone) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.
Buprenorphine –In some trials, intramuscular buprenorphine is 25 times more potent than intramuscular morphine, and sublingual buprenorphine is 15 times more potent than intramuscular morphine.

Advertencies:

Risk of prolonged QT with doses >20mcg/h.
Precaution in respiratory disease, hypothyroidism, mixedeme, Addison Disease, central nervous system disease
Is not expected to cause significant alteration of other drugs’ metabolism because of the low plasma concentrations reached after transdermal application. Fentanyl TD and buprenorphine TD can be useful in patients with nausea, vomiting, problems with swallowing, constipation and poor compliance.

Level Grade PMID Nº

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Fentanyl and buprenorphine (via the t.d. or i.v. route) are the safest opioids in patients with chronic kidney disease stages 4 or 5 (estimated glomerular filtration rate < 30 mL/min)

Tapentadol – it is a more potent mu-receptor agonist and a noradrenaline reuptake inhibitor, although a much weaker serotonin reuptake inhibitor – better adverse effect profile 3

(because it has low plasma protein binding activity and is not metabolized by the CYP system). It proved non-inferior to standard opioids like morphine or oxycodone in the management of moderate-to-severe cancer pain.

Proved efficacy in nociceptive and neuropathic pain. Advertencies:

Nausea, vomiting, somnolence, and dizziness
Should not be associated with buprenorphine, SSRI (associated with serotoninergic syndrome), cetoconazol or fluconazole (excretion inhibition of Tapentadol)

Methadone – treatment of complex pain associated with advanced cancer and neuropathic pain syndromes in which conventional opioids were no longer effective. Its big concern is the individual variability in metabolism and the difficulty in titrating the correct dose.

Adverse effects: myoclonus, sedation, confusion, nausea, and vomiting

A different opioid should be considered in the absence of adequate analgesia (despite opioid dose escalation) or in the presence of unacceptable opioid side effects. 3

Step IV – interventional approaches: nerve blocks, neurolytic blocks and intrathecal drug delivery

Interventional techniques include nerve blocks, neurolytic blocks (including spinal neurolytic blocks and cordotomy) and intrathecal (i.t.) drug delivery (spinal or epidural). Employed to provide an immediate pain control after surgical procedures and to alleviate refractory chronic oncologic pain when oral analgesics fail to provide a satisfactory pain relief, or when is hindered by debilitating adverse effects of the medications.

These interventional strategies are not appropriate in patients with infections, coagulopathy, or very short life expectancy.

- Intrathecal drug delivery

Intraspinal techniques (both epidural and intrathecal routes) should be considered when patient experiences pain in: head and neck, upper and lower extremities and trunk, although it is more likely to be useful for pain below the diaphragm.

This form of pain relief includes percutaneous catheters, tunnelled catheters, and implantable programmable pumps.

When compared with epidural, i.t. drug delivery presents fewer catheter problems, smaller drug dose requirement and fewer adverse effects.

- Peripheral nerve blocks – when pain occurs in the field of one or more peripheral nerves, or if pain is caused by complications such as pathological fracture or vascular occlusion.

Used together with systemic combined analgesia.

- Neurolytic blockade– limited to patients with short life expectancy (produce a block lasting 3– 6months).

It can be used for the sympathetic system for visceral pain as well as for spinal neurolytic purposes for somatic pain. Spinal neurolytic blocks are used when pain is localised to a few dermatomes.

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Coeliac plexus block (CPB) is useful when pain is of visceral aetiology only, and due to cancer in the upper abdomen or pancreas. 2

CPB appears to be safe and effective for the reduction of pain in patients with pancreatic cancer, with a significant advantage over standard analgesic therapy until 6 months. Cordotomy (also called spinothalamic tractotomy) should be considered in patients with poorly controlled cancer-related pain. 5

It results in selective reduction of pain and temperature perception on the contralateral side, up to several segments below the level of the disruption – via percutaneous, open, endoscopic, or trans discal approach.

The use of open cordotomy has diminished significantly in recent years because of the advent of other less invasive approaches.

Other therapies

For advanced cancer patients with pain not fully alleviated by opioid therapy, the additive effect of different cannabis-based therapies to the ongoing opioid treatment remains 2

unclear.

Farmacotherapy

Step I

Paracetamol: 500-1000mg (PO or IV). Maximum dose of 4000mg/24h. It can be combined with codeine or tramadol (step II) 2
Metamizol: 500-2000 mg (PO or IM) each 8h; rectal route 1g/6-12h. 8000mg/24h.
Ibuprofen: 200-600mg/per os/6-8h. 1200mg/24h (maximum dose). I
Cetorolac: 10-30mg/PO/6h; 10mg/IM/single dose; 30mg/rectal route/single dose. 40mg/24h (maximum dose). Ib Cetorolac 10mg/IM/single dose is as effective as cetorolac 30mg/IM/single dose.
If CV risk factors, should be prescribed naproxen (1 g/24 h) or low dose ibuprofen (<1200 mg/24 h). If high risk of upper GI complications, NSAIDs should be avoided; for those in whom it is essential, celecoxib (200 mg/24 h) plus a proton pump inhibitor has been recommended.

WHO step II

Codeine: 30mg/PO/4-6h. Maximum dose 240mg/24h PO (because of association with paracetamol). If > 360mg/24h, should be done rotation to a strong opioid (step III) 2a
Tramadol: prolonged release, 400mg/24h PO. IV dose is about 50% of the oral dose.

WHO step III

- Morphine: PO treatment should be started with immediate release 5mg (if opioid naïve) or 10mg (if opioid tolerant). In PO treatment manutention the modified-release are I

preferred: start with 10-30mg in 12/12h. If IV, IM or SC route used: 10-20mg/mL. 60mg/24h PO, 30mg/24h SC.

Starting a low-dose strong opioid (e.g., ≤30 mg/day oral morphine) has been shown to give better pain relief than using weak opioids such as codeine

The NCCN Guidelines (2015) recommend starting with immediate-release oral morphine or equivalents at 5–15 mg. If pain does not diminish or increases, the dose should be 2

increased by 50–100%; if pain decreases, but remains severe, the same dose should be repeated, up to a maximum of three doses. If pain decreases, the same dose should be

maintained for 24 h, then changed to oral or transdermal administration.

If the pain improves, the dose should be calculated for 24 h and divided into 4–6 h intervals.

Oxycodone: 30-40mg/24h PO.
Hydromorphone: initial dose of 4mg/24h and increment of 4-8mg/24h.
Oxycodone or hydromorphone, in both immediate-release and modified-release formulations for oral administration.

There are no differences between morphine, oxycodone, and hydromorphone. Treatment typically starts with immediate-release doses every 4 h.

Fentanyl TD: 600mcg/24h = 25 mcg/h patch. Effective systemic analgesic concentrations reached in 3-24h (steady state plasma concentrations 36-48h). Similar absorption in thorax, abdomen, and thigh (rotation of the region in each application).

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Buprenorphine TD – 600 mcg/24 h = 25 mcg/h patch. Analgesic effect in 30 minutes. Similar absorption in thorax, abdomen, and thigh (rotation of the region in each 2a application).
Tapentadol: prolonged release, start with 50mg 12/12h.

Doses of Tapentadol may be increased at least up to 400-500 mg/day, which corresponds to the range of 60-150 mg/day of oral morphine equivalents.

Methadone is available as a liquid suspension (5mg/ml) and oral tablet (5mg, 10mg) which is administered by oral, buccal, sublingual routes and less preferred being rectal, intravenous, subcutaneous, and intrathecal routes.
A different opioid should be considered in the absence of adequate analgesia (despite opioid dose escalation) or in the presence of unacceptable opioid side effects (namely nausea for >1 week or sedation for more than 2 to 3 days).

If refractory obstipation occurs, rotation to fentanyl or methadone is explicitly recommended.

The SC route is simple and effective for the administration of morphine, diamorphine and hydromorphone and it should be the first-choice alternative route for patients unable to 3 receive opioids by oral or TD routes.
IV infusion should be considered when SC administration is contraindicated (peripheral oedema, coagulation disorders, poor peripheral circulation and need for high volumes and doses).
IV administration is an option for opioid titration when rapid pain control is needed.

Fourth step WHO ladder: nerve blocks, neurolytic blocks and intrathecal drug delivery

Intrathecal drug delivery

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References

PMID: 30822530. Mercadante S.; Adile C.; Masedu F; Valenti M; Aielli F. Breakthrough Cancer Pain in Patients With Abdominal Visceral Cancer Pain. J Pain Symptom Manage, 2019. DOI: 10.1016/j.jpainsymman.2019.02.014
PMID 30379615. Grundy L; Erickson A; Brierley S.M. Visceral Pain. Annu Rev Physiol, 2019. DOI: 10.1146/annurev-physiol-020518-114525
PMID: 33961156. Hao D; Sidharthan S; Cotte J; Decker M; Orhurhu M.S.; Olatoye D; et al. Interventional Therapies for Pain in Cancer Patients: a Narrative Review. Curr Pain Headache Rep, 2021. doi: 10.1007/s11916-021-00963-2.
PMID: 29729775. Portenoy R.; Ahmed E. Cancer Pain Syndromes. Hematol Oncol Clin North Am, 2018. DOI: 10.1016/j.hoc.2018.01.002
PMID: 30052758. Fallon M, Giusti R, Aielli F, Hoskin P, Rolke R, Sharma M, Ripamonti C.I. Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines. European Society for Medical Oncology, 2018. DOI: 10.1093/annonc/mdy152.
PMID: 21243067. Wesselmann U; Baranowski A.P.; Borjesson M; Curran N.C; et al. EMERGING THERAPIES AND NOVEL APPROACHES TO VISCERAL PAIN. Drug Discov Today Ther Strateg, 2009. doi: 10.1016/j.ddstr.2009.05.001.
PMID: 30042373. Yam, Mun Fei; Loh, Yean Chun; Tan, Chu Shan; Adam, Siti K.; Manan, Nizar A.; Basir, Rusliza. General Pathways of Pain Sensation and the Major Neurotransmitters Involved in Pain Regulation. Int J Mol Sci. 2018. DOI: 10.3390/ijms19082164.
PMID: 31980005. Chapman, E.J., Edwards, Z., Boland, J.W., Maddocks, M., Fettes, L., Malia, C., Et al. Practice review: Evidence-based and effective management of pain in patients with advanced cancer. Palliat Med, 2020. doi: 10.1177/0269216319896955.
PMID: 21856077. Valente, M.A.F., Ribeiro, J.L.P., Jensen, M.P. Validity of four pain intensity rating scales. Pain, 2011. doi: 10.1016/j.pain.2011.07.005.
PMID: 28326952. Lara-Solares, Argelia; Olea, Marisol A.; Pinos, Amparito A.; et al. Latin-American guidelines for cancer pain management. Pain Manag. 2017. DOI: 10.2217/pmt-2017-0006.
PMID: 32119322. Anekar A, Cascella M. WHOAnalgesic Ladder. StatPearls, 2021.
PMID: 28265859. Candido, Kenneth; Kusperm Teresa M.; Knezevic, Nebojsa N. New Cancer Pain Treatment Options. Curr Pain Headache Rep. 2017. DOI: 10.1007/s11916-017-0613-0
PMID: 28220448. Liu, Weiyang C.; Zheng, Zhong X.; Tan, Kian H; Meredith, Gregory J. Multidimensional Treatment of Cancer Pain. Curr Oncol Rep. 2017. DOI: 10.1007/s11912-017-0570-0.
PMID: 7500538. Jadad AR, Browman GP. The WHO analgesic ladder for cancer pain management: Stepping up the quality of its evaluation. JAMA. 1995. Doi:10.1001/jama.1995.03530230056031
PMID: 12703331. Burton, AW. Acute, chronic, and cancer pain. Clinical management. Methods Mol Med. 2003. DOI: 10.1385/1-59259-379-8:267

IRRUPTIVE PAIN

Authors: Tomás Cabral Dinis, André Pires and Bruno Moura Fernandes.

Definition

Breakthrough cancer pain (BTcP), also known as “episodic pain” (1), can be defined, although not unanimously, as “a transitory flare of pain that occurs on a background of relatively well controlled baseline pain” (2). Some studies distinguish BTcP from end-dose pain flares (increased pain intensity occurring when the effect of opioids does not last until the next dose is scheduled (3)), since patients must be already on analgesic treatment, usually, but not necessarily, on an opioid regimen (1,4–10).

Its reported prevalence varies depending on the definition, diagnostic criteria, and clinical setting. Deandrea et al. estimated, in a systematic review, a 59% prevalence of BTcP on cancer patients with pain (11).

BTcP is associated with poor overall pain control, negatively influencing the quality of life (QoL) of patients and their caregivers (7,12,13).

Symptoms and signs

Background pain is defined as the presence of pain for ≥12h/day during previous week (or that would be present if not taking analgesia) (2,7). For the background pain to be adequately controlled, it must be reported of mild to moderate intensity (rated≤4 on a verbal numerical scale or visual analogue scale, ranging from 0 to 10) (1,2,5,10,12).

BTcP can be considered when there are ≤4 episodes per day of well distinguished peaks from background pain intensity (≥7/10) (8,12). These episodes must be acute in onset (< 10 minutes to reach peak intensity) and of relatively short duration (~30 minutes) (2,7,10,12,13). A circadian variation in the occurrence of BTcP exists, with most patients experiencing it during the day (10,13). BTcP often occurs at the same location as the background pain and is referred to with similar qualitatively pain descriptors (10). It can also be described in more than one site, especially in patients with metastatic cancer (14).

Clinical algorithms have been proposed (7) and can be useful in day-to-day clinical practice (Figure 1).

Patients may not always refer to pain during medical examination or not be able to express it at all, thus clinicians should be alert to certain pain-related signs and symptoms. BTcP can result (2,7) in:

Physical complications: immobility, insomnia
Psychological complications: anxiety, depression.
Social complications: changes in routine activity, unemployment, social isolation.

Etiology

Breakthrough pain may be associated to several different causes (cancer-related, treatment-related, concomitant illness) and different pathophysiology’s (nociceptive, neuropathic, mixed) (7,14), being very important to specify the type of pain perceived by the patient. It is the scope of this chapter to address specifically cancer related aetiology (BTcP).

BTcP occurs in patients with cancer growth affecting bone, soft tissue, viscera, and the nervous system and depending on tumour location and pathophysiology, several syndromes have been described (3,10,14). Also, in patients with haematological malignancies pain syndromes have been observed (14).

Several classifications have been proposed. BTcP can be classified into (3,7,15):

Spontaneous pain (“idiopathic pain”): episodes are not related to an identifiable precipitant, being unpredictable in nature, requiring a preventive therapy rather than an as needed medication.
Incident pain (“precipitated pain”): episodes are related to an identifiable precipitant, and so are somewhat predictable in nature, giving patient the possibility to take an active role in their pain management:
- Volitional incident pain – is brought on by a voluntary act (e.g., walking in patients with skeletal pain, swallowing in patients with mucositis);
- Non-volitional incident pain – is brought on by an involuntary act (e.g., Valsalva maneuver caused by coughing or sneezing);
- Procedural pain – is related to a therapeutic intervention (e.g., wound dressing, radiotherapy positioning).

Evidence

Level Grade PMID Nº

Studies Level Grade PMID Nº

The assessment of BTcP should include evaluations of both background pain intensity and worst pain intensity. It should start by taking a detailed history focusing on (2,3,9,10,13,14):

Pain assessment:

Type and quality of pain.
Pain history (eg, onset, duration, course);
Pain intensity (ie, pain experienced at rest; with movement) using a verbal numerical scale or visual analogue scale.
Location(s).
Referral pattern.
Radiation of pain.
Associated factors that exacerbate or relieve the pain.
Current pain management plan.
Patient’s pain experience and response to current or prior pain therapies.
Breakthrough or episodic pain inadequately managed with existing pain regimen. Patient assessment:
Clinical situation by means of a thorough physical examination and review of appropriate laboratory and imaging studies.
Presence and intensity of signs, physical and/or emotional symptoms associated with cancer pain syndromes.
Impact of pain (ie, interference with activities such as work, sleep, and interpersonal interactions).
Presence of comorbidities (i.e., diabetic, renal and/or hepatic failure, etc.), alcohol and/or substance abuse.
Performance status.
Psychosocial factors (eg, patient distress, family/caregiver and other support, psychiatric history, risk factors for undertreatment of pain).
Other special issues relating to pain (eg, opiophobia, misconception related to pain treatment, meaning of pain for patient and family/caregiver; cultural beliefs toward pain, spiritual or religious considerations and existential suffering).

The patient perspective should be an integral part of the assessment. Satisfaction and expectations of pain management should be discussed with family or caregivers included (9,10). Clinical tools for the assessment of cancer pain, such as mnemonics (14) and numeric rating scales (9) can be useful in day-to-day clinical practice (Figure 2).

Therapeutic Strategy

Cancer – related pain treatment must be based on clinical circumstances and patient wishes, with the goal of maximizing function and QoL (9). Its successful management requires a combination of adequate assessment, appropriate treatment, and frequent re-assessment for the need of optimization of scheduled analgesia (2,13,15).

Initially, cancer patients should have their chronic background pain appropriately controlled, which is conventionally considered to b≤4/10, on a numerical scale 0-10 (8).

Providing that background pain is adequately managed, use of drugs as needed (“rescue doses”) in addition to the continuous analgesic medication is the conventional treatment of BTcP (2,6,9,10,15). The repeated need for numerous rescue doses per day may indicate the necessity to adjust the baseline treatment. On the other hand, opioid dose reduction, by 10-20%, should be considered if patient never or rarely needs breakthrough analgesic (9).

Short half-life opioid agonists have been the mainstay approach for the management of BTcP, as they can be more easily titrated. This drug class includes morphine, hydromorphone, fentanyl, and oxycodone (2,9). Immediate-release formulations (rapid onset and short duration of action) should be preferred in BTcP management (2,6).

There is strong evidence to support individualization of pain treatment due to individual differences in opioid receptors and opioid metabolism (10).

Short acting opioids (SAOs):

Short acting opioids (SAOs) have traditionally been the standard treatment approach for BTcP, with oral formulations of morphine being available (10,16).

Its effective dose used to treat BTcP is calculated as a proportion of the daily dose of opioid analgesics administered at fixed intervals (15,17). Efficacy and adverse effects (AE) should be assessed every 60 minutes (when given p.o.) or 15 minutes (IV/sc), to determine if subsequent dose is needed (9):

If the pain score remains unchanged or is increased: further increase in opioid rescue dose by 50 to 100% is recommended.
If the pain is reduced but still inadequately controlled, the same opioid dose is repeated, and second reassessment should be performed (same time intervals as mentioned before).
If pain score remains unchanged upon reassessment after 2 to 3 cycles of the opioid, in patients with moderate to severe pain, changing the route of administration form p.o. to iv/sc should be considered.
If the pain score decreases to a level where it is adequately controlled, the current effective dose can be continued “as needed” over na initial 24h before proceeding to subsequent management strategies.

Parenteral approaches can be considered, with intravenous administration providing the most immediate effect for severe cancer pain requiring rapid pain relief. It may also be administered by the patients, with the use of a patient-controlled analgesia. Despite of being a safe route of administration, it´s not usually a practical one. Thus, if oral route is viable, it should be preferred (4,6,10,15).

However, the pharmacokinetic and pharmacodynamic profiles of oral opioids (morphine, hydromorphone, and oxycodone), with low bioavailability due to hepatic first-pass metabolism (onset of analgesia: 20 -30 minutes; peak analgesia: 6-90 minutes; duration of effect: 3-6 hours) do not tend to mirror the temporal characteristics of most BTcP episodes, resulting in delayed or ineffective analgesia and in ongoing adverse effects (2,10,18).

Thus, more recent recommendations have underlined that orally administered opioids are unsuitable for pains with a short onset and duration. Rather, they appear effective when given timely before pain occurs or in well characterized BTcP events with a gradual onset. For example, the slow analgesic peaks achieved with oral opioids could be useful when administered 15–30 min before starting physical activity in patients with predictable incident pain, or during opioid titration phase (2,4,15).

Rapid onset opioids (ROOs):

The rapid onset and relatively short duration of BTcP poses a therapeutic challenge (17,18). Different formulations, such as rapid onset opioids (ROOs), have been developed to provide fast pain relief.

ROOs are delivered by non-invasive routes: oral, transmucosal buccal tablet, sublingual tablet, buccal soluble film, sublingual, and intra-nasal spray (2,18). Oral/nasal transmucosal administration, due to its characteristics (large surface of area, stable pH, good permeability, and high vascularity), allow rapid absorption and avoidance of first-pass metabolism, thus producing clinically observable effect 1-15 min after drug administration, matching the temporal profile of BTcP (2,9,10,15–17). There is no evidence for the superiority of any particular formulation. Hence, selection of the most suitable formulation, according to patient clinical situation, and considering its pros and cons alongside with him is advised (10,16). Unlike oral morphine, different formulations of fentanyl mustnt´ be switched on a μg to μg basis due to distinct pharmacokinetic profiles (16,19).

Studies with these formulations have been performed in opioid-tolerant patients, showing good efficacy, and the current recommendation is only for patients receiving doses of oral morphine equivalents of at least 60mg (2,4,15). An opioid equi-analgesic conversion table is available (Table 1).

Not all drugs are suitable for transmucosal administration. Fentanyl is a μ-opioid receptor agonist with an analgesic potency approximately 80–100 times greater than that of morphine, with well documented efficacy on the treatment of cancer pain. Its highly lipid-soluble being readily absorbed through the oral mucosa and crossing the blood-brain barrier, providing fast analgesia, making it suitable for BTcP management (9,10,15,18).

Fentanyl is metabolized by cytochrome enzymes, and any drug that induces or inhibits cytochrome P450 can affect its metabolic conversion (6,10,16).

Although transmucosal formulations have been shown to be effective for the treatment of BTcP, the rapid onset of BTcP is such that pain may still reach peak intensity before appreciable plasma drug concentrations have been attained (18).

Opioid-induced adverse effects:

Adverse effects (AE) are a cause of bad compliance and treatment inefficacy and should be closely monitored by clinicians. The potency and rapid onset of analgesia achieved mainly by ROOs, raise concerns about its misuse and overdoses, potentially causing opioid-induced hyperalgesia (2,10,16).

Opioids AEs are formulation, route of administration and dose related. Most common AEs include nausea, dizziness, somnolence, and less frequently asthenia, constipation, confusion, insomnia, vomiting, peripheral oedema, diarrhoea, and dyspnoea (6,16).They´se also associated with impaired mental and/or physical ability to operate heavy machinery, and patients must be advised against it (19).

The longer the duration of opioid therapy, the less frequent the adverse effects, fact that can be explainable by the tendency to develop tolerance with prolonged opioid use (12).

Level Grade PMID Nº

Therapeutic Strategy Level GradeEvidence

Fentanyl is metabolized by cytochrome enzymes, and any drug that induces or inhibits cytochrome P450 can affect its metabolic conversion (6,10,16).

Opioid-induced adverse effects:

Opioids AEs are formulation, route of administration and dose related. Most common AEs include nausea, dizziness, somnolence, and less frequently asthenia, constipation, confusion, insomnia, vomiting, peripheral oedema, diarrhoea, and dyspnoea (6,16).They´re also associated with impaired mental and/or physical ability to operate heavy machinery, and patients must be advised against it (19).

The longer the duration of opioid therapy, the less frequent the adverse effects, fact that can be explainable by the tendency to develop tolerance with prolonged opioid use (12).

Immediate-release opioids should be used to treat BTcP that is opioid-responsive and for which background cancer pain management has been optimised.(2,6) I A
Transmucosal fentanyl formulations (oral, buccal, sublingual, and intranasal) have a role in unpredictable and rapid-onset BTcP.(2) I A
There are indications for standard normal-release oral opioids (e.g., morphine) that include a slow-onset BTcP or a pre-emptive administration of oral opioids ~30 minutes 2 B before a predictable BTcP triggered by known events.(2)

Pharmacotherapy

PMID Nº

Breakthrough cancer pain

Short acting opioids (SAOs):

The effective dose of oral opioid preparations used to treat BTcP is calculated as a proportion of the daily dose of opioid a nalgesics administered at fixed intervals (15,17):

Opioid-naïve patients: 5-15mg p.o. or 2-5mg IV morphine sulphate or equivalent.

Note: A sc route of administration can be substituted for IV, but the time to peak effect is generally longer (~30min) (9);

Opioid-tolerant patients, a rescue dose equivalent to 10-20% of the total opioid taken in the previous 24h should be given, every hour as needed during severe exacerbations of pain (4,9).

Morphine sulphate:
- Sevredol® 10, 20mg (tablet).
- Oramorph® 20mg/mL (oral liquid).

Max. dose: –

Administration: oral. Pills can be smashed and swallowed but should not be chewed.

Onset of action: 30-45 minutes.

Bioavailability: 30%.

CI: acute respiratory depression; acute alcoholism; risk of paralytic ileus; raised intracranial pressure or head injury; phaeo chromocytoma.

Precautions: renal impairment; hepatic impairment; older and debilitat ed patients; hypothyroidism; convulsive disorders; decreased respiratory reserve and acute asthma; hypotension; prostatic hypertrophy; pregnancy and breastfeeding.

Rapid onset opioids (ROOs):

To minimize the risk of significant adverse events, optimal doses of transmucosal fentanyl formulations are suggested to be determined by dose titration(17). Dosing recommendations have been developed for the transmucosal formulations as a group, and these share a low initial dose followed by dose titration to an effective dose (2).

Oral transmucosal fentanyl citrate (OTFC-):(15)

o Actiq® 200, 400, 600, 800µg (oral lozenge).

Max. dose: 1600 µg.

Max. frequency: 4 doses/24h (> 4h interval). Max. of 2 doses/episode.

Administration: Oral. Should not be chewed or swallowed. Prior oral hydration is recommended. May not be ideal for patients with oral irritations (mucositis, xerostomia, local infection). Patient compliance is required (4,10,15,17).

Onset of action: 15 minutes.

Bioavailability: 50%

– Sublingual fentanyl (SLF):(19)

o Vellofent ® 133, 267, 400, 533, 800µg.

o Abstral® 100, 200, 300, 400, 600, 800µg.

Max. dose: 800 µg.

Max. frequency: 4 doses/24h (> 4h interval).

Administration: sublingual. Should not be chewed or swallowed. Prior oral hydration is recommended.

Onset of action: 6-10 minutes; If pain control is not achieved upon 15 -30 min of re-assessment, dose can be repeated without further adverse effects (4).

Bioavailability: 54-70%

– Fentanyl buccal tablet (FBT):(15,19)

o Breakyl® 200, 400, 600, 800, 1200µg (buccal film).

Max. dose: 1200 µg.

Max. frequency: 4 doses/24h (> 2h interval).

Administration: buccal. Should not be chewed or swallowed. Should not be used with more than 4 formulations simultaneously.

Onset of action: 10 minutes.

Bioavailability: 71%

– Intranasal fentanyl spray (INFS):(15)

o PecFent® 100, 200, 400, 800µg/spray.

o Instanyl® 50, 100, 200µg/spray (not available in Portugal).

Max. dose: 800µg/episode.

Max. frequency: 4 inhalations/24h (> 4h interval).

Administration: intranasal.

Onset of action: 5-10 minutes.

Bioavailability: 90-120%

Fentanyl specifications (regardless of route of administrations) (6,16):

Common adverse effects: nausea, vomiting, constipation, dry mouth, biliary spasm, respiratory depression, muscle rigidity, apnoea, myoclonic movements, bradycardia, hypotension, abd ominal pain, anorexia, dyspepsia, mouth ulcer, taste disturbance, vasodilation, anxiety, drowsiness, diaphoresis.

Contraindications: acute respiratory depression; acute asthma; paralytic ileus; concomitant use with, or use within 14 days after ending, monoamine oxidase inhibitor therapy; raised intracranial pressure and/or head injury if ventilation not controlled; coma.

I A

Precautions: impaired respiratory function; bradycardia; asthma; hypotension; shock; obstructive or inflammatory bowel disorders; biliar y tract disease; convulsive disorders; hypothyroidism; adrenocortical insufficiency; diabetes mellitus; impaired consciousness; acute pancreatitis; myasthenia gravis; hepatic impairment; renal impairment;

toxic psychosis; (patc hes:) increased serum levels in patients with fever >40 °C (104 °F).

Possible drug interactions (* for severe): amiodarone, beta- adrenergic blockers, calcium channel blockers, CNS depressants, imidazole antifungals, macrolide antibiotics, monoamine oxidase inhibitors*, naloxone*, naltrexone*, neuroleptics, nitrous oxide, opioid antagonists/partial agonists, phenytoin, protease inhibitors.

Management of opioid-induced adverse eﬀects

Laxatives must be routinely prescribed for both the prophylaxis and the management of opioid -induced constipation (OIC). (2)

Naloxegol (peripherally acting μ -opioid receptor) has been shown to be highly eﬀective in OIC, but to date, there is no speciﬁc reported experience in the cancer population.(2)

Metoclopramide and antidopaminergic drugs should be recommended for treatment of opioid-related nausea/vomiting. (2)

Psychostimulants (e.g. Methylphenidate) to treat opioid -induced sedation are only advised when other methods to treat this have been tried (e.g. if it is not possible to rationalise all medication with a sedative side eﬀect). (2)

receptor antagonists (e.g. naloxone) must be used promptly in the treatment of opioid-induced respiratory depression. (2)

2 B

1 B

Others

Figure 1. Clinical algorithm for the assessment of breakthrough cancer pain (BTcP). Adapted from (2)

= pain present for ≥ 12h/day

background pain?

Does the patient have

YES

Patient has BTcP.

during previous week (or would

YES NO be if not taking analgesia)

Does the patient have transient exacerbations of pain (≤ 4 /day)?

Patient does not have BTcP but does have uncontrolled background pain.

Is the background pain

adequately controlled (intensity of pain ≤ 4/10)?

Patient does not have BTcP.

Figure 2 . Clinical tools for pain assessment

S ite

O nset

C haracter

R adiation

A ssociated factors

T iming

E xacerbation/relieving factors

Clinical mnemonic on pain characteristics (14).

Numerical Rating Scale. Reprinted from (9).

The Faces Pain Rating Scale. Reprinted from (9).

Route of administration	Drug	Unit	Opioid equi-analgesic dose
Oral	Codeine	mg	60	90	180	210	Has a maximum dose*
	Tramadol		25	50	75	100	150	200	300	400	Has a maximum dose*
	Morphine		5	10	15	20	30	40	60	80	100	120	160	180	200	240	320
	Tapentadol							100	150	200	250	300	400	450	500
	Hydromorphone							8		16		24	32		40	48	64
Transdermal	Buprenorphine	μg/h							35		53	70	88	105		140
Transdermal	Fentanyl	μg/h					12,5		25		38	50	63	75		100	125
IV/s.c.	Morphine	mg			5		10		20		30	40	50	60		80	110
IV/s.c.	Tramadol	mg					100		200
* Maximum dose: 360mg (isolated) or 240mg (associated with paracetamol) ** Maximum dose: 400mg (adult); 300mg (elderly); 150mg (poor performance status, malnutrition)

Table 1: Opioid equi-analgesic conversion table. Adapted from (4,6).

References

Løhre ET, Klepstad P, Bennett MI, Brunelli C, Caraceni A, Fainsinger RL, et al. From “breakthrough” to “episodic” Cancer Pain? A European Association for Palliative Care Research Network Expert Delphi Survey Toward a Common Terminology and Classification of Transient Cancer Pain Exacerbations. Journal of Pain and Symptom Management. 2016 Jun 1;51(6):1013–9.
Fallon M, Giusti R, Aielli F, Hoskin P, Rolke R, Sharma M, et al. Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines. Annals of Oncology. 2018 Oct 1;29:iv166–91.
Mercadante S, Radbruch L, Caraceni A, Cherny N, Kaasa S, Nauck F, et al. Episodic (breakthrough) pain: Consensus conference of an expert working group of the European Association for Palliative Care. Cancer. 2002 Feb 1;94(3):832–9.
Ritto C, Rocha FD, Costa I, Diniz L, Raposo MB, Pina PR, et al. Manual de Dor Crónica. 2a ed. Lisboa; 2017.
Boceta J, de la Torre A, Samper D, Farto M, Sánchez-de la Rosa R. Consensus and controversies in the definition, assessment, treatment and monitoring of BTcP: results of a Delphi study. Clinical and Translational Oncology. 2016 Nov 1;18(11):1088–97.
WHO guidelines for the pharmacological and radiotherapeutic management of cancer pain in adults and adolescents. Geneva: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO.
Davies AN, Dickman A, Reid C, Stevens AM, Zeppetella G. The management of cancer-related breakthrough pain: Recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. Vol. 13, European Journal of Pain. 2009. p. 331–8.
Mercadante S, Valle A, Porzio G, Aielli F, Adile C, Ficorella C, et al. Relationship between background cancer pain, breakthrough pain, and analgesic treatment: A preliminary study for a better interpretation of epidemiological and clinical studies. Current Medical Research and Opinion. 2013 Jun;29(6):667–71.
Swarm RA, Youngwerth JM, Agne JL, Anghelescu DL, Are M, Buga S, et al. NCCN Guidelines Version 1.2022 Adult Cancer Pain Continue NCCN Guidelines Panel Disclosures [Internet]. 2022. Available from: https://www.nccn.org/home/member-
Løhre ET, Thronæs M, Klepstad P. Breakthrough cancer pain in 2020. Vol. 14, Current opinion in supportive and palliative care. NLM (Medline); 2020. p. 94–9.
Deandrea S, Corli O, Consonni D, Villani W, Greco MT, Apolone G. Prevalence of breakthrough cancer pain: A systematic review and a pooled analysis of published literature. Vol. 47, Journal of Pain and Symptom Management. Elsevier Inc.; 2014. p. 57–76.
Mercadante S, Lazzari M, Reale C, Cuomo A, Fusco F, Marchetti P, et al. Italian Oncological Pain Survey (IOPS): A multicentre Italian study of breakthrough pain performed in different settings. Clinical Journal of Pain. 2015 Mar 13;31(3):214–21.
Webber K, Davies AN, Zeppetella G, Cowie MR. Development and validation of the breakthrough pain assessment tool (BAT) in cancer patients. Journal of Pain and Symptom Management. 2014 Oct 1;48(4):619–31.
Caraceni A, Shkodra M. Cancer pain assessment and classification. Cancers. 2019 Apr 1;11(4).
Mercadante S. The use of rapid onset opioids for breakthrough cancer pain: The challenge of its dosing. Vol. 80, Critical Reviews in Oncology/Hematology. 2011. p. 460–5.
Capelas ML, Monteiro C, Simões C, Ferreira C, Pires C, Pereira C, et al. Dor irruptiva: consenso. 2nd ed. Laboratórios Angelini; 2018.
Shimoyama N, Gomyo I, Katakami N, Okada M, Yukitoshi N, Ohta E, et al. Efficacy and safety of sublingual fentanyl orally disintegrating tablet at doses determined by titration for the treatment of breakthrough pain in Japanese cancer patients: a multicenter, randomized, placebo-controlled, double-blind phase III trial. International Journal of Clinical Oncology. 2015 Feb 1;20(1):198–206.
Rauck R, Reynolds L, Geach J, Bull J, Stearns L, Scherlis M, et al. Efficacy and safety of fentanyl sublingual spray for the treatment of breakthrough cancer pain: A randomized, double-blind, placebo-controlled study. Current Medical Research and Opinion. 2012 May;28(5):859–70.
Garnock-Jones KP. Fentanyl Buccal Soluble Film: AReview in Breakthrough Cancer Pain. Vol. 36, Clinical Drug Investigation. Springer International Publishing; 2016. p. 413–9.

BONE PAIN

Author: Dr. Salvador Gámez Casado, Cláudia Franco de Sá and Carolina Trabulo.

Introduction

Metastatic cancer-induced bone pain (CIBP) is a type of chronic pain with unique and complex pathophysiology characterized by nociceptive and neuropathic components (1). In addition, the pain state is often unpredictable, and the intensity of the pain is highly variable, making it difficult to manage (2).

CIBP can occur anywhere in the metastized bone. Depending on primary tumour site, the incidence of bone metastases varies extensively, with prostate, breast, lung, as well as myeloma accounting for over 85% of patients with metastatic disease. The most common sites of metastases are vertebrae, pelvis, long bones, and ribs.

Up to 70% of patients will have bone metastases at the moment of death, even if they haven’t had symptoms. Only a third of patients with bone metastases develops bone pain. It is not yet clear why some bone metastases cause pain and others do not (3).

Once tumours metastasize to bone, they are a major cause of morbidity and mortality as the tumour induces significant skeletal remodelling, pathological fractures, pain, hypercalcemia, spinal cord compression with or without neurological deficits and anaemia (4).

Etiology

Bone cancer pain has both a nociceptive and neuropathic component. The nociceptive component is driven by the release of allogenic substances by tumour and their associated stromal cells, acidosis caused by bone-destroying osteoclasts, and mechanical destabilization and fracture of the bone. The neuropathic component is induced by tumour cell growth, which injures and destroys the distal ends of nerve fibres that normally innervate the bone as well as by inducing a highly pathological sprouting of both sensory and sympathetic nerve fibres (9).

Animal and clinical studies of bone cancer have reported that the antiresorptive effects of bisphosphonate therapies simultaneously reduce bone cancer pain, tumour-induced bone destruction, and tumour growth within the bone (10). Bisphosphonates are a class of antiresorptive compounds which display high affinity for calcium ions, causing them to bind to the mineralized matrix of bone rapidly and avidly. Bisphosphonates, once taken up by the osteoclasts, induce loss of function and ultimately apoptosis of the osteoclasts. (4)

Symptoms

20% of patients with cancer presents pain or a pathological bone fracture as the first symptom of the oncologic disease. Usually, pain occurs spontaneously, and it varies in severity and character depending on the disease extension (5). Most patients initially experience intermittent dull aches, but as the disease progresses, pain becomes constant and more severe (6).

Pain upon palpation is often found around metastatic bone lesions. If the tumour keeps growing within the bone usually leads to another type of cancer pain: breakthrough

(episodic) pain. This is defined as recurrent episodes of extreme pain breaking through the regimen administered to treat background pain. Its clinical manifestation comprises a temporary intensification of pain experienced by patients (7). It is usually acute, piercing, and very severe.

In clinical practice, observations of patients with bone metastases reveal that breakthrough (episodic) pain often poses a greater therapeutic problem more than background pain.

This is caused by the temporal aspect of this type of pain (in more than half of patients, the time to maximum pain intensity is very short—less than 5 minutes—and the pain lasts less than 15 minutes), as well as its unpredictability, severe intensity, and negative impact on daily functioning and quality of life (QoL) (8). These factors play a crucial role in the selection of drugs to treat breakthrough (episodic) pain. At a later stage, when the destruction of bone is extensive, pathological fractures with concomitant compression and damage to nervous system structures (spinal cord, nerve roots, plexuses, or peripheral nerves) may occur.

Treatment

Evidence

Level Grade PMID Nº

Opioids therapy as the mainstay of cancer pain treatment to provide freedom from cancer pain I A
Bisphosphonates is a class of medication which may be used to treat pain and reduce morbidity associated with metastatic bone cancer lesions. I A Reduce tumour-induced bone destruction and bone cancer pain

Unwanted side effects (including induction of arthralgias and osteonecrosis of the jaw), Bisphosphonates increase the survival of patients with bone cancer

Evidence Level Grade PMID Nº

Monoclonal antibody therapy with specific affinity for RANKL has been proven to inhibit osteoclast genesis. The use of the MAb denosumab has been shown to not only reduce I B pain, but to also reduce tumour size and increase time to skeletal related events (which include fracture and pain) (11).
Radiotherapy is performed to control a bone affected from metastasis. Radiotherapy has been proven to provide tumour shrinkage, pain reliever, prevent pathological fractures I A

as well as spinal cord compression and delay neurological dysfunction.

Pharmacotherapy

The WHO’s approach to cancer pain treatment involves the use of a three-step ladder which provides a guideline for clinicians to treat patients who struggle from cancer pain syndromes.

Th three-step ladder (fig. 1) system was created for cancer pain relief in the adult patient population. The first step in the ladder includes treatments with non-opioid pain medications, with or without an adjuvant medication. The second step in the ladder includes treatment with lower potency opioids for mild-to-moderate pain in conjunction with nonopioid pain medications and adjuvant medications. The last and third step includes treatments with higher potency opioids for moderate-to-severe pain with nonopioid and adjuvant medications. After undergoing treatment within the final step of the ladder, patients are to achieve ‘freedom from cancer pain’, and it is reported by the WHO that this three-step approach to cancer pain treatment with the ‘right drug, in the right dose, at the right time’ will be 80–90% effective in a patient’s treatment plan [4].

Therapeutic Strategy

Invasive treatments

Surgery

It is indicated when the bone pain is uncontrolled, neurological compromise, risk of fracture or a consolidated fracture. I A

Radiotherapy

It is used to treat a vast of bone metastasis which cause pain and it is also used to avoid and treat spinal cord compression and pathological bone fractures. It is prescribed by a I A

radiation oncologist who will protect adjacent healthy organs from unwanted radiation.

The goals of radiotherapy are to improve quality of life, reduces analgesic requirements and maintain ameliorate skeletal function. This treatment is usually well tolerated and effective.
Pain flare is described as a temporary increase in bone pain at the treated metastatic site, during or shortly after radiotherapy completion. This is the reason it may be necessary to increase the analgesic/ anti-inflammatory medication during the radiotherapy treatment.
Single fraction radiotherapy schedule (8Gy in 1 fraction) is recommended as standard of care for treatment of a symptomatic and uncomplicated bone metastasis.
In case of spinal cord compression, it is necessary use corticosteroids because of the oedema caused by the compression and radiotherapy treatment. Usually, the scheme used is 20 Gy in 5 fractions or 30 Gy in 10 fractions.
Combined modality treatment, surgery, and radiotherapy, should be offered for fit and functional patients with spinal cord compression, while radiotherapy alone is best reserved for the unfit, already incapacitated patients with poor prognosis.

Non-invasive treatments I A

Bisphosphonates work by inhibiting the remodelling process at the site of the metastatic bone cancer lesion. By reducing both bone resorption and bone formation,

bisphosphonates may reduce the inflammatory pain generator and the number of complication events. It is reported that bisphosphonates may also have a direct action on tumour cells by inducing apoptosis, inhibiting matrix metalloproteinases and by inhibiting the adhesion of tumour cells to bone.

This class of medication is widely used due to the evidence of reducing the risk of fractures, hypercalcemia, and the need for palliative radiation.
Bisphosphonates are not recommended in patients with renal failure with clearance of creatinine < 30 ml/min and in case of use it is necessary adjustment of dose. The common adverse events are hypocalcaemia and osteonecrosis of the jaw. All patients must have supplements of calcium and vitamin D, unless they have hypercalcemia.

Denosumab is a humanized monoclonal antibody (IgG2) which binds with high affinity to RANKL avoiding its union with RANK which is in the membrane of osteoclasts. This way, I B the bone remodelling is inhibited.

All patients must have supplements of calcium and vitamin D unless they have hypercalcemia.

28148890

26237249

28148890

WHO’s cancer paln treatment ladder Freedom from

cancer pain

Figure 1. WHO’s recommended three-step ladder approach to cancer pain treatment.

Non-opiold

+- adjuvant

2 Opioid for mild to moderate to pain

+- non-opiold

+- adjuvant

Opioid for moderate to

severe pain

+- non-opiold

+- adjuvant

References

Zajączkowska R, Kocot-Kępska M, Leppert W, Wordliczek J. Bone Pain in Cancer Patients: Mechanisms and Current Treatment. Int J Mol Sci. 2019 Nov 30; 20(23):6047. doi: 10.3390/ijms20236047. PMID: 31801267; PMCID: PMC6928918.
Falk S, Dickenson AH. Pain and nociception: mechanisms of cancer-induced bone pain. J Clin Oncol. 2014 Jun 1; 32(16):1647-54. doi: 10.1200/JCO.2013.51.7219. Epub 2014 May 5. PMID: 24799469.
Kane CM, Hoskin P, Bennett MI. Cancer induced bone pain. BMJ. 2015 Jan 29; 350:h315. doi: 10.1136/bmj.h315. PMID: 25633978.
Jimenez-Andrade JM, Mantyh WG, Bloom AP, Ferng AS, Geffre CP, Mantyh PW. Bone cancer pain. Ann N Y Acad Sci. 2010 Jun; 1198:173-81. doi: 10.1111/j.1749-6632.2009.05429.x. PMID: 20536932; PMCID: PMC5642911.
Figura, N.; Smith, J.; Yu, H. Mechanisms of, and Adjuvants for, Bone Pain. Hematol. Oncol. Clin. N. Am. 2018, 32, 447–458. doi: 10.1016/j.hoc.2018.01.006 ; PMID: 29729780
Mantyh, P. Bone cancer pain: Causes, consequences, and therapeutic opportunities. Pain 2013, 154, 54–62. doi: 10.1016/j.pain.2013.07.044; PMID: 23916671.
Li, B.T.; Wong, M.H.; Pavlakis, N. Treatment and prevention of bone metastases from breast cancer: A comprehensive review of evidence for clinical practice. J. Clin. Med. 2014, 3, 1–24. doi: 10.3390/jcm3010001; PMID: 26237249; PMCID: PMC4449670
Fleetwood–Walker, S.M.; Colvin, L.A.; Fallon, M. Translational medicine: Cancer pain mechanisms and management. Br. J. Anaesth. 2008, 101, 87–94. doi: DOI: 10.1093/bja/aen100; PMID: 18492671
Mantyh PW. Bone cancer pain: from mechanism to therapy. Curr Opin Support Palliat Care. 2014 Jun; 8(2):83-90. doi: 10.1097/SPC.0000000000000048. PMID: 24792411; PMCID: PMC4068714.
Lipton A. Emerging role of bisphosphonates in the clinic—antitumor activity and prevention of metastasis to bone. Cancer Treat Rev. 2008; 34 (Suppl 1): S25–S30.
Body JJ, et al. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin. Cancer Res. 2006; 12:1221–1228.
Francesca De Felice, Andrea Piccioli, Daniela Musio,Vincenzo Tombolini. The role of radiation therapy in bone metastases management. Oncotarget. 2017. Jan 26.doi:10.18632/oncotarget.14823; PMID: 28148890; PMCID: PMC5421962.

EMESIS

CANCER-ASSOCIATED EMESIS

Authors: Marina Meri Abad, Carolina Capucho Pereira and Ana Mafalda Baleiras

Symptoms and signs

Vomiting is established in three different phases: pre-ejection, ejection, and post-ejection. In the initial phase the nauseous sensation that announces the vomiting, accompanied by sweating, hypersalivation and pallor. In the second phase, the arches first appear and subsequently vomiting. Vomiting involves contraction synergy of the respiratory and abdominal muscles that causes the expulsion of gastric contents.

Learning objectives

To recognize emesis as one of the most frequent and bothersome symptoms for cancer patients.
To understand that emesis is often multifactorial, and treatment should be directed at the underlying causes.

Introduction

Nausea and vomiting are frequently experienced symptoms in cancer patients. Approximately 60% of advanced stage cancer patients will experience nausea and vomiting during the course of their disease. The aetiology is often multifactorial. Hence, identifying the underlying causes is important for subsequent management. Common mistakes when treating cancer-associated emesis are using inappropriate antiemetics or multiple drugs with the same mechanism of action.

Etiology

Emesis is a complex process based on the antiperistaltic reflex in response to stimuli. Patients can experience nausea, vomiting or retching, and although these are diferent entities, they often occur together. Emesis is frequently multifactorial, being related to the primary disease, anti-cancer treatments, medication and comorbidities. In advanced cancer, gastric stasis and chemical disturbance are the most common causes for nausea and vomiting, excluding anti-cancer therapies. Different mechanisms responsible for triggering

Evidence

Level Grade PMID Nº

vomiting are summarized in figure table 1.

Figure Table 1. Causes for cancer-related emesis.

Stimulus	Receptors involved	Causes
Vagal stimulation	Ach 5HT3	Visceral or serosal disease: Distention of the liver capsule, faecal impaction Gastroparesis (paraneoplastic visceral neuropahy and dyspepsia syndrome) Irritation of the digestive mucosa (drugs, infection, radiotherapy) Extrinsic compression of digestive structures Peritoneal irritation Mediastinal disease Cough
Direct stimulation of vomiting center	D2 Ach H1	Intracranial hypertension Meningeal irritation (infection, carcinomatosis) Brain radiotherapy Intracranial metastasis
Trigger zone stimulation	D2 5HT3 NK1	Drugs (opioids, antibiotics) Bacterial toxins Metabolic disorders: hypercalcemia, renal impairment, hypokalemia, hyponatremia

Studies Evidence

Complete patient examination should search for signs of intestinal obstruction, ascites and hepatomegaly, which may suggest gastric stasis. Rectal examination should be Level Grade PMID Nº

performed if faecal impaction is suspected, in the absence of neutropenia. Neurological examination should be conducted to exclude signs of raised intracranial pressure or focal neurology suggestive of parenchymal lesions or a base of skull tumour.

Further investigations depend on the goals of care. High tests burden should be avoided in a patient under exclusive best supportive care. Specific blood tests and imaging are recommended to rule out treatable causes of emesis (see table 1).

Pharmacotherapy

Effective antiemetics vary according to the underlying causes of nausea and vomiting in specific circumstances (see table 2). Parenteral hydration should be offered if there is overall benefit, but clinicians should be vigilant to signs of fluid overload, particularly in terminally ill patients.

For persistent nausea and vomiting, antiemetics should be prescribed regularly, with a second line antiemetic prescribed on an “as required” basis. The oral route of administration is preferred in the absence of vomiting, malabsorption or severe gastric stasis. In these circumstances, parenteral administration is indicated. The subcutaneous route is less invasive than intravenous, and a continuous infusion may be beneficial. Intramuscular administration should be avoided as this is painful and can cause haematomas in predisposed patients.

Antiemetics titration is frequently needed. A study found that the median time to resolution of symptoms was two days. During this time, antiemetics with competing mechanisms of action or similar receptor profiles should not be combined (eg. metoclopramide and cyclizine, or metoclopramide and domperidone, respectively). When selective first line antiemetics fail, agents with broader mechanisms of action can be effective as second line agents (eg. levomepromazine or olanzapine). Dexamethasone can be useful in addition to other antiemetics in malignant bowel obstruction or intracranial hypertension, typical dosing ranges from 4-16 mg daily.

Side effects of antiemetic drugs should also be taken into account. Metoclopramide can lead to extrapyramidal side effects and should be avoided in Parkinson’s disease, while domperidone is safe in this setting. Seizure threshold may be reduced by levomepromazine and haloperidol, but less in the latter. Cardiac conduction may be disturbed by domperidone, haloperidol, levomepromazine, cyclizine and 5HT3 antagonists such as ondansetron and granisetron. Of note, most antiemetics discussed in this chapter can be sedative, so doses should be titrated cautiously.

In the case of refractory symptoms, nasogastric tube placement can be useful to decompress the stomach and allow for drainage of gastric contents.

Table 2. Treatment for reversible causes of cancer-related emesis (sc: subcutaneous, SSRI: selective serotonin reuptake inhibitor, NSAID: nonsteroidal anti-inflammatory drug)

Cause

Triggers

Firstline

Secondline

Chemical

Drugs (opioids, digoxin, antibiotics, antifungals, iron, SSRIs, NSAIDs, dopamine agonists)

Chemotherapy

Metabolic (renal or liver failure, hypercalcaemia, hyponatraemia, ketoacidosis)

Toxins (ischaemic bowel, tumour products, infection)

Haloperidol 0.5-1.5 mg oral or sc, 3 times daily

Levomepromazine 3.125-6.25 mg oral or sc 3 times daily

Visceral or serosal

Bowel obstruction

Severe constipation or faecal impaction Liver capsule stretch

Ureteric distension Mesenteric metastases

Difficult expectoration or pharyngeal stimulation

Cyclizine 50 mg oral or sc 3 times daily

Levomepromazine 3.125-6.25 mg oral or sc 3 times daily

Evidence Level Grade PMID Nº

Gastric stasis	Drugs (opioids, tricyclics, phenothiazines, anticholinergics) Tumour ascites Hepatomegaly Autonomic dysfunction Tumour infiltration	Domperidone 10 mg oral 4 times daily before meals	Metoclopramide 10 mg 3 to 4 times daily before meals
Cranial	Raised intracranial pressure (tumour, bleed, infarction) Meningeal infiltration Radiotherapy	Cyclizine 50 mg oral or sc 3 times daily Add dexamethasone 8-16 mg oral or sc daily if raised intracranial pressure	Haloperidol 0.5-1.5 mg oral or sc, 3 times daily
Vestibular	Drugs (opioids) Motion sickness Base of skull tumour	Cyclizine 50 mg oral or sc 3 times daily	Levomepromazine 3.125-6.25 mg oral or sc 3 times daily
Cortical	Anxiety Pain	Lorazepam 0.5-1 mg sublingual 4 times daily as needed	Levomepromazine 3.125-6.25 mg oral or sc 3 times daily

Metoclopramide (1)
Dexamethasone (2)
Haloperidol (3)
Levosulpiride (4)
Tropiseron (5)

Therapeutic Strategy

Evaluation: anamnesis, physical exploration, review of medication.
Depending on clinical exploration: blood test (metabolic disorder); abdominal Rx (intestinal occlusion); abdominal CT scan (retroperitoneal disease); abdominal ultrasound (obstructive uropathy); cerebral CT scan (CNS lesions)
General measures: correction of diet; oral hygiene; quiet atmosphere; oral or parenteral hydration if required; parenteral administration of essential medication.
Etiological treatment: antitussives (cough); laxatives (constipation); corticoids (endocranial hypertension); CNS lesions (radiotherapy if indicated); correction of metabolic disorders; antibiotics (infection).
Antiemetic drugs: metoclopramide or domperidone (vagal stimulation); haloperidol (trigger center); dexamethasone (CNS stimulation). If there is no adequate control after first

Refelinreetnrecatemse:nt: Metroclopramie + dexamethasone (vagal stimulation); haloperidol + dexamethasone (trigger center and CNS stimulation).

II II II III II

III III

III

A 10908823

B 15471656

A 11503632

B 8537694

B 9740088

C 27664248 27896642

Bruera E, Belzile M, Neumann C, Harsanyi Z, Babul N, Darke A. A double-blind, crossover study of controlled-release metoclopramide and placebo for the chronic nausea and dyspepsia of advanced cancer. J Pain Symptom Manage. 2000 Jun;19(6):427–35.
Bruera E, Moyano JR, Sala R, Rico MA, Bosnjak S, Bertolino M, et al. Dexamethasone in addition to metoclopramide for chronic nausea in patients with advanced cancer: a randomized controlled trial. J Pain Symptom Manage. 2004 Oct;28(4):381–8.
Critchley P, Plach N, Grantham M, Marshall D, Taniguchi A, Latimer E, et al. Efficacy of haloperidol in the treatment of nausea and vomiting in the palliative patient: a systematic review. J Pain Symptom Manage. United States; 2001. p. 631–4.
Corli O, Cozzolino A, Battaiotto L. Effectiveness of levosulpiride versus metoclopramide for nausea and vomiting in advanced cancer patients: a double-blind, randomized, crossover study. J Pain Symptom Manage. 1995 Oct;10(7):521–6.
Mystakidou K, Befon S, Liossi C, Vlachos L. Comparison of the efficacy and safety of tropisetron, metoclopramide, and chlorpromazine in the treatment of emesis associated with far advanced cancer. Cancer. 1998 Sep;83(6):1214–23.
Collins E, Mather H. Nausea and vomiting in palliative care. BMJ 2015;351:h6249.
Leach C. Nausea and vomiting in palliative care. Clinical Medicine 2019 Vol 19, No 4: 299–301.

IATROGENIC EMESIS

Author: Helena Guedes, Sandra Custódio and Alexandra Guedes

Definition

For many cancer patients, nausea and vomiting are the most feared treatment side effects. Vomiting can be directly perceived and quantified, but nausea, which often accompanies emesis (vomiting and/or retching), is a subjective sensation. Even though nausea and vomiting can result from surgery, radiation therapy or even pain medication, chemotherapy-induced nausea, and vomiting (CINV) is potentially the most severe. Its incidence is affected by age, gender, and the drug’s emetogenic potential.

Symptoms and signs

Emesis and/or nausea can be very distressing, with severe impact on the patient’s quality of life. Persistent vomiting might lead to anorexia and dehydration, as well as various nutritional deficiencies and metabolic imbalances. Bedridden patients might even develop aspiration pneumonia. The patient’s performance status often deteriorates, with potential adverse implications on scheduled treatment protocols and efficacy.1 Aetiology

Vomiting results from stimulation of multistep pathway controlled by the brain. 2Vomiting is triggered by afferent impulses to the vomiting center (located in the medulla) from the chemoreceptor trigger zone, pharynx, and gastrointestinal tract (via vagal afferent fibres), and cerebral cortex. Vomiting occurs when efferent impulses are sent from the vomiting center to the salivation center, abdominal muscles, respiratory center, and cranial nerves. 1Causes of Nausea and/or Vomiting: Multiple causes for emesis have been identified, including:

Gastrointestinal: gastric stasis (often induced by opioids and anticholinergics), pancreatic carcinoma, peritonitis, cholangitis, partial or complete bowel obstruction, malignant ascites, vesicular dysfunction, or other intra-abdominal causes.
Central nervous system: primary or metastatic brain tumor, intracranial hypertension.
Vestibular: labyrinthitis, Meniere’s disease, acoustic neuroma, primary or metastatic brain tumor.
Metabolic: hypercalcemia, hyperglycemia, hyponatremia, ketoacidosis.
Pharmacological: cytostatic drugs, opioids, diuretics, oral antidiabetics, antibiotics such as amoxicillin, metronidazole, trimethoprim.
Others: cough, pharyngeal irritation from infection/respiratory secretions, radiotherapy.

In most cases, the aetiology is multifactorial, and a thorough evaluation is necessary to correctly identify the contributing factors and decide upon the most appropriate intervention.

Types of nausea and/or vomiting: CINV is commonly classified as acute, delayed, anticipatory, breakthrough, or refractory.

ACUTE: usually occurs within few minutes to several hours after administration of certain anticancer agents and commonly resolves within the first 24 hours. The intensity of acute-onset emesis generally peaks after 5 to 6 hours. 13
DELAYED-ONSET: develops more than 24 hours after the anticancer agent administration.1,4
ANTICIPATORY: occurs before patients receive their next anticancer treatment. Because it is primarily considered a conditioned response, anticipatory emesis typically occurs after a previous negative experience with anticancer agents. Its incidence ranges from 18% to 57%, and nausea is more common than vomiting. 5
BREAKTHROUGH: occurs despite prophylactic antiemetic treatment and/or requires rescue with antiemetics. 6
REFRACTORY: occurs during subsequent treatment cycles after guideline directed prophylactic antiemetic agents have failed in earlier cycles.7 There are several factors that that contribute to the severity of CINV:
Individual patient variability: younger age, female gender, prior anticancer agents; history of little or no alcohol use, morning sickness, motion sickness, anxiety.
Chemotherapy drug’s emetogenic potential.

Chemotherapy agents are divided into four levels of emetogenicity according to the percentage of patients who experience acute emesis in the absence of antiemetic prophylaxis. 8

HIGH EMETIC RISK – more than 90% of patients experience acute emesis.
MODERATE EMETIC RISK – more than 30% to 90% of patients experience acute emesis.
LOW EMETIC RISK – 10% to 30% of patients experience acute emesis.
MINIMAL EMETIC RISK – fewer than 10% of patients experience acute emesis.

Evidence

Level Grade PMID Nº

Table 1 – Emetic Risk Groups – Single IV Agents

HIGH

Anthracycline/cyclophosphamide combination* Carmustine

Cisplatin

Cyclophosphamide > 1500 mg/m² Dacarbazine

Mechlorethamine Streptozocin

MODERATE

Alemtuzumab Azacitidine Bendamustine Carboplatin Clofarabine

Cyclophosphamide < 1500 mg/m²

Cytarabine > 1000 mg/m²

Daunorubicin Doxorubicin Epirubicin Idarubicin Ifosfamide

Irinotecan

Oxaliplatin Romidepsin Temozolomide** Thiotepa

Trabectedin

LOW

Aflibercept Belinostat Blinatumomab Bortezomib Brentuximab Cabazitaxel Carfilzomib Catumaxumab Cetuximab

Cytarabine < 1000 mg/m²

Docetaxel

Eribulin Etoposide

5-Fluorouracil Gemcitabine Ipilimumab Ixabepilone Methotrexate Mitomycin Mitoxantrone Nab- paclitaxel

Paclitaxel

Panitumumab Pemetrexed Pegylated liposomal doxorubicin Pertuzumab Temsirolimus Topotecan

Trastuzumab-emtansine

Vinflunine

MINIMAL

Bevacizumab Bleomycin Busulfan

2-Chlorodeoxyadenosine Cladribine

Fludarabine Nivolumab

Ofatumumab

Pembrolizumab Pixantrone Pralatrexate Rituximab Trastuzumab Vinblastine Vincristine

Vinorelbine

** The combination of an anthracycline and cyclophosphamide in patients with breast cancer should be considered highly emetogenic.; ** No direct evidence found for temozolomide IV. Classification is based on oral temozolomide since all sources indicate a similar safety profile.

Evidence Level Grade PMID Nº

Table 2 – Emetic Risk Groups – Adults – Single Oral Agents.

HIGH

Hexamethylmelamine

Procarbazine

MODERATE

Bosutinib Ceritinib

Crizotinib

Cyclophosphamide Imatinib

Temozolomide

Vinorelbine

LOW

Afatinib Axatinib Capecitabine Dabrafenib Dasatinib Everolimus Etoposide

Fludarabine

Ibrutinib Idelalisib Lapatinib Lenalidomide Olaparib Nilotinib

Pazopanib

Ponatinib Regorafenib Sunitinib Tegafur Uracil Thalidomide Vandetanib

Vorinostat

MINIMAL

Chlorambucil Erlotinib Gefitinib Hydroxyurea

Melphalan

Methotrexate

L-Phenylalanine mustard Pomalidomide

Ruxolitinib

Sorafenib

6-Thioguanine Vemurafenib

Vismodegib

Pharmacotherapy

Routine antiemetic premedication may not be required for continuous dosing of some low emetic risk parenteral agents or some moderate to high risk emetic risk oral agents; an individualized approach is appropriate in these settings.1

Table 3 – CINV Prophylaxis according to each drug’s emetogenic potential.

Evidence

Level Grade PMID Nº

	Drug	Dose on the day of treatment
	High Emetic	Risk: cisplatin and other agents; anthracyclines combined with cyclophosphamide
5-HT3 Receptor Antagonist	Ondansetron	Single 24 mg dose administered by tablets, successive dissolving tablets, or oral dissolving film applications before the start of chemotherapy or 8 mg or 0.15 mg/kg IV
	Granisetron	2 mg PO or 1 mg or 0.01 mg/kg IV or 1 transdermal patch or 10 mg subcutaneous
	Dolasetron	100 mg PO only
	Palonosetron	0.50 mg PO or 0.25 mg IV
	Tropisetron	5 mg PO or IV
	Ramosetron	12 mg PO or IV

Evidence Level Grade PMID Nº

	Drug	Dose on the day of treatment Dose(s) on Subsequent Days
Neurokinin – 1 – Receptor Antagonist	Aprepitant	125 mg PO or 130 mg IV	80 mg PO on days 2 and 3
	Fosaprepitant	150 mg IV
	Netupitant – Palonesetron	300 mg netupitant/ 0.5 mg palonosetron PO in single capsule
	Fosnetupitant – Palonosetron	235 mg fosnetupitant/ 0.25 mg palonosetron IV
	Rolapitant	180 mg PO
Corticosteroids	Dexamethasone	20 mg PO or IV	8 mg PO or IV twice daily on
		If aprepitant, netupita-nt palonosetron or fosnetupitant – palonosetron are used:
		12 mg PO or IV	8 mg PO or IV once daily on days 2-4
		If rolapitant is used:
		12 mg PO or IV	8 mg PO or IV twice daily on days 2 – 4
		If fosaprepitant is used:
		12 mg PO or IV	8 mg PO or IV on day 2; 8 mg PO or IV twice daily on days 3-4
Atypical antipsychotics	Olanzapine	5 or 10mg PO	5 or 10mg PO on days 2-4
Moderate Emetic Risk
5-Ht3 Receptor Antagonist		Refer to “High Emetic Risk: Cisplatin and other agents”
Corticosteroid	Dexamethasone	8 mg PO or IV	8 mg PO or IV on days 2-3
Low Emetic Risk
5-HT3 Receptor Antagonist		Refer to “High Emetic Risk: Cisplatin and other agents”
Corticosteroid	Dexamethasone	8 mg PO or IV

Table 4 – CINV prophylaxis in Advanced Cancer.

Evidence Level Grade PMID Nº

	Drug
First line agents	Metoclopramide
First line agents	Haloperidol
Second line agents	Methotrimeprazine
Second line agents	Olanzapin
Third line agents	Levosulpiride
Third line agents	Tropisetron

Therapeutic Strategy

II	A	34398289
II	A	34398289
II	B	34398289
II	B	34398289
III	B	34398289
II	B	34398289
I	A
I	B
I	A
II	B
II	B
II	B

Table 5 – Guideline recommendations for CINV prophylaxis.

Prevention of Acute Nausea and Vomiting Following Non-AC Chemotherapy of High Emetic Risk.

A three-drug regimen including single doses of a 5-HT3 receptor antagonist, dexamethasone and an NK1 receptor antagonist (aprepitant, fosaprepitant, netupitant* or rolapitant), given before chemotherapy is recommended.

Prevention of Delayed Nausea and Vomiting Following Non-AC Chemotherapy of High Emetic Risk.

In patients receiving non-AC highly emetogenic chemotherapy treated with a combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist and dexamethasone to prevent acute nausea and vomiting, dexamethasone on days 2 to 4 is suggested to prevent delayed nausea and vomiting.

Prevention of Acute Nausea and Vomiting Following Anthracycline-Cyclophosphamide-Based Chemotherapy of High Emetic Risk.

In women with breast cancer, a three-drug regimen including single doses of a 5-HT3 receptor antagonist, dexamethasone and an NK1 receptor antagonist (aprepitant, fosaprepitant, netupitant* or rolapitant), given before chemotherapy is recommended.

Prevention of Delayed Nausea and Vomiting Following Anthracycline-Cyclophosphamide-Based Chemotherapy of High Emetic Risk.

In women with breast cancer treated with a combination of a 5-HT3 receptor antagonist, dexamethasone and a NK1 receptor antagonist to prevent acute nausea and vomiting, aprepitant or dexamethasone should be used on days 2 and 3 or none if fosaprepitant, netupitant or rolapitant has been used in day 1.

Prevention of Acute and Delayed Nausea and Vomiting Following Non-AC and AC Chemotherapy of High Emetic Risk.

In patients treated with non-AC highly emetogenic chemotherapy or in women with breast cancer treated with AC chemotherapy olanzapine may be considered with a 5-HT3 receptor antagonist plus dexamethasone, plus an NK1 receptor antagonist, particularly when nausea is an issue.

Prevention of Acute Nausea and Vomiting in Moderately Emetogenic Chemotherapy

For the prevention of acute nausea and vomiting in moderately emetogenic chemotherapy-treated patients, a 5-HT3 receptor antagonist plus dexamethasone is recommended.

Prevention of Delayed Nausea and Vomiting in Moderately Emetogenic Chemotherapy.

In patients receiving moderately emetogenic chemotherapy with known potential for delayed nausea and vomiting,the use of dexamethasone for days 2 to 3 can be considered

Prevention of Acute Nausea and Vomiting in Patients Receiving Carboplatin-Based Chemotherapy.

A combination of an NK1 receptor antagonist, 5-HT3 receptor antagonist, and dexamethasone is recommended for the prophylaxis of nausea and vomiting induced by carboplatin-based chemotherapy.

III C

II B

Prevention of Delayed Nausea and Vomiting in Patients Receiving Carboplatin-Based Chemotherapy.

If aprepitant 125 mg is used on day 1, aprepitant 80 mg on days 2 to 3 is recommended for the prevention of delayed nausea and vomiting. If other NK1 receptor antagonists are used on day 1, no additional prophylaxis for delayed nausea and vomiting prevention is suggested.

Prevention of Acute Nausea and Vomiting in Patients Receiving Low Emetogenic.

A single antiemetic agent, such as dexamethasone, a 5-HT3 receptor antagonist, or a dopamine receptor antagonist, such as metoclopramide, may be considered for prophylaxis in patients receiving chemotherapy of low emetic risk.

Prevention of Acute Nausea and Vomiting in Patients Receiving Minimally Emetogenic Chemotherapy.

No antiemetic should be routinely administered before chemotherapy to patients without a history of nausea and vomiting.

Prevention of Delayed Nausea and Vomiting in Patients Receiving Minimally Emetogenic Chemotherapy.

No antiemetic should be administered for prevention of delayed nausea and vomiting induced by low or minimally emetogenic chemotherapy.

Prevention of Nausea and Vomiting in Patients Receiving Multiple-Day Cisplatin.

Patients receiving multiple-day cisplatin should receive a 5-HT3 receptor antagonist plus dexamethasone plus NK1 receptor antagonist for acute nausea and vomiting and dexamethasone for delayed nausea and vomiting.

Prevention of Nausea and Vomiting in Patients Receiving High-Dose Chemotherapy.

For patients receiving high-dose chemotherapy for stem cell transplant, a combination of a 5-HT3 receptor antagonist with dexamethasone and NK1 receptor antagonist is recommended before chemotherapy.

Guideline for Breakthrough Nausea and Vomiting

The available evidence for breakthrough nausea and vomiting suggests the use of 10 mg PO olanzapine, daily for 3 days.

Prevention of Anticipatory Nausea and Vomiting.

The best approach for the prevention of anticipatory nausea and vomiting is the best possible control of acute and delayed nausea and vomiting.

Behavioural therapies (progressive muscle relaxation training, in particular), systematic desensitisation, and hypnosis may be used to treat anticipatory nausea and vomiting. Benzodiazepines can reduce the occurrence of anticipatory nausea and vomiting.

*netupitant is administered with palonosetron as part of the fixed-dose combination agent NEPA.

ADDITIONAL RECOMMENDATIONS:

Antineoplastic Combinations: Adults treated with antineoplastic combinations should be offered antiemetics appropriate for the component antineoplastic agent of greatest emetic risk. 10
Adjunctive Drugs : Lorazepam is a useful adjunct to antiemetic drugs, but is not recommended as a single-agent antiemetic.10
Cannabinoids: Evidence remains insufficient for a recommendation regarding medical marijuana for the prevention of nausea and vomiting in patients with cancer receiving chemotherapy. 10 Complementary and Alternative Therapies: Evidence remains insufficient for a recommendation for or against the use of ginger, acupuncture/acupressure, and other complementary or alternative therapies for the prevention of nausea and vomiting in patients with cancer.
High Dose Chemotherapy with Stem Cell or Bone Marrow Transplant: Adult patients treated with high-dose chemotherapy and stem-cell or bone marrow transplantation should be offered a three drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone. A four-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, dexamethasone, and olanzapine may be offered to adults treated with high-dose chemotherapy and stem-cell or bone marrow transplantation.10
Breakthrough Nausea or Vomiting: Adults who experience nausea or vomiting despite optimal prophylaxis, and who did not receive olanzapine prophylactically, should be offered olanzapine in addition to continuing the standard antiemetic regimen. Adults who experience nausea or vomiting despite optimal prophylaxis, and who have already received olanzapine, may be offered a drug of a different class (e.g. an NK1 receptor antagonist, lorazepam or alprazolam, a dopamine receptor antagonist, dronabinol, or nabilone) in addition to continuing the standard antiemetic regimen.10
Anticipatory Nausea and Vomiting. Clinicians should use such regimens with initial antineoplastic treatment, rather than assessing the patient’s emetic response with less effective antiemetic treatment. If a patient experiences anticipatory emesis, clinicians may offer behaviour therapy with systematic desensitization. 10

Evidence Level Grade PMID Nº

II B

IV D

II B

II A

References: Level GradeEvidence

PMID Nº

National Comprehensive Cancer Network. NCCN.pdf. https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf (2022).
Herrstedt, J. Antiemetics: An update and the MASCC guidelines applied in clinical practice. Nat. Clin. Pract. Oncol. 5, 32–43 (2008).
Warr, D. G., Street, J. C. & Carides, A. D. Evaluation of risk factors predictive of nausea and vomiting with current standard-of-care antiemetic treatment: Analysis of phase 3 trial of aprepitant in patients receiving adriamycin-cyclophosphamide-based chemotherapy. Support. Care Cancer 19, 807–813 (2011).
Kris, M. G. et al. Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J. Clin. Oncol. 3, 1379–1384 (1985).
Moher, D., Arthur, A. Z. & Pater, J. L. Anticipatory nausea and/or vomiting. Cancer Treat. Rev. 11, 257–264 (1984).
Roila, F. et al. Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the 2004 Perugia International Antiemetic Consensus Conference. Ann. Oncol. 17, 20–28 (2006).
Navari, R. M. Management of chemotherapy-induced nausea and vomiting: Focus on newer agents and new uses for older agents. Drugs 73, 249–262 (2013).
Grunberg, S. M. et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity – State of the art. Support. Care Cancer 19, 2–6 (2011).
Aapro, M., Gralla, R. J., Roila, F., Herrstedt, J. & Molassiootis, A. MASCC / ESMO Antiemetic Guideline 2016 with Updates in 2019. Multinatl. Assoc. Support. Care Cancer 1–55 (2019).

ONCOLOGIC EMERGENCIES

SPINAL COMPRESSION SYNDROME

Authors: Teresa Fraga, Catarina Almeida and Diana Correia

Introduction [1]-[6]

- - Spinal Cord Compression (SCC) is an oncological emergency.
  - SCC is one of most common neurological complications in patients with cancer second only to brain metastases.
  - Up to 5% of cancers can complicate with SCC.
  - SCC can lead to extensive neurologic deficits when not promptly recognized and treated.
  - Lung, breast and prostate are the types of cancer most frequently associated with SCC, followed by multiple myeloma, renal cell carcinoma and non-Hodgkin lymphoma.
  - SCC can be the initial manifestation of a previously undiagnosed malignancy in around 20% of patients.• The most common site for compression is in the thoracic segment of the spine (~60% of all cases).
  - Survival in patients with multiple spinal metastases and cord compression is generally less than 6 months.

Etiology [1]-[6]

- - The mechanism of the compression is multifactorial.
  - Haematogenous vertebral corpus metastases are the most common mechanism in adults.
    - Epidural venous plexus obstruction may lead to vasogenic oedema of the white matter (early stages) and increase inflammatory reactions that result in hypoxic injury of the spinal cord. This injury induces the release of Vascular Endothelial Growth Factor (VEGF) which leads to more vascular permeability and interstitial oedema.
  - Other mechanisms include the local spread from a tumour near the spine and a direct metastasis to the epidural space (rare).
  - Early decompression increases the probability of recovery, with the opposite leading to irreversible spinal cord damage and debilitating sequelae.

Clinical Manifestations [1]-[6]

- - SCC arises in the thoracic segment of the spine in more than half of all cases (approximately 60%), and in the lumbosacral and cervical spine in 30% and 10% of cases, respectively.
  - In almost one third of all patients imaging of the entire spine reveals multiple levels of compression.
  - Key presenting features include back pain, motor weakness, sensory deficits, and bowel or bladder dysfunction.
  - Signs and symptoms vary according to pathophysiology (upper or lower motor lesion) and spinal location.
  - SCC usually presents with pain (back pain), which is reported in 80-95% of patients.
    - Pain is constant and it worsens at night and with the Valsalva manoeuvre (i.e.: coughing, sneezing).
    - Radicular pain may manifest in cases of advanced disease.
    - Back pain and tenderness in the site are typical and may precede neurologic features by several weeks.
  - Motor deficits are found in 35 to 75% of cancer patients.
  - Sensory loss is less common but can be found in 40-90% of cancer patients. The level of sensory deficit may correlate poorly with the level of the spine lesion.
  - Although rarely the presenting complaint, patients can also have autonomic deficits such as bowel or bladder dysfunction. These tend to occur later, along with worsening motor weakness, and are associated with a poorer functional outcome after treatment.

Evidence

Level Grade PMID Nº

Studies [1]-[6] Level GradeEvidence

PMID Nº

- - Gadolinium contrast-enhanced Magnetic Resonance Imaging (MRI) is the gold standard (sensitivity 93%, specificity 97%).
  - Since multilevel disease may be present and the symptoms may not correlate with the level of the lesion, the entire spine should be imaged with and without contrast.
  - Bone scan computed tomography (CT) and positron emission tomography (PET) are less useful.
  - CT is only recommended when MRI is contraindicated.

Differential Diagnosis [1]

- - Benign musculoskeletal diseases (muscle spasm, spinal stenosis, and intervertebral disc diseases).
  - Infectious diseases (spinal epidural abscess).
  - Radiation myelopathy and metastatic disease with vertebral metastases without SCC.
  - Brain metastases should be ruled out.

Therapeutic Strategy [1]-[7]

- - The goals of care consist of pain control and preservation of neurological function and performance status.
  - Prolonged loss of motor function cannot be restored by either surgery or radiation therapy (RT). The timeliness of treatment initiation influences the resulting outcomes in both RT and surgery with superior results if treatment starts within 48 hours of diagnosis.
  - Although this is a common complication in cancer patients, data from randomized controlled trials is scarce.
  - The treatments most commonly include the use of steroids, RT and surgery.
  - Surgery is indicated in patients with spinal instability or severe compression on MRI with neurologic deficits.
CORTICOSTEROIDS
- First-line treatment for most patients. I A
- Glucocorticoid (GC) therapy results in the downregulation of VEGF and prostaglandin E2, with a corresponding decrease in spinal cord oedema.
- GC reduce neurologic impairment and pain, however there is no consensus on the optimum loading and maintenance doses.
- Patients with paraparesis or paraplegia:

– High-dose” corticosteroid treatment (96 mg intravenous [i.v.] dexamethasone, followed by 24 mg qid for 3 days, and then tapered over 10 days)

- Patients with pain but minimal neurological dysfunction:

“Low-dose” corticosteroid treatment (10mg dexamethasone i.v. bolus, followed by 16mg id)

- Management decisions must be individualized and need to take into consideration: spinal stability, degree of neurologic compromise, radiosensitivity of the tumour, and the patient’s overall health status and goals of care.
SURGERY
- The Spinal Instability Neoplastic Score (SINS) is a classification that has been developed to determine whether surgery is appropriate to correct instability.
- Radiation is usually administered after surgical decompression.

22547256

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16770986

Evidence Level Grade PMID Nº

- Early surgical intervention in patients with metastatic spine lesions before the patients become non-ambulatory is supported by retrospective evidence that patients with preoperative ambulatory function are twice more likely to maintain the ability to walk after decompressive surgery.
- Surgical treatment resulted in a longer survival time, maintenance of continence, and a reduction in the need for corticosteroids and analgesics.
- Decompressive surgery followed by RT may have better outcomes than RT alone in selected patients, such as:
  - patients with radioresistant primary tumours – displacement of spinal cord on MRI – a single area of cord compression
  - loss of motor function less than 48 hours – estimated survival longer than three months

•Surgery is also an option for the treatment of spinal tumor Tumour? recurrence after RT.

RADIOTHERAPY
- Key factors in undergoing surgery before RT include spinal stability, presence of neurologic deficits, and patient prognosis.
- RT with or without surgery is the recommended treatment for SCC.
- Radiation can be given at previously treated sites if the prior dose was moderate. The cumulative amount is limited to avoid spinal cord damage.
- Treatment with either single fraction or multiple fractionated RT has shown equivalent efficacy.
- Single fraction of 8 Gy is as effective for bone metastases as more protracted schedules, with a shorter, more convenient delivery for patients with poor prognosis.
- Extended treatment and higher fractionated doses are used if longer survival is anticipated.
- Stereotactic body radiation therapy (SBRT) provides tumour control, pain relief, and minimal risk of radiation myelopathy but may not prevent progressive vertebral fracture and kyphosis.
  - Tumours such as melanoma, sarcoma, and renal cell carcinoma (resistant to standard fractionated RT) appear to respond as well to SBRT
  - The current evidence primarily supports the use of spine SBRT in spine metastases without cord compression.
  - SBRT can be utilized to manage residual tumour after decompressive surgery for SCC
INTERVENTIONAL THERAPY
- Percutaneous radiofrequency ablation (PRA) is a useful to reduce pain and related disability in patients with end-stage spinal metastases when there are no other options.
  - Lesions within 1 cm of the spinal cord are considered ineligible because of the risk of thermal injury to the spinal cord.

References

- [1] ESMO, ESMO Handbook of Oncological Emergencies. 2016.
- [2] J. Spring and L. Munshi, “Oncologic Emergencies: Traditional and Contemporary,” Crit. Care Clin., vol. 37, no. 1, pp. 85–103, 2021, doi: 10.1016/j.ccc.2020.08.004.
- [3] A. E. Ropper and A. H. Ropper, “Acute Spinal Cord Compression.,” N. Engl. J. Med., vol. 376, no. 14, pp. 1358–1369, 2017, doi: 10.1056/NEJMra1516539.
- [4] A. J. Lawton et al., “Assessment and management of patients with metastatic spinal cord compression: A multidisciplinary review,” J. Clin. Oncol., vol. 37, no. 1, pp. 61–71, 2019, doi: 10.1200/JCO.2018.78.1211.
- [5] E. S. C. Ribas and D. Schiff, “Spinal cord compression,” Curr. Treat. Options Neurol., vol. 14, no. 4, pp. 391–401, 2012, doi: 10.1007/s11940-012-0176-7.
- [6] T. R. Halfdanarson, W. J. Hogan, and T. J. Moynihan, “Oncologic emergencies: Diagnosis and treatment,” Mayo Clin. Proc., vol. 81, no. 6, pp. 835–848 2006, doi: 10.4065/81.6.835.
- [7] M. H. Suppli, “Approaches to radiotherapy in metastatic spinal cord compression,” Dan Med J., Apr;65(4):B5451, 2018, PMID: 29619931

III I

III

B 22547256

33190777

22547256

28379788

A 22547256 28379788

16770986 29619931

B 22547256

29619931

C 22547256

SUPERIOR VENA CAVA SYNDROME

Authors: Inês Nobre-Góis, Marta Freitas and Helena Guedes

Definition

Superior vena cava (SVC) syndrome (SVCS) is a medical emergency resultant from the partial or complete obstruction of blood flow through the SVC.

Symptoms and Signs [1]-[3]

Most common presenting symptoms include:
- - Facial, neck and upper arms swelling and cyanosis.
  - Respiratory symptoms including dyspnoea, orthopnoea, cough, hoarseness, stridor and chest pain, aggravated if concomitant pleural effusion.
Less common presenting symptoms include:
- Neurologic manifestations due to cerebral oedema (including headache, confusion and visual disorders), potentially leading to life-threatening brainstem herniation.
The severity of symptoms depends on the grade of the SVC calibre reduction, the time course (and hence the possibility to recruit venous collaterals) and the probable association with acute thrombosis.
On physical examination there may be distension of neck and chest wall veins, facial and arm oedema and cyanosis, and facial plethora.

Etiology

Most frequent causes of SVCS include:

Intrathoracic malignancies (60 to 85% of all cases), causing direct SVC invasion or it’s extrinsic compression and potential subsequent thrombosis[4]-[6] .
- Bronchogenic carcinoma, including non-small cell lung cancer (approximately 50%) and small cell lung cancer (25 to 35%)[7]-[9] .
- Non-Hodgkin lymphoma (10 to 15%)[10] .
- Other less common: thymoma and other thymic neoplasms[11] , mesothelioma, germ cell neoplasms[12] and solid metastatic tumours[13].
Benign or non-malignant causes (15- 40% of all cases)[14]-[15] .
- Latrogenic thrombus formation or device-related SVCS with rising incidence, related to the increased use of intravascular devices (e.g.: pacemaker and implantable cardioverter-defibrillator (ICD) wires and intravascular catheters used for or chemotherapy or haemodialysis).
- Other benign conditions (e.g.: fibrosing mediastinitis, post-radiation fibrosis).

Studies

Upper body and vasculature imaging studies:[4],[16]-[8]

Chest X-Ray.

-May show enlarged superior mediastinum.

Contrast enhanced computed tomography (CT).
- Can demonstrate the site, level, and extent of venous obstruction, map collateral vessels, and often identify the underlying cause of venous blockage.
- Sensitivity of 96-98% and specificity of 97-99%.
Magnetic resonance (MRI).
- Can provide information complementary information to CT.
Ultrasound (US) of the jugular, subclavian, brachiocephalic and axillary veins .
- Can provide indirect findings to suggest SCV obstruction as SVC cannot be directly imaged by US.
- Can identify a luminal thrombus in the above-mentioned draining system.
Venography.
- Can be used as diagnostic and therapeutic strategy.

Evidence

Level Grade PMID Nº

Pharmacotherapy Level GradeEvidence

PMID Nº

Glucocorticoids, in known steroid-responsive malignancies (e.g.: lymphoma or thymoma)[10]. 2C

C	6368759
D	9135892
C	7234887
C	16502166
C	16502166
B	6368759
A	33357528
A	22319249
B	19620456
B	12555872
B	6368759
C	16429916
C	28979481

Glucocorticoids, in patients receiving Rt[19]. 2C
Diuretics and avoiding overhydration[20]. 2C
Thrombolytic techniques (mechanical preferable to pharmacological) in SVCS due to thrombus, or in selected cases after stenting[21]. 2C
Anticoagulation therapy in SVCS due to thrombus and after stenting[21]. 2C
Chemotherapy agents, for patients with chemo-sensitive tumours (e.g.: lymphoma, small cell lung cancer, germ cell tumours)[10]. 2C
Mechanical strategies (e.g.: head elevation to decrease the hydrostatic pressure in the head and neck)[22].
Patient stabilization in severe cases (ABC: airway, breathing and circulation)[23].
Endovascular treatment, including SVC stenting for recanalization[24]. 2A
Radiotherapy, as an alternative or complement to endovascular treatment strategies[25]. 2A
Chemotherapy, for patients with chemo-sensitive tumours[10]. 2C
Surgical venous bypass in highly selected patients[26]. IV
Removal of intravascular catheter in SVCS due to thrombus (if present and possible[27]. 3A

References

Drouin L, Pistorius MA, Lafforgue A, et al. [Upper-extremity venous thrombosis: A retrospective study about 160 cases]. La Revue de medecine interne. 2019;40(1):9-15. doi:10.1016/j.revmed.2018.07.012
Zimmerman S, Davis M. Rapid Fire: Superior Vena Cava Syndrome. Emerg Med Clin North Am. 2018;36(3):577-584. doi:10.1016/j.emc.2018.04.011
Carmo J, Santos A. Chronic Occlusion of the Superior Vena Cava. N Engl J Med. 2018;379(1):e2. doi:10.1056/NEJMicm1711273
Friedman T, Quencer KB, Kishore SA, Winokur RS, Madoff DC. Malignant Venous Obstruction: Superior Vena Cava Syndrome and Beyond. Semin Intervent Radiol. 2017;34(4):398-408. doi:10.1055/s-0037-1608863
Kalra M, Sen I, Gloviczki P. Endovenous and Operative Treatment of Superior Vena Cava Syndrome. Surg Clin North Am. 2018;98(2):321-335. doi:10.1016/j.suc.2017.11.013
García Mónaco R, Bertoni H, Pallota G, et al. Use of self-expanding vascular endoprostheses in superior vena cava syndrome. Eur J Cardiothorac Surg. 2003;24(2):208-211. doi:10.1016/s1010-7940(03)00293-8
Rice TW, Rodriguez RM, Light RW. The superior vena cava syndrome: clinical characteristics and evolving etiology. Medicine. 2006;85(1):37-42. doi:10.1097/01.md.0000198474.99876.f0
Yellin A, Rosen A, Reichert N, Lieberman Y. Superior vena cava syndrome. The myth–the facts. Am Rev Respir Dis. 1990;141(5 Pt 1):1114-1118. doi:10.1164/ajrccm/141.5_Pt_1.1114
Markman M. Diagnosis and management of superior vena cava syndrome. Cleve Clin J Med. 1999;66(1):59-61. doi:10.3949/ccjm.66.1.59
Perez-Soler R, McLaughlin P, Velasquez WS, et al. Clinical features and results of management of superior vena cava syndrome secondary to lymphoma. J Clin Oncol. 1984;2(4):260-266. doi:10.1200/JCO.1984.2.4.260
Dib HR, Friedman B, Khouli HI, Gerber DR, Weiss RL. Malignant thymoma. A complicated triad of SVC syndrome, cardiac tamponade, and DIC. Chest. 1994;105(3):941-942. doi:10.1378/chest.105.3.941
Holbert BL, Libshitz HI. Superior vena caval syndrome in primary mediastinal germ cell tumors. Can Assoc Radiol J. 1986;37(3):182-183.
Chen JC, Bongard F, Klein SR. Acontemporary perspective on superior vena cava syndrome. Am J Surg. 1990;160(2):207-211. doi:10.1016/s0002-9610(05)80308-3
Rozmus G, Daubert JP, Huang DT, Rosero S, Hall B, Francis C. Venous thrombosis and stenosis after implantation of pacemakers and defibrillators. J Interv Card Electrophysiol. 2005;13(1):9-19. doi:10.1007/s10840-005-1140-1
van Putten JW, Schlosser NJ, Vujaskovic Z, Leest AH, Groen HJ. Superior vena cava obstruction caused by radiation induced venous fibrosis. Thorax. 2000;55(3):245-246. doi:10.1136/thorax.55.3.245
de Potter B, Huyskens J, Hiddinga B, et al. Imaging of urgencies and emergencies in the lung cancer patient. Insights Imaging. 2018;9(4):463-476. doi:10.1007/s13244-018-0605- 6
Cansu A, Soyturk M, Ozturk MH, Kul S, Pulathan Z, Dinc H. Diagnostic value of color Doppler ultrasonography and MDCT angiography in complications of hemodialysis fistulas and grafts. Eur J Radiol. 2013;82(9):1436-1443. doi:10.1016/j.ejrad.2013.03.015
Ko SF, Huang CC, Ng SH, et al. MDCT angiography for evaluation of the complete vascular tree of hemodialysis fistulas. AJR Am J Roentgenol. 2005;185(5):1268-1274. doi:10.2214/AJR.04.1553
Ostler PJ, Clarke DP, Watkinson AF, Gaze MN. Superior vena cava obstruction: a modern management strategy. Clin Oncol (R Coll Radiol). 1997;9(2):83-89. doi:10.1016/s0936- 6555(05)80445-5
Schraufnagel DE, Hill R, Leech JA, Pare JA. Superior vena caval obstruction. Is it a medical emergency? Am J Med. 1981;70(6):1169-1174. doi:10.1016/0002-9343(81)90823-8
Uberoi R. Quality assurance guidelines for superior vena cava stenting in malignant disease. Cardiovasc Intervent Radiol. 29(3):319-322. doi:10.1007/s00270-005-0284-9
Azizi AH, Shafi I, Shah N, et al. Superior Vena Cava Syndrome. JACC Cardiovasc Interv. 2020;13(24):2896-2910. doi:10.1016/j.jcin.2020.08.038
Thim T, Krarup NHV, Grove EL, Rohde CV, Løfgren B. Initial assessment and treatment with the Airway, Breathing, Circulation, Disability, Exposure (ABCDE) approach. Int J Gen Med. 2012;5:117-121. doi:10.2147/IJGM.S28478
Lanciego C, Pangua C, Chacón JI, et al. Endovascular stenting as the first step in the overall management of malignant superior vena cava syndrome. AJR Am J Roentgenol. 2009;193(2):549-558. doi:10.2214/AJR.08.1904
Rowell NP, Gleeson F v. Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus: a systematic review. Clin Oncol (R Coll Radiol). 2002;14(5):338-351. doi:10.1053/clon.2002.0095
Messner GN, Azizzadeh A, Huynh TT, Estrera AL, Porat EE, Safi HJ. Superior vena caval bypass using the superficial femoral vein for treatment of superior vena cava syndrome. Tex Heart Inst J. 2005;32(4):605-606.
Wall C, Moore J, Thachil J. Catheter-related thrombosis: A practical approach. J Intensive Care Soc. 2016;17(2):160-167. doi:10.1177/1751143715618683

Others

- National Cancer Institute grading system (Common Terminology Criteria for Adverse Events [CTCAE]) to stratify SVCS occurring as an adverse event during cancer therapy

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Asymptomatic; incidental finding of SVC

Symptomatic;

medical intervention indicated

Severe symptoms; multimodality intervention

Life-threatening consequences;

Death

thrombosis

(eg, anticoagulation, radiation, or chemotherapy)

indicated (eg, anticoagulation, chemotherapy, radiation, stenting)

urgent multimodality intervention indicated (eg, lysis, thrombectomy, surgery)

Reproduced from: Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, November 27, 2017, National Institutes of Health, National Cancer Institute.

Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5×11.pdf

Evidence Level Grade PMID Nº

TUMOR HYPERCALCEMIA

Authors: Michele Ghidini, Patricia Chow Liu, Victor Sacristan Santos and Lara Otero Plaza

Definition

Hypercalcemia of malignancy (HCM) is one of the most common paraneoplastic syndromes. It constitutes the most frequent cause of hypercalcemia in hospitalized patients. Its incidence had decreased in the past years due to bisphosphonates usage in patients with bone metastases . It occurs in 20-30% of all cancer patients, and is specially found in breast, lung and kidney cancer as well as multiple myeloma. It often indicates a more advanced disease and thus, worse prognosis.

Symptoms (Feldenzer KL, 2018; Shane E, 2022)

Symptoms and signs will depend upon speed and absolute levels of calcium increase, as well as previous patients’ comorbidities. It´s commonly observed that patients with HCM have higher calcium levels and its onset is more acute compared to other hypercalcemia causes. Therefore, HCM patients are more likely to develop more pronounced symptoms.

Mild hypercalcemia [serum calcium <12 mg/dL (3 mmol/L)]: It can be either asymptomatic or with unspecific symptoms:

- Neurological: anxiety, depression and fatigue;
- Gastrointestinal: constipation, anorexia and abdominal pain;
- Renal: polyuria (caused by nephrogenic diabetes insipidus);
- Cardiovascular: shortened QT interval, depressed ST segment and prolonged PR and QRS. Moderate hypercalcemia [serum calcium of 12-14 mg/dL (3-3.5 mmol/L)]:
- Neurological: altered mental status and hyporeflexia;
- Gastrointestinal: nausea, vomiting and weight loss (chronic);
- Renal: dehydration, nephrolithiasis (chronic);
- Cardiovascular: symptoms and signs similar to that of mild hypercalcemia;
- Musculoskeletal: weakness, bone pain (rare).

Severe hypercalcemia [serum calcium >14 mg/dL (>3.5 mmol/L)]:

- Neurological: lethargy, confusion, stupor and coma;
- Gastrointestinal: pancreatitis and peptic ulcer disease (rare);
- Renal: acute kidney injury and renal failure;
- Cardiovascular: elevation ST segment, arrhythmias, ventricular tachycardia and cardiac arrest;
- Musculoskeletal: weakness, bone pain (rare).

Etiology (Horwitz MJ, 2022; Zagzag J, 2018)

HCM is caused by three mainly mechanisms:

- Humoral HCM (80%): Tumour production of parathyroid hormone-related protein (PTHrP) is the most frequent pathway. It is correlated with squamous cell malignancies (lung, head and neck), kidney, bladder, breast and ovarian cancer, and also with other non-solid tumours. PTHrP has a similar structure than PTH (parathyroid hormone). Moreover, because of this reason, PTHrP bonds to the same receptor as PTH (PTH-1) and it can develop some of PTH actions. On the one hand, osteoblasts are stimulated by PTHrP and they secrete the Receptor Activator for Nuclear Factor κ B Ligand (RANKL) so it bonds to its receptor (RANK) in the osteoclasts. This stimulates its maturation and ultimately the calcium resorption and its release into the blood stream. On the other hand, it promotes calcium reabsorption in the kidney. It is less common that PTHrP stimulates calcitriol production (an active metabolite of vitamin D) and so it doesn´t increase calcium intestinal absorption like PTH really does. Bringing all of these together, it leads to a higher calcium concentration in the bloodstream, which consequently contributes to HCM development.
- Osteolytic HCM (20%): Local induction of osteolysis is a more frequent cause of HCM in multiple myeloma and bone metastases due to solid tumours such as breast cancer. These tumours activate certain cytokines that promote osteoclast production and activity, leading to calcium release. Moreover, in breast cancer cells PTHrP is more commonly produced and so it leads to HCM development.
- Vitamin-D secreting (<1%): An extrarenal production of calcitriol is the cause of HCM in lymphomas. Its raise promotes intestinal and bone absorption of calcium and it also decrease its urinary excretion.

It has been described another infrequent HCM related mechanism: ectopic PTH secretion.

Evidence

Level Grade PMID Nº

Pharmacotherapy Level GradeEvidence

PMID Nº

SALINE HYDRATION
- Isotonic saline corrects possible volume depletion due to hypercalcemia-induced urinary salt wasting and, in some cases, vomiting. Hypovolemia exacerbates hypercalcemia I A by impairing the renal clearance of calcium.
- Saline therapy requires careful monitoring since it can lead to fluid overload in patients who cannot excrete the administered salt because of impaired renal function, which can be induced by hypercalcemia or heart failure.
- Patients often require 1 or 2 liters as an initial bolus and then a maintenance rate of 150 to 300 cm3/hour to maintain adequate urine output. Care must be taken to avoid volume overload, especially in patients with renal insufficiency or heart failure.
BIPHOSPHONATES (BPs)
- After initial resuscitation, the next step includes intravenous administration of bisphosphonates. Through direct mechanisms they induce osteoclast apoptosis, and through I A indirect mechanisms acting on the osteoblasts they can reduce osteoclastic bone resorption. BPs should be given within 48 hours of diagnosis, because it takes 2 to 4 days for

them to have effect and response to therapy can last for 1 to 3 weeks.

- The two most commonly used are pamidronate (60-90 mg intravenously over 2-6 hours) and zoledronic acid (4 mg intravenously over 15-30 minutes). Retreatment with zoledronic acid may be considered for persistent hypercalcemia, but no sooner than 7 days after the initial dose.
- Nephrotoxicity must be taken into account when prescribing BPs. Thus, dose reductions have to be made depending on the glomerular filtration rate (GFR 50-60 mL/min, 3.5mg; GFR 40-49mL/min, 3.3mg; and GFR 30-39 mL/min, 3.0 mg. Other side effects include flu-like symptoms (fever, arthralgias, myalgia, fatigue, bone pain), uveitis, hypocalcemia, hypophosphatemia and osteonecrosis of the jaw.
- Oral bisphosphonates are not efficacious in the setting of HCM. They don´t lead to serum concentrations that are high enough to deactivate osteoclasts.

GLUCOCORTICOIDS
- Corticosteroid administration results in decreased bone resorption via inhibition of osteoclast maturation. It also diminishes the number of calcitriol receptors present in bone. I B Glucocorticoids serve to impede intestinal calcium absorption and cause an increase in renal calcium excretion. They are usually given as hydrocortisone 200 to 400 mg/day intravenously for three to four days and then prednisone 10 to 20 mg/day for seven days, or prednisone 40 to 60 mg/day for 10 days. Dexamethasone can be also useful in a dose

of 0,1-0,22mg/kg subcutaneously or intravenously every 12 hours. The duration of response is uncertain.

DENOSUMAB
- Denosumab is a fully human monoclonal antibody that binds to RANKL to prevent ligand interaction with RANK receptors on precursor osteoclasts. It interferes with osteoclast maturation, function and survival and reduces bone resorption. Its dose is 120 mg subcutaneously every 4 weeks and it can have a loading dose on days 8 and 15.
- Due to the fact that denosumab, unlike bisphosphonates, is not cleared by the kidney, there is no restriction of its use in patients with chronic kidney disease. However, it can I B cause renal impairment in patients with GFR <30 ml/min or on hemodialysis.
- Denosumab can lead to hypocalcemia, especially in patients with vitamin D deficiency, and osteonecrosis of the jaw. Further side effects include bone pain, nausea, diarrhea, and shortness of breath.
CALCITONIN
- It reduces the serum calcium concentration by increasing renal calcium excretion and by decreasing bone resorption via interference with osteoclast function. Calcitonin (4-8 I B U/kg intramuscularly or subcutaneously every 12 hours) has a rapid onset of action, lowering serum calcium levels by a maximum of approximately 2 mg/dL (0.5 mmol/L) for up

to 72 hours, beginning within four to six hours. It´s especially useful as an initial strategy along with hydration while waiting for other treatments to take effect.

- The efficacy of calcitonin is limited to the first 48 hours, but it has mild side effects.

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DYALISIS
- Dialysis may be indicated in patients with severe malignancy-associated hypercalcemia and renal insufficiency or heart failure, in whom hydration cannot be safely II A administered. Renal replacement therapy with low or calcium-free dialysate is highly effective at restoring normal calcemia with reductions of 3–5 mg/dL achieved over a 3–4

hour. Hypophosphatemia induced by hemodialysis should be searched for and corrected as appropriate.

LOOP DIURETICS
- They are no longer a strong recommendation because of the electrolyte abnormalities that they could cause. IV D
- They may be useful to prevent fluid overload in patients with renal insufficiency or heart failure.
- Specially if furosemide is used, potassium and phosphorus need to be monitored and replaced.

Therapeutic Strategy

Indication of treatment is based on the severity of the hypercalcemia and the nature of associated symptoms.

MILD HYPERCALCEMIA

[serum calcium <12 mg/dL (3 mmol/L)]

Asymptomatic or mildly symptomatic: do not require immediate treatment.

- Avoid factors that aggravate hypercalcemia (e.g. thiazide diuretics, volume depletion, inactivity, high calcium diet).
- Adequate hydration (at least 6-8 glasses of water per day).
- Treat the underlying cause.

MODERATE HYPERCALCEMIA

[serum calcium of 12-14 mg/dL (3-3.5 mmol/L)]

- Chronic hypercalcemia: proceed as mild hypercalcemia (see “Mild hypercalcemia”).
- Acute hypercalcemia: proceed as severe hypercalcemia (see “Severe hypercalcemia”).

SEVERE HYPERCALCEMIA

[serum calcium >14 mg/dL (>3.5 mmol/L)]

- Require treatment regardless of symptoms.

VERY SEVERE

[serum calcium of 18 – 20 mg/dL (4.5 – 5 mmol/L)]

- Proceed as severe hypercalcemia (see “Severe hypercalcemia”).Dialysis may be indicated in patients with severe malignancy-associated hypercalcemia and renal insufficiency or heart failure, in whom hydration cannot be safely administered. Renal replacement therapy with low or calcium-free dialysate is highly effective at restoring normal calcemia with reductions of 3-5 mg/dL achieved over a 3-4 hour. Hypophosphatemia induced by hemodialysis should be searched for and corrected as appropriate.

SALINE HYDRATION I B

Initial rate: 200-300 mL/hour » adjust to maintain urine output at 100-150 mL/hour.
Onset of action: hours. Duration of action: during infusion.
Monitor for fluid overload if renal impairment or elderly
Loop diuretics rarely used and only if fluid overload develops; not effective for reducing serum calcium. Avoid thiazide diuretics.

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CALCITONIN

- Initial dose: 4 IU/kg SC or IM every 12 hours » 4-8 IU/kg every 6 hours. I B
- Onset of action: 4-6 hours. Efficacy limited to the first 48 hours.
- Monitor serum calcium in several hours.

BISPHOSPHONATES

- Zoledronic Acid: 4 mg IV diluted 100 mL over 15-30 minutes. I A
- Alternative: Pamidronate: 60-90 mg IV over 2-6 hours.
- Onset of action: 2-4 days. Duration of action: 1-3 weeks.
- Adjust to renal function. Monitor serum calcium response.

If refractory hypercalcemia or contraindication of BPs due to severe renal impairment. I B

Denosumab: 120 mg SC every week for 4 weeks » monthly.

- Onset of action: 4-10 days. Duration of action: 4-15 weeks. If hypercalcemia associated with excess of vitamin D

Glucocorticoids: I B

- e.g. Hydrocortisone 200-400 mg IV per day for 3-4 days and then Prednisone 10-20 mg per day for 7 days; Prednisone 40-60 mg per day for 10 days.
- Onset of action: 2-5 hours. Duration of action: days to weeks.

If hypercalcemia due to parathyroid carcinoma, in hemodialysis patients with an elevated calcium-phosphorous product and secondary hyperparathyroidism 2 B

Calcimimetics (cinacalcet)

- Onset of action: 2-3 days. Duration of action: during therapy.

In case of very severe hypercalcemia consider DIALYSIS. 2 A

- Onset of action: hours. Duration of action: during treatment.

Relevant published studies

A randomized study including patients with HCM compared a single infusion of ibandronate (2 or 4 mg) with pamidronate (15,30,60 or 90 mg) (Pecherstorfer M, 2003). The administered dose was dependent on the severity of hypercalcemia and the study primary endpoint was lowering of albumin-corrected serum calcium (CSC) at day 4. The most frequently administered doses were 4 mg for ibandronate and 60 mg for pamidronate. Mean lowering of CSC at day 4 was 0.6 mmol/L for ibandronate and 0.41mmol/L for pamidronate. Ibandronate was at least as effective as pamidronate in the treatment of HCM. Moreover, in patients with higher baseline CSC (> 3.5 mmol/L), ibandronate appeared to be more effective than pamidronate. The median time to CSC re-increase after response was longer for ibandronate (14 days) than pamidronate (4 days) (p=.0.0303). Pamidronate was compared to zoledronic acid in patients with advanced multiple myeloma or breast cancer (Rosen LS, 2003). A total of 1648 patients received either 4 or 8 mg of zoledronic acid or pamidronate 90 mg. The primary endpoint was the proportion of patients with at least one skeletal-related event (SRE). After 25 months of follow-up, zoledronic acid was superior to pamidronate in reducing the proportion of patients with an SRE and the skeletal morbidity rate. Moreover, zoledronic acid at the 4 mg dose reduced the overall risk of developing skeletal complications including HCM by an additional 16% (p=0.030). Zoledronic acid was tested in patients with bone metastases secondary to solid tumors other than breast or prostate cancer (Rosen LS, 2003). A total of 773 patients were randomized to receive either zoledronic acid (4 or 8 mg) or placebo every 3 weeks for 9 months. Zoledronic acid at the 4 mg dose demonstrated a 30% risk reduction for SRE including HCM compared to placebo (p=0.006). Fewer patients treated with zoledronic acid developed at least one SRE at 21 months compared to placebo (39% of those treated with 4 mg dose [p=.0127], 36% of those treated at the 8/4 mg dose [p=0.023] compared with 46% of those treated with placebo). Moreover, 4 mg of zoledronic acid reduced significantly delayed the median time to first SRE (236 days versus 155 days with placebo, p=0.009) (Rosen LS, 2004).

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In patients with advanced breast cancer and bone metastases, the anti-RANK monoclonal antibody denosumab was superior to zoledronic acid in delaying time to first SRE (HR 0.82, 95% CI 0.71-0.95, p=0.01) and subsequent SREs (HR 0.77, 95% CI 0.66-0.89, p=0.001) (Stopeck A, 2010). Denosumab prolonged the time to first SRE or HCM by 18% (HR 0.82, 95% CI 0.70-0.95, p=0.007) (Martin M, 2012). In a patient-level data evaluation from two phase III trials including cancer patients with breast cancer and other solid tumours (excluding breast or prostate cancer) or multiple myeloma, denosumab significantly delayed the time to first on-study HCM (37% reduction, HR 0.63, 95% CI 0.41-0.98, p=0.042) and reduced the risk of developing recurrent HCM by 52% (RR 0.48, 95% CI 0.29-0.81, p=0.006). HCM was less frequent in patients receiving denosumab compared to zoledronic acid (1.7% versus 2.7%; P = 0.028) (Diel IJ, 2015).

References

Agraharkar, M. “Hypercalcemia treatment and management”. Medscape. Las updated Feb 17, 2021.
Austin LA, Heath H 3rd. Calcitonin: physiology and pathophysiology. N Engl J Med. 1981; 29;304:269-78. PubMed PMID: 7003392.
Carroll, F. and Schade, D. A Practical Approach to Hypercalcemia. Am Fam Physician. 2003;67:1959-1966. PubMed PMID: 12751658.
Cicci JD, Buie L, Bates J, et al. Denosumab for the management of hypercalcemia of malignancy in patients with multiple myeloma and renal dysfunction. Clin Lymphoma Myeloma Leuk. 2014;14:e207-11. PubMed PMID: 25128013.
Daniels E, Sakakeeny C. Hypercalcemia: Pathophysiology, Clinical Signs, and Emergent Treatment. JAm Anim Hosp Assoc. 2015;51:291-9. PubMed PMID: 26355578.
Diel IJ, Body J-J, Stopeck AT et al. The role of denosumab in the treatment of hypercalcaemia of malignancy in cancer patients with metastatic bone disease. Eur J Cancer 2015;51:1467-75. PubMed PMID: 25976743.
Feldenzer KL, Sarno J. Hypercalcemia of Malignancy. JAdv Pract Oncol. 2018;9:496-504. PubMed PMID: 31086686.
Goldner W. Cancer-Related Hypercalcemia. J Oncol Pract. 2016;12:426-32. PubMed PMID: 27170690.
Green, T. “Hypercalcemia in Emergency Medicine”. Medscape. Last updated: Apr 29, 2020.
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Martin M, Bell R, Bourgeois H et al. Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid. Clin Cancer Res. 2012 1;18:4841-9. PubMed PMID: 22893628.
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Pecherstorfer M, Steinhauer EU, Rizzoli R et al. Efficacy and safety of ibandronate in the treatment of hypercalcemia of malignancy: a randomized multicentric comparison to pamidronate. Support Care Cancer. 2003;11:539-47. PubMed PMID: 12783289.
Rosen LS, Gordon D, Tchekmedyian S et al. Zoledronic Acid Versus Placebo in the Treatment of Skeletal Metastases in Patients With Lung Cancer and Other Solid Tumors: A Phase III, Double-Blind, Randomized Trial—The Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003;21:3150-7. PubMed PMID: 12915606.
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ENDOCRANIAL HYPERTENSION

Authors: Ricardo Prat Acín, Andrés Beltrán Giner and Alexandra Guedes

Definition

Elevated intracranial pressure (ICP) is a potentially devastating complication of neurologic injury. Elevated ICP may complicate, central nervous system (CNS) tumours, and derived hydrocephalus.

ICP is normally <=15 mmHg in adults, and pathologic intracranial hypertension (ICH) is present at pressures>=20 mmHg. ICP is normally lower in children than adults, Homeostatic mechanisms stabilize ICP, with occasional transient elevations associated with physiologic events, including sneezing, coughing, or Valsalva manoeuvres.

In adults, the intracranial compartment is protected by the skull, a rigid structure with a fixed internal volume of 1400 to 1700 mL. Under physiologic conditions, the intracranial contents include (by volume):

Brain parenchyma – 80 percent.
Cerebrospinal fluid (CSF) – 10 percent.
Blood – 10 percent.

Pathologic structures, including mass lesions, also may be present within the intracranial compartment. Since the overall volume of the cranial vault cannot change, an increase in the volume of one component, or the presence of pathologic components, necessitates the displacement of other structures, an increase in ICP, or both. Thus, ICP is a function of the volume and compliance of each component of the intracranial compartment, an interrelationship known as the Monro-Kellie doctrine.

The volume of brain parenchyma is relatively constant in adults, although it can be altered by mass lesions or in the setting of cerebral oedema. The volumes of CSF and blood in the intracranial space vary to a greater degree. Abnormal increases in the volume of any component may lead to elevations in ICP. CSF is produced by the choroid plexus and elsewhere in the central nervous system (CNS) at a rate of approximately 20 mL/hour (500 mL/day). CSF is normally resorbed via the arachnoid granulations into the venous system.

The interrelationship between changes in the volume of intracranial contents and changes in ICP defines the compliance characteristics of the intracranial compartment.

Intracranial compliance can be modelled mathematically (as in other physiologic and mechanical systems) as the change in volume over the change in pressure (dV/dP).

The compliance relationship is nonlinear, and compliance decreases as the combined volume of the intracranial contents increases. Initially, compensatory mechanisms allow volume to increase with minimal elevation in ICP. However, when these compensatory mechanisms have been exhausted, significant increases in pressure develop with small increases in volume, leading to abnormally elevated ICP.

Cerebral perfusion pressure (CPP) is a clinical surrogate for the adequacy of cerebral perfusion. CPP is defined as mean arterial pressure (MAP) minus ICP. Conditions associated with elevated ICP, including mass lesions and hydrocephalus, can be associated with a reduction in CPP. This can result in devastating focal or global ischemia.

Symptoms and signs

Global symptoms of elevated ICP include headache, which is probably mediated via the pain fibers of cranial nerve (CN) V in the dura and blood vessels, depressed global consciousness due to either the local effect of mass lesions or pressure on the midbrain reticular formation, and vomiting.

Signs include CN VI palsies, papilledema secondary to impaired axonal transport and congestion spontaneous periorbital bruising, and a triad of bradycardia, respiratory depression, and hypertension (Cushing triad, sometimes called Cushing reflex or Cushing response) [3]. While the mechanism of Cushing triad remains controversial, many believe that it relates to brainstem compression. The presence of this response is an ominous finding that requires urgent intervention.

Focal symptoms of elevated ICP may be caused by local effects in patients with mass lesions or by herniation syndromes. Herniation results when pressure gradients develop between two regions of the cranial vault. The most common anatomic locations affected by herniation syndromes include subfalcine, central trans tentorial, uncal trans tentorial, upward cerebellar, cerebellar tonsillar/foramen magnum, and trans calvaria.One notable false localizing syndrome seen following neurologic injury, referred to as Kernohan’s notch phenomenon, consists of the combination of contralateral pupillary dilatation and ipsilateral weakness. Because the diagnostic accuracy of signs and symptoms is limited, the findings described above may be inconstant or unreliable in any given case. Use of radiologic studies may support the diagnosis; however, the most reliable method of diagnosing elevated ICP is to measure it directly.

Evidence

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15046669

The major causes of increased ICP include:

- Intracranial mass lesions (e.g., tumour, hematoma).
- Cerebral oedema .
- Increased CSF production (e.g., choroid plexus papilloma).
- Decreased CSF absorption (e.g., arachnoid granulation adhesions after tumoral bleeding meningitis)• Obstructive hydrocephalus.
- Obstruction of venous outflow .

Studies

ICP monitoring

Empiric therapy for presumed elevated ICP is unsatisfactory because cerebral perfusion pressure (CPP) cannot be monitored reliably without measurement of ICP. Furthermore, most therapies directed at lowering ICP are effective for limited and variable periods of time. In addition, these treatments may have serious side effects. Therefore, while initial steps to control ICP may, by necessity, be performed without the benefit of ICP monitoring, an important early goal in management of the patient with presumed elevated ICP is placement of an ICP monitoring device.

The purpose of monitoring ICP is to improve the clinician’s ability to maintain adequate CPP and oxygenation. The only way to reliably determine CPP (defined as the difference between mean arterial pressure [MAP] and ICP) is to continuously monitor both ICP and blood pressure (BP). In general, these patients are managed in intensive care units (ICUs) with an ICP monitor and arterial line.

Indications

In general, invasive monitoring of ICP is indicated in patients who are:

- Suspected to be at risk for elevated ICP.
- Comatose (Glasgow Coma Scale [GCS] <8).
- Diagnosed with a process that merits aggressive medical care.

Although computed tomography (CT) scans or magnetic resonance imaging (MRI) may suggest elevated ICP based on the presence of mass lesions, midline shift, or effacement of the basilar cisterns patients without these findings may have elevated ICP.

Types of monitors

Intraventricular – Intraventricular monitors are considered the “gold standard” of ICP monitoring catheters. They are surgically placed into the ventricular system and affixed to a drainage bag and pressure transducer with a three-way stopcock. Intraventricular monitoring has the advantage of accuracy, simplicity of measurement, and the unique characteristic of allowing for treatment of some causes of elevated ICP via drainage of cerebrospinal fluid (CSF).

Intraparenchymal – Intraparenchymal devices consist of a thin cable with an electronic or fibreoptic transducer at the tip. The most widely used device is the fibreoptic Camino system. These monitors can be inserted directly into the brain parenchyma via a small hole drilled in the skull. Advantages include ease of placement and a lower risk of infection and haemorrhage (<1 percent) than with intraventricular devices.

Waveform analysis

ICP is not a static value; it exhibits cyclic variation based on the superimposed effects of cardiac contraction, respiration, and intracranial compliance. Under normal physiologic conditions, the amplitude of the waveform is often small, with B waves related to respiration and smaller C waves (or Traube-Hering-Mayer waves) related to the cardiac cycle.

Pathological A waves (also called plateau waves) are abrupt, marked elevations in ICP of 50 to 100 mmHg, which usually last for minutes to hours. The presence of A waves signifies a loss of intracranial compliance and herald’s imminent decompensation of autoregulatory mechanisms. Thus, the presence of A waves should suggest the need for urgent intervention to help control ICP.

Non-invasive systems – Several devices designed to record ICP noninvasively have been studied, but most have not demonstrated reproducible clinical success or have not been studied in large clinical trials. They include Transcranial Doppler (TCD), Tissue resonance analysis (TRA), Ocular sonography, Intraocular pressure, and Tympanic membrane displacement.

11889475

3598682

1436417

1782538

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Osmotic therapy and diuresis – With growing familiarity of use, hypertonic saline has increasingly been employed as a first-line agent, supplanting mannitol at numerous institutions.

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Hypertonic saline bolus – Hypertonic saline in bolus doses can acutely lower ICP; however, the effect of this early intervention on long-term clinical outcomes remains unclear. The volume and tonicity of saline (7.2 to 23.4 percent) used in these reports have varied widely.

Mannitol and hypertonic saline have been compared in at least eight randomized trials of patients with elevated ICP from a variety of causes (traumatic brain injury, stroke, tumours) Meta-analyses of these trials have found that hypertonic saline appears to have greater efficacy in managing elevated ICP, but clinical outcomes have not been systematically examined

Mannitol – Osmotic diuretics reduce brain volume by drawing free water out of the tissue and into the circulation, where it is excreted by the kidneys, thus dehydrating brain parenchyma The most used agent is mannitol. It is prepared as a 20 percent solution and given as a bolus of 1 g/kg. Repeat dosing can be given at 0.25 to 0.5 g/kg as needed, generally every six to eight hours. Use of any osmotic agent should be carefully evaluated in patients with renal insufficiency.

The effects are usually present within minutes, peak at approximately one hour, and last 4 to 24 hours. Some have reported a “rebound” increase in ICP; this probably occurs when mannitol after repeated use, enters the brain though a damaged blood-brain barrier and reverses the osmotic gradient. Useful parameters to monitor in the setting of mannitol therapy include serum sodium, serum osmolality, and renal function. Concerning findings associated with the use of mannitol include serum sodium >150 mEq, serum osmolality >320 mOsm, or evidence of evolving acute tubular necrosis (ATN). In addition, mannitol can lower systemic blood pressure (BP), necessitating careful use if associate with a fall in cerebral perfusion pressure (CPP). Patients with known renal disease may be poor candidates for osmotic diuresis.

Other agents – Furosemide, 0.5 to 1.0 mg/kg intravenously, may be given with mannitol to potentiate its effect. However, this effect can also exacerbate dehydration and hypokalaemia

Glycerol and urea were used historically to control ICP via osmoregulation; however, use of these agents has decreased because equilibration between brain and plasma levels occurs more quickly than with mannitol. Furthermore, glycerol has been shown to have a significant rebound effect and to be less effective in ICP control.

Antiseizure therapy – Seizures can both complicate and contribute to elevated ICP. Anticonvulsant therapy should be instituted if seizures are suspected; prophylactic treatment may be warranted in some cases. There are no clear guidelines for the latter, but examples include high-risk mass lesions, such as those within supratentorial cortical locations, or lesions adjacent to the cortex, such as subdural hematomas or subarachnoid haemorrhage.

Glucocorticoids – The vasogenic oedema that surrounds many brain tumours contributes significantly to morbidity and requires treatment in conjunction with specific measures directed against the tumour. Although glucocorticoids are an important component of therapy when peritumoral oedema is contributing to increased ICP, additional interventions during the first 24 to 72 hours may be required to lower persistent elevated ICP. Systemic glucocorticoids should be considered in all patients who have symptomatic peritumoral oedema. Dexamethasone is the standard agent for peritumoral oedema management because its high potency and relative lack of mineralocorticoid activity reduce the potential for fluid retention. In addition, dexamethasone can be given orally or intravenously (IV) with a 1:1 conversion ratio. The antioedema effects of dexamethasone are dose dependent, and the starting dose should be individualized based on the extent of oedema and the severity of symptoms. Because most side effects are also dose dependent, the goal is always to use the lowest dose necessary to control symptoms. Once patients have responded and stabilized clinically on a given dose of dexamethasone, a gradual taper should be attempted, if possible. This is particularly important for patients on high initial doses of dexamethasone (e.g., >8 mg daily).

Therapeutic Strategy

The best therapy for intracranial hypertension (ICH) is resolution of the proximate cause of elevated ICP. Examples include evacuation of a blood clot, resection of a tumour, cerebrospinal fluid (CSF) diversion in the setting of hydrocephalus, or treatment of an underlying metabolic disorder.

Regardless of the cause, ICH is a medical emergency, and treatment should be undertaken as expeditiously as possible. In addition to definitive therapy, there are manoeuvres that can be employed to reduce ICP acutely. Some of these techniques are generally applicable to all patients with suspected ICH; others (particularly glucocorticoids) are reserved for specific causes of ICH such as brain tumours.

Resuscitation – The urgent assessment and support of oxygenation, blood pressure (BP), and end-organ perfusion are particularly important. If elevated ICP is suspected, care should be taken to minimize further elevations in ICP during intubation through careful positioning, appropriate choice of paralytic agents (if required), and adequate sedation. Large shifts in BP should be minimized, with particular care taken to avoid hypotension. Although it might seem that lower BP would result in lower ICP, this is not the case. Hypotension, especially in conjunction with hypoxemia, can induce reactive vasodilation and elevations in ICP. Pressors have been shown to be safe for use in most patients with ICH, and may be required to maintain cerebral perfusion pressure (CPP) >60 mmHg.

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Urgent situations – Life-saving measures may need to be instituted prior to a more detailed workup (e.g., imaging or ICP monitoring) in a patient who presents acutely with history or examination findings suggestive of elevated ICP. Many of these situations will rely upon clinical judgment, but the following combination of findings suggests the need for urgent intervention:

- A history that suggests elevated ICP (e.g., sudden severe headache suggesting tumoral haemorrhage).
- An examination that suggests elevated ICP (unilateral or bilaterally fixed and dilated pupil[s], decorticate or decerebrate posturing, bradycardia, hypertension and/or respiratory depression).
- AGlasgow Coma Scale (GCS) ≤8.
- Potentially confounding and reversible causes of depressed mental status, such as hypotension (systolic BP [SBP] <60 mmHg in adults), hypoxemia (PaO2 <60 mmHg), hypothermia (<36oC), or obvious intoxication, are absent.

In such patients, osmotic diuretics may be used urgently.

In addition, standard resuscitation techniques should be instituted as soon as possible:

- Head elevation.
- Hyperventilation to a PCO2 of 26 to 30 mmHg.
- Intravenous mannitol (1 to 1.5 g/kg).

Concomitant with these measures should be aggressive evaluation of the underlying diagnosis, including neuroimaging, detailed neurologic examination, and history gathering. If appropriate, ventriculostomy is a rapid means of simultaneously diagnosing and treating elevated ICP.

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Monitoring and the decision to treat – If a diagnosis of elevated ICP is suspected and an immediately treatable proximate cause is not present, then ICP monitoring should be instituted.

The goal of ICP monitoring and treatment should be to keep ICP <20 mmHg. Interventions should be utilized only when ICP is elevated above 20 mmHg for >5 to 10 minutes.

Fluid management – In general, patients with elevated ICP do not need to be severely fluid restricted. Patients should be kept euvolemic and normo- to hyperosmolar. Serum osmolality should be kept >280 mOsm/L, and often is kept in the 295 to 305 mOsm/L range. Hyponatremia is common in the setting of elevated ICP.

Hypertonic saline in bolus doses may acutely lower ICP, but further investigations are required to define a role, if any, for this approach in the management of elevated ICP.

Sedation – Keeping patients appropriately sedated can decrease ICP by reducing metabolic demand, ventilator asynchrony, venous congestion, and the sympathetic responses of hypertension and tachycardia [73]. Establishing a secure airway and close attention to BP allow the clinician to identify and treat apnoea and hypotension quickly.

Propofol has been utilized to good effect in this setting, as it is easily titrated and has a short half-life, thus permitting frequent neurologic reassessment.

Blood pressure control – In general, BP should be sufficient to maintain CPP >60 mmHg. As discussed above, pressors can be used safely without further increasing ICP. This is particularly relevant in the setting of sedation when iatrogenic hypotension can occur. Hypertension should generally only be treated when CPP >120 mmHg and ICP >20 mmHg. Caution should be taken to avoid CPP <50 mmHg or, normalization of BP in patients with chronic hypertension in whom the autoregulatory curve has shifted to the right. Position – Patients with elevated ICP should be positioned to maximize venous outflow from the head. Important manoeuvres include reducing excessive flexion or rotation of the neck, avoiding restrictive neck taping, and minimizing stimuli that could induce Valsalva responses, such as endotracheal suctioning.

Patients with elevated ICP have historically been positioned with the head elevated above the heart (usually 30 degrees) to increase venous outflow. It should be noted that head elevation may lower CPP; however, given the proven efficacy of head elevation in lowering ICP, most experts recommend raising the patient’s head as long as the CPP remains at an appropriate level.

Fever – Elevated metabolic demand in the brain results in increased cerebral blood flow (CBF) and can elevate ICP by increasing the volume of blood in the cranial vault. Conversely, Level Grade PMID Nº

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decreasing metabolic demand can lower ICP by reducing blood flow.

Fever increases brain metabolism and has been demonstrated to increase brain injury in animal models. Therefore, aggressive treatment of fever, including acetaminophen and mechanical cooling, is recommended in patients with increased ICP. ICH is a recognized indication for neuromuscular paralysis in selected patients.

Hyperventilation – Use of mechanical ventilation to lower PaCO2 to 26 to 30 mmHg has been shown to rapidly reduce ICP through vasoconstriction and a decrease in the volume of intracranial blood; a 1 mmHg change in PaCO2 is associated with a 3 percent change in cerebral blood flow (CBF). Hyperventilation also results in respiratory alkalosis, which may buffer post-injury acidosis. The effect of hyperventilation on ICP is short-lived (1 to 24 hours). Following therapeutic hyperventilation, the patient’s respiratory rate should be tapered back to normal over several hours to avoid a rebound effect.

Therapeutic hyperventilation should be considered as an urgent intervention when elevated ICP complicates cerebral oedema, intracranial haemorrhage, and tumour. Hyperventilation should not be used on a chronic basis, regardless of the cause of increased ICP.

Barbiturates – The use of barbiturates is predicated on their ability to reduce brain metabolism and CBF, thus lowering ICP and exerting a neuroprotective effect. Pentobarbital is generally used, with a loading dose of 5 to 20 mg/kg as a bolus, followed by 1 to 4 mg/kg per hour. Treatment should be assessed based on ICP, CPP, and the presence of unacceptable side effects. Continuous electroencephalography (EEG) monitoring is generally used; EEG burst suppression is an indication of maximal dosing.

Barbiturate therapy can be complicated by hypotension, possibly requiring vasopressor support. The use of barbiturates is also associated with a loss of the neurologic examination, requiring accurate ICP, hemodynamic, and often EEG monitoring to guide therapy.

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Therapeutic hypothermia – First reported as a treatment for brain injury in the 1950s, induced or therapeutic hypothermia has remained a controversial issue in the debate concerning the management of elevated ICP. It is not currently recommended as a standard treatment for increased ICP.

Hypothermia decreases cerebral metabolism and may reduce CBF and ICP. Initial studies of hypothermia were limited by systemic side effects, including cardiac arrhythmias and severe coagulopathy. However, later work suggested that hypothermia can lower ICP and may improve patient outcomes. Hypothermia also appeared to be effective in lowering ICP after other therapies have failed.

Removal of CSF -* When hydrocephalus is identified, a ventriculostomy should be inserted. Rapid aspiration of cerebrospinal fluid (CSF) should be avoided because it may lead to obstruction of the catheter opening by brain tissue. CSF should be removed at a rate of approximately 1 to 2 mL/minute, for two to three minutes at a time, with intervals of two to three minutes in between until a satisfactory ICP has been achieved (ICP <20 mmHg) or until CSF is no longer easily obtained. Slow removal can also be accomplished by passive gravitational drainage through the ventriculostomy. Alumbar drain is generally contraindicated in the setting of high ICP due to the risk of trans tentorial herniation.

Decompressive craniectomy – Decompressive craniectomy removes the rigid confines of the bony skull, increasing the potential volume of the intracranial contents and circumventing the Monroe-Kellie doctrine. There is a growing body of literature supporting the efficacy of decompressive craniectomy in certain clinical situations. Importantly, it has been demonstrated that in patients with elevated ICP, craniectomy alone lowered ICP 15 percent, but opening the dura in addition to the bony skull resulted in an average decrease in ICP of 70 percent Decompressive craniectomy also appears to improve brain tissue oxygenation. Obvious mass lesions associated with an elevated ICP should be removed, if possible.

Potential complications of surgery include herniation through the skull defect, spinal fluid leak, wound infection, and epidural and subdural hematoma.

References

PMID 15258230 Hadjikoutis S, Carroll C, Plant GT. Raised intracranial pressure presenting with spontaneous periorbital bruising: two case reports. J Neurol Neurosurg Psychiatry. 2004;75(8):1192-1193. doi:10.1136/jnnp.2003.016006
PMID 15046669 Binder DK, Lyon R, Manley GT. Transcranial motor evoked potential recording in a case of Kernohan’s notch syndrome: case report. Neurosurgery. 2004;54(4):999-1003. doi:10.1227/01.neu.0000115674.15497.09
PMID 11889475 Dennis LJ, Mayer SA. Diagnosis and management of increased intracranial pressure. Neurol India. 2001;49 Suppl 1:S37-S50.
PMID 3598682 Ostrup RC, Luerssen TG, Marshall LF, Zornow MH. Continuous monitoring of intracranial pressure with a miniaturized fiberoptic device. J Neurosurg. 1987;67(2):206-209. doi:10.3171/jns.1987.67.2.0206
PMID 1436417 Gambardella G, d’Avella D, Tomasello F. Monitoring of brain tissue pressure with a fiberoptic device. Neurosurgery. 1992;31(5):918-922. doi:10.1227/00006123-199211000-00014

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PMID 1782538 Hayashi M, Handa Y, Kobayashi H, Kawano H, Ishii H, Hirose S. Plateau-wave phenomenon (I). Correlation between the appearance of plateau waves and Level Grade PMID Nº

CSF circulation in patients with intracranial hypertension. Brain. 1991;114 ( Pt 6):2681-2691. doi:10.1093/brain/114.6.2681

PMID 9012577 Manno EM. Transcranial Doppler ultrasonography in the neurocritical care unit. Crit Care Clin. 1997;13(1):79-104. doi:10.1016/s0749-0704(05)70297-9
PMID 18272864 Koenig MA, Bryan M, Lewin JL 3rd, Mirski MA, Geocadin RG, Stevens RD. Reversal of transtentorial herniation with hypertonic saline. Neurology. 2008;70(13):1023-1029. doi:10.1212/01.wnl.0000304042.05557.60
PMID 21242790 Kamel H, Navi BB, Nakagawa K, Hemphill JC 3rd, Ko NU. Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: a meta- analysis of randomized clinical trials. Crit Care Med. 2011;39(3):554-559. doi:10.1097/CCM.0b013e318206b9be
PMID 21942722 Mortazavi MM, Romeo AK, Deep A, et al. Hypertonic saline for treating raised intracranial pressure: literature review with meta-analysis. J Neurosurg. 2012;116(1):210-221. doi:10.3171/2011.7.JNS102142
PMID 12576970 Polderman KH, van de Kraats G, Dixon JM, Vandertop WP, Girbes AR. Increases in spinal fluid osmolarity induced by mannitol. Crit Care Med. 2003;31(2):584-590. doi:10.1097/01.CCM.0000050287.68977.84
PMID 6415245 Pollay M, Fullenwider C, Roberts PA, Stevens FA. Effect of mannitol and furosemide on blood-brain osmotic gradient and intracranial pressure. J Neurosurg. 1983;59(6):945-950. doi:10.3171/jns.1983.59.6.0945
PMID 1907077 García-Sola R, Pulido P, Capilla P. The immediate and long-term effects of mannitol and glycerol. A comparative experimental study. Acta Neurochir (Wien). 1991;109(3-4):114-121. doi:10.1007/BF01403005
PMID 6202480 Gabor AJ, Brooks AG, Scobey RP, Parsons GH. Intracranial pressure during epileptic seizures. Electroencephalogr Clin Neurophysiol. 1984;57(6):497-506. doi:10.1016/0013-4694(84)90085-3
PMID 30883663 Chang, S. M., Messersmith, H., Ahluwalia, M., Andrews, D., Brastianos, P. K., Gaspar, L. E., Gatson, N. N., Jordan, J. T., Khasraw, M., Lassman, A. B., Maues, J., Mrugala, M., Raizer, J., Schiff, D., Stevens, G., Sumrall, A., Van den Bent, M., & Vogelbaum, M. A. (2019). Anticonvulsant prophylaxis and steroid use in adults with metastatic brain tumors: summary of SNO and ASCO endorsement of the Congress of Neurological Surgeons guidelines. Neuro-oncology, 21(4), 424–427. https://doi.org/10.1093/neuonc/noz034
PMID 19957014 Ryken, T. C., McDermott, M., Robinson, P. D., Ammirati, M., Andrews, D. W., Asher, A. L., Burri, S. H., Cobbs, C. S., Gaspar, L. E., Kondziolka, D., Linskey, M. E., Loeffler, J. S., Mehta, M. P., Mikkelsen, T., Olson, J. J., Paleologos, N. A., Patchell, R. A., & Kalkanis, S. N. (2010). The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline. Journal of neuro-oncology, 96(1), 103–114. https://doi.org/10.1007/s11060-009-0057-4
PMID 10961490 Procaccio, F., Stocchetti, N., Citerio, G., Berardino, M., Beretta, L., Della Corte, F., D’Avella, D., Brambilla, G. L., Delfini, R., Servadei, F., & Tomei, G. (2000). Guidelines for the treatment of adults with severe head trauma (part I). Initial assessment; evaluation and pre-hospital treatment; current criteria for hospital admission; systemic and cerebral monitoring. Journal of neurosurgical sciences, 44(1), 1–10.
PMID 15259863 Smith, E. R., & Madsen, J. R. (2004). Cerebral pathophysiology and critical care neurology: basic hemodynamic principles, cerebral perfusion, and intracranial pressure. Seminars in pediatric neurology, 11(2), 89–104. https://doi.org/10.1016/j.spen.2004.04.001
PMID 31194438 Munakomi, S., & M Das, J. (2022). Intracranial Pressure Monitoring. In StatPearls. StatPearls Publishing.
PMID: 1404521 Schmoker, J. D., Shackford, S. R., Wald, S. L., & Pietropaoli, J. A. (1992). An analysis of the relationship between fluid and sodium administration and intracranial pressure after head injury. The Journal of trauma, 33(3), 476–481. https://doi.org/10.1097/00005373-199209000-00024
PMID: 33828517 Musick, S., & Alberico, A. (2021). Neurologic Assessment of the Neurocritical Care Patient. Frontiers in neurology, 12, 588989. https://doi.org/10.3389/fneur.2021.588989
PMID 3772451 Rosner, M. J., & Coley, I. B. (1986). Cerebral perfusion pressure, intracranial pressure, and head elevation. Journal of neurosurgery, 65(5), 636–641. https://doi.org/10.3171/jns.1986.65.5.0636
PMID 1919695 Muizelaar, J. P., Marmarou, A., Ward, J. D., Kontos, H. A., Choi, S. C., Becker, D. P., Gruemer, H., & Young, H. F. (1991). Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial. Journal of neurosurgery, 75(5), 731–739. https://doi.org/10.3171/jns.1991.75.5.0731
PMID 6856064 Rea, G. L., & Rockswold, G. L. (1983). Barbiturate therapy in uncontrolled intracranial hypertension. Neurosurgery, 12(4), 401–404. https://doi.org/10.1227/00006123-198304000-00005
PMID 848367 James, H. E., Langfitt, T. W., Kumar, V. S., & Ghostine, S. Y. (1977). Treatment of intracranial hypertension. Analysis of 105 consecutive, continuous recordings of intracranial pressure. Acta neurochirurgica, 36(3-4), 189–200. https://doi.org/10.1007/BF01405391
PMID: 22381845 Di Rocco, F., Jucá, C. E., Zerah, M., & Sainte-Rose, C. (2013). Endoscopic third ventriculostomy and posterior fossa tumors. World neurosurgery, 79(2 Suppl), S18.e15–S18.e19. https://doi.org/10.1016/j.wneu.2012.02.018
PMID 8065488 Jourdan, C., Convert, J., Mottolese, C., Bachour, E., Gharbi, S., & Artru, F. (1993). Evaluation du bénéfice clinique de l’hémicraniectomie décompressive dans l’hypertension intracranienne non contrôlée par le traitement médical [Evaluation of the clinical benefit of decompression hemicraniectomy in intracranial hypertension not controlled by medical treatment]. Neuro-Chirurgie, 39(5), 304–310.

ACUTE BLEEDING

Authors: Teresa Puértolas Hernández, Ana María Comín Orce and Belén López Roldán

Symptoms Level GradeEvidence

PMID Nº

Acute bleeding is associated with symptoms such as dizziness, cold and clammy skin, hypotension, blanching, tachycardia, dyspnoea, and asthenia. (1)
Depending on the location of the bleeding we can also find:
- Haemoptysis. It consists of the emission of blood with expectoration from the trachea-bronchial tree or the lungs. Its magnitude can vary from blood streaks to massive haemoptysis (loss of 600 cc/day or more than 50-75 cc/hour or when appear signs and symptoms of hypovolemia or respiratory failure regardless of its amount)
- Upper gastrointestinal bleeding. It is the one that occurs between the oral cavity and Treize ligament. It appears like:
  - hematemesis or vomiting with fresh undigested blood
  - melaena or stools foul-smelling blackish, with digested or partially coagulated blood
  - haematochezia or bloody stools
- Low digestive bleeding. It manifests itself like a rectal bleeding or emission of red blood from the rectum.
- Intracranial bleeding is associated with some neurological deficit such as aphasia, hemiplegia, hemiparesis, instability, etc. Headache and vomiting usually also appear and in massive haemorrhages it can manifest with drowsiness, stupor and/or coma.
- Haematuria or bleeding in the urine. May associate pain if bleeding is with blood clots

Aetiology

The occurrence of acute bleeding is due to adverse causes: platelet alterations, the effect of chemotherapy and radiotherapy, local tumour invasion, coagulation defects, anticoagulant therapy, fibrinolysis, surgical and / or invasive procedures.

Platelet alterations or thrombopenia: it is a decrease in the blood platelet count (less than 100,000 platelets/mm3). The risk of bleeding appears when the platelet count is less than 20,000 platelets/mm3. The causes can be:
- production deficit in the bone marrow due to infiltration by the tumour
- increased destruction by antibodies or chemotherapy
- a greater consumption by the formation of thrombus
- greater dilution in cases of extra fluid intake or mass transfusion
- platelet sequestration in the spleen due to splenomegaly and/or portal hypertension
Alterations in coagulation. Decreased or defective production of coagulation factors due to:

a )Liver failure, either due to metastasis or drugs: as most of the proteins involved in coagulation and fibrinolysis are synthesized in the liver, a decrease in their function will favour bleeding.

b) Oral anticoagulants. They may promote bleeding in cases where there is renal or hepatic insufficiency, thrombocytopenia, antiplatelet agents are used or there is a history of gastrointestinal bleeding. They should be used with caution in patients with unresected mucous tumours, patients requiring surgery, and in those with untreated tumours or metastases in the central nervous system.

Fibrinolysis. We differentiate:

a) primary Fibrinolysis: due to local or systemic activation of the fibrinolytic system. It is observed in patients with sarcomas, breast cancer, colon, thyroid, and stomach cancer mainly. b)Fibrinolysis secondary to Disseminated Intravascular Coagulation (DIC). DIC consists of a state of generalized hypercoagulability, which can lead to a multi-organ dysfunction syndrome. As platelets and clotting factors are consumed, bleeding may also occur. DIC occurs as an acute complication in patients with severe sepsis, neoplasms, or severe trauma.

Vascular defects. Due to defects in the blood vessels causing petechiae, bruising and haematomas. Severe haemorrhages son rare, have been described in hereditary haemorrhagic telangiectasia, in cases where there is a deficit of vascular and perivascular collagen (Ehlers-Danlos syndrome) and in hereditary connective tissue disorders (Marfan syndrome)

Studies

The studies should focus on identifying the cause of the bleeding, so they depend on the source of bleeding.

In general, we can do:

History, blood pressure and exploration
Review concurrent medications, focused on non-steroidal anti-inflammatory drugs and/or anticoagulants.

– Analytics: Complete blood counts, coagulation profiles. Sometimes urinalysis or blood in the stool can be helpful.

Specific tests to focus on the origin of acute bleeding:

Brain CT or body CT, abdominal ultrasound.
Endoscopic studies such as gastroscopy, colonoscopy, bronchoscopy, cystoscopy, hysteroscopy.

– Angiography studies.

Pharmacotherapy

Level Grade PMID Nº

VITAMIN K (Fistomenadione). When there is a deficit of coagulation factors. 2B C

Doses of 2.5-10 mg are recommended. The best route of administration is unclear: high intravenous doses (1-10 mg), low intravenous doses (<0.5 mg), subcutaneous (1-10 mg) or oral (2.5-5 mg). (1-10mg) or oral (2.5-5mg).

VASOPRESSIN/DESMOPRESSIN. Doses between 0.1- 0.4 mg continuous infusion. Useful in bleeding from tumours of the upper digestive tract. 2B C Vasoconstrictor effects on myocardium, mesenteric and cerebral circulation should be considered.
SOMATOSTATIN ANALOGUES. Dose in acute bleeding: a bolus of 50 microg intravenous or subcutaneous, followed by a continuous infusion of 50 microg/hour for 48h. 2B C

Used in upper gastrointestinal bleeding.

High doses may cause nausea, abdominal discomfort, and diarrhoea.

TRANEXAMIC ACID. The recommended intravenous dose is 10mg/kg 3-4 times daily, infused over one hour. 3 D
AMINOCAPROIC ACID. The dose is 4-5 g in 250 ml over one hour and thereafter 1g/h in 50 ml administered as an 8-hour continuous infusion until bleeding is controlled. 3 D
RADIOTHERAPY. It can be administered in different regimens: single doses of 8-10Gy, intermediate regimen of 4-8 Gy in 3-5 doses or long regimen of 30-45Gy in 10-15 sessions. 2B C Useful in haemoptysis due to lung cancer, in vaginal, skin, rectal and bladder bleeding and in head and neck, oesophageal and gastric tumours.

Therapeutic Strategy

Due to the multiple presentations of bleeding in cancer patients, as well as its severity, there are no randomised studies that support the use of one treatment over another. The treatment must be individualised and depends on:

- The probability of reversing or controlling bleeding depending on the underlying aetiology. – The risk-benefit depending on the tumour situation.
- The patient’s life expectancy and quality of life.

There are two lines of action:

SYSTEMIC TREATMENT:
- Stabilise the patient: fluids, volume expanders and blood components. Remove anti-inflammatory drugs and anticoagulants. – Vitamin K
- Vasopressin – Somatostatin analogues – Tranexamic acid – Symptomatic treatment of end-of-life patients
LOCAL INTERVENTION:
- Dressings, local compression, haemostatic agents, tamponades – Balloon catheters: Foley catheter or Sengstaken-Blakemore catheter
- Radiotherapy – Endoscopy – Transcutaneous arterial embolization – Surgery

PLASMA FLUIDS AND/OR EXPANDERS in case of haemodynamic instability. 2B B
BLOOD COMPONENTS OF: HEMATIA, PLATELETS OR FRESH PLASMA, depending on whether there is symptomatic anaemia, thrombocytopenia or if there is an alteration in 2A B platelet function respectively.
VITAMIN K, in cases where an elevated INR or prolongation of the prothrombin time is detected in the blood test. 2B C
VASOPRESIN, in bleeding from tumours of the upper digestive tract, vasopressin can stop bleeding in up to 50% of cases. Its vasoconstrictor effects on the myocardium, mesenteric

and cerebral circulation must be considered.

SOMATOSTATIN ANALOGUES are also used in upper gastrointestinal bleeding, although surgery would be more effective. 2B C
TRANEXAMIC ACID inhibits the lysis of fibrin clots. In vitro it is ten times more potent than amino caproic acid. 3 D
DRESSINGS, LOCAL COMPRESSION, TAMPONADE. They are useful in cases where there is superficial bleeding. Tamponades can be used in nosebleeds, vaginal or rectal 2A B bleeding, with different swabs, which can be coated with chemicals to facilitate haemostasis.

HEMOSTATIC AGENTS, applied to the area of superficial bleeding, such as epinephrine, thrombin/thromboplastin, prostaglandins E2 and F2, or silver nitrate among others.

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Level Grade PMID Nº

BALLON CATHETERS, such as Foley catheter or Sengstaken-Blakemore catheter in oesophageal bleeding. These are temporary measures because prolonged pressure can 3 D cause local ischaemia.
RADIOTHERAPY. It has been shown to be effective in haemoptysis due to lung cancer (up to 80%), rectal bleeding (controls up to 85%), haematuria in bladder cancer (controls up to 2B C

60%), vaginal and skin bleeding, as well as in head and neck tumours and bleeding due to oesophageal and gastric tumours. Bleeding is usually controlled within 24-48 hours of starting treatment. Different treatment regimens can be used: single doses of 8-10 Gy, intermediate doses of 4-8 Gy in 3-5 doses or long doses of 30-45 Gy in 10-15 sessions.

ENDOSCOPY. It can be useful in bleeding from the upper digestive tract, lung, and bladder. This technique can be used to cauterise bleeding vessels, either with argon, by placing

clips, with injection of epinephrine or sclerosing agents, or with laser. 2C C

TRANSCUTANEOUS ARTERIAL EMBOLISATION. For patients with tumours of the head and neck, pelvis, lung, and gastrointestinal tract. 2B B
SURGERY. This may be the last option for patients in whom previous treatments have failed. It consists of vessel ligation or resection of the bleeding tumour.

References

1.- Rodríguez Sánchez, C, Cruz Hernández, J, Ruiz Martin, MI. (2011). Urgencias respiratorias y cardiovasculares. Ed. Luzan Manual de Urgencias en Oncología, 2011; pág:51-83 2.- Jose Pereira, Tien Phan. Management of bleeding in patients with advanced cancer. The Oncologist 2004;9:561-570

3.- Candice Johnstone, Shayna E. Rich. Bleeding in cancer patients and its treatment: a review. Ann Palliat Med 2018;7(2):265-273

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4.- J. Garnacho-Montero, E. Fernández-Mondéjar, R. Ferrer-Roca, M.E. Herrera-Gutiérrez, J.A. Lorente, S. Ruiz-Santana y A. Artigas. Cristaloides y coloides en la reanimación del paciente crítico Med Intensiva. 2015;39(5):303—315 5.- Green B, Cairns S, Harvey R et al. Phytomenadione or menadiol in the management of an elevated international normalized ratio (prothrombin time). Aliment Pharmacol Ther 2000;14:1685-1689

6.- Shields RC, McBance RD, Kuiper JD et al. Efficacy and safety of intravenous phytonadione (vitamin K1) in patients on long-term oral anticoagulant therapy. Mayo Clinic Proc2001;76:260-266 7.- ADean, P Tuffin. Fibrinolytic inhibitors for cancer-associated bleeding problems. J Pain Symptom Manage. 1997 Jan;13(1):20-4

8.- Ker K, Edwards P, Perel P, et al. Effect of tranexamic acid on surgical bleeding: Systematic review and cumulative meta-analysis. BMJ 2012;344:e3054.

9.- Ker K, Prieto-Merino D, Roberts I. Systematic review, meta-analysis and meta-regression of the effect of tranexamic acid on surgical blood loss. Br J Surg 2013;100:1271-9. 10.- Hunt BJ. The current place of tranexamic acid in the management of bleeding. Anaesthesia 2015;70Suppl 1:50-3, e18.

11.- Pringle MB, Beasley P, Brightwell AP. The use of Merocel nasal packs in the treatment of epistaxis. J Laryngol Otol 1996;110:543-546. 12.- Thomas S. Alginate dressings in surgery and wound management: Part 2. Wound Care 2000;9:115-119.

13.- Patsner B. Topical acetone for control of life-threatening vaginal hemorrhage from recurrent vaginal gynaecological cancer. Eur J Gynaecol Oncol 1993;1433-1435.

14.- Sirlak M, Eryilmaz S, Yazicioglu L et al. Comparative study of microfibrillar collagen hemostat (Colgel) and oxidized cellulose (Surgicel) in high transfusion-risk cardiac surgery. J Thorac Cardiovasc Surg 2003;126:666-670. 15.- Schenk WG, Burks SG, Gagne PJ et al. Fibrin sealant improves hemostasis in peripheral vascular surgery: a randomized prospective trial. Ann Surg 2003;237:871-876.

16.- Gross M, Schiemann U, Muhlhofer Aet al. Meta-analysis: efficacy of therapeutic regimens in ongoing variceal bleeding. Endoscopy 2001;33:737-746 17.- Dirix P, Vingerhoedt S, Joniau S, et al. Hypofractionated palliative radiotherapy for bladder cancer. Support Care Cancer. 2016;24:181-6.

18.- Duchesne GM, Bolger JJ, Griffiths GO, et al. A randomized trial of hypofractionated schedules of palliative radiotherapy in the management of bladder carcinoma: Results of medical research council trial BA09. Int J Radiat Oncol Biol Phys 2000;47:379-88.

19.- Yan J, Milosevic M, Fyles A, et al. Ahypofractionated radiotherapy regimen (0-7-21) for advanced gynaecological cancer patients. Clin Oncol (R Coll Radiol) 2011;23:476-81.

20.- Sundstrom S, Bremnes RM, Aasebo U et al. Hypofractionated palliative radiotherapy (17Gy/2fractions) is comparable with standard fractionation in advanced non small cell lung cancer. Results from a national phase III trial. J Clin Oncol 2004;5:801-810.

21.- Crane CH, Janjan NA, Abbruzzese JL, et al. Effective pelvic symptom control using initial chemoradiation without colostomy in metastatic rectal cancer. Int J Radiat Oncol Biol Phys 2001;49:107-16. 22.- Thosani N, Rao B, Ghouri Y, et al. Role of argon plasma coagulation in management of bleeding GI tumors: Evaluating outcomes and survival. Turk J Gastroenterol 2014;25Suppl 1:38-42.

23.- Delgal A, Cercueil JP, Koutlidis N, et al. Outcome of transcatheter arterial embolization for bladder and prostate hemorrhage. J Urol 2010;183:1947-53.

24.- Ginat DT, Saad WE, Turba UC. Transcatheter renal artery embolization for management of renal and adrenal tumors. Tech Vasc Interv Radiol 2010;13:75-88. 25.- Hague J, Tippett R. Endovascular techniques in palliative care. Clin Oncol (R CollRadiol) 2010;22:771-80.

INFUSION REACTIONS

Authors: Inês Leão, Ema Neto and Pedro Simões

Definition

Most anticancer treatments carry a risk for infusion reactions (IR), defined as an adverse reaction to the infusion of a drug that is non-dose related, unpredictable, unrelated to the drug’s pharmacological activity, and usually resolve after the treatment is terminated (type B reaction). According to the European Academy of Allergy and Clinical Immunology and World Allergy Organization the term hypersensitivity reaction (HSR) should be used to describe a subset of IR objectively reproducible and initiated by exposure to a defined stimulus at a dose normally tolerated by patients.

IR can be divided in allergic reaction and non-immune related reactions. The cytokine-release syndrome (CRS), which results from widespread degranulation of mast cells, is an acute non-immune related HSR that can be associated monoclonal antibody therapy. Anaphylaxis is a specific subset of HRS, that includes both allergic (allergic anaphylaxis) and non-allergic reactions (non-allergic anaphylaxis or anaphylactoid reactions), characterised by a severe, life-threatening, systemic acute inflammatory reaction.

Table 1. NCI CTCAE v5.0 classification

Grade	Infusion-related reaction	Cytokine release syndrome	Allergic reaction	Anaphylaxis
1	Mild and transient reaction; infusion interruption or intervention not indicated.	Fever with/without constitutional symptoms.	Systemic intervention not indicated.
2	Therapy or infusion interruption indicated but responds promptly to symptomatic treatment; prophylactic medications indicated for <=24 hrs.	Hypotension responding to fluids; hypoxia responding to <40% O2.	Oral intervention indicated.
3	Prolonged (not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae.	Hypotension managed with one pressor; hypoxia requiring ≥40% O2.	Bronchospasm; hospitalization indicated for clinical sequelae; intravenous intervention indicated.	Symptomatic bronchospasm, with or without urticaria; parenteral intervention indicated; allergy-related oedema/angioedema; hypotension.
4	Life-threatening consequences: urgent intervention indicated.	Life-threatening consequences: urgent intervention indicated.	Life-threatening consequences: urgent intervention indicated.	Life-threatening consequences: urgent intervention indicated.
5	Death.	Death.	Death.	Death.

Adapted from: Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, published November 27, 2017 [Internet]: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf

Symptoms

Onset of symptoms is usually fast, in minutes after exposure to the drug, but can happen within the first 6h of administration – this is called an immediate HSR. Non-immediate / delayed HSR occurs at any time from 1h after the initial drug administration, commonly after many days. Rapid onset reactions are usually more severe than those with delayed onset. Severe reactions are rare but may be fatal without appropriate intervention.

Evidence

Level Grade PMID Nº

Typical symptoms of IR include mucocutaneous manifestations (90% of patients), respiratory (40%), circulatory (30%–35%) or abdominal symptoms, that appears minutes to Level GradeEvidence

hours after exposure to the drug. The same drug might produce different clinical symptoms and signs in different individuals.

Mucocutaneous symptoms: flushing, urticaria, pruritus (see Chapter 91 Skin Hypersensitivity)
Upper airway symptoms: rhinorrhoea, coryza, sternutation
Lower airway symptoms: wheezing, dyspnoea, cough, chest tightness, oxygen desaturation
Gastrointestinal symptoms: nausea, vomiting, diarrhoea, abdominal cramps, bloating, reflux
Circulatory symptoms: tachycardia, syncope, hypertension, hypotension
Neuromuscular symptoms: numbness, weakness, seizures, unusual taste
Influenza-like symptoms: chills, fever, headache, myalgia, arthralgia, fatigue, diaphoresis

In non-immediate / delayed HSR other organs may be affected, and symptoms may include lymphadenopathy, hepatitis, renal failure, pneumonitis, anaemia, neutropenia, and thrombocytopenia.

Although their mechanism is due to the direct action of the chemotherapy agents, two specific syndromes can either appear in association or be confused with IR:

Acute laryngopharyngeal dysesthesia: sensation of dyspnoea, difficulty in swallowing or talking, jaw tightness, “tingling” / “itchy” sensation in the tongue and/or pharynx; occurs during or after oxaliplatin infusion, often related to cold air inhalation / cold beverage ingestion.
Irinotecan-related cholinergic syndrome: diarrhoea, emesis, diaphoresis, abdominal cramps, hyper lacrimation, rhinorrhoea; occurring within the first 24h of irinotecan administration.

Cytokine-Release Syndrome

Fever (≥38ºC) is the hallmark of the diagnosis of CRS. Other clinical manifestations vary in terms of intensity, onset (usually 1-3 days after CAR-T cell therapy or allogeneic transplantation, or minutes to hours after antibody infusion) and duration (usually less than one week).

In mild CRS cases, fever is usually associated with flu-like symptoms such as fatigue, headache, rash, diarrhoea, nausea, arthralgia, and myalgia. In more severe CRS cases, it may be associated with tachycardia, hypotension, chest pain and dyspnoea, and may progress to uncontrolled systemic inflammatory response syndrome (SIRS) with circulatory collapse, vascular leakage, peripheral and pulmonary oedema, renal failure, cardiac dysfunction, neuropsychiatric symptoms (such as aphasia, altered level of consciousness, motor weakness or seizures) and multiorgan system failure.

Anaphylaxis

The diagnosis of anaphylaxis is purely clinical, and it is likely if at least one of the criteria summarized on Table 2 is fulfilled.

Table 2. Clinical criteria for diagnosing anaphylaxis.

Illness of acute onset (minutes to hours since exposure to trigger)with cutaneous / mucous involvement (e.g. hives, generalised pruritus, glossal / uvular

swelling) and at least one of:

Respiratory symptoms (e.g. dyspnoea, wheezing, stridor, hypoxaemia)
Reduced blood pressure or symptoms of end-organ dysfunction (e.g. hypotonia [collapse], syncope, incontinence)

Illness of acute onset with two or more of:

Cutaneous / mucous membranes involvement (see above)
Respiratory symptoms (see above)
Reduced blood pressure or symptoms of end-organ dysfunction (see above)
Persistent gastrointestinal symptoms (e.g. abdominal cramps, nausea and/or vomiting)

Reduced blood pressure of acute onset after exposure to known trigger for that patient (defined by a systolic blood pressure of < 90 mmHg or > 30%

decrease from baseline)

Adapted from: PMID 28881914: Roselló S, Blasco I, Fabregat LG, Cervantes A, Jordan K. Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Annals of Oncology. 2017 Jul 1;28:iv100–18. DOI: 10.1093/annonc/mdx216

PMID Nº

Etiology

Treatment schemes combining different drugs are very common and it is crucial to recognise the features of an IR to determine which drug is most likely to have caused it and act accordingly.

Table 3. Characteristics of IRs with some drugs.

Evidence

Level Grade PMID Nº

Drug Incidence of IRs Onset Signs / Symptoms
Anthracyclines	7%–11% with PEGylated liposomal doxorubicin and daunorubicin.	Most IRs occur on the first infusion.	Chest pain, pruritus, syncope, flushing, chills, fever, urticaria, angioedema, rash, tachycardia, hypotension, dyspnoea, nausea, vomiting, headache, back pain.
Atezolizumab	1% – 2%	Most IRs occur on the first infusion.	Chills, itching, flushing, shortness of breath, swelling, dizziness, fever, pain.
Bevacizumab	IRs <3% during the first infusion. Severe in<1%.	Most IRs occur on the first infusion. The likelihood pf an IR declines with each subsequent course of therapy.	Dyspnoea, flushing, rash, blood pressure changes, chest pain, rigours, nausea, vomiting.
Bleomicine	1%	Immediate or delayed for several hours, usually after the first or second dose.	Hypotension, mental confusion, fever, chills, wheezing.
Carboplatin	12%	Highly variable (minutes to hours). The risk increases with cumulative doses. Highest incidence 8th course.	Rash, itching, erythema on palms and soles, abdominal cramps, facial oedema, bronchospasm, hypotension, tachycardia, dyspnoea, chest pain.
Cetuximab	90% on the first infusion. Severe 2%–5%.	Most IRs occur on the first infusion. The likelihood pf an IR declines with each subsequent course of therapy.	Flushing, rash, fever, urticaria, chills, bronchospasm, dyspnoea, nausea, vomiting, blood pressure changes, angina, myocardial infarction.
Daratumumab	IRs 40%–50%, most mild to moderate in severity. 82%–95% on the first infusion.	Most IRs occur on the first infusion. The likelihood pf an IR declines with each subsequent course of therapy.	Nasal congestion, chills, cough, allergic rhinitis, throat irritation, dyspnoea and nausea. Less frequent: bronchospasm, hypertension and hypoxia.
Daratumumab

Evidence

Level Grade PMID Nº

Docetaxel	30% IRs without premedication. 2% severe reactions with premedication.	First or second dose, within the first 10 min of infusion.	Hypotension, dyspnoea, bronchospasm, urticaria, skin reactions, angioedema, flushing, pruritus, tachycardia, chest or back pain.
Etoposide	Anaphylactic reactions 1%–3%.	Usually after first doses.	Hypotension, fever, chills, urticaria, bronchospasm, angioedema, chest discomfort.
Ipilimumab	2%–5%, the majority grade 2 IRs. More common after the first dose.	Most IRs occur on the first infusion.	Pruritus, maculopapular rash, cough, shortness of breath, chills, rigors, facial flushing, chest, abdominal or back pain.
Nivolumab	5%, including grade 3–4 IRs.		Facial flushing, hives, angioedema.
Oxaliplatin	HSR 0.5%–25%. Severe reactions <1%.	Within 60 min after the start of infusion (typically 5–10 min). Highest incidence seventh to eighth course.	Sweating, watering, pruritus, rash, back or chest pain, laryngospasm, dyspnoea, fever, urticaria, bronchospasm, hypotension.
Paclitaxel	30% IRs without premedication. Severe anaphylactic reactions in 2%–4%.	First or second dose, within the first 10 min of infusion.	Flushing, skin reactions, dyspnoea, Hypotension, tachycardia, bronchospasm, angioedema, urticaria.
Panitumumab	IRs in 4% of patients. Severe in<1%.	Most IRs occur on the first infusion. The likelihood pf an IR declines with each subsequent course of therapy.	Chills, dyspnoea, flushing, blood pressure changes, pyrexia, tachycardia, vomiting, anaphylaxis, angioedema, bronchospasm.
Pembrolizumab	3% IRs. Grade 3 <1%.		Pyrexia, chills.
Rituximab	77% on the first infusion. Severe reactions 10%.	Most IRs occur on the first infusion. The likelihood pf an IR declines with each subsequent course of therapy.	Fever, chills, rash, dyspnoea, hypotension, nausea, rhinitis, urticaria, pruritus, asthenia, angioedema, bronchospasm. May be associated with features of tumour lysis syndrome.
Trastuzumab	20%–40% on the first infusion. Severe reactions <1%.	Most IRs occur on the first infusion. The likelihood pf an IR declines with each subsequent course of therapy.	Chills, fever, blood pressure changes, bronchospasm, itching, dyspnoea, wheezing, arrhythmia, angioedema.

Studies

The initial diagnostic approach to the patient with a presumed IR is clinical and involves a complete history of the drugs taken (types, doses, duration), a detailed description of the symptoms and signs (types, onset, localization, and evolution).

Blood tests may reflect the systemic inflammatory response, therefore helping on the diagnosis or its severity classification:

Haematology: leucocytosis may appear due to the systemic inflammatory response or treatment with glucocorticoids; anaemia, leukopenia, neutropenia, or thrombocytopenia may occur due to the underlying malignancy or its treatment.
Electrolytes: electrolyte abnormalities such as hypophosphatemia, hypokalaemia, or hyponatremia occur commonly in cytokine-release syndrome.
End-organ function: abnormalities of renal and/or liver function tests are common, especially in more severe cases.
Inflammation markers: nonspecific markers of inflammation like C-reactive protein or ferritin may be elevated.
Biochemical mediators released during the degranulation of mast cells and basophils: plasma histamine begins to rise within 5 min and remains elevated for 15-60min. Urinary histamine metabolites, may be found for up to 24h after onset of anaphylaxis. Serial measurements of tryptase levels 15 min to 3h after onset of an IR and their comparison to the baseline tryptase level after recovery.

– Normal levels of tryptase or histamine do not rule out the clinical diagnosis of anaphylaxis.

Skin prick tests should not be performed with vesicant agents, such as anthracyclines or vinca alkaloids. Testing should be performed at least 4-6 weeks after and withing 6 months of the initial reaction to avoid false negatives. The results should be interpreted at 15-20 minutes, and after 24 and 72 hours if a non-immediate HSR is suspected. Usually have high specificity but low sensitivity. If negative, intradermal tests may be considered.

Therapeutic Strategy

Evidence

Level Grade PMID Nº

Before the administration of the drug: assess patient´s medical history and concomitant treatment. Ensure appropriate pre-medications. V C
Primary prophylaxis: Antihistamines (H1 / H2 antagonists) and / or glucocorticoids, if drugs with high incidence of infusion reactions (e.g. paclitaxel, docetaxel, cabazitaxel or asparaginase).

Acute management of IR

Stop the infusion and maintain i.v. access. V C
Vital signs, ABCs (airway, beathing, circulation) and consciousness.
If hypotension, place the patient in the trendelenburg position
If respiratory distress, the patient should be sitting up
If unconscious, place the patient in a recovery position
Oxygen if hypoxia.

Anaphylaxis suspected: intramuscular adrenaline (immediately), fluid resuscitation, antihistamines combination, corticosteroids, glucagon (in patients taking beta blockers), IV B vasopressor (if hypotension refractory to epinephrine and fluid resuscitation).

HSR suspected / Cytokine-release: IV B

Grade 1: slow rate of infusion

Grade 2: short-term cessation of infusion. Antihistamines (H1 + H2 antagonists) and corticosteroids. Restart infusion at 50% rate and titrate to tolerance Grade 3/4: stop the infusion. Antihistamines (H1 + H2 antagonists) and corticosteroids. Rechallenge discouraged in severe reaction.

Post-reaction: vital signs closely monitored (>24h in severe reactions) and recurrence symptoms controlled In case of severe HSR or anaphylaxis consider allergist / V C immunologist evaluation. Desensitization protocol may be indicated. V B

Secondary prophylaxis: Antihistamines (H1 / H2 antagonists) and / or glucocorticoids.

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H1 antagonists: chlorpheniramine 10 mg i.v., dexchlorpheniramine 5 mg i.v., diphenhydramine 25-50 mg i.v., clemastine 2 mg i.v., cetirizine 10 mg i.v.
H2 antagonists: famotidine 20 mg i.v., ranitidine 50 mg i.v.

The combined use of H1 and H2 histamine blockers is superior to their use alone.

Glucocorticoids: methylprednisolone i.v. 1-2mg/kg (different protocols).
Adrenaline i.m. immediately at a dose of 0.01 mg/kg (maximum total dose of 0.5 mg) and can be repeated every 5-15 minutes.
Atropine 600 g i.v. (if bradicardia).

V C

I B

V C

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Vasopressor: Dopamine 2-20mg/kg/min and titrated to clinical response.	IV	D	28881914
Glucagon 1–5 mg i.v. infusion over 5 min followed by an infusion 5–15 µg /min titrated to clinical response.	V	C	28881914

References

PMID 28881914: Roselló S, Blasco I, Fabregat LG, Cervantes A, Jordan K. Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Annals of Oncology. 2017 Jul 1;28:iv100–18. DOI: 10.1093/annonc/mdx216.
Castells MC, Matulonis UA, Horton TM. Infusion reactions to systemic chemotherapy. UpToDate, topic last updated January 19, 2021 [Internet]: https://www.uptodate.com/contents/infusion- reactions-to-systemic-chemotherapy
LaCasce AS, Castells MC, Burstein HJ, Meyerhardt. Infusion-related reaction to therapeutic monoclonal antibodies used for cancer therapy. UpToDate, topic last updated September 15, 2021 [Internet]: https://www.uptodate.com/contents/infusion-related-reactions-to-therapeutic-monoclonal-antibodies-used-for-cancer-therapy

EMERGENCY KIT

Authors: Joana Marinho, Tania Duarte and Ana Leonor Matos

Definition

An oncologic emergency can be broadly defined as any complication related to cancer or anticancer therapy that requires immediate intervention. While some complications are insidious and may take weeks or months to develop, others manifest in a few hours and quickly lead to severe outcomes.

Symptoms

Evidence

Level Grade PMID Nº

Most oncologic emergencies can be classified as metabolic, hematologic, structural, or treatment-related and symptoms can vary according to the aetiology and organ, or system involved.

Etiology

Etiology will vary according to the condition leading to the emergency: metabolic, cardiovascular, infectious, neurologic, hematologic, or respiratory. These conditions require prompt recognition and treatment.

IV fluid challenge: 20-30 mL/Kg saline, dextrose 5%.
Adrenaline for anaphylaxis: Intramuscular (IM) adrenaline (0.5 mg (which is 0.5 mL of a 1 mg in 1 mL ampoule of adrenaline)) into the anterolateral thigh as soon as anaphylaxis is suspected. Repeat the IM adrenaline if there is no improvement in the patient’s condition after about 5 min.

Therapeutic Strategy

All hospital staff should be able to rapidly recognise cardiac arrest, call for help, start cardiopulmonary resuscitation (CPR), and defibrillate rapidly (<3 min) when appropriate.
European hospitals should adopt a standard “cardiac arrest call” telephone number (2222) .
Hospitals should have a resuscitation team that immediately responds to in hospital cardiac arrest (IHCA) or to patients who are critically ill or at risk of clinical deterioration.

Initial rescue should follow:

Airway:
- Ensure patient’s airway.
- Treat life-threatening hypoxia with 100% inspired oxygen. Once SpO2 can be measured reliably or arterial blood gas values are obtained, titrate the inspired oxygen to achieve an arterial oxygen saturation of 94-98% or PaO2 75-100kPa.
Breathing:
- Assess respiratory rate, accessory muscle use, ability to speak in full sentences, pulse oximetry, percussion and breath sounds, request chest X-ray.
- Consider non-invasive ventilation if respiratory distress and safe to do so.
- If an advanced airway is required, only rescuers with a high tracheal intubation success rate should use tracheal intubation.
Circulation:
- Assess heart rate and blood pressure, place the patient on a cardiac and oxygen saturation monitor and obtain ECG.
- Obtain intravenous (IV) access to enable drug delivery and blood collection.
- Consider IV fluids (crystalloids) and/or vasoactive drugs to support the circulation.
Disability:

-Check patient’s neurological status (Glasgow coma scale) and vital signs periodically.

Exposure:

-Maintain normothermia.

In the case of cardiac arrest
- Activate cardiac arrest protocol according to your institution (call 2222).
- Start CPR – Alternate 30 chest compressions to 2 ventilations. If you are unable to provide ventilations, give continuous chest compressions.
- Apply an Automated External Defibrillator and follow instructions.
- If an advanced airway is required, only rescuers with a high tracheal intubation success rate should use tracheal intubation.
- Follow existing protocols after resuscitation team arrives.
In case of suspected anaphylaxis
- Recognizing is essential, by the presence of airway (swelling), breathing (wheeze or persistent coughing), or circulation (hypotension) problems with or without skin and mucosal changes.

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- Identify and remove or stop the trigger.
- Give intramuscular (IM) adrenaline (0.5 mg (which is 0.5 mL of a 1 mg in 1 mL ampoule of adrenaline)) into the anterolateral thigh as soon as anaphylaxis is suspected. Repeat the IM adrenaline if there is no improvement in the patient’s condition after about 5 min.
- Stabilize and follow the previous outline (ABCD).
- Follow existing guidelines for the investigation and follow-up care of patients with suspected anaphylaxis.
In case of oncologic emergencies, it is important to exclude Hypo- Hyperkalaemia/ electrolyte disorders; Hypoxia, Hypovolemia, Hypothermia, Venous thromboembolism, cardiac tamponade, sepsis/infection, treatment-related causes such as hypersensitivity or infusion reactions/anaphylaxis.

References

Perkins GD, Graesner JT, Semeraro F, Olasveengen T, Soar J, Lott C, Van de Voorde P, Madar J, Zideman D, Mentzelopoulos S, Bossaert L, Greif R, Monsieurs K, Svavarsdóttir H, Nolan JP; European Resuscitation Council Guideline Collaborators. European Resuscitation Council Guidelines 2021: Executive summary. Resuscitation. 2021 Apr;161:1-60. Erratum in: Resuscitation. 2021 May 4;163:97-98. PMID: 33773824.
Lott C, Truhlář A, Alfonzo A, Barelli A, González-Salvado V, Hinkelbein J, Nolan JP, Paal P, Perkins GD, Thies KC, Yeung J, Zideman DA, Soar J; ERC Special Circumstances

Writing Group Collaborators. European Resuscitation Council Guidelines 2021: Cardiac arrest in special circumstances. Resuscitation. 2021 Apr;161:152-219. Epub 2021 Mar 24. Erratum in: Resuscitation. 2021 Oct;167:91-92. PMID: 33773826.

Soar J, Berg KM, Andersen LW, Böttiger BW, Cacciola S, Callaway CW, Couper K, Cronberg T, D’Arrigo S, Deakin CD, Donnino MW, Drennan IR, Granfeldt A, Hoedemaekers

CWE, Holmberg MJ, Hsu CH, Kamps M, Musiol S, Nation KJ, Neumar RW, Nicholson T, O’Neil BJ, Otto Q, de Paiva EF, Parr MJA, Reynolds JC, Sandroni C, Scholefield BR, Skrifvars MB, Wang TL, Wetsch WA, Yeung J, Morley PT, Morrison LJ, Welsford M, Hazinski MF, Nolan JP; Adult Advanced Life Support Collaborators. Adult Advanced Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation. 2020 Nov;156:A80-A119. Epub 2020 Oct 21. PMID: 33099419; PMCID: PMC7576326.

Soar J, Becker LB, Berg KM, Einav S, Ma Q, Olasveengen TM, Paal P, Parr MJA. Cardiopulmonary resuscitation in special circumstances. Lancet. 2021 Oct 2;398(10307):1257-

1268. doi: 10.1016/S0140-6736(21)01257-5. Epub 2021 Aug 26. PMID: 34454688.

Evidence Level Grade PMID Nº

IMMUNOTHERAPY-ASSOCIATED TOXICITIES

Authors: Marcos Pantarotto, Patricia Garrido and Claudia Matos.

Introduction Level GradeEvidence

PMID Nº

The use of immune-checkpoint inhibitors (ICI) started a new era of benefits for cancer patients. However, the diverse mechanism of action brought new challenges to oncologists, mainly associated with immune-related adverse events (irAEs), which are very different from the side effects caused by commonly used cytotoxic drugs.

Given the broad spectrum of clinical manifestations and syndromes related to immune modulation, we emphasize the importance of a multidisciplinary approach.

Infusional reactions

1. Incidence according to treatment modality:
  - For anti-CTLA4 only: 2-6%
  - For anti-PD(L)1 only: 4% (avelumab associated with higher incidence of infusion reaction: 21-29% with 0-3% grade ≥3)
2. Clinical Presentation:
  - Short-lived; time frame: from immediate up to 1h post-infusion.
  - Symptoms include chest tightness, cough, wheezing, back pain, tongue swelling, dizziness/syncope, rash, pruritus, fever, dyspnoea, angioedema, tachycardia, hypo or hypertension, flushing/headache, hypoxia, arthralgia/myalgia.
3. Classification (CTCAE) and management.

Grade 1		Grade 2	Grade 3 / Grade 4
Recommendation	Evaluate and monitor the patient. EKG as per clinical presentation.
ICI treatment	Hold infusion and resume when symptoms cease. Next cycle: consider premedication (H1 and H2 -blockers; acetaminophen).	Hold infusion and treat the reaction with supportive medications (including hydrocortisone, antihistamines, and beta-agonists). Resume with half -rate when symptoms cease. Consider premedication as for grade 1 reactions.	Hold infusion and treat the reaction (DO NOT DELAY epinephrin administration; life support measures as needed; consider treatment with hydrocortisone, antihistamines, and beta – agonists). Consider patient admission if there is no improvement or if the patient worsens after initial improvement
Other comments			Consider changing the ICI for another drug with a similar mechanism of action

Fatigue

1. Incidence according to treatment modality:
For anti-CTLA4 and anti-PD(L)1 combination: 36% (4% grade ≥ 3) – For anti-CTLA4 only: 25% (2% grade ≥ 3)
For anti-PD(L)1 only: 21% (1% grade ≥ 3)
1. Clinical Presentation:
  - Most likely to occur after the first month following initiation of ICI therapy.

Evidence Level Grade PMID Nº

- - Patients experiencing fatigue should be evaluated for conditions that may cause or contribute to fatigue. Laboratory tests should include complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone (TSH), free-T4 (fT4), morning cortisol, and adrenocorticotropic hormone (ACTH).
1. Classification (CTCAE) and management:

– Address any abnormality found. – Hold or consider discontinuing immunotherapy if grade 3, after ruling out reversible causes.

Gastrointestinal IrAEs

Diarrhoea and colitis

Incidence according to treatment modality:
- For anti-CTLA4 and anti-PD(L)1 combination: 44% (10% grade ≥ 3) – For anti-CTLA4 only: 36% (8% grade ≥ 3)
- For anti-PD(L)1 only: 11% (1% grade ≥ 3)
Clinical Presentation:

Diarrhoea must be closely followed by the oncologist. Severe diarrhoea can be, per se, clinically relevant, and its presence can also translate to the presence of colitis. Colitis is a potentially life-threatening adverse event related to immune therapy, as it may cause bowel perforation, ischemia with necrosis, haemorrhage, and megacolon.
Symptoms vary and include watery diarrhoea, abdominal pain/cramps, and fever. The presence of more than four bowel movements a day should prompt medical evaluation and the presence of blood or mucus in the stool.

Classification (CTCAE) and management:

Grade 1		Grade 2	Grade 3 / Grade 4
Recommendations	Loperamide/dietary modification; encourage hydration. If persistent, check lactoferrin/calprotectin on the stool (if positive, treat as grade 2)	Rule out infections; Consider abdominopelvic CT scan; Consider GI consultation (with endoscopic examination)	Rule out infections; Consider an abdominopelvic CT scan Consider GI consultation (with endoscopic examination)
ICI treatment	Consider holding ICI	Hold ICI; Start prednisone-equivalent (1-2mg/kg/day) If there is no improvement in 2 – 3 days, keep steroids and consider infliximab/vedolizumab	Discontinue anti-CTLA4 / Hold anti-PD(L)1. For grade 4 — permanently discontinue ICI; Patient admission; IV methylprednisolone 1-2mg/kg/day. If there is no improvement in 1-2 days, keep steroids and consider infliximab/vedolizumab
Steroids wean		Within 4 weeks	Within 4 weeks

If there is (a) no improvement with steroids, (b) recurrence after steroids tapering, or (c) ulcerative colitis: administer infliximab 5mg/kg IV at weeks 0, 2, 6.
In case of persistent symptoms after the second dose of infliximab, treatment should change to vedolizumab 300mg at weeks 0, 2, 6.
Infliximab/vedolizumab appears safe for patients with HIV, Hepatitis B, or tuberculosis, and administration should not be delayed. Nevertheless, patients should be tested for these conditions, and appropriate treatment should ensue as clinically indicated.

AST/ALT elevation

Incidence according to treatment modality:
- For anti-CTLA4 and anti-PD(L)1 combination: 19% (9% grade ≥ 3) – For anti-CTLA4 only: 5% (2% grade ≥ 3)
- For anti-PD(L)1 only: 5% (1% grade ≥ 3)
Clinical Presentation:

Evidence Level Grade PMID Nº

– Generally asymptomatic. Alanine or aspartate transaminase (ALT/AST) elevations typically are the initial manifestation of liver toxicity and manifest in 1-15 weeks after treatment.

Classification (CTCAE) and management:

Grade 1		Grade 2	Grade 3	Grade 4
Recommendations	Differential diagnosis: rule out virus infections, metastatic infiltration, drug toxicity, OTC medications/alcohol abuse. Provide abdominal CT scan	Differential diagnosis: rule out virus infections, metastatic infiltration, drug toxicity, OTC medications/alcohol abuse. Provide abdominal CT scan	Differential diagnosis: rule out virus infections, metastatic infiltration, drug toxicity, OTC medications/alcohol abuse. Provide abdominal CT scan Inpatient care / GI consultation	Differential diagnosis: rule out virus infections, metastatic infiltration, drug toxicity, OTC medications/alcohol abuse. Provide abdominal CT scan Inpatient care / GI consultation
ICI treatment	Consider holding ICI; Weekly check for AST/ALT values	Hold ICI; Weekly check for AST/ALT values; Consider prednisone – equivalent (0,5-1mg/kg/day) If there is no improvement in 3 days, treat as grade 3	Hold ICI; Start prednisone -equivalent (1-2mg/kg/day) If there is no improvement in 1- 2 days, add MMF If there is no improvement with MMF, consider ATG	Permanently discontinue ICI Start prednisone -equivalent (1-2mg/kg/day) If there is no improvement in 1- 2 days, add MMF If there is no improvement with MMF, consider ATG
Steroids wean		Within 4-6 weeks	Within 4-6 weeks	Within 4-6 weeks

ATG = antithymocyte globulin; MMF = mycophenolate mofetil; OTC = off the countyATG = antithymocyte globulin; MMF = mycophenolate mofetil; OTC = off the county

Laboratory evaluation for grade 2 toxicities should include AST/ALT, Alkaline phosphatase, coagulation tests, serum bilirubin, iron studies, hepatitis virus, autoimmune hepatitis panel (ANA; ANCA, AMA, ASMA);
Infliximab should not be used in patients with liver toxicity (GRADE 1). Tacrolimus and ATG should be considered instead.
If there is no improvement to grade ≤ 1 in 10-14 days of MMF, consider liver biopsy and rule out CMV infection.

Acute Pancreatitis Evidence

Clinical Presentation:
- The median time to amylase/lipase elevation is 9-20 weeks.
- ICI can cause elevation of amylase and lipase; nevertheless, pancreatitis is a rare irAE, with few cases reported in the literature. For the clinical diagnosis, consider the presence of compatible epigastric pain or radiographic changes (abdominal CT scan with IV contrast or cholangiopancreatography MRI), together with amylase/lipase elevation.
- Amylase/lipase elevations with no corresponding signs/symptoms of pancreatitis should be kept under surveillance.
Classification (CTCAE) and management:

Level Grade PMID Nº

Grade 2		Grade 3	Grade 4
Recommendations	Treat the patient for acute pancreatitis, with IV hydration as indicated. Exclude other causes, such as alcohol abuse, hyperlipemia, and cholelithiasis. Gastroenterology referral.
ICI treatment	Consider holding;	Hold ICI; Start prednisone-equivalent (0,5-1mg/kg/day)	Permanently discontinue. Start prednisone-equivalent (1-2mg/kg/day)
Steroids wean		After improvement to grade ≤ 1, taper over 4-6 weeks.

Cutaneous IrAEs

Very common, cutaneous IrAEs generally appear early during immunotherapy, on average 3-4 weeks after the beginning of treatment. Severe reactions are rare and demand prompt diagnosis, with referral to a Dermatologist.

Rash

Incidence according to treatment modality:
- For anti-CTLA4 and anti-PD(L)1 combination: 41% (5% grade ≥ 3)
- For anti-CTLA4 only: 23% (1% grade ≥ 3)
- For anti-PD(L)1 only: 10% (1% grade ≥ 3)
Clinical Presentation
- Onset: 2-5 weeks; often with pruritus. Diverse presentations: acneiform, maculo-papular, papulopustular. CTCAE classification according to type of rash.
Classification (CTCAE) and management

Grade 1		Grade 2	Grade 3	Grade 4
Recommendations	Differential diagnosis: rule out virus infections, metastatic infiltration, drug toxicity, OTC medications/alcohol abuse. Provide abdominal CT scan		For grades 3/4: same as grades 1 / 2, additionally consider patient admission and GI consultation.
ICI treatment	Consider holding ICI. Weekly check for AST/ALT values	Hold ICI. Weekly check for AST/ALT values. Consider prednisone- equivalent (0,5-1mg/kg/day) If there is no improvement in 3 days, treat as grade 3	Hold ICI. Start prednisone-equivalent (1- 2mg/kg/day) If there is no improvement in 1 – 2 days, add MMF If no improvement with MMF, consider ATG	Permanently discontinue ICI Start prednisone -equivalent (1 – 2mg/kg/day) If there is no improvement in 1-2 days, add MMF If there is no improvement with MMF, consider ATG
Steroids wean	After improvement to grade ≤ 1, taper over 4-6 weeks.

Pruritus

Incidence according to treatment modality:
- For anti-CTLA4 and anti-PD(L)1 combination: 34% (2% grade ≥ 3) – For anti-CTLA4 only: 25% (1% grade ≥ 3)
- For anti-PD(L)1 only: 15% (0% grade ≥ 3)
Clinical presentation:
- May present with no skin lesion in 50% of cases.
- Special attention to the examination of the skin; the presence of bullous formation or mucosal involvement should raise concerns of a more severe process in development.
Classification (CTCAE) and management:

Evidence

Level Grade PMID Nº

Grade 1		Grade 2	Grade 3
Recommendations	Whole-body skin examination
ICI treatment	Continue ICI; Oral anti-H1 Topical Steroids	Continue ICI. Oral anti-H1 in association with gabapentin / high-potency topical steroids. Dermatology consultation.	Hold ICI. Systemic steroids indicated: prednisone-equivalent (0,5 – 1mg/kg/day) Associate gabapentin / other adjuvant treatment (as aprepitant) Dermatology consultation
Steroids wean			After improvement to grade ≤ 1, taper over 4-6 weeks.

Stevens-Johnson syndrome _Level _Grade^Evidence

PMID Nº

Stevens-Johnson syndrome is an uncommon but potentially life-threatening complication that may develop from less severe skin toxicity that fails to improve with treatment; generally associated with mucosal involvement.

Urgent dermatologic consultation is warranted. Treatment involves steroids in immunosuppressive doses, eventually associated with IV immune-globulin.

Pulmonary adverse events

* Pneumonitis

Incidence and risk factors:
- Pneumonitis is the most common lung toxicity related to ICI, with an overall incidence of 2,7% (1% grade ≥3). There is no known risk factor for the development of this complication.
- For anti-CTLA4 and anti-PD(L)1 combination: 3,6% – For anti-PD(L)1 only: 1,3%
- Median time to onset: 2,8 months (9 days – 19,2 months). An earlier onset is seen in NSCLC patients (median 2,1 months) and with combination regimens (2,7 vs. 4,6 months), irrespective of dosage.
Clinical presentation:
- Patients can be asymptomatic but may develop progressive dyspnoea (53%) and cough (35%); more than half of the patients (58%) present with additional immune toxicity (e.g., rash and colitis). In asymptomatic or mildly symptomatic patients, severity can be assessed by resting oximetry and 6- minutes walking test plus respiratory function tests with pulmonary diffusing capacity.
- The differential diagnosis can be challenging in patients with previous respiratory comorbidities; perform a thoracic high-resolution CT scan with contrast in the presence of new or progressive respiratory symptoms. Bronchoscopy with BAL (bronchoalveolar lavage with a high percentage of lymphocytes and T-cell infiltrate) may be helpful to establish the differential diagnosis with infection, oncological progression, or inflammatory conditions, e.g., sarcoidosis, and is especially recommended in symptomatic patients. Alung biopsy (transbronchial per-endoscopy or video-assisted thoracoscopic surgery) can establish the diagnosis in selected cases.
Severity Grade and management pathway:

Grade 1		Grade 2	Grade 3 Grade 4
Recommendations	Referral to a pulmonologist. For grade ≥2 and steroids treatment, antibiotic prophylaxis with cotrimoxazole 480mg bid, 3 times/week, oral).
	Consider treatment delay;	Hold ICI Prednisolone 1mg/Kg/day oral	Permanently discontinue ICI Hospital admission
ICI treatment	Close follow – up (re-evaluate in 48h)	Antibiotic (if suspicion of infection) If there is no improv ement within 48h , treat as grade ≥3	Methylprednisolone 2-4mg/kg/day, i.v. Antibiotic (empiric) If not improving within 48h: Infliximab 5mg/kg or MMF (if concurrent hepatic toxicity) over at least 8 weeks
Steroids wean		Taper over 4 – 6 weeks

Re-challenge:

– Re-challenge is feasible after clinical resolution of grade 1-2 pneumonitis. Discussion in a multidisciplinary board for each patient is advised; recurrent pneumonitis is described in 25% of the cases and treated with the same measures.

Other pulmonary toxicities Evidence

Level Grade PMID Nº

I. For NSCLC patients treated with ICI, sarcoid-like granulomas and tuberculosis are possible complications.Although there are no studies focusing on the management of sarcoidosis or tuberculosis as side effects of ICI therapy, recommendations are based on clinical experience and case report publications.

Sarcoid-like granulomas Tuberculosis

Time to onset: 9 months ICI treatment was not associated with TB development; however, the steroid used to manage irAEs and other underlying conditions (i.e., CPOD) can be a risk factor

Asymptomatic or cough, fatigue, dyspnoea (latent TB infection – IGRA test before ICI).

Micronodular opacities/GGO lesions resemble recurrence or disease Asymptomatic or cough, fatigue, dyspnoea progression with many organs involved (mainly lymph nodes, lungs, skin)

Micronodular opacities/GGO lesions resemble recurrence or disease

Diagnosis: bio psy with histological epithelioid non -necrotizing granulomas

surrounded by CD4+ and CD8+ T -lymphocytes; BAL with increased CD4:CD8 Diagnosis of co ex- istent tuberculosis and lung cancer requires clinical, ratio; once diagnosis establish is mandatory, eye and cardiac check-up radiological, and microbiological evidence.

ICI therapy must be withheld, and steroids prescribed in extensive disease ICI therapy may be withheld in case of TB infection ; however, concurrent (stage ≥2) plus extra -pulmonary lesions involving critical organs (ocular, tuberculostatic treatment is feasible and well-tolerated; the decision is myocardium, neurologic, renal), progressive radiographic/lung function controversial and should be taken by a multidisciplinary board for each patient. worsening, pulmonary symptoms escalation, or hypercalcemia

Neurologic adverse events

Several neurologic irAEs are described in the literature with more involvement of the peripheral nervous system compared with the central nervous system. There are no risk factors identified. Neurology referral is advised for all patients suspicious of neurologic irAEs grade ≥ 2.

Incidence:
- For anti-CTLA4 and anti-PD(L)1 combination: 12% – For anti-CTLA4 only: ≤4%
- For anti-PD(L)1 only: 6% – grade ≥ 3-4 is less than 1% in all treatments
Clinical presentation:
- Median time to onset: 4 weeks
- Usually nonspecific, with headache, seizures, focal neurological abnormalities, altered mental status, or PRES (with acute confusional state, drowsiness or sometimes stupor, visual impairment, seizures).
- The differential diagnosis is complex and includes disease progression, infection (especially viral – HSV), seizures, metabolic derangement, vitamin B12 deficiency, diabetic neuropathy, vasculitis – ANCA, paraneoplastic syndromes, and autoimmune encephalopathies.
Severity Grade and management pathway:
- Obtain a complete anamnesis and physical examination with a thorough neurologic exam.
- Baseline hematologic and biochemical panel (i.e., complete blood count, renal function test, electrolytes, C – reactive protein ± procalcitonin, calcium, liver function tests, thyroid panel)
- Evaluation, in most cases, with MRI brain and spine imaging, Nerve conduction studies and EMG (in cases with sensory symptoms or weakness), EEG (to rule out subclinical seizures)
- Lumbar puncture (LP) with opening pressure measurement and CSF analysis: cell count, protein, glucose, gram stain, culture, PCR for HSV or other viral infection, cytology, oligoclonal bands, autoimmune encephalopathy panel

Endocrine Evidence

Level Grade PMID Nº

The median time to onset of endocrine IrAEs ranges from 1.4 to 4.9 months with anti-PD1 therapy and from 1.75 to 5 months with ipilimumab. ICI-related endocrine toxicities often persist after therapeutic interventions and the conclusion of ICI therapy, requiring lifelong hormonal supplementation. Endocrinologists play an important role in the management of severe or complex cases.

Hypothyroidism

Incidence and risk factors:
- For anti-CTLA4 and anti-PD(L)1 combination: 15% (0-2% ≥ grade 3) – For anti-PD(L)1 only: 8%
- For anti-CTLA4 only: 3%
Clinical Presentation:

Diagnosis is based on plasma TSH assay since clinical signs are nonspecific. Routine monitoring of thyroid function is necessary during ICI treatment; TSH and fT4 should be tested every 4-6 weeks and should continue to be tested every 6-12 months following the conclusion of immunotherapy.
Symptoms vary and may include fatigue, weight gain, bradycardia, and constipation. III.Classification (CTCAE) and management:

	Elevated TSH and normal fT4	Elevated TSH and Low fT4
Recommendations	If there are no symptoms, repeat measure next visit. If symptomatic, consider thyroxine if TSH > 10 mIU/L	If there are no symptoms , repeat measure next visit ; If symptom atic, initiate thyroxin
ICI treatment	Continue
Steroids	Not usually recommended

Levothyroxine should be administered to patients with hypothyroidism at 0.5 – 1.5mcg/kg/day. In elderly patients or those with heart disease, start at lower doses.
Patients with hypothyroidism symptoms or elevated TSH and low fT4 should be tested for morning cortisol to identify possible concurrent adrenal insufficiency.

Hyperthyroidism

Incidence and risk factors:
- For anti-CTLA4 and anti-PD(L)1 combination: 8% – For anti-PD(L)1 only: 5% – For anti-CTLA4 only: 4%
Clinical Presentation:
- Except in severe cases of thyrotoxicosis, the diagnosis can be challenging. Routine monitoring of thyroid function follows the same recommendations as for hypothyroidism. Thyroid autoantibodies measurement can be helpful for differential diagnosis.
- Symptoms vary and may include fatigue, nervousness, weight loss, heat intolerance, fine tremor, and palpitations.
Classification (CTCAE) and management:

Low TSH	Elevated fT4	Low fT4
Recommendations	If there are no symptoms, repeat measure next visit. If there are symptoms of hyperthyroidism start beta blockers	Check morning cortisol (may indicate hypopituitarism)
ICI treatment	For symptomatic hyperthyroidism (grade ≥ 2) consider holdingICI and resuming after completion of workup and improvement of symptoms and fT4
Steroids	Not usually recommended

Consider treatment with beta-blockers (10-20 mg every 4-6 hours for symptoms as needed) until thyrotoxicosis resolves. Atenolol or metoprolol can be considered.
Thyrotoxicosis often evolves into hypothyroidism (50-90%), requiring treatment with thyroid hormone replacement.
Patients with low/normal TSH and low fT4 should be tested for ACTH levels and morning cortisol to identify possible Hypophysitis.
Patients with persistently low TSH and high fT4 should be evaluated for Graves’ disease (ICI thyrotoxicosis usually lasts 4-6 weeks).

Hypophysitis

Incidence and risk factors:
- For anti-CTLA4 and anti-PD(L)1 combination: 9-11% – For anti-CTLA4 only: 4% – For anti-PD(L)1 only: 1%
Clinical Presentation:
- ICI-induced Hypophysitis is most frequently manifested as secondary adrenal insufficiency due to ACTH deficiency and less commonly due to TSH, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) deficiency. ACTH, morning cortisol, TSH, fT4, FSH, LH, testosterone in males, and oestrogen in premenopausal females should be tested.
- Patients may present with different complaints, including fatigue, nausea/emesis, anorexia, dizziness, headache, and gonadotrophic deficiency (including loss of libido or erectile dysfunction).
- Headache and visual disturbances require immediate evaluation and differentiation with cerebral metastasis, leptomeningeal disease, or cerebrovascular disease. On brain MRI, pituitary enlargement and enhancement can be seen.
Classification (CTCAE) and management:

Management
Recommendations	Treat with hormone replacement if indicated: Steroid replacement (hydrocortisone 20 mg PO every AM and 10 mg PO every PM) if secondary adrenal insufficiency (low ACTH, low cortisol); an endocrinologist should guide further titration. In central hypothyroidism (low TSH, low fT4), proceed to thyroid hormone replacement Consider testosterone supplementation in males and oestrogen in premenopausal females if central hypogonadism (low LH, low FSH, low sex hormones).
ICI treatment	Hold if grade ≥ 2 until resolution and hormone replacement is initiated
Steroids	If acute severe symptoms such as optic chiasm compression or mass effec,t consider high dose steroids: prednison-e equivalent 1 mg/kg/day until symptoms resolve (1-2 weeks), then rapid taper to physiologic replacement

Renal IrAEs

Acute kidney injury (AKI) describes a condition in which kidney function is severely impacted or lost and may occur via a number of aetiologies, but the most common ICI-related reported underlying pathology is acute tubulointerstitial nephritis. AKI is common in patients receiving ICI therapy, but it is not the direct result of ICI toxicity in most cases. It is essential to differentiate between all-cause AKI (e.g., hypovolemia or acute tubular necrosis) and ICI-induced AKI.

Evidence Level Grade PMID Nº

Acute kidney injury

Incidence and risk factors:
- For anti-CTLA4 and anti-PD(L)1 combination: 5% (0-2% ≥ grade 3) – For anti-CTLA4 only: 2% – For anti-PD(L)1 only: 2%
Clinical Presentation:
- Patients with possible ICI-related AKI should have a urinalysis and quantification of proteinuria with a spot urine protein to creatinine ratio.
- In cases of potential ICI-related AKI, concomitant toxic medications (e.g., NSAIDs, proton pump inhibitors, and some antibiotics) should be discontinued. If an antibiotic is implicated and ongoing treatment of infection is required, an antibiotic from a different class should be used.
Classification (CTCAE) and management:

Grade 1 Grade 2 Grade 3 / Grade 4
Recommendations	Differential diagnosis: Review hydration status, medications, urine test/culture if urinary tract infection symptoms Renal ultrasound +/- doppler to exclude obstruction/clot Repeat creatinine weekly	Rule out other causes. Review creatinine in 48h-72h. Repeat creatinine/K+ every 48h Consider nephrologist consultation	Rule out other causes. Admit patient for monitoring and fluid balance. Grade 4: patients should be managed in a hospital where renal replacement therapy is available. Repeat creatinine every 24h. Consider nephrologist consultation
ICI treatment	Consider holding ICI	Hold ICI. Start prednisone-equivalent (0.5- 1mg/kg/day) If there is no improvement in 1 week, titrate steroids to 1- 2mg/kg/day	Hold ICI. Start prednisone -equivalent (1 – 2mg/kg/day)
Steroids wean		Within 2-4 weeks	Over ≥ 4 weeks

- Given the lack of specific clinical features for ICI-related AKI, renal biopsy should be considered when feasible in grade ≥ 2.
- Patients with glomerular disease should receive standard therapy for the underlying lesion.
- If sustained grade > 2 kidney injury after 4-6 weeks of steroids, consider adding azathioprine, cyclophosphamide, cyclosporine, infliximab, or mycophenolate mofetil.
- Patients with renal allografts may receive ICIs, but only after extensive counselling on the associated risks and high probability of rejection and subsequent dialysis dependence, particularly with anti-PD-(L)1 antibodies.

Evidence Level Grade PMID Nº

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Imoto, K., Kohjima, M., Hioki, T., Kurashige, T., Kurokawa, M., Tashiro, S., Suzuki, H., Kuwano, A., Tanaka, M., Okada, S., Kato, M., & Ogawa, Y. (2019). Clinical Features of Liver Injury Induced by Immune Checkpoint Inhibitors in Japanese Patients. Canadian Journal of Gastroenterology & Hepatology, 2019, 6391712. https://doi.org/10.1155/2019/6391712
Naidoo, J., Wang, X., Woo, K. M., Iyriboz, T., Halpenny, D., Cunningham, J., Chaft, J. E., Segal, N. H., Callahan, M. K., Lesokhin, A. M., Rosenberg, J., Voss, M. H., Rudin, C. M., Rizvi, H., Hou, X., Rodriguez, K., Albano, M., Gordon, R.-A., Leduc, C., … Hellmann, M. D. (2017). Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 35(7), 709–717. https://doi.org/10.1200/JCO.2016.68.2005
Schneider, B. J., Naidoo, J., Santomasso, B. D., Lacchetti, C., Adkins, S., Anadkat, M., Atkins, M. B., Brassil, K. J., Caterino, J. M., Chau, I., Davies, M. J., Ernstoff, M. S., Fecher, L., Ghosh, M., Jaiyesimi, I., Mammen, J. S., Naing, A., Nastoupil, L. J., Phillips, T., … Bollin, K. (2021). Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. Journal of Clinical Oncology, 39(36), 4073–4126. https://doi.org/10.1200/JCO.21.01440
Wright, J. J., Powers, A. C., & Johnson, D. B. (2021). Endocrine toxicities of immune checkpoint inhibitors. Nature Reviews. Endocrinology, 17(7), 389–399.
Yoo, M. J., Long, B., Brady, W. J., Holian, A., Sudhir, A., & Gottlieb, M. (2021). Immune checkpoint inhibitors: An emergency medicine focused review. The American Journal of Emergency Medicine, 50, 335–344.
Zivelonghi, C., & Zekeridou, A. (2021). Neurological complications of immune checkpoint inhibitor cancer immunotherapy. Journal of the Neurological Sciences, 424, 117424.

Annex A

CTCAE v5 grading for the disorders presented in this chapter

Common t e rminology c r i t e r i a f o r adverse events c l assification. The complete document with definitions i s available a t https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_60

CTCAE term	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
		Therapy or infusion	Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae
		interruption indicated but
	Mild transient	responds promptly to
Infusion Related Reaction	reaction; infusion interruption not indicated; intervention	symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV		Life-threatening consequences; urgent intervention indicated	Death
	not indicated	fluids); prophylactic
		medications indicated for
		<=24 hrs

Fatigue	Fatigue relieved by rest	Fatigue not relieved by rest; limiting instrumental ADL	Fatigue not relieved by rest; limiting self-care ADL
Diarrhea	Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline	Increase of 4 6 stools per day over baseline; moderate increase in ostomy output compared to baseline; limiting instrumental ADL	Increase of >=7 stools per day over baseline; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL	Life-threatening consequences; urgent intervention indicated	Death
AST/ALT	> ULN – 3xULN if baseline was normal; 1.5 – 3x baseline is baseline was abnormal.	>3.0 – 5.0 x ULN if baseline was normal; >3.0 – 5.0 x baseline is baseline was abnormal.	>5.0 – 20.0 x ULN if baseline was normal; >5.0 – 20.0 x baseline is baseline was abnormal.	>20.0 x ULN if baseline was normal; >20 x baseline is baseline was abnormal.
Acute Pancreatitis		Enzyme elevation; radiologic findings only	Severe pain; vomitin; medical intervention indicated (e.g., analgesia, nutritional support)	Life-threatening consequences; urgent intervention indicated
Pruritus	Mild or localized; topical intervention indicated	Widespread and intermittent; skin changes from scratching (e.g., edema, papulation, excoriations, lichenification, oozing/crusts); oral intervention indicated; limiting instrumental ADL	Widespread and constant; limiting self care ADL or sleep; systemic corticosteroid or immunosuppressive therapy indicated		Death

Stevens-Johnson syndrome			Skin sloughing covering <10% BSA with associated signs (e.g., erythema, purpura, epidermal detachment, and mucous membrane detachment)	kin sloughing covering 10 – 30% BSA with associated signs (e.g., erythema, purpura, epidermal detachment and mucous membrane detachment)	Death
Pneumonitis	Asymptomatic; clinical or diagnostic observations only; intervention not indicate	Symptomatic; medical intervention indicated; limiting instrumental ADL	Severe symptoms; limiting self care ADL; oxygen indicated	Life-threatening respiratory compromise; urgent intervention indicated (e.g., tracheotomy or intubation)
Hypothyroidism / hyperthyroidism	Asymptomatic; clinical or diagnostic observations only; intervention not indicated	Symptomatic; thyroid replacement indicated; limiting instrumental ADL	Severe symptoms; limiting self care ADL; hospitalization indicated	Life-threatening consequences; urgent intervention indicated	Death
Hypophisitis	Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated	Moderate; minimal, local or noninvasive intervention indicated; limiting age- appropriate instrumental ADL	Severe or medically significant but not immediately life- threatening; hospitalization or prolongation of existing hospitalization indicated; limiting self care ADL	Life-threatening consequences; urgent intervention indicated
Hypophisitis					Death
Acute Kidney Injury			Hospitalization indicated	Life-threatening consequences; dialysis indicated	Death

Death

NEUROLOGICAL ALTERATIONS

ENCEPHALOPATHIES

Authors: Alexandra Guedes, Helena Guedes, Rafael Matias and Henrique Costa

Definition and Etiology

Encephalopathy refers to an acute cerebral dysfunction in the absence of primary structural brain disease and can lead to clinical delirium, decreased level of consciousness or even coma.

Symptoms

Symptoms may range from apathy, impaired attention, memory loss and temporospatial disorientation to agitation and psychosis. Patients may also suffer from headaches, nausea and vomiting, visual impairment, sleep disturbances, focal deficits, and seizures.

Etiology

In the cancer patient, four main etiological categories should be considered.

Metabolic. Metabolic derangements are the most common cause of altered levels of consciousness in cancer patients
Electrolyte disturbances such as hyponatremia (associated or not with the syndrome of inappropriate antidiuretic hormone secretion (SIADH)), hypercalcemia or hypomagnesemia place cancer patients at special risk for seizures.
Hypo- and hyperglycaemic syndromes, as well as renal and hepatic failure, are also possible causes for encephalopathy.
Nutritional deficiencies (especially folic acid and B-complex vitamins) are important in the oncological population, given the prevalence of malnutrition and chemotherapy induced nausea and vomiting.
Infectious. Infections are common in immunocompromised cancer patients. Seventy percent of patients with bacteraemia have neurological symptoms ranging from lethargy to coma and more than eighty percent have abnormalities on the electroencephalogram.
In a cancer patient presenting with fever, septic encephalopathy is one of the most common causes of CNS dysfunction
One must keep in mind that immunosuppressed cancer patients are susceptible to rare opportunistic infections with viruses (e.g., Herpes simplex (HSV) or JC virus reactivation resulting in progressive multifocal leukoencephalopathy), fungus (e.g., Cryptococcus spp or Aspergillus spp) or bacteria (e.g., Listeria spp or M. tuberculosis) causing meningoencephalitis.
Associated with treatment. Multiple treatment modalities can have neurologic complications, either from radiotherapy, surgical procedures, chemotherapy, or adjunctive medication.
Radiation-induced cognitive impairment represents a spectrum of severity; when administered to a large brain volume, radiation may cause acute encephalopathy within weeks to years. Acute injury develops during or immediately after radiation therapy, manifesting mainly by headache, nausea, and vomiting; it involves acute oedema, thus being steroid responsive. Early delayed injury occurs beyond a month and up to 6 months from completion of radiation therapy and fatigue or cognitive symptoms are more prominent. These changes are reversible, and improvement may also be seen with steroids. Late injury is associated with permanent irreversible leukoencephalopathy and cognitive impairment, resulting in severe dementia; very severe forms may be seen in patients treated with combination treatment such as methotrexate administered concomitantly with radiation. Nowadays, with WBRT being generally administered in fractions of ≤3 Gy, the risk has become very reduced.
Ifosfamide and high-dose methotrexate are both associated with a transient acute encephalopathy which resolves spontaneously within a few days.
Posterior reversible encephalopathy syndrome (PRES) is a clinic-radiological syndrome characterised by headache, seizures, altered mental status and visual impairment associated with the presence of white matter vasogenic oedema affecting the parieto-occipital lobes on RMN. Besides uncontrolled hypertension and preeclampsia/ eclampsia, several chemotherapy and immunosuppressant drugs have been implicated, including platinum-based agents, VEGF inhibitors or cyclosporine. If recognized and treated early, the clinical syndrome commonly resolves within 1-2 weeks.

Evidence Level Grade PMID Nº

-Finally, support therapies may also be associated with some degree of neurotoxicity. Opioids, for example, may cause neurological disturbances raging from mild confusion to Evidence

hallucinations, delirium, and seizures. This is more likely to occur when using opioids with active metabolites, such as codeine or morphine, and usually develops within days to weeks after introducing the medication.

Diagnostic Approach

Acomprehensive initial evaluation should be carried out in order to identify possible precipitating factors.

Obtain the patient’s clinical history with corroboration from caretakers, medication review (check for recent changes in prescription), physical and neurological examination.
Biochemical blood work with renal function, electrolytes and hepatic panel with albumin and coagulation studies, glucose levels, thyroid function and vitamin status, namely B1, B12 and folate.
Ammonia levels if severe hepatic failure is suspected, although they can be within normal range.
Arterial blood gas analysis if there’s evidence of dyspnoea or abnormal chest exam.
In the presence of fever, look for white blood cell count, urinalysis and c-reactive protein and consider blood and urine cultures.
Rule out HIV infection.
All patients with suspected encephalitis require a lumbar puncture unless there is a significant contraindication (eg, risk of herniation on brain imaging); the analysis should include cell count and differential, protein, glucose, CSF/serum glucose ratio, albumin quotient, IgG index and synthesis rate, oligoclonal bands, broad viral studies including HSV1/2 PCR and varicella zoster virus (VZV) PCR and IgG/IgM and bacterial/fungal cultures when appropriate. Testing for neuronal autoantibodies associated with paraneoplastic autoimmune encephalopathy is recommended in case of high clinical suspicion, and these are tested in the patient’s serum and liquor. Keep in mind that its absence does not exclude the disease.
Being more accessible, order a head computed tomography scan (CT-scan) to quickly rule out space-occupying lesions and vascular complications, which may be part of the differential diagnosis. Perform Magnetic resonance imaging (MRI) to look for specific patterns. If PLE is suspected, look for signal hyperintensities on FLAIR or T2-weighted images in the medial temporal lobes; HSV encephalitis may have a similar appearance, but it characteristically spares the basal ganglia and frequently presents with haemorrhage. In PRES, both parietal-occipital lobes are characteristically enhanced. In cases of PCD, MRI may reveal cerebellar atrophy months after the symptom onset.
EEG to check for specific patterns of activity, especially in the presence of negative MRI findings or epileptic activity. Look for sharp and slow waves in PLE, triphasic waves in metabolic encephalopathies or delta brushes in NMDAR encephalitis.
If an autoimmune paraneoplastic syndrome is suspected at patient presentation, initial cancer screening with CT of the chest, abdomen and pelvis with contrast is a reasonable approach given its lower cost compared with FDG-PET.

Therapeutic Strategy

Level Grade PMID Nº

Medication or therapy withdrawal in patients undergoing treatment with drugs associated with encephalitis.

Bisphosphonates (such as i.v. zoledronic acid) to control severe hypercalcaemia.

Discontinuation of contributing medications, fluid restriction and adequate oral salt intake for the management of confirmed SIADH. Patients with severe hyponatraemia may require controlled slow correction of sodium levels to avoid central pontine myelinolysis.

Magnesium replacement is recommended for the management of hypomagnesaemia.

Methylene blue is not recommended for the prevention and treatment ofIfosfamide-induced acute encephalopathy.

In cases of PRES, cessation of anticancer therapy and adequate blood pressure control is paramount, with antiepileptic treatment in case of seizures.

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Start empiric CNS doses of intravenous acyclovir and standard coverage for bacterial meningitis (consider including ampicillin to cover for Listeria monocytogenes according to the patient’s immunological status) until infectious causes are ruled out. These can later be discontinued if CS F bacterial and viral studies return negative.

Once infection is ruled out based on CSF results, start acute immunotherapy with high dose corticosteroids for suspected autoimmune encephalitis. It is impractical and potentially hazardous to delay immunotherapy while awaiting antibody confirmation.

If there is no clinical, radiological or electrophysiological improvement by the end of the initial treatment cycle, add IVIG or plasma exchange.

Consider starting with a combination therapy from the beginning (as opposed to sequentially) in patients with severe initial presentation.

Pharmacotherapy for suspected autoimmune encephalitis

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Evidence Level Grade PMID Nº

Intravenous methylprednisolone: 1 g per day for 3 –7 days.

Intravenous Ig (IVIg): 2 g/kg over 2 –5 days.

Plasma exchange: 5 –10 sessions every other day.

References:

Jordan, B., Margulies, A., Cardoso, F., Cavaletti, G., Haugnes, H., Jahn, P., le Rhun, E., Preusser, M., Scotté, F., Taphoorn, M., & Jordan, K. (2020). Systemic anticancer therapy- induced peripheral and central neurotoxicity: ESMO–EONS–EANO Clinical Practice Guidelines for diagnosis, prevention, treatment and follow-up. Annals of Oncology, 31(10), 1306–1319. https://doi.org/10.1016/j.annonc.2020.07.003
Bush, S., Lawlor, P., Ryan, K., Centeno, C., Lucchesi, M., Kanji, S., Siddiqi, N., Morandi, A., Davis, D., Laurent, M., Schofield, N., Barallat, E., & Ripamonti, C. (2018). Delirium in adult cancer patients: ESMO Clinical Practice Guidelines. Annals of Oncology, 29, iv143–iv165. https://doi.org/10.1093/annonc/mdy147
Abboud, H., Probasco, J. C., Irani, S., Ances, B., Benavides, D. R., Bradshaw, M., Christo, P. P., Dale, R. C., Fernandez-Fournier, M., Flanagan, E. P., Gadoth, A., George, P., Grebenciucova, E., Jammoul, A., Lee, S. T., Li, Y., Matiello, M., Morse, A. M., Rae-Grant, A., Titulaer, M. J. (2021). Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. Journal of Neurology, Neurosurgery & Psychiatry, 92(7), 757–768. https://doi.org/10.1136/jnnp-2020-325300
Dalmau, J., & Rosenfeld, M. R. (2008). Paraneoplastic syndromes of the CNS. The Lancet Neurology, 7(4), 327–340. https://doi.org/10.1016/s1474-4422(08)70060-7
1. WAKEFULNESS-SLEEP RHYTHM DISTURBANCES

Authors: Sérgio Costa Monteiro and Andreia do Carmo Lopes

Definition

- - Circadian rhythm sleep-wake diseases are a class of sleep disorders caused by alterations of the circadian time-keeping system, its mechanisms, or a misalignment of the endogenous circadian rhythm and the external environmental. These are characterized by a desynchrony between the internal circadian timing system and desired sleep-wake times or an alteration in the timing system itself. (1,2)
  - The prevalence rates of nocturnal sleep-wake disturbances range from 31%–75% in cancer patients. (3)
  - In circadian rhythm sleep-wake disorders, the timing of primary sleep episode is either earlier or later than desired, irregular from day-to-day, and sleep occurs at the wrong circadian time. (4)
  - Pathophysiology: The suprachiasmatic nucleus (SCN) is a central circadian pacemaker. The disease can occur at the level of input to the SCN or within the SCN itself, resulting in reduced amplitude or mistiming of rhythms. (4)

Symptoms and signs Evidence

- - Insomnia.
  - Excessive sleepiness.

Etiology

- - Cancer related factors: Pain. Activity-rest. Hormone secretion. Cytokine production. Nervous central system tumors. Cancer treatments. (2, 5)
  - Predisposing factors: Female gender. Older age. Hyperarousability as a trait. Personal or family history. Mood or anxiety disorders. Poor sleep hygiene. Caffeine intake. Alcohol intake. Smoking. (2, 5)
  - Precipitant factors: Cancer treatments that alter levels of inflammatory cytokines or disrupt circadian rhythms or sleep-awake cycles. Side-effects of cancer treatment.
  - Menopausal symptoms. Hospitalization. Distress in response to cancer diagnosis. Co-occurring symptoms (e.g., pain or fatigue). Medications. (2, 5)
  - Perpetuating behavioural factors: Excessive daytime sleeping, long-term use of medications or use of inappropriate medications. Maladaptive cognitions. (2, 5)
  - Side effects of cancer treatment that affect the sleep-wake cycle include Pain. Anxiety. Night sweats/hot flashes. Gastrointestinal disturbances (e.g., incontinence, diarrhoea, constipation, or nausea). Genitourinary disturbances (e.g., incontinence, retention, or irritation). Respiratory disturbances. Fatigue. (2, 5)

Studies

- - Clinical interview: Surveys (Pittsburgh Sleep Quality Index. Epworth Sleepiness Scale. Insomnia. Severity Index. Stop-Bang. Brief Fatigue Inventory.). Characterization of sleep. Documentation of predisposing factors. Evaluation of emotional status. Assessment of exercise, activity levels and diet. Medical history. Current medication (e.g., Opiate. Sedative-hypnotics. Stimulant. Anti-epileptic.). (1,2,3)
  - Complete physical examination. (1,2,3)
  - Laboratorial studies: Anaemia. Hypothyroidism. Electrolyte abnormalities. Ferritin level. (1,2,3)
  - Collection of salivary dim light melatonin onset: Time-consuming. Expensive. Lacks established guidelines for normal values. (6,7)
  - Urinary 6-sulfatoxy melatonin (a metabolite of melatonin) measurement at 24 hours urine sample to assess circadian pattern. (8)

Diagnosis

- - Complaint of insomnia, excessive sleepiness, or both. (1,2,4)
  - Disruption of the normal circadian sleep-wake cycle. (1,2,4)
  - At least two of the following symptoms:
Decreased daytime performance. (1,2,4)
Altered appetite and gastrointestinal function. (1,2,4)
An increase in the nocturnal awakening. (1,2,4)
General malaise. (1,2,4)
- - Polysomnography and the multiple sleep latency test demonstrate loss of a normal sleep-wake pattern evidence. (2,4)

Pharmacotherapy

DRUG

POSOLOGY

Melatonin receptor agonist (MRA) a

Ramelteon Tasimelteon

–

8 mg

0.5-10 mg

Melatonin

2 mg

- - These agents do not treat difficulties staying asleep but also carry much less risk of cognitive/motor impairments and dependence. (3) Taken one hour prior to desired bedtime. (4)

Level Grade PMID Nº

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Therapeutic Strategy (4, 9, 10)

Bright light therapy

Exogenous melatonin

Chronotherapy

Motivational enhancement (to improve adherence)

Sleep hygiene

Hypnotic medication is not recommended

Encourage exercise on regular basis.

Encourage to have healthy dietary habits. Maintain a normal weight. Avoid alcohol (< 30 mL/day) and tobacco use.

References:

(1)Goldstein, C. Overview of circadian sleep-wake ehythm disorders. UpToDate. Literature review current through: Jul 2022. Topic last uptadet: May 12, 2022. Acessed August 08, 2022.

2)American Academy of Sleep Medicine: The International Classification of Sleep Disorders: Diagnostic & Coding Manual. 2nd ed. American Academy of Sleep Medicine, 2005. 3)Sleep Disorders (PDQ®) – Health Professional Version. https://www.cancer.gov/about-cancer/treatment/side-effects/sleep-disorders-hp-pdq. AcessedAugust 08, 2022.

Duffy JF., et al.. (2021) Workshop report. Circadian rhythm sleep-wake disorders: gap and opportunities. Sleep. 44(5). (PMID 33582815)
Clark J., et al. (2004) Sleep-Wake Disturbances in People With Cancer Part II: Evaluating the Evidence for Clinical Decision Making. Oncology Nursing Forum. 31(4) (6)Pullman RE, et al. (2012) Laboratory validation of an in-home method for assessing circadian phase using dim light melatonin onset (DLMO). Sleep Medicine. 13(6):703-706 (7)Burgess HJ, et al. Home dim light melatonin onsets in delayed sleep phase disorder. Journal of Sleep Research. 25(3):314-317
Flynn-Evans EE, et al. (2014) Circadian Rhythm disorders and melatonin production in 127 blind women with and without light perception. Journal of Biological Rhytms. 29(3):215- 224.
Auger R., et al. (2015) Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015. An American Academy of Sleep Medicine Clinical Practice Guideline. Journal of Clinical Sleep Medicine. 11(10): 1199-1236. (PMID 26414986)
Morgenthaler TI., et al. (2007) Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 30(11): 1445-1459.

Evidence Level Grade PMID Nº

IV C 26414986

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INSOMNIA

Authors: Tânia Duarte and Luísa Leal da Costa

Definition

ISBN 9780415375306

Sleep is an essential circadian process for the physical and psychological recovery of individuals. Insomnia is a subjective experience that can be defined, based on the International Classification of Sleep Disorders, 3rdedition (ICSD-3), as difficulty in falling asleep (initial insomnia), difficulty in staying asleep with prolonged nocturnal awakenings (middle insomnia), early-morning awakening with the inability to resume sleep (terminal insomnia), or the complaint of non-restorative or poor-quality sleep. Cancer-related insomnia (CRI) occurs in 19% to 63% of patients and is twice as prevalent as in the general population.

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Etiology

There are cancer-specific precipitating factors that lead to insomnia, whereas others may affect anyone in the healthy population. Etiologic factors in cancer-related insomnia are:

- Predisposing factors: older age, female, familial or personal history of insomnia, psychiatric disorders and/or hyperarousability trait.

ISBN 9780415375306

Evidence Level Grade PMID Nº

2414259

- Precipitating factors: bone marrow transplantation, psychiatric disorders, acute distress related to cancer/treatment, concomitant cancer symptoms (pain, fatigue, delirium), mutilating surgery (aesthetic or functional impairment), hospitalization, radiotherapy, chemotherapy, hormonal fluctuations, tumours that increase corticosteroid production, symptoms from tumour invasion and/or medications antidepressants (SSRIs), antiemetics (prochlorperazine, metoclopramide), corticosteroids (dexamethasone), hormonal therapy (tamoxifen, leuprolide), opioids, sedatives, hypnotics, neuroleptics, diet supplements (caffeine).
- Perpetuating factors: maladaptive behaviours (excessive amount of time spent in bed, irregular sleep-wake schedule, engaging in sleep interfering activities in the bedroom) and/or faulty beliefs and attitudes (unrealistic sleep expectations and faulty appraisals of sleep difficulties).

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Symptoms

7ISBN 978-1-4419-1225-1

- The most common consequences of CRI are fatigue and excess daytime sleepiness. Other adverse outcomes of CRI include impaired cognitive and psychomotor skills, such as difficulties in sustained attention, working memory, memory retention, decision making and hand–eye coordination, secondary anxiety and depression. These can affect daytime function and quality of life, decreasing work productivity and increasing treatment costs and substance abuse.

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Diagnostic/Assessment

ISBN 9780415375306

- Insomnia is a complex pathology. No single parameter has been validated for screening insomnia in the general population or in cancer patients. The nature, history and severity of CRI must be determined.

2-week sleep diaries are used as subjective measures, but they may overestimate insomnia. Two validated questionnaires for screening insomnia in cancer patients are the Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index Sleep.

There are also two tools for objective sleep measurement: polysomnography (PSG) and actigraphy, although none of them has a good correlation with subjective measures.

Therapeutic Strategy

12,13Survivorship and Palliative Care Guidelines NCCN 2022

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Assess for and treat contributing factors: pain, depression, anxiety, delirium, and nausea.

Based on evidence, Cognitive Behavioural Therapies for Insomnia (CBT-I) is the preferred first -line treatment for CRI.

Pharmacotherapy should only be used after all other methods have been deemed unsuccessful or have failed.

At end of life, assess patient´s desire to have insomnia and sedation treated .

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Nonpharmacologic Treatments Evidence

Level Grade PMID Nº

12,13Survivorship and Palliative Care Guidelines NCCN 2022, 14PMID: 23008320

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Therapy	Goal	Procedure
CBT-I	Combination of cognitive therapy, behavioural interventions (stimulus control therapy and sleep restriction therapy) and education (sleep hygiene), with or without relaxation therapy
Stimulus control therapy	Establish a regular sleep -wake rhythm	Go to bed when sleepy/tired, when unable to fall asleep get out of bed; wake up at the same time every morning; no napping during the day
Sleep restriction therapy	Improve sleep continuity and efficiency	Restrict the time in bed to sleep time, then gradually increasing time in bed as sleep efficiency improves
Sleep hygiene therapy	Change health practices and environmental factors that interfere with sleep	Keep a regular schedule; exercise regularly but not too late in the evening; do not eat heavy/spicy meal before bedtime; avoid stimulants or alcohol near bedtime; maintain a quiet and dark sleep environment
Cognitive therapy	Changing dysfunctional attitudes and beliefs about sleep	Identify sleep cognitive distortions; challenge validity of the sleep misconceptions; reframe dysfunctional cognition into more adaptive thoughts
Relaxation training	Reducing tension or levels of arousal interfering with sleep	Progressive muscle relaxation, guided imagery, abdominal breathing, hypnosis, biofeedback, meditation
Exercise/Yoga

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Pharmacotherapy Evidence

Level Grade PMID Nº

12,13Survivorship and Palliative Care Guidelines NCCN 2022, 16PMID 27136449, 21PMID 28875581

Drug	Dose	Notes
Benzodiazepine Recep	tor Agonists
Zolpidem	5-15 mg PO at bedtime	Rapid onset of action; short -intermediate duration of action; helps with sleep initiation; short-term or periodic use
Zolpidem CR	12.5 mg PO at bedtime	Rapid onset of action; intermediate -long duration of action; indicated for sleep initiation and maintenance; short -term or periodic use
Benzodiazepines
Temazepam	7.5-30 mg PO at bedtime	Intermediate onset of action; intermediate duration of action; indicated for sleep initiation and maintenance; short -term or periodic use
Lorazepam	0.5-1 mg PO at bedtime	Intermediate onset of action; intermediate duration of action; indicated for sleep initiation and maintenance; short -term or periodic use
Antipsychotics
Quetiapine	12.5-25 mg PO	Indicated for patients with concomitant bipolar disorder or depression
Melatonin Receptor Agonist
Ramelteon	8 mg PO 30 min before bedtime	Rapid onset of action; short duration of action; helps with sleep initiation
Melatonin	3-20 mg PO 30 min before bedtime	Helps with sleep initiation and improves sleep quality
Antidepressants
Trazodone	25-150 mg PO	Onset of action: 0.5h -2h; duration of action: 8h; indicated for sleep maintenance; short-term use
Mirtazapine	7.5-30 mg PO	Onset of action: 1.2 -1.6h; duration of action: 20 -40h; indicated for patients with concomitant anxiety or anorexia
Doxepin	3-6 mg PO 30 min before bedtime	Indicated for sleep initiation and maintenance; short -term use

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Evidence Level Grade PMID Nº

References:

Catane R et al. ESMO Handbooks: ESMO Handbook of Advanced Cancer Care (European Society for Medical Oncology Handbooks, Volume 1, CRC PRESS, 2005
Davis MP, Khoshknabi D, Walsh D, Lagman R, Platt A. Insomnia in patients with advanced cancer. Am J Hosp Palliat Care. 2014 Jun;31(4):365-73
Ito E, Inoue Y. The International Classification of Sleep Disorders, third edition. American Academy of Sleep Medicine. Nihon Rinsho. 2015 Jun;73(6):916-23. 4.Induru RR, Walsh D. Cancer-related insomnia. Am J Hosp Palliat Care. 2014 Nov;31(7):777-85
Savard J, Morin CM. Insomnia in the context of cancer: a review of a neglected problem. J Clin Oncol. 2001 Feb 1;19(3):895-908
Jafari-Koulaee A, Bagheri-Nesami M. The effect of melatonin on sleep quality and insomnia in patients with cancer: a systematic review study. Sleep Med. 2021 Jun;82:96- 103
Olver IN. The MASCC Textbook of Cancer Supportive Care and Survivorship, Multinational Association for Supportive Care in Cancer Society, 2011
Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213
Beck SL, Schwartz AL, Towsley G, Dudley W, Barsevick A. Psychometric evaluation of the Pittsburgh Sleep Quality Index in cancer patients. J Pain Symptom Manage. 2004 Feb;27(2):140-8
Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001 Jul;2(4):297-307 11.Savard MH, Savard J, Simard S, Ivers H. Empirical validation of the Insomnia Severity Index in cancer patients. Psychooncology. 2005 Jun;14(6):429-41 12.Sanft T et al. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines), Survivorship, 2022 Mar
Dans M et al. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines), Palliative Care, 2022 Mar
Pachman DR, Barton DL, Swetz KM, Loprinzi CL. Troublesome symptoms in cancer survivors: fatigue, insomnia, neuropathy, and pain. J Clin Oncol. 2012 Oct 20;30(30):3687-96
Nzwalo I, Aboim MA, Joaquim N, Marreiros A, Nzwalo H. Systematic Review of the Prevalence, Predictors, and Treatment of Insomnia in Palliative Care. Am J Hosp Palliat Care. 2020 Nov;37(11):957-969
Qaseem A et al. Clinical Guidelines Committee of the American College of Physicians. Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016 Jul 19;165(2):125-33
Johnson JA, Rash JA, Campbell TS, Savard J, Gehrman PR, Perlis M, Carlson LE, Garland SN. A systematic review and meta-analysis of randomized controlled trials of cognitive behavior therapy for insomnia (CBT-I) in cancer survivors. Sleep Med Rev. 2016 Jun;27:20-8. doi: 10.1016/j.smrv.2015.07.001. Epub 2015 Aug 1. PMID: 26434673. 18.Sprod LK, Palesh OG, Janelsins MC, Peppone LJ, Heckler CE, Adams MJ, Morrow GR, Mustian KM. Exercise, sleep quality, and mediators of sleep in breast and prostate cancer patients receiving radiation therapy. Community Oncol. 2010 Oct;7(10):463-471
Lin PJ et al. Influence of Yoga on Cancer-Related Fatigue and on Mediational Relationships Between Changes in Sleep and Cancer-Related Fatigue: A Nationwide, Multicenter Randomized Controlled Trial of Yoga in Cancer Survivors. Integr Cancer Ther. 2019 Jan-Dec;18:1534735419855134.
Kwak A, Jacobs J, Haggett D, Jimenez R, Peppercorn J. Evaluation and management of insomnia in women with breast cancer. Breast Cancer Res Treat. 2020 Jun;181(2):269-277
Riemann D et al. European guideline for the diagnosis and treatment of insomnia. J Sleep Res. 2017 Dec;26(6):675-700
1. MYELOPATHIES

Author: Marcos Dumont Bonfim Santos, Pedro Miguel Antunes Meireles and Tomás Dinis

Symptoms and signs

Back pain.
Motor findings (weakness; paraplegia)
Sensory findings
Sphincter dysfunction (bladder and bowel dysfunction)
Ataxia
Cauda equina syndrome daytime function and quality of life, decreasing work productivity and increasing treatment costs and substance abuse.

Etiology

Vascular: ischemic; haemorrhagic.
Previous treatment: radiation induced; chemotherapy (cytarabine, methotrexate, cisplatin, carmustine, thiotepa)
Infectious: Epstein-Barr virus, varicella zoster virus, cytomegalovirus, herpes simplex virus, huma herpesvirus 6.
Paraneoplastic
Primary spinal cord tumours
Secondary to cancer: metastatic (spinal cord compression, intramedullary; leptomeningeal, intravascular).

Studies

Myelopathies are neurological complications of cancer. Several causes may be associated, from metastatic neoplasms to infectious causes. The treatment decision must be individualized. Magnetic Resonance is an allied exam in the definition of severity and whenever possible it should be requested.
Assessment of cord instability, cancer histology, and radiosensitivity assessment will guide treatment decisions about initial surgery, radiation, and/or systemic therapy.
Radiosensitive tumours are lymphoma, myeloma, small cell lung cancer, germ cell tumours, prostate, and breast cancer. Radioresistant tumours are melanoma, renal cell carcinoma, non-small cell lung cancer, gastrointestinal cancers, and sarcoma.

Pharmacotherapy

Initial 10 mg intravenous bolus of dexamethasone followed by 16 mg daily.

Venous thromboembolism prophylaxis

Therapeutic Strategy

Evidence Level Grade PMID Nº

24142594

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Definitive treatment includes the degree of neurologic compromise, the oncologic characteristics of the primary tumour , the mechanical stability of the spine, and the systemic burden of cancer and medical comorbidities (the Neurologic, Oncologic, Mechanical, Systemic [NOMS] framework)

Surgery in case of patients with unstable spine and radioresistant tumours .

Radiotherapy (includes radiosensitive tumours ).

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References: Evidence

Metastatic Spinal Cord Compression and Steroid Treatment: A Systematic Review.Kumar A, Weber MH, Gokaslan Z, Wolinsky JP, Schmidt M, Rhines L, Fehlings MG, Laufer I, Sciubba DM, Clarke MJ, Sundaresan N, Verlaan JJ, Sahgal A, Chou D, Fisher CG .Clin Spine Surg. 2017;30(4):156.

The NOMS framework: approach to the treatment of spinal metastatic tumors.Laufer I, Rubin DG, Lis E, Cox BW, Stubblefield MD, Yamada Y, Bilsky MH.Oncologist. 2013;18(6):744. Epub 2013 May 24.

8Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial.Maranzano E, Trippa F, Casale M, Costantini S, Lupattelli M, Bellavita R, Marafioti L, Pergolizzi S, Santacaterina A, Mignogna M, Silvano G, Fusco V .Radiother Oncol. 2009;93(2):174.

Effectiveness of radiation therapy without surgery in metastatic spinal cord compression: final results from a prospective trial.Maranzano E, Latini P .Int J Radiat Oncol Biol Phys. 1995;32(4):959.

Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial.Patchell RA, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ, Mohiuddin M, Young B .Lancet. 2005;366(9486):643.

Local disease control for spinal metastases following “separation surgery” and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients.Laufer I, Iorgulescu JB, Chapman T, Lis E, Shi W, Zhang Z, Cox BW, Yamada Y, Bilsky MH .J Neurosurg Spine. 2013 Mar;18(3):207-14. Epub 2013 Jan 22.

Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial.Maranzano E, Bellavita R, Rossi R, De Angelis V, Frattegiani A, Bagnoli R, Mignogna M, Beneventi S, Lupattelli M, Ponticelli P, Biti GP, Latini P.J Clin Oncol. 2005;23(15):3358.

incidence and risk factors for preoperative deep venous thrombosis in 314 consecutive patients undergoing surgery for spinal metastasis. Zacharia BE, Kahn S, Bander ED, Cederquist GY, Cope WP, McLaughlin L, Hijazi A, Reiner AS, Laufer I, Bilsky M .J Neurosurg Spine. 2017;27(2):189. Epub 2017 Jun 2.

Level Grade PMID Nº

5.5 PERIPHERAL AND CRANIAL NERVE NEUROPATHY

Authors: Ema Neto and Sandra Silva and Helena Guedes

Symptoms

Peripheral neuropathy: The most common manifestation is neuropathic pain that might be associated with balance disturbance, difficulty in fine motor skills and muscle weakness. Autonomic features (including mottled skin, sweating, redness and swelling) can also be present.
Cranial neuropathy: Less common. Clinical manifestations may suggest specific cranial nerves involvement. Can be associated with neuropathic pain and neurologic symptoms. Clinical manifestations that may elucidate for specific cranial nerve involvement include: 1) Oculomotor, trochlear or abducens nerve – Diplopia 2) Trigeminal nerve – Facial pain, paraesthesia, and numbness 3) Facial nerve – Weakness of upper face (i.e. difficulty closing the eye completely, decreased eyebrow raise) and the lower face facia

4) Cochlear nerve – Unilateral or bilateral sensorineural hearing loss 5) Lower cranial nerves – Dysarthria, dysphagia, or hoarseness The symptoms can last from months to years after the insult and can lasts beyond expected period of healing

Neuropathic cancer pain (NCP): Usually chronic, either persisting continuously or characterised by recurrent painful episodes of hypersensitivity (dysesthesia/paraesthesia, allodynia, and hyperalgesia) and/or hyposensitivity symptoms (hypoesthesia and hypoalgesia). Anaesthesia dolorosa (pain felt in an anaesthetic/numb area or region) may also be present. NCP is divided into several categories including plexopathy, radiculopathy, peripheral neuropathy, paraneoplastic sensory neuropathy, leptomeningeal metastasis, cranial

neuralgia, and malignant painful radiculopathy.

Chemotherapy-induced peripheral neuropathy (CIPN): Sensory symptoms are usually symmetrically distributed in the distal fingers or toes (glove-stocking distribution). The symp- toms range from early post-treatment pain to chronic peripheral sensory neuropathy. Typically, symptoms begin in the first two months of treatment, worsen as treatment progresses and then stabilise soon after cessation, but it can persist for several months to years, even after discontinuation of chemotherapy, and may never be eliminated.

Neurologic Symptoms: Headache accompanied with nausea, vomiting and dizziness ((increased intracranial pressure) with or without neck pain or stiffness exacerbated by head movements (meningeal irritation); altered mental status (confusion, forgetfulness, disorientation, subtle personality changes, and/or lethargy), seizures and other neurologic symptoms can also be present.

Etiology

Can be secondary to direct invasion, compression, or lesion of components of the central or peripheral somatosensory nervous system caused by the primary tumour or metastases, treatment (chemotherapy, surgery, and radiotherapy), paraneoplastic syndrome, and comorbidities such as diabetic polyneuropathy and postherpetic neuralgia.

Cranial neuropathies are less common than peripheral. They can be secondary to nerve compression due to high intracranial pressure, related to intracranial primary tumours or metastasis (including leptomeningeal carcinomatosis) but also consequence of nerve lesion caused by surgery, radiotherapy, or chemotherapy.

Many chemotherapeutic agents can cause peripheral (CIPN) and central neuropathy. The most common are platinum agents (cisplatin, oxaliplatin, and carboplatin), taxanes (taxol and docetaxel), vinca alkaloids (vincristine and vinorelbine), thalidomide and proteasome inhibitors (bortezomib). CIPN is usually a dose-dependent and cumulative side- effect.

Paraneoplastic neurological syndromes can also occur, resulting from remote effects of cancer mediated by the immune system. The most frequent paraneoplastic neurological syndromes are paraneoplastic cerebellar degeneration and sensory neuronopathy.

Studies

Anamneses
1. Evaluate pre-existing neuropathy, neurological disease or muscle spasticity from disorders of the motor system
2. Evaluate the presence of conditions that predispose to neuropathy such as diabetes and/or a family or personal history of hereditary peripheral neuropathy
3. Collect information about cancer treatment history and comorbid conditions, psychosocial and psychiatric history (including substance use)
In case of painful neuropathy
1. Initial comprehensive pain assessment that should include pain descriptors, associated distress, functional impact, and related physical, psychological, social, spiritual factors and prior treatments for the pain.
2. Evaluate the probability of neuropathic pain – IASP – NeuPSIG grading system
3. Screening and assessment questionaries – LANSS, DN4, PDQ, NPS and NPSI
Physical exam including full neurological examination
Confirmatory tests (generally limited to specialist context) – electrophysiological studies, quantitative sensory testing (QST) and evaluation of intraepidermal nerve fibres (IENFs) via skin biopsy.
Other exams – particularly in case of cranial nerve involvement and neurologic symptoms – TC and MRI; lumbar puncture and liquor analysis; Neurology and/or Neurosurgery urgent evaluation (+++ if acute onset)

Evidence Level Grade PMID Nº

Therapeutic Strategy Evidence

Step 1 Evaluation and diagnosis

1.1. Evaluate pain and establish the diagnosis of peripheral or central neuropathy. If uncertain about the diagnosis, refer to a p ain specialist or neurologist

1. Identify and evaluate possible treatable causes of NP – high intracranial pressure, nerve compression, bone lesions, paraneoplastic syndrome – discuss the plan in a multidisciplinary team meeting or refer to urgent observation by the intervenient specialis t (surgeon, radio -oncologist, medical oncologist, other)
2. Identify relevant comorbidities ( e.g., cardiac, renal, or hepatic disease, depression, gait instability) that might be relieved or exacerbated by treatments, or that might require dose adjustment or additional monitoring of therapy.
3. Explain the diagnosis and treatment plan to the patient and stablish realistic expectations

Step 2 – Initiate Treatment

2.1 Initiate therapy for the primary cause of neuropathy, if appropriate – initiate treatment directed to cancer or its complications, including surgery, chemo and/or radiotherapy.

2.2. Initiate pharmacologic symptomatic treatment

2.2 Evaluate for non -pharmacologic treatments, and initiate if appropriate

Step 3 – Reassess symptoms and health -related quality of life frequently In case of neuropathic pain (NP):

3.1. If substantial pain relief ( e.g., average pain reduced to ≤ 3/10) and tolerable side effects – Continue treatment

1. If partial pain relief ( e.g., average pain remains 4/10) after an adequate trial – switch to an alternative first -line medication
2. If no or inadequate pain relief ( e.g., < 30% pain reduction) at target dose after an adequate trial – switch to an alternative first line medication;

Step 4 – If trials of first -line medications alone fail, consider second and third -line medications or referral to a specialist

Neuropathic pain in patients with active cancer – Patients with active cancer usually have mixed pain syndrome, involving both nociceptive and neu ropathic components – opioid analgesics or tramadol may be used alone or in combination with one of the first -line therapies (co -adjuvants). Consider optimizing analgesic treatment before adding a co -adjuvant. Cancer Survivors with no active disease usually present with treatment related neuropathic pain, which in most cases are purely

neuropathic in nature, and poorly responsive to opioids alone.

Localized peripheral neuropathic pain – Consider initiate treatment with topical analgesics alone +/ – one of the first -line medications.

Prevention chemotherapy induced peripheral neuropathy (CIPN) –Clinicians should assess the risks and benefits of agents known to cause CIPN among patients with underlying neuropathy and with conditions that predispose to neuropathy such as diabetes and/or a family or personal his tory of hereditary peripheral neuropathy. No drugs are available, with proven beneficial effects, for the prevention of CIPN. Clinicians should not offer, and should d iscourage use of, acetyl -L-carnitine for the

prevention of CIPN in patients with cancer

Chemotherapy – induced peripheral neuropathy (CIPN) management – Clinicians should assess, and discuss with patients, the appropriateness of dose delaying, dose reduction, or stopping chemotherapy (or substituting with agents that do not cause CIPN) in patients who develop intolerable neuropathy and/or functional nerve

impairment during treatment. For patients with cancer experiencing painful CIPN, clinicians may offer Duloxetine.

Cranial neuropathies and/or neurologic symptoms – Due to its association with potentially fatal and irreversible conditions, including intracranial high pressure and permanent loss of vision and/or audition, patients should be promptly evaluated (urgent if acute onset of de novo symptoms), and the symptoms managed by a multidisciplinary team including a neurologist and/or neurosurgeon. Corticoids might be helpful if the symptoms are secondary to intracranial high pressure and

compression.

Trigeminal and glossopharyngeal neuropathy – For patients with cancer experiencing painful neuropathy, first option is Carbamazepine.

IV	C	20402746
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II	A	30860637

Level Grade PMID Nº

Pharmacotherapy for neuropathic cancer pain (NCP) Evidence

Level Grade PMID Nº

Except for CIPN, best practices in the management of cancer-related neuropathic pain are generally extrapolated from guidelines developed for chronic noncancer conditions. Recovery requires several months to years, even after recovery from injury.

Local analgesics Alone or in combination with systemic agents for focal peripheral neuropathy

First Line

– Lidocaine 5% Dose:1-3 plasters 12h/day.

Second – Line Capsaicin 8% Dose: 1 – 4 patches/ 3 months; Available in a limited number of pain units;

–

Botulinum toxin A Dose: 50 300 U/3 months; Available in a limited number of pain units;

Third Line Capsaicin ≤0,1% Topical application

Lidocaine i.v Dose: 3 – 7,5 mg/kg (usually 5mg/kg) over 30-60 minutes, once a week for 4 weeks;

Systemic analgesics

First-Line

Analgesic antidepressants Consider as first option in patients who suffer from depression; Duloxetine appears safer and more effective over TCA’s.

Tricyclic Antidepressants Initial dose: 10-25mg once nightly; Increasing dose: 25mg every 5 -7 days, if tolerated; Target dose: 150 – 300 mg nightly; Nortriptyline, Desipramine, Analgesia typically appears within a week of starting dose.

Amitriptyline, Imipramine

Serotonin – Norepinephrine Reuptake Inhibitors (SNRI’s)

Duloxetine

Duloxetina is preferable over Venlafaxine (more high-quality trials yielding positive results; Duloxetine is the only considered Venlafaxine a first line option in 2018 ESMO guidelines)

Analgesic antiepileptics Initial dose: 30 mg once daily; Increasing dose: 30mg per week, if tolerated; Target dose: 60- 120 mg once daily. First option in CIPN.

Gabapentin Initial dose: 37,5 mg once daily; Increasing dose: 37,5mg per week, if tolerated; Target dose: 75 – 225mg daily.

Gabapentin is preferable over Pregabalin (most recent high-quality trials have yielded negative results, with a balance between efficacy and adverse effects lower for pregabalin than that for gabapentin, based on a high-quality comparative trial)

Pregabalin

Initial dose: 100-300mg once nightly; Increasing dose: Dose increments of 50-100% every 3 days and dose frequency to 2- times a day; Target dose: 900-3600 mg daily in divided doses 2-3 times a day.

Initial dose: 25 mg once nightly; Increasing dose: Dose increments of50-100% every 3 days and dose frequency to 2-3 times a day; Maximum dose: 600 mg daily in divided doses 2-3 times a day.

31390582

29929349

I-II B

I B

II C

I-II C

I A

32276788

31390582

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25575710

32276788

25575710

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30052758

31390582

30884837

32276788

17920770

32276788

31390582

30884837

32663120

30052758

31390582

I B-C

I A

30884837

32276788

32663120

32276788

31390582

30884837

32276788

17920770

30052758

31390582

32276788

Evidence Level Grade PMID Nº

I A-B

IV B

II B

II C

25575710

30480345

34295184

30480345

34295184

17920770

30052758

34295184

17920770

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I C 30052758

34295184

II C

Second-Line

Weak Opioids

Tramadol Initial dose: 50 mg every 4 to 6 hours as needed Increasing dose: as needed and tolerated to 50 to 100 mg every 4 to h6ours; Maximum dose: 400 mg/day.

Strong Opioids Clinicians should assess the potential risks and benefits when initiating treatment that will incorporate lon-gterm use of opioids and incorporate a universal precautions approach to minimize abuse, addiction, and adverse consequences of opioid use such as opioid-related deaths, particularly in cancer survivor patients.

Morphine Initial dose: 5 to 30 mg every 4 hours as needed or scheduled around the clock. Titration: may increase the fixed scheduled dose by 30% to 100% of the total dose taken in the prior 24-hour period, while taking into consideration the total amount of rescue medication used; if pain score decreased, continue current effective dosing;To reduce risk of overdose, use caution when increasing opioid dosage to ≥50 MME/day and avoid increasing dosage to ≥90 MME/day.

Oxycodone Initial dose: 2.5 to 10 mg every 4 to 6 hours as needed or scheduled around the clock; Usual maintenance dosage range: 5 to 15 mg every 4 to 6 hours as needed or scheduled around the clock; Titration: Adjust dose according to patient response; if needed, increase the fixed scheduled dose by 30% to 100% of the total dose taken in the prior 24-hour period including total amount of rescue medication used; if pain score decreased and functional assessment improved, continue current effective dosing.

Fentanyl (Patches) Dose: 25-75µg/72h. Initial dose: ½ to 2/3 of the 24-hour morphine dosage equivalent; Titration: Do not titrate more frequently than every 3 days after the initial application or every 6 days thereafter. When increasing the dose, base the new doseon the daily requirement of supplemental opioids required by the patient during the second or third day of initial application.

Buprenorphine (Patches) Initial dose: 5 µg/hour applied once every 7 days. Titration: May increase dose in 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour increments (using no more than two patches), based on patient’s supplemental short -acting analgesic requirements, with a minimum titration interval of 72 hours. Maximum dose: 20 mcg/hour applied once every 7 days. Risk for QTc prolongation increases with doses >20 mcg/hour patch.

Combinations TCA/Duloxetine + Gabapentin TCA/Duloxetine + Opioids

II B

32276788

30052758

Evidence Level Grade PMID Nº

Third and Fourth Line In third – and fourth -line patients should be referred to a pain specialist or multidisciplinary pain centres. Pain management may include clinical trial with drugs with inconsistent results or lack of efficacy in major studies. Examples include other strong opioids (e.g. methadone and Tapentadol), cannabinoids (e.g. transmucosal nabiximols and oral THC), serotonin-selective reuptake inhibitors (e.g. citalopram, Esctialopram and paroxetine), dopamine reuptake inhibitors (e.g. Bupropion) and other convulsiveness (e.g. carbamazepine, ox carbamazepine, lamotrigine, locasamide and topiramate).

Dexamethasone

Initial dose: 10 or 16 mg i.v. followed by oral dosing of 16 mg/day (usually given in 2 to 4 divided doses). Once definitive treatment is underway, taper gradually over 1 to 2 weeks until discontinuation. Corticosteroids are not recommended for long-term use in cancer survivors solely to relieve chronic pain. Should be considered in case of nerve compression and palliative setting (refractory pain).

Carbamazepine

Initial: 200 to 400 mg/day, gradually increasing (eg, over several weeks) in increments of 200 mg/day as needed. Usual maintenance dose: 600 to 800 mg/day; maximum dose: 1.2 g/day; First line in trigeminal and glossopharyngeal neuralgia.

Intrathecal drug (i.t) delivery

Intraspinal techniques delivered and monitored by a skilled team should be included as part of the cancer pain management strategy. May be useful in patients with inadequate pain relief despite systemic opioid escalating

doses and appropriate adjuvant analgesia and non-effective response to switching the opioid or the route of administration, as well as when side effects increase because of dose escalation.

II C

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17920770

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30052758

Recommendations against use of certain drugs

Ketamine There is a lack of evidence to support the routine use

Levetiracetam There are strong recommendations against the use Mexiletine

Interventional treatments Interventional treatments of NP ((e.g. peripheral nerve or plexus blocks, transcutaneous electrical nerve stimulation (TENS), repetitive transcranial magnetic stimulation (rTMS), pulsed radiofrequency (PRF), percutaneous electrical nerve stimulation (PENS), conventional spinal cord stimulation (SCS), epidural adhesiolysis, long-wave diathermy and nerve decompression) are based on weak or inconclusive evidence and Should be restricted to patients with NP syndromes other than those related to cancer; Might be considerate in

refractory cancer pain, in case-by-case basis.

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Bennett MI, Eisenberg E, Ahmedzai SH, Bhaskar A, O’Brien T, Mercadante S, Krčevski Škvarč N, Vissers K, Wirz S, Wells C, Morlion B. Standards for the management of cancer-related pain across Europe-A position paper from the EFIC Task Force on Cancer Pain. Eur J Pain. 2019 Apr;23(4):660-668. doi: 10.1002/ejp.1346. Epub 2019 Jan 6. PMID: 30480345; PMCID: PMC7027571.

Loprinzi CL, Lacchetti C, Bleeker J, Cavaletti G, Chauhan C, Hertz DL, Kelley MR, Lavino A, Lustberg MB, Paice JA, Schneider BP, Lavoie Smith EM, Smith ML, Smith TJ, Wagner-Johnston N, Hershman DL. Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update. J Clin Oncol. 2020 Oct 1;38(28):3325-3348. doi: 10.1200/JCO.20.01399. Epub 2020 Jul 14. PMID: 32663120.

Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, Nurmikko T. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010 Sep;17(9):1113-e88. doi: 10.1111/j.1468-1331.2010.02999.x. Epub 2010 Apr 9. PMID: 20402746.

Haanpää M, Attal N, Backonja M, Baron R, Bennett M, Bouhassira D, Cruccu G, Hansson P, Haythornthwaite JA, Iannetti GD, Jensen TS, Kauppila T, Nurmikko TJ, Rice ASC, Rowbotham M, Serra J, Sommer C, Smi

5.6 DELIRIUM IN CANCER PATIENT

Authors: Ribeiro Alves, João Fonseca, André da Silva Ribeiro and Inês Guimarães Rento

Definition and Etiology

Delirium is an acute and confusional state of mind and represents a sudden and significant decline from a previous level of functioning, most of the time when an external stressor is superior to the cerebral reservoir5.
It´s very important to distinguish delirium from dementia. The main difference is that the last one has a very slow cognitive decline. However, it is not infrequent the coexistence of both since a certain degree of dementia increases the risk of delirium5.
Delirium can affect any person of any age5.
This dysfunction seems to gain importance in Palliative Units despite many times being underdiagnosed. Palliative patients develop delirium throughout all hospital admission from 13–42% on admission to 88% in the last weeks–hours of life7.
The diagnosis is based on the clinical history (more often near the family) and the physical examination. Complementary exams will not diagnose this condition; however, they can help find the cause of delirium5.
Some scales can help with the recognition of delirium; the Confusion Assessment Method (CAM) is one of them. When well applied, this scale has a specificity of 99% and a sensibility of 82% in the diagnosis of delirium. It is now approved to be used in palliative care units4. .

Evidence Level Grade PMID Nº

Symptoms and signs

Abnormal attention or arousal is the cardinal feature and means distractibility, inability to focus, drowsiness or semi-consciousness5,6.
It is marked by sudden onset, a fluctuating course, inattention, and often abnormal level of consciousness5,6.
There are three types of delirium:
Hypoactive: more common; the patient presents somnolent.
Hyperactive: the patient presents agitated.
Mixed: fluctuation between hypoactive and hyperactive.
Sleep disturbances and disruption in the circadian circle, disorientation, memory deficit, disturbances in language, visuospatial ability, or perception are frequent2.
Other prodromal features include irritability, anxiety, and restlessness2.

Etiology

Acommon risk factor model for delirium distinguishes predisposing from precipitating factors5.
Predisposing factors are chronic conditions that increase the patient’s vulnerability to develop delirium; these predisposing factors include pre-existing cognitive impairment, multiple comorbid conditions, polypharmacy, impaired sensation or functional ability5.
Precipitating factors are acute conditions that start delirium5; The mnemonic PINCH ME can be used to remember the main causes of delirium, as seen in figure 1.
The more predisposing factors the fewer precipitating factors are needed to develop delirium.

P	Pain
I	Infection
N	Nutrition
C	Constipation
H	Hydration
M	Medication
E	Environment

Figure 1 Mnemonics for Delirium’s precipitating factors

Therapeutic Strategy Evidence

Level Grade PMID Nº

Treat the underlying cause for delirium

Optimize sleep-wake pattern

Patient orientation

Avoid sensory deprivation (by restoring a patient’s glasses or hearing aid)

Monitor hydration and nutrition

Monitor bladder and bowel function

Encourage mobility

Stop or reduce, if possible, a medication that might increase the risk of developing delirium such as tricyclic

antidepressants, anticholinergic medications, benzodiazepines, antihistamines andopioid analgesics.

I	A	30927352
IIb	C	7922932
IIb	C	7922932
IIb	C	7922932
IIb	C	7922932
IIb	C	7922932
IIb	C	7922932
IIb	C	7922932

Pharmacotherapy

Nonpharmacologic interventions and treatment of underlying conditions are initial steps to prevent and manage delirium. The use of this medication should be for a short period as adjunctive use while addressing underlying causes of severe symptoms and if distressing symptoms, such as agitation, anxiety, and combative behaviour, are present. The lowest possible dose is recommended for these individuals.

Medication	Posology	Observations
Risperidone	Oral: 0.5 mg/day in 2 divided doses;	These should be carefully used when the patient has prolonged QTc on ECG and Parkinson’s Disease (risk for EPE).
Quetiapine	Oral: Initial: 25 mg at bedtime; may increase the dose gradually (e.g., weekly) based on response and tolerability up to 75 mg twice daily
Olanzapine	Oral: Initial: 1.25 to 5 mg once daily; titrate daily based on symptoms in 2.5 to 5 mg increments up to 20 mg/day
Haloperidol	IV, IM or oral: Initial: 0.5 to 1 mg; if needed, may repeat every 30 minutes until calm. Maximum 5 mg/day

IIa A 30927352

IIb A 30927352

IIa A 30927352

Chlorpromazine

IV: 12.5 mg every 4-12 hour

Rectal: 25 mg every 4-12 hour

Indicated in terminal cancer

patients

Benzodiazepine

Should not be used in nonspecific delirium.

These may increase the risk

of delirium.

Diazepam: 5 to 10 mg IV every 5 to 10 minutes, until the appropriate level of sedation is achieved.
If diazepam is unavailable, we

favour Midazolam for rapid symptom control.

These should be used in alcohol withdrawal and benzodiazepines withdraw

References:

AGS/NIA Delirium Conference Writing Group, Planning Committee and Faculty. The American Geriatrics Society/National Institute on Aging Bedside-to-Bench Conference: Research Agenda on Delirium in Older Adults. JAm Geriatr Soc. 2015 May;63(5):843-52. doi: 10.1111/jgs.13406. Epub 2015 Mar 31. PMID: 25834932; PMCID: PMC5407494.
Bush SH, Tierney S, Lawlor PG. Clinical Assessment and Management of Delirium in the Palliative Care Setting. Drugs. 2017 Oct;77(15):1623-1643. doi: 10.1007/s40265-017- 0804-3. PMID: 28864877; PMCID: PMC5613058.
Clegg A, Young JB. Which medications to avoid in people at risk of delirium: a systematic review. Age Ageing. 2011 Jan;40(1):23-9. doi: 10.1093/ageing/afq140. Epub 2010 Nov 9. PMID: 21068014.
Cole MG, Primeau FJ, Bailey RF, Bonnycastle MJ, Masciarelli F, Engelsmann F, Pepin MJ, Ducic D. Systematic intervention for elderly inpatients with delirium: a randomized trial. CMAJ. 1994 Oct 1;151(7):965-70. PMID: 7922932; PMCID: PMC1337283.
Davis D, Searle SD, Tsui A. The Scottish Intercollegiate Guidelines Network: risk reduction and management of delirium. Age Ageing. 2019 Jul 1;48(4):485-488. doi: 10.1093/ageing/afz036. PMID: 30927352.
Hasuo H, Kanbara K, Fujii R, Uchitani K, Sakuma H, Fukunaga M. Factors Associated with the Effectiveness of Intravenous Administration of Chlorpromazine for Delirium in Patients with Terminal Cancer. J Palliat Med. 2018 Sep;21(9):1257-1264. doi: 10.1089/jpm.2017.0669. Epub 2018 May 14. PMID: 29757064.
Holbrook AM, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of benzodiazepine use in the treatment of acute alcohol withdrawal. CMAJ. 1999 Mar 9;160(5):649-55. PMID: 10101999; PMCID: PMC1230110.
Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med.

1990 Dec 15;113(12):941-8. doi: 10.7326/0003-4819-113-12-941. PMID: 2240918.

Mattison MLP. Delirium. Ann Intern Med. 2020 Oct 6;173(7):ITC49-ITC64. doi: 10.7326/AITC202010060. PMID: 33017552.
Trzepacz, Paula & Breitbart, William & Franklin, J. & Levenson, J. & Martini, R. & Wang, P.. (2006). Practice guideline for the treatment of patients with delirium. American Psychiatric Association Practice Guidelines for the Treatment of Psychiatric Disorders. 1-38.
Watt CL, Momoli F, Ansari MT, Sikora L, Bush SH, Hosie A, Kabir M, Rosenberg E, Kanji S, Lawlor PG. The incidence and prevalence of delirium across palliative care settings: A systematic review. Palliat Med. 2019 Sep;33(8):865-877. doi: 10.1177/0269216319854944. Epub 2019 Jun 11. PMID: 31184538; PMCID: PMC6691600.
Young J, Murthy L, Westby M, Akunne A, O’Mahony R; Guideline Development Group. Diagnosis, prevention, and management of delirium: summary of NICE guidance. BMJ.

2010 Jul 28;341:c3704. doi: 10.1136/bmj.c3704. PMID: 20667955.

Evidence Level Grade PMID Nº

IIa B 29757064

III A 21068014

I A 10101999

ENDOCRINOLOGICAL ALTERATIONS

HYPOPHYSITIS

Authors: Sara Gabriela Esteves Ferreira, Joana Guimarães and Márcia Alves

Definition

Hypophysitis refers to conditions presenting with inflammation of the pituitary gland and infundibulum. It usually results in hypopituitarism, with deficiency of one or more pituitary hormones, and gland enlargement. In cancer patients, it occurs mostly in the setting of therapy with immune checkpoint inhibitors (ICI). It usually presents from 5 to 36 weeks from initiation of treatment, with a mean of 9 weeks.

Symptoms and signs

Clinical signs and symptoms derive from either mass effect from pituitary enlargement or the hormonal disturbances from the gland inflammation and are frequently non- specific. The most common are headaches, usually reported as the first symptom. Profound fatigue or weakness, nausea and dizziness are also frequent. Other symptoms include anorexia, diarrhoea, confusion, hallucination, memory loss, erectile dysfunction, loss of libido, cold intolerance, and insomnia. Visual disturbances due to compression of the optic nerves and/or cranial nerves in the cavernous sinuses can also appear but are uncommon in patients with ICI-induced Hypophysitis, in whom the gland enlargement is often modest.

As with other adverse events on patients with cancer therapy, the Common Terminology Criteria for Adverse Events (CTCAE) has been used to grade the severity of immunotherapy related Hypophysitis.

Grade 1	Grade 2
Absent or mild symptoms	Moderate symptoms
Tiredness, fatigue, weight loss, susceptibility to infection, normal BP with no postural drop
Grade 3		Grade 4	Grade 5
Severe, disabling or medically significant symptoms		Life – threatening consequences	Death
Hypotension (systolic BP <90 mmHg), postural h-ypotension (>20 mmHg drops in BP from standing to sitting), dizziness/collapse, hypovolemic shock, abdominal pain,tenderness or guarding, nausea, vomiting, tachycardia +/ cardiac arrythmias, fever confusion/delirium, coma, hyponatraemia, hyperkalaemia, hypoglycaemia, pre-renal/renal failure

Etiology

Hypophysitis is a rare condition in cancer patients. However, since the introduction of immune checkpoint inhibitors (ICI), there has been a growing interest in this clinical entity, as it has been described as one of the immune-related adverse events (IRAE) associated with these drugs. Hypophysitis can occur in up to 14% of patients receiving immunotherapy and is the most common endocrine IRAE associated with treatment with Ipilimumab. Hypophysitis has also been described in patients treated with interleukin 2 and interferon. Differential diagnosis is important with other causes of hypopituitarism, including pituitary metastasis, most often from breast cancer, radiation-induced hypopituitarism following radiation for brain, nasopharyngeal, face and neck tumours and primary pituitary lymphoma.

Studies

- 1. Biochemical testing: A biochemical profile should be obtained before institution of treatment with ICI, regularly during treatment and whenever there is suspicion of Hypophysitis – in patients with suggestive symptoms, hyponatremia, pituitary deficiency and/or abnormal pituitary imaging (Table 2). Of note, a decrease in TSH may precede immunotherapy associated Hypophysitis by several weeks, so a fall in TSH should prompt closer monitoring.

Baseline profile

Plasma sodium
TSH, free T4
08:00h serum cortisol (in the absence of treatment with corticosteroids)
LH, FSH and testosterone (in men)
LH, FSH and oestradiol (in pre-menopausal women with irregular periods, in the absence of other aetiologies)
FSH (in post-menopausal women)
In premenopausal women not taking hormonal contraceptives, the a ctivity of the gonadotropin axis should be evaluated by the regularity of cycles

Monitoring during treatment

Clinical and biochemical monitoring is advised during immunotherapy at each appointment for the first 6 months, at every second appointment over the following 6 months and then on appearance of clinical signs.

Clinical monitoring for signs or symptoms of Hypophysitis.
Plasma sodium
TSH, free T4
08:00h serum cortisol
Testosterone (in men)
Patients with possible adrenal insufficiency (table 3) should be referred for dynamic testi ng under endocrine supervision

Suspicion of Hypophysitis

Blood electrolytes
TSH, free T4
Blood glucose
Prolactin
LH, FSH and oestradiol (in premenopausal women not taking oral contraceptives)
FSH (in postmenopausal women)
LH, FSH and total testosterone (in men)
08:00h ACTH and serum cortisol (in the absence of treatment with synthetic glucocorticoids)
In case of suspicion of acute adrenal insufficiency, plasma cortisol should be measured regardless of the time of day
In the presence of symptoms suggestive of DI, such as polyuria and polydipsia, plasma and urine osmolality should be assessed
Patients with suggestive MRI abnormalities should be subjected to weekly monitoring of 08:00h cortisol for 1 month

Serum cortisol	08:00 cortisol <7 ug/dL (<200 nmol/L) Random cortisol <3 ug/dL (<100 nmol/L)	Adrenal insufficiency likely Measure ACTH
	08:00 cortisol 7-16 ug/dL (200-450 nmol/L) Random cortisol 3-16 ug/dL (100-450 nmol/L)	Adrenal insufficiency possible Measure ACTH
	>16 ug/dL (>450 nmol/L)	Adrenal insufficiency unlikely
TSH	Within/below reference range, with free T4 below reference range	May indicate hypopituitarism Check cortisol

- 1. Imaging monitoring: Imaging studies are important to confirm the diagnosis, evaluate for mass effect and eliminate differential diagnosis, such as pituitary abscess, apoplexy, infiltrative disease, or metastasis. Pituitary MRI is the most sensitive imaging technique and should be performed as soon as possible. Changes in pituitary MRI can precede clinical and biochemical alterations by several weeks in up to 50% of these patients. Patients with an abnormal MRI suggestive of Hypophysitis should be subject to closer monitoring. It typically evolves to an early decrease in pituitary volume. Since these alterations are transient and not present in all patients, a normal MRI should not exclude the diagnosis of Hypophysitis. Imaging monitoring is advised in the first 3 months after diagnosis to rule out a differential diagnosis, since at this time point immunotherapy-related enlargement should be resolved.
  2. Histological testing: Diagnosis of immunotherapy induced Hypophysitis is presumptive and biopsy for histological confirmation can be dismissed in the absence of suspicion of other pituitary pathology, such as metastasis.

Pharmacotherapy

Hormone deficiencies arising from Hypophysitis can be life-threatening, so appropriate and timely treatment is crucial. Most importantly, avoiding an adrenal crisis is a priority. Corticotropin deficiency can be fatal and is irreversible in most patients, so hormone replacement should be instituted early after the diagnosis and prolonged treatment is frequently required. High-dose glucocorticoids (GC) can be used in Hypophysitis, though with high recurrence rates and don’t seem to be of added benefit in ICI-induced disease. Nonetheless, GC can safely be used without negatively affecting anti-tumour responses. Patient medication should be thoroughly reviewed, since any supraphysiological dose of glucocorticoid can suppress the adrenal axis (including steroid inhalers, nasal sprays, creams, and intra-ocular injections). Thyrotropin and gonadotropin deficiencies are frequently reversible in the first months, so immediate treatment is not mandatory and can be delayed under close clinical and biochemical follow-up. Additionally, thyroid, and gonadal function may be suppressed in acute and subacute illness and recover spontaneously. It is important to point out that initiation of GC therapy based on these recommendations should not be taken as a definitive diagnosis of adrenal insufficiency. Rather, it is meant to ensure patient safety until a definitive diagnosis can be sought.

Corticosteroids
1. Patients with severe/life-threatening symptoms (CTCAE grade 3-4):
  1. Immediate bolus injection of 100mg hydrocortisone i.v. or i.m. followed by continuous intravenous infusion of 200mg hydrocortisone per 24h (alternatively, 50m hydrocortisone per i.v. or i.m. injection every 6h). Treatment initiation should not be delayed while waiting for laboratory results.

1.1.2. Rehydration with rapid intravenous infusion of 1000mL of isotonic saline infusion within the first hour, followed by further intravenous rehydration as required (usually 4–6L in 24h; monitor for fluid overload in case of renal impairment and in elderly patients)

1.1.3. Continue infusion of hydrocortisone until clinically stable (usually 24-48h)

1.1.4. Once clinically stable, convert to oral hydrocortisone (initially 40 mg/ divided in three daily doses – 20/10/10 mg: progressive tampering to maintenance dose of 10/5/5 mg) or oral prednisolone (maintenance dose of 3-5mg per day)

1 C 30400055

29930025

1 C 29930025

1.1.5. If other pharmacological dose CG are administered for other non-endocrine immune complications, additional hydrocortisone is not required

1.1.6. If there is not a significant improve once cortisol deficiency has been corrected over the first 24h, additional diagnosis should be explored

1.2. Patients with mild/moderate symptoms (CTCAE grade 1-2):

1.2.1. If 08:00 cortisol <200 nmol/L (<7 ug/dL) or random cortisol <100 nmol/L (<4 ug/dL): start oral hydrocortisone (divided in three daily doses – 10/5/5 mg) or oral prednisolone (3-5mg per day). Refer to Endocrinology.

1.2.2. If 08:00 cortisol 7-16 ug/dL (200-450 nmol/L) or random cortisol 3.5-16 ug/dL (100-450 nmol/L): Refer to Endocrinology. If delay in Endocrinology referral, start oral hydrocortisone (divided in three daily doses – 10/5/5 mg) or oral prednisolone (3-5mg per day).

1.3. If random serum cortisol >16 ug/dL (>450 nmol/L), adrenal insufficiency management should be stopped; reassess other causes of signs and symptoms.

1.4. High dose GC can be used in cases of serious mass-effect related symptoms, such as severe and refractory headaches and visual field disturbances, or significant hyponatremia

1.4.1. Methylprednisolone 1-2 mg/kg/day i.v. can be administered for 3-5 days, followed by oral prednisone 1-2 mg/kg, with gradual tampering in 4 weeks

1.4.2. Alternatively, dexamethasone 4mg i.v. every 6h for 7 days can be used, followed by gradual titration up to 0,5 mg/day and then switching to hydrocortisone at equivalent doses

1.5. Since ICI therapy can also cause adrenalitis, primary adrenal insufficiency should be considered in patients in whom hypotension and hyponatremia persist after GC supplementation.

1.6. Patients receiving daily doses of dexamethasone >0,75 mg or prednisolone >3mg may have a suppressed hypothalamic pitu-itary adr-enal axis but, as long as the treatment is ongoing, they are not adrenally insufficient. The can, however, need higher doses of GC when clinically unwell. Consult with an Endocrinologist

2. Levothyroxine

2.1. Treatment with levothyroxine should be considered on an individual basis, depending on the severity of the deficiency, clinical tolerance and/or clinical and biochemical evolution seen after thyroid tests are carried out at 1 month

2.2. Levothyroxine should be deferred until hypocortisolism has been treated, as it can trigger an adrenal crisis

2.3. Patients with secondary hypothyroidism should be referred to an Endocrinologist

3. Reproductive hormones

3.1. Testosterone and oestrogen supplementation should be considered in men and premenopausal women with hypogonadotropic hypogonadism, respectively,

depending on the evolution of the gonadotropin deficiency in the first 3 months and after evaluation for contraindications

3.2. Patients with hypogonadotropic hypogonadism should be referred to an Endocrinologist

4. Growth hormone

4.1. Growth hormone replacement is contraindicated in active malignancy

5. Diabetes Insipidus

5.1. Confirmed cases of DI should be systematically treated

5.2. Patients with DI should be offered therapy with DDAVP, which should be individualized and tailored to meet patient requi rements

Best practice		29930025
Best practice		29930025
1	C
1	C
Best practice		29930025
2	C	30400055
		29313945
2	C	28881921
2	C
Best practice		29930025
Best practice		29930025

2	C
1	C
Best practice		29930025
2	C	30400055
		29313945
Best practice		29930025
1	B	30400055
		29313945
1	C	30400055
Best practice		27736313

Therapeutic Strategy

29313945

|Immunotherapy can be delayed in the acute phase of Hypophysitis

Treatment with ICI can be resumed as soon as the patient is clinically stable

A history of pituitary pathology does not contraindicate treatment with ICI. Dose adjustment may be necessary in patients on hormone replacement therapy.

All patients with chronic adrenal insufficiency should be educated in terms of stress dosing: doubling daily GC dose during febrile illness

situations that require administration of i.v. or i.m. GC, such as prolonged vomiting or diarrhoea, preparation for colonosco

acute trauma or surgery

All patients with adrenal insufficiency should be provided with a Hydrocortisone Emergency Injection kit (100 mg hydrocortisone) and be taught how to self- administer hydrocortisone, as well as a parent/partner

All patients with adrenal insufficiency should be provided with a Steroid Emergency Card and be encouraged to wear medical alert bracelets

All cases of suspected or possible Hypophysitis should be referred to an Endocrinologist. Patients should be regularly monitored in specialist consultations.

2 C	30400055
2 C	29930025
2 C	30400055
1 A	30400055
	29930025
	27935813
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	27935813
Best practice	27935813
Best practice	30400055

29930025

References PMID: 31311002 PMID: 26186958 PMID: 25416723 PMID: 26998595 PMID: 25957829 PMID: 29380110 PMID: 29974330 PMID: 19165221 PMID: 30400055 PMID: 29313945

6.2 DIABETES MELLITUS

Authors: Sara Pereira Bravo and Filipa Coroado Ferreira

Definition

Diabetes mellitus (DM) is a group of diseases characterized by sustained hyperglycaemia caused by improper function or diminished secretion of insulin. [1]

Diagnosis[2,3,7]

Symptoms of hyperglycaemia AND raised plasma glucose detected once – fasting ≥ 126mg/dL or random ≥ 200mg/dL OR
Raised plasma glucose on two separate occasions – fasting≥ 126mg/dL, random≥ 200mg/dL or oral glucose tolerance test (2h value ≥ 200mg/dL) OR HbA1c ≥ 6,5%

Symptoms and signs

Asymptomatic hyperglycaemia  Polyuria/Polydipsia/Polyphagia  Unexplained weight loss  Visual blurring  Genital Trush  Lethargy

Etiology

Type 1 DM is caused by insulin deficiency from autoimmune destruction of insulin-secreting pancreatic beta cells. Patients must have insulin and are prone to ketoacidosis and weight loss. Usually, onset in adolescence but may occur at any age. Latent autoimmune diabetes of adults (LADA) is a form of type 1 DM, with slower progression to insulin dependence in later life. [3,4]
Type 2 DM can be caused by a decreased insulin secretion with or without increased insulin resistance. It is associated with obesity, lack of exercise, calorie, and alcohol excess intake. Most are over 40 years, but teenagers are being diagnosed type 2 DM. Maturity onset diabetes of the young (MODY) is a rare autosomal dominant form of type 2 DM affecting young people. [3,4]
Specific types of diabetes due to other causes, e.g., diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), cancer (especially pancreatic cancer), drugs or chemical induced diabetes (such as with glucocorticoid use or after organ transplantation) [3] and certain chemotherapy drugs and targeted terapy treatments.
Gestational diabetes mellitus (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation). [3]

Diabetes and cancer

Persistent hyperglycaemia leads to the damage and dysfunction of various organs (kidneys, heart, eyes, blood vessels or nerves). Additionally, there is a strong association between DM and carcinogenesis. The clearest association is observed in type 2 diabetes mellitus. [1] The possible biological links between DM and cancer comprise hyperinsulinemia, hyperglycaemia and fat-induced chronic inflammation.

Although the strongest association refers to pancreas and liver, there are many organs involved in carcinogenesis. Type 2 DM increases the risk of pancreatic, liver, breast, endometrium, bladder and kidney cancer, and non-Hodgkin lymphoma. Type 1 DM is one of the factors that elevate the risk of stomach, cervix, endometrium, squamous cell skin cancers and acute lymphatic leukaemia. [1,6]

There is a bidirectional relationship between pancreatic cancer and diabetes. Diabetes improves after pancreatic resection; it is suggested that DM is both a consequence and a cause of pancreatic cancer. On the other hand, new-onset hyperglycaemia and DM are early signs of pancreatic cancer. [8]

Recent studies suggest that there is also association between cancer incidence and anti-diabetic medications. It was observed that some drugs decrease the risk of carcinogenesis and some increase that risk. Metformin is considered to have antineoplastic features and may inhibit tumorigenesis. [1,5]

Prevention and Treatment Strategies

Predict and prevent type 2 diabetes in the general population is challenging. However, individuals at high risk, including those with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), obesity, close relatives with type 2 diabetes, or who are members of certain ethnic groups are appropriate candidates for preventive interventions.

Weight loss

Achieve and maintain >5% weight loss is recommended for most people with type 2 DM and overweight or obesity. Additional weight loss usually results in further improvements in control of diabetes and CV risk.

Diet

Choose a dietary pattern of healthful foods, such as the Dietary Approaches to Stop Hypertension (DASH) or Mediterranean-style diet, rather than focusing on a specific nutrient. This approach allows greater flexibility and personal preference in diet and may improve long-term adherence.

Physical Activity

Physical activity is recommended according to the patient’s tolerance and whenever there is no contraindication.

Adults at high risk for diabetes are encouraged to perform 30 to 60 minutes of moderate-intensity aerobic activity on most days of the week (at least 150 minutes of moderate-intensity aerobic exercise per week)

Smoking Cessation

The effect of smoking cessation on diabetes risk is variable and may depend upon individual patient factors. Smoking cessation may reduce

diabetes risk by reducing systemic inflammation. On the other hand, smoking cessation is often associated with weight gain, which will increase the risk of diabetes.

Alcohol consumption

Alcohol restriction is recommended in patients with DM and pre-DM with hypertension.

Immunizations

Preventing avoidable infections not only directly prevents morbidity but also reduces hospitalizations, which may additionally reduce risk of acquiring infections.

Cancer Screening

Patients with diabetes should be encouraged to undergo recommended age- and sex-appropriate cancer screenings and to reduce their modifiable cancer risk factors (obesity, physical inactivity, and smoking).

When considering appropriate pharmacologic therapy, it is important to determine whether the patient is insulin-deficient, insulin-resistant, or both. Treatment options are divided into noninsulin therapies – insulin sensitizers, secretagogues, alpha-glucosidase inhibitors, incretins, and sodium-glucose cotransporter 2 (SGLT2) inhibitors – and insulin therapies (insulin and insulin analogues). [10] Insulin formulations on table 1.

I B 35221470

I A 35221470

I A 31497854

I A 35221470

I B 31902143

Biguanides (Metformin) – First-line therapy on type 2 DM; No hypoglycaemia; Contraindicated with eGFR <30mL/min/1.73m2; GI side effects common	I	A	35221470
SGLT2 inhibitors (Empagliflozin, Dapagliflozin, Canagliflozin) – No hypoglycaemia; Weight loss; Benefit on Heart failure (HF) and Chronic Kidney failure; Glucose-lowering effects is lower for iSGLT2 at lower eGFR; DKA risk; Genitourinary infections	I	A	35221470
GLP-1 RAs (Liraglutide, Dulaglutide, Semaglutide) – No hypoglycaemia; Weight loss; CV and renal benefits. No dose adjustment for liraglutide, dulaglutide and Semaglutide; GI side effects; Subcutaneous administration only; Injection site reactions	I	A	35221470
DPP-4 inhibitors (Sitagliptin, Vildagliptin) – No hypoglycaemia; Contraindicated with eGFR <50mL/min/1.73m2; No dose adjustment required for linagliptin; Side effects – Joint pain and discontinue if pancreatitis suspected. Avoid if on GLP-1 RA.
Saxagliptin is not recommended in patents with type 2 DM and a high risk of heart failure.	III	B	23992601
Thiazolidinediones (Pioglitazone, Rosiglitazone) – No hypoglycaemia; Weight gain; Increased risk of HF; No adjustment dose required; Side effects – Fluid retention, Congestive HF; Bladder cancer (Pioglitazone); Risk of bone fractures	II	B	20554718
Thiazolidinediones are not recommended in patients with heart failure.	III	A	31497854
Later generation Sulfonylureas may be used (Glipizide, Glimepiride) – Risk of hypoglycaemia; Weight gain	II	C	27340828
Alpha-glucosidase inhibitors (Acarbose) – No hypoglycaemia; Target – Postprandial hyperglycaemia; Contraindicated with eGFR <50mL/min/1.73m2 and inflammatory bowel disease; GI side effects common	III	C	26512331
Human Insulin – Type 1 DM or type 2 uncontrolled; Higher risk of hypoglycaemia (more than insulin analogues); Weight gain; Lower insulin doses required with a decreased in eGFR; Injection site reactions	I	A	34964831
Insulin Analogues – Type 1 DM or type 2 uncontrolled; Risk of hypoglycaemia; Weight gain; Lower insulin doses required with a decreased in eGFR; Injection site reactions	I	A	34964831
Diabetic Ketoacidosis (DKA) and Hyperosmolar Hyperglycaemic State (HHS)

DKAand HHS are two of the most serious acute complications of diabetes.
They differ clinically according to the presence of ketoacidosis and, usually, the degree of hyperglycaemia.
DKA diagnostic criteria: Serum glucose >250 mg/dL, arterial pH <7.3, serum bicarbonate <18 mEq/L, and at least moderate ketonuria or ketonemia >0.6. Normal laboratory values vary; check local lab normal ranges for all electrolytes.
HHS diagnostic criteria: Serum glucose >600 mg/dL, arterial pH >7.3, serum bicarbonate >15 mEq/L, and minimal ketonuria and ketonemia. Normal laboratory values vary; check local lab normal ranges for all electrolytes.
Treatment – Fig.1

Fig. 1 – Treatment of DKA and HHS [9]

Check capillary glucose and serum/urine ketones to confirm hyperglycemia and ketonemia/ketonuria (DKA)

Severe hypovolemia

Administer 0,9% NaCl (1L/hour)

IV fluids

Determine volume status

Mild hypovolemia

Evaluate corrected serum Na+

Cardiogenic shock

Hemodynamic monitoring pressors

Insulin

IV regular insulin: 0,1 units/kg body weight as IV bolus

0,1 units/kg/hour IV continuous insulin infusion

If serum glucose does not fall by 50-70 mg/dL in 1st hour, double

K+ < 3.3mEq/L

Hold insulin and give K+, 20 to 30 mEq/hour IV until K+ > 3.3mEq/L

Potassium

Establish adequate renal function (urine output approximately 50mL/hour)

K+ 3.3 to 5.3 mEq/L Give 20 to 30mEq K+ in each liter of IV fluid to keep serum K+ between 4-5mEq/L

K+ > 5.3mEq/L

Do not give K+ but check serum K+ every 2 hours

Serum Na+ high/ Serum Na+ normal

0.45% NaCl (250-

500mL/h) depending on hydration state

Serum Na+ low

0.9% NaCl (250-

500mL/h) depending on hydration state

insulin dose

DKA – Assess need for bicarbonate

pH < 6,9 – Dilute NaHCO3 (10 mmol) in 400mL H2O with 20 mEq KCl. Infuse over two hours. Repeat NaHCO3 administration every two hours until pH > 7

pH ≥ 6,9 – No HCO3

DKA: When serum glucose reaches 200mg/dL, change to 5% dextrose with 0.45% NaCl at 150-250mL/h and reduce regular insulin infusion to 0.05 units/kg/hour IV.

Keep serum glucose between 150-200mg/dL until resolution of DKA.

HHS: When serum glucose reaches 300mg/dL, change to 5%dextrose with 0.45% NaCl at 150-250mL/h and reduce regular insulin infusion to 0.05 units/kg/hour IV.

Keep serum glucose between 250-300mg/dL until patient is mentally alert.

Endocrinology & Diabetes, 124(05), 263-275.

1. Wojciechowska, J., Krajewski, W., Bolanowski, M., Kręcicki, T., & Zatoński, T. (2016). Diabetes and cancer: a review of current knowledge. Experimental and Clinical

Wexler, D.J. (2022). Initial management of hyperglycemia in adults with type 2 diabetes mellitus. In J E Mulder (Ed.), UpToDate. Retrieved April 19, 2022,
American Diabetes Association. (2022). Standards of Medical Care in Diabetes—2022 Abridged for Primary Care Providers. Clinical diabetes, 40(1), 10-38.
Wilkinson, IB., Raine, T. & Wiles, K. (2017). Oxford handbook of clinical medicine. (10th edition) Oxford: Oxford University Press.
Giovannucci, E. et al. (2010). Diabetes and cancer: a consensus report. Diabetes care, 33(7), 1674-1685.
Suh, S., & Kim, K. W. (2019). Diabetes and cancer: cancer should be screened in routine diabetes assessment. Diabetes & Metabolism Journal, 43(6), 733
World Health Organization. (2019). Classification of diabetes mellitus. Available on https://www.who.int/publications/i/item/classification-of-diabetes-mellitus
Khadka, R., Tian, W., Hao, X., & Koirala, R. (2018). Risk factor, early diagnosis and overall survival on outcome of association between pancreatic cancer and diabetes mellitus: Changes and advances, a review. International Journal of Surgery, 52, 342-346.
Hirsch, I.B, Emmett, M. (2022). Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment. In J E Mulder (Ed.), UpToDate. Retrieved May 25, 2022,
Skugor, M. (2018). Diabetes Mellitus Treatment. The Cleveland Clinic Foundation. Retrieved April 19 2022, from
Draznin, B. et al. (2022). 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care, 45(Supplement_1), S125-S143
Hu, Y. et al. (2018). Smoking cessation, weight change, type 2 diabetes, and mortality. New England Journal of Medicine.
DiNicolantonio, J. J., Bhutani, J., & O’Keefe, J. H. (2015). Acarbose: safe and effective for lowering postprandial hyperglycaemia and improving cardiovascular outcomes. Open heart, 2(1), e000327.
Cosentino, F. et al. (2020). 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: The Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). European heart journal, 41(2), 255-323.
Rados, D. V. et al. (2016). The association between sulfonylurea use and all-cause and cardiovascular mortality: a meta-analysis with trial sequential analysis of randomized clinical trials. PLoS medicine, 13(4), e1001992.

Authors: Leonor Naia and Margarida Eulálio.

Introduction

Thyroid hormones are responsible for multiple functions in the organism. For the maintenance of the euthyroid state, the normal functioning of all regulatory steps from the hypothalamus to the thyroid gland is necessary.

Thyroid disorders are relatively common in cancer patients, occurring after some cancer treatments, as well as being related to some types of cancer. Thyroid disorders induced by radiotherapy and other drugs, such as tyrosine kinase inhibitors, remain underestimated and underdiagnosed.

HYPOTHYROIDISM:

Definition

Hypothyroidism is the most reported thyroid disorder. It is more frequent in women and can occur in any age group. Hypothyroidism can be classified into:

primary (95%), presenting increased thyroid-stimulating hormone (TSH), and low free thyroxine (T4)
secondary, presenting normal TSH, and low free T4.
tertiary, presenting decreased T4, triiodothyronine (T3), TSH, and thyrotropin-releasing hormone (TRH).
subclinical, when TSH is increased but free T4 is normal.

Etiology, signs, and symptoms

The most common aetiologies in high income countries are(1):

- autoimmune, namely Hashimoto’s thyroiditis – positive anti-peroxidase or anti-thyroglobulin antibodies.
- post-radiotherapy of the head and neck.
- post-radioiodine or thyroidectomy.

· secondary to drugs.

Worldwide, environmental iodine deficiency is the most common cause of hypothyroidism.(1)

The clinical manifestations of hypothyroidism are nonspecific and highly variable. Patients may present with intolerance to cold, weight gain, asthenia, muscle cramps, depression, periorbital or lower limb oedema, dry skin, constipation, hair loss.

Treatment

Treatment is based on hormone replacement with levothyroxine at a dose of 1.6 µg/Kg/day.(2-3-4) In elderly, frail, or coronary heart disease patients, 1/4 to 1/2 of the expected dose should be started. Patients with central hypothyroidism or who are submitted to a total thyroidectomy or radioiodine therapy may require higher doses.(1)

Thyroid hormone evaluation should be repeated 4 to 8 weeks after starting supplementation. If the TSH levels remain above the reference range, the dose can be increased by 12.5-25 µg/day in older patients or more in younger patients.

Once the adequate maintenance dose is reached, the time period for patient reassessment can be spaced out (every 6 months or annually).(1)

SUBCLINICAL HYPOTHYROIDISM:

Subclinical hypothyroidism is characterized by elevated TSH levels with normal serum free T4 and T3 levels.

The analytical study should be repeated within 2 to 3 months for confirmation, and it is recommended to evaluate anti-peroxidase and anti-thyroglobulin antibodies.(1-5)

TSH> 10 mU/L – start replacement therapy with levothyroxine,1-5
TSH< 10 mU/L – start treatment in patients < 65 years of age with symptoms of hypothyroidism, or with a study suggestive of autoimmune thyroiditis (with high titers), or in patients with infertility or pregnant,
In patients > 80 years of age with TSH <10 mU/L, a ‘wait-and-see’ vigilance strategy should be adopted.(5)

The recommended dose of levothyroxine is 1.5 µg/Kg/day, with evaluation every month or every two months. For patients with cardiac ischemic disease or elderly, the recommended started dose is 25-50 Vg/day.(5)

MYXEDEMACOMA:

Definition

Myxoedema coma is an extreme and severe presentation of hypothyroidism, associated with high mortality.

Diagnosis is based on clinical history, physical examination, and exclusion of other causes of coma. It should be suspected in a patient with an altered state of consciousness, who has a thyroidectomy scar or a history of radiotherapy or iodine therapy and a previous diagnosis of hypothyroidism.

Analytically, patients have elevated serum TSH, with decreased free T4 and T3 levels.

Signs and symptoms

Clinical manifestations are nonspecific and multiple. In addition to altered consciousness (from lethargy to coma, including seizures), the patient may experience cardiovascular and respiratory disorders, generalized oedema, hypothermia, and hypoglycaemia (especially if associated with adrenal insufficiency).

Old age, refractory hypothermia, sepsis, need for invasive mechanical ventilation and heart failure are predictors of mortality.

Treatment

Treatment should be started as soon as possible once there is clinical suspicion, even without prior laboratory confirmation.

It is based on the administration of intravenous levothyroxine at a dose of 200-500 µg, followed by 50-100 µg/day. Systemic corticoid therapy with hydrocortisone 100 mg every 8 hours must be initiated until the exclusion of adrenal insufficiency is made.

It is essential to determine and treat the precipitating cause and provide the patient with supportive care.

HYPERTHYROIDISM

Definition

Hyperthyroidism is characterized by suppressed TSH with high levels of free T4. It is more common in females and in elderly(6).

Etiology, signs, and symptoms

In most cases, hyperthyroidism is secondary to Graves’ disease, toxic multinodular goitre, and toxic adenoma.(7) Patients may be asymptomatic or present complaints of palpitations, anxiety or irritability, tremor, heat intolerance, profuse sweating, atrial fibrillation, diarrhoea, and weight loss.

Treatment

Treatment is based on the use of drugs that inhibit the synthesis and release of T4 and T3 hormones, such as methimazole 20-30 mg in a single daily dose or propylthiouracil 50-150 mg every 8 hours.(6) Once euthyroidism is reached, tapering off antithyroid drugs should begin with periodic assessment of thyroid hormones.

Beta blockers (propranolol10-40 mg every 8 hours; atenolol 25-100 mg every 12 hours) are also recommendedfor heart rate and systolic blood pressure control in all patients with symptomatic thyrotoxicosis.(7)

Surgical treatment and ablation with radioactive iodine may be considered.

Prior to initiating with anti-thyroid drugs, it is recommended that patients have a baseline complete blood count and liver profile.(3-7) In patients on anti-thyroid drugs, a periodic analytical study should be performed, due to the risk of neutropenia, agranulocytosis, or hepatotoxicity.(7)

An assessment of free T4 and TSH should be performed 4 weeks after initiation of therapy, and the dose of anti-thyroid drugs adjusted accordingly. Evaluation of patients is recommended every 4-8 weeks until euthyroidism is achieved with the minimum drug dose.(7)

SUBCLINICAL HYPERTHYROIDISM

In subclinical hyperthyroidism, the patient presents low or suppressed TSH with a normal free T4 and T3 levels. Serum TSH and T4 levels should be monitored every 6 to 12 months. Treatment is recommended in patients who have persistent TSH <0.1 mU/L (within 3-6 months) and in patients > 65 years of age, in postmenopausal women, and in patients with heart disease or osteoporosis.(7)

THYROID STORM / THYROTOXIC CRISIS

Definition

Thyroid storm is an endocrine emergency that occurs in <1% of patients with hyperthyroidism and presents a high mortality rate if not immediately diagnosed and treated.(6) It is characterized by suppressed TSH with increased free T4 and T3 levels.

Signs and symptoms

Thyroid storm is characterized by multisystem involvement, namely cardiovascular, hepatic, and neurological, which define the clinical severity.

It should be suspected in a patient with previously diagnosed hyperthyroidism, who presents with hyperthermia, psychomotor agitation or coma, tachycardia, hypotension, heat intolerance, profuse sweating, nausea, and vomiting.

Treatment

Treatment should aim at:

1. controlling the symptoms associated with adrenergic hyperactivity with beta-adrenergic blockade (propranolol 60-80 mg every 4 hours),
2. inhibiting the peripheral conversion of T4 to T3 with systemic corticosteroids (hydrocortisone 100 mg every 8 hours),
3. inhibiting the synthesis of thyroid hormones with antithyroid drug therapy (propylthiouracil 200-250 mg every 4 hours or methimazole 60-80 mg daily),
4. inhibiting the release of thyroid hormones with iodine (lugol’s solution 5-8 drops every 6 hours),
5. acting on the enterohepatic circulation of thyroid hormones with cholestyramine 4 g every 6 hours. Treatment should also be focused on treating the precipitating cause and supportive care.

When to refer for the endocrinology consultation?

Patients should be referred to an Endocrinology Consultation in the following situations:

Clinical and subclinical hyperthyroidism
Central hypothyroidism
Hypothyroidism in pregnancy and women who wish to get pregnant
Treatment-refractory hypothyroidism
Hypothyroidism associated with immune checkpoint inhibitors or tyrosine kinase inhibitors

HYPOTHYROIDISM

Hypothyroidism treatment is based on hormone replacement with levothyroxine in monotherapy

Thyroid hormone evaluation should be repeated 4 to 8 weeks after starting supplementation with levothyroxine

SUBCLINICAL HYPOTHYROIDISM

After the first evaluation, the analytical study should be repeated within 2 to 3 months to confirm of diagnosis of subclinical hypothyroidism

It is recommended to evaluate anti-peroxidase and anti-thyroglobulin antibodies

Patients with TSH > 10 mU/L, even in the absence of symptoms, should start replacement therapy with levothyroxine, given theincreased risk of progression to clinical

hypothyroidism and increased associated cardiovascular mortality

With TSH < 10 mU/L, it is recommended to start treatment in patients younger than 65 years of age with symptoms suggestive of hypothyroidism

In patients over 80 years of age with TSH <10 mU/L, a ‘wait-and-see’ vigilance strategy should be adopted

The recommended dose of levothyroxine is 1.5 µg/Kg/day, with evaluation every month or every two months in order to normalize TSH levels

HYPERTHYROIDISM

Beta blockers are recommended for heart rate and systolic blood pressure control in all patients with symptomatic thyrotoxicosis

Prior to initiating anti-thyroid drugs, it is recommended that patients have a baseline complete blood count and liver profile

SUBCLINAL HYPERTHYROIDISM

Treatment is recommended in patients who have persistent TSH <0.1 mU/L (within 3 -6 months) and in patients over 65 years of age

Treatment is recommended in patients who have persistent TSH <0.1 mU/L (within 3 -6 months) and in patients with heart disease or osteoporosis

THYROID STORM

Treatment is based on beta-adrenergic blockade, systemic corticosteroids, antithyroid drug therapy and lugol’s solution

Thyroid disorders are a complex and common pathology in cancer patients. Given the complexity of these patients and the need for a long-term follow-up, the approach should be multidisciplinary and individualized to each patient.

Asummary table of thyroid disorders is presented below:

1 A 23246686

2 b 23246686

2 A 24783053

1 B 23246686

2 B 24783053

3 A 24783053

3 A 21700562

3 B 21700562

3 A 30283735

2 B 21700562

Thyroid disorder

Definition

Etiology

Signs and symptoms

Treatment

–

Primary (++) TSH and free T4 Secondary free T4 and N TSH Tertiary T4, T3, TSH and TRH Subclinical TSH and N free T4

Iodine deficiency (+++) Highly variable and

nonspecific

Income countries :

Levothyroxine at a dose of 1.6 µg/Kg/day

Hypothyroidism

autoimmune disease, post-radiotherapy, post-radioiodine, post-thyroidectomy, secondary to drugs

– Subclinical TSH and N free T4

Intolerance to cold Weight gain Asthenia Muscle cramps Depression Periorbital or lower limb edema Dry skin Constipation Hair loss Asymptomatic or nonspecific

1/4 to 1/2 of the expected dose should be started in elderly, frail, or heart disease patients

TSH > 10 mU/L: start levothyroxine at a dose of 1.5 µg/Kg/day

Subclinical hypothyroidism

TSH < 10 mU/L: start treatment if < 65 years and symptoms of hypothyroidism, infertility/pregnant and autoimmune thyroiditis

> 80 years and TSH

<10 mU/L: wait-and- see

Severe presentation of hypothyroidism. Diagnosis is based on clinical history, physical examination, and exclusion of other causes of coma

Myxedema coma

Analytically: TSH and free T4

Highly variable and nonspecific

Lethargy to coma Seizures Bradycardia Hypotension Acute heart failure Oedema Hypothermia Hypoglycaemia

Started as soon as
possible without

prior laboratory confirmation

IV levothyroxine at a dose of 200-500 µg,

followed by 50 -100 µg/day

Hydrocortisone 100 mg every 8 hours until the exclusio n of adrenal insufficiency

Supportive care and treatment of precipitating cause

TSH and free T4

Hyperthyroidism

Subclinical: TSH and N free T4 and T3

(+++) Secondary to Graves’ disease, toxic multinodular goitre and toxic adenoma

Highly variable and nonspecific

Palpitations Anxiety Irritability tremor

Heat intolerance Profuse sweating Atrial fibrillation Diarrhoea Weight loss

Antithyroid drug therapy:

– methimazole 20- 30 mg in a single daily dose

-propylthiouracil 50- 150 mg every 8 hours

Beta blockers:

-propranolol 10-40 mg every 8 hours

-atenolol 25-100 mg every 12 hours Surgical treatment and/or

ablation with radioactive iodine

Subclinical hyperthyroidism	– Subclinical:	TSH	and N free T4	Asymptomatic or	Start treatment if TSH
Subclinical hyperthyroidism	and T3			nonspecific	<0.1 mU/L and in patients >65 years of age, in patients with heart disease or osteoporosis and in postmenopausal women
Thyroid storm	Endocrine emergency Analytically: TSH and T3		free T4 and	Multisystem involvement Hyperthermia Psychomotor agitation to coma Tachycardia Hypotension Heat intolerance Profuse sweating Nausea / vomiting	Beta-adrenergic blockade: propranolol 60-80 mg every 4 hours AND Corticosteroids: hydrocortisone 100 mg every 8 hours AND Antithyroid drug therapy: propylthiouracil 200 -250 mg every 4 hours or methimazole 60-80 mg daily
					Cholestyramine 4g every 6 hours Supportive care and treatment of precipitating cause

Garber J, Cobin R, Gharib H, Hennessey J, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18(6):988-1028
Krashin E, Piekielko-Witkowska A, Ellis M, Ashur-Fabian O. Thyroid Hormones and Cancer: AComprehensive Review of Preclinical and Clinical Studies. Front Endocrinol. 2019;10:59
Hartmann K. Thyroid Disorders in Oncology Patient. Adv Pract Oncol. 2015;6(2):99-106
Okosieme O, Gilbert J, Abraham P, BoelaertK, el al. Management of primary hypothyroidism: statement by the British Thyroid Association Executive Committee. Clin Endrocrinol. 2016;84(6):799-808. Epub2015
Pearce S, Brabant G, Duntas L, Monzani F, et al. ETAGuideline: Management of Subclinical Hypothyroidism. Eur Thyroid J. 2013;2:215-228
Kahaly G, Bartalena L, Hegedüs L, Leenhardt L, et al. European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism. Eur Thyroid J. 2018;7(4):167-186
Bahn R, Burch H, Cooper D, Garber J, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocr Pract. 2011;17(3):457-511

ADRENAL ALTERATIONS

Authors: João Oliveira, Ines Pinheiro and Maria Menezes.

Physiology

The adrenal glands are anatomically constituted by two parts: the cortex (more external, responsible for the secretion of steroids) and the medulla (more internal, responsible for neuroendocrine secretion).(1,2)

The adrenal cortex is subdivided into three zones: glomerulosa zone (external), fasciculate zone (intermediate) and reticularis zone (internal) that segregate, respectively, mineralocorticoids, glucocorticoids, and precursors of androgens, especially dehydroepiandrosterone (DHEA).(1,2)

The adrenal medulla secretes catecholamine hormones (epinephrine and norepinephrine) and small amounts of dopamine.(1,2)

Mineralocorticoids (e.g., aldosterone) are a class of corticosteroids involved in maintaining the balance between water and salt in the body.(1)

Glucocorticoids (e.g., cortisol) are a class of stress-mediating corticosteroids, resting homeostasis regulators (metabolism of carbohydrates, proteins, and fats) and immune response modulators. (1)

Androgen precursors are converted into active sex steroids in gonads and peripheral tissues playing a key role in puberty of both sexes and constituting the main source of testosterone in women. (2)

Catecholamines are involved in the escape-fight response of the sympathetic nervous system (increase blood pressure and serum glucose).(2)

The renin-angiotensin-aldosterone system (RAAS) and serum potassium levels are the primary regulators of aldosterone (mineralocorticoid) secretion. In response to decreased renal perfusion, the kidney releases an angiotensinogen-converting angiotensinogen into angiotensin I (AT-I) which converts to angiotensin II (AT-II) by the action of the angiotensin-converting enzyme (ECA) in the lung. AT-II promotes aldosterone synthesis in the glomerulae zone. (2)

The hypothalamic-pituitary-adrenal (HPA) axis is responsible for the production of glucocorticoids and androgen precursors in the fasciculate and reticularis zone, respectively. Responding to circadian rhythm and stress stimuli, paraventricular neurons in the hypothalamus secrete the corticotropin-reusing hormone (CRH) that stimulates the synthesis of adrenocorticotrophic hormone (ACTH) in the anterior pituitary gland. ACTH induces the synthesis of glucocorticoids in the fasciculate zone (which negatively feedback the hypothalamus and pituitary gland inhibiting the secretion of CRH and ACTH). (2)

Types of IS:

- 1. Primary IS: results from direct insufficiency of the adrenal gland caused by its injury/destruction. Glucocorticoid deficit leads to a loss of negative cortisol feedback in the hypothalamus and pituitary gland by increasing CRH and ACTH levels. Additionally, aldosterone deficit increases the production of renin in the kidney.

The causes of ISP are idiopathic (Addison’s disease), autoimmune, infectious, neoplastic, hemorrhagic, surgical (bilateral adrenelectomy), infiltrative, genetic and drug according to the following mechanisms:

- - - Enzymatic inhibition: ketoconazole, fluconazole, itraconazole, etomide, aminoglutethylate, metirapona, trilostane, osilodrostat;
    - Adrenolytic effect and increased cortisol metabolism: mitotane.
    - Inflammation: immune checkpoints inhibitors.(1,2)
  1. Secondary: involves the pituitary gland impairing the synthesis and/or secretion of ACTH compromising the production of cortisol and DHEA in the adrenal gland. Aldosterone synthesis is not affected since RAAS remains unchanged.

The causes of ISS are neoplastic, iatrogenic (surgery, radiotherapy), traumatic and vascular, autoimmune, genetic, infiltrative, infectious and drug (immune checkpoints inhibitors, opioids, and interferon α).(1,4)

- 1. Tertiary: involves the hypothalamus leading to decreased CRH secretion. Endogenous causes are like those of ISS although affecting the hypothalamic region. STIs is also observed in Cushing’s Disease/Syndrome. More often it is the exogenous administration of glucocorticoids that is responsible for STIs. Decreased CRH secretion inhibits ACTH secretion leading to restriction of cortisol and DHEA production. Differentiation of ISS and IST is difficult and both can occur simultaneously hence the term ISS is often used for both forms. (1,2)

Tertiary adrenal insufficiency is a known result of chronic treatment with glucocorticoids (widely used as palliative therapy) in patients treated with an equivalent dose of more than 30 mg/day hydrocortisone or 7.5 mg/day of prednisolone for more than 3 weeks. Adrenal insufficiency should be considered in all patients with a history of abrupt discontinuation of chronic administration of glucocorticoids who complain of general malaise. (3)

Normal adrenal gland function may take months or years to recover after prolonged glucocorticoids treatment. On the other hand, the risk of adrenal insufficiency in patients who have been given high-dose but relatively short-term glucocorticoids remains a debatable issue. (3)

Symptoms:

The decrease of hormone produced by the adrenal gland affects all systems of the human body generating a wide diversity of symptoms (A: specific symptoms of glucocorticoide deficit; B: specific symptoms of mineralocorticoide deficit; C: specific symptoms of adrenal androgen deficiency):

Central Nervous System: anorexia(A), weight loss(A), nausea(A), salt craving(B), dizziness(B).
Cardiovascular System: hypotension and/or dehydration(B).
Hematological System: anemia(A), lymphocytosis, eosinophilia(A).
Blood Electrolytes: hyponatremia(AB), hyperkalemia(B), hypercalcemia(A)
Neuropsychiatric System: ACdepression, fatigue A, decreased libido(C);
Gastroenterological system: diarrhoea, vomiting(A), abdominal pain(A);
Musculoskeletal system: myalgia(A), joint pain, weakness(A);
Dermatological System: dry skin, hyperpigmentation (ISP), hypopigmentation (ISS), loss of pubic hair(C). (1,5)

Signs and symptoms of mild and progressive chronic deficit of glucocorticoids are often nonspecific. Therefore, these nonspecific signs are generally not recognized as SI by health professionals, leading to delay in diagnosis or wrong diagnoses. (1)

Clinical manifestations of Childhood SD include growth deficit, recurrent infections, family history of neonatal deaths or early postnatal deaths, ambiguous genitalia at birth, and hepatitis. (1st)

The adrenergic crisis may be the first presentation of SI. Its pathophysiology that integrates an acute cortisol deficit is not yet well understood. Adrenergic crisis is a life- threatening emergency that requires immediate diagnosis and treatment. (1) The risk factors for the development of an adrenergic crisis are:

Patients with established diagnosis or suspected ISP (Addison’s disease, congenital adrenal hyperplasia, bilateral adrenalectomy, adrenal haemorrhage).
Patients with established diagnosis or suspected ISP/STIs (hypopituitarism by pituitary and/or hypothalamic pathology who perform permanent glucocorticoid replacement or require replacement during an intercurrence/stress).
Patients receiving exogenous glucocorticoids equivalent to or greater than a dose of prednisolone 5mg/day for 4 weeks or more for all routes of administration.
Patients receiving more than 40mg/day of prednisolone more than a week or equivalent or repeated short cycles of oral doses.
First year after discontinuation of treatment with long-term oral glucocorticoid. (4)

In addition, these include the existence of previous seizures, age over 65 years, childhood, adolescence and other clinical conditions such as diabetes mellitus or other non-endocrine pathologies. The use of short-term glucocorticoids and low dose may increase the incidence of an adrenergic crisis. Patients with thyroid pathology under L-thyroxine therapy or patients with Severe Disease hyperthyroidism may precipitate a crisis by rapid cortisol inactivation. Drugs that inhibit cortisol production or increase its elimination may also trigger an adrenergic crisis(1,4). The main precipitating factor of an adrenergic crisis is gastroenteritis/food poisoning. Other precipitating factors are infections of other causes, surgical and dental procedures, trauma, acute myocardial infarction, allergic reactions, hypoglycemia in diabetic patients, severe psychological stress and discontinuation of glucocorticoid therapy in patients with adrenal insufficiency. (5) Symptoms of adrenergic crisis are general malaise, fatigue, nausea, vomiting, abdominal pain (sometimes with peritoneal irritation), headache, myalgia/cramps, dehydration, hypotension, shock, cognitive changes, loss of consciousness and coma. Analytically hyponatremia, hyperkalemia, increased serum creatinine, hypoglycemia, and hypercalcemia may occur.(5)

Diagnosis:

The clinical diagnosis of adrenal insufficiency can be confirmed by demonstrating inadequately low cortisol secretion, determining whether this deficit is secondary or primary, therefore dependent or independent of the ACTH deficit, and finally investigating the etiology.(6)

The following diagnostic tests are suggested:

Morning serum cortisol concentration and ACTH: Serum cortisol concentrations determined at 8am < to 5 μg/dL (140 nmol/L) in combination with plasma ACTH > 2 times the upper limit of the reference range is a given consistent with ISP.( 6,7) In individuals whose morning cortisol levels are ≥ 5 μg/dL (140 nmol/L) an ACTH stimulation test should be performed. A morning serum cortisol <100 nmol/L in combination with a low or low-normal ACTH level confirms ISS while a morning serum cortisol of > 450 nmol/l excludes ISS (1,6,7) .
ACTH stimulation test (standard dose): a standard dose of 250 μg synthetic ACTH may be useful for assessing the proper functioning of the adrenal glands. A peak of serum cortisol concentration of <450 nmol/L 30 min after ACTH stimulation or <500 nmol/L 60 min after diagnosis of adrenal insufficiency.(1,6,7)
Insulin tolerance test: Is considered the ISS confirmation test. Insulin tolerance testing can determine the integrity of HPA by inducing a severe hypoglycemic state that activates HPA and all insulin counterregulatory hormones (cortisol and growth hormone). Due to the lower risk and greater ease of performance, the ACTH stimulation test is the most widely performed for the diagnosis of ISS. (1.6)
Plasma renin and aldosterone concentration: In ISP, plasma ACTH concentration at 8:00 a.m. is elevated and is associated with increased plasma-renin concentration or activity, low concentrations of aldosterone, hyperkalemia, and hyponatremia. In ISS or IsT, plasma concentrations of ACTH are low or normal-low associated with normal values of plasma concentrations of renin and aldosterone.( 6.7)

Treatment

Patients with ISP have deficit of glucocorticoids and mineralcorticoids and require replacement of both together with salt intake, according to needs. On the other hand, patients with ACTH deficit due to hypothesis or hypothalamic dysfunction after steroid use usually require only glucocorticoid replacement. Patients with ISP andISS also have a deficit of androgens although their replacement is not clearly defined. (6)

Glucocorticoids Replacement
- Hydrocortisone (15-25 mg) or cortisone acetate (20-35 mg) in two or three divided oral doses per day; the highest dose should be given in the morning at awakening and the following in the early afternoon (2 h after lunch; two-dose regimen) or at lunch and in the afternoon (three dose regimen). Higher frequency regimens and weight-adjusted doses may be beneficial in individual cases.
- As an alternative to hydrocortisone, prednisolone (3-5 mg/day) is suggested, administered orally once or twice a day. Glucocorticoid replacement should be monitored by clinical findings (weight, blood pressure, signs of excess glucocorticoids).( 7)
Mineralcorticoids replacement
- Fludrocortisone (starting dose of 50 to 100 μg/day). Monitoring of mineralocorticoid dosage is recommended through clinical findings (edema, postural hypotension, and salt craving) and blood electrolyte levels. In patients who develop hypertension, a decrease in the fludrocortisone dose is suggested. If hypertension is maintained, it is suggested the introduction of antihypertensive therapy and continued treatment with fludrocortisone.( 7)
DHEA Replacement
- DHEA (25 to 50 mg/day in the morning) should be considered in premenopausal women with ISP and decreased libido, depression, anxiety, and asthenia despite optimized replacement of glucocorticoids and mineralocorticoids. It is important to evaluate the clinical efficacy and potential side effects of therapy. Treatment should be monitored by measuring the morning serum levels of DHEA prior to administration. An initial period of 6 months of DHEA therapy is suggested. If there is no benefit, treatment should be discontinued. (6.7)
Treatment and Prevention of adrenergic crisis
- Hydrocortisone 100 mg EV in bolus followed by 200 mg EV in 5% continuous glucose in 24h or 50 mg IM every 6h;
- Resuscitation with NaCl 0.9% 500mL in 15 minutes followed by electrolyte replacement;
- Hydration with NaCl 0.9% 3-4 L in 24h with monitoring of electrolytes and water balance;
- Water-free intake;
- Cardiac monitoring (if necessary, transfer the patient to intensive care unit);
- The etiology of adrenergic crisis should be identified and treated;
- The prevention of adrenergic crisis involves the education/instruction of the patient about his pathology and administration of therapy; presence of an emergency card with information on additional administration of glucocorticoids; presence of hydrocortisone self-injection kits for emergency management; anti-influenza and antipneumococcal vaccination (>60 years). (4,5,6,7)

References

Hahner, S., Ross, R. J., Arlt, W., Bancos, I., Burger-Stritt, S., Torpy, D. J., . . . Quinkler, M. (11 de Março de 2021). Adrenal insufficiency. Nature Reviews – Disease Primers, pp. 1- 24.
Dutt, M., Wehrle, C. J., & Jialal, I. (9 de Maio de 2021). Physiology, Adrenal Gland. Obtido de StatPearls: https://www.ncbi.nlm.nih.gov/books/NBK537260/
Felicetti, F., Nervo, A., Gatti, F., Rosso, D., Brignardello, E., & Arvat, E. (6 de Dezembro de 2021). Stress Axis in the Cancer Patient: Clinical Aspects and Management. Endocrines, pp. 502-513.
Simpson, H., Tomlinson, J., Wass, J., Dean, J., & Arlt, W. (2020). Guidance for the prevention and emergency management of adult patients with adrenal insuffciency. Clinical Medicine, pp. Vol 20, No 4: 371–8.
Husebye, E. S., Pearce, S. H., Krone, N. P., & Kämp, O. (13 de Fevereiro de 2021). Adrenal insuficiency. Seminar – Lancet, pp. Vol 397: 613-629.
Nicolaides, N. C., Chrousus, G. P., & Charmandari, E. (14 de Outubro de 2017). Adrenal Insufficiency. Obtido de Endotext: https://www.ncbi.nlm.nih.gov/books/NBK279083/
Bornstein, S. R., Allolio, B., Arlt, W., Barthel, A., Don-Wauchope, A., Hammer, G. D., . . . Torpy, D. J. (Fevereiro de 2016). Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism, pp. 101(2):364–389.

CARCINOID SYNDROME

Authors: Diana Borges and Raquel G. Martins.

Definition

Carcinoid syndrome (CS) is a debilitating disease caused by the production of a variety of biologically active substances by functional neuroendocrine tumours (NETs).(1) It is the most frequent hormonal complication accompanying NETs and is defined by chronic diarrhoea and/or flushing in the presence of systemic elevated levels of serotonin or its metabolite 5-hydroxyindolacetc acid (5-HIAA).(2) While the reported frequency of CS among NET patients has been inconsistent, the negative impact on patient quality of life is clearly established.(3-5)

Symptoms and signs

Diarrhoea is often the presenting symptom of CS; it is defined as alterations in stool consistency, frequency, volume, and weight.2

Flushing, a clinical hallmark of CS, is an intermittent or persistent sensation of warmth together with skin erythema, usually involving the head, neck, and upper part of the torso, with telangiectasia in longstanding disease. In CS, flushing is usually not associated with sweating (‘dry flushing’).2

Bronchospasm is a rare manifestation of the CS, tending to develop concurrently with flushing, sneezing and dyspnoea and linked to histamine and serotonin secretion by the tumour. (2)

Carcinoid crisis is a potentially life-threatening complication of uncontrolled CS; it is defined by abrupt flushing, severe shifts in blood pressure with haemodynamic instability, profuse diarrhoea, and distressing bronchospasm with wheezing. (2)

Carcinoid heart disease (CHD)is a rare and complex cardiac complication occurring in patients with advanced NETs and CS, usually manifesting mainly as right-sided heart valves regurgitation/stenosis and eventually leading to right heart failure. (2)

Other rare features of CS result from diversion of dietary tryptophan for synthesis of serotonin; patients may develop pellagra (skin rashes, glossitis, stomatitis, dementia/mental

Etiology

CS is predominantly encountered in patients with NETs of intestinal origin, followed by lung, and only in a minority of patients with pancreatic, ovarian, thymic, or unknown origin NETs. (2)

Numerous active substances are potential mediators of the clinical features of CS; the most prominent being 5-hydroxytryptamine (serotonin).(6) Foregut NETs secrete 5- hydroxytryptophan (5-HTP) instead of 5-HT (atypical carcinoid syndrome). 6Other co-secreted peptide hormones and amines include tachykinins (substance P and neurokinin A), bradykinins, histamine, and prostaglandins. (6)

Carcinoid syndrome occurs when enough tumour-released bioactive products reaches the systemic circulation, escaping the first pass inactivation in the liver.(1,7) Carcinoid syndrome is thus predominantly encountered in patients with midgut NETs with liver metastases, in which these bioactive products escape inactivation in the liver. (7)

Ovarian NETs and large retroperitoneal metastases from midgut NETs are associated with CS in the absence of liver metastases as bioactive amines are released directly into the systemic circulation, bypassing hepatic inactivation. (7)

Studies

PMID 10080605; PMID 27214300; PMID 29330194; PMID 27918724

Pharmacotherapy

Drug Posology

2b 3b

Octreotide-long-acting release (LAR)	Initial dose for CS treatment: 30mg/ 4 weeks intramuscularly , may increase up to 30mg/2-3 weeks or 60mg/4 weeks.
Lanreotide-Autogel®	Initial dose for CS treatment: 120mg/ 4 weeks subcutaneously , may increase up to 120mg/2 weeks.
Short-acting octreotide	Uncontrolled CS ( in association with long-acting SSA): 100μg to 500μg subcutaneously every 6–8 h, for up to 2 weeks Carcinoid crisis prophylaxis: 100–500μg subcutaneously every 6–8 hor intravenous octreotide infused at a starting dose of 50μg/h , may increase up to 100–200μg/h.
Telostristat ethyl	Oral: 250mg 3 times daily
Niacin	Oral: 200-250mg once daily

2b 3b

1b 4

Therapeutic Strategy

2a 2b

Long-acting release (LAR) formulation octreotide or lanreotide Autogel are the first line treatment of CS.

When CS symptoms are moderate/severe, administration of the long-acting SSA (octreotide LAR or lanreotide Autogel®) should be combined with short-acting octreotide for up to 2 weeks or as a rescue therapy when CS is not controlled.

Worsening of CS 2–3 weeks after SSA injection may imply tachyphylaxis; more frequent doses of octreotide LAR or lanreotide Autogel® can be considered.

Hepatic resection should be applied with curative intent (R0 resection of metastatic lesions) or considered for symptom relief as cytoreductive (debulking) surgery, based on tumour operability/metastatic type

Loco-regional therapies (hepatic trans-arterial embolization / chemoembolization / radioembolization), may be considered for patients with predominant liver inoperable metastases, requiring CS control

Peptide Receptor Radionuclide Therapy with 177Lutetium-DOTATATE represents an effective option for patients. with positive somatostatin receptor imaging and refractory carcinoid syndrome

Telostristat ethyl should be added to SSA for control of refractory carcinoid syndrome-associated diarrhoea.

Short-acting octreotide prior to and during invasive procedures should be administered when major surgical/loco – regional interventions are considered or when there is concurrent carcinoid heart disease.

Nutrition counselling is recommended to improve nutrition status, control diarrhoea, and avoid foods that trigger carcinoid symptoms.

2b 3b 3a

1b 3b

A 35613326

B 35613326

A 35613326

A 30608900 10679645

A 35613326

B 35613326

A 35613326

B 3561332

A 3561332

4 A

Patients with niacin deficiency or pellagra should be started on niacin or nicotinamide

Surgical valve replacement is the established treatment for severe symptomatic cardiac heart disease with at least 12 months of anticipated post-operative NEN-related survival.

3b A

3561332

Hofland J, Herrera-Martínez AD, Zandee WT, de Herder WW. Management of carcinoid syndrome: a systematic review and meta-analysis. Endocr Relat Cancer. 2019;26(3):R145-R156. doi:10.1530/ERC-18- 0495
Grozinsky-Glasberg S, Davar J, Hofland J, et al. European Neuroendocrine Tumor Society (ENETS) 2022 Guidance Paper for Carcinoid Syndrome (CS) and Carcinoid Heart Disease (CHD). Journal of Neuroendocrinology. Published online April 25, 2022:e13146. doi:10.1111/JNE.13146
Fröjd C, Larsson G, Lampic C, von Essen L. Health related quality of life and psychosocial function among patients with carcinoid tumours. A longitudinal, prospective, and comparative study. Health and Quality of Life Outcomes. 2007;5(1):1-9. doi:10.1186/1477-7525-5-18/TABLES/5
Beaumont JL, Cella D, Phan AT, Choi S, Liu Z, Yao JC. Comparison of health-related quality of life in patients with neuroendocrine tumors with quality of life in the general US population. Pancreas. 2012;41(3):461-466. doi:10.1097/MPA.0B013E3182328045
Pearman TP, Beaumont JL, Cella D, Neary MP, Yao J. Health-related quality of life in patients with neuroendocrine tumors: an investigation of treatment type, disease status, and symptom burden. Support Care Cancer. 2016;24(9):3695-3703. doi:10.1007/S00520-016-3189-Z
Ito T, Lee L, Jensenc RT. Carcinoid-syndrome: recent advances, current status and controversies. Curr Opin Endocrinol Diabetes Obes. 2018;25(1):22. doi:10.1097/MED.0000000000000376
Fanciulli G, Ruggeri RM, Grossrubatscher E, et al. Serotonin pathway in carcinoid syndrome: Clinical, diagnostic, prognostic and therapeutic implications. Reviews in Endocrine and Metabolic Disorders. 2020;21(4):599-612. doi:10.1007/S11154-020-09547-8/TABLES/6

OPHTALMOLOGIC DISORDERS

ENTROPION AND ECTROPION

Authors: Joana Providência and André Coutinho

Definition

Ectropion is an outward turning of the eyelid margin, usually the inferior eyelid. Superior eyelid eversion is rare.
Entropion is an inward turning of the eyelid margin. Consequently, the lids are directed towards the ocular surface, causing abrasion of the cornea and conjunctiva.

Symptoms and signals

- - Patients with ectropion may experience symptoms related to ocular exposure, namely foreign body sensation, pain, ocular redness and blurred vision.
  - Entropion can cause corneal and conjunctival damage, namely corneal ulcers, scaring, neovascularisation, thinning and perforation.
  - Patients with entropion may present foreign body sensation, redness and tearing.

Etiology

- - Amechanical ectropion can occur in association with tumours of the eyelids, that displace the lower lid margin.
  - A cicatricial ectropion can be caused by shortening the skin of the periocular area, which can be associated with previous surgeries or trauma.
  - Involutional entropion can occur in association with increased laxity of the periocular structures, commonly in elderly patients.
  - Chemotherapy agents causing periocular tissues lesions:
    - Docetaxel
    - Docetaxel plus Anti Her-2
    - Pemetrexed
    - Pemetrexed plus platinum salts
    - Panitumumab )
    - Cetuximab
    - Erlotinib
    - 5FU
    - Biphosphonates (due to maxillary osteonecrosis)

Therapeutic Strategy

- - Refer to ophthalmologist.
  - Definite management of both entropion and ectropion conditions is surgical. The surgical plan is individualized to each patient’s facial structure by a specialized Oculoplastic Surgeon. Surgery is considered safe and effective.

Pharmacotherapy

Medical management is not definitive but can improve symptoms related to ocular surface exposure and inadequate lubrification.

Evidence

Level Grade PMID Nº

21283030

35814986 31749208

21187510

32642599

22584020

17237697

840160

24922331

Lubrification of the ocular surface with artificial tears applied frequently during the day and ocular ointments at night.
Botulinum toxin can be used for the treatment of some cases of entropion.

I B 28796122

I C 32270340

Taping of the eyelid can prevent ocular exposure during the night and/or day.
A therapeutic contact lens can be used to prevent symptoms related to ocular surface exposure.

References:

Wright M, Bell D, Scott C, Leatherbarrow B. Everting suture correction of lower lid involutional entropion. Br J Ophthalmol. 1999 Sep;83(9):1060-3.
Bashour M, Harvey J. Causes of involutional ectropion and entropion – age-related tarsal changes are the key. Ophthal Plast Reconstr Surg. 2000 Mar;16(2):131-41.
Christiansen G, Mohney BG, Baratz KH, Bradley EA. Botulinum toxin for the treatment of congenital entropion. Am J Ophthalmol. 2004
American Academy of Ophthalmology Focal Points: Ectropion and Entropion, Volume 12, Number 10, 1994

I B 29055359

Thulasi P, Djalilian AR. Update in Current Diagnostics and Therapeutics of Dry Eye Disease. Ophthalmology. 2017 Nov;124(11S):S27-S33. doi: 10.1016/j.ophtha.2017.07.022. PMID: 29055359; PMCID: PMC6660902.

KERATITIS / KERATO-CONJUNCTIVITES SICCA

Authors: Diogo Lima Lopes, André Coutinho and Andreia Silva

Definition

Characterized by:

- - Corneal oedema. • Infiltration of inflammatory cells. • Ciliary congestion.

Corneal inflammation:

- - may be ulcerative (a breach in the corneal epithelium with underlying infiltration of inflammatory cells) or nonulcerative.
  - may result from infectious or non-infectious causes. (1)

Symptoms and signs

Stinging pain, burning, foreign body sensation, blurred vision, photophobia, and increased tearing are some of the most common complaints.
Pentos Tatin: lesions generally occur bilaterally and are associated with pain and photophobia.

Etiology

The causes of keratitis can be divided into infectious and non-infectious, where chemotherapy agents can be included.
Cetuximab, panitumumab, amivantamab, erlotonib, gefitinib, and erdafitinib are some of the agents that are associated with dry eye, keratitis, corneal erosions, corneal thinning, and poor healing of the epithelial layer of the cornea leading to persistent epithelial defects that increase the risk of bacterial keratitis. The delayed wound healing may be explained by the essential role of at least two members of the epidermal growth factors receptor (EGFR) family in the cornea healing process.(4)
- Chemotherapy agents can also be associated with corneal epithelial defects that predispose to infectious keratitis.
- Agents targeting the epidermal growth factor receptor (EGFR) and the fibroblast growth factor receptor (FGFR) have some of the highest frequencies of corneal anterior segment toxicities.
- Some traditional chemotherapy agents (such as fluorouracil, cytarabine and pentostatin) are also frequently related to corneal side effects, including keratitis, corneal epithelial microcysts, and corneal epithelial punctate erosions.
- Antibody-drug conjugates, including belantamab mafodotin, enfortumab vedotin, and tisotumab vedotin, can also be very toxic to the cornea, and generally wearing contact lenses is discouraged due to concerns that the antibody-drug might achieve high concentration in the contact lens and exacerbate toxicity.
- Pentos Tatin has been associated with keratitis with corneal dendritic ulcerations of similar morphology to herpes simplex keratitis. However, these lesions generally occur bilaterally and are associated with pain and photophobia.

Evidence

Level Grade PMID Nº

V	19512896
IV	C	34144781
II	B	32712806

Macroscopic examination: redness, loss of corneal transparency, and sometimes a white/tan-coloured round lesion can be seen on the cornea on gross observation if there is an associated infiltrate.
Slit lamp examination is generally necessary to identify small ulcers and other findings such as corneal thinning, corneal epithelial defects, and corneal edema.

Therapeutic Strategy and Management

In the setting of ocular toxicity, many cases of eye symptoms can be managed symptomatically, maintaining the anticancer drug treatment. However, if vision is threatened, the decision to stop or continue cancer therapy must be individualized (benefits of continuing the specific chemotherapy drug vs the risks and consequences of ongoing ocular toxicity) and should be made jointly by the patient, the oncologist, and the ophthalmologist

Standard treatment

Frequent artificial tears may be enough to treat and solve most of the cases of corneal toxicity related to chemotherapy.
Generally, it is also recommended that patients with corneal erosions receive topical antibiotics (eye drops or ointment) to prevent superinfection.

Patients receiving anti-EGFR agent:

Generally, epithelial defects caused by agents targeting the EGFR are reversible with cessation of treatment. V
Regular follow-ups with an ophthalmologist in any patient who develops ocular symptoms like blurred vision, dry eyes, burning or stinging of the eyes, to manage symptoms and

monitor for signs of superinfection.

The decision to continue or stop the anti-EGFR therapy must be individualized, considering the risks and the availability of alternative treatments.

Antibody-drug conjugates, such as belantamab mafodotin, enfortumab vedotin, and tisotumab vedotin:

Artificial tears at least 4 times daily are recommended during the treatment and an ophthalmic examination is advised if ocular symptoms occur or do not resolve.
Contact lenses wearing should be avoided during treatment unless directed by an ophthalmologist.

Pentos Tatin: if complaints of pain and photophobia persist for several days patient must be referred to an ophthalmologist to help distinguish the aetiology. Fludarabine: Symptomatic management with artificial tears generally allows complete corneal healing after 14 to 21 days of treatment. V

References:

Sharma S. Keratitis. Biosci Rep [Internet]. 2001;21(4):419–44. Available from: https://doi.org/10.1023/A:1017939725776
Johnson KS, Levin F, Chu DS. Persistent corneal epithelial defect associated with erlotinib treatment. Cornea. 2009 Jul;28(6):706–7.

19512896

20224467

Shin E, Lim DH, Han J, Nam D-H, Park K, Ahn M-J, et al. Markedly increased ocular side effect causing severe vision deterioration after chemotherapy using new or investigational epidermal or fibroblast growth factor receptor inhibitors. BMC Ophthalmol [Internet]. 2020;20(1):19. Available from: https://doi.org/10.1186/s12886-019-1285-9
Nakamura Y, Sotozono C, Kinoshita S. The epidermal growth factor receptor (EGFR): role in corneal wound healing and homeostasis. Exp Eye Res. 2001 May;72(5):511–7.
Schmid KE, Kornek G V, Scheithauer W, Binder S. Update on ocular complications of systemic cancer chemotherapy. Surv Ophthalmol. 2006;51(1):19–40.
Farooq A V, Degli Esposti S, Popat R, Thulasi P, Lonial S, Nooka AK, et al. Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody-Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study. Ophthalmol Ther. 2020 Dec;9(4):889–911.
Liu C, Francis J, Abramson D. Ocular side effects of systemically administered chemotherapy [Internet]. UpToDate. 2021. Available from: https://www.uptodate.com/contents/ocular-side- effects-of-systemically-administered-chemotherapy/print
Spiers AS, Ruckdeschel JC, Horton J. Effectiveness of pentostatin (2′-deoxycoformycin) in refractory lymphoid neoplasms. Scand J Haematol. 1984 Feb;32(2):130–4.
Bishop RJ, Ding X, Heller CK 3rd, Illei G, Caruso RC, Cunningham D, et al. Rapid vision loss associated with fludarabine administration. Retina. 2010 Sep;30(8):1272–7.

CONJUNCTIVITIS

Authors: André Manuel da Silva Coutinho, Andreia Silva and Diogo Lopes.

Definition

Conjunctivitis, or inflammation of the conjunctiva, is a general term that refers to a diverse group of diseases/disorders that affect primarily the conjunctiva (1). Most conjunctivitis is a self-limited process, however, depending on the immune status of the patient and the aetiology, conjunctivitis can progress to a increasingly severe sight-

threatening condition (2).

Etiology

Conjunctivitis can be classified as infectious or non-infectious. The disease can also be classified into acute, hyperacute, and chronic according to the mode of onset and the severity of the clinical response (3).

Infectious causes:

Viral: the most common cause of infectious conjunctivitis in adult population and is more prevalent in the summer
Bacterial: the second most common cause of infectious conjunctivitis in adult population, it is observed more frequently from December through April
Fungus
Parasitic conjunctivitis

Non-infectious causes:

Allergic: the most frequent cause of conjunctivitis and is observed more frequently in the spring and summer
Toxic
Secondary to systemic causes: immune-mediated diseases
Neoplastic process

Toxic conjunctivitis in cancer patients:

Radiotherapy – when eyes are part of the treatment field
- Acute radiation effects
- Chronic radiation effects
Chemotherapy:

– 5-fluorouracil	– Ifosfamide	– Cyclophosphamide	– Nitrosoureas	– Cytosine	– Arabinoside	– Doxorubicin
– Mitomycin	– Methotrexate	– Deoxy formycin	– Carmustine	– Epirubicin	– Oprevelkin

Symptoms/signals

Conjunctival redness • Chemosis • Increase tearing
Discharge (purulent that crusts over the eyelashes in bacterial conjunctivitis) • Itchy eyes (especially in allergic conjunctivitis)
Gritty feeling • Burning eyes • Photophobia
Blurred vision • Swollen eyelids

Hyperacute bacterial conjunctivitis presents with a severe copious purulent discharge and decreased vision. There is often accompanying eyelid swelling, eye pain on palpation, and preauricular adenopathy. It is often caused by Neisseria gonorrhoeae and carries a high risk for corneal involvement and subsequent corneal perforation (4). They should be immediately managed.

Evidence

Level Grade PMID Nº

Studies

Patients’ history is important, such as contact with someone with infectious conjunctivitis or associated symptoms of seasonal allergies. (5)

Although in the primary care setting an ocular examination is often limited because of lack of a slit lamp, useful information may be obtained with a simple penlight. The eye examination should focus on the assessment of the visual acuity, type of discharge, corneal opacity, shape and size of the pupil, eyelid swelling, and presence of proptosis (3).

Labs and cultures are rarely indicated to confirm the diagnosis of conjunctivitis. Eyelid cultures and cytology are usually reserved for cases of recurrent conjunctivitis, those resistant to treatment, suspected gonococcal or chlamydial infection, suspected infectious neonatal conjunctivitis, and adults presenting with severe purulent discharge (6).

These severe cases of conjunctivitis should be reserved for Ophthalmologists

Therapeutic Strategy

According with American Academy of Ophthalmology (1), patients with conjunctivitis who are evaluated by no ophthalmologist health care providers should be referred promptly to the ophthalmologist in any of the following circumstances:

- Visual loss • Moderate or severe pain • Severe, purulent discharge • Corneal involvement
- Conjunctival scarring • Lack of response to therapy • Recurrent episodes • History of HSV eye disease
- History of immunocompromise • Contact lens users should stop wearing lens and referred to Ophthalmology. Treatment will depend on the cause
  - Higienic measures – Hands wash, avoid contact with family members or those with an impaired immune system, do not share towels or sheets with anyone, remove pus and discharge
  - Cold compressAvoid allergens in allergic conjunctivitis
  - Not wearing contact lenses

Pharmacotherapy

- Artificial tears- in all forms of conjunctivitis.
- Topical Antibiotics – bacterial conjunctivitis.
- Topical Antihistamines – allergic conjunctivitis.
- Topical Mast cell stabilizers – allergic conjunctivitis.
- Topical Nonsteroidal anti-inflammatory drugs (NSAIDs) – allergic conjunctivitis.
- Topical Corticosteroids – Should be reserved for Ophthalmologists.

References:

Conjunctivitis Preferred Practice Pattern – AAO
Acute Conjunctivitis (Pink Eye) – Emedicine 3 . Amir A. Azari, MD and Neal P. Barney, MDASystematic Review of Diagnosis and Treatment JAMA. 2013 October 23; 310(16): 1721–1729. doi:10.1001/jama.2013.280318.

4. Mannis, MJ.; Plotnik, RD. Bacterial conjunctivitis. In: Tasman, W.; Jaeger, EA., editors. Duanes Ophthalmology on CD-ROM. Lippincott Williams & Wilkins; 2006 5-. https://www.ncbi.nlm.nih.gov/books/NBK541034/Yanoff, M, Duker, J. Ophthalmology 5th Edition [Internet]. [cited 2020 Nov 13]. 1440 p. Available from

https://jhoponline.com/images/jhop/2015/March2015/JHOP_March2015_Vol5_No1_Pg14_Tbl2_Prophylaxes.png

Evidence

Level Grade PMID Nº

OROPHARYNGEAL DISORDERS

OROPHARYNGEAL CANDIDIASIS

Authors: Laura Martins Sobral Falcão Baptista and Tiago Valente

Definition and Etiology

Oropharyngeal candidiasis, also known as thrush, occurs as a result of the infection involving mucosal membranes caused by Candida species, usually Candida albicans (although non-Candida albicans has been reported in patients with advanced stages of cancer), and it is seen in both immunocompetent and immunocompromised patients
Among cancer patients on cytotoxic therapy, it is one of the most common manifestations, and invasion into deeper tissues can occur if not treated promptly.

Risk Factors

Evidence

Level Grade PMID Nº

Immunocompetent patients:
Denture wearers.
Patients with xerostomia.
Recent treatment with broad-spectrum antibiotics.
Inhaled corticosteroids.
Immunocompromised patients (e.g., compromised cell mediated immunity, which usually keeps fungal infections in check).
Hematologic malignancies. – Transplant recipients.
Patients receiving chemotherapy. – Treatment with corticosteroids.
Radiation therapy to the head and neck.

Symptoms

Most cases asymptomatic.
Cottony feeling in the mouth, loss of taste, and, in some cases, pain while eating and swallowing.

Signs

Pseudomembranous form (the most common): white plaques on the buccal mucosa, palate, tongue, and/or the oropharynx.
Caution: patients presenting with a white coating solely on their tongue rarely have candidiasis; this condition is usually caused by hypertrophic papillae.
Atrophic form: found under upper dentures and is characterized by erythema without plaques.

Studies

N/A.
The diagnosis of oropharyngeal candidiasis is usually made clinically in patients with risk factors for infection and characteristic findings on exam.

Therapeutic strategy

Oropharyngeal candidiasis should be treated at once when diagnosed, as immunocompromised patients may be at risk for progressive disease, such as invasive candidemia. The initial choice of therapy is usually based upon the severity of the disease (Table 1).

Table 1 – Pharmacotherapy

Mild disease: I A
- lotrimazole troches, 10 mg 5 times daily, OR miconazole mucoadhesive buccal 50-mg tablet applied to the mucosal surface over the canine fossa once daily for 7–14 days are recommended.

26679628

Evidence Level Grade PMID Nº

Alternatives for mild disease:
- Nystatin suspension (100 000 U/mL) 4–6 mL 4 times daily, OR 1–2 nystatin pastilles (200 000 U each) 4 times daily, for 7–14 days (strong recommendation; moderate- quality evidence).

* Moderate to severe disease:	I	A	26679628
Oral fluconazole, 100–200 mg daily, for 7–14 days is recommended.
* Fluconazole-refractory disease:	II	A	26679628
Itraconazole solution, 200 mg once daily OR posaconazole suspension, 400 mg twice daily for 3 days then 400 mg daily, for up to 28 days are recommended.
* Alternatives for fluconazole-refractory disease:	II	A	26679628
Voriconazole, 200 mg twice daily, ORAmB deoxycholate oral suspension, 100 mg/mL 4 times daily.
* Other alternatives for refractory disease:	II	B	26679628
Intravenous echinocandin (caspofungin: 70-mg loading dose, then 50 mg daily; micafungin: 100 mg daily; or anidulafungin: 200-mg loading dose, then 100 mg daily) OR * Chronic suppressive therapy is usually unnecessary. If required for patients who have recurrent infection, fluconazole, 100 mg 3 times weekly, is recommended.	I	A	26679628
*For denture-related candidiasis, disinfection of the denture, in addition to antifungal therapy is recommended.	II	A	26679628
References:

II A

26679628

intravenous AmB deoxycholate, 0.3 mg/kg daily.

Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, Reboli AC, Schuster MG, Vazquez JA, Walsh TJ, Zaoutis TE, Sobel JD. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Feb 15;62(4):e1-50. doi: 10.1093/cid/civ933. Epub 2015 Dec 16. PMID: 26679628; PMCID: PMC4725385.
Pankhurst CL. Candidiasis (oropharyngeal). BMJ Clin Evid. 2013 Nov 8;2013:1304. PMID: 24209593; PMCID: PMC3821534.
Sangeorzan JA, Bradley SF, He X, Zarins LT, Ridenour GL, Tiballi RN, Kauffman CA. Epidemiology of oral candidiasis in HIV-infected patients: colonization, infection, treatment, and emergence of fluconazole resistance. Am J Med. 1994 Oct;97(4):339-46. doi: 10.1016/0002-9343(94)90300-x. PMID: 7942935.
Akpan A, Morgan R. Oral candidiasis. Postgrad Med J. 2002 Aug;78(922):455-9. doi: 10.1136/pmj.78.922.455. PMID: 12185216; PMCID: PMC1742467.
Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, Reboli AC, Schuster MG, Vazquez JA, Walsh TJ, Zaoutis TE, Sobel JD. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Feb 15;62(4):e1-50. doi: 10.1093/cid/civ933. Epub 2015 Dec 16. PMID: 26679628; PMCID: PMC4725385.
Wilberg P, Hjermstad MJ, Ottesen S, Herlofson BB. Oral health is an important issue in end-of-life cancer care. Support Care Cancer. 2012 Dec;20(12):3115-22. doi: 10.1007/s00520-012-1441-8. Epub 2012 Mar 21. PMID: 22434497.
Shay K, Truhlar MR, Renner RP. Oropharyngeal candidosis in the older patient. JAm Geriatr Soc. 1997 Jul;45(7):863-70. doi: 10.1111/j.1532-5415.1997.tb01517.x. PMID: 9215341.
Epstein JB, Freilich MM, Le ND. Risk factors for oropharyngeal candidiasis in patients who receive radiation therapy for malignant conditions of the head and neck. Oral Surg Oral Med Oral Pathol. 1993 Aug;76(2):169-74. doi: 10.1016/0030-4220(93)90199-e. PMID: 8361726.
Peterson DE, Boers-Doets CB, Bensadoun RJ, Herrstedt J; ESMO Guidelines Committee. Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2015 Sep;26 Suppl 5:v139-51. doi: 10.1093/annonc/mdv202. Epub 2015 Jul 4. PMID: 26142468.

ORAL MUCOSITIS AND STOMATITIS

Authors: Duarte Domingues, Cecília Caramujo de Sá and João Boavida Ferreira

Definition

Oral mucositis refers to erythematous and ulcerative lesions of the oral mucosa observed in cancer patients being treated with chemotherapy and/or radiation therapy to fields involving the oral cavity. [1]
Stomatitis refers more generally to any inflammatory condition of oral tissues. This term should be used for oral complaints not related to chemotherapeutic agents or ionising radiation, such as the ones due to immunotherapy or targeted therapies (e.g., mammalian target of rapamycin (mTOR) inhibitors, or tyrosine kinase inhibitors). [2]

Symptoms

Xerostomia, erythema, ulceration, dysgeusia, oral pain, dysphagia, difficulty talking, and halitosis. [3]
Oral mucositis can be very painful and can significantly affect nutritional intake, mouth care, and quality of life. [1]
If the duration of symptoms is not consistent with oral mucositis, an underlying infection may be developing, or an alternative diagnosis might be more probable [4].
Infections associated with oral mucositis can cause life-threatening systemic sepsis during periods of profound immunosuppression. [1]
Chemotherapy-induced oral mucositis usually develops fully 4-5 days after chemotherapy administration, and peaks at 5 days after the beginning of symptoms [5].
Radiotherapy-induced oral mucositis starts developing after 10 Gy of radiation, with ulceration developing after 30 Gy (around the 3rd week of treatment) [5]. The dose of radiotherapy administered has a cumulative effect on the severity of lesions [4]. The extent of mucositis depends on the radiation field [4]. Oral mucositis symptoms may extend for several weeks after radiotherapy [4].
For patients receiving high-dose chemotherapy prior to hematopoietic stem-cell transplantation (HSCT), oral mucositis has been reported to be the single most debilitating complication of transplantation. [1]
Oral mucositis and stomatitis, especially if of a high-grade, may lead to hospitalisation, delays in cancer treatment, worse prognosis, and higher financial costs.

Etiology

Oral mucositis develops in approximately 20-40% of solid tumour patients receiving chemotherapy [6]. That percentage goes up to 80% in patients receiving high-dose chemotherapy prior to hematopoietic stem cell transplantation (HSCT) [7], and virtually all head and neck cancer patients treated with chemoradiation therapy develop oral mucositis [7].
In general, chemotherapeutic agents that target the deoxyribonucleic acid (DNA) cell cycle are more prone to causing mucositis than those that are not cell phase-specific [8].
Chemotherapy regimens containing fluorouracil, methotrexate, etoposide, melphalan, cytarabine, and doxorubicin [8,9] are associated with a particularly increased risk of mucositis, but this can also occur with other chemotherapeutic agents in dose-dense regimens [9].
Methotrexate and etoposide may be excreted in the saliva, thereby aggravating their potential for mucositis [8].
Oral mucositis caused by chemo- and radiotherapy can be described by a five-stage model [1,5,8,9]:
- 1. Initiation: chemotherapy and radiotherapy produce reactive oxygen species (ROS), causing cellular damage in the basal epithelial cells. During this state, the mucosa seems mostly normal.
  2. Upregulation and message: tissue damage activates second messengers, like p53 and NF-κB, leading to the production of pro-inflammatory cytokines, like TNF-α, IL-1β, and IL-6.
  3. Signal amplification: the pro-inflammatory cytokines are upregulated, leading to cell injury and death, further amplifying the molecular pathways. During this stage, oral mucositis may still be subclinical.
  4. Ulceration: during this stage, the cellular damage becomes visible in the form of mucosal lesions. The loss of mucosal integrity induces colonization by the oral microorganisms, including bacteria, inducing further amplification of pro-inflammatory cytokines.
  5. Healing: when there is a cessation of the tissue damage that triggered the mucositis, the epithelium once again proliferates and restores the integrity of the epithelium.

Evidence

Level Grade PMID Nº

Evidence

Stomatitis is observed in patients treated with targeted treatments, namely mTOR inhibitors (73% of patients treated with tensirolimus and everolimus) and tyrosine kinase Level Grade PMID Nº

inhibitors (72% of patients treated with afatinib, and 30-40% of patients treated with sunitinib, sorafenib, lenvatinib and regorafenib) [8]. For other TKIs and immunotherapy, the percentages are lower.

It is not clear whether the pathogenesis of stomatitis (caused by molecular-targeted therapies) is comparable with mucositis caused by chemo- and radiotherapy. [2]
The most frequent infections arising from oral mucositis involve the yeasts Candida [10] and the Herpes simplex virus [11], in the context of chemotherapy-induced immunosuppression and radiotherapy-induced xerostomia [4].
Other causes of oral mucositis in cancer patients are loose-fitting dental prosthetics, trauma, poor dental hygiene, low nutritional status, dehydration, smoking, alcohol intake, low pre-treatment neutrophil counts, and hematologic malignancies. [3,9].

Studies

The Pharmacotherapy and Therapeutic Strategy sections were based on the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) 2019-2020 Guideline, by Elad et al. (2020) [12]
Levels of evidence were attributed according to the Oxford University Centre for Evidence-Based Medicine, Great Britain, and Northern Ireland, and were retrieved from Burns et al. (2011) [13].
Grades of recommendation were attributed according to the American Society of Plastic Surgeons evidence-based clinical practice guidelines (retrieved from Burns et al. (2011)) [13] and are presented following the recommendation by the MASCC/ISOO 2019-2020 Guideline [12]. Spielberger, R. et al. (2004); Palifermin for oral mucositis after intensive therapy for hematologic cancers N Engl J Med Dec 16;351(25):2590-8. https://doi/10.1056/NEJMoa040125
Rugo, H.S. et al. (2017); Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial; Lancet Oncol May;18(5):654-662. https://doi/10.1016/S1470-2045(17)30109-2
Cerchietti. L.C.A. et al. (2003); Effect of topical morphine for mucositis-associated pain following concomitant chemoradiotherapy for head and neck carcinoma; Cancer 2002; 95:2230; https://doi/10.1002/cncr.10938
Carnel, S.B. et al. (1990); Treatment of radiation- and chemotherapy-induced stomatitis; Otolaryngol Head Neck Surg, Apr;102(4):326-30; https://doi/10.1177/019459989010200404
Coda, B.A. et al. (1997); Comparative efficacy of patient-controlled administration of morphine, hydromorphone, or sufentanil for the treatment of oral mucositis pain following bone marrow transplantation; Pain 1997; 72:333; https://doi/10.1016/s0304-3959(97)00059-6
Mohammadi, F. et al. (2022); Effectiveness of sodium bicarbonate and zinc chloride mouthwashes in the treatment of oral mucositis and quality of life in patients with cancer under chemotherapy; Nurs Open, Feb 16., https://doi/10.1002/nop2.1168
Epstein, J.B. et al. (2001); Benzydamine HCl for prophylaxis of radiation-induced oral mucositis: results from a multicenter, randomized, double-blind, placebo-controlled clinical trial; Cancer, Aug 15;92(4):875-85; https://doi/10.1002/1097-0142(20010815)92:4<875::aid-cncr1396>3.0.co;2-1

Pharmacotherapy

DRUG POSOLOGY

- - 1. A

Benzydamine mouthwash for the prevention of oral mucositis in patients with head and neck cancer receiving a moderate dose of RT (< 50 Gy)

Rinse 15 ml of 0.15% benzydamine hydrochloride solution for 2 minutes, 4 -8 times daily

Benzydamine mouthwash for the prevention of oral mucositis in patients

with head and neck cancer receiving chemoradiation therapy

Rinse 15 ml of 0.15% benzydamine hydrochloride solution for 2 minutes, 4 -8 times

daily

- - 1. C

32786044

Evidence

DRUG POSOLOGY

Level Grade PMID Nº

28314691

Dexamethasone mouthwash for prevention of stomatitis in patients taking everolimus	Swish and spit 10 ml of non -alcoholic dexamethasone solution (0.5 mg dexamethasone/5 ml oral solution), for 2 minutes, 4 times daily, for 8 weeks; the patient should not eat for 1 h after swishing the dexamethasone solution
Oral glutamine for the prevention of oral mucositis in patients with head and neck cancer who receive chemoradiation therapy	No standardised posology
Palifermin intravenously for the prevention of oral mucositis in patients with hematologic cancer undergoing autologous HSCT with a conditioning regimen that includes high-dose chemotherapy and total body irradiation	60 µg/kg-day for 3 days before conditioning treatment (total body irradiation or high dose chemotherapy) and for 3 days post-transplant
Saline or bicarbonate rinses	Rinse of 7.5 ml of a solution of sodium bicarbonate at 5%, for 2 minutes, every 8 h
Systemic corticotherapy: to be considered in patients with refractory mTOR inhibitor mucositis	No standardised posology
Topical morphine for the treatment of oral mucositis-associated pain in patients with head and neck cancer who receive chemoradiation therapy	Swish and spit 15 ml of 0.2% morphine sulphate solution (2 mg morphine ml water) for 2 minutes, every 3 hours, 6 times per day

II	C	32786044
I	A	32786044
III	D	35170247
III	C	32786044

HSCT – hematopoietic stem cell transplantation, PMID – PubMed identifier

Directed therapeutic strategy

Treatment of oral mucositis/stomatitis takes a stepwise approach, from mild to severe symptoms [3,9]:

Water soluble lubricants: bland rinses with normal saline or salt and soda. In the case of oral mucositis secondary to everolimus, start with dexamethasone mouthwash.
Topical analgesics such as morphine In the case of oral mucositis secondary to everolimus, consider systemic steroids for refractory mucositis;
Systemic analgesics, namely opiates.

Strategy

Oral hygiene: brushing the teeth with a soft toothbrush, twice a day, with daily flossing

Diet modifications: As prevention, avoid starchy, acidic, rough, or sharp foods (e.g.: potato chips); should be applied after the onset of mucositis, to limit further trauma because of chewing—avoid spicy, rough or sharp foods

Benzydamine mouthwash for the prevention of oral mucositis in patients with head and neck cancer receiving a moderate dose of RT (< 50 Gy)

Benzydamine mouthwash for the prevention of oral mucositis in patients with head and neck cancer receiving chemoradiation therapy

Dexamethasone mouthwash for prevention of stomatitis in patients taking everolimus

Honey for the prevention of oral mucositis in patients with head and neck cancer who receive treatment with either radiotherapy or chemoradiotherapy

Multi-agent combination oral care , including bland mouth rinses, toothbrushes, and flossing procedures during chemotherapy, head, and neck radiotherapy, and HSCT

Oral cryotherapy: ice chips swished around the mouth, beginning 5 minutes before administration ofchemotherapy, and replenished as needed for up to 30 minutes,

in patients receiving bolus 5-FU-containing chemotherapy, or pre-autologous HSCT high-dose melphalan

Oral glutamine for the prevention of oral mucositis in patients with head and neck cancer who receive chemoradiation therapy (please note that there was a higher

mortality rate in patients undergoing HSCT who had parenteral glutamine administered as prevention of oral mucositis [14])

II A

32048926

32786044

28314691

32786044

Palifermin intravenously for the prevention of oral mucositis in patients with hematologic cancer undergoing autologous HSCT with a conditioning regimen that includes high-dose chemotherapy and total body irradiation

Patient education may improve adherence to treatment protocols

Photobiomodulation intra-orally using low-level laser therapy for the prevention of oral mucositis in adults receiving chemoradiation therapy for head and neck cancer

Photobiomodulation intra-orally using low -level laser therapy for the prevention of oral mucositis in adult patients receiving HSCT conditioned with high -dose chemotherapy, with or without total body irradiation

Photobiomodulation intra-orally using low-level laser therapy for the prevention of oral mucositis in adults receiving radiotherapy to the head and neck

Professional oral assessment for prevention of local and systemic infections from odontogenic sources, limited or no evidence for the prevention of oral mucositis

Saline or bicarbonate rinses

Systemic corticotherapy: to be considered in patients with refractory mTOR inhibitor mucositis

Topical morphine for the treatment of oral mucositis-associated pain in patients with head and neck cancer who receive chemoradiotherapy

Parenteral nutrition and fluid replacement: in patients developing severe mucositis, without being able to swallow

I	A	32786044
III	D	32786044
I	A	32786044
I	A	32786044
II	A	32786044
III	D	32786044
III	D	32786044
III	B	32786044
		18154865

HSCT – hematopoietic stem cell transplantation, PMID – PubMed identifier

Other therapeutic strategies

Other sensible strategies include:

Strategy

Antibiotherapy for treating underlying infections

Diet modifications: avoid spicy, acidic, rough, or sharp foods (e.g., potato chips). Also, avoid alcohol and tobacco

Hydration should be maintained, so as to keep the mouth moist

Nasogastric tube in patients who are no longer able to take their food orally (some centresprophylactically place nasogastric tubes for the prevention of oral mucositi-s associated malnourishment and decreased quality of life)

Parenteral nutrition and fluid replacement: in patients developing severe mucositis, without being able to swallow

Percutaneous endoscopic gastrostomy (PEG)in patients who are no longer able to take their food orally, and for whom a nasogastric feeding tube is contraindicated (some centres prophylactically place PEGs for the prevention of oral mucositis-associated malnourishment and decreased quality of life)

Speech therapy: the pharyngeal muscles are especially sensitive to radiotherapy, and, as other muscles of the body, need practice to be fully functional. Thus, head

and neck cancer patients submitted to radiotherapy or chemoradiotherapy should be prompted to maintain the ingestion of food orally and to keep swallowing during their treatment. After treatment, all patients should be referred to a speech pathologist to retrain their pharyngeal muscles and improve their swallowing

Topical agents, e.g., fibrin glue, gelatine sponge, aminocaproic acid, tranexamic acid: to be considered in patients who experience bleeding, especially if they have thrombocytopenia and/or a coagulation disorder (or are taking an anticoagulant)

References:

1. Lalla, R.V., Sonis, S.T., Peterson, D.E.; “Management of Oral Mucositis in Patients with Cancer”; Dent Clin North Am. 2008 Jan; 52(1): 61–viii. https://doi.org/10.1016/j.cden.2007.10.002
2. Peterson, D.E., Boers-Doets, C.B., Bensadoun, R.J.; Herrstedt, J. on behalf of the ESMO Guidelines Committee; Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up (2015); Annals of Oncology 26 (Supplement 5): v139–v151, 2015; https://doi.org/10.1093/annonc/mdv202
3. O’Brien, C.P.; Management of stomatitis (2009); Can Fam Physician. Sep; 55(9): 891–892.
4. Lalla RV, Saunders DP, Peterson DE (2014). Chemotherapy or radiation-induced oral mucositis. Dental Clinics of North America, 58(2):341-349. Doi: 10.1016/j.cden.2013.12.005
5. Sonis ST (2007). Pathobiology of Oral Mucositis: Novel Insights and Opportunities. Journal of Supportive Oncology, 5(9 supplement 4):3-11. PMID: 18046993
6. Jones JA, Avritscher EB, Cooksley CD, Michelet M, Bekele BN, Elting LS (2006). Epidemiology of treatmentassociated mucosal injury after treatment with newer regimens for lymphoma, breast, lung, or colorectal cancer. Supportive Care in Cancer, 14(6):505–515. Doi: 10.1007/s00520-006-0055-4
7. Vera-Llonch M, Oster G, Ford CM, Lu J, Sonis S (2007). Oral mucositis and outcomes of allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies. Supportive Care in Cancer, 15(5):491–496. Doi: 10.1007/s00520-006-0176-9
8. Negrin, R.S.; Treister, N.S.; Oral toxicity associated with systemic anticancer therapy; UpToDate, retrieved February 27, 2022 from https://www.uptodate.com/contents/oral-toxicity-associated-with- systemic-anticancer-therapy/print
9. Brown, T.J.; Gupta, A. (2020); Management of Cancer Therapy–Associated Oral Mucositis; JCO Oncology Practice 16:3, 103-109
10. Nicolatou-Galitis O, Velegraki A, Sotiropoulou-Lontou A, Dardoufas K, Kouloulias V, Kyprianou K, Kolitsi G, Skarleas C, Pissakas G, Papanicolaou VS, Kouvaris J (2006). Effect of fluconazole antifungal prophylaxis on oral mucositis in head and neck cancer patients receiving radiotherapy. Supportive Care in Cancer, 14(1):44-51. Doi: 10.1007/s00520-005-0835-2
11. Schubert MM (1991). Oral manifestations of viral infections in immunocompromised patients. Current opinion in dentistry, 1(4):384-397. PMID: 1666308
12. Sharon Elad, Karis Kin Fong Cheng, Rajesh V Lalla, Noam Yarom, Catherine Hong, Richard M Logan, Joanne Bowen, Rachel Gibson, Deborah P Saunders, Yehuda Zadik, Anura Ariyawardana, Maria Elvira Correa, Vinisha Ranna, Paolo Bossi, Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) (2020). MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer, 126(19):4423-4431. Doi: 10.1002/cncr.33100
13. Burns, P. B., Rohrich, R. J., Chung, K. C. (2011). The Levels of Evidence and their role in Evidence-Based Medicine. Plastic and Reconstructive Surgery, 128(1), 305-310. Doi: 10.1097/PRS.0b013e318219c171
14. Noam Yarom, Allan Hovan, Paolo Bossi, Anura Ariyawardana, Siri Beier Jensen, Margherita Gobbo, Hanan Saca-Hazboun, Abhishek Kandwal, Alessandra Majorana, Giulia Ottaviani, Monica Pentenero, Narmin Mohammed Nasr, Tanya Rouleau, Anna Skripnik Lucas, Nathaniel Simon Treister, Eyal Zur, Vinisha Ranna, Anusha Vaddi, Karis Kin Fong Cheng, Andrei Barasch, Rajesh V Lalla, Sharon Elad, Mucositis Study Group of the Multinational Association of Supportive Care in Cancer / International Society of Oral Oncology (MASCC/ISOO) (2019). Systematic review of natural and miscellaneous agents for the management of oral mucositis in cancer patients and clinical practice guidelines-part 1: vitamins, minerals, and nutritional supplements. Supportive Care in Cancer, 27(10):3997-4010. doi: 10.1007/s00520-019-04887-x
15. Spielberger, R. et al. (2004); Palifermin for oral mucositis after intensive therapy for hematologic cancers N Engl J Med Dec 16;351(25):2590-8. https://doi/10.1056/NEJMoa040125
16. Rugo, H.S. et al. (2017); Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial; Lancet Oncol May;18(5):654-662. https://doi/10.1016/S1470-2045(17)30109-2
17. Cerchietti. L.C.A. et al. (2003); Effect of topical morphine for mucositis-associated pain following concomitant chemoradiotherapy for head and neck carcinoma; Cancer 2002; 95:2230; https://doi/10.1002/cncr.10938
18. Carnel, S.B. et al. (1990); Treatment of radiation- and chemotherapy-induced stomatitis; Otolaryngol Head Neck Surg, Apr;102(4):326-30; https://doi/10.1177/019459989010200404
19. Coda, B.A. et al. (1997); Comparative efficacy of patient-controlled administration of morphine, hydromorphone, or sufentanil for the treatment of oral mucositis pain following bone marrow transplantation; Pain 1997; 72:333; https://doi/10.1016/s0304-3959(97)00059-6
20. Mohammadi, F. et al. (2022); Effectiveness of sodium bicarbonate and zinc chloride mouthwashes in the treatment of oral mucositis and quality of life in patients with cancer under chemotherapy; Nurs Open, Feb 16., https://doi/10.1002/nop2.1168
21. Epstein, J.B. et al. (2001); Benzydamine HCl for prophylaxis of radiation-induced oral mucositis: results from a multicenter, randomized, double-blind, placebo-controlled clinical trial; Cancer, Aug 15;92(4):875-85; https://doi/10.1002/1097-0142(20010815)92:4<875::aid-cncr1396>3.0.co;2-1
22. Elad, S. et al. (2020); MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy; Cancer, Oct 1; 126(19): 4423–4431; https://doi/10.1002/cncr.33100
23. XEROSTOMIA

Authors: Cecília Caramujo de Sá and João Boavida Ferreira

Definition

Patient-reported, subjective sensation of oral dryness and decreased salivary flow.

Symptoms

Dry mouth sensation, which can alter taste and may impair speech and swallowing, with consequent impaired oral intake and malnutrition [1,2]
Patients with dry mouth also seem to be at higher risk for the development of caries and secondary fungal infections. [2]
Dry, uncomfortable mucosal tissues and thick, ropy saliva.
Some patients may present with dry mucous membranes of varying severity
Patients with xerostomia may also complain of dysgeusia. [3,4]
Chemotherapy-related xerostomia can be associated with oropharyngeal and oesophageal mucositis. It is especially deleterious for head and neck cancer patients submitted to concomitant chemoradiotherapy.

Etiology

Most frequent causes of xerostomia with reduced salivary flow: radiation therapy (RT), chemotherapy, surgery (particularly for head and neck cancers), drugs (anticholinergics, antidepressants, antihypertensive drugs, opioids, anxiolytics, antihistamines, beta-blockers), dehydration (diabetes mellitus, diarrhoea, vomiting, haemorrhage, reduced fluid intake), Sjögren syndrome, salivary calculi (sialolithiasis), mumps, sarcoidosis, parotid agenesis, and oral infections. [1,5]
Xerostomia with normal salivary flow may be psychogenic. [1]
Xerostomia is the most common long-term complication of RT and chemoradiotherapy for head and neck cancer patients. Patients often refer to xerostomia as their single most upsetting chronic symptom, causing a severe decrease in quality of life.
Changes in quantity and composition of saliva may occur shortly after the initiation of RT (within 1 to 2 weeks). [6,7] The Etiology of the acute reaction of salivary gland cells in patients undergoing RT is still unclear. [8-10]. These effects are possibly related to the irradiation of both major salivary glands bilaterally (parotid, submandibular, sublingual) and minor salivary glands that are scattered throughout the upper aerodigestive tract.
Permanent reduction in the production of saliva can be noted with cumulative radiation doses as low as 10 to 15 Gy to the parotid gland. [6,11-13]
Mean radiation doses greater than 24 to 26 Gy cause permanent damage to the parotid glands, typically resulting in more than a 75% reduction in salivary gland function. [6,11-13]
Impairment in oral intake, often related to mucositis or dysgeusia, also contributes to a decrease in saliva production.
Other comorbid conditions and pharmacological treatments may also increase the risk of both acute and long-term xerostomia.

Pharmacotherapy

Evidence

Level Grade PMID Nº

DRUG POSOLOGY

1B C 34283635

Bethanechol

No standardized posology

Evidence

DRUG POSOLOGY

Level Grade PMID Nº

Oral pilocarpine (post radiation therapy in patients with head and neck cancer)

Xerostomia associated with head and neck cancer: Oral: Initial: 5 mg 3 times daily; may titrate dose based on response and tolerability; usual dosage range: 15 to 30 mg/day; maximum: 10 mg/dose

Dosage adjustment if hepatic impairment.

Oral cevimeline (post radiation therapy in patients with head and neck cancer)

Oral: 30 mg 3 times/day.

Saliva substitutes and mucosal lubricants

No standardized posology

1B A

1A B

Therapeutic Strategy

•Although xerostomia often improves with time, [15] it usually lasts for a long time and becomes permanent. Quality of life may be significantly diminished for patients affected by 1A B xerostomia. The management of xerostomia aims to provide alternative wetting agents and maximize residual function of the salivary glands. The evidence for these strategies

is scarce.

V D

Intensity-modulated radiation therapy (IMRT) as salivary glands-sparing radiation modality

Other salivary glands-sparing radiation modalities

Saliva substitutes and mucosal lubricants may be offered to improve xerostomia induced by nonsurgical cancer therapies

Sugar-free lozenges, acidic (nonerosive and sugar-free special preparation if dentate patients) candies, or sugar-free, nonacidic chewing gum

Gustatory and masticatory salivary reflex stimulation may be offered to produce transitory increased saliva flow rate and transitory relief from xerostomia by stimulating residual capacity of salivary gland tissue

Oral pilocarpine and cevimeline (post radiation therapy in patients with head and neck cancer)

May be offered after radiation therapy in patients with head and neck cancer fortransitory improvement of xerostomia and salivary gland hypofunction by stimulating residual capacity of salivary gland tissue. However, improvement of salivary gland hypofunction may be limited.

Bethanechol may be offered during radiation therapy for head and neck cancer to reduce the risk of salivary gland hypofunction and xerostomia

Acupuncture may be offered during radiation therapy for head and neck cancer to reduce the risk of developing xerostomia andafter radiation therapy for improvement of xerostomia in the long-term.

Transcutaneous electrostimulation or acupuncture-like transcutaneous electrostimulation of the salivary glands(post radiation therapy in patients with head and neck cancer)

1A B

1B B

1B A

1B C

2A C

1B C

34283635

Evidence

Relevant publications ^Level ^Grade ^PMID ^Nº

•The Pharmacotherapy and Therapeutic Strategy sections were based on the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology/American Society of Clinical Oncology (MASCC/ISOO/ASCO) 2021 Guideline, by Mercadante et al. (2021). [5]

•Levels of evidence were attributed according to the Oxford University Centre for Evidence-Based Medicine, Great Britain and Northern Ireland, and were retrieved from Burns et al. (2011). [14]

•Grades of recommendation were attributed according to the American Society of Plastic Surgeons evidence-based clinical practice guidelines (retrieved from Burns et al. (2011)), [14] and are presented following the recommendation by the MASCC/ISOO/ASCO 2021 Guideline. [5]

References:

Sweeney, M. P., & Bagg, J. (2000). The mouth and palliative care. American Journal of Hospice and Palliative Medicine®, 17(2), 118–124. https://doi.org/10.1177/104990910001700212
Bruera, E., & Dev, R. (2021). Overview of managing common non-pain symptoms in palliative care. In J. Givens (Ed.), UpToDate. Retrieved January 4, 2022, from https://www.uptodate.com/contents/overview-of-managing-common-non-pain-symptoms-in-palliative-care

3 . Peterson DE, Schubert MM. Oral toxicity. In: The Chemotherapy Source Book, 3rd ed, Perry MC (Ed), Williams and Wilkins, Baltimore 2001.

Negrin, R.S., (2021). Oral toxicity associated with chemotherapy. In D. MF Savarese (Ed.), UpToDate. Retrieved January 4, 2022, from https://www.uptodate.com/contents/oral-toxicity-associated- with-chemotherapy
Mercadante, V., Jensen, S. B., Smith, D. K., Bohlke, K., Bauman, J., Brennan, M. T., Coppes, R. P., Jessen, N., Malhotra, N. K., Murphy, B., Rosenthal, D. I., Vissink, A., Wu, J., Saunders, D. P., & Peterson, D. E. (2021). Salivary Gland Hypofunction and/or Xerostomia Induced by Nonsurgical Cancer Therapies: ISOO/MASCC/ASCO Guideline. Journal of clinical oncology:official journal of the American Society of Clinical Oncology, 39(25), 2825–2843. https://doi.org/10.1200/JCO.21.01208
Thomas Galloway, T. & Amdur, R.J., (2021). Management and prevention of complications during initial treatment of head and neck cancer. In S. Shah (Ed.), UpToDate. Retrieved January 4, 2022, from https://www.uptodate.com/contents/management-and-prevention-of-complications-during-initial-treatment-of-head-and-neck-cancer
Burlage, F. R., Coppes, R. P., Meertens, H., Stokman, M. A., & Vissink, A. (2001). Parotid and submandibular/sublingual salivary flow during high dose radiotherapy. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology, 61(3), 271–274. https://doi.org/10.1016/s0167-8140(01)00427-3
Avila, J. L., Grundmann, O., Burd, R., & Limesand, K. H. (2009). Radiation-induced salivary gland dysfunction results from p53-dependent apoptosis. International journal of radiation oncology, biology, physics, 73(2), 523–529. https://doi.org/10.1016/j.ijrobp.2008.09.036
Abok, K., Brunk, U., Jung, B., & Ericsson, J. (1984). Morphologic and histochemical studies on the differing radiosensitivity of ductular and acinar cells of the rat submandibular gland. Virchows Archiv. B, Cell pathology including molecular pathology, 45(4), 443–460. https://doi.org/10.1007/BF02889885
Nagler, R., Marmary, Y., Fox, P. C., Baum, B. J., Har-El, R., & Chevion, M. (1997). Irradiation-induced damage to the salivary glands: the role of redox-active iron and copper. Radiation research, 147(4), 468–476.
Deasy, J. O., Moiseenko, V., Marks, L., Chao, K. S., Nam, J., & Eisbruch, A. (2010). Radiotherapy dose-volume effects on salivary gland function. International journal of radiation oncology, biology, physics, 76(3 Suppl), S58–S63. https://doi.org/10.1016/j.ijrobp.2009.06.090
Chao, K. S., Deasy, J. O., Markman, J., Haynie, J., Perez, C. A., Purdy, J. A., & Low, D. A. (2001). A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: initial results. International journal of radiation oncology, biology, physics, 49(4), 907–916. https://doi.org/10.1016/s0360-3016(00)01441-3
Blanco, A. I., Chao, K. S., El Naqa, I., Franklin, G. E., Zakarian, K., Vicic, M., & Deasy, J. O. (2005). Dose-volume modeling of salivary function in patients with head-and-neck cancer receiving radiotherapy. International journal of radiation oncology, biology, physics, 62(4), 1055–1069. https://doi.org/10.1016/j.ijrobp.2004.12.076
Burns, P. B., Rohrich, R. J., Chung, K. C. (2011). The Levels of Evidence and their role in Evidence-Based Medicine. Plastic and Reconstructive Surgery, 128(1), 305-310. https://doi: 10.1097/PRS.0b013e318219c171
Braam, P. M., Roesink, J. M., Moerland, M. A., Raaijmakers, C. P., Schipper, M., & Terhaard, C. H. (2005). Long-term parotid gland function after radiotherapy. International journal of radiation oncology, biology, physics, 62(3), 659–664. https://doi.org/10.1016/j.ijrobp.2004.12.015

GASTROINTESTINAL DISORDERS

DIARRHOEA

Authors: Ana Isabel Paiva Santos and Clara Maria Dias Pinto

Definition

Diarrhoea is defined as the evacuation of soft or watery stools at least 3 times a day.

It can have a psychological and physical impact, significantly affecting the functional status of the patient.

Table 1 – CTCAE v5.0 classification

Degree	Description
1	Increase in < 4 stool per day over baseline; mild increase in ostomy output compared to patient baseline
2	Increase of 4-6 stool per day over baseline; moderate increase in ostomy output compared to the patient’s baseline; Limiting instrumental ADL
3	Increase of ≥ 7 stool per day over baseline; hospitalization indicated; severe increase in ostomy output compared to the patient’s baseline; limiting self- care ADL
4	Life threatening consequences: urgent intervention indicated
5	Death

Etiology

Possible causes unrelated to the neoplastic process, such as food and liquid snit management in previous days, recent trips, use of proton pump inhibitors (PPI), contact with people with the same symptomatology, use of laxatives, previous history of diarrhoea, history of gastrointestinal diseases (such as inflammatory bowel disease) should be excluded.

Diarrhoea may arise due to:

- 1. Primary neoplasm

Diarrhoea appears as a symptom most often in neuroendocrine tumours and colorectal cancer.

In neuroendocrine tumours there is release of bioactive amines (mainly serotonin) that cause carcinoid syndrome, which is characterized by aqueous diarrhoea, flushing, bronchospasm and hypotension.

In colorectal cancer, diarrhoea may appear in alternating with constipation.

However, it may also arise as a manifestation of pancreatic tumours, especially islet cell tumours (Zollinger-Ellison syndrome), due to malabsorption of bile salts. Less often, diarrhoea may arise as a manifestation of intestinal lymphoma and medullary thyroid carcinoma.

- 1. Surgery

Surgery is the first therapeutic approach in some types of neoplasms and causes mechanical, functional, and physiological changes due to increased transit time, gastroparesia, fat malabsorption, lactose intolerance, hydro electrolytic imbalance or dumping syndrome.

Diarrhoea can thus arise because of a celiac plexus blockage, cholecystectomy, esophagogastrostomy, gastrectomy, duodenal pancreatectomy, intestinal resection (by malabsorption – short bowel syndrome) or vagotomy.

Chemotherapy

Chemotherapy usually causes an increase in the secretion of electrolytes and fluids, which can lead to diarrhoea. It may be limiting for the dose of chemotherapy agents used in the treatment of neoplasia.

Evidence

Level Grade PMID Nº

29931177

263892112

356534563

29931177

26389211

35653456

30519783

24373918

3510147

Evidence The most frequently caused diarrhoea are 5-fluorouracil (5-FU), irinotecan, capecitabine and taxanes (cabazitaxel, docetaxel, paclitaxel Nand Nab-paclitaxel), and may cause Level Grade PMID Nº diarrhoea in up to 50% of patients. Less often, anthracyclines can cause up to 15% of patients.

For cisplatin and carboplatin, the prevalence of diarrhoea is low if administration is intravenous but increases if administration is carried out intraperitoneally. Hyperthermal intraperitoneal chemotherapy (HIPEC) is thus associated with more severe and prolonged diarrhoea.

Radiotherapy

The damage occurs due to direct absorption of radiation or the effect of released free radicals. It occurs most often if the radiated area is abdominal and/or pelvic.

Its severity is related to body mass index (worse if low), patient comorbidities (diabetes mellitus, hypertension, inflammatory bowel disease), history of smoking, previous bowel surgeries, amount of radiation, volume of irradiated intestine and need for concomitant chemotherapy.

Chronic radiation enteritis may remain even after the end of therapy and sometimes involves pharmacological treatment and/or surgical intervention, as well as dietary modification due to lack of absorption of some nutrients.

Targeted therapies

It is mainly due to the use of tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, but also to vascular endothelial growth factor receptor (VEGFR) inhibitors, epidermal growth factor receptor inhibitors (EGFR), and mammalian rapamycin target inhibitors (mTOR).

Therapeutic regimens with various TKIs (such as erlotinib, gefitinib, lapatinib, sorafenib, sunitinib and others) have a significantly higher risk of having diarrhoea of all grades and of high degree.

Immunotherapy

Diarrhoea occurs most frequently in T lymphocyte antiantigen-4 (anti-CTLA-4) threated patients, and colitis may even occur.

Hormonotherapy

Although diarrhoea is rare in hormone therapy, the ones most associated with diarrhoea are those used in breast and prostate cancer (abiraterone, enzalutamide, apalutamide, fulvestrant).

Bone-marrow transplant

Graft-versus-host disease is one of the main complications of allogeneic transplantation and can occur between 7 and 100 days after transplantation. The gastrointestinal tract is one of the most frequently affected organs and can cause severe abdominal pain, nausea, vomiting, cramps and watery and green diarrhoea.

Clostridium difficile infection

The use of antibiotics (mainly penicillin and cephalosporins) can cause alteration of the intestinal flora, allowing their colonization by Clostridium difficile that causes watery diarrhoea.

Although less frequent, it may also arise after chemotherapy.

Pterthenation

Glutamine, celecoxib, probiotics, activated charcoal and racecadotril have been suggested in chemotherapy-induced prophylaxis, but there is no evidence to prove the efficacy

of these measures. There are still no effective pharmacological options in preventing radiotherapy-induced diarrhoea.

Objective examination

The objective examination of the patient with diarrhoea is essential and should include:

Evaluation of vital signs, including blood pressure, heart rate, peripheral oxygen saturation, temperature.
Evaluation of the skin and mucous membranes (as a complement to the evaluation of the patient’s hydration), as well as an assessment of their nutritional status.
Inspection, auscultation, and palpation of the abdomen (which may allow exclude peritonitis).
Rectal touch, to exclude perianal abscess.

It is important to observe faecal contents to exclude blood or mucus presence.

The alarm signs related to diarrhoea, which indicate a potentially complicated evolution are severe dehydration, fever, peritonitis, hematic losses, delirium, acute kidney injury, febrile neutropenia or sepsis, shock, hydro-electrolytic disorders, abdominal cramps that do not relieve after loperamide therapy, oral loss, and history of grade 4 diarrhoea.

251860487

29931177

Laboratory tests or other complementary diagnostic tests

Overall, the choice of complementary means used is based on the patient’s clinical status, the duration of symptoms and the presence of a causal factor. A broader approach is recommended in patients with a history of previous complications of diarrhoea.

In summary:

Blood count with differential leukocyte count: allow the evaluation of leucocytosis or neutropenia after chemotherapy, hematic losses or haemoconcentration.
Potassium, sodium, calcium, and magnesium dosing allows evaluation of the presence of some electrolyte disorder.
Creatinine and urea: evaluation of renal function.
Coagulation tests: assessment of bleeding risk;
C-reactive protein and procalcitonin dosing: infection markers.

– Arterial and lactate pH: evaluation of the presence of acidosis.

Patients under Antibiotherapy, or with a history of recent Antibiotherapy, screening for clostridium difficile should be considered in the stool. In patients with fever, at least two blood cultures should be collected for bacteriemia screening.

Abdominal ultrasonography may be useful for assessing peristalsis, thickening of the intestinal wall, and intra-abdominal tumour manifestations. In the presence of clinical skirt of peritoneal involvement, computed tomography is the preferred method for diagnosing other complications (such as intestinal perforation, malignant intestinal obstruction, or enterocolitis).

For endoscopic studies, these are usually not indicated in the initial approach of the patient with diarrhoea. It can be weighted in situations of chronic diarrhoea would be refractory to therapy; duodenal biopsies should be collected for the diagnosis of cytomegalovirus or Giardia lamblia. However, in neutropenic enterocolitis, colonoscopy is not recommended for the risk of intestinal perforation.

Therapeutic strategy

Patients with mild to moderate diarrhoea should be managed conservatively, in the outpatient clinic, while patients with severe diarrhoea or with some risky conduction that may exacerbate this situation (abdominal pain, nausea, vomiting, fever, sepsis, neutropenia or melena/haematoquecia) should be treated at hospital level.

Treatment of chemo-induced diarrhoea may include both pharmacological and non-pharmacological measures, as well as a careful assessment of the response to the measures instituted, to rule out significant dehydration or other factors that may require hospitalization.

Non-pharmacological measures include the eviction of both foods that aggravate diarrhoea and milk or other dairy products, spicy foods, alcohol, products containing caffeine, foods high in fibre, fat or high sugar content. These measures may be sufficient in the presence of patients with uncomplicated, mild to moderate diarrhoea (grade 1 or 2) should also be instructed to record the number of ejections, as well as report possible life-threatening symptoms (such as fever or orthostatic hypotension). Caution is required for patients with incontinence at the risk of pressure ulcers. (Level of evidence I, grade B)

Patients with mild to moderate diarrhoea may initiate pharmacological therapy with loperamide, an oral opioid, at the initial dose of 4 milligrams, followed by 2 milligrams every 4 hours or after each diarrheic ejection (Evidence Level II, grade B). ) Loperamide may be suspended after 12 hours without diarrheic stools.

In persistent diarrhoea and resistant to loperamide, octreotide, a synthetic somatostatin analogue, should be initiated at a dose of 100-150 micrograms subcutaneously three times a day, with possible dose escalation to 500 micrograms until diarrhoea is controlled and Antibiotherapy is necessary. (Level of evidence II, grade C)

References:

Bossi P, Antonuzzo A, Cherny NI, et al. Diarrhea in adult cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol. 2018;29 Suppl 4:iv126-iv142

Evidence

Level Grade PMID Nº

29931177

21789126

15254061

PDQ Supportive and Palliative Care Editorial Board. Gastrointestinal Complications (PDQ®): Health Professional Version. In: PDQ Cancer Information Summaries. Bethesda (MD): National Cancer Institute (US); July 29, 2022.
Gould Rothberg BE, Quest TE, Yeung SJ, et al. Oncologic emergencies and urgencies: Acomprehensive review [published online ahead of print, 2022 Jun 2]. CACancer J Clin. 2022
Bruckstein AH. Acute diarrhea. Am Fam Physician. 1988;38(4):217-228.
Pessi MA, Zilembo N, Haspinger ER, et al. Targeted therapy-induced diarrhea: Areview of the literature. Crit Rev Oncol Hematol. 2014;90(2):165-179.
McDonald GB, Shulman HM, Sullivan KM, Spencer GD. Intestinal and hepatic complications of human bone marrow transplantation. Part I. Gastroenterology. 1986;90(2):460-477.
Andreyev J, Ross P, Donnellan C, Lennan E, Leonard P, Waters C, et al. Guidance on the management of diarrhea during cancer chemotherapy. The Lancet Oncology. setembro de 2014;15(10):e447–60.
Stein A, Voigt W, Jordan K. Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol. 2010;2(1):51-63.
Benson AB 3rd, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004;22(14):2918-2926.

ADNEXA

Figure 1 – Diarrhea diagnosis algorithm.

INTESTINAL OCCLUSION

Author: Rodrigo Santos Vicente and Diana Neto da Silva

Definition

Intestinal occlusion is a mechanical or functional obstruction which prevents the passage of bowel contents.

Symptoms and signs

Generally, obstruction causes abdominal pain and distention, nausea, vomiting, inability to eat, obstipation or diarrhoea. The clinical presentation and evolution depend on the level of obstruction and if the bowel becomes either partially or completely blocked. [1-5]

Small bowel:

Symptoms appear shortly after onset.

Obstipation, with complete obstruction or diarrhoea if the obstruction is partial.
The vomiting tends to be more frequent, in larger volumes, and bilious.
Abdominal pain is described as intermittent and colicky but improves with vomiting.
Hyperactive, metallic, or high-pitched peristalsis coinciding with cramps.
Dilated loops of bowel may be palpable.
If infarction occurs, the abdomen becomes tender, and auscultation reveals a silent abdomen or minimal peristalsis.

Large bowel:

Symptoms are usually milder and develop gradually.
Increasing obstipation and abdominal distention.
Vomiting occurs usually several hours after onset of other symptoms but is not common, which typically presents as intermittent and feculent.
Distended abdomen with loud borborygmi.
Amass corresponding to the site of an obstructing tumour may be palpable.

Volvulus happens when a loop of intestine twists around itself and its mesenteric attachment base, causing an abrupt onset of bowel obstruction. Pain is continuous with concurrent waves of colicky pain. [6]

Risk factors

Intestinal obstructions are similar in incidence in both males and females. The identified risk factors for the onset in a cancer patient are: [1]

Prior abdominal surgery.
Intra‐abdominal primary cancer or non-intra‐abdominal primary cancer with clear intraperitoneal disease.
Previous abdominal or pelvic irradiation.

Other known risk factors:

Chronic intestinal inflammatory disease.
Existing abdominal wall and/or an inguinal hernia.
Foreign body ingestion.

Evidence

Level Grade PMID Nº

Etiology

There are many aetiologies of small and large bowel obstructions that are classified as 1) functional or mechanical, 2) extrinsic or intrinsic, 3) intraluminal or extraluminal. In the general population, small bowel obstructions and extrinsic sources are the most common. Lower bowel blockade comprises 10% to 15% of all intestinal obstructions. [1,7]

- The most cause of small bowel is the post-surgical adhesions. It is estimated that at least two-thirds of patients with previous abdominal surgery have adhesions.
- Cancer is a common extrinsic source, which causes compression of the bowel leading to obstruction.
- Inguinal and umbilical hernias are a less common extrinsic cause.
- Intraluminal causes of small bowel are not common and occurs when there is an ingested foreign body that causes impaction within the lumen of the bowel or unable to pass the ileocecal valve.
- The most common cause of all lower bowel is adenocarcinoma, followed by diverticulitis and volvulus. Colonic obstruction is most seen in the sigmoid colon.
- Crohn disease is the most common cause of benign stricture seen in the adult population, due to an insidious onset of bowel wall thickening.
- Functional obstruction resulting from an impairment of intestinal motility in patients with tumour infiltration of the mesentery or nerves concerned in intestinal motility, in patients with paraneoplastic neuropathy resulting from a secondary paralytic ileus (intra-abdominal infection, intraperitoneal effusion, intra- or retroperitoneal pain), and in patients receiving specific drugs (opioid or anticholinergic drugs). [1,7,8]

The definition of malignant bowel obstruction is not consensual through the literature. It occurs most frequently with ovarian and colorectal cancers but can be seen with other abdominal or nonabdominal malignancies. In a cancer patient, intestinal occlusion may be directly related to the tumour, its treatment (e.g., radiation enteritis), or benign aetiologies (e.g., adhesions or internal hernia). In a review of 334 patients with bowel obstruction and advanced malignancy, obstructions happen due to tumour‐related causes in 68%,

adhesion‐related in 20%, and of unclear Etiology in 12%. [9]

Diagnosis

- Detailed medical history, including physical exam, inquiring about the onset and significant risk factors related to bowel obstruction.
- Abdominal radiography both supine and upright are an appropriate initial complementary examination in patient with suspected intestinal obstruction.
- Abdominal computed tomography with intravenous or enteric contrast is recommended in patients with suspected intestinal obstruction.
- Laboratory evaluation – Complete blood count with differential; electrolytes, including blood urea nitrogen and creatinine. If systemic signs of illness were identified (fever, tachycardia, hypotension, altered mental status), additional laboratory investigation should include arterial blood gas, serum lactate and blood cultures. [10,11]

Studies

- N/A.

Pharmacotherapy

Evidence

Level Grade PMID Nº

I A 18359221

Action

Drug

Posology/notes

Hydration

[12,13]

Isotonic fluid

10-20mL/Kg/day, intravenous

Depending on the clinical evidence of dehydration and fluid toleration

25462210

Evidence Level Grade PMID Nº

I A

Anti-secretory [14,15]	Octreotide	0.2-0.9mg/day, intravenous or subcutaneous, bolus or perfusion
	Scopolamine	40-120mg/day, intravenous or subcutaneous, bolus or perfusion. Useful for breakthrough nausea and vomiting or colic in patients on octreotide
	Ranitidine Not available	200mg/day, intravenous or subcutaneous. May be given in association to Octreotide or to Dexamethasone
Anti-emetic, pro-kinetic agents [14] Only for partial or functional occlusions	Metoclopramide	30-240mg/day, intravenous or subcutaneous, bolus or perfusion
	Olanzapine	5mg/day, oral
	Haloperidol	5-15 mg/day, intramuscular
Laxative [16] Only for partial or functional occlusions	Amidotrizoate	25-50 ml, oral, once
Anti-inflammatory and anti-oedema [14,17]	Dexametasona	Intravenous, 6-16mg/day, during 5-7 days followed by weaning
Analgesic Strong opioids [12]	Morphine	Naïve patients: 2.5-5mg q1h Patient treated with opioids previously: 1/6 of daily total dose Intravenous or subcutaneous According to the WHO guidelines

I B

2B C

34390398 15357519

34390398

2A	C	34390398
2A	C	34390398
2B	C	34390398
2B	C	15471659

2A	C	34390398
		10796761
I	C	18359221

Orientations

Clinically stable patients should be treated with bowel rest, tube decompression, fluid resuscitation and according to the pharmacotherapy mentioned before; [3,18,19]

Signs of peritonitis, clinical instability, leucocytosis, leukopenia, and acidosis are concerning for abdominal sepsis, ischemia, or perforation, and mandate immediate surgical exploration; [20]

Facing the clinical evidence of compromise bowel (i.e., ischemia, necrosis, or perforation) or infection, antibiotics should be provided with coverage against gram- negative organisms and anaerobes; [21,22]

Admission to or consultation with a surgical service should occur upon diagnosis of intestinal obstruction; [20,23,24]

Surgical exploration is recommended for most patients in whom three to five days of nonoperative management is ineffective, o r who clinically deteriorate at any point during hospitalization: [25-30]

A closed-loop obstruction should be treated as a surgical emergency. [20, 31,32]

Algorithmic approach to clinical and surgical management of malignant bowel obstruction

2A A

I C

2B B

2A B

I C

11036136 17230614

16250544

24112637

7774478

19759886

24112637 25886702

11602902

12549688 15906139

22472395 23271094

12632527 16310687

1448971 24112637

20217412

Yes

Abdominal CT

Yes Concern for ischemia

or perforation?

Urgent surgical exploration

Yes

Treatment of ileus/ pseudoobstructio n

Is malignant obstruction confirmated?

Palliative management

Conservative management trial (see above)

Bowel rest, GI descompression, Parenteral fluid therapy

Did it resolved?

Yes

Initiate diet as tolerated

If stentable lesion, refer to stent; If not, consider surgery

Surgical candidate?

Palliative management

Legend: CT – Computed tomography scan; GI – Gastrointestinal

Symptoms and a abdominal radiography consistent with bowel obstruction in a patient with a known (or suspected) malignancy

Candidate for surgery?

– Smith DA, Kashyap S, Nehring SM. Bowel Obstruction. [Updated 2022 May 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441975/
– Cheadle WG, Garr EE, Richardson JD. The importance of early diagnosis of small bowel obstruction. Am Surg. 1988 Sep;54(9):565-9
– Markogiannakis H, Messaris E, Dardamanis D, Pararas N, Tzertzemelis D, Giannopoulos P, Larentzakis A, Lagoudianakis E, Manouras A, Bramis I. Acute mechanical bowel obstruction: clinical presentation, etiology, management and outcome. World J Gastroenterol. 2007;13(3):432
– Perea García J, Turégano Fuentes T, Quijada García B, Trujillo A, Cereceda P, Díaz Zorita B, Pérez Díaz D, Sanz Sánchez M. Adhesive small bowel obstruction: predictive value of oral contrast administration on the need for surgery. Rev Esp Enferm Dig. 2004 Mar;96(3):191-200
– Aslar AK, Ozdemir S, Mahmoudi H, Kuzu MA. Analysis of 230 cases of emergent surgery for obstructing colon cancer–lessons learned. J Gastrointest Surg. 2011 Jan;15(1):110-9. Epub 2010 Oct 26 6 – Lau KC, Miller BJ, Schache DJ, Cohen JR. Astudy of large-bowel volvulus in urban Australia. Can J Surg. 2006 Jun;49(3):203-7
– Ansari P. Intestinal Obstruction. MSD Manual Professional Edition. [online] MSD Manual Professional Edition 2021. Available at: https://www.msdmanuals.com/professional/gastrointestinal- disorders/acute-abdomen-and-surgical-gastroenterology/intestinal-obstruction [Accessed 31 May 2022]
-Laval G, Marcelin- Benazech B, Guirimand F, Chauvenet L, Copel L, et al. Recommendations for bowel obstruction with peritoneal carcinomatosis. J Pain Symptom Manage. 2014 Jul;48(1):75-91 9 – Pujara D, Chiang Y, Comier JN, Bruera E, Badgwell B. Selective Approach for Patients with Advanced Malignancy and Gastrointestinal Obstruction. JAm Coll Surg. 2017 Jul;225(1):53-59
– Wangensteen OH. Understanding the bowel obstruction problem. Am J Surg. 1978;135(2):131-149
– Jackson P, Cruz MV. Intestinal Obstruction: Evaluation and Management. Am Fam Physician. 2018;98(6):362-367
Ripamonti C, Easson A, Gerdes H. Management of malignant bowel obstruction. Eur J Cancer. 2008 May;44(8):1105-15
– Currow DC, Quinn S, Agar M, Fazekas B, Hardy J, McCaffrey N, Eckermann S, Abernethy AP, Clark K. Double-blind, placebo-controlled, randomized trial of octreotide in malignant bowel obstruction. J Pain Symptom Manage. 2015 May;49(5):814-21
– Davis M, Hui D, Davies A, Ripamonti C, Capela A, DeFeo G, Del Fabbro E, Bruera E. Medical management of malignant bowel obstruction in patients with advanced cancer: 2021 MASCC guideline update. Support Care Cancer. 2021 Dec;29(12):8089-8096
– Ripamonti C, Mercadante S. How to use octreotide for malignant bowel obstruction. J Support Oncol. 2004 Jul-Aug;2(4):357-64
– Mercadante S, Ferrera P, Villari P, Marrazzo A. Aggressive pharmacological treatment for reversing malignant bowel obstruction. J Pain Symptom Manage. 2004 Oct;28(4):412-6.
– Feuer DJ, Broadley KE. Corticosteroids for the resolution of malignant bowel obstruction in advanced gynaecological and gastrointestinal cancer. Cochrane Database Syst Rev. 2000;2000(2):CD001219
– Miller G, Boman J, Shrier I, Gordon PH. Etiology of small bowel obstruction. Am J Surg. 2000;180(1):33-36.
– Hayanga AJ, Bass-Wilkins K, Bulkley GB. Current management of small-bowel obstruction. Adv Surg. 2005;39:1-33.
– Di Saverio S, Coccolini F, Galati M, Smerieri N, Biffl WL, Ansaloni L, Tugnoli G, Velmahos GC, Sartelli M, Bendinelli C, Fraga GP, Kelly MD, Moore FA, Mandalà V, Mandalà S, Masetti M, Jovine E, Pinna AD, Peitzman AB, Leppaniemi A, Sugarbaker PH, Goor HV, Moore EE, Jeekel J, Catena F. Bologna guidelines for diagnosis and management of adhesive small bowel obstruction (ASBO): 2013 update of the evidence-based guidelines from the world society of emergency surgery ASBO working group. World J Emerg Surg. 2013 Oct 10;8(1):42
– Zanoni FL, Benabou S, Greco KV, et al.; Mesenteric microcirculatory dysfunctions and translocation of indigenous bacteria in a rat model of strangulated small bowel obstruction. Clinics (Sao Paulo). 2009;64(9):911-919.
– Schmocker R, Vang X, Cherney Stafford L, Leverson G, Winslow E. Involvement of a surgical service improves patient satisfaction in patients admitted with small bowel obstruction. Am J Surg. 2015;210(2):252-257.
– Malangoni MA, Times ML, Kozik D, Merlino JI. Admitting service influences the outcomes of patients with small bowel obstruction. Surgery. 2001;130(4):706-711 , discussion 711–713 25 – Fevang BT, Jensen D, Svanes K, Viste A. Early operation or conservative management of patients with small bowel obstruction?. Eur J Surg. 2002;168(8–9):475-481.

26 – Williams SB, Greenspon J, Young HA, Orkin BA. Small bowel obstruction: conservative vs. surgical management. Dis Colon Rectum. 2005;48(6):1140-1146. 27 – Leung AM, Vu H. Factors predicting need for and delay in surgery in small bowel obstruction. Am Surg. 2012;78(4):403-407.

– Schraufnagel D, Rajaee S, Millham FH. How many sunsets? Timing of surgery in adhesive small bowel obstruction: a study of the Nationwide Inpatient Sample. J Trauma Acute Care Surg. 2013;74(1):181-187 , discussion 187–189.
– Shih SC, Jeng KS, Lin SC, et al.; Adhesive small bowel obstruction: how long can patients tolerate conservative treatment?. World J Gastroenterol. 2003;9(3):603-605. 30 – Bickell NA, Federman AD, Aufses AH. Influence of time on risk of bowel resection in complete small bowel obstruction. JAm Coll Surg. 2005;201(6):847-854.
– Margenthaler JA, Longo WE, Virgo KS, et al.; Risk factors for adverse outcomes following surgery for small bowel obstruction. Ann Surg. 2006;243(4):456-464.
– Zielinski MD, Eiken PW, Bannon MP, et al.; Small bowel obstruction—who needs an operation? A multivariate prediction model. World J Surg. 2010;34(5):910-919.

CONSTIPATION

Author: Cecília Caramujo de Sá, Maria João Ramos and Raquel Borrego

Definition

Subjectively experienced disturbance in bowel movements (BM).
Usually defined by three or fewer BM in a week. However, the term constipation has varied meanings for different people and this definition is not universally applicable.
The frequency of BM is usually underestimated. [1]
Formal criteria are available to define chronic functional constipation (the Rome IV criteria), [2,3] although the analysis of these criteria is behind the scope of this chapter.

Symptoms

Defecatory straining.
Sensation of incomplete evacuation.
Sensation of anorectal obstruction/blockage.
Abdominal pain and distension.
Hard and dry stool.
Different stool consistency.
Fewer than three spontaneous bowel movements per week.
Severity of constipation should be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) – version 5.0 (Table 1.)

Etiology

Constipation is a common problem in patients with cancer and a significant source of major morbidity and distress. [4]
Risk factors for constipation (in cancer patients, especially at an advanced stage): older age, decreased physical activity, low-fibre diet, depression, cognitive impairment, haemorrhoids, and polypharmacy.
Medications that cause/exacerbate constipation: opioids, calcium channel blockers, diuretics, anticholinergic drugs, iron, serotonin antagonists, and chemotherapy (vinca alkaloids, thalidomide, vandetanib). [5]
Other causes: neurological (e.g., epidural spinal cord compression) and metabolic (e.g., hypercalcemia and hypothyroidism). [5]

Diagnostic Studies

If constipation develops or worsens in parallel with changes in the opioid regimen, no further evaluation is needed.
When there is no clear precipitant: assessment for alternative or contributory with a complete evaluation.
Physical examination should be focused to determine if an organic problem exists to account for symptoms [3] and should include:

– Abdominal examination, perineal inspection and a careful digital rectal examination (DRE) to identify structural issues and faecal impaction.

Investigations are not routinely necessary.
If suspected clinically: corrected calcium levels and thyroid function should be assessed.
More extensive investigation (e.g. abdominal plain radiograph, colonoscopy) is warranted for those with severe symptoms, sudden changes in number and consistency of BMs or blood in the stool, and for older patients relative to their health and stage of disease. [6]

Evidence

Level Grade PMID Nº

Pharmacotherapy

Evidence

Level Grade PMID Nº

DRUG POSOLOGY

V B 30016389

Suppositories containing glycerine	Constipation: Rectal: One adult suppository once daily as needed or as directed
Suppositories containing bisacodyl oxyphenisatin (veripaque)	Constipation: Rectal: Enema, suppository: 10mg (1 enema or suppository) once daily
Suppositories containing CO2-releasing compounds	–
Polyethylene glycol (PEG)	Constipation, occasional: Oral: 17 g (~1 heaping tablespoon) dissolved in 120 to 240 mL of beverage, once daily; do not use for >1 to 2 weeks
Lactulose	Prevention: Oral: 20 to 30 g (30 to 45 mL) 2 to 4 times daily; may adjust dose every 1 to 2 days to achieve 2 to 3 soft stools/day Treatment: Oral: Initial: 20 to 30 g (30 to 45 mL) every 1 to 2 hours to induce ~2 soft stools/day, then reduce to 20 to 30 g (30 to 45 mL) 2 to 4 times daily; may adjust dose every 1 to 2 days to achieve 2 to 3 soft stools/day. Rectal (alternative route): Retention enema: 200 g (300 mL) in 700 mL NS or water, retain for 30 to 60 minutes; may repeat every 4 to 8 hours based on responsiveness to therapy.

V B 30016389

V C 30016389

Evidence Level Grade PMID Nº

Magnesium and sulphate salts	Constipation: Oral: 2 to 4 level teaspoons (~10 to 20 g) of granules dissolved in 240 mL of water; may repeat in 4 hours. Do not exceed 2 doses per day
Senna / Cascara	–
Bisacodyl	Constipation: Oral: 5 to 15 mg once daily
Sodium Picosulphate	Bowel cleansing: depending on preparation
Methylnaltrexone	Opioid-induced constipation with advanced illness: Administer 1 dose every other day as needed; maximum: 1 dose/24 hours (dosing is according to body weight): <38 kg: 0.15 mg/kg (round dose up to nearest 0.1 mL of volume) 38 to <62 kg: 8 mg 62 to 114 kg: 12 mg >114 kg: 0.15 mg/kg (round dose up to nearest 0.1 mL of volume) **Dosage adjustment if renal impairment.
Naloxegol	Opioid-induced constipation: Oral: 25 mg once daily. If not tolerated, reduce dose to 12.5mg once daily. Discontinue treatment if opioid pain medication is discontinued. Discontinue all maintenance laxative therapy prior to use. May reintroduce laxatives as needed if suboptimal response to naloxegol after 3 days. *Dosage adjustment if renal impairment.

V	C	30016389
V	C	30016389
V	C	30016389
V	C	30016389
II	B	30016389

II B 30016389

Therapeutic Strategy

Evidence

Level Grade PMID Nº

Enemas are contraindicated in:

neutropenia or thrombocytopaenia, – severe colitis, inflammation, or infection of the abdomen,
paralytic ileus or intestinal obstruction, – toxic megacolon,
recent colorectal or gynaecological surgery, – undiagnosed abdominal pain,
recent anal or rectal trauma, – recent radiotherapy to the pelvic area.

Abdominal massage can be beneficial in reducing gastrointestinal symptoms and improving bowel efficiency

The key factor is prevention:

– Ensuring privacy and comfort, adequate positioning, increase fluid intake, increase activity and mobility, anticipatory management of constipation when opioids are prescribed

First line therapy if full rectum on DRE or faecal impaction:

– Suppositories containing glycerine, bisacodyl oxyphenisatin (veripaque) and CO2-releasing compounds

If laxatives are needed, preferred options include:

Osmotic laxatives (polyethylene glycol (PEG), lactulose or magnesium andsulphate salts)
Stimulant laxatives (senna, cascara, bisacodyl and sodium picosulfate)

Unless contraindicated by pre-existing diarrhoea, all patients receiving opioid analgesics should be prescribed a concomitant laxative

In case of opioid induced constipation:

– Stimulant laxatives (senna, cascara, bisacodyl and sodium picosulfate)

In unresolved opioid induced constipation:

– Peripheral opioid antagonists (methylnaltrexone or Naloxegol)

V	D	20940182
II	B	20940182
V	B	30016389
V	B	30016389
V	C	30016389
V	B	30016389
V	D	30016389
II	B	30016389

Evidence Level Grade PMID Nº

If faecal impaction:

– Dis impaction (usually through digital fragmentation and extraction of the stool), followed by implementation of amaintenance bowel regimen to prevent recurrence

V B 30016389

Appendix

Table 1. Adapted from “Common Terminology Criteria for Adverse Events (CTCAE)” version 5.0

CTCAE Term	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
	Occasional or intermittent symptoms;	Persistent symptoms with regular use of	Obstipation with manual evacuation	Life-threatening consequences: urgent	Death
Constipation	occasional use of stool softeners, laxatives, dietary modification, or enema	laxatives or enemas; limiting instrumental ADL	indicated, limiting self- care ADL	intervention indicated

Definition: A disorder characterized by irregular and infrequent or difficult evacuation of the bowels. ADL, Activities of daily living

References:

- 1. Sandler, R. S., & Drossman, D. A. (1987). Bowel habits in young adults not seeking health care. Digestive diseases and sciences, 32(8), 841–845. https://doi.org/10.1007/BF01296706
  2. Longstreth, G. F., Thompson, W. G., Chey, W. D., Houghton, L. A., Mearin, F., & Spiller, R. C. (2006). Functional bowel disorders. Gastroenterology, 130(5), 1480–1491. https://doi.org/10.1053/j.gastro.2005.11.061
  3. Mearin, F., Lacy, B. E., Chang, L., Chey, W. D., Lembo, A. J., Simren, M., & Spiller, R. (2016). Bowel Disorders. Gastroenterology, S0016-5085(16)00222-5. Advance online publication. https://doi.org/10.1053/j.gastro.2016.02.031
  4. Laugsand, E. A., Jakobsen, G., Kaasa, S., & Klepstad, P. (2011). Inadequate symptom control in advanced cancer patients across Europe. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 19(12), 2005–2014. https://doi.org/10.1007/s00520-010-1051-2
  5. Erichsén, E., Milberg, A., Jaarsma, T., & Friedrichsen, M. (2016). Constipation in specialized palliative care: factors related to constipation when applying different definitions. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 24(2), 691–698. https://doi.org/10.1007/s00520-015-2831-5
  6. Larkin, P. J., Cherny, N. I., La Carpia, D., Guglielmo, M., Ostgathe, C., Scotté, F., Ripamonti, C. I., & ESMO Guidelines Committee (2018). Diagnosis, assessment and management of constipation in advanced cancer: ESMO Clinical Practice Guidelines. Annals of oncology : official journal of the European Society for Medical Oncology, 29(Suppl 4), iv111–iv125. https://doi.org/10.1093/annonc/mdy148

COLITIS

Evidence

Level Grade PMID Nº

Author: Ana Teijo Quintáns, Marta Teijo Quintáns and Guillermo Estrada Riolobos.

Definition

Gastrointestinal disorder, characterized by inflammation and/or ulcerative lesion of the colon tissue and by extension of the entire large intestinal tract resulting from chemotherapy or ionising radiation. The concept encompasses a wide variety of processes, from chronic to acute or transitory, depending of the type of treatment (1).

Symptoms and signs

The symptoms depend on the type of treatment and the dose that the patient received.
Diarrhea is a common sympton and complication in patients receiving chemotherapy. It is a disorder characterised by frequent and watery bowel movements. It can produce both a decrease in the patient’s quality of life and important medical complications due to volume depletion and electrolyte disturbances. Its severity is evaluated based on the number of bowel movements/day, the presence of nocturnal bowel movements, the need for intravenous treatment and the presence of mucus and/or blood in the stool.
Constipation is the most common intestinal complication in patients with cancer and chemotherapy treatment. It consists of a decrease in the number of bowel movement (less than twice a week) associated with greater hardness of the stool.
We can see abdominal pain in almost all patients.
With the use of some chemotherapy like Citarabine, Gemcitabine or Bevacizumab, we can see necrosis and intestinal perforation. It is manifested by acute abdominal pain, for which a meticulous examination is essential.
Gastrointestinal bleeding: when they arise in the context of cytostatic treatments usually be due to a gastroesophageal mechanical injury associated with postchemotherapy emesis (Mallory-Weiss syndrome) favored by thrombocytopenia and coagulation disorders. It evolves well with conservative treatment although surgical repair is often necessary. (2)

Etiology

The normal mucosa of digestive tract is a tissue in constant renewal at the expense of the basal layer cells. The biological process triggered by direct damage to dividing cells of the epithelium results in depletion of the basal layer. It development is considered to be modulated by the inmune system, inflammatory processes and possible infections of the bacterial and fungal flora. (3)
The vascular damage (capillary damage) mediated by endothelial apoptosis plays a fundamental role.
Histopahological examination of colitis reveals superficial ulcerations with inflammatory infiltrate, cellular debris, fibrin and interstitial exudate. Also the changes in the composition of the microflore result in absorption and other intestinal function dysregulation. (4)

Studies

Diagnosis is based on duration, severity, and presence of alarm features that may require hospital admission (5). Patients should undergo a complete blood count, serum electrolyte profile, serum albumin and serum C-reactive protein. Stool analyses for enteropathogens and Clostridium difficile toxin analysis should be carried out (6,7). Abdominal imaging is not routinely required in patients with grade 1–2 diarrhea. In severe cases, abdominal CT may be indicated to rule out complications (8). Flexible sigmoidoscopy or colonoscopy should be performed in patients with bloody diarrhea or those with persistent ≥ grade 2 diarrhea.

Metronidazole	High	Weak in favour
Ciprofloxacin	High	Weak in favour
Octreotide	High	Weak in favour
Sulfasalazine	Moderate	Weak in favour
Amifostine	Low	Weak in favour
Sucralfate enemas	Moderate	Weak in favour
Loperamida	Moderate	Strong in favour
Corticosteroids	Moderate	Weak in favour

Grade	Recommendations

		22990077
		9797360
		31398712
		10650568
		11050915
		10650568
		28506439
		14697914

Amifostine	≥340 mg/m2, to prevent radiation proctitis in patients receiving radiation therapy.	High	Strong in favour
Sulfasalazine	500 mg administered orally twice a day, be used to prevent radiation – induced enteropathy in patients receiving radiation therapy to the pelvis.	Low	Weak in favour
Octreotide	≥100 μg s.c. twiceor three timesdaily, be used to treatdiarrhoea induced by standard- or high-dose chemotherapy associated with HSCT, if loperamide is ineffective.	High	Strong in favour
Hyperbaric oxygen	Be used to treat radiation-induced proctitis in patients receiving radiation therapy for a solid tumour.	Moderate	Strong in favour
Corticosteroids	Depends on witch one. Low doses in short periods of disease less than 60mg/day curses with less problems.	Moderate	Weak in favour
Probiotics	Containing Lactobacillus species be used to prevent diarrhoea in patients receiving chemotherapy and/or radiation therapy for a pelvic malignancy.	Moderate	Weak in favour
Metronidazole	500mg/8h orally or 250mg/6h orally. Clostridium dificcile	High	Weak in favour
Ciprofloxacin	500mg/12h orally for 7 days	High	Weak in favour
Sucralfate enemas	6g/day orally.	Moderate	Weak in favour
Misoprostol	400 one hour before radiotherapy	Low	Weak in favour
Loperamida	4 mg followed by 2mg every two or four hours	Moderate	Strong in favour
Soluble Fibre	Prebiotic nutriment.	Moderate	Strong in favour
Arginine	500 mg/kg/day	Very low	Weak in favour
Nutrional Supplements	Enriched with EPA y DHA	High	Strong in favour

Agent	Process / Posology / Others	Grade	Recommendations

				11050915
				11050915
				31398712
				35048686
				14697914
				12190202
				22990077
				9797360
				10650568
				10950043
				28506439
				11827762
				10729239
				26325092

Level Grade PMID Nº

Agent Process / Posology / Others Grade Recommendations

12721240

Glutamine	30g/day seven days before radiotherapy	Low	Weak in favour
Bowel rest	The duration of bowel rest will depend on severity and clinical response, but in general most improve within 2 -3 days (although it is thought to take 1–-2 weeks for the colon to heal)	High	Weak in favour
Fluid resuscitation	Intravenous fluid resuscitation and blood glucose control.	Low	Weak in favour
Nutrition path	Sources of trauma should be eliminated and painful stimuli such as hot foods and drinks and hard, sharp, or spicy foods should be avoided.	Low	Strong in favour
Oral hygiene	It is important that patients be appropriately educated about oral complications before treatment.	Low	Strong in favour
Regular dental examinations	Patients should also be advised to have in order to have the oral cavity assessed and that they should inform the health care professional at first signs and symptoms of oral complications.	Low	Strong in favour

25559486

15043287

31425601

24615748

References:

- 1. Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut [Internet]. 2019;68(Suppl 3):s1-106. Disponible en: http://dx.doi.org/10.1136/gutjnl-2019-318484
  2. Stein A, Voigt W, Jordan K. Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol [Internet]. 2010;2(1):51-63. Disponible en: http://dx.doi.org/10.1177/1758834009355164
  3. Grondin JA, Kwon YH, Far PM, Haq S, Khan WI. Mucins in intestinal mucosal defense and inflammation: Learning from clinical and experimental studies. Front Immunol [Internet]. 2020;11. Disponible en: http://dx.doi.org/10.3389/fimmu.2020.02054
  4. Erben U, Loddenkemper C, Doerfel K, Spieckermann S, Haller D, Heimesaat MM, et al. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int J Clin Exp Pathol. 2014;7(8):4557-76.
  5. Del Castillo M, Romero FA, Argüello E, Kyi C, Postow MA, Redelman-Sidi G. The spectrum of serious infections among patients receiving immune checkpoint blockade for the treatment of melanoma. Clin Infect Dis [Internet]. 2016;63(11):1490-3. Disponible en: http://dx.doi.org/10.1093/cid/ciw539
  6. Grover S, Rahma OE, Hashemi N, Lim RM. Gastrointestinal and hepatic toxicities of checkpoint inhibitors: Algorithms for management. Am Soc Clin Oncol Educ Book [Internet]. 2018;38(38):13-

9. Disponible en: http://dx.doi.org/10.1200/EDBK_100013

Nishino M, Ramaiya NH, Hatabu H, Hodi FS. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat Rev Clin Oncol [Internet]. 2017;14(11):655-68. Disponible en: http://dx.doi.org/10.1038/nrclinonc.2017.88
Messmer M, Upreti S, Tarabishy Y, Mazumder N, Chowdhury R, Yarchoan M, et al. Ipilimumab-induced enteritis without colitis: A new challenge. Case Rep Oncol [Internet]. 2016;9(3):705-13. Disponible en: http://dx.doi.org/10.1159/000452403

Level Grade PMID Nº

Joseph J, Singhal S, Patel GM, Anand S. Clostridium difficile colitis: review of the therapeutic approach. Am J Ther [Internet]. 2014;21(5):385-94. Disponible en: http://dx.doi.org/10.1097/MJT.0b013e318245992d
Turunen UM, Färkkilä MA, Hakala K, Seppälä K, Sivonen A, Ogren M, et al. Long-term treatment of ulcerative colitis with ciprofloxacin: a prospective, double-blind, placebo-controlled study. Gastroenterology [Internet]. 1998;115(5):1072-8. Disponible en: http://dx.doi.org/10.1016/s0016-5085(98)70076-9
Lamberts SWJ, Hofland LJ. ANNIVERSARY REVIEW: Octreotide, 40 years later. Eur J Endocrinol [Internet]. 2019;181(5):R173-83. Disponible en: http://dx.doi.org/10.1530/EJE-19-0074
Valls A, Pestchen I, Prats C, Pera J, Aragón G, Vidarte M, et al. Multicenter double-blind clinical trial comparing sucralfate vs placebo in the prevention of diarrhea secondary to pelvic irradiation. Med Clin (Barc) [Internet]. 1999 [citado 29 de mayo de 2022];113(18):681-4. Disponible en: https://pubmed.ncbi.nlm.nih.gov/10650568/
Dunst J, Semlin S, Pigorsch S, Müller AC, Reese T. Intermittent use of amifostine during postoperative radiochemotherapy and acute toxicity in rectal cancer patients. Strahlenther Onkol [Internet]. 2000;176(9):416-21. Disponible en: http://dx.doi.org/10.1007/pl00002350
Valls A, Pestchen I, Prats C, Pera J, Aragón G, Vidarte M, et al. Multicenter double-blind clinical trial comparing sucralfate vs placebo in the prevention of diarrhea secondary to pelvic irradiation. Med Clin (Barc) [Internet]. 1999 [citado 29 de mayo de 2022];113(18):681-4. Disponible en: https://pubmed.ncbi.nlm.nih.gov/10650568/
Wu PE, Juurlink DN. Clinical review: Loperamide toxicity. Ann Emerg Med [Internet]. 2017;70(2):245-52. Disponible en: http://dx.doi.org/10.1016/j.annemergmed.2017.04.008
Navarro F. Treatment of inflammatory bowel disease: safety and tolerability issues. Am J Gastroenterol [Internet]. 2003;98(12):S18-23. Disponible en: http://dx.doi.org/10.1016/j.amjgastroenterol.2003.11.001
Nakao M, Ogura Y, Satake S, Ito I, Iguchi A, Takagi K, et al. Usefulness of soluble dietary fiber for the treatment of diarrhea during enteral nutrition in elderly patients. Nutrition [Internet]. 2002;18(1):35-9. Disponible en: http://dx.doi.org/10.1016/s0899-9007(01)00715-8
Ersin S, Tuncyurek P, Esassolak M, Alkanat M, Buke C, Yilmaz M, et al. The prophylactic and therapeutic effects of glutamine- and arginine-enriched diets on radiation-induced enteritis in rats. J Surg Res [Internet]. 2000;89(2):121-5. Disponible en: http://dx.doi.org/10.1006/jsre.1999.5808
Schwanke RC, Marcon R, Bento AF, Calixto JB. EPA- and DHA-derived resolvins’ actions in inflammatory bowel disease. Eur J Pharmacol [Internet]. 2016;785:156-64. Disponible en: http://dx.doi.org/10.1016/j.ejphar.2015.08.050
Kozelsky TF, Meyers GE, Sloan JA, Shanahan TG, Dick SJ, Moore RL, et al. Phase III double-blind study of glutamine versus placebo for the prevention of acute diarrhea in patients receiving pelvic radiation therapy. J Clin Oncol [Internet]. 2003;21(9):1669-74. Disponible en: http://dx.doi.org/10.1200/JCO.2003.05.060
Brandt LJ, Feuerstadt P, Longstreth GF, Boley SJ, American College of Gastroenterology. ACG clinical guideline: epidemiology, risk factors, patterns of presentation, diagnosis, and management of colon ischemia (CI). Am J Gastroenterol [Internet]. 2015;110(1):18-44; quiz 45. Disponible en: http://dx.doi.org/10.1038/ajg.2014.395
Medina C, Vilaseca J, Videla S, Fabra R, Armengol-Miro JR, Malagelada JR. Outcome of patients with ischemic colitis: review of fifty-three cases. Dis Colon Rectum [Internet]. 2004;47(2):180-4. Disponible en: http://dx.doi.org/10.1007/s10350-003-0033-6
Lalla RV, Brennan MT, Gordon SM, Sonis ST, Rosenthal DI, Keefe DM. Oral mucositis due to high-dose chemotherapy and/or head and neck radiation therapy. J Natl Cancer Inst Monogr [Internet]. 2019;2019(53). Disponible en: http://dx.doi.org/10.1093/jncimonographs/lgz011
Lalla RV, Bowen J, Barasch A, Elting L, Epstein J, Keefe DM, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy: MASCC/ISOO Mucositis Guidelines. Cancer [Internet]. 2014;120(10):1453-61. Disponible en: http://dx.doi.org/10.1002/cncr.28592
Bonaventura A. Complications of cytotoxic therapy -part 1. Aust Prescr [Internet]. 1995;18(3):65-7. Disponible en: http://dx.doi.org/10.18773/austprescr.1995.066
Peterson DE, Boers-Doets CB, Bensadoun RJ, Herrstedt J, ESMO Guidelines Committee. Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol [Internet]. 2015;26 Suppl 5(suppl 5):v139-51. Disponible en: http://dx.doi.org/10.1093/annonc/mdv202
Pérez Escutia MA, Samper Ots P, Cabeza Rodríguez MA. Prevención y tratamiento de la toxicidad digestiva. Oncol (Barc) [Internet]. 2005 [citado 29 de mayo de 2022];28(2):47-57. Disponible en: https://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S0378-48352005000200008
Galán Cerrato, Mª Nieves. Síndrome diarreico producido por quimioterapia. 2ª Jornada sobre urgencias en Oncología. Mesa Zaragoza. Google.com. [citado 29 de mayo de 2022]. Disponible en: https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&cad=rja&uact=8&ved=2ahUKEwiDq-iBsoT4AhV5hv0HHV4fCnYQFnoECAUQAQ&url= https%3A%2F%2Fseom.org%2Fseomcms%2Fimages%2Fstories%2Frecursos%2Fmasmir%2Fpdf%2FgrowingUp%2FNieves_Galan.pdf&usg=AOvVaw3BwsKli4c41vGhlXQB_fc1
1. POST-RADIATION THERAPY PROCTITIS

Evidence

Level Grade PMID Nº

Author: Luis Moreno Sánchez , Maria Ribeiro Gomes and Inês da Conceição Félix Pinto

Introduction

Radiotherapy alone or in combination with chemotherapy, either as neoadjuvant or adjuvant treatment, is used in a variety of pelvic neoplasms, the most frequent being prostate, cervix, rectum, and endometrium. The techniques and technologies to treat these neoplasms are increasingly modern and precise, reducing the appearance of acute and chronic toxicities by a high percentage, however, the appearance of some of these secondary effects such as radiation proctitis are still frequent and, there is no standard diagnosis and management, and there are few controlled or prospective studies with a limited number of patients.

Although most cases resolve spontaneously, some become chronic and are characterized by the presence of diarrhoea, tenesmus, urgency and/or persistent rectal bleeding, leading to the appearance of iron deficiency anaemia requiring blood transfusions.

There are several therapeutic options, including non or minimally invasive ones such as butyrate, sucralfate enemas, 5-ASA derivatives, corticosteroids, metronidazole, formalin, topical sucralfate, aloe vera, and hyperbaric oxygen, which have been used with some success. There are also invasive approaches such as endoscopic dilation, endoscopic lasers and cryoablation, bipolar electrocoagulation and thermal probe, endoscopic argon plasma coagulation (APC), endoscopic radiofrequency ablation (RFA), and surgical management such as colostomy, ileostomy, and repair – reconstruction but associated with higher morbidity and mortality.

Symptoms

In the acute phase, diarrhea, presence of mucus in the stool, tenesmus, proctalgia and / or mild rectal bleeding may occur; on the other hand, the chronic phase can be characterized by profuse rectal bleeding, intestinal obstruction, rectal urgency, incontinence, stenosis and to a lesser extent presence of rectovaginal, vesicoureteral or vesicovaginal fistulas.

Etiology

During treatment or after it, the acute phase of radiation proctitis may occur, histologically inflammation of the mucosa, epithelial damage with meganucleosis, and eosinophilic infiltration of the submucosa, atrophy, and formation of micro abscesses in the crypts, accompanied days or weeks later by vascular lesions characterized by thrombosis of venules and arterioles. All the above directly results from radiation by causing non-specific inflammation.

The chronic phase usually occurs in less than 5% of patients, usually between 6 months and 2 years after the end of radiotherapy. Enteritis obliterans can be observed with ulceration and induration of the intestine, with the presence of vasculopathy of small vessels characterized by telangiectasias of venules and narrowing of arterioles. Macroscopically there may be ulceration, decreased rectal lumen and eventually perforation, which characterizes the previously described symptomatology.

Studies

There is no standard management for the diagnosis and treatment of radiation proctitis.

The diagnosis can be made through the clinical history, and be confirmed with colonoscopy or recto sigmoidoscopy, and in them a pale and friable mucosa with telangiectasias, compatible with radiation lesions, is usually observed.

It is important to highlight the need to know the anorectal situation of patients who will be treated with radiotherapy to the pelvis, therefore, recto sigmoidoscopy can be considered prior to treatment.

The biopsy of the mucosa could help to exclude other causes of proctitis, however, it could be a condition in the development of rectal fistulas, and therefore, if considered necessary should be performed with great caution.

Pharmacotherapy

Evidence

Level Grade PMID Nº

Therapeutic Strategy

2+ B

2+ C

Butyrate: the main short-chain grade acid used by colonocytes in nutrition, attributing to this its effect accelerating the recovery from radiation injuries.

Sucralfate: It is administered in the form of enemas. It is a basic salt of polyanionic aluminum with a negative charge that acts locally on the lesion or ulcer of the intestinal mucosa, does not get into itself, and is excreted more than 95% through the feces. Due to the above it forms a complex with the proteins with positive charge present in high

Derivatives of Amino salicylic Acid 5-ASA (Mezalacin/Sulfasalazine): It is administered orally. It inhibits the production of prostaglandins.It acts locally by precisely deflating

It acts locally by precisely deflating the affected area and has wide dispersion in the colon. About 90% of the drug is excreted through the feces and only 10% is absorbed

Corticosteroids: Prednisone or dexamethasone are used. They are usually administered orally and exert their potent anti-inflammatory effect by binding to intracellular steroid receptors, thus preventing the cellular response with the consequent reaction in cascade of the inflammatory process.

Metronidazole: Itis a nitroimidazole and its mechanism of action is believed to be produced by reducing the nitro group in ananaerobic environment.

Formalin: The success in controlling bleeding liesin the precise and exact location and application in all affected areas, which produces local chemical cauterization closing the ulcers and vascularized telangiectatic spots.

Aloe Vera: Topical use. One of its active ingredients is salicylic acid, which can be converted into salicylate and therefore inhibit prostaglandin synthesis and inflammation. It is considered that it could facilitate healing, exerting its effects because of antioxidant and immunomodulatory properties, suppressing cyclooxygenase 2.

2+ B

2++ B

1+ B

2+ B

1+ B

2+ B

1+ B

2+ B

2+ C

2+ B

1+ B

4 D

2+ B

Hyperbaric Oxygen: It is considered that it can inhibit bacterial growth, preserves marginally perfused tissue, and inhibits the production of toxins. Thas an angiogenic effect and has been shown to increase the vascular density of soft tissues to 8 or 9 times.

Endoscopic Dilation: To be effective in patients with radiotherapy-related stenosis, and who do not respond to stool softeners, itis important that the compromised segment is short.

Endoscopic Lasers and Cryoablation: Endoscopic treatment include the use of Argon laser Nd: YAG or the KTP of potassium phosphate titanium and can be used for coagulation of ecstatic vessels. Unfortunately, it is not an economical option, and they are not widely distributed.

Bipolar Electrocoagulation and Thermal Probe: Advantages and disadvantages have been pointed out when compared with laser treatment is. Among the advantages are less tissue lesions, possibility of tangential use of cautery, economy, and wide availability of equipment. As a disadvantage they mention the decrease in the effectiveness of the treatment due to the formation of charcoal at the tip of the probe, in addition to requiring continuous cleaning

2+ B

2- C

1+ B

2+ B

1+ B

2+ B

1+ B

2+ B

1+ B

2+ B

24280407

11072942

24280407

23006660

14666326

24280407

14666326

24280407

14666326

24280407

10962052

24280407

14666326

11967906

15933799

28618234

32404169

17728120

24280407

16337705

14666326

22147960

24280407

14666326

17728120

24280407

14666326

8886636

22147960

24280407

17728120

14666326

22147960

Evidence Level Grade PMID Nº

Endoscopic Coagulation with Argon Plasma (APC): Uses high-frequency energy transmitted to the tissue by ionized gas. Itis less expensive, easier, safer, and accessible. Through this technique the current passes from the probe to the lesion and the arch breaks when the tissue dries. In theory there is a uniform, more predictable and limited coagulation depth (0.5 to 3 mm), reducing the risks of fistula appearance, perforation and / or stenosis.

Endoscopic Radiofrequency Ablation (RFA): When compared with other techniques have reported benefits limits the penetration of energy by restricting the treatment to the superficial mucosa; allows the simultaneous treatment of large areas; The energy administered to the surface is constant and reproducible, reducing operator dependency and overtreatment.

Colostomy or Ileostomy: They are performed with the intention of diverting intestinal transit, with the intention of reducing the symptoms: pain, tenesmus, incontinence, stenosis.

Reconstruction/Repair: Technically possible but are limited by the presence of poorly vascularized tissues and low rates of resolution.

2+ B

1+ B

2+ B

3 D

2+ B

2+ C

2+ B

References:

Sarin A, Safar B. Management of radiation proctitis. Gastroenterol Clin North Am. 2013 Dec;42(4):913-25. doi: 10.1016/j.gtc.2013.08.004. PMID: 24280407.

17728120

24280407

23006660

14666326

22147960

20593010

24280407

22147960

24280407

33143666

22147960

24280407

Zimmermann FB, Feldmann HJ. Radiation proctitis. Clinical and pathological manifestations, therapy, and prophylaxis of acute and late injurious effects of radiation on the rectal mucosa. Strahlenther Onkol. 1998 Nov;174 Suppl 3:85-9. PMID: 9830466.
Leiper K, Morris AI. Treatment of radiation proctitis. Clin Oncol (R Coll Radiol). 2007 Nov;19(9):724-9. doi: 10.1016/j.clon.2007.07.008. Epub 2007 Aug 28. PMID: 17728120.
Pérez R, Luis A. Calvo M, Felipe A. Therapeutic Guide for Support in Radiation Oncology. Clinical Research Group in Radiation Oncology (GICOR). Edt. Masson. 2004.
Cotti G, Seid V, Araujo S, Souza AH Jr, Kiss Dr, Habr-Gama A. Conservative therapies for hemorrhagic radiation proctitis: a review. Rev Hosp Clin Fac Med Sao Paulo. 2003 Sep-Oct;58(5):284-92. doi: 10.1590/s0041-87812003000500008. Epub 2003 Nov 11. PMID: 14666326.
Cavcić J, Turcić J, Martinac P, Jelincić Z, Zupancić B, Panijan-Pezerović R, Unusić J. Metronidazole in the treatment of chronic radiation proctitis: clinical trial. Croat Med J. 2000 Sep;41(3):314-8. PMID: 10962052.
Chruscielewska-Kiliszek MR, Regula J, Polkowski M, Rupinski M, Kraszewska E, Pachlewski J, Czaczkowska-Kurek E, Butruk E. Sucralfate, or placebo following argon plasma coagulation for chronic radiation proctitis: a randomized double-blind trial. Colorectal Dis. 2013 Jan;15(1): e48-55. doi: 10.1111/codi.12035. PMID: 23006660.
Huang X, Zhong Q, Wang H, Zhao J, Kuang Y, Guan Q, He Y, Qin Q, Wang H, Ma T. Diverting colostomy is an effective procedure for ulcerative chronic radiation proctitis patients after pelvic malignancy radiation. BMC Surg. 2020 Nov 3;20(1):267. doi: 10.1186/s12893-020-00925-2. PMID: 33143666; PMCID: PMC7607838.
Vernia P, Fracasso PL, Casale V, Villotti G, Marcheggiano A, Stigliano V, Pinnaro P, Bagnardi V, Caprilli R. Topical butyrate for acute radiation proctitis: randomised, crossover trial. Lancet. 2000 Oct 7;356(9237):1232- 5. doi: 10.1016/s0140-6736(00)02787-2. PMID: 11072942.
Jones K, Evans AW, Bristow RG, Levin W. Treatment of radiation proctitis with hyperbaric oxygen. Radiother Oncol. 2006 Jan;78(1):91-4. doi: 10.1016/j.radonc.2005.11.004. Epub 2005 Dec 7. PMID: 16337705.
Rustagi T, Mashimo H. Endoscopic management of chronic radiation proctitis. World J Gastroenterol. 2011 Nov 7;17(41):4554-62. doi: 10.3748/wjg. v17.i41.4554. PMID: 22147960; PMCID: PMC3225092.
de Parades V, Etienney I, Bauer P, Bourguignon J, Meary N, Mory B, Sultan S, Taouk M, Thomas C, Atienza P. Formalin application in the treatment of chronic radiation-induced hemorrhagic proctitis–an effective but not risk-free procedure: a prospective study of 33 patients. Dis Colon Rectum. 2005 Aug;48(8):1535-41. doi: 10.1007/s10350-005-0030-z. PMID: 15933799.
Sahebnasagh A, Ghasemi A, Akbari J, Alipour A, Lashkardoost H, Ala S, Salehifar E. Successful Treatment of Acute Radiation Proctitis with Aloe Vera: A Preliminary Randomized Controlled Clinical Trial. J Altern Complement Med. 2017 Nov;23(11):858-865. doi: 10.1089/acm.2017.0047. Epub 2017 Jun 15. PMID: 28618234.
Sahebnasagh A, Ghasemi A, Akbari J, Alipour A, Lashkardoost H, Ala S, Hosseinimehr SJ, Salehifar E. Prevention of acute radiation induced Proctitis by Aloe vera: a prospective randomized, double-blind, placebo controlled clinical trial in Pelvic Cancer patients. BMC Complement Med Ther. 2020 May 13;20(1):146. doi: 10.1186/s12906-020-02935-2. PMID: 32404169; PMCID: PMC7222341.
Luna-Pérez P, Rodríguez-Ramírez SE. Formalin instillation for refractory radiation-induced hemorrhagic proctitis. J Surg Oncol. 2002 May;80(1):41-4. doi: 10.1002/jso.10095. PMID: 11967906.
Barbatzas C, Spencer GM, Thorpe SM, Sargeant LR, Bown SG. Nd: YAG laser treatment for bleeding from radiation proctitis. Endoscopy. 1996 Aug;28(6):497-500. doi: 10.1055/s-2007-1004349. Erratum in: Endoscopy 1997 Jan;29(1):47. Carbatzas C [corrected to Barbatzas C]. PMID: 8886636.
Zhou C, Adler DC, Becker L, Chen Y, Tsai TH, Figueiredo M, Schmitt JM, Fujimoto JG, Mashimo H. Effective treatment of chronic radiation proctitis using radiofrequency ablation. Therap Adv Gastroenterol. 2009 Jan 1;2(3):149-156. doi: 10.1177/1756283×08103341. PMID: 20593010; PMCID: PMC2893353.

HEPATO-BILIARY DISORDERS

LIVER FAILURE AND CHEMOTHERAPY

Authors: João Diogo Faustino and Cláudia Rosado

Definition

Acute liver failure (ALF) is characterized by acute liver injury, hepatic encephalopathy, and an elevated prothrombin time/international normalized ratio (INR) [1]. As most chemotherapeutic drugs tend to be lipophilic compounds that are taken up readily by the liver but cannot be excreted easily unchanged in bile or urine, their “prolonged” metabolization in the liver may prompt liver toxicity and damage culminating in liver failure [2]

Symptoms and signs

Many of the initial symptoms in patients with acute liver failure are nonspecific [3]

- - Fatigue/malaise • Lethargy • Anorexia • Nausea and/or vomiting
  - Right upper quadrant pain • Pruritus • Jaundice • Abdominal distension from ascites

As the liver failure progresses, patients who were initially anicteric may develop jaundice, and those with subtle mental status changes (e.g., lethargy, difficulty sleeping) may become confused or eventually comatose.

Beyond the symptoms and signs mentioned, liver failure can also be identified through laboratory tests. Laboratory test abnormalities typically seen in patients with acute liver failure include:

- - Prolonged prothrombin time, resulting in an INR ≥1.5 (this finding is part of the definition of acute liver failure and thus must be present)
  - Elevated aminotransferase levels (often markedly elevated).
  - Elevated bilirubin level.
  - Low platelet count (≤150,000/mm3), but this is variable and has been associated with portal hypertension.

Note that decreasing aminotransferase levels may indicate spontaneous recovery but could also signal worsening of the liver failure with loss of hepatocyte mass.

Etiology

Cytotoxic chemotherapy agents exhibit their affects by interfering with DNA and RNA synthesis as well as cell division [4]. These include alkylating agents, anti-metabolites, anti- tumour antibiotics, isomerase inhibitors, mitotic inhibitors. Also, advances in understanding cancer cell biology have led to the development of molecular therapies, which target specific signalling pathways. Many of these agents affect multiple targets, and therefore have the potential to inhibit molecules that are critical to unsuspected pathways, causing toxicity that can sometimes be unpredictable [5]. Replication oh hepatocytes is low in normal liver but may reach a high-level during liver regeneration after massive hepatocellular death or partial hepatectomy. In the healthy liver, with its low replication rate, inhibition of hepatocellular replication during chemotherapy thus is not of primary matter. Nevertheless, systemic application of chemotherapeutics affecting DNA, RNA, or protein synthesis, may affect hepatocellular function in several ways through sinusoidal obstructive syndrome, hepatic steatosis, pseudocirrhosis culminating in liver failure. [6]

In the following table we present the most common chemotherapeutic agents used and associated toxic liver effects:

Evidence

Level Grade PMID Nº

[7]

Drug name

Liver toxic effects

Frequency

Severity

Dose modification

Fluorouracil (5-FU)

Steatosis Hepatotoxicity

Common Rare

Subclinical Subclinical

No dose adjustment

Oxaliplatin

Sinusoidal obstruction syndrome

Increased Bilirubin, AST or AP

Common (20-80%)

Might increase morbidity, but not mortality

No dose adjustment

12853359

[8]

17764887

Evidence

Drug name Liver toxic effects Frequency Severity Dose modification

Level Grade PMID Nº

[8]

Irinotecan	Steatosis and steatohepatitis Increase Bilirubin and AST/ALT	Common (25-50%) > 25% patients	Increase morbidity Reversible	If neutropenia and diarrhoea
Capecitabine	Hyperbilirubinemia without increased AP or G-GT	Common (25%)	Transient	No dose adjustment
Cisplatin	Increased aminotransferases Steatosis and cholestasis	Common (high dose) Rare	Transient Transient	No dose adjustment Renal excretion
Dacarbazine	Report of fulminate liver failure (thrombotic occlusions)	Rare	Life threatening	—
Doxorubicin	Idiosyncratic reactions including increased aminotransferases and bilirubin	Rare	Transient	Adjustment when high bilirubin levels
Etoposide	Pre-existing mild to moderate liver disease: no pharmacokinetic effect Severe liver impairment: myelosuppression, mucositis. Hypoalbuminemia increases unbound drug concentration leading to hepatotoxicity, veno-occlusive disease, or even severe hepatocellular damage	Rare (more common ~10% e bone marrow transplant)	Severe to life-threatening
Gemcitabine	Increased aminotransferases and/ or bilirubin Case reports of fatal cholestatic hepatotoxicity	Very common (>60%) Rare	Transient and reversible Can be fatal	No dose adjustment in aminotransferases increase
Imatinib	Increased aminotransferases or bilirubin Liver necrosis	5-8% Rare	— Reported fatality	Stop treatment if toxicity
Sorafenib	Hepatic clearance non-influenced by pre-existing liver disease	—	—	Adjustment when high bilirubin levels

17764887

[9]

16044340

[10]

6548368

[11]

7379000

[10]

6548368

[13;14]

8558207

2007774

In summary, we present the following table with the degree of hepatotoxicity of the most commonly used drugs [6]:

[15]

17625301

[16; 17]

17219077

20564754

[12]

17634483

Drug	Hepatotoxicity	Drug	Hepatotoxicity
Methotrexate	+++	Etoposide	+
Asparaginase	++	Gemcitabine	+
Carmustine	++	Mitomycin C	+

Drug	Hepatotoxicity	Drug	Hepatotoxicity
Mercaptopurin	++	Busulfan	(+)
Capecitabine	+	Cisplatin	(+)
Chlorambucil	+	5-FU	(+)
Cyclophosphamide	+	Irinotecan	(+)
Cytarabine	+	Imatinib	(+)
Dacarbazine	+	Oxaliplatin	(+)
Doxorubicin	+	Vincristine	(+)
Bevacizumab	0	Hydroxyurea	0
Cetuximab	0	Rituximab	0
Epirubicin	0

+++ very often; ++ often; + rare; (+) very rare; 0 no hepatotoxicity

Pharmacotherapy and Therapeutic strategies

The most important initial step in terms of management of suspected ALF due to chemotherapeutic drug is to discontinue the implicated agent. In many cases, spontaneous recovery occurs, without the need for any treatment or specific measure. In fact, spontaneous recovery after discontinuation of the offending drug is an important criterion in the causality assessment.

The evolution of ALF is highly unpredictable, especially hyperacute clinical presentations. All patients with a significant ALI should be considered for transfer to a liver transplantation or tertiary care unit (Table 10). Even in those who are unlikely to be candidates for liver transplantation should be considered for transfer to offer improved chances of survival.

Diagnosis of ALF should be always considered with respect to the full clinical picture; appropriate investigations and discussion with a tertiary centre should be undertaken.

Frequent senior clinical review (twice daily minimum) and assessment of physiological parameters, blood results and metabolic status should be carried out

Clinical deterioration with extrahepatic organ involvement should result in transfer to critical care and tertiary centre

III 1

28417882

Most patients are volume depleted at presentation and require crystalloid volume resuscitation

Persistent hypotension requires critical care management, with application of vaso-pressive agents guided by appropriate monitoring techniques

Norepinephrine is the vasopressor of choice

Hydrocortisone therapy does not reduce mortality but does decrease vasopressor requirements

Standard sedation and lung protective ventilator techniques should be utilised in patients with ALF

Avoid of excessive hyper or hypocarbia

Patients with ALF have increased resting energy expenditure. Therefore, enteral or parenteral nutrition are warranted

Avoid nasogastric feeding in those with progressive encephalopathy

PPI administration should be balanced against the risk of ventilator associated pneumonia and Clostridium difficile infection

Consider stopping PPI when enteral feeding has been established

Hypoglycaemia is common in patients with ALF, is associated with increased mortality and needs to be corrected avoiding hyperglycaemia

Hyponatraemia is detrimental to outcome and should be corrected to maintain concentrations 140–150 mmol/L

Early institution of extracorporeal support (RRT) should be considered for persistenthyperammonaemia, control of hyponatraemia and other metabolic abnormalities, fluid balance and potentially temperature control

Continuous RRT should always be undertaken in the critically ill patient with ALF as opposed to intermittent haemodialysis

Haemoglobin target for transfusion is 7 g/dl

Venous thrombosis prophylaxis should be considered in the daily review

II-1	1	28417882
II-3	1	28417882
III	1	28417882
II-1	1	28417882
II-2	1	28417882
III	1	28417882
II-3	1	28417882
III	1	28417882
II-3	1	28417882
III	1	28417882
II-3	1	28417882
II-2	1	28417882
III	1	28417882
III	1	28417882
II-2	1	28417882
III	1	28417882

Prophylactic antibiotics, non-absorbable antibiotics, and antifungal have not been shown to improve survival in ALF

Regular periodic surveillance cultures should be performed in all patients with ALF

Early anti-infection treatments should be introduced upon appearance of progression of hepatic encephalopathy, clinical signs of infections, or elements of SIRS

In patients with grade 3 or 4 encephalopathy, intubation should be undertaken to provide a safe environment and prevention of aspiration. Regular evaluation for signs of intracranial hypertension should be performed

Invasive intracranial pressure monitoring should be considered in a highly selected subgroup of patients, who have progressed to grade 3 or 4 coma, are intubated and ventilated and deemed at high risk of ICH, based on the presence of more than one of the followingvariables: a) young patients with hyperacute or acute presentations, b) ammonia level over 150 -200 lmol/L that does not drop with initial treatment interventions (RRT and fluids), c) renal impairment and d) vasopressor support (>0.1 lg/kg/min)

Mannitol or hypertonic saline should be administered for surges of ICP with consideration for short-term hyperventilation (monitor reverse jugular venous saturation to prevent excessive hyperventilation and risk of cerebral hypoxia). Mild hypothermia and ni domethacin may be considered in uncontrolled ICH, the latter only in the context of hyperaemic cerebral blood flow

Prognosis is worse in patients with more severe liver injury, extrahepatic organ failure and subacute presentations

Transplantation should be considered in those patients fulfilling Clichy or Kings College criteria

II-2	1	28417882
III	1	28417882
II-3	1	28417882
III	1	28417882
II-3	1	28417882
II-2	1	28417882
II-3	1	28417882
II-2	1	28417882

References:

Lee WM, Squires RH Jr, Nyberg SL, et al. Acute liver failure: Summary of a workshop. Hepatology 2008; 47:1401.
Teoh NC, Farrell GC. Liver Disease Caused by Drugs. In: Fledman M, Friedman LS, Brandt LJ (eds). Gastrointestinal and Liver Disease. 2nd. Ed. Philadelphia: Saunders Elsevier; 2006, p 1807
European Association for the Study of the Liver. Clinical practice guidelines panel, Wendon, J, et al. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol 2017; 66:1047.
Torrisi JM, Schwartz LH, Gollub MJ, Ginsberg MS, Bosl GJ, Hricak H. CT findings of chemotherapy-induced toxicity: what radiologists need to know about the clinical and radiologic manifestations of chemotherapy toxicity. Radiology 2011;258:41-56.
Bar J, Onn A. Combined anti-proliferative and anti-angiogenic strategies for cancer. Expert Opin Pharmacother 2008;9:701-715.
Ramadori G, Cameron S. Effects of Systemic Chemotherapy on the liver. Annals of Hepatology; April-June, Vol. 9 No 2, 2010: 133-143
Fleming GF, Schilsky RL, Shumm LP, Meyerson Aet al. Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucoverin in patients with organ dysfunction. Ann Oncol 2003; 14(7): 1142-7
Morris-Stiff G, Tan YM, Vauthey JN. Hepatic complications following preoperative chemotherapy with oxaliplatin or irinotecan for hepatic colorectal metastases. Eur J Surg Oncol 2008; 34 (6): 609-14
Nikolic-Tomasevic Z, Jelic, Cassidy J, Filipovic-Ljeskovic I, et al. Fluoropyrimidine therapy: hyperbilirubinemia as a consequence of hemolysis. Cancer Chemother Pharmacol 2005; 56 (6): 594-602
Aviles A, Herrera J, Ramos E et al. Hepatic injury during doxorubicin therapy. Arch Patol Lab Med 1984; 108: 912-13
Asbury RF, Rosenthal SN, Descalzi ME et al. Hepatic veno-occlusive disease due to DTIC. Cancer 1980; 45 (10): 2670-4
Miller AA, Murray DJ, Owar K. Pharmacokinetic and phase I study of sorafenib for solid tumors and hematologic malignancies in patients with hepatic or renal dysfunction: CALGB 60301. 25, abstr. 3538 ed. 2007
Joel SP, Shah R, Clark PI, Slevin ML. Predicting etoposide toxicity: relationship to organ function and protein binding. J Clin Oncol 1996; 14: 257-67
Tran A, Housset C, Boboc B, Tourani JM et al. Etoposid (VP 16-213) induced hepatitis. Report of three cases following standard dose treatments. J Hepatol 1991; 12: 36-9
Saif MW, Shahrokni A, Cornfeld D. Gemcitabine-induced liver fibrosis in a patient with pancreatic cancer. JOP 2007; 8(4): 460-7
Mindikoglu AL, Regev A, Bejarano PA etal. Imatinib mesylate (Gleevec) hepatotoxicity. Dig Dis Sci 2007; 52(2): 598-601
Fontana RJ, Seeff LB, Andrade RJ, Björnsson E, Day CP, Serrano J, et al. Standardization of nomenclature and causality assessment in druginduced liver injury: summary of a clinical research workshop. Hepatology 2010;52:730–742
1. HEPATIC ENCEPHALOPATY

Authors: Tiago Rabadao and Marta Riquito

Introduction

Hepatic encephalopathy (HE), a metabolic encephalopathy, describes a potentially reversible syndrome (3) of impaired neuropsychiatric function associated with liver dysfunction and/or portal-systemic shunting. It´s one of most debilitating complications of cirrhosis, also affecting patient´s caregivers; it also occurs in patients with cancer. Despite the frequency of this condition, the mechanisms causing brain dysfunction in liver failure are not fully elucidated (2, 5). Nevertheless, the treatment should be initiated as soon as the diagnostic is considered.

Definition

HE describes an impaired neuropsychiatric function caused by liver dysfunction and/or portal-systemic shunting (2, 5, 6); it can be acute and reversible or chronic and progressive (4). Its manifestations include a wide spectrum of neurological and/or psychiatric abnormalities ranging from subclinical alterations to coma (2, 5, 6).

Pathophysiology

It´s usually multifactorial (7), and involves:

Ammonia (plays a central role)
Inflammatory cytokines
Interactions with faecal microbiota (changed in cirrhotic patients)

Clinical manifestations

Hepatic encephalopathy produces a large range of nonspecific neurological and psychiatric manifestation.

In HE lower expression, patients have subtle cognitive deficits that are not apparent without specialized testing (psychometric tests oriented toward attention, working memory, psychomotor speed, and visuospatial ability) (2, 6). As HE progresses, the signs and symptoms start to be overt (2):

Personality changes (apathy, irritability, disinhibition)
Alterations in consciousness
Disturbances in the sleep-wake cycle (insomnia and hypersomnia)
Mood changes (euphoria or depression)
Disorientation
Inappropriate behaviour
Acute confusional state (agitation or somnolence)
Unconsciousness
Neuromuscular impairment (ataxia, hyperreflexia, positive Babinski)
Extrapyramidal dysfunction (hypomimia, muscle stiffness, bradykinesia, slurred speech, parkinsonian-like tremor, dyskinesia with diminished voluntary movements)
Asterixis

Normally, the onset of overt HE is usually marked by disorientation and/or asterixis (2, 5).

Evidence

Level Grade PMID Nº

Classification

HE is categorized according to four factors (Table 1):

Underlying disease:
- Type A: Due to Acute Liver Failure (ALF)
- Type B: Resulting predominantly from portosystemic bypass or shunting
- Type C: Resulting from cirrhosis (portal hypertension)
Severity of manifestations:
- Minimal: Abnormal results on psychometric or neurophysiological testing without clinical manifestations
- GRADE I: Euphoria or anxiety, shortened attention span, slurred speech, sleep disorder
- GRADE II: Lethargy or apathy, disorientation for time, obvious personality change, inappropriate behaviour, dyspraxia, asterixis
- GRADE III: Somnolence to semi-stupor, responsive to stimuli, confused, gross disorientation, bizarre behaviour, incoherent speech
- GRADE IV: Coma, unresponsive to pain
Time course:
- Episodic HE
- Recurrent HE: bouts that occur within a time interval of 6 months or less
- Persistent HE: a pattern of behavioural alterations that are always present and interspersed with relapses of overt HE
Precipitating factors (see Diagnosis):
- Non-precipitated
- Precipitated

Type	Grade (West Haven Criteria)		Time course	Spontaneous or precipitated
A	MHE	Covert	Episodic	Spontaneous
	1
B	2	Overt	Recurrent
	3			Precipitated (specify)
C	4		Persistent

Table 1 – Hepatic Encephalopathy classification including West Haven Criteria (WHC) (2)

Evidence

Level Grade PMID Nº

Differential diagnoses

It is important to consider other possible causes that alter the level of consciousness:

Infections (not only CNS infections) and/or sepsis • Hypo or hyperglycaemia
Alcohol intoxication/ abstinence • Drugs (e.g., benzodiazepines, opioids…)
Electrolyte (Hyponatremia/Hypernatremia, hypercalcemia/hypocalcaemia, hypomagnesemia/hypermagnesemia…) and acid-base disorders
Non-convulsive epilepsy • Intracranial bleeding or stroke
Psychiatric disorders • Thiamine deficiency (Wernicke-Korsakoff)
Uremic encephalopathy • Hypercapnic encephalopathy
Hypothyroidism • Hashimoto encephalopathy
Suprarenal insufficiency • Dementia
Brain lesions • Severe anaemia
Posterior reversible encephalopathy syndrome (chemotherapy, metastasis) • Autoimmune (anti-MDMA)

Diagnosis and testing

The diagnosis is clinical. It requires the detection of signs suggestive of HE in a patient with or without severe liver disease who does not have another obvious cause for the brain dysfunction.

It is not hard to detect cognitive dysfunction; the difficulty is to assign it to HE (2). That is why HE remains a diagnosis of exclusion (2). The diagnostic approach to HE should include:

Complete history and physical examination – detect signs of chronic liver disease or any neuromuscular and/or cognitive impairments to grad according to West Haven Criteria (WHC) (table 1)
Consider alternate diagnosis (see differential diagnosis)
- Should not delay prompt treatment
Serum laboratory testing
- Full blood count
- Glucose, electrolytes (Na+, K+, Ca2+, Mg2+), inflammatory markers
- Arterial blood gas
- Blood alcohol level
- Ammonia
- Thyroid-stimulating hormone
- Screening for psychoactive drugs
Computed tomography (CT) scan of the brain – exclude other causes of mental status changes / diagnosis doubts / non-response to treatment
Consider:
- Thorax X-ray, EKG, urine exam
- Paracentesis (!)
- Lumbar puncture or Electroencephalogram
- Other blood tests: virus, autoimmunity (ALF suspected), thiamine levels
- Abdominal Doppler (signs of liver disease / portal hypertension/ malignancy/ thrombosis)
- Upper endoscopy

Evidence

Level Grade PMID Nº

Evaluation of possible precipitating causes (5,8) (*- most common)
Increased ammonia production
- Gastrointestinal bleeding*
- Infection*
- Constipation*
- Renal production: renal failure*, hypokalaemia*, alkalosis
- Increased protein intake (including enteral feeding)
- Increased catabolism: seizures, corticosteroid use, starvation, malignancy (hepatic carcinoma, multiple myeloma, leukaemia, treatment with asparaginase), excessive exercise, trauma, burns…
- Others: Shock, Blood transfusions, Salicylate intoxication
Decreased ammonia elimination
- Dehydration*: diuretics, paracentesis, vomits, diarrhoea
- Liver disease (cirrhosis – progression; acute liver failure; reduced liver perfusion; hepatic or portal vein thrombosis)
- Medications: valproate, topiramate, carbamazepine, 5-Flurouracil
Neurotransmissors changes (e.g., Benzodiazepines)
Hepatocellular damage
- Alcohol
- Carcinoma / metastasis
Others
- Medication non-compliance – lactulose and/or rifaximin*
- Surgery
- Hypoxemia, hypoglycaemi
Psychometric and neurophysiologic tests

For patients with mild degrees of HE (Minimal and Grade I), may be helpful to establish the diagnose, especially when cirrhosis is already present.

Glasgow Coma Scale

For patients with more severe hepatic encephalopathy (grade III or IV), may be useful to get a stratified description of neurologic impairment.

Ammonia (2,8)

Normal levels – Negative predictive value (!)
Linked to HE severity
Should not be used to guide therapy
Consider other causes of elevated ammonia (see precipitating causes)
Blood should be collected without tourniquet and without muscle contractions

Type A EH (9)

Without chronic liver disease
Subacute/ sub fulminant course of ALF (-> EH)
- ALF: 2-3x elevation of transaminases + jaundice and coagulopathy
- Acute ALF: severe coagulopathy + mild jaundice
- Subacute ALF: milder increase of transaminases + deep jaundice + mild-moderate encephalopathy
Causes of ALF include:
- Viral: hepatitis A, E, B (also CMV, HSV, VZV)
- Drugs/toxins: paracetamol, Amanita phalloides, chemotherapy, statins, penicillin’s, anti-tuberculous
- Vascular: Budd-Chiari, Hypoxic hepatitis
- Malignant: Lymphoma, metastasis
- Pregnancy: HELLP, fatty liver of pregnancy, pre-eclamptic liver rupture

– Others: Hemophagocytic lymph histiocytosis, Wilson disease, autoimmune

Thiamine deficiency: causes (10)

Poor intake: chronic alcoholism, gastric bypass surgery, parental nutrition
Poor absorption: malnutrition, gastric bypass surgery, malabsorption syndrome
Increased loss: diarrhoea, hyperemesis gravidarum, diuretics, renal replacement therapy
Increased thiamine utilization: pregnancy, hyperthyroidism, refeeding syndrome

Treatment

All stages (covert and overt)
Avoid dehydration and electrolyte abnormalities
Nutritional support (dietary protein restriction is not recommended)
- Includes vitamin/micronutrient supplementation
Correction of precipitating factors
Medication to lower ammonia production and absorption (2,4,5)
- Lactulose (30-45mL orally two to four times per day / rectal enemas) with or without
- Rifaximin (400mg orally three times daily or 550 mg orally two times per day)
Secondary prophylaxis
- After first episode: Lactulose
- After second episode: Rifaximin
- Prior to TIPS placement: Rifaximin

Level Grade PMID Nº

Not recommended: zinc supplementation, faecal microbiota transplantation
Driving (!) – patients/caregivers should be informed about the risks associated and about the appropriateness of formal driving assessment with the relevant authorities
Overt encephalopathy (1)
Grade 3-4 (look for ACLF) – consider ICU admission
Consider referral to a transplant centre to evaluation
Liver transplant is the only choice to treat refractory HE
Obliteration of accessible portal-systemic shunts (recurrent/persistent)
Replacement of animal protein with vegetable and dairy protein (recurrent/persistent)
Primary prophylaxis: gastrointestinal bleeding (lactulose or mannitol nasogastric tube or lactulose enemas)

Conclusion

Hepatic encephalopathy is frequently seen in the emergency room and sometimes it can be related to cancer. Being a diagnose of exclusion, is very important to rule out the many differential diagnosis, to initiate the proper treatment as early as possible.

References:

EASL Clinical Practice Guidelines on the management of hepatic encephalopathy, European Association for the Study of the Liver, https://doi.org/10.1016/j.jhep.2022.06.001
Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases, American Association for the Study of Liver Diseases, European Association for the Study of the Liver
Abordagem Clínica da Cirrose Hepática: Protocolos de atuação (1ª edição Fevereiro 2018) – Serviço de Gastrenterologia do Hospital Prof. Dr. Fernando Fonseca
Harrison’s Manual of Medicine 18th edition
Diagnosis and Management of Hepatic Encephalopathy, UpToDate
Hepatic Encephalopathy: Novel insights into classification, pathophysiology and theraphy, Christopher F Rose et al., J Hepatol. 2020 Dec;73(6):1526-1547. doi: 10.1016/j.jhep.2020.07.013.
Hepatic Encephalopathy, BMJ Best Practice
Ammonia: what adult neurologists need to know, Rick Meijer et al.
EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure, European Association for the Study of the Liver 10.Vitamin B1 Thiamine Deficiency, Kimberly D. Wiley; Mohit Gupta.

BILIARY OBSTRUCTION

PMID Nº

Authors: Pedro Marílio Cardoso and José Miguel Martins

Definition

- - Blockage of the biliary duct system causing impairment of bile flow.
  - In biliary obstruction, both conjugated and unconjugated bilirubin accumulate in blood.
  - Diagnosis usually established with non-invasive and invasive imaging methods.
  - The treatment is stablished according to the symptoms and aetiology of the obstruction.

Symptoms

Patients may report jaundice, right upper quadrant or epigastric pain, nausea/emesis, anorexia, pruritus, pale stools and dark urine. Jaundice, right upper quadrant or epigastric pain, pale stools and dark urine on physical examination suggest biliary obstruction.

Disease progression may accentuate symptoms and clinical findings.

Etiology

Obstructive disorders of the biliary tract include occlusion of the bile duct lumen, intrinsic disorders of the bile ducts, and extrinsic biliary compression. Intrinsic obstruction:

- - Benign conditions
    - Choledocholithiasis
      - Luminal occlusion by a stone (most common cause of biliary obstruction)
    - Bile Duct Diseases
    - Intrinsic narrowing of the bile ducts
    - Inflammatory (primary sclerosing cholangitis and primary biliary cholangitis, toxics…)
    - Infectious (viral hepatitis)
    - Infiltrative diseases (sarcoidosis, tumours, abscess, and cysts).
    - Congenital disorders (cysts and biliary atresia)
    - Neoplasia’s (Cholangiocarcinoma)
    - Others – Drug-induced liver injury, AIDS cholangiopathy, iatrogenicity of chemotherapeutic compounds or surgical injury.
  - Malignant aetiologies
    - Malignant infiltration
    - Biliary tract neoplasia’s: Cholangiocarcinoma Extrinsic Compression
  - Benign aetiologies (for example, Mirizzi syndrome)
  - Malignant aetiologies: pancreatic head cancer (leading to distal common bile duct stricture), ampullary carcinoma or adenoma, hepatic cell carcinoma, peri- portal lymph nodes enlarged by metastatic tumour or lymphoma.
  - Other – Infectious

Level GradeEvidence

Studies Evidence

Biliary obstruction may be the first presentation of pancreatobiliar carcinoma (pancreatic, cholangiocarcinoma, ampullary cancer and gallbladder cancer).

Diagnosis may be suspected by anamnesis, physical examination, and laboratory test results. Imaging studies identify biliary obstruction and may help differentiate benign and malignant causes.

Laboratory tests should include total bilirubin, conjugated bilirubin, alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST). Bilirubin levels are a strong predictor of malignant disease, the higher the bilirubin level at presentation, the greater the likelihood of malignant disease.

Transabdominal ultrasonography (TUS) computed tomography (CT) scan, or magnetic resonance imaging (MRI) and cholangiopancreatography (MRCP) are first-line imaging studies in diagnosis confirmation.

CT-scan and MRCP confirm biliary/pancreatic duct dilatation identify the lesion and stage of the disease (tumour extension, vascular involvement and the presence or the absence of metastases).

Endoscopic ultrasonography with fine-needle aspiration (EUS-FNA) or endoscopic retrograde cholangiopancreatography (ERCP) are invasive exams that provide additional information regarding the extension of the lesion and tissue acquisition.

Imaging studies identify patients with resectable disease who benefit from curative surgery and patients who will benefit from chemotherapy (neoadjuvant or palliative).

Pharmacotherapy

There is no strong evidence or recommendations for the use of pharmacotherapy for the treatment of malignant biliary obstruction. There are symptomatic drugs that have efficacy proved for other aetiologies that might be used for symptomatic relief such as:

Ursodeoxycholic acid: an orally administered bile acid that potently stimulates bile flow
Symptomatic drugs for hyperbilirubinemia (not the scope of this topic)
Additional treatments for cholestatic disorders that are directed toward complications that are independent of hyperbilirubinemia, such as malabsorption of fat-soluble vitamins (A, D, E, and K), and pruritus.

Therapeutic Strategy

Obstructive Jaundice – typically directed at relieving the obstruction.

Interventional endoscopic or radiologic approaches : sphincterotomy, balloon dilation of focal strictures, placement of drains or stents – percutaneous drainage with PTC with internal and external drainage;

- - Focal intrahepatic strictures may be amenable to an interventional radiologic approach.
  - Lesions distal to the bifurcation of the hepatic ducts may be more suitably managed endoscopically.

When ERCP is not feasible, percutaneous transhepatic biliary drainage (PTBD) is to be considered. Personalised case-by-case discussions with the interventional radiologist are encouraged. More information in Table 1.

Surgery – usually considered for neoplasms :

- - Advanced disease
    - Palliation with endoscopic biliary stenting and chemoradiotherapy or photodynamic therapy
    - Percutaneous transhepatic Endo biliary radiofrequency ablation along with biliary stenting
    - Duodenal stenting in ampullary carcinoma
  - Resect able disease
    - Excision with clear margins and bilioenteric anastomosis
  - Pancreatic head carcinoma
    - Whipple procedure/pylorus-preserving pancreaticoduodenectomy
  - Ampullary carcinoma
    - Whipple procedure
  - Gallbladder malignancy
    - Cholecystectomy with liver resection and lymph node clearance

Level Grade PMID Nº

Nonobstructive Jaundice (caused by liver disease) – treatment directed toward the underlying disorder. Pharmacologic therapeutics approach above mentioned.

Endoscopic biliary stenting

Preoperative biliary drainage – reserved for patients with cholangitis, severe symptomatic jaundice or delayed surgery, or for before neoadjuvant chemotherapy in jaundiced patients; 10-mm diameter self-expandable metal stent (SEMS).

Palliative biliary drainage – SEMS insertion for palliative drainage of extrahepatic malignant biliary obstruction.

Drainage of suspected malignant biliary obstruction – recommendation against the insertion of uncovered SEMS for the drainage of extrahepatic biliary obstruction of unconfirmed etiology.

Preoperative drainage of malignant hilar strictures – recommendation against routine preoperative biliary drainage in patients with malignant hilar obstruction.

Periprocedural and technical aspects of biliary stenting – recommendation for prophylaxis of post-ERCP pancreatitis – routine administration of 100 mg of diclofenac or indomethacin intrarectally immediately before or immediately after ERCP in every patientwith no contraindication.

Surgery when in presence of resectable pancreaticobiliary malignancy[7]

Table 1: Advantages and disadvantages of the different techniques for biliary drainage [8]

Level GradeEvidence

		300865
1	B
1	A
1	C
2	C
1	B
I	A	27664259

	Advantages		Disadvantages
ERCP (Endoscopic retrograde cholangiopancreatography)	Widely available Relative low complication rate (compared to PTBD and EUS-BD)		Not feasible in case of inaccessible papilla
PTBD (Percutaneous transhepatic biliary drainage)	Available rescue therapy for ERCP failure		High complication rate (bleeding- infection) External catheter Contraindicated if ascites
EUS-BD (Endoscopic ultrasonography-guided biliary drainage)	Different possible approaches (Hepatogastric anastomosis, Choledochoduodenostomy, Transgallbladder drainage, Rendezvous) Internal drainage		Not widely available High endoscopic ERCP/EUS expertise required Not yet standardized algorithm
	Same session of failed ERCP Fewer re-interventions	Table adapted from: Sa on EUS- guided biliary	lerno R, Davies SEC, Mezzina N, Ardizzone S. drainage. World J Gastrointest Endosc 2019;	Comprehensive review 11(5): 354-364

References:

PMID Nº

Fernandez Y. Viesca, M. and M. Arvanitakis, Early Diagnosis And Management Of Malignant Distal Biliary Obstruction: A Review On Current Recommendations And Guidelines. Clinical and Experimental Gastroenterology, 2019. 12: p. 415 – 432.
Feldman, M.F.L.S.B.L.J., Sleisenger and Fordtran’s gastrointestinal and liver disease : pathophysiology/diagnosis/management. 2016, Philadelphia, PA: Saunders/Elsevier. 3.Coucke, E.M., et al. Biliary Obstruction. [Updated 2022 May 1] 2022 Jan-]; Available from: https://www.ncbi.nlm.nih.gov/books/NBK539698/?report=classic
Dumonceau, J.-M., et al., Endoscopic biliary stenting: Indications, choice of stents, and results: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline – Updated October 2017. Endoscopy, 2018. 50.
Devane, A.M., et al., Society of Interventional Radiology Quality Improvement Standards for Percutaneous Cholecystostomy and Percutaneous Transhepatic Biliary Interventions. J Vasc Interv Radiol, 2020. 31(11): p. 1849-1856.

6.2021 ESMO Essentials for Clinicians Gastrointestinal Tract Tumours Chapter. 2021, European Society for Medical Oncology: Switzerland.

7.Valle, J.W., et al., Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2016. 27(suppl 5): p. v28-v37. 8.Salerno, R., et al., Comprehensive review on EUS-guided biliary drainage. World journal of gastrointestinal endoscopy, 2019. 11(5): p. 354-364.

CARDIOVASCULAR DISORDERS

HIGH BLOOD PRESSURE

Author: Carlos Manuel Oliveira Soares da Costa

Abbreviations

- - ACE-I – Angiotensin-converting enzyme inhibitors • ARB – Angiotensin receptor blockers • BP – Blood pression
  - DHP – CCB – Dihydropyridine calcium channel blockers • ESC – European society of cardiology • ESH – European society of hypertension
  - EGF – Epidermal growth factor • HTN – Hypertension • NO – Nitric oxide
  - PGI2 – Prostacyclin I2 • RAS – Renin angiotensin system • VEGF – Vascular endothelial growth factor
  - TKIs – Tyrosine Kinase Inhibitors .

Introduction

Hypertension (HTN) is the most common cardiovascular comorbidity reported during cancer therapy. An elevated blood pression (BP) has been reported in more than one-third of the patients (1, 2). This can be due to the high prevalence of HTN at an age in which cancer is also common, but it is also due to cancer drugs such as conventional chemotherapy (fluoropyrimidines, anthracyclines, bicalutamide, cisplatin, enzalutamide, abiraterone), targeted therapies: anti-VEGF receptor (e.g., ramucirumab), VEGF-ligand-binding fusion proteins (e.g., aflibercept), anti-VEGF monoclonal antibodies (e.g., bevacizumab), VEGFR-TKIs (e.g., sorafenib) and non-cancer drugs such as corticosteroids and non-steroidal anti- inflammatory drugs. Additionally, other known factors may be involved such pain, excessive alcohol consumption, untreated sleep apnoea, renal impairment, obesity, and reduced exercise (3,4). Appropriate monitoring, management, and treatment of HTN should be aimed at reducing the risk of mortality and morbidity due to congestive heart failure, myocardial infarction, stroke or renal insufficiency, while ensuring the optimal effective dosing of anticancer agents for treatment (5).

VEGF signaling pathway

Conventional chemotherapy treatments often fail due to the development of multidrug-resistant tumor cells. Given the heterogeneity of solid tumours and potential crosstalk between key signalling pathways, multitargeted agents may be the best route forward, through targeted inhibition of a single signalling pathway, such as the vascular endothelial growth factor receptor (VEGFR) or the epidermal growth factor receptor (EGFR) pathway (6).

Angiogenesis is an essential process for growth, progression, invasion, and metastasis in many solid tumours. Research and clinical practice demonstrated that VEGF pathway has an essential role in tumour associated angiogenesis (8). Therefore, the blockage of this signalling pathway by targeted therapies anti-VEGF has become a major approach for cancer treatment (7, 8, 9). Although the exact mechanisms underlying the development of HTN are not entirely clear, the mechanism seems to be directly related to its anti-VEGF effect, predominantly through VEGFR-2 receptor, including: 1) an impaired angiogenesis leading to a reduce in the micro vessel density (a process described as rarefaction); 2) a production of molecules in response to hypoxia, which leads to an increase vascular tone; 3) an endothelial dysfunction associated with a decrease in nitric-oxide production in the wall of arterioles and vessels as well as prostacyclin I2 (PGI2); 4) a downregulation of endothelial NO synthase; 5) an enhanced secretion of endothelin-1which is a potent vasoconstrictor peptide and 6) a decreased glomerular filtration rate and increased sodium and water retention, similar to pre-eclampsia-associated HTN, which has been linked to placental-derived soluble antiangiogenic factors including VEGF (5, 7, 8, 10, 11, 12). VEGF not only stimulates endothelial cell proliferation, but also promotes endothelial cell survival (inhibits apoptosis and senescence) and helps maintain vascular integrity (11).

HTN is a class-type adverse effect of VEGF inhibitors. Fatigue, diarrhoea, nausea, decreased appetite, stomatitis and hand-foot syndrome are other adverse effects experienced by patients (5). Also, the usage of VEGF-TKIs such as sorafenib, sunitinib or vandetanib, could be linked to posterior reversible encephalopathy syndrome, which is a clinic- radiological event that includes nausea, headaches, visual loss, seizures and acute HTN (8)

The probability of HTN varies in line with tumour type and the type of VEGFR used (8). A meta-analysis published in 2016 enrolled around 1.500 patients demonstrated that the risk of HTN change substantially with VEGFR- TKI used. The risk of developing high grade and all grade HTN with cabozantinib was 12% and 27.8%, respectively, which is significantly higher when compared with other VEGFR-TKIs such as sorafenib, sunitinib, vandetanib and pazopanib (5).

Evidence

Level Grade PMID Nº

Management

Usually, the rise of BP occurs during the first months after starting the anticancer therapy. Therefore, office BP should be measured weekly during the initial part of the therapy first cycle of therapy and at least every 2–3 weeks thereafter until a stable BP has been reached and then monitored at the time of the routine clinical evaluations or assessed by home blood pressure monitoring (2, 11, 13).

The recommended BP threshold for treatment and BP targets depend upon the cancer prognosis: curable or metastatic and expected lifetime prognosis (figure 1). The cancer survivors should be treated according to the latest 2018 European Society of Cardiology (ESC)/European Society of Hypertension (ESH) Guidelines for the management of Arterial Hypertension (2, 4).

Home BP (mmHg)	Cancer survivors	Curable cancer during treatment	Metastatic cancer Prognosis >3 years	Metastatic cancer Prognosis 1–3years	Metastatic cancer Prognosis <1 year
>160	Treat	Treat	Treat	Treat	Treat
140-159	Treat	Treat	Treat	Consider treatment	May treat
135-139	Treat	May treat	Consider treatment	May treat	None
130-134	May treat	None	None	None	None
<130	None	None	None	None	None

Figure 1. Recommended threshold for asymptomatic HTN treatment in different clinical scenarios. BP, blood pressure; CS, cancer survivors (adapted from 2022 ESC Guidelines on cardio-oncology).

Class IIb

Class IIa

Class I

Evidence

Level Grade PMID Nº

The 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Haematology Association (EHA), the European Society for Therapeutic Radiology Level GradeEvidence

and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS) (table 1) recommend the use of Angiotensin-converting enzyme inhibitors (ACE-I) or Angiotensin receptor blockers (ARB) as the first-line antihypertensive drugs for BP management in patients with cancer (class of recommendation I, level of evidence B) (4). These drugs have the added merits of enhancing endothelial function and microvessel density. Dihydropyridine Calcium Channel Blockers (DHP-CCB) are recommended as second-line for patients with cancer with uncontrolled BP (class of recommendation I, level of evidence C). A systolic BP target < 140 mmHg and diastolic < 90 mmHg is recommended during cancer therapy (class of recommendation I, level of evidence C) and a systolic BP target <130 mmHg and diastolic BP < 80 mmHg may be considered during cancer therapy provided that the treatment is well tolerated (class of recommendation IIb, level of evidence C) (4).

If systolic BP ≥ 160 mmHg and diastolic BP ≥100 mmHg the combination therapy with a Renin angiotensin system (RAS) blocker and a DHP-CCB is recommended due to the more rapid onset of BP control compared with ACE-I/ARB monotherapy (class of recommendation I, level of evidence C) (4). Diltiazem and Verapamil are not recommended (class of recommendation III level of evidence C) due to their drug–drug interactions and the of inhibition of Cytochrome CYP3A4, which is involved in some metabolic pathway of anticancer agentes such as VEGFIs, increasing the drug’s levels and leading to potential toxicity (2, 4, 5, 14). Therefore, DHP-CCB, such as Amlodipine or Nifedipine are the preferred class of CCB (4).

Although cancer therapy takes an obvious priority, if severe hypertension is diagnosed (systolic BP ≥180 mmHg or diastolic BP ≥110 mmHg), the patient should be evaluated by a multidisciplinary team and the therapy associated with HTN should be deferred or temporarily withheld until the BP is properly controlled to values <160 mmHg systolic BP and <100 mmHg diastolic BP (class of recommendation I, level of evidence C) (2, 4).

In patients with resistant cancer therapy-related hypertension, defined as BP being uncontrolled despite treatment with optimal or best-tolerated doses of three or more drugs including a diuretic, and confirmed by ambulatory and home BP monitoring, beta-blockers, spironolactone, oral or transdermal nitrates, and/or hydralazine should be considered (class of recommendation II, level of evidence A) (4).

Antihypertensive agents should be individualized to suit the patient’s medical condition and health status. If there is evidence of high sympathetic tone, stress, and/or pain, beta- blockers should be considered. Nebivolol or carvedilol are preferred in patients on VEGFi (4). Diuretics, preferably spironolactone, may be considered if there is evidence of increased fluid retention, with monitoring of electrolytes and renal function (4). According to the British Columbia Cancer Agency recommendations for the management of adverse effects of bevacizumab, a thiazide diuretic should be the first-line treatment and a RAS blocker can be the second line (15, 16).

Effective treatment of cancer therapy-induced arterial hypertension to prevent cancer treatment interruption and CV complications is recommended

BP target < 140 mmHg systolic and <90 mmHg diastolic is recommended during cancer therapy

A BP target <130 mmHg systolic and <80 mmHg diastolic may be considered during cancer therapy provided that the treatment is well tolerated

In selected asymptomatic patients with metastatic cancer, a systolic BP 140 –160 mmHg and diastolic BP 90–100 mmHg treatment threshold may be considered provided there is ongoing BP monitoring

The competing cancer and CV risk evaluation is recommended if the systolic BP is

≥180 mmHg or diastolic BP ≥110 mmHg, and any cancer therapy associated with hypertension should be deferred or temporarily withheld until the BP is controlled to values < 160 mmHg systolic and <100 mmHg diastolic

I C

IIB C

I C

PMID Nº

Evidence Level Grade PMID Nº

ACE-I or ARB are the first-line antihypertensive drugs recommended for BP management in patients with cancer

Dihydropyridine CCB are recommended as second-line antihypertensive drugs for patients with cancer with uncontrolled BP

Combination therapy with ACE-I or ARB and DHP-CCB is recommended in patients with cancer with systolic BP≥160 mmHg and diastolic BP≥100 mmHg

Diltiazem and Verapamil are not recommended to treat arterial hypertension in patients with cancer due to their drug–drug interactions

References:

Table 1. Recommendations for the management of arterial hypertension in patients receiving anticancer treatment (adapted from 2022 ESC Guidelines on cardio-oncology).

I B

I C

III C

Jain M, Townsend RR. Chemotherapy agents and hypertension: a focus on angiogenesis blockade. CurrHypertens Rep 2007;9:320–328.
Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, Clement DL, Coca A, de Simone G, Dominiczak A, Kahan T, Mahfoud F, Redon J, Ruilope L, Zanchetti A, Kerins M, Kjeldsen SE, Kreutz R, Laurent S, Lip GYH, McManus R, Narkiewicz K, Ruschitzka F, Schmieder RE, Shlyakhto E, Tsioufis C, Aboyans V, Desormais I; ESC Scientific Document Group. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018 Sep 1;39(33):3021-3104.
Hassen LJ, Lenihan DJ, Baliga RR. Hypertension in the cardio-oncology clinic. Heart Fail Clin 2019; 15:487–495.
Alexander R Lyon, Teresa López-Fernández, Liam S Couch, Riccardo Asteggiano, Marianne C Aznar, Jutta Bergler-Klein, Giuseppe Boriani, Daniela Cardinale, Raul Cordoba, Bernard Cosyns, David J Cutter, Evandro de Azambuja, Rudolf A de Boer, Susan F Dent, Dimitrios Farmakis, Sofie A Gevaert, Diana A Gorog, Joerg Herrmann, Daniel Lenihan, Javid Moslehi, Brenda Moura, Sonja S Salinger, Richard Stephens, Thomas M Suter, Sebastian Szmit, Juan Tamargo, Paaladinesh Thavendiranathan, Carlo G Tocchetti, Peter van der Meer, Helena J H van der Pal, ESC Scientific Document Group, 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS): Developed by the task force on cardio-oncology of the European Society of Cardiology (ESC), European Heart Journal, 2022; 2022 Aug 26: 72-74.
Xi Zhang, Yongjie Shao & Kunjie Wang (2016) Incidence and risk of hypertension associated with cabozantinib in cancer patients: a systematic review and meta-analysis, Expert Review of ClinicalPharmacology, 9:8, 1109-1115.
Qi WX, Shen Z, Lin F, Sun YJ, Min DL, Tang LN, He AN, Yao Y. Incidence and risk of hypertension with vandetanib in cancer patients: a systematic review and meta-analysis of clinical trials. Br J Clin Pharmacol. 2013 Apr;75(4):919-30.
Qi WX, Shen Z, Tang LN, Yao Y. Risk of hypertension in cancer patients treated with aflibercept: a systematic review and meta-analysis. Clin Drug Investig. 2014 Apr;34(4):231-40.
Liu B, Ding F, Liu Y, Xiong G, Lin T, He D, Zhang Y, Zhang D, Wei G. Incidence and risk of hypertension associated with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: a comprehensive network meta-analysis of 72 randomized controlled trials involving 30013 patients. Oncotarget. 2016 Oct 11;7(41):67661-67673.
Qi WX, He AN, Shen Z, Yao Y. Incidence and risk of hypertension with a novel multi-targeted kinase inhibitor axitinib in cancer patients: a systematic review and meta-analysis. Br J Clin Pharmacol. 2013 Sep;76(3):348-57.
Wu S, Chen JJ, Kudelka A, Lu J, Zhu X. Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol. 2008 Feb;9(2):117-23.
Qi WX, He AN, Shen Z, Yao Y. Incidence and risk of hypertension with a novel multi-targeted kinase inhibitor axitinib in cancer patients: a systematic review and meta-analysis. Br J Clin Pharmacol. 2013 Sep;76(3):348-57.
Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, Figlin RA, Baum MS, Motzer RJ. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2011 May 4;103(9):763-73.
Maitland ML, Bakris GL, Black HR, Chen HX, Durand JB, Elliott WJ, et al. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst 2010; 102:596–604.
Chang HM, Okwuosa TM, Scarabelli T, Moudgil R, Yeh ETH. Cardiovascular complications of cancer therapy: best practices in diagnosis, prevention, and management: Part 2. J Am Coll Cardiol 2017; 70:2552–2565.
Syrigos, K.N., Karapanagiotou, E., Boura, P. et al. Bevacizumab-Induced Hypertension. BioDrugs 25, 159–169 (2011).
Chen J, Lu Y, Zheng Y. Incidence and risk of hypertension with bevacizumab in non-small-cell lung cancer patients: a meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2015 Aug 18; 9:4751-60.

CONGESTIVE HEART FAILURE

Author: Sérgio Costa Monteiro

Definition

- - Heart failure (HF) is a clinical syndrome due to a structural and/or functional abnormality of the heart that results in elevated intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise. (1)
  - Traditionally, HF has been divided into distinct phenotypes based on the measurement of left ventricular ejection fraction (LVEF):
    - HF with reduced ejection fraction (LVEF ≤ 40%);
    - HF with mildly reduced ejection fraction (LVEF between 41% and 49%);
    - HF with preserved ejection fraction (LVEF ≥ 50%). These group include patients with symptoms and signs of HF, with evidence of structural and/or functional cardiac abnormalities and/or raised natriuretic peptides, and with an LVEF ≥50%. (1)

Symptoms

- - Typical symptoms include breathlessness, orthopnea, paroxysmal nocturnal dyspnea, reduced exercise tolerance, fatigue, tiredness, increased time to recover after exercise and ankle swelling. Other symptoms include nocturnal cough, wheezing, bloated feeling, loss of appetite, confusion (especially in the elderly), depression, palpitation, dizziness, syncope.
  - More specific signs of HF are elevated jugular venous pressure, hepatojugular reflux, third heart sound (gallop rhythm) and laterally displaced apical impulse. Other clinical signs include weight gain (>2 kg/week), weight loss (in advanced HF), tissue wasting (cachexia), cardiac murmur, peripheral oedema (ankle, sacral, scrotal), pulmonary crepitations, pleural effusion, tachycardia, irregular pulse, tachypnoea, Cheyne-Stokes respiration, hepatomegaly, ascites, cold extremities, oliguria and narrow pulse pressure. Symptoms and signs lack sufficient accuracy to be used alone to make the diagnosis of HF. (1)

Etiology

- - Individual and lifestyle risk factors: Female sex. Age (>75 years old or <10 years old). Diabetes mellitus (pre-existing). Hypercholesterolemia. Obesity. Smoking exposure (current or previous). High alcohol intake. Sedentary habit. Genetic factors. Renal failure. (2,3,5,6)
  - Cardiovascular factor before the treatment: HF. Left ventricular dysfunction. Coronary heart disease. Moderate and severe valvular disease. Cardiomyopathy. Hypertension (before or at the time of diagnosis). Significant cardiac arrhythmia. Peripheral vascular disease. Stroke. Pulmonary hypertension. Elevated cardiac biomarkers before initiation of anticancer therapy. Baseline systolic left ventricular function with LVEF <50%. (2,3,5,6)
  - Previous cardiotoxic cancer treatment: Prior anthracycline use (Lifetime cumulative dose of 450 mg/m2; higher doses lead to an exponential increase in risk). Infusion and total bolus dose. Previous high-dose radiotherapy (>30Gy) to chest or mediastinum. Previous combined treatment with trastuzumab and an anthracycline. (2,3,5,6)
  - Anthracyclines (dose dependent) – Left ventricular systolic dysfunction and HF. CARDIOTOXICITY TYPE I. (2,3,5,6) Doxorrubicin >450 mg/m2. Idarubicin >90 mg/m2. Epirubicin >600 mg/m2. Mitoxanthone >120 mg/m2. Liposomal anthracyclines >900 mg/m2. Toxicity is dose dependent. Lower doses may cause cardiotoxicity according the presence of other risk factors. Acute toxicity occurs immediately after infusion and is usually reversible. Elevation of cardiac biomarkers may identify patients at risk for long-term cardiotoxicity. Early toxicity occurs in first year of treatment. Late toxicity manifest after several years (median of 7 years after treatment). Mechanism: Generation of reactive oxygen species and lipid peroxidation of the cell membrane can damage cardiomyocytes and induce cardiac remodeling. (2,3,5,6)
  - Other conventional chemotherapies
    - Alkylating agents – Heart block. Tachyarrhythmia. HF. Myopericarditis. (2,3,5,6) Cyclophosphamide (>140 mg/kg). Cisplatin. Ifosfamide 12.5-16 g/m2. Mechanism: Endothelial damage. The use of these agents involves the administration of a high intravenous volume to avoid platin-related toxicity. The consequent volume overload in patients with pre-existing myocardial impairment is often the cause of first or recurrent episodes of HF. (2,3,5,6)
    - Antimicrotubule agents – Bradycardia/AV block. Atrial and ventricular arrythmias. Myocardial ischemia. (2,3,5,6) Taxanes (paclitaxel and docetaxel). Mechanism: The absolute cardiotoxic risks with taxanes are unknown. The toxicity occurs mainly when associated with anthracyclines. (2,3,5,6)

Evidence

Level Grade PMID Nº

- - Immunotherapies and target therapies
Inhibition of human epidermal growth factor receptor 2 – Left ventricular systolic dysfunction and HF. CARDIOTOXICITY TYPE II. (2,3,5,6) MONOCLONALANTIBODIES: Trastuzumab. Pertuzumab. Trastuzumab-Emtansine. TYROSINE CYNASE INHIBITOR: Lapatinib. Mechanism: Structural and/or functional changes in contractile proteins and mitochondria, but it rarely leads to a cell death. Concomitant or previous use of anthracyclines increases the cardiotoxicity of trastuzumab. Applying trastuzumab after anthracyclines, or using anthracycline-free chemotherapy regimen reduced the rate of clinical HF. Trastuzumab-toxicity typically manifests during treatment and left ventricular dysfunction and HF are usually reversible with trastuzumab interruption and/or with HF therapies. The cardiotoxicity of other agents appears similar to that of trastuzumab. (2,3,5,6)
Inhibition of the vascular endothelial growth factor signal pathway – Hypertension. Myocardial ischemia. Left ventricular dysfunction. QTc prolongation. Arterial thromboembolic events. (2,3,5,6) MONOCLONAL ANTIBODIES: Bevacizumab. Aflibercept. Ramucirumab. TYROSINE CYNASE INHIBITOR: Sunitinib. Pazopanib. Axitinib. Afatinib. Sorafenib. Ponatinib. Cabozantinib. Levantinib. Vandetanib. Regorafenib. mTOR: Everolimus. Temsirolimus. Some of the VEGF inhibitors can cause reversible or irreversible cardiac side effects, particularly when used with or after conventional chemotherapies. The risk of relatively specific tyrosine kinase inhibitors is similar to relatively non-specific. Mechanism: Inhibition of multiple signaling pathways that can result in reversible or irreversible cardiac side effects. Can cause hypertension. (2,3,5,6)
Inhibition of BCR-ABL kinase – Accelerated atherosclerosis. Peripheral artery disease. Acute coronary syndrome. Stroke. Arterial hypertension. Hyperglycemia. Hypercholesterolemia. Pericardial effusion. Pulmonary arterial hypertension. QTc prolongation. Occasionally, left ventricular systolic dysfunction. (2,3,5,6) Imatinib. Dasatinib. Bosutinib. Nilotinib. Ponatinib. Mechanism: Cardiotoxicity unknown. (2,3,5,6)
- - Proteasome inhibitors – Left ventricular systolic dysfunction and HF. Arterial hypertension. Myocardial ischemia. (2,3,5,6) Bortezomib. Carfilzomib. Ixazomib. Mechanism: Proteasomes, protein complexes responsible for degrading dysfunctional or unneeded proteins, have an important maintenance function in the cardiomyocyte, and cardiac dysfunction may be expected when this maintenance function is impaired. The incidence is higher with carfilzomib. (2,3,5,6)
  - Radiotherapy Mechanism: Interstitial myocardial fibrosis with lesions of variable volumes and distribution. Systolic dysfunction occurs mainly when radiotherapy is combined with anthracyclines. Mediastinal and left-side chest radiation and certain chemotherapeutic and target agents can affect the heart and vascular system and it is recommended that cardiovascular safety be monitored. (2,3,5,6)

Studies

- - Evaluation
    - Assessment of risk factors for cardiovascular disease. (3,7)
    - Clinical history and physical examination. (3,7)
Imaging: Electrocardiography. Echocardiography. Nuclear cardiac imaging. Cardiac Magnetic Resonance. (3,7)
Serum biomarkers: Troponin. Natriuretic peptides. (3,7)
- - Electrocardiography (ECG): All patients before and during treatment must perform and ECG, with measure of heart rate QTc: QTc are abnormal when ≥450ms in men and

≥460ms in women. Resting tachycardia. ST-T wave changes. Conduction disturbance. QT interval prolongation or arrythmias. These alterations can be only transitory. Early detection of cardiotoxicity. (3,7)

- - Echocardiography: Best method for the detection of myocardial dysfunction before, during and after cancer therapy. Cancer therapeutics-related cardiac dysfunction is defined as a decrease in the LVEF of >10%, to a value below the lower limit of normal. This decrease should be confirmed in 2-3 weeks after. Should be repeat during follow-up. Inter-observer variability. Variants: Contrast echocardiography. Stress echocardiography. Doppler myocardial imaging. Echocardiographic assessment of left ventricular function is recommended before initiation of potentially cardiotoxic cancer treatment in all patients. (3,7)
  - Nuclear cardiac imaging: Multigated radionuclide angiography. Exact determination of LVEF. It is constrained by radiation exposure and provides only limited additional information on cardiac structure and hemodynamic. Option when echocardiogram is not available. (3,7)
  - Cardiac magnetic resonance: Evaluation of cardiac structure and function. Determine the cause of left ventricular dysfunction and clarify left and right ventricular function in challenge cases. Evaluate the pericardium, especially in patients with chest irradiation. Also detect scarring or fibrosis. Recommended if the quality of echocardiogram is suboptimal or when echocardiogram is not available. (3,7)
  - Biomarkers: Early detection of cardiotoxicity. Mainly in high-risk patients and those receiving high doses of cardiotoxic agent. (3,7)
  - Endomyocardial biopsy: Should be considered if the diagnosis is highly suspected with otherwise negative work-up. (3,7)

Evidence Level Grade PMID Nº

Diagnosis:

- - Diagnostic criteria: Left ventricular disfunction: a decrease in cardiac LVEF, that is either global or more severe in septum; symptoms of congestive HF; associated signs of congestive HF, including but not limited to S3 gallop, tachycardia or both; and decline in LVEF of at least 5% to below 55% with accompanying signs or symptoms of congestive HF, or a decline in LVEF of at least 10% to below 55% without accompanying signs or symptoms. (3,7)
  - Anti-cancer therapy-related cardiac dysfunction: Absolute decrease in the LVEF of >20% or Absolute decrease in the LVEF of ≥10% to a value <50% or Absolute decrease in the LVEF to a value <50%. (3,7)
  - Subclinical cardiac dysfunction: Absolute decrease from baseline in the global longitudinal strain (GLS) of ≥5% or Relative decrease from baseline in the GLS of ≥12% or Troponins elevation from baseline. (3,7)

Pharmacotherapy(1, 2, 8, 9)

Evidence

Level Grade PMID Nº

DRUG POSOLOGY

– –

Angiotensin-converting enzyme inhibitor (ACEi)	–
CAPTOPRIL	Starting dose: 6.25 mg t.i.d. \| Target dose: 50 mg t.i.d.
ENALAPRIL	Starting dose: 2.5 mg b.i.d. \| Target dose: 10 -20 mg b.i.d.
LISINOPRIL	Starting dose: 2.5-5 mg o.d. \| Target dose: 20-35 mg o.d.
RAMIPRIL	Starting dose: 2.5 mg b.i.d. \| Target dose: 5 mg b.i.d.
Angiotensin receptor-neprilysin inhibitor (ARNI) SACUBITRIL/VALSARTAN	– Starting dose: 49/51 mg b.i.d. \| Target dose: 97/103 mg b.i.d.
Beta-blockers (BB)	–
BISOPROLOL	Starting dose: 1.25 mg o.d. \| Target dose: 10 mg o.d.
CARVEDILOL	Starting dose: 3.125 mg b.i.d. \| Target dose: 25 mg b.i.d.
METOPROLOL	Starting dose: 12.5 -25 mg o.d. \| Target dose: 200 mg o.d.
NEBIVOLOL	Starting dose: 1.25 mg o.d. \| Target dose: 10 mg o.d.
Mineralocorticoid receptor antagonist (MRA) EPLERENONE SPIRONOLACTONE	– Starting dose: 25 mg o.d. \| Target dose: 50 mg o.d. Starting dose: 25 mg o.d. \| Target dose: 50 mg o.d.
SGLT2 inhibitor DAPAGLIFLOZIN EMPAGLIFLOZIN	– Starting dose: 10 mg o.d. \| Target dose: 10 mg o.d. Starting dose: 10 mg o.d. \| Target dose: 10 mg o.d.
Angiotensin-receptor blocker (ARB)	–
CANDESARTAN	Starting dose: 4 mg o.d. \| Target dose: 32 mg o.d.
VALSARTAN	Starting dose: 40 mg b.i.d. \| Target dose: 160 mg b.i.d.
LOSARTAN	Starting dose: 50 mg b.i.d. \| Target dose: 150 mg o.d.
Diuretics	–
FUROSEMIDE	Starting dose: 20 -40 mg \| Target dose: 40 -240 mg
BUMETANIDE	Starting dose: 0.5-1 mg \| Target dose: 1 -5 mg
TORASEMIDE	Starting dose: 5-10 mg \| Target dose: 10 -20 mg
HIDROCHLOROTHIAZIDE	Starting dose: 25 mg \| Target dose: 12.5 -100 mg
METOLAZONE	Starting dose: 2.5 mg \| Target dose: 2.5 -10 mg a
INDAPAMIDE	Starting dose: 2.5 mg \| Target dose: 2.5 -5 mg

II B

– –

II B

– –

II B

– –

II B

– –

II B

– –

II B

– 34447992

34447992

–

34447992

– 34447992

34447992

– 34447992

34447992

– 34447992

34447992

– 34447992

34447992

Evidence

DRUG	POSOLOGY
Other agents	–
IVABRADINE	Starting dose: 5 mg b.i.d. \| Target dose 7.5 mg b.i.d.
DIGOXIN	Starting dose: 62.5 mcg o.d. \| Target dose: 250 mcg o.d.
DEXRAZOXANE	Dose ratio of dexrazoxane to doxorubicin is 10:1 b

Level Grade PMID Nº

a Can be weekly, daily, or prn (Pro re Nata)

b Solution is administered as an infusion up to 15 minutes in duration with a 30-minute fixed interval from the completion of dexrazoxane infusion to the initiation of doxorubicin.

Therapeutic Strategy (1, 8, 9)

II B

II C

I A

Baseline clinical evaluation and assessment of cardiovascular risk factors and comorbidities in all patients.

Screening and treatment of modifiable cardiovascular risk factors and diseases accordincgurrent guidelines (smoking, hypertension, diabetes, dyslipidemia and obesity).

Patients with hyperlipidemia benefit from treatment during active anticancer therapy.

A baseline ECG, including measurement of QTc, is recommended.

Baseline evaluation of LVEF and diastolic function is mandatory for basal evaluation cardiac function before cardiotoxic therapy.

Echocardiography is the standard procedure for basal assessment of cardiac structure and function.

Left ventricular GLS can detect cardiac dysfunction at an earlier stage. Can be used for monitoring left ventricular systolicfunction.

Cardiac biomarkers should be considered in high-risk patients.

If cardiac biomarker elevation is documented, do an echocardiography / GLS assessment and initiate cardioprotective treatments.

Prophylactic use of ACEi / ARNI / ARBs and/or BBs may be considered to reduce the development of cardiotoxicity.

Dexrazoxane has been validated as a primary prevention in patients that received >300 mg/m2 of anthracycline based chemotherapy.

Anthracyclines should not be used in patients with LVEF ≤ 40% unless there is no effective alternative cancer treatment.

Trastuzumab should not be used in patients with LVEF ≤ 40% unless there is no effectivealternative cancer treatment.

In patients with an LVEF decrease of ≥ 10% or to a value of LVEF < 50% but ≥40%, medical therapy with an ACEi / ARNI / ARB and/or BB is recommended before

potential cardiotoxic treatment.

If subclinical cardiac dysfunction is documented, a treatment with ACEi may prevent LVEF reduction and associated cardiac events.

If patient develops left ventricular dysfunction with LVEF≤ 40% should be treated with standard guideline-based HF therapy.

An ACEi, a BB and MRA is recommended for patients with HF with LVEF ≤ 40%.

An ARB is recommended in symptomatic patients unable to tolerate an ACEi or ARNI.

Diuretics are recommended in patients with congestion and HF with LVEF >40% and ≤ 50% in other to alleviate signs and symptoms.

An ACEi / ARNI /ARB, a BB and/or a MRA may be considered in patients with LVEF >40% and ≤ 50%.

Dapagliflozin or empagliflozin are recommended for patients with HF with LVEF ≤ 40%.

Sacubitril/valsartan is recommended as a replacement for ACEi in patients with HF with LVEF ≤ 40%.

Ivabradine should be considered in symptomatic patients with LVEF≤ 35%, in sinusal rhythm and a resting heart frequency ≥ 70 bpm, despite treatment with an

evidence-based dose of beta-blocker, ACEi / ARNI / ARB and an MRA.

I A

III C

III A

III C

II B

II C

IV A

II A

I A

I B

I A

34447992

31959335

22997448

31959335

22997448

34447992

Evidence Level Grade PMID Nº

Digoxin may be considered in patients with symptomatic HF with LVEF ≤ 40% in sinus rhythm despite treatment with an ACEi/ARB or ARNI, a beta-blocker and an MRA.

Diuretics are recommended in patients with LVEF ≤ 40% with signs and/or symptoms of congestion to alleviate HF symptoms, improve exercise capacity and reduce

HF hospitalizations.

Diuretics are recommended in congested patients with LVEF ≥ 50% in order to alleviate symptoms and signs.

For a patient undergoing treatment with any cardiotoxic agent presenting with unexplained signs and symptoms such as sinus tachycardia, rapid weight gain, dyspnea,

peripheral oedema or ascites, reassessing of LVEF and potentially measuring cardiac biomarkers is recommended.

In patients with HF with an LVEF≤ 40%, the same assessments as those for an LVEF ≥ 40% are recommended. In addition, anticancer therapy should be withheld until

the cardiac status has stabilized.

For a patient in whom anticancer therapy has been interrupted, whose LVEF is ≥ 40% and/or whose signs and symptoms of HF has resolv ed, resumption should be

considered, supported by continued medical therapy for HF, periodic cardiac biomarker assessments and periodic LVEF assessments during ongoing treatment.

For a patient in whom anticancer therapy has been interrupted, whose LVEF is < 40% and/or whose signs and symptoms of HF do n ot resolve, resumption should be

considered if no alternative therapeutic option exists.

Periodic screening for the development of left ventricular dysfunction with cardiac biomarkers and cardiac imaging should beconsidered at 6-12 months, at 2 years post-

treatment and possibly periodically thereafter.

In patients with mediastinal chest radiotherapy, evaluation of coronary artery disease and ischemia, as well as valvular disease is recommended, even if asymptomatic,

starting at 5 years post-treatment and then at least every 3- 5 years thereafter.

HF therapy should be continued indefinitely unless normal systolic left ventricular function remains stable after cessation of HF therapy and no further anticancer therapyis planned.

Long-term surveillance should be considered for those who developed evidence of cardiotoxicity during treatment and for those in whom cardioprotecti ve medication

has been initiated.

Encourage exercise on regular basis.

Encourage to have healthy dietary habits. Maintain a normal weight. Avoid alcohol (< 30 mL/day) and tobacco use.

II	B	34447992
I	C	34447992
I	C	34447992
III	A	31959335
I	A	31959335
III	B	31959335
IV	C	31959335
III	B	31959335
I	A	31959335
III	B	31959335
III	B	31959335
III	B	31959335
IV	B	31959335

References:

McDonagh T., Metra M., Adamo M., Gardner R., Baumbach A., Böhm M., Burri H., et al. (2021) ESC Guidelines for the diagnosis and treatment of acute and chronic HF. European Heart Journal 42(36): 3599-3726 (PMID 34447992)
Zamorano J., Lancellotti P., Munoz D., Aboyans V., Asteggiano R., Galderisi M., Habib G., et al. (2016) ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines. European Heart Journal 37: 2768-2801
Bloom M., Hamo C., Cardinale D., Ky B., Nohria A., Baer L., Skopicki H., et al. (2016) Cancer Therapy-Related Cardiac Dysfunction and HF, Part 1: Definitions, Pathophysiology, Risk factors, and Imaging. Circ Heart Fail. 9:e002661
Hamo C., Bloom M., Cardinale D, Ky B., Nohria A., Baer L., Skopicki H., et al. (2016) Cancer Therapy-Related Cardiac Dysfunction and HF, Part 2: Prevention, Treatment, Guidelines, and Future Direction. Circ Heart Fail. 9:e002843
Armenian S., Laccheti C., Barac A., Carver J., Constine L., Denduluri N., Dent S., et al. (2017) Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology 35: 893-911
Brana I., Tabernero J. (2010) Cardiotoxicity. Annals of Oncology 21 (Supplement 7): vii173-vii179
Alexandre J., Cautela J., Ederhy S., Damaj GL., Salem JE, Barlesi F., Farnault L., et al. (2020) Cardiovascular Toxicity Related to Cancer Treatment: A Pragmatic Approach to the American and European Cardio-Oncology Guidelines. Journal of American Heart Association 9:e018403.
Bovelli D., Plataniotis G., Roila F. (2010) Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO Clinical Practice Guidelines. Annals of Oncology 21 (Supplement 5): v277-v282 (PMID 22997448)
Curigliano G., Lenihan D., Fradley M., Ganatra S., Barac A., Blaes A., Herrman J. et al. (2020) Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations., Annals of Oncology 31 (Issue 2): 171-190 (PMID 31959335)
1. PERICARDIAL EFFUSION

Authors: Francisco Javier Garcia Navalón and Claudio Avila Andrade

Definition

- - Accumulation of >50 cc of liquid between both leaves of the pericardium.

Symptoms

- - The clinical presentation is highly variable and depends on the filling speed, the amount of effusion and the distension capacity of the pericardium.
  - If it occurs acutely, it can cause cardiac tamponade. Then symptoms such as sudden dyspnoea, oppressive chest pain, low cardiac output syndrome symptoms (oliguria, impaired level of consciousness, poor peripheral perfusion) and finally cardiogenic shock are usually present. Beck’s triad (hypotension, increased jugular venous pressure, and attenuated heart sounds) can be seen in patients with acute pericardial effusion.
  - If it occurs sub acutely, the clinic is more latent. Being able to present progressive dyspnoea, cough, orthopnoea, and oedema. On examination, oedema, hepatomegaly, jugular engorgement, muffled heart tones, and pulsus paradoxus may be observed.

Etiology

- - The most common cause of pericardial effusion is acute pericarditis (idiopathic or viral).
  - Pericardial effusions of tumour origin represent around 23% of cases. They can be caused by direct extension of the tumour, pericardial lymphatic obstruction or metastatic spread. Its presence is more frequently associated with symptomatic and haemorrhagic pericardial effusions. Metastases in the pericardium are more frequent in lung cancer (35%), breast cancer (25%) and lymphomas (15%). Primary pericardial tumours (mesothelioma, fibrosarcoma, etc.) are very rare.
  - Cancer patients may also present the appearance of pericardial effusion secondary to treatment with chemotherapy, radiotherapy, or thoracic surgery.
  - Other possible causes could be an effusion secondary to an oedematous state (cirrhosis, heart failure or nephrotic syndrome), autoimmune diseases (lupus, rheumatoid arthritis) or tuberculosis.

Studies

- - Is necessary to establish the diagnostic by echocardiogram, assess its hemodynamic impact, rule out cardiac tamponade and try to establish the cause.
  - Alterations can be observed in different tests:
Electrocardiogram: in symptomatic pleural effusions, nonspecific alterations are observed, such as low voltages or flattening of the T wave. Electrical alternans is a very specific finding, being pathognomonic if it is associated with P wave alternans.
Chest X-ray: alterations can be observed when there are more than 250cc of liquid in the pericardium. An increase in the cardiothoracic index and blurring of the left border of the cardiac silhouette will be observed.
Echocardiogram: It is the test of choice, since it allows determining the amount of pericardial fluid, assessing hemodynamic repercussion, and serves as a guide for invasive therapeutic procedures. When there is hemodynamic compromise we can observe an end-diastolic collapse of the right atrium and diastolic collapse of the right ventricle.
CT/MRI: allows to detect and quantify the amount of fluid, characterize nature, and detect if there are tumour masses or pericardial implants that are causing the effusion.
- - For the etiological study it may be necessary to carry out analytical and invasive tests:
Blood analysis: biochemistry with kidney and liver profile, thyroid hormones, autoimmunity profile, HIV serology.
Mantoux test.
Diagnostic pericardiocentesis: recommended when neoplastic, tuberculous, or bacterial origin is suspected. And in severe effusions of unknown aetiology that do not respond to anti-inflammatory treatment. A cytological study, a cell count, biochemical analysis, bacterial culture, and mycobacteria should be requested. Tumour markers in fluid have low sensitivity and specificity.
Pericardial biopsy: usually has low profitability. It is recommended for recurrent symptomatic pericardial effusions of unknown aetiology that do not respond to treatment

Evidence

Level Grade PMID Nº

Pharmacotherapy Evidence

Level Grade PMID Nº

ASPIRIN 500-1000mgr. every 6-8 hours. Duration weeks-months. Decrease doses by 250-500mgr. every 1-2 weeks

IBUPROFEN 600mgr. every 8hours. Duration weeks-months. Decrease doses by 200-400mgr. every 1-2 weeks.

INDOMETHACIN 25-50mgr. every 8hours. Duration weeks-months. Decrease doses by 25mgr every 1-2 weeks

COLCHICINE 0’5mgr. twice or 0’5mg.r daily. Duration at least 6 months.

CORTICOSTEROID THERAPY. Starting dose 0’25-0’5 mgr./kg/day prednisone. Every decrease in prednisone dose should be done only if the patient is asymptomatic and C-reactive protein is normal, particularly for doses <25 mg/day. Is not recommended as a first line-approach. IIIB

Therapeutic Strategy

Therapy of pericardial effusion should be targeted at the aetiology as much as possible. In about 60% of cases, the effusion is associated with a known disease and the essential treatment is that of the underlying disease (2-3).

When pericardial effusion is associated with pericarditis, management should follow that of pericarditis (5).

When a pericardial effusion becomes symptomatic without evidence of inflammation or when empiric anti-inflammatory drugs are not successful, drainage of the effusion should be considered (5).

In the absence of inflammation, NSAIDs, colchicine and corticosteroids are generally not effective (5).

Pericardiocentesis alone may be necessary for the resolution of large effusions, but recurrences are also common, and pericardiectomy or pericardial window should be considered whenever fluid reaccumula

ASPIRIN/NSAIDs/COLCHICINE. Is recommended when pericardial effusion is associated with systemic inflammation.

PERICARDIOCENTESIS OR CARDIAC SURGERY: is indicated for cardiac tamponade or for symptomatic moderate to large pericardial effusions not responsive to medical therapy, and for suspicion of unknown bacterial or neoplastic aetiology.

Pericardiocentesis with prolonged pericardial drainage of up to 30 ml/24h may be considered to promote adherence of pericardial layers and prevent further accumulation of fluid.

PERICARDIECTOMY OR PERICARDIAL WINDOWS. For frequent and highly symptomatic recurrences resistant to medical treatment.

It is recommended to target the therapy of pericardial effusion at the aetiology

Empirical anti-inflammatory therapies should be considered to control chest pain

References:

I A

III B

I C

IIa C

I C

IIa C

Zamorano JL, Lancellotti P, Rodríguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for Cancer Treatments and Cardiovascular Toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(36):2768–801.
López-Fernández T, Martín-García A, Santaballa Beltrán A, Montero LA, García Sanz R, Mazón Ramos P, et al. Cardio-onco-hematology in clinical practice. Position paper and

recommendations. Rev Esp Cardiol (Engl Ed). 2017;70(6):474–86.

Desai MY, Jellis CL, Kotecha R, Johnston DR, Griffin BP. Radiation-associated cardiac disease a practical approach to diagnosis and management. JAm Coll Cardiol Img. 2018;11:1132–49.
Chen MH, Kerkela R, Force T. Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics. Circulation. 2008;118:84–95.
Yehuda Adler, Philippe Charron, Massimo Imazio, et al. Guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC) Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS), European Heart Journal, Volume 36, Issue 42, 7 November 2015, Pages 2921–2964.
Massimo Imazio, Yehuda Adler, Management of pericardial effusion, European Heart Journal, Volume 34, Issue 16, 21 April 2013, Pages 1186–1197

RESPIRATORY DISORDERS

PULMONARY FIBROSIS

Authors: Alexander Ariel Padrón González, David Silva Gomes and Flávia Machado Fernandes

Symptoms

Pulmonary fibrosis (PF) or Idiopathic pulmonary fibrosis is a chronic and progressive interstitial lung disease. Throughout Europe and North America, the estimated incidence of IPF has been reported to range between 2.8 and 19 cases per 100 000 people per year. Approximately 0.7% of all deaths that occurred between 2004 and 2016 had a diagnosis of pulmonary fibrosis. (1)

PF is characterised by worsening dyspnoea, decline in forced vital capacity (FVC) and deterioration in patients’ health-related quality of life. The incidence of PF increases with older age, with presentation typically consisting of insidious onset of dyspnoea in the sixth and seventh decades. While PF is ultimately fatal, its clinical course is variable and unpredictable, with some cases experiencing a rapid decline in lung function while others progress much more slowly. There are also descriptions of acute exacerbations in some patients with sudden deteriorations in symptoms and respiratory function during periods of relative stability, but the cause of this evolution is unknown. (2) Patients with PF experience increasingly symptoms like cough, dyspnoea, fatigue, weight loss, bibasilar inspiratory crackles, and/or digital clubbing that occur without constitutional or other symptoms that suggest a multisystem disease. (3)

Etiology

Several risk factors such as smoking, air pollution, inhaled toxins, high body mass index and infectious agents are involved in the pathogenesis of PF, but until now is still unknown its aetiology Although previous research disputed whether it is an autonomic acceleration of fibrotic process or an aggravation caused by external stimuli. The mechanistic and physiological relationship of all these risk factors to disease development and progression are unknown

Mostafaei and collaborators in a systematic review and meta-analyse, selected different studies in America, European, Asia and Africa. The pooled prevalence for viral and bacterial infections were 53.72% and 31.21%, respectively. The highest and lowest prevalence of viral infections was HSV, EBV and Influenza A respectively. Whereas the highest and lowest prevalence in bacterial infections were related to Streptococcus sp. and Raoultella respectively. They confirmed that the presence of viral and bacterial infections are risk factors in the pathogenesis of PF. (4)

Patients with PF also have other comorbidities that include emphysema, lung cancer, pulmonary hypertension, sleep apnoea, and coronary artery disease. There are also genetic

forms with extrapulmonary manifestations in bone marrow and liver. In some cases of PF biological members of the family also have the diseases, suggesting genetic predisposition. (5)

There are published histopathological analyses of COVID-19 lungs post mortem with the presence of pulmonary fibrosis. Abnormal pulmonary architecture and functions have also been reported in many recovering COVID-19 patients. This evidence suggests persisting fibrotic abnormalities, pending large-scale and long-term follow up studies. SARS-CoV- 2 virus induce the secretion of pro-fibrotic factors including TGFβ suggesting pulmonary fibrosis both as a disease risk and a possible complication of COVID-19. (6) The pathogenic events of lung fibrosis are thought to be initiated by perpetuated microinjuries to the alveolar epithelium that engenders a dysregulated wound healing response characterized by abnormal activation of alveolar epithelial cells, fibroblasts and myofibroblasts accumulation, and excessive extracellular matrix (ECM) formation. Recent studies reported the role between inflammation and aging immunity in pulmonary fibrosis progression. In the direct aetiology immune dysfunction do not appear to be the first event, but proinflammatory molecules and cells can permit, promote, or suppress fibroproliferation driven by native lung fibroblasts. (7-9)

Studies

Over time, criteria for diagnosing IPF have changed considerably, from a predominantly histopathological assessment to a multidisciplinary team approach based on clinical, radiologic and histopathologic correlation. (10)

Evidence

Level Grade PMID Nº

The accuracy of diagnosis of PF increases with clinical, radiologic, and histopathologic correlation and can be accomplished with a multidisciplinary discussion among experienced clinical expert. The clinician interprets the history and physical exam to develop a clinical context, the thoracic radiologist interprets the pattern present on high resolution computerized tomographic (CT) scanning of the chest and, if needed, the pathologist interprets the histopathologic pattern seen on lung biopsy. All this information must be shared using a common language, in order for clinical decision-making to occur. Discordant histologic patterns on surgical lung biopsy specimens obtained from different segments have been described. This supports the obtainment of surgical lung biopsies from multiple lobes in patients with suspected PF. (5)

Clinical Practice Guideline was endorsed by the Pulmonary Pathology Society in October 2018. Previously defined patterns of usual interstitial pneumonia (UIP) were refined to patterns of UIP, probable UIP, indeterminate for UIP, and alternate diagnosis. There is a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other interstitial lung disease. (11)

The S2K Guideline for Diagnosis of Idiopathic Pulmonary Fibrosis in 2021 provides tools to exclude known causes of interstitial lung disease including standardized questionnaires, serologic testing, and cellular analysis of bronchoalveolar lavage. High-resolution computed tomography remains crucial in the diagnostic workup. If it is necessary to obtain specimens for histology, transbronchial lung cryobiopsy is the primary approach, while surgical lung biopsy is reserved for patients who are fit for it and in whom a bronchoscopy diagnosis did not provide the information needed. PF is a diagnosis of exclusion, then multidisciplinary discussion remains the golden standard of diagnosis. (12)

Pharmacotherapy

Recommendations for an Intervention

Level Grade PMID Nº

I 1B

Clinicians should use nintedanib# (a tyrosine kinase inhibitor) in patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF), who live in an area where nintedanib is available and without moderate or severe hepatic impairment (Child Pugh B or C),due to demonstrated clinical benefit, but considering its frequent minor adverse outcomes (mostly diarrhoea and nausea) and high cost of therapy.

Clinicians should use pirfenidone## (an antifibrotic agent) in patients with mild-to-moderate IPF who live in an area where pirfenidone is available, due to demonstrated clinical benefit, but considering its frequent minor adverse outcomes (mostly gastrointestinal) and high cost of therapy.

Clinicians might use nintedanib in patients with severe-to-very severe IPF and/or patients with IPF who live in an area where nintedanib is not widely available, without moderate or severe hepatic impairment (Child Pugh B or C), due to demonstrated clinical benefit, but considering its frequentminor adverse outcomes (mostly diarrhoea and nausea), high cost of therapy and that it is still unknown whether the therapeutic benefits would differ in patients with a more severe impairment in pulmonary function testing.

Clinicians might use regular antiacid treatment (such as proton pump inhibitors (PPIs)) in patients with IPF, due to potential clinical benefit, low cost of therapy and small proportion of potential adverse outcomes. A phase 3 trial is ongoing to evaluate if IPF progresses slower if treated with PPIs, with the following “ClinicalTrials.gov Identifier”: NCT04965298.

↑↑, Strong recommendation;

⊕⊕⊕⊕, high

26915984

quality of the evidence)

I 1B

↑↑, Strong recommendation;

⊕⊕⊕⊕, high

27876247

quality of the evidence)

I 2B

↑, Conditional recommendation;

⊕⊕⊕⊝,

moderate quality

of the evidence)

I 2B

↑, Conditional recommendation;

⊕⊕⊕⊝,

moderate quality

of the evidence)

III 2D

26915984

27876247

24429201

↑, Conditional recommendation;

⊕⊝⊝⊝, very low

quality of the evidence)

21700909

Recommendations Against an Intervention Level Grade PMID Nº

II 1A

Clinicians should not use interferon gamma-1b in patients with IPF, due to no demonstrated clinical benefit, potential adverse outcomes and high cost of therapy.

Clinicians should not use etanercept (a tumour necrosis factor (TNF) inhibitor) in patients with IPF, due to no demonstrated clinical benefit, potential adverse outcomes and high cost of therapy.

Clinicians should not use imatinib (a tyrosine kinase inhibitor) in patients with pulmonary fibrosis, due to no demonstrated clinical benefit and high cost of therapy.

Clinicians should not use simtuzumab (a monoclonal antibody against lysyl oxidase-like 2 (LOXL2)) in patients with IPF, due to no demonstrated clinical benefit, potential adverse outcomes, and high cost of therapy.

Clinicians should not use co-trimoxazole or doxycycline in patients with IPF, in addition to usual care, due to no demonstrated clinical benefit and potential adverse outcomes.

Clinicians should not use warfarin anticoagulation in patients with IPF who do not have a known indication for its use, due to potential adverse outcomes such as death.

Clinicians should not use the combination therapy of prednisone, azathioprine, and N-acetylcysteine in patients with pulmonary fibrosis, due to potential adverse outcomes such as death and hospitalization.

Clinicians should not use ambrisentan (a selective ER-A endothelin receptor antagonist) in patients with IPF, regardless of the presence or absence of pulmonary hypertension, due to no demonstrated clinical benefit and potential adverse outcomes such as disease progression and hospitalizations.

Clinicians might not use sildenafil (a phosphodiesterase-5 inhibitor) in the treatment of IPF due to no demonstrated major clinical benefit (although there was a slight improvement in quality of life), potential drug-related adverse outcomes and high cost of therapy.

Clinicians might not use bosentan or macitentan (dual endothelin receptor antagonists (ER-A and ER-B)) in the treatment of IPF due to no demonstrated major clinical benefit (although a composite outcome of death or disease progression appeared improved) and high cost of therapy.

Clinicians might not use N-acetylcysteine (a precursor of the antioxidant glutathione) in patients with IPF due to no demonstrated major clinical benefit.

Clinicians might not use a combined treatment of nintedanib and pirfenidone in patients with IPF, due to no demonstrated clinical superiority over either of them in monotherapy. Nevertheless, this therapy combination appears to have a reasonable safety and tolerability profile, and discontinuation rates as expected with either treatment alone. A phase 4 trial is ongoing to evaluate the efficacy and tolerance of the pirfenidone and nintedanib combination in IPF, with the following “ClinicalTrials.gov Identifier”: NCT03939520.

Pharmacotherapies Still on Phase 3 Trials

Treatment with pentraxin-2 (serum amyloid P) in patients with IPF resulted in a slower decline in lung function over 28 weeks when compared to placebo,in a phase 2 study. It was also well tolerated, with positive effects on the percentage of predicted forced vital capacity (FVC) and the 6-min walking distance, in an open-label extension of the previous study. A phase 3 trial is still ongoing, to evaluate the efficacy, safety, and pharmacokinetics (PK) of pentraxin-2 in subjects with IPF, having

the following “ClinicalTrials.gov Identifier”: NCT04552899.

↑↑, Strong recommendation;

⊕⊕⊕⊕, high

19570573

quality of the evidence)

II 1B

↑↑, Strong recommendation;

18669816

⊕⊕⊕⊕, moderate quality of the evidence)

II 1B

↑↑, Strong recommendation;

20007927

27939076

⊕⊕⊕⊕, moderate quality of the evidence)

II 1B

II 1C

↑↑, Strong recommendation;

⊕⊕⊕⊕, low

quality of the evidence)

II 1C

↑↑, Strong recommendation;

⊕⊕⊕⊕, low

quality of the evidence)

II 1C

↑↑, Strong recommendation;

⊕⊕⊕⊕, low

quality of the evidence)

II 2B

↑↑, Strong recommendation;

⊕⊕⊕⊕, moderate

quality of the evidence)

II 2C

↑↑, Strong recommendation;

⊕⊕⊕⊕, low

quality of the evidence)

33974018

22561965

22607134

23648946

20484178

30220235

17901413

21474646

23682110

↑↑, Strong

16135167 22257422

recommendation; 24836309 27161257

⊕⊕⊕⊕, low

quality of the evidence)

III

↑↑, Strong

29946005

recommendation;

⊕⊕⊕⊕, low quality of the evidence)

No recommendation to be made

28889759

29800034

currently.

Treatment with pamrevlumab (also known as FG-3019, a fully recombinant human monoclonal antibody against connective tissue growth factor (CTGF)) resulted in attenuated progression of IPF and was well tolerated, in a phase 2 study. Two phase 3 trials are still ongoing, to evaluate the safety and efficacy of pamrevlumab in subjects with IPF, having the following “ClinicalTrials.gov Identifier”: NCT03955146 and NCT04419558.

Treatment with inhaled Treprostinil (a prostacyclin analogue) in patients with interstitial lung disease and pulmonary hypertension resulted in improved exercise capacity from baseline, assessed with the use of a 6-minute walk test, as compared with placebo. It was also associated with improvements in FVC versus placebo at 16 weeks, and this difference was most evident in patients with idiopathic interstitial pneumonia, particularlyIPF. A phase 3 trial is still ongoing, to evaluate the safety and efficacy of inhaled Treprostinil in subjects with IPF, having the following “ClinicalTrials.gov Identifier”: NCT04708782.

Treatment with ziritaxestat (also known as GLPG1690, an autotaxin inhibitor) in patients with IPF resulted in positive effects on the FVC at week 12, ina phase 2a study, although with documented potential adverse outcomes. Two phase 3 trials – having the following “ClinicalTrials.gov Identifier”: NCT03711162 and NCT03733444–

in subjects with IPF were terminated (the benefit-risk profile no longer supported continuing the study), still with no results published.

Further evidence is needed.

No recommendation to be made currently.

Further evidence is needed.

No recommendation to be made currently.

Further evidence is needed.

31122893

33440084

34214475

29792287

* Based on: OCEBM Levels of Evidence Working Group*. “The Oxford 2011 Levels of Evidence”. Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/index.aspx?o=5653

** Based on: The GRADE Working Group, 2013. Available from: http://www.guidelinedevelopment.org/handbook # Nintedanib recommended dosage: 150 mg q12hr, taken orally with food

## Pirfenidone recommended dosage: 801 mg TID (2403 mg/day), taken orally with food (an initial titration during the first 14 days of therapy is warranted: 267 mg TID (801 mg/day) on the first week followed by 534 mg TID (1602 mg/day) on the second week, and recommended dosage onwards)

Studies

As previously stated, IPF is a complex disease characterized by a deterioration of quality of life. Thefore, all available therapeutics (pharmacological or non-pharmacological) that help to handle the patient’s symptons are important. In the next tables there are recommendations about the treatment of complications and comorbidities in patients with IPF along with the non-pharmacological treatment .

Lots of research have been done in IPF and there are some promising therapeutics, such as microbiota and stem cells. The Gut-Lung microbiota has an important role in the pathogenesis of the chronic respiratory disease, as IPF, through immunomodulation. Thus, probiotic administration and fecal microbiota transplantation could be a treatment option in the IPF. (13) However,more scientific evidence to approve these treatments in clinical pratice are still needed.

Some studies have showed that the lower airway bacterial burden is related to the decline of lung funtion, due to repetitive alveolar injury and aberrant repairing process. The association between lower airway microbiota and the imunnological profile needs to be elucidated, but may provide novel target therapies. (14)

In a meta-analysis, Deng-Yuan et al demonstrated that mesenchymal stem cell therapy can improve the fibrosis score in animals. The best way to deliver this treatment and the long-term effects remain unclear. The transition to clinical studies is the next step in order to evaluate the safety and efficacy of this treatment in humans. (15)

I 1B

↑↑, Strong recommendation;

⊕⊕⊕⊕, high

Clinicians should refer all patients to a centre with expertise in IPF and discuss the se patients with known or suspected IPF with the multidisciplinary team.

Treatment of Complications and Comorbidities

Treatment of acute exacerbation: Clinicians should treat acute deterioration in respiratory function, despite the poor prognosis associated with an acute exacerbation. The management could include broad-spectrum antibiotics, corticoid therapy, mechanical ventilatory support and a potential lung transplantation

34024402

28365056

quality of the evidence)

↑↑, Strong recommendation;

⊕⊕⊝⊝, low

28345369

quality of the evidence)

II ↑↑2, tDrong

Treatment of pulmonary hypertension: Clinicians might treat pulmonary hypertension, but the beneficial of treating pulmonary hypertension in patients with IPF still lacks evidence.

Treatment of gastroesophageal reflux: Clinicians might use drugs (such as proton pump inhibitors) or surgical procedures in patients with IPFand symptomatic gastroesophageal reflux disease.

Supportive Care: Palliative care should be integrated in the patient f-ollow up early after the diagnosis, due to the need of relieving symptoms suchas dyspnoea, pain and anxiety.

Non-pharmacological treatment

Home Oxygen Therapy: Clinicians should use oxygen supplementation in patients with advanced disease who present dyspnoea caused by hypoxemia.

Pulmonary Rehabilitation: Patients might be included in a respiratory rehabilitation program.

Lung Transplant: Patients with evidence of disease progression, that do not respond to diseas-e modifying therapies, should be referred for evaluation in a lung transplant unit, in the absence of contraindications for the surgical procedure. The optimum timing to referral is still unknown.

recommendation;

29471816

⊕⊝⊝⊝, very lowe quality of the evidence)

II ↑↑2, tDrong

recommendation;

34024402

23742884

⊕⊝⊝⊝, very lowe quality of the evidence)

I ↑↑1, tBrong

recommendation;

29471816

32437841

⊕⊕⊕⊝, moderate quality of the evidence)

I ↑↑1, tBrong

recommendation;

32437841

⊕⊕⊕⊝, moderate quality of the evidence)

↑↑, Strong recommendation;

31484664

23237694

References:

Kaul B, Cottin V, Collard HR, Valenzuela C. Variability in Global Prevalence of Interstitial Lung Disease. Front Med (Lausanne). 2021;8:751181. doi:10.3389/fmed.2021.751181

⊕⊕⊕⊝, moderate quality of the evidence)

↑↑, Strong recommendation;

⊕⊕⊕⊝, moderate

quality of the evidence)

31484664

28365056

28345369

Richeldi L, Cottin V, M du Bois R, Selman M, Kimura T, Bailes Z. Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS trials. Respiratory Medicine 113 (2016) 74-79.
Cox IA, Borchers Arriagada N, de Graaff B, Corte TJ, Glaspole I, Lartey S et al. Health-related quality of life of patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis.. European Respiratory Review Dec 2020, 29 (158) 200154; DOI: 10.1183/16000617.0154-2020
Mostafaei S, Sayad B, Azar MEF, et al. The role of viral and bacterial infections in the pathogenesis of IPF: a systematic review and meta-analysis. Respir Res. 2021;22(1):53. doi:10.1186/s12931-021- 01650-x
Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. American Journal of Respiratory and Critical Care Medicine. 198 (5). pp 788–824, 2011. DOI: 10.1164/rccm.2009-040G
Ntatsoulis K, Karampitsakos T, Tsitoura E, et al. Commonalities Between ARDS, Pulmonary Fibrosis and COVID-19: The Potential of Autotaxin as a Therapeutic Target. Front Immunol. 2021;12:687397. doi:10.3389/fimmu.2021.687397
Desai O, Winkler J, Minasyan M, Herzog EL. The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis. Front Med (Lausanne). 2018;5:43. doi:10.3389/fmed.2018.00043
Li Y, Wang C, Peng M. Aging Immune System and Its Correlation With Liability to Severe Lung Complications. Front Public Health. 2021;9:735151. doi:10.3389/fpubh.2021.735151
Ishikawa G, Liu A, Herzog EL. Evolving Perspectives on Innate Immune Mechanisms of IPF. Front Mol Biosci. 2021;8:676569. doi:10.3389/fmolb.2021.676569
Khor YH, Yvonne Ng, Barnes H, Goh NSL, McDonald CF, Holland AE. Prognosis of idiopathic pulmonary fibrosis without anti-fibrotic therapy: a systematic review. European Respiratory Review Sep 2020, 29 (157) 190158; DOI: 10.1183/16000617.0158-2019
Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2018. 198(5):e44-e68.
Behr J, Günther A, Bonella F, Dinkel J, Fink L, Geiser T et al. S2K Guideline for Diagnosis of Idiopathic Pulmonary Fibrosis. Respiration 2021;100:238-271. doi: 10.1159/000512315
Shi, C. Y., C. H. Yu, W. Y. Yu, and H. Z. Ying. 2021. “Gut-Lung Microbiota in Chronic Pulmonary Diseases: Evolution, Pathogenesis, and Therapeutics.” Can J Infect Dis Med Microbiol 2021: 9278441. https://doi.org/10.1155/2021/9278441.
Wang, J., M. Lesko, M. H. Badri, B. C. Kapoor, B. G. Wu, Y. Li, G. C. Smaldone, R. Bonneau, Z. D. Kurtz, R. Condos, and L. N. Segal. 2017. “Lung microbiome and host immune tone in subjects with idiopathic pulmonary fibrosis treated with inhaled interferon-γ.” ERJ Open Res 3 (3). https://doi.org/10.1183/23120541.00008-2017.
Li, D. Y., R. F. Li, D. X. Sun, D. D. Pu, and Y. H. Zhang. 2021. “Mesenchymal stem cell therapy in pulmonary fibrosis: a meta-analysis of preclinical studies.” Stem Cell Res Ther 12 (1): 461. https://doi.org/10.1186/s13287-021-02496-2.

PNEUMONITIS

Authors: Charo Garcia Campelo, Beatriz Alonso de Castro, Sofia Silva Diaz, Martín-Igor Gómez-Randulfe, Manuel Fernandez Bruno, Joaquin Mosquera Martinez and Patricia Cordeiro Gonzalez.

Definition

- - Pneumonitis is defined as the inflammation of the lung parenchyma, identified on a chest image study, usually with cough and dyspnoea, caused by oncologic treatments and with exclusion of pulmonary infection, tumour progression, and other reasons (1, 2).

Symptoms and signs

- - Clinical presentation is variable and nonspecific, with one-third of patients asymptomatic, and most with dyspnoea, cough and decrease activity tolerance (3).
  - Less frequent symptoms include fever and chest pain. It is important to exclude infection in patients with fever (2).
  - Onset of symptoms can occur at any time, although the median is 2.8 months, with a range from 9 days to 19.2 months (3). An earlier onset of clinical disease can appear in lung cancer patients compared with melanoma and lymphoma, due to a higher pulmonary tumour burden among lung cancer patients (4).
  - The course of the disease can be acute, subacute, chronic, and occult (2).
  - Chronic pneumonitis is defined as the persistence of toxicity despite treatment discontinuation and more than 3 months of corticosteroids (1).
  - Pulmonary auscultation is characterized by Velcro crackles, while other patients can appear with normal auscultation (2).
  - It is common to find concomitant infection or cardiac insufficiency, and in those cases, we can find moist rales (2).
  - In patients with Checkpoint inhibitor-related (ICIs) pneumonitis we can find other immunotherapy toxicities like hypothyroidism, arthralgias, diarrhoea, psoriasis… (5)
  - Pneumonitis is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events fifth version (CTCAE v.5) on a severity symptoms scale (1, 6):
    - Grade 1: Asymptomatic. Confined to one lobe or <25% of lung parenchyma. Only radiological findings.
    - Grade 2: Symptomatic, limiting instrumental Activities of Daily Living (ADL). Involves more than one lobe or 25-50% of lung parenchyma.
    - Grade 3: Severe symptoms, limiting self-care ADL. Involves all lung lobes or >50% of lung parenchyma. Hospitalization required.
    - Grade 4: Life-threatening respiratory comprise. Urgent intervention indicated.
    - Grade 5: Death.

Etiology

- - ICIs: Clinical trials reported an incidence rate between 0% to 10.6% (7). PD-1 inhibitors (pembrolizumab, nivolumab) are associated with a higher incidence of pneumonitis than antiCTLA4 (ipilimumab) or PDL-1 inhibitors (atezolizumab, durvalumab, avelumab) (1, 7). Dyspnoea and cough are the most frequent symptoms, but one third of patients are asymptomatic (7). Time to onset of pneumonitis is about 2.8 months after the administration of the first immunotherapy cycle (7).
  - Chemotherapy: Pulmonary toxicity has been described with taxanes (docetaxel, paclitaxel, and newer formulations of paclitaxel, including nanoparticle albumin-bound paclitaxel) and gemcitabine, with higher rates in combination with taxanes. It is difficult to establish the overall incidence of taxane-induced pulmonary toxicity because is a rarely reported side-effect in clinical trials. A retrospective study reveals a incidence of 4.6% for non-small cell lung cancer (NSCLC) patients receiving docetaxel therapy (7). Clinical presentation is characterized by dyspnoea, dry cough, fever, and bilateral pulmonary interstitial infiltrates and in some cases with hypoxia and respiratory failure (7). Onset of symptoms are more common to appear within three weeks after taxane administration (3, 7).
  - Tyrosine Kinase Inhibitors (TKI): Pneumonitis has been reported in clinical trials for TKIs with an incidence rate of 0-5.7%, becoming more frequent with afatinib (10%) and Osimertinib (4%) compared with gefitinib (1%) (7). Time of onset is typically within 4 initial weeks of treatment (7). Most presented with dyspnoea and hypoxia, while cough and fever are less common (7).
  - Antibody-drug conjugate: The recent incorporation of Trastuzumab-Deruxtecan in the management of metastatic breast cancer compels us to learn about the security profile. In Destiny-Breast03 pneumonitis was identified in 10.5% patients that received Trastuzumab-Deruxtecan and in 1.9% who received Trastuzumab-Emtansine, with no events grade 4 or 5 in each treatment group (8).

Evidence

Level Grade PMID Nº

- - Radiotherapy: The exact incidence of radiation pneumonitis is unknown, it depends on tumour location, radiographic changes, and clinical symptoms, but has been estimated approximately in 10-30% (7). Patients with breast or other thoracic malignancies like lymphoma, metastatic pulmonary disease or oesophageal cancer are at risk of pulmonary pneumonitis. Usually occurs between 1 and 3 months after radiotherapy (10). Classic symptoms are dyspnoea, cough and fever (9). Although it is difficult to distinguish radiation pneumonitis of other types, the key is that the first one usually occurs in the radioactive field (9).
  - Risk factors:
Previous lung disease: Chronic obstructive pulmonary disease (COPD), asthma, interstitial lung disease (ILD), pulmonary fibrosis, pneumothorax, pleural effusion (10).
Smoking status: previous or current (10).
Age: older than 70 years (10).
Tumour type: It remains equivocal the risk of pneumonitis and tumour type, some meta-analyses showed a significant increased risk of pneumonitis in NSCLC compared with melanoma or other tumour types (1,7). Although it seems that squamous NSCLC have a higher incidence of pneumonitis than adenocarcinoma (10).
Combination Therapy: It is important to realize that the incidence of pneumonitis increases with combination therapies like ICIs and chemotherapy, TKIs, other immunotherapies and thoracic radiation (7, 9, 10).

Studies

Laboratory examination: normal or elevated white blood cells and/or neutrophils. C-reactive protein and erythrocyte sedimentation rate are often elevated.
Chest radiography: initial screening tool (3).
Computed Tomography (CT) scan: Can better distinguish pneumonitis subtypes:
- Organizing pneumoniae (OP): 23%. Bilateral peribronchovascular and subpleural ground-glass with airspace opacities, in mid-to lower-lung predominance (3).
- Nonspecific interstitial pneumoniae (NSIP): 8%. Symmetric ground-glass and reticular opacities with basilar predominance (3).
- Hypersensitivity pneumonitis (HP): 16%. Diffuse or centrilobular ground-glass nodules, mid-to upper-lobe predominance (3).
- Acute interstitial pneumonia (AIP) – acute respiratory distress syndrome (ARDS): 10%. Patchy or diffuse ground glass or consolidative opacities. Majority lung involvement.
- Bronchiolitis: 6%. Centrilobular nodules with tree-in-bud nodularity (3).
Positron Emission Tomography (PET) scan: The role in pneumonitis is nuclear because of the lack of specify (3).
Biopsy: Usually transbronchial lung biopsy is not required, but can help us to rule out acute infection, lymphangitic spread or other lung disease. A video-assisted thoracoscopic surgery biopsy is more specific but with more risk for the patient. Bronchoscopy and bronchoalveolar lavage is recommended in any symptomatic pneumonia, with the aim to identify opportunistic or atypical agents (1,11).
Histologic findings: Organizing pneumonia is the most common pattern seen, often admixed with vague non-necrotizing granulomas in the airspaces (5).

Pharmacotherapy

Prednisone 1mg/kg/day orally

(Metil)prednisolone 2-4 mg/Kg i.v.

Infliximab 5 mg/kg i.v, second dose 14 days later at the discretion of the physician.

Mycophenolate mofetil 1 -1.5 g twice a day (BID) orally, then taper in pulmonary service.

IV	B	28881921
IV	B	28881921
II	A	35390769.
II	A	35390769.

	II A	35390769
	II A	35390769
	N/A N/A	28881921
	N/A N/A	28881921
Therapeutic Strategy
	IV-V B	28881921
	IV-V B	28881921
	IV-V B II A	28881921 35390769

Cyclophosphamide 1 – 2 mg/kg/day orally

Intravenous Immunoglobulin (IVIG): Total dosing 2 g/kg, in daily divided doses over 2–5 days of 400 -500 mg/kg

Cotrimoxazole 800mg/160mg Monday, Wednesday, Friday.

Calcium & Vitamin D 1000mg/800UI diary

Grade 1:

-Consider holding treatment.

-Monitor symptoms every 2 – 3 days.

-If worsen treat as grade 2 or 3 -4.

Grade 2:

-Withhold ICIs.

-Consider empiric broad-spectrum antibiotics (including atypical pathogens) if f suspicion of infection.

-Prednisone 1mg/kg/day orally, tapered over 4 – 6 weeks after recovery.

-Pneumocystis prophylaxis and Calcium-Vitamin D supplementation.

-Monitor every 3 – 7 days.

-Reintroduction of ICIs when daily dose of steroids equals 10mg or less of oral prednisone.

Grade 3/4:

Hospitalised.
Discontinue ICIs permanently.
(Metil)prednisolone 2 – 4 mg/Kg i.v. Assess response in 48 hours and taperover ≥ 6 weeks
Empiric broad – spectrum antibiotics.
Pneumocystis prophylaxis and Calcium -Vitamin D supplementation.

If no improvement in 48 hours:

Infliximab.
Mycophenolate mofetil: If concurrent hepatic toxicity.
Cyclophosphamide.
Intravenous Immunoglobulin (IVIG).

References: Level Grade PMID Nº

Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. J Clin Oncol. [Internet] 2021 Dec 20 [13 July 2022];39(36):4073-4126. doi: 10.1200/JCO.21.01440. Epub 2021 Nov 1. Available at: https://ascopubs.org/doi/10.1200/JCO.21.01440?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
Wang H, Guo X, Zhou J, Li Y, Duan L, Si X, et al. Clinical diagnosis and treatment of immune checkpoint inhibitor-associated pneumonitis. Thorac Cancer. [Internet] 2020 Jan [13 July 2022];11(1):191-197. doi: 10.1111/1759-7714.13240. Epub 2019 Nov 24. Available at: https://onlinelibrary.wiley.com/doi/10.1111/1759-7714.13240.
Kalisz KR, Ramaiya NH, Laukamp KR, Gupta A. Immune Checkpoint Inhibitor Therapy-related Pneumonitis: Patterns and Management. Radiographics. [Internet] 2019 Nov-Dec. [20 July 2022];39(7):1923-1937. doi: 10.1148/rg.2019190036. Epub 2019 Oct 4. https://pubs.rsna.org/doi/10.1148/rg.2019190036?url_ver=Z39.88- 2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
Nishino M, Ramaiya NH, Awad MM, Sholl LM, Maattala JA, Taibi M, et al. PD-1 Inhibitor-Related Pneumonitis in Advanced Cancer Patients: Radiographic Patterns and Clinical Course. Clin Cancer Res. [Internet] 2016 Dec 15 [3 July 2022];22(24):6051-6060. doi: 10.1158/1078-0432.CCR-16-1320. Epub 2016 Aug 17. Available at: https://aacrjournals.org/clincancerres/article/22/24/6051/257684/PD-1-Inhibitor-Related-Pneumonitis-in-Advanced.
Larsen BT, Chae JM, Dixit AS, Hartman TE, Peikert T, Roden AC. Clinical and Histopathologic Features of Immune Checkpoint Inhibitor-related Pneumonitis. Am J Surg Pathol. [Internet]. 2019 Oct [4 July 2022];43(10):1331-1340. doi: 10.1097/PAS.0000000000001298. Available at: https://journals.lww.com/ajsp/Abstract/2019/10000/Clinical_and_Histopathologic_Features_of_Immune.5.aspx.
Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the Common Terminology Criteria for Adverse Events (CTCAE – Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr (Engl Ed). [Internet]. 2021 Jan [5 July 2022];112(1):90-92. English, Spanish. doi: 10.1016/j.ad.2019.05.009. Epub 2020 Sep 3. PMID: 32891586. Available at: https://www.sciencedirect.com/science/article/pii/S0001731020302866?via%3Dihub
Long K, Suresh K. Pulmonary toxicity of systemic lung cancer therapy. Respirology. [Internet]. 2020 Nov [27 June 2022];25 Suppl 2:72-79. doi: 10.1111/resp.13915. Epub 2020 Jul

29. Available at: https://onlinelibrary.wiley.com/doi/10.1111/resp.13915.

Cortés J, Kim SB, Chung WP, Im SA, Park YH, Hegg R, et al. DESTINY-Breast03 Trial Investigators. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. [Internet]. N Engl J Med. 2022 Mar 24 [24 July 2022];386(12):1143-1154. doi: 10.1056/NEJMoa2115022. Available at: https://www.nejm.org/doi/10.1056/NEJMoa2115022
Ullah T, Patel H, Pena GM, Shah R, Fein AM. Acontemporary review of radiation pneumonitis. [Internet]. Curr Opin Pulm Med. 2020 Jul [17 July];26(4):321-325. doi: 10.1097/MCP.0000000000000682. Available at: https://journals.lww.com/co- pulmonarymedicine/Abstract/2020/07000/A_contemporary_review_of_radiation_pneumonitis.3.aspx
Zhai X, Zhang J, Tian Y, Li J, Jing W, Guo H, Zhu H. The mechanism and risk factors for immune checkpoint inhibitor pneumonitis in non-small cell lung cancer patients. [Internet]. Cancer Biol Med. 2020 Aug 15 [17July 2022];17(3):599-611. doi: 10.20892/j.issn.2095-3941.2020.0102.

Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476083/pdf/cbm-17-599.pdf

Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, Jordan K; ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. [Internet]. Ann Oncol. 2017 Jul 1 [13 July 2022];28(suppl_4):iv119-iv142. doi: 10.1093/annonc/mdx225. Erratum in: Ann Oncol. 2018 Oct 1;29(Suppl 4):iv264-iv266. Available at: https://www.esmo.org/guidelines/guidelines-by-topic/supportive-and-palliative-care/toxicities-from-immunotherapy
Thompson JA, Schneider BJ, Brahmer J, Achufusi A, Armand P, Berkenstock MK, et al. Management of Immunotherapy-Related Toxicities, Version 1.2022, NCCN Clinical Practice Guidelines in Oncology. [Internet]. J Natl Compr Canc Netw. 2022 Apr [15 July 2022];20(4):387-405. doi: 10.6004/jnccn.2022.0020. Available at: https://jnccn.org/view/journals/jnccn/20/4/article-p387.xml

PLEURAL EFFUSION

Authors: Inês Ferreira Gomes and David Silva Gomes

Definition

- - Pleural effusion is the pathological accumulation of fluid in the pleural space.

Symptoms1,2

Symptoms of pleural effusion are correlated to the underlying disease.
Dyspnoea is the most common symptom; the severity of this symptom is roughly related to the size of the effusion.

3 Chest pain: implies involvement of the pleura, ribs, or chest wall, suggesting an exudative cause. It is usually a pleuritic chest pain, that is, a pain exacerbated by deep inspiration, sneezing and coughing. It can either be localized or referred (e.g., diaphragmatic irritation can cause a pain that radiates to the shoulder).

Cough: non-specific symptom, usually non-productive, dry cough, caused by pleural inflammation or lung compression due to a large effusion. Productive cough is suggestive of an infective aetiology.
Constitutional symptoms might be also present (night sweats, weight loss, anorexia, and malaise), and might suggest malignant causes.

Physical Examination3

1. Breath sounds can be unilateral or bilaterally diminished or absent in the bases. 2. Pleural rub can be present in the initial stage of a parapneumonic effusion.

3. Dullness to percussion on the side of the effusion. 4.Tachypnoea might be present when there’s a large effusion. According to certain signs and/or symptoms, there are more probable causes, as shown in table 1.

Table 1 – Signs and symptoms and probable aetiology

Evidence

Level Grade PMID Nº

Signs

Ascites	Hepatic hydrothorax Ovarian cancer Meigs syndrome
Dyspnoea on exertion, orthopnoea, peripheral oedema, elevated jugular venous pressure	Heart failure Constrictive pericarditis
Pericardial friction rub	Pericarditis
Unilateral lower extremity swelling Pulmonary embolism
Symptoms
Pneumonia
Fever Empyema
Tuberculosis
Malignancy
Haemoptysis	Lung cancer Pulmonary embolism Tuberculosis
Weight loss	Malignancy Tuberculosis Anaerobic bacterial pneumonia

Etiology

The differential diagnosis of pleural effusion is extensive. The most common cause of pleural effusion is heart failure, followed by parapneumonic effusions and malignancy(4). The biochemical classification into transudate or exudate is also related to possible etiological causes, as shown in table 2 (5).

Table 2 – Causes of pleural effusions

Transudate	Exudate
Common causes
Left ventricular failure Cirrhotic liver disease	Malignancy Parapneumonic effusion/empyema Tuberculosis
Less common causes
Hypoalbuminemia Hypothyroidism Peritoneal dialysis	Pulmonary embolus (with infarction) Rheumatoid arthritis Systemic Lupus Erythematosus
Pulmonary embolus (10-20%) Malignancy (5%) Nephrotic syndrome Mitral stenosis	Other connective tissue disease Benign Asbestos Pleural Effusion Pancreatitis Oesophageal rupture
Constrictive pericarditis	Drugs
Urinothorax	Fungal infections
	Chylothorax
	Pseudo chylothorax (cholesterol effusion)
	Hydatid disease (ruptured cyst) Haemothorax Meigs,s syndrome

Studies1-3,5-7

History and examination

Agood clinical history can guide the clinician to an underlying aetiology, as already stated in the symptoms section.

A pharmacological history is essential, as the list of drugs that can cause exudative effusion has been increasing (mainly associated with amiodarone, phenytoin, nitrofurantoin, and methotrexate).

Evidence

Level Grade PMID Nº

Questioning patients about occupational exposure environments is also an important part of the clinical history, given the increasing incidence of mesothelioma cases, and Level GradeEvidence

should include dates and degree of exposure.

Physical examination may confirm features of malignancy, connective tissue disease or left ventricular failure.

The combination of the clinical history and physical examination may be sufficient to determine the cause of a transudative effusion, and in certain clinical situations it may not be necessary to perform thoracentesis and pleural fluid analysis (e.g., pleural effusion in the setting of heart failure).

Imaging techniques

When a pleural effusion is suspected, a posteroanterior chest x-ray should be obtained. It is possible to observe radiological alterations in the presence of about 200 mL of pleural fluid.

Chest ultrasound is useful and is better than computerized tomography at revealing pleural septa and it can be used to help perform thoracentesis, reducing the risks of iatrogenic pneumothorax.

Chest computerized tomography can reveal pleural effusions than cannot be seen on conventional x-ray. It also helps in distinguish pleural fluid from pleural tissue proliferation and it can provide clues to potential causes, like pneumonia, malignant mass, or pulmonary embolism.

Thoracocentesis

Diagnostic thoracocentesis is indicated when there is a pleural effusion of unknow cause, since pleural fluid analysis is the most useful test in the differential diagnose. Therefore, pleural fluid aspiration should be performed in all cases of radiologically confirmed pleural effusion, except for patients with a clinical context suggestive of a transudative process (e.g., heart failure).

Pleural fluid analysis

The aspirated fluid should be tested, and 20-40 mL of pleural fluid is necessary for a complete analysis, that should be divided in four sterile tubes: one for biochemistry, one for white blood cell count and differential, one for microbiology and one for cytology. Tests usually performed on pleural fluid include cell count differential, protein, lactate dehydrogenase (LDH), glucose, pH, cytology, and microbiology if infection is suspected.

1. The appearance of the pleural fluid might be useful for establishing the diagnosis. For example, if the aspirated fluid is purulent, it is an empyema. If pleural fluid is milky, it might be an empyema or a high lipid effusion (chylothorax or pseudo chylothorax). A bloodstained fluid can be suggestive of malignancy (the most common cause), trauma, pulmonary embolism, or pneumonia. The potential causes according to the pleural fluid appearance are described in table 3.

Table 3 – Appearances of pleural fluid that can suggest a probable aetiology

PMID Nº

Pleural Fluid Appearance	otential Etiology
Pale yellow/Straw yellow	Transudate Some exudates
Turbid	Exudate
Purulent	Empyema
White (milky)	Chylothorax Pseudo chylotho,rax (cholesterol effusion) Some empyema s
Bloodstained	Malignancy (most common) Trauma Pulmonary embolism Parapneumonic effusion

Blood	Haemothorax
Yellow green	Rheumatoid pleurisy
Dark green	Bili thorax
Brown	Long-standing bloody effusion Rupture of amoebic liver abscess
Anchovy Paste	Amoebic liver abscess
	Aspergillus Niger
	Metastatic melanoma
Black	Bronchogenic adenocarcinoma
	Chronic haemothorax
	Pancreatic-pleural fistula
	Oesophageal perforation during treatment with activated charcoal

1. Determination if the fluid is a transudate or an exudate should be one of the first steps, because in case it is a transudate, the etiological possibilities are much more limited. The discrimination is commonly done using Light’s criteria (table 4), which includes protein and LDH ratio between fluid and serum. The possible causes accordingly are described in table 2. In patients with congestive heart failure under diuretic therapy, especially if an effective diuresis has been obtained, the pleural fluid can be misclassified as an exudate by Light’s criteria. In such cases, serum-pleural fluid gradient for albumin might be applied. If it is superior to 1.2 g/dl, it indicates a transudate (8,9).

Table 4 – Light’s criteria

One or more criteria classifies the fluid an exudate

1.Pleural fluid protein divided by serum protein >0.5 2.Pleural fluid LDH divided by serum LDH >0.6

3.Pleural fluid LDH> 2/3 the upper normal limit for serum LDH

1. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a sensitive marker of systolic and diastolic cardiac failure and both levels in blood and pleural fluid correlate closely with congestive heart failure. The use of this test may avoid repeating possible invasive investigations in patients where there is a strong suspicion of cardiac failure.
2. Pleural fluid differential blood cell count can help in narrowing the list of possible causes but are not specific. A predominant lymphocytic count (>50% cells are lymphocytes) is common in tuberculosis, longstanding pleural effusions, or malignant etiology. Very high lymphocytic counts (>80%) mostly occur in tuberculosis, lymphoma, chronic rheumatoid pleurisy, or sarcoidosis. An elevated concentration of neutrophils is more related to acute processes and might be present in case of parapneumonic effusion, empyema end effusion due to pulmonary embolism. Pleural effusions in which ≥10% of cells are eosinophils are defined as eosinophilic and the most common cause of pleural fluid eosinophilia is air or blood in the pleural space, but malignancy is also a common cause.
3. pH values are important specially when an infective cause is suspected since pleural fluid acidosis can be found in parapneumonic effusions.
4. LDH levels above 1000 IU/L are characteristic of complicated parapneumonic pleural effusion/empyema but can also be found in rheumatoid pleurisy and tuberculous pleurisy.
5. Low glucose concentration (<60 mg/dL) in pleural effusion is found in complicated parapneumonic pleural effusion/empyema, tuberculosis, malignancy, rheumatoid pleuritis and oesophageal syndrome.
6. Elevated adenosine deaminase (ADA) is typical of tuberculosis (especially if >35 to 50 U/L) but can also be found in complicated parapneumonic effusion/empyema, rheumatoid pleurisy and malignancy.
7. Amylase might be elevated in pleural fluid in case of pancreatitis.
8. Elevated cholesterol (>250 mg/dL) defines a cholesterol effusion, when triglyceride levels are low.

k.Elevated triglyceride (>110 mg/dL) supports the diagnosis of a chylothorax.

Pleural fluid/serum creatinine ratio >1 is a confirmatory test for urinothorax
Pleural fluid/serum haematocrit ratio ≥50% confirms the presence of haemothorax, but values of 25-50% are also suggestive
The cytology of pleural fluid can confirm the malignant nature of the fluid in 50% of lung cancers and 60% of all cancers.

5.Thoracoscopy

If malignancy is suspected but cytology of pleural fluid is nondiagnostic, thoracoscopy should be considered. It provides a very high diagnostic sensitivity (~95%), as it allows to take vision-guided biopsies. Furthermore, the clinician can drain pleural fluid and perform pleurodesis by the talc poudrage technique. Bleeding diathesis, anticoagulation and lack of patient cooperation are relative contraindications. Complications are infrequent and usually minor (10).

Pharmacotherapy

Treatment of pleural effusion is directed at the cause and should be according to de underlying disease process.2	2	A	27147861
Exudative causes often require removal of fluid for symptomatic relief .2			20696690

Therapeutic Strategy

It will depend on the cause of the pleural effusion, namely whether it is of malignant or non-malignant origin.

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General strategies

Thoracentesis should be performed in all patients with more than a minimal pleural effusion unless clinically evident heart failure is present

Thoracentesis should be performed with ultrasound guidance

Light s criteria should be used to distinguish between a pleural fluid exudate and transudate

If malignancy is suspected and pleural fluid cytologic examination is nondiagnostic, thoracoscopy should be

considered.

Non-malignant pleural effusion

For symptomatic patients who have persistent or a first recurrence, the effusion should be redrained rather than proceeding directly to a definitive therapy. Fluid analysis should be repeated to reconfirm thesuspected diagnosis or rule out other causes.

Patients who are symptomatic and recur despite repeated thoracentesis (eg, >2 to 3) and optimal medical

therapy, may place an indwelling pleural catheter or pleurodesis rather than repeatthoracentesis

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Malignant pleural effusion

Most of the patients with symptomatic pleural effusion benefit form therapeutic large volume thoracocentesis as the initial intervention. In all cases, if indicated, the underlying malignancy should be simultaneously treated; select tumours may respond to antitumor therapy including breast, ovarian, and prostate cancer, germ cell tumours, lymphoma, and small cell lung cancer. Thoracocentesis determines the symptomatic response to drainage, the ability of the lung to reexpand completely, and the rate of subsequent reaccumulation, all of which inform future more definitive treatments should the effusion reaccumulate.

Patients with rapidly recurrent symptomatic pleural effusion, who have an expandable lung, drainage via an indwelling pleural catheter is a better option than pleurodesisin some patients. However, pleurodesis is a reasonable alternative in other patients and when an indwelling pleural catheter isn´t available. Use of thoracentesis in this setting is generally limited to patients with very bad prognosis.

In patients undergoing talc pleurodesis, the use of either talc poudrage or talc slurry has similar efficacy. Local expertise might be more determinant.

Patients with slow reaccumulation (e.g., longer than one month), drainage with indwelling pleuralcatheter is preferable rather than repeat thoracentesis.

Pleurodesis may not be needed in this population especially when the rate of accumulation is very slow.

In patients with symptomatic malignant pleural effusions withnon-expandable lung, failed pleurodesis, or loculated effusion, the use of indwelling pleural catheter over chemical pleurodesis might be preferred.

In patients with known or suspected MPE who are asymptomatic, therapeutic pleural interventions might not be performed.

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References:

Porcel JM, Light RW. Diagnostic approach to pleural effusion in adults. American family physician. 2006 Apr 1;73(7):1211-20.
Rahman NM, Chapman SJ, Davies RJ. Pleural effusion: a structured approach to care. British medical bulletin. 2004 Jan 1;72(1):31-47.
Jany B, Welte T. Pleural effusion in adults—etiology, diagnosis, and treatment. Deutsches Ärzteblatt International. 2019 May;116(21):377.
Loddenkemper, R., & Janssen, J. Pleural Effusion. In: Palange, P., & Rohde, G. G. U. Respiratory Medicine. European Respiratory Society (2019).
Saguil A, Wyrick K, Hallgren J. Diagnostic approach to pleural effusion. American family physician. 2014 Jul 15;90(2):99-104.
Karkhanis VS, Joshi JM. Pleural effusion: diagnosis, treatment, and management. Open access emergency medicine: OAEM. 2012;4:31.
Maskell N, Butland R. BTS guidelines for the investigation of a unilateral pleural effusion in adults. Thorax. 2003 May;58(Suppl 2):ii8.

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Romero-Candeira S, Fernández C, Martı́n C, Sánchez-Paya J, Hernández L. Influence of diuretics on the concentration of proteins and other components of pleural transudates in patients with heart failure. The American journal of medicine. 2001 Jun 15;110(9):681-6.
Roth BJ, Cragun WH. Serum-effusion albumin gradient in separation of transudative and exudative pleural effusions. Chest. 1994 Mar 1;105(3):974-5.
Antony VB, Loddenkemper R, Astoul P, Boutin C, Goldstraw P, Hott J, Panadero FR, Sahn SA. Management of malignant pleural effusions. European Respiratory Journal. 2001 Aug 1;18(2):402-19.

BRONCHIAL HYPERSECRETION

Authors: Daniela Meireles, Teresa Fraga and Isabel Domingues

Introduction [1]-[3]

In health, mucus is secreted to coat the airway, limit water loss, and trap inhaled debris, which is then eliminated via mucociliary clearance. Airway blockage can result from pathologic mucus hypersecretion and inadequate mucus clearance. Bronchorrhea or bronchial hypersecretion is defined as the excessive production of these watery secretions (>100 mL/day). The presence of bronchorrhea has a negative impact in the quality of life of any patient as this increased production of secretions is associated with dyspnoea, cough, and respiratory infections.

Several pharmacological and non-pharmacological therapies have been studied to reduce bronchial secretions, but the results are still insufficient to establish recommendations with a strong degree of evidence.

Etiology [2],[3]

Bronchial hypersecretion occurs either by the increase in the production of mucus or from the difficulty in externalizing it. It is often found in patients with lung cancer (in bronchioloalveolar carcinoma incidence of bronchorrhea is ~6%) or head and neck cancer but has also been seen in patients with benign conditions such as cardiorespiratory or neuromuscular pathologies. Difficulty in externalizing secretions is usually related to ineffective cough, which is due to muscle weakness and/or incoordination of the respiratory muscles.

Mucin synthesis and secretion can be triggered by signalling through the epidermal growth factor receptor (EGFR), which is activated by epidermal growth factor as well as transforming growth factor , heparin-binding epidermal growth factor, amphiregulin, epiregulin, and -cellulin. Many stimuli have been demonstrated to boost EGFR ligand expression however the mechanism of this expression has not been determined. As part of the innate immune response, mucin production can also be triggered and signalled by Toll-like receptors. This has been shown to be significant in host defence against gastrointestinal parasites as well as in cancer.

Therapeutic Strategy [1],[2],[4]- [8]

There is little evidence for successful pharmacological therapy of bronchorrhea, which makes it difficult to devise treatment recommendations. The aim is to treat the underlying cause and taking into account local availability, treatment costs, and tolerability, the following pragmatic measures are suggested: first-line treatment should be a corticosteroid or macrolide antibiotic. If either gefitinib or erlotinib (anti-EGFR) is regarded as an anticancer therapy, concomitant bronchorrhea can support this decision. If available, inhaled indomethacin can be considered as a second-line treatment.

Table 1: Different pharmacological treatments for bronchorrhea in Malignant Disease

-Blockade of prostaglandin production through inhibition of COX-2

Indomethacin

-Subsequent inhibition of chloride secretion and glandular secretion by enhancement of sodium absorption through airway mucosa

Evidence

Level Grade PMID Nº

Octreotide

Erythromycin

Corticosteroids

-Inhibition of the secretion of pituitary and gastrointestinal hormones

-Reduction of secretin-induced chloride efflux from bronchial epithelial cells

-Reduced chloride excretion

-Inhibition of glycoprotein and chloride secretions

-Inhibition of gene encoding inducible cyclooxygenase

-Direct inhibition of glycoconjugate secretion

Gefitinib -Inhibition of mucin production in lung cancer cells

In order to better direct treatment, some authors often divided patients into two categories: those who have an “effective” cough (coughing with enough force to loosen and carry mucus through the airways without causing them to narrow and collapse) and those who do not. In the first group, treatment approaches will promote sputum, increase the fluidity of secretions and improve the effectiveness of the cough. Patients in the second group, without the ability to produce an “effective “cough, the main objective is symptomatic relief.

Table 2 – Management

Patients WITH an effective cough

Goals: promote sputum, increase fluidity of secretions, and improve cough effectiveness

Adequate hydration to fluidify secretions

Respiratory kinesitherapy with breathing techniques, percussion, postural drainage.

Some techniques such as assisted coughing and percussion physiotherapy were effective but have no proven benefit in end-of-life patients.

Avoid cough suppressants. If necessary, consider using it at night (to avoid insomnia caused by coughing)

Mucolytic drugs aim to reduce the viscosity and change the structure of mucus secretions, facilitating their elimination, without increasing the volume. Examples of mucolytic drugs:

–Carbocisteine: in syrup, capsules or powder for oral solution, 500 to 750mg, 3id.

After response: consider maintaining 1.5 g/day, divided into different doses;

–Acetylcysteine: in effervescent tablets or granules, 200 mg 3id, or 400-600mg/day in a single dose.

–Bromhexine: in syrup, 8 – 16 mg 3id.

–Ambroxol (bromhexine metabolite): in tablets or syrup, up to 120 mg/day divided into 2 or 3 times/day.

All these drugs are associated with gastrointestinal side effects such as nausea and vomiting. Use with caution in patients with a history of peptic ulcer disease.

Mucolytic drugs aim to reduce the viscosity and change the structure of mucus secretions, facilitating their elimination, without increasing the volume. Examples of mucolytic drugs:

–Carbocisteine: in syrup, capsules or powder for oral solution, 500 to 750mg, 3id.

After response: consider maintaining 1.5 g/day, divided into different doses;

–Acetylcysteine: in effervescent tablets or granules, 200 mg 3id, or 400-600mg/day in a single dose.

–Bromhexine: in syrup, 8 – 16 mg 3id.

–Ambroxol (bromhexine metabolite): in tablets or syrup, up to 120 mg/day divided into 2 or 3 times/day.

All these drugs are associated with gastrointestinal side effects such as nausea and vomiting. Use with caution in patients with a history of peptic ulcer disease.
Use with caution in asthmatic patients or patients under nitro-glycerine, in the case of acetylcysteine.

Antibiotics if microbial infection is suspected. Choose the drug according to local guidelines.

If possible collect sputum for cultures to guide the use of antibiotics.

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Patients WITHOUT an effective cough

Goals: symptomatic relief

Reduce non-essential fluid therapy and/or enteral feeding

Antimuscarinic drugs to reduce secretion production:

–Ipratropium bromide or nebulized glycopyrronium

–Atropine 1% sol. Ophthalmic, 1-2 drops sublingually 4/4 hours

–Butyl scopolamine 20mg 6-6h or 8-8h SC/IV (bolus or continuous infusion). Oral formulation has no effect on reducing secretions

–Scopolamine hydrobromide transdermal 1.5mg every 72 hours

IV route allows for a faster onset of action but shorter duration than the subcutaneous route in inhibiting salivary secretions.

Inhaled fluticasone

-A decrease in the volume of secretions of 75% has been described, 48 hours after the start of administration.

-Administering systemic corticosteroids decreases bronchial secretions in the first administrations, an effect that is lost with dose reduction, and may even worsen bronchorrhea.

Aspiration of secretions

-Gentle oropharyngeal suctioning may be considered if secretions accumulate and should be limited.

Patient positioning

-Frequent patient positioning may allow clearance of oropharyngeal secretions

-It is of great importance that pharmacological treatment is associated with interventions, such as this, alternating betweensupine and lateral decubitus, or even sitting.

Mechanical insufflator/ exsufflator (“Cough Assist”)

-facilitates mobilization of bronchial secretions in some situations

-there are some situations where this is contraindicated such as the presence of haemoptysis, severe chronic obstructive pulmonary disease, severe asthma and intracranial hypertension.

Antibiotics if microbial infection is suspected

Avoid cough suppressants. If necessary, consider using it at night (to avoid insomnia caused by coughing):

-codeine (central narcotic action)

-dextromethorphan (non-drug central action)

-or others such as tablets and liquids with honey (peripheralaction)

Psychological monitoring of the patient’s caregiver, especially in patients with rales. It occurs with the loss of coughing and swallowing.

Generally, crackle is little perceived by the patient, but causes anxiety for caregivers.

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References:

[1]C. Rémi, J. Rémi, and C. Bausewein, “Pharmacological Management of Bronchorrhea in Malignant Disease: A Systematic Literature Review,” J. Pain Symptom Manage., vol. 51, no. 5, pp. 916–925, 2016, doi: 10.1016/j.jpainsymman.2015.12.335.

[2]J. F. Arcuri, E. Abarshi, N. J. Preston, J. Brine, and V. A. Pires Di Lorenzo, “Benefits of interventions for respiratory secretion management in adult palliative care patients – A systematic review,” BMC Palliat. Care, vol. 15, no. 1, pp. 5–7, 2016, doi: 10.1186/s12904-016-0147-y.

[3]B. K. Rubin, K. N. Priftis, H. J. Schmidt, and M. O. Henke, “Secretory hyperresponsiveness and pulmonary mucus hypersecretion,” Chest, vol. 146, no. 2, pp. 496–507, 2014, doi: 10.1378/chest.13-2609.

[4]C. Bausewein and S. T. Simon, “Shortness of breath and cough in patients in palliative care,” Dtsch. Arztebl. Int., vol. 110, no. 33–34, pp. 563–572, 2013, doi: 10.3238/arztebl.2013.0563.

[5]A. Molassiotis et al., “Clinical expert guidelines for the management of cough in lung cancer: Report of a UK task group on cough,” Cough, vol. 6, no. 1, pp. 1–8, 2010, doi: 10.1186/1745-9974-6-9.

[6]M. Bennett, V. Lucas, M. Brennan, A. Hughes, V. O’Donnell, and B. Wee, “Using anti-muscarinic drugs in the management of death rattle: Evidence-based guidelines for palliative care,” Palliat. Med., vol. 16, no. 5, pp. 369–374, 2002, doi: 10.1191/0269216302pm584oa.

[7]G. B. Crawford et al., “Care of the adult cancer patient at the end of life: ESMO Clinical Practice Guidelines ☆,” ESMO Open, vol. 6, no. 4, 2021, doi: 10.1016/j.esmoop.2021.100225.

Evidence

Level Grade PMID Nº

HAEMOPTYSIS

Authors: Maria Bairos Menezes and Margarida Batista Caldeira Massas

Introduction [1-3]

- - Haemoptysis is the expectoration of blood directly from the tracheobronchial tree. It has multiple causes, ranges in severity, and it is classified based on the volume of expectorated blood:
    - Scant haemoptysis refers to expectoration of sputa that are tinged or streaked with blood
    - Frank haemoptysis is characterized by sputa that are grossly bloody but of a low volume (less than 100-200mL in 24 hours)
    - Massive haemoptysis is inconsistently defined but generally refers to expectoration of at least 200mL of blood within a 24-hour period. Some authors limit the definition to expectoration of more than 600mL of blood in 24 hours. It is potentially acutely life threatening.
  - Pseudo haemoptysis, which is the expectoration of blood from a source other than the lower respiratory tract (oral cavity, nares, pharynx), may cause diagnostic confusion when it triggers the cough reflex or when aspiration of hematemesis into the lower respiratory tract occurs. The sputum can also be red and be confused with haemoptysis when the oropharynx is colonized with Serratia marcescens, a red-pigment-producing aerobic gram-negative rod.
  - The goal of the initial assessment of a case of haemoptysis is to detect any life-threatening bleeding and evaluating the patient’s oxygenation.
  - Clinical signs of impaired exchange of gases include cyanosis, dyspnoea, tachypnoea, disturbance of consciousness, and increased work of breathing.

Etiology [1,3,6]

- - The underlying disease-causing haemoptysis may involve the airway, the pulmonary parenchyma, or the pulmonary veins themselves. The most common cause is airway disease, such as bronchiectasis, acute and chronic bronchitis, pneumonia, tuberculosis, and lung cancer. Table 1 summarises the main causes of haemoptysis.

Table 1 – Main aetiologies of haemoptysis. [1,3,6]

Airway disease

Inflammatory diseases: bronchiectasis and bronchitis.
Cancer: squamous cell lung carcinoma, small-cell lung carcinoma, metastatic melanoma, metastatic colorectal cancer, metastatic breast cancer, bronchial carcinoid, sarcoma.
Fistulas between the tracheobronchial tree and blood vessels (thoracic aorta aneurysms);
Trauma, foreign bodies, injury.
Dieulafoy’s disease of the bronchus (abnormal bronchial artery contiguous to the bronchial mucosa).

Pulmonary parenchymal disease

Infections: necrotising pneumonia (Klebsiella spp, Staphylococcus spp, Legionella spp), tuberculosis, lung abscess, fungal infections (aspergilloma).
Inflammatory or immunological disease (diffuse alveolar haemorrhage): Goodpasture syndrome, systemic lupus erythematosus (SLE), granulomatosis with polyangiitis (Wegener’s), microscopic polyarteritis.
Clotting disorders: thrombocytopenia, hereditary coagulopathy, anticoagulant, or antiplatelet treatment.
Complications from techniques: transbronchial lung biopsy, fine needle aspiration biopsy.
Other: antiangiogenics (bevacizumab), cocaine inhalation, nitrogen dioxide exposure, catamenial haemoptysis (endometriosis).

Pulmonary vessel disease

Intrinsic pulmonary vessel disease: pulmonary embolism, arteriovenous malformations, aneurysms and pseudoaneurysm.
Increased pulmonary capillary pressure: mitral pressure, left heart failure.
Iatrogenic: pulmonary artery perforation during Swan-Ganz catheter placement.
Same as those causing pulmonary parenchyma disease.

Studies – Assessment and Diagnosis [1-6]

- - After the initial assessment to determine any threat to the patient’s life, the main goals of the diagnostic work-up in haemoptysis is to identify the cause and location of the bleeding.
  - Targeted clinical history and physical examination can provide the data needed to make an initial assessment, evaluate the severity of the haemorrhage and guide diagnostic and therapeutic measures, as required.
  - Initial complementary tests include clinical laboratory tests with total blood cell count, coagulation, renal and liver function.
  - Pulse oximetry and arterial blood gases to determine the impact of haemoptysis, oxygenation and ventilation should be performed.
  - Active haemoptysis is an absolute contraindication to spirometry testing. After bleeding control, spirometry is used to determine the patient’s respiratory function, which is essential if the patient is a candidate for deferred surgical intervention (strong recommendation 1C).
  - Electrocardiogram: if pulmonary thromboembolism or heart disease is suspected.
  - Transthoracic echocardiogram: detect endocarditis, mitral valve stenosis, congenital heart disease, signs of pulmonary hypertension or arteriovenous malformations.
  - Sputum microbiology (including fungal and mycobacterial cultures), cytology study, blood cultures or serologies: if infectious disease is suspected.
  - Chest radiograph (anterior-posterior and lateral) is the initial imaging test performed but can be normal in patients with haemoptysis due to bronchiectasis or malignant disease.
  - Chest multidetector computed tomography (CT) must be performed in all patients with frank haemoptysis, in those with blood-streaked sputum and suspected bronchiectasis, without intravenous contrast.
  - Chest multidetector CT with intravenous contrast should be performed in patients with blood-streaked sputum and high-risk factors for lung cancer (> 40 years of age with a cumulative tobacco consumption of >30 pack-years, CPOD) and those with pathological findings on X-rays (strong recommendation, 1A).
  - Multidetector CT with angiography, from the base of the neck to the renal arteries could be made in patients with life-threatening haemoptysis and active bleeding, who may be eligible for embolization (weak recommendation, 2C).

Level Grade PMID Nº

- - Flexible bronchoscopy allows an examination of the mucosa, hence its fundamental role in confirming and locating the source of bleeding, as well as diagnosing the cause of bleeding. It is recommended that bronchoscopy should be performed during active haemoptysis or within 24-48h after cessation, rather than at a delayed time, although the diagnostic yield seems to be similar in both cases (strong recommendation, 1C).
  - In the case of life-threatening haemoptysis in an unstable patient, a bronchoscopy must be performed as soon as possible after intubation, since, in addition to monitoring the airway, the bronchoscope can be withdrawn if oxygenation deteriorates, or the bronchoscope is obstructed by clots.
  - Flexible bronchoscopy can also be used to collect samples for cytology and microbiological studies, bronchial aspirate, bronchoalveolar lavage (for example, when alveolar bleeding is suspected) and biopsies and/or bronchial brushing, if malignancy is suspected.
  - Patients with a negative result in both CT and bronchoscopy have a very low chance of being diagnosed with a malignant disease (1%) after a follow-up of 6 months. A follow-up chest multidetector CT is only advisable several weeks to months after an acute episode of haemoptysis to evaluate the progress of parenchymal changes which may hide

Treatment [3-13]

- - Treatment varies depending on the cause of the bleeding. However, life-threatening haemoptysis generally requires immediate intervention regardless of the cause.
  - Hospital management of active haemoptysis includes:
    - Monitoring vital signs (blood pressure, heart and breathing rate, oxygen saturation) and quantification of the haemoptysis.
    - Supplementary oxygen, if required.
    - Lateral decubitus bed rest with the bleeding side down (preventing the flow of endobronchial blood into unaffected lung segments).
    - Blood concentrates should be urgently reserved in case of massive haemoptysis. In case of altered coagulation times, patients may benefit from receiving fresh frozen plasma. Patients treated with antiplatelet agents, as well as those with thrombocytopenia, should receive platelet transfusion.
    - Empiric antibiotic treatment is useful in haemoptysis associated with respiratory infection and to prevent subsequent complications.
    - Total fasting to avoid Broncho aspiration and to facilitate the performance of urgent tests, such as bronchoscopy, CT, or angiogram.
    - Aminocaproic acid has been used in isolated case series, mostly in the intracavitary treatment of aspergillomas, but no randomized controlled studies have been performed to determine its efficacy.
  - If respiratory failure is severe or the patient cannot eliminate blood from the tracheobronchial tree, orotracheal intubation with a large diameter tube (8-9mm) should be performed to confirm the presence of bleeding and to facilitate interventional bronchoscopy. Blockage of the bleeding bronchial segment may also be necessary to preserve the ventilation of the healthy lung.
  - Most cases of haemoptysis resolve with treatment of the underlying infection or inflammatory process or with removal of the offending stimulus.
  - Endobronchial lesions can be treated with a variety of interventions during broncho scopically, including directly instilling adrenaline, iced saline or topical coagulant or photocoagulation laser therapy.
  - Angiographic embolization requires the injection of intravenous contrast, to localise the arterial circulation involved and identify the bleeding site. Once localised the source, occlusive material is inserted into the bleeding vessel, which usually resolves the bleeding. This intervention should be entertained only in the most severe and life-threatening cases of haemoptysis, because of the risk of unintentional spinal-artery embolization and consequent paraplegia.
  - When all previous measures have failed, surgical resection of the affected region of the lung is considered. Since mortality rates are high (> 20%), patients should be specifically selected and have a good previous pulmonary function. In some cases, such as aortic aneurysm rupture, hydatid cysts, chest trauma, lung cancer or necrotizing pneumonia where vessels or bronchus are disrupted, surgery may be the only effective approach and should be considered upfront.

Level Grade PMID Nº

Figure 1 – Diagnosis and treatment of haemoptysis. CT, computed tomography; ICU, Intensive Care Unit [3-6]

- - Depending on the patient’s underlying disease and/or performance status, the patient may benefit only from an exclusively palliative management. It is important to share prognostic information of patients with chronic or life-threatening conditions to establish appropriate goals of care and treatment.
  - The palliative treatment of haemoptysis is primarily related to managing the experience of the patient and family/care givers. Dark towels can be used to diminish the visual impact and distress caused by the bleeding. Symptom management involve positioning the patient with the affected lung dependent to decrease blood flow and current practice advocates the use of sedatives as the pharmacological management of massive haemoptysis, commonly midazolam 0,2mg/kg or 5mg intravenous or intranasal or subcutaneous, to reduce awareness and distress. Certain guidelines propose the use of opioids in the case of overt pain or dyspnoea. In patients who are identified as being at risk, a bedside crisis pack should be available containing prepared sedatives, while carefully considering the psychological impact and the pharmacological stability of the already prepared drugs.

Pharmacotherapy

Evidence

Level Grade PMID Nº

- - Tranexamic acid can reduce both the duration and volume of bleeding, with a low short-term risk of thromboembolic disease. Intravenous dose 0,5-1g, 2-3 times a day II B (1mL/min). Oral dose 500mg (tablets): 1-1,5g, 2-3 times a day.
  - Undiluted tranexamic acid applied on the focus of bleeding at an initial dose of 500mg. II C

Therapeutic Strategy [3-13]

- - Rigid bronchoscopy in combination with flexible bronchoscopy is the most comprehensive and safest procedure in life-threatening haemoptysis, since it can be used to: I C

Ensure the patient is adequately ventilated
Ensure patency of the airway by aspiration of bloody remains with large-calibre tubes
Perform haemostasis directly on the areas of bleeding by applying pressure with the external wall of the distal tip of the rigid bronchoscope, or with the administration of vasoconstrictors or endobronchial clotting agents
Access the distal bronchial tree with use of the flexible bronchoscope
- - If lesions are highly vascularized, some authors recommend during flexible bronchoscopy, the instillation of 1-2mL of adrenaline diluted at 1:20 000 before samples are II C collected, to reduce the risk of new bleeding.
  - To minimize cardiovascular effects in at-risk patients, some authors have suggested replacing adrenaline with antidiuretic hormone, such as terlipressin or onipressin. II C
  - Bronchial lavage with cold saline solution (4oC) using 50 mL aliquots until bleeding ceases, without exceeding a total volume of 500mL. II C
  - In case of bleeding tumours, laser photocoagulation by bronchoscopy stops haemorrhage from 60 to 74% and reduce bleeding in up to 94% of cases. I C
  - Argon plasma electrocoagulation is useful to stop haemorrhage in 100% of active bleeding endobronchial lesions. I C
  - Contact electrocautery may also be effective in lung cancer haemoptysis. I C
  - Endovascular embolization is indicated in all patients with life-threatening or recurrent haemoptysis in whom pathological arteries are observed on angio-multidetector CT and I B must be performed by expert interventional vascular radiology team with digital subtraction equipment. For good haemoptysis management, all pathological arteries must be embolized.
  - Surgery is reserved for life-threatening haemoptysis when the cause of bleeding can be treated by the intervention and the origin of the bleeding has been specifically and I B reliably located.

Complications and mortality rates are much higher when surgical resection is performed during active haemorrhage, and significantly reduced in patients in whom surgery can be delayed following cessation of bleeding using arterial embolization and support measures.

- - If the tumour is inoperable, external radiation therapy can be applied in the case of a endobronchial or peripheral tumour. I C Endobronchial brachytherapy can be useful for endoluminal lesions, if there is no ulceration of the tumour mucosa, since this is a contraindication for this technique.

References:

ESMO, Esmo Handbook of Oncological Emergencies, 2016
Lee Goldman, Approach of the Patient with Respiratory Disease, Goldman-Cecil Medicine, 2020
Cordovilla R, Bollo de Miguel E, Nuñez Ares A, Cosano Povedano FJ, Herráez Ortega I, Jiménez Merchán R. Diagnosis and Treatment of Hemoptysis, Archivos de Bronconeumología, 2016; 62: 368-3778. PMID: 26873518
Ittrich H, Bockhorn M, Klose H, Simon M, The Diagnosis and Treatment of Hemoptysis. Dtsch Arztebl Int 2017; 114: 371-81. DOI: 10.3238/arztebl.2017.037. PMID: 28625277
Radchenko C, Alraiyes A.H, Shojaee S, A systematic approach to the management of massive hemoptysis, Journal of Thoracic Disease, 2017; 9: S1069-S1086. PMID: 29214066

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Lordan JL, Gascoigne A, Corris PA, The pulmonar physician in critical care – Illustrative case 7: Assessment and management of massive haemoptysis, Thorax, 2003, DOI: 10.1136/thorax.58.9.814. PMID: 12947147
Moen CA, Burrell A, Dunning J. Does tranexamic acid stop haemoptysis. Interact. Cardiovasc Thorac Surg. 2013;17:991–4. PMID: 23966576
Tuller C, Tuller D, Tamm M, Brutsche MH. Hemodynamic effects of endobronchial application of ornipressin versus terlipressin. Respiration. 2004;71:397–401. PMID: 15316215
Han CC, Prasetyo D, Wright GM. Endobronchial palliation using Nd:YAG laser is associated with improved survival when combined with multimodal adjuvant treatments. J Thorac Oncol. 2007;2:59–64. PMID: 17410011
Chun JY, Morgan R, Belli AM. Radiological management of hemoptysis: a comprehensive review of diagnostic imaging and bronchial arterial embolization. Cardiovasc Interv Radiol. 2010;33:240–50. PMID: 20058006
Andréjak C, Parrot A, Bazelly B, Ancel PY, Djibré M, Khalil A, et al. Surgical lung resection for severe hemoptysis. Ann Thorac Surg. 2009;88:1556–65. PMID: 19853112
Paul S, Andrews W, Nasar A, Port JL, Lee PC, Stiles BM, et al. Prevalence and outcomes of anatomic lung resections for hemoptysis: an analysis of the Nationwide Inpatient Sample database. Ann Thorac Surg. 2013;96:391–8. PMID: 23816414
Simoff MJ, Lally B, Slade MG, Goldberg WG, Lee P, Michaud GC, et al. Symptom management in patients with lung cancer: Diagnosis and management of lung, 3rd ed: American College of Chest Physicians. Evidence-based clinicalvpractice guidelines. Chest. 2013;143:e455S–97S. PMID: 23649452

Annex A

CTCAE v5 grading for the disorders presented in this chapter

Common terminology criteria for adverse events classification. The complete document with definitions is available at https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_60

Evidence Level Grade PMID Nº

CTCAE term	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Bronchopulmonary hemorrhage	Term Definition: A disorder characterized by bleeding from the bronchial wall and/or lung parenchyma.
Bronchopulmonary hemorrhage	Mild symptoms; intervention not indicated	Moderate symptoms; invasive intervention not indicated	Transfusion indicated; invasive intervention indicated; hospitalization	Life-threatening consequences; intubation or urgent intervention indicated	Death
Tracheal hemorrhage	Term Definition:
Tracheal hemorrhage

RHEUMATOLOGICAL ALTERATIONS

BONE DISORDERS

Authors: Claudio Ávila Andrade and Rafael Matías

- - In patients with cancer, the bones can be affected by various mechanisms, including those related to the primary tumour (bone metastases that are discussed in Chapter 123??), as well as breast cancer, prostate cancer (70% bone metastases), followed by lung cancer 40%, bladder, kidney, and haematological tumours. The decrease in bone mass is another mechanism produced by the different treatments aimed to treat cancer, causing the risk of pathological fractures. When these occur, they lead to a significant decrease in the patient’s [1,2,3]

Etiology and pathophysiology

Hormonotherapy Women with breast cancer, whose tumour expresses positive hormone receptors (ER+) receive aromatase inhibitors (AI) as part of the adjuvant treatment. AI produce bone loss and increased risk of fractures.
There are human and animal studies that show that osteoclasts play an important role in bone loss induced by neoplasia.
The main regulator of osteoclasts, the receptor activator of nuclear factor-κB (RANK) ligand (RANKL), together with chemokines, induce the colonization of tumour cells in the bone microenvironment [3]
Tumour stromal cells secrete a variety of substances (prostaglandins, bradykinin, tumour necrosis factor alpha, endothelin, interleukins 1,6, epidermal growth factor, platelet- derived growth factor, among others) that stimulate afferent neurons.
In common, factors such as parathyroid hormone-related protein (PTHrP), Interleukin 11 (IL-11), induce the production of RANKL, IL-3, IL-6, tumour necrosis factor (TNF-α), jagged 1 that stimulate osteoclast activation. [7]
There are other factors for bone loss in patients without metastatic bone lesions, including chronic corticosteroid therapy, chemotherapy-induced hypogonadism, endocrine therapy, surgical castration, radiation therapy, or a combination of these [3,4,5].
Different chemotherapy schemes have been shown to produce hypogonadism, including cyclophosphamide, methotrexate, fluorouracil (CMF), FEC (fluorouracil, Epirubicin- doxorubicin, cyclophosphamide), used in the treatment of breast cancer.
Of these cytotoxic agents, cyclophosphamide produces more hypogonadism, causing amenorrhea, premature menopause, being dose dependent. In some studies cisplatin at high doses has produced hypogonadism in testicular neoplasia. [3]
In premenopausal women with breast cancer, adjuvant tamoxifen treatment is associated with osteopenia. Nonsteroidal (anastrozole and letrozole) and steroidal (exemestane). Al (use in menopausal breast cancer patients) reduces oestrogen levels and inhibit androgen aromatization by blocking the aromatase enzyme.
The presence of osteoporosis is more common in patients who have started aromatase inhibitor after menopause. Bone loss is accompanied by a significant risk of vertebral and nonvertebral fractures. [3,5,6]
GnRH agonists are effective in the treatment of endometriosis and breast cancer in premenopausal women by suppressing oestrogen levels, but they induce bone loss. There has been no evidence of an increased risk of fracture in women with normal bone mass evidenced by bone densitometry (DXA).
Androgen deprivation therapy in patients with castration-sensitive prostate cancer, whether surgical or chemical, reduces extension and tumour growth and improves survival but on the contrary increases the risk of bone fractures. [4,5,6]
Patients who have received treatment with radiotherapy to the brain, pelvic (ovarian, testicular), may associate risk of hypogonadism.
Cases of bone fracture in previously irradiated ribs or pelvis have been reported.

Signs and symptoms Bone Pain

,• Main symptom [8],

Most patients experience pain with moderate to severe intensity, and it is the main cause of chronic pain in these patients.
It is subjective, described as a dull, poorly defined pain that worsens at night, of constant presentation that increases over time [8,10].
Cancer induced bone pain involves both neuropathic and inflammatory pain pathways, associated with tumor and adjacent tissues. [7, 10]

Evidence

Level Grade PMID Nº

Pathological fractures

- A fracture that occurs in a bone with a pathological surface, when there is destruction of almost all of the bone tissue, but no fracture has yet occurred, is known as an impending fracture.
- It is a complication of patients with bone metastases. Although they can occur in benign lesions such as osteoporosis.
- There are different studies that analyse which patients have a higher risk of presenting pathological fractures but there is no uniformity of criteria. [12-13)
- The most common sites of fracture include the vertebrae (60%), hip or femur (30%) and humerus, tibia.

Diagnosis

- A fracture that occurs in a bone with a pathological surface, when there is destruction of almost all of the bone tissue, but no fracture has yet occurred, is known as an impending fracture.
- It is a complication of patients with bone metastases. Although they can occur in benign lesions such as osteoporosis.
- There are different studies that analyse which patients have a higher risk of presenting pathological fractures but there is no uniformity of criteria. [12-13)
- The most common sites of fracture include the vertebrae (60%), hip or femur (30%) and humerus, tibia.

Evidence

Level Grade PMID Nº

X-ray absorptiometry (DXA)	A standard technique for measuring bone mineraldensity (BMD) is dual energy X-ray absorptiometry (DXA) [3 bone disorders]. The T score represents the standard deviation from an ideal bone mass. The interval between densitometry is usually every 1-2 years, individualizing each case. Normal T score > 1 ●Osteopenia T score <1 >2.5 ●Osteoporosis T score <2.5 Severe Osteoporosis T score <2.5evidence fracture
X Ray	Cheap, available in most centres, its main problemlies in its low sensitivity and specificity.
Computed Axial Tomography (CT scan)	Standard technique in most tumours with asensitivity of 73% and a specificity of 95%, especially in osteoblastic lesions (such as prostatecancer).
Bone scan 99m- technetium methylene bisphosphonate (99mTc-MDP)	It is based on increased activity of osteoblasts in the vicinity of metastases, resulting in increased accumulation of the marker at sites of bone formation Sensitivity 79% •Specificity 82% Deficiency its low specificity [14]
Magnetic Resonance (MRI)	Better sensitivity (95%) and specificity (96%) Plays an important role in the detection of bone metastases, improved sensitivity compared to CT scan and bone scintigraphy
PET Fluorodeoxyglucose (FDG)	Precise detail of the anatomy, location andpresence of metastases, as well as the primary Sensitivity 87% •Specificity 97% Sensitivity can increase to 94% when associated with computed tomography. One of the main disadvantages is that although it isinmanyhealth centres it is still not presentin many health centres worldwide
Biomarkers	Not disease specific May present elevation of alkaline phosphatase inthe presence of bone metastases.

Therapeutic Strategy

- Optimal management requires a multidisciplinary team.

Evidence

Level Grade PMID Nº

I A 24675403

Radiotherapy

Management of cancer pain

The mechanism by which it produces an analgesic effect is unknown. By acting on tumocells, it produces their destruction and decreases nociceptivereceptors.

External Beam RadiationTherapy (EBRT)

Effective treatment with response rates around 85%

Stereotactic Body Radiation Therapy (SBRT)

Radionuclide therapy

Strontium-89

Beta emitter, used in the treatment of prostate cancerTime to start of action 3-4 weeks Low pain control.

Radium 223

alpha emitter

Treatment of castration-resistant prostate cancer

Targeted Therapies

Abiraterone

Androgen production inhibitor, along with prednisone demonstrated an improvementin pain control, in patients with prostate cancer.

Bisphosphonates

Bisphosphonates reduce bone destruction and pain due to cancer and inhibit osteoclast mediated bone resorption.

Nitrogen-containing bisphosphonates include: pamidronate, alendronate, ibandronate risedronate and zoledronic acid [5 bone disorders.]

Zoledronic Acid

Requires dental evaluation and renal function control during treatment due to the risk o Osteo mandibular necrosis. Treatment or prevention of postmenopausal osteoporosis

Administration form Prevention of skeletal-relatedevents

Zoledronic acid 4 mg IV every 3 – 4 weeks.

Prevention of treatment-induced bone loss

Zoledronic acid 4mg IV every 6 months.

33060614

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Evidence Level Grade PMID Nº

Denosumab

RANKL agonist, potent inhibitor of osteoclast-mediated bone resorption.

Treatment of osteoporosiswith high risk of fracture or treatment with AIfor breast cancer

Form of administration Prevention of skeletal-relatedevents

Denosumab 120 mg s.c. every 28 days.

Prevention of treatment-induced bone loss

Denosumab 60 mg s.c every 6 months.

Surgery

Recommended in cases of spinal cord compression in conjunction with radiotherapy

Calcium and vitamin D

should be recommended to patients.

Supplementation with calcium and/or vitamin D was associated with fewer hypocalcaemia

Supplementsof Calcium intake > 800 – 1000mgper day + Vitamin D 400 -800 UI (Normally 400 Ui), prevent osteoporosis

2 A 26093811

33237064

Intravenous i.v. subcutaneous s.c

References:

1.Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006 Oct 15;12(20 Pt 2):6243s-6249s. doi: 10.1158/1078-0432.CCR-06-0931. PMID: 17062708. 2.Pockett RD, Castellano D, McEwan P, Oglesby A, Barber BL, Chung K. The hospital burden of disease associated with bone metastases and skeletal-related events in patients with breast cancer, lung cancer, or prostate cancer in Spain. Eur J Cancer Care (Engl). 2010 Nov;19(6):755- 60. doi: 10.1111/j.1365-2354.2009.01135.x. PMID: 19708928; PMCID: PMC3035821.

Rizzoli R, Body JJ, Brandi ML, Cannata-Andia J, Chappard D, El Maghraoui A, Glüer CC, Kendler D, Napoli N, Papaioannou A, Pierroz DD, Rahme M, Van Poznak CH, de Villiers TJ, El Hajj Fuleihan G; International Osteoporosis Foundation Committee of Scientific Advisors Working Group on Cancer-Induced Bone Disease. Cancer-associated bone disease. Osteoporos Int. 2013 Dec;24(12):2929-53. doi: 10.1007/s00198-013-2530-3. Epub 2013 Oct 22. PMID: 24146095; PMCID: PMC5104551.
Van Poznak CH. Bone health in adults treated with endocrine therapy for early breast or prostate cancer. Am Soc Clin Oncol Educ Book. 2015:e567-74. doi: 10.14694/EdBook_AM.2015.35.e567. PMID: 25993224.
Coleman R, Body JJ, Aapro M, Hadji P, Herrstedt J; ESMO Guidelines Working Group. Bone health in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol. 2014 Sep;25 Suppl 3:iii124-37. doi: 10.1093/annonc/mdu103. Epub 2014 Apr 29.
Gough N, Miah AB, Linch M. Nonsurgical oncological management of cancer pain. Curr Opin Support Palliat Care. 2014 Jun;8(2):102-11. doi: 10.1097/SPC.0000000000000043. PMID: 24675403.
Milgrom DP, Lad NL, Koniaris LG, Zimmers TA. Bone Pain and Muscle Weakness in Cancer Patients. Curr Osteoporos Rep. 2017 Apr;15(2):76-87. doi: 10.1007/s11914-017-0354-3. PMID: 28497213; PMCID: PMC5778907.
Costa L, Badia X, Chow E, Lipton A, Wardley A. Impact of skeletal complications on patients’ quality of life, mobility, and functional independence. Support Care Cancer. 2008 Aug;16(8):879- 89. doi: 10.1007/s00520-008-0418-0. Epub 2008 Apr 8. Erratum in: Support Care Cancer. 2008 Oct;16(10):1201. PMID: 18392862.
Fornetti J, Welm AL, Stewart SA. Understanding the Bone in Cancer Metastasis. J Bone Miner Res. 2018 Dec;33(12):2099-2113. doi: 10.1002/jbmr.3618. Epub 2018 Nov 26. PMID: 30476357.
Jimenez-Andrade JM, Mantyh WG, Bloom AP, Ferng AS, Geffre CP, Mantyh PW. Bone cancer pain. Ann N Y Acad Sci. 2010 Jun; 1198:173-81. doi: 10.1111/j.1749-6632.2009.05429.x. PMID: 20536932; PMCID: PMC5642911.
Falk S, Dickenson AH. Pain and nociception: mechanisms of cancer-induced bone pain.0 J Clin Oncol. 2014 Jun 1;32(16):1647-54. doi: 10.1200/JCO.2013.51.7219. Epub 2014 May 5. PMID: 24799469. 12.Angelini A, Trovarelli G, Berizzi A, Pala E, Breda A, Maraldi M, Ruggieri P. Treatment of pathologic fractures of the proximal femur. Injury. 2018 Nov;49 Suppl 3:S77-S83. doi: 10.1016/j.injury.2018.09.044. PMID: 30415673
Jairam V, Lee V, Yu JB, Park HS. Nationwide Patterns of Pathologic Fractures Among Patients Hospitalized With Bone Metastases. Am J Clin Oncol. 2020 Oct;43(10):720-726. doi: 10.1097/COC.0000000000000737. PMID: 32694296.
O’Phelan KH, Bunney EB, Weingart SD, Smith WS. Emergency neurological life support: spinal cord compression (SCC). Neurocrit Care. 2012 Sep;17 Suppl 1:S96-101. doi: 10.1007/s12028-012- 9756-3. PMID: 22956117.
Sutcliffe P, Connock M, Shyangdan D, Court R, Kandala NB, Clarke A. A systematic review of evidence on malignant spinal metastases: natural history and technologies for identifying patients at high risk of vertebral fracture and spinal cord compression. Health Technol Assess. 2013 Sep;17(42):1-274. doi: 10.3310/hta17420. PMID: 24070110; PMCID: PMC4781430.
Coleman RE, Croucher PI, Padhani AR, Clézardin P, Chow E, Fallon M, Guise T, Colangeli S, Capanna R, Costa L. Bone metastases. Nat Rev Dis Primers. 2020 Oct 15;6(1):83. doi: 10.1038/s41572-020- 00216-3. PMID: 33060614.
Body JJ, Bone HG, de Boer RH, Stopeck A, Van Poznak C, Damião R, Fizazi K, Henry DH, Ibrahim T, Lipton A, Saad F, Shore N, Takano T, Shaywitz AJ, Wang H, Bracco OL, Braun A, Kostenuik PJ. Hypocalcaemia in patients with metastatic bone disease treated with denosumab. Eur J Cancer. 2015 Sep;51(13):1812-21. doi: 10.1016/j.ejca.2015.05.016. Epub 2015 Jun 17. PMID: 26093811.
Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall’Oglio M, Franzén L, Coleman R, Vogelzang NJ, O’Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland ØS, Sartor O; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23. doi: 10.1056/NEJMoa1213755. PMID: 23863050.
Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, Naini V, Molina A, Rathkopf DE; COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015 Feb;16(2):152-60. doi: 10.1016/S1470-2045(14)71205-7. Epub 2015 Jan 16. PMID: 25601341.
Liu C , Kuang X , Li K , Guo X , Deng Q , Li D . Effects of combined calcium and vitamin D supplementation on osteoporosis in postmenopausal women: a systematic review and meta- analysis of randomized controlled trials. Food Funct. 2020 Dec 1;11(12):10817-10827. doi: 10.1039/d0fo00787k. Epub 2020 Nov 25. PMID: 33237064.

CHEMOTHERAPY AND HORMONOTHERAPY ASSOCIATED RHEUMATIC COMPLICATIONS

Authors: Paulo Vilas-Boas and Inês Cunha

Introduction

Musculoskeletal disorders may arise as the result of the treatment of malignant disease. Because on immune cells chemotherapy may result in harmful overactivity of the immune system against self. Several rheumatic manifestations have been reported due to chemotherapy, however pathogenies, work-up and best treatment approach are still unclear. Aromatase inhibitors (AIs) play an important role in both breast cancer prevention and treatment; however, it may lead to osteoarticular manifestations such arthralgias and osteoporosis.

Evidence

Level Grade PMID Nº

Postchemotherapy Rheumatism

Postchemotherapy rheumatism represents a poor defined identity based on several case reports(1-3). It is described as a self-limited non inflammatory syndrome causing generalized myoartrhalgias 1-4 months after chemotherapy termination. Most patients are female and breast cancer is the most common associated oncologic condition. Cyclophosphamide was identified as main causative agent since its part of the drug regimen in all reported cases.

Symptoms consist of migratory arthralgias affecting small and large joints. No serum inflammatory markers elevation or auto-immunity laboratory alterations are found, and so it is considered a diagnosis of exclusion. Treatment is symptomatic, however response to non-steroidal anti-inflammatory (NSDAIs) is poor and responses to corticosteroid therapy is variable. Spontaneous remission is expected in 12 months.

Chemotherapy-Related Arthropathy

Chemotherapy-related arthropathy is defined as a symmetrical polyarthritis affecting the small joints of the hands and feet, leading to inflammatory pain and morning stiffness. Musculoskeletal findings develop independently of the chemotherapeutic regimen(4). Symptoms occur during or in a short period after finishing chemotherapy. Conventional disease- modifying antirheumatic drugs (cDMARDs), with or without concomitant corticosteroid therapy, usually allows a complete clinical response. Early diagnosis and early refer leads to a better prognosis.

1. Specific rheumatic QT drugs events

2.1.1Bleomycin

Several cases of cutaneous fibrosis indistinguishable from that encountered in progressive systemic sclerosis with accompanying Raynaud phenomenon have been reported among cancer patients undergoing chemotherapy with bleomycin(5). Animal models show that induces skin and lung fibrosis(6).

- 1. Taxanes

Taxanes, such as paclitaxel and docetaxel, can cause severe myalgias and arthralgias beginning 24-48 hours after the drug administration and generally ending after 5 days ( taxane acute pain syndrome)(7-9)

Low-dose oral prednisone, gabapentin and Shakuyaku-kanzo-to (Japanese herbal medicine) showed benefit in reducing or preventing arthralgias and myalgias.(10,11,12)

- 1. Gemcitabine

Vascular digital ischemia may occur rarely due to gemcitabine use secondary to microvascular damage and a hypercoagulability induced state.(13) In patients with autoimmune disorders consider carefully using gemcitabine in combination with platinum agents.

1. Aromatase Inhibitor Musculoskeletal Syndrome (AIMSS)

Epidemiology

Aromatase inhibitors (AIs) play an important role in both breast cancer prevention and treatment.
Third generation Ais such as anastrozole, letrozole and exemestane frequently cause musculoskeletal side effects.
Aromatase inhibitor musculoskeletal syndrome usually occurs between 0,4-10 months after the AI initiation(14). Prevalence is estimated to be 50%, with widely variables intensity degrees(15).
It is an important cause of non-compliance(16).

Symptoms Level Grade PMID Nº

Symptoms include bilateral symmetric myalgias, arthralgias and paresthesia affecting mainly the wrists, knees, and the small hand joints.
Carpal tunnel syndrome, manifesting as paresthesia affecting the first, second and third hands’ fingers, is also a possible complication.

Therapeutic strategy

No interventions have yet been identified that prevent development of AIMSS.
Initial strategy for management includes NSAIDs use (minimum effective dose) and a regular exercise regimen, ideally including moderate aerobic exercise for 150 minutes per week(17).
For women who NSAIDs and exercise is not successful temporary discontinuation of AI for 2-8 weeks, followed by initiation of a different AI must be considered(18).
Duloxetine (30mg daily, followed by 60mg daily) and acupuncture may alleviate symptoms by a minor degree(19,20).
Opioids are not recommended.
If patients are unable or unwilling to continue treatment with AI, consider switch to tamoxifen.
- NSAIDs 4 B
- Duloxetine 2 B
1. Aromatase inhibitor-induced bone loss

Epidemiology

Treatment with AIs results in bone loss due to estrogen deficiency. Women who will be initiating AIs require fracture risk assessment.
Clinical risk fractures include physical inactivity, advancing age, prior history of fragility fracture, chronic glucocorticoid use, low body mass index, parental history of hip fracture, cigarette smoking and excess alcohol.

Symptoms

Osteoporosis is an asymptomatic disease, leading to increased risk of fragility fracture.

Diagnosis

Bone mineral density measured by dual-energy x-ray absorptiometry (DXA) should be obtained in women starting AIs.
Clinical history and DXAestimates the risk of fracture using the Fracture Risk Assessment Tool (FRAX), however it´s use in women with breast cancer may underestimate fracture risk(21).
Women with the highest risk of fracture are the ones most likely to benefit from drug therapy. This includes woman with osteoporosis (Tscore ≤-2.5 or history of fragility fracture).
If DEXAT-scores are between -1,0 and -2,5, FRAX can be used to select candidates for osteoporosis treatment, which is considered cost-effective if the 10-year probability of hip fracture or combined major osteoporotic fracture is ≥2.5% or ≥9 %, respectively. Consensus guidelines recommends ticking the “rheumatoid arthritis” box in FRAX to allow the for the fracture effect of starting AIs(22).

Treatment

All modifiable risk factors should be corrected with lifestyle changes.
The pharmacologic agents available for the prevention of AI-induced bone loss in postmenopausal women are bisphosphonates and denosumab.
Intravenous zoledronic acid and subcutaneous denosumab should be considered in case of oral intolerance, malabsorption, dementia, and non-compliance.
Raloxifene should not be given to breast cancer patients. Recombinant human parathyroid hormone is contraindicated in patients who were exposed to radiotherapy due to risk of osteogenic sarcoma.

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Bisphosphonates are preferred over denosumab as initial therapy. Oral and intravenous bisphosphonates are both acceptable options, depending on the patients’ preferences. Oral bisphosphonates should be avoided in patients with upper gastrointestinal issues. Dosing regimens are the same as women with osteoporosis unrelated to breast cancer treatment.
Prior to bisphosphonate initiation, serum calcium levels, vitamin D and renal function should be obtained, and patients should be periodically monitored for several complications, including transient flu-like symptoms, renal insufficiency, hypocalcemia, and osteonecrosis of the jaw. Hypocalcemia, severe renal insufficiency (GFR<30 ml/min), pregnancy and lactation are contraindications for both oral and intravenous bisphosphonate use.
Denosumab is administered every six months by subcutaneous injection. No dose adjustment is necessary in patients with chronic kidney disease. Calcium levels should be assessed before each dose and two weeks after the first dose. Patients should be encouraged to report hypocalcemia symptoms (tingling in the hands, feet, and face). When denosumab is stopped, there is an increased risk in multiple vertebral fractures. Bisphosphonate treatment should be started after completion of denosumab treatment.
Adequate calcium and vitamin D intake can result in positive calcium balance and a reduction in the rate of bone loss. Three servings of dairy products per day (milk, cheese, or yogurt) deliver most of the recommended calcium intake for the general population. If adequate intake of calcium (1,000 to 1,200 mg/d) and vitamin D (at least 800 to 1,000 IU/d) is not being consumed, then supplements to reach those levels are recommended(23).
DXA assessment should not be repeated within less than 2 years. The absence of new low trauma fractures, the stability or improvement of BMD over >2 years, and a guaranteed adherence to therapy are consistent with a satisfactory course of treatment. For women who are not candidates for therapy, BMD should be measured in one to two years.

Level Grade PMID Nº

- Bisphosphonates I A
- Denosumab I A

References:

1)Smith DE. Additional cases of postchemotherapy rheumatism. Journal of Clinical Oncology 11, no. 8 (August 01, 1993) 1625-6. Doi: 10.1200/JCO PMID: 8336200 2)Siegel JE. Postchemotherapy rheumatism: is this a menopausal symptom? J Clin Oncol. 1993 Oct;11(10):2051. PMID: 8410131.

3)Loprinzi CL, Duffy J, Ingle JN. Postchemotherapy rheumatism. J Clin Oncol. 1993 Apr;11(4):768-70. doi: 10.1200/JCO.1993.11.4.768. PMID: 8478669. 4)Kim MJ, Ye YM, Park HS, Suh CH. Chemotherapy-related arthropathy. J Rheumatol. 2006 Jul;33(7):1364-8. PMID: 16821271.

5)Finch WR, Rodnan GP, Buckingham RB, Prince RK, Winkelstein A. Bleomycin-induced scleroderma. J Rheumatol. 1980 Sep-Oct;7(5):651-9. PMID: 6160247. 6)Wu M, Varga J. In perspective: murine models of scleroderma. Curr Rheumatol Rep. 2008 Jul;10(3):173-82. doi: 10.1007/s11926-008-0030-9. PMID: 18638424.

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Chiu N, Chiu L, Chow R, Lam H et al. Taxane-induced arthralgia and myalgia: A literature review. J Oncol Pharm Pract. 2017 Jan;23(1):56-67. doi: 10.1177/1078155215627502. Epub 2016 Jun 23. PMID: 26811404.
Fernandes R, Mazzarello S, Hutton B, Shorr R, Ibrahim MFK, Jacobs C, Ong M, Clemons M. A Systematic Review of the Incidence and Risk Factors for Taxane Acute Pain Syndrome in Patients Receiving Taxane-Based Chemotherapy for Prostate Cancer. Clin Genitourin Cancer. 2017 Feb;15(1):1-6. doi: 10.1016/j.clgc.2016.07.018. Epub 2016 Jul 28. PMID: 27554586.
Markman M, Kennedy A, Webster K et al. Use of low-dose oral prednisone to prevent paclitaxel-induced arthralgias and myalgias. Gynecol Oncol. 1999 Jan;72(1):100-1. doi: 10.1006/gyno.1998.5226. PMID: 9889038.
Nguyen VH, Lawrence HJ. Use of gabapentin in the prevention of taxane-induced arthralgias and myalgias. J Clin Oncol. 2004 May 1;22(9):1767-9. doi: 10.1200/JCO.2004.99.298. PMID: 15118009. 11)Yamamoto K, Hoshiai H, Noda K. Effects of shakuyaku-kanzo-to on muscle pain from combination chemotherapy with paclitaxel and carboplatin. Gynecol Oncol. 2001 May;81(2):333-4. doi:

10.1006/gyno.2001.6168. PMID: 11330975.

So E, Crees ZD, Crites D, Wang-Gillam A. Digital Ischemia and Necrosis: A Rarely Described Complication of Gemcitabine in Pancreatic Adenocarcinoma. J Pancreat Cancer. 2017 Aug 1;3(1):49-52. doi: 10.1089/pancan.2017.0012. PMID: 30631842; PMCID: PMC5933482.
Dasanu CA. Gemcitabine: vascular toxicity and prothrombotic potential. Expert Opin Drug Saf. 2008 Nov;7(6):703-16. doi: 10.1517/14740330802374262. PMID: 18983217.
Henry NL, Giles JT, Ang D, Mohan M, Dadabhoy D, Robarge J, Hayden J, Lemler S, Shahverdi K, Powers P, Li L, Flockhart D, Stearns V, Hayes DF, Storniolo AM, Clauw DJ. Prospective characterization of musculoskeletal symptoms in early stage breast cancer patients treated with aromatase inhibitors. Breast Cancer Res Treat. 2008 Sep;111(2):365-72. doi: 10.1007/s10549-007-9774-6. Epub 2007 Oct 6. PMID: 17922185; PMCID: PMC3081690.
Henry NL, Giles JT, Ang D, Mohan M et al. Prospective characterization of musculoskeletal symptoms in early stage breast cancer patients treated with aromatase inhibitors. Breast Cancer Res Treat. 2008 Sep;111(2):365-72. doi: 10.1007/s10549-007-9774-6. Epub 2007 Oct 6. PMID: 17922185; PMCID: PMC3081690.
Beckwée D, Leysen L, Meuwis K, Adriaenssens N. Prevalence of aromatase inhibitor-induced arthralgia in breast cancer: a systematic review and meta-analysis. Support Care Cancer. 2017 May;25(5):1673-1686. doi: 10.1007/s00520-017-3613-z. Epub 2017 Feb 15. PMID: 28204994.
Lombard JM, Zdenkowski N, Wells K, Beckmore C, Reaby L, Forbes JF, Chirgwin J. Aromatase inhibitor induced musculoskeletal syndrome: a significant problem with limited treatment options. Support Care Cancer. 2016 May;24(5):2139-2146. doi: 10.1007/s00520-015-3001-5. Epub 2015 Nov 10. PMID: 26556210.
Irwin ML et al. Randomized exercise trial of aromatase inhibitor-induced arthralgia in breast cancer survivors. J Clin Oncol. 2015 Apr 1;33(10):1104-11. doi: 10.1200/JCO.2014.57.1547. Epub 2014 Dec 1. PMID: 25452437; PMCID: PMC4372849.
Henry NL et al. Predictors of aromatase inhibitor discontinuation as a result of treatment-emergent symptoms in early-stage breast cancer. J Clin Oncol. 2012 Mar 20;30(9):936-42. doi: 10.1200/JCO.2011.38.0261. Epub 2012 Feb 13. PMID: 22331951; PMCID: PMC3341106
Henry NL et al. Randomized, Multicenter, Placebo-Controlled Clinical Trial of Duloxetine Versus Placebo for Aromatase Inhibitor-Associated Arthralgias in Early-Stage Breast Cancer: SWOG S1202. J Clin Oncol 2018
Hershman DL et al. Effect of Acupuncture vs Sham Acupuncture or Waitlist Control on Joint Pain Related to Aromatase Inhibitors Among Women With Early-Stage Breast Cancer: A Randomized Clinical Trial. JAMA. 2018 Jul 10;320(2):167-176. doi: 10.1001/jama.2018.8907. PMID: 29998338; PMCID: PMC6583520.
Leslie WD et al. Performance of FRAX in Women with Breast Cancer Initiating Aromatase Inhibitor Therapy: A Registry-Based Cohort Study. J Bone Miner Res. 2019 Aug;34(8):1428-1435. doi: 10.1002/jbmr.3726. Epub 2019 May 9. PMID: 31069862.
Hadji P et al. Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol. 2017 Mar 23;7:1-12. doi: 10.1016/j.jbo.2017.03.001. PMID: 28413771; PMCID: PMC5384888

PARANEOPLASTIC RHEUMATIC MANIFESTATIONS

Authors: Pedro Bernardo Santos and Inês Cunha

Introduction

Many clinical presentations of cancer mimic rheumatic symptoms through means other than mass effect or metastasis.(1.2) Even though these syndromes occur in only 10% of patients with cancer, they may be the first sign of an underlying malignancy and they can be severe enough to be life-threatening. They can be associated to hematologic, lymphoproliferative, and solid malignancies.(3)

Certain musculoskeletal symptoms may arise in consequence of local or distant spread of the tumor cells; also some neoplastic transformation may be the result of a dysregulated immune system in an individual with a previous diagnosis of an autoimmune disease.

An example demonstrated by several studies is the higher incidence of non-Hodgkin’s lymphoma in individuals with primary Sjögren’s syndrome, rheumatoid arthritis, and systemic lupus erythematosus.(4) The clinical history should be focused on some topics that should put the physician on track in searching for an occult malignancy: personal or family history of malignancy, advanced age at onset, significant constitutional upset, unusual clinical picture for the rheumatic syndrome, and inadequate response to conventional therapy.(5)

Rheumatic Manifestation

Arthropathy

Hypertrophic osteoarthropathy

Symptoms: arthralgia; tibial and femoral bone pain(2)

Physical examination: soft tissue tenderness in the symptomatic regions, synovitis of the adjacent joints and clubbing of the digits5; acanthosis palmaris(6)

Evidence

Level Grade PMID Nº

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Exams: Conventional radiographs periosteal osseous proliferation; technetium bone scan: increased uptake in the periosteum and involved joints(2); synovial fluid analysis: Level Grade PMID Nº

increased viscosity and a paucity of white blood cells(5)

Etiology: malignancies of the pulmonary and gastrointestinal systems(5); production of platelet-derived growth factor and vascular endothelial growth factor (VEGF)(7)

Pharmacotherapy:

Nonsteroidal anti-inflammatory drugs 4 C
Zoledronato(8) 3 D
Pamidronato(9) I A

Therapeutic strategy:

4 C

Removal of the underlying tumor(10)

Carcinomatous polyarthritis

Epidemiology: M/F ratio 1.7:1, median age of onset 54.2 years(2)

Symptoms: acute onset, RA-like polyarthritis, asymmetric distribution (++ lower limbs rather than wrist and hands)(5)

Physical examination: usually tenderness and swollen of MCP and PIPs joints, wrist, MTPs joints

Exams: significantly elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR); 27.2% positive rheumatoid factor and 19.0% positive antinuclear antibodies(6); anticitrullinated protein antibodies can also be positive in a lesser extent(11)

Etiology: hematologic and lymphoproliferative malignancies are one third of the cases(6); solid tumors: oropharynx, larynx, esophagus, stomach, colon, lung, breast, ovary and pancreas(12)

Pharmacotherapy:

4 C

Lack of response to CS and other DMARDs(2)

Therapeutic strategy:

Treatment of the associated cancer(13) 4 C

Palmar fasciitis and polyarthritis syndrome

Symptoms: sudden onset of diffuse painful swelling of both the hands along with marked stiffness; palmar fasciitis

Physical examination: synovitis of MCP, PIP and wrist; adhesive capsulitis of the shoulders; nodular thickening of the palmar fascia, flexion contractures; 20% plantar fascia involvement; woody hands, groove sign(2)

Exams: 70% mild elevation CRP and 50% near-normal ESR(14)

Etiology: Underlying female reproductive tract malignancy (36.8% ovarian adenocarcinoma; others include endometrioid carcinoma, poor tumor differentiation, stromal proliferation of fibrous tissue), nonresectable tumors with ascites and peritoneal metastatic seeding(13)

Pharmacotherapy: 4 C

Lack of response to CS or chemotherapy(15)

Therapeutic strategy:

Poor prognosis15 4 C

Remitting seronegative symmetric synovitis with pitting edema (RS3PE)

Epidemiology: elderly(6)

Symptoms: arthralgias of small joints and notion of swelling of hands and feet; no clinical differences between paraneoplastic and idiopathic cases(6) Physical examination: symmetric synovitis of smalls joints in extremities associated with significant pitting edema; boxing-glove appearance of the hands(5) Exams: increase of ESR and CRP; absence of RF and anti-CCP antibodies(5)

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Etiology: associated to solid tumors: stomach, colon, prostate, ovary and endometrium; hematologic and lymphoproliferative malignancies5; elevated levels of VEGF, matrix Level Grade PMID Nº

metalloproteinase 3(15)

Pharmacotherapy:

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- Delayed response to low-dose CS(16)

Therapeutic strategy:

- Removal of the underlying malignancy(16)

Multicentric reticulohistiocytosis

Epidemiology: rare

Symptoms: symmetric and erosive polyarthritis of the IP joints, wrists, elbows, shoulders, hips, knees, ankles and feet; mutilating arthritis; papulonodular eruption at the ears, nose, scalp, back of the hands, forearms and elbows

Physical examination: coral-red papular skin lesions (Kobner’s phenomenon); involvement of tendon sheath, synovium, bone, and less commonly liver, salivary glands, kidneys, lymph nodes, heart and lungs(17)

Exams: skin biopsy with dermal infiltration of CD68-positive histiocytes and multinucleated giant cells possessing an eosinophilic ground-glass cytoplasm

Etiology: associated to a positive skin tuberculin test (12-50%), systemic vasculitis and underlying malignancies in 15-30% of cases (bronchial, breast, stomach, cervical and liver carcinomas)(18)

Pharmacotherapy:

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- Resistant to GC, MTX and HCQ
- TNF-α inhibition
- Alendronate

Therapeutic strategy:

- Removal of the underlying malignancy(2)

Polymyalgia rheumatica

Epidemiology: elderly; earlier age of onset (before 50 years) in malignant cases(5) Symptoms: pain and stiffness in the proximal muscles; constitutional symptoms (++ fatigue) Physical examination: shoulder and hip girdle muscle pain and stiffness

Exams: anemia of chronic diseases; sedimentation rate less than 40 or more than 100 mm/h(22)

Etiology: associated with malignancies of the kidney, lung, colon and multiple myeloma(5)

Pharmacotherapy:

- Not so responsive to low-dose CS like idiopathic ones

Therapeutic strategy:

4 C

- Treatment of the underlying malignancy(23)

Tumor-induced osteomalacia

Epidemiology: rare

Symptoms: bone pain, weakness, recurrent fractures

Physical examination: gait abnormalities, stunted growth, skeletal changes

Exams: diffuse osteopenia, pseudofractures, coarsening of trabeculae on x-ray; hypophosphatemia, phosphaturia; inappropriately normal or low serum 1,25-dihydroxyvitamin D level; elevated or inappropriately normal FGF23(23)

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Etiology: associated with small mesenchymal tumor, prostate cancer, oat cell cancer, hematologic malignancies, neurofibromatosis, and polyostotic fibrous dysplasia; secretion Level Grade PMID Nº

of phosphaturic hormone and fibroblast growth factor 23(23)

Pharmacotherapy: 4 C

- Phosphorus and calcitriol(5)

Therapeutic strategy: 4 C

-Treatment of the underlying malignancy(22)

Myopathy

Polymyositis (PM) / Dermatomyositis (DM)

Epidemiology: up to 28% of the cases of PM; 6 to 60% of patients with diagnosed DM; male sex, age at onset greater than 50 years. Symptoms: weakness of proximal muscles; lower risk of cancer: interstitial lung disease, joint involvement and Raynaud phenomen(5) Physical examination: shawl sign, distal weakness, weakness of the pharynx and diaphragm; lack of lung involvement

Exams: increased creatine kinase level, increased ESR, CRP; presence of anti-p155-140 (anti-transcriptional intermediary factor-1y) or anti-NXP2 (nuclear matrix protein) antibody(24); tissue biopsy: leukocytoclastic vasculitis (LCV), skin ulceration/necrosis/vasculitis(5); lower risk: presence of anti-synthetase, anti-Ro52 or systemic sclerosis associated antibodies(24)

Etiology: associated with malignancies of the ovarian, lung, gastric, and nasopharyngeal type(5)

Pharmacotherapy: 4 C

- Difficult-to-treat disease(25)

Therapeutic strategy:

- Treatment of the underlying malignancy can lead to improvement of the associated myopathy and cutaneous manifestations(25) 4 C

Vascular

Cancer-associated Vasculitis

Epidemiology: up to 8% of patients with malignancy(5)

Symptoms: malaise, weight loss, pain in the abdomen, joints and muscles; paresthesia; orchitis; 10% of the cases limited to skin involvement; hyperviscosity symptoms: vertigo, encephalopathy, cephalgia and stroke (type I cryoglobulinemia)(26)

Physical examination: fever, palpable purpura of the legs, livedoid changes, nodules and ulcers; urticaria, erythema elevatum diutinum; high blood pressure; ischemia or hemorrhage in various organs

Exams: LCV and polyarteritis nodosa are the most frequent; also central nervous and cardiovascular systems may be involved; hematuria or proteinuria caused by ruptured microaneurysms of the kidneys; generally seronegative for antineutrophil cytoplasmic autoantibodies (ANCA); absence of glomerulonephritis or pulmonary capillaritis; type I cryoglobulinemia – increased monoclonal IgM that precipitates at cold temperatures (< 37 degrees C)(10)

Etiology: associated more commonly with lymphoproliferative and myeloproliferative diseases than solid tumors (liver, colon, bladder, lung and hypopharynx); type I cryoglobulinemia associated with Waldenström macroglobulinemia and multiple myeloma(10)

Pharmacotherapy: systemic steroids may be effective and, in some cases, steroid-sparing agents such as cyclophosphamide, methotrexate, or azathioprine(5)

Therapeutic strategy:

- - Treatment of the underlying malignancy(5) 4 C

Erythromelalgia

Epidemiology: M/F ratio 1:1, median age of onset 49.1 years(27)

Symptoms: redness, warmth, and burning pain, most notably affecting the extremities; usually affects the lower extremities (most commonly feet) or may involve upper extremities (hands) in few cases(27); worsened by exercise, heat and dependency; improvement with cooling and elevation of the affected part2; the face and ears can also be involved(27)

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Physical examination: swelling, redness and warmth of the skin(27)

Exams: thrombocythemia; arterial ultrasound: without evidence of arterial circulatory compromise(2)

Etiology: associated with myeloproliferative disorders, usually polycythemia vera and essential thrombocythemia (18% of the cases), agnogenic myeloid metaplasia, myelofibrosis and chronic myelogenous leukemia; also, breast, prostate, ovary and colon carcinomas(28)

Pharmacotherapy:

Level Grade PMID Nº

- Single daily dose of acetylsalicylic acid(2) 4 C

Therapeutic strategy:

- Removal of the underlying malignancy(28)

Raynaud Phenomenon

Epidemiology: patients > 50 years, up to 15% of patients admitted for an initial occurrence of digital ischemia are associated with an occult cancer(29)

Symptoms: severe, asymmetric pattern with tendency towards gangrene

Physical examination: associated digital necrosis(29)

Exams: abnormal changes in capillaroscopy; screening of the possible involved organ

Etiology: associated with lymphoid neoplasia; also gastrointestinal, lung, ovarian, renal carcinomas, squamous cell carcinoma and sarcomas(30)

Pharmacotherapy:

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- Calcium channel blockers, Angiotensin II Inhibitors, Selective Serotonin Reuptake Inhibitors, Phosphodiesterase-5 inhibitors, Nitrates; Prostacyclin agonists(24)

Therapeutic strategy:

- Treatment the underlying malignancy(24)

Cutaneous Eosinophilic fasciitis

Epidemiology: rare, female predilection

Symptoms: pain and swelling of the limbs with notion of induration of the skin

Physical examination: symmetric limb or trunk erythema and edema followed by an orange peel ‘peau d’orange’ appearance of the skin ; spares the skin of hands and feet(2); elevation of an affected limb causes visible indentation along the course of the superficial veins (groove sign)(24)

Exams: hypereosinophilia, hypergammaglobulinemia, and increased ESR(5)

Etiology: associated with Hodgkin lymphoma, lymphoproliferative disorder, angioimmunoblastic lymphadenopathy, and peripheral T-cell lymphoma(5)

Pharmacotherapy:

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- Poor response to CS

Therapeutic strategy:

- Removing the underlying malignancy(2)

Sweet syndrome (acute febrile neutrophilic dermatosis)

Symptoms: arthralgia; painful and nonpruritic erythematous skin lesions

Physical examination: fever, erythematous, tender, vesicular or pustular, skin lesions

Exams: neutrophilia; tissue biopsy: nonvasculitic dermal neutrophilic infiltration(31)

Etiology: associated with myelogenous leukemia and myelodysplastic syndromes; also, lymphomas and plasma cell dyscrasias(20)

Pharmacotherapy:

- - Responsive to Cs(2)

Therapeutic strategy:

- - Removing the underlying malignancy(2)

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Pseudoscleroderma

Epidemiology: rare

Symptoms: cutaneous lesions similar to those seen in systemic sclerosis

Etiology: associated with metastatic melanoma, osteoclastic myeloma, plasmacytomas, carcinoids; and gastric, breast and lung tumors(13)

Pharmacotherapy: in investigation

Therapeutic strategy:

Level Grade PMID Nº

- Removing the underlying malignancy(5) 4 C

Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes syndrome (POEMS)

Epidemiology: rare

Symptoms: polyradiculoneuropathy, organomegaly, endocrinopathy, skin changes (sclerodermoid appearance)(24)

Physical examination: papilledema, extravascular volume overload, organomegaly(24)

Exams: thrombocytosis; monoclonal protein band; sclerotic bone lesions on x-rays;

Etiology: secondary to a plasma cell dyscrasia, elevated levels of vascular endothelial growth factor(32)

Therapeutic strategy:

- Removing the underlying malignancy(32) 4 C

Conclusion

It is very challenging for the clinician to get on the right track when musculoskeletal and mucocutaneous features are present before a malignant condition become evident. In fact, the neoplastic machine can exert distant effects through paraneoplastic phenomena. A systematic clinical history focused on the presented sign and symptoms is crucial for the physician to consider the more appropriate work-up for each patient. An earlier diagnosis may not only allow to choose the best treatment, as well achieve better long-term prognosis.

References:

– Kankeleit H. Uber primare nichteirige Polymyositis. Dtsch Arch Klin Med 1916; 120:335–49.
– Hashefi M. Rheumatologic Manifestations of Malignancy. Clin Geriatr Med. 2017 Feb;33(1):73-86. doi: 10.1016/j.cger.2016.08.006
– Schoen FJ, Mitchell RN. Neoplasia. In: Robbins & Cotran pathologic basis of disease. 9th edition. Philadelphia, PA: Saunders/Elsevier; 2015. p. 265–340.
– Zintzaras E, Voulgarelis M, Moutsopoulos HM. The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch Intern Med 2005;165(20): 2337–44. 5 – Khan F, Kleppel H, Meara A. Paraneoplastic Musculoskeletal Syndromes. Rheum Dis Clin North Am. 2020 Aug;46(3):577-586. doi: 10.1016/j.rdc.2020.04.002
– Manger B, Schett G. Paraneoplastic syndromes in rheumatology. Nat Rev Rheumatol 2014;10(11):662–70.
– Dickinson CJ, Martin JF. Megakaryocytes and platelet clumps as the cause of finger clubbing. Lancet 1987;2:1434–5
– Jayakar BA, Abelson AG, Yao Q. Treatment of hypertrophic osteoarthropathy with zoledronic acid: case report and review of the literature. Semin Arthritis Rheum 2011;41:291–6. 9 – Slobodin G, Rosner I, Feld J, et al. Pamidronate treatment in rheumatology practice: a comprehensive review. Clin Rheumatol 2009;28(12):1359–64.

10 – Manzini CU, Colaci M, Ferri C, et al. Paraneoplastic rheumatic disorders: a narrative review. 2018. Available at: https://wwwreumatismoorg/indexphp/reuma. 11 – Kisacik B, Onat AM, Kasifoglu T, et al. Diagnostic dilemma of paraneoplastic arthritis: case series. Int J Rheum Dis 2014;17(6):640–5

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12 – Gamage KKK, Rifath MIM, Fernando H. Migratory polyarthritis as a paraneoplastic syndrome in a patient with diffuse large B cell lymphoma: a case report. J Med Case Rep 2018;12(1):189. 13 – Sendur OF. Paraneoplastic rheumatic disorders. Archives of Rheumatology 2012; 27(1):18–23.

14 – Manger B, Schett G. Palmar fasciitis and polyarthritis syndrome—systematic literature review of 100 cases. Semin Arthritis Rheum 2014;44(1):105–11. 15 – Medsger TA, Dixon JA, Garwood VF. Palmar fasciitis and polyarthritis associated with ovarian carcinoma. Ann Intern Med 1982;96:424–31

– Origuchi T, Arima K, Kawashiri SY, et al. High serum matrix metalloproteinase 3 is characteristic of patients with paraneoplastic remitting seronegative symmetrical synovitis with pitting edema syndrome. Mod Rheumatol 2012;22:584–8.
– Tajirian AL, Malik MK, Robinson-Bostom L, et al. Multicentric reticulohistiocytosis. Clin Dermatol 2006;24:486–92.
– Hu L, Mei JH, Xia J, et al. Erythema, papules, and arthralgia associated with liver cancer: report of a rare case of multicentric histiocytosis. Int J Clin Exp Pathol 2015;8(3):3304–7.
– Goto H, Inaba M, Kobayashi K, et al. Successful treatment of multicentric reticulohistiocytosis with alendronate: evidence for a direct effect of bisphosphonate on histiocytes. Arthritis Rheum 2003;48(12):3538.
– Solimena M, Folli F, Aparisi R, et al. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990;322(22): 1555–60
– Rakocevic G, Floeter MK. Autoimmune stiff person syndrome and related myelopathies: understanding of electrophysiological and immunological processes. Muscle Nerve 2012;45(5):623–34. 22 – Chong WH, Molinolo AA, Chen CC, et al. Tumor-induced osteomalacia. Endoc Relat Cancer 2011;18(3):R53–77.
– Pereira J, Eugénio G, Calretas S, et al. More than just a case of polymyalgia rheumatica. Eur J Case Rep Intern Med 2016;3.
– Manger B, Schett G. Rheumatic paraneoplastic syndromes – A clinical link between malignancy and autoimmunity. Clin Immunol. 2018 Jan;186:67-70. doi: 10.1016/j.clim.2017.07.021. 25 – Ponyi A, Constantin T, Garami M, et al. Cancer-associated myositis: clinical features and prognostic signs. Ann N YAcad Sci 2005;1051(1):64–71.

26 – Stone JH. Immune complex–mediated small-vessel vasculitis. In: Kelley and Firestein’s textbook of rheumatology. 10th edition. Philadelphia, PA: Saunders/Elsevier; 2017. p. 1571–80. 27 – Jha SK, Karna B, Goodman MB. Erythromelalgia. 2021 Jul 6. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 32491719.

– Han JH, Lee JB, Kim SJ, et al. Paraneoplastic erythromelalgia associated with breast carcinoma. Int J Dermatol 2012;51(7):878–80.
– Vaseer S, Chakravarty EF. Musculoskeletal syndromes in malignancy. In: Kelley and Firestein’s textbook of rheumatology. 10th edition. Philadelphia, PA: Saunders/Elsevier; 2017. p. 2048–65, e2046. 30 – Le Besnerais M, Miranda S, Cailleux N, et al. Digital ischemia associated with cancer: results from a cohort study. Medicine (Baltimore) 2014;93(10):e47.

31 – Cohen PR, Kurzrock R. Sweet’s syndrome revisited: a review of disease concepts. Int J Dermatol 2003;42:761–78.

32 – Dispenzieri A. POEMS syndrome. Blood Rev. 2007 Nov;21(6):285-99. doi: 10.1016/j.blre.2007.07.004. Epub 2007 Sep 11.

MALIGNANT DISEASES WITH MUSCULOSKELETAL MANIFESTATIONS

Authors: Carolina Mazeda and Inês Cunha

Introduction

In malignant and rheumatological diseases, there is often an overlap of signs and symptoms that requires that neoplasms be considered as a differential diagnosis. Rheumatological manifestations associated with neoplasia include: bone and joint invasion by tumor cells, synovial reaction to the presence of neoplastic cells in juxta-articular tissues, secondary gout and paraneoplastic syndromes.(1,2,3) Direct involvement of musculoskeletal structures by primary or metastatic disease leads to local interference with the function of these structures, including connective tissues, muscles, bones, and synovium.(2) When rheumatic symptoms are the first manifestation of the disease, diagnosis may be difficult because, at the time of the initial presentation, signs of malignancy may be absent.(4,5) Thus, it is necessary to have a high index of suspicion, in which an explosive onset of musculoskeletal symptoms that do not respond to therapy such as glucocorticoids or disease-modifying anti-rheumatic medication should lead to further investigation, as well as the presence of arthralgias disproportionate to the findings of the physical examination.(1)

Lymphoproliferative and myelodysplastic disorders are the main neoplastic diseases related to joint and systemic rheumatologic manifestations.

- 1. Leukaemias

Symptoms:

Musculoskeletal manifestations are common, often presenting with arthralgias and arthritis;
In acute leukemia, it usually presents early in the course of disease,(6,7) with a prevalence of 12-65% in children (especially in acute lymphocytic leukemia), and 6-12%in adults; ( 1)
In chronic leukemias musculoskeletal manifestations occur later and with a more symmetrical pattern;

Evidence

Level Grade PMID Nº

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These manifestations can be associated to both lymphoblastic and myeloid types of leukaemia; (5)

•The pattern of joint involvement can be either distal and symmetric or asymmetric with a predilection for larger joints. Effusions are generally small, and joint pain is characteristically severe usually disproportionate to findings on physical examination, with significant nocturnal pain, and unresponsive to conventional antirheumatic medications;

These patients are also at increased risk of septic arthritis, which can occur during the course of the disease associated with iatrogenic neutropenia as a consequence of severe immunosuppression.(5)

Pathogenesis:

These alterations result from infiltration of leukaemic cells into synovial tissue, intra- or periarticular hemorrhages, synovial reaction to periosteal or capsular infiltration, and immune-complex-induced synovitis.(5)

Diagnosis:

A simple radiography of the envolved area is the first step to diagnosis. Bone radiographic abnormalities include diffuse osteopenia (16-41%), radiolucent metaphyseal bands, periosteal reaction, osteolytic lesions mainly in the metaphysis of long bones, osteosclerosis, permeative bone destruction, pathological fractures, and avascular osteonecrosis. None of these radiological alterations is pathognomonic of this pathology;( 5- 6)
Synovial biopsy is the gold standard for diagnosis however because infiltration is often focal, it can be missed; (1,5,7)

Therapeutic strategy:

Usually, leukemia treatment leads to a rapid and significant improvement in musculoskeletal complaints.( 5,7,8) In some cases, adjunctive radiotherapy to the affected joints may be necessary.(9)

Level Grade PMID Nº

- Treatment of the underlying leukaemia may relieve bone and joint symptoms. 4 C
- Adjunctive radiation therapy to affected joints may be necessary to control symptoms. 4 C
  1. Lymphomas

Symptoms:

Osteoarticular involvement in lymphomas is the most common musculoskeletal feature and is usually associated with disseminated disease and, unlike leukaemia, arthritis involvement is rarely seen;(1,10)
These manifestations has been described in 20-30% of children and 10-20% of adults with non-Hodgkin lymphoma (NHL) and in up to 25% of Hodgkin’s disease in all age groups; (5)
Monoarticular and polyarticular involvement can occur.
Other rheumatologic manifestations can occur, such as septic arthritis, in the neutropenic phases, secondary gout or hypertrophic pulmonary osteoarthropathy in cases of disease localization in the mediastinum.(11,12)

Pathogenesis:

The mechanism of arthritis in lymphomas is not fully understood. Some of the suggested mechanisms were direct synovial involvement by lymphoma cells as a result of direct extension from bone, cytokine-driven synovial inflammation and host response to tumor antigens.(5,11 )

Diagnosis:

Rheumatoid factor (RF) and anti-CCP antibody can be present , leading to misdiagnosis; (12)
Plain radiographs show lytic and sclerotic lesions and soft tissue masses and magnetic resonance imaging (MRI) shows synovial thickening, adjacent marrow edema and bony erosions. Synovial proliferation can be distinguished from a joint effusion after administration of intravenous contrast. MRI may demonstrate bony erosions, and the extent of marrow and soft tissue involvement.(13, 14)
Synovial fluid analysis may show the presence of atypical lymphocytes in a sterile inflammatory fluid; (1,5,12)
A synovial biopsy is usually necessary for definitive diagnosis of intra-articular tumors.

Therapeutic strategy:

The successful treatment of the lymphoma will lead to a complete resolution of the arthritis.(15)
- The only efective treatment is that of the malignant disease 5 C

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- 1. Multiple Myeloma

Symptoms:

Rheumatological manifestations are well documented in multiple myeloma (MM). Bone disease is the most frequent feature of MM, being present in approximately two-thirds of patients at diagnosis and nearly all patients during the course of their disease; (15)
Osteoporosis or osteopenia, osteolytic lesions and pathological fractures are the most frequent manifestations;
Patients often present with bone pain, particularly low back pain which is present in up to 58% of patients;
Other reported manifestations are septic arthritis and symmetrical or asymmetrical polyarthritis, mainly involving the knee, hand and foot joints;
Articular manifestations in the MM are often related to amyloidosis, metabolic complications, and sometimes immunoglobulin deposit; (17)
Hyperuricemia and secondary gout may also occur.

Pathogenesis:

The bone destruction in MM results from an increase in osteoclast formation and activity, linked to suppressed or absent osteoblast differentiation and activity.

Diagnosis:

The first-line test used is plain radiography. It can detect lytic lesions which are typically bone holes in the flat bones of the skull and pelvis and diffuse osteopenia;(18)
The most frequent sites of skeletal involvement detected are the vertebrae (65%), ribs (45%), skull (40%), shoulders (40%), pelvis (30%) and long bones (25%); (17)
In inflammatory arthritis, synovial fluid analysis shows polymorphonuclear leukocytes, without crystals, and sometimes with amyloid infiltration.

Therapeutic strategy:

Osteoclastic inhibitors are essential in the treatment of skeletal changes associated with MM and their main objective is to prevent the development of new lesions. This
therapy should be administered concomitantly with the therapy directed at the MM;
Its initiation is recommended when patients have lytic disease on plain radiographs or other imaging studies. Bisphosphonates should also be started in patients with multiple myeloma with osteopenia or osteoporosis, but no radiographic evidence of lytic bone disease;(19,20)

Patients with creatinine clearance > 60 mL/min	Pamidronate intravenous	90 mg intravenously over at least 2 hours every 4 weeks
	Zoledronic Acid	4 mg intravenously over at least 15 min every 4 weeks
	Denosumab	120 mg subcutaneously every 4 weeks
Patients with creatinine clearance ≤ 60 mL/min	Denosumab	120 mg subcutaneously every 4 weeks

The efficacy of zoledronic acid and denosumab are similar, and the choice is mainly based on the clinical characteristics of the patient such as renal function, cost and time administration;
It is recommended that bone-targeted treatment continue for up to 2 years and less-frequent dosing has been evaluated and should be considered in patients with responsive or stable disease;(19,20)
Data from several studies demonstrate a steep increase in bone turnover markers and a rapid decrease in bone mineral density after discontinuation of denosumab e therefore bisphosphonate therapy should be considered to reduce or prevent the rebound and potential excess risk for vertebral fractures; (20)
Pathologic fractures or impending fractures of long bones may require stabilization and when spinal cord compression occur due to vertebral body collapse or pathological fractures, radiotherapy may be the treatment of choice.(5,19,21)

Level Grade PMID Nº

- 1. Myelodysplastic syndromes

	Level Grade	PMID Nº
– Zoledronate, pamidronate or denosumab should be initiated at diagnosis of MM.	I A	32801018
– Denosumab is the agent of choice in MM patients with renal impairment.	I B	32801018
– Therapy with a bisphosphonate can be interrupted after 2 years in patients in remission.	2 B	32801018
– Denosumab should be administered every 4 weeks. Extending intervals beyond this frequency cannot currently be recommended.	3 D	32801018
– Bisphosphonate treatment to suppress rebound osteolysis is recommended if denosumab is discontinued for more than 6 months.	3 B	32801018
– Low-dose radiotherapy (up to 30 Gy) can be used as palliative treatment for uncontrolled pain, for impending pathological fracture or impending spinal cord compression.	2 A	33549387

Symptoms:

Several rheumatologic manifestations have been reported in myelodplastic syndromes and approximately 10% of these manifestations develop during the course of the disease. They often present with arthralgias and non-erosive acute symmetrical polyarthritis. More rarely, monoarthritis are described.(1,5)

In table 1 we will make a description of the main neoplastic diseases with rheumatologic manifestations.

References:

Condition	Pathogenesis	Rheumatological manifestations
Leukaemias	Infiltration of synovium (more frequently)	Arthritis and arthralgia Intra-articular haemorrhage Septic arthritis Secondary gout (rare)
Lymphomas	Metastases or invasion of bone, rarely joint	Intra-articular lymphoma Poly or monoarticular arthritis (rare) Septic arthritis Secondary gout Hypertrophic pulmonary osteoarthropathy
Multiple Myeloma	Metastasis or invasion of bone, hyperuricemia	Bone pain Osteoporosis/osteopenia Osteolytic bone lesions Pathological fractures Septic arthritis Symmetrical or asymmetrical polyarthritis Gout
Myelodysplastic syndromes		Arthralgias and non- erosive acute symmetrical polyarthritis Monoarthritis (rare)

- - 1. Ravindran V, Anoop P. Rheumatologic manifestations of benign and malignant haematological disorders. Clin Rheumatol. 2011 Sep;30(9):1143-9. doi: 10.1007/s10067-011-1799-x. Epub 2011 Jun 23. PMID: 21698399.
    2. Jesus G, Barcelos A, Neves C, Crespo J. Manifestações reumáticas e neoplasias. Acta Reumatol Port. 2006 Oct- Dec;31(4):305-21. Portuguese. PMID: 17334043.
    3. Hashefi M. The Relationship Between Rheumatologic Disorders and Malignancies. Rheum Dis Clin North Am. 2018 Aug;44(3):405-418. doi: 10.1016/j.rdc.2018.03.003. Epub 2018 Jun 13. PMID: 30001783.
    4. Fam AG, Voorneveld C, Robinson JB, Sheridan BL. Synovial fluid immunocytology in the diagnosis of leukemic synovitis. J Rheumatol. 1991 Feb;18(2):293-6. PMID: 1827162.
    5. Hochberg MC, Gravallese EM, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH. Rheumatology. Seventh edition. Elsevier. 2019
    6. Sinigaglia R, Gigante C, Bisinella G, Varotto S, Zanesco L, Turra S. Musculoskeletal manifestations in pediatric acute leukemia. J Pediatr Orthop. 2008 Jan-Feb;28(1):20-8. doi: 10.1097/BPO.0b13e31815ff350. PMID: 18157042.
    7. Usalan C, Ozarslan E, Zengin N, Büyükaýk Y, Güllü YH. Acute lymphoblastic leukaemia presenting with arthritis in an adult patient. Postgrad Med J. 1999 Jul;75(885):425-7. doi: 10.1136/pgmj.75.885.425. PMID: 10474730.
    8. \-+-Leukemic synovitis as a presentation of myelomonocytic blast crisis of chronic myeloid leukemia. Saudi Med J. 2001 Sep;22(9):808-11. PMID: 11590459.
    9. Acree SC, Pullarkat ST, Quismorio FP Jr, Mian SR, Brynes RK. Adult leukemic synovitis is associated with leukemia of monocytic differentiation. J Clin Rheumatol. 2011 Apr;17(3):130-4. doi: 10.1097/RHU.0b013e318214befe. PMID: 21441820.
    10. Mody GM, Cassim B. Rheumatologic features of hematologic disorders. Curr Opin Rheumatol. 1996 Jan;8(1):57-61. doi: 10.1097/00002281-199601000-00011. PMID: 8867541.
    11. Birlik M, Akar S, Onen F, Ozcan MA, Bacakoglu A, Ozkal S et al. Articular, B-cell, non-Hodgkin’s lymphoma mimicking rheumatoid arthritis: synovial involvement in a small hand joint. Rheumatol Int. 2004 May;24(3):169-72. doi: 10.1007/s00296-003-0373-5. Epub 2003 Dec 5. PMID: 14658004.
    12. Firestein GS, Gabriel SE, McInnes IB, O’Dell JR. Kelley and Firestein’s textbook of rheumatology. Tenth edition. Elsevier. 2017.
    13. Visser J, Busch VJ, de Kievit-van der Heijden IM, ten Ham AM. Non-Hodgkin’s lymphoma of the synovium discovered in total knee arthroplasty: a case report. BMC Res Notes. 2012 Aug 20;5:449. doi: 10.1186/1756-0500-5-449. PMID: 22905907.
    14. Donovan A, Schweitzer ME, Garcia RA, Nomikos G. Chronic lymphocytic leukemia/small lymphocytic lymphoma presenting as septic arthritis of the shoulder. Skeletal Radiol. 2008 Nov;37(11):1035-9. doi: 10.1007/s00256-008-0512-x. Epub 2008 Jun 3. PMID: 18521594.
    15. Jean-Baptiste G, De Ceulaer K. Osteoarticular disorders of haematological origin. Baillieres Best Pract Res Clin Rheumatol. 2000 Jun;14(2):307-23. doi: 10.1053/berh.2000.0067. PMID: 10925747.
    16. Zamagni E, Cavo M. The role of imaging techniques in the management of multiple myeloma. Br J Haematol. 2012 Dec;159(5):499-513. doi: 10.1111/bjh.12007. Epub 2012 Aug 11. PMID: 22881361. 17)Ardalan MR, Shoja MM. Multiple myeloma presented as acute interstitial nephritis and rheumatoid arthritis-like polyarthritis. Am J Hematol. 2007 Apr;82(4):309-13. doi: 10.1002/ajh.20796. PMID: 17022047.

Dimopoulos M, Terpos E, Comenzo RL, Tosi P, Beksac M, Sezer O et al. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple Myeloma. Leukemia. 2009 Sep;23(9):1545-56. doi: 10.1038/leu.2009.89. Epub 2009 May 7. PMID: 19421229.
Kenneth Anderson, Nofisat Ismaila, Patrick J. Flynn, Susan Halabi, Sundar Jagannath, Mohammed S. Ogaily et al. Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2018 36:8, 812-818.
Coleman R, Hadji P, Body JJ, Santini D, Chow E, Terpos E et al. ESMO Guidelines Committee. Bone health in cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2020 Dec;31(12):1650-1663. doi: 10.1016/j.annonc.2020.07.019. Epub 2020 Aug 12. PMID: 32801018.
Dimopoulos MA, Moreau P, Terpos E, Mateos MV, Zweegman S, Cook G et al. EHA Guidelines Committee. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow- up. Ann Oncol. 2021 Mar;32(3):309-322.

AUTOANTIBODIES ASSOCIATED TO RHEUMATIC DISEASE IN CANCER PATIENTS

Authors: Carolina Mazeda and Inês Cunha

Introduction

Autoantibodies found in a cancer patient may be classified into two categories:

specific antibodies to antigens that are not directly associated with the tumour;
antibodies against specific tumour antigens (tumour-associated antigens) as oncoproteins, tumour suppression genes, onconeural antigens.(1)

The development of autoantibodies is the consequence of breakdown of immunologic tolerance and as we’ve seen it’s not exclusive to systemic rheumatologic diseases and may be present in other pathologies, namely neoplastic diseases.(2,3)

Antinuclear antibody (ANA) testing is useful for screening and diagnosis systemic rheumatic diseases, but positive ANA results, not associated with an autoimmune disease, can be a confounding factor in the differential diagnosis of patients with cancer.(2 )

In neoplasms, the appearance of autoantibodies has classically been considered to be epiphenomena probably related to the release of tumor neoantigens proteins, although the interpretation of positive serologic findings in this setting remains controversial.”(2,3) Some studies suggested that the presence of these antibodies may be related to cancer prognosis and early detection of some tumors.(1,3,4)

The relationship between ANA levels and the therapeutic response to the immune-check point inhibitors, namely non-small cell lung cancer with anti-programmed cell death protein 1 treatment, has also been investigated.(5)

ANAs detection is made by immunofluorescent imaging technique using tissue cells such HEp2, derived from patient with cervix carcinoma, as a substract and it is a method with high sensivity. Results are reported by the title of the antibodies and by the staining pattern produced by these antibodies.(2,6 )

Finding a positive ANA without clinical signs of autoimmune disorder may draw attention to the possibility of neoplastic disease. Studies reported that, in almost30% of patients with positive ANAs and no established rheumatic diseases , a neoplasia was found.(1,7)

Evidence

Level Grade PMID Nº

Rheumatoid factor (RF) an autoantibody directed against the fragment crystallizable region of immunoglobulin G8 often linked with systemic rheumatologic diseases, such Level Grade PMID Nº

as rheumatoid arthritis, can be found in other contexts such as neoplasms. IgA RF was associated with cancer, whereas IgM RF was linked to a cancer favorable prognosis.(8,9) In fact, rheumatoid factor can be found in high titers in other diseases but also in healthy people (1-5%). RF can be detected in the blood of 10-20% cancer patients, reaching 26% in non-small lung cancer patients. Such a prevalence increases with age. This association was investigated for the first time in a small study performed as part of a long-term health survey in the Reykjavik area, beginning in 1967.(9) An analysis carried out in 2016 with 295,837 South Koreans without rheumatoid arthritis showed that RF significantly increased the risk of all-cause mortality and cancer.(9) Other studies were carried out at the time evaluating the risk of neoplasia, recurrence, and response to immunotherapy treatments, but the clinical significance and health outcomes of RF in cancer patients are incompletely known.(10)

References:

Nisihara R, Machoski MCC, Neppel A, Maestri CA, Messias-Reason I, Skare TL. Anti-nuclear antibodies in patients with breast cancer. Clin Exp Immunol. 2018 Aug;193(2):178-182. doi: 10.1111/cei.13136. Epub 2018 Jun 14. PMID: 29645079.
Vlagea A, Falagan S, Gutiérrez-Gutiérrez G, Moreno-Rubio J, Merino M, Zambrana F et al. Antinuclear antibodies and cancer: A literature review. Crit Rev Oncol Hematol. 2018 Jul;127:42-49. doi: 10.1016/j.critrevonc.2018.05.002. Epub 2018 May 26. PMID: 29891110.
Fernández-Suárez A, Muñoz-Colmenero A, Ocaña-Pérez E, Fatela-Cantillo D, Domínguez-Jiménez JL, Díaz-Iglesias JM. Low positive rate of serum autoantibodies in colorectal cancer patients without systemic rheumatic diseases. Autoimmunity. 2016 Sep;49(6):383-387. doi: 10.1080/08916934.2016.1203905. Epub 2016 Jul 16. PMID: 27424781.
Fernández Madrid F, Maroun MC, Olivero AO, Long M, Stark A Grossman LI et al. Autoantibodies in breast cancer sera are not epiphenomena and may participate in carcinogenesis. BMC Cancer. 2015; 15:407. doi: 10.1186/s12885-015-1385-8
Wang R, Zhao H, Liu Y, Kang B, Cai J. Antinuclear Antibodies With a Nucleolar Pattern Are Associated With a Significant Reduction in the Overall Survival of Patients With Leukemia: A Retrospective Cohort Study. Front Oncol. 2021 Feb 26;11:631038. doi: 10.3389/fonc.2021.631038. PMID: 33718211.
Morimoto K, Yamada T, Nakamura R, Katayama Y, Tanaka S, Takumi C et al. Impact of preexisting antinuclear antibodies on combined immunotherapy and chemotherapy in advanced non-small cell lung cancer patients. Med Oncol. 2020 Nov 11;37(12):111. doi: 10.1007/s12032-020-01440-3. PMID: 33175248.
Wu J, Li X, Song W, Fang Y, Yu L, Liu S, et al. The roles and applications of autoantibodies in progression, diagnosis, treatment and prognosis of human malignant tumours. Autoimmun Rev (2017) 16:1270–81. doi: 10.1016/ j.autrev.2017.10.012
Shiel WC, Jason M. The diagnostic associations of patients with antinuclear antibodies referred to a community rheumatologist. J Rheumatol 1989; 16:782–5 9)Ugolini A, Nuti M. Rheumatoid Factor: ANovel Determiner in Cancer History. Cancers (Basel). 2021 Feb 3;13(4):591. doi: 10.3390/cancers13040591. PMID: 33546243.

10)Ahn JK, Hwang J, Chang Y, Ryu S. Rheumatoid factor positivity increases all-cause and cancer mortality: a cohort study. Rheumatol Int. 2017 Jul;37(7):1135-1143. doi: 10.1007/s00296-017-3738-x. Epub 2017 May 17. PMID: 28516237.

IMMUNE CHECKPOINT INHIBITOR ASSOCIATED RHEUMATIC CONDITIONS

Authors: Paulo Vilas-Boas and Inês Cunha

Introduction

Immune checkpoint inhibitors (ICI) enhance the self-immune response against tumor cells; however, these drugs can lead to several adverse effects, mostly inflammatory conditions due to the implied immune system activation. Side effects can affect basically every organ and system, being called immune related adverse events (ir-AEs). Clinical features range widely from begin transient symptoms to presentations mirroring classic rheumatic diseases. The widespread of ICIs over the last few years has provided important data on their side effect proﬁle. Therefore, the rheumatic adverse events from ICI therapy require a multidisciplinary approach with both the oncologist and rheumatologist collaboration to decide the best course of action for the patient. The decision to hold or to continue the cancer immunotherapy is complex, being based on the severity of rheumatic immune- related adverse events, the extent of required immunosuppression and the tumor response, in a shared decision with the patient(1).

Patients with preexisting rheumatic diseases are likely to suffer from a flare due to ICIs treatment (~33%). Fewer adverse effects are seen in patients being treated with immunosuppressive therapy at the time ICIs were started(2). Patients with established rheumatic diseases should continue to be monitored closely by their rheumatologist and oncologist, when starting therapy with an ICI.

Evidence

Level Grade PMID Nº

- 1. Inflammatory arthralgia and arthritis

Epidemiology:

Inflammatory arthralgia (1-43%) and arthritis (5-7%) are the most common reported rheumatic ir-AEs(3).
Joint manifestations can occur almost any time during ICI therapy, from the first treatment administration to over 2 years after immunotherapy, even after ICIs cessation(3).
Regarding specific ICIs some studies suggest that patients treated with PD-L1 monotherapy are more likely to have small joint involvement, while CTLA-4 and PD-1 inhibition are associated with asymmetrical large joint involvement(4).

Clinical Manifestations:

Mild arthralgias are relatively common, being of no clinical significance and showing a good response to analgesics.
A subset of patients presents with more pronounced pain and joint swelling, suggestive of arthritis. Presentation can range from small-joint polyarthritis similar to rheumatoid arthritis (RA) or large joint oligoarthritis with or without back pain .

Diagnosis:

Diagnosis is made clinically based on new-onset arthritis after ICI initiation, without preceding symptoms.
Inflammatory markers elevation has low practical utility due to the base malignant disorder. Rheumatoid factor and cyclic citrullinated peptide are usually negative(5).
Imaging study with plain radiography and ultrasound can help in the diagnosis.
Other conditions that may mimic ICI´s inflammatory arthritis must be considered and excluded such as paraneoplasic syndromes, myoartralgias due to fibromyalgia and bone metastasis (usually presenting with marked erosive radiographic changes).

Therapeutic Strategy:

Mild pain with associated arthritis and lack of severe functional compromise should be treated with NSAIDs or acetaminophen. NSAIDs should be used with the lowest dose necessary and for a short duration and no evidence indicates a preference to any specific NSAID.
Moderate pain limiting daily activities associated with joint swelling refractory to symptomatic treatment should be treated with systemic corticotherapy. Since glucocorticoids may impair the activation of tumor-infiltrating neutrophile it is preferable to initiate therapy with glucocorticoid equivalent of 10-20mg prednisolone and if improvement, slowly taper aiming to reach <10mg/day within 3 months
Severe pain with irreversible joint damage or symptoms not responding to <10mg/day prednisolone or equivalent after 3 months. Temporary ICI therapy discontinuation should be considered and oncologists should be encouraged to consult rheumatologists in order to evaluate the need for conventional or biologic disease-modifying antirheumatic drugs(6,7)

Level Grade PMID Nº

- NSDAIs 4 C
- Glucocorticoids 4 C
- Hydroxychloroquine 5 C
- Methotrexate 5 C
- Tumor necrosis factor (TNF)-alpha inhibitors 5 C
  1. Polymyalgia Rheumatica-Like Syndrome

Epidemiology

Polymyalgia Rheumatica-Like Syndrome has a 2-3% prevalence in patients receiving ICIs.
The majority of cases of this syndrome tend to occur within the first months of therapy and, such as the idiopathic form of the disease, in adults older than 50 years(9,10)

Clinical Manifestations

Polymyalgia rheumatica-Like Syndrome presents with acute/subacute bilateral proximal muscle pain affecting the shoulders, hip girdle, and neck, associated with morning stiffness and fatigue.
Common complains include difficulties in pulling on a shirt or coat, or transferring from the supine or seated position to standing.
It is of paramount importance to question the patient for signs of temporal arteritis, such as headache and vision loss.

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Diagnosis

Diagnosis is made clinically based on patient history and physical examination supported by inflammatory markers elevation.
Serum creatine phosphokinase and other muscle enzymes are normal.
If there is diagnostic uncertainty, magnetic resonance imaging (MRI) or ultrasound (US) of the involved joints may be helpful.

Therapeutic Strategy

Initial treatment with low-dose glucocorticoids is recommended starting with 15-20mg prednisolone or equivalent.
Typically, clinical remission is achieved in 1-2 weeks. Once achieved, glucocorticoid therapy should be slowly tapered.
There is no consensus regarding an optimal tapering regimen. Small decrements should be made (between 1-2.5 mg/day prednisolone decrement every four weeks) to avoid relapsing, with careful monitoring.
Most patients run a self-limited course. In the idiopathic form about one half of patients, treatment can be stopped after 1-2 years(14).
If the patients suffers a relapse, glucocorticoid dosage should be resumed at the original dose that managed symptoms. Lack of symptom control after treatment initiation or frequent relapses should prompt a rheumatology refer.

Level Grade PMID Nº

- NSAIDs 4 C
- Glucocorticoids 4 D
- Tumor necrosis factor (TNF)-alpha inhibitorsIL-6 4 C
- Antagonist (Tocilizumab) 4 C
  1. Inflammatory myopathies

Epidemiology

Inflammatory myopathies, such as dermatomyosistis and polymyositis have been described as a ir-AEs(11).
It generally occurs early after ICI initiation, within two months of ICIs therapy(13) .
Only few cases of ICI-induced myositis have been reported, indicating a low prevalence of this condition (1%)(14).

Clinical Manifestations

Inflammatory myopathies present with rapidly developing severe weakness of the proximal muscles groups. Axial and oculobulbar weakness, dysphagia, diaphragmatic weakness and rash are some of the other symptoms.
Presence of life- threatening manifestations, including dyspnoea, palpitations, chest pain or syncope should alert on a possible concurrent myocarditis.
Myalgia is not a prominent feature.
ICI-induced myositis has atypical features compared to idiopathic forms of the disease and carries a high mortality risk, suggesting that this is the most serious musculoskeletal ir- AE.

Diagnosis

Diagnosis is based upon a complete rheumatologic and neurologic physical examination, including muscle strength and skin examination.
Inflammatory markers and serum muscle enzyme (CK, myoglobin, AST, ALT, LDH and aldolase) are usually markedly elevated.
Myositis- associated autoantibodies are mostly negative.
Troponin evaluates myocardial involvement.
Electromyography and/or muscle magnetic resonance imaging can aid if the diagnosis is uncertain. The role of muscle biopsy is unclear in ICI induced inflammatory myopathy.
Astrong response to ICI cessation with or without corticosteroid therapy favors the diagnosis.

Treatment

Immunotherapy suspension should be always strongly considered, especially if life threatening respiratory or bulbar muscle involvement.
Glucocorticoids are the mainstay of treatment, usually starting with 1-2 mg/kg/day prednisolone or equivalent. Milder myopathy clinical phenotypes with low serum muscle

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More aggressive treatment including plasma exchange, intravenous immunoglobulin (IVIG) and immunosuppressants are used if symptoms and CK levels do not improve after 4-6 Level Grade PMID Nº

weeks.

It is not clear whether ICI treatment can be re-administered after clinical remission(15). Always refer to a rheumatologist 4 B
- Glucocorticoids 4 C
- Intravenous Immunoglobulin 4 C
- Tumor necrosis factor (TNF)-alpha inhibitors 4 C
- Rituximab

4 .Sicca/Sjogren´s Syndrome

Epidemiology

Immune checkpoints inhibitors therapy can lead to the development of sicca symptoms, especially anti-PD(L)1 therapy(18).
Clinical trials showed an incidence rate ranging from 1.2% to 24.2%(17).
Onset can be abrupt, with a 3,8 months median time from treatment initiation(17).
In comparison to primary Sjogren´s Syndrome (SS), patients with sicca symptoms induced by ICIs are more likely to be male(16).

Clinical Manifestations

SS is a rheumatic disease clinically characterized by xerophthalmia and xerostomia. In ir-AE SS dry mouth is the most common symptom and ocular and oral dryness seldom coexist.
Parotid swelling has rarely been observed.
Other ocular manifestations including uveitis, peripheral ulcerative keratitis, and other forms of ocular inflammation have also been reported in patients with ICI-induced sicca.(19)

Diagnosis

Diagnosis is clinical based on sicca symptoms complains after ICI initiation and exclusion of other causes such as diabetes or use of certain sicca-induced drugs (e.g.: antidepressants).
The majority of patients have negative antinuclear antibodies, extractable nuclear antigens and rheumatoid factor.
Alow incidence of abnormal ocular tests is seen in patients with ICI-induced sicca and less than half of salivary gland biopsies are typical for SS(20).

Treatment

In patients with dry mouth symptoms, dental care, saliva substitutes and sialagogues are used to relieve symptoms and remain the basis of treatment.
If severe xerostomia that causes feeding problems, ICI therapy should be temporally discontinued and resumed after approximately three months if sicca symptoms improve(21). Prednisone 20 to 40 mg for 2-4 weeks, followed by a taper is used in severe cases(21).
In patients with dry eyes, artificial tears and xerophthalmia induced drugs avoidance are the mainstay of the treatment. If severe or refractory symptoms, referral to an ophthalmology is indicated

5. Sarcoid Reactions

Epidemiology

Several cases of ICI-induced sarcoidosis or sarcoid-like reactions have been described mostly following treatment with anti-CTLA4 or anti-PD1(22).
New-onset sarcoidosis has been mainly reported in association with melanoma ICI treatment, with a prevalence of 0.2%(23).
Onset of sarcoid-like reactions varies, occurs between three weeks and two years following ICI initiation(24) Clinical Manifestations
ICI-induced sarcoidosis can manifest as cutaneous sarcoidosis such as nodules and rash or can be systemic with pulmonary, lymphatic, neurological, ocular and articular involvement.

• Lungs and skin are the most frequently affected organs(25). However, patients developing ICI-induced sarcoid-like reactions are usually asymptomatic.

19650371

31393660

29567210

32357515

Diagnosis

Biopsy of the affected organ is mandatory for diagnosis.
Pulmonary involvement may present with mediastinal or hilar lymphadenopathy in CT and so sarcoid-like reactions may be misdiagnosed with disease progression. Lymph node biopsies should be performed in these cases to exclude cancer recurrence or progression.

Therapeutic Strategy

Since patients are usually asymptomatic, most cases do not mandate permanent ICI discontinuation or systemic treatment(26).
ICI discontinuation and treatment became necessary for resolution of granulomatous reactions in selected cases.
For cutaneous sarcoidosis, topical steroids are effective(27).

6 . Vasculitis

Epidemiology

There have been reports of vasculitic ir-AE affecting large, medium and small vessels.(27)
Cases appear to be relatively uncommon. Giant cell arteritis (GCA), isolated aortitis and vasculitis of the nervous system are the most common described.
Melanoma is the most frequent malignancy associated with ICI-induced vasculitis.

Clinical Manifestations

Clinical presentation depends on the affected vascular site.
CGApresents with episodes of transient vision loss (amaurosis fugax), severe headache, temporal scalp tenderness and jaw claudication.
Small and medium vessel vasculitis are multisystemic conditions that may present with constitutional symptoms, both peripheral and central neurologic deficits, cutaneous findings such as palpable purpura, hematuria and proteinuria, and symptoms due to gastrointestinal and pulmonary involvement.

Diagnosis

Inflammatory serum markers are increased, however this may also be due to malignancy and are only useful in this setting if baseline data is available. If inflammatory markers are normal, vasculitis is unlikely.
ANA, antineutrophil cytoplasmic antibodies and cryoglobulin are rarely positive.
In patients in whom GCAis suspected, temporal artery biopsy confirms the diagnosis.
Small and medium size vasculitis definitive diagnosis requires histologic analysis of the affected organ.

Therapeutic strategy

Vasculitis frequently are associated with target organ damage and so ICIs should be promptly discontinued followed by high dose steroid treatment.
Maintenance therapy is needed. Refer to a rheumatologist is strongly advisable.

References:

Level Grade PMID Nº

Cappelli LC, Gutierrez AK, Bingham CO Shah AA. Rheumatic and Musculoskeletal Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors: A Systematic Review of the Literature. Arthritis Care Res (Hoboken). 2017 Nov;69(11):1751-1763. doi: 10.1002/acr.23177. Epub 2017 Sep 21. PMID: 27998041; PMCID: PMC5478477.
Kostine M, Truchetet ME, Schaeverbeke T. Clinical characteristics of rheumatic syndromes associated with checkpoint inhibitors therapy. Rheumatology (Oxford). 2019 Dec 1;58(Suppl 7):vii68-vii74. doi: 10.1093/rheumatology/kez295. PMID: 31816082; PMCID: PMC6900916.
Kostine M et al FHU ACRONIM. Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study. Ann Rheum Dis. 2018 Mar;77(3):393-398. doi: 10.1136/annrheumdis-2017-212257. Epub 2017 Nov 16. PMID: 29146737.
Cappelli LC et al. Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen. Semin Arthritis Rheum. 2018 Dec;48(3):553-557. doi: 10.1016/j.semarthrit.2018.02.011. Epub 2018 Mar 22. PMID: 29573850; PMCID: PMC6150859..
Belkhir R et al. Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment. Ann Rheum Dis. 2017 Oct;76(10):1747-1750. doi: 10.1136/annrheumdis-2017- 211216. Epub 2017 Jun 9. PMID: 28600350.
Draghi A et al. Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses: implications for the management of irAEs. Int J Cancer. 2019 Sep 1;145(5):1408-1413. doi: 10.1002/ijc.32080. Epub 2019 Jan 7. PMID: 30575963.
Chang CY et al. Immune Checkpoint Inhibitors and Immune-Related Adverse Events in Patients With Advanced Melanoma: A Systematic Review and Network Meta-analysis. JAMA Netw Open. 2020 Mar 2;3(3):e201611. doi: 10.1001/jamanetworkopen.2020.1611. PMID: 32211869; PMCID: PMC7097702. J.
Haanen JBAG et al. ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017 Jul 1;28(suppl_4):iv119-iv142. doi: 10.1093/annonc/mdx225. Erratum in: Ann Oncol. 2018 Oct 1;29(Suppl 4):iv264-iv266. PMID: 28881921.
Kostine M et al. EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors, Ann Rheum Dis. 2021 Jan;80(1):36-48. doi: 10.1136/annrheumdis-2020-217139. Epub 2020 Apr 23. PMID: 32327425; PMCID: PMC7788064.
Calabrese C et al. Polymyalgia rheumatica-like syndrome from checkpoint inhibitor therapy: case series and systematic review of the literature. RMD Open. 2019 Apr 25;5(1):e000906. doi: 10.1136/rmdopen-2019-000906. PMID: 31168414; PMCID: PMC6525600.
Calabrese C et al. Rheumatic immune-related adverse events of checkpoint therapy for cancer: case series of a new nosological entity. RMD Open. 2017 Mar 20;3(1):e000412. doi: 10.1136/rmdopen- 2016-000412. Erratum in: RMD Open. 2017 Dec 6;3(2):e000412corr1. Kontzias, K [corrected to Kontzias, A]. PMID: 28405474; PMCID: PMC5372131.
Hunter G, Voll C, Robinson CA. Autoimmune inflammatory myopathy after treatment with ipilimumab. Can J Neurol Sci. 2009 Jul;36(4):518-20. doi: 10.1017/s0317167100007939. PMID: 19650371.
Tison A. et al, Groupe de Cancérologie Cutanée, Groupe Français de Pneumo-Cancérologie, and Club Rhumatismes et Inflammations. Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease: ANationwide, Multicenter Cohort Study. Arthritis Rheumatol. 2019 Dec;71(12):2100-2111. doi: 10.1002/art.41068. Epub 2019 Oct 21. PMID: 31379105
Docken WP. Polymyalgia rheumatica can recur years after discontinuation of corticosteroid therapy. Clin Exp Rheumatol. 2009 Jan-Feb;27(1 Suppl 52):S25-7. PMID: 19646342.
Delyon, J et al. PATIO Group. Immune checkpoint inhibitor rechallenge in patients with immune-related myositis. Ann Rheum Dis. 2019 Nov;78(11):e129. doi: 10.1136/annrheumdis-2018-214336. Epub 2018 Sep 21. PMID: 30242031.. Ann. Rheum Dis. 2019,
Ortiz Brugués et al. Sicca Syndrome Induced by Immune Checkpoint Inhibitor Therapy: Optimal Management Still Pending. Oncologist. 2020 Feb;25(2):e391-e395. doi: 10.1634/theoncologist.2019-0467. Epub 2019 Nov 6. PMID: 32043780; PMCID: PMC7011671.
Warner B.M et al. Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy. Oncologist. 2019 Sep;24(9):1259-1269. doi: 10.1634/theoncologist.2018-0823. Epub 2019 Apr 17. PMID: 30996010; PMCID: PMC6738284.
Abdel-Wahab N, Suarez-Almazor ME. Frequency and distribution of various rheumatic disorders associated with checkpoint inhibitor therapy. Rheumatology (Oxford). 2019 Dec 1;58(Suppl 7):vii40-vii48. doi: 10.1093/rheumatology/kez297. PMID: 31816084; PMCID: PMC6900912.
Antoun J, Titah C, Cochereau I. Ocular and orbital side-effects of checkpoint inhibitors: a review article. Curr Opin Oncol. 2016 Jul;28(4):288-94. doi: 10.1097/CCO.0000000000000296. PMID: 27136135. 20-Ortiz Brugués, A et al. Sicca Syndrome Induced by Immune Checkpoint Inhibitor Therapy: Optimal Management Still Pending. Oncologist. 2020 Feb;25(2):e391-e395. doi: 10.1634/theoncologist.2019- 0467. Epub 2019 Nov 6. PMID: 32043780; PMCID: PMC7011671.
Warner BM, Baer AN, Lipson EJ, et al. Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy. Oncologist 2019
Cornejo CM, Haun P, English J 3rd, Rosenbach M. Immune checkpoint inhibitors and the development of granulomatous reactions. J Am Acad Dermatol. 2019 Nov;81(5):1165-1175. doi: 10.1016/j.jaad.2018.07.051. Epub 2018 Aug 6. PMID: 30092327.
Le Burel S et al. Prevalence of immune-related systemic adverse events in patients treated with anti-Programmed cell Death 1/anti-Programmed cell Death-Ligand 1 agents: A single-centre pharmacovigilance database analysis. Eur J Cancer. 2017 Sep;82:34-44. doi: 10.1016/j.ejca.2017.05.032. Epub 2017 Jul 10. PMID: 28646772.
Chopra A, Nautiyal A, Kalkanis A, Judson MA. Drug-Induced Sarcoidosis-Like Reactions. Chest. 2018 Sep;154(3):664-677. doi: 10.1016/j.chest.2018.03.056. Epub 2018 Apr 24. PMID: 29698718.
Lomax, A.J. et al. Immunotherapy-induced sarcoidosis in patients with melanoma treated with PD-1 checkpoint inhibitors: Case series and immunophenotypic analysis. Int J Rheum Dis. 2017 Sep;20(9):1277-1285. doi: 10.1111/1756-185X.13076. Epub 2017 May 8. PMID: 28480561.Int. J. Rheum. Dis. 2017
Rambhia, P.H. et al. Rambhia PH, Reichert B, Scott JF, Feneran AN, Kazakov JA, Honda K, Koon H, Gerstenblith MR. Immune checkpoint inhibitor-induced sarcoidosis-like granulomas. Int J Clin Oncol. 2019 Oct;24(10):1171-1181. doi: 10.1007/s10147-019-01490-2. Epub 2019 Jul 18. PMID: 31321613.
Melissaropoulos K et al. Rheumatic Manifestations in Patients Treated with Immune Checkpoint Inhibitors. Int J Mol Sci. 2020 May 11;21(9):3389. doi: 10.3390/ijms21093389. PMID: 32403289; PMCID: PMC7247001.
Watanabe, R et al. Immune checkpoint dysfunction in large and medium vessel vasculitis. Am J Physiol Heart Circ Physiol. 2017 May 1;312(5):H1052-H1059. doi: 10.1152/ajpheart.00024.2017. Epub 2017 Mar 17. PMID: 28314758; PMCID: PMC5451585.

RADIOTHERAPY TREATMENT ASSOCIATED RHEUMATIC COMPLICATIONS

Authors: Paulo Vilas-Boas and Inês Cunha

Introduction

- 1. Radiotherapy in patients with connective tissue diseases
Patients with connective tissue diseases, such as systemic sclerosis, systemic lupus erythematosus or rheumatoid arthritis could suffer from an increased incidence of either acute or late radiotherapy related toxicity.
Observational studies suggest an increased risk of fibrosis, osteonecrosis and bone fractures(1). The actual magnitude of the risk is unknown.
A cautious approach for patients with active connective tissue diseases should be taken in account when formulating the treatment plan, however data from published studies is not clear enough to support an absolute contraindication for radiotherapy in these patients.
- 1. Radiation Fibrosis Syndrome – Rheumatic Complications
Radiation fibrosis syndrome is usually a late complication of radiation therapy, that may not manifest clinically for years, defined by a progressive fibrotic tissue sclerosis with various clinical symptoms depending on the type of tissue exposed.

Clinical Manifestations

Musculoskeletal involvement is mainly due to shortening and contractures of the tendons and ligaments, thus resulting in in loss of range of motion and muscle strength and the development of limb edema and pain.
Muscle atrophy and painful muscle spasms than can lead to head drop and torticollis in the context of head and neck cancer radiotherapy.
Other rheumatic complications include trismus, osteoradionecrosis, osteoporosis and osteopenia.

Diagnosis

Patients should be evaluated, before radiotherapy treatment, about past radiation treatment history, comorbidities such as tendonitis, neuropathies, and radiculopathies and presence of connective tissue disorders.
Magnetic resonance imaging is the best imaging method to evaluate musculoskeletal fibrosis(2).

Therapeutic Strategies

Management of this syndrome is a complex process comprising medication, education, rehabilitation, and physical and occupational therapy.
Early initiation of active and passive physical therapy measures is helpful in patients considered to be at high risk for radiation-induced fibrosis.
Muscular pain, contractures and spasms are managed symptomatically with nonsteroidal anti-inflammatory drugs, along with muscle relaxants such as benzodiazepines and baclofen(3). In refractory cases, intramuscular injection of local anesthetics to areas of muscle spasm and injection of botulinum toxin has a proven benefit in radiation-induced painful muscle spasms, including trismus(4).
Patients should adhere to a maintenance exercise program leading to benefits in muscle strength, range of motion, and overall QoL(5).
In patients with established symptomatic subcutaneous fibrosis, pentoxifylline has been used alone and in combination with tocopherol to reverse superficial radiation-induced fibrosis. The optimal dose and duration of therapy are unknown. Data suggest that a prolonged course of treatment may be necessary to induce maximal regression of radiation- induced fibrosis and to maintain benefit6,(7). Improved range of articular motion and muscle strength and decreased limb edema and pain is reported(8).
- Muscle Relaxant
- Botulinum toxin
- Pentoxifylline

Evidence

Level Grade PMID Nº

5 C 15477643

5 C 18359354

2 B 19540105

References:

Hölscher T, Bentzen SM, Baumann M. Influence of connective tissue diseases on the expression of radiation side effects: a systematic review. Radiother Oncol. 2006 Feb;78(2):123-30. doi: 10.1016/j.radonc.2005.12.013. Epub 2006 Jan 30. PMID: 16445999.
Hojan K, Milecki P. Opportunities for rehabilitation of patients with radiation fibrosis syndrome. Rep Pract Oncol Radiother. 2013 Aug 8;19(1):1-6. doi: 10.1016/j.rpor.2013.07.007. PMID: 24936313; PMCID: PMC4056465.
Lussier D, Huskey AG, Portenoy RK. Adjuvant analgesics in cancer pain management. Oncologist. 2004;9(5):571-91. doi: 10.1634/theoncologist.9-5-571. PMID: 15477643.
Hartl DM, Cohen M, Juliéron M, Marandas P, Janot F, Bourhis J. Botulinum toxin for radiation-induced facial pain and trismus. Otolaryngol Head Neck Surg. 2008 Apr;138(4):459-463. doi: 10.1016/j.otohns.2007.12.021. PMID: 18359354
Spence RR, Heesch KC, Brown WJ. Exercise and cancer rehabilitation: a systematic review. Cancer Treat Rev. 2010 Apr;36(2):185-94. doi: 10.1016/j.ctrv.2009.11.003. Epub 2009 Dec 4. PMID: 19962830. 6-Magnusson Met al. Pentoxifylline and vitamin E treatment for prevention of radiation-induced side-effects in women with breast cancer: a phase two, double-blind, placebo-controlled randomised clinical trial (Ptx-5). Eur J Cancer. 2009 Sep;45(14):2488-95. doi: 10.1016/j.ejca.2009.05.015. Epub 2009 Jun 17. PMID: 19540105.
Gothard L et al. Double-blind placebo-controlled randomised trial of vitamin E and pentoxifylline in patients with chronic arm lymphoedema and fibrosis after surgery and radiotherapy for breast cancer. Radiother Oncol. 2004 Nov;73(2):133-9. doi: 10.1016/j.radonc.2004.09.013. PMID: 15542159.
Okunieff P et al. Pentoxifylline in the treatment of radiation-induced fibrosis. J Clin Oncol. 2004 Jun 1;22(11):2207-13. doi: 10.1200/JCO.2004.09.101. PMID: 15169810.
CONSTITUTIONAL

CANCER RELATED AND IATROGENIC ASTHENIA

Authors: José Miguel Martins and Joana Graça

Definition

- - Subjective feeling of incapacity, deep tiredness and fatigue, both mental and physical, reported by the patient, related to the disease or the cancer treatment, which is not proportional to the recent activity and which interferes with the activities of daily living. (1,2,3)
  - Also referred as asthenia-fatigue syndrome or cancer-related fatigue. (1)
  - Asthenia is the symptom most frequently reported by cancer patients, present in up to 80-90% (4,5). It is most prevalent in advanced cancer stages. (2)
  - Cancer-related asthenia is usually classified into primary and secondary fatigue. In cancer patients, primary fatigue seems to be due to the tumour itself, either due to central changes (deregulation of the hypothalamus-pituitary-supra-renal axis or changes in serotoninergic metabolism) or peripheral changes (such as energy consumption). Secondary fatigue is associated with metabolic changes or comorbidities such as anaemia, cachexia, fever, infections, or sedative drugs used for symptomatic control. (3)

Symptoms and signs

- - Profound tiredness after small efforts, loss of muscle strength, unpleasant and anticipatory sensation of generalized weakness and fatigue. (1)
  - Decreased capacity for intellectual work, impaired concentration, loss of memory and emotional lability. (1)

Etiology

- - Asthenia has a multifactorial etiology. In cancer patients, it results from a complex pathophysiological process involving the tumour, host responses, and oncologic treatment (radio/chemotherapy or symptomatic drugs). (1,3,4,6)
  - There are several factors that contribute to asthenia such as uncontrolled symptoms, cachexia, anaemia, infection, muscle abnormalities/immobility, antitumour treatment, metabolic problems, electrolyte changes or organ failure, psychological distress, sleep-wake cycle disorders and pain/drug side effects. (1,2,8)

Assessment

- - Whenever possible, the patient should self-assess their symptoms, namely through the use of scales such as the ESAS (Edmonton Symptom Assessment Scale). If this is not possible, asthenia may be measured using scales such as Eastern Cooperative Oncology Group – Performance Status (ECOG‐PS) or Karnofsky Performance Status (KPS). (1,8)
  - Recent changes in medication, sleep pattern, weight variations, recent infections should be investigated, and potentially treatable causes such as pain, anaemia, malnutrition,

depression, anxiety, delirium, should be investigated. (7)

Therapeutic Strategy

Treatment goals should be individualised, considering the stage of the disease, the prognosis, and should be defined with the patient and his or her family. (8)

Pharmacological therapy

Pharmacotherapy should not be used routinely to reduce fatigue severity in cancer patients. (4) However, there are some drugs that may have benefit in the treatment of asthenia in cancer patients.

Evidence

Level Grade PMID Nº

A II b

Drug	Information	Start of action	Posology
Methylphenidate	Administration for short periods (inferior to 8 weeks) and under close monitoring is recommended. Discontinue if no benefit.	Fast (24 to 48 hours)	Initial dose: 5mg twice daily gradually increase to 40-60mg daily
Modafinil			Initial dose: 200mg/day (max 400mg/day) (Elderly patients or patients with hepatic insufficiency, start with 100mg/day)
Erythropoietin	May be indicated in patients with anaemia and haemoglobin < 12 g/dl . No indication in terminal stage, as it takes 12 weeks to have an effect.		Unable to recommend dosage
Darbepoetin	May be indicated in patients with anaemia and haemoglobin < 12 g/dl.

A II a

A IIb/III

20844926

29719440

22233850

29719440

18695134

29719440

18695134

Antidepressants, progestational steroids, appetite stimulants, testosterone and corticosteroids have been proposed but have proved no benefit in asthenia reduction. (3,4,8,9,10)

The treatment of certain situations such as cachexia, infection, hydro electrolytic alterations, depression, among others, must be considered on an individual basis. (8,10)

Non-pharmacological therapy

Non-pharmacological therapy is the first-line of treatment in asthenia in cancer patients. Exercise, psychosocial interventions (cognitive-behavioural therapy, relaxation therapy, support groups), and nutritional support appear to be beneficial. (8) Relaxation exercises are the most effective during cancer treatment. After that, relaxation exercises are no longer the best choice. (11)

Regarding Cognitive Behavioural Therapy, it is effective in fatigue reduction in early stages and is likely to prove its efficiency in the palliative setting. (12)

It is advisable to adapt daily activities, namely by listing and prioritising them, delegating the most demanding activities to others. Good communication between the patient and health professionals, adaptation of daily activities according to physical capacity, the use of walking aids or physiotherapy exercises can all contribute to improve the patient’s quality of life. (8,10)

Integrative therapies may provide an alternative in tackling fatigue in cancer patients. (13)

Physical activity:

Relaxation exercises, Yoga, resistance or aerobic training or Cognitive Behavioural Therapy (CBT) combined with physical activity show moderate-to-high effects in asthenia reduction.

Relaxation exercises such as massage proved to be the most effective during cancer treatment.

Patient preference should be taken in consideration in modality selection.

28501804

31567463

II a

Psychological intervention:

CBT is effective in asthenia reduction during cancer treatment.

CBT is effective in asthenia reduction and quality of life improvement in advanced cancer.

Psychostimulants:

Methylphenidate is effective in reducing asthenia but should not be used routinely due to increased risk of non-serious adverse events (sleep and appetite disturbances)

Modafinil may be an alternative but there is some controverse regarding is effectiveness inasthenia reduction.

Hematopoietic Growth Factors:

Erythropoietin – Limitedly effective in reducing asthenia but should not be used routinely due to venothrombotic events and worse survival potential.

Integrative Therapies:

During cancer treatment, CBT plus hypnosis and American Ginseng are likely to be effective inasthenia reduction.

After cancer treatment, Acupressure, Mindfulness-based CBT and Qigong/Tai Chi Easy are likely to be effective in asthenia reduction.

A II a

31912784

22233850

29719440

18695134

29719440

31567463

References:

PEIXOTO DA SILVA S, SANTOS JMO, COSTA E SILVA MP, GIL DA COSTA RM, MEDEIROS R. CANCER CACHEXIA AND ITS PATHOPHYSIOLOGY: LINKS WITH SARCOPENIA, ANOREXIA AND ASTHENIA. J CACHEXIA SARCOPENIA MUSCLE. 2020 JUN;11(3):619-635. DOI: 10.1002/JCSM.12528. EPUB 2020 MAR 6. PMID: 32142217; PMCID: PMC7296264. AVAILABLE AT HTTPS://PUBMED.NCBI.NLM.NIH.GOV/32142217/
PORTELATEJEDOR MA, SANZ RUBIALES A, MARTÍNEZ M, CENTENO CORTÉS C. ASTENIA EN CÁNCER AVANZADO Y USO DE PSICOESTIMULANTES [ASTHENIA IN ADVANCED CANCER AND THE USE OF PSYCHOSTIMULANTS]. AN SIST SANIT NAVAR. 2011 SEP-DEC;34(3):471-9. SPANISH. DOI: 10.4321/S1137-66272011000300013. PMID: 22233850 AVAILABLE AT HTTPS://PUBMED.NCBI.NLM.NIH.GOV/22233850/
JANKOWSKI C, BERGER A, ARANHA O, ETAL. CANCER-RELATED FATIGUE. NATIONAL COMPREHENSIVE CANCER NETWORK GUIDELINES VERSION 2.2022 – FEBRUARY 9, 2022 AVAILABLE AT HTTPS://WWW.NCCN.ORG/PROFESSIONALS/ PHYSICIAN_GLS/PDF/FATIGUE.PDF
TOMLINSON D, ROBINSON PD, OBEROI S, CATAUDELLA D, CULOS-REED N, DAVIS H, DUONG N, GIBSON F, GÖTTE M, HINDS P, NIJHOF SL, VAN DER TORRE P, CABRAL S, DUPUIS LL, SUNG

L. PHARMACOLOGIC INTERVENTIONS FOR FATIGUE IN CANCER AND TRANSPLANTATION: A META-ANALYSIS. CURR ONCOL. 2018 APR;25(2):E152-E167. DOI: 10.3747/CO.25.3883. EPUB 2018 APR 30. PMID: 29719440; PMCID: PMC5927795 AVAILABLEAT HTTPS://PUBMED.NCBI.NLM.NIH.GOV/29719440/

POORT H, PETERS MEWJ, VAN DER GRAAF WTA, NIEUWKERK PT, VAN DE WOUW AJ, NIJHUIS-VAN DER SANDEN MWG, BLEIJENBERG G, VERHAGEN CAHHVM, KNOOP H. COGNITIVE BEHAVIORAL THERAPY OR GRADED EXERCISE THERAPY COMPARED WITH USUAL CARE FOR SEVERE FATIGUE IN PATIENTS WITH ADVANCED CANCER DURING TREATMENT: A RANDOMIZED CONTROLLED TRIAL. ANN ONCOL. 2020 JAN; 31 ( 1 ) : 115 – 122 . DOI: 10 . 1016 / J . ANNONC. 2019 . 09 . 002 . PMID: 31912784 AVAILABLE AT HTTPS://PUBMED.NCBI.NLM.NIH.GOV/31912784/
HAYWOOD A, DUC J, GOOD P, KHAN S, RICKETT K, VAYNE-BOSSERT P, HARDY JR. SYSTEMIC CORTICOSTEROIDS FOR THE MANAGEMENT OF CANCER-RELATED BREATHLESSNESS (DYSPNOEA) IN ADULTS. COCHRANE DATABASE SYST REV. 2019 FEB 20;2(2):CD012704. DOI: 10.1002/14651858.CD012704.PUB2. PMID: 30784058; PMCID: PMC6381295 AVAILABLE HTTPS://PUBMED.NCBI.NLM.NIH.GOV/30784058/
YENNURAJALINGAM S & BRUERA E (2007). PALLIATIVE MANAGEMENT OF FATIGUE AT THE CLOSE OF LIFE “IT FEELS LIKE MY BODY IS JUST WORN OUT”. JAMA. 298(2), 295-304. DOI:10.1001/JAMA.298.2.217 AVAILABLEAT HTTP://JAMA.JAMANETWORK.COM/ARTICLE.ASPX?ARTICLEID=207858
BARBOSAA, REIS PINA P, TAVARES F, GALRIÇA NETO I, MANUAL DE CUIDADOS PALIATIVOS, 3ª EDIÇÃO, LISBOA: NÚCLEO DE CUIDADOS PALIATIVOS – CENTRO DE BIOÉTICA, FACULDADE DE MEDICINADAUNIVERSIDADE DE LISBOA, 2016. 211-217. ISBN 978-972-9349-37-9
MINTON O, RICHARDSON A, SHARPE M, HOTOPF M, STONE P. A SYSTEMATIC REVIEW AND META-ANALYSIS OF THE PHARMACOLOGICAL TREATMENT OF CANCER-RELATED FATIGUE. J NATL CANCER INST. 2008 AUG 20;100(16):1155-66. DOI: 10.1093/JNCI/DJN250. EPUB 2008 AUG 11. PMID: 18695134 AVAILABLEAT HTTPS://PUBMED.NCBI.NLM.NIH.GOV/18695134/
RADDBRUCH L, STRASSER F, ELSNER F, FERRAZ GONÇALVES J, LOGE J, KAASA S, STONE P&RESEARCH STEERING COMMITTEE OF THE EUROPEAN ASSOCIATION FOR PALLIATIVE CARE (EAPC) (2008). FATIGUE IN PALLIATIVE CARE PATIENTS – AN EAPC APPROACH. PALLIAT MED,22, 13-23. DOI: 10.1177/0269216307085183 AVAILABLE AT HTTP://PMJ.SAGEPUB.COM/CONTENT/22/1/13
HILFIKER R, MEICHTRY A, EICHER M, NILSSON BALFE L, KNOLS RH, VERRA ML, TAEYMANS J. EXERCISE AND OTHER NON-PHARMACEUTICAL INTERVENTIONS FOR CANCER-RELATED FATIGUE IN PATIENTS DURING OR AFTER CANCER TREATMENT: A SYSTEMATIC REVIEW INCORPORATING AN INDIRECT-COMPARISONS META-ANALYSIS. BR J SPORTS MED. 2018 MAY;52(10):651-658. DOI: 10.1136/BJSPORTS-2016-096422. EPUB 2017 MAY 13. PMID: 28501804; PMCID: PMC5931245 AVAILABLEAT HTTPS://PUBMED.NCBI.NLM.NIH.GOV/28501804/
GOEDENDORP MM, PETERS ME, GIELISSEN MF, WITJES JA, LEER JW, VERHAGEN CA, BLEIJENBERG G. IS INCREASING PHYSICALACTIVITY NECESSARY TO DIMINISH FATIGUE DURING CANCER TREATMENT? COMPARING COGNITIVE BEHAVIOR THERAPY AND A BRIEF NURSING INTERVENTION WITH USUAL CARE IN A MULTICENTER RANDOMIZED CONTROLLED TRIAL. ONCOLOGIST. 2010; 15( 10): 1122- 32. DOI: 10. 1634/ THEONCOLOGIST.2010- 0092. EPUB 2010 OCT 7. PMID: 20930100; PMCID: PMC3227893 AVAILABLE AT HTTPS://PUBMED.NCBI.NLM.NIH.GOV/20930100/
ARRING NM, BARTON DL, BROOKS T, ZICK SM. INTEGRATIVE THERAPIES FOR CANCER-RELATED FATIGUE. CANCER J. 2019 SEP/OCT;25(5):349-356. DOI: 10.1097/PPO.0000000000000396. PMID: 31567463; PMCID: PMC7388739 AVAILABLEAT HTTPS://PUBMED.NCBI.NLM.NIH.GOV/31567463/
LAWRENCE JA, GRIFFIN L, BALCUEVA EP, GROTELUSCHEN DL, SAMUEL TA, LESSER GJ, NAUGHTON MJ, CASE LD, SHAW EG, RAPP SR. A STUDY OF DONEPEZIL IN FEMALE BREAST CANCER SURVIVORS WITH SELF-REPORTED COGNITIVE DYSFUNCTION 1 TO 5 YEARS FOLLOWING ADJUVANT CHEMOTHERAPY. J CANCER SURVIV. 2016 FEB;10(1):176-84. DOI: 10.1007/S11764-015-0463-X. EPUB 2015 JUL 1. PMID: 26130292; PMCID: PMC4930878 AVAILABLEAT HTTPS://PUBMED.NCBI.NLM.NIH.GOV/26130292/
REID J, MILLS M, CANTWELL M, CARDWELL CR, MURRAY LJ, DONNELLY M. THALIDOMIDE FOR MANAGING CANCER CACHEXIA. COCHRANE DATABASE SYST REV. 2012 APR 18;2012(4):CD008664. DOI: 10.1002/14651858.CD008664.PUB2. PMID: 22513961; PMCID: PMC6353113 AVAILABLEAT HTTPS://PUBMED.NCBI.NLM.NIH.GOV/22513961/
MÜCKE M; MOCHAMAT, CUHLS H, PEUCKMANN-POST V, MINTON O, STONE P, RADBRUCH L. PHARMACOLOGICAL TREATMENTS FOR FATIGUE ASSOCIATED WITH PALLIATIVE CARE. COCHRANE DATABASE SYST REV. 2015 MAY 30;2015(5):CD006788. DOI: 10.1002/14651858.CD006788.PUB3. PMID: 26026155; PMCID: PMC6483317. AVAILABLE AT HTTPS://PUBMED.NCBI.NLM.NIH.GOV/26026155/

ANOREXIA CACHEXIA

Author: Catarina Lopes de Almeida

Symptoms

- - Anorexia is defined as lack or loss of appetite for food and it affects up to 80% of people with an advanced oncologic disease, either due to the treatment or to the disease itself.
  - This could eventually lead to cachexia, which is a multifactorial syndrome characterized by loss of skeletal muscle, which could be accompanied by fat loss, anorexia itself, weakness, fatigue, impaired immune function, and a global functional impairment, leading to a great decrease in the patient’s quality of life (QOL).

– Often this condition may not be fully reversed by conventional nutrition support.

Etiology

- - Anorexia may have as consequence inadequate nutrient intake and ultimately may lead do cachexia.
    - The decrease of appetite is associated to hypothalamic dysfunction that affects neuropeptide Y and the metabolism of leptin and ghrelin.
    - Another mediator are cytokines released by macrophages, monocytes, and lymphocytes in response to trauma, sepsis and malignancy, such as tumour necrosis factor (TNF), interleukins (IL)-1 and IL-6.
  - Anorexia contributes to an inadequate nutrient intake, but there are also other causes.
    - The causes related to the cancer itself could be obstruction or perforation of the GI tract, intestinal secretory abnormalities, malabsorption, intestinal dysmotility and fluid and electrolyte abnormalities.

Evidence

Level Grade PMID Nº

- - - - There may also exist causes to the decreased nutrient intake as consequence of the treatments.

Regarding chemotherapy, this may be due to anorexia itself, altered sense of taste, learned food aversion, nausea and vomiting, mucositis, diarrhoea and ileus.

Surgery (mostly concerning GI tract tumours) may cause malabsorption, adhesion-induced obstruction, odynophagia, dysphagia, fluid and electrolyte abnormalities and vitamin and mineral abnormalities.

Radiation therapy may induce anorexia, altered taste, mucositis, xerostomia, dysphagia, obstruction, perforation, and stricture; this affects mainly patients with tumours from head and neck and upper GI tract.

- - - - Finally, there are other etiological factors, such as opioid-induced constipation, GI tract abnormalities associated with fungal, viral, or bacterial infection, fatigue, pain or mood disorders such as depression.
  - However, anorexia and abnormal nutrient intake alone are not solely responsible for the profound weight loss in patients with cachexia. It is the result of the combination of decreased energy intake with increased energy expenditure.
    - These patients frequently present other medical abnormalities contributing for increased resting energy expenditure, such as increased hepatic glucose production, lipolysis, protein turnover, transformation of white to brown adipose tissue and insulin resistance

Studies

There are three diagnostic stages and the progression across them depends on the tumour type and stage, inflammation, food intake and response to treatment.
- Precachexia is the involuntary loss of <5% of body weight, associated with anorexia or poor glucose control
- Cachexia is the involuntary loss of >5% of body weight over 6 months, or a body mass index <20 kg/m2 and >2% of weight loss, or signs of sarcopenia and >2% of weight loss.

– Refractory cachexia is defined as rapidly progressive cancer unresponsive to treatment, World Health Organization performance status (WHO PS) of 3-4 and life expectancy <3 moths.

Patients at risk should be referred to nutritional and metabolic status assessment, which includes body weight, weight change, body composition, food intake, performance status and systemic inflammation.
To provide better care to these patients, it is fundamental to implement screening tools to assess the nutrition status.

– There is no consensus on the best tool to use, but there are several validated options: Malnutrition Universal Screening Tool (MUST), Nutrition Risk Screening 2002 (NRS- 2002), Short Nutritional Assessment Questionnaire (SNAQ) and the Malnutrition Screening Tool (MST).

There is not a single preconized treatment for cachexia, as it is a multifactorial syndrome. The three areas of intervention are adequate antitumor treatment, nutrition counselling and supportive pharmacologic intervention. Those who respond better to oncologic therapy often have better results concerning cachexia.

Pharmacotherapy

Level Grade PMID Nº

Progesterone analogues such as megestrol acetate (MA) can be used to significantly improve appetite, weight gain and QOL, but not muscle mass, physical function, or survival. The initial dose of MA is 160 mg/day and should be increased according to the patient’s response, up to a maximum of 800 mg/day. It should be maintained for at least two months to assess its efficacy. It is associated with an increased risk of thromboembolism, fluid retention, adrenal insufficiency, and hypogonadism in male patients.
Corticosteroids increase appetite and improve anorexia, cancer-related fatigue and QOL. The antianorexic effect is transient (3-4 weeks) and long-term use could be associated with loss of muscle mass, insulin resistance and immunosuppression. However, in terminal patients the benefit usually outweighs the harm. There is limited data to recommend one drug over another, but prednisolone, methylprednisolone and dexamethasone can be used.
Olanzapine is an antagonist of dopamine and serotonin receptors. There is moderate evidence suggesting this drug causes weight gain and reduces nausea in patients with advanced cancer.
The routine use of medical marijuana or its derivatives to alleviate anorexia is not recommended because of insufficient evidence.

I B

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Therapeutic Strategy Level Grade PMID Nº

- Every patient with cachexia should be offered a multimodal approach with the goal of alleviating symptoms, providing adequate nutrient intake, muscle training and II B psychological and social support when adequate.
- In patients with a life expectancy superior to several months and under anticancer treatment, nutritional interventions should escalate as needed. In other situations, less II A invasive strategies are preferred.
- Oral nutritional supplements can induce energy intake and weight gain. These consist in macro and micronutrients available in variable presentations, flavours and formulations, II B such as pudding, milk, juice or yoghurt.
- The oral route should be preferred for nutritional support, provided it is safe. In case of dysphagia or inadequate nutrient intake for more than a few days, enteral tube feeding I A should be considered.
- If the prevision of enteral feeding surpasses 4 weeks, then percutaneous endoscopic gastrostomy should be preferred rather than nasogastric tube feeding. II C
- Domiciliary parenteral nutrition can be offered to patients with WHO PS 0-2 and low burden of disease whose QOL and life expectancy are clearly impaired due to malnutrition. V B However, it is not routinely recommended.
- Moderate physical exercise such as aerobic, resistance and flexibility two to three times per week guided by aa professional is recommended to all patients with cachexia to II D maintain and improve muscle mass.

References:

Arends J, Strasser F, Gonella S, et al. Cancer cachexia in adult patients: ESMO Clinical Practice Guidelines☆. ESMO Open. 2021;6(3):100092. doi:10.1016/j.esmoop.2021.100092
Esper DH, Harb WA. The cancer cachexia syndrome: a review of metabolic and clinical manifestations. Nutr Clin Pract. 2005;20(4):369-376. doi:10.1177/0115426505020004369
Mattox TW. Cancer Cachexia: Cause, Diagnosis, and Treatment. Nutr Clin Pract. 2017;32(5):599-606. doi:10.1177/0884533617722986

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Ruiz Garcia V, López-Briz E, Carbonell Sanchis R, Gonzalvez Perales JL, Bort-Marti S. Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database Syst Rev. 2013;2013(3):CD004310. Published 2013 Mar 28. doi:10.1002/14651858.CD004310.pub3
de van der Schueren MAE, Laviano A, Blanchard H, Jourdan M, Arends J, Baracos VE. Systematic review and meta-analysis of the evidence for oral nutritional intervention on nutritional and clinical outcomes during chemo(radio)therapy: current evidence and guidance for design of future trials. Ann Oncol. 2018;29(5):1141-1153. doi:10.1093/annonc/mdy114
Baldwin C, Spiro A, Ahern R, Emery PW. Oral nutritional interventions in malnourished patients with cancer: a systematic review and meta-analysis. J Natl Cancer Inst. 2012;104(5):371-385. doi:10.1093/jnci/djr556
Lee JLC, Leong LP, Lim SL. Nutrition intervention approaches to reduce malnutrition in oncology patients: a systematic review. Support Care Cancer. 2016;24(1):469-480. doi:10.1007/s00520-015-2958-4
Bouleuc C, Anota A, Cornet C, et al. Impact on Health-Related Quality of Life of Parenteral Nutrition for Patients with Advanced Cancer Cachexia: Results from a Randomized Controlled Trial. Oncologist. 2020;25(5):e843-e851. doi:10.1634/theoncologist.2019-0856
Hall CC, Cook J, Maddocks M, Skipworth RJE, Fallon M, Laird BJ. Combined exercise and nutritional rehabilitation in outpatients with incurable cancer: a systematic review. Support Care Cancer. 2019;27(7):2371-2384. doi:10.1007/s00520-019-04749-6

NUTRITION IN CANCER PATIENTS

NUTRITIONAL RISK PATIENT

Author: Diana Pessoa

Definition

- - Malnutrition associated in the Oncology setting is a common feature in cancer patients and it is estimated to be present in about 40-80% of these population. It occurs because of the inflammatory cytokines response to this chronic condition, metabolic alterations, and concomitant inadequate availability of nutrients, resulting from a deficit in energy, protein, and micronutrient intake resulting in changes in body composition, due to anorexia caused both by the disease and the systemic treatments.
  - Malnutrition and the loss of muscle mass (also known as sarcopenia) it’s highly prevalent in cancer patients, which in turn can negatively impact clinical outcomes (less adherence to treatments, increased toxicity, worsens overall survival and poor quality of life). Robust evidence indicates that nutritional issues should be taken in consideration since the time of cancer diagnosis, within a diagnostic and therapeutic pathway, and should be running in parallel to anticancer treatments.
  - Prolonged malnutrition can result in cachexia, a specific form of malnutrition characterised by progressive, involuntary weight loss with depletion of lean body mass, muscle wasting and weakness, oedema, impaired immune responses, and declines in motor and mental function that is different from simple starvation. In this case, muscle mass deterioration happens at a fast rate and fat tissue loss can occur.
  - The demands and aggressiveness of treatments such as chemotherapy, surgical procedures and radiotherapy, urges the need to assess as soon as possible the nutritional status and predict future complications, in order to improve both overall survival and quality of life.

Symptoms and signs

- - The main symptoms are driven or caused by the weight loss, low body mass index and low skeletal muscle mass, which might be either from low food intake and assimilation, or the disease burden and inflammatory state.
  - It is assumed that the patient has an appropriate BMI, within the normal range or slightly inferior, has 75% or more of adequate nutritional intake and has no reversible cause of malnutrition such as anaemia or vitamin deficit.
  - Gastroparesis is common in patients with cancer, and it can contribute to weight loss because of inability to take in sufficient calories. In cancer patients, the Etiology of gastroparesis and early satiety is often multifactorial and can include chemotherapy-induced autonomic dysfunction and medications such as opioids or anticholinergics, radiation enteritis, and tumour infiltration, or it can be the result of a paraneoplastic syndrome.
  - There are common causes for a poor nutrient intake in cancer patients, such as deterioration in taste, smell and appetite, as a consequence of the tumour and/or therapy; altered food preferences/food avoidance/food aversion; eating problems (teeth, chewing); dysphagia, odynophagia or partial/total gastrointestinal obstruction; early satiety, nausea and vomiting; soreness, xerostomia, sticky saliva, painful throat, trismus; oral lesions and oesophagitis; radiotherapy/chemotherapy induced mucositis; acute or chronic radiation enteritis during and after radiotherapy; dyspnoea ; fatigue; depression, anxiety and pain (especially epigastric or abdominal).
  - All of these may compromise and affect the nutritional state of the individual and deserve prompt specialized attention and early detection.
  - Among patients with cancer, some treatments are associated with sarcopenia (androgen deprivation therapy, sorafenib, bevacizumab), which may also contribute to decreased lean body mass.

Etiology

There are different causes associated with malnutrition in cancer patients.

Tumour related mechanisms:

Several mechanisms have been proposed for the malnutrition-caquexia syndrome, although it remains unclear. Some state mechanical and functional alterations, especially in otorhinolaryngological and digestive tumours and the release of catabolic hormones, cytokines, and mobilizing factors that favour hypermetabolism and cachexia, which may

Evidence

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affect energy expenditure and the metabolism of protein, fat, and carbohydrate. The increased turnover of liver and muscle proteins also plays an important role. The gluconeogenesis from amino acids of muscle origin and APP synthesis in the liver are thought to contribute to the rapid muscle wasting seen in cancer-associated malnutrition. Other system is the impaired ratio of catabolic to anabolic hormones, resulting in elevated catabolism, and failure to accumulate lean body mass, even when nutritional intake is normal. And last, the tumour derived catabolic hormones, such as lipid mobilising factor (LMF) and proteolysis-inducing factor (PIF), increase lipid mobilisation promoting loss of body fat and induce skeletal muscle wasting.

Patient related mechanisms: Personal habits, physical deterioration, anorexia, and psychological factors
Treatment’s related mechanisms, with the side effects of the surgery, radiotherapy or chemotherapy being the main culprits. Mucositis, emesis, and diarrhoea make intake difficult and favour malabsorption and loss of nutrients.

Studies

General assessment of body weight, anthropometric measures, and body composition.

Assessment of the nutritional risk and nutritional status is important to identify those at risk and implement specific strategies to minimize risks, improving cancer patient’s quality of life. After carefully looking at the available evidence, we suggest the following process for the assessment of nutritional risk and status:

Application of MST or NRS, followed by PG-SGA.
Assessment of energy intake and nutrient balance using the usual food intake recall and the food frequency questionnaires.
Measurement of body weight, assessment of weight change over a specific time period and body mass index (BMI) estimation.
Evaluation of body composition with computed tomography scans at the level of the 3rd vertebra (CT), bioelectrical impedance analysis (BIA), or dual-energy X-ray absorptiometry (DEXA).
Measurement of biochemical and inflammation markers, such as transferrin, albumin, pre-albumin, C reactive protein, and tumour necrosis factor-α
Assessments of muscle function with the handgrip strength and walking speed tests (gait speed).
Measurement of physical performance with the ECOG performance status and Karnofsky scales.

The assessment of nutritional status of the cancer patient helps us understand the patient’s condition and to improve clinical outcomes in a fragile population.

Nutritional risk assessment tools

The first approach to assess nutritional risk and consequent management in oncologic patients, is the use of a validated screening instrument, as suggested from ESPEN guidelines, assessing food intake, changes in weight, and BMI.

NRS 2002

It is recommended for hospitalized patients to identify malnourished patients who are likely to benefit from nutritional support. The main advantages are its practical and quick use, around 3 min. It starts with a pre-screening of four questions. If one is answered with “yes,” a complete screening must be performed. The NRS 2002 is based on impairment of nutritional status (percentage of weight loss, general condition, BMI, and recent food intake), disease severity (stress metabolism), and age. Each category is rated from 0 (normal) to 3 (severe), and an age ≥70 years adds 1 point. Total scores range from 0 to 7 points. Patients with a total score ≥3 classified as “at nutritional risk” could benefit from nutritional support and improved clinical outcome.

Malnutrition Universal Screening Tool (MUST)

The Malnutrition Screening Tool (MST) was developed for use in acutely hospitalized patients and validated for use in cancer. It is recommended for outpatient screening by the ESPEN Society and includes the following criteria: , weight loss in three to six months, BMI and anorexia for five days due to disease). Each criterion is rated from 0 to 2 ; ≥2 are classified as at nutritional risk.

Mini Nutrition Assessment (MNA)

The Mini Nutritional Assessment (MNA) consists of a global assessment and subjective perception of health, as well as questions specific to diet, and a series of body measurements, mainly in geriatric population. The MNA includes eighteen items in four categories: anthropometric, general, dietary, and subjective assessment. The long time is a downside of applying the MNA(15 min). The range score ranges from 0 to 30. Scores of 17–23.5 indicate risk for malnutrition; with <17 indicating malnutrition.

Level Grade PMID Nº

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Malnutrition Screening Tool (MST)

Level Grade PMID Nº

It is a quick and easy screening tool, both in and outpatients, analysing appetite, food intake, and recent weight loss. The score ranges from 1 to 5, and if the patient scores more than 2, it is a sign of possible malnutrition.

Patient- Generated Subjective Global Assessment (PG-SGA)

The PG-SGA has been validated in cancer patients and is the most accepted and widely used screening tool for this population, as it identifies nutritional risk and predicts clinical outcomes. It incorporates information from patients (weight history, food intake, functional status, symptoms affecting food intake), assessments made by health care professionals (comorbid conditions, corticosteroid use, fever), and assessments made by physical examination.

Nutriscore

The Nutriscore was recently developed for oncology outpatients as an expert consensus from different dietetic and nutrition units from the Catalan Institute of Oncology based on the MST (52). It includes questions to unintentional weight loss. Additionally, it includes specific oncologic parameters such as tumour location and anti-cancer treatment, ranges from 0 to 11 points (total score ≥ 5 points indicate referral to dietist)

Despite efforts to find a standardized test to detect these patients at nutritional risk, universal consensus has not yet been reached. It is estimated that about 50% of patients are not diagnosed as at risk, thus increasing the harmful consequences of this condition, as mentioned above.

Pharmacotherapy

A II a

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Megestrol acetate 160 mg/day (increase up to 3x/day if necessary), to increase appetite
Progestational agent, has been shown to yield weight gain in patients with anorexia and cachexia. It has not shown benefit in increasing muscle mass, only fat tissue.
Patients should be monitored for oedema and worsening of congestive heart failure, impaired function of the corticoadrenal axis, deep venous thrombosis, and muscle weakness. Weak, high.

Corticosteroids for a restricted period (1-3 weeks), to increase appetite
Patients should be monitored for muscle wasting, insulin resistance, infections (Weak, high)

In patients with advanced cancer undergoing chemotherapy at risk of malnutrition, we suggest supplementation with long-chain N3 fatty acids or fish oil
It has been shown to stabilize or improve appetite, food intake, lean body mass and body weight (week low)

In patients with early satiety symptoms, consider prokinetic agents

Be aware of possible extrapyramidal side effects with metoclopramide, and alterations of the cardiac rhythm with domperidone (weak, moderate).
There are insufficient consistent clinical data to recommend cannabinoids to improve taste disorder or anorexia in cancer patients.

IV A

Therapeutic Strategy

V A

To detect nutritional disturbances at an early stage, evaluate nutritional intake, weight change and body mass index (BMI)

In patients with abnormal screening, we recommend objective and quantitative assessment of nutritional intake, nutrition impact symptoms, muscle mass, physical performance and the degree of systemic inflammation.

All cancer patients should be screened at the time of diagnosis and throughout treatment using a validated malnutrition screening tool.

Total energy expenditure is the same a healthy patient, thus we recommend 25-30 Kcal/Kg/day.

IV A

IV B

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Level Grade PMID Nº

We recommend that protein intake should be 1-1.5 g/Kg/day.

We recommend that vitamins and minerals be supplied in the recommended daily allowance (=RDA).

Enteral nutrition, if oral intake remains inadequate despite nutritional counselling, and parenteral nutrition, if enteral nutrition is not sufficient or feasible (severe radiation

enteritis or malabsorption).

Physical exercise in cancer patients to support or improve muscle mass and function.

Management within an ERAS program is recommended for all cancer patients undergoing either curative or palliative surgery.

In severe mucositis or in obstructive tumours of the head-neck or thorax, enteral feeding is recommended using nasogastric or gastrostomy tubes.

In advanced terminal phases of the disease, artificial nutrition is unlikely to provide any benefit for most patients.

In weight-losing cancer patients with insulin resistance, we recommend increase ratio of energy from to energy from carbohydrates.

Fat sources at least 50% of non-protein calories B IV.

Do not use dietary provisions that restrict energy intake in patients with or at risk of malnutrition.

The patients should be given dietary advice (encourage intake of protein, energy rich foods and fluids well tolerated). Also, offering oral nutritional supplements is advised.

IV	B	29043569 3085914
IV	B	21683485 22019489
V	B	24703049 25008853 19032398 24406425
II	A	21091401
II	A	32190779
IV	B	29043569 24844870
IV	B	32432946
IV	B	19631039
IV	B	10509772 19647909
IV	C	15632335 21794124
IV	C	27637832

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‘Malnutrition Universal Screening Tool’ predicts mortality and length of hospital stay in acutely ill elderly.Stratton RJ, King CL, Stroud MA, Jackson AA, Elia M. Br J Nutr. 2006;95(2):325.
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Nutritional support and parenteral nutrition in cancer patients: an expert consensus report. Virizuela JA, Camblor-Álvarez M, Luengo-Pérez LM, Ocón-Bretón MJ et al. Clin Transl Oncol. 2018 May;20(5):619-629.
Efficacy of arginine-enriched enteral formulas in the reduction of surgical complications in head and neck cancer: a systematic review and meta-analysis. Vidal-Casariego A, Calleja-Fernández A, Villar-Taibo R, Kyriakos G, Ballesteros-Pomar MD. Clin Nutr. 2014 Dec;33(6):951-7.
Management of Cancer Cachexia: ASCO Guideline. Roeland EJ, Bohlke K, Baracos VE, Loprinzi CL et al. J Clin Oncol. 2020 Jul 20;38(21):2438-2453.
Obesity, insulin resistance, and cancer prognosis: implications for practice for providing care among cancer survivors. Parekh, N., Okada, T., & Lu-Yao, G. L. 2009 Journal of the American Dietetic Association, 109(8), 1346–1353.
Increased lipid utilization in weight losing and weight stable cancer patients with normal body weight. Körber J, Pricelius S, Heidrich M, Müller MJ. Eur J Clin Nutr. 1999 Sep;53(9):740-5.
Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial. Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ. JAMA. 2005 Jan 5;293(1):43-53.
Energy expenditure in malnourished cancer patients. Knox LS, Crosby LO, Feurer ID, Buzby GP, Miller CL, Mullen JL. Ann Surg. 1983 Feb;197(2):152-62.
Dietary intake and resting energy expenditure in relation to weight loss in unselected cancer patients. Bosaeus I, Daneryd P, Svanberg E, Lundholm K. Int J Cancer. 2001 Aug 1;93(3):380-3.
Total energy expenditure in patients with small-cell lung cancer: results of a validated study using the bicarbonate-urea method. Gibney E, Elia M, Jebb SA, Murgatroyd P, Jennings G. Metabolism. 1997 Dec;46(12):1412-7.
Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food. Deutz NE, Safar A, Schutzler S, Memelink R, Ferrando A, Spencer H, et al. Clinical nutrition (Edinburgh, Scotland). 2011;30:759-68.
Branched chain amino acids as the protein component of parenteral nutrition in cancer cachexia. Hunter DC, Weintraub M, Blackburn GL, Bistrian BR. The British journal of surgery. 1989;76:149-53.
Improved protein kinetics and albumin synthesis by branched chain amino acid-enriched total parenteral nutrition in cancer cachexia. Tayek JA, Bistrian BR, Hehir DJ, Martin R, Moldawer LL, Blackburn GLAprospective randomized crossover trial. Cancer. 1986;58:147-57.
How many cancer patients use complementary and alternative medicine: a systematic review and metaanalysis. Horneber M, Bueschel G, Dennert G, Less D, Ritter E, Zwahlen M. Integrative cancer therapies. 2012;11:187-203.
The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Bolland MJ, Grey A, Gamble GD, Reid IR. The lancet Diabetes & endocrinology. 2014;2:307-20.
Vitamin E and C supplementation and risk of cancer in men: posttrial follow-up in the Physicians’ Health Study II randomized trial. Wang L, Sesso HD, Glynn RJ, Christen WG, Bubes V, Manson JE, et al. The American journal of clinical nutrition. 2014;100:915-23.
Randomized study of percutaneous endoscopic gastrostomy versus nasogastric tubes for enteral feeding in head and neck cancer patients treated with (chemo)radiation. Corry J, Poon W, McPhee N, Milner A, Cruickshank D, Porceddu S, et al. Journal of medical imaging and radiation oncology. 2008;52:503-10.
The prognosis of incurable cachectic cancer patients on home parenteral nutrition: a multi-centre observational study with prospective follow-up of 414 patients. Bozzetti F, Santarpia L, Pironi L, Thul P, Klek S, Gavazzi C, et al. Annals of oncology : official journal of the European Society for Medical Oncology. 2014;25:487-93.
1. MALNUTRITION IN CANCER PATIENT

Authors: Marília Sousa Ferreira and Ana Cláudia Salgado.

Definition

Malnutrition can be defined as “a state resulting from lack of intake or uptake of nutrition that leads to altered body composition (decreased fat free mass) and body cell mass leading to diminished physical and mental function and impaired clinical outcome from disease”. Malnutrition can result from starvation, disease or advanced ageing (e.g. >80 years), alone or in combination. [1]

When observing the patient, malnutrition can be diagnosed by following the criteria in table 1.

Weight loss is frequently the first sign of the nutritional alterations that occur in the course of the disease and is associated with poor prognosis, reduced quality of life and morbidity. [2] However, when used alone, this parameter is ineffective to detect malnutrition due to low sensitivity to metabolic changes in the cancer patient. Body Mass Index (BMI) also has low sensitivity to detect changes in nutritional status, especially in obese patients. Both weight loss and BMI should be assessed early and regularly and combined with nutritional intake, inflammatory status and other assessment tools. [2]

Cancer cachexia can be defined as “a multi-factorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support. It leads to progressive functional impairment. Its pathophysiology is characterized by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism”. [1,2] The pathophysiology of cachexia is understood as host-tumour interactions redirecting metabolism and driving the brain to reduce appetite, cause alterations in taste and smell, impact gastrointestinal function, induce fatigue and decrease daily physical activity. In factors related to tumour, is included systemic inflammation which has been extensively and reliably associated with poor clinical outcome. [3]

The agreed diagnostic criteria for cachexia is weight loss > 5% or weight loss > 2% in individuals already showing depletion of body weight (BMI < 20 kg/m2) or of skeletal muscle (sarcopenia). Note that sarcopenia can occur regardless of weight or fat mass loss. Thus, a phenotype that may arise in cancer patients is characterized by sarcopenia with excess fat mass. [2]

Malnutrition is frequent in cancer patients as a consequence of metabolic changes of the disease, as well as the effect of antineoplastic therapies. [4,5,6,7] It is now unquestionable that malnutrition has a negative impact on treatments and on the quality of life of patients, with malnourished patients showing greater toxicity induced by therapies, resulting in interruptions and early therapeutic discontinuation, compromising survival.[4,5,6]

Evidence

Level Grade PMID Nº

Malnutrition	Defined by three criteria: a positive malnutrition screening test combined with one phenotypical and one aetiological criteri on.
	Mandatory Screening	Malnutrition risk predicted by a validated screening test, e.g., NRS– 2002, MUST, MNA, MST or other
	Phenotypical criteria	Loss of or low body mass as defined by at least one of the following A1: weight loss > 5% in 6 months A2: body mass index below 20 kg/m2 A3: low muscle mass
	Aetiological criteria	Reduced food availability (B1) and/or increased catabolism (B2) B1 (starvation type): reduction in food availability B1a: food intake < 50% for > 1 week B1b: any reduction in food intake for > 2 weeks B1c: chronic malabsorption B2 (cachexia type): increased acute or chronic systemic inflammation

Level Grade PMID Nº

Cachexia	A disease -related subtype of malnutrition identified by malnutrition screening, at least one phenotypical criterion and systemic inflammation
	Malnutrition Screening	As described above
	Phenotypical criteria	As described above
	Aetiological criteria	B2 (systemic inflammation; described above)

Table 1: Criteria for the diagnosis of malnutrition (Adapted from European Society for Medical Oncology) [3]

Nutritional screening

The clinical guidelines of the various official organizations, i.e., American Society for Parenteral and Enteral Nutrition (ASPEN), European Society for Medical Oncology (ESMO) and European Society for Clinical Nutrition and Metabolism (ESPEN), widely advocate the importance of early screening and nutritional intervention in oncology. [4,8,9]

Nutritional screening should be done as early as possible, preferably at the time of diagnosis or hospital admission (preferably in the first 24-48 hours), and repeated throughout the therapeutic process for timely referral for nutritional assessment and intervention; nutritional screening is also recommended in those patients with an expected survival of more than a few (i.e. 3-6) months. [1,2,3,4,7,8]

The adequate tool for screening undernutrition should be brief and easy to fill, inexpensive, highly sensitive and have good specificity. [10]

ESPEN and ESMO recommend the following to identify the risk of malnutrition: Nutritional Risk Screening 2002 (NRS 2002), Malnutrition Universal Screening Tool (MUST), Mini Nutrition Assessment (MNA) and the Malnutrition Screening Tool (MST). [1,2,8]

Nutritional Assessment

Positive identification of nutritional risk should be followed by a detailed assessment of nutritional and metabolic status and evaluation of food intake impairment and gastrointestinal function. [3]

This assessment should be global, objective and should include quantification of nutritional intake, severity of symptoms with nutritional impact, assessment of muscle mass, functional capacity and degree of systemic inflammation. [2,4] In addition to these parameters, anorexia should be considered as an early indicator of malnutrition risk. Appetite change may occur regardless of the patient’s initial weight. [8]

So, assessing nutritional status should include objective assessment of the following: [3]

Body weight (BW)
Weight changes during the preceding months.
Body composition with a focus on muscle mass.
Food intake with a focus on energy and protein.
PS [Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO)].
Information regarding the presence and degree of systemic inflammation.

Body composition should be assessed using imaging methods since it allows the detection of loss of muscle mass as well as the infiltration of adipose tissue into muscle. Available Level Grade PMID Nº

methods are dual X-ray absorptiometry (DEXA), computed tomography at the level of the 3rd vertebra or bioimpedance analysis (BIA). An assessment of factors that are impeding or that might interfere with maintaining nutritional status should include evaluation of:

Nutrition impact symptoms, such as anorexia, nausea, taste and smell alterations, mucositis, constipation, dysphagia, chronic pain, abdominal pain (e.g. cramping) and diarrhoea, as well as aspects of GI function potentially responsible for these symptoms.
Fatigue, physical activity, shortness of breath and psychosocial distress.

All this information allows the determination of the most appropriate nutritional intervention to prevent/reverse malnutrition. Early and individualized nutritional therapy has in fact the ability to alleviate the symptomatic burden and to improve quality of life, body composition, and treatment efficacy, resulting in improved overall oncological prognosis survival [2,8,11,12]

It seems there is no consensus on the best method to perform this assessment, but SGA (Subjective Global Assessment) and PG-SGA (Patient Generated-Subjective Global Assessment) have been validated for nutritional assessment of adult oncology patients. [2]

Category	Parameter	Recommended tool(s)
Nutritional Status	Whole body status Weight loss Food intake Energy and protein intake Micronutrient or macronutrient deficiencies Body composition	Body weight % of usual healthy weight % of required amount Kcal/kg/day, g/kg/day Food diary or 24-hour recall and software-based analysis Anthropometry, BIA; CT or DEXA
Metabolic Status	Systemic Inflammation Energy expenditure	Modified Glasgow Prognostic Score Indirect calorimetry
Functional status	PS Physical activity Dependency Grip Strength Gait speed	ECOG/WHO Index ADL Northwick Park Dependency Score Dynamometry 4-metre gait speed test
Nutritional barriers	Nutrition impact symptoms	PG-SGA Nutritional impact checklist
GI dysfunctions	Chewing, taste, swallowing, gut motility, constipation, diarrhea, stenosis, malabsortion	Diagnostic interview, imaging tests, functional tests, visual analogue scales

Adverse events of medication	Possible adverse effects on appetite, gastrointestinal tract, central nervous system, fatigue	Pharmacological counselling
Tumour status	Extent and activity of cancer disease, likelihood of responde to anticancer treatment	Oncological counselling

Table 2: Parameters of comprehensive cachexia assessment and recommended tools (Adapted from ESMO) [3]

Pharmacotherapy Interventions

Pharmacological intervention is another strategy used to treat or improve the consequences of cancer cachexia. However, of the various drugs studied, only corticosteroids and progestins have shown benefits in appetite and/or body weight. [3]

Corticosteroids may be used to increase appetite for a short period of up to 2-3 weeks.
Progestins may be used to increase appetite and Body Weight, but not muscle mass, QoL or physical function in patients. The risk of serious sideeffects, including thromboembolic events, must be considered.
There is insufficient evidence to support the use of medical cannabis or its derivatives to alleviate anorexia or early satiety in patients with cancer cachexia.
As there is evidence of no beneficial effect in terms of improvement in muscle mass, androgens are not recommended.
There is moderate evidence to suggest considering the use of olanzapine to treat appetite and nausea in patients with advanced cancer. (Adapted from ESMO) [3]

Pharmacotherapy Interventions

Nutritional therapy should preferably be initiated when patients are not yet severely malnourished. [9] Different cancer types or locations display different nutritional patterns that require tailored nutritional therapy.

Proper nutrition can alleviate symptom burden, improve health across the cancer continuum, support cancer survivor ship and is a hallmark of successful cancer treatment. [2] The first form of nutrition support, in patients able to eat, should be nutrition counselling to help manage symptoms and encourage the intake of protein-and energy-rich foods and fluids that are well tolerated. A diet enriched in energy and protein is the preferred way to maintain or improve nutritional status. Nutritional counselling includes nutritional history, diagnosis, and nutrition therapy. This incorporates calculation of energy and nutrient requirements, food preparation and/or modifying of texture or nutrient content, increasing meal frequency by distribution of foods to several small meals, enriching dishes with energy- and protein-dense additives (e.g. by adding fat/oils, protein powder), offering oral nutritional supplements, a meal set-up plan that emphasizes supportive interventions to improve oral food intake. [3,8]

The additional use of Oral Nutritional Suplemments (ONS) is advised when an enriched diet is not effective in reaching nutritional goals, and to try to prevent nutritional deterioration during the course of treatments. Monitoring compliance with the selected nutritional intervention is essential. [2,8]

Medical Nutrition Therapy is indicated if patients are unable to eat adequately (e.g. no food for more than one week or less than 60% of requirement for more than 1 e 2 weeks). If a decision has been made to feed a patient, enteral nutrition is recommended if oral nutrition remains inadequate despite nutritional interventions (counselling, oral nutritional supplements), and parenteral nutrition if enteral nutrition is not sufficient or feasible. [8]

If oral food intake has been decreased severely for a prolonged period, is recommended to increase (oral, enteral or parenteral) nutrition only slowly over several days and to take additional precautions to prevent a refeeding syndrome. [9]

Refeeding syndrome (RS) is a severe disruption in electrolyte or fluid balance that is precipitated in malnourished subjects when feeding (oral, enteral or parenteral nutrition) is begun too aggressively after a period of inadequate nutrition. Screening for patients at risk of RS includes one or more of the following: BMI 15% in 3 e 6 months; little or no intake for

>10 days; or low potassium, phosphate and magnesium before feeding. If two or more of the following factors exist a risk of RS should also be considered: BMI 10% in 3 e 6 months; little or no nutritional intake for >5 days; or a history of alcohol misuse or chronic drug use (insulin, antacids, diuretics). [13]

I B

II D

II B

34144781

Regular nutritional screening and nutritional support, including (if necessary) enteral nutrition or Parenteral nutrition, is recommended in all patients receiving anticancer treatment and in those with an expected survival of more than a few months.
Standardised screening for nutritional risk at regular intervals is recommended for all patients undergoing anticancer treatment and those with a life expectancy of at least a few (i.e. 3-6) months.
For patients identified as being at nutritional risk, an objective assessment of nutritional and metabolic status (including weight, weight loss, body composition, inflammatory state, nutritional intake and physical activity) and examination for the presence of factors interfering with the maintenance or improvement of this status (including nutrition impact symptoms, GI dysfunction, chronic pain and psychosocial distress) is recommended.
Patients found to be at no immediate risk of malnutrition by screening should be re-screened at regular intervals (typically every 3 months or at staging for anticancer treatment) or, in cases where anticancer treatment with a high risk of inducing malnutrition is planned (e.g. combined-modality treatments, high-dose chemotherapy, highly emetogenic agents), prophylactic nutritional support should be considered.
In patients with inadequate food intake, nutritional interventions are recommended to increased oral intake. In patients with expected survival of more than several months and in those receiving anticancer therapy, these interventions should be escalated, as required. In other situations, low-risk interventions (counselling and ONSs) are preferred.
If safe, the oral route should be the first option for nutritional support. Enteral tube feeding may be used in cases of dysphagia if the small bowel function is preserved. PN should be considered if oral intake and tube feeding are not tolerated or remain inadequate.
Nutritional interventions should aim to fulfil energy and nutrient requirements.
To maintain nutritional status, at least 25-30 kcal/kg BW is recommended, adjusting the regimen as required.
At least 1.2 g protein/kg BW/day should be provided.
Dietary counselling should be the first choice of nutritional support offered to improve oral intake and possibly weight gain in patients who are able to eat, should emphasize protein intake, and increased number of meals per day, treatment of nutrition impact symptons and offering nutritional supplements when necessary.
ONS can be supplied as part of dietary counselling to improve energy intake and induce weight gain.
Patients receiving chemotherapy, radiotherapy or chemoradiotherapy may be offered N3P-ONSs to increase BW, attenuate loss of lean body mass and improve Quality of Life (QoL).
For patients with head and neck or upper GI cancers, especially those undergoing anticancer treatment, tube feeding to maintain BW or to reduce weight loss is recommended if oral feeding including ONSs is expected to remain inadequate for more than a few days.
In a patient undergoing curative anticancer drug treatment, if oral nutrition remains inadequate despite nutritional interventions (counseling, ONS), Enteral Nutrition (EN) is recommended. If EN is not sufficient or feasible Parenteral Nutrition (PN) is recommended.
There is insufficient evidence to routinely recommend supplemental PN in hypophagic, malnourished patients receiving chemotherapy to improve QoL and nutrition parameters.

V B

II A

V B

II B

II C

I A

V B

34144781

References: Level Grade PMID Nº

Cederholm T, Barazzoni R, Austin P, Ballmer P, Biolo G, Bischoff SC, et al. ESPEN guidelines on definitions and terminology of clinical nutrition. Clin Nutr. 2017;36(1):49–64.
Ravasco P. Nutrition in cancer patients. Vol. 8, Journal of Clinical Medicine. 2019.
Arends J, Strasser F, Gonella S, Solheim TS, Madeddu C, Ravasco P, et al. Cancer cachexia in adult patients: ESMO Clinical Practice Guidelines☆. ESMO Open [Internet]. 2021;6(3):100092. Available from: https://doi.org/10.1016/j.esmoop.2021.100092
Muscaritoli M, Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, et al. ESPEN practical guideline: Clinical Nutrition in cancer. Clin Nutr [Internet]. 2021;40(5):2898–913. Available from: https://doi.org/10.1016/j.clnu.2021.02.005
Bossi P, Delrio P, Mascheroni A, Zanetti M. The spectrum of malnutrition/cachexia/sarcopenia in oncology according to different cancer types and settings: A narrative review. Nutrients. 2021;13(6):1–16.
Muscaritoli M, Molfino A, Gioia G, Laviano A, Fanelli FR. The “parallel pathway”: A novel nutritional and metabolic approach to cancer patients. Vol. 6, Internal and Emergency Medicine. 2011. p. 105–12.
Walsh D, Szafranski M, Aktas A, Kadakia KC. Malnutrition in Cancer Care: Time to Address the Elephant in the Room. J Oncol Pract. 2019;15(7):357–9.
Arends J, Baracos V, Bertz H, Bozzetti F, Calder PC, Deutz NEP, et al. ESPEN expert group recommendations for action against cancer-related malnutrition. Clin Nutr [Internet]. 2017;36(5):1187–96. Available from:http://dx.doi.org/10.1016/j.clnu.2017.06.017
Krznarić Ž, Bender DV, Laviano A, Cuerda C, Landi F, Monteiro R, et al. A simple remote nutritional screening tool and practical guidance for nutritional care in primary practice during the COVID-19 pandemic. Clin Nutr. 2020;39(7):1983–7.
Reber E, Gomes F, Vasiloglou MF, Schuetz P SZ. Nutritional Risk Screening and Assessment _ Enhanced Reader.pdf. Vol. 8, J Clin Med. 2019. p. 1065.
Beirer A. Malnutrition and cancer, diagnosis and treatment. Memo – Mag Eur Med Oncol. 2021;14(2):168–73
August DA, Huhmann MB. A.S.P.E.N. Clinical guidelines: Nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. J Parenter Enter Nutr. 2009;33(5):472–500.
Boateng A.A.Sriram K.Meguid M.M.Crook M.Refeeding syndrome: treatment considerations based on collective analysis of literature case reports. Nutrition. 2010; 26: 156-167

GENITO-URINARY DISORDERS

IATROGENIC MENOPAUSE

Author: Sofia Pedrosa

Definition

- - Menopause: is defined as the last menstruation, resulting from permanent ovarian failure.
  - Iatrogenic menopause: results from the destruction or removal of the ovarian follicular heritage by various methods such as chemo or radiotherapy and surgical removal.
  - Early menopause: one that occurs before the age of 45, but after the age of 40.
  - Late menopause: one that occurs after the age of 54.
  - Premature ovarian failure: menopause that occurs before the age of 40.
  - The diagnosis of menopause is clinical.

Symptoms and signs

- - The symptoms are related to the decrease in ovarian follicular reserve and consequent hypoestrogenism. In the short-term vasomotor symptoms, sleep disorders and emotional disturbance appear. In the medium term genitourinary menopausal syndrome and possibly cutaneous changes can occur. Late repercussions are cardiovascular complications, osteoporosis and neurocognitive diseases such as Alzheimer’s disease.
  - Vasomotor symptoms are common. These are episodes of cutaneous vasodilation of the upper trunk, neck and face, with variable duration. They typically begin with a sudden feeling of heat lasting about 2 to 4 minutes, often associated with profuse sweating and occasionally with palpitations. In some cases, show a nocturnal predominance, which may interfere with sleep. The frequency is variable. These symptoms are frequent in perimenopause, especially in the immediate post menopause, and more intense after bilateral oophorectomy in women.
  - Many women report changes in cognitive function in the perimenopause, including memory disturbances and difficulty concentrating. These alterations seem to be related to alterations in the hippocampus and prefrontal cortex mediated by hypoestrogenism. Physiological changes related to age, symptoms associated with menopause, stress, an increased incidence of anxiety and depression, as well as obstructive sleep dyspnoea and cardiovascular disease may justify sleep disturbances.
  - The Genitourinary Menopause Syndrome result from oestrogen deficiency in the female genitourinary system, including the vulva, vagina, urethra and bladder. Symptoms include vaginal disturbances as dryness, burning and irritation; urinary disorders, such as dysuria, urgency, and repeating urinary tract infections; and sexual, such as dyspareunia.
  - Cardiovascular disease appears to be determined by an increase in the androgen/oestrogen ratio and a decrease in the sex hormone binding globulin. These changes favour an increase in visceral fat, insulin resistance and the risk of type 2 diabetes mellitus and the risk of high blood pressure, atherosclerosis, and heart disease.

Etiology

Iatrogenic menopause main mechanism results from hypoestrogenism from the destruction of the ovarian follicular reserve:

- - Surgical – bilateral anexectomy;
  - Radiotherapy;
  - Chemotherapy;
  - Uterine artery embolization.

The woman should be informed about the possibility of iatrogenic menopause following a medical or surgical intervention. Iatrogenic cause is common in particularly in context of oncological diseases.

The effects of chemo and radiotherapy on ovarian reserve depend on the type of drug, the dose used, the previous reserve and the age of administration. Patients undergoing pelvic radio or chemotherapy with alkylating agents or anthracyclines present a high risk and allogeneic bone marrow transplantation is associated with a very high risk.

Evidence

Level Grade PMID Nº

11915855

25225714

33281418

26278873

32852449

33141539

31995690

24012626

27178194

31561815

33251828

17974956

32654893

27802832

Diagnostic Studies

AThe diagnosis of menopause is clinical and retrospective, after 12 months of amenorrhea.

- - Serum FSH level
  - Serum Estradiol level

Determining serum FSH and estradiol levels may be helpful in confirming of the diagnosis of menopause in women aged between 40 and 45 years with menopause symptoms, including menstrual cycle changes, or in women under 40 years of age with suspected premature ovarian failure. The analytic diagnosis should be based on an oligo/amenorrhea with more than 4 months, associated with two measurements of FSH >25-40IU/L with interval > 4-6 weeks.

Osteoporosis evaluation

- - Bone mineral densitometry: basal and every 2-5 years if bone density decreased at baseline

Therapeutic Strategy

Before starting any therapy, a preliminary assessment must be carried out.

- - Clinical history

– Assessment of symptoms and concerns;

- - - Risk factors assessment for general diseases;
    - Risk factors assessment for most prevalent diseases in menopause;
    - Cardiovascular risk assessment using American Heart Association Cardiovascular Risk Calculator;
    - Breast cancer risk assessment using National Cancer Institute Breast Cancer Risk Assessment Tool.
  - Physical exam
    - Calculate Body Mass Index; Waist/hip measurement; Blood pressure measurement;
    - Gynecological and breast exam;

– Thyroid palpation.

- - Promoting healthy lifestyles
    - Regular physical exercise
      - 150 minutes per week of moderate-intensity exercise;
      - 2 resistance exercise sessions/week;
      - Weight loss about 5-10% improves insulin resistance syndrome.

-Healthy diet

- - - - Several daily servings of vegetables and fruits, cereals, fish twice a week;
      - Low fat intake (olive oil is recommended);
      - Limited salt consumption;
      - Alcohol should not exceed 20 g/day in women;
      - Tobacco should be avoided.
    - Socializing and being physically and mentally active

Evidence

Level Grade PMID Nº

26872610

27008889

26444994

24084921

24463691

Hormonal Therapy systemic

An early initiation and its maintenance until the average age of menopause should be recommended to prevent cardiovascular disease and fracture risk.

Priority should be given to the use of 17β-estradiol and micronized naturalprogesterone.

The transdermal route is associated with lower thromboembolic risk.

II	C	26872610
II	C	32896176
II	B	27912889

II B

27340881 19332659

20738314

III D 27008889

II B

I A

19424093 26731686

28640161

26707589 26261035

24463691 27008889

26641959

24806158

19113798 21343402

24768128 16675169

22433977 16932241

22516278

16096172

I A 26676059 29452777

Hormonal contraception may be a therapeutic option if there is no reproductive intention. However, thebone mineral density and cardiovascular health benefit less than with hormonal therapy.

LocalHormonal Therapy

Despite systemic hormonal therapy, local estrogens should be associated.

Prasterone is an effective option in moderate to severe SGUM and has been shown to additional benefits in sexual function.

Moisturizers and lubricants are effective in treating vaginal dryness.

Non Hormonal Therapy ( antidepressants; phytoestrogens; pollen extract; yoga, acupuncture, etc)

The indications for non-hormonal therapy are based on the treatment of vasomotor symptoms when there is a contraindication to the use of estrogens.

The use of drugs that interfere with the metabolism of cytochrome P450 in women under tamoxifen is contraindicated.

Venlafaxine, paroxetine and escitalopram are effective in reducing hot flashes and hot flushes in postmenopausal women.

Gabapentin is effective but with more side effects.

Trials with phytoestrogens and soy isoflavones have shown contradictory results, however some studies have shown effectiveness in reducing the frequency of vasomotor symptoms.

Melatonin improves sleep disturbances in postmenopausal women without causingcentral nervous system depression.

Exercise and yoga can improve sleep quality and mood.

Osteoporosis

Bisphosphonates and denosumab are bone resorption inhibitors and are effective in the prevention andtreatment of vertebral, non-vertebral and from the hip.

Teriparatide is a bone-forming agent with reduced fracture risk vertebral and non-vertebral. It has no effect on hip fracture.

Hormonal therapy decreases the incidence of all fractures.

Tibolone increases body mineral density and reduces the risk of vertebral and non-vertebral fractures.

The combination of equinoconjugated estrogen and bazedoxifene prevents the loss of bone mass associated with menopause and reduces the risk of vertebral and non-vertebral fractures.

I A 11943033 16495394

I A 15769903 25431028

I A 31673731 26872610

I A 18703472

I A 18665787 19635615

Supplementation with calcium and vitamin D is recommended in the treatment of osteoporosis.

Special Considerations

Hormonal Tumours (breast, endometrium, ovary, gastric, lung and bladder).

o Hormonal therapy should not be used after diagnosis of hormonaltumours.

Breast cancer mutation carriers.

o There is no evidence of an increased risk of breast cancer with systemic hormotherapy inhealthy women carrying the breast cancer mutation. 1/2 pathogenic variants.

Meningioma and Glioma.

o Hormotherapy should be avoided in patients treated for gliomas or meningiomas.

References:

PMID 11915855 Utian, W. (1999). International Menopause Society menopause-related terminology definitions. Climacteric, 2, 284–286.
A
C

II C

25419719 29602163

28650869 26937135

28783064 27376135

26840041 30447915

27504919 18812548

33406487

29081037

PMID 25225714 Shifren, J. L., Gass, M. L. S., Kagan, R., Kaunitz, A. M., Liu, J. H., Pinkerton, J. A. V., Schnatz, P. F., Stuenkel, C. A., Allam, S. H., Allen, R. H., Bachmann, G. A., Merz, C. N. B., Bergfeld, W. F., Block, J. A., Clarkson, T. B., Clayton, J. A., Cwiak, C., Davis, S. R., Diab, D., Schiff, I. (2014). The North American Menopause Society recommendations for clinical care of midlife women. Menopause, 21(10), 1038–1062. https://doi.org/10.1097/gme.0000000000000319
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1. ERECTILE DYSFUNCTION

Authors: Duarte Vieira e Brito, Bruno Jorge Pereira, Mario Lourenço,Ricardo Godinho and Carlos Rabaça.

Definition

Erectile dysfunction (ED) as defined by the NIH Consensus Development Panel on Impotence, 1993, is characterized as the persistent inability to obtain or maintain an erect penis for a satisfactory sexual performance. This can be a long term or short-term problem. Patients with ED can sometimes have sufficient erection to allow for sexual relation but not in all situations. Some patients present with erection, but it does not last long enough for a fulfilling sexual relation. It is estimated that ED currently affects over 150 million men worldwide, increasing to 322 million in 2025.

Symptoms

Manifestations of erectile dysfunction vary substantially according to its aetiology. Organic ED is characterized by a gradual onset of symptoms, their persistency and constant evolution, absence of nocturnal and morning spontaneous erections, and weak or absent non-coital erection. Psychogenic ED manifests itself by an abrupt onset of symptoms, has a sporadic or situational variation, erratic evolution and is inconstant, with some periods of normal erection. Nocturnal and morning erection are usually present as are non-coital erections and are normal and rigid. This entity is more frequent in younger individuals.

Aetiology

Diagnosis of erectile dysfunction is most frequent after the age of 40, in one of the most important studies, the Massachusetts Male Aging Study. This study accessed a population of 1290 men from 40 to 70 years and calculated a global rate of ED of 52%, with the following distribution by severity grade: severe erectile dysfunction 10%, moderate 25% and mild 17%. Normal sexual function requires a complex coordination process between psychological, endocrine, vascular, and neurologic systems. As such, its aetiology can be multifactorial and is classified in relation to its origin as psychogenic, organic (vasculogenic, neurological, hormonal, anatomical and iatrogenic) or mixed. Nowadays, most cases of ED are recognized as of mixed origin (organic and psychogenic). Factors that predispose, precipitate, and maintain psychogenic ED are inadequate sexual education, cultural and religious beliefs, previous traumatic sexual experiences, poor communication between partners, marital conflicts, sense of shame, stress, anxiety, depression, guilt, insecurity, lack of confidence, felling on inadequacy, excessive care, fear of rejection from partner, among other causes.

An organic component to ED is present in 80% of all patients. Of all organic causes the most frequent are vascular alterations relating to aging, presence of cardiovascular risk factors that predispose to insufficient arterial supply of the cavernous arteries such as arterial hypertension, dyslipidaemia, diabetes mellitus, smoking, obesity, sedentary lifestyle, and after pelvic radiotherapy. Atherogenic erectile dysfunction originates from endothelial dysfunction, a common denominator in most cardiovascular risk factors. Endothelial dysfunction reduces the ability of the arterial vessels to relax, and therefore dilate from exposure to vascular nitric oxide as its bioavailability is reduced. In addition, the presence of atherosclerosis in the cavernous, pudendal, hypogastric, or common iliac vessels produces stenosis of the vessels, reducing blood flow and therefore compromising erection capacity. The increase in sympathetic peripheral tonus, vascular structural alterations and increase in inflammatory mediators are other mechanisms that enhance atherogenic erectile dysfunction. Vascular disease is believed to be co-responsible for at least 70 to 80% of all cases of ED. The Princeton Consensus recognised ED as a symptom, being a strong predictor of presence of cardiovascular disease, particularly coronary disease. Inman et al. (2009) concluded that when ED was first diagnosed before the age of 60, it was associated with a higher risk of a future cardiovascular events comparing to men without ED. Montorsi et al. (2005) showed that the relationship between ED and coronary disease was justified by the differences in arterial lumen, as atherosclerosis is a systemic phenomenon. Being the luminal area of the cavernous arteries (1 to 2 mm) smaller than coronary arteries (3-4 mm) the effects of atherosclerosis would be more pronounced in the cavernous arteries. As such, patients with ED rarely present with complains of coronary disease, while patients with established coronary disease report ED very frequently. Patients with ED and coronary artery disease present with higher levels of inflammatory markers and prothrombotic cytokines (ex: IL-6 and fibrinogen) than those who present only with coronary disease. The COBRA trial reported that ED can precede 2 to 3 years the occurrence of a coronary event, revealing ED as a marker of vascular health and asymptomatic cardiovascular disease. Thus the manifestation of ED is an opportunity for primary prevention and intervention on cardiovascular risk factors in men, in order to avoid a future cardiovascular event.

Vasculogenic dysfunction can also originate from the venous system. Although much less frequent, venous leak is a condition where drainage of the corpus cavernosum supersedes arterial influx. Veno-occlusive dysfunction of the cavernous system can be primary (affecting mostly younger patients) or caused by degenerative conditions (like diabetes mellitus), functional or anatomical alteration of the albuginea (radiation, pelvic surgeries, Peyronie disease, among others).

Evidence

Level Grade PMID Nº

Neurogenic erectile dysfunction can have different origins and can be differentiated into central (brain or spine) or peripheral. Diseases such as stroke, brain tumours, multiple Level Grade PMID Nº

sclerosis, temporal lobe epilepsy, Parkinson disease, Alzheimer disease, encephalitis, myelitis, medullar compression, and vertebral or medullary trauma are frequently associated with neurogenic central erectile dysfunction. The most common peripheral neuropathy associated with ED is the iatrogenic lesion of the cavernous nerves during pelvic surgery, in which radical prostatectomy is a clear example. Currently the development of new surgical techniques and alternative treatments has contributed to the decrease in the rate of ED. Nevertheless, other diseases can also be responsible for ED by affecting the peripheral nerves, such as, diabetes mellitus, HIV and other viral infections, chronic alcoholism, polyneuropathies, chronic kidney disease, systemic lupus, hypothyroidism, hemochromatosis, and intoxication by heavy metals.

Endocrine alterations such as low testosterone or hypogonadism, hyperprolactinemia and thyroid disease can influence sexual behaviour and cause sexual dysfunction. Androgens play a major role in libido but also on the expression of penile nitric oxide synthetase and phosphodiesterase 5. On the other hand, low testosterone correlates with cardiovascular morbidity and mortality. Hyperprolactinemia inhibits the release of gonotrophic release hormone (GnRH) and reduces the secretion of luteinizing hormone (LH), responsible for stimulating testosterone production and secretion, thus causing hypogonadism.

Anatomical or structural deformities such as congenital penile curvature, Peyronie disease, cavernous tunica albuginea rupture, cavernous fibrosis, hypospadias or epispadias, can also be responsible for ED or painful erections.

Iatrogenic ED can be caused not only by surgeries or pelvic radiation but also because of drugs by distinct mechanisms. Drugs utilized in the treatment of arterial hypertension such as diuretics (mainly thiazide), alpha-blockers and beta-blockers are the ones most frequently responsible for the worsening of erectile function. Treatment with angiotensin- converting-enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) are less associated with ED and are a good option for patients with hypertension and erectile disfunction drug-related. Antiarrhythmic agents, such as amiodarone, digoxin and disopyramide are also thought to cause erectile dysfunction. Psychotropic medication and antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and antipsychotics, risperidone, and olanzapine, cause erectile dysfunction and other sexual impairments. As described before low testosterone levels causes ED, as such drugs that supress the hypothalamic–pituitary-testicular axis result in ED, agonists (triptorelin, leuprorelin, gosereline) of the axis work by stimulating the axis in a continuous form, eliminating the pulsatile nature of the axis needed for its continuous function and antagonist (degarelix) of GnRH, who block GnRH receptors, and peripheral antiandrogens (bicalutamide, flutamide, nilutamide, cyproterone) utilized in treating prostate cancer and ketoconazole, cimetidine, spironolactone, and others H2 receptors blockers can cause ED. In the same way, new agents utilized in treating prostate cancer (abiraterone, enzalutamide, apalutamide, daroluatamide) have the same side effect due to their mechanisms of action. Paradoxically, statins were implied in some studies as a cause of ED, while other studies and consensus do not support this theory. Recreational drugs as marijuana, cocaine, opioids, nicotine, and alcohol are responsible for changes in erectile function.

As previously mentioned, aging is one of the main risk factors for ED. Nevertheless, lifestyle and systemic diseases contribute in a major way for the onset of this disease, accelerating the normal effect of aging. Diabetes mellitus type 2 represents the second most frequent risk factor for ED. In fact, ED can be present in 50 to 75% of diabetic patients and has a 3 times higher incidence in diabetic patients when compared to non-diabetic (49,3% vs. 15,6%) and can in up to 12% of patients be the first manifestation of DM.

Psychogenic

– Factors psychological and emotional generalized – Factors psychological and emotional situational

Vasculogenic

Arterial Hypertension – Diabetes mellitus – Dyslipidaemia
Atherosclerosis – Smoking – Sedentarism
Obesity – Cardiovascular disease

-Major pelvic surgery (radical prostatectomy, cystectomy, anterior resection of the rectum, abdominoperineal amputation)

Pelvic Radiotherapy

Neurogenic

Central

Multiple sclerosis – Parkinson disease – Temporal lobe epilepsy
Braintumours – Stroke – Encephalitis and myelitis
Medullar compression and vertebral trauma

Level Grade PMID Nº

	Peripheric Diabetes mellitus – Alcoholism – Chronic kidney disease Systemic Lupus – Polyneuropathies – HIV and other viral infections Hypothyroidism and hemochromatosis – Major pelvic surgery
Endocrinological	Diabetes mellitus – Hypogonadism /Low testosterone Hyperprolactinemia -Thyroid dysfunction Peyronie and congenital penile curvature – Fracture of cavernous bodies Cavernous bodies fibrosis after priapism – Micropenis, hypospadias and epispadias
or Hormonal
Cavernosa, Anatomical
or Structural
Iatrogenic or Secondary to drugs	Antihypertension (mainly diuretics, alfa and beta blockers) Antiarrhythmic agents – Antidepressants – Antipsychotic Antiandrogens – H2 receptor blockers – Recreational drugs

Studies

Table 1: Aetiology of erectile dysfunction

A detailed clinical history is the first step in the diagnosis of ED. The main goal is to assess if the patient presents with erectile dysfunction or other alterations relation to sexuality (low libido, orgasm or ejaculatory alteration, among others). Evaluate the probable causes of ED, presence of risk factors and other potentially serious conditions. Medical, psychosocial, and sexual history must be collected, being as detailed as possible, in a calm and private environment, and if possible, in a later portion of the interview the patient partner should be summarily evaluated. It is important to understand and clarify how the patient and partner evaluate its sexuality and sexual performance, what are their expectations, and prejudices. The beginning, duration, frequency, and severity must be defined. Prior medical history is paramount and can give clues as to the origin of ED and must be questioned, use of drugs, smoking, food habits and alcohol consumption should also be questioned.

The use of standardized questionnaires can be an important tool, the International Index of Erectile Function (IIEF) (Rosen, 1997) or its shorter version , the IIEF-5, also called Sexual Health Inventory for Men (SHIM) (Rosen, 1999) are among the most commonly utilized, other questionnaires such as the Brief Male Sexual Function Inventory (BMSFI) (O’Leary, 1995), Dysfunction Inventory for Treatment Satisfaction (EDITS) (Althof, 1999), Derogatis Sexual Function Inventory (Derogaris e Melisaratos, 1979), Centre for Marital and Sexual Health Questionnaire (Glick, 1997), Male Sexual Function Scale (Rosen, 2004) are also validated and can be used. By utilizing the IIEF-5 questionnaire diagnosis of erectile dysfunction is simplified, quicker, more selective and comparable between observers. With only five questions, scoring from 1 to 5, it evaluates the patients last 6 months of sexual activity. With a maximum score of 25, patients scoring less than 21 present with some degree of ED (mild, moderate, severe) it also allows for the monitoring of response from given treatment.

IIEF-5

01. How do you rate your confidence that you could getand keep an erection?

02. When you had erections with sexual stimulation, how often were your erections hard enough for penetration?

03. During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner?

04. During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse?

05. When you attempted sexual intercourse, how often was it satisfactory for you?

Table 2. IIEF-5 questionnaire

A directed physical exam should be performed, assessing cardiovascular and neurological status ( body habit, blood pressure, heart rate, palpation of peripheral pulses, Level Grade PMID Nº

sensation particularly genital/perineal, sphincter tonus and presence of bulbocavernosus reflex), signs of hypogonadism (absence of secondary sexual characters, testicular dimension, symmetry and consistency), penile deformities (dimension and presence of a plaque), and exclusion of prostatic disease ( digital rectal exam), this part of the physical exam is an ideal time to educate, reassure and correct the patients of any misconceptions.

Due to the strong correlation between erectile dysfunction and cardiovascular disease, all patients should be stratified in accordance with their risk in low, medium, and high (table3).

Low risk	Intermediate risk	High risk
Asymptomatic with less than 3 risk factors for coronary disease (excluding male sex)	 3 risk factors for coronary disease (excluding male sex)	High risk Arrythmias
Mild stable angina	Moderate stable angina	Unstable Angina or refractory angina
Uncomplicated previous acute myocardial infarction	Recent previous acute myocardial (between 2 to 6 weeks)	Acute myocardial (less than 2 weeks)
Left ventricular dysfunction/Congestive heart failure (level I or II of NYHA)	Left ventricular dysfunction/Congestive heart failure (level III of NYHA)	Left ventricular dysfunction/Congestive heart failure (level IV of NYHA)
After successful cardiac revascularization	Non cardiac sequela of atherosclerosis (Stroke, peripheral vascular disease)	Hypertrophic cardiomyopathy and other cardiomyopathies
Controlled arterial hypertension		Uncontrolled arterial hypertension
Mild valvular disease		Moderate to severe valvular disease
Orientation
Sexual activity can be maintained, and prescription of medication can be made.	A detailed cardiovascular evaluation is required to reclassify the patient before treatment	Stop sexual activity. Treat underlying condition first. Should be observed by a cardiologist before beginning treatment.

Table 3. Cardiovascular risk stratification based on the Princeton III Consensus Recommendations for the Management of Erectile Dysfunction and Cardiovascular Disease, 2012.

Complementary exams

Further investigation on patients with erectile dysfunction should include a metabolic and hormonal evaluation, with the objective of identifying cardiovascular risk factors, metabolic syndrome and endocrine alteration that can cause ED. Fasting glucose, glycated haemoglobin (HbA1c) and a lipid profile ( total cholesterol, HDL and triglycerides), non- HDL cholesterol reflects in a more accurate form the atherosclerotic risk of the patient, and can be calculated by the Friedwald formula (total cholesterol – HDL cholesterol = non-HDL cholesterol). Total and free testosterone should be measured and in the case of low levels a deeper investigation should be performed by measuring prolactin, LH and TSH, in patients over 45-50 years total PSAshould be obtained.

The use of more complex and further exams is not recommended in the absence of a clear justification, as they increase cost and are invasive procedures that will not change most patients’ treatment options. There are although some indication for additional investigations summarized in table 4.

Table 4. Indication for specific additional exams

Indication for specific additional exams

Primary erectile dysfunction

History of pelvic or perineal trauma

Congenital penile deformities

Penile fibrosis (Peyronie or after priapism)

Major psychiatric disease

Diseases of the central nervous system

Complex endocrine diseases

Severe cardiovascular disease

Lack of response to treatment

Penile Eco Doppler with vasoactive medication, is considered a minimally invasive exams, assuming an important role in assessing the vascular state of the penis, exclude and diagnose other aetiologies for ED and help target treatment. A normal Eco Doppler, systolic peak velocities superior to 35 cm/s, resistance index >0,8 and diastolic velocity <5 cm/s, dispenses additional vascular investigation.

In recent years techniques aiming to evaluate the presence of cavernous endothelial dysfunction have emerged (Endo-PAT2000), measure of nitric oxide and endoteln-1, C reactive protein and circulating endothelial progenitor cells.

Exams	Benefits	Limitations
Questionnaires	Validated and easy to use Assess severity and presence of erectile dysfunction	Does not identify the cause
Nocturnal penile erection assessment (RigiScan)	Allow to differentiate between o rganic and psychogenic erectile dysfunction	Nocturnal erections can be caused by a different pathway Does not detect sensitive erectile dysfunction False positives in patients with sleep disturbance Only assess radial rigidity and not axial Does not correlate with IIEF-5 score
Vasoactive test	Quick and easy to perform Evaluates severity	Risk of prolonged erection and priapism
Penile Eco Doppler	Allows for the diagnosis of arteriogenic erectile dysfunction Can suggest the presence of other vascular diseases	Less accurate for the diagnosis of venous erectile dysfunction Insufficient smooth muscle relaxations due to anxiety or sympathetic tonus increase can cause false positives Redosing and retesting are frequently required


Cavernosometry and dynamic cavernosography	Diagnosis venous erectile dysfunctions Monitors intracavernous pressure Identifies the venous leak cause and cavernous anomalies	Invasive Insufficient smooth muscle relaxations due to anxiety or sympathetic tonus increase can cause false positives
Selective angiography	Anatomical evaluation of the arterial branches in the case of planned surgery for congenital or trauma induced erectile dysfunction	Invasive Can be influenced by methodology and timing
Neurological evaluation tests	Evaluation of somatic nervous pathways	Does not evaluate autonomic nervous function Are not universally accepted or reproduceable Complex and time consuming

Table 5. Benefits and limitations of additional studies in the diagnosis of erectile dysfunction

Treatment

A wide range of therapeutic strategies are available for treatment of erectile dysfunction. Oral treatment with phosphodiesterase type 5 inhibitors (PDE5) are the most common drug utilized. In most cases treatment of ED in noncurative, it allows the patient to have sexual intercourse without treating the cause, only in particular cases can treatment aim to be curative as in the case of psychogenic, endocrine disturbances, penile revascularization surgery in traumatic ED.

1. Lifestyle modifications and correction of risk factors

Modification of lifestyle and control of associated comorbidities should represent a priority in these group of patients, correcting risk factors has a recognized health benefit and is among the safest therapies. Patient education is paramount to ensure compliance to treatment, and benefits of behavioural changes must be made clear to the patient. Regular exercise, weight loss, food education and diet changes, reduction or if possible, elimination of alcohol and smoking should be promoted. Lifestyle changes can prevent or even accelerate regression of initial manifestations of ED and help control the patients’ other comorbidities and cardiovascular risk factors. Sedentary patients present a rate of ED between 43 and 70%. Regular exercise lowers the risk of ED to a third and it is estimated that 60 minutes of exercise a day 3 to 4 days a week at 70 to 80% of maximal aerobic capacity may increase the frequency of sexual intercourse, quality of erections, higher score on the IIEF-5 questionnaire and can even normalize testosterone levels in patients suffering from ED. Additionally, regular exercise can diminish the risk of acute myocardial infarction during sexual intercourse.

In a large study with 37724 men without ED, an increase in the risk of erectile dysfunction of 40% was found in men who became obese, demonstrating that weight loss, a healthy diet and reduced caloric ingestion is associated with better erectile function. Weight loss associated with regular exercise, interferes, in a positive way, in endothelial dysfunction, insulin resistance and reduction of the inflammatory state associated with diabetes mellitus and metabolic syndrome.

Regarding smoking, former smokers present lower rates of erectile dysfunction when compared to current smokers (2.0% vs 3.7%). In another study, a rapid and significant benefit in erectile function was found in patients with a smoking load above 30 pack-years who stopped smoking. However, in general lifestyle changes can take up to two years to produce positive effects on erectile function, as such, patients should be reassured and encouraged to maintain a healthy lifestyle. A combined approach using phosphodiesterase type 5 inhibitors (PDE5i) can produce results in 3 months. A regular follow-up and a multidisciplinary team seem to motivate and commit patients to changes in lifestyle in a more effective way.

1. Sexual therapy

The use of psychotherapy and sexual therapy are indicated when there is a relevant psychological disorder contributing to erectile dysfunction. Therapy should be performed by a sexual therapist and should include the couple to improve communication between partners and increase patients’ self-confidence. The main techniques used include sensate focus exercises, sexual education, and interpersonal therapy. These treatments can also be useful in men with organic ED as an adjuvant to medical or surgical treatments.

1. Oral treatment with phosphodiesterase type 5 inhibitors (PDE5i)

With the introduction of sildenafil in 1998, PDE5i, became the first line treatment for ED. These medications aim to promote erection by inhibiting the enzyme phosphodiesterase type 5, responsible for the metabolism of cGMP in the cavernous smooth muscle. By increasing available cGMP, smooth muscle relaxation is maintained, and expansion of the sinusoidal spaces is promoted, resulting in a prolonged and stronger erection. In this context, it is important to understand that PDE5i do not initiate the erectile process and require previous sexual stimulus to act.

Currently the most universally available PDE5i on the market are sildenafil (Viagra), vardenafil (Levitra), tadalafil (Cialis) and avanafil (Spedra). Sildenafil and tadalafil are currently available as a generic. These medications differ on the molecular level having a different pharmacokinetic profile and different selectivity, something determinant in terms of side effects profile (table 6).

	Sildenafil	Vardenafil	Tadalafil	Avanafil
Date of launch	1998	2003	2003	2013
Dosage	25, 50 100 mg Maximum dosage 100 mg/day	5, 10 20 mg Maximum dosage 20 mg/day	5, 10 20 mg Maximum dosage 20 mg/day	50, 100 200 mg Maximum dosage 200 mg/day
Posology	On demand	On demand	On demand or daily	On demand
Time to action	30-60 minutes	30 minutes	45 minutes	15-30 minutes
Duration	4-8 hours	4-8 hours	Up to 36 hours	Over 6 hours
Food and alcohol interactions	Food interferers must be administered fasted. No interaction with alcohol	Food interferers must be administered fasted. No interaction with alcohol	No interaction with food and alcohol	No interaction with food and alcohol
Side effects	Headache, flushing, dyspepsia, acyanopsia/bluish vision	Headache, flushing, dyspepsia, rhinorrhoea	Headache, flushing, dyspepsia, rhinorrhoea, lumbar pain, myalgia	Headache, less common side effects due to higher selectivity
Contraindications	Nitrates, severe cardiovascular events, optical neuropathy, and alpha- blockers	Like sildenafil and type 1 and 3 antiarrhythmic drugs Prolonged QT syndrome	Like sildenafil	Like sildenafil

Table 6. Pharmacokinetic profile and side effects.

Tadalafil is currently the only PDE5i approved for daily usage in the 5 mg form and is also approved for treatment of male Lower Urinary Tract Symptoms (LUTS) caused by benign prostatic hyperplasia, particularly in men with concomitant ED. Taken every day, tadalafil, allows for a more spontaneous sexual relation and is preferred by patients with a higher frequent sex life. Some studies indicate that regular usage of PDE5i can have beneficial effects on endothelial function and may even function in patients nonresponsive to an on- demand posology.

Success rate of PDE5i is of less than 65%. The most difficult patients to treat are patients with diabetes mellitus, severe neurological diseases, and peripheral neuropathy as well as patients submitted to pelvic surgery. It is established that independently of the drug utilized, each medication should be tried for at least four times before assuming the patient as nonresponsive. Due to the profound effects of vasodilation, concomitant usage with nitrates is forbidden due to the risk of severe vasodilation and hypotension with ischemia risk. They should also be utilized with caution in patients on alpha-blockers, particularly in less selective drugs (doxazosin and alfuzosin). Contrarily to popular belief, these medications do not increase the risk of acute myocardial infarction or death by cardiovascular causes and are safe medications. Daily tadalafil can also be combined with on-demand additional administrations with a good response in patients with severe ED.

1. Testosterone replacement therapy

Testosterone replacement therapy is recommended in men with ED and low testosterone. Hypogonadal patients present with reduced libido in association with ED and can also present, less frequently, with ejaculatory and orgasm dysfunctions. Even though testosterone values needed for an erection are low, a metanalysis of 16 studies on hormonal repositioning with testosterone clearly demonstrated a benefit on erectile function in hypogonadal men, when compared to placebo (57,0% vs 16,7%). It can further turn PDE5i nonresponsive men into responsive.

Transdermal and intramuscular formulations are available for use. In the intramuscular formulation testosterone enanthate and ester (250 mg) are administered every 2-4 weeks, while testosterone undecanoate (1000mg) is given in a trimestral formulation, requiring less frequent injections. Hormonal repositioning is generally safe and offers systemic metabolic benefits in regards of bone mineralization, increase in muscle mass, motivation, energy, and global quality of life. The potential side effects should be monitored like erythrocytosis, (controlled with periodic hemograms), hypertension, hepatic toxicity, sleep apnoea and LUTS worsening. There is theoretical potential risk for developing prostate cancer, but the subject is controversial and men on testosterone replacement should have the same values as normal and therefore the same risk. Testosterone replacement should be avoided in men seeking to be fathers as testosterone supplements can reduce spermatogenesis and induce infertility.

1. Topical and intraurethral treatment with Alprostadil

Alprostadil, a prostaglandin E1 (PGE1), has been for many years administered as an intracavernous drug and can currently also be administered in a less invasive way, as a urethral suppository (Muse 125 to 1000 mcg) or as a topical cream (Vitaros 300 mcg). In both cases absorption occurs through the urethral mucosa, and erection begins 5 to 20 minutes after application of the drug. It has a success rate of 43-65% and systemic side effects are rare, but local symptoms such as erythema, burning and urethral or penile pain may occur.

1. Vacuum erection devices (VED)

VED promote erection with the application of a negative pressure created by a manual or electric pump, producing a passive engorgement of the penis. This action is complemented with the use of a penile constriction ring at the base of the penis, locking the blood in the cavernous bodies and thus maintaining erection. These devices can be uncomfortable to use but are generally safe and present with a very high success rate of around 80 to 90%. They can also be very economical specially if used for long periods of time. Blood constriction should not surpass 30 minutes due to the risk of penile ischemia. The main disadvantage of VED is the creation of a non-natural erection with a cold and purple penis and may cause penile pain or hypoesthesia, bruising, petechiae and ejaculatory dysfunction.

1. Low intensity shockwave treatment (Li-SWT)

Treatment with low intensity shockwave has been investigated and applied in the past decade. It is considered a safe treatment, virtually without side effects and that functions by generating microtrauma and inducing mechanical stress on endothelial cells. This phenomenon activates perivascular stem cells and produces angiogenic factors (VEGF, NO- synthetase and von Willebrand factors). Conceptually the combination of these events would stimulate angiogenesis, increase blood flow and vascularization of the tissues and optimization of endothelial function. It can also, theoretically, reverse tissue fibrosis and regenerate neuronal damage.

Globally Li-SWT seems to significantly increase IIEF score and Erection Hardness score in patients with mild and moderate ED and in patients who do not respond to PDE5i or in combination with PDE5i. Most studies and metanalysis report encouraging results although many question remain unanswered such as what is the best equipment? What is the best protocol? Which is the better probe? Should radial or linear shockwaves be used? Where should treatment be applied? Which energy density should be used and to what limit? Which is the ideal number of pulses and sessions? Should the number of sessions vary accordingly to ED severity? Which is the optimal frequency of sessions? Can treatment cycles be repeated? And so on.

The arrival of low intensity shockwaves 20 years after the launch of the first PDE5i brought a breath of fresh air in the treatment of ED, and it is presently the only potential curative therapy. Nevertheless, long-term consolidated results are still needed.

1. Intracavernous treatment with Alprostadil

Evidence

Alprostadil (Caverject) was the first and only drug approved for intracavernous injection in the 5 to 40 mcg dosage in monotherapy. By stimulating cAMP, it promotes smooth Level Grade PMID Nº

trabecular muscle relaxation and unlike others PDE5i it works independently of penile enervation and sexual stimulus. Currently used as a second line therapy, it can be the treatment of choice for patients with neurogenic ED or in the rehabilitation of penile function after pelvic surgery. E1 prostaglandin is directly injected into the cavernous bodies, perpendicularly to the lateral zone of the penis with care to avoid the dorsal neurovascular bundle and the urethra. Injections should be taught by a health professional to the patient or partner so it can be safely administered at home. Erection occurs after 5 to 15 minutes. Alprostadil can also be combined with papaverine and phentolamine.

The most common side effects are penile pain after injection, priapism, and cavernous fibrosis. Patients with recurrent priapism or coagulopathies should not use this medication. The main limitation for its use is the unwillingness of the patients to administer the medication and represents the reason why more than half the patients abandon treatment. Success rate is of around 70% even in difficult-to-treat subgroups. Its rapid onset of action is the main reason why patients who regularly and consistently use this drug present with a high satisfaction rate (87 to 94%).

1. Penile prosthesis

Penile prosthesis is regarded as the last resort treatment for organic ED, employed when other options are unsuccessful or declined by the patient. Penile prosthesis surgery is an irreversible procedure since the trabecular tissue is destroyed to allow for the placement of the prosthetic cylinders. Currently two main types of prothesis are available: semirigid rods and inflatable or hydraulic (of 2 or 3 components). The first consists of two rigid cylinders that are placed inside the cavernous bodies and are repositioned for sexual intercourse. The main advantages of this type of prothesis are being easier to place and less difficulty in its use in patients with low dexterity. Most patients prefer the 3 components inflatable prothesis as they are the most similar ones to a natural erection. These prothesis are made of two inflatable cylinders, inflated with fluid that circulates between the cylinders and a reservoir placed in the abdomen and activated by a pump in the scrotum. To induce erection patients have to press the pump thus initiating the passage of fluid from the reservoir to the cylinders. The penis returns to its flaccid state by pressing a small button on the pump that promote the fluid return to the reservoir.

The most common complications are infection (in 2 to 4% of patients) and mechanical failure that can be as high as 5% in 5 years. In most cases penile prosthesis implant surgery is a safe and efficient treatment for erectile dysfunction and grants a high satisfaction rate, up to 70% for the patients and 90% for the partner.

10 .Vascular surgery

Arterial bypass surgery is indicated in traumatic lesions of the penile arteries and venous ligation can be useful in younger patients with venous leak erectile dysfunction.

Nowadays they are used only in very well selected patients due to the high success rate of less invasive treatments.

11. Future treatments

Despite the demand and current investigations on treatments for erectile dysfunction many patients still present with incomplete or unsatisfactory results and may not be candidates for more invasive treatments. There is also an intent to develop treatments that reverse molecular and tissue changes in patients with ED. The most recent treatment with this aim is the use of low intensity shockwaves with its theoretical curative potential. Other emerging treatments aim to regenerate the neuronal and vascular endothelium. Preliminary studies with steam cells have showed that these treatments can be safe, well tolerated, and effective. Genetic therapies are also in development for treatment of ED. Injection of intracavernous platelets enriched plasma aims to regenerate tissue by stimulating the secretion of vascular growth factors. Intracavernous botulin toxin is being used as a cavernous smooth muscle relaxing agent for the treatment of ED in a clinical trial. Endovascular techniques with placement of stents and balloon angioplasties on the pudendal arteries are being experimented with the aim to mitigate the effects of atherosclerosis. External penile prosthesis are under development, being simpler to install, more accessible and easier to activate.

Therapeutic Strategy

- - Lifestyle modification (regular exercise and decrease in BMI) can improve erectile function.
  - Initiate lifestyle changes and risk factor modification prior to, or at the same time, as initiating ED treatments.
  - Treat a curable cause of ED first, when found.
  - Use PDE5i as first-line therapeutic option.
  - Use topical/intraurethral alprostadil as an alternative first-line therapy in well-informed patients who do not wish or are not suitable for oral vasoactive therapy, and in patients who do not wish to initiate intracavernous injections.
  - Use low intensity shockwave treatment (LI-SWT) in patients with mild vasculogenic ED or as an alternative first-line therapy in well-informed patients who do not wish or are not suitable for oral vasoactive therapy or desire a curable option. Use LI-SWT in vasculogenic ED patients who are poor responders to PDE5i.
  - Use vacuum erection devices (VEDs) as first-line therapy in well-informed patients with infrequent sexual intercourse and co-morbidity requiring non-invasive, drug-free management of ED.
  - Use implantation of a penile prosthesis if other treatments fail or based upon patient preference.

Weak Weak Strong Weak

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DYSPAREUNIA AND DECREASED FEMALE LUBRIFICATION

Authors: Carmen Salvador-Coloma, Inmaculada Soler-Ferrero and Alejandra Giménez Ortiz.

Introduction

The most common issues interfering quality of life of cancer survivors are sexual health concerns (1-2). Different treatments as surgery, radiation, hormonotherapy, and chemotherapy cause difficult biologic and psychological changes that interferes how women feel about their sexuality (3). Among female cancer survivors or women who are receiving treatments, vaginal dryness, and related painful intercourse, also called dyspareunia, is one of the most frequently reported concerns (4-6). Other symptoms include itching, dysuria, irritation, and urinary tract infections. All of these problems lead to early discontinuation of treatment or poor compliance, which may have an impact on cancer outcome (7-8).

Therefore, cancer diagnosis and treatment have a complex impact of sexual health. Managing sexual problems is important, but might involve different therapies, treatments or a combination of them (2-4).

Symptoms

Cancer is an increasingly common disease; survivors is also increasing due to early diagnosis and more effective treatments. Patients who receive chemotherapy, pelvic surgery, radiation to the ovaries or hormonotherapy, particularly young women, are more likely to suffer from dyspareunia, vaginal dryness, decreased libido, difficulty in reaching orgasm, itching, burning, or pain/discomfort all the time, not just during sexual activity (9-10).

Etiology

Decrease in vaginal lubrication is caused by a lack or decrease of oestrogen to the vaginal tissue or changes in the body. Pelvic surgery, chemotherapy, radiation to the ovaries and hormonal therapy can all cause these changes. This drop in oestrogen levels causes the vaginal tissue to thin and produce less natural lubrication (figure 1)(2).

Figure 1. Drop in estrogen levels causes pain with vaginal penetration due to vaginal atrophy and dryness. Adapted from Astalos Chism L, Magnan MA. Talking to cancer survivors about dyspareunia and self-management. Nursing. 2017;47(10): 24-29 (2).

Treatment

Non-hormonal therapy:

Vaginal lubricants and moisturiser:

This treatment is effective in treating dyspareunia and vaginal dryness when used regularly (3-5) times per week) and benefit for sexual comfort. Although there is limited evidence in breast cancer survivors (10-11). There are 3 types:

Polycarbophil gels
Water-based gels
Pectin-based gels

Evidence

Level Grade PMID Nº

Evidence

Loprinzi et al. (12) performed a trial with Polycarbophil gels resulted in significant improvement in dyspareunia in 60% of patients (12). A randomized trial in patients with tamoxifen Level Grade PMID Nº

who complained of vaginal dryness found that polyacrylic acid was superior to a lubricant in sexual dysfunction (13=. Furthermore, the OVERcome study showed a significant improvement in sexual function, dyspareunia, and quality of life over time (P < 0.001) in breast cancer survivors (14).

Vaginal laser therapy:

Fractional micro ablative CO2 laser therapy (3 treatments over 12 weeks) was compared versus placebo in 77 postmenopausal women with vulvovaginal atrophy. It was associated with a significant improvement of sexual function and satisfaction with sexual life in postmenopausal women with vulvovaginal atrophy symptoms (15). Another study with fractional CO2 laser therapy in breast cancer survivors as a therapeutic method for vulvovaginal atrophy dyspareunia was compared versus placebo too. It appeared to be a feasible and effective treatment for vulvovaginal atrophy dyspareunia in breast cancer survivors with contraindications to hormonal treatments(16). It is a promising technology, but to date no randomized trials and no data for women on ongoing anti-oestrogen therapy.

Hormonal therapy:

Vaginal oestrogen therapy:

The decision to use this treatment should be made on an individual basis, considering the patient’s tumour characteristics, symptoms, risk factors and potential benefits (10=. Vaginal oestrogen appears to be safe, especially if not breast cancer. In breast cancer survivors was recommended only for patients who are unresponsive to non-hormonal remedies. There have been no clinical trials of vaginal oestrogen therapy, only small studies, in breast cancer survivors. Patients with very pronounced vaginal symptoms may be treated with local, low-dose oestrogens. However, it should be avoided or used for very short periods of time (10). No association between vaginal oestrogen and breast cancer recurrences have been documented, estriol instead of oestradiol has been proposed as a better option in breast cancer survivors (10-17).

So that, non-hormonal approaches are the first-line choices during or after treatment for breast cancer. For patients with hormonal receptor positive breast cancer experiencing urogenital symptoms, vaginal oestrogen should be reserved for those patients who do not benefit from non-hormonal treatments. This decision must be coordinated between the oncologist and other specialists (18).

Oral hormone therapy:

Oral hormone therapy can be given in women with cancer, not considered hormonally driven. Routinely done after ovarian, endometrial, cervical cancer. Oral hormone therapy, however, may not be safe after hormonal receptor positive breast cancer.

The randomized HABITS study compared hormone therapy for menopausal symptoms with best management without hormones among women with previously treated breast cancer. This trial was stopped early due to suspicions of an increased risk of new breast cancer events following hormone therapy. The extended follow-up of this trial showed there was a clinically and statistically significant increased risk of a new breast cancer event in hormonal receptor positive breast cancer survivors who took hormone therapy (19).

Some other hormone therapy:

Dehydroepiandrosterone (DHEA): has been proposed to treat vulvovaginal atrophy. Three-arm randomized, controlled trial evaluated DHEA 3.25 mg and DHEA 6.5 mg, each compared to a plain moisturizer over 12 weeks, to improve the severity of vaginal dryness or dyspareunia. Postmenopausal women with a history of breast or gynaecologic cancer who had completed primary treatment, had no evidence of disease, and reported at least moderate vaginal symptoms were eligible. Plain moisturizer and DHEA improved vaginal symptoms. However, vaginal DHEA, 6.5 mg, significantly improved sexual health. However, vaginal DHEAwarrants further investigation in women with a history of cancer (20).
Ospemifene: is a selective oestrogen receptor modulator (SERM). It is indicated for the treatment of moderate to severe symptomatic dyspareunia (secondary to vulvovaginal atrophy) in postmenopausal women who are not candidates for local vaginal oestrogen therapy. However, it should not be used in women with known or suspected breast cancer or with a history of breast cancer (10,21,22=. Although preclinical data suggest that ospemifene has a neutral or inhibitory effect on mammary carcinogenesis, further studies are necessary to know its safety in breast cancer patients (10,23).

Pharmacotherapy

The first choice for treating vaginal dryness and soreness are hormone-free lubricants and moisturisers (e.g. water-based gel, hyaluronic acid gel)(23).	II	B	32979513
If hormone-free measures are not effective, low-dose oestrogen containing vaginal medication may be used (23).	II	B	32979513
The value of local testosterone application and of invasive measures like vaginal laser or hyaluronic acid injections is still unclear (23).	V	C	32979513

Therapeutic Strategy Level GradeEvidence

PMID Nº

Sexuality must be managed as a part of treatment to improve quality of life in cancer survivors. It should be addressed through a multidisciplinary team.
Exercises to regain confidence in the sexual response. Psychologist intervention to improve sexual health.
Partners should be included in support programmes.
The use of vaginal lubricants is recommended for vaginal dryness.
Topical oestrogen treatment for vaginal symptoms can be used but only after discussion with the treating oncologist, as clinical trials have not been undertaken in women with breast cancer.

References:

De Simone M, Spriggs E, Gass JS, et al. Sexual dysfunction in female cancer survivors. Am J Clin Oncol. 2014;37(1): 101-106.
Astalos Chism L, Magnan MA. Talking to cancer survivors about dyspareunia and self-management. Nursing. 2017;47(10): 24-29.
Sadovsky R, Basson R, Krychman M, et al. Cancer and sexual problems. J Sex Med. 2010;7(1 Pt 2):349-373
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American Cancer Society. Vaginal Dryness. 2020. Found at: http://www.cancer.org/treatment/ treatmentsandsideeffects/physicalsideeffects/sexualsideeffectsinwomen/sexualityforthewoman/sexuality- for-women-with-cancer-vaginal-dryness
National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: Survivorship. 2021.
Ussher JM, Perz J, Gilbert E. Changes to sexual well-being and intimacy after breast cancer. Cancer Nurs. 2012;35(6):456-465
Sussman TA, Kruse ML, Thacker HL, Abraham J. Managing Genitourinary Syndrome of Menopause in Breast Cancer Survivors Receiving Endocrine Therapy. J Oncol Pract. 2019; 15:363-370.
Morales L, Neven P, Timmerman D, et al: Acute effects of tamoxifen and third-generation aromatase inhibitors on menopausal symptoms of breast cancer patients. Anticancer Drugs 15:753-760, 2004
Candy B, Jones L, Vickerstaff V, Tookman A, King M. Interventions for sexual dysfunction following treatments for cancer in women. Cochrane Database Syst Rev. 2016 Feb; 2:CD005540.
Mendoza N, Carrión R, Mendoza-Huertas L, Jurado AR. Efficacy and Safety of Treatments to Improve Dyspareunia in Breast Cancer Survivors: A Systematic Review. Breast Care 2020;15:599–607. DOI: 10.1159/000506148.
Mazzarello S, Hutton B, Ibrahim M, et al. Management of urogenital atrophy in breast cancer patients: a systematic review of available evidence from randomized trials. Breast Cancer Res. Treat. 152 (1) (2015) 1–8.
Loprinzi CL, Abu-Ghazaleh S, Sloan JA, et al. Phase III randomized double-blind study to evaluate the efficacy of a polycarbophil-based vaginal moisturizer in women with breast cancer. J Clin Oncol. 1997 Mar;15(3):969-73. doi: 10.1200/JCO.1997.15.3.969. PMID: 9060535.
Juliato PT, Rodrigues A.T, Stahlschmidt R, et al. Can polyacrylic acid treat sexual dysfunction in women with breast cancer receiving tamoxifen? Climacteric 23 (November) (2016) 1–5
Juraskova I, Jarvis S, Mok K, et al. The acceptability, feasibility, and efficacy (phase I/II study) of the OVERcome (Olive Oil, Vaginal Exercise, and MoisturizeR) intervention to improve dyspareunia and alleviate sexual problems in women with breast cancer, J. Sex. Med. 10 (10) (2013) 2549–2558.
Salvatore S, Nappi RE, Parma M, et al. Sexual function after fractional microablative CO₂ laser in women with vulvovaginal atrophy. Climacteric. 2015 Apr;18(2):219-25. doi: 10.3109/13697137. 2014.975197. PMID: 25333211.
Pieralli A, Fallani MG, Becorpi A, et al. Fractional CO2 laser for vulvovaginal atrophy (VVA) dyspareunia relief in breast cancer survivors. Arch Gynecol Obstet. 2016 Oct;294(4):841-6. doi: 10.1007/s00404-016-4118-6. Epub 2016 May 12. PMID: 27170261.
Melisko ME, Goldman M, Rugo HS, Amelioration of sexual adverse effects in the early breast cancer patient, J. Cancer Surviv. 4 (3) (2010) 247–255.
http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Gynecologic-Practice/The-Use-of-Vaginal-Estrogen-in-Women-With-a-History-of-Estrogen-Dependent- Breast-Cancer
Holmberg L, Iversen OE, Rudenstam CM, et al. HABITS Study Group. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst. 2008 Apr 2;100(7):475-82. doi: 10.1093/jnci/djn058. Epub 2008 Mar 25. Erratum in: J Natl Cancer Inst. 2008 May 7;100(9):685. PMID: 18364505.
Barton DL, Sloan JA, Shuster LT, et al. Evaluating the efficacy of vaginal dehydroepiandosterone for vaginal symptoms in postmenopausal cancer survivors: NCCTG N10C1 (Alliance). Support Care Cancer. 2018 Feb;26(2):643-650. doi: 10.1007/s00520-017-3878-2. Epub 2017 Sep 18. PMID: 28921241; PMCID: PMC5754227.
Ospemifene tablets, Prescribing Information. Shionogi Inc. Florham Park, NJ. Available at: https://www.duchesnayusa.com/files/pdf/osphena_prescribing_information.pdf.
Cui Y, Zong H, Yan H, et al. The efficacy and safety of ospemifene in treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy: a systematic review and meta-analysis, J. Sex. Med. 11 (2) (2014) 487–497.
Wurz GT, Soe LH, Degregorio MW. Ospemifene, vulvovaginal atrophy, and breast cancer, Maturitas 74 (2013) 220–225.
Cardoso F, Paluch-Shimon S, Senkus E, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol. 2020 Dec; 31 (12) :1623-1649. doi: 10.1016/j.annonc. 2020.09.010. PMID: 32979513; PMCID: PMC7510449.

Others

- For women with hormone receptor positive breast cancer experiencing urogenital symptoms, vaginal oestrogen should be reserved for those patients who do not benefit from non-hormonal remedies.
- Data do not show an increased risk of cancer recurrence among women currently undergoing treatment for breast cancer or those with a personal history of breast cancer who use vaginal oestrogen to relieve urogenital symptoms.
- Oral hormone therapy can be given in women with cancer, not considered hormonally driven. Routinely done after ovarian, endometrial, cervical cancer.
- Oral hormone therapy, however, may not be safe after hormonal receptor positive breast cancer.

RADIATION THERAPY INDUCED CYSTITIS

Authors: Bruno Moura Fernandes, Carolina Carvalho and Tomás Cabral Dinis Evidence

Introduction Level Grade PMID Nº

- - Radiation Therapy (RT) induced cystitis refers to a collection of symptoms and signs defined by haematuria, low urinary tract symptoms (LUTS) and cystoscopy findings indicative of underlying urothelial damage. It is often an adverse event in patients previously submitted to pelvic irradiation for urological, gynecological or rectal malignancy.
  - The probability of developing tissue injury is mainly related to total radiation dose, RT technique and radiation dose per fraction. The use of modern radiation therapy techniques such as Intensity Modulated Radiation Therapy (IMRT) and Volumetric Modulated Arc Therapy (VMAT) have reduced the radiation dose delivered to the bladder wall and therefore reduced the risk of radiation induced cystitis.

Symptoms

- - Acute Cystitis – Develops up to 3 to 6 months after RT treatment.
    - LUTS
    - Suprapubic discomfort or pain.
    - Haematuria – rare in acute phase.
    - Urinary retention – rare.

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- - Chronic Cystitis – >6 months after RT but can develop more than 10 years after the end of treatment.
    - LUTS
    - Pelvic pain;
    - Urinary incontinence;
    - Urinary retention – Urethral or bladder neck strictures or secondary to obstructing blood clots.
    - Haematuria – Most common symptom in chronic radiation induced cystitis.
      - Microscopic.
      - Macroscopic.
  - It can be divided in two major subtypes:
    - Inflammation predominant form of radiation induced cystitis:
      - Storage (Pollakiuria, Dysuria, nocturia, urgency, incontinence) or voiding (Low urinary flow, incomplete emptying of the bladder, hesitancy in micturition) LUTS.
    - Bleeding predominant form of radiation induced cystitis:
      - Predominant Haematuria.
  - Severity of haematuria should be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) – version 5.0 (Table 1.)

Etiology

- - Acute radiation urethritis and cystitis is a very common side effect with reported incidence of up to 50% of irradiated patients.
  - Severe chronic radiation cystitis is less common and affects 5-10% of irradiated patients.
  - Estimated prevalence of radiation induced haemorrhagic cystitis varies widely according to the literature and primary tumour location. 9-21% following prostate cancer treatment, 3-6.7% following cervical cancer treatment and 2-47% following bladder cancer treatment.
  - Individual patient factors may also contribute for this incidence variation such as vascular or connective tissue diseases, diabetes mellitus, previous surgeries, smoking and concurrent chemotherapy.
  - Acute radiation cystitis and chronic radiation cystitis are generally considered separate pathological processes with early signs of urothelial damage occurring until 3 months after RT and pathological changes occurring 6-12 months after RT.
    - Acute: Urothelial desquamation, atypia, and eosinophilic infiltration.
    - Chronic: Vascular and muscle changes with hyperplasia, endothelial cell damage and perivascular fibrosis resulting in ischemia and obliterative arteritis with subsequent decreased bladder capacity and compliance. These changes contribute to haematuria, mucosal ulceration and even perforation or fistulae.
  - The exact mechanism by which radiation causes damage to the bladder wall is not entirely understood but it’s believed to be multifactorial:
    - Histological studies have demonstrated increased urothelial proliferation in the months after radiation exposure.
    - Damage to tight cellular junctions and the loss of the normal polysaccharide layer allow for increased permeability of urine bacteria and metabolites causing increased damage to the underlying tissue. This altered permeability is thought to play an important role in the development of post-radiation urinary symptoms.
    - Usual evolution of histopathological findings are diffuse mucosal oedema vascular telangiectasia submucosal haemorrhage Interstitial fibrosis.
    - Cumulative subendothelial proliferation progressively depletes blood supply resulting in endarteritis obliterans causing acute and chronic ischemia Subsequent development of revascularization with superficial, fragile vessels that are responsible for bleeding Progressive lack of oxygenation with eventual tissue ischemia and necrosis.
  - It can be of late appearance with symptoms onset recorded up to 20 years after radiation treatment.
  - Multiple studies have shown significant impact on patient-related quality of life through validated scales.

Evidence Level Grade PMID Nº

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Etiology

- - Detailed medical interview with symptom characterization and previous RT treatment record.
  - Physical examination.
  - It’s imperative to rule out other causes of haematuria such as malignancy or infection.
  - Full blood count, blood urea, serum creatinine and coagulation profile.
  - Urinalysis, urine culture and cytology.
  - Rigid Cystoscopy
    - Should be performed in all patients.
    - Findings
      - Inflammation predominant form of radiation induced cystitis:

Oedema, mucosal pallor, and possible ulcer.

- - - - Bleeding predominant form of radiation induced cystitis:

Friability, spontaneous haemorrhage, and telangiectasia.

- - - - Mixed form of radiation induced cystitis
    - Confirm diagnosis of radiation cystitis and rule out local malignancy.
      - Can be both diagnostic and therapeutic.AT
  - CT with intravenous pyelography may be needed to rule out upper tract bleeding.
  - Other studies may be needed to rule out other Etiology for haematuria if rigid cystoscopy is inconclusive such as pelvic magnetic resonance imaging.

·Treatment Options

- - High-quality evidence is still lacking. Several attempts to make recommendations on treatment algorithms have been done. Treatments should follow the order from least invasive to more invasive approaches (summarized in Treatment Algorithm 1.)

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Treatment strategy should be based on severity, timing, and chronicity of patient , s symptoms and on treatment availability according to the hospital resources.

Inflammation predominant Radiation cystitis

Storage LUTS

oAnticholinergics:

Are very effective in the treatment of storage LUTS but may cause bothersome adverse symptoms such as dry mouth, constipation, post void residual urine or, in rare cases, retention.
Are recommended as first-line treatment in these patients.

oβ3-agonists:

More recent therapeutic approach. Promotes muscle relaxation and consequent reduction of intravesical pressure.
Seems to have a comparable efficacy to the anticholinergics.
Can be used in combination with anticholinergics (in case of insufficient efficacy) or instead of (in case of intolerable side effects).

Voiding LUTS

oα1-blockers:

Act by relaxing the contracting elements of the hyperplasic prostate tissue.
Reduce both bladder storage and voiding symptoms, improve urine flow and reduce post void residual urine.
Should be the first treatment option in these patients.

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oCorticosteroids:

Reduce swelling around the urethra in order to avoid urinary retention.
May be used during RT if symptoms increase during treatment.

Pain:

oAccording to WHO guidelines for the pharmacological and radiotherapeutic management of cancer pain in adults and adolescents, first line treatment of pain should be either paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) or opioids.

oPain originating from the lower urinary tract does not respond well to opioids and urinary retention is a rare complication of their use. In this contex,t first-line pain therapy should consist of paracetamol and/or NSAIDs.

oParacetamol.

oNSAIDs.

Bleeding predominant Radiation cystitis

If active bleeding:

oPatient stabilization with fluids.

oInsertion of large 24-36Fr 3-way indwelling catheter.

oManual washout with extensive clot evacuation.

oContinuous bladder irrigation.

Intravesical treatment:

oIntravesical Hyaluronic acid:

Immunomodulatory properties that enhance connective tissue healing by mediating the repair of the normal glycosaminoglycan la yer of the bladde. r
Well studied in the treatment of interstitial cystitis and painful bladder syndrome.
Randomized trial comparingintravesical hyaluronic acid against HyperbaricOxygen Therapy (HBOT) found no statistically significant difference between the two groups.
Beyond treatment of haemorrhagic post irradia,tion cystitis, it is also useful treating patients with significant LUTS.
It has a slow onset of action therefore shouldn t be used in patients with acute severehaematuria.

oIntravesical Aluminum:

Acts by precipitating proteins on the internal surface of the bladder withdecreasing capillary permeability and vasoconstriction.
Bladder should be free of clots prior to instillation.
Not as effective as intravesical formalin but has a much-improved side-effect profile.
Well tolerated with few to nonadverse systemic reactions. Common side effects: bladder spasms, suprapubic discomfort, and clotting of the catheter due to precipitant formation.
Special caution should be applied in patients with poor renal function. The development of lethargy, confusion, metabolic acidosis, or elevated aluminum serum concentration requires cessation of treatment.
May represent an early treatment option if initial more conservative measures are unsuccessful.
May be used if ablative techniques are not available.

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oIntravesical Epsilon aminocaproic acid:

It is a lysine analogue and acts as an inhibitor of fibrinolysis to counteract urokinase on exposed telangiectatic vessels, thereby stabilizing endogenous clotting mechanisms.
A study of 37 patients with radiation or chemotherapy induced haemorrhage cystitis reported a partial or complete response in 34 patients but no further evidence was

published since 1992.

oIntravesical formalin instillation:

Acts by precipitating cellular proteins within the epithelial layer causing occlusion of thetelangiectatic vasculature.
Historical treatment. There is limited recent evidence on the use of formalin. Furthermore, severe complications such as patient mortality are described in 2-4% along with other severe side effects such as contracted, painful, and noncompliant bladder. Patient monitoring is needed for potential side effects.
Toxicity depends more on the concentration of the solution used and less on the duration of exposure.
Rapid onset of action.
A cystogram must be performed prior toinstillation to rule out vesicoureteral reflux and avoid urethral damage. If reflux is found on cystogra,m ureteral occlusion balloons may be used to protect the ureters during formalin instillation.
Treatment must be done under anaesthesia due to its caustic nature and associated pain.
Recommended only in cases of intractable haemorrhagic cystitis refractory to less invasive treatments or in patients that predictably will require urinary diversion.

Systemic treatment:

oPentosan polysulfate:

Semisynthetic polysaccharide.
Acts by repleting the deficient protective glycosaminoglycan layer of the bladderwall.
It has been previously shown to be effective in the treatment of interstitial cystitis.
Onset of action is 1 to 8 weeks and therefore shouldn , t be used in the acute setting.
Must be considered as frontline treatment.

oOral aminocaproic acid:

Different success rates described. ,
Prior exclusion of blood dyscrasias before use it s mandatory.
Must be used with caution due to short duration of studies and lack of continuity of use.

oRecombinant factor VIIa:

Promotes the formation of a fibrin clot at the site of vascular injury.
Its use is approved for other diseases but for radiation inducedhaemorrhagic cystitis the use is off label.
Successful use has been described when other methodshave failed.
Patients must meet the following criteria:
Haematocrit >24%.
Fibrinogen 50-100mg/dL.
Platelets higher than 50,000 x109.
pH>7,2.

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Physical procedures:

oHyperbaric chamber:

100% O2 atmosphere with 2.0 to 2.5 ATM pressures allowing for tissue hyperoxygenation.
Hyperoxia induces neo-angiogenesis restoring normal reparation of granulocytes and fibroblasts.
It is the most studied treatment option for radiation induced haemorrhagic cystitis. However, evidence for long-term efficacy is lacking.
Complete resolution of haematuria occurs in 34-87.5% but increases to 96% if started within 6 months afteronset.
Typically, around 40 treatments are needed.

oAblative techniques:

Ablation and coagulation either with laser therapy or argon beam therapies have advantages since they can immediately control haemorrhage and are associated with complete response in 75-97.5%.
Disadvantages: Need anaesthesia.

oTrans arterial Embolization:

Increasing experience in interventional radiology allows for accurate selective or super selectivetrans arterial embolization.
Preference should be given to selective or super selective embolization to reduce possible sideeffects.
Limited evidence.
Long term resolution of haematuria ranges from 70-81%.
Ischemic complications occur in 10-62.5% – Skin or bladder necrosis, gluteal paresis, Brown Sequard syndrome, perineal or buttock pain (Claudication.)
It is associated with a non-negligible mortality rate.
Shouldn’t be considered upfront in a stable patient.

oUrinary diversion:

Only when all the other less invasive treatment modalities failed.
42% of patients develop complications.
90-day mortality is 16%.
Can be done in the form of bilateral nephrostomy tubes.
This line of therapy may be used at any point in treatment course.

oCystectomy:

High morbidity and mortality.
Should only be used in those who have failed previously available therapy orwith life threatening haemorrhagic cystitis.

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Therapeutic Strategy

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Storage LUTS:

oAnticholinergics:

Oxibutinine:
Oral: 5mg, 2 to 3 times a day.
If elderly, hepatic dysfunction or renal dysfunction: 2.5mg 2 to 3 times a day.

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Flavoxate:
Oral: 100-200mg, 3 to 4 times a day.
Darifenacine:
Oral: 7.5 – 15 mg per day.
If elderly, severe hepatic dysfunction or renal dysfunction: 7.5mg per day.
Propiverine:
Oral: 15mg, 1 to 3 times a day.
Solifenacine:
Oral: 5-10mg per day.
Tolterrodine:
Oral: 4mg once a day.
If severe hepatic dysfunction: 2mg once a day

oβ3-agonists:

Mirabegron:
Oral: 50mg once daily.
If mild or moderate renal dysfunction or mild hepatic dysfunction: 25mg per day.

Voiding LUTS

oα1-blockers:

Tansulosine:
Oral: 0.4mg once daily.
Preferably with the breakfast.
Alfuzosine:
Oral: 2.5mg, 3 times a day or 10mg once daily (extended-release tablet).
Doxazosine:
Oral: 4mg once daily. If needed, 8mg once daily is acceptable.
Silodosine:
Oral: 8mg once daily.
If moderate renal dysfunction starts with 4mg once daily during a week and then increase to 8mg once daily.
Terazosine:
Start with 1mg once daily and double the dose weekly according to patient response. Typical daily dose is 5-10mg per day.
Maximum dose is 10mg per day.
Should be taken at night before sleep.

oCorticosteroids:

Prednisone 5mg twice daily.

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Pain

oParacetamol:

500-1000mg 3 to 4 times a day.
Maximum dose 4000mg.

oNon-steroidal anti inflammation drugs:

Dosage according to chosen drug.
Example: Ibuprofen 200 to 800mg, 3 to 4 times a day

Bleeding predominant Radiation cystitis

If active bleeding:

oPatient stabilization with fluids.

oInsertion of large 24-36Fr 3-way indwelling catheter. oManual washout with extensive clot evacuation. oContinuous bladder irrigation.

Intravesical treatment:

oIntravesical hyaluronic acid:

After emptying the bladder, instillation of 40mg of the product diluted in 50mL of saline solution.
Intravesical instillation once weekly for a month and then monthly for two months or untildisappearing of symptoms.

oEpsilon aminocaproic acid:

200mg of epsilon aminocaproic acid per liter of 0.9% sodium chloride solution.
Continuous bladder irradiation until clear urine.

oIntravesical Aluminum:

It is prepared as an 1% solution (5g aluminum dissolved in 5 litres of sterile water) irrigating continuously the bladder at a rate of 250 – 300 ml/h.

oBladder formalin instillation:

In still intravesical formalin 1-2% concentration for 10-15 minutes under spinal or general anaesthesia with a bladder free of clots and after evaluating for vesicoureteral

reflux.

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Systemic treatment

oPentosan polysulfate:

100mg 8-8 hours.
Therapeutic response should be evaluated every 6 months.
If good response is observed treatment should be maintained chronically until recurrence.
The onset of action is 1 to 8 weeks.

oOral aminocaproic acid:

Dose 150mg/Kg/d for 21 days.

oRecombinant factor VIIa:

Single dose of 90ug/Kg. If success is not achieved, a second dose may be administered 20 minutes later.

Physical procedures

oHyperbaric chamber:

90min, 5-7 days a week in a hyperbaric chamber with 100% concentration of oxygen and 2-2.5ATM pressure.
Number of sessions vary across series but usually 15-60 treatments are needed before considering other therapeutic options.

oAblative techniques:

Ablation and coagulation either with laser therapy or argon beam.

oTrans arterial Embolization:

It is an option for both unstable patient with acute bleeding as well asfor refractory bleeding patient.

oUrinary diversion:

Should be used when other less invasive therapeutic approaches have failed.

oCystectomy:

Should be used in patients with life-threatening haemorrhagic cystitis or when other less invasive therapeutic approaches have failed.

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Treatment algorithm ^Evidence

Selective or supra-selective arterial embolization

Intravesical instillations

Ablative techniques

Inflammation predominant

Bleeding predominant

Radiation induced Cystitis

Level Grade PMID Nº

Intermittent loss

Severe active loss

-Stop/reduce anticoagulants if possible

-Hydration

-If available: Hyperbaric oxygen therapy

Yes

Oral drugs:

-Pentosan polysulfate

–

Oral aminocaproic acid

Rigid Cystoscopy with clot evacuation and continuous bladder irrigation

Stabilize

-Recombinant factor VIIa

Hemodynamically stable?

Pain

Voiding LUTS

Storage LUTS

Paracetamol Or NSAIDs

α1 blocker

Anticholinergic Or Mirabegron

Physical exam Rule out other causes

Cystectomy

Urinary Diversion

Evidence Level Grade PMID Nº

Appendix

Table 1. Adapted from “Common Terminology Criteria for Adverse Events” version 5.0

CTCAE Term	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
	Microscopic haematuria; minimal	Moderate haematuria moderate increase in	Gross haematuria: transfusion, IV	Life-threatening consequences: urgent	Death
Cystitis noninfective	increase in frequency, urgency, dysuria, or nocturia; new onset of	frequency, urgency, dysuria, nocturia or incontinence; urinary	medications, or hospitalization indicated; elective	invasive intervention indicated
	Incontinence	catheter placement or bladder irrigation indicated; limiting	invasive intervention indicated
		instrumental ADL

Definition: A disorder characterized by inflammation of the bladder which is not caused by an infection of the urinary tract. ADL, Activities of daily living

References:

Martínez-Rodríguez R, Areal Calama J, Buisan Rueda O, et al. Practical treatment approach of radiation induced cystitis. Actas Urológicas Españolas (English Ed. 2010;34(7):603-609. doi:10.1016/s2173- 5786(10)70148-7
Gacci M, Sebastianelli A, Spatafora P, et al. Best practice in the management of storage symptoms in male lower urinary tract symptoms: a review of the evidence base. Ther Adv Urol. 2018;10(2):79. doi:10.1177/1756287217742837
Goucher G, Saad F, Lukka H, Kapoor A. Canadian Urological Association Best Practice Report: Diagnosis and management of radiation-induced hemorrhagic cystitis. Can Urol Assoc J. 2019;13(2):15-23. doi:10.5489/cuaj.5788
Vanneste BGL, Van Limbergen EJ, Marcelissen TA, et al. Development of a Management Algorithm for Acute and Chronic Radiation Urethritis and Cystitis. Urol Int. 2022;106(1):63-74. doi:10.1159/000515716
Tachibana I, Calaway AC, Abedali Z, et al. Definitive surgical therapy for refractory radiation cystitis: Evaluating effectiveness, tolerability, and extent of surgical approach. Urol Oncol Semin Orig Investig. 2021;39(11):789.e1-789.e7. doi:10.1016/j.urolonc.2021.05.038
Oelke M, Bachmann A, Descazeaud A, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2013;64(1):118- 140. doi:10.1016/j.eururo.2013.03.004
Jara C, del Barco S, Grávalos C, et al. SEOM clinical guideline for treatment of cancer pain (2017). Clin Transl Oncol. 2018;20(1):97-107. doi:10.1007/s12094-017-1791-2
World Health Organization. WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents.; 2018.
Deeks ED. Mirabegron: AReview in Overactive Bladder Syndrome. Drugs. 2018;78(8):833-844. doi:10.1007/s40265-018-0924-4
Andren J, Bennett MH. An observational trial to establish the effect of hyperbaric oxygen treatment on pelvic late radiation tissue injury due to radiotherapy. Diving Hyperb Med. 2020;50(3):250-255. doi:10.28920/dhm50.3.250-255
Xavier VF, Gabrielli FCG, Ibrahim KY, et al. Urinary infection or radiation cystitis? A prospective evaluation of urinary symptoms in patients submitted to pelvic radiotherapy. Clinics. 2019;74(12):1-5. doi:10.6061/clinics/2019/1388
Helissey C, Cavallero S, Dusaud M, Chargari C, François S. Chronic Inflammation and Radiation-Induced Cystitis:Molecular Background and Therapeutic Perspectives. Published online 2021:1-20.
Helissey C, Cavallero S, Dusaud M, Chargari C, François S. Chronic Inflammation and Radiation-Induced Cystitis:Molecular Background and Therapeutic Perspectives. Published online 2021:1-20.
Villeirs L, Tailly T, Ost P, et al. Hyperbaric oxygen therapy for radiation cystitis after pelvic radiotherapy: Systematic review of the recent literature. Int J Urol. 2020;27(2):98-107. doi:10.1111/iju.14130 15.Dautruche A, Delouya G. Acontemporary review about the management of radiation-induced hemorrhagic cystitis. Curr Opin Support Palliat Care. 2018;12(3):344-350. doi:10.1097/SPC.0000000000000375
Cardinal J, Slade A, McFarland M, Keihani S, Hotaling JN, Myers JB. Scoping Review and Meta-analysis of Hyperbaric Oxygen Therapy for Radiation-Induced Hemorrhagic Cystitis. Curr Urol Rep. 2018;19(6). doi:10.1007/s11934-018-0790-3
Ziegelmann MJ, Boorjian SA, Joyce DD, Montgomery BD, Linder BJ. Intravesical formalin for hemorrhagic cystitis: Acontemporary cohort. Can Urol Assoc J. 2017;11(3-4):E79-E82. doi:10.5489/cuaj.4047
Mangano MS, De Gobbi A, Ciaccia M, Lamon C, Beniamin F, Maccatrozzo L. Actinic cystitis: causes, treatment and experience of a single centre in the last five years. Urologia. 2018;85(1):25-28. doi:10.5301/uj.5000273

HAEMATOLOGICAL ALTERATIONS

ANEMIA

Authors: Paula Alexandra Sousa Mesquita, Raquel Monteiro Vieira and Mónica Mata Patricio

Definition

- - Anaemia is defined as a reduction in one or more of the major red blood cell (RBC) measurements obtained as a part of the complete blood count (CBC), namely haemoglobin concentration, haematocrit or RBC count.[1], [2], and leads to a decrease in the blood’s capacity to effectively carry oxygen. Anaemia is common in oncology patients due to a variety of aetiologies, of which the most prevalent is cancer therapy, which gives rise to chemotherapy-induced anaemia (CIA) [2], [3].

Symptoms and signs [3] [4] [5]

- - Fatigue, weakness, irritability • Headache • Dizziness, especially postural
  - Vertigo • Tinnitus • Syncope
  - Dyspnoea, especially with increased physical activity (exercise intolerance) • Chest pain, palpitations
  - Tachycardia • Tachypnoea • Pale conjunctiva
  - Difficulty sleeping or concentrating • Thirst • Anorexia
  - Decreased urine output/bowel irregularity • Decreased libido or impotence

Etiology

CIA is associated with malignant invasion of normal tissue leading to blood loss, bone marrow infiltration with disruption of erythropoiesis and functional iron deficiency because of inflammation. [3]

There are different mechanisms by which chemotherapy causes anaemia: [3], [6] [9]

- - Stem cell death with long-term myelosuppression can occur following chemotherapy with non-cell-cycle-dependent drugs such as alkylators (mitomycin, melphalan), often in a dose-dependent fashion.
  - Long-term myelodysplasia, often leading to acute myeloid leukaemia, may be a consequence of the use of alkylating agents and inhibitors of topoisomerase II.
  - Non-myeloablative doses of chemotherapy agents (myelotoxic doses that do not require stem cell rescue) such as cytarabine, methotrexate, anthracyclines, etoposide, and hydroxyurea can cause actively proliferating committed progenitor cells to die, invariably yielding early short-term myelosuppression. Although usually short term, treatment- related myelosuppression may worsen in duration and severity as the number of treatment courses increases.
  - Suppression of hematopoietic growth factor synthesis, especially erythropoietin.
  - Oxidative damage to mature hematopoietic cells.
  - Induction of immune-mediated hematopoietic cell destruction (e.g., cisplatin, oxaliplatin);
  - Exacerbation of an underlying autoimmune haemolytic anaemia associated with the patient’s malignancy, as in fludarabine treatment of chronic lymphocytic leukaemia.
  - Induction of microangiopathic haemolytic anaemia, as in chemotherapy-induced thrombotic microangiopathy.
  - Acute bone marrow stromal damage with intramedullary serofibrinous exudate and haemorrhage, particularly from high dose chemotherapy.

Prevention and Treatment Strategies

Evidence

Level Grade PMID Nº

- - Prophylactic treatment in non-anaemic patients. [9]
  - Support anti-thrombotic therapy to decrease venous thromboembolism in patients with malignancy receiving ESA (Erythropoiesis-Stimulating Agents). [10]

III A

IIb C

33768441

29471514

- - Risk assessment for developing CIA with measurement of reticulocyte count, iron stores, vitamin B12 and folate with appropriate repletion and correction prior to initiation of I C cytotoxic therapy. [10]

29471514

Therapeutic Strategy

Evidence

Level Grade PMID Nº

Erythropoiesis-Stimulating Agents (ESAs) [8], [9], [10]

Patients with solid tumours and symptomatic anaemia under treatment with chemotherapy.

Patients with solid tumours and symptomatic anaemia under treatment with chemoradiotherapy.

Patients with Hgb levels < 10 g/dl, or asymptomatic anaemia with Hgb levels < 8 g/dl after correction of iron levels and other underlying causes.

Achieving Hgb > 12 g/dl with ESAs will improve survival in patients receiving chemoradiotherapy.

ESAs should be avoided in patients receiving therapy for curative intent and in patients with advanced tumours but long-term survival expectations, even if they develop anaemia secondary to treatment.

ESAs should not be used in patients who are not receiving chemotherapy.

ESAs should be administered until stable Hgb values that avoid or reduce the need for red blood cell transfusion have been achieved, without exceeding 12 g/dl.

Increasing the dose or switching drugs after 6 – 8 weeks of treatment in non-responders is not recommended, except in the case of epoetin theta; instead, treatment should be suspended.

ESAs should not be used in patients with poorly controlled hypertension.

ESAs are indicated following correction of iron deficiency and other causes of anaemia in patients with CIA who are symptomatic with a haemoglobin level <10 g/dL or for patients who are asymptomatic with a haemoglobin level <8 g/dL.

Red Blood Cell (RBC) Transfusions [8], [9]

In patients with Hgb < 7- 8 g/dl and/or symptomatic anaemia, red blood cell transfusion should be considered before ESAs.

Consider red blood cell transfusion in patients with Hb < 7 – 8 g/dl (and < 9 g/dl if cardiovascular risk factors are present) and/or severe symptoms of anaemia that require rapid correction of Hgb levels.

Intravenous Iron Supplementation [8], [9], [11]

Iron supplementation should be considered in patients undergoing chemotherapy who have anaemia with Hgb ≤ 11 g/dl or Hgb decrease ≥ 2 g/dl from a baseline level ≤ 12 g/dl.

IV iron should be given before or after chemotherapy or at the end of a treatment cycle.

If iron supplementation was given in conjunction with ESAs, intravenous iron is superior to oral iron in improving haemoglobin response rate.s

Intravenous iron to treat CRA without ESA may be considered in patients with inefficiency, intolerance, or malabsorption of oral iron.

I	A	33768441
II	B	33768441
I	A	33768441
II	C	33768441
IV	C	33768441
I	A	33768441
IV	B	33768441
II	B	33768441
I	A	33768441
I	C	33768441
II	B	33768441
II	B	33768441
I	C	33768441
III	C	33768441
I	B	33768441
I	C	33768441

Evidence Level Grade PMID Nº

IV iron + ESA is recommended to treat functional iron deficiency (ferritin 30–500 ng/ml, TSI (transferrin saturation index) < 50%, serum Fe < 30μ/dl).

Oral or intravenous iron is recommended to treat absolute iron deficiency (ferritin < 30 ng/ml, TSI < 20%, serum Fe < 30 μ /dl ). If no response is obtained with oral treatment after four weeks, switch to IV iron.

Neither ESA nor iron supplementation is recommended to treat possible functional iron deficiency (ferritin 500 –800 ng/ml and TSI > 50%) All iron supplementation should be suspended when ferritin > 800 ng/dl and TSI > 50%.

II	A	33768441
II	A	33768441
II	A	33768441

References

Glaspy, J., 2001. Anemia and fatigue in cancer patients. Cancer, 92(S6), pp.1719-1724.
Radziwon P, Krzakowski M, Kalinka-Warzocha E. Anemia in cancer patients-expert group recommendations. Oncol Clin Pract. 2017;13(5):202–210.
UpToDate. 2021. Causes of anemia in patients with cancer. [online] Available at: <https://www.uptodate.com/contents/causes-of-anemia-in-patients-with- cancer?search=tratamento%20anemia%20quimioterapia&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3#H18> [Accessed 1 August 2022].
Gilreath JA, Stenehjem DD, Rodgers GM. Diagnosis and treatment of cancer-related anemia. Am J Hematol. 2014;89(2):203–212
Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol. 2007;25(9):1027–1032
Blasiak, J., 2017. DNA-Damaging Anticancer Drugs – A Perspective for DNA Repair- Oriented Therapy. Current Medicinal Chemistry, 24(15).
Henry D. Haematological toxicities associated with dose-intensive chemotherapy, the role for and use of recombinant growth factors. Ann Oncol. 1997;8(Suppl 3):S7–S10.
Koeller JM. Clinical guidelines for the treatment of cancer-related anemia. Pharmacotherapy. 1998;18(1):156–169.
Escobar Álvarez, Y., de las Peñas Bataller, R., Perez Altozano, J., Ros Martínez, S., Sabino Álvarez, A., Blasco Cordellat, A., Brozos Vázquez, E., Corral Jaime, J., García Escobar, I. and Beato Zambrano, C., 2021. SEOM clinical guidelines for anaemia treatment in cancer patients (2020). Clinical and Translational Oncology, 23(5), pp.931-939.
Aapro M, Beguin Y, Bokemeyer C, et al. Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2018;29(Suppl 4):iv96–iv110.
Steensma DP, Sasu BJ, Sloan JA, Tomita DK, Loprinzi CL (2015) Serum hepcidin levels predict response to intravenous iron and darbepoetin in chemotherapy-associated anemia. Blood 125(23): 3669–3671
Aapro, M., Beguin, Y., Bokemeyer, C., Dicato, M., Gascón, P., Glaspy, J., Hofmann, A., Link, H., Littlewood, T., Ludwig, H., Österborg, A., Pronzato, P., Santini, V., Schrijvers, D., Stauder, R., Jordan, K. and Herrstedt, J., 2018. Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines. Annals of Oncology, 29, pp.iv96-iv110.

APPENDIX

[ESMO Clinical Practice Guidelines: Management of anaemia and iron deficiency in patients with cancer – Table 1.]

[ESMO Clinical Practice Guidelines: Management of anaemia and iron deficiency in patients with cancer – Table 2.]

1. THROMBOCYTOPENIA

Authors: Ana Carolina Vasques and André Ferreira

Learning objectives

- - Classification of the severity of thrombocytopenia
  - Identify the main pathophysiology mechanisms of thrombocytopenia
  - Understand the major causes of thrombocytopenia in hospitalized and ambulatory patients
  - Learn how to approach a patient with thrombocytopenia
  - Differentiate a thrombocytopenic emergency
  - Recognize situations where platelet transfusion is advised

Introduction

Thrombocytopenia is a disorder defined by a platelet count below 150,000/microL (150×109/L) and it may be associated with a variety of conditions. The lack of specificity of the clinical manifestations and the many possible causes, may lead to a challenge in the diagnosis of the etiology. The severity is classified in mild (100,000 to 150,000/microL), moderate (99,000 to 50,000/microL) and severe (less 50,000/microL). Usually, severe thrombocytopenia is associated with a greater risk of bleeding, however the correlation between platelet count and the risk of bleeding varies according to the underlying condition.1

In cancer patients undergoing chemotherapy, bleeding disorders are due to thrombocytopenia in 9-15% of cases. The risk factors for chemotherapy-induced thrombocytopenia are history of bleeding, bad bone marrow function, bone metastases and poor performance status.5 In general population, according to the literature, the clinical predictors of bleeding are prior episodes of bleeding and other factors may affect the risk of bleeding such as liver disease and congenital disorders.1

The incidence, severity and duration of thrombocytopenia vary with the chemotherapy regimen. The drugs with the highest incidence of thrombocytopenia are carboplatin and gemcitabine, being higher with the association of these drugs, as shown in table 1. Another drug with high incidence of thrombocytopenia is the antibody-drug conjugate trastuzumab- emtansine (T-DM1).

Evidence

Level Grade PMID Nº

Table 1. Frequencies of Thrombocytopenia With Selected Chemotherapy Regimens(7)

Symptoms

The symptoms vary according to the severity. The patients may be asymptomatic or present with petaechia, purpura, bleeding and even thrombosis. 5Thrombosis is rare in patients with thrombocytopenia, but it is important to be aware because urgent treatment may be needed. Some examples include the heparin-induced thrombocytopenia, vaccine- induced thrombotic thrombocytopenia, antiphospholipid syndrome, disseminated intravascular coagulation, thrombotic microangiopathy. (1)

Etiology

The mechanisms of pathophysiology are varied: decreased platelet production, platelet destruction, consumption, dilution and sequestration.

Decreased platelet production – decreased production depends on the function of hemopoietic stem cells in the bone marrow and the thrombopoietin production in the liver. This may be affected in diseases such as myelodysplastic syndromes, aplastic anaemia, nutrient deficiencies, chronic liver disease. (1)
Platelet destruction – destruction of platelets in less time than their usual survival time (8-10 days) can be related to an antibody-mediated mechanism. Primary and secondary immune thrombocytopenia, associated with lupus or the ingestion of some medications/foods can be responsible for this. (1,2)
Consumption – the consumption of platelets in thrombi can happen in disseminated intravascular coagulation (DIC), thrombocytopenic purpura (TTP), haemolytic uremic syndrome (HUS) (1)
Dilution – in cases of massive fluid resuscitation or several transfusions can reduce the number of platelets. (1)
Sequestration – this mechanism is caused by hypersplenism. Any mechanism that causes splenic enlargement, for example, chronic liver disease and cirrhosis can decrease the number of circulating platelets. (1)

Level GradeEvidence

PMID Nº

Causes		Mechanism
Pregnancy	5-10% of woman develop gestational thrombocytopenia, it is usually mild, asymptomatic, in the 3 rd trimester and resolves spontaneously.
Chronic liver disease	Two mechanisms are involved: the decrease production of thrombopoietin by the liver and the sequestration by the enlarged spleen.	1,5
Immune Thrombocytopenia	Common cause of thrombocytopenia where the other lines are unaltered. The main mechan,ismis platelet destruction mediated by antibodies. This is an exclusion diagnosis when there isn t an alternative hypothesis.	2
Congenital disorders	Several congenital disorders may be associated with thrombocytopenia, usually, the diagnostic is in childhood but in some rare cases, it can happen in adulthood. Some examples are Wiskott-Aldrich syndrome, Alport syndrome, MYH-9, Bernard-Soulier syndrome, Gray platelet syndrome.
Infection	Almost any microorganism can cause thrombocytopenia, mainlyby bone marrow suppression, destruction and consumption. In viral infections it is commonly auto-limited, except in HIV and viral hepatitis infections.	1,2,3
Drug induced immune thrombocytopenia	Any medications can cause thrombocytopenia by the development of drug-dependent platelet- reactive antibodies. The most common causes are antibiotics (sulphonamides, ampicillin, piperacillin, vancomycin, rifampin), antiepileptic agents (carbamazepine, phenytoin) and quinine. Typically resolves one week after discontinuation of drug.2	2
Heparin induced thrombocytopenia	This condition is characterized by the presence of antibodies against the platelet factor 4/heparin complex, it causes platelet activation resulting in thrombosis and platelet consumption. It happens 5-10 days after the exposure to heparin and there can benecrotic skin lesions at the sites of heparin injection.	3
Thrombotic microangiopathy	This condition presents with microangiopathic haemolytic anaemia and thrombocytopenia, in some cases associated with fever, neurologic alterations and renal failure. Some examples are thrombotic thrombocytopenic purpura (TTP), haemolytic uremic syndrome (HUS) and drug induced (quinine, calcineurin inhibitors).	3
Chemo and radiotherapy	Cytotoxic agents can c,ause dose-dependent bone marrow suppression and immune-mediated thrombocytopenia. It s characteristic of platinum, gemcitabine and irinotecan regimens. The recovery is predictable after discontinuation.2	1,2
Nutrient deficiency	The lack of nutrients such as folate, B12 vitamin necessary for haematopoiesis can cause thrombocytopenia. Patients may be asymptomatic, can show signs of anaemia or even neurologic symptoms.	1
Bone marrow disorders	Several primary hematologic conditions are able to cause thrombocytopenia, many of them affecting more than one cell line. Myelodysplastic syndrome, aplastic anaemia, acute leukaemia, have to excluded if there is any suspicion.	1

Evidence

Approach Level Grade PMID Nº

The patient personal and family history and previous platelet counts are important to assess the gravity of the situation. It is crucial to rule out the introduction of newly medications, recent travel, infections and vaccinations. A thorough physical examination to look for petechia, purpura, ecchymosis, hepatosplenomegaly and lymphadenopathies is needed.

The approach of a patient with thrombocytopenia includes repeating a complete blood count to confirm, coagulation, liver and kidney function studies and a peripheral blood smear to exclude morphologic abnormalities. There should be an investigation of probable infectious causes, HIV, HVC, HVB. In some situations, a bone marrow biopsy, imaging studies and anti-platelet antibody studies can be required.

In cancer patients undergoing chemotherapy, if the platelet counts below 50,000/microL, the treatment should be postponed.

In some cases, such as, massive bleeding, urgent need of invasive procedure, pregnancy, primary hematologic disorders and thrombotic microangiopathies, accompanied by severe thrombocytopenia, should be treated as a medical emergency. In this situation, the patient should initiate immediate treatment with platelet transfusion, and balance the need for corticosteroids and intravenous immune globulin.

The indications for platelet transfusion, in thrombocytopenia are active bleeding and preparation for surgery. The controversy of prophylactic transfusion with platelet counts below 10,000/microL remains. Balancing the risk of spontaneous bleeding with the potential complications of unnecessary platelet transfusion is crucial. The underlying condition and prior bleeding episodes should help decide. In TTP and HUS a life-saving transfusion in case of severe bleeding should not be withheld due to concerns about the thrombotic risk. After transfusion, the peak of platelets should be achieved 10 minutes to an hour and decreases in the following 72 hours.(1)

In case of immune thrombocytopenia, treatment is advised, when platelet counts drop below 30,000/microL with corticosteroids. It is recommended a short course of steroids with either prednisone (0.5-2.0 mg/kg per day) or dexamethasone (40 mg per day for 4 days). If this does not improve the platelet count, other strategies, such as rituximab and immunoglobulin may be required, but the haematologist opinion is crucial.(6)

The use of anticoagulants in patients with thrombocytopenia should be balanced with the risk of bleeding. Thrombocytopenia does not protect against thrombosis, but the risk of bleeding may be high, so decisions should be made individually in each case and multidisciplinary. (1)

Advised platelet counts1, 4

Procedure	Platelet countlimit
General Surgery	>50,000/microL
Neurosurgery Major cardiac surgery Orthopedic surgery	>100,000/microL
Invasive procedure Chemotherapy induced thrombocytopenia	>30,000/microL
Fever, sever mucositis, biopsy	>20,000/microL

Evidence

Therapeutic Strategy ^Level ^Grade ^PMID ^Nº

- - Transfusing hospitalized adult patients, with therapy-induced hypoproliferative thrombocytopenia, with a platelet count of 10,000/microL or less to reduce the risk for spontaneous bleeding.(3)
  - Prophylactic platelet transfusion for patients having elective central venous catheter placement with a platelet count less than 20,000/microL. (3)
  - Prophylactic platelet transfusion for patients having elective diagnostic lumbar puncture with a platelet count less than 50,000/microL. (3)
  - Prophylactic platelet transfusion for patients having major elective nonneuraxial surgery with a platelet count less than 50,000/microL.( 3)
  - Platelet transfusion for patients having bypass who exhibit perioperative bleeding with thrombocytopenia and/or evidence of platelet dysfunction. (3)
  - Platelet transfusion for patients receiving antiplatelet therapy who have intracranial hemorrhage. (3)

Conclusions

Thrombocytopenia is a rather common condition and due to its varied causes and pathophysiological mechanisms, it is important that the physician has some skill in managing these patients. Even though, in most cases it presents without symptoms and it is self-limited, it is crucial to recognize emergency situations and, when necessary, request help from a hematologist.

References

Arnold, D., Cuker, A. (2021). Diagnostic approach to the adult with unexplained thrombocytopenia. In L. Leung (Ed), UpToDate. Retrieved December 9th, 2021, from https://www.uptodate.com/contents/diagnostic-approach-to-the-adult-with-unexplained-thrombocytopenia?search= trombocitopenia&source= search_result&selectedTitle=1~150&usage_type=default&display_rank=1
Arnold, D., Cuker, A. (2021). Drug-induced immune thrombocytopenia. In L. Leung (Ed), UpToDate. Retrieved December 9th, 2021, from https://www.uptodate.com/contents/drug- i n d u c e d – i m m u n e t h r o m b o c y t o p e n i a ? s e a r c h = t r o m b o c i t o p e n i a % 2 0 i n d u z i d a % 2 0 p o r % 2 0 d r o g a s & s o u r c e = s e a r c h _ r e s u l t & s e l e c t e d T i t l e

=1~150&usage_type=default&display_rank=1

Kaufman RM, Djulbegovic B, Gernsheimer T, Kleinman S, Tinmouth AT, Capocelli KE, Cipolle MD, Cohn CS, Fung MK, Grossman BJ, Mintz PD, O’Malley BA, Sesok-Pizzini DA, Shander A, Stack GE, Webert KE, Weinstein R, Welch BG, Whitman GJ, Wong EC, Tobian AA; AABB. Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2015 Feb 3;162(3):205-13. doi: 10.7326/M14-1589. PMID: 25383671.
Yuan, S. (2021). Platelet transfusion: indications, ordering and associated risks. In A. Silvergleid (Ed), UpToDate. Retrieved December 9th, 2021, from https://www.uptodate.com/contents/platelet-transfusion-indications-ordering-and-associated- risks?search=transfus%C3%A3o%20de%20plaquetas&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
Martinelli, E., Sforza, V., Cardone, C. (2016). Bleeding Disorders in M. Pulla (Ed) ESMO Handbook of Oncological Emergencies. ISBN: 978-88-906359-9-1. p. 233-242
Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia [published correction appears in Blood Adv. 2020 Jan 28;4(2):252]. Blood Adv. 2019;3(23):3829-3866. doi:10.1182/bloodadvances.2019000966
Kuter DJ. Managing thrombocytopenia associated with cancer chemotherapy. Oncology (Williston Park). 2015 Apr;29(4):282-94. PMID: 25952492.
A
D

VI D

VI C

LEUCOPENIA

Authors: Beatriz Alonso de Castro, Joaquín Mosquera Martínez and Sofía Silva Díaz

Introduction

The term Leukopenia refers to a reduced number of white blood cells in the peripheral blood, usually less than 3000/ μl. The granulocytic series are made up of neutrophils, monocytes, eosinophils, and basophils, all of them in a small proportion except for neutrophils. Accordingly, the terms granulocytopenia and neutropenia are often used as synonyms. Leukopenia is usually due to neutropenia and lymphopenia, but in cancer population, acquired neutropenia is the most frequent cause, regarding treatment or bone marrow infiltration (1).

Symptoms

Leukopenia is normally asymptomatic, and the occurrence of clinical development depends on the degree and duration of neutropenia and lymphopenia.

In patients with neutropenia, fever is often the first sign, with concomitant constitutional symptoms, chills, diaphoresis, arthromyalgias and weight loss, which may indicate the presence of an infection. Other signs or symptoms we must pay attention to are gingivitis, swelling, oral ulceration, dental pain, abnormal respiratory exam, inflamed joints, lymphadenopathy, hepatomegaly, and splenomegaly. Cancer patients usually have venous catheters, and infections in these locations can produce skin erythema, ulcerations, and fissures (2).

In 30% of neutropenia patients, a Gram-negative bacilli, or Gram-positive cocci (Staphylococcus spp) can be isolated, whereas fungi are often involved as secondary infective agents, it represents less than 10%. In this context, it is very important to administer antibiotics promptly to avoid the risk of septicaemia and septic shock which could be more than 60%. Otherwise, an early treatment may attenuate the clinical findings being fever the only one (3) .

In patients with lymphopenia the development of opportunistic infections by Pneumocystis, Varicella-Zoster Virus (VZV) and Cytomegalovirus (CMV) is very common. Pneumocystis carinii causes a severe pneumonia in patients with chemotherapy treatment. They generally present dyspnoea, non-productive cough, haemoptysis, and low-

grade fever lasting several weeks. Physical examination typically reveals an increase respiratory rate, tachycardia, cyanosis, and fine crackles on lung auscultation (4).

After a primary infection causing varicella, VZV establishes latency in sensory ganglia and can usually reactivate later, with an increased risk in patients with chemotherapy, high dose corticoids and biologic agents’ treatment. Clinically patients with herpes zoster (HZ) report headache, malaise and neuropathic pain in an erythematous maculopapular rash beginning with vesicles and continuing with pustulation in the ganglia dermatome. Cutaneous lesions can be atypical in immunocompromised patients, with simultaneous involvement of multiple non-contiguous dermatomes. Complications of HZ include postherpetic neuralgia, encephalitis, myelitis, cranial and peripheral-nerve palsies, and a syndrome of delayed contralateral hemiparesis. Disseminated disease can happen in immunocompromised patients, most of them limited to the skin, yet some developed visceral disease (pneumonitis, encephalitis, or hepatitis among others). (5) .

Cytomegalovirus is a major pathogen for oncologic patients, mostly after hematopoietic stem cell transplantation. The infection can be presented as an asymptomatic viremia, or with a fatal disease like colitis, pneumonia, and encephalitis (6) .

Anaemia and thrombocytopenia are usually present in patients with neutropenia and lymphopenia, where mucocutaneous pallor/cyanosis or bleeding/petechiae can help us in the diagnose.

Etiology

Neutropenia:
- Bone marrow invasion by tumour cells.
- Nutritional deficiency: Deficit in B12 vitamin, folate, or copper, generally causes neutropenia alone or in association with other cytopenia’s.
- Infection: During or after the recovery of a viral (hepatitis, human immunodeficiency virus (HIV), Epstein-Barr virus (EBV)), bacterial or parasitic infection.
- Iatrogenic: (7,8)
Chemotherapy: One of the most important items in the risk assessment of neutropenia is the type of chemotherapy. Below we include the highest risk regimens to induce neutropenia: NCCN neutropenia supportive guidelines.

Evidence

Level Grade PMID Nº

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Bladder cancer: Dose-dense MVAC (Methotrexate, Vinblastine, Doxorubicin, Cisplatin).
Bone cancer: Combinations with vincristine, doxorubicin, Ifosfamide and etoposide.
Breast cancer: Combinations with doxorubicin, cyclophosphamide, paclitaxel or docetaxel/carboplatin/trastuzumab.
Colorectal cancer: FOLFOXIRI.
Head and Neck Squamous Cell Carcinoma: Docetaxel, Cisplatin, 5-Fluorouracilo.
Kidney cancer: Doxorubicin/Gemcitabine.
Melanoma: Combination with dacarbazine IL-2, Ifn-alfa.
Ovarian cancer: Topotecan, Docetaxel.
Pancreatic cancer: FOLFIRINOX.
Small Cell Lung Cancer: Topotecan.
Soft Tissue Sarcoma: MAID (mesna, doxorubicin, Ifosfamide, dacarbazine), Doxorubicin, Ifosfamide/Doxorubicin.
Testicular Cancer: Combinations with Ifosfamide.

Target therapies: Anti-CD20 agents (rituximab), anti-CD52 (alemtuzumab), interleukin-1 inhibitors (anakinra, canakinumab), interleukine-6 inhibitors (tocilizumab), interferon-α, TNF- α inhibitors (adalimumab, etanercept infliximab).
Radiotherapy.
Non anticancer drugs: analgesics and nonsteroidal anti-inflammatory drugs, antiepileptic drugs, antithyroid drugs, cardiovascular drugs, anti-infective agents.
- Hematologic malignancies: Hematologic malignancies frequently present neutropenia in the context of pancytopenia. Examples: Large granular lymphocyte (LGL) leukaemia, hairy cell leukaemia, myelodysplastic syndromes…
- Other circumstances with independence of a cancer diagnose: Rheumatologic disorders (Rheumatoid arthritis, systemic lupus erythematosus), Autoimmune Neutropenia, Chronic Idiopathic Neutropenia, Familial Neutropenia and Congenital Neutropenia.
Lymphopenia: (9).
- Nutritional deficiency: Malnutrition with zinc deficiency and alcohol abuse.
- Infection: Viral (HIV, SARS-CoV-2, influenza, hepatitis…), Bacterial (Mycobacterium Tuberculosis), Fungal (Histoplasmosis)…
- Iatrogenic:

a. Target therapies: rituximab, alemtuzumab, antilymphocyte globulin.

Chemotherapy: fludarabine, cladribine, hematopoietic cell transplantation.
Radiotherapy.
Non anticancer drugs: steroids.
- Hematologic malignancies: Lymphoma is the main cause of lymphopenia in this context.
- Other circumstances previous than cancer diagnose present in the patient: Autoimmune disorder (e.g., systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome), sarcoidosis, renal failure, pancytopenia, Cushing’s syndrome, immunodeficiencies.

Level Grade PMID Nº

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Studies (10,11,5)

The first approach is to repeat complete blood count (CBC) to confirm our suspicion of low white blood cell count (WBC) and to assess each haematological cell lineage, like platelets and erythrocytes levels. After this first diagnose of leukopenia, it is important to make a peripheral blood smear to study the type of deficient cell and the features of the presentation.

To make a specific diagnosis we should carry out the determination of:

Blood cultures.
Human immunodeficiency virus (HIV) serology and viral load.
Polymerase chain reaction (PCR) for: Cytomegalovirus, Herpes simplex viruses hepatitis viruses…
Pneumocystis carinii pneumonia could be isolated in Bronchoalveolar lavage (BAL) and induced sputum. However, open lung biopsy is the gold standard, still rarely performed.
Herpes Zoster is usually diagnosed by clinical presentation. In atypical presentation cases, a laboratory confirmation is mandatory, with culture, immunofluorescence assay or PCR (useful for detecting varicella-zoster virus DNAin fluid and tissues).
Serum assays for drugs associated with neutropenia or lymphopenia.
Serologies for autoimmune disease (antinuclear antibody (ANA), rheumatoid factor), Immunoglobulins…
Peripheral blood flow cytometry for: B and T cell lymphoma markers, large granular lymphocytes…
Consider genetic sequencing to identify mutations in genes associated with neutropenia: more appropriate in children, with no associated anomalies to guide testing.
Bone marrow aspirate and biopsy: it is not routinely done for mild-moderate chronic leukopenia or drug-associated. Almost all cases are related to diagnose myelodysplasia, acute leukaemia, severe neutropenia, or generalized marrow failure.

Other laboratory data that should be determined are: Complete metabolic panel (B12 vitamin, folic acid transcobalamin deficiency), liver enzymes, Prothrombin time (PT) and partial thromboplastin time (PTT).

Pharmacotherapy

Level Grade PMID Nº

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Antibiotic Prophylaxis: Antibiotic prophylaxis with fluoroquinolones reduce infection and mortality in neutropenic patients. In many meta-analysis different antibiotic regimens with fluoroquinolones were used with a decrease in the number of infections.

Colony-stimulating factors (CSFs): Reduce the risk of febrile neutropenia when is approximately 20% or higher with a chemotherapy regimen and we do not have another alternative treatment.

Filgrastim: 5ug/kg per day sc 1-3 days after chemotherapy until reaching ANC >= 2 to 3 x10 9/L.

Pegfilgrastim: 6mg once 1 to 3 days after chemotherapy.

Pneumocystis Pneumoniae:

Treatment:

Trimethoprim-Sulfamethoxazole: 15-20mg/kg – 75-100mg/kg per day intravenous for 2 weeks. Prednisone: 60mg or more of daily.

Prophylaxis:

Trimethoprim-Sulfamethoxazole: 160mg/800mg three times per week.

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Virus Varicella Zoster (VZV):

Treatment:

Antiviral therapy: Acyclovir, Valacyclovir, Famciclovir. Valacyclovir 1000mg every eight hours.

Famciclovir 500mg every eight hours.

Acyclovir 800mg five times daily.

Corticosteroids:

Improve neuropathic pain and healing in combination with acyclovir.

It is assumed that valacyclovir and famciclovir are equally, but not studied in clinical trials.

Prophylaxis: Attenuated varicella zoster vaccine reduces the incidence and severity of herpes zoster in adults.

Cytomegalovirus (CMV):

Treatment:

Ganciclovir: Induction with 5mg/kg twice a day 7-14 days and 5mg/kg per day after. Valganciclovir: 900mg twice a day.

Foscarnet: The posology depends on the type of infection.

Cidofovir: Induction with 8mg/kg one time per week by two consecutive weeks and after 5mg/kg one time biweekly.

Prophylaxis:

The three drugs (intravenous ganciclovir, oral valganciclovir and oral ganciclovir) are used in half standard dose. Letermovir 480mg per day is indicated after the HCT and until 100 days post-HCT.

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Therapeutic Strategy

Colony-stimulating factors (CSFs):

Primary prophylaxis is recommended in patients with a febrile neutropenia higher o equal to 20%, related to patients, disease, and treatment factors. Secondary prophylaxis is recommended after a previous neutropenic complication.

It is not indicated in neutropenia afebrile or in concurrent chemo-radiotherapy.

Antibiotic Prophylaxis: Initiated when the patient becomes neutropenic or with chemotherapy initiation until peripheral granulocyte count reached mor e than 0.5 x 10⁹

cells/L or more than 1.0 x 10⁹ cells/L or until 6 weeks of treatment.

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Pneumocystis:

Treatment:

Trimethoprim-Sulfamethoxazole is the gold standard for severe pneumocystis pneumonia. Prednisone daily resulted in a better outcome for severe infection.

Prophylaxis:

Patients who receive corticosteroids in an equivalent dose of 16mg prednisone or more for a period of eight weeks should receive prophylaxis with Trimethoprim- Sulfamethoxazole.

Virus Varicella Zoster (VVZ):

Treatment:

Antiviral therapy: Valacyclovir and famciclovir are preferred over acyclovir because of a simpler dosage regimen.

Corticosteroids: Recommended for neuropathic pain in combination with Acyclovir.

Prophylaxis: Universal childhood vaccination is recommended.

Cytomegalovirus: 1.Treatment:

Ganciclovir and valganciclovir are the first line agents.

Antiviral resistance to ganciclovir can be managed by switching to foscarnet and cidofovir.

2. Prophylaxis:

There are three drugs (intravenous ganciclovir, oral valganciclovir and oral ganciclovir) that can we use.

Letermovir, which provides a lower risk of CMV infection in hematopoietic-cell transplantation, was recently approved

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References:

Onuoha C., Arshad J., Astle J., Xu M., & Halene S. (2016). Novel Developments in Leukopenia and Pancytopenia. Prim Care, 43(4), 559-73.
Boxer L. A. (2012). How to approach neutropenia. Hematology 2010, the American Society of Hematology Education Program Book, 2012(1), 174-182.
Andersohn F., Konzen C., & Garbe E. (2007). Systematic review: agranulocytosis induced by nonchemotherapy drugs. Annals of internal medicine, 146(9), 657-665.
Thomas Jr C. F. & Limper A. H. (2004). Pneumocystis pneumonia. New England Journal of Medicine, 350(24), 2487-2498.
Gnann J., Whitley J. R. (2002). Herpes Zoster. New England Journal of Medicine, 347 (5).
Cho, S. Y., Lee, D. G., & Kim, H. J. (2019). Cytomegalovirus infections after hematopoietic stem cell transplantation: current status and future immunotherapy. International journal of molecular sciences, 20(11), 2666.
Andrès, E., Lorenzo Villalba, N., Zulfiqar, A. A., Serraj, K., Mourot-Cottet, R., & Gottenberg, J. E. (2019). State of art of idiosyncratic drug-induced neutropenia or agranulocytosis, with a focus on biotherapies. Journal of clinical medicine, 8(9), 1351.
Newburger, P. E., & Dale, D. C. (2013, July). Evaluation and management of patients with isolated neutropenia. In Seminars in hematology (Vol. 50, No. 3, pp. 198-206). WB Saunders.
Warny, M., Helby, J., Nordestgaard, B. G., Birgens, H., & Bojesen, S. E. (2018). Lymphopenia and risk of infection and infection-related death in 98,344 individuals from a prospective Danish population-based study. PLoS medicine, 15(11), e1002685.
Dale, D. C. (2016). How I diagnose and treat neutropenia. Current opinion in hematology, 23(1), 1.
Wazir, J. F., & Ansari, N. A. (2004). Pneumocystis carinii infection: Update and review. Archives of pathology & laboratory medicine, 128(9), 1023-1027.
1. FEBRILE NEUTROPENIC SYNDROME

Authors: Iria Parajó Vázquez, Joaquín Mosquera Martínez, Patricia Cordeiro González and Martín Igor Gómez-Randulfe Rodríguez

Definition

Febrile neutropenic syndrome is defined as a decrease in the absolute neutrophil count under 0.5 x10^9/L in the presence of an oral temperature of >38.3°C or two consecutive readings of >38.0°C for 2 hours.

Symptoms

Symptoms of febrile neutropenia can range from none to toxic death secondary to immunosuppression.

Fever is often the only sign or infection symptom, although clinicians must be mindful that profoundly immunocompromised patients may present severe infections while staying afebrile.

Etiology

Neutrophils are the first immune cell population recruited to the primary site of infection. They respond in a direct way by attacking bacterial cells or fungal hyphae, but they also release cytoquines that trigger the inflammatory cascade. Therefore, quantitative, or qualitative deficits in neutrophils secondary to cytotoxic chemotherapy put the patients at risk for developing severe infections due to bacterial and fungal organisms in particular.

The most common source of infection in neutropenic patients is loss of digestive or urinary mucosal integrity and secondary bacterial translocation into the bloodstream. Additionally, it is important to highlight the role of vascular catheters as a cause of infection, since the number of patients carrying these devices is increasing. Gram-negative bacteria, especially Enterobacteriaceae (Escherichia coli, Klebsiella) and Pseudomonas are the most common agents causing infections among this population. In patients with altered skin barrier (vascular catheters, skin toxicity…) gram positive microorganisms (coagulase-negative Staphylococcus, Streptococcus spp) become a frequent etiologic agent.

Studies

First, the patient must be interviewed for recording a detailed history. Then, a detailed physical examination has to be performed, paying special attention to mucosa, catheter insertion sites, skin, and perianal area. Clinicians should include some details such as the nature and timing of cytotoxic therapy, prior episodes of febrile neutropenic syndrome, history of recent antimicrobials provided or the use of C-GSF or corticosteroids. It is also important to check the past microbiological isolations (especially if antibiotic-resistant microorganisms were identified).

Second, urgent full blood counts (including lactate, C-reactive protein and procalcitonine) must be obtained within the first contact with medical care. Before administering empiric antibiotics (regimens discussed below), two sets of blood cultures from a peripheral vein and one from a central venous catheter (if present) should be performed.

The systematic research of potential foci of infection will guide the subsequent microbiological studies, being mindful that neutropenic patients may be suffering severe infections with scarcely expressed symptoms or signs.

For instance, in the presence of respiratory symptoms, all patients should undergo a chest radiograph or CT-scan. Sputum cultures and respiratory viral tests (particularly during epidemic seasons) should be considered even in the absence of pathological imaging. In patients with pulmonary consolidations and profound immunosuppression, early bronchoscopy with bronchoalveolar lavage may be useful.

In the case of diarrhoea, abdominal pain or anal pain, stool samples for cultures and C. Difficile toxin testing should be obtained. Abdominal CT-scan is preferable to abdominal radiograph in suspicion of abdominal focus (typhlitis, enterocolitis…).

Any other samples for microbiological studies will be obtained depending on the clinical suspicion (urine, cerebrospinal fluid, mucosal or skin lesions…).

Evidence

Level Grade PMID Nº

Pharmacotherapy

Evidence

Level Grade PMID Nº

Initial empiric antibiotic treatment should be based on a monotherapy with a beta-lactam with antipseudomonal activity but that preserves activity against Gram positive (meropenem 1g/ 8 h i.v., imipenem-cilastatin 500 mg/6 h i.v., piperacillin-tazobactam 4.5 g/6 h i.v. or cefepime 2 g/8 h i.v.).

For patients with low-risk febrile neutropenia, who are going to receive oral antibiotic treatment as an outpatient (after first parenteral dose in the Emergency Department), recommended regimens include amoxicillin-clavulanic acid 875/125 mg/8 h in association either with ciprofloxacin 750 mg/12 h or levofloxacin 750 mg/day.

If catheter related infection is suspected, or skin/soft tissue infection is present, a glycopeptide such as vancomycin (15 -20 mg/kg/8-12 h) should be administered in addition to the beta-lactam. Daptomycin is an emerging alternative to glycopeptides (although more experience in neutropenic patients is needed).

If severe of pneumonia is documented (hypoxia, extensive infiltrates, suspicion of MRSA), addition of linezolid 600 mg/12 i.v. or vancomycin 15-20 mg/kg/8-12 h to the beta-lactam (preferably a carbapenem) is recommended.

In the presence of diarrhoea and/or abdominal cramping, C. Difficile infection should be suspected, and oral therapy with vancomycin or metronidazole may be initiated.

In penicillin allergic patients, the beta -lactam must be substituted by aztreonam 1g/8 h i.v. in addition to vancomycin/linezolid/daptomycin according to previous recommendations.

As Pseudomonas aeruginosa may be resistant to Aztreomam, initial addition of amikacin 15-20 mg/kg/day i.v should be considered.

Therapy with granulocyte-colony stimulating factor (G-CSF) is only recommended in patients at a high risk of infectious complications (<100 neutrophils/mm3, age > 65 years, hemodynamic instability, widespread infections).

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Therapeutic Strategy

An initial prognostic evaluation by applying validated scales for risk stratification (CISNE/MASCC) of febrile neutropenia isrecommended in order to choose between an ambulatory or hospitalized treatment regimen.

Antibiotic prophylaxis of febrile neutropenic syndrome is not routinely recommended for patients with solid tumours.

Primary prophylaxis with C-GSF is recommended if the risk of FN is > 20%

Primary prophylaxis with C-GSF with intermediate risk of FN (10-20%) should be individualized.

Secondary prophylaxis with C-GSF is recommended in patients with a previous episode of FN in whom chemotherapy delays or dose reduction might reduce surviva.l

Empirical antibiotic therapy should be initiated within the first contact withmedical attention, after taking samples for blood cultures.

Patients with low-risk febrile neutropenia assessed by validated predictive tools (without prior prophylaxis with quinolones), after first parenteral dose of antibiotic, oral antibiotic treatment as an outpatient is safe if clinical surveillanceis possible within the next 48 hours.

Patients with high risk febrile neutropenia must be hospitalized, immediately monitored and treated with broad spectrum antibiotics withoutdelay, since the risk of severe sepsis is very high.

Once infectious focus is clinically or microbiologically documented, antibiotic spectrum and duration of therapy should be adjusted to findings.

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If no source of infection is identified, but the patient stays afebrile for 48 h, antibiotic intravenous therapy may be changed to oral until marrow recovery or even discontinued if neutrophil recount is >0.5×10^9 (after a minimum of 7 days treatment).

If no source of infection is identified, and the patient stays febrile at 48 h, but clinically stable, initial antibiotic regime should be continued until marrow recovery (neutrophil recount >0.5×10^9/L).

If the patient stays febrile at 48 h, clinically unstable, antimicrobial spectrum should be broadened to cover resistant Gram-negative bacilli, Gram positive bacteria and anaerobes.

If the patient stays febrile after 4-7 days of broad spectrum antibacterialtreatment, empirical antifungal therapy should be considered in the absence of an identified focus.

II A

II B

References:

1. Klastersky J, de Naurois J, Rolston K, Rapoport B, Maschmeyer G, Aapro M, et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol [Internet]. 2016.
2. Zimmer AJ, Freifeld AG. Optimal management of neutropenic fever in patients with cancer. J Oncol Pract [Internet]. 2019;15(1):19–24.

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1. Carmona-Bayonas A, Jimenez-Fonseca P, de Castro EM, Mata E, Biosca M, Custodio A, et al. SEOM clinical practice guideline: management and prevention of febrile neutropenia in adults with solid tumors (2018). Clin Transl Oncol [Internet]. 2019.
2. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis [Internet]. 2011;52(4):e56-93.
3. Virizuela JA, Carratalà J, Aguado JM, Vicente D, Salavert M, Ruiz M, et al. Management of infection and febrile neutropenia in patients with solid cancer. Clin Transl Oncol [Internet]. 2016;18(6):557–70.

BLOOD HYPER VISCOSITY

Authors: Raquel Barros Pereira and Filipa Pontes

Introduction

Haematological alterations are common manifestations of cancer.

It has been shown that cancer favours the activation of blood coagulation, creating a blood hyper viscosity state or chronic disseminated intravascular coagulation.

Cancer-associated thrombosis is a major cause of morbidity and mortality in patients with cancer and over the past 2 decades, enormous advances have been made in its management.

Furthermore, the incidence of cancer-associated thrombosis is increasing worldwide associated with multiple factors: cancer type, the use of central venous catheters for chemotherapy and other associated surgical and medical anticancer treatments (e.g., radiotherapy, antiangiogenic agents, immunomodulatory drugs, hormonal therapy, and erythropoiesis stimulating agents).

According to Sengupta, A., Int J Cancer Clin Res 2020, effective treatment may cause a fall in blood viscosity, but the specific mechanism remains largely unanswered. Future studies should focus on the role played by immunoglobulins, cytokines, cancer cell density and other anti-inflammatory markers.

Pharmacotherapy for prevention and treatment of established VTE in patients with cancer is complex.

A validated risk assessment model (e.g., Khorana risk score) should be used to assess VTE risk at the initiation of systemic therapy and during the evolution of treatment and disease.

Evidence

Level Grade PMID Nº

Manifestations

Deep venous thrombosis • Pulmonary embolism • Arterial Thrombosis • Chronic Disseminated • Intravascular Coagulation

Etiology

The pathogenesis of blood coagulation activation in cancer is complex and multifactorial.

However, it is known to be related to expression of tumour cell-associated clot promoting properties that lead to:

activation of the clotting cascade
generation of thrombin and fibrin
stimulation of platelets, leukocytes and endothelial cells which expose their cellular procoagulant features

Risk Factors

Anumber of various factors may increase the risk of thrombotic events in cancer patients:

Evidence

Level Grade PMID Nº

Individual Patient Risk Factors:
1. immobility
2. old age
3. comorbidities
4. previous history of VTE
Cancer-Associated Risk Factors
1. cancer type (pancreatic cancer +)
2. cancer histological subtype
3. advanced-stage cancer
4. timing after diagnosis (immediate period following diagnosis +)
Cancer-Treatment-Associated Risk Factors
1. surgery and hospitalisation
2. chemotherapy
3. angiogenesis inhibitors
4. central venous catheters

Pharmacotherapy

Pharmacotherapy for venous thromboembolism prevention
1. Recommendations for VTE prevention in hospitalized medical oncology patients. I A

Tinzaparin is safe in patients with renal impairment and CrCl =20% and does not bioaccumulate with severe renal impairment and CrCl <20 mL/min. I B
LMWH or fondaparinux (when CrCl is ≥30 mL/min) or UFH recommended in hospitalized patients with cancer and reduced mobility.
LMWH, UFH, or fondaparinux with or without PCD for patients with no contraindication to anticoagulation. 2 A
Anticoagulant prophylaxis should be considered for hospitalized patients with cancer with acute medical illness in the absence of contraindications. LMWHs are the preferred I B agents.

LMWH: low-molecular-weight heparin; CrCl: creatinine clearance; UFH: unfractionated heparin; PCD: pneumatic compression device.

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1. Recommendations for VTE prevention in ambulatory medical oncology patients
A validated risk assessment model should be used to assess VTE risk at the initiation of systemic therapy and during the evolution of treatment and disease. 2 C
Primary prophylaxis with LMWH, VKAs, or DOACs is not recommended routinely in ambulatory patients on systemic anticancer therapy. I B
Primary prophylaxis with LMWH is indicated in ambulatory patients with locally advanced or metastatic pancreatic cancer on systemic anticancer therapy who have a low risk I B of bleeding.
Primary prophylaxis with DOAC (apixaban or rivaroxaban) is recommended in ambulatory patients on systemic anticancer therapy at intermediate-to-high VTE risk, identified I B by cancer type (i.e., pancreatic) or by a validated risk assessment model (i.e., KRS ≥2), and not actively bleeding or at a high risk of bleeding.
Consider apixaban or rivaroxaban for up to 6 months in high-risk patients with cancer (KRS ≥2) starting a new chemotherapy regimen. 2 A
In patients treated with immunomodulatory drugs combined with steroids or other systemic cancer therapies, primary prophylaxis is recommended. I A In this setting, VKAs at low or therapeutic doses, LMWH at prophylactic doses, and low-dose aspirin have been effective. 2 C
Recommend discussing the indication for thromboprophylaxis and the risks and benefits. Patients should be closely monitored. I B

Recommend educating patients about risk factors and symptoms of VTE 2 A

VTE, venous thromboembolism; LMWH, low-molecular-weight heparin; DOAC, direct oral anticoagulant; KRS, Khorana risk score; VKA, vitamin K antagonist.

1. Guideline recommendations for thromboprophylaxis in patients undergoing cancer surgery.
In the absence of contraindications, all patients undergoing major surgery should receive pharmacologic thromboprophylaxis. I A
LMWH (if CrCl≥≥30 mL/min) once daily or low-dose UFH three times a day is recommended. Pharmacologic prophylaxis should be started 2–12 hours preoperatively and I A

continued for at least 7–10 days. No data to suggest one LMWH superior to another (grade 1A).

Extended prophylaxis (4 weeks) with LMWH to prevent postoperative VTE after major laparotomy (grade 1A) and laparoscopic surgery (grade 2C) is indicated in patients I A with a high VTE risk and low bleeding risk. 2 C
Out-of-hospital VTE prophylaxis is recommended for up to 4 weeks post-surgery for high risk patients with abdominal or pelvic cancer. 2 A
Mechanical thromboprophylaxis is not recommended as monotherapy, except when pharmacologic prophylaxis is contraindicated. 2 B
IVC filters are not recommended for routine prophylaxis. I A

LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; CrCl, creatinine clearance; IVC, inferior vena cava; PCD, pneumatic compression device; VTE venous thromboembolism.

Pharmacotherapy for cancer-associated venous thromboembolism treatment

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2.1 Guideline recommendations for treatment of cancer associated VTE
Tinzaparin is safe in patients with renal impairment and CrCl =20% and does not bioaccumulate with severe renal impairment and CrCl <20 mL/min.	I	A	33464938
Other LMWH is recommended over UFH for initial treatment unless CrCl ≥30 mL/min.	I	B	31492632
Rivaroxaban or edoxaban (after initial LMWH/UFH for 5 days) can be used for initial treatment if CrCl ≥30 mL/min and if patient is not at high risk of GI or GU bleeding.	I	B	31492632

UFH can be used for initial treatment when LMWH or DOACs are contraindicated or not available. 2 C
Fondaparinux can also be used for initial treatment if CrCl ≥30 mL/min. 2 D
LMWH or DOACs should be continued for at least 6 months. I A
Consider catheter-directed pharmacomechanical thrombolysis for DVT in patients at low risk for bleeding but at risk for limb loss or severe persistent symptoms despite 2 A anticoagulation.
Consider systemic or catheter-directed thrombolysis (category 2A) or embolectomy (category 2B) for patients with hemodynamically unstable PE at low risk for bleeding. 2 A

2 B

Consider IVC filter (retrievable preferred) if anticoagulation is contraindicated for acute VTE (within 1 month of diagnosis). Recommend filter retrieval once patient is tolerating 2 A anticoagulation.
Incidental PE should be treated similarly to symptomatic PE. 2 C
Treatment of isolated incidental subsegmental PE or superficial vein thrombosis should be individualized. It is suggested to consider anticoagulation. 2 A
Recommended duration of anticoagulation therapy is for as long as the patient’s cancer is active or under treatment. Providers should continue to discuss the risks and 2 B benefits.
For recurrent VTE on UFH, recommend considering HIT, antiphospholipid syndrome (check UFH anti-Xa level), increase dose of UFH, or switch to LMWH or DOAC. 2 B
For recurrent VTE on LMWH, recommend considering HIT, switch to twice-daily injections or increase dose or switch to fondaparinux or DOAC. 2 B
For recurrent VTE on fondaparinux, recommend considering HIT or switching to UFH, LMWH, or DOAC. 2 B
For recurrent VTE on warfarin, recommend switching to LMWH, UFH, fondaparinux, or DOAC.For recurrent VTE on DOAC, recommend switching to LMWH or fondaparinux. 2 B

CrCl, creatinine clearance; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; HIT, heparin-induced thrombocytopenia; IVC, inferior vena cava; LMWH, low-molecular- weight heparin; PE, pulmonary embolism; UFH, unfractionated heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Anticoagulation in special populations
1. Renal insufficiency

In general, anticoagulation for prevention or treatment of VTE in patients with cancer does not require specific adjustment in patients with mild renal insufficiency. Tinzaparin is safe in patients with renal impairment and CrCl =20% and does not bioaccumulate with severe renal impairment and CrCl <20 mL/min.

DOAC selection in the setting of severe renal impairment should focus on agents with limited renal clearance and requires shared decision making between the prescriber, patient, and entire health care team.

1. Extremes of body weight

LMWHs and DOACs may be considered in extremes of body weight, but adjustments based on weight should be made when applicable, especially for those with low body weight.

More challenging is the selection and dosing of DOACs in patients with increased BMI and body weight.

The ASCO guidelines recommend measuring peak and trough levels when DOACs are used in patients at extremes of body weight. However, there are limited data correlating DOAC drug levels with clinical outcomes and adjusting drug doses based on levels. Therefore, the clinical utility of this approach to management approach remains unclear.

1. Previous GI surgery

Also challenged by limited RCT data, DOAC use in patients with cancer, VTE, and a history of proximal GI surgery, either for tumor resection or weight reduction, remains a subject of much debate.

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1. Thrombocytopenia

Many patients with cancer have thrombocytopenia and it is not a contraindication to anticoagulation if platelet count > 50.000/microL. However, anticoagulation is typically contraindicated in those with platelet count <20.000/microL.

The decision should be individualized and based upon the risk of serious complications from VTE and the risk of bleeding associated with anticoagulation.

1. Incidental and small subsegmental pulmonary embolism

Bauer, K. A., in UpToDate Jun 2021, generally consider incidental (i.e., asymptomatic) PE and small subsegmental PE in patients with cancer as an indication for therapeutic anticoagulation for a minimum of three months.

This preference is based upon the presumption that in the absence of therapeutic anticoagulation, there is a high incidence of developing symptomatic PE in the future due to clot extension or recurrence in this population.

1. Arterial thromboembolism

Arterial thromboembolism is less common than venous thromboembolism in patients with cancer.

Embolism to the digits, brain or solid organs can be a paraneoplastic manifestation of solid tumours and are particularly associated with the myeloproliferative disorders. Typically, these patients have indication to anticoagulation.

Contraindications to anticoagulation (in hospitalized cancer patients)

Absolute contraindications of pharmacological prophylaxis:

Recent bleeding in CNS • Active major bleeding • Platelet count <20×109/L. Relative contraindications:
Relevant chronic bleeding (duration >48 h) • Initial period of post neurosurgery • Spinal or intracranial lesions
Platelet count 20–50×109/L • Drug related platelet dysfunction or uraemia • Underlying coagulopathy. Wait 12h after last prophylactic-dose LMWH administration for lumbar puncture or spinal anaesthesia.

Thromboprophylaxis is not required in cancer patients hospitalized exclusively to receive oncologic treatment (except in case of immobilization). In case of contraindication, apply physical antithrombotic measures.

References:

Level Grade PMID Nº

Bauer, K. A., et al., Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy, UpToDate, Jun 2021
Farge, D.; Frere, C.; Connors, J. M., et al., 2019 International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer, Lancet Oncol 2019
Muñoz, J. M.; Jimenez-Fonseca, P.; Carmona-Bayonas, A., et al., TESEO, cancer-associated thrombosis registry from the Spanish Society of Medical Oncology (SEOM), Clinical and Translational Oncology (2020) 22:1423–1424
Pachón, V.; Trujillo-Santos, J.; Domènech, P., et al., Cancer-Associated Thrombosis: Beyond Clinical Practice Guidelines – A Multidisciplinary (SEMI–SEOM–SETH) Expert Consensus, TH Open Vol. 2 No. 4/2018
Razak, N. B. A.; Jones, G.; Bhandari, M., et al., Cancer-Associated Thrombosis: An Overview of Mechanisms, Risk Factors, and Treatment, Cancers 2018, 10, 380; doi:10.3390/cancers10100380
Sengupta, A., Haemoheological Studies in Cancer – Future Scope, Int J Cancer Clin Res 2020, 7:135
Streiff, M. B.; Abutalib, S. A., Farge, D., et al., Update on Guidelines for the Management of Cancer-Associated Thrombosis, The Oncologist 2021;26:e24–e40 www.TheOncologist.com
Streiff, M. B.; Bjorn H.; Dana A., et al., Cancer-Associated Venous Thromboembolic Disease, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology, JNCCN, Volume 19, Issue 10, October 2021
Vathiotis I. A.; Syrigos N. K.; Dimakakos E.P., et al., Tinzaparin Safety in Patients With Cancer and Renal Impairment: ASystematic Review, Clin Appl Thromb Hemost., 2021 Jan-Dec; 27: 1076029620979592

SKIN DISORDERS

18.1 RADIATION THERAPY EPITELITIS

Authors: Bárbara de Castro, Inês Félix Pinto and Catarina Martins Silva Evidence

Definition Level Grade PMID Nº

Cutaneous inflammatory reaction occurring as a result of exposure to biologically effective levels of ionizing radiation. [1] It is one of the most common adverse effects of radiation therapy. [2] This effect is expected in the treatment of superficial targets such as breast, head and neck, lung and soft tissue of the limbs. The majority of patients will experience a mild to moderate reaction. [2]

Symptoms [3]

The skin changes include erythema, edema, pigment changes, hair loss, and dry or moist desquamation. These changes are correlated to the radiation dose; in a conventionally fractionated course of radiotherapy (1.8 – 2 Gy per fraction), progressive dermatitis can be expected such as:

Erythema at 12 – 20 Gy;
Dry descamation at 20 Gy;
Moist descamation at 50 Gy or higher.

The acute dermatitis typically continues to progress up to 10 to 14 days after completion of radiation therapy. Re-epithelialization usually begins within 10 days after radiation exposure.

Radiation dermatitis can have a negative impact on patients’ quality of life, mainly in the physical domain (due to itching, burning, and irritation), followed by the emotional and functional domains. [4]

Etiology

After the first dose of radiation, immediate effects can be seen: [5]

At a cellular level: ionization of cellular water and generation of short-lived free radicals, irreversible double-stranded breaks in nuclear and mitochondrial DNA and inflammation;
At the tissue level: (1) highly radiosensitive cells such as basal keratinocytes are largely destructed, unbalancing the self-renewing property of the epidermis – at a first instance, there is an increase in the mitotic activity in response to the aggression, leading to the dry desquamation; repeated exposures do not allow time for basal skin cells to replenish in order to maintain optimal renewal of the epidermis causing depletion of epidermal cells resulting in moist desquamation and loss of tissue integrity; (2) stem cells in the hair follicles and melanocytes are also damaged resulting in dry skin, hair loss and hyperpigmentation.

The mechanism of radiation-induced inflammation, although not fully understood, involves transendothelial migration of leukocytes and other immune cells from circulation to irradiated skin. [5]

Numerous cytokines and chemokines have been implied with acute radiation skin toxicity, in particular interleukin (IL) 1-alpha, IL-1-beta, tumor necrosis factor (TNF)-alpha, IL-6, IL-8, chemokine ligand (CCL)4, cysteine-X- cysteine motif chemokine ligand (CXCL)10, and CCL2;
Late radiation-induced fibrotic changes are thought to be mediated by the Transforming growth factor (TGF)-beta whereas fibroblasts are a key cell type responsible for the late/delayed effect of radiation;
Imbalances in antioxidant status and redox control have also been implied in radiation skin injury contributing to an associated impairing of wound healing.

Various factors can contribute towards a higher risk to develop radiation dermitis: [2]

1. Patient-related factors:
  - Increased age, obesity, poor nutritional status, chronic sun exposure, and smoking appear to increase the risk of radiation dermatitis by impairing tissue healing;
  - Connective tissue disorders, mainly scleroderma, have been poorly associated with increased risk of severe acute and chronic radiation dermatitis; skin thickening localized to the field of irradiation has been reported to occur in approximately half of the patients with scleroderma;
  - Inherited diseases associated with impaired DNA repair capacity, such as ataxia-telangiectasia, Bloom syndrome, Fanconi anemia, Gorlin syndrome, or xeroderma pigmentosum are at risk of developing severe radiation dermatitis; nevertheless, even in the absence of a known genetic disease, some individuals may present with an increased susceptibility to radiation dermatitis;
2. Treatment-related factors:
  - Total dose, dose per fraction, volume and surface area exposed to radiation can influence the risk of radiation dermatitis; the use of bolus as a means of delivering full dose to the surface also leads to an increased skin reaction;
  - The concomitant use of systemic treatment such as chemotherapy can aggravate the adverse reaction to radiation; the use of cetuximab is particularly associated with increased risk of severe dermatitis, with combination of radiation-induced dry or moist desquamation with the xerosis and papulopustular inflammatory reaction associated with epidermal growth factor receptor (EGFR) inhibition;
3. Others:

– The use of chemical agents in the skin such as deodorants, perfumes or alcohol-based lotions, thermal agents such as extreme water temperatures and physical agents that result in abrasion of the skin can increase the risk of developing and worsening radiation dermatitis.

Studies

The diagnosis of acute radiation dermatitis is clinical and based upon the finding of skin inflammation in a patient undergoing radiation therapy; particularly, the sharp demarcation of the skin changes consistent with the irradiated areas are characteristic of this entity.

Other skin conditions can develop during or after completing the treatment and should be considered in the differential diagnosis such as allergic contact dermatitis, intertrigo and herpes zoster. Radiation recall is an acute inflammatory skin reaction limited to the area that was previously irradiated that is triggered by chemotherapeutic agents (anthracyclines, taxanes or antimetabolites) or other drugs; it is drug-specific for each individual and can occur weeks to months to years after radiation therapy. The reaction usually resolves within one to two weeks after withdrawal of the drug.

The severity of radiation dermatitis can be assessed by several grading systems. The most commonly used are the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) and the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) toxicity criteria.

NCI CTCAE v.5 [1]

Level Grade PMID Nº

Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Faint erythema	Moderate to brisk	Moist desquamation in	Life-threatening	Death
or dry	erythema; patchy moist	areas other than skin	consequences; skin
desquamation	desquamation, mostly confined to skin folds and	folds and creases; bleeding induced by	necrosis or ulceration of full thickness
	creases; moderate edema	minor trauma or abrasion	dermis; spontaneous bleeding from
			involved site; skin
			graft indicated

RTOG/EORTC[6]

Level Grade PMID Nº

Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Follicular, faint	Tender or bright	Confluent, moist	Ulceration,	Death
or dull erythema / epilation / dry	erythema, patchy moist desquamation / moderate	desquamation other than skin folds, pitting	hemorrhage, necrosis
desquamation / decreased	edema	edema
sweating

Non-Pharmacologycal Treatment and Management of Epitelitis

Prevention of Epitelitis

Hygiene

It is recommended a gentle washing with warm/tepid water, with or without a mild soap/shampoo, of the body part in treatment. At the end, pat dry with a soft towel, preferably 2 made of cotton.
According to some studies, it is reported a trend in favor of washing as there is evidence of less patients with a maximum toxicity grade of ≥2 when washing is permitted.
Given the important psychosocial benefit of allowing patients to maintain their normal hygienic routine, the practice of allowing washing with water and mild soap is generally accepted as standard clinical practice.

Moisturizing

Keep the skin moisturized to prevent dryness. There is no evidence that any specific cream or product is better for this than another, but it should be a moisturizer that is water- I based.

Antiperspirant / Deodorant use I

It is safe to allow the use of antiperspirants during chest / breast radiotherapy.
There was no evidence to suggest that the use of antiperspirants resulted in increased toxicities.
This decision will be driven by the values and preferences of the patient. Education should include that deodorant/antiperspirant does not seem to cause harm, sweating is decreased, and the risk of grade 2 or 3 radiodermatitis is not increased.

Lifestyle and well-being

It is recommended to be very gentle with the skin in the treated area and to wear loose, comfortable clothing, preferably made of cotton. 3
Protect the treated skin from wind and direct sunlight. If it cannot be cover, use sunscreen with an SPF of 30 or higher.
It is not recommended the use of perfumed products, powders, cosmetics, shaving cream and aftershave, as they may contain irritating chemicals components.
Body hair removal should be done using an electric machine (it is not recommended the use of a razor, wax or depilatory creams during radiotherapy). Semipermeable Dressings
Semipermeable dressings in addition to standard washing/skincare regimen rather than standard washing/skincare regimen alone is recommended to minimize the I

development of radiodermatitis.

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The use of dressings prophylactically resulted in a moderate reduction in the risk of the development of grade 2 or greater radiodermatitis, a moderate reduction in the development of moist desquamation, a moderate reduction in tenderness, discomfort, or pain, and a moderate reduction in pruritus.

Intensity-Modulated Radiation Therapy (IMRT)

It has been showed a reduced skin toxicity in patients with breast cancer receiving IMRT versus conventional 3D radiation therapy. 2
Treatment with IMRT is associated with a significant decrease both in the time spent during treatment with Grade 2/3 dermatitis and in the maximum severity of dermatitis compared with that associated with conventional radiation.

Treatment and Control of Epitelitis

In cases of Grade 2 Radiodermatitis:

Promote a cleaned and damp environment of the wound. 2

It is recommended to perform a gently cleanse with saline.
Apply dressings that maintain hydration and which have low adhesion: extra-thin hydrocolloids, non-stick film with silicone or gelled (hydrogel) dressings.In cases of Grade 3. Radiodermatitis:

Control bleeding, odor and/or excessive exudation of the wound.

It is recommended to perform a gently cleanse with saline.
Apply dressings that maintain hydration and which have low adhesion: extra-thin hydrocolloids, non-stick dressings and according to the degree of exudation: 2
- Abundant exudate: material absorbent (ex: foams, hydrofiber);
- Very thick exudate: wet dressings with hydrogel;
- Bleeding wound: dressing with haemostatic material (ex: alginate, spongostan, local epsicaprom).

Pain Control

Cover open areas with low adhesion dressings to protect the nerve endings. 2
Manage prescribed analgesic therapy (non-opioid analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for mild pain; weak opioids (codeine, tramadol) with or without non-opioid analgesics for moderate pain; potent opioids (morphine, fentanyl, oxycodone, buprenorphine, tapentadol, hydromorphone) with or without non-opioid analgesics for severe pain).

Infection Prevention

Watch for signs and symptoms of infection (ex: fever, pain, oedema, increased exsudate, erythema, local warmth, induration). 2
Perform microbiological study with swab.
Consider antibiotic/antifungal therapy with doctor’s prescription.

Pharmacotherapy

Topical treatment 2

Topical steroid cream (Ex: Betamethasone or mometasone cream)

It may be recommended the use of topical steroids in addition to standard washing/skincare regimen rather than standard washing/skincare regimen alone for the minimization of radiodermatitis.
Steroids may reduce the development of grade 2 or greater radiodermatitis and on the development of moist desquamation.

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The use of topical steroids may result in a large reduction of pain during and after radiotherapy treatment.
It can be applied prophylactically from the first day of radiation therapy until 2 weeks after the completion of treatment thrice daily in the irradiated area.
Patients should not apply topical steroid cream on the irradiated area immediately before radiation treatment to avoid extra skin dose which may worsen the skin reaction.
It should be ceased once the skin becomes disrupted and not intact. Silicone-based film forming gel dressing (Ex: StrataXRT®)
It has been found to be effective if applied prophylactically twice daily from the first day of radiation therapy to 4 weeks after the completion of treatment to prevent and delay the 2 development of acute RD.
The gel does not require removal before radiation treatment.
Consider the cost-effectiveness in terms of the hospital or patient.

Trolamine emulsion (Ex: Biafine®) and Dexpanthenol cream (Ex: Bepanthen®) 2

Although being extensively used in Europe, multiple RCT failed to demonstrate any advantage of trolamine emulsions over supportive care or even placebo in treating epitilitis.
It can be applied prophylactically from the first day of radiation therapy thrice daily in the irradiated area. Aloe Vera
Not recommended for patients to manage acute radiation dermatitis. I

Systemic treatment

It Oral curcumin I

Oral curcumin reduced the development of moist desquamation compared to placebo but did not reduce radiodermatitis severity at the end of treatment.
Curcumin has drug interactions and is contraindicated in patients on anticoagulation agents and in patients on certain chemotherapeutic agents.
There is currently no recommendation in favour of oral curcumin for the management of epitelitis.

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References

Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, November 2017, National Institutes of Health, National Cancer Institute. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5×11.pdf (Accessed July 29, 2022).
Sourati A, Ameri A, Malekzadeh M. Acute Side Effects of Radiation Therapy. Springer International Publishing; 2017; Available from: http://dx.doi.org/10.1007/978-3-319-55950-6
Mendelsohn FA, Divino CM, Reis ED, Kerstein MD. Wound care after radiation therapy. Adv Skin Wound Care 2002; 15:216.
Rzepecki A, Birnbaum M, Ohri N, et al. Characterizing the Effects of Radiation Dermatitis on Quality of Life: AProspective Survey-Based Study. JAm Acad Dermatol 2019.
López E, Guerrero R, Núñez MI, et al. Early and late skin reactions to radiotherapy for breast cancer and their correlation with radiation- induced DNA damage in lymphocytes. Breast Cancer Res 2005; 7:R690.
Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Cox JD et al. Int J Radiat Oncol Biol Phys. 1995 Mar 30;31(5):1341-6. PMID 7713792

ALOPECIA AND OTHER HAIR IATROGENIC DISORDERS

Authors: Diana Neto da Silva, Luísa Leal da Costa and Leonor Fernandes

Introduction

- - A common adverse event related to anti-neoplastic drugs is hair changes. They are expected to occur in 65% of patients receiving cytotoxic therapy, 15% with targeted therapy, 2% on immunotherapy, and up to 100% in areas treated with radiotherapy (1). The spectrum of hair disorders in cancer patients includes all hair changes, as alopecia, pigmentary changes, textural changes, and cycle alterations. (2)

Definition

Alopecia:

- - The term alopecia refers to the partial or complete absence of hair from any area of normal hair growth within the body.
  - Alopecia is a transient and usually (although not always) reversible consequence of systemic cancer therapy that can be psychologically and socially devastating. (3)
  - Chemotherapy-induced alopecia (CIA) is most prominent on the scalp, with a predilection for areas with low total hair densities, particularly the crown and frontal areas of the scalp, where there is slower hair recovery. (4) Alopecia can be accompanied by dysesthesia, pruritus and dryness of the skin.
  - Although endocrine therapy-induced alopecia (EIA) is usually less mentioned, it is likely to be more frequently present than it has been reported. (5)
  - CIA usually starts 1-3 weeks after initiating therapy and the severity mainly depends on type, dose, method of administration and time of intervals between infusions. Hair will start growing again 2-3 months after ChT completion and grow at a rate of approximately 1cm/ month. (6)
  - Approximately 65% of patients report changes in colour and texture in newly grown hair. (7)

Etiology

- - In general, alopecia can be the result of one or both of two mechanisms (8):
  - Severe inhibition of proliferation of the hair follicle matrix keratinocytes, the hair may separate at the bulb and shed, a process referred to as anagen effluvium. Agents with greater toxicity on hair matrix keratinocytes, will lead to severe alopecia but possibly more rapid hair regrowth.
  - Thinning of the hair shaft can occur at the time of maximal ChT effect, resulting in Pohl-Pinkus constrictions. As a result, the hair shaft may break at the follicular orifice during the resting phase of the hair cycle.

Depending on the mechanism and drug, we can classify anti-neoplastic-induced alopecia (ANIA) into three groups:

- - - follicle destruction – mainly chemotherapy and radiotherapy
    - follicle miniaturization – mainly endocrine and targeted therapies
    - hair cycle blockage – mainly immunotherapy.

Table 1. Main characteristics of hair disorders according to the anticancer therapies used (adapted from references 9-16).

Evidence

Level Grade PMID Nº

Treatment Type

Clinical Topography

Main Incriminated Mechanism(s)

Time to Onset

Reversibility

Frequency (%) and Range ([])

Chemotherapy

Diffuse and +/−

total

Cell division

blockage and apoptosis Destruction of the

2–3 weeks after

first administration

Average: 3 –6

months post- treatment Irreversible (with

≈65 [<10–100]

follicle

certain regimens,

e.g. taxanes)

Endocrine therapy	Hair thinning AGA-like pattern	Miniaturization of the follicle	1–91 months after first administration	Not systematic	≈5 [0–25]
Targeted therapy	Very variable (target dependent)	Miniaturization of the follicle (+/− destruction)	Variable	Possible even during treatment. Irreversible with some molecules	≈15 [2–60]
Radiotherapy (<43 Gy)	Depending on the radiation field	Destruction of the follicle	1–3 weeks after first administration	Average: 2 –4 months post- irradiation	≈75–100
Radiotherapy (≥43 Gy)	Depending on the radiation field	Destruction of the follicle	≈100 weeks	No (scaring alopecia)	≈75–100
Immunotherapy	Variable	Cycle blockage and dysimmunity	Variable	Variable	≈1–2

Severity Grading

An alopecia grading scale for treatment-related alopecia is provided in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, v5.0)

(17) (Table 2)

Table 2: National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, v5.0)

Adverse event	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Alopecia	Hair loss of <50% normal for that	Hair loss >50% normal for that
	individual that is	individual that is
	not obvious from a	readily apparent to
	distance but only on	others; a wig or hair
	close inspection; a	piece is necessary if
	different hairstyle	the patient desires to
	may be required to	completely
	cover hair loss, but	camouflage the hair
	it does not require a	loss; associated with
	wig or hair piece to camouflage	psychosocial impact

Risk factors

The ability of antineoplastic agents to cause alopecia depends on the specific agent and the route, dose, and schedule of drug administration.

Specific agent frequency of alopecia (Tables 3, 4 and 5)
Regimen:
High dose, intermittent, intravenous chemotherapy – high incidence of grade 2 alopecia.
Low dose, oral administration and weekly intravenous regimens are less likely to induce grade 2 alopecia.
Combination ChT more likely than single agents.
- - Concomitant factors:
Poor drug metabolism (e.g., patients with liver dysfunction may have unexpected, significant alopecia).
Prior exposure to scalp irradiation.
Older age.
Androgenic alopecia.
Use of prior chemotherapy causing alopecia.
The presence of graft-versus-host disease in patients who have undergone hematopoietic cell transplantation
- - - Not associated:
Hair type,

Frequency of CIA	Chemotherapeutic agents
	Cyclophosphamide
	Daunorubicin
	Docetaxel
Often >50%	Doxorubicin Epirubicin Etoposide
	Ifosfamide
	Irinotecan
	Paclitaxel
	Topotecan
	Vindesine
	Vinorelbine
	5-FU
	Amsacrine
	Bleomycin
	Busulfan
	Cytarabine
Occasional 10- 50%	Gemcitabine Lomustine Melphalan
	Thiotepa
	Vinblastine
	Vincristine
	6-Mercaptopurine
	Capecitabine
	Carboplatin
Rare <10%	Carmustine Cisplatin Fludarabine
	Methotrexate
	Mitoxantrone
	Procarbazine
	Raltitrexed
	Streptozotocin

Ethnicity
Race.

Table 3: Frequency of

CIA in classical chemotherapeutic agents (adapted from references 18 and 19)

Table 4: Frequency of TIA in targeted therapies (adapted from references 20-23)

Frequency of TIA	Molecule (class)
60%	SMOi (vismodegib specifically)
25-30%	Mul-I (e.g., sorafenib, regorafenib)
20-25%	BRAFi (e.g., dabrafenib, vemurafenib)
5-15%	EGFRi (e.g., afatinib, erlotinib) VEGFRi (e.g., axitinib, cabozantinib, pazopanib, sunitinib) Anti-VEGF (bevacizumab) Anti-EGFR (e.g., cetuximab) ALKi (e.g., crizotinib) MEKi (e.g., trametinib)

Table 5: Frequency of EIA in endocrine therapies (adapted from references 24-26)

Frequency of EIA	Molecule (class)
>30%	Letrozole (AI) + ribociclib (CDK4/6i)
20-30%	Anastrozole (AI) + gosereline (aGnRH) Letrozole (AI) + palbociclib (CDK4/6i)
10-20%	All types of endocrine therapies (when used in combination) Tamoxifen (SERM) Leuproreline (aGnRH) Exemestane (AI) + aminoglutethimide
<10%	AI + fulvestrant (AE) Fulvestrant (AE) Anastrozole, letrozole, exemestane (AI) Flutamide, bicalutamide, nilutamide, abiraterone, enzalutamide (ADT)

Radiotherapy induced alopecia:

- - Radiation-induced alopecia (RIA) must be considered in two situations: central nervous system primary tumours and brain metastases.
  - Predictive factors of RIA: doses (per fraction and total), the type of ionizing radiations (photons vs. protons), the surface and volume of irradiation, concomitant treatment, hair capital and the genetic constitution of the patient. (27)
  - RIA appearance is relatively abrupt and occurs within 1-3 weeks after treatment initiation. It concerns 75-100% of PERT-treated patients (since the dose per fraction is -2 Gy) with a regrowth around 2-4 months post-protocol. (28)
  - Persistent RIA(pRIA) is defined as the presence of alopecia over 6 months post-RT; it is estimated to occur in 60% of PERT-treated patients, notably through scarring alopecia.
  - Hair often grows back in 3 to 6 months after treatment has ended. If you received a very high dose of radiation your hair may grow back thinner or not at all on the part of your body that received radiation.

Management:

Prevention:

- - Scalp hypothermia (scalp cooling):
The mechanism of action includes local vasoconstriction of blood vessels, resulting in reduced delivery of chemotherapy to the scalp, decreased follicle cell metabolic rate, and reduced cellular drug uptake.
Efficacy is variable and dependent on the type and intensity of planned chemotherapy, with significantly less hair preservation in patients receiving anthracyclines compared with non-anthracycline-based regimens. (29)
Not all patients should use scalp hypothermia.
Contraindications:
- Paediatric patients.
- Patients receiving continuous-infusion ChT regimens over one day or longer that result in alopecia.
- Patients undergoing whole-brain or targeted brain irradiation.
- Cold agglutinin disease, cryoglobulinemia, and post-traumatic cold dystrophy.
- Small cell or squamous cell lung cancer.
- Skin cancers, including melanoma, squamous cell carcinoma, or Merkel cell carcinoma.
- Hematologic malignancies (including leukaemia and some forms of lymphoma).
- Patients undergoing bone marrow or stem cell transplantation with myeloablative doses of chemotherapy and/or radiation therapy.

Evidence

Level Grade PMID Nº

Therapeutic options: Small molecules and biologic agents have been tested and may reduce or prevent alopecia by protecting the hair bulb from the damaging effects of chemotherapy. The only interventions tested in humans include topical bimatoprost, minoxidil, and calcitriol.

At present, there are no pharmacologic interventions that have been approved by regulatory agencies for this indication. Global approach:

- - Hair status evaluation and differential diagnoses eviction (anamnesis, clinical examination, biological assessment, trichoscopy, trichogram, +/− biopsy)
  - Haircut before treatment initiation:
Hair prosthesis and textile accessories (e.g., wig, scarf, or turban)
Camouflage techniques (e.g., pigmentation, keratin powder)
Early accompaniment (medical, paramedical, psychologist, cancer support group)

•treat your hair gently (e.g., use a hairbrush with soft bristles or a wide-tooth comb; do not use hair dryers, irons or products that may hurt the scalp; wash the hair with a mild shampoo, less often and dry it with a soft towel)

Evidence

Level Grade PMID Nº

Topical bimatoprost :

Topical 0.03% bimatoprost , a prostaglandin analogue, has been used successfully on the upper e yelid margin to enhance eyelash growth in patients with eyelash hypotrichosis. (30)
While topical bimatoprost could be considered for the treatment of chemotherapy -induced eyelash alopecia, there is no data supporting a preventive benefit, and safety during chemotherapy has not be evaluated.

Topical minoxidil :

Minoxidil is thought to modify the hair cycle by prolonging the anagen phase.
It may also increase hair follicle size, thereby counteracting miniaturization of the hair follicle, which is the characteristic histologic finding of androgenetic alopecia.
An uncontrolled study of 41 patients showed significant improvement in 25% and moderate improvement in 40% of patients treated with minoxidil 5% daily. (25)
Minoxidil has been FDA cleared for the treatment of androgenetic alopecia , and it has been used in

women with endocrine therapy-induced alopecia, although efficacy data is limited.

Finasteride:

Finasteride, a type II 5 -alpha-reductase inhibitor, is approved for the treatment of benign prostatic hyperplasia decreasing symptoms, reducing the risk of acute urinary retention or the need for surgical procedures, and treating male pattern hair loss.
There is limited data on its efficacy in women with female pattern alopecia, with variable success.
Finasteride is not recommended for the treatment or prevention of CIA, neither in women with breast cancer with EIA, due to safety concerns, as this drug has been shown to increase serumoestrogen levels in 34 percent of patients. and has been associated with male gynecomastia. (31)

Spironolactone:

Spironolactone has been used to treat women with androgenetic alopecia, with limited but clear efficacy in some patients.
Concern has been raised about the potential for increasedoestrogen levels with spironolactone, but this has not been consistently shown, and an analysis of three studies totalling 49,298 patients suggested that there is no increased risk of female breast cancer while on spironolactone for alopecia. (31)
As the risk-benefit assessment does not justify routine use, spironolactone is not recommended.

Evidence Level Grade PMID Nº

Topical calcitriol :

Pre-treatment with topical calcitriol (1,25(OH)2D3; the most active metabolite of vitamin D) protects rats from cyclophosphamide-, etoposide-, and doxorubicin-induced alopecia.
Effects may be mediated by direct biological activity or modulation of other factors. Specific receptors for calcitriol are present in rat, murine, and human skin cells, and calcitriol induce s differentiation of murine epidermal keratinocytes.
A phase I trial of 12 patients receiving anthracycline – and cyclophosphamide -containing ChT for breast cancer failed to demonstrate any benefit in preventing CIA. (32) Furthermore, concerns about potential protection of the cancer cells from the effects of chemotherapy have been raised.
This treatment is not recommended for prevention of chemotherapy-induced alopecia.

Therapeutic Strategy (according to the prevention and management of dermatological toxicities related to anticancer agents: ESMO Clinical Practice Guidelines) (33):

- - Scalp cooling is recommended to prevent CIA 2 B
  - Biotin and Orth silicic may stimulate hair growth but are not generally recommended 4 C
  - Minoxidil can be considered to stimulate hair growth after CIAor EIA 4 C
  - Spironolactone is not recommended because the risk benefit analysis does not justify its routine useBimatoprost ophthalmic solution may result in growth of eyelashes in some 3 C patients but is not generally recommended

Persistent CIA (pCIA):

- - pCIA is defined by the presence of alopecia beyond 6 months after chemotherapy completion. It can exhibit various clinical aspects: mostly diffuse and non-scarring (≈50% of cases), with possible scarring involvement.
  - Histologically, destruction of the follicular epithelial stem cell pool and follicular miniaturization are the main suspected mechanisms. (34)
  - It is more frequently observed in patients treated for breast cancer (BC) with taxane-based protocols. (35) A prospective study has shown that BC patients treated with taxanes exhibited pCIAin ≈40% at 6 months, with persistence at 3 years. (36)
  - pCIAalso exhibits modifications in hair quality. It has been estimated that up to 75% of patients with pCIA still had hair thinning at 3 years post- chemotherapy.

Other hair iatrogenic disorders

Textural and pigmentary hair changes are frequent with anticancer therapies.

Hyperpigmentation:

- - Methotrexate and some targeted biologic agents may temporarily affect the follicle melanocytes, inducing hyperpigmentation of scalp hair, eyebrow hair, and eyelashes.
  - This tends to occur in bands that alternate with the normal colour, a feature known as the “flag sign.”
  - Hair depigmentation has been described as a possible marker of tumour response in 14 patients receiving anti PD1 and antiPDL-1 therapy for lung cancer. (37)

Hair curling and dyspigmentation:

- - Straight hair may become curly or wavy in 65% of patients with cancer after treatment with cytotoxic chemotherapy. (38) With targeted therapies, hair growth on the scalp can slow down and become finer, curlier, and more brittle. (39)
  - Small molecule inhibitors and monoclonal antibodies targeting epidermal growth factor receptor (EGFR), BRAF, Bruton tyrosine kinase (BTK), Bcr/Abl, cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4), KIT, and platelet-derived growth factor receptor (PDGFR)/vascular endothelial growth factor receptor (VEGFR) may result in partial alopecia, hair curling, and dyspigmentation.

Hair thinning:

- - Additional agents may cause partial (mild) alopecia, including targeted biologic agents, antibody-drug conjugates, and standard endocrine therapy (particularly tamoxifen and aromatase inhibitors) used in the adjuvant or metastatic setting.
  - Hair thinning with adjuvant endocrine therapy for early-stage breast cancer has been associated with poor adherence with therapy.

Hirsutism, hypertrichosis and trichomegaly

- - Excessive hair growth around the periocular area, hirsutism, and trichomegaly have been reported as an AE of EGFR inhibitors.
  - Eyelash trichomegaly also has been reported after fibroblast growth factor receptor inhibitor therapy. (40)
  - These alterations usually resolve after discontinuation of treatment, although in some cases they can persist for several months.
  - Endocrine therapies may also cause excessive hair growth in androgen-dependent areas of the body in women (hirsutism), the low incidence is likely related to underreporting.

Table 6: Selected anticancer therapies (representative) commonly causing hair changes

Evidence

Level Grade PMID Nº

Hair disorders	Cancer therapy	Frequency
Pigmentary hair changes (41-43)	Targeted therap y: cabozantinib pazopanib sorafenib sunitinib imatinib PD-1 and PD-L1 inhibitors (44)	30%
Textural hair changes	Targeted therap y: (45-46) erlotinib cetuximab gefitinib lapatinib panitumumab and BRAF inhibitors. Cytotoxic chemotherap y: (47) cyclophosphamide taxanes	30% 65%
Hirsutism and hypertrichosis	EGFR/MEK inhibitors : (46,48) erlotinib cetuximab gefitinib afatinib lapatinib panitumumab	50%
Eyelash trichomegaly	Targeted therap y: EGFR inhibitors (49- 51)	8 case reports

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SKIN HYPERSENSITIVITY

Authors: Pedro Simões, Joana Duarte Albuquerque and Madalena Machete

Symptoms

Most anticancer treatments carry a risk for infusion reactions, or hypersensitivity reactions (HSR). They are defined as undesired adverse reactions to a drug that are non-dose related, unpredictable, unrelated to the drug’s pharmacological activity, and usually resolve after the treatment is stopped.

Typical symptoms include: mucocutaneous manifestations (up to 90% of patients); respiratory (40%); circulatory (30%–35%); abdominal symptoms; and others. While cutaneous symptoms are the most frequent, there are many other possible clinical presentations; even when administered at the same dose via the same route, the same drug may produce different clinical symptoms and signs in different individuals.

This chapter will focus on the description of the possible mucocutaneous manifestations (skin hypersensitivity). Other HSR-related symptoms, including the definitions of cytokine-release syndrome and anaphylaxis, were described elsewhere (see Chapter 13 Infusion Reactions).

- 1. Mucocutaneous reactions (skin hypersensitivity)

These manifestations may be divided according to their time of onset:

Immediate reactions (onset within one hour of exposure): urticaria; angioedema; conjunctivitis
Delayed reactions (onset after one hour of exposure, typically appear days after treatment): late-occurring or delayed urticaria, maculopapular rash or acneiform rash are the most common late manifestations. Others include: fixed drug eruptions; leukocytoclastic vasculitis; blistering diseases (such as toxic epidermal necrolysis, Stevens-Johnson syndrome, generalized bullous fixed drug eruptions, erythema multiforme), drug-induced hypersensitivity syndrome (DiHS) / drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), symmetrical drug-related intertriginous and flexural exanthemas (SDRIFE)

Evidence

Level Grade PMID Nº

21561350

32850076

The specific diagnostic criteria for each underlined cutaneous manifestation are described in Table 1.

Table 1. Mucocutaneous manifestations of drug hypersensitivity

Reaction:	Mucocutaneous involvement:	Systemic symptoms:
Urticaria 1	Blanching, raised, palpable wheals ( hives), with central swelling and surrounding cutaneous erythema Can be confluent, forming urticarial plaques Can be l inear, annular or serpiginous Can occur on any skin area May be migratory Usually are transient Intense pruritus is common	N/A
Angioedema 2	Rapid onset dermal / subdermal swelling Usually happens in the face, lips, tongue, larynx, limbs and genitals	N/A
Fixed drug eruption 3	Painful and itchy patch / plaque / bulla Reappears in the same location (including lips, genitals and hands) with drug re-exposition	N/A
Leukocytoclastic vasculitis 4	Includes a range of possible cutaneous forms: palpable purpura (64%), petechiae and purpuric macules (36%), vesicles and bullae (16%), ulcers (9%), subcutaneous nodules (3%) Most common site is the lower extremities, especially above the ankles	Mild fever, myalgia, arthralgia End-organ lesion occur in up to50% of patients (small – vessel vasculitis pattern)

Toxic epidermal necrolysis (TEN) 5

First phase: development of target lesions (pale and edematous macules with surrounding erythema and central purpura / bulla)
Second phase : widespread blister formation with mucous membrane involvement
Lesions are Nikolsky’s sign – positive (slight rubbing of the skin results in exfoliation of the outermost layer)
Involves > 30% of body surface area (BSA)
High mortality rate due to sepsis and multiorgan failure

Fever and influenza – like symptoms 1 -3 days before mucocutaneous lesions
Dehydration and major electrolyte imbalances
Hematologic abnormalities (anemia and neutropenia)
Respiratory involvement occurs in up to 40% of patients (pulmonary edema, atelectasis, interstitial lung disease…)
GI involvement (with protein -rich diarrhea) is possible
Acute kidney injury occurs in 20% of the cases, often with proteinuria
Hepatitis can occur in up to 10% of TEN (mild elevations in AST/ALT are

present in 50%)

Stevens-Johnson syndrome (SJS)

Same characteristics as TEN, but with <10% of BSA involvement
If 10 -30% of BSA involvement:

SJS-TEN overlap

Same as TEN

Generalized bullous fixed drug eruption (GBFDE)

Same characteristics as SJS/TEN, but less mucosal involvement
Different histopathologic features (less granulysin and CD56 expression, higher Foxp3

expression)

Same as SJS/TEN

Erythema multiforme 6

Raised, oedematous papules/plaques that evolve into pathognomonic target or iris lesions within 72 hours
Target lesions (dusky central area or blister, surrounded by a pale ring of oedema, and an erythematous peripheric halo)
Acral distribution with centripetal spread
If erythema multiforme minor , is mild and self-limited
If erythema multiforme major , may be severe and life – threatening, and may involve mucosal membranes
When there is epidermal detachment, it always involves

less than 10% of BSA

May occur in erythema multiforme major: fever, malaise, myalgias, arthralgias

DiHS / DRESS 7

Drug-induced hypersensitivity syndrome (DiHS) = drug reaction with eosinophilia and systemic symptoms (DRESS)
The cutaneous involvement includes a n erythematous morbilliform rash (rose -red macular / maculopapular lesions, with healthy -looking intervening skin, may be confluent)
May be related to human herpes virus-6 (HHV-6) reactivation
Mortality rate of 10%

Fever
Lymphadenopathy
Hepatitis
Eosinophilia, leucocytosis
Interstitial pulmonary infiltrates (5%)
Kidney disfunction , may have proteinuria
Others ( cardiac, CNS…)

Acute generalized exanthematous pustulosis (AGEP) 8

Erythematous pustular rash (pinhead-sized pustules ), starting in the main folds (axillary, inguinal, submammary) and spreading to the trunk and limbs
Mucous membranes are affected in 25% of the cases (usually only on one site)
Mortality rate of approximately 5%

Fever, leucocytosis, eosinophilia, hypocalcemia a nd hypoalbuminemia may occur
Systemic involvement occurs in 17% of cases (enlarged lymph nodes, hepatocellular disfunction, cholestasis, nephritis, respiratory

failure)

Symmetrical drug-related intertriginous and flexural exanthemas (SDRIFE) 9

Also called “baboon syndrome”
Well-demarcated erythematous patches distributed symmetrically on the buttocks, upper inner thighs and armpits

N/A

CNS – central nervous system; GI – gastrointestinal; N/A– non applicable

Adapted from: PMID 10756214: Greaves M. Chronic urticaria. Journal of Allergy and Clinical Immunology. 2000 Apr 1;105(4):664–72. DOI: 10.1067/mai.2000.105706.

ISSN 2165-8048: Boussetta N, Ghedira H, Hamdi M, Ariba B, Metoui L, Ghasallah I, et al. Acquired Angioedema Revealing a B cell Non Hodgkin Lymphoma in ATunisian Man. Intern Med. 2017;07(05). DOI: 10.4172/2165-8048.1000259.

PMID 32494527: Chango Azanza JJ, Calle Sarmiento PM, Lopetegui Lia N, Alexander SA, Modi V. Leukocytoclastic Vasculitis: An Early Skin Biopsy Makes a Difference. Cureus. 12(5):e7912. DOI: 10.7759/cureus.7912.

PMID 29188475: Lerch M, Mainetti C, Terziroli Beretta-Piccoli B, Harr T. Current Perspectives on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Clinic Rev Allerg Immunol. 2018 Feb 1;54(1):147–76. DOI: 10.1007/s12016- 017-8654-z.

PMID 24388722: Cho Y-T, Lin J-W, Chen Y-C, Chang C-Y, Hsiao C-H, Chung W-H, et al. Generalized bullous fixed drug eruption is distinct from Stevens-Johnson syndrome/toxic epidermal necrolysis by immunohistopathological features. J Am Acad Dermatol. 2014 Mar;70(3):539–48. DOI: 10.1016/j.jaad.2013.11.015.

PMID 6345608: Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. JAm Acad Dermatol. 1983 Jun;8(6):763–75. DOI: 10.1016/s0190-9622(83)80003-6.

PMID 34743720: Muto Y, Kuse N, Inomata M, Awano N, Tone M, Takada K, et al. Drug-induced hypersensitivity syndrome caused by minodronic acid hydrate. BMC Pulmonary Medicine. 2021 Nov 7;21(1):350. DOI: 10.1186/s12890-021-01709-x. PMID 20606889: Khalel MH, Fattah Saleh SA, F El-Gamal A-H, Najem N. Acute generalized exanthematous pustulosis: an unusual side effect of meropenem. Indian J Dermatol. 2010;55(2):176–7. DOI: 10.4103/0019-5154.62759.

PMID 27472323: Feldmeyer L, Heidemeyer K, Yawalkar N. Acute Generalized Exanthematous Pustulosis: Pathogenesis, Genetic Background, Clinical Variants and Therapy. Int J Mol Sci. 2016 Jul 27;17(8):1214. DOI: 10.3390/ijms17081214.

PMID 29340257: Li DG, Thomas C, Weintraub GS, Mostaghimi A. Symmetrical Drug-related Intertriginous and Flexural Exanthema Induced by Doxycycline. Cureus. 2017 Nov 10;9(11). DOI: 10.7759/cureus.1836.

1, 4 – property of James Heilman, MD; licensed under Creative Commons Attribution License CC BY-SA 3.0. 2 – property of Boussetta et al., DOI: 10.4172/2165-8048.1000259; licensed under Creative Commons Attribution License CC BY 4.0 .

3 – unknown author; public domain. 5 – unknown author; licensed under Creative Commons Attribution License CC BY 4.0. 6 – property of James Heilman, MD; licensed under Creative Commons Attribution License CC BY-SA 3.0. 7 – property of Muto et al., DOI: 10.1186/s12890-021-01709-x; licensed under Creative Commons Attribution License CC BY 4.0.

– property of Khalel et al., DOI: 10.4103/0019-5154.62759; licensed under Creative Commons Attribution License CC BY 4.0.
– property of Li et al., DOI: 10.7759/cureus.1836; licensed under Creative Commons Attribution License CC BY 3.0

Etiology

In HSR can be divided into allergic (immune) reactions and non-immune reactions. In addition, allergic HSR can be classified according to their mechanism:

- Type I: immediate reactions, mediated by drug-specific IgE antibodies that activate mast cells and basophils (fast onset, minutes to hours). Includes urticaria and angioedema
- Type II: delayed reactions mediated through IgG antibody-mediated destruction and complement-dependent cytotoxicity (late-onset, days).
- Type III: delayed reactions mediated through immune (antigen-antibody) complexes (late-onset, days to weeks). Includes small vessel vasculitis with skin involvement (leukocytoclastic vasculitis).
- Type IV: delayed reactions mediated by T cells (late-onset, days to weeks). They can have severe and potentially fatal presentations, such as TEN, SJS and DRESS, or other patterns such as maculopapular exanthema, SDRIFE, and AGEP.

Almost all anticancer treatments have the potential of inducing HSR. Some examples include:

- Anthracyclines: incidence is rare but is higher with pegylated liposomal doxorubicin and daunorubicin (7-11% of patients); symptoms occur during the initial minutes of the infusion in the first or second cycle.
- Platinum-based agents: usually IgE mediated (but can be non-IgE mediated or mixed); incidence is directly related to number of exposures (5-27% of patients); cross- reactivity between carboplatin and oxaliplatin may occur in up to 45% of patients, but is lower with cisplatin.
- Taxanes: usually non-IgE mediated (typically anaphylactoid reactions); incidence varies between <4% for nab-paclitaxel and 10% for paclitaxel; contrary to platinum-based agents, symptoms occur mainly during the first cycle, within minutes of starting the infusion; HSR may be caused either by the drug or by the vehicle in which it is dissolved (Cremophor for paclitaxel, polysorbate 80 for docetaxel), and cross-reactivity between docetaxel and paclitaxel seems to happen in 50% of patients (less frequently for nab-paclitaxel).
- Other chemotherapeutical agents (cyclophosphamide, gemcitabine, irinotecan, fluorouracil): HSR are rare.
- Monoclonal antibodies: incidence during first administration varies between 15% for cetuximab, 40% for trastuzumab and 77% for rituximab (may also happen with other antibodies such as panitumumab, pertuzumab, bevacizumab or brentuximab); usually non-IgE mediated.
- Tyrosine kinase inhibitors (TKI): incidence is unknown, but cases of immediate and non-immediate HSR have been reported with various TKI, such as regorafenib, ribociclib

/ palbociclib, or dabrafenib / vemurafenib.

- Immunotherapy: rare, usually non-IgE mediated.

Studies

The initial diagnostic approach to the patient with a presumed HSR is clinical and involves a complete history of the drugs taken (types, doses, duration), a detailed description of the symptoms and signs (types, onset, localization, and evolution), and a complete examination of the skin and mucous membranes (including the mouth, eyes, and genitals). Common blood tests may reflect the systemic inflammatory response, therefore helping on the diagnosis or its severity classification (see Chapter 13 Infusion Reactions).

A definitive diagnosis of HSR is recommended so that adequate treatment options and preventive measures may be instituted. Wrongly classifying the symptoms as an HSR may interfere with the available treatment options, sometimes leading to the use of either more-expensive or less-effective drugs; therefore, while not universally available and not carried out on an emergency basis (especially in the case of anaphylaxis), some tests may be of use when suspecting of drug allergy and are explained in Table 2.

Evidence

Level Grade PMID Nº

Table 2. Diagnostic tests for hypersensitivity reactions

Test:	Characteristics:
Skin tests	Skin prick tests are available in specialised centres for some chemotherapeutic drugs and monoclonal antibodies, such as platins, taxanes, cyclophosphamide, gemcitabine, irinotecan, fluorouracil, rituximab, cetuximab, trastuzumab, pertuzumab, bevacizumab and brentuximab. Skin testing should not be performed with vesicant agents, such as anthracyclines or vinca alkaloids. If negative, intradermal tests may be considered. Testing should be performed at least 4 -6 weeks after and withing 6 months of the initial reaction to avoid false negatives. The results should be interpreted at 15-20 minutes, and after 24 and 72 hours if a non- immediate HSR is suspected. Usually have high specificity but low sensitivity.
Skin biopsy	Not routinely necessary for the diagnosis of exanthematous drug eruptions. The histopathologic findings (vacuolar interface dermatitis, tissue eosinophilia) may support the diagnosis but are usually nonspecific. May be necessary if the diagnosis is uncertain, or there is a concern for a more severe HSR, especially in delayed reactions.
Total IgE	May be elevated in IgE-mediated HSR. Has low sensitivity and specificity .
Specific IgE	Mostly studied for platinum-based agents. Has high specificity (75-100%) but low sensitivity (35-75%).
Serum tryptase	Blood samples are optimally obtained 15 minutes to 3 hours after symptom onset. Serial measurements of tryptase levels during an anaphylactic episode and their comparison to the baseline tryptase level after recovery (cut-off: [baseline x 1.2] + 2) increase sensitivity.

Evidence

Level Grade PMID Nº

Adapted from: PMID 34045179: Vega A, Jimenez-Rodriguez T-W, Barranco R, Bartra J, Diéguez MC, Doña I, et al. Hypersensitivity Reactions to Cancer Chemotherapy: Practical Recommendations of ARADyAL for Diagnosis and Desensitization. J Investig Allergol Clin Immunol. 2021 Oct;31(5):364–84. DOI: 10.18176/jiaci.0712.

Bircher AJ, Trautmann A. Exanthematous (maculopapular) drug eruption, topic last updated December 7, 2021 [Internet]: https://www.uptodate.com/contents/ exanthematous-maculopapular-drug-eruption

Finally, the risk stratification of the HSR is essential to define the best treatment and the possibility of a rechallenge. There are various available classifications for the severity of HSR, but the more commonly used ones are the Brown classification (Table 3) and the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) classification (Table 4; see Chapter 13 Infusion Reactions for the CTCAE classification of infusion-related reactions, cytokine release syndrome, allergic reactions and anaphylaxis).

Table 3. Brown Classification of Hypersensitivity Reactions
Grade	Definition
1: Mild HSR	Only affects skin and subcutaneous tissues : Generalized erythema Urticaria Periorbital edema Angioedema
2: Moderate HSR	Includes features suggesting respiratory, cardiovascular, or gastrointestinal involvement : Dyspnea, stridor, wheezing, throat tightness Nausea, vomiting, abdominal pain Presyncope, diaphoresis, chest tightness
3: Severe HSR	Includes signs of hypoxia, hypotension, or neurologic compro mise: Cyanosis or SpO 2 ≤ 92% Systolic blood pressure < 90 mmHg Confusion, collapse, loss of consciousness, incontinence

Adapted from: PMID 15316518: Brown SGA. Clinical features and severity grading of anaphylaxis.

J Allergy Clin Immunol. 2004 Aug;114(2):371–6. DOI: 10.1016/j.jaci.2004.04.029

Table 4. NCI CTCAE v5.0 classification for mucocutaneous manifestations
Grade	Eczema	Maculopapular rash	Acneiform rash	Urticaria	Bullous dermatitis
1	Asymptomatic or mild symptoms; additional medical intervention not indicated.	Macules/papules covering <10% BSA.	Papules and/or pustules covering <10% BSA.	Urticarial lesions covering <10% BSA; topical intervention indicated.	Asymptomatic; blisters covering <10% BSA.


2	Moderate; topical or oral intervention indicated; additional medical intervention over baseline indicated .	Macules/papules covering 10 to 30% BSA; limiting instrumental ADL; rash covering >30% BSA with or without mild symptoms .	Papules and/or pustules covering 10 – 30% BSA; associated with psychosocial impact; limiting instrumental ADL; papules and/or pustules covering > 30% BSA with or without mild symptoms .	Urticarial lesions covering 10 – 30% BSA; oral intervention indicated.	Blisters covering 10 – 30% BSA; painful blisters; limiting instrumental ADL.
3	Severe or medically significant but not immediately life- threatening; IV intervention indicated.	Macules/papules covering >30% BSA with moderate or severe symptoms; limiting self-care ADL.	Papules and/or pustules covering >30% BSA with moderate or severe symptoms; limiting self-care ADL; associated with local superinfection with oral antibiotics indicated.	Urticarial lesions covering >30% BSA; IV intervention indicated.	Blisters covering >30% BSA; limiting self-care ADL.
4	–	–	Life-threatening consequences; papules and/or pustules covering any % BSA, which are associated with extensive superinfection with IV antibiotics indicated .	–	Blisters covering >30% BSA; associated with fluid or electrolyte abnormalities; ICU care or burn unit indicated .
5	–	–	Death.	–	Death.

Grade	Purpura	Stevens- Johnson Syndrome	Toxic epidermal necrolysis	Erythema multiforme	Vasculitis
1	Combined area of lesions covering <10% BSA.	–	–	Target lesions covering <10% BSA and not associated with skin tenderness .	Asymptomatic, intervention not indicated.
2	Combined area of lesions covering 10 – 30% BSA; bleeding with trauma .	–	–	Target lesions covering 10 – 30% BSA and associated with skin tenderness .	Moderate symptoms, medical intervention indicated.
3	Combined area of lesions covering >30% BSA; spontaneous bleeding.	Skin sloughing covering <10% BSA with associated signs (e.g., erythema, purpura, epidermal detachment, and mucous membrane detachment) .	–	Target lesions covering >30% BSA and associated with oral or genital erosions.	Severe symptoms, medical intervention indicated (e.g., steroids).
4	–	Skin sloughing covering 10 – 30% BSA with associated signs .	Skin sloughing covering >=30% BSA with associated signs (e.g., erythema, purpura, or epidermal detachment) .	Target lesions covering >30% BSA; associated with fluid or electrolyte abnormalities; ICU care or burn unit indicated.	Life-threatening consequences; evidence of peripheral or visceral ischemia; urgent intervention indicated.
5	–	Death.	Death.	Death.	Death.

Adapted from: Common Terminology

Criteria for Adverse Events (CTCAE)

version 5.0, published November 27, 2017 [Internet]:https://ctep.cancer.gov/protocol development/electronic_applications/doc s/ctcae_v5_quick_reference_5x7.pdf

Pharmacotherapy Level Grade PMID Nº (See also Chapter 13 Infusion Reactions)

Primary pharmacologic prophylaxis with H1 histamine blockers, H2 histamine blockers, glucocorticoids, or a combination of these is recommended for drugs with high 4 B

incidence of infusion reactions, such as paclitaxel, docetaxel, cabazitaxel or asparaginase.

Possible H1 histamine blockers include: chlorpheniramine 10 mg i.v., dexchlorpheniramine 5 mg i.v., diphenhydramine 25-50 mg i.v., clemastine 2 mg i.v., cetirizine 10 mg i.v. 5 C
Possible H2 histamine blockers include: famotidine 20 mg i.v., ranitidine 50 mg i.v. 5 C
The combined use of H1 and H2 histamine blockers is superior to their use alone. I B
Possible glucocorticoids include: oral prednisolone / prednisone; oral or IV dexamethasone; IV methylprednisolone (various doses depending on the protocol). 5 C
Secondary prophylaxis with histamine blockers and glucocorticoids should be considered when drug rechallenge is planned (see below for criteria to choose drug 5 C rechallenge).
Pharmacologic treatment of mild to moderate HSR usually includes a combination of histamine blockers and glucocorticoids. 5 C
If given, the dosing of i.v. glucocorticoids should be equivalent to 1-2 mg/kg of (methyl)prednisolone, every 6 to 12 hours. 5 C
Pharmacologic treatment of severe HSR should include fluid resuscitation with normal saline, inhaled salbutamol and supplemental oxygen when needed, H1 and H2 histamine 4 B blockers, and/or adrenaline 0.01 mg/kg i.m. (can be repeeted every 5-15 min and switched to i.v. adrenaline if failure of prompt response) when criteria of anaphylaxis are

fulfilled.

Pharmacologic symptomatic treatment of minor/moderate delayed skin reactions may include medium-potency or high-potency topical corticosteroids (e.g. 5 C betamethasone dipropionate/valerate, clobetasol propionate, diflucortolone valerate, mometasone furoate, or triamcinolone acetonide, cream / lotion / ointment / gel, once or twice per day, 7-10 days) and oral H1 antihistamines (e.g. diphenhydramine 20-50 mg orally every 4-6 hours, hydroxyzine 25 mg orally every 6-8 hours, cetirizine 5 mg orally

every 12-24 hours, loratadine 10 mg orally every 24 hours, desloratadine 5 mg orally every 24 hours, bilastine 20 mg orally every 24 hours).

In the absence of clinical response to topical steroids in minor/moderate delayed skin reactions, a short course of oral corticosteroids (e.g. prednisolone 0.5-1 mg/kg/day for 3-5 5 D days) may be helpful, but empirical treatment without a dermatology referral and evaluation should be avoided.

5 Therapeutic Strategy

(See also Chapter 13 Infusion Reactions)

A correct risk assessment before the administration of the drug is essential. The patient should be questioned about their medical background, previous HSR to other drugs and 5 C known risk factors for anaphylaxis (age-related factors, chronic respiratory or cardiovascular diseases, mastocytosis, severe atopic disease, concurrent medications such as - adrenergic blockers or angiotensin-converting enzyme inhibitors).
An updated protocol of HSR management and the medical equipment needed for resuscitation should be always available. 5 C
Premedication is not completely protective (especially in cases of anaphylaxis) and closely monitoring patients during and immediately after all chemotherapy infusions is 2 C essential.
When an HSR is identified, drug administration should be readily stopped, and vital signs, airway and level of consciousness should be assessed regularly. 5 C
Glucocorticoids are not critical in the management of acute HSR but may be effective in preventing biphasic reactions and therefore may also be considered. 5 D
Post-reaction, vital signs should be closely monitored (for a minimum of 24h in severe reactions), and recurrence symptoms should be controlled. 5 C
Infusion may be reinitiated at half the initial infusion rate in mild to moderate HSR or cytokine release syndrome with good response to initial therapeutic measures. 4 CB
The possibility of drug rechallenge depends on the severity and nature of the reaction, the drug class, individual clinical risk factors for subsequent serious reactions, and the 5 C potential clinical benefit of further treatment.

28881914

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Level Grade PMID Nº

Immunoallergology referral and specific allergy work-up should be considered and carried out 4-6 weeks after complete resolution of all clinical symptoms and signs. 4 D
Rechallenge with a reduced infusion rate and additional premedication (such as corticosteroids and antihistamines) can be attempted in mild to moderate HSR (Brown grades 1- 5 C 2, NCI CTCAE grades 1-2).
Drug rechallenge without referral to immunoallergology and specific allergy work-up should never be attempted in HSR to platinum-based drugs, in severe HSR (Brown grade 3, 5 C NCI CTCAE grades 3-4), or in cases of confirmed anaphylaxis, due to the risk of subsequent reactions (that can be severe or even fatal).
If a patient is a possible candidate for continuation of therapy after a severe reaction or an allergic reaction to platinum-based drugs (e.g. in cases of potential clinical benefit of 5 C further treatment and absence of other reasonable alternatives), inclusion in a desensitization protocol by an experienced allergologist may be considered.
Treatment of delayed skin HSR should be managed depending on the symptoms and the clinical presentation, and referral to dermatology should be considered. 5 C
Treatment of minor delayed skin reactions (e.g. fixed drug eruption, urticaria, maculopapular drug eruption) is largely symptomatic and aimed at the relief of pruritus, and can 5 C include topical corticosteroids and oral H1 antihistamines.
In moderate delayed skin reactions or minor reactions with no response to symptomatic treatment, discontinuation of the offending drug and a short course of systemic 5 C corticosteroids can be considered, but empirical treatment without a dermatology referral and evaluation should be avoided.
Severe delayed HSR (e.g. TEN, SJS, erythema multiforme major, DiHS/DRESS, AGEP) should be swiftly identified and inpatient treatment with i.v. corticosteroids / other 4 D immunosuppressive agents may be necessary depending on the clinical presentation.
The presence of a severe delayed HSR should always be suspected whenever systemic symptoms are present (e.g. fever, lymphadenopathies, jaundice), severe cutaneous 4 D involvement is identified (presence of blisters or pustules, erythroderma, erythematous facial swelling or mucosal involvement), or no clinical benefit is seen after initial symptomatic treatment.
Oral mucosal involvement may be managed with various measures, including pain relief (mouthwashes containing lidocaine, systemic analgesics), topical and/or oral 4 D corticosteroids, and nutritional / lifestyle measures.
Ocular mucosal involvement should be immediately referred to an ophthalmologist for adequate assessment and treatment to minimize risk for long-term sequelae (such as 4 D conjunctival scarring and visual impairment).

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References

Bircher AJ, Trautmann A. Exanthematous (maculopapular) drug eruption. UpToDate, topic last updated December 7, 2021 [Internet]: https://www.uptodate.com/contents/exanthematous-maculopapular- drug-eruption.
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, November 27, 2017 [Internet]; https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ docs/ctcae_v5_quick_reference_5x7.pdf.
Wetter DA. Erythema multiforme: Management. UpToDate, topic last updated October 26, 2021 [Internet]: https://www.uptodate.com/contents/erythema-multiforme-management.
ISSN 2165-8048: Boussetta N, Ghedira H, Hamdi M, Ariba B, Metoui L, Ghasallah I, et al. Acquired Angioedema Revealing a B cell Non Hodgkin Lymphoma in A Tunisian Man. Intern Med. 2017;07(05). DOI: 10.4172/2165-8048.1000259.
PMID 15316518: Brown SGA. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol. 2004 Aug;114(2):371–6. DOI: 10.1016/j.jaci.2004.04.029.
PMID 32494527: Chango Azanza JJ, Calle Sarmiento PM, Lopetegui Lia N, Alexander SA, Modi V. Leukocytoclastic Vasculitis: An Early Skin Biopsy Makes a Difference. Cureus. 12(5):e7912. DOI: 10.7759/cureus.7912.
PMID 24388722: Cho Y-T, Lin J-W, Chen Y-C, Chang C-Y, Hsiao C-H, Chung W-H, et al. Generalized bullous fixed drug eruption is distinct from Stevens-Johnson syndrome/toxic epidermal necrolysis by immunohistopathological features. JAm Acad Dermatol. 2014 Mar;70(3):539–48. DOI: 10.1016/j.jaad.2013.11.015.
PMID 24697291: Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, et al. International Consensus on drug allergy. Allergy. 2014 Apr;69(4):420–37. DOI: 10.1111/all.12350.
PMID 27472323: Feldmeyer L, Heidemeyer K, Yawalkar N. Acute Generalized Exanthematous Pustulosis: Pathogenesis, Genetic Background, Clinical Variants and Therapy. Int J Mol Sci. 2016 Jul 27;17(8):1214. DOI: 10.3390/ijms17081214.
PMID 10756214: Greaves M. Chronic urticaria. Journal of Allergy and Clinical Immunology. 2000 Apr 1;105(4):664–72. DOI: 10.1067/mai.2000.105706.
PMID 6345608: Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol. 1983 Jun;8(6):763–75. DOI: 10.1016/s0190-9622(83)80003-6.
PMID 20606889: Khalel MH, Fattah Saleh SA, F El-Gamal A-H, Najem N. Acute generalized exanthematous pustulosis: an unusual side effect of meropenem. Indian J Dermatol. 2010;55(2):176–7. DOI: 10.4103/0019-5154.62759.
PMID 29188475: Lerch M, Mainetti C, Terziroli Beretta-Piccoli B, Harr T. Current Perspectives on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Clinic Rev Allerg Immunol. 2018 Feb 1;54(1):147–76. DOI: 10.1007/s12016-017-8654-z.
PMID 29340257: Li DG, Thomas C, Weintraub GS, Mostaghimi A. Symmetrical Drug-related Intertriginous and Flexural Exanthema Induced by Doxycycline. Cureus. 2017 Nov 10;9(11). DOI: 10.7759/cureus.1836.
PMID 34743720: Muto Y, Kuse N, Inomata M, Awano N, Tone M, Takada K, et al. Drug-induced hypersensitivity syndrome caused by minodronic acid hydrate. BMC Pulmonary Medicine. 2021 Nov 7;21(1):350. DOI: 10.1186/s12890-021-01709-x.
PMID 34045179: Vega A, Jimenez-Rodriguez T-W, Barranco R, Bartra J, Diéguez MC, Doña I, et al. Hypersensitivity Reactions to Cancer Chemotherapy: Practical Recommendations of ARADyAL for Diagnosis and Desensitization. J Investig Allergol Clin Immunol. 2021 Oct;31(5):364–84. DOI: 10.18176/jiaci.0712.
PMID 28881914: Roselló S, Blasco I, Fabregat LG, Cervantes A, Jordan K. Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Annals of Oncology. 2017 Jul 1;28:iv100–18. DOI: 10.1093/annonc/mdx216
PMID 27317286. D. Creamer,1S.A. Walsh, et al. U.K. guidelines for the management of Stevens–Johnson syndrome/toxic epidermal necrolysis in adults 2016. British Journal of Dermatology. 2016 Jun;174(6):1194-227. doi: 10.1111/bjd.14530
PMID 22788803: Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol. 2012;51(8):889-902

PHOTOSENSITIZATION

Authors: Valter Duarte, Tiago Valente and José Miguel Martins

Symptoms

Photosensitization consists in a chemical reaction involving a component, a substrate, or a target, initiated by electronic absorption of UV/visible radiation by the photosensitizer (1), which is clinically demonstrated by photo dermatoses.

These chemical reactions are classified into phototoxic and photoallergic reactions when photosensitizer is known (4). The photosensitizers can be endogenous (due to metabolic disorders) or exogenous (2).

Symptoms and signs

Exaggerated sunburn-like reactions with erythema, itching and burning (phototoxic reactions) or pruritic eczematous eruption (photoallergic reactions).
Photo distributed eruptions in the face, the V of the neck, forearms, and hands, sparing non-sun-exposed sites. It may spread outside exposed areas.
Other manifestations of photosensitivity can include lichenoid eruptions, onycholysis, erythema multiforme, hyperpigmentation, telangiectasia, or pseudo porphyria.

Diagnosis is primarily based on the history and the clinical appearance of the eruption (3). Photo testing, photo patch testing and rechallenge testing may also be used to improve diagnosis (2).

It is important to distinguish true photo sensivity from photo recall reactions, which are commonly associated to chemotherapeutic agents. In photo recall reactions, there is the re-appearance of sunburn-like eruptions in previously exposed areas in the absence of sunlight (2).

Etiology

The photosensitization can be either induced by a direct toxicity/production of free radicals (phototoxic reaction) or by an immune-mediated type IV hypersensitivity (photoallergic reaction) (2). Although is difficult to determine which type of reactions are the cause of photosensitization, the therapeutic approach is similar.

Evidence

Level Grade PMID Nº

Photo dermatoses can be classified as (4):

Primary photo dermatoses:
Idiopathic: Solar urticarial (SU), Polymorphous light eruption (PLE), Hydroa vacciniforme, Actinic prurigo (AP), Chronic actinic dermatitis (CAD);
With known photosensitizer (drugs, cosmetics, xenobiotics, plants) (table 1);
Secondary photo dermatoses:
Xeroderma pigmentosum, Cockayne syndrome, Trichothiodystrophy, Lupus erythematosus (LE), Dermatomyositis, Porphyria’s, Pellagra, Darier’s disease.

Drugs associated with photo sensivity (5)				Cosmetics associated with photo sensivity (6)
– Amiodarone	– Amivantanab	– Chlorpromazine	– Dacarbazine	Excipient Fragrance Formaldehyde Geraniol Methyldibromoglutaronitrile Hydroxy citronellal Paraben	Plant derivatives
-Dasatinib	– Doxycycline	– Erlotinib	– Fluorouracil/Capecitabine		Oat
– Hydrochlorothiazide	– Imatinib	– Methotrexate	– Nab-paclitaxel		Soy
– Naproxen	– Nilotinib	– Quinolone antibiotics – Vandetanib			Sesame
– Vemurafenib	– Vinblastine	– Voriconazole			Wheat

Table 1.– Most common photosensitizer’s drugs and cosmetics (by alphabetic order)

Studies

The literature about photo sensivity is manly based on case reports and case series. It is crucial the establishment of more controlled trials to accurately demonstrate some evidence about drug’s photosensitizing potential and therapeutic approach (1). (Case reports and Case series are IIB)

Drug	Posology
All photo dermatoses in general
Topical corticosteroids (Milder forms)	Twice daily
Prednisone (Severe forms)	0.5– 1.0 mg/kg/d (or equivalent), tapered within 10–14 days (or shorter course)
Antihistamine Desloratadine Fexofenadine Cetirizine (Only if pruritus is present)	5 mg, twice daily 180 mg, twice daily 10 mg, twice daily
Idiopathic and secondary photo dermatoses
Topical tacrolimus 0.1%	Twice daily for 3 weeks followed by once daily until lesions disappeared
Montelukast (SU)	10 mg per day
Cyclosporine (PLE, AP)	2,5 mg per day followed by a reduction
Azathioprine (PLE, AP, CAD)	50 to 100 mg per day
Thalidomide (PLE, AP, LES)	Initial dose: 100-200 mg/day, with reduction of the dose to 25 to 50 mg a week
Hydroxychloroquine (PLE, LES)	125-500 mg per day
Psoralen + UV-A (PLE, SU, AP, CAD)	Low dose

Evidence

Level Grade PMID Nº

Pharmacotherapy


	2	B		17469754
	2	B		11069465
				7021612
	2	B		30828851

	2	B		24278069
				26612794
	2	B	29124691	12010338
	2	B	29124691	10540941 2688737
	2	B		29124691
	2	B	29124691	28112801
	2	B	26612794	2713261 15793518

Therapeutic Strategy Level Grade PMID Nº

Evidence

Photoprotection is the main approach to both prevention and treatment of photo sensivity. It is highly recommended to avoid sunlight exposure and to use sunscreens, along with appropriate treatment of the underlying disease (7).

- Advice about photoprotective measures:
  - Avoidance of sunlight.
  - Protective clothing: long sleeved shirts and pants, broad brim hats.
  - Window films that block ultraviolet radiation for cars and homes.
  - Broad spectrum sunscreen (not alone).
- Topical corticosteroids and/or emollients may help in moderate forms.

I A 17693182

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2 B 12752180

- Short-course oral corticosteroids could be use in severe forms. 2 B
- Non-sedating antihistamines could be use if pruritus is intense. 1 A
- Discontinuation of the known photosensitizer when is possible.
- Photochemotherapy (PUVA, psoralene + UV-A) could be use in some idiopathic photo dermatoses. 2 B
- Other drugs as topical calcineurin inhibitor, antimalarials or immunomodulatory therapies have been used and are effective in some severe forms of idiopathic and 2 A secondary photo dermatoses.

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References

– Baptista MS, Cadet J, Greer A, Thomas AH. Photosensitization Reactions of Biomolecules: Definition, Targets and Mechanisms. Photochem Photobiol. 2021 Nov;97(6):1456-1483. doi: 10.1111/php.13470. Epub 2021 Jul 8. PMID: 34133762. Available at https://pubmed.ncbi.nlm.nih.gov/34133762/
– Claessens N, Piérard-Franchimont C, Piérard GE. Lucites par photosensibilisation [Photodermatoses by photosensitization]. Rev Med Liege. 2005;60 Suppl 1:71-82. French. PMID: 15909558. Available at https://pubmed.ncbi.nlm.nih.gov/15909558/
-Blakely KM, Drucker AM, Rosen CF. Drug-Induced Photosensitivity-An Update: Culprit Drugs, Prevention and Management. Drug Saf. 2019 Jul;42(7):827-847. doi: 10.1007/s40264-019-00806-5. PMID: 30888626. Available at https://pubmed.ncbi.nlm.nih.gov/30888626/
– Lehmann P, Schwarz T. Photodermatoses: diagnosis and treatment. Dtsch Arztebl Int. 2011 Mar;108(9):135-41. doi: 10.3238/arztebl.2011.0135. Epub 2011 Mar 4. PMID: 21442060; PMCID: PMC3063367. Available at https://pubmed.ncbi.nlm.nih.gov/21442060/
– Kim WB, Shelley AJ, Novice K, Joo J, Lim HW, Glassman SJ. Drug-induced phototoxicity: A systematic review. J Am Acad Dermatol. 2018 Dec;79(6):1069-1075. doi: 10.1016/j.jaad.2018.06.061. Epub 2018 Jul 10. PMID: 30003982. Available at https://pubmed.ncbi.nlm.nih.gov/30003982/
– González-Muñoz P, Conde-Salazar L, Vañó-Galván S. Allergic contact dermatitis caused by cosmetic products. Actas Dermosifiliogr. 2014 Nov;105(9):822-32. English, Spanish. doi: 10.1016/j.ad.2013.12.018. Epub 2014 Mar 20. PMID: 24656778. Available at https://pubmed.ncbi.nlm.nih.gov/24656778/
– Millard TP, Hawk JL. Photosensitivity disorders: cause, effect and management. Am J Clin Dermatol. 2002;3(4):239-46. doi: 10.2165/00128071-200203040-00002. PMID: 12010069. Available at https://pubmed.ncbi.nlm.nih.gov/12010069/
– Lugović L, Situm M, Ozanić-Bulić S, Sjerobabski-Masnec I. Phototoxic and photoallergic skin reactions. Coll Antropol. 2007 Jan;31 Suppl 1:63-7. PMID: 17469754. Available at https://pubmed.ncbi.nlm.nih.gov/17469754/
– Patel DC, Bellaney GJ, Seed PT, McGregor JM, Hawk JL. Efficacy of short-course oral prednisolone in polymorphic light eruption: a randomized controlled trial. Br J Dermatol. 2000 Oct;143(4):828-31. doi: 10.1046/j.1365-2133.2000.03840.x. PMID: 11069465. Available at https://pubmed.ncbi.nlm.nih.gov/11069465/
– Greenwald JS, Parrish JA, Jaenicke KF, Anderson RR. Failure of systemically administered corticosteroids to suppress UVB-induced delayed erythema. J Am Acad Dermatol. 1981 Aug;5(2):197-202. doi: 10.1016/s0190-9622(81)70088-4. PMID: 7021612. Available at https://pubmed.ncbi.nlm.nih.gov/7021612/
– Snast I, Lapidoth M, Uvaidov V, Enk CD, Mazor S, Hodak E, Levi A. Real-life experience in the treatment of solar urticaria: retrospective cohort study. Clin Exp Dermatol. 2019 Jul;44(5):e164-e170. doi: 10.1111/ced.13960. Epub 2019 Apr 13. PMID: 30828851. Available at https://pubmed.ncbi.nlm.nih.gov/30828851/
– Gutfreund K, Bienias W, Szewczyk A, Kaszuba A. Topical calcineurin inhibitors in dermatology. Part I: Properties, method and effectiveness of drug use. Postepy Dermatol Alergol. 2013 Jun;30(3):165-9. doi: 10.5114/pdia.2013.35619. Epub 2013 Jun 20. PMID: 24278069; PMCID: PMC3834721. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834721/
– Goetze S, Elsner P. Solar urticaria. J Dtsch Dermatol Ges. 2015 Dec;13(12):1250-3. doi: 10.1111/ddg.12809. PMID: 26612794. Available at https://pubmed.ncbi.nlm.nih.gov/26612794/
– Guarrera M. Polymorphous Light Eruption. Adv Exp Med Biol. 2017;996:61-70. doi: 10.1007/978-3-319-56017-5_6. PMID: 29124691. Available at https://pubmed.ncbi.nlm.nih.gov/29124691/
– Farr PM, Diffey BL. Treatment of actinic prurigo with PUVA: mechanism of action. Br J Dermatol. 1989 Mar;120(3):411-8. doi: 10.1111/j.1365-2133.1989.tb04169.x. PMID: 2713261. Available at https://pubmed.ncbi.nlm.nih.gov/2713261/
– Crouch R, Foley P, Baker C. Actinic prurigo: a retrospective analysis of 21 cases referred to an Australian photobiology clinic. Australas J Dermatol. 2002 May;43(2):128-32. PMID: 11982570. Available at https://pubmed.ncbi.nlm.nih.gov/11982570/
– Lestarini D, Khoo LS, Goh CL. The clinical features and management of actinic prurigo: a retrospective study. Photodermatol Photoimmunol Photomed. 1999 Oct;15(5):183-7. doi: 10.1111/j.1600- 0781.1999.tb00082.x. PMID: 10540941. Available at https://pubmed.ncbi.nlm.nih.gov/10540941/
– Umaña A, Gómez A, Durán MM, Porras L. Lymphocyte subtypes and adhesion molecules in actinic prurigo: observations with cyclosporin A. Int J Dermatol. 2002 Mar;41(3):139-45. doi: 10.1046/j.1365- 4362.2002.01419.x. PMID: 12010338. Available at https://pubmed.ncbi.nlm.nih.gov/12010338/
– Murphy GM, Maurice PD, Norris PG, Morris RW, Hawk JL. Azathioprine treatment in chronic actinic dermatitis: a double-blind controlled trial with monitoring of exposure to ultraviolet radiation. Br J Dermatol. 1989 Nov;121(5):639-46. doi: 10.1111/j.1365-2133.1989.tb08197.x. PMID: 2688737. Available at https://pubmed.ncbi.nlm.nih.gov/2688737/
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– Chasset F, Bouaziz JD, Costedoat-Chalumeau N, Francès C, Arnaud L. Efficacy and comparison of antimalarials in cutaneous lupus erythematosus subtypes: a systematic review and meta-analysis. Br J Dermatol. 2017 Jul;177(1):188-196. doi: 10.1111/bjd.15312. Epub 2017 May 5. PMID: 28112801. Available at https://pubmed.ncbi.nlm.nih.gov/28112801/
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HAND-FOOT ERYTRHODYSESTESIA

Authors: João Barbosa Martins, André Ferreira and Carolina Carvalho

MESH term: Hand-foot syndrome.

Other synonyms: Hand-foot skin reaction, acral erythema, palmoplantar erythrodysesthesia, hand-foot toxic erythema and Burgdorf reaction.

Symptoms

Hand-foot syndrome (HFS) is a condition characterized by skin alterations of hands or feet soles, presenting pallor, redness, swelling, tingling, marked discomfort and pain. Hands are usually more frequently affected and may be the only location of this disorder. These alterations are more prominent on the lateral aspect of fingers and distal fat pads, but also, dorsum of hands and intertriginous areas may be involved.
First symptoms include palms and/or feet soles dysesthesia, starting with tickling, later developing into bilateral burning pain, swelling and erythema, resulting in consequent hyperkeratosis. These lesions may progress to blisters, desquamation, erosions, ulcerations and ultimately bleeding, accompanied by moderate-to-severe pain, pruritus, sensory impairment, or paraesthesia.
Post-inflammatory hyperpigmentation is frequent, particularly with capecitabine, and it may become macular at palms (Fig. 1), presenting a diffuse distribution or allocating among the crease lines.
These skin alterations may predispose to infection. However, rare reports of tissue necrosis requiring amputation and complicated bacterial superinfection have been reported.
Although rarely life-threatening or requiring hospital admittance, HFS may reduce therapy compliance, interfering with activities of daily living and impairing quality of life, as some patients became unable to wear shoes, walk or properly use their hands to hold items.

Evidence

Level Grade PMID Nº

Unusual presentations:

Intertriginous forms involving armpits, inframammary, inguinal, antecubital or buttocks folds.
Involvement of the penis and scrotum.
Unilateral spread.
Development of multiple eruptive lentigo-maligna-like skin lesions.
Severe bullous variant, progressing to full-thickness epidermal necrosis and sloughing. This is typically associated to cisplatin, cytarabine and methotrexate and is more often reported in the pediatric setting.

Other distinct forms are:

HFS associated to docetaxel, presented as periarticular thenar erythema with oncolysis (PATEO) syndrome, characterized by dorsal involvement, rather than palmar lesions.
Targeted multikinase inhibitors (MTKi) hand-foot skin reaction (HFSR) which is different from classic HFS and presents distinct clinical and histologic patterns. Usually presents as focal hyperkeratotic callus-like lesions with an erythematous base, located in flexural, pressure-bearing and friction areas (joints, fingertips, metatarsal areas, heels, interdigital web spaces and lateral aspects of the feet). These lesions are frequently accompanied by numbness, tingling, and burning sensation. Contrarily to HFS, HFSR usually affects predominantly the soles and rarely bullae.

Figure 1. Palmar hyperpigmentated macular lesions in a patient with metastatic rectal adenocarcinoma treated with de Gramont plus bevacizumab.

Etiology

HFS pathogenic mechanisms are yet poorly understood, but a direct toxic effect may be the most likely cause. Several hypotheses have been proposed:

Palms and soles exposure to friction and trauma may play an important role in HFS local pathogenesis. Also, the rich capillary network and augmented blood flow throw these areas, may increase local chemotherapeutic drugs concentrations.
Chemotherapeutic agents may be eliminated through the eccrine system, whose glands are numerous in hands and foots.
Certain chemotherapeutics hydrophilic coating may prompt the agent transportation by sweat, making it more concentrated on skin surface.

Evidence Level Grade PMID Nº

Reduction of skin natural antioxidant activity as consequence of the increased reactive oxygen species (ROS), which may therefore promote tissue damage.
Particularly for capecitabine, this agent may promote tissue damage leading to cyclooxygenase (COX) activation. Also, keratinocytes may have increased enzymatic activity (such as thymidine phosphorylase), that converts capecitabine to its active form, increasing local concentration.
Genetic predisposition affecting enzymes implicated in fluoropyrimidines metabolism, such as dihydropyrimidine dehydrogenase (DPD) deficiency and cytidine deaminase mutations.

HFSR pathologic mechanism are likewise uncertain. Several hypotheses have been proposed:

Mechanical stress may similarly contribute to HFSR pathogenesis, as MTKi action may exacerbate tissue damage, through uncomplete vessel and tissue repair.
Targets of MTKi such as PDGFR and c-KIT are highly expressed in the ductal epithelium of eccrine glands, which are abundant in the palms and soles, therefore increasing its local toxicity.
Genetic polymorphisms may also explain the higher incidence of MTKi HFSR verified in Asian patients, when compared with Westerns’. Symptoms will reappear with repeated exposure to the provocative agent. Occurrence and severity have been associated to treatment response. Proposed risk factors

For HFS:

- Female gender. • Dosage and time of exposure.
- Liposome-encapsulated forms of chemotherapeutic drugs are more often associated. • Long infusions may increase the risk. For MTKi HFSR:
- Female gender. • Good performance status. • Dose dependent.
- Tumour type (renal cell carcinoma and hepatocellular carcinoma). • Liver metastases and affected number of organs.
- Normal pre-treatment white blood cell count. • Exposure to total body irradiation.
- Asian populations may be more susceptible. The most frequent drugs implicated are detailed in Table 1.

Evidence

Level Grade PMID Nº

Table 1. Drugs potentially causing HFS or HFSR. Reported incidences and relevant particularities.
CAPECITABINE	Incidence of 28 – 74%. Capecitabinetoxicity is usually dose related and may be connected to genetic polymorphisms of thymidylate synthase(TYMS) and dihydropyrimidine dehydrogenase (DPYD).
5-FLUOROURACIL	Incidence of 6 – 13% for bolus and 34% for continuous infusion. More associated to prolonged infusions and rare with bolus schemes.
TEGAFUR/GIMERACIL/OTERACIL (S-1)	Incidence of 5.4 – 45%.
DOCETAXEL	Incidence of 6 – 58%.

Level Grade PMID Nº


PEGYLATED LIPOSOMAL DOXORUBICIN	Incidence of 40 – 50%. More associated to initial doses greater than 40mg/m2.
DOXORUBICIN	Incidence of 22 – 29%. Usually dose related.
CYTARABINE	Incidence of 14 – 33%. Usually dose related.
DOXORUBICIN PLUS5-FU/CAPECITABINE	Incidence of 89%.
DOCETAXEL PLUS CAPECITABINE	Incidence of 56 – 63%.
MTKi	Incidence: Sorafenib 10– 62%; Regorafenib 47%; Sunitinib 10 – 50%; Pazopanib 4.5 – 29%; Axitinib 29%; Sorafenib plus bevacizumab 79%. Vandetanib, Lenvatiniband cabozantinib incidence is rare.
BRAF INHIBITORS (vemurafenib, dabrafenib or encorafenib)	Incidence 19 – 60%. Vemurafenib incidence of 60%.
Other drugs possibly implicated: cisplatin, cyclophosphamide, daunorubicin, doxifluridine, etoposide, floxuridine, hydroxyurea, mercaptopurine, methotrexate, mitotane, paclitaxel, tegafur, vinorelbine, epirubicin and gefitinib.

Diagnostic Studies

HFS and HFSR have a clinical diagnosis, obtained by physical examination.
The differential diagnosis of HFS and MFSR may include erythema multiforme, vasculitis, cellulitis, erythromelalgia, septic emboli, chemotherapy-induced Raynaud’s syndrome, acral bleomycin toxicity or other drug reactions and graft-versus-host disease.

HFS

HFS symptoms usually develop within days or weeks after therapy initiation, usually within the 2nd and the 21st day. Nevertheless, it may appear up 6 or 10 months later, for oral capecitabin or continuous infusions of cytarabine.
HFS typically resolute within 2 weeks after chemotherapy is stopped.
HFS histological alterations are usually nonspecific and consistent with toxic dermatitis findings. Histologic

findings are dispersed necrotic keratinocytes with vascular degeneration of the basal layer or full epidermal necrosis. Also, papillary dermal oedema with perivascular lymphocytic infiltrate and ductal epithelial changes or eccrine squamous syringometaplasia may be present.

Biopsy is not necessary for diagnosis and may by inaccurate to distinguish HFS from other skin differential diagnosis.
In cases of severe capecitabine or 5-FU related HFS, if not previously performed, the lack of the enzyme DPYD should be investigated before re-introduction.

HFSR

HFSR symptoms may develop within 2-6 weeks of treatment.
HFSR presents a distinct histologic pattern characterized by a well-defined horizontal band of discohesive dyskeratotic keratinocytes, located inside the epidermis.
Biopsy is not necessary for diagnosis. .

Treatment Options Level Grade PMID Nº

General options

10% Topical urea —Prevention. Use b.i.d or t.i.d. and after washing hands. 2

Topical keratolytic moisturizers — Treatment of hyperkeratotic areas before cancer therapy. (e.g., with ammonium lactate 12% or salicylic acid 5%). 4

Topical steroids — Treatment of skin inflammation (e.g., with clobetasol propionate 0.05% i.d./b.i.d). 4

Vitamin E — Treatment. Doses of 100-300mg orally per day. 5

Pain control with NSAIDs/Gaba agonists (e.g. pregabalin)/Narcotics. The following agents are described in low evidence bibliography and its interpretation must be careful, since its efficacy is unclear and further validation is necessary: Topical 99% dimethyl sulfoxide (DSMO); Topical sildenafil; Nicotine patches; Topical Henna; Cetirizine; Narrow-band ultraviolet B phototherapy

For capecitabin induced HFS

Pyridoxin (vitamin B6) — Prevention. Daily 150, 200 or 400mg. NOT RECOMMENDED. I

Celecoxib — Prevention. Celecoxib 200 mg b.i.d. 2

For doxorubicin (or PEGylated doxorubicin) and taxanes induced HFS

Local cold during therapy Prevention.

Oral dexamethasone — Prevention. 8 mg b.i.d. for 5 days (staring the day before infusion, then 4 mg b.i.d. for 1 day, then 4 mg once daily for 1 day). 4

For MTKi induced HFSR 4

Topical lidocaine Treatment of pain. 5% patches or cream.

Topical keratolytic creams —Treatment of hyperkeratosis (e.g., with salicylic acid 5-10% or urea 10-40%). 4

Antiseptic creams —Treatment of erosions and ulcerations (e.g., with silver sulfadiazine 1%, polyhexanide 0.02-0.04%). 4

The following agents are described in low evidence bibliography and its interpretation must be careful, since its efficacy is unclear and further validation is 4

necessary: Cetirizine; Narrow-band ultraviolet B phototherapy; Prednicarbate ointment, Fusidic acid cream; and Moisturizer dexpanthenol

.i.d., once a day; b.i.d., twice daily; GABA, gamma-aminobutyric acid; NSAIDs, non-steroidal anti-inflammatory drugs; t.i.d., three times daily.

Therapeutic Strategy

PREVENTION Grade 0	.
	Treatment of predisposing factors before starting anticancer therapy ( e.g., apparent hyperkeratosis).
	Avoid hands and feet mechanical stress (e.g., vigorous exercise;heavy carrying without gloves or long walkswithout socks/cushioned shoes). Bathe or shower in tepid water.Avoid chemical stress: solvents,disinfectants, or skin irritants.
	Application of a cream with 10% urea concentrationb.i.d/t.i.d. and after washing hands
	Capecitabine (in addition to the above)	Celecoxib 200 mg b.i.d.
	Doxorubicin (or PEGylated doxorubicin) andtaxanes (in addition to the above)	Cooling of hands and feet during infusions.

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TREATMENT Grade 1 Minimal skin changes or dermatitis without pain (e.g., erythema, oedema or hyperkeratosis)	treatment at current dose and monitor toxicity. Continue with the recommendations above, adding the following:
	Application of topical high -potency steroid b.i.d. (p.e. clobetasol propionate 0.05%).
	MTKi (in addition to the above)	Application of lidocaine 5% patches or cream
	Doxorubicin (or PEGylated doxorubicin) and taxanes (in addition to the above)	Cooling of hands and feet during infusions
TREATMENT Grade 2 Painful skin changes (e.g., dermatitis, peeling, blisters, fissures, oedema or hyperkeratosis); limiting instrumental ADLs	Continue treatment at current dose and monitor toxicity. Continue with the recommendations above, adding the following:
	Application of topical high-potency steroid b.i.d. (p.e. clobetasol propionate 0.05%).
	MTKi (in addition to the above)	Application of lidocaine 5% patches or cream
		Oral analgesics opioids, NSAIDs or GABA agonists
	Doxorubicin (or PEGylated doxorubicin) and taxanes (in addition to the above)	Cooling of hands and feet during infusions AND Application of topical high- potency steroid b.i.d. (e.g., lobetasol propionate 0.05%) AND 8 mg b.i.d. of oral dexamethasone for 5 days (staring the day before infusion, then 4 mg b.i.d. for 1 day, then 4 mg once daily for 1 day).
	Re-evaluate after 2 weeks (bypatient self-report orhealth care professional). If worst or do not recover, advance to next step.
TREATMENT Grade ≥3 or intolerable grade 2 Painful severe skin changes; limiting self- care ADLs	Interrupt the treatment until severity diminishes to grade 0 or 1. Continue with the recommendations above, adding the following:
	Application of topical high-potency steroid b.i.d. (e.g., clobetasol propionate 0.05%).
	MTKi (in addition to the above)	Application of lidocaine 5% patches or cream.
		Topical keratolytic creams (e.g., with salicylic acid 5-10% or urea 10-40%).
		Antiseptic creams (e.g., silver sulfadiazine 1%; polyhexanide 0.02-0.04%).
		Oral analgesics opioids, NSAIDs and/or GABA agonists.

Level	Grade	PMID Nº
4	C	33248228
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5	C	18779536

Level Grade PMID Nº


	Doxorubicin (or PEGylated doxorubicin) and taxanes (in addition to the above)	Cooling of hands and feet during infusions AND Application of topical high- potency steroid b.i.d. (p.e. Clobetasol propionate 0.05%) AND 8 mg b.i.d. of oral dexamethasone for 5 days (staring the day before infusion, then 4 mg b.i.d. for 1 day, then 4 mg once daily for 1 day)
	Re-evaluate after 2 weeks. If worst or no improve, consider treatment interruption or discontinuation per protocol.
	Consider referral to dermatologist if symptoms persist.
ADL, activity of daily living; b.i.d., twice daily; CTCAE, Common Terminology Criteria for Adverse Events; GABA, gamma-aminobutyric acid; NSAIDs, non-steroidal anti-inflammatory drugs; t.i.d., three times daily.

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HFS and HFSR management is complex and relies in the combination of patient education, prevention, symptomatic treatment, and dose managing. The most effective approach is dose delay, modification, or treatment discontinuation. Alternatively, treatment can be switched to a better tolerated regimen.

References

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Balagula Y, Wu S, Su X, Feldman DR, Lacouture ME. The risk of hand foot skin reaction to pazopanib, a novel multikinase inhibitor: A systematic review of literature and meta-analysis. Invest New Drugs. 2012; 30(4):1773–81. doi: 10.1007/s10637-011-9652-2.
Rosmarin D, Palles C, Church D, Domingo E, Jones A, Johnstone E, et al. Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: Investigation in the QUASAR2 study, systematic review, and meta-analysis. J Clin Oncol. 2014; 32(10):1031–9. doi: 10.1200/JCO.2013.51.1857.
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UNGUAL ALTERATIONS

Authors: Luísa Leal da Costa, Diana Neto da Silva, Carlota Baptista and Rita Bizarro

Definition Level GradeEvidence

PMID Nº

Colour change, destruction, inflammation or detachment of fingernails, toenails, or both during cancer treatments.
These changes can happen in the nail bed, folds or in the nail plate itself; they are generally well-tolerated and are reversible on cessation of treatment (1).
While chemotherapy mainly affects the nail bed and nail matrix, target therapies affect periungual areas.
Ungual alterations are very common and often lead to a need of dose reduction or treatment discontinuation.
Preventive measures and a proactive management are the key element of this side effect.

Symptoms and signs

Changes in pigmentation (change in colour of the nail plate, e.g., chromonychia, melanonychia).
Beau´s lines (transverse linear depressions in the dorsum of the nail plate).
Leukonychia (white lines or dots on the nail plate).
Onychomadesis (proximal separation of the nail plate from the nail matrix).
Onychoschizia and Onychorrhexis (brittle nails and nail splitting).
Onycholysis (separation of the nail plate from the underlying nail bed).
Paronychia or Pyogenic granuloma (an inflammatory reaction involving the nail folds; the presence of pus may be an indication of bacterial infection).

Etiology

There are several causes for ungual alterations. While these changes are usually mild at the beginning of treatment, they may worsen with accumulating toxicity. Toxic effects on the nail plate and changes to the nail bed occur more frequently with cytotoxic chemotherapies. By contrast, periungual lesions are the most common and debilitating manifestations in patients treated with target anticancer therapies(1) .

Paronychia and/or pyogenic granulomas result from damage to the perionychium and occur frequently with epidermal growth factor receptor inhibitors (EGFRis) target therapies, either monoclonal antibodies or tyrosine kinase inhibitors (TKIs) (cetuximab, panitumumab, erlotinib, gefitinib, lapatinib, vandetanib) and the newly approved irreversible ErbB family blockers (dacomitinib, afatinib). Although is less commonly observed, similar periungual lesions have been also described with MEKis (selumetinib, cobimetini and trametinib) and mTOR inhibitors (everolimus, tensirolimus) (2).
Taxanes are the most frequent chemotherapeutic agents inducing nail toxicities, and severe onycholysis almost exclusively occurs with taxanes. The all-grade nail toxicity incidence is 43.7% and 34.9% with paclitaxel and docetaxel, respectively(2) . They may induce an exudative paronychia with or without progression to frank abscess(3).
Mild-to-moderate onycholysis can also be noted with other chemotherapeutic agents (capecitabine, etoposide, cytarabine, cyclophosphamide and doxorubicin), and, to a lesser extent, with target therapies (mTOR inhibitors, EGFRis or MEKis)(2) . The occurrence and disappearance of nail changes are delayed relative to the initiation and interruption of systemic treatments because of the kinetics of nail formation and growth(1) .

Pharmacotherapy

(for paronychia and taxane-induced onycholysis, according to ESMO Clinical Practice Guidelines regarding prevention and management of dermatological toxicities related to anticancer agents (2) ).

Nail plate changes do not usually require specific treatment. Pre-emptive strategies such as patient education and self-care are fundamental for managing toxicities.

Evidence

Level Grade PMID Nº

- Biotin supplements (paronychia prevention; improvement nail strength).
- Topical povidone iodine 2%, topical antibiotics/corticosteroids for grade 1 paronychia.
- Topical povidone iodine 2%/topical beta-blocking agents/topical antibiotics and corticosteroids for grade 2 or 3 paronychia.
- Oral antibiotics for grade 2 or 3 paronychia..
- Topical emollients, nail lacquers (onycholysis prevention).
- Oral antibiotic with anti-staphylococcus aureus and gram-positive coverage if grade 1, 2 or 3 onycholysis with nail bed superinfection.

5 C 33248228

3 B 33248228

4 B 33248228

2 B 33248228

4 B 33248228

Evidence

Therapeutic Strategy Level Grade PMID Nº

(for paronychia and taxane-induced onycholysis, according to ESMO Clinical Practice Guidelines regarding prevention and management of dermatological toxicities related to anticancer agents(2) ).

The evidence on these strategies is scarce. Although these alterations often disappear on cessation of treatment, they might cause pain and functional impairment and thus a significant impact in quality of life.

- Patient education regarding preventive measures.
- Wearing comfortable shoes and gloves while cleaning; avoiding nail biting or cutting the nails too short (paronychia prevention).
- Preventive correction of nail curvature; avoiding repeated friction and trauma/excessive pressure; (paronychia prevention).
- The use of antimicrobial soaks and washing with cleansers and water (paronychia prevention).
- Daily application of topical emollients to cuticles and periungual tissues (paronychia prevention).
- Topical emollients, nail lacquers; avoiding damaging or irritant regimens; wearing cotton gloves (onycholysis prevention).
- Consider frozen gloves and frozen socks (onycholysis prevention).
- Consider partial nail avulsion if grade 3 paronychia.
- If painful haematoma or subungual abscess is suspected, partial or total nail avulsion is required.

4 B 33248228

2 B 33248228

2 A 33248228

5 B 33248228

4 A 33248228

References

. C. Robert et al., “Nail toxicities induced by systemic anticancer treatments,” Lancet Oncol., vol. 16, no. 4, pp. e181–e189, Apr. 2015, doi: 10.1016/S1470-2045(14)71133-7. 2 . M. E. Lacouture et al., “Prevention and management of dermatological toxicities related to anticancer agents: ESMO Clinical Practice Guidelines☆,” Ann. Oncol., vol. 32, no. 2, pp. 157–170, Feb. 2021, doi:

10.1016/j.annonc.2020.11.005.

3. V. Sibaud et al., “Dermatological adverse events with taxane chemotherapy,” Eur. J. Dermatology, vol. 26, no. 5, pp. 427-443, Sep. 2016, doi: 10.1684/ejd.2016.2833.

SKIN TOXICITY INDUCED BY TARGETED THERAPIES: Anti-EGFR Monoclonal Antibodies

Authors: Juan Carlos Mellídez Barroso, Filipa Coroado Ferreira and Sara Bravo

Definition Level GradeEvidence

PMID Nº

Skin lesions or changes (papulopustular/acneiform rash, xerosis and pruritus), skin attachments (nails, hair), ocular alterations (occlusal surfaces, tear and sebaceous glands, eyelash), (Lacouture et al. 2017) and mucoses, induced by monoclonal antibodies inhibitors of epithelial growth factor receptor (EGFR).
Those toxicities cause psychological burden and impairment of quality of live (QOL) (Michelle Joy Naughton, ASCO 2013)
The prompt and correct management of the anti-EGFR-related skin toxicity is warranted to optimize the treatment´s results in terms of both efficacy and quality of life. Interruption or modification of anti EGFR treatment should be avoided.
Follicular acneiform rash develops early (2-3 weeks) in 70 – 100% of patients. ( with a wide variety of presentations, from mild to severe forms, potentially disfiguring). Pruritic xerosis and painful fissures may also occ
Treatment of skin toxicity may be preventive (before symptoms appear) or rective.
- The preventive treatment decreases the incidence and severity of skin AEs in anti-EGFR I A
- MoAbs treatmentThe reactive treatment is less effective than preventive treatment I A

AE: adverse events; anti-EGFR MoAbs: anti – epithelial growth factor receptor Monoclonal Antibodies.

21278044

21630130

33392769

17010747

27214209

Etiology Level GradeEvidence

PMID Nº

EGFR Inhibitors: Cetuximab and panitumumab.

Symptoms and signs

- 1. Skin
    - Rash: Aseptic papulo-pustular/acneiform rash: Appears in the first two weeks after the start of treatment anti-EGFR. (25798804)

CTCAE v5.0	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Rash acneiform	Term Definition: A disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, upper chest and back.
Rash acneiform	Papules and/or pustules covering <10% BSA, which may or may not be associated with symptoms of pruritus or tenderness	Papules and/or pustules covering 10 – 30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL	Papules and/or pustules covering >30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; limiting self -care ADL; associated with local superinfection with oral antibiotics indicated	Papules and/or pustules covering any % BSA, which may or may not be associated with symptoms of pruritus or tend erness and are associated with extensive superinfection with IV antibiotics indicated: life-threatening consequences	Death
Rash maculo-papular	Term Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbilliform rash, it is one of the most common cutaneous adverse events, frequently affecting the upper trunk, spreading centripetally and associated with pru ritus
Rash maculo-papular	Macules/papules covering <10% BSA with or without symptoms (e.g., pruritus, burning, tightness)	Macules/papules covering 10 – 30% BSA with or without symptoms (e.g., pruritus, burning, tightness); limiting instrumental ADL	Macules/papules covering >30% BSA with or without associated symptoms, limiting self-care ADL	–	–

BSA: Body surface area; ADL: Activities of daily living; IV: intravenous

Preventive treatment is recommended for all patients initiating treatment with Anti EGFR inhibitors. In severe cases refer to a dermatologist ( 31264159)

Preventive treatment

Nonpharmacological preventive measures: Skin moisturizer (face, hands, feet, neck, back and chest daily, in the morning) + sunscreen (PABA free, >15 UVA and UVB I A protection, in sun exposed areas) (4) I A
Preventive antibiotic treatment should begin in the first day of anti-EGFR therapy administration 2a B
Topical antibiotics can be used but may induce xerosis and skin irritation.
Preventive skin moisturizer (face, hands, feet, neck, back and chest daily, in the morning) + sunscreen (PABA free, >15 UVA and UVB protection, in sun exposed areas) + topic I A steroid hydrocortisone cream 1% in face, hands, feet, neck, back and chest daily, at bedtime + doxycycline 100 mg 12-12 h) I A
Preventive tetracyclines treatment, during anti-EGFR treatment, can significantly reduce the incidence and severity of cutaneous acneiform rash.If tetracyclines are contraindicated, macrolides erythromycin or clarithromycin erythromycin or clarithromycin combine antibiotic and anti-inflammatory effect I B
Preventive clarithromycin: 200mg 12-12h + skin moisturizer + sunscreen + topical steroids if > grade 2 toxicity, start day 1 and during all treatment time I B
Preventive oral minocycline (100 mg once a day) + skin moisturizer + reactive topical steroid. Preventive topical vitamin K1 twice a day, 8 weeks. 2b C
Avoid topical antibiotics in papulopustular or acneiform eruption, because drying and irritative consequences and risk of rosacea. 3 C
Avoid sunbaths, direct sun light, hot ambient and humidity. 1 C
Avoid topical retinoids because high potential of irritation 3 B

. PABA: Para-aminobenzoic Acid; UVA: Ultraviolet A; UVB: Ultraviolet B; anti-EGFR: (anti – epithelial growth factor receptor)

21630130

27449521

29576427

29727211

20142600

27214209

27449521

34345969

29360920

26504047

29576427

19793151

30890624

Adapted from Hofheinz RD, et al. Recommendations for the Prophylactic Management of Skin Reactions Induced by Epidermal Growth Factor Receptor Inhibitors in Patients with Solid Tumors. Oncologist. 2016 Dec;21(12):1483-1491.

Studies are extremely limited (31264159). The objective is to reduce, to postpone or to interrupt exposure to EGFR (from grade 3 or 4 toxicity to grade 1-2)
Skin moisturizer + sunscreen + topic steroid + antibiotics.	I	B	29576427
Systemic steroids (methylprednisolone, prednisone), intramuscular antihistamine, oral retinoids (low dose isotretinoin), intravenous antibiotics.	2	B	22930641
Topical cream of Fusidic acid + betamethasone, twice a day, 2 weeks + dermo-cosmetic measures.	2a	C	31264159

Therapeutic algorithm for skin rash

Dry skin/xerosis: First symptoms appear 1-2 months after initiation anti-EGFR treatment .

Level Grade PMID Nº

17522250

BSA: Body surface area; ADL: Activities of daily living

Treatment

Moisturizers I C
Emollients I C
Cyanoacrylate tissue adhesives (fissures) I C
Corticosteroids (eczema) I C
Pruritusy

19258241

17289377

10466300

18159647

ADL: Activities of daily living

Treatment
Moisturizers	I	C	19258241
Antihistamines	I	B	25798804
Emollients	I	C	17289377

- 1. Nail abnormalities
Paronychia

ADL: Activities of daily living

Level Grade PMID Nº

CTCAE v4.0 Term

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Paronychia

Term Definition : A disorder characterized by an infectious process involving the soft tissues around the nail.

Nail fold oedema or erythema; disruption of the cuticle

Localized intervention indicated; oral intervention indicated (e.g., antibiotic, antifungal, antiviral); nail fold oedema or erythema with pain; associated with discharge or nail plate separation; limiting

instrumental A DL

Surgical intervention or IV antibiotics indicated: limiting self-care ADL

Almost all patient under EGFRI can develop nail abnormalities .
Paronychia appears 4-8 weeks after the beginning of Anti-EGFR treatment .
Paronychia is, at the beginning, a sterile lesion which can become infected due the cutaneous barrier alteration. Antibiogram may be needed in severe cases. Paronychia- associated infections may be caused by Enterococcus and Pseudomonas as well as Staphylococcus; therefore, broad-spectrum antibiotics are useful.

Treatment

To prevent mild paronychia from becoming infected, topical treatment with an antibiotic cream containing mupirocin 3 C
White vinegar in water (1:10) 15 min. Baths once a day. Gentamycin ointment 4-5 weeks, diluted chloramine bath, corticosteroid (clobetasol) once a day I C
Silver nitrate weekly, trichloroacetic acid, liquid nitrogen I C
Gentamycin ointment 4-5 weeks, diluted chloramine bath, corticosteroid (clobetasol) once a day I C
Grade 2: local intervention, oral antibiotics (CTCAE)
Grade 3: Surgical intervention or IV antibiotics indicated
- 1. Hair growth abnormalities
Alopecia

Treatment: No medical treatment for alopecia.

19466958

24723942

19470276

29576427

19470276

*Ref 28

29576427

Hypertrichosis (CTCAE v5.0)A Level Grade PMID Nº

Acneiform eruption in the scalp – Treatment
Oil bath and topical steroid.Oil bath + oral antibiotics if infected eruption. I B
Oral doxycycline 100 mg twice daily, topical aluminum acetate astringent soaks, clindamycin 1 percent lotion, and clobetasol propionate 0.05 percent cream three times daily. 2a C
Topical antibiotics are not recommended in scalp. 3 B

3. Ocular abnormalities

Ocular abnormalities can be broadly categorized as changes in the eyelids, changes in the tear film and miscellaneous changes. Early recognition and management of these adverse ocular reactions are necessary. Mild eyelid and tear film changes usually can be managed by the oncology and nursing staff. More severe ocular reactions require involvement of an ophthalmologist. Many ocular side effects require prompt examination by an ophthalmologist to quickly treat the sometimes-severe discomfort and prevent ocular injury.

Conjunctivitis

ADL: Activities of daily living

Treatment: Refer to an ophthalmologist

Dryness/dry eye (dysfunctional tear syndrome).

Is the most common ocular symptom in Anti-EGFR treated patients . It is associated with decreased tear production, which lead to conjunctivitis sicca. Patients complaint about ocular burning or grittiness, red eye and vision fluctuation, which may occur within less a week of EGFR initiation.

19793151

23552005

1766698

17666986

19470276

Mild dry eye: Liquid supplemental tears, 4-6 times daily, 2 weeks	I	C	23151647
Moderate to severe dry eye: tear film + anti-inflammatory (loteprednol or fuorometholone) + cyclosporine drops, under supervision of an ophthalmologist.	I	C	19470276
Treatment: Refer to an ophthalmologist
Trichomegaly (eyelash hypertrophy) Occurs after months of treatment. Long eyelashes can burn the cornea, originating corneal erosion or corneal ulcer or corneal perforation . Treatment
Trimming eyelashes, removing eyelashes (by an ophthalmologist)	I	C	17237698
Erythromycin ophthalmic ointments.	I	C	29576427
Refer to ophthalmologist in moderate-severe cases or if no response after 1 week of primary treatment .			29576427
Photophobia

ADL: Activities of daily living

Treatment: Refer to an ophthalmologist

Blepharitis

Is the inflammation of the eyelid margin, with irritation and severe discomfort. The symptoms are mild redness to severe oedema and pain with small pustules and crusts in the base of the eyelashes.

Treatment

Mild blepharitis: lid scrubs and warm compresses: twice a day. I B
Careful eyelid hygieneModerate blepharitis: Eye ointment (antibiotic and topic steroid eye ointment) I B
Severe blepharitis: Doxycycline 50 mg twice a day two weeks + doxycycline 50 once a day 4 weeks I B
Corneal lesions

The corneal lesions (corneal erosion or perforation) need to be treated by an ophthalmologist

19470276

23151647

19470276

23151647

Treatment of corneal ulcer: Refer to an ophthalmologist

References

White KJ, Roydhouse JK, Scott K. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor-inhibitor treatment. Clin J Oncol Nurs. 2011 Feb;15(1):88-96. doi: 10.1188/11.CJON.88-96. PMID: 21278044.
Michelle Joy Naughton et al. Journal of Clinical Oncology 2013 31:15_suppl, 3611-3611. DOI: 10.1200/jco.2013.31.15_suppl.3611.
Lacouture ME, Anadkat MJ, Bensadoun RJ, Bryce J, Chan A, Epstein JB, Eaby-Sandy B, Murphy BA; MASCC Skin Toxicity Study Group. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer. 2011 Aug;19(8):1079-95. doi: 10.1007/s00520-011-1197-6. Epub 2011 Jun 1. PMID: 21630130.
Agero AL, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol. 2006 Oct;55(4):657-70. doi: 10.1016/j.jaad.2005.10.010. PMID: 17010747.
Raimondi A, Corallo S, Lonardi S, Antoniotti C, Rimassa L, Amatu A, Tampellini M, Racca P, Murialdo R, Clavarezza M, Zaniboni A, Toscano G, Tomasello G, Petrelli F, Antonuzzo L, Giordano M, Cinieri S, Longarini R, Niger M, Antista M, Ambrosini M, Pagani F, Prisciandaro M, Randon G, de Braud F, Di Bartolomeo M, Pietrantonio F, Morano F. Systemic doxycycline for pre-emptive treatment of anti-EGFR-related skin toxicity in patients with metastatic colorectal cancer receiving first-line panitumumab-based therapy: a post hoc analysis of the Valentino study. Support Care Cancer. 2021 Jul;29(7):3971-3980. doi: 10.1007/s00520-020- 05972-2. Epub 2021 Jan 3. PMID: 33392769.
Petrelli F, Borgonovo K, Cabiddu M, Coinu A, Ghilardi M, Lonati V, Barni S. Antibiotic prophylaxis for skin toxicity induced by antiepidermal growth factor receptor agents: a systematic review and meta-analysis. Br J Dermatol. 2016 Dec;175(6):1166-1174. doi: 10.1111/bjd.14756. Epub 2016 Sep 30. PMID: 27214209.
Jaka A, Gutiérrez-Rivera A, López-Pestaña A, del Alcázar E, Zubizarreta J, Vildosola S, Arregui MA, Sarasqueta C, Lobo C, Tuneu A. Predictors of Tumor Response to Cetuximab and Panitumumab in 116 Patients and a Review of Approaches to Managing Skin Toxicity. Actas Dermosifiliogr. 2015 Jul-Aug;106(6):483-92. English, Spanish. doi: 10.1016/j.ad.2015.01.006. Epub 2015 Mar 19. PMID: 25798804.
Annunziata MC, De Stefano A, Fabbrocini G, Leo S, Marchetti P, Romano MC, Romano I. Current Recommendations and Novel Strategies for the Management of Skin Toxicities Related to Anti-EGFR Therapies in Patients with Metastatic Colorectal Cancer. Clin Drug Investig. 2019 Sep;39(9):825-834. doi: 10.1007/s40261-019-00811-7. PMID: 31264159.
Lacouture ME, Anadkat MJ, Bensadoun RJ, Bryce J, Chan A, Epstein JB, Eaby-Sandy B, Murphy BA; MASCC Skin Toxicity Study Group. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer. 2011 Aug;19(8):1079-95. doi: 10.1007/s00520-011-1197-6. Epub 2011 Jun 1. PMID: 21630130.
Hofheinz RD, Deplanque G, Komatsu Y, Kobayashi Y, Ocvirk J, Racca P, Guenther S, Zhang J, Lacouture ME, Jatoi A. Recommendations for the Prophylactic Management of Skin Reactions Induced by Epidermal Growth Factor Receptor Inhibitors in Patients With Solid Tumors. Oncologist. 2016 Dec;21(12):1483-1491. doi: 10.1634/theoncologist.2016-0051. Epub 2016 Jul 22. PMID: 27449521.
Lacouture ME, Anadkat M, Jatoi A, Garawin T, Bohac C, Mitchell E. Dermatologic Toxicity Occurring During Anti-EGFR Monoclonal Inhibitor Therapy in Patients With Metastatic Colorectal Cancer: A Systematic Review. Clin Colorectal Cancer. 2018 Jun;17(2):85-96. doi: 10.1016/j.clcc.2017.12.004. Epub 2017 Dec 13. PMID: 29576427.
Beech J, Germetaki T, Judge M, Paton N, Collins J, Garbutt A, Braun M, Fenwick J, Saunders MP. Management and grading of EGFR inhibitor-induced cutaneous toxicity. Future Oncol. 2018 Oct;14(24):2531-2541. doi: 10.2217/fon-2018-0187. Epub 2018 May 4. PMID: 29727211.
Lacouture ME, Mitchell EP, Piperdi B, Pillai MV, Shearer H, Iannotti N, Xu F, Yassine M. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-Emptive Skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Mar 10;28(8):1351-7. doi: 10.1200/JCO.2008.21.7828. Epub 2010 Feb 8. PMID: 20142600.
Nakata K, Komori T, Saso K, Ota H, Kagawa Y, Morita S, Noura S, Hayashi N, Uemura M, Matsuda C, Satoh T, Mizushima T, Murata K, Doki Y, Eguchi H; Multicenter Clinical Study Group of Osaka, Colorectal Cancer Treatment Group (MCSGO). Pre-emptive oral clarithromycin reduces the skin toxicity of panitumumab treatment for metastatic colorectal cancer. Int J Colorectal Dis. 2021 Dec;36(12):2621-2627. doi: 10.1007/s00384-021-04002-9. Epub 2021 Aug 3. PMID: 34345969.
Hofheinz RD, Lorenzen S, Trojan J, Ocvirk J, Ettrich TJ, Al-Batran SE, Schulz H, Homann N, Feustel HP, Schatz M, Kripp M, Schulte N, Tetyusheva M, Heeger S, Vlassak S, Merx K. EVITA-a double-blind, vehicle- controlled, randomized phase II trial of vitamin K1 cream as prophylaxis for cetuximab-induced skin toxicity. Ann Oncol. 2018 Apr 1;29(4):1010-1015. doi: 10.1093/annonc/mdy015. PMID: 29360920.
Yamada M, Iihara H, Fujii H, Ishihara M, Matsuhashi N, Takahashi T, Yoshida K, Itoh Y. Prophylactic Effect of Oral Minocycline in Combination with Topical Steroid and Skin Care Against Panitumumab-induced Acneiform Rash in Metastatic Colorectal Cancer Patients. Anticancer Res. 2015 Nov;35(11):6175-81. PMID: 26504047.
Ocvirk J, Cencelj S. Management of cutaneous side-effects of cetuximab therapy in patients with metastatic colorectal cancer. J Eur Acad Dermatol Venereol. 2010 Apr;24(4):453-9. doi: 10.1111/j.1468- 3083.2009.03446.x. Epub 2009 Sep 27. PMID: 19793151.
Chayahara N, Mukohara T, Tachihara M, Fujishima Y, Fukunaga A, Washio K, Yamamoto M, Nakata K, Kobayashi K, Takenaka K, Toyoda M, Kiyota N, Tobimatsu K, Doi H, Mizuta N, Marugami N, Kawaguchi A, Nishigori C, Nishimura Y, Minami H. Adapalene Gel 0.1% Versus Placebo as Prophylaxis for Anti-Epidermal Growth Factor Receptor-Induced Acne-Like Rash: A Randomized Left-Right Comparative Evaluation (APPEARANCE). Oncologist. 2019 Jul;24(7):885-e413. doi: 10.1634/theoncologist.2019-0156. Epub 2019 Mar 19. PMID: 30890624
Fuloria J. Safety profiles of current antiangiogenic therapies for metastatic colorectal cancer. Onco Targets Ther. 2012;5:133-42. doi: 10.2147/OTT.S31412. Epub 2012 Aug 17. PMID: 22930641.
Lynch TJ Jr, Kim ES, Eaby B, Garey J, West DP, Lacouture ME. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007 May;12(5):610-21. doi: 10.1634/theoncologist.12-5-610. PMID: 17522250.
de Noronha e Menezes NM, Lima R, Moreira A, Varela P, Barroso A, Baptista A, Parente B. Description and management of cutaneous side effects during erlotinib and cetuximab treatment in lung and colorectal cancer patients: a prospective and descriptive study of 19 patients. Eur J Dermatol. 2009 May-Jun;19(3):248-51. doi: 10.1684/ejd.2009.0650. Epub 2009 Mar 3. PMID: 19258241.
Galimont-Collen AF, Vos LE, Lavrijsen AP, Ouwerkerk J, Gelderblom H. Classification and management of skin, hair, nail and mucosal side-effects of epidermal growth factor receptor (EGFR) inhibitors. Eur J Cancer. 2007 Mar;43(5):845-51. doi: 10.1016/j.ejca.2006.11.016. Epub 2007 Feb 7. PMID: 17289377.
Hashimoto H. Superglue for the treatment of heel fissures. J Am Podiatr Med Assoc. 1999 Aug;89(8):434-5. doi: 10.7547/87507315-89-8-434. PMID: 10466300.
Segaert S, Van Cutsem E. Clinical management of EGFRI dermatologic toxicities: the European perspective. Oncology (Williston Park). 2007 Oct;21(11 Suppl 5):22-6. PMID: 18159647.
Osio A, Mateus C, Soria JC, Massard C, Malka D, Boige V, Besse B, Robert C. Cutaneous side-effects in patients on long-term treatment with epidermal growth factor receptor inhibitors. Br J Dermatol. 2009 Sep;161(3):515-21. doi: 10.1111/j.1365-2133.2009.09214.x. Epub 2009 Apr 10. PMID: 19466958.
Chanprapaph K, Vachiramon V, Rattanakaemakorn P. Epidermal growth factor receptor inhibitors: a review of cutaneous adverse events and management. Dermatol Res Pract. 2014;2014:734249. doi: 10.1155/2014/734249. Epub 2014 Mar 2. PMID: 24723942.
Burtness B, Anadkat M, Basti S, Hughes M, Lacouture ME, McClure JS, Myskowski PL, Paul J, Perlis CS, Saltz L, Spencer S. NCCN Task Force Report: Management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. J Natl Compr Canc Netw. 2009 May;7 Suppl 1:S5-21; quiz S22-4. doi: 10.6004/jnccn.2009.0074. PMID: 19470276.
Skin alterations by molecular targeted therapies (I), EGFR inhibitors. J.C.. Mellídez Barroso, T.. Costa, I.. Julião, D.. Domingues. Vol. 1. Núm. 1. P. 13-22 (jan. 2012) in REGIO. Revista Internacional de Grupos en Investigación en Oncología
Wiznia LE, Choi JN. Unique presentations of epidermal growth factor receptor inhibitor-induced papulopustular eruption related to bacterial superinfection. Dermatol Online J. 2013 Mar 15;19(3):8. PMID: 23552005.
Basti S. Ocular toxicities of epidermal growth factor receptor inhibitors and their management. Cancer Nurs. 2007 Jul-Aug;30(4 Suppl 1):S10-6. doi: 10.1097/01.NCC.0000281759.23823.82. PMID: 17666986.
Borkar DS, Lacouture ME, Basti S. Spectrum of ocular toxicities from epidermal growth factor receptor inhibitors and their intermediate-term follow-up: a five-year review. Support Care Cancer. 2013 Apr;21(4):1167- 74. doi: 10.1007/s00520-012-1645-y. Epub 2012 Nov 15. PMID: 23151647.
Lane K, Goldstein SM. Erlotinib-associated trichomegaly. Ophthalmic Plast Reconstr Surg. 2007 Jan-Feb;23(1):65-6. doi: 10.1097/IOP.0b013e31802d9802. PMID: 17237698.

METABOLIC DISORDERS

19.1 DEHYDRATION

Authors: Jéssica Sobreiros Krowicki, Bárbara Paracana and Ana Sofia Montez Evidence

Definition Level Grade PMID Nº

- Dehydration is defined as the loss of total body water at a greater rate than the body can replace it. It is estimated that the adult will trade around 6% of his total content of water daily.

Symptoms and signs

- Dehydration can be grouped in mild, moderate or severe. According to the degree of dehydration the symptoms and signs will also vary.
- Therefore, the mains symptoms are thirst, fatigue, dizziness, headache, dark coloured urine and hypotension.
- The signs related to de degree of dehydration can be grouped as follow:

Chart 1: Clinical signs of dehydration according to dehydration percentage %.

Dehydration percentage %	Clinical signs
5%	Not detectable
5-6%	Diminished skin turgor
6-8%	Dry mucous membranes; Sunken eyes; slightly increased capillary refill time; Skin pinch goes back slowly.
10-12%	Marked increased capillary refill time; Signs of hemodynamic instability such as: hypotension, tachycardia, cold extremities
12-15%	Hypovolemic shock; death at any time

Etiology

The oncological patient might face, during the various stages of his illness, episodes of dehydration. These patients will mostly have hypovolemic dehydration in which there is a true loss in the body water content (volume depletion).

Dehydration in these patients might occur due to excessive loss of fluids (such as in vomiting or diarrhoea), as a side effect of the treatment (radiotherapy or chemotherapy) or simply due to diminished intake.

Types of dehydration

Isonatremia dehydration: the loss of water by the intravascular compartment are proportional to the loss of water by the extracellular compartment. Sodium serum levels will be between 130 -150 mEq/L.

Hyponatremia: the sodium concentration levels will be inferior to 130 mEq/L. There will be net solute loss more than water loss.

Hypernatremia the sodium concentration levels will be superior to 150 mEq/L. It will reflect water loss more than solute loss.

Evidence

Laboratory testing Level Grade PMID Nº

- The serum sodium concentration is determined by the ratio between sodium salts and water in the extracellular fluid. Therefore, there might be hyponatremia, isonatremia or hypernatremia according to the underlying mechanism.
- Blood count: haemoconcentration with elevated haematocrit.

Methods for calculating water loss and replacement rate

Degree of dehydration measurement: calculated by diving the difference between the pre-illness and illness weights by the pre-illness weight, then multiplying by 100.

Water deficit: 10 x % dehydration x pre-illness weight (kg).
Insensible losses: 1mL/kg/h per diuresis; 1-2L sweat; 5mL/kg/day for respiratory losses; 5mL/kg/day for skin losses. Normal daily fluid and electrolyte requirements:

25–30 ml/kg/day water.

1 mmol/kg/day sodium, potassium, chloride.

50 -100 g/day glucose.

Treatment

- Define type of dehydration by serum sodium concentration.
- Avoid raising sodium concentration more than 4-6mEq/day or lowering it less than 12mEq/day as it might cause cerebral damage.

Chart 2: Dehydration treatment and administration route.

Oral water replacement if suitable.	Per os
If oral route is not available, consider fluid therapy replacement with isotonic crystalloid solutions (e.g., saline): for patients with isotonic dehydration and hyponatremia.	IV
If severe hyponatremia: add sodium 3% (dehydration % x weight x 0.6). Start with half in 12h (0.5 -1mEq/L/h) the rest in 36h.	IV
If hypernatremia is present hypotonic fluids or dextrose 5% might be administer.	IV

References

Nadal JW, Pedersen S, Maddock WG. Acomparison between dehydration from salt loss and from water deprivation. J Clin Invest. 1941;20:691–703
Rikkert M.G.M.O. Hoefnagels W.H.L. Deurenberg P. Age-related changes in body fluid compartments and the assessment of dehydration in older age. in: Arnaud M. Vellas B.J. Albarede J.L. Garry P.J. Hydration and Aging. Springer Publishing Company, New York, NY1998: 13-32
Thomas D.R., Tariq S.H., Makhdomm S., Haddad R., Moinuddin A. Physician misdiagnosis of dehydration in older adults. JAm Med Dir Assoc. 2003; 4: 251-254
Volkert D, Beck AM, Cederholm T, et al. ESPEN guideline on clinical nutrition and hydration in geriatrics. Clin Nutr. 2019;38:10–47.
Hooper L, Bunn DK, Downing A, et al. Which frail older people are dehydrated? The UK DRIE Study. J Gerontol A Biol Sci Med Sci. 2016;71:1341–1347.

TUMOR LYSIS SYNDROME

Authors: Daniela Meireles, Inês Pintor and João Faia

Definition

- - Tumour lysis syndrome (TLS) occurs when large amounts of abolished met are released into the bloodstream after destruction of neoplasm cells. They increase extracellular levels of uric acid, phosphorus and potassium that can threaten cardiac and kidney function and increase calcium levels, which can cause neurological symptoms.

Signs and symptoms

- - Symptoms usually reflect underlying metabolic disorders.
  - Nausea, vomiting, diarrhoea, prostration, myalgia, cramps, muscle spasms, tetany, paraesthesia’s, seizures, cardiac arrhythmias, and syncope can lead to death.

Aetiology

- - The lysis of neoplastic cells releases many solutes overloading the mechanisms of homeostasis.

In the presence of pre-existing kidney disease, increased baseline levels of these ions and rapid accumulation of solutes increase the risk of TLS.

- - The presentation is usually between the start of chemotherapy and the following week. Spontaneous LTS or, in the absence of cytotoxic therapy, is rare.

Diagnosis

Evidence

Level Grade PMID Nº

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- - Analytical criteria: 2 or more analytical changes (hyperuricemia, hyperphosphatemia, hyperkalaemia, hypocalcaemia) II B Clinical criteria: laboratory criteria + symptoms

(see tables 1 and 2).

- - With laboratory criteria: 2 or more analytical changes (hyperuricemia, hyperphosphatemia, hyperkalaemia, hypocalcaemia) II B With clinical criteria: laboratory criteria + symptoms

(see tables 1 and 2)

Risk factors

- - LTS most often occurs after the start of cytotoxic chemotherapy in patients with hematologic malignancies.
  - Although rare, it can also be seen in solid tumours.
  - It is rare in the absence of cytotoxic therapy
  - Factors that increase the risk of TLS include:

high tumour burden
neoplasms with rapid proliferation power
pre-existing renal insufficiency or renal involvement due to neoplasia
age
specific treatments with high potential for cell lysis
concomitant use of other drugs that increase uric acid levels (ascorbic acid, aspirin, caffeine, cisplatin, diazoxide, thiazide diuretics, adrenaline, ethambutol, levodopa, methyldopa, nicotinic acid, pyrazinamide, phenothiazines and theophylline).
- - In TLS risk stratification, leukocyte count is also considered, with a higher risk if ≥100,000/μL and serum LDH (lactate dehydrogenase) level if elevated more than 2 times the upper limit of normal (ULN).

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Drug therapy Level Grade PMID Nº

Treatment requires a multidisciplinary team that includes a haematologist/oncologist, nephrologist, and intensive care medicine (Grade 1C).

- - - Fluid therapy with urinary flow scans > 100 ml/m2/h 2

Opt for isotonic or balanced solutions, depending on the ionic changes present.

- - - Analytical monitoring (calcium, phosphorus, and renal function) every 4-6 hours in the first 24 hours
    - When SLT is established, in the absence of contraindications, start Rasburicase 0.2 mg/kg/day at 50 cc NaCl/30 min. to clinical improvement 1B
    - Allopurinol is used if the patient has glucose-6-phosphate dehydrogenase (G6PD) deficiency or Rasburicase allergy.
    - In the presence of hyperkalaemia >=6 mmol/L or +25% of normal) cardiac monitoring should be performed 2C
    - Hyperkalaemia correction: 500mL Glycosate Serum 5% with 15U Rapid Insulin +/- Calcium Gluconate 10%, 10ml iv **
    - If hypocalcaemia is symptomatic, it should be treated with 10% Calcium Gluconate, 10 mL iv (in bolus of 10 minutes if severe symptoms, in infusion with 20-30ml of calcium I

gluconate in 1L of G5% in 12 to 24h, if symptoms are moderate) **

- - - If there is hyperphosphatemia should be treated with aluminum-hydroxide iv oral 50-150mg/Kg/day (30mg of 6/6h for 1 or 2 days) **
    - In case of water overload, hyperkalaemia, hyperuricemia, hyperphosphatemia, or intractable hypocalcaemia there is an indication of dialysis** 1A
    - ** If hyperuricemia, hyperkalaemia, hyperphosphatemia, hypocalcaemia, or water overload are not corrected, dialysis is indicated.
    - If started, dialysis should be required until recovery of renal function, resolution of severe electrolyte disorders, and recovery of urinary flow. 1A
    - Peritoneal dialysis is not recommended
    - Asymptomatic hypocalcaemia should not be treated 1C
    - Allopurinol is not the drug of choice in treatment* 1B
    - Potassium should not be added to fluid therapy 1A
    - Alkalinization of urine is not recommended 1C

Prophylaxis

In patients with haematological malignancies undergoing chemotherapy, the risk of TLS should be assessed, and appropriate prophylaxis initiated . 1B

- - - Low risk: 2C

CBC monitoring and oral hydration.

Consider fluid therapy iv and allopurinol if necessary.

- - - Intermediate risk: 2C

Prophylactic allopurinol for 7 days and increase iv hydration after treatment.

In intermediate risk, allopurinol should be administered at a dose of 100 mg/m2 every 8 hours, 48 h after the start of chemotherapy (maximum 800 mg/day, for renal function only).

- - - Allopurinol is not recommended as prophylaxis for patients with pre-treatment uricemia equal to or greater than 7.5 mg/dL. In this case, Rasburicase is recommended.

C 25876990 21554259

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- - - Intermediate risk:

Analytical monitoring every 12h

Level Grade PMID Nº

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- - - High risk:

Prophylactic Rasburicase and hydration booster iv

- - - Fluid therapy up to 3L/m2/day

In the absence of obstructive pathology, diuresis can be stimulated with low doses of furosemide up to 2 ml/kg/hour.

- - - In the absence of LTS criteria in high-risk patients, a • single 3 mg dose of Rasburicase can be given if clinical and laboratory monitoring is maintained, and Rasburicase can 2C be repeated if necessary.
    - High risk:

Analytical monitoring every 6h

- - - Avoid Rasburicase if there is a G6PD deficiency. Strengthen fluid therapy and add allopurinol. 2C
    - In patients taking Rasburicase, the blood sample should be transported on ice to the laboratory to avoid falsely low results. 1B
    - If Rasburicase was started, the association with Allopurinol is unnecessary, and may even reduce its effectiveness. 2C
    - Urine alkalinisation is not recommended. 1C

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References

9487416; 15384972; 15571272; 19380431; 21554259; 21561350; 21858793; 25876990; 25961554; 28478879; 32850076.

Annexes

Table 1: Definition of laboratory tumour lysis syndrome according to Cairo-Bishop (2004)

Uric acid	≥ (476 μmol/L) or a 25% increase in baseline
Potassium	≥ 6 mEq/L (6.0 mmol/L) or a 25% increase in baseline
Phosphorus	≥ 4.48 mg/dL (1.45 mmol/L) or a 25% increase in baseline
Calcium	≤ 7 mg/dL (1.75 mmol/L) or a 25% reduction at baseline

- - - - It requires the presence of 2 or more laboratory criteria between days 3 and 7 after the start of chemotherapy. These criteria assume that the patient is under adequate hydration and uric acid reducing agents.

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Table 2: Definition of the Second Clinical Syndrome of Tumour Lysis Cairo-Bishop (2004)

Creatinine	≥ 1.5 x Lower normal limit
Cardiac arrhythmia or sudden death
Convulsion

It requires the presence of one clinical criterion and at least two analytical criteria.

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Risk	Diagnosis	Additional risk factor
Very high	Stage III/IV Burkitt lymphoma Acute lymphoblastic leukaemia Acute myeloid leukaemia	LDH >2x ULN Leuc >100×109/L ou LDH >2x ULN Leuc >100×109/L
Intermediate	Burkitt lymphoma Upper-intermediate-grade non-Hodgkin lymphoma in adults	LDH <2x ULN LDH >2x ULN
	Stage III/IV lymphoblastic lymphoma Paediatric upper-intermediate grade non-Hodgkin lymphoma Paediatric stage III/IV anaplastic large cell lymphoma	LDH >2x ULN
	Acute lymphoblastic leukaemia
	Acute myeloid leukaemia	Leuc <100×109/L ou LDH <2x ULN
	Chronic lymphoid leukaemia	Leuc 25-100 x109/L ou Leuc <25×109/L e LDH >2x ULN
	Chronic myeloid leukaemia	If treated with fludarabine/rituximab or Leuc >50×109/L
		If history of previous blast crisis
Low	Indolent non-Hodgkin lymphoma Anaplastic lymphoma of large cells Upper-intermediate-grade non-Hodgkin lymphoma in adults Stage I/II lymphoblastic lymphoma Hodgkin lymphoma Acute myeloid leukaemia	LDH <2x ULN LDH <2x ULN Leuc <25x 109/L e LDH <2x ULN
	Chronic lymphocytic leukaemia Acute myeloid leukaemia Multiple myeloma	In the absence of other risk factors

Table 3: Haematological pathologies associated with tumour lysis syndrome. Leuc: leukocytes; LDH: Lactate dehydrogenase; ULN: upper limit of normal.

Evidence

Level Grade PMID Nº

Evidence Level Grade PMID Nº

- Fluxogram 1: Decision-making in case of suspected tumour lysis syndrome. CKD: chronic kidney disease; SLT:

Tumour lysis syndrome.

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SODIUM METABOLISM DISORDERS

Authors: Leonor Naia, Diogo Abreu and Margarida Eulálio

Introduction

- - Hydroelectrolytic disorders are quite frequent in daily clinical practice. Sodium imbalances are often underdiagnosed and undertreated, and are related to increased morbidity, mortality and length of stay.(1-2)

Hyponatremia

Definition

- - Hyponatremia is defined as a serum sodium concentration of 135 mmol/L or less.(1 )

Diagnosis / Etiology

The diagnosis must be based on:

Differentiation between pseudo-hyponatremia and hyponatremia:
Pseudo-hyponatremia:
Normal serum osmolarity (280-295mOsm/Kg): hypertriglyceridemia (more in patients with pancreatitis) or hyperproteinemia (more in multiple myeloma if serum monoclonal protein concentration >10g/dL).
Increased serum osmolarity (> 295mOsm/Kg): common in hyperglycemia (more diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome) or increased unmeasured/unaccounted osmoles (mannitol, glycerol, sorbitol).
Hyponatremia: Decreased serum osmolarity (< 280mOsm/Kg): most frequent cause of hyponatremia.
Once hyponatremia associated to decreased serum osmolarity is assumed, the study should be directed to finding its cause:
Hypervolemic: heart failure or cirrhosis (ascites, pleural effusion or edema/anasarca), nephrotic syndrome, advanced chronic kidney disease.
Euvolemic: SIADH is the most frequent cause (associated with neoplasms, central nervous system pathology, drug iatrogenesis, pulmonary pathology); other causes are hypothyroidism, polydipsia (frequent in psychiatric disorders), malnutrition and beer potomania.
Urinary osmolarity of <100mOsm/Kg is suggestive of “psychogenic” polydipsia.
Hypovolemic:
Urinary Na+ concentration <25mEq/L  extrarenal losses: dehydration, gastrointestinal losses, fluid shifts (“third spacing”) (pancreatitis, sepsis). In metabolic alkalosis secondary to vomiting, urinary sodium may increase transiently to >25mEq/L, but with urinary chloride concentration of <25mEq/L.
Urinary Na+ concentration >40mEq/L renal losses: diuretic therapy (thiazide diuretics), ACEIs, Addison’s disease, cerebral salt wasting.

Thus, a detailed clinical history with emphasis on the patient’s medication and a complete physical examination (ruling out neurological symptoms that require timely initiation of correction) will help in classifying the hyponatremia in hypovolemic, euvolemic or hypervolemic which is essential to direct treatment.

It is also important to try to establish the speed of onset of the hyponatremia as well as the severity of symptoms, since these also have therapeutic implications. The diagnosis should be complemented with laboratory tests, namely:

Complete blood count
Glucose, ionogram, kidney function, liver enzymology
Plasma osmolarity
Urinary osmolarity
Urinary ionogram (useful for distinguishing between renal and extrarenal losses in hypovolemic hyponatremia)
Lipid panel and thyroid hormones (depending on clinical suspicion)

Evidence

Level Grade PMID Nº

Evidence

Symptoms and Signs Level Grade PMID Nº

The Mostly present when the onset is acute or under the presence of serum sodium concentrations of <120mEq/L.2

Acute onset (<48 hours) VS Chronic onset (>48 hours)

There is a varied and nonspecific spectrum of clinical manifestations, ranging from asymptomatic or mildly symptomatic patients to life-threatening symptoms.1-2 When the development of hyponatremia is acute the symptoms are due to cerebral edema and increased intracranial pressure:

Mild (130-135mEq/L): nausea, anorexia, apathy, and lethargy
Moderate (125-129mEq/L): headache and disorientation
Severe (<125 mEq/L): vomiting, convulsions, arreflexia, coma, Cheyne-Stokes respiration, and death

If the onset of hyponatremia is slower, symptoms such as muscle clamps, dizziness, confusion and lethargy, nausea and vomiting may occur.

Treatment

Treatment depends on the underlying cause, speed of onset and severity of symptoms.(1-2)

The goal of treatment is to increase the serum sodium concentration by 4 to 6mEq/L in 24 hours (usually not higher than 8mEq/L in 24h).

In patients with acute hyponatremia or severe symptoms the speed of correction should be faster due to the risk of brain herniation: 4 to 6mEq/L in the first hours, maintaining the correction rate below 8-10mEq/L/24h.(3) In these cases, correction should be performed with 3% hypertonic NaCl and begin infusion of 150mL for 20 minutes (Grade D1 evidence). Administration should be repeated until an increase of 4-6mEq/L (Grade 2D evidence) or improvement of symptoms has been achieved (usually 2-3 administrations are suficient).(1)

Serum sodium concentration should be assessed hourly. After the initial rise of 4-6mEq/L the monitoring interval can be prolonged (to 6-12h and then every 24h) and the 3% hypertonic NaCl discontinued, switching to 0.9% NaCl. (Evidence grade 2D).(1)

In patients with chronic hyponatremia:

Mild: suspension of contributing drugs; fluid restriction and/or initiation of diuretic therapy with loop diuretics (in hypervolemic hyponatremia). Initiation of treatment with saline solution not recommended (evidence grade 2C).(1)
Moderate to severe:
- If severe symptoms or known intracranial pathology: perform 150mL 3% hypertonic NaCl in 20 minutes.
- If asymptomatic or mild to moderate symptoms and absence of intracranial pathology: if severe hyponatremia treat as acute hyponatremia; if moderate hyponatremia treat with fluid restriction, diuretic therapy and suspension of potentiating drugs.(1)

In hypovolemic hyponatremia is recommended to restore the extracellular volume with isotonic saline solution at 0.5-1mL/Kg/h (grade of evidence 1B).(1)

The correction rate should not exceed the above cut-offs to avoid complications, namely osmotic demyelination syndrome, which is more frequent when the correction is >10- 12mEq/L in 24 hours or >18mEq/L in 48 hours.

SIADH: first-line treatment is water restriction (<500-800mL/day) – evidence grade 2D. As second-line treatment, loop diuretics can be used as well as supplementation with salt tablets – grade of evidence 2D (9g of oral NaCl is equivalent to the amount of sodium present in 1 liter of isotonic saline and 1g of oral NaCl is equivalent to 35mL of 3% saline).(1) Vaptans, lithium or demeclocycline are not recommended.(3)

Hypernatremia

Definition

- - Hypernatremia is defined as a serum sodium concentration greater than 145mmol/L.(4 )

Diagnosis / Etiology

The main cause is volume depletion(4):

By decreased water intake: mostly in infants/children and elderly unable to hydrate autonomously. May also occur if an hypothalamic lesion/disease is affecting the thirst center (hypodipsia)
By increased losses:
- Gastrointestinal
- Renal: central or nephrogenic diabetes insipidus, osmotic diuresis (azotemia, hyperglycemia, mannitol)
- Cutaneous: sweat losses (increased with fever, extensive burns, heat exposure, exercise) and insensible losses
Other etiologies:
- Cells water entry: rhabdomyolysis, intense exercise, seizure
- Sodium overload: hypertonic saline serums, sodium bicarbonate
- Drug iatrogenesis: excessive diuretic therapy

A detailed clinical history and thorough physical examination are essential to help determine the etiology and treatment. Diagnosis should be complemented with laboratory tests, namely:

Complete blood count
Glucose, ionogram, renal function
Plasma osmolarity
Urinary osmolarity and ionogram
- If urinary osmolarity is low and lower than serum osmolarity: suggestive of nephrogenic or central diabetes insipidus
- If urinary osmolarity is between 300-600mOsm/Kg: suggestive of osmotic diuresis or diabetes insipidus
- If urinary osmolarity if higher than 600mOsm/Kg: suggestive of extrarenal losses, use of diuretic therapy, hypodipsia or dehydration

Symptoms and Signs

Clinical manifestations will depend on the speed of onset and degree of increase in natremia.

In acute onset hypernatremia, psychomotor slowing, lethargy, weakness, seizures, coma, and eventually death (especially if serum sodium >180mEq/L) may occur. In more severe cases, intracranial hemorrhage may occur from sudden contraction of brain cells.(5)

Treatment

The therapeutic approach will vary according to the underlying etiology and the rate of onset.

In chronic hypernatremia is recommended to start dextrose 5% up to a maximum infusion rate of 150mL/h. If hypovolemia is present start by performing volume expansion with isotonic saline.(5)

Provide oral hydration if level of consciousness is adequate and patient is cooperating, otherwise hydrate the patient by nasogastric tube. If hyperglycemia is present, start hypotonic saline solution.

The goal is to decrease serum sodium concentration by up to 10mEq/L in 24 hours, avoiding excessive correction (>12mEq/L in 24 hours or >0.5mEq/L/h).(4-6)

In acute hypernatremia, dextrose 5% at 3-6mL/Kg/h is recommended. After reaching a serum concentration of 145mEq/L, the rate should be reduced to 1mL/Kg/h. If hyperglycemia is present, start hypotonic saline solution at 12mL/Kg/h.

The goal is to achieve a reduction in sodium concentration of 1 to 2 mEq/L/h (do not exceed 12mEq/L in 24 hours).(5)

Evidence

Level Grade PMID Nº

References

Spasovski G, Vanholder R, Allolio B, Annane D, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014. 25;170(3):G1-47. PMID: 24569125.
Kheetan M, Ogu I, Shapiro JI, Khitan ZJ. Acute and Chronic Hyponatremia. Front Med. 2021. 3;8:693738. PMID: 34414205
Hoorn EJ, Zietse R. Diagnosis and Treatment of Hyponatremia: Compilation of the Guidelines. JAm Soc Nephrol. 2017.28(5):1340-1349. PMID: 28174217
Adrogué HJ, Madias NE. Hypernatremia. N Engl J Med. 2000.18;342(20):1493-9. PMID: 10816188.
Lindner G, Funk GC. Hypernatremia in critically ill patients. J Crit Care. 2013.28(2):216.e11-20. PMID: 22762930.
Sterns RH. Disorders of plasma sodium–causes, consequences, and correction. N Engl J Med. 2015.1;372(1):55-65. PMID: 25551526.

POTASSIUM METABOLISM

Authors: Joana Carvalho Mendonça and Sergio Pascual Solaz

Evidence

19.4.1 Hypokalaemia Level Grade PMID Nº

- - Hypokalaemia is defined as a low blood potassium (< 3,5 mEq/L). According to the blood potassium level, hyperkalaemia can be classified as mild (3-3,5 mEq/L), moderate (3- 2,5 mEq/L) and severe (<2,5 mEq/L).

Symptoms

- - Hypokalaemia is asymptomatic in most patients. Symptoms generally do not become manifest until the serum potassium is below 3.0 mEq/L. Common symptoms are muscle weakness or rhabdomyolysis, pain, cramps, constipation, nausea, vomiting… In severe hypokalaemia symptoms can be psychosis, delirium, depression and cardiac alterations as bradycardia and even cardiac arrest.

Etiology

Decreased intake, increased translocation into the cells and increased losses (most often) can lead to a hypokalaemia. The major causes in the cancer patients are:

- - Cancer related: anorexia and reduced potassium intake; low intestinal absorption due to tumour infiltration or constipation; tumours with high cell turnover, as acute leukaemia; neuroendocrine tumours may produce some hormones, as cortisol or mineralocorticoids that may induce secretory diarrhoea or renal potassium loss.
  - Cancer treatment related: many chemotherapy agents, target therapies and immunotherapy cause diarrhoea and/or emesis, with the consequent potassium loss.
  - Related to other therapeutics: thiazide diuretics, insulin, granulocyte colony stimulating factor (by promoting knew cell formation, with the need of higher potassium levels), beta- 2-agonists, glucocorticoids.

Other than these causes, cancer patients are also exposed to the same factors as the general population, that may contribute to hypokalaemia, as illustrated in table 99.1.2-1.

Cell redistribution

Insulin .
Beta-2-adrenergic activity increase.
α-adrenergic antagonism .
Renal stimulation of the Na+/K+ transporter : theophylline , caffeine.
Anabolic state :

Intake of B12 vitamin , folic acid, iron, epoetin… Granulocyte colony stimulating factors.

Tum or with a high replication rate.

Hypothermia
Anorexia and malnutrition .
Gastrointestinal mucosa lesions .

Reduced intake

Table 99.1.2-1: Hypokalaemia Etiology

Increased excretion	Renal	Drugs: diuretics, penicillin derivates, amphotericin, aminoglycosides, foscarnet, cisplatin, Ifosfamide. Mineralocorticoids excess, primary or secondary hyperaldost eronism, paraneoplastic syndrome. Osmotic diuresis, with hypomagnesemia. Diabetic ketoacidosis.
Increased excretion	Gastrointestinal	Diarrhoea, emesis, aspiration.

Subtitle: Adapted from Martins Baptista, António (2016) “O Guia do Jovem Internista”, Sociedade Portuguesa de Medicina Interna. AMI -acute myocardial infarction; TBI – traumatic brain injury

Diagnostic

- - Hypokalaemia diagnosis is made throw potassium blood values, but to determine the Etiology and potential complications more exams are needed, as showed in table 99.1.3-1.

Evidence Level Grade PMID Nº

99.1.3-1 – Diagnostic studies
Medical history and physical examination	Vomiting, diarrhoea, diuretic intake, insulin…
Blood potassium	Arterial gasometr y is more accurate.
Renal function and urinary potassium	If urinary potassium is above 30mEq/L, is a sign of renal loss.
pH, glucose, magnesium , osmolarity in urine and plasma	To evaluate the ionic cell exchanges.
ECG	Possible changes: T wave flattening. ST segment depression. QT prolongation. U wave.

Pharmacotherapy

- - Potassium chloride – oral tablets, 600mg every 12 hours 2
  - Potassium chloride – intravenous infusion (10-20mEq/L rases the potassium blood levels in 0.25mEq/h) 2
In a peripheral venous catheter do not exceed 40mEq/L and 20mEq/h (ex: 20mEq/500mL/1h or 40mEq/1L/2h).
If there is the need to infuse higher concentrations or at a faster pace, use a ventral vein catheter under continuous heart monitoring.
- - Potassium sparing diuretics – amiloride, spironolactone. 2

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Therapeutic Strategy

Evidence

Level Grade PMID Nº

- - Discontinue drugs that increase potassium excretion or its intracellular movement. 2
  - Potassium enriched food (vegetables, meat, poultry, and fish) 2
  - Treat concomitant hypomagnesemia. 2
  - Approach, if possible, the hypokalaemia Etiology. 2
  - Mild hypokalaemia (serum potassium levels of 3,0-3,5 mEq/L)

Oral replacement – Potassium chloride oral tablets. 2

Potassium sparing diuretics (if refractory) – amiloride, spironolactone.

- - Moderate or Severe hypokalaemia (blood potassium levels < 3,0 mEq/L)

Intravenous replacement – potassium chloride intravenous infusion. 2

19.4.2 Hyperkalaemia

- - Hyperkalaemia is defined as a high blood potassium (> 5,5 mEq/L). According to the blood potassium level, hyperkalaemia can be classified as mild (5,5 – 6,0 mEq/L), moderate (6,0 – 7 mEq/L) our severe (> 7 mEq/L).

Symptoms

- - Hyperkalaemia is asymptomatic in most patients and the presentation may be unspecific and dominated by the acute illness that caused the potassium increase. There is not so much correlation between levels of potassium and symptoms. The symptoms are related to the hyperkalaemia severity, the installation speed (more important) and the patient previous health status.

The symptoms may vary from muscle weakness, flaccid paralysis, decreased tendon reflexes, paraesthesia’s and palpitations, to arrhythmias or cardiac arrest. Simultaneous metabolic disturbances may modulate hyperkalaemia effects by altering potassium redistribution between the cell and their surroundings:

Hypernatremia, hypercalcemia and alkalemia may reduce the effects.
Hyponatremia, hypocalcaemia and acidaemia may increase them.

Etiology

Other than the hyperkalaemia causes known for the general population, as renal disfunction, drugs and hyperglycaemia, in the oncologic patient we must consider some specific causes. The most severe is the tumour lysis syndrome, in tumours with a high proliferative index, as leukaemia our small cell lung carcinoma, due to the rapid destruction of a high cell number. Chemotherapy agents may grant additional toxicity, as the platinum agents that may aggravate the renal function. Consider also pseudo-hyperkalaemia, associated to haemolysis after taking venous blood, which is more frequent in patients with thrombocytosis and leucocytosis.

Table 99.2.2-1 illustrates with more detail the aetiologies of hyperkalaemia.

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Increased intake	Nutritional: banana, tomato, citrus. Iatrogenic: parental nutrition, EV our oral supplementation.
Cell redistribution	Serum hyperosmolarity. Radiological contrast. Mannitol. Hypertonic glucose. Drugs: digoxin, beta blockers. Acidosis. Massive cellular catabolism: TLS, sepsis, trauma, rhabdomyolysis.

Level Grade PMID Nº

Low excretion

Chronic kidney disease / Acute renal lesion with oliguria.
Renin-angiotensin-aldosterone axis inhibition: ACEI, AII-RA, spironolactone, plerenone, amiloride, triamterene, trimethoprim.
Decreased renal distal port: CHF, volume depletion.
Nephrotoxic drugs: cisplatin, Ifosfamide, mitomycin C, gemcitabine, methotrexate, bisphosphonates, interferon, somatostatin analogues.
Primary hypoaldosteronism.
Hyporeninaemic hypoaldosteronism: diabetes, COX-2 inhibitors, cyclosporine, tacrolimus, tubulointerstitial diseases (SLE, sickle cell anaemia, obstructive uropathy).
Primary adrenal insufficiency: adrenal metastasis, autoimmune disease, infiltration, adrenal infarction.

Pseudo- hyperkalaemia

Post-harvest haemolysis.
Thrombocytosis, leucocytosis, erythrocytosis.

- Subtitle: Adapted from Martins Baptista, António (2016) “O Guia do Jovem Internista”, Sociedade Portuguesa de Medicina Interna. TLS – Tumour lysis syndrome, ACEI – angiotensin converting enzyme inhibitors, AII-RA – angiotensin II receptor antagonists, CHF – congestive heart failure.

Diagnostic

- - Hyperkalaemia diagnosis is made throw potassium blood values. Other exams are important to determine hyperkalaemia cause and severity. ECG is essential, and the alterations are progressive, as the potassium level increases.

Table 99.2.3-1 shows the exams needed to the correct hyperkalaemia approach.

Table 99.2.3-1: Diagnostic studies
Blood potassium	Arterial gasometry is more accurate.
Renal function and urinary potassium	To evaluate the kidney function.
Sodium, pH, glucose, and serum osmolarity	To evaluate cellular exchanges
LDH, uric acid, phosphor e calcium	Exclude Tumour lysis syndrome
Blood count	Pseudo-hyperkalaemia due to thrombocytosis our leucocytosis
ECG	Determine the need for emergent treatment. Expected alterations: K: 6 – 6,5 mEq/L – spiked T waves. K: 6,5 – 7,5 mEq/L – wider PR interval and P wave flattening. K: 7,5 – 8 mEq/L – wider QRS complex, QRS and T wave convergence. K>8mEq/L – ventricular fibrillation and asystole.

Pharmacotherapy Level Grade PMID Nº

- - Potassium Exchange resin 2
  - Loop diuretics (furosemide 1mg/Kg) 2
  - Fast acting insulin 10 U + 25 g of glucoses in an IV 15-30 min perfusionInhaled salbutamol 2
  - Sodium bicarbonate 50mmol in a 5-minute IV perfusion if metabolic acidosis is present. 2
  - 10% Calcium chloride 6.8 mmol in a 5-10 min IV perfusion. 2
  - 10% Calcium Gluconate 2.26 mmol/l of calcium in a 5-10 min IV perfusion. 2

Therapeutic Strategy

- - Discontinue potassium supplements (oral, IV and parenteral nutrition) 2
  - Discontinue nephrotoxic drugs 1
  - Discontinue, at least temporarily, drugs that reduce potassium excretion (ACEI, AII-RA, beta-blockers, potassium-sparing diuretics) 1
  - Low potassium diet 1

Approach, if possible, the hyperkalaemia Etiology 2

- - Mild Hyperkalaemia (5,5 – 6,0 mEq/L)

Potassium Exchange resin (oral or by retention enema) – start of action in 1 to 5 days 2

Sodium polystyrene sulfonate 15 g diluted in 45-60 ml of water, 3-4 times a day
Calcium polystyrene sulfonate 20 g diluted in 150 ml of water, 1-3 times a day

Loop diuretics (furosemide 1mg/Kg) in hypervolemic patient and good kidney function.

- - Moderate Hyperkalaemia (6,0 – 6,5 mEq/L) with normal ECG

Measures applied in mild hyperkalaemia: 2

Fast acting insulin 10 U + 25 g of glucoses in an IV 15-30 min perfusion – start of action in 15-30min. If the patient is hyperglycaemic do not give glucoses

Monitor the capillary blood glucoses.

- - Severe Hyperkalaemia (> 6,5 mEq/L) with normal ECG 2

Measures applied in mild and moderate hyperkalaemia

Heart monitoring

Inhaled salbutamol 5mg. You may need several doses (10-20mg) – Start of action in 15-30min.

Sodium bicarbonate 50mmol in a 5-minute IV perfusion if metabolic acidosis is present – Start of action in 15-30min.

- - Hyperkalaemia with ECG alterations

Measures applied in mild and moderate hyperkalaemia 2

Continue heart monitoring

Calcium Salts (be careful with in patients with digitalis intoxication) – start of action in 3 min

10% Calcium chloride 1000mg in a 5-10 min IV perfusion – single dose
10% Calcium Gluconate 1000-3000mg in a 5-10 min IV perfusion – several doses may be needed, which you may repeat after 5-10 min
- - Consider dialysis if the patient is oliguric and hyperkalaemia is resistant to medical treatment. 2

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References

1. Kardalas E, Paschou SA, Anagnostis P, Muscogiuri G, et al. Hypokalemia: a clinical update. Endocr Connect. 2018 Apr;7(4):R135-R146. doi: 10.1530/EC-18-0109. Epub 2018 Mar 14. PMID: 29540487. 2.Castro D, Sharma S. Hypokalemia. 2021 Jul 20. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 29494072.

Clase CM, Carrero JJ, Ellison DH, Grams ME, Hemmelgarn BR, et al. Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2020 Jan;97(1):42-61. doi: 10.1016/j.kint.2019.09.018. Epub 2019 Oct 10. PMID: 31706619.
Rafique Z, Chouihed T, Mebazaa A, et al. Current treatment and unmet needs of hyperkalaemia in the emergency department. Eur Heart J Suppl. 2019 Feb;21(Suppl A):A12-A19. doi: 10.1093/eurheartj/suy029. Epub 2019 Feb 26. PMID: 30837800.
Ben Salem C, Badreddine A, Fathallah N, et al. Drug-induced hyperkalemia. Drug Saf. 2014 Sep;37(9):677-92. doi: 10.1007/s40264-014-0196-1. PMID: 25047526.
Cupisti A, Kovesdy CP, D’Alessandro C, et al. Dietary Approach to Recurrent or Chronic Hyperkalaemia in Patients with Decreased Kidney Function. Nutrients. 2018 Feb 25;10(3):261. doi: 10.3390/nu10030261. PMID: 29495340.
Pulla, Mariano Probencio (2016) ESMO Handbook of oncological emergencies, Lugano: Taylor&Francis.
Martins Baptista, António (2016) “O Guia do Jovem Internista”, Sociedade Portuguesa de Medicina Interna, com o apoio Novartis
Alberdi Bellón, Montserrat et all (2016) “Manual de tratamento de soporte en el paciente oncológico basado en la evidencia, 2ª edicion internacional, Espanha: Elsevier.
Manual de diagnóstico y terapéutica médica. Hospital Universitario 12 de Octubre.
Algoritmo de tratamiento de la hiponatremia en el paciente oncológico. Y. Escobar, F. Henao, R. de las peñas, CA. Sánchez. SEOM.

MAGNESIUM METABOLISM

Authors: Clara Pinto and Inês Pinheiro

Evidence

Definition Level Grade PMID Nº

Hypomagnesemia (HypoMg2+)– serum magnesium levels < 1.8 mg/dL
Hypermagnesemia (HyperMg2+)– serum magnesium levels > 2.2 mg/dL

Hypomagnesemia is the most frequent change in cancer patients, since the kidney has the ability to eliminate excess magnesium, avoiding, in most cases, the development of hypermagnesemia. Both disorders are associated with a worse prognosis.

Symptoms

In both HipoMg2+ and HiperMg2+clinical manifestation is often nonspecific.

1. HipoMg2+

Ss moderate and often confused with the underlying pathology/treatment: anorexia, nauseas, and fatigue. It is classified to different degrees according to the main Oncology Societies:

Table 1– Classification of hypomagnesemia according to serum levels (CTCAE v.)

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Grey	Mg2+	eric (mg/dL)	Signs and symptoms
1	1.2≥1.7		Few or no symptoms; fatigue
2	0.9≥1.2		Muscle weakness; fasciculations
3	0.7≥0.9		Neurological deficits; atrial fibrillation
4	<0.7		Psychosis, seizures, nystagmus, severe arrhythmias

1. HyperMg2+

Moderate symptoms like hypomagnesemia.

There is no degree in the severity of hypermagnesemia, although clinical manifestations may be associated according to serum levels of Mg2+:

Table 2 – Clinical manifestation according to serum levels of Mg2+

Mg2+ eric (mg/dL)

Signs and symptoms

7 12

Hyporeflexia, confusionalstate, drowsiness, headache, hypotension, decreased visual acuity

>12

Muscle parrhesia, paralytic ileus, bradycardia, increased PR interval and QRS on ECG; may

culminate in cardiac arrest

It is often associated with other hydro electrolytic disorders, such as hyperkalaemia, hyperphosphatemia, and hypocalcaemia.

Etiology

HipoMg2+

Table 3 – Causes of hypomagnesemia and underlying mechanisms

Etiology	Mechanism
Decreased intake	Anorexia (either by neoplasia or by the underlying treatments), leading to a decrease in the daily intake of micronutrients
Transcellular distribution	Hypercalcemia treatment with pamidronate promotes the entry of Mg2+ into cells. Blood transfusions may decrease mg 2+ ionized because citrate works as chelator. In critically ill patients, the use of catecholamines stimulates β -adrenergic receptors, promoting the entry of Mg2+ into cells.
Gastrointestinal losses	Vomiting and diarrhoea (either by neoplasia or by iatrogenic effect of drugs)
Return losses	Thiazidic diuretics (increase renal excretion by increased potassium excretion) and Ansa (decrease Mg2+ resorption in Henle loop) – drugs often used in these patients;
Drugs used to treat cancer	Monoclonal anti -EGF antibodies : Cetuximab and panitumumab for loss of magnesium in urine. Cisplatin: direct renal toxicity, interfering with resorption mechanisms in the Henle loop and distal tube; gastrointestinal losses due to vomiting or diarrhoea caused by the drug. May persist up to 6 years after treatment is over. HER-2 inhibitors: Transtuzumab and pertuzumab due to decreased resorption in the distal bypassed tube Calcineurin inhibitors : by intestinal loss and absorption

Other concomitant pathologies such as hyperparathyroidism, hyperthyroidism and diabetes mellitus may induce hypomagnesemia in cancer patients. Similarly, the Etiology of hypomagnesemia in these patients may be a reflection of other ongoing drugs, such as diuretics, β-blockers or antibiotics.

Level Grade PMID Nº

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HiperMg2+

Table 4 – Causes of Hypermagnesemia and underlying mechanisms

Aetiology	Mechanism
Tumour lysis syndrome	Ion flow (potassium and magnesium) from Intracellular space to the bloodstream
Drugs	Antacids or laxatives in patients with impaired renal function. Opioids that decrease intestinal motility by increasing the absorption of Mg2+
Impairment of renal function	Decreased elimination, as Mg2+ is mostly eliminated renally

Diagnostic study

The diagnosis is made by analytical findings.

In hypomagnesemia, for the distinction between gastrointestinal and urinary losses, it is possible to request urinary ionogram with magnesium dosing in 24-hour urine or in an occasional sample, using the formula:

U – Mg 2+concentration in urine | P – Mg2+ concentration in plasma | Cr (S) – Serum creatinine | Cr (U) – Urinary creatinine
If >2% is in favour of loss of the Nh’s (see Annex 1).

Treatment

HipoMg2+

In cases without acute symptomatology, it may be treated with oral supplementation.

Table 5 – Oral formulations of Magnesium and their advantages and disadvantages

Level Grade PMID Nº

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Supplement	Advantage/Disadvantage
Magnesium Oxide	Requires high doses for complete replacement; may trigger diarrhoea
Magnesium Hydroxide	Avoid in patients with Creatinine Clearance <30mL/min
Magnesium Citrate	Diarrhoea is a common effect. Avoid in patients with Creatinine Clerance <30mL/min
Magnesium Gluconate	Excessive doses potentiate diarrhoea
Magnesium Chloride	Slow absorption, little renal excretion; rarely causes diarrhoea
Magnesium Sulphate	Slow absorption, little renal excretion; rarely causes diarrhoea
Magnesium Lactate	Prolonged release
Magnesium aspartate	Causes diarrhoea
Protein-magnesium complex	Causes less diarrhoea; frequently used at paediatric level.

HiperMg2+

Table 6– Treatment of hypermagnesemia according to severity

Level Grade PMID Nº

Patients who were not symptomatic

Creatinine Clearance >30 mg/dL

Discontinue potentiating drugs and maintain vigilance; Consider using loop diuretics to accelerate renal elimination

Creatinine Clearance 15-29 mg/dL

Suspend potentiating drugs, start loop diuretic (e.g., Furosemide 20-40mg IV for 4 hours) and Fluid therapy with isotonic serum (e.g., NaCl 0.9% at 150cc/hour)

Symptomatic patients

If hypotension and respiratory impairment, regardless of renal function, haemodialysis is indicated.

Administer 100 -200mg of calcium gluconate to reverse the effects of hypermagnesemia at neuromuscular level.

If the patient is not anuric, it is also indicated to administer loop diuretic and fluid therapy.

Therapeutic strategy

In Treatment of mild to moderate hypomagnesemia asymptomatic is questionable and is associated with worse outcomes. 2b
In the treatment of hypomagnesemia consider the magnitude of deficits and aetiology, correcting the underlying cause. I
Intramuscular replacement can also be considered in severe patients, but absorption is slower by deposition in muscle reserves. I
In patients with CKD, as magnesium is mostly excreted renally, magnesium replacement should be monitored for the risk of cardiac arrest. I
In patients with colorectal cancer with cetuximab-induced hypomagnesemia, oral supplementation is not well tolerated (for diarrhoea). Patients with HipoMg2+ grade 2 may I require weekly parenteral replacement (4g of Magnesium Sulphate); in grade 3-4 a replacement of 6-10g/day is required.
Amiloride promotes the retention of Mg2+, and can be considered in patients with cancer and refractory hypomagnesemia. 2a
SGLT2 inhibitors are associated with high Mg2+ levels and may be considered in patients with refractory cancer and hypomagnesemia who are indicated for their use. 2b
In severe cases of hypermagnesemia, haemodialysis should be considered. I

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References

Workeneh, B. T., Uppal, N. N., Jhaveri, K. D. & Rondon-Berrios, H. Hypomagnesemia in the Cancer Patient. Kidney360 2, 15 -166 (2021).
Takahashi, M. & Uchino, N. Risk factors of hypermagnesemia in end-stage cancer patients hospitalized in a palliative care unit. Ann. Palliat. Med. 9, 4308–4314 (2020).
Krupesh, V. R. et al. Hypermagnesemia in critically ill patients with cancer: Acase report. Mol. Clin. Oncol. 14, (2021).
Gile, J., Ruan, G., Abeykoon, J., McMahon, M. M. & Witzig, T. Magnesium: The overlooked electrolyte in blood cancers? Blood Rev. 44, (2020).
Berardi, R. et al. Electrolyte disorders in cancer patients: a systematic review. J. Cancer Metastasis Treat. 2019, (2019).
Lajer, H. & Daugaard, G. Cisplatin and hypomagnesemia. Cancer Treat. Rev. 25, 47–58 (1999).
Cheungpasitporn, W., Thongprayoon, C. & Qian, Q. Dysmagnesemia in Hospitalized Patients: Prevalence and Prognostic Importance. Mayo Clin. Proc. 90, 1001–1010 (2015).

Anexos

Figure 1 – Algorithm of diagnostico and treatment of hypomagnesemia.

Berardi, R. et al. Electrolyte disorders in cancer patients: a systematic review. J. Cancer Metastasis Treat.

2019, (2019).

CALCIUM METABOLISM

Authors: Mafalda Miranda Baleiras and Ana Rocha Barbosa

Evidence

Learning objectives Level Grade PMID Nº

- - To recognize hypercalcemia as one of the most common metabolic oncologic emergencies.
  - To identify the main mechanisms and clinical presentations in cancer-related hypercalcemia.
  - To outline the treatment strategies available for malignancy-related hypercalcemia.

Introduction

Hypercalcemia is one of the most well-known oncologic emergencies, occurring in 10-30% of patients with malignancy. It is most associated with breast cancer, lung cancer, and hematologic malignancies, such as non-Hodgkin´s lymphoma and multiple myeloma1. Depending on the serum calcium levels, hypercalcemia can be categorized into three categories: mild (10,5-11,9 mg/mL), moderate (12-13,9 mg/mL) and severe (≥14 mg/mL). Approximately, 40% of the serum calcium is bound to albumin. Therefore, once hypercalcemia is suspected, free or ionized calcium levels – its physiologically active form- should be measured. The corrected calcium concentration may be calculated through the following formula: serum calcium + 0.8 x (4.0 – patient’s albumin level {g/dl})2.

Hypercalcemia is most common in later-stage malignancies and predicts a poor prognosis3. Frequent causes include humoral hypercalcemia mediated by parathyroid-related peptide, osteolytic cytokine production, and increased 1,25-dihydroxy vitamin D production. Nevertheless, the basis of cancer-related hypercalcemia can include any cause besides malignancy, such as primary hyperparathyroidism or granulomatous diseases.

Aetiology

Calcium homeostasis is mediated by parathyroid hormone (PTH), 1,25-dihydroxy vitamin D (1,25[OH]2D), calcitonin, serum calcium, and serum phosphorus. Hypercalcemia is a metabolic abnormality resulting from a mismatch between bone formation (stimulated by osteoblasts) and bone resorption (stimulated by osteoclasts)(2). PTH is secreted from parathyroid glands in response to low blood serum calcium concentration and plays its role through its effects on bone, kidney, and intestine.

There are several mechanisms of malignancy-induced hypercalcemia. The most frequent is mediated by the production of parathyroid-related peptide (PTHrP) also known as humoral hypercalcemia of malignancy (HHM), responsible for 80% of hypercalcemia in cancer patients. PTHrP increases bone resorption through activation of osteoclasts and promotes calcium resorption in the kidney. Usually, patients diagnosed with HHM have advanced disease and carry a poor prognosis. Squamous cell cancers (head, neck, and lungs), renal and bladder cancers, breast and ovarian cancers, and a few haematological malignancies account for most cancers leading to HHM(2, 4).

The second most common mechanism, contributing to 20% of malignancy-related hypercalcemia, is osteolytic hypercalcemia. It is associated with extensive bone metastases and the release of local cytokines from the tumour, triggering osteoclast activation. It commonly occurs in multiple myeloma and metastatic breast cancer(2).

Responsible for 1% of cases of hypercalcemia in malignancy is the extrarenal production of 1,25-dihydroxy vitamin D. It is commonly seen with Hodgkin and non-Hodgkin lymphoma and with non-malignant granulomatous diseases such as sarcoidosis and tuberculosis(2, 4).

Symptoms

Patients can present with a wide spectrum of symptoms, depending on the level of serum calcium and the rate of change of the serum calcium(2).

Mild hypercalcemia can be asymptomatic, or it can result in mild nonspecific symptoms such as mood changes, anorexia, nausea, vomiting, constipation, and musculoskeletal pain. Moderate and severe hypercalcemia can be associated with volume depletion and acute renal failure (in part due to the osmotic diuresis), as well as neurocognitive symptoms ranging from lethargy to coma. Severe hypercalcemia can mimic ST-segment elevation myocardial infarction and develop ventricular arrhythmias such as ventricular fibrillation. Cardiac arrest may occur with levels >15 mg/dl(1-3).

Evidence

Diagnosis Level Grade PMID Nº

Initial laboratory workup should include both total calcium and ionized calcium level. If ionized calcium is not available, a correct calcium value may be calculated through the following formula: corrected calcium level = measured calcium level + (0.8 x [4.0 – serum albumin level {g/dl}]). Other ions such as phosphorus should also be measured. The second step once hypercalcemia is confirmed is to determine whether the cause is PTH mediated or not. Since 80% of cancer-related hypercalcemia is attributed to PTHrP, this should be measured. Additional laboratory analysis includes 25(OH)D, and 1,25(OH)2D values. When the aetiology is still not clear based on the above work-up, then a 24-hour urine analysis for calcium and creatinine should be performed. This will help distinguish between primary hyperparathyroidism and familial hypocalciuric hypercalcemia (2, 3).

As electrolyte derangements may occur, an electrocardiogram (ECG) should be obtained; it may show prolonged PR, widened QRS, shortened QT, and ventricular dysrhythmias(1).

Diagnostic studies
Medical history and physical examination	Nausea, vomiting, constipation, polyuria, musculoskeletal pain, neurocognitive symptoms…
Blood calcium and albumin	If ionized calcium is not available, a correct calcium value may be calculated
Serum creatinine, urea, phosphorus, PTH, PTHrP,1,25(OH)2D), 25(OH)D)	Evaluation of hypercalcemia mechanisms
24-hour urine analysis for calcium and creatinine	When the aetiology is still unclear
ECG	Possible changes: prolonged PR; widened QRS, shortened QT, ventricular dysrhythmias

Pharmacotherapy2,3

Intravenous (IV) fluid administration (initial bolus of 1000-2000mL of isotonic fluid followed by an infusion maintenance rate of 200-300mL/hour to achieve a urine output of	2	B	27170690 26713296
100-150mL/hour).
Loop diuretics (e.g.: furosemide 20-40 mg IV). Bisphosphonates (e.g.: zoledronic acid 4mg IV over 15 minutes or pamidronate 60 to 90 mg IV over 2 hours).	2 2I	C B	27170690 27170690 26713296
Attention: zoledronic acid dose may be adjusted to renal function and be avoided in patients with creatinine clearance < 30mL/min
GFR 60 mL/min, 4 mg; GFR 50-60 mL/min3.5mg; GFR 40-49mL/min 3.3mg; GFR 30-39 mL/min: 3.0 mg Calcitonin (4 to 8 UI/Kg subcutaneously every 6 to 12h).	2	C	27170690 26713296
Glucocorticoids (e.g.: IV hydrocortisone 200-400 mg/day followed by prednisone 20-40 mg orally).	2	C	27170690 26713296
Dialysis or continuous renal replacement therapy (reserved for oliguric renal failure or refractory severe hypercalcemia).			26675713

Therapeutic Strategy1-7

Mild hypercalcemia or asymptomatic patients with serum calcium <14 mg/dL can be referred for outpatient management. Moderate or severe hypercalcemia should be hospitalized and receive an intervention to lower serum calcium levels.

Evidence

Level Grade PMID Nº

Intravenous (IV) fluid administration is first-line therapy for those with acute renal failure due to volume depletion. 2
Loop diuretics increase calciuresis but have limited efficacy. Hence, they should be reserved only for patients with congestive heart failure and those who need diuresis. 2
Bisphosphonates inhibit osteoclasts and are the mainstay of long-term therapy. They should be given within 48h of diagnosis and their dose must be adjusted based on renal 2

function. Their calcium-lowering effect is usually reached within 2-4 days. Zoledronic acid is preferred. Their main side effects include osteonecrosis of the jaw and nephrotoxicity.

Calcitonin prevents bone resorption and enhances urinary calcium excretion. It has a rapid onset of action and functions as a bridge while other therapeutics are reaching its 2

effect, such as bisphosphonates.

Glucocorticoids inhibit the conversion of 25-hydroxyvitamin D to calcitriol, decreasing intestinal absorption and renal reabsorption of calcium. They are most effective in 2

haemato-oncological diseases.

Dialysis or continuous renal replacement therapy.

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References

Klemencic S, Perkins J. Diagnosis and Management of Oncologic Emergencies. West J Emerg Med. 2019 Mar;20(2):316-322. doi: 10.5811/westjem.2018.12.37335. Epub 2019 Feb 14.
Goldner W. Cancer-Related Hypercalcemia. J Oncol Pract. 2016 May;12(5):426-32. doi: 10.1200/JOP.2016.011155. PMID: 27170690.
Mirrakhimov AE. Hypercalcemia of Malignancy: An Update on Pathogenesis and Management. N Am J Med Sci. 2015 Nov;7(11):483-93. doi: 10.4103/1947-2714.170600. PMID: 26713296; PMCID: PMC4683803.
Vakiti A, Mewawalla P. Malignancy-Related Hypercalcemia. [Updated 2021 Jul 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482423/
Hillel Sternlicht H, Glezerman I: Hypercalcemia of malignancy and new treatment options. Therapeutics and Clinical Risk Management. 2015 Dec 4 (11):1779-88. doi:10.2147/TCRM.S8368; PMID: 26675713; PMCID: PMC4675637.
Renaghan AD, Rosner MH: Hypercalcemia, etiology and management. Nephrology Dialysis Transplantation, 2018 April; 33(4): 549–551, doi.org/10.1093/ndt/gfy054 Shane
Shane E, Berenson JB: Treatment of hypercalcemia. UpToDate. Last updated, April 08, 2022.

KIDNEY DISORDERS

20.1 PROTEINURIA / NEPHROTIC SYNDROME

Authors: José Leão Mendes, Ana Carolina Vasques and Ana Catarina Brás Evidence

Definition Level Grade PMID Nº

- Nephrotic syndrome (NS) comprises the signs and symptoms resulting from aggravated urinary loss of albumin and consists of:
  - nephrotic-range proteinuria (spot urine showing a protein-to-creatinine ratio > 3 to 3.5mg or albuminuria > 3 to 3.5g/24 hours).
  - hypoalbuminemia < 25 g/L.
  - peripheral oedema.
  - hyperlipidaemia, often present, is not mandatory for diagnosis.

Signs, symptoms, and complications

- Peripheral oedema
  - the main sign of NS, results from decreased oncotic pressure due to albuminuria.
  - edema tends to accumulate in dependent areas, ranging from pedal oedema and morning periorbital oedema to ascites, pleural effusion, or anasarca.
- Foamy urine: due to heavy proteinuria.
- Weight gain: due to fluid retention.
  - although there is often weight gain, a loss of lean body mass is common.
- Hypertension is frequent, although mainly a nephritic feature.
- Symptoms correlate with the oedema extension:
  - anorexia and nausea: due to ascites and gastrointestinal tract oedema.
  - exertion dyspnoea in patients with anasarca or pleural effusion.
- A series of conditions contribute to increased prevalence of both venous (VTE) and arterial thromboembolism (ATE):
  - urinary loss of procoagulant mediators.
  - increased hepatic synthesis of prothrombotic factors and hyperfibrinogenaemia.
  - increased platelet activation.
  - hypoalbuminemia is the most significant independent predictor factor of thrombotic risk, especially for values < 20 g/L.
- Urinary loss of immunoglobulins and complement factors increases infection risk, especially caused by encapsulated bacteria.

Etiology

- NS mostly associated with solid cancer:
  - Membranous Nephropathy (MN) is the most common glomerular disease in cancer patients. Proposed mechanisms include in situ immune complex formation, when anti- cancer antibodies cross-react with podocyte antigens, or circulating immune complex formation and subsequent trapping in glomerular capillaries. Both mechanisms are associated with Immunoglobulin (Ig) G 1 and 2 subtypes deposition on glomeruli (versus IgG 4), > 8 inflammatory cells per glomeruli, and absence of circulating anti- podocyte transmembrane glycoprotein M-type phospholipase A2 receptor (PLA2R) antibodies. Also, nerve epidermal growth factor-like 1 (NELL1) associated MN was recently linked to malignancy and is characterized by incomplete capillary loop staining and IgG1-predominance. MN predominates in gastric and lung cancer, but also occurs in renal cell carcinoma, prostate cancer and thymoma, while rarely associated with hematologic cancer, namely Chronic Lymphocytic Leukaemia (CLL).
  - IgA Nephropathy (IgA-N) is typically present in the form of Berger’s disease, which is limited to the kidney and is characterized by gross or microscopic haematuria and proteinuria. Rarely, it can be revealed by a NS. Proposed mechanisms include intestinal mucosa damage, which could be due to cancer infiltration or alcohol consumption,

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and IgA production by intestinal plasma cells leading to increased circulating IgA level with ulterior mesangial deposits. IgA-N is mostly associated with renal cell carcinoma, Level GradeEvidence

as well as tumours from buccal cavity and respiratory tract, although the latter could be fortuitous or strengthened by alcoholism, a shared risk factor.

- AA Amyloidosis (AAA) has a strong link to renal cell carcinoma. Of all carcinomas associated with amyloidosis, 25%–33% are renal cell carcinomas, although this tumour accounts for only 2%–3% of all carcinomas. The pathophysiology could involve an excessive production of Interleukin 6 by renal tumour cells.
- NS mostly associated with hematologic cancer:
  - Minimal Change Disease (MCD) is the most frequent paraneoplastic manifestation of Hodgkin lymphoma (HL), frequently presenting before the tumour diagnosis. C- maf–inducing protein (c-mip) was recently demonstrated to be selectively induced both in podocytes and in Hodgkin/Reed-Sternberg cells in patients with MCD, but not in patients with HL without MCD, suggesting its potential involvement in the pathogenesis. Other proposed mechanisms include immunologic disorders involving macrophages and TH2 lymphocytes cytokine secretion, namely interleukin 13, which appears to relate to nephrotic-range proteinuria and podocyte injury on kidney biopsy. As far as solid tumours are concerned, MCD is strongly linked with thymoma.
  - Dysproteinaemias result from overproduction of monoclonal immunoglobulin (Ig) and associate with NS through immune deposition phenomena in glomeruli. AIg Amyloidosis is the most common glomerular lesion associated with monoclonal gammopathy, with light chain (AL) amyloidosis being the most common subtype, and should be suspected in patients with NS, axonal neuropathy, and restrictive cardiomyopathy. Monoclonal Ig Deposition Disease (MIDD) is another important group of glomerular deposition disorders. MIDD is often due to light chain deposition, whilst heavy chain disease is associated with heavier proteinuria. Multiple Myeloma is the most common underlying entity, with Waldenström macroglobulinemia, Chronic Lymphocytic Leukaemia and other B cell proliferative disorders also associated.
- Chemotherapy associated NS
  - Thrombotic Microangiopathy (TMA) and Focal Segmental Glomerulosclerosis (FSGS) are both associated with several chemotherapy drugs, most of which by modulation of Vascular endothelial growth factor (VEGF) pathway. VEGF balance was shown to be critical in the development of renal lesion: while overexpression of VEGF leads to a collapsing variant of FSGS, under expression is associated with TMA. VEGF target therapy results in impaired glomerular endothelial fenestrations and massive proteinuria, likely due to inhibition of VEGF production in podocytes. Moreover, both Tyrosine Kinase Inhibitors (TKI) and mammalian target of rapamycin (mTOR) inhibitors interfere with VEGF mediated angiogenesis and associate with NS. Proteinuria is the primary renal manifestation in patients with mTOR inhibition and can have complications such as TMA and FSGS as noted in renal transplant patients. Reported cases of collapsing FSGS developed also during treatment with Interferon (IFN), with earlier NS linked to IFN-α when compared to IFN-ß.
  - Immune checkpoint inhibitors (ICI) are associated with NS in several case reports. MCD has been reported with both pembrolizumab and durvalumab, which block PD-1 and PD-L1 connection, and ipilimumab, an anti-CTLA4 antibody. Proposed mechanisms are based on the rationale that underlying tumour-directed antibodies might be increased by immunotherapy. On these case reports, however, the patients shared previous predisposing conditions for NS, namely prior proteinuria, or exposure to other drugs such as mitomycin C, which has a strong link to TMA. Nonetheless, ICI could precipitate NS in the presence of prior glomerular lesion. MCD has also been described with IFN therapy and associated with complete remission of proteinuria.
- Hematopoietic stem cell transplant (HSCT) associated NS
  - MN accounts for most glomerular diseases following HSCT. Although no clear link has been established, MN has been associated with both chronic graft-versus-host disease (GVHD) T cell mediated activity (in which donor T cells recognize significant histocompatibility complex mismatch) and B cell activity (IgG 3 and 4 subtypes with absent PLA2R antibodies).

Diagnostic Studies

- Regarding cancer related NS, criteria proposed by Ronco et al have served a matrix for establishing the link to malignancy: (i) remission in renal disease occurs after complete surgical removal of the tumour, or with medical anti-neoplastic therapy; (ii) relapse of kidney disease is accompanied by relapse in the cancer; and (iii) a biologic link is established between cancer and kidney disease.
- Initial investigation should include history, physical examination, a complete blood count and chemistry panel.
- Aspot urine protein-to-creatinine ratio can be used instead of 24-hour urine collection to confirm nephrotic-range proteinuria.
- Diagnostic work-up should exclude alternative aetiologies: haemoglobin A1c, hepatitis panel, human immunodeficiency virus panel, rapid plasma regain, serum free light chains with κ per λ ratio, protein electrophoresis, auto-immunity panel with antinuclear antibodies, double-stranded DNA antibodies, Smith antibodies, anti-Ro (SSA) and anti- La (SSB), complement, anti-thrombospondin type-1 domain-containing 7A(THSD7A) and PLA2R).
- Kidney biopsy is considered the “gold standard” for the diagnostic evaluation of glomerular diseases and is mandatory for histologic diagnosis of the underlying lesion. Pathology findings include histology on light and electronic microscopy, as well as immunofluorescence staining.

PMID Nº

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Therapeutic Strategy Level GradeEvidence

PMID Nº

- Although the main treatment regarding NS is correcting the underlying cause, reducing blood pressure (BP) and proteinuria have proven to be key factors in the overall approach, namely symptomatic control.
- When treating peripheral oedema, loop diuretics are the preferred agents, while human albumin should be considered in refractory cases. Dietary sodium intake should be < 2-3 g/day (d) and fluid intake restricted up to 1.5 L/d.
- Like oedema, hypertension and proteinuria management has experienced few changes in the last decade. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are the therapy mainstay and should be used at maximally tolerated dose, with systolic BP <120mmHg being the target for most adult patients. Potassium-wasting diuretics may be useful in optimizing ACEi or ARB titration. Proteinuria goal is variable depending on histologic lesion. Regarding IgAN, renin-angiotensin system should be antagonized irrespective of hypertension if the patient has proteinuria >0.5g/d, while proteinuria <1g/d is a surrogate for improved kidney function in IgAN and therefore a rational target.
- Corticosteroids and other immunosuppressive therapies are often used in NS treatment, even though the clinical benefit is not well established in the literature. When given, corticosteroid tapering should start 2 weeks after NS remission.
  - Regarding MN, immunosuppression is best validated in PLA2R positive NS, which is often not the case in cancer patients. An updated systematic review on immunosuppressive treatment for MN failed to sturdily advocate this strategy in NS control, stating that it is probably superior to non-immunosuppressive therapy regarding remission induction and avoiding end-stage kidney failure. Cyclophosphamide combined with a glucocorticoids regimen had short‐ and long‐term benefits, but this was associated with a higher rate of adverse events. Tacrolimus was non-inferior to cyclophosphamide. Novel treatments with rituximab or adrenocorticotropic hormone require further investigation.
- Nonetheless, in patients with MN and both albuminemia <25g/L and proteinuria >3.5g/d that does not reduce by half after 6 months of ACEi/ARB therapy, a 6-month period of immunosuppression should be equated, according to Executive summary of KDIGO 2021 glomerular diseases guidelines, irrespective of estimated glomerular filtration rate (eGFR), namely with rituximab or cyclophosphamide and alternate month glucocorticoids. Another option could be tacrolimus-based therapy.
  - Patients diagnosed with NS and MCD should be initiated glucocorticoids 1mg/kg with a maximum of 80mg/day. High-dose glucocorticoid treatment for MCD should be given for no longer than 16 weeks. Alternatives include cyclophosphamide, tacrolimus or mofetil mycophenolate.
  - When FSGS is documented in a patient with NS, glucocorticoid therapy should be initiated or a trial of tacrolimus if intolerant to glucocorticoids.
- The tandem around VTE prophylaxis in cancer patients remains an ongoing conversation. When NS takes place, multiple factors add to increasing risk of both VTE and ATE. Hypoalbuminemia is the single most recognized factor which correlates with both VTE and ATE risk. Evidence lacks regarding NS specifically in cancer patients. Prophylactic anticoagulation should be equated when high-risk histologic lesions are found.
  - When NS occurs with MN, patients could be started an anticoagulant or aspirin if there is high risk for bleeding. Aspirin is insufficient to prevent VTE, but warfarin is sufficient to prevent ATE. An algorithm is presented on Executive summary of KDIGO 2021 glomerular diseases guidelines: patients with serum albumin <20g/L with bromocresol purple or <25g/L with bromocresol green are considered high-risk and should be given aspirin irrespective of bleeding risk, plus warfarin or a low-molecular- weight heparin (LMWH) if assessed bleeding risk is low.
  - A systematic review from Lin et al. offers a decision algorithm also based on serum albumin and kidney biopsy, favouring prophylaxis in primary Membranous Glomerulonephritis. Regarding other histology, prophylactic warfarin/LMWH is recommended for all patients with serum albumin <25g/L and low bleeding risk (HAS-BLED 0-1).
- Lipid-lowering agents may be considered in patients with NS and dyslipidaemia, although they have not proven to be beneficial symptom-wise. Similarly, prophylactic antibiotics are not recommended in patients with NS unless glucocorticoid prolonged exposure applies.
ACEi and ARB should be used at maximally tolerated dose for a systolic BP target of <120mmHg. Dietary sodium intake should be reduced to < 2-3 g/d and fluid intake I restricted up to 1.5 L/d.
Regarding IgAN, renin-angiotensin system should be antagonized irrespective of hypertension if the patient has proteinuria >0.5g/d, while proteinuria <1g/d is a I surrogate for improved kidney function in IgAN and therefore a rational target.
In patients with MN, albuminemia <25g/L and proteinuria >3.5g/d that does not reduce by half after 6 months of ACEi/ARB therapy, a 6-month period of I immunosuppression should be equated, with rituximab/cyclophosphamide/tacrolimus and alternate month glucocorticoid, irrespective of eGFR.
High-dose glucocorticoids are suitable for patients with NS and both MCD or FSGS. Patients should be given 1mg/kg with a maximum of 80mg/day, tapered after no I longer than 16 weeks. Tacrolimus could be used as an alternative.
Prophylactic warfarin/LMWH is recommended for all patients with serum albumin <25g/L and low bleeding risk. I
Lipid-lowering therapy should not be initiated solely to treat the manifestations of NS. I
Prophylactic antibiotics are not recommended in patients with NS unless glucocorticoid prolonged exposure applies. I

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B 34556300 34778952

C 34556300

B 34556300 34778952

C 26977832 34556300

References

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Lewis JB, Neilson EG. Glomerular Diseases. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20th ed. McGraw Hill; 2018.
PMID: 26977832: Kodner C. Diagnosis and Management of Nephrotic Syndrome in Adults. Am Fam Physician. 2016;93(6):479-485.
PMID: 30454752: Wang CS, Greenbaum LA. Nephrotic Syndrome. Pediatr Clin North Am. 2019;66(1):73-85. doi:10.1016/j.pcl.2018.08.006
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Kelepouris, E. Rovin, BH. Overview of heavy proteinuria and the nephrotic syndrome. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on February 16, 2022.)
Rosner MH, Perazella MA, Magee, CC. Overview of kidney disease in the cancer patient. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on February 20, 2022.)
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PMID: 16941021: Lefaucheur C, Stengel B, Nochy D, et al. Membranous nephropathy and cancer: Epidemiologic evidence and determinants of high-risk cancer association. Kidney Int. 2006;70(8):1510- 1517. doi:10.1038/sj.ki.5001790
PMID: 33344486: Moroni G, Ponticelli C. Secondary Membranous Nephropathy. A Narrative Review. Front Med (Lausanne). 2020;7:611317. Published 2020 Dec 3. doi:10.3389/fmed.2020.611317
PMID: 32828756: Caza TN, Hassen SI, Dvanajscak Z, et al. NELL1 is a target antigen in malignancy-associated membranous nephropathy. Kidney Int. 2021;99(4):967-976. doi:10.1016/j.kint.2020.07.039
PMID: 18790651: Bacchetta J, Juillard L, Cochat P, Droz JP. Paraneoplastic glomerular diseases and malignancies. Crit Rev Oncol Hematol. 2009;70(1):39-58. doi:10.1016/j.critrevonc.2008.08.003 14.PMID: 30146584: Kitamura M, Hisano S, Kurobe Y, et al. Membranous Nephropathy with Crescent after Hematopoietic Cell Transplantation. Intern Med. 2019;58(1):91-96.

doi:10.2169/internalmedicine.1251-18

PMID: 23103439: Huang X, Qin W, Zhang M, Zheng C, Zeng C, Liu Z. Detection of anti-PLA2R autoantibodies and IgG subclasses in post-allogeneic hematopoietic stem cell transplantation membranous nephropathy. Am J Med Sci. 2013;346(1):32-37. doi:10.1097/MAJ.0b013e318267b5cd
PMID: 17429054: Lai KW, Wei CL, Tan LK, et al. Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats. J Am Soc Nephrol. 2007;18(5):1476-1485.

doi:10.1681/ASN.2006070710

PMID: 20200355: Audard V, Zhang SY, Copie-Bergman C, et al. Occurrence of minimal change nephrotic syndrome in classical Hodgkin lymphoma is closely related to the induction of c-mip in Hodgkin- Reed Sternberg cells and podocytes. Blood. 2010;115(18):3756-3762. doi:10.1182/blood-2009-11-251132
PMID: 29114004: Leung N, Drosou ME, Nasr SH. Dysproteinemias and Glomerular Disease. Clin JAm Soc Nephrol. 2018;13(1):128-139. doi:10.2215/CJN.00560117
PMID: 30918151: Kanzaki G, Okabayashi Y, Nagahama K, et al. Monoclonal Immunoglobulin Deposition Disease and Related Diseases. J Nippon Med Sch. 2019;86(1):2-9. doi:10.1272/jnms.JNMS.2019_86-1
PMID: 23364518: Jhaveri KD, Shah HH, Calderon K, Campenot ES, Radhakrishnan J. Glomerular diseases seen with cancer and chemotherapy: a narrative review. Kidney Int. 2013;84(1):34-44.

doi:10.1038/ki.2012.484

PMID: 30918151: Kanzaki G, Okabayashi Y, Nagahama K, et al. Monoclonal Immunoglobulin Deposition Disease and Related Diseases. J Nippon Med Sch. 2019;86(1):2-9. doi:10.1272/jnms.JNMS.2019_86-1
PMID: 20203164: Markowitz GS, Nasr SH, Stokes MB, D’Agati VD. Treatment with IFN-{alpha}, -{beta}, or -{gamma} is associated with collapsing focal segmental glomerulosclerosis [published correction

appears in Clin JAm Soc Nephrol. 2010 Jul;5(7):1353]. Clin JAm Soc Nephrol. 2010;5(4):607-615. doi:10.2215/CJN.07311009

PMID: 34524642: Wakabayashi K, Yamamoto S, Hara S, et al. Nivolumab-induced membranous nephropathy in a patient with stage IV lung adenocarcinoma. CEN Case Rep. 2022;11(2):171-176. doi:10.1007/s13730-021-00645-3
PMID: 34622115: Toda MG, Fujii K, Kato A, et al. Minimal Change Disease Associated With Durvalumab. Kidney Int Rep. 2021;6(10):2733-2734. Published 2021 Sep 1. doi:10.1016/j.ekir.2021.08.021
PMID: 32257470: Cruz-Whitley J, Giehl N, Jen KY, Young B. Membranoproliferative Glomerulonephritis Associated with Nivolumab Therapy. Case Rep Nephrol. 2020;2020:2638283. Published 2020 Feb 24. doi:10.1155/2020/2638283
PMID: 10411717: Ronco PM. Paraneoplastic glomerulopathies: new insights into an old entity. Kidney Int. 1999;56(1):355-377. doi:10.1046/j.1523-1755.1999.00548.x
PMID: 33121631: Politano SA, Colbert GB, Hamiduzzaman N. Nephrotic Syndrome. Prim Care. 2020;47(4):597-613. doi:10.1016/j.pop.2020.08.002
PMID: 34556300: Rovin BH, Adler SG, Barratt J, et al. Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4):753-779. doi:10.1016/j.kint.2021.05.015
PMID: 32274450: Lin R, McDonald G, Jolly T, Batten A, Chacko B. A Systematic Review of Prophylactic Anticoagulation in Nephrotic Syndrome. Kidney Int Rep. 2019;5(4):435-447. Published 2019 Dec 12.

doi:10.1016/j.ekir.2019.12.001

PMID: 34778952: von Groote TC, Williams G, Au EH, et al. Immunosuppressive treatment for primary membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2021;11(11):CD004293. Published 2021 Nov 15. doi:10.1002/14651858.CD004293.pub4

Evidence

Others Level Grade PMID Nº

- IAdapted from Jhaveri KD, Shah HH, Patel C, Kadiyala A, Stokes MB, Radhakrishnan J. Glomerular diseases associated with cancer, chemotherapy, and hematopoietic stem cell transplantation. Adv Chronic Kidney Dis. 2014;21(1):48-55. Abbreviations: IgG, immunoglobulin G; MN, membranous nephropathy; PLA2 R phospholipase A2 receptor.

Adapted from Lin R, McDonald G, Jolly T, Batten A, Chacko B. A Systematic Review of Prophylactic Anticoagulation in Nephrotic Syndrome. Kidney Int Rep. 2019;5(4):435-447. Published 2019 Dec 12. doi:10.1016/j.ekir.2019.12.001 ; Rovin BH, Adler SG, Barratt J, et al. Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4):753-779. doi:10.1016/j.kint.2021.05.015 Abbreviations: SA, Serum albumin; MN, membranous nephropathy; VTE, Venous thromboembolism

GN tools assessment link: http://www.med.unc.edu/gntools/

NEFROTOXICITY

Author: Telma Santos

The intersections between cancer and kidney diseases are diverse: some examples of these are the renal effects of chemotherapy, or the direct and indirect effects of neoplastic Level GradeEvidence

cells on the kidneys (egs. paraprotein related nephropathy, obstructive uropathy caused by metastatic or intrabdominal tumours, etc). The recognition that cancer patients have a several fold increase in the risk of kidney disease when compared with other patients gave rise to a subspeciality of Onconephrology, that is rapidly evolving in the last years.

The objective of this chapter is to present the most common clinical scenarios of kidney injury in the cancer patients and their management.

Symptoms

Kidney diseases in the cancer patients present the same manner as in other patients.

Acute kidney injury-AKI (an acute rise in serum creatinine or a decrease in urinary output as defined by the KDIGO criteria) can be caused by pre-renal, renal and post-renal factors. In fact, AKI is the most frequent type of kidney disease in cancer patients. Symptoms of AKI are nonspecific, ranging from asymptomatic disease only perceived by an increase in nitrogenous waste products, to nausea, vomiting and a reduction of urinary output perceived by the patient.

Less frequently, cancer cells and cancer therapies can be associated with glomerulonephritis and the nephrotic syndrome. Glomerulonephritis presents with glomerular haematuria, proteinuria of several degrees and hypertension, with or without AKI. Nephrotic syndrome manifests with oedema, nephrotic range proteinuria and hypoalbuminemia.

It is important to recognise that an isolate rise in serum creatinine may represent a progression of a previously non-diagnosed chronic kidney disease, especially in the diabetic patients or those with other CKD risk factors (as cardiac failure or chronic hypertension).

Etiology

AKI is a very common complication of cancer and cancer treatments. On the other side, sometimes it may be the first presentation of a non-diagnosed neoplastic disease (egs: myeloma kidney in multiple myeloma; paraneoplastic glomerular diseases).

Pre-renal factors are the most frequently implicated:

Dehydration secondary to chemotherapy side effects
Sepsis secondary to immunosuppression
Hypercalcemia of malignancy
Use of nonsteroidal anti-inflammatory drugs.

Some specific syndromes of AKI must be considered in Onconephrology:

Tumor lysis syndrome, after chemotherapy or spontaneous – in high grade lymphomas and leukaemia
Light chain cast nephropathy – in multiple myeloma
Thrombotic microangiopathy and different forms of tubular damage – mainly caused by chemotherapy and novel immune therapies (table 3).

PMID Nº

- Less frequently, some solid and hematologic malignancies and some cancer therapies can be associated with glomerulonephritis and the nephrotic syndrome. The pathophysiology of these renal diseases, in the majority of the cases, is not fully understood, but autoimmune processes are thought to be involved, similar to what happens in cancer-associated membranous nephropathy (which pathophysiology has recently emerged to knowledge).

Studies

When a cancer patient has complained that suggest kidney injury, it is important to check and monitor the urinary output, serum creatinine and urea, ionogram, the urine sediment, proteinuria in spot urine and to perform a renal ultrasound (to check signs of chronicity and to exclude obstructive nephropathy).
The findings that are suggestive of pre-renal AKI are – elevated urea/creatinine level; fractional excretion of sodium <1%; normal urinary sediment; rise in urinary output after a trial of fluid therapy.
The findings that are suggestive of tumour lysis syndrome are – AKI PLUS potassium > 6mmol/L, uric acid >8mg/dL, phosphate >4.5mg/dL and calcium <7mg/dL.
Myeloma kidney often presents with AKI and Bence-Jones proteinuria, and an elevated serum free-light chain ratio.
Glomerulonephritis and nephrotic syndrome are associated with abnormal urinary sediment and glomerular proteinuria, therefore, in the presence of these findings, it must be considered asking for expert Nephrology advice.
If CKD is suspected, it is important to check for the previous labs of the patient (serum creatinine, history of low-grade albuminuria in diabetic patients) and if there are signs suggestive of chronicity in the renal ultrasound.

Pharmacotherapy and Therapeutic Strategy Level Grade PMID Nº

There is only a limited number of recommendations based on good quality evidence.

Platinum salts

Before administration of cisplatin, estimate GFR or CrCl. Ensure euvolemia is present. 2 C
Dosage adjusts cisplatin dosage according to the patient’s renal function.
Administer the platinum slowly. Use a saline solution infusion that produces a brisk diuresis. Urine flow should be targeted at 3-4 L/24 h the preceding day and for the next 2-3 days. Do not use diuretics (except for those already on diuretic for other concomitant disease).
After administration, when feasible, determine serum creatinine -5 days after completion of the course. Monitor magnesium levels routinely and supplement when necessary. Avoid co-administration of nephrotoxic drugs. Re-evaluate renal function before the next course.

High-dose methotrexate

Nephrotoxicity is managed with parenteral crystalloid and alkalinization (to provide adequate urine output), high-dose leucovorin, dialysis-based methods of methotrexate 2 C removal, and thymidine. For patients with delayed methotrexate excretion and high plasma concentrations, use of the recombinant enzyme carboxypeptidase-G2 (CPDG2)

cleaves methotrexate to inactive metabolites, potentially lowering plasma methotrexate concentrations.

Angiogenesis inhibitors (i.e., sunitinib, sorafenib)

Patients require regular measurement of blood pressure, urinalysis for early detection of hypertension and proteinuria, and proactive administration of antihypertensive agents 2 C for sufficient control of blood pressure. If proteinuria manifests, temporary withdrawal of angiogenesis inhibitors or continued treatment with reduced doses are reasonable

options; however, in the case of grade 1 proteinuria, for patients with advanced cancer, another option is to continue treatment upon consideration of the risks and benefits. When proteinuria is grade 2 or higher, angiogenesis inhibitors are temporarily withdrawn or reduced, and the patient is treated by a nephrologist as necessary.

Myeloma cast nephropathy

In patients with light chain cast nephropathy, rapidly initiate anti-myeloma therapy with bortezomib-based chemotherapy (such as bortezomib, cyclophosphamide, and I B dexamethasone) rather than other regimens to decrease light chain production.
Start intravenous or oral fluid therapy, to achieve urine output of 3L/24h (+-150ml/h), unless contraindicated (eg, heart failure or persistent oligoanuric AKI). 2 C
Reserve the use of loop diuretics for patients who develop hypervolemia.
In patients with AKI and oliguria, a trial of fluid therapy within 24 hours, should reverse oliguria; if oliguria persists, slow or discontinue fluids to prevent volume overload. 2 C
Discontinue all potentially nephrotoxic agents 2 C
Correct hypercalcemia, if present.
Dialysis should be started for the usual indications and not solely for the removal of free light chains. When these indications are present, then the use of extracorporeal light 2 B chain removal using plasmapheresis or high cut-off haemodialysis is recommended. This is based upon a possible reduction in dialysis dependency among survivors. Extra

corporeal therapy remains to be controversial.

Paraneoplastic glomerular diseases

In the presence of proteinuria or nephrotic syndrome in patients with multiple myeloma or other monoclonal gammopathies, kidney biopsy is generally required to establish a 2 C diagnosis.
Treatment of these disorders should be directed at eliminating the clonal proliferation of plasma cells or B cells that is responsible for producing the pathogenic proteins. 2 C

Tumour lysis syndrome prevention

For all patients at high or intermediate risk, start aggressive fluid hydration (2 to 3 L/m2daily) to achieve a urine output of at least 80 to 100 mL/m2/hour. I A
There is no evidence that urinary alkalinization is of benefit: intravenous administration of sodium bicarbonate should not be routinely used. I B
For the initial management of most paediatric and adult patients at high risk, especially those with impaired renal or cardiac function, use rasburicase rather than allopurinol

(except in G6PD). A single dose of rasburicase (0.2 mg/kg) is recommended rather than multiple-day therapy.

Level Grade PMID Nº

If this single-dose therapy is used, uric acid levels must be monitored closely, and with additional doses given when uric acid level remains high. Allopurinol treatment can also be started once the serum uric acid levels are low or normal.

For the initial management of adult and paediatric patients at intermediate risk, allopurinol rather than rasburicase is recommended, as long as pre-treatment uric acid levels are 2 B not elevated (ie, <8 mg/dL).

However, administration of a single dose of rasburicase (0.15 mg/kg) is a reasonable alternative.

For patients with a low risk, a watch and wait approach with hydration and close monitoring is recommended rather than prophylactic allopurinol or rasburicase. 2 C

Treatment of established tumour lysis syndrome

Patients who present with or develop TLS during therapy should receive intensive nursing care with continuous urine output and cardiac monitoring and measurement of 2 C electrolytes, creatinine, and uric acid every four to six hours.
Effective management involves the combination of treating specific electrolyte abnormalities and/or acute kidney injury, wash out of the obstructing uric acid crystals with IV 2 C fluids and a loop diuretic, and the appropriate use of renal replacement therapy.
If it was not given initially, start rasburicase rather than allopurinol if pre-treatment uric acid levels are ≥8 mg/dL in a single dose strategy rather than multiple-day therapy. I B
Febuxostat may be used in patients with hyperuricemia who cannot tolerate allopurinol in a setting in which rasburicase is not available or is contraindicated. 2 C
Indications for renal replacement therapy include: severe oliguria or anuria, refractory severe hyperkalaemia, hyperphosphatemia-induced symptomatic hypocalcaemia or a I A calcium-phosphate product ≥70 mg2/dL2.

Immune checkpoint inhibitor (ICPI)

Patients who develop stage 1 AKI should be evaluated for reversible causes of renal injury–such as prerenal azotaemia, urinary obstruction, or drug-induced injury from other 2 C agents –and ICPI therapy should be held until the AKI has resolved.
Patients with persistent stage 1 AKI, and those who develop stage 2 or 3 AKI, should be referred to nephrology for consultation and consideration of kidney biopsy.

In the setting of suspected ICPI-AKI, in which an effective therapy exists for most patients (i.e., glucocorticoids), there is a temptation to treat empirically without a biopsy. However, kidney biopsy is important in most cases to definitely diagnose the lesion and potentially guide therapy.

ICPI discontinuation (at least temporary) and corticosteroid therapy are recommended for acute tubulointerstitial nephritis.
The use prednisone 1 mg/kg daily as a starting dose, with a slow taper over 2–3 months is recommended. Rapid tapers may lead to AKI recurrence; however, in some patients with side effects from steroids, shorter tapers can be considered. In patients with severe ICPI-AKI requiring inpatient hospitalization, intravenous steroids (e.g., methylprednisolone 250–500 mg daily for 3 days) may be used as initial therapy.
Regardless of the treatment strategy, prompt initiation of immunosuppressive therapy in patients with ICPI-AKI is recommended.
It is unclear whether re-exposure is appropriate; it should perhaps be considered in patients with limited therapeutic options. When this approach is taken, patients should be closely monitored for recurrence of acute kidney injury.

KIDNEY FUNCTION ASSESSMENT

Author: Nuno Figueiredo

Introduction

Importance of Kidney function evaluation in oncology:

- - Adjustment of dose in kidney-excreted drugs
  - Identify acute kidney injury (AKI) linked to cancer or its treatment
  - Determine a baseline status to monitor any future changes
  - Determine eligibility for clinical trials of novel agents.

Evidence

Level Grade PMID Nº

Nevertheless, 2 main problems remain unsolved:

- - How to adequately measure or estimate the glomerular filtration rate (GFR) in cancer patients.
  - How to spot a kidney damage that also include tubular dysfunction and even vascular dysfunction.

Anticancer drugs have a narrow therapeutic index, many of which exhibit decreased clearance with impaired kidney function. Consequently, accurate patient-specific dosing and agent selection based on drug clearance and exposure are crucial to ensure safety while maintaining anticancer activity.

- - Overestimation of kidney function may lead to overdosing or inappropriate agent selection, leading to a corresponding increase in toxicity.
  - Underestimation of kidney function may lead to underdosing or inappropriate agent exclusion, leading to therapeutic failure.

ASSESSMENT OF GFR (Glomerular Filtration Rate) IN CLINICAL PRACTICE

GFR is measured by renal clearance techniques, which estimate the volume of plasma from which a particular substance can be totally cleared in each time. GFR may be:

- - Measured (mGFR) directly by determining clearance of exogenous markers, although this is not clinically practical due to time, cost, and convenience.
  - Estimated (eGFR) based on endogenous serum creatinine (SCr) values.(1-3 )One way of determining kidney function has been to use creatinine clearance (CrCl), reported in milliliters per minute, as surrogate for GFR. The Cockcroft-Gault (CG) formula is now, the bedside equation for estimated CrCl (eCrCl). Nevertheless, this equation is imprecise due to its inability to adequate make up for several non-GFR determinants of SCr.(4,5,6), the CG formula has been widely used into clinical practice owing to its convenience and perceived accuracy and has become the most common measure by which recommendations for kidney function-based drug dosing and agent selection are made.(7 )

Improved methods for eGFR have been developed in the last 20 years:

- - The Modification of Diet in Renal Disease (MDRD) Study equation
  - The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)

The CKD-EPI cystatin C equations.(1,3,5,8,9)These equations determine eGFR values closer to the true GFR compared to the CG formula, mainly for older patients. and report eGFR indexed for body surface area (BSA) in milliliters per minute per 1,73 m2. The CKD-EPI equation is recommended for use in routine clinical, but this recommendation has not yet been fully adopted by many non-nephrology specialties, including oncology.(10-12) The models for GFR estimation were not developed in cancer populations, patients with advanced cancer may suffer from sarcopenia even before treatment and the reduction of muscle mass develops during treatment in as many as 70% of patients. Consequently, their usefulness in oncological settings remains uncertain.(13)

KIDNEY FUNCTION ESTIMATES IN PATIENTS WITH CANCER

Patients with cancer frequently present with underlying impaired kidney function. Over one half and up to one fifth of patients with solid tumors have eCrCl (milliliters per minute) or eGFR (milliliters per minute per 1.73 m2) values of <90 and <60, respectively.(14) These numbers likely underestimate the true prevalence of decreased GFR in patients with cancer, due to the studies from which they were created excluded patients with hematological malignancies, which have a high frequency of kidney impairment. Cancer rates are steadily increasing, 18.1 million new cases of cancer in 2018 alone.(15) Of these, patients with solid cancers are commonly older, who frequently suffer from CKD. Thus age-based modifications to the definition of CKD have been suggested.(16 )

Precisely measuring GFR and determining kidney function becomes patently important when considering that many cancers chemotherapeutic drug have narrow therapeutic windows. As such, small over- or underestimations of kidney function may lead to overdosing with serious toxicity, while underdosing will lead ineffectively low plasma drug levels, inappropriate agent selection or disqualification from a treatment protocol. An example is with platinum derivatives (e.g., carboplatin) for which dose are calculated using the historical Calvert formula, which determines a target area under the plasma drug concentration-time curve (AUC) by using measured GFR or eGFR. (17)

CKD-EPI equation adjusted for BSA was the most accurate and least biased estimate of GFR currently used in patients with cancer, when compared with radio isotopic clearance with 51Cr-EDTA.(18 )

When assessing the change of GFR, is necessary to differentiate disease and/or treatment-related change from intrinsic biological and analytical variation. The within-subject biological variation in mGFR was like that in eGFR, implying no disadvantage to the use of simple estimates of GFR when monitoring patients over time.(22 )

Level Grade PMID Nº

Cystatin C is considered an alternative filtration marker for eGFR and is favoured by some to creatinine-based equations or CrCl used in obese or malnourished noncancer Level Grade PMID Nº

patients. Cancer cells may, however, produce cystatin C, leading to an underestimation of GFR, and remains of uncertain use in cancer patients.(23)(The CKD-EPI or the Janowitz formula gives a better estimate of GFR.(25)

When taken together, based on the available evidence, the use of the CKD-EPI equation adjusted for BSAseems the best option among creatinine-based equations.(3 )

Several clinical oncology groups, including the International Society of Geriatric Oncology (SIOG) and the National Comprehensive Cancer Network (NCCN), recommend an assessment of kidney function to adjust dose an reduce toxicity before chemotherapy, even when SCr is within normal range. However, there are currently no universal guidelines stating which method of estimating kidney function is preferred in patients with cancer. The NCCN vaguely recommends use of SCr in their guidelines concerning elderly adults and “GFR calculations” in their guidelines related to adolescent and young adults (see NCCN tables to identify recommendation and evidence), whereas the SIOG does not state a preferred estimation method.(26-28) Many oncology clinicians continue to use CG-based eCrCl to guide anticancer drug dosing for kidney function and selection, and some groups and investigators even use multiples of SCr upper limit of normal to determine enrolment in clinical trials.(29 )

Many anticancer drugs are routinely dosed according to BSA in an effort to account for the effect of body size on pharmacokinetics, although this often does nothing to reduce variability in exposure.(30 )The most commonly method of estimating kidney function in oncology remains the CG formula that is not indexed to BSA. This is problematic, because small patients will be penalized for having a low absolute kidney function, although their drug dose will already accommodate this size difference. In a post hoc analysis of a study using the CG formula (millilitres per minute) to stratify oxaliplatin-treated patients, with impaired kidney function, to develop dosing guidelines, it was revealed that BSA indexing of eCrCl (millilitres per minute per 1.73M2) did alter dose classification of several patients versus absolute eCrCl classification. Although this re-classification did not change the results of dose guidelines for kidney function determined by the study, it does show that dose stratification of patients can be affected by whether values of kidney function are indexed for BSA, and this can have potential clinical implications.(31,32) Therefore, it would seem pertinent to use BSA-indexed estimates of kidney function for drugs dosed by BSAand to use absolute estimates of kidney function (not BSA-indexed) for drugs that are dosed absolutely so that the units are congruent.(29)

eGFR equation(ref.)	Formula
Cockcroft- Gault6	[(140-Age) x BW/SCr x72] x (0,85 if female)
CKD-EPI9	142 x min (SCr/kappa, 1) alpha x max (SCr /kappa,1)-1.2 x 0,9938Age x Sex Factor -Females: Sex Factor=1,012; alpha=-0,241; kappa=0,7 -Males: Sex Factor=1; alpha=-0,302; kappa=0,9
MDRD42	175 x (SCr)-1,154 x (Age)-0,203 x 0,742 (if female) x 1,212 (if Black)
Janowitz & Williams18	√GFR = 1,8140 + 0,01914xAge + 4,7328xBSA – 3,7162xlog (SCr) – 0,9142xlog (SCr)2 + 1,0628xlog (SCr)3 – 0,0297xAge x BSA + (if Male: 0,0202 + 0,0125xAge)

ASSESSMENT OF RENAL FUNCTION IN AKI DUE TO CANCER OR ITS TREATMENT

All eGFR equations have been developed in CKD patients and assume a stable state of kidney function, which is the antagonism of AKI.33 AKI is a highly dynamic state with a rapid decline in GFR, and consequently the creatinine-based formulas may become less precise. Furthermore, due to renal damage starts from the tubules, a rise in SC and eGFR changes are relatively late. Moreover, an increase in single nephron GFR may compensate for a decrease in nephron number.

To overcome these limitations, several urinary markers have been proposed:

- - - neutrophil gelatinase-associated lipocalin (NGAL), proinflammatory cytokines (interleukin-6 and -8),
    - kidney injury molecule-1, and cell cycle markers such as urinary tissue inhibitor of metalloproteinases-2
    - Insulin-like growth factor-binding protein-7.(34-36)

Presently no evidence is available on its use in oncological settings, although the direct production of NGAL in cancer may limit its use as marker of tubular damage. Likewise, Level Grade PMID Nº

plasma uric acid is, again, ineffective to establish kidney function in cancer patients. (37)

Recently a simple way to assess tubular function consists in determining fasting urine osmolarity.38When tubular damage appears, eGFR may be normal whereas the first sign of kidney injury is the reduced ability to concentrate urine. This method is inexpensive and simple and can be done at bedside.

MEASURING GFR IN REAL TIME (FLUORESCENCE METHODS)

A new approach for real-time mGFR has been proposed, the ratio of large and small dextran’s in plasma level (hematic sample or skin capillaries) and urine level 39-41 At present, this technology is only available in animal models.

TOTAL NUMBER OF NEPHRONS AND RENAL RESERVE

Distinguishing the functional from structural cause of the GFR decline is clinically important for the nephron-oncologist to establish a prognosis and a therapy. Two main methods are now available, but so far, none of them has entered oncological practice:

- - Kidney biopsy: measuring of density of intact glomeruli and tubules (fractal dimension). In a study by Nigro et al, eGFR correlated with the tubular density across dif ferent glomerular conditions.(37) No data are available in oncological settings.
  - Stimulate kidney function and measure the consequent increase in GFR, like the heart stress test used by cardiologists. A study in renal reserve is available in oncology.(4) Unfortunately, the method is inconvenient.

SUMMARY

Estimation of kidney function in patients with cancer directly influences drug dosing, agent selection, and eligibility for clinical trials of novel agents. It would seem clear that the most accurate estimates of kidney function should be used to reduce unexplained variability in decision making and ultimately, the therapeutic outcomes of toxicity and clinical benefit. There are many discrepancies between eGFR and true GFR, highlighting the demand for additional studies investigating the validity of currently used formulas and clinical harmonization of kidney function estimates across all patients with cancer.

References

1-Hudson JQ,Nolin TD: Pragmatic use of kidney function estimates for drug dosing: The tide is turning. Adv Chronic Kidney Dis 25: 14–20, 2018

Launay-et al; Renal Insufficiency and Cancer Medications (IRMA) Study Group: Prevalence of renal insufficiency in cancer patients and implications for anticancer drug management: The renal insufficiency and anticancer medications (IRMA) study. Cancer 110: 1376–1384, 2007
Levey AS, Inker LA, Coresh J: GFR estimation: From physiology to public health. Am J Kidney Dis 63: 820–834, 2014
Launay-Vacher V, Chatelut E, Lichtman SM,Wildiers H, Steer C, Aapro M; International Society of Geriatric Oncology: Rena insufficiency in elderly cancer patients: International Society of Geriatric Oncology clinical practice recommendations. Ann Oncol 18: 1314–1321, 2007
Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, Kusek JW, Manzi J, Van Lente F, Zhang YL, Coresh J, Levey AS; CKD-EPI Investigators: Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 367: 20–29, 2012
CockcroftDW,GaultMH:Predictionof creatinine clearance from serum creatinine. Nephron 16: 31–41, 1976
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Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F; Chronic Kidney Disease Epidemiology Collaboration: Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 145: 247–254, 2006
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration): A new equation to estimate glomerular filtration rate. Ann Intern Med 150: 604–612, 2009
GroupKDIGO KCW: KDIGO2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 3: 1–150, 2013
Inker LA, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA, Kurella Tamura M, Feldman HI: KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis 63: 713–735, 2014
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13 . Jolanta Malyszko et al: How to assess kidney function in oncology patients. Kidney International 2020

JanusN, Launay-VacherV, Byloos E,Machiels JP,Duck L, Kerger J, WynendaeleW, Canon JL, LybaertW,Nortier J,DerayG, Wildiers H: Cancer and renal insufficiency results of the BIRMA study. Br J Cancer 103: 1815–1821, 2010
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Hommos MS, Glassock RJ, Rule AD. Structural and functional changes in human kidneys with healthy aging. JAm Soc Nephrol. 2017;28:2838–2844.
Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989;7:1748–1756.
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Lamb EJ, Stevens PE. Estimating and measuring glomerular filtration rate: methods of measurement and markers for estimation. Curr Opin Nephrol Hypertens. 2014;23:258–266.
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Coresh J, Inker LA, Sang Y, et al. Metabolomic profiling to improve glomerular filtration rate estimation: a proof-of-concept study. Nephrol Dial Transplant. 2019;34:825–833.
Rowe C, Sitch AJ, Barratt J, et al. Biological variation of measured and estimated glomerular filtration rate in patients with chronic kidney disease. Kidney Int. 2019;96:429–435.
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KIDNEY DISORDERS

Author: Ritu Dave

Introduction

Cancer has now become a chronic disease with the advances in treatment happening at a rapid pace leading to an increase in the overall survival rates of cancer patients. Hence an increasing number of cancer patients are at risk of developing kidney diseases either due to the malignancy or its treatment.

This chapter focuses on the spectrum of kidney diseases that may affect a patient with cancer at some point in their care journey. This spectrum includes acute kidney injury (AKI), chronic kidney disease (CKD), glomerular disorders (nephrotic syndrome, proteinuria) and various electrolyte disorders.

Epidemiology of kidney disease in cancer patients

AKI: defined as an increase >50% in serum creatinine,
- - 27% of patients developed AKI and 7.6-10% of patients developed severe AKI and AKI requiring dialysis support over a period of 5 years. The highest risk of AKI was among patients with kidney cancer, liver cancer and multiple myeloma (MM).(1, 2)
CKD :
- - CKD may pre-exist in a substantial number of patients with cancer. This is likely because of comorbid conditions, such as diabetes mellitus and hypertension, that are highly prevalent in the population. CKD and ESRD appear to be risk factors for the development of kidney cancer and urothelial cancer.
  - A substantial proportion of the cancer population had clinically significant CKD that might affect care (such as drug dosing).(3)
  - Patients with breast cancer, lung cancer, prostate cancer, gynaecologic cancer, and colorectal cancer had a glomerular filtration rate (GFR) ≥90 mL/minute/1.73 m2 at the time of therapy initiation between 38,6% and 27,6%. (4,5)

Etiology

Table 1. Causes of kidney disease in cancer patients:

Evidence

Level Grade PMID Nº

Causes	Mechanisms
Antineoplastic drugs -Chemotherapeutic agents -Targeted therapies	-Direct nephrotoxicity (e.g., cisplatin) -Hypertension and/or proteinuria (e.g., VEGF[Rs]-targeted agents) -TMA (e.g., VEGF-targeted agents) -Interstitial nephritis and other glomerulonephritis -Autoimmune nephropathies (e.g., anti-CTLA4 and anti-PD1/PDL1 antibodies) -Indirect toxicities (e.g., nausea/vomiting, diarrhea, dysgeusia) leading to dehydration/volume depletion
Other drugs used in cancer patients -Anti-pain drugs -Bisphosphonates	-Direct nephrotoxicity (e.g., NSAIDs, bisphosphonates)
Radiation therapy	-Still ill defined
Contrast medium	-Direct nephrotoxicity
Paraneoplastic renal syndromes	-Autoimmune mechanism

VEGF(Rs), vascular endothelial growth factor (receptors); TMA, thrombotic microangiopathies; CTLA4, cytotoxic T-lymphocyte antigen 4; PD1, programmed cell death 1;


Nephrectomy -For cancer -For other causes	-Loss of nephrons -AKI
Obstruction/compression	Mechanical injury Tumour causing Bladder outlet obstruction
Tumour Infiltration	-Kidney infiltration
Comorbidities	-Hypertension -Pre-existing CKD -Diabetes mellitus -AKI -Previous use of nephrotoxic cancer therapies

PDL1, programmed cell death ligand 1; NSAIDs, nonsteroidal anti-inflammatory drugs. Adapted from American society of Nephrology

Evidence Level Grade PMID Nº

AKI

Definition:

The Kidney Disease: Improving Global Outcomes (KDIGO)guidelines define AKI as follows (6):

-Increase in serum creatinine by≥0.3 mg/dL (≥26.5 micromol/L) within 48 hours, or

-Increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the prior seven days, or

-Urine volume <0.5 mL/kg/hour for six hours

Staging:

Using the kidney disease: Improving Global Outcomes (KDIGO) criteria, AKI is staged as follows (6):

Stage 1- Increase in serum creatinine to 1.5 to 1.9 times baseline or increase in serum creatinine by ≥0.3 mg/dL (≥26.5 micromol/L), or reduction in urine output to <0.5 mL/kg/hour for 6 to 12 hours.

Stage 2 – Increase in serum creatinine to 2.0 to 2.9 times baseline, or reduction in urine output to <0.5 mL/kg/hour for ≥12 hours.

Stage 3 – Increase in serum creatinine to 3.0 times baseline or increase in serum creatinine to ≥4.0 mg/dL (≥353.6 micromol/L), or reduction in urine output to <0.3 mL/kg/hour for≥24 hours, or anuria for ≥12 hours, or the initiation of kidney replacement therapy, or, in patients <18 years, decrease in estimated glomerular filtration rate (eGFR) to <35 mL/min/1.73 m2.

Causes of AKI (7):

Spectrum of Glomerular Pathology in Cancer Patients:

Fig 1. Causes of AKI. ACE-I, Angiotensin converting enzyme inhibitors;

NSAIDS, Non-steroidal anti-inflammatory drugs Adapted from J Am Soc Nephrol 16: 151-161, 2005

Figure 2. Glomerular Diseases Associated with Solid Tumours and Hematologic Malignancies. CLL indicates chronic lymphocytic leukaemia; FSGS, focal segmental glomerulosclerosis; GN, glomerulonephritis; MGUS, monoclonal gammopathy of unclear significance; MN, membranous nephropathy; MPGN, membranoproliferativ glomerulonephritis. Adapted from: Jhaveri, 2015.166

CKD

Definition:

CKD is defined as abnormalities of kidney structure or function, present for > 3 months, with implications for health. Criteria for CKD (either of the following present for > 3 months) (8)

1. Markers of kidney damage (one or more)
Albuminuria (Albumin excretion rate (AER) > or =30 mg/24 hours; Albumin-to-creatinine ratio (ACR) > or =30 mg/g [> or = 3 mg/mmol])
Urine sediment abnormalities
Electrolyte and other abnormalities due to tubular disorders
Abnormalities detected by histology
Structural abnormalities detected by imaging History of kidney transplantation
1. Decreased GFR: GFR < 60 ml/min/1.73 m2 (GFR categories G3a–G5)

CKD classification based on GFR and Albuminuria (8):

Table 2: GFR stages and Albuminuria stages

AER, Albumin Excretion Rate; Adapted from Kidney International Supplements (2013)

Evidence

Level Grade PMID Nº

.Causes of CKD (9):

-Prior episodes of acute kidney injury

-Nephrotoxic anticancer agents

-Reduction in kidney mass following nephrectomy for renal cell (RCC) or urothelial cancers

-Chronic obstructive nephropathy

-Kidney irradiation

Level Grade PMID Nº

Figure 3: Risk Factors for Development of Chronic Kidney Disease (CKD) in Patients With Malignancy. GFR indicates glomerular filtration rate. Adapted from CA CANCER J CLIN 2021;71:47–77

Causes of AKI and CKD following Hematopoietic stem cell transplantation (HSCT) (9):

Figure 4: Aetiologies of Acute Kidney Injury and Chronic Kidney Disease with Hematopoietic Stem Cell Transplantation. BK indicates BK polyomavirus.

Adapted from CA CANCER J CLIN 2021;71:47-77

Symptoms and Signs of AKI/CKD:

•Uremic symptoms: anorexia, nausea, vomiting, metallic taste, and altered mental status, oedema, pericardial rub.

•Volume overload.

•Acid base disturbances: Metabolic acidosis/alkalosis.

•Electrolyte imbalance.

•Hyponatremia, Hyperkalaemia, Hypocalcaemia, Hyperphosphatemia, Hypomagnesemia/ Hypermagnesemia, Hyperuricemia.

•Hypertension / Hypotension.

Anaemia.
Dyslipidaemia.
Uremic bleeding – due to impaired platelet function.

•Symptoms related to the underlying cancer.

Investigations:

Creatinine: Serum creatinine levels only roughly track with the GFR because of factors such as age, gender, muscle mass, meat intake, race, and intake of creatine supplements. (10) In addition, a significant proportion (range, 10%-40%) of creatinine excretion in the urine is because of proximal tubular secretion, which can lead to erroneous overestimation of the GFR if only the serum creatinine is used. Thus, clinically significant falls in GFR that may affect drug clearance may not be detectable by rises in serum creatinine. Finally, serum creatinine is an insensitive indicator of kidney function, as patients can lose significant amounts of GFR without changes in creatinine values, and the changes in serum creatinine can lag from 24 to 72 hours after a kidney insult. (11)
Estimation of GFR:There are two principal pathways for drug excretion by the kidney: glomerular filtration and tubular secretion. Glomerular filtration plays a major role with non-protein-bound small molecules (ie, of a size that can pass through the glomerular capillary wall). Such molecules cannot be filtered if they are protein bound in the circulation; these drugs, if they are renally excreted, enter the urine by secretion in the proximal tubule.

For those drugs in which renal excretion is an important determinant of elimination of the intact drug or an active metabolite, dose adjustment is often required if kidney function is impaired. Although the prevalence of an elevated serum creatinine is low in cancer patients (<10 percent), the prevalence of a reduced glomerular filtration rate (GFR) is relatively high (50 to 53 percent in two cohort studies) (12,13)

Dose adjustment is typically based upon two factors: an estimation of GFR, which serves as an index of the number of functioning nephrons, and evaluation of clinical signs of drug toxicity (e.g., neutropenia, thrombocytopenia). Clinicians should use the method to estimate GFR that provides the most accurate assessment of GFR (14-16). A creatinine clearance (CrCl) calculation based upon a 24-hour collection of urine is cumbersome and subject to error due to incomplete urine collection. Estimation equations for CrCl (e.g., Cockcroft-Gault) and estimates of GFR using the Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations based upon a stable serum creatinine concentration also correlate with the measured GFR. These three methods are now the most common methods used in routine clinical practice to estimate kidney function, due primarily to convenience.

There is currently no consensus on the optimal formula to estimate GFR in cancer patients. While some suggest that all bedside formulae provide similar levels of concordance in estimation of GFR for the purpose of dosing renally excreted cancer drugs (17), others consider the Cockcroft-Gault formula to be the least precise and body surface area (BSA)- adjusted CKD-EPI to be the most accurate (16,18)

One exception is the use of a dose-determining formula based on GFR (Calvert formula). This formula uses a drug target area under the curve (AUC) as well as the GFR to calculate a drug dose. This approach has been well documented for carboplatin dosing, with a target AUC of 4 to 6 mg/mL/minute determined to be the most appropriate therapeutic range. (19)

- Urinalysis :24-hour urine collection to determine total protein excretion in patients with glomerular disease. Early morning urine sample (preferred) for
1. urine albumin-to-creatinine ratio (ACR);
2. urine protein-to-creatinine ratio (PCR)
3. other urinary sediments
- Measurement of serum electrolytes – sodium, potassium, calcium, phosphate, magnesium, uric acid
- Arterial blood gas analysis to look for metabolic acidosis
- Renal Biopsy to establish a specific diagnosis

•Specific tests pertaining to establishing the cause of the renal dysfunction e.g.: Serum protein electrophoresis with immunofixation, Serum free light chain assay, Bone marrow examination for diagnosis of multiple myeloma

- Special mention of Tumour Lysis Syndrome:

Tumour lysis syndrome describes the metabolic complications of either rapid tumour cell turnover or chemotherapy-induced tumour cell lysis. The syndrome is characterized by hyperuricemia, hyperphosphatemia, hypocalcaemia, hyperkalaemia and ARF (20,21) .TLS is defined both by laboratory criteria and by clinical features.

Level Grade PMID Nº

Table 3: Cairo Bishop Definition of Laboratory TLS:

Clinical tumour lysis syndrome defined as laboratory tumour lysis syndrome plus at least one clinical complication which includes

– AKI OR

Seizures OR
Cardiac arrhythmias
- Pathophysiology:

Two forms of ARF are thought to occur but may coexist: ARF associated with large increases in plasma uric acid and with large increases in plasma phosphate. The pathophysiology of uric acid nephropathy includes intratubular precipitation of uric acid causing mechanical obstruction, direct toxicity to epithelial and endothelial cells, and potentially activation of the innate immune system (22-24). The pathos physiology of hyperphosphatemia associated ARF is thought to involve intrarenal calcium phosphate precipitation and direct tubular toxicity of phosphate (25,26).

Prevention and Management of Hyperuricemia:

Figure 6: Treatment algorithm for prevention and management of hyperuricemia.

Adapted from J Clin Oncol 26:2767-2778.

Level Grade PMID Nº

~~Mechanisms of renal toxicity in tumour lysis syndrome~~

Figure 5: Renal toxicity in TLS.

Table 4: Anti-cancer drug related nephrotoxicity:

Level Grade PMID Nº

Chemotherapeutics	Clinical kidney syndrome	Histopathology	Prevention	Treatment
Gemcitabine, mitomycin C, or cisplatin (rare)	Acute kidney injury: hypertension (new or worsened); haematuria; proteinuria	Thrombotic microangiopathy	Gemcitabine should be used with caution in patients with renal insufficiency	Drug discontinuation and supportive care; if drug-induced thrombotic microangiopathy does not improve, the use of eculizumab (C5 inhibitor) should be considered
Platins (cisplatin, carboplatin, or oxalaplatin)	Acute kidney injury; thrombotic microangiopathy; Fanconi-like syndrome; nephrogenic diabetes insipidus; syndrome of inappropriate antidiuresis; Na⁺ and Mg²⁺ wasting with hypomagnesaemia	Acute tubular injury and vasoconstriction in the renal microvasculature	Intravenous fluids with K⁺ and Mg²⁺; dose adjustment; substitution of cisplatin with a less toxic carboplatin; repeat courses of cisplatin should not be given until serum creatinine is <1·5 mg per day	Discontinuation of cisplatin; treatment of hypomagnesaemia with high-dose magnesium sulphate might be required since raising the plasma Mg²⁺ increases urinary Mg²⁺ wasting
Ifosfamide	Acute kidney injury; proximal tubulopathy (hypophosphatemia, Fanconi syndrome, renal tubular acidosis type 2); distal tubulopathy (renal tubular type 1, nephrogenic diabetes insipidus); syndrome of inappropriate antidiuresis	Acute tubular injury and acute interstitial nephritis (rare)	Intravenous fluids; dose adjustment; reducing the cumulative Ifosfamide dose	NA
Pemetrexed	Acute kidney injury; proximal tubulopathy; Fanconi syndrome; renal tubular acidosis type 2; nephrogenic diabetes insipidus	Acute tubular injury, interstitial edoema, and interstitial fibrosis	Intravenous fluids: CT scans with contrast should be done a few days to 1 week after pemetrexed administration	NA
Methotrexate	Acute kidney injury; syndrome of inappropriate antidiuresis	Crystalline nephropathy and acute tubular injury	Dose reduction; intravenous fluids; urinary alkalinisation; high dose leucovorin, suspending medications that interfere with methotrexate clearance	Continuing to administer alkalinised intravenous fluids with the addition of acetazolamide to keep urine pH >7; use of extracorporeal techniques has mixed results; use of glucarpidase in patients with delayed methotrexate clearance due to impaired renal function (toxic methotrexate plasma concentrations >1 µM despite adequate preventive measures)
Anti-metabolites (azacytidine, capecitabine, clofarabine, fludarabine, 5-fluorouracil, mercaptopurine, or thioguanine)	Acute kidney injury; Fanconi syndrome; nephrogenic diabetes insipidus	Acute tubular injury	Intravenous fluids; dose reduction	NA
Vincristine or cyclophosphamide	Syndrome of inappropriate antidiuresis; haemorrhagic cystitis (cyclophosphamide)	No renal histopathological lesion	Intravenous fluids; use mesna to reduce haemorrhagic cystitis with cyclophosphamide	NA
Targeted Therapies
Anti-VEGF drugs (bevacizumab or aflibercept)	Acute kidney injury: proteinuria (might be nephrotic); hypertension	Thrombotic microangiopathy	NA	Treatment of thrombotic microangiopathy with drug discontinuation and supportive care
Tyrosine kinase and multikinase inhibitors (sunitinib, sorafenib, pazopanib, or imatinib)	Acute kidney injury; proteinuria; hypertension	Thrombotic microangiopathy, focal segmental glomerulosclerosis, acute interstitial nephritis, and acute tubular injury (all these histopathology’s have	NA	Treatment of thrombotic microangiopathy with drug discontinuation and supportive care

Targeted Therapies
Anti-VEGF drugs (bevacizumab or aflibercept)	Acute kidney injury: proteinuria (might be nephrotic); hypertension	Thrombotic microangiopathy	NA	Treatment of thrombotic microangiopathy with drug discontinuation and supportive care
Tyrosine kinase and multikinase inhibitors (sunitinib, sorafenib, pazopanib, or imatinib)	Acute kidney injury; proteinuria; hypertension	Thrombotic microangiopathy, focal segmental glomerulosclerosis, acute interstitial nephritis, and acute tubular injury (all these histopathology’s have been seen with imatinib)	NA	Treatment of thrombotic microangiopathy with drug discontinuation and supportive care
BRAF inhibitors (vemurafenib or dabrafenib)	Acute kidney injury; electrolyte disorders	Acute tubular injury, allergic acute, and interstitial nephritis	NA	NA
ALK inhibitors (crizotinib)	Acute kidney injury; electrolyte disorders; hypophosphatemia; proteinuria; haematuria; renal microcysts on ultrasound	Acute tubular injury and acute interstitial nephritis	NA	NA
Rituximab	Acute kidney injury (in tumour lysis syndrome); electrolyte disturbances	Crystalline (uric acid) nephropathy and acute tubular injury	Intravenous fluids	NA
Immunotherapy
Interferons	Acute kidney injury; nephrotic proteinuria	Thrombotic microangiopathy and focal segmental glomerulosclerosis	NA	Treatment of thrombotic microangiopathy with drug discontinuation and supportive care
IL-2 (high dose)	Capillary leak syndrome with acute kidney injury (prerenal injury or acute tubular injury	No kidney lesions (prerenal) or acute tubular injury	Intravenous fluids; reduce NSAID exposure	NA
CTLA-4 inhibitors (ipilimumab)	Acute kidney injury; proteinuria	Acute interstitial nephritis, lupus-like glomerulonephritis, acute tubular injury, minimal change disease, and thrombotic microangiopathy	Consider low-dose steroids with drug re-exposure	Treatment of thrombotic microangiopathy with drug discontinuation and supportive care
PD-1 inhibitors (nivolumab or pembrolizumab)	Acute kidney injury; proteinuria; electrolyte disorders	Acute interstitial nephritis, acute tubular injury, minimal change disease, immune complex glomerulonephritis, and thrombotic microangiopathy	Consider low-dose steroids with drug re-exposure	Treatment of immune-related nephrotoxicity with drug discontinuation and supportive care; use of systemic steroids (depending on the severity of symptoms)
CAR T cells	Cytokine release syndrome complicated by capillary leak syndrome with acute kidney injury (prerenal injury or acute tubular injury); electrolyte disorders	No pathology or acute tubular injury	Reduce tumour burden with chemotherapy and steroid prophylaxis prior to CAR T-cell therapy; IL-6 receptor antagonism when cytokine release syndrome is severe	NA
Other Cancer drugs
Pamidronate	Nephrotic syndrome; acute kidney injury	Focal segmental glomerulosclerosis and acute tubular injury	Dose adjustment; increase infusion time	NA
Zoledronate	Acute kidney injury; nephrotic syndrome (rare)	Acute tubular injury	Dose adjustment; increase infusion time; contraindicated when GFR is <30 mL/min	NA

Na⁺=sodium ion. Mg²⁺=divalent magnesium ion. K⁺=potassium ion. NA=not available. NSAID=non-steroidal anti-inflammatory drugs. CAR=chimeric antigen receptor. GFR=glomerular filtration rate. Adapted from Lancet 2020; 396: 277–87

Treatment Options Level GradeEvidence

PMID Nº

Referral to a nephrologist at the onset of renal dysfunction is advised for further management in collaboration with the primary treating oncologist.

AKI

-In the absence of haemorrhagic shock, isotonic crystalloids rather than colloids (albumin or

starches) are used as initial management for expansion of intravascular volume

-use of vasopressors in conjunction with fluids in patients with vasomotor shock

-not using diuretics to treat AKI, except in the management of volume overload.

-administering 0.8–1.0 g/kg/d of protein in non-catabolic AKI patients without need for dialysis,

1.0–1.5 g/kg/d in patients with AKI on RRT, and up to a maximum of 1.7 g/kg/d in patients on continuous renal replacement therapy (CRRT) and in hypercatabolic patients.

-total energy intake of 20–30 kcal/kg/d in patients with any stage of AKI.

Initiate RRT emergently when life -threatening changes in fluid, electrolyte, and acid-base balance exist.
- Pulmonary oedema
- Hyperkalaemia >6.5 mEq/L, hyperkalaemia associated with symptoms or signs (i.e., cardiac conduction abnormalities, muscle weakness), or hyperkalaemia

>5.5 mEq/L if there is ongoing tissue breakdown ( e.g., rhabdomyolysis) or ongoing potassium absorption (e.g., significant gastrointestinal bleeding)

- Signs of uraemia, such as pericarditis, or an otherwise unexplained decline in mental status
- Severe metabolic acidosis (pH <7.1) and hypervolemia, unless acidosis can be rapidly resolved by quickly correcting the under lying aetiology (eg, diabetic ketoacidosis)

-using CRRT, rather than standard intermittent RRT, for hemodynamically unstable patients

CKD

-dialysis be initiated when one or more of the following are present: symptoms or signs attributable to kidney failure (serosi tis, acid-base or electrolyte abnormalities,

pruritus); inability to control volume status or blood pressure; a progressive deterioration in nutritional status refractory to dietary intervention; or cognitive impairment. This often but not invariably occurs in the GFR range between 5 and 10 ml/min/1.73 m 2.

– Managing complications of CKD -Anaemia, metabolic bone disease, hypertension and cardiovascular diseases

TLS

– Hydration: 2 to 3 L/m2/d (or 200 mL/kg/d

if 10 kg; volume adapted to patient age, cardiac function, and urine output) IV of a solution consisting of one quarter of normal saline/5% dextrose

-Hyperuricemia- Allopurinol Dosing: 100 mg/m2

/Dose every 8 hours (10 mg/kg/d divided every 8 hours) PO (maximum, 800 mg/d) or 200 -400 mg/m2/d in 1-3 divided doses; IV (maximum, 600 mg/d) Reduce dose by 50% or more in renal failure

Rasburicase: Contraindicated in glucose-6-phosphate dehydrogenase–deficient patients, as well as in patients with a known history of anaphylaxis or hypersensitivity reactions, haemolytic reactions, or

methemoglobinemia reactions to Rasburicase or any of the excipients

Administration: intravenously over 30 minutes according to dosages recommended in Table 8

Uric acid levels should be monitored regularly and used as a guide to modulate dosing; to measure uric acid levels place bloo d sample immediately on ice to avoid continual pharmacologic ex vivo enzymatic degradation

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Evidence Level Grade PMID Nº

– Hyperphosphatemia

Moderate > 2.1 mmol/L Avoid IV phosphate administration Administration of phosphate binder

Severe -Dialysis

-Hypocalcaemia < 1.75 mmol/L Asymptomatic -No therapy

Symptomatic -Calcium gluconate 50-100 mg/kg IV administered slowly with ECG monitoring

Hyperkalaemia

Moderate and asymptomatic, = 6.0 mmol/L Avoid IV and oral potassium ECG and cardiac rhythm monitoring

Sodium polystyrene sulphonate

Severe (> 7.0 mmol/L) and/or symptomatic Same as above, plus:

Calcium gluconate 100-200 mg/kg by slow IV infusion for life-threatening arrhythmias

Sodium polystyrene sulphonate

Severe (> 7.0 mmol/L) and/or symptomatic Same as above, plus:

Calcium gluconate 100-200 mg/kg by slow IV infusion for life-threatening arrhythmias Regular insulin (0.1 U/kg IV) D25 (2 mL/kg) IV

Sodium bicarbonate (1-2 mEq/kg IV push) can be given to induce influx of potassium into cells. However, sodium bicarbonate and calcium should not be administered through the same line.

Dialysis

Renal dysfunction (uraemia) Fluid and electrolyte management Uric acid and phosphate management

Adjust renally excreted drug doses Dialysis (hemo- or peritoneal)

5 D

References

Christiansen CF, Johansen MB, Langeberg WJ, Fryzek JP, Sørensen HT. Incidence of acute kidney injury in cancer patients: a Danish population-based cohort study. Eur J Intern Med. 2011 Aug;22(4):399- 406. doi: 10.1016/j.ejim.2011.05.005.
Kitchlu A, McArthur E, Amir E, et al. Acute kidney injury in patients receiving systemic treatment for cancer: a population-based cohort study. J Natl Cancer Inst. 2019;111:727-736.
Iff S, Craig JC, Turner R, et al. Reduced estimated GFR and cancer mortality. Am J Kidney Dis. 2014;63:23-30.
Launay-Vacher V, Janus N, Deray G. Renal insufficiency and cancer treatments. ESMO Open. 2016;1:e000091.
Janus N, Launay-Vacher V, Byloos E, et al. Cancer and renal insufficiency: results of the BIRMAstudy. Br J Cancer. 2010;103:1815-1821.
Kidney Disease: Improving Global Outcomes (KDIGO). Acute Kidney Injury Work Group. KDIGO clinical practice guidelines for acute kidney injury. Kidney Int Suppl 2012; 2:1
Benjamin D. Humphreys,Robert J. Soiffer, Colm C. Magee. Renal Failure Associated with Cancer and Its Treatment: An Update. JAm Soc Nephrol 16: 151–161, 2005. doi: 10.1681/ASN.2004100843
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 1–150
Mitchell H. Rosner, Kenar D. Jhaveri, Blaithin A. McMahon, Mark A. Perazella. Onconephrology: The Intersections Between the Kidney and Cancer. CA CANCER J CLIN 2021;71:47–77. doi: 10.3322/caac.21636
Kashani K, Rosner MH, Ostermann M. Creatinine: from physiology to clinical application. Eur J Intern Med. 2020;72:9-14.
Launay-Vacher V, Izzedine H, Rey JB, et al. Incidence of renal insufficiency in cancer patients and evaluation of information available on the use of anticancer drugs in renally impaired patients. Med Sci Monit. 2004;10:CR209-CR212.
Launay-Vacher V, Oudard S, Janus N, Gligorov J, Pourrat X, Rixe O, Morere JF, Beuzeboc P, Deray G; Renal Insufficiency and Cancer Medications (IRMA) Study Group. Prevalence of Renal Insufficiency in cancer patients and implications for anticancer drug management: the renal insufficiency and anticancer medications (IRMA) study. Cancer. 2007 Sep 15;110(6):1376-84. doi: 10.1002/cncr.22904. PMID: 17634949.
Launay-Vacher V. Epidemiology of chronic kidney disease in cancer patients: lessons from the IRMA study group. Semin Nephrol. 2010 Nov;30(6):548-56. doi: 10.1016/j.semnephrol.2010.09.003. PMID: 21146120.
Launay-Vacher V, Chatelut E, Lichtman SM, Wildiers H, Steer C, Aapro M; International Society of Geriatric Oncology. Renal insufficiency in elderly cancer patients: International Society of Geriatric Oncology clinical practice recommendations. Ann Oncol. 2007 Aug;18(8):1314-21. doi: 10.1093/annonc/mdm011. Epub 2007 Jul 13. PMID: 17631561.
Matzke GR, Aronoff GR, Atkinson AJ Jr, Bennett WM, Decker BS, Eckardt KU, Golper T, Grabe DW, Kasiske B, Keller F, Kielstein JT, Mehta R, Mueller BA, Pasko DA, Schaefer F, Sica DA, Inker LA, Umans JG, Murray P. Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011 Dec;80(11):1122-37. doi: 10.1038/ki.2011.322. Epub 2011 Sep 14. PMID: 21918498.
Chancharoenthana W, Wattanatorn S, Vadcharavivad S, Eiam-Ong S, Leelahavanichkul A. Agreement and Precision Analyses of Various Estimated Glomerular Filtration Rate Formulae in Cancer Patients. Sci Rep. 2019 Dec 18;9(1):19356. doi: 10.1038/s41598-019-55833-0. PMID: 31852941; PMCID: PMC6920413.
Dooley MJ, Poole SG, Rischin D. Dosing of cytotoxic chemotherapy: impact of renal function estimates on dose. Ann Oncol. 2013 Nov;24(11):2746-52. doi: 10.1093/annonc/mdt300. Epub 2013 Aug 7. PMID: 23928359.
Sprangers B, Abudayyeh A, Latcha S, Perazella MA, Jhaveri KD. How to determine kidney function in cancer patients? Eur J Cancer. 2020 Jun;132:141-149. doi: 10.1016/j.ejca.2020.03.026. Epub 2020 Apr 30. PMID: 32361629.
Janowitz T, Williams EH, Marshall A, et al. New model for estimating glomerular filtration rate in patients with cancer. J Clin Oncol. 2017;35:2798-2805.
Jeha S: Tumor lysis syndrome. Semin Hematol 38[Suppl 10]: 4 – 8, 2001
Davidson MB, Thakkar S, Hix JK, Bhandarkar ND, Wong A, Schreiber MJ: Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med 116: 546 –554, 2004.
Conger JD: Acute uric acid nephropathy. Med Clin North Am 74: 859 – 871, 1990
Johnson RJ, Kivlighn SD, Kim YG, Suga S, Fogo AB: Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am J Kidney Dis 33: 225–234, 1999.
Jerome KR, Corey L: The danger within. N Engl J Med 350: 411– 412, 2004
Boles JM, Dutel JL, Briere J, Mialon P, Robasckiewicz M, Garre M: Acute renal failure caused by extreme hyperphosphatemia after chemotherapy of an acute lymphoblastic leukemia. Cancer 53: 2425–2429, 1984
Zager RA: Hyperphosphatemia: A factor that provokes severe experimental acute renal failure. J Lab Clin Med 100: 230 –239, 1982

CLOTTING DISORDERS

21.1 PULMONARY THROMBOEMBOLISM

Authors: Ricardo Jorge Teixeira Pinto and Diogo Augusto Ribeiro Soares Evidence

Introduction Level Grade PMID Nº

- Venous Thromboembolism (VTE), presenting in the form of Deep Vein Thrombosis (DVT) or Pulmonary Thromboembolism (PTE), represents an entity of relevance in cancer patients, which occurs in up to 20% of patients undergoing antineoplastic treatment. [1]
- PTE is considered a common and life-threatening event with a four-fold increased risk of occurrence in cancer patients compared to the general population. [2]
- The proper diagnosis and treatment of this entity are essential for the prevention of recurrent thromboembolic events, associated with a substantial increase in morbidity/mortality. [3]

Symptoms

Diagnosing PTE through clinical signs and symptoms is challenging, as they do not have enough sensitivity or specificity to diagnose or exclude pathology in most clinical situations. [4-7] Pulmonary auscultation as part of the physical exam usually does not provide diagnostic information. [5]

The most common signs or symptoms in the presentation are:

- - Dyspnoea at rest (50%) or with exertion (27%) • Pleuritic chest pain (39%) • Extremity oedema suggestive of DVT (24%) Other signs or symptoms that may be present:
  - Cough without haemoptysis (23%) • Respiratory distress (16%) • Substernal chest pain (15%)
  - Dizziness (12%) • Diaphoresis (12%)

Some manifestations are less common, but may be the initial presentation of PTE with hemodynamic impact, so it is important to identify:

- - Cough with haemoptysis (8%) • Syncope (6%) • Shock (systolic blood pressure <90 mmHg or cyanosis) [5,7]

It is important to recognize that PTE shares signs and symptoms with other pathologies, such as pneumonia, pneumothorax, acute coronary syndrome or thoracic aortic dissection, so other causes should always be excluded. [4]

Aetiology

- PTE is defined as a blockage of the pulmonary arteries by a blood clot. [4-7]
- Virchow described in the 19th century the pathophysiology of VTE that includes three variables: vascular statism, endothelial damage and hypercoagulability, situations improved by the nature of oncological pathology. [5.7]
- VTE of the lower extremities is more likely to embolize (15-32%) and cause PTE, while DVT of the twin veins is rarely embolized to the pulmonary vessels. However, it can, in about 33% of cases, progress to more proximal veins and increase the potential for embolization. Upper extremity DVT rarely (6%) presents with PTE. [5.7]
- After embolization of its point of origin, the thrombus, through the vena cava and the right chambers of the heart, can reach the pulmonary arteries, and can lodge in the main arterial bifurcation, depending on its dimensions, and establish severe hemodynamic compromise or lead to death. It can, on the other hand, fragment and reach the peripheral pulmonary arteries, causing pulmonary infarction with associated pain. [5.7]

PTE can be classified as:

- Massive PTE – Systolic arterial shock or systolic blood pressure <90 mmHg for more than 15 minutes requiring ionotropic support, absence of heart rate or bradycardia of <40 beats per minute.
- Sub massive PTE – No changes in blood pressure, but with right ventricular dysfunction (confirmed by imaging or elevation of cardiac markers).
- Low-risk PTE – Hemodynamic stability maintained without right ventricular dysfunction. [9]

Diagnostic strategy


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Pharmacotherapy
Treatment of PTE scans with direct oral anticoagulants (ACODs) requires dose adjustments in patients with renal impairment with creatinine clearance < 50 ml/min and are

contraindicated if creatinine clearance < 15 ml/min and/or if platelet counts < 50×109/L are contraindicated. [1.2]

Article	Methodology
Suspected PTE with Hemodynamic instability	Recommendation for an emergency thoracic echocardiogram or computed tomography (CT) scan.
Suspected PTE with Hemodynamic instability	Immediate initiation of anticoagulation with unfractionated heparin (UFH) in patients with high suspicion of diagnosis.
Suspected PTE without Hemodynamic instability	Diagnosis of PTE according to criteria of validation and evaluation of scores clinical probability – Wells score.
Suspected PTE without Hemodynamic instability	Initiation of anticoagulation in patients with intermediate/high probability for PTE as a diagnostic process.
D-Dmins Dosage	Dosage with high sensitivity tests, recommended in patients with low/intermediate clinical probability, to reduce exposure, considered positive if > 500 ng/ml.
	The D-Ders limit should be adjusted according to age (age x 10 μg/L) patients >50 years of age, or relevant clinical condition.
	Dosing should not be performed routinely in patients with high clinical probability, as a normal result not excludes the presence of PTE.
Thoracic CT	Diagnosis excluded in case of negative examination in a patient with low/intermediate clinical probability.
	Positive diagnosis if a segmental or more proximal vascular filling defect is identified in a patient with intermediate/high clinical probability
	Diagnosis excluded in case of negative test in a patient with probability high clinic.
Ventilation/perfusion scan	To consider the exclusion of the P TE DIAGNOSIS in a patient with high clinical probability with unchanged CHEST CT.

- In the case of the use of low molecular weight heparins (LMWH), the therapeutic dose should be optimized in patients with creatinine clearance between 15-30 ml/min and in patients with platelet thrombocytopenia between 20-50×109/L. If counts are lower, pharmacological hypo coagulation is contraindicated (consider transfusion of platelet concentrates in patients at high thrombotic risk for prescribing therapeutic doses of LMWH). [1-3]
- Situations, to assess therapeutic efficacy or associated complications, consider blood dosing of ACOD according to the form of administration and monitoring of anti-Xa activity in patients receiving LMWH. [3]

Drug		Dosage
	Apixaban	Starting dose: 10 mg 12/12 h for 7 days Maintenance dose: 5 mg 12/12 h
DOAC	Edoxaban	Maintenance dose: 60 mg/day (after 5 to 7 days of LMWH)
	Rivaroxaban	Starting dose: 15 mg 12/12 h for 21 days Maintenance dose: 20 mg/day
	Dalteparin	Initial dose: 100 IU/kg of 12/12 h or 200 IU/kg for 1 month \| Maintenance dose: 180 IU/kg/day
LMWH	Tinzaparin	Standard dose: 175 IU/kg/day:
LMWH	Tinzaparin	Tinzaparin is safe in patients with renal impairment and CrCl >20ml/min and does not bioaccumulate with severe renal impairment and CrCl <20 mL/min.
	Enoxaparin	Standard dose: 100 IU/kg (1 mg/kg) of 12/12 h or 150 IU/kg (1.5 mg/kg/day) after the acute phase
	Acenocoumarol	Starting dose: 4 mg/day (2 mg/day in frail patients) maintain LMWH up to 2 consecutive INR controls in therapeutic interval (INR between 2-3) Maintenance dose: Daily dose adjustments according to ISR
VKA	Warfarin	Starting dose: 5 mg/day (2.5 mg/day in frail patients) maintain LMWH up to 2 consecutive inR controls in therapeutic interval (INR between 2-3) Maintenance dose: Daily dose adjustments according to ISR
	Fondaparinux	Standard dose: <50 kg: 5 mg/day \| 50-100 kg: 7.5 mg/day \| > 100 kg: 10 mg/day
Other	UFH	Starting dose: 80 IU/kg IV or bolus followed by 18 IU/kg IV Maintenance dose: Dose adjustment according to aPTT value


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\| Legend DOAC – \| Direct Oral Anticoagulant – VKA Vitamin K Antagonists \| LMWH – Low molecular weight heparin \| UFH – Unfractionated heparin

ISR – International Standard Reason

T

herapeutic Strategy Level Grade PMID Nº

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Article	Methodology
Start of Hypo coagulation	Initial hypo coagulation with LMWH, UFH, fondaparinux, rivaroxaban or apixaban
Start of Hypo coagulation	If parenteral hypo coagulation is initiated, LMWH is preferable to UFH in the initial period of five to ten days.
Extension of Hypo coagulation	Prolonged hypo coagulation for 6 months should be performed with LMWH, rivaroxaban, edoxaban or apixaban, given the increased efficacy of VKA.
	VKA can be weighted in prolonged treatment if LMWH or DOAC are not adequate or in case of unavailability.
	To assess the possible increased risk of bleeding in patients hypo coagulated with DOAC, particularly in cases of gastrointestinal or genitourinary neoplasia.
	Careful evaluation of possible drug interactions prior to the institution of hypo coagulation with DOAC.
	The degree of anticoagulation beyond 6 m should be considered in patients with evidence of active disease (metastatic disease or in treatment), safeguarding the risk/benefit.
VCI Filter	Insertion of the IVC filter should be considered in patients with absolute contraindication of anticoagulant therapy (acute phase – up to 4 weeks after PTE diagnosis), if the event poses a potential risk to life.
VCI Filter	Consider the insertion of the IVC filter in patients under therapeutic anticoagulation with progressionof the thrombotic event (recurrence or extension).
Peculiarities	Patients with primary or metastatic disease at the level of the nervous or central system with documented P TE, should carry out anticoagulant therapy, with careful selection of the drug and patients who benefit the most (individualized assessment).
	Incidental PTE should be approached similarly to symptomatic venous thromboembolic events in the cancer patient.
	Treatment of incidentally diagnosed subsegmental P TE should be evaluated individually, considering the potential risks and benefits of the anticoagulant therapy institution.
Thrombolysis	Patients diagnosed with PTE with echocardiogram and biomarkers compatible with right ventricular dysfunction without hemodynamic involvement should perform hypo coagulation without the need for thrombus lysis.
Thrombolysis	Patients with hemodynamic instability and established diagnosis of PTE scan should be candidates for thrombolysis, followed by therapeutic hypo coagulation.

Legend IVC – Inferior Vena Cava

Clinical Trials Level Grade PMID Nº

- CLOT | study | Agnes Y.Y. Lee et al, Low molecular weight heparin versus coumarin for the prevention of recurrent venous thromboembolism in cancer patients, N Engl J Med 2003; 349: 146-153
- of the ONCENOX | study Steven R Deitcher et al, Secundary prevention of venous thromboembolic event in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period, Clin Appl Thromb Hemost 2006, 4:389-96
- CATCH: A randomized clinical trial comparing long-term tinzaparin versus warfarin for treatment of acute venous thromboembolism in cancer patients, BMC cancer 2013; 13:284
- Selectd-D | study | Young A et al, Anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism: results of select-d Pilot Trial, Blood 2017; 130:625
- of the Hokusai VTE Cancer | study Raskob GE et al, Edoxaban for the treatment of cancer-associated venous thromboembolism, N Engl J Med 2018; 378: 615-24
- Caravaggio | Giancarlo Agnelli, M.D. et al, Apixaban for the treatment of venous thromboembolism associated with cancer, N Engl J Med 2020; 382: 1599-1607

References

Stockler M. R. et al, ASCO updated recommendations for preventing and treating VTE in adults with cancer, Ann Intern Med., 2020
Michael B. et al, Cancer-Associated Venous Thromboembolic Disease, version 2.2021, NCCN Clinical Practice Guidelines in Oncology, J Natl Compr Canc Netw, 2021
Stavros V. et al, ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS), European Heart Journal, 2020
Huisman M. V., et al, Pulmonary Embolism, Nature Vol. 4, No. 18028, 2018
Essien E., et al, Pulmonary Embolism, Medical Clinics of North America Vol. 103, No. 3, 2019
Toplis E., Mortimore G., The Diagnosis and Management of Pulmonary Embolism, British Journal of Nursing Vol. 29, No. 1, 2020
Pollack C. V., et al., Clinical Characteristics, Management, and Outcomes of Patients Diagnosed With Acute Pulmonary Embolism in the Emergency Department, Initial Report of EMPEROR, Journal of the American College of Cardiology Vol. 57, No. 6, 2011
Turetz M., et al, Epidemiology, Pathophysiology, and Natural History of Pulmonary Embolism, Seminars in Interventional Radiology Vol. 35 No. 2, 2018
Jaff M. R., et al, Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension – A Scientific Statement From the American Heart Association, American Heart Association, 2011

DEEP VEIN THROMBOSIS

Authors: Inês Fontes Almeida Pintor and Joana Liz-Pimenta

Definition and Epidemiology

- - Deep vein thrombosis (DVT) is defined as the development of a blood clot in the veins, that most commonly occurs in the lower limbs (in 90% of the cases) and rarely affects veins in the upper limbs, abdomen, or brain.
  - It is important to distinguish between the terms thrombosis and embolism, which is defined as dislodgement of the clot from the blood vessel where it was developed and getting stuck in another location, generally in the lungs, causing a pulmonary embolism (PE). Rarely PE can develop in the absence of a DVT.
  - Venous thromboembolism (VTE) includes DVT and PE. Patients with cancer have a higher risk of initial (four to sevenfold) and recurrent VTE (threefold) when compared to the general population, resulting in considerable morbidity and mortality. Making VTE the second cause of death in cancer patients. The risk of arterial thromboembolism is also higher in this population. Also, these patients have a two-fold higher risk of anticoagulation-associated bleeding. These complications occur due to the systemic effects of the tumour.
  - The cumulative incidence of venous thrombosis in cancer patients varies between 1-8% and it is rising. Besides, it is estimated that 20-30% of all initial VTE are cancer related.
  - The most common presentation of DVT is leg swelling and the gold standard diagnostic method is duplex venous scanning, due to its high sensitivity and specificity.
  - DVT and PE are the most common preventable causes of hospital death. It is important to identify patients who are most likely to benefit from pharmacologic prophylaxis and the effective treatment to reduce recurrence and mortality. The most important goal of thromboprophylaxis is to prevent complications and death (mostly fatal PE).

Evidence

Level Grade PMID Nº

24939044

33275332

29703467

15564173

23908465

11861986

30402189

Symptoms and signs Level Grade PMID Nº

- - DVT can be divided into symptomatic or incidental. Classical symptoms include swelling (80%), pain (75%), alteration in sensitivity and change in the temperature or colour of the limb, that becomes blue or reddish (26%). PE presents with shortness of breath, chest pain, palpitations, or collapse.
  - There are a limited number of studies comparing the clinical presentation of DVT in patients with and without cancer. Bilateral DVT is more common in patients with cancer than in noncancer patients.
  - Iliofemoral thrombosis may present with Phlegmasia cerulea dolens, an uncommon but potentially life-threatening complication. It presents with marked swelling of the limb, with pain and cyanosis. The massive limb swelling may be associated with arterial thrombosis, gangrene, amputation and even death.
  - Postphlebitic syndrome is a state of chronic venous insufficiency due to loss of venous valvular function during the reorganization of the thrombus. It develops in 20-50% of patients with DVT, even when effective anticoagulant therapy was used. Clinical manifestations may include chronic leg pain with activity limitation, swelling and leg ulcers.
  - VTE may be the first sign of cancer. Eight percent of idiopathic VTE will have cancer diagnosed in the first 12 months after VTE. Therefore, occult cancer should be excluded in the case of idiopathic VTE.

Etiology

- - The causes of thrombosis are summarized in Virchow´s triad, which includes stasis of blood, alteration in the composition of blood and changes in the vessel wall. The risk of VTE in cancer is increased in the first three to six months after diagnosis. It is the result of factors related to cancer, patients, treatment, and biomarkers:
    - Thrombocytosis (tumours produce thrombin, tissue factor, factor VIII, and fibrinogen, increasing thrombogenic potential).
    - Compression and invasion of the tumour to adjacent vessels.
    - Location of cancer (highest risk for the pancreas and gastric, followed by urologic tumours (except prostate), gynaecologic tumours, central nervous system (CNS) and lung). Hematologic cancer such as lymphoma and myeloma also have increased risk, but the pathophysiology is not entirely the same.
    - Metastatic disease and high stage cancer.
    - Advanced age.
    - Obesity.
    - Prior history of venous thrombosis.
    - Comorbidities (≥3 comorbid conditions).
    - Anaemia, thrombocytosis, and leucocytosis
    - Ethnicity (highest risk for African Americans and lowest for Asians).
    - Hospitalization and prolonged immobility.
    - Therapy: surgery (the risk of 90-day postoperative VTE is twice as high as in noncancer patients), chemotherapy (annual incidence: 11 to 20%, highest for platinum agents and gemcitabine), hormonal therapy (especially tamoxifen), targeted treatment agents (a major role for anti-VEGFRs and CDK4/6 inhibitors), thalidomide/lenalidomide, radiotherapy, red blood cell transfusions, erythropoietin-stimulating agents, and central venous catheters.
    - Prothrombotic mutations (cancer patients with factor V Leiden have a twofold increased risk of VTE compared with noncarriers with cancer).
  - From the study of these risk factors, risk scores were created, to predict which patient would be at increased risk of VTE. The most validated score is the Khorana score..

Diagnosis

- - In oncologic patients, there must be a high index of suspicion for the presence of DVT and PE, especially when there is present some of the already mentioned risk factors. Early diagnosis and treatment are essential given thrombus propagation and PE potential.
  - The diagnosis of DVT requires a combination of clinical assessment, pre-test probability and objective diagnostic testing.
  - A physical examination should be performed to look for dilated superficial veins, unilateral swelling with inflammatory signs (warmth, tenderness, or erythema) and pain along the course of the involved veins. However, these signs and symptoms lack specificity.

24939044

30402189

15564173

27913509

23908465

17692901

18223291

8173368

16284987

33570602

23908465

15564173

19381022

22859911

16145406

11861986

9308616

8667510

15564173

- - Leg swelling is the most common indication for duplex venous scan, but it is not predictive of DVT. Some studies have shown that a discrepancy of less than 2 cm in the calf circumference of the involved and the normal limb predicted the absence of DVT in 93% of patients.
  - Studies have also shown an association between PE, history of malignancy or previous DVT and a positive result on the duplex scan. One study found that in patients with PE confirmed by pulmonary angiogram or ventilation-perfusion scan, the incidence of acute DVT detected by duplex scan was 43%. Though, if the diagnosis of PE was clinical, the incidence of DVT was only 10%.
  - The pre-test probability is made by a clinical decision rule that classifies the probability of DVT. The best-studied scoring system is modified Wells Score, which includes the following components:

Modified Wells Score	Points
Active cancer	1
Recent immobilization of the lower limbs	1
Recently bedridden (> three days) or major surgery (<four weeks)	1
Localized tenderness along with deep vein system	1
Swelling of an entire inferior limb	1
Calf swelling	1
Pitting oedema greater in the symptomatic leg	1
Collateral no varicose superficial veins	1
Previous history DVT (documented)	1
Alternative diagnosis more or equally likely than DVT	2

- - This score divides patients into “likely” (score ≥2) or “unlikely” (score ≤1) to have DVT.
Patients classified as “unlikely” should be referred for D-dimer testing. DVT is excluded if the value is normal (<500ng/mL). If the value is increased (>500ng/mL), ultrasonography of the inferior limb should be performed. If ultrasonography is negative, DVT is excluded.
Patients classified as “likely” should be referred for lower limb ultrasonography. In these patients, the D-dimer value cannot be reliably used to exclude DVT. If ultrasonography is negative, DVT is excluded.
- - In one study, the sensitivity, specificity, positive predictive value and negative predictive value of a low pre-test probability Wells score in combination with a negative D-dimer result were 99%, 33%, 29% and 99%, respectively. In cancer patients, D-dimer does not work so well as a discriminator factor, because they may be risen due to cancer proinflammatory state.
  - Duplex venous ultrasound is the gold standard for diagnosis of DVT, with an overall sensitivity and specificity around 95% and 100%, respectively.

17112931

11686356

18558426

31155730

2202232

Therapy

- - In cancer patients the treatment and prophylaxis are based on anticoagulation.
  - Absolute contraindications for the use of anticoagulation include:
    - Active major, serious, or potentially life-threatening bleeding is not reversible with medical or surgical intervention.
    - Uncontrolled malignant hypertension.
    - Severe coagulopathy or platelet dysfunction (severe thrombocytopenia: < 20000/mL) or inherited bleeding disorder.
    - High-risk invasive procedure in a critical site (lumbar puncture, spinal anaesthesia, epidural catheter placement, …).
    - Concurrent use of potent P-glycoprotein or CYP3A4 inhibitors or inducers (DOAC specific).
  - Relative contraindications for the use of anticoagulation include intracranial or spinal lesion at high risk for bleeding; active GI ulceration at high risk of bleeding; active but non – life-threatening bleeding; intracranial bleeding (< 4 weeks); recent high-risk surgery or bleeding event; persistent thrombocytopenia (<50000/mL).
    - In the case of thrombocytopenia is important to access whether the anticoagulation should be reduced or stopped or if their platelet transfusion should be done.

31381464

34878173

29363105

26210891

29231094

29746227

29506866

33570602

- - Anticoagulation showed benefit in incidental VTE, CNS VTE and palliative settings, but more studies are ongoing in these populations.
  - In a patient with DVT, anticoagulation may be initiated with Low Molecular Weight Heparin (LMWH), and Direct-Acting Oral Anticoagulants (DOACs). In special circumstances, Unfractionated Heparin (UFH) or Fondaparinux may also be used. The initial period of treatment includes the first five to ten days. Only two DOACs (Rivaroxaban and Apixaban) have been approved for the treatment of VTE in the initial period. Tinzaparin is the LMWH with better results in cancer patient trials. UFH may be the first option for patients with renal impairment. Fondaparinux should be considered for patients with heparin-induced thrombocytopenia background.
  - Meta-analyses studies confirm the superiority of LMWH relatively to Vitamin K antagonist (VKA) in reducing the risk of VTE recurrence in cancer patients, as well as adverse effects. Therefore, VKAshould not be used routinely in cancer patients.
  - In the meta-analysis, DOACs had a lower risk of VTE, but a higher risk of major bleeding compared with LMWH, with no significant difference in mortality. In patients with an increased risk of bleeding (use of antiplatelet agents, renal or hepatic impairment, thrombocytopenia, history of gastrointestinal bleeding, gastrointestinal cancers, and polypharmacy), LMWH is safer. There is limited information on DOAC use in patients with primary malignancy or metastasis of the central nervous system as well as its use in catheter-related thrombosis.
  - For VTE treatment besides anticoagulation, a vena cava filter can be an option for very selected patients.
  - In cancer patients with VTE, the standard duration of anticoagulation is six months. Nonetheless, duration beyond this time or indefinite anticoagulation may be beneficial in reducing the recurrence but not the mortality. Treatment for only three months can be evaluated in cases of incidental and peripheral VTE or catheter-related thrombosis. Anticoagulation can be discontinued when patients do not present VTE at imaging exams nor clinical VTE signs and when they are no longer under active cancer . A periodic revaluation should be done every 3-6 months. Looking for risk of thrombosis and bleeding, cancer status and prognosis, treatments, comorbidities, and costs and one of the most important factors: patient preferences and values.
  - Recurrence may occur in patients already in use of standard-dose anticoagulation (five to seven per cent). In these cases, treatment compliance should be assessed, as well as looking for any mechanical compression caused by the tumour or heparin-induced thrombocytopenia. If the patient is under DOAC it should be changed to LMW. If already in LMWH should be considered a 25% increase in the dosage. Adding a vena cava filter to LMWH is considered the last line of treatment.
  - Age is a risk factor for bleeding. However, anticoagulation should be offered to older patients if there are no contraindications. Anticoagulants should be used with caution in special populations, such as patients with renal impairment, fall risk, cognitive impairment, poor functional status or without family or medical support.
  - Renal impairment increases the risk of bleeding, especially in cancer patients. Limited data suggest that LMWH may accumulate with therapeutic doses if the creatinine clearance is inferior to 30 mL/min, increasing at least two-fold the risk of bleeding when compared to patients with normal renal function. In patients with cancer and renal impairment, UFH and VKAare wiser choices for initial and long-term therapy, respectively.
  - The recommended doses of anticoagulants for initial treatment are:

– LMWH at least during first five days: (Evidence: 1a, A, PMID: 28182249, 29363105, 31381464, 19147527, 16082604) :

Dalteparin 100 U/kg every 12 hours or 200 U/kg once daily for one month and then 150 U/Kg once daily.
Tinzaparin 175 U/kg once daily.
Enoxaparin 1 mg/kg every 12 hours or 1.5 mg/kg once daily.
- - - DOACs:
      - Rivaroxaban 15mg orally every 12 hours for 21 days, followed by 20mg once daily (Evidence: 1a, A, PMID: 29746227, 31381464)
      - Apixaban 10mg orally twice daily for seven days, followed by 5mg twice daily (Evidence 1a, A, PMID: 32223112, 28837207, 31381464).
  - Regarding thromboprophylaxis:
    - Nowadays ambulatory cancer patients with a Khorana score equal to or more than two and no contraindications should start thromboprophylaxis: six months, LMWH or DOAC – same criteria for the choice in VTE treatment applied, but reduced doses.
    - Patients with Multiple Myeloma under thalidomide or lenalidomide with chemotherapy and/or dexamethasone also should be under thromboprophylaxis.
    - In hospitalized patients, thromboprophylaxis with LMWH is the treatment of choice if active cancer and with no complications, during the period of internment.
    - In surgical cancer patients, thromboprophylaxis with LMWH is also the treatment of choice and is recommended in cases of major surgery, for a minimum of seven-ten days, and in abdominal/pelvic surgery for 4 weeks.

30482768

16670137

27344439

Ia A

It is recommended to use anticoagulation with DOAC or LMWH for an initial five to ten days, assuming a normal renal function (creatinine clearance ≥30 mL/min).

Tinzaparin is safe in patients with renal impairment and CrCl ≥ 20 ml/min and does not bioaccumulate with severe renal impairment and CrCl<20 mL/min.

For long-term anticoagulation in patients with VTE and active cancer, LMWH or DOAC are preferred,and the duration should be at least six months.

Anticoagulation beyond six months may be used in selected patients, as those with active cancer, metastatic diseaseor chemotherapy,

The insertion of a vena cava filter should not be offered to patients with established VTE (diagnosis > four weeks), nor to patients with temporary contraindications to anticoagulant therapy, but may be offered to patients with absolute contraindications to anticoagulant therapy with VTE diagnosed within less than four weeks if it is considered lifethreatening.

In patients with cancer, incidental VTE (PE, DVT) should be treated similarly to symptomatic VTE, as they have identical clinical outcomes.

In oncology patients with recurrent VTE, despite receiving a therapeutic dose of LMWH, an alternative anticoagulantor supratherapeutic dose of LMWH may be considered

In oncology patients with recurrent VTE, despite receiving a therapeutic dose of LMWH, the addiction of vena cava filter to LMWH is considered the last treatment option

Therapy with anticoagulants is not recommended to improve survival in oncology patients without VTE

Ia A

Ia B

2b C

2a C

2b B

3 C

3 A

34878173 28182249

29746227 28837207

16670137

33464938

29231094 29746227

25827941 29948754

29920657

31381464 28719850

31381464 15302635

31381464 21555690

26469193

33570602 19245418

25851122

33570602 31381464

29106448 34622445

27721250

References

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COAGULOPATHY

Authors: João Ricardo Cordeiro de Campos Faia, Clara Maria Dias Pinto and Ana Isabel Paiva Santos

Definition

- - Cancer induces an acquired state of hypercoagulability characterized by an activation of the coagulation cascade, whose clinical manifestations range from an asymptomatic prothrombotic state, only with analytical changes, to the appearance of thrombosis of large vessels, which can culminate in haemorrhagic events associated with disseminated intravascular coagulation.
  - The pathogenesis of cancer-associated coagulopathy is complex and multifactorial associated with multiple cancer-related risk factors, such as its anatomical location but also with the patient and treatment. Among the mechanisms associated with neoplasia we find the expression of haemostatic proteins by tumour cells (eg: Tissue factor), the production of inflammatory cytokines, proangiogenic factors, among others
  - Forms of presentation:
    - Superficial migratory thrombophlebitis – Trousseau syndrome.
    - Deep vein thrombosis and pulmonary thromboembolism.
    - Nonbacterial thrombotic endocarditis – Marathic endocarditis.
    - Disseminated intravascular coagulation.
    - Thrombotic Microangiopathy – Thrombotic Thrombocytopenic Purpura.
    - Arterial thrombosis.

Thromboprophylaxis in Oncology Patients

Inpatient Thromboprophylaxis

Evidence

Level Grade PMID Nº

15925818

22777060

25054907

24862149

Primary inpatient prophylaxis 2

Prophylaxis with low molecular weight heparin (LMWH) or Fondaparinux is recommended when the glomerular filtration rate ≥ 30 ml/min/1.73 m², or unfractionated heparin (UFH). (Table 3)

Oral anticoagulants are not recommended.

Thromboprophylaxis in Surgical Patients

Primary prophylaxis in surgical patient

I 2 I

All cancer patients undergoing major surgery should undergo thromboprophylaxis with LMWH or UFH if there is no contraindication to active bleeding or high bleeding risk. (Table 3)

Prophylaxis should be started in the perioperative period of 2 to 12 h before the procedure.

Thromboprophylaxis is recommended in cancer patients undergoing major surgery 7 to 10 days after surgery.

B 10477777 15289368

16439370 22077144

23388003 24384102

31381464 31492632

33861298

A 27591773 31381464

11442521 31492632

B 24966161 27849664

31381464 31492632

A 31381464 11442521

31492632

Table 1 – Caprini Score

Thromboprophylaxis is recommended up to 4 weeks after surgery with LMWH in cancer patients undergoing laparotomy, abdominal laparoscopy, or pelvic surgery and who have other risk factors such as mobility restriction, obesity, among others.

Cases of minor surgery should be evaluated on a case-by-case basis.

Thromboprophylaxis combined with mechanical and pharmacological methods may be considered especially in high-risk

patients

Thromboprophylaxis by mechanical methods is not recommended as monotherapy, except when there is a high

haemorrhagic risk

It is recommended to use models to assess the risk of venous thromboembolism such as the Caprini Score (Table 1)

2 A 24253138 26887853

20456751 16881934

28577378 29097086

28846822 31492632

31381464

2 B 30027281 27591773

31492632 31381464

I B 30027281 31492632

31381464

2 B 26386868 29397103

30638566

Risk assessment
1 point	2 points	3 points	5 points
41 – 60 years	61 – 74 years	≥75 years	Stroke (< 1 month)
Minor Surgery	Arthroscopic surgery	History venous thromboembolism	Elective arthroplasty
BMI > 25 mg/m2	Open major surgery (duration > 45 min)	Family history of venous thromboembolism	Hip, pelvis, or lower limb fracture
Edema of the lower extremities	Laparoscopic surgery (duration > 45 min)	Factor V Leiden	Spinal cord injury (< 1 month)
Varicose veins	Immobilization in bed (>72h)	Prothrombin 20210th
Pregnancy or postpartum	Immobilization with gypsum splint	Lupus Anticoagulant
History of recurrent miscarriage or unexplained abortion	Central venous access	Anticardiolipin antibody
Oral contraception or hormone replacement therapy		Hiperhomocisteinemia
Sepsis < 1 month		Heparin-induced thrombocytopenia


Severe lung disease < 1 month		Acquired or congenital thrombophilia’s
Abnormal lung function
Acute coronary syndrome
Decompensated heart failure (< 1 month)
History of inflammatory bowel disease
Immobilization in bed
Interpretation
Punctuation	Surgical risk	Risk of venous thromboembolism in the absence of thromboprophylaxis
0	Too low	< 0.5%
1 to 2	Low	1,5%
3 to 4	Moderate	3%
≥ 5	High	6%

Outpatient thromboprophylaxis

Primary outpatient prophylaxis

I B 27906452 28949077

Routine thromboprophylaxis is not recommended for all cancer patients

The use of risk scores, such asKhorana risk score (Table 2) is recommended for thrombotic risk assessment in cancer patients under chemotherapy.

Patients with cancer at high thrombotic risk (Khorana score ≥2) should receive thromboprophylaxis with Apixaban, Rivaroxaban or LMWH if there are no significant bleeding risk factors or drug interactions. (Table 3)

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*User ratings for Khorana*
Risk factor		Punctuation
Tumour location	Very High risk Stomach Pancreas	2
	High risk – Lung – Lymphoma Gynaecological Bladder Testicle	1
	Other locations	0
Platelet count ≥ 350,000 microL		1
Haemoglobin < 10 g/dL or use of erythrocyte growth factors		1
Prechemotherapy leukocytes ≥ 11×10/L		1
BMI ≥35 kg/m²		1

.Thromboprophylaxis in the patient with multiple myeloma

Primary prophylaxis in patients with multiple myeloma

Thromboprophylaxis is recommended inpatients undergoing immunomodulatorytechnique (thalidomide, lenalidomide or pomalidomide).
Patients on immunomodulatory therapy	With ≥ 2 risk factors or high doses of dexamethasone (> 480 mg per month) or chemotherapy regimens containing anthracycline are indicated for thromboprophylaxis with LMWH or Warfarin. (Table 3)
	Not being on high-dose dexamethasone therapy or chemotherapy regimens containing anthracycline and with fewer than two risk factors should perform acetylsalicylic acidthromboprophylaxis.

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31492632

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- - Risk factors for venous thromboembolism:
Previous venous thromboembolism.
Hereditary thrombophilia.
Central venous catheter or pacemaker support.
Heart disease (e.g., heart failure, a history of stent, coronary bypass);
Diabetes Mellitus.
Acute infection.
Immobilization.
Use of erythropoietin.
Chronic kidney disease.
BMI ≥ 30 kg/m2.

Table 3 – Primary thromboprophylaxis regimens and their doses

Level Grade PMID Nº

Primary thromboprophylaxis regimens and their doses
Inpatient	Unfractionated heparin	5,000 U 8/8h
	Dalteparin	5,000 U daily
	Enoxaparin	40 mg daily
	Fondaparinux	2.5 mg daily
	Tinzaparin	4500 U daily
Surgical Patient	Unfractionated heparin	5,000U 2-4 hours preoperative and then after 8/8h
	Dalteparin	2,500U 2-4 hours preoperative and then 5,000U daily
	Dalteparin	5,000U 2-4 or 10-12 hours preoperative and then 5,000U daily
	Enoxaparin	40 mg 2-4 or 10-12 hours preoperative, 40mg 12 hours postoperative and then 40 mg daily
	Fondaparinux	2.5 mg daily, 6-8h postoperative
	Tinzaparin	4500 U 12 hours preoperative, 4500 U 12h postoperative and then 4500U daily

Table 3 – Primary thromboprophylaxis regimens and their doses

Evidence

Level Grade PMID Nº

Primary thromboprophylaxis regimens and their doses
Inpatient	Unfractionated heparin	5,000 U 8/8h
	Dalteparin	5,000 U daily
	Enoxaparin	40 mg daily
	Fondaparinux	2.5 mg daily
	Tinzaparin	4500 U daily
Surgical Patient	Unfractionated heparin	5,000U 2-4 hours preoperative and then after 8/8h
	Dalteparin	2,500U 2-4 hours preoperative and then 5,000U daily
	Dalteparin	5,000U 2-4 or 10-12 hours preoperative and then 5,000U daily
	Enoxaparin	40 mg 2-4 or 10-12 hours preoperative, 40mg 12 hours postoperative and then 40 mg daily
	Fondaparinux	2.5 mg daily, 6-8h postoperative
	Tinzaparin	4500 U 12 hours preoperative, 4500 U 12h postoperative and then 4500U daily
Outpatient	Dalteparin	5,000 U daily
	Enoxaparin	40 mg daily
	Tinzaparin	4500U daily
	Fondaparinux	2.5mg daily
	Apixaban	2,5mg 12/12h
	Rivaroxaban	10 mg daily

Other considerations about anticoagulation

- - Tinzaparin is safe in patients with renal impairment and CrCl ≥ 20 ml/min and does not bioaccumulate with severe renal impairment and CrCl <20 mL/min. I A

Absolute and relative contraindications to anticoagulation

- - Absolute contraindications:
    - Active, severe, and life-threatening bleeding. – Severe uncontrolled hypertension.
    - Haemorrhagic diathesis. – Persistent and severe thrombocytopenia (< 20,000/ml);
    - Invasive procedures (e.g., lumbar puncture, spinal anaesthesia).
  - Relative contraindications:
    - Intracranial or spinal cord injury with high risk of bleeding. – Active ulceration of the gastrointestinal tract with high risk of bleeding.
    - Active, but not life-threatening bleeding. – Bleeding in the central nervous system in the past 4 weeks.
    - Recent high-risk surgery or recent bleeding event. – Persistent thrombocytopenia (< 50,000/ml)

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DISSEMINATED INTRAVASCULAR COAGULATION (DIC) AND MALIGNANCY

Authors: Soraia Marques Carvalho, Catarina Almeida, Alexandre Sarmento, Mariana Teixeira and Lúcia Borges.

Definition

- - An acquired syndrome characterized by activation of coagulation pathways, resulting in formation of intravascular thrombi and depletion of platelets and coagulation factors. [1, 2]

Symptoms and signs

- - Clinical course typically less intense compared with DIC caused by sepsis/severe infection or major trauma. [2]
  - DIC in patients with malignancies include haemorrhagic complications, thrombosis of large or mid-sized vessels, thrombotic microangiopathy, or a combination of these. [2,3,4]
  - Often manifests with insidious and protracted clinical symptoms of platelet and clotting factors consumption. [2,4]
  - Affected patients may be fully nonsymptomatic and only detected by abnormalities in laboratory tests. [2,3,4]
  - The ongoing consumption may result in bleeding complications, usually the first clinical manifestation of DIC, frequently localized at the site of the tumor or distant metastases. [3]
  - An alternative clinical scenario is dominated by thrombotic complications, ranging from clinically manifest vascular thrombosis to microvascular platelet plugs. [2,4,5]
  - Mild forms of DIC commonly occur as a complication of adenocarcinomas and some types of onco hematological conditions. [2,6,7]
  - Hematological cancers (promyelocytic or monocytic leukemia), are frequently accompanied by severe bleeding. [3,4,6,8]
  - Thrombotic complications are typical for solid cancers, especially adenocarcinomas, including prostate cancer, pancreas tumors, or other gastrointestinal malignancies [3,4,5,7].
  - For practical purposes there are three types of cancer-related DIC: procoagulant, hyper fibrinolytic and subclinical. [8]

Types of cancer -related DIC	Definition
Procoagulant	Excess thrombin generation causes thrombosis in microvascular and macrovascular fields
Hyper fibrinolytic	Activation of the fibrinolytic system dominates the picture
Subclinical	The amount of thrombin and plasmin generated do not cause obvious clinical manifestations Can be reflected in laboratory markers of coagulation or fibrinolysis activation

Etiology

- - DIC can be triggered by multiple causes. [1,2,5]
  - Common causes of DIC in malignancy: acute promyelocytic leukemia, mucinous tumors (eg, pancreatic, gastric, ovarian), and brain tumors.
  - Solid tumors (such as metastatic adenocarcinomas), chemotherapy, Tumor lysis syndrome (TLS), and Trousseau syndrome are strong risk factors in DIC development. [1,2]
  - Significant risk factors for the development of DIC include age >60 years, male sex, breast cancer, tumor necrosis, and advanced stage disease. [6]

Pathophysiology

- - DIC is characterized by systemic intravascular coagulation activation (leading to deposition of intravascular platelets and fibrin) and simultaneous consumption of coagulation proteins and thrombocytes (which may cause bleeding complications). [2,3,4]
  - Tissue factor (TF) and possibly cancer procoagulant (CP), both expressed on malignant cells, can initiate the activation of coagulation; and impaired physiological anticoagulant pathways and unbalanced fibrinolysis also play a pivotal role. [2,3]
  - Radio- and chemotherapy may cause endothelial cell disruption, providing of a suitable surface for the assembly of a platelet-fibrin clot. [3]

Evidence

Level Grade PMID Nº

Diagnosis

- - Diagnosis is clinical and based on laboratory findings.
  - In patients with cancer and DIC, abnormal coagulation tests are quite common. [1,2,3,8]
  - Platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), fibrinogen and D-dímer/fibrin degradation products (FDPs) must be ordered to all suspected DIC patients.
  - In some cases, all of the typical coagulation abnormalities related to DIC, are present, whereas others will only display a moderately decreased platelet count or nearly normal clotting assay results due to adequate compensation of the consumed platelets and coagulation factors. [2,5,8]
  - Often a low platelet count is the most prominent indicator of DIC, due to an increase of clotting protein synthesis that camouflages the constant consumption of clotting proteins. [5,8]
  - Imaging studies or other tests must be ordered depending on the underlying disorder and location of thrombosis or bleeding. [1]
  - Dynamic viscoelastic point-of-care tests [thromboelastography (TEGⓇ) or thromboelastometry (ROTEMⓇ)] provide a potential laboratory method in the diagnostic work-up and prognostication, especially sensitive to hyper-fibrinolisis and hypo-coagulability, are mainly designed to detect severe coagulation disturbances and guide treatment in the bleeding patient.[8]
  - Modified viscoelastic assays with added tissue plasminogen activator (tPA) are potentially more sensitive to hyper- and hypo- fibrinolysis but warrants further confirmation.[8]
  - Other emerging tests may be useful in the near future.[1]

Laboratory Testing	Findings
Platelet Count	Decreased, 50-100×109/L Initial evaluation and monitoring
Clotting Times	PT and aPTT often prolonged in 50 -70% of patients TT often prolonged PT useful in initial evaluation and monitoring aPTT used in monitoring
Fibrinogen	Decreased Elevated in early phases as an acute phase reactant Initial evaluation and monitoring
D-dímer/FDPs	Elevated Initial evaluation and monitoring

- - There are no validated scoring algorithms for DIC in cancer patients.
  - The Japanese Association for Acute Medicine (JAAM) DIC scoring algorithm may be useful in establishing a correct diagnosis, especially in patients with both solid tumours and haematological malignancies.[1,2]
  - The JAAM DIC scoring algorithm includes several variables: criteria of systemic inflammatory response syndrome (SIRS), platelet count, FDPs, fibrinogen and PT.
  - JAAM DIC Score ≥ 4 supports a diagnosis of DIC.
  - The scoring system of the International Society of Thrombosis and Haemostasis (ISTH) is more specific for CID caused by sepsis.[1]

Evidence

Level Grade PMID Nº

Therapeutic Strategy

Evidence

Level Grade PMID Nº

The management of DIC is complex. [7] Most of the therapeutic measures are surprisingly not based on high levels of evidence. [7,8] There are clinical presentations that may require additional supportive strategies specifically aimed at the amelioration of the coagulopathy. [2,5,7,8]

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References

	Posology
LMWH (Prophylaxis) Prophylactic therapy to all patients. Contraindicated if active bleeding or low platelet count <20×109/L. Therapeutic doses reserved to patients with venous thromboembolism and severe thrombotic manifestations (purpura fulminans or acral ischaemia).	Enoxaparin (e.g.) Prophylactic dose (40 mg/24h) Therapeutic dose (1mg/Kg/12h) Dosage adjustment in renal impairment may be needed.
	Tinzaparin. No dose adjustment is needed in renal impairment
Platelet concentrates Indication: active bleeding or platelet count <20×109/L; major bleeding or need for invasive procedures and platelet count <50×109 /L	1-2 units of platelet concentrates per 10 kg of body weight, or 1 single donor apheresis unit daily
Fresh frozen plasma (FFP) Indication: active bleeding, need for invasive procedures, TP or aPTT > 1,5 normal values	15-30 ml/Kg
Fibrinogen Concentrate (FC) Indication: active bleeding, TP or aPTT > 1,5 normal value, Fibrinogen levels <1,5 g/l	30 mg/Kg
Vitamin K Indication: vitamin K deficiency	–
Tranexamic acid Indication: hyperfibrinolysis with major bleeding. Otherwise contraindicated.	10 mg/Kg-/6h iv

Wang, H. (2021). Disseminated intravascular coagulation Straight to the point of care. BMJ Best Practice. Retrieved August 6, 2022, from https://bestpractice.bmj.com/topics/en- gb/184?q=Disseminated%20intravascular%20coagulation&c=recentlyviewed
Levi, M. (2019). Disseminated intravascular coagulation in cancer: An update. Seminars in Thrombosis and Hemostasis, 45(4), 342–347. https://doi.org/10.1055/s-0039-1687890
Feinstein DI. Disseminated intravascular coagulation in patients with solid tumors. Oncology (Williston Park) 2015;29(02):96–102
Levi M. Clinical characteristics of disseminated intravascular coagulation in patients with solid and hematological cancers. Thromb Res 2018;164(Suppl 1):S77–S81
Wada H, Thachil J, Di Nisio M, et al; The Scientific Standardization Committee on DIC of the International Society on Thrombosis Haemostasis. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost 2013 (e-pub ahead of print). doi:10.1111/jth.12155
Sallah S, Wan JY, Nguyen NP, et al. Disseminated intravascular coagulation in solid tumors: clinical and pathologic study. Thromb Haemost 2001; 86:828.
Thachil, J., Falanga, A., Levi, M., Liebman, H., & di Nisio, M. (2015). Management of cancer-associated disseminated intravascular coagulation: Guidance from the SSC of the ISTH. Journal of Thrombosis and Haemostasis, 13(4), 671–675. https://doi.org/10.1111/jth.12838
Adelborg, K., Larsen, J. B., & Hvas, A. M. (2021). Disseminated intravascular coagulation: epidemiology, biomarkers, and management. In British Journal of Haematology (Vol. 192, Issue 5, pp. 803–818). Blackwell Publishing Ltd. https://doi.org/10.1111/bjh.17172

BLEEDING IN CANCER PATIENT

Authors: José Pedro Cidade, Tânia Duarte and Rehab Ahmed .

Introduction [1,2,3,4]

Bleeding in cancer patients can occur from chronic occult bleeding to clinically significant macroscopic bleeding or profound bleeding from large blood vessels which may cause sudden death1. It can be the first symptom or develop later along with disease progression. It has been estimated that bleeding occurs in approximately 6-10% of patients with advanced cancer; for at least some of these patients, bleeding will be the direct cause of death.

Etiology [3,4,5]

It is universally accepted that cancer patients present an increased risk of bleeding, and that risk is multifactorial in its aetiology, potentially attributed to several factors:

Local infiltration of blood vessels by tumour: There may be anatomical or radiographic signs of tumour near a major blood vessel where direct infiltration can lead to a sudden bleed. Warning signs of visible pulsations in malignant wounds, or a sudden increase in pain should prompt a swift assessment of the patient.
Cancer treatments such as radiotherapy, chemotherapy, or surgery: Chemoradiotherapy-induced myelosuppression commonly manifests as thrombocytopenia and often results in increased risk of bleeding. In addition, newer agents such as Bevacizumab have direct effects on tumour angiogenesis, with recognised complications of bowel perforation and delayed healing after surgery. Local inflammation around surgery or radiotherapy sites also results in an increased risk of bleeding.
Systemic complications of cancer: Liver disease, biliary obstruction or bowel problems can lead to deficiencies in clotting factors and an increased bleeding tendency. Some patients may have an underlying coagulopathy due to the illness itself. Disseminated Intravascular Coagulation (DIC) is seen in many forms of cancer. Thrombocytopenia and platelet dysfunction is also commonly seen in haematological malignancies and other condition such as thrombotic thrombocytopenic purpura due to cancer or chemotherapy.
Drug treatments such as anticoagulants or non-steroidal anti-inflammatory agents: There are many drugs that interfere with platelet function (such as aspirin, clopidogrel), usually prescribed to patients with tumours. The use of anticoagulants such as warfarin and low molecular weight heparin will also increase bleeding risk.
Concurrent illness, including infection: Local infection within tumour cavities can also increase the risk of bleeding. If an infection is suspected antibiotic therapy should be considered to reduce this risk.

Symptoms [6,7]

Bleeding is a frequent problem for patients with advanced cancer, with approximately 10% of all patients having at least one episode and almost 30% in patients with hematologic malignancies (2). These episodes may range from low-grade oozing to major episodic bleeding or even catastrophic bleeds. Patients may develop acute catastrophic bleeding, episodic major bleeding, or low-volume oozing. Bleeding may present as bruising, petechiae, epistaxis, haemoptysis, hematemesis, haematochezia, melena, haematuria, or vaginal bleeding.

Diagnosis/Assessment [6]

In the event of severe haemorrhage, or if the risk of a bleed is thought to be significant, a decision should be made regarding the most appropriate place of care for the patient. A multidisciplinary discussion may be needed to reach an informed decision about possible treatment options. Facilities for highly specialised interventions (e.g., specialist surgery, radiotherapy, or interventional radiology) may not be available in smaller centres. So, the decisions about what is required to manage a patient’s bleeding problem should be made at an early stage.

General approach to the management of bleeding in cancer patients

The following steps are a suggested means of assessing a cancer patient who presents with bleeding. It should only be used as a guide, and should not undermine a patient- tailored approach:

Where is/are the site(s) of bleeding?
1. For external bleeding: apply a dressing to reduce bleeding and protect the wound from trauma and infection.

Evidence

Level Grade PMID Nº

How large is the bleed?

The following should be considered:

1. Pulse, lying and standing BP (a postural blood pressure drop is often the first sign of blood loss)
2. Blood analysis with complete blood count, coagulation profile and a metabolic panel should be mandatory (to check for dehydration; also a disproportionately high urea may suggest a gastrointestinal bleeding source). Consider securing IV access at this point.
3. Fluid resuscitation to maintain blood pressure and vital organ perfusion. Indications may include a positive shock index characterized by a pulse rate (in beats per minute) greater than the systolic blood pressure (in mmHg).

Are there any reversible local or systemic causes?
1. Review medications and consider stopping any drugs that adversely affect clotting. For patients on anticoagulant drugs for deep venous thrombosis (DVT) or a pulmonary embolus (PE), an overall assessment of likely risks versus benefit on continuing treatment needs to be made and ideally communicated with the patient.
2. Where there appears to be bleeding from several different sites, consider an underlying coagulopathy and whether this should be corrected (may need to consult a local haematologist for advice).
3. If infection is thought to precipitate haemorrhage, consider wound swabs and cultures for microbiological identification of pathogens and antimicrobial sensitivities
Are there any immediate local measures that can be used?
Decide on most appropriate place of care for the patient, both now and in the event of deterioration.
Regularly review the treatment plan and ensure that planned management is documented and communicated clearly to all staff involved in the patient’s treatment.

Analysis should include a complete blood count, coagulation profile, and a complete metabolic panel with assessment of liver enzymes and function. It may be useful to perform imaging studies including computed tomography or angiography of the area suspected of bleeding, and/or endoscopy. Possible contributing factors including comorbidities, medications, and recent therapeutic interventions should be examined. If the patient is on anticoagulation therapy, the risks of further bleeding versus those of clotting should be examined and discussed. Use of oral anticoagulants has been associated with genitourinary cancer in atrial fibrillation patients with haematuria, so it is important to consider stopping it, and to carefully evaluate these patients for the cause of haematuria.

Therapeutic Strategy [8,9,10.11,12,13,14,15,16,17]

Evidence Level Grade PMID Nº

- - The goal of care is to consider therapies in patients at high risk of bleeding or suffering from its effects. It is also important to consider the patient’s estimated life expectancy, which I may involve the use of prognostic models.
  - Individualized treatment depends on several factors, including the underlying cause(s), the likelihood of reversing or controlling the underlying aetiology. I
  - If the patient’s life expectancy and overall quality of life warrants it, then management of an acute bleeding episode consists of general resuscitative measures. I
  - If the patient’s goals of care are palliative, then management may include measures to stop the bleeding without full resuscitative measures. Comfort measures only may be most I appropriate for end-stage patients.
  - In catastrophic bleeding, patients and their families should be prepared for the visually and mentally disturbing effects. Encourage the use of dark sheets, towels, blankets, and 2 clothing. Fast acting sedatives such as intravenous or subcutaneous midazolam should be available.
  - Discontinuation of causative/exacerbating agents: anti-inflammatories, anticoagulants, delay chemotherapy or radiation therapy. I
  - Consider systemic versus local therapy strategies. 2

A 3382303 24122413

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- - Transfusions of whole blood or blood products can be given to resuscitate patients who are hemodynamically unstable and actively bleeding. I A
  - Vitamin K can be used to correct coagulation for patients on warfarin or those with deficiencies of the vitamin K-dependent clotting factors (factors II, VII, IX, X). Vitamin K can be I A given orally, subcutaneously, or intravenously.
  - Tranexamic acid has not been studied in advanced cancer, but it reduces mortality due to bleeding, blood loss and transfusion requirements by approximately one-third. The 2 B recommended dose is 10 mg/kg per dose given IV every 6–8 hours, with no benefit to doses above 1 gram.

Local Therapies

Therapy Procedure

Dressings, packing, and topical agents • Use topical agents including absorbable gelatine or collagen for bleeding skin lesions. Nasal, vaginal, or rectal bleeding can be limited 3 B with packing. Use topical application of Moh’s paste and Monsel’s solution for vaginal bleeding.

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Radiation therapy (RT)

Endoscopic procedures Transcutaneous embolization

Surgery

RT decreases gastrointestinal bleeding. haemoptysis, haematuria, and vaginal bleeding. In hemodynamically stable patients who can 2 be transported to the radiation department, RT to palliate bleeding can be effective within the first 24 to 48 hours. Treatment regimens: single treatments of 8-10 Gy, intermediate courses of 4-8 Gy given in 3-5 treatments, or longer courses of 30-45 Gy in 10-15 treatments. Fewer side effects with shorter treatment courses.
To identify and treat bleeding tumours in the visualized organs. Treatment options: cauterization, argon plasma coagulation, implantation I of clips, injections of epinephrine or other sclerosing agents, or laser therapy.
In patients able to lie down, bleeding can be identified and selectively catheterized and embolized. Pre-existing coagulopathies must be 2 correct, and the patient must be well hydrated. Successful haemostasis is reached in 70-99% of patients, but rebleeding may occur. Complications include bruising or hematoma at the site, bleeding, spring migration, vessel occlusion, or post-embolization syndrome.
Procedures to relieve bleeding may include vessel ligation or resection of a bleeding tumour and/or organ. It is also important to consider 3 the anaesthesia risk.

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Treatment for selected sites of haemorrhage

Site Procedure

Skin lesions

Hemoptysis

Use of non-adherent dressings, surgical excision, RT, or other ablative therapy; superficial lesions may be treated sufficiently with laser 2 B or cryotherapy; palliative RT with a short, hypo fractionated regimen such as 20 Gy delivered in 5 daily fractions or 20 Gy in 2 weekly

fractions. Electrochemotherapy that combines a cytotoxic drug (e.g., bleomycin) with electrical impulses has been shown to have response rates of 77-87%.

Therapies include bronchoscopy interventions, angiography and embolization, or radiation therapy. Rigid bronchoscopy is more useful 2 B for rapid suctioning of large volume bleeding, options for interventions may include balloon tamponade, iced saline lavage, Nd-YAG laser coagulation, electrocautery, or argon plasma coagulation. Haemostasis has been reported in 60% (for Nd-YAG laser) to 100% (for argon

plasma coagulation). Bronchial artery angiography and embolization may be appropriate for lesions that are not amenable to bronchoscopy. RT results in haemostasis in 80–97% of haemoptysis patients.

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Vaginal bleeding

Gastrointestinal bleeding Haematuria

Topical therapies include application of Moh’s paste or Monsel’s solution to areas of vaginal bleeding, or vaginal packing which may 3 soaked with paraformaldehyde. Interventional radiology services can perform uterine or iliac artery embolization, using mechanical devices such as coils or sclerosing agents. A more invasive treatment option can be surgical ligation of vessels. Palliative RT can also be directed at the uterus and/or cervix.
Palliative RT has been used to treat bleeding from a variety of gastrointestinal tumours. Haemostasis has been reported in 50–73% of 2 patients with locally advanced gastric cancer treated with radiation.
Initial therapies include bladder irrigation and discontinuing medications that increase bleeding risk. Surgical options may include transurethral resection of the bladder with coagulation, or cystectomy with urinary diversion. RT achieves 50-92% haemostasis, with a range of 3-8 Gy/fraction. Embolization of branches of the anterior trunk of the iliac can also be performed. Alum or prostaglandins can be 2 instilled into the bladder, with varying rates of haemostasis.

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References

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Cartoni C, Niscola P, Breccia M, et al. Hemorrhagic complications in patients with advanced hematological malignancies followed at home: An Italian experience. Leuk Lymphoma 2009;50:387-91
JP Dutcher. Hematologic abnormalities in patients with nonhematologic malignancies. Hematol Oncol Clin North Am 1987; 1: 281–299.
Escobar A, Salem AM, Dickson K, Johnson TN, Burk KJ, Bashoura L, Faiz SA. Anticoagulation and bleeding in the cancer patient. Support Care Cancer. 2022 Oct;30(10):8547-8557. doi: 10.1007/s00520-022-07136-w. Epub 2022 May 17. PMID: 35579752.
Johnstone C, Rich SE. Bleeding in cancer patients and its treatment: a review. Ann Palliat Med. 2018 Apr;7(2):265-273. doi: 10.21037/apm.2017.11.01. Epub 2017 Dec 18. PMID: 29307210.
Reuben DB, Mor V, Hiris J. Clinical symptoms and length of survival in patients with terminal cancer. Arch Intern Med 1988;148:1586-91.
Krishnan MS, Epstein-Peterson Z, Chen YH, et al. Predicting life expectancy in patients with metastatic cancer receiving palliative radiotherapy: The TEACHH model. Cancer 2014;120:134-41.
Hutten BA, Prins MH, Gent M, et al. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: A retrospective analysis. J Clin Oncol 2000;18:3078-83
Ker K, Edwards P, Perel P, et al. Effect of tranexamic acid on surgical bleeding: Systematic review and cumulative meta-analysis. BMJ 2012;344:e3054.
Crane CH, Janjan NA, Abbruzzese JL, et al. Effective pelvic symptom control using initial chemoradiation without colostomy in metastatic rectal cancer. Int J Radiat Oncol Biol Phys 2001;49:107-16.
Inoperable non-small-cell lung cancer (NSCLC): A Medical Research Council randomised trial of palliative radiotherapy with two fractions or ten fractions. Report to the Medical Research Council by its Lung Cancer Working Party. Br J Cancer 1991;63:265-70.
McLaren DB, Morrey D, Mason MD. Hypofractionated radiotherapy for muscle invasive bladder cancer in the elderly. Radiother Oncol 1997;43:171-4.
Yan J, Milosevic M, Fyles A, et al. Ahypofractionated radiotherapy regimen (0-7-21) for advanced gynaecological cancer patients. Clin Oncol (R Coll Radiol) 2011;23:476-81.
Hartsell WF, Scott CB, Bruner DW, et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 2005;97:798-804.
Hague J, Tippett R. Endovascular techniques in palliative care. Clin Oncol (R Coll Radiol) 2010;22:771-80.
Macbeth FR, Bolger JJ, Hopwood P, et al. Randomized trial of palliative two-fraction versus more intensive 13-fraction radiotherapy for patients with inoperable non-small cell lung cancer and good performance status. Medical Research Council Lung Cancer Working Party. Clin Oncol (R Coll Radiol) 1996;8:167-75.
Eleje GU, Eke AC, Igberase GO, et al. Palliative interventions for controlling vaginal bleeding in advanced cervical cancer. Cochrane Database Syst Rev 2015;5:CD011000.
Khatib R, Ludwikowska M, Witt DM, Ansell J, Clark NP, Holbrook A, Wiercioch W, Schünemann H, Nieuwlaat R. Vitamin K for reversal of excessive vitamin K antagonist anticoagulation: a systematic review and meta-analysis. Blood Adv. 2019 Mar 12;3(5):789-796. doi: 10.1182/bloodadvances.2018025163. PMID: 30850385; PMCID: PMC6418499.
Chen YI, Barkun AN, Soulellis C, et al. Use of the endoscopically applied hemostatic powder TC-325 in cancer-related upper GI hemorrhage: Preliminary experience (with video). Gastrointest Endosc 2012;75:1278-81.
Leblanc S, Vienne A,Dhooge M,et al.Early experience with a novel hemostatic powder used to treat upper GI bleeding related to malignancies or after therapeutic interventions(with videos).Gastrointest Endosc 2013;78:169-75.
Shabunin AV, Bagateliya ZA, Korzheva IY, Lebedev SS. Neotlozhnaia khirurgicheskaia pomoshch’ bol’nym rakom tolstoĭ i priamoĭ kishki, oslozhnennym krovotecheniem [Urgent surgical care for patients with colon cancer complicated by hemorrhage]. Khirurgiia (Mosk). 2017;(12):46-51. Russian. doi: 10.17116/hirurgia20171246-51. PMID: 29286030.
Kähler KC, Egberts F, Gutzmer R. Palliative treatment of skin metastases in dermato-oncology. J Dtsch Dermatol Ges. 2013 Nov;11(11):1041-5; quiz 1046. doi: 10.1111/ddg.12197. Epub 2013 Sep 9. PMID: 24015966.
Chaw CL, Niblock PG, Chaw CS, et al. The role of palliative radiotherapy for haemostasis in unresectable gastric cancer: Asingle-institution experience. Ecancermedicalscience 2014;8:384
Cameron MG, Kersten C, Vistad I, et al. Palliative pelvic radiotherapy of symptomatic incurable rectal cancer – a systematic review. Acta Oncol 2014;53:164-73.
Abt D, Bywater M, Engeler DS, et al. Therapeutic options for intractable hematuria in advanced bladder cancer. Int J Urol 2013;20:651-60.

SEDATION

22.1 SEDATION IN CANCER PATIENT

Authors: Inês Pinheiro and Nuno A. Cordeiro Evidence

Definition Level Grade PMID Nº

Therapeutic measure for the treatment of severe and refractory symptoms (commonly pain, dyspnea, seizures, delirium and psychomotor agitation) or emerging clinical conditions (e.g., massive bleeding or suffocation). It consists of the use of sedative drugs to induce a decrease in the state of consciousness, to alleviate suffering not treatable by other methods and in a way that is ethically acceptable to the patient, family, and health team.

Concepts

- We define refractory symptoms to those in which available therapeutic options (i) do not adequately alleviate suffering, (ii) do not provide relief within an appropriate time frame, or (iii) are associated with intolerable adverse effects.
- The Richmond Agitation Sedation Scale – Palliative Version (RASS-PAL) is often used to assess the degree of sedation and agitation of palliative patients (recommended by the European Palliative Care Association.

Richmond Agitation Sedation Scale – Palliative Varsion (RASS-PAL)

25210083 28432090

19858355 18411017

32967659 18685365

28432090 25210083

24684942 32967659

https://www.interiorhealth.ca/sites/default/files/PDFS/826582-richmond-agitation-sedation-scale.pdf

General indications and measures

- Indicated for all patients with terminal illness, to relieve severe symptoms refractory to other forms of treatment.
- The patient should be evaluated by a Palliative Care Specialist to find out if they have reversible/treatable factors that may be contributing to the patient’s deterioration, as well as to ensure that available treatments have already been provided.
- Requires multidisciplinary team evaluation and prior discussion with the patient and family.

Sedative therapy

Administration of sedative therapy usually requires an initial dose (bolus) to promote adequate relief of symptoms, followed by maintenance therapy (infusion or intermittent bolus). Usually, the level of sedation should be that necessary to alleviate suffering. The route of administration may be intravenous (IV), intramuscular (IM), subcutaneous (SC) or rectal. In certain situations, medications may be administered by stomata or gastrostomies.

- Drugs
  - Opioids: many patients are already on opioid therapy to relieve dyspnoea or pain; the dose can be titrated and should not be discontinued when the patient feels comfortable.
  - Benzodiazepines and other therapies: Midazolam is the drug that is normally used because it has a short onset of action and can be combined with other drugs; chlorpromazine, levopromazina, and phenobarbital are other options.

The drugs used in palliative sedation are shown in Table 1, detailing in pharmacology and recommended doses. Since there are no randomized studies in this area, the level of evidence for its use is V, based on expert opinion and case series.

Evidence Level Grade PMID Nº

25210083

32967659

21378301 32961218

25210083 22412129

32967659 8089815

22412129 19858355

Evidence

Drug	Pharmacology	Dose	Peak of action	Notes
1ST LINE
Midazolam	Short-acting GABAA agonist Quickly penetrates the CNS Short duration of action Infusion is necessary to maintain the effect	Bolus: 1 to 5 mg SC or IV up to 5/5 minutes to achieve rass -PAL -2 level of consciousness. Infusion: if necessary to maintain the level of consciousness of RASS-PAL -2, 0.5- 1mg/h IV or SC with dose titration at 50% after 4h if the effect is insufficient, always with bolus of 5mg in SOS up to 1/1h.	IV – 2.5 min SC – 20 min	It can be combined with morphine or haloperidol. In case of malnutrition, hepatic or renal failure, the initial dose should be shorter and the interval between each titration longer. Disadvantage: risk of paradoxical agitation and apnoea
2ND LINE
Lorazepam	GABAA Agonist Slow start of action Longer effect compared to midazolam	Bolus: 1 to 4 mg IV every 2 to 6 hours or 1 to 2 mg SC every 6 to 8 hours Infusion: 0.01 to 0.1mg/Kg/h IV or SC	2h	Can be combined with antipsychotic drugs Disadvantage: prolonged onset of action, with risk of overdose
Levomepromazine	Muscarinic antagonist, Alpha1, Alpha2, 5HT2A, H1 and dopaminergic D2 Analgesic and anaesthetic effect Start of action in 20-40 minutes	Bolus: 12.5 -25mg IV, SC ou IM Infusion: 2 -3mg/h 12.5mg in 1/1h SOS if needed	0.5-1.5h	Maximum daily dose of 300mg It is commonly used in agitation and may be associated with Midazolam
Chlorpromazine	Like levopromazina	Bolus 12.5 -25mg IV or IM every 4 -12 hours Infusion: 3 -5mg/h	15 minutes	There is rectal formulation 100mg 6 -6h or 12-12h Disadvantage: no sc formulation (due to risk of tissue damage and pain)

Level Grade PMID Nº

V B 25210083

8089815

22412129

V	B	25210083
		8089815
		22412129
V	B	25210083
		8089815
		22412129

V B 25210083

8089815

22412129

Evidence Level Grade PMID Nº


Propofol	Ultrafast-acting	Bolus: 0.5mg-	1.5-2 min
	anaesthetic, which	1.5mg/Kg
	provides global CNS	Infusion: IV 0.3 –
	depression, through	3mg/Kg/h
	GABAA
	potentiation and
	possibly glutamate
	inhibition

V B 25210083

8089815

22412129

Therapeutic strategy
End-of-life strategies, including palliative sedation, should be addressed beforehand with the patient and family, explaining the risks/benefits and goals.	V	C	19858355	25210083
Identify situations in which palliative sedation is indicated: symptoms that cause intolerable suffering, do not yield to other therapies, or that available therapies do not provide	V	B	19858355	25210083
relief within an appropriate time frame or are associated with intolerable adverse effects.
– Most common symptoms: dyspnoea, psychomotor agitation, pain, seizures, and delirium. Continuous sedation should be considered only in terminal situations where death is expected to occur within hours or a few days.	V	B		25210083
Intermittent sedation may be indicated to promote temporary relief, pending the benefit of other therapeutic strategies.	V	C		25210083
Sedation may be considered for non-physical symptoms such as refractory depression, anxiety, and agitation (no consensus).	V	C		25210083
Candidate patients should be evaluated by a physician to try palliative care.	V	B	19858355	25210083
Patient evaluation requires the exclusion of treatable/reversible complications such as sepsis, metabolic events, iatrogenic drugs (e.g., pleural effusion, urinary retention, etc.).	V	B		19858355
The decision to maintain nutrition and hydration should be independent of the palliative sedation strategy. There is no consensus in this area, and it should be discontinued or	V	C	19858355	25210083
reduced if there are adverse effects associated with (e.g. exacerbation of suffering) with artificial nutrition/hydration.

References

1.Cherny, N. I. ESMO clinical practice guidelines for the treatment of refractory symptoms at the end of life and the use of palliative sedation. Ann. Oncol. 25, (2014). 2.Abarshi, E. et al. International variations in clinical practice guidelines for palliative sedation: Asystematic review. BMJ Supportive and Palliative Care 7, (2017). 3.Cherny, N. I. et al. Framework recommended by the European Palliative Care Association (EAPC) for the use of sedation in palliative care. Palliat. Med. 23, (2009).

Rietjens, J. A.C. et al. Palliative sedation in a specialized acute palliative care unit in an oncology hospital: comparison of patients who die with and without palliative sedation. J. Management of pain symptoms. 36, (2008).
Kremling, A. & Schildmann, J. What do you mean by “palliative sedation”? BMC Palliat. Care 19, (2020). 6.Eisenchlas, J. H. Palliative sedation. Curr. Think. Support. Palliat. Care 1, 207–212 (2007).

7.Bush, S. H. et al. The Modified Richmond Agitation-Sedation Scale for Palliative Care Inpatients (RASS-PAL): A pilot study exploring validity and feasibility in clinical practice. BMC Palliat. Care 13, (2014). 8.Ghafoor, V. L. & Silus, L. S. Development of policies, standard orders and quality assurance monitoring for palliative sedation therapy. Am. J. Heal. Pharm. 68, (2011).

9.Arantzamendi, M. et al. Clinical aspects of palliative sedation in prospective studies. Asystematic review. Journal of Pain and Symptom Management 61, (2021). 10.Maltoni, M., Scarpi, E. & Nanni, O. Palliative sedation in end-of-life care. Current Opinion in Oncology 25, (2013).

Cherny, N. I. & Portenoy, R. K. Sedation in the Management of Refractory Symptoms: Guidelines for Evaluation and Treatment. J. Palliat. Care 10, (1994). 12.Maltoni, M. et al. Palliative sedation in end-of-life care and survival: a systematic review.Journal of Clinical Oncology 30, (2012).

23. PROTHESIS AND ENDOPROTHESIS

Authors: Irene López Rojo, Óscar Alonso Casado, Gloria Ortega Pérez and Santiago González Moreno.

Evidence

Level Grade

SELF-EXPANDING METALLIC STENT VERSUS EMERGENCY SURGERY

23.1 MANAGEMENT OF OBSTRUCTIVE COLON CANCER.

Introduction

Bowel obstruction is a frequent complication in oncologic patients, characterized by the impossibility of intake and/or absence of transit (1). It is a complication that usually overshadows the oncologic outcome (2). Diagnosis is based on clinical findings (absence of intestinal transit, bloating, nausea and vomiting, abdominal pain) and imaging tests to assess location and possible associated complications (3).

Obstruction represents 80% of the emergencies produced by colorectal cancer, affecting 15-30% of these patients, compared to intestinal perforation, which affects 1-10%, representing 20% of the remaining emergencies (4). Between 7-29% of malignant colorectal malignancies debut with intestinal obstruction, 70% of them affecting the left colon (5). Obstruction requires urgent decompression (6), but the management will depend on the location of the obstruction (Figure 1) and the individual features of the patient.

Learning objetives

To understand the differences in the management of colon obstructive cancer depending on its location.
Become familiar with the current controversy regarding surgery or stenting of left colon tumours.
To know the advantages and disadvantages of each therapeutic options.
Current status for decision making in obstructive colon cancer. Latest guidelines
1. LEFT COLON CANCER:

For decades, the treatment of obstructive tumours of the left colon consisted of emergency stomas with or without tumour resection, implying greater morbidity and mortality than elective surgery and a worse oncologic outcome. In this context, the appearance of colonic self-expandable metallic stents (SEMS) appears as an alternative to emergency surgery, with good results and less clinical impairment. However, there is still controversy concerning one or another approach, each having its own benefits and associated risks and complications (Table 1).

- 1. SURGERY

Surgical treatment options for obstructive left colon cancer are diverse and controversial. For years, the gold standard has been resection of the primary tumour, presenting a high rate of complications and temporary or permanent stomas, of which around 70% never receive stoma reversal surgery, thus significantly reducing their quality of life, and those who do receive it, present a morbidity of around 36% (2). Some authors have demonstrated the possibility of performing anastomosis in urgent surgery in selected patients with low risk of anastomotic dehiscence (absence of peritoneal contamination, low morbidity, good nutritional status, and young patients) (7) with the aim of minimizing the reduction in quality of life and the need for further surgeries (8). In this context, resection of the primary tumour with terminal colostomy, despite being the safest surgical option due to the absence of anastomotic complications, presents a significant reduction in quality of life and problems associated with reconstructive surgery (Table 1).

The alternative to this surgical procedure is the performance of a diverting colostomy to solve the intestinal obstruction, followed by the resection of the primary tumour in a second surgery (with or without colostomy closure) and possible stoma reversal in a third time. This alternative allows intestinal preparation and good pre-surgical staging; however, many patients do not complete the two or three surgeries initially planned (2).

A Cochrane systematic review could not conclude which of the two surgical alternatives (resection and colostomy vs. diverting colostomy) was more favourable for the treatment of obstructive left colon cancer (9). However, current guidelines recommend the Hartmann procedure (tumour resection and colostomy) leaving derivative colostomy for patients with high surgical risk and unresectable tumours in which SEMS could not be placed (3).

Regarding the extent of colonic resection, the 2017 WSES (World Society of Emergency Surgery) guidelines (3) recommend segmental resection versus total or subtotal colectomy (except for those cases with ischemia or perforation of the cecum or suspected synchronous tumour in the right colon).

PMID Nº

- 1. SEMS (self-expandable metallic stents)

Endoscopic SEMS placement is proposed as a therapeutic option in two situations: palliative treatment and bridge to surgery. This procedure allows the correct oncological staging, avoiding two-stage surgery and reducing the probability of definitive colostomy with the consequent worsening of quality of life and associated complications (2).

The most successful tumour location for SEMS placement are those tumours located in the left colon, between the splenic angle and the rectum (about 10cm from the annus). A stent placement success rate of 88.9% and a clinical success rate of 77.8% have been described (5).

MAIN COMPLICATIONSASSOCIATED WITH THE USE OF SELF-EXPANDABLE METALLIC STENTS:

Patients in whom a stent has been placed may present these stent-specific complications (10) (Table 1):

- Perforation. 5-30% may be immediate or delayed and is the most serious complication. Higher risk in patients with previous radiotherapy or treatment with bevacizumab (11).
- Migration: 8.4% (5.5-11.3%). More frequent if the stent falls short of the lesion, in coated stents or in extraluminal obstructions (12).

-• Abdominal pain.

-• Tenesmus. In rectal stents

- Bleeding: around 5%.
- Recurrence of obstruction: 13.1% (9.6-16.6%), in relation to tumor growth within the stent (11).
- Non-resolution of the obstruction: 4.5% (2.3-6.8%), failure in the technique, or existence of obstruction at another level (11).

Both perforation and bleeding or failure of stent self-expansion require urgent surgery, with a 30-day mortality rate of around 4%, directly associated with SEMS placement (13). A correlation has been observed between colonic perforation during SEMS placement and the use of bevacizumab (14), and therefore it is recommended to avoid it in patients in whom it is being or is expected to be used (15).

Besides the vital risk, incidental perforation is of concern because of its relationship with worsening oncologic outcome. This complication has been associated with a higher rate of global, locoregional (16, 17) and peritoneal recurrence (18). The manipulation of the tumour itself during colonoscopy can produce tumour cell dissemination to the peripheral circulation, or embolisms in the lymphatic channels. A meta-analysis has recently been published that relates colonic decompression with SEMS to a higher rate of perineural and lymphatic invasion, proposing that the pathological characteristics are modified, worsening the prognosis, and increasing the risk of locoregional (1.7 times) and peritoneal (2.4 times) recurrence (18).

An increase in circulating ctDNA (circulating cell free DNA) has been observed in 83% of cases after stenting, with an increase in its concentration as the days passed (19). This finding raises the question of the ideal time to perform surgery after stent decompression. On one hand, if the interval is widened, the patient’s general conditions improve, and the risk of surgical complications is reduced (15). On the other hand, early surgery in the first 7 days seems to be related to a better oncologic prognosis (20), despite having a longer hospital stay, a lower number of laparoscopic surgeries and a higher stoma rate than those surgeries that are postponed for more than 10 days after stenting (21).

SEMS placement as a bridge to surgery allows improving the general condition of the patient, performing intestinal preparation, and proposing minimally invasive surgeries in resectable patients (2, 22). It increases the possibility of laparoscopic surgery at a second time, against the need for open surgery when this is performed as an emergency in the context of intestinal obstruction (6).

- 1. WHICH IS THE BEST OPTION?

A meta-analysis was published in 2015(12) comparing SEMS placement with emergency surgery for obstructive colon cancer. In terms of early complications, surgery presented greater morbidity (29.7% vs. 12.3% in SEMS), with these data being inverted in late complications (13.6% surgery vs. 24.3% in SEMS). SEMS related mortality was 2.3% (1.4-2.8%) compared to 8.6% (7.2-10%) in the surgical group, demonstrating that prosthesis placement reduced the risk of mortality associated with obstruction, improved survival, and allowed early initiation of chemotherapy treatment. The need for a permanent stoma was significantly lower in the prosthesis group (10.9% vs. 40.9%). However, prosthesis placement was associated with a higher rate of tumour perforation (7.4% vs. 0.5%) due to erosion of the colonic walls by the prosthesis ends (12). In a meta-analysis published in 2017, despite describing a similar morbidity and mortality between both approaches, it reported a lower rate of temporary and permanent stomas and a higher success of primary anastomosis when this is performed after a prosthesis decompression (28). In terms of quality of life, it seems that stent placement is superior to surgery both in the short and long term, justified by the rapid recovery and absence of stoma (12).

The long-term oncologic safety of colonic stents remains a matter of controversy. On one hand, meta-analyses have been published that find no differences in overall and disease-free survival between urgent surgery and stent placement and differed surgery (23). Recent studies (12) report similar overall and disease-free survival for patients in both groups. In addition, a recently published randomized clinical trial (24) (ESCO trial) also found no differences. On the other hand, two meta-analyses of randomized controlled clinical trials (18, 25) report a higher recurrence rate in those patients in whom decompression of the tumour obstruction was performed by stenting (37% with stenting vs. 25.9% after emergency surgery) despite maintaining the same overall and disease-free survival at 3 years. However, emergency surgery presents a morbidity of 30-60% with an associated mortality of 10-30% (5).

Level Grade PMID Nº

Table 1 : Benefits and risks of treating obstructive left colon cancer by stent decompression or emergency surgery. SEMS (self-expandable metallic stents).

1. RECTAL CANCER:

Neoadjuvant chemoradiotherapy in rectal cancer has demonstrated its benefit in reducing locoregional recurrence and tumour staging (2). In addition, there is an increasing tendency to associate chemotherapy before and after the chemoradiotherapy regimen to improve the control of micro metastases and help organ preservation (26).

Obstructed rectal tumours should be considered locally advanced tumours and as such should be managed in a multidisciplinary manner, directing surgical manoeuvres exclusively to the resolution of the obstruction (3). It is recommended to avoid resection of the primary tumour in favour of performing a lateral transverse colostomy to allow correct tumour staging and treatment with neoadjuvant chemoradiotherapy (3). The placement of rectal SEMS is not recommended since their placement has been associated with chronic pain and tenesmus (3).

1. RIGHT COLON CANCER:

Obstructive right colon cancer has traditionally been treated with urgent surgery, with published rates of 86-97% of cases with resection and primary anastomosis (27, 28), even in elderly patients. However, morbidity (54% vs 30%), anastomotic leak rate (16% vs 4%) and mortality (14.5% vs 2.6%) are significantly higher in emergency surgery versus scheduled surgery (27).

However, the performance of ileostomies has been reserved for patients with hemodynamic instability and high peritoneal contamination, due to their morbidity (acute renal failure, dehydration, etc.), generating a dilemma among surgeons regarding the risk of an anastomotic complication versus a stoma-related morbidity (2).

In the case of the right colon, the indication of colonic prosthesis as a bridge to programmed surgery is very controversial due to the technical impossibility when the obstruction is in the cecum or ileocecal valve, as well as the difficulty of accessing the distal right colon (27). For this reason, there is little literature comparing emergency surgery with stent placement, and the existing literature presents many selection biases. Currently, it is only recommended for those cases with high surgical risk.

Level Grade PMID Nº

Conclusions

Bowel obstruction is a common complication in oncologic patients. Depending on its location and Etiology, there are different management options.
The diagnosis is clinical, but imaging tests allow us to identify the level of the obstruction and the related complications.
Obstructive colon cancer in the right colon is usually managed surgically. SEMS placement in obstructive right colon cancer is technically complex and not always feasible.
In the case of left obstructive colon cancer, there is controversy between urgent surgery or the use of SEMS as a bridge to deferred surgery.
Emergency surgery for obstructive colon cancer of the left colon is a resolutive treatment but it is associated with high morbimortality, and poor quality of life associated with the stomas’ creation that in many cases cannot be reversed.
SEMS placement as a bridge to surgery allows better staging of the patient, improvement of his general condition and minimally invasive surgical approaches.
SEMS placement improves the quality of life with respect to emergency surgery, and is associated with lower initial morbidity and mortality, although it presents its own complications and less definitive resolution of the obstructive problem than emergency surgical treatment.
Colon perforation is the most feared complication of SEMS, both because of the life risk and the possible worsening of the oncologic prognosis. It is recommended to avoid SEMS placement in patients treated with bevacizumab or other antiangiogenic agents.
There is controversy regarding long-term oncologic safety after stent placement, having been published a higher rate of recurrences, so it is recommended for patients in whom surgical morbimortality is high or the tumour is not potentially curable.
In rectal tumours, priority should be given to surgical resolution of the obstructive condition, avoiding colonic resections, and starting multidisciplinary neoadjuvant treatment as soon as possible.
In the case of extracolonic obstructions, the use of SEMS seems to have a lower clinical success rate.

References

CárdenasJ., Agamez, C. y Parra, S. Obstrucción intestinal maligna. Revisión de tema. Rev Colomb Cancerol. 2013;17(2):77-85
Yoo RN, Cho HM, Kye BH. Management of obstructive colon cancer: Current status, obstacles, and future directions. World J Gastrointest Oncol. 2021;13(12):1850-1862
Pisano M, Zorcolo L, Merli C, Cimbanassi S, Poiasina E, Ceresoli M, et al. 2017 WSES guidelines on colon and rectal cancer emergencies: obstruction and perforation. World J Emerg Surg. 2018(13);13:36
Endo S, Isohata N, Kojima K, Kadono Y, Amano K, Otsuka H, et al. Japan Colonic Stent Safe Procedure Research Group. Prognostic factors of patients with left-sided obstructive colorectal cancer: post hoc analysis of a retrospective multicenter study by the Japan Colonic Stent Safe Procedure Research Group. World J Surg Oncol. 2022;20(1):24
Flor-Lorente B, Báguena G, Frasson M, García-Granero A, Cervantes A, Sanchiz V, et al. Self-expanding metallic stent as a bridge to surgery in the treatment of left colon cancer obstruction: Cost-benefit analysis and oncologic results. Cir Esp. 2017;95(3):143-151
Recuenco CB, Septiem JG, Díaz JA, Vasallo IJT, de la Madriz AA, Carneros VJ, et al. Effect of self-expandable metal stent on morbidity and mortality and oncological prognosis in malignant colonic obstruction: retrospective analysis of its use as curative and palliative treatment. Int J Colorectal Dis. 2022;37(2):475-484
Biondo S, Parés D, Frago R, Martí-Ragué J, Kreisler E, De Oca J, Jaurrieta E. Large bowel obstruction: predictive factors for postoperative mortality. Dis Colon Rectum. 2004;47(11):1889-97
Breitenstein S, Rickenbacher A, Berdajs D, Puhan M, Clavien PA, Demartines N. Systematic evaluation of surgical strategies for acute malignant left-sided colonic obstruction. Br J Surg. 2007;94(12):1451-60
De Salvo GL, Gava C, Pucciarelli S, Lise M. Curative surgery for obstruction from primary left colorectal carcinoma: primary or staged resection? Cochrane Database Syst Rev. 2004(2):CD002101
Takahashi H, Okabayashi K, Tsuruta M, Hasegawa H, Yahagi M, Kitagawa Y. Self-Expanding Metallic Stents Versus Surgical Intervention as Palliative Therapy for Obstructive Colorectal Cancer: A Meta- analysis. World J Surg. 2015;39(8):2037-44
Watt AM, Faragher IG, Griffin TT, Rieger NA, Maddern GJ. Self-expanding metallic stents for relieving malignant colorectal obstruction: a systematic review. Ann Surg. 2007;246(1):24-30
Ribeiro IB, de Moura DTH, Thompson CC, de Moura EGH. Acute abdominal obstruction: Colon stent or emergency surgery? An evidence-based review. World J Gastrointest Endosc. 2019;11(3):193-208
Lee JM, Byeon JS. Colorectal Stents: Current Status. Clin Endosc. 2015;48(3):194-200
van Halsema EE, van Hooft JE, Small AJ, Baron TH, García-Cano J, Cheon JH et al. Perforation in colorectal stenting: a meta-analysis and a search for risk factors. Gastrointest Endosc. 2014;79(6):970-82
Van Hooft JE, Veld JV, Arnold D, Beets-Tan RGH, Everett S, Götz M, van Halsema EE, et al. Self-expandable metal stents for obstructing colonic and extracolonic cancer: European Society of Gastrointestinal Endoscopy (ESGE) Guideline – Update 2020. Endoscopy. 2020;52(5):389-407
Foo CC, Poon SHT, Chiu RHY, Lam WY, Cheung LC, Law WL. Is bridge to surgery stenting a safe alternative to emergency surgery in malignant colonic obstruction: a meta-analysis of randomized control trials. Surg Endosc. 2019;33(1):293-302
Balciscueta I, Balciscueta Z, Uribe N, García-Granero E. Long-term outcomes of stent-related perforation in malignant colon obstruction: a systematic review and meta-analysis. Int J Colorectal Dis. 2020;35(8):1439-1451
Balciscueta I, Balciscueta Z, Uribe N, García-Granero E. Perineural invasion is increased in patients receiving colonic stenting as a bridge to surgery: a systematic review and meta-analysis. Tech Coloproctol. 2021;25(2):167-176
Takahashi G, Yamada T, Iwai T, Takeda K, Koizumi M, Shinji S et al. Oncological Assessment of Stent Placement for Obstructive Colorectal Cancer from Circulating Cell-Free DNA and Circulating Tumor DNA Dynamics. Ann Surg Oncol. 2018;25(3):737-744
Kye BH, Kim JH, Kim HJ, Lee YS, Lee IK, Kang WKet al. The optimal time interval between the placement of self-expandable metallic stent and elective surgery in patients with obstructive colon cancer. Sci Rep. 2020;10(1):9502
Veld JV, Kumcu A, Amelung FJ, Borstlap WAA, Consten ECJ, Dekker JWT et al. Time interval between self-expandable metal stent placement or creation of a decompressing stoma and elective resection of left-sided obstructive colon cancer. Endoscopy. 2021;53(9):905-913
Arezzo A, Passera R, Lo Secco G, Verra M, Bonino MA, Targarona E et al. Stent as bridge to surgery for left-sided malignant colonic obstruction reduces adverse events and stoma rate compared with emergency surgery: results of a systematic review and meta-analysis of randomized controlled trials. Gastrointest Endosc. 2017;86(3):416-426
Amelung FJ, Burghgraef TA, Tanis PJ, van Hooft JE, Ter Borg F, Siersema PD, et al. Critical appraisal of oncological safety of stent as bridge to surgery in left-sided obstructing colon cancer; a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2018;131:66-75
Arezzo A, Forcignanò E, Bonino MA, Balagué C, Targarona E, Borghi F, Giraudo G, Ghezzo L, Passera R, Morino M; collaborative ESCO study group. Long-term Oncologic Results After Stenting as a Bridge to Surgery Versus Emergency Surgery for Malignant Left-sided Colonic Obstruction: A Multicenter Randomized Controlled Trial (ESCO Trial). Ann Surg. 2020;272(5):703-708
Yang P, Lin XF, Lin K, Li W. The Role of Stents as Bridge to Surgery for Acute Left-Sided Obstructive Colorectal Cancer: Meta-Analysis of Randomized Controlled Trials. Rev Invest Clin. 2018;70(6):269-278
Yoo RN, Kim HJ. Total neoadjuvant therapy in locally advanced rectal cancer: Role of systemic chemotherapy. Ann Gastroenterol Surg. 2019;3(4):356-367
Boeding JRE, Ramphal W, Rijken AM, Crolla RMPH, Verhoef C, Gobardhan PD, et al. A Systematic Review Comparing Emergency Resection and Staged Treatment for Curable Obstructing Right-Sided Colon Cancer. Ann Surg Oncol. 2021;28(7):3545-3555
Manceau G, Mege D, Bridoux V, Lakkis Z, Venara A, Voron T, et al. French Surgical Association Working Group. Emergency Surgery for Obstructive Colon Cancer in Elderly Patients: Results of a Multicentric Cohort of the French National Surgical Association. Dis Colon Rectum. 2019;62(8):941-951.

24. SURGICAL COMPLICATIONS

24.1 SEROMAS, BRUISES

Author: Alice Pimentel

Postoperative fluid collections, like seromas and hematomas, represent sequelae of procedures that ultimately contribute to impaired healing.(1)

SEROMA

Definition

Aseroma is a palpable collection of serous fluid containing blood plasma and/or lymph fluid located within the soft tissue.(2)

Etiology

Seroma is caused by a combination of various factors, including:

Surgical dead space.(3) • Shearing between tissue surfaces.(1) • Transection of lymphatic channels (e.g., mastectomy, lymph node excision).(3,4,5)

Complications

The presence of a seroma can contribute to complications such as:

Wound infection • Wound dehiscence and delayed healing • Skin-flap necrosis • Delayed recover (6)

Prevention

When large seroma collections are expected, due to wide dissection or lymphatic channel disruption, prophylactic measures include:

Compression dressings
Drainage
- Suction-closed drains are preferred
- Timing of drain removal varies (usually when drainage is less than 20-40ml per 24h)
- After drain removal, fluid re accumulation is not uncommon (7)

Treatment

Small seromas
- Usually treated with needle aspiration and compression dressings
- Repeated needle aspiration is often necessary8
- Compression occludes lymphatic leaks and limits fluid re accumulation
- Small collections typically resolve in a few weeks, but more persevering collections can be seen, persisting for months in some cases, with subsequent inconvenience and patient disability7
Large/persisting seromas
- Negative pressure wound therapy – ideal for open wounds with persistent lymph leaks
- Surgery
  - Reserved for large persisting seromas
  - Exploration should be done in the operating room4
  - The fibrotic capsule of the seroma should be completely removed or cauterized7 .

Evidence

Level Grade PMID Nº

HEMATOMA

Definition

Collection of blood and clot. In a post-surgical scenario, this event results in elevation and discoloration of the wound edges, local swelling, and discomfort. It can also occur in deeper locations of surgical dissection resulting in fluid collections at risk of infection.(4)

Etiology

Post-surgical hematoma is caused by a combination of various factor, including:

Inadequate hemostasis.(4) • Dissection of large amount of soft tissue.(1) • Patient’s haemostatic profile.

Complications

The presence of a hematoma can contribute to complications such as:

Superficial (wound) and deep infection.(4) • Wound dehiscence and delayed healing.
Compromised airway – if rapidly expansion of a neck hematoma (e.g., thyroidectomy) . •Anaemia and haemorrhagic chock- if active profuse bleeding.

Prevention

The following measures should be routinely implemented to reduce the risk of hematoma formation:

Assessment of potential coagulopathy and cessation of antiplatelet and anticoagulant medications. • Cautious surgical haemostasis.
Placement of prophylactic drains – recommended in case of moderate/severe bleeding during surgery or wide dissection, especially of soft tissues.(1)
Compression dressings.

Treatment

Small hematomas
- Usually reabsorbed – this process is fast in serous cavities (e.g., peritoneum), but slower within soft tissues.(7)
- Ice therapy and compression dressings in wound hematomas.
Large wound hematomas (> 3- 4cm).
- Needle aspiration – if liquefied. – Drainage of clots.
  - Through a small incision or reopening of the wound. • Under sterile conditions and local anaesthesia.

Evidence Level Grade PMID Nº

Large deep tissue hematomas .
- May be reabsorbed. – Should be drained either surgically or percutaneously guided by image.
Rapidly enlarged hematomas.
- Should prompt urgent surgical intervention and proper haemostasis. – If rapidly expansion of a neck hematoma – emergent surgical drainage.
- A short-term drain can be left in place if necessary.

References

Bullocks, J., Basu, C., Hsu, P., & Singer, R. (2006). Prevention of Hematomas and Seromas. Seminars in Plastic Surgery, 20(4), 233–240.doi:10.1055/s-2006-951581
De Rooij, L., Bosmans, J. W. A. M., van Kuijk, S. M. J., Vissers, Y. L. J., Beets, G. L., & van Bastelaar, J. (2020). A systematic review of seroma formation following drain-free mastectomy. European Journal of Surgical Oncology.doi:10.1016/j.ejso.2020.10.010
Janis, J. E., Khansa, L., & Khansa, I. (2016). Strategies for Postoperative Seroma Prevention. Plastic and Reconstructive Surgery, 138(1), 240–252.doi:10.1097/prs.000000000000224 4.Chu D.I., & Agarwal S (2014). Postoperative complications. Doherty G.M.(Ed.), CURRENT Diagnosis & Treatment: Surgery, 14e. McGraw Hill.
Aho, J. M., Nickerson, T. P., Thiels, C. A., Saint-Cyr, M., & Farley, D. R. (2016). Prevention of postoperative seromas with dead space obliteration: A case-control study. International Journal of Surgery, 29, 70–73.doi:10.1016/j.ijsu.2016.03.004
Carless, P. A., & Henry, D. A. (2006). Systematic review and meta-analysis of the use of fibrin sealant to prevent seroma formation after breast cancer surgery. British Journal of Surgery, 93(7), 810–819.doi:10.1002/bjs.5432
Schein, M., Rogers, P. N., Leppäniemi, A., & Rosin, D. (2013). Schein’s Common Sense Prevention and Management of Surgical Complications: For surgeons, residents, lawyers, and even those who never have any complications (1st ed.). TFM Publishing.
Hashemi, E., Kaviani, A., Najafi, M., Ebrahimi, M., Hooshmand, H., & Montazeri, A. (2004). World Journal of Surgical Oncology, 2(1), 44. doi:10.1186/1477-7819-2-44

LYMPHEDEMA

Authors: Alícia Guadalupe da Silva Oliveira and Mariana Estevam

Introduction

Lymphedema is defined as the abnormal accumulation of interstitial fluid and fibroadipose tissues. It can be classified as primary or secondary depending on aetiology and presentation. [1]

This chapter pretends to summarize this problematic.

Symptoms

- - Insidious onset.

For patients who had previously undergone a lymph node dissection and/or radiation, lymphedema is typically characterized by slowly progressive ipsilateral swelling of an arm following axillary node dissection or a leg following inguinal node dissection [2].

- - Pain in the affected limb.

Affected patients may initially experience aching pain in the affected limb.

- - Feeling of heaviness, tightness, and discomfort. This feeling commonly accompanies swelling.
  - Changes in skin.

At onset, swelling in the affected limb is typically characterized as “soft” and “pitting.” Pitting reflects movement of the excess interstitial water in response to pressure. Testing for pitting involves applying firm pressure to the oedematous tissue for at least five seconds. If an indentation remains after the pressure is released, pitting oedema is present. Pitting is variable in patients with lymphedema and is generally absent with progressive lymphedema. With worsening lymphedema, dermal thickening becomes clinically apparent and the skin becomes dry and firm with less pitting due to cutaneous fibrosis and adipose deposition. The overlying skin of the affected limb also becomes hyperkeratotic, which can lead to verrucous and vesicular skin lesions.

- - Location.

The swelling may first be apparent only in the proximal portion of the limb, or it can affect only a portion of the distal limb, including the digits. It may also include the corresponding quadrant of the trunk. As an example, a patient with breast cancer may complain of swelling over the ipsilateral breast and/or upper chest wall.

- - Effects on motion.

Patients may develop a restricted range of motion in the affected limb as a result of the increased weight, which may limit their ability to perform activities of daily living (ADLs) and affect body image.

3. Physical exam and clinical classification

The physical exam should evaluate the vascular system, skin, and soft tissue and include palpation of the lymph nodes [2].

A positive Stemmer sign is indicative of lymphedema [3]. It is characterized by a thickened skin fold at the base of the second toe or second finger. The examiner’s inability to lift the skin of the affected limb compared with the contralateral limb is a positive sign. It is also described as difficulty lifting the skin of the dorsum of the fingers or toes of the affected limb [4]. A positive Stemmer sign can be found in any stage of lymphedema. While it is possible to have a false negative Stemmer sign, a false positive sign is rare.

Evidence

Level Grade PMID Nº

Clinical severity — Several classification systems are used to describe the severity of lymphedema as mild (grade or stage I), moderate (grade or stage II), or severe (grade or Level Grade PMID Nº

stage III), based on the physical condition of the extremity (e.g., limb girth, limb volume, skin changes).

Clinical classification

Clinical stage –staging system of the International Society of Lymphology (ISL) to characterize the severity of lymphedema [5]. It combines two criteria to diagnose and classify lymphedema: the “softness” or “firmness” of the limb (reflecting fibrotic soft tissue changes) and the outcome after elevation.

Stage 0 – Stage 0 (or Ia) lymphedema is a subclinical or latent condition where swelling is not yet evident despite impaired lymph transport, subtle alterations in tissue fluid/composition, and changes in subjective symptoms. Most patients are asymptomatic, but some report a feeling of heaviness in the limb. Stage 0 can be transitory or may exist months or years before overt lymphedema occurs (ie, stage I, II, or III).
Stage I – Stage I lymphedema represents an early accumulation of fluid relatively high in protein content (in comparison with “venous” oedema) that subsides with limb elevation, usually within 24 hours (picture 1). Pitting may occur. An increase in various types of proliferating cells may also be seen. This is sometimes called reversible oedema. Stage I corresponds to a mild grade of lymphedema.
Stage II – Stage II lymphedema involves more changes in solid structures, limb elevation alone rarely reduces tissue swelling, and pitting is manifest (picture 2). Later in Stage II, the limb may not pit as excess subcutaneous fat and fibrosis develop. This is sometimes called spontaneously irreversible lymphedema. Stage II corresponds roughly to a moderate grade of lymphedema above.
Stage III – Stage III lymphedema encompasses lymphostatic elephantiasis where pitting can be absent and trophic skin changes such as acanthosis, alterations in skin character and thickness, further deposition of fat and fibrosis, and warty overgrowths have developed (picture 3). Stage III corresponds to a severe grade of lymphedema above. It should be noted that a limb may exhibit more than one stage, which may reflect alterations in different lymphatic territories.

Extremity girth — The American Physical Therapy Association (APTA) uses girth as an anthropometric measurement to classify lymphedema. The maximum girth difference between the affected and unaffected limb is used to determine the class of lymphedema [6]:

Mild lymphedema – Maximum girth difference <3 cm
Moderate lymphedema – 3 to 5 cm difference
Severe lymphedema – Difference >5 cm

Clinical grade — The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) categorizes lymphedema based upon exam findings and the presence of functional impairment [7]. These correspond roughly to the clinical stages described below.

Grade 1 – Trace thickening or faint discoloration
Grade 2 – Marked discoloration, leathery skin texture, papillary formation, limiting instrumental activities of daily living (ADL)
Grade 3 – Severe symptoms limiting self-care and activities of daily living

Etiology

Lymphedema occurs when the lymphatic load exceeds the transport capacity of the lymphatic system, which causes filtered fluid to accumulate in the interstitium [2]. This imbalance between interstitial fluid production and transport may be due to primary or secondary causes. Persistent accumulation of lymphatic fluid promotes proliferation of adipocytes and deposition of collagen fibres in the extracellular matrix and around capillary and collecting lymphatics and can produce tissue fibrosis. Secondary lymphedema occurs as the result of other conditions or treatments.

Estimates of the prevalence of lymphedema range widely and depend upon age, gender, and aetiology [8-10]. Worldwide, the most common cause of lymphedema is filariasis

but in the developed world, the majority of cases of lymphedema are secondary and due to malignancy or its treatment [9,11].

Cancer-associated lymphedema can occur in several ways: Obstruction of lymphatic channels or nodes – Tumour compression of lymphatic channels or nodes can result in the development of lymphedema.

- Infiltration of lymphatic vessels
- Lymphatic dissection/lymphadenectomy – Lymphadenectomy is associated with an increased risk of lymphedema regardless of the cancer type. It is the primary cause of lymphedema in patients with breast cancer, prostate cancer, endometrial cancer, cervical cancer, and melanoma [1,11-12].
- Regional lymph node irradiation can destroy lymphatic channels, decreasing lymphatic transport. However, radiation therapy alone is rarely enough to result in development of lymphedema.
- Medication effects [13].

There are other malignancies that are also associated with an increased risk of lymphedema (16%) [9,11,14] and can be distributed as follows: Sarcoma – 30%, Lower extremity melanoma – 28%, Gynaecologic cancer – 20%, Genitourinary cancer – 10%, Head and neck cancer – 3%.

The most common cancer-associated with lymphedema is breast cancer related to lymphatic dissection. The greatest incidence is within the first two years following the cancer diagnosis. It is estimated that nearly three fourths of women who will develop lymphedema after axillary lymph node dissection do so within three years of surgery [11-14-16]. Nowadays treatment of breast cancer does not mandate axillary node dissection in women with a clinically node-negative axilla. Instead, many women undergo sentinel lymph node biopsy, which is associated with a significant reduction in lymphedema [17].

Risk factors for lymphedema supported by the best evidence following surgery for breast cancer include [16]:

- Axillary node dissection (hazard ratio [HR] 2.5-2.6)
- Increasing number of axillary nodes removed (HR 1.2)
- Mastectomy rather than wide local excision (odds ratio [OR] 2.7-7.4)

Other factors that can increase the risk in post-operative patients include [11]: Extent of primary surgery, tumor location, delayed wound healing, postoperative infection, postoperative hematoma or seroma.

Radiation therapy –Radiation therapy is an additive risk factor for those who have undergone axillary node dissection [18-19], despite existing a risk for lymphedema following adjuvant radiation therapy.

Factors significantly associated with an increased risk of lymphedema included:

- Pathologically involved nodes (11 versus 6%, if nodes were negative)
- Removal of more than 14 nodes at surgery (9.5 versus 6 %)
- Presence of extracapsular extension (13.4 versus 6.9 %)
- Grade 2 or 3 breast tumour (11 versus 3 %)
- Administration of adjuvant chemotherapy (10.5 versus 7 %)

Obesity — Obesity is an independent risk factor for lymphedema, particularly in cancer survivors in patients with a BMI (kg/m2) >30.

Diagnostic studies

An adequate history and physical examination- additional imaging is reserved for cases in which the history and physical do not yield a definitive diagnosis, in cases where lymphatic obstruction is suspected, or to rule out other causes.

History and physical — A careful medical history is important in the evaluation of the patient with suspected lymphedema [1,14]. Components of the history that should be addressed include the age of onset, areas of involvement, associated symptoms, progression of symptoms (e.g. pain, swelling, tightness), past medical history (e.g., infections, radiation therapy), surgical history, travel history, family history and current medications.

The presence of lymphedema is usually suggested by the following findings:

- The oedema is typically localized and characterized by slowly progressive ipsilateral swelling of an upper extremity following axillary node dissection or lower extremity following inguinal node dissection [1].
- A history of cancer treatment or trauma.
- Absence of a cause of generalized oedema (e.g., heart failure, nephrotic syndrome). Occasional patients have both lymphedema and generalized oedema
- The presence of cutaneous and subcutaneous thickening, which is seen in severe lymphedema [4].
- Nonpitting oedema is suggestive of lymphedema; but pitting may be present in early stages of lymphedema.

Extremity measurements

Limb circumference — Circumferential measurements on the affected and contralateral arm – simple and inexpensive [20-21]. A difference >2 cm between the affected and contralateral arm is considered clinically significant. Changes in circumference may be more difficult to detect in obese patients and they are subject to variation due to differences in muscle mass.

Level Grade PMID Nº

Limb volume — Limb volume can be estimated from limb circumference measurements or determined through water displacement, optoelectronic volumetry, or calculation of limb volume using the truncated cone formula.

- Water displacement – Water displacement detects changes in volume of <1%. For patients with limb lymphedema, volume difference of 200 mL or more between the affected and opposite limbs is typically considered as a cut-off point to define lymphedema [20-21]. This method is the usual method to measure extremity lymphedema in clinical trials. Traditional volumeters are large, expensive, and prone to leakage.
- Optoelectronic volumetry – Volume can also be assessed utilizing infrared, optoelectronic measurements. This technique uses infrared beams to scan the limb and calculate a volume. The optoelectronic volumetry method is more reliable than water displacement volumetry for the measurement of upper extremity lymphedema [22,23].
- Limb volume calculation with the truncated cone formula – In this technique, upper or lower limb measurements are performed at 4 cm intervals beginning at the wrist and ankle, respectively. The measurements are then converted to volume using the truncated cone formula [22,23].

Further evaluation

Duplex ultrasound – can be used to exclude other aetiologies in the differential diagnosis (eg deep venous thrombosis [DVT], venous insufficiency) but also directly aids in the diagnosis by identifying the cause of lymphatic compression and tissue alterations [2].

Imaging the lymphatic system –lymphoscintigraphy, computed tomography (CT), magnetic resonance (MR) imaging/MR lymphography, and indocyanine green (ICG) lymphangiography. All these imaging studies suffer from a lack of standardized techniques, resulting in variable results. [24,25]

Treatment

Lymphedema is a chronic condition that can be managed but is generally not cured [1] and is often difficult to treat, particularly if progression to later stages has already occurred, it tends to progress over time and to impact day-to-day activities [26].

Lifelong care, in combination with psychosocial support, with a multimodal therapy in order to improve patient comfort and to reduce limb volume [1,27].

Conservative approaches should be administered in clinics with expertise in the treatment of lymphedema. In patients whom conservative treatment options fail, may be candidates for surgical therapy, which may include lymphatic surgery, or soft tissue reduction.

Conservative, multimodal therapy consists of general measures for self-care which are applicable to all stages of lymphedema, along with varying levels of compression therapy and physiotherapy, with the choice of specific intervention depending upon the stage of disease (mild, moderate, severe). It is important to note that there is limited and predominantly low-quality evidence to support any of the treatment options [1,28].

Pharmacotherapy

Pharmacologic treatments are not generally used, as no drug has definitively been shown to be beneficial. Other treatments are considered experimental. A limited number of patients who fail conservative treatment options may be candidates for surgical therapy, which may include lymphatic surgery, or soft tissue reduction

Level Grade PMID Nº

There are no recommended pharmacologic agents for patients with lymphedema.Diuretics are of little benefit in the management of chronic lymphedema and may promote the II development of volume depletion.

Experimental therapies:

- - Low-level laser therapy – possible benefits: potential decrease in fibrosis, stimulation of macrophages and the immune system, and a suggested role in encouraging lymph II angiogenesis, which may both stimulate surviving lymphatic pathways and encourage the formation of new pathways.
  - Pharmacological therapy – Preclinical reports have suggested that anti-inflammatory therapies targeting the T cell-mediated inflammatory response may be beneficial in preventing lymphedema after lymphatic injury.

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Therapeutic Strategy Level Grade PMID Nº

General measures- Although there is no scientific evidence supporting the efficacy of any of these measures, they are reported in the International Society of Lymphology (ISL). IV

- - Self-monitoring – Patients should be taught how to monitor their lymphedema, including serial measurement of limb circumference. They should be counselled to report any changes.
  - Limb elevation – Simple elevation of the affected limb may reduce swelling, particularly in the early stage of lymphedema. However, elevation alone is not an effective long- term therapy.
  - Diet and exercise – Maintenance of ideal body weight should be encouraged. Besides being a contributory factor for the development of lymphedema, obesity may also limit the effectiveness of compression pumps or sleeves. Exercise and weight training are generally safe and should be allowed, with a properly fitted compression garment worn during exercise.
  - Avoid skin infection/injury – Meticulous skin hygiene and nail care should be maintained to prevent infection that may result in cellulitis (skin moisturizers and topical antibiotic solutions, wearing gloves, sunscreen). Whenever possible, patients should avoid medical procedures in the affected limb, exposure to temperature extremes. All episodes of cellulitis should be treated with antibiotics that have adequate coverage for gram-positive cocci.

Conservative treatment by severity

- - At risk for postoperative lymphedema – ISL stage 0, in additional to general measures, physiotherapy to improve mobility. However, there is insufficient evidence II regarding the effectiveness of preventive treatments containing manual lymphatic drainage to recommend their use in this population.
  - Mild lymphedema – ISL stage I, in addition to general measures, physiotherapy may be done (simple lymphatic drainage, a commonly taught self-help manoeuvre) and II compression garments. The degree of compression should be guided by the patient’s vascular status and their ability to tolerate compression. Manual lymphatic drainage is safe and may offer an additional benefit to compression therapy for reducing limb volume in those with lymphedema following breast surgery.
  - Moderate lymphedema – ISL stage II, in additional to general measures, it is suggested that intensive physiotherapy is performed, usually in the form of complete II decongestive therapy. The treatment is like that of mild lymphedema, but with a more intensive treatment schedule for physiotherapy and compression, and generally under

the care of a physiotherapist, rather than self-directed. Support for the efficacy of manual lymphatic drainage (MLD) comes from both observational studies, and from small, randomized trials. However, not all studies have found a benefit for MLD over standard management for reducing limb volume.

- - Severe lymphedema – ISL stage III, in addition to general measures, intensive physiotherapy, usually in the form of complete decongestive therapy, for those without specific II contraindications. Patients may also benefit from intermittent pneumatic compression (IPC), in addition to general measures and intensive physiotherapy. If the lymphedema

is controlled and can be reduced with IPC, a compression garment should be worn to maintain limb girth and prevent further swelling.

Compression therapy

- - Compression bandaging – In early stages of lymphedema, external compression is used to diminish ultrafiltration and is achieved with repetitively applied, multi-layered II padding materials and short-stretch (also called low-stretch) bandages. For more severe disease, compression bandaging is applied to the affected limb after manual lymphatic drainage. Apossible alternative to standard bandages is kinesio tape.
  - Compression garments – Once the lymphedema reaches its nadir, compression garments (lymphedema compression sleeve and gauntlet or hosiery) are used to provide maintenance therapy to prevent fluid reaccumulation. The highest compression tolerated by the patient is likely to be the most beneficial. Compression bandages or garments may lead to the onset or progression of lymphedema if they are restrictive or not properly fitted. When correctly fitted and worn properly, compression garments may reduce swelling.
  - Intermittent pneumatic compression – (IPC; also called sequential pneumatic compression) is another method of compression therapy. IPC may be most effective in addition to a multimodality lymphedema treatment and may also be an alternative maintenance program for lymphedema patients who have difficulty in performing self- manual lymphatic drainage secondary to weakness, fatigue, or range of motion deficits. It may also be beneficial for lymphedema patients that are unable to use compression bandaging or garments due to skin allergies from the materials used in these compression products. However, for the management of patients with lymphedema, the ideal pressure for the pump is not known. IPC is usually applied daily or five times per week. The optimal duration of IPC is also unknown.
  - Physiotherapy – Manual lymphatic drainage (MLD) is a massage-like technique that is performed by specially trained physical therapists. A multimodality program combining MLD with meticulous skin and nail care, therapeutic exercise, and limb compression using repetitively applied multi-layered padding materials and short-stretch bandages is referred to as complete decongestive therapy.

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- - Compression bandaging – In early stages of lymphedema, external compression is used to diminish ultrafiltration and is achieved with repetitively applied, multi-layered padding materials and short-stretch (also called low-stretch) bandages. For more severe disease, compression bandaging is applied to the affected limb after manual lymphatic drainage. Apossible alternative to standard bandages is kinesio tape.
  - Compression garments – Once the lymphedema reaches its nadir, compression garments (lymphedema compression sleeve and gauntlet or hosiery) are used to provide maintenance therapy to prevent fluid reaccumulation. The highest compression tolerated by the patient is likely to be the most beneficial. Compression bandages or garments may lead to the onset or progression of lymphedema if they are restrictive or not properly fitted. When correctly fitted and worn properly, compression garments may reduce swelling.
  - Intermittent pneumatic compression – (IPC; also called sequential pneumatic compression) is another method of compression therapy. IPC may be most effective in addition to a multimodality lymphedema treatment and may also be an alternative maintenance program for lymphedema patients who have difficulty in performing self- manual lymphatic drainage secondary to weakness, fatigue, or range of motion deficits. It may also be beneficial for lymphedema patients that are unable to use compression bandaging or garments due to skin allergies from the materials used in these compression products. However, for the management of patients with lymphedema, the ideal pressure for the pump is not known. IPC is usually applied daily or five times per week. The optimal duration of IPC is also unknown.
  - Physiotherapy – Manual lymphatic drainage (MLD) is a massage-like technique that is performed by specially trained physical therapists. A multimodality program combining MLD with meticulous skin and nail care, therapeutic exercise, and limb compression using repetitively applied multi-layered padding materials and short-stretch bandages is referred to as complete decongestive therapy.

Phases – Complete decongestive therapy generally consists of a two-phase treatment program. Success is dependent in part upon the availability of physicians, nurses, and physical therapists who are trained in these techniques.

- - - First phase – includes meticulous skin and nail care to prevent infection, therapeutic exercise, manual lymphatic drainage, and limb compression using repetitively applied, multi-layered padding materials and short-stretch bandages. The patients receive daily therapy five days per week, with monitoring of limb circumference. The usual duration of the first stage is two to four weeks.
    - Second phase (maintenance phase) is intended to conserve and optimize the benefit obtained in the first phase. It consists of compression garments worn during waking hours and, if necessary, self-compression bandaging at night, skin care, continued exercises, and as necessary, self-manual lymphatic drainage. Limb circumference and volume measurements should be monitored every six months.
  - Contraindications – Experts have described several possible contraindications and/or precautions to complete decongestive therapy, and in particular, to manual lymphatic drainage. Although commonly followed, these contraindications are predominantly based upon theoretical concerns, and there are few clinical data to support them.

Level Grade PMID Nº

- - - Active cellulitis, neoplasm, or other inflammations of the infected limb.
    - Moderate-to-severe heart failure.
    - Acute deep vein thrombosis.
  - Relative contraindications, such that patients may be treated but may warrant monitoring, include:
    - Uncontrolled hypertension
    - Diabetes mellitus
    - Asthma
    - Limb paralysis
  - Modifications for patients in palliative care – As many as 85% at the end of life have oedema, and it can severely affect comfort, mobility, and quality of life. For these patients, the clinical context and goals of care must be carefully considered.

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Monnin-Delhom ED, Gallix BP, Achard C, et al. High resolution unenhanced computed tomography in patients with swollen legs. Lymphology 2002; 35:121.
Ripley B, Wilson GJ, Lalwani N, et al. Initial Clinical Experience with Dual-Agent Relaxation Contrast for Isolated Lymphatic Channel Mapping. Radiology 2018; 286:705.
Casley-Smith JR. Alterations of untreated lymphedema and it’s grades over time. Lymphology 1995; 28:174.
Leung EY, Tirlapur SA, Meads C. The management of secondary lower limb lymphoedema in cancer patients: a systematic review. Palliat Med 2015; 29:112.
Stuiver MM, ten Tusscher MR, Agasi-Idenburg CS, et al. Conservative interventions for preventing clinically detectable upper-limb lymphoedema in patients who are at risk of developing lymphoedema after breast cancer therapy. Cochrane Database Syst Rev 2015; :Cd009765.
Shaitelman SF, Cromwell KD, Rasmussen JC, et al. Recent progress in the treatment and prevention of cancer-related lymphedema. CACancer J Clin 2015; 65:55.
Shaw C, Mortimer P, Judd PA. Arandomized controlled trial of weight reduction as a treatment for breast cancer-related lymphedema. Cancer 2007; 110:1868.
Showalter SL, Brown JC, Cheville AL, et al. Lifestyle risk factors associated with arm swelling among women with breast cancer. Ann Surg Oncol 2013; 20:842.
Devoogdt N, Christiaens MR, Geraerts I, et al. Effect of manual lymph drainage in addition to guidelines and exercise therapy on arm lymphoedema related to breast cancer: randomised controlled trial. BMJ 2011; 343:d5326.
De Groef A, Van Kampen M, Dieltjens E, et al. Effectiveness of postoperative physical therapy for upper-limb impairments after breast cancer treatment: a systematic review. Arch Phys Med Rehabil 2015; 96:1140.
Ezzo J, Manheimer E, McNeely ML, et al. Manual lymphatic drainage for lymphedema following breast cancer treatment. Cochrane Database Syst Rev 2015; :Cd003475.
Huang TW, Tseng SH, Lin CC, et al. Effects of manual lymphatic drainage on breast cancer-related lymphedema: a systematic review and meta-analysis of randomized controlled trials. World J Surg Oncol 2013; 11:15.
Andersen L, Højris I, Erlandsen M, Andersen J. Treatment of breast-cancer-related lymphedema with or without manual lymphatic drainage–a randomized study. Acta Oncol 2000; 39:399.
Pappas CJ, O’Donnell TF Jr. Long-term results of compression treatment for lymphedema. J Vasc Surg 1992; 16:555.
Hara H, Hamanaka N, Yoshida M, et al. Variability in compression pressure of multi-layer bandaging applied by lymphedema therapists. Support Care Cancer 2019; 27:959.
Partsch H, Flour M, Smith PC, International Compression Club. Indications for compression therapy in venous and lymphatic disease consensus based on experimental data and scientific evidence. Under the auspices of the IUP. Int Angiol 2008; 27:193.
Martins Jde C, Aguiar SS, Fabro EA, et al. Safety and tolerability of Kinesio Taping in patients with arm lymphedema: medical device clinical study. Support Care Cancer 2016; 24:1119.
Brennan MJ, Miller LT. Overview of treatment options and review of the current role and use of compression garments, intermittent pumps, and exercise in the management of lymphedema. Cancer 1998; 83:2821.
Poage E, Singer M, Armer J, et al. Demystifying lymphedema: development of the lymphedema putting evidence into practice card. Clin J Oncol Nurs 2008; 12:951.
Badger CM, Peacock JL, Mortimer PS. A randomized, controlled, parallel-group clinical trial comparing multilayer bandaging followed by hosiery versus hosiery alone in the treatment of patients with lymphedema of the limb. Cancer 2000; 88:2832.
Dini D, Del Mastro L, Gozza A, et al. The role of pneumatic compression in the treatment of postmastectomy lymphedema. Arandomized phase III study. Ann Oncol 1998; 9:187.
Desai SS, Shao M, Vascular Outcomes Collaborative. Superior Clinical, Quality of Life, Functional, and Health Economic Outcomes with Pneumatic Compression Therapy for Lymphedema. Ann Vasc Surg 2020; 63:298.
Zuther E. Pathology. In: Lymphedema Management: The Comprehensive Guide for Practitioners, Von Rohr M (Ed), Thieme Medical Publishers Inc, New York 2005. p.45
Steindal SA, Ranhoff AH, Bredal IS, et al. Last three days of life in the hospital: a comparison of symptoms, signs and treatments in the young old and the oldest old patients using the Resident assessment instrument for palliative care. Int J Older People Nurs 2013; 8:199.
Maiya AG, Olivia ED, Dibya A. Effect of low-level laser therapy in the management of postmastectomy lymphoedema. Physiotherapy Singapore 2008; 11:2.
Gardenier JC, Kataru RP, Hespe GE, et al. Topical tacrolimus for the treatment of secondary lymphedema. Nat Commun 2017; 8:14345.
Kilbreath SL, Ward LC, Lane K, et al. Effect of air travel on lymphedema risk in women with history of breast cancer. Breast Cancer Res Treat 2010; 120:649. 51.Graham PH. Compression prophylaxis may increase the potential for flight-associated lymphoedema after breast cancer treatment. Breast 2002; 11:66.
Kerchner K, Fleischer A, Yosipovitch G. Lower extremity lymphedema update: pathophysiology, diagnosis, and treatment guidelines. JAm Acad Dermatol 2008; 59:324.
Tomita K, Yokogawa A, Oda Y, Terahata S. Lymphangiosarcoma in postmastectomy lymphedema (Stewart-Treves syndrome): ultrastructural and immunohistologic characteristics. J Surg Oncol 1988; 38:275.
McWayne J, Heiney SP. Psychologic and social sequelae of secondary lymphedema: a review. Cancer 2005; 104:457.
Ogawa Y. Recent advances in medical treatment for lymphedema. Ann Vasc Dis. 2012;5(2):139-144. doi:10.3400/avd.ra.12.00006

Others

Air travel – Although, in theory, lymphedema may be exacerbated at high altitude or during air travel, since the ambient atmosphere pressure is less than the relative outlet transcapillary pressure within the superficial tissues, studies suggest that the risk from air travel of precipitating or worsening lymphedema is very low [1,50]. The use of compression sleeves is debated but some suggest that compression devices may be helpful in longer duration air travel >4.5hours [51].

Complications

Skin infection – Lymphedematous skin is at risk for recurrent infections, including cellulitis, erysipelas, and lymphangitis [52]. Typical manifestations include erythema, pain, and tenderness and systemic signs, such as fever, may not be present.

Lymphangiosarcoma – A rare secondary malignant tumor, can occur in patients with chronic lymphedema. It is usually seen in patients with massive and protracted edema. It is classically described as occurring in the postmastectomy patient (Stewart-Treves syndrome) [53].

Psychological morbidity – Lymphedema results in psychological morbidity and a reduced quality of life, including aspects of emotional, functional, physical, and social well-being [54]. Psychological problems seen in women with chronic lymphedema after treatment for breast cancer include anxiety, depression, sexual dysfunction, social avoidance, and exacerbation of existing psychiatric illness.

Surgical referral

Surgical referral is appropriate for any patient with lymphedema, particularly those in whom conservative management has failed or if the patient is motivated to pursue additional treatments. Lymphedema may be surgically treated with physiologic interventions designed to restore lymphatic circulation including lymph node transplantation and lymphovenous bypass, which have shown promising results, particularly in patients with early-stage lymphedema. Reductive (excisional) procedures that aim to remove fibrofatty tissues deposited in lymphedematous limbs may be useful for patients with late-stage lymphedema.

FISTULA

Authors: Alice Pimentel and Joana Noronha

A fistula is an abnormal connection between two epithelialized hollow spaces or organs and can occur in many parts of the body. There is a wide range of cancer-related fistula. Level GradeEvidence

The most common originate in the GI system, between two segments of the intestine, between the intestine and other hollow viscus or between the intestine and the skin.1 The most frequent cancer-related fistula are:

- - Enterocutaneous (between GI tract and the skin). • Colo-vesical (between colon and urinary bladder). • Rectovaginal (between the rectum and the vagina).

Definition

Enterocutaneous fistulas communicate between the lumen of the gastrointestinal tract and the skin. Entero-atmospheric fistulas communicate between the lumen of the gastrointestinal tract and the wound of an open abdomen.(2)

Classification

Enterocutaneous fistulas can be classified according to source, output volume, and etiology:

– By organ of origin:

- - type I (abdominal, esophageal, gastroduodenal) • type II (small bowel) • type III (large bowel) • type IV (entero-atmospheric, regardless of origin)
By the quantity of their output:
- - Alow-output fistula drains less than 200 mL/day • Amoderate-output fistula drains between 200 and 500 mL/day • A high-output fistula drains more than 500 mL/day
By etiology:
Iatrogenic/Postoperative (75 – 85%):
- Caused by anastomotic leak (50%), missed enterotomy (45%) or erosion by foreign material.(8)
- More frequent in oncologic surgery associated with extensive adhesiolysis
- Preoperative factors that increase the likelihood of the development of a postoperative fistula include Crohn disease, malnutrition, immunosuppression, traumatic injury, infection, smoking, and emergency procedures.(9, 10)
Spontaneous (15-25%): inflammatory bowel disease (most common), malignancy, appendicitis, diverticulitis, radiation, tuberculosis/actinomycosis, and ischemia.(3)

Presentation and diagnosis

Enterocutaneous fistulas may have various presentations, ranging from small, localized abscesses to septic shock:

Typically, patients will present with a suspected surgical site infection with or without hound enteric drainage.
There should be a high index of suspicion in patients who present with a localized wound infection several weeks postoperatively.
It is not uncommon an initial purulent drainage followed by enteric contents within the subsequent days.
The diagnosis of an enterocutaneous fistula is made once an enteric drainage is confirmed through the abdominal wall. (4)

Evaluation modalities

Imaging with gastrointestinal oral contrast, or injection of contrast into the fistulous tract (fistulogram) usually confirms the diagnosis.

A CT-scan with oral contrast is often the initial imaging study:

Highly specific in delineating the fistulous tract anatomy
Rules out the presence of an abdominopelvic abscess and other differential diagnosis
Assists with surgical planning

MRI is used when a fistula is not revealed in the CT-scan, but clinical suspicion remains. Magnetic resonance imaging has the advantage of better soft tissue characterization.

PMID Nº

Management Level GradeEvidence

The rate of spontaneous enterocutaneous fistulas closure varies between 15 and 75%. Fistulas are significantly less likely to close spontaneously after 4 weeks. (6)

Conservative management

The initial treatment of an enterocutaneous fistula is conservative and imperative due to the ongoing gastrointestinal losses:.

Fluid resuscitation
- Should be aggressive and initiated promptly .
Electrolyte repletion.
- Hyponatremia, hypokalemia, and acidosis are frequent.
Antibiotics.
Nutritional support.
- Volume differs according to fistula output.
- Total parenteral nutrition is usually needed if: fistula output >1.5 L/day, less than 75 cm of intestinal length prior to the fistula, or intestinal discontinuity. (6)
Drainage of abscesses.
Control of fistula drainage.
- No oral intake.
- Agents that decrease fistula output: anticathartics (loperamide), somatostatins analogues (octreotide), antisecretory drugs (omeprazole) and cholestyramine.(7)
Skin protection.

Conservative treatment should be adapted according to the clinical scenario:

Low-output fistula: a trial of bowel rest for several days after initial fluid and electrolyte resuscitation and sepsis control may lead to spontaneous closure of the fistula.
High output fistulas: Fluid and electrolyte losses should be replaced intravenously to avoid dehydration and profound metabolic instability.(6)
Sepsis: Major cause of mortality. Immediate attention to goal-directed fluid resuscitation, electrolyte correction, and critical care support is essential. The underlying intra- abdominal septic source must be controlled, and broad-spectrum antibiotics covering enteric organisms should be initiated rapidly. Source control may be obtained with percutaneous drainage.(4)

Surgical treatment

Indicated in fistulas that do not close spontaneously (approximately 40%).
Should always be preceded by optimization of the patient’s status.
Associated with decreased mortality if performed after 6 months.(4)
The aim is to restore gastrointestinal tract continuity
Multiple surgical procedures may be necessary
Treatment should be individualized based on the patient’s overall medical condition and radiologic and intraoperative finding
Should always entail a bowel resection and primary anastomosis. Oversewing or wedge resection of the fistula invariably results in a higher recurrence rate.(6)

References

J. Pfeifer; G. Tomasch; S. Uranues (2011). The surgical anatomy and etiology of gastrointestinal fistulas., 37(3), 209–213. doi:10.1007/s00068-011-0104-7
Sheldon, Rowan; Eckert, Matthew (2017). Surgical Critical Care. Surgical Clinics of North America, 97(6), 1425–1447. doi:10.1016/j.suc.2017.08.002
Gribovskaja-Rupp, I., & Melton, G. (2016). Enterocutaneous Fistula: Proven Strategies and Updates. Clinics in Colon and Rectal Surgery, 29(02), 130–137.doi:10.1055/s-0036-1580732
Bhama, Anuradha R. (2019). Evaluation and Management of Enterocutaneous Fistula. Diseases of the Colon & Rectum, 62(8), 906–910. doi:10.1097/DCR.0000000000001424 5.Tuma F, Crespi Z, Wolff C J, et al. (April 22, 2020) Enterocutaneous Fistula: A Simplified Clinical Approach. Cureus 12(4): e7789. doi:10.7759/cureus.7789
Dumas RP, Moore SA, Sims CA. Enterocutaneous Fistula: Evidence based Management. Clin Surg. 2017; 2: 1435.
Polk, T. M., & Schwab, C. W. (2011). Metabolic and Nutritional Support of the Enterocutaneous Fistula Patient: A Three-Phase Approach. World Journal of Surgery, 36(3), 524- 533.doi:10.1007/s00268-011-1315-0
Osborn C, Fischer JE. How I do it: gastrointestinal cutaneous fistulas. J Gastrointest Surg 2009; 13:2068.
Burlew CC, Moore EE, Cuschieri J, et al. Sew it up! AWestern Trauma Association multi-institutional study of enteric injury management in the postinjury open abdomen. J Trauma 2011; 70:273.
Hu D, Ren J, Wang G, et al. Persistent inflammation-immunosuppression catabolism syndrome, a common manifestation of patients with enterocutaneous fistula in intensive care unit. J Trauma Acute Care Surg 2014; 76:725.

PMID Nº

25. EXERCISE IN CANCER PATIENTS

25.1 EXERCISE IN CANCER PATIENTS

Authors: Helena Guedes, Sofia Viamonte, Alberto Alves and Ana Joaquim

Definition

Evidence

Level Grade

PMID Nº

Cancer affected about 19.3 million people worldwide, being responsible for about 10 million deaths in 2020 .(1) Consequently, there are more cancer survivors – people living with and beyond cancer, from the moment of diagnosis until the end of life, with sequelae regarding the disease and therapy performed, as well as comorbidities associated with both.(2) Many survivors have physical and/or psychological side effects of cancer and treatments, with depression, pain and fatigue being the most frequent. Patients also report high sedentary lifestyle and physical inactivity, with physical deconditioning.(3,4)

Physical exercise across the cancer experience (PEACE), emphasize that physical exercise may have important implications for cancer control across the entire cancer experience(5) , with several studies showing that physical activity is an effective tool, eliciting benefits from prevention to post-treatment of this disease.(3)

The World Health Organization (WHO) defines physical activity as any bodily movement produced by skeletal muscles that requires energy expenditure. On the other hand, exercise is physical activity that is planned, structured, repetitive, and purposive in the sense that improvement or maintenance of one or more components of physical fitness is an objective. (6)

According to the latest guidelines of the American College of Sports Medicine (ACSM), exercise training and testing is generally safe for cancer survivors and every survivor should ´´avoid inactivity´´(3,7)” In addition, there is strong evidence coming from randomized clinical trials to conclude that specific doses of aerobic, combined aerobic plus resistance training, and/or resistance training could improve common cancer-related health outcomes, including anxiety, depressive symptoms, fatigue, physical functioning, and health-related quality of life. Implications for other outcomes, such as peripheral neuropathy and cognitive functioning, remain uncertain.(3)

Although, most of the evidence comes from studies in breast, prostate and coloretal cancer, which limits the ability to extrapolate their findings to other cancer types or advanced disease, physical activity should be encouraged by the multidisciplinary teams and physical exercise prescribed individually and adapted to the physical condition and comorbidities of each patient. The supervision by exercise professionals duly certified, increases the safety and effectiveness of the prescribed physical exercise.(2)

Symptoms and signs

The benefits of physical exercise are present throughout the cancer patient’s journey, demarcated in six periods: two prediagnosis (prescreening and screening/diagnosis) and four postdiagnosis (pretreatment, treatment, posttreatment, and resumption), according to the PEACE Framework. (5)

Regarding prevention, The Physical Activity Guidelines Advisory Committee (PAGAC) determined that, when comparing the incidence among individuals in the highest category of physical activity with individuals in the lowest, strong evidence demonstrated reduced risks of bladder, breast, colon, endometrial, esophageal adenocarcinoma, renal and gastric cancers, with relative risk reductions ranging from approximately 10 % to 20 %. (8,9)
Before treatments, as tool for optimizing the general state and functional of the patient (prehabilitation).(10-13) A systematic review of randomised controlled trials that investigated the effects of prehabilitation in patients undergoing intra-abdominal surgery for cancer, reported that although the content of prehabilitation programmes were heterogeneous ,there is unequivocal evidence that prehabilitation had beneficial effects on postoperative outcomes. (12) As well, a pilot study demonstrated that a supervised outpatient physical exercise training program for individual patients with locally advanced resectable rectal cancer during neoadjuvant chemoradiotherapy is safe, feasible for a large part of the patients, and seems able to prevent an often seen decline in physical fitness during treatment. (11)
During and after treatments: improves cardiorespiratory capacity, muscle strength, quality of life, sleep, fatigue and depression (grade 1, level A). (3,14-16) . According to the American Society Guidelines (ASCO) recent published Oncology providers should recommend regular aerobic and resistance exercise during active treatment with curative intent and may recommend preoperative exercise for patients undergoing surgery for lung cancer.(7)

From a general point of view, although with lower levels of evidence, physical exercise also seems to contribute to reducing the risk of relapse (17), for reduction of cancer and all- cause mortality (3) , as well as for the improved efficacy and tolerance to anticancer treatment . (18,19)

Therapeutic Strategys Level GradeEvidence

PMID Nº

Structured physical exercise lacks an integrated or other existing pathologies (2) . Evidence shows that physical exercise is safe during and after treatment and that the benefits are greater in exercise programs supervised compared to unsupervised exercise.(20,21)The teams must include health and physical exercise professionals, being the contact with the clinicians essential in the implementation and monitoring of training programs. All patients must undergo an assessment prior to exercise prescription, whose initial phase involves collecting data on the characterization of the oncological disease, previous comorbidities, physical activity habits, sleep assessment, psycho-emotional factors, as well as identification of factors that may influence adherence to treatment such as patient preference, issues related to accessibility, health literacy, among others; followed by the assessment of the physical fitness of each patient: cardiovascular parameters, flexibility, balance and coordination; muscle strength; cardiorespiratory fitness; and assessment of body composition. (18) When individuals are on active cancer cancer treatment, working closely with the oncology treatment team is recommended. (3)It is important that the patient has medical clearance – approval from a medical professional to engage exercise. (3)The role of the clinical care team, both in hospital and in health care, is fundamental.

Table 1 – Expected patient benefits from exercise training by mode, adapted from Exercise Guidelines for Cancers Survivors (3)

Aerobic

Resistance

Aerobic plus Resistance

Reduced anxiety Less fatigue Reduced anxiety

Fewer depressive symptoms Better QoL Fewer depressive symptoms

Less fatigue No risk of exacerbating Less fatigue lymphedema

Better Quality of life (QoL) Improved perceived Better QoL physical function

Improved perceived physical function Improved perceived physical function

Table 2 – Adapted from Exercise Guidelines for Cancers Survivors and national comprehensive cancer network triage approach based on risk of exercise-induced adverse events. (3)
Description of Patients	Evaluation, prescription, and programming recommendations
No comorbidities	No further preexercise medical evaluation Follow general exercise recommendations
Peripheral neuropathy, arthritis/musculoskeletal issues, poor bone health (e.g., osteopenia or osteoporosis), lymphedema	Recommend preexercise medical evaluation Modify general exercise recommendations based on assessments Consider referral to trained personnel
Lung or abdominal surgery, ostomy, cardiopulmonary disease, ataxia, extreme fatigue, severe nutritional deficiencies, worsening/changing physical condition (i.e., lymphedema exacerbation), bone metastases	Preexercise medical evaluation and clearance by physician before exercise Referral to trained personnel

Once the patient is cleared, an individualized exercise program should be prescribed including the following components: aerobic, muscle strengthening, balance and flexibility. All training sessions must start with a warm-up and finish with a cool-down period. The prescription should take into account the most recent publication of the ACSM (3) and the Position Statement of Exercise and Sports Science Australia .(22)

An effective exercise prescription most consistently addresses health-related outcomes experienced due to a cancer diagnosis and cancer treatment includes moderate- intensity aerobic training at least three times per week, for at least 30 min, for at least 8 to 12week. The addition of resistance training to aerobic training, at least two times per week, using at least two sets of 8 to 15 repetitions at least 60% of one repetition maximum, appears to results in similar benefits (Table 3).(3) Exercise programs that only prescribe resistance training are also efficacious at improving most health-related outcomes, though for some specific outcomes the evidence is either insufficient or suggestive that resistance training alone may not be enough (e.g., depressive symptoms).

31626055

Table 3 – Physical Exercise Recommendations – Oncological Disease, adapted (3,18,22)
	Type	Duration/Volume (per session of training)	Intensity	Frequency(days)
Aerobic training+	Exercises : rhythmic, prolonged, continuous or with intervals, wich request the big muscler groups	20 to 60 minutes	60% to 80% of maximum heart rate or maximal oxygen consumption (VO2max); and RPE: 13-15*	≥3 sessions/week, without more than 2 consecutive days without perform aerobic training
Muscle strengthening training++	No additional charge, with free weights, elastic bands or weight machines	5 to 10 differentt exercises; 1 to 3 sets per exercise; each set with 8 to 15 repetitions	60% to 85% 1- RPE: 13-15*	Minimum of 2 sessions/week in no consecutive days
Balance training	Static or dynamic exercises	no duration specified	Mild to moderate	2 to 3 sessions/week
Flexibility training	Static, dynamic or PNF*** exercises	2 to 4 repetitions of 30 seconds in each exercise.	Up to the point of slight discomfort	2 to 3 sessions/week
+ At least 150 minutes a week of moderate physical activity, or 75 minutes of vigorous physical activity ; ++ The increase ni intensity and volume should be gradual. RPE: ratings of perceived exertion, on a 6-20 point subjective perceived exertion scale; * RM: Repetition maximum; *** PNF: Proprioceptive Neuromuscular Facilitation.

Multidimensional approach, which must necessarily include education for health, and nutritional and psycho-emotional support. It is also important to establish realistic goals based on personal limitations, managing patient expectations. (3)

Evidence

Level Grade PMID Nº

Table 4 – Exercise programming considerations for specific cancer survivors, adapted from Exercise Guidelines for Cancers Survivors (PMID 31626055)and The Exercise and Sports Science Australia position statement (PMID: 31277921).
Bone loss/bone metastases:	Avoid contraindicated movements that place an excessively high load on fragile skeletal sites. Example: high-impact loads, hyperflexion or hyperextension of the trunk, flexion or extension of the trunk with added resistance, and dynamic twisting motion.(3) Be aware of signs and symptoms of bone metastases in survivors, as well as common locations where these occur (i.e., spinal vertebrae, ribs, humerus, femur, pelvis). Bone pain can be an initial sign of skeletal metastases thus, exercise trainers should refer survivors who report pain back to the medical team for clinical evaluation before continuing exercise. (3) Preventing falls must also be a goal of therapy, since falls play an important role in fracture etiology. (23)
Lymphedema:	To date, there is insufficient evidence to support or refute this clinical advice to wear a compression garment during exercise to prevent or reduce symptoms of breast cancer – related upper body lymphedema. For resistance training, a general progressive program focused on large muscle groups performed two to three times per week, with the principle of `start low`, progress slow” is safe when supervised by a fitness professional.(3)
	Being overweight or deconditioned have been associated with a higher risk of developing cancer-related lymphedema in observational studies, at this time there is insufficient evidence that weight loss or improving aerobic fitness can lower the risk of developing cancer- related lymphedema. (24)
Older adults	Exercise professionals will need to combine ACSM guidelines on exercise programming for older adults. (25) Integrate fitness and functional assessments before beginning an exercise program to more accurately determine baseline functional abilities.
	Older survivors and/or survivors treated with neurotoxic chemotherapy (typical for breast, colon, lung, ovarian cancers) may especially benefit from a standard assessment of balance and mobility to assess fall risk. (26)

C	II a	31626055
C	II a	11748343
B	II b	31626055
A	I
C	II b	23008299
A	I	19516148
C	I	21226685

Evidence Level Grade PMID Nº

Ostomy	Empty ostomy bag before starting exercise Weightlifting/resistance exercises should start with low resistance and progress slowly under the guidance of trained exercise professionals. People with an ostomy may be at an increased risk of parastomal hernia. Modify any core exercises which cause excessive intra-abdominal pressure, namely a feeling of pressure or observed bulging of the abdomen. Those with an ileostomy are at increased risk of dehydration. Get medical advice on ways to maintain optimum hydration prior, during and after exercise. Those doing contact sports or where there is a risk of a blow to the ostomy may wish to wear an ostomy protector/shield. (3)
Peripheral neuropathy	Stability, balance, and gait should be assessed before engaging in exercise; consider balance training as indicated. Consider alternative aerobic exercise (stationary biking, water exercise) rather than walking if neuropathy affects stability or use treadmill with safety handrails. Consider alternative aerobic exercise (stationary biking, water exercise) rather than walking if neuropathy affects stability or use treadmill with safety handrails.
Peripheral neuropathy	Resistance training recommendations: Monitor discomfort in hands when using hand-held weights Consider using dumbbells with soft/rubber coating, and/or wear padded gloves Consider resistance machines over free weights. (26)
Stem cell transplantation	Home-based exercise encouraged A full recovery of the immune system recommended before return to gym facilities with the public
Sun safety	Exercise professionals should recommend that cancer survivors engage in sun protective practices when exercising outdoors.(28)
Under chemotherapy	Blood counts that contraindicate exercise: severe anemia, neutropenia with a neutrophil count less than 1000/mcL severe thrombocytopenia that increases the risk of bleeding. Symptomatic anemia: functional mobility exercises only, minimise fall or impact risk, emphasise normal breathing (avoid Valsalva manoeuvre)(3,18,29) monitor bruising and bleeding should be performed during the day. In case of neutropenia, you should avoid training in gyms that are too crowded and frequenting public swimming pools.

31626055

C	II a	31626055
C	II a	24927670
		31626055
A	I	25089104
		31277921
		31626055
		30191843

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10 Minnella EM, Bousquet-Dion G, Awasthi R, Scheede-Bergdahl C, Carli F. Multimodal prehabilitation improves functional capacity before and after colorectal surgery for cancer: a five-year research experience. Acta Oncol (Madr). 2017;56(2):295–300.

Heldens AFJM, Bongers BC, de Vos-Geelen J, van Meeteren NLU, Lenssen AF. Feasibility and preliminary effectiveness of a physical exercise training program during neoadjuvant chemoradiotherapy in individual patients with rectal cancer prior to major elective surgery. Eur J Surg Oncol [Internet]. 2016;42(9):1322–30. Available from: http://dx.doi.org/10.1016/j.ejso.2016.03.021
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West MA, Loughney L, Lythgoe D, Barben CP, Sripadam R, Kemp GJ, et al. Effect of prehabilitation on objectively measured physical fitness after neoadjuvant treatment in preoperative rectal cancer patients: Ablinded interventional pilot study. Br JAnaesth [Internet]. 2015;114(2):244–51. Available from: http://dx.doi.org/10.1093/bja/aeu318
Segal R, Zwaal C, Green E, Tomasone JR, Loblaw A, Petrella T. Exercise for people with cancer: A clinical practice guideline. Curr Oncol. 2017;24(1):40–6. 15.Roland NJ, Rogers SN. Exercise interventions on health-related quality of life for cancer survivors. Clin Otolaryngol. 2012;37(5):393–4.

16.Strasser B, Steindorf K, Wiskemann J, Ulrich CM. Impact of resistance training in cancer survivors: A meta-analysis. Med Sci Sports Exerc. 2013;45(11):2080–90. 17.Cormie P, Zopf EM, Zhang X, Schmitz KH. The impact of exercise on cancer mortality, recurrence, and treatment-related adverse effects. Epidemiol Rev. 2017;39(1):71–92.

Rodrigues B, Carraça E, Joaquim A, Viamonte S, Dinis J. Exercício físico para pessoas com doença crónica:Guia de consulta rápida Adultos & Idosos. 2021;
Hojman P, Gehl J, Christensen JF, Pedersen BK. Molecular Mechanisms Linking Exercise to Cancer Prevention and Treatment. Cell Metab [Internet]. 2018;27(1):10–21. Available from: https://doi.org/10.1016/j.cmet.2017.09.015
Sweegers MG, Altenburg TM, Brug J, May AM, Van Vulpen JK, Aaronson NK, et al. Effects and moderators of exercise on muscle strength, muscle function and aerobic fitness in patients with cancer: Ameta-analysis of individual patient data. Br J Sports Med. 2019;53(13):812.
Buffart LM, Kalter J, Sweegers MG, Courneya KS, Newton RU, Aaronson NK, et al. Effects and moderators of exercise on quality of life and physical function in patients with cancer: An individual patient data meta-analysis of 34 RCTs. Cancer Treat Rev [Internet]. 2017;52:91–104. Available from: http://dx.doi.org/10.1016/j.ctrv.2016.11.010
Cormie P, Atkinson M, Bucci L, Cust A, Eakin E, Hayes S, et al. Clinical oncology society of australia position statement on exercise in cancer care. Med J Aust [Internet]. 2018;209(4):184–7. Available from: https://doi.org/10.5694/mja18.00199
Frost HM. Should future risk-of-fracture analyses include another major risk factor? The case for falls. J Clin Densitom. 2001;4(4):381–3.
Paskett ED, Dean JA, Oliveri JM, Harrop JP. Cancer-related lymphedema risk factors, diagnosis, treatment, and impact: Areview. J Clin Oncol. 2012;30(30):3726–33.
Chodzko-Zajko WJ, Proctor DN, Fiatarone Singh MA, Minson CT, Nigg CR, Salem GJ, et al. Exercise and physical activity for older adults. Med Sci Sports Exerc. 2009;41(7):1510–30.
Drootin M. Summary of the updated american geriatrics society/british geriatrics society clinical practice guideline for prevention of falls in older persons. JAm Geriatr Soc. 2011;59(1):148–57. 27.Streckmann F, Zopf EM, Lehmann HC, May K, Rizza J, Zimmer P, et al. Exercise intervention studies in patients with peripheral neuropathy: a systematic review. Sports Med.

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Lau SCM, Chen L, Cheung WY. Protective skin care behaviors in cancer survivors. Curr Oncol. 2014;21(4):531–40.
Mina DS, Langelier D, Adams SC, Alibhai SMH, Chasen M, Campbell KL, et al. Exercise as part of routine cancer care. Lancet Oncol. 2018;19(9):e433–6.
OTHER
1. FUNGAL INFECTIONS

Authors: Raquel Monteiro Vieira, Paula Alexandra Mesquita and Cláudia Raquel Barbosa Rosado

Introduction

A wide range of fungal infections are described, either nosocomial endemic environmental fungi or opportunistic infections, this last becoming a leading cause of death in cancer patients, especially among those with leukaemia or hematopoietic stem cell transplant. Reactivation of latent infections is also common in these patients. [1] Most common risk factors are severe neutropenia (especially if prolongated), chemotherapy (leading to prolonged and severe CD4 lymphocytopenia), immunosuppressive treatments, mucocutaneous barriers’ disruption, catheter infection, radiation promoted tissular damage, graft versus host disease, mucositis and flora changes induced by broad-spectrum antibacterial and antifungal therapies. [1]

The agents most frequently associated with infection are the yeasts Candida and Cryptococcus species (spp.), the molds Aspergillus, Fusarium and Scedosporium spp., and Histoplasma, Coccidioides and Blastomyces spp. [1]

CANDIDIASIS Etiology

- Only 20 from 160 Candida spp. cause human infection and C. albicans is the main responsible. [2]
- Candida spp. from human commensal flora may promote local or disseminated infection, sometimes leading to multiple organ failure in predisposed individuals, depending on their immune response. [2]
- Among Candida infections we may distinguish the further entities:
  - Local mucocutaneous infection, including oropharyngeal candidiasis esophagitis and vulvovaginitis, chronic mucocutaneous candidiasis (CMCC), balanitis and mastitis.
  - Candidemia and Invasive Candida infection.
  - Hepatosplenic candidiasis (HC) or Chronic disseminated candidiasis (CDC). [2]

Symptoms, signs, and diagnosis

A1. Oesophageal candidiasis

- Main responsible agent is C.albicans. Occasionally C. glabrata or C. krusei may also be identified. [3, 4]
- Odynophagia usually referred by patients in retrosternal area is the hallmark. [2]
- In 90% of cases there is concomitant oropharyngeal candidiasis (thrush). [2]
- Diagnosed by presence of white mucosal plaque-like lesions on endoscopic examination, and confirmed by both culture (positive for Candida spp) and biopsy (mucosal invasion by yeast and pseudo hyphae). [2]
- A fluconazole therapeutic proof may be considered as an alternative diagnostic method. [4, 5]

A2. Vulvovaginal candidiasis

- It is considered the most common mucosal infection by Candida spp. and a main cause of vulvovaginal itching and discharge. [2]
- C. albicans is responsible for 80-92% of the episodes but non-albicans infections are increasing. [6
- Main clinical manifestations: vulvar pruritus (itching) and discharge; dyspareunia, dysuria, and vaginal irritation may also be present. [2, 7-9]
- At physical examination: vulvovaginal erythema, vulvar swelling and usually a white and curd-like vaginal discharge; less frequently (25% of cases) vulvar

excoriation and fissures may be observed. [2, 9]

- In Candida glabrata infections these manifestations may be attenuated. [2]
- Diagnosis requires the combination of symptoms, physical examination, vaginal pH determination (usually normal) and microscopy examination. [7, 9]
- Culture confirms the diagnosis but is only recommended when there is a typical presentation and negative microscopy, or in cases of persistent or recurrent infections presumably by non-albicans agents’ infection or azole resistance. If positive it overestimates prevalence when there is no clinical correlation. [7, 9]

Evidence Level Grade PMID Nº

A3. Chronic mucocutaneous candidiasis

It represents a group of syndromes where chronic non-invasive Candida infections of the skin, nails, and mucous membranes is the common feature. Resistance to topical treatment and absence of invasive infections are commonly seen. [2, 10, 11]

Evidence Level Grade PMID Nº

Classic CMCC is caused by immune system genetic defects, namely autoimmune regulator gene (AIRE) and signal transducer and activator of transcription 1 gene (STAT1) pathogenic variants, and most patients (usually with endocrinopathies) are diagnosed in childhood. A primary immunodeficiency should be evaluated in all patients. [2, 11]
Clinical manifestations: severe and recurrent thrush, vaginitis, onychomycosis, and chronic non-invasive skin lesions, sometimes assuming a hyperkeratotic appearance on the face, scalp, and hands. [10, 11]
Diagnosis is based on clinical findings and genetic testing is the only definitive diagnostic test. [10, 11]

A4. Candidemia and Invasive Candida infection

Invasive candidiasis consists of a systemic Candida spp. infection, whether candidemia (Candida spp. in the blood) is present or not, and it may invade different focal locations. [2]
Clinical manifestations are quite variable, ranging from fever to a severe sepsis (septic shock syndrome). Some patients usually present with eye or skin lesions (sudden onset pustules, nodules, or maculae on an erythematous background). [2, 12]
Diagnosis is performed by Gram stain or culture, showing yeasts from the pustular base scraping, or alternatively by histopathology and culture examination from damaged skin punch biopsies. [2, 12]
If candidemia is present, patients should be evaluated for metastatic foci of infection, namely undergoing a meticulous ophthalmologic examination, echocardiography, and abdominal imaging. [2, 12]
Also, to establish candidemia’s clearance, it is mandatory to obtain daily blood cultures, or every other day after the beginning of antifungal therapy and catheter removal. [2, 12]

A5. Hepatosplenic candidiasis or Chronic disseminated candidiasis

This Candida spp. infection affects both liver and spleen and is almost only seen in hematologic cancer patients who have recently recovered from a neutropenia episode and frequently with a prior candidemia episode. C. albicans plays the main role. [2, 13]
Clinical manifestations: persistent fever (high and spiking, poor response to antibiotics), sometimes associated with abdominal pain, nausea, vomiting, and anorexia. [2, 13]
Diagnosis requires imaging, namely ultrasound (US), magnetic resonance imaging (MRI), or computed tomography (CT) scan, that may reveal persistent liver, spleen, and even kidneys’ micro-abscesses. Blood cultures at the time of presentation are usually negative with a prior history of candidemia, thought to be dur to portal circulation invasion.

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Pharmacotherapy

Drug	Posology
Oesophageal candidiasis
Fluconazole (1st line)	400 mg orally (po) or 400 mg intravenous (IV) once followed by 200 -400 mg daily. In refractory disease dose is doubled to the maximum of 800 mg daily
Echinocandins	Anidulafungin 200 mg daily or Caspofungin 70 mg daily or Micafungin 150 mg IV daily
Amphotericin B	Lipid formulation 3 mg/kg IV daily (preferable) or Deoxycholate 0.3 to 0.7 mg/kg IV daily.
Itraconazole	Oral solution – 200 mg daily
Posaconazole	Oral suspension – 400 mg twice daily or delayed-release tablet – 300 mg once daily
Voriconazole	200 mg orally or 200 mg IV twice daily
Isavuconazole (isavuconazonium)	744 mg orally as a single dose, then 186 mg once daily or 744 mg once weekly
Uncomplicated Vulvovaginal Candidiasis
Fluconazole (1st line)	A single oral dose of 150 mg (po)
Topical azole therapy	Clotrimazole, Butoconazole, Miconazole, Tioconazole, or Terconazole (cream or oinment formulations) for 3-7 days
Complicated Vulvovaginal Candidiasis

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Fluconazole (1st line, except for C.glabrata and C. krusei)	150 mg po every 72 hours for 2-3 doses (depends on severity) If compromised host, oral or topical therapy for 7-14 days. If recurrent infection, it is maintained fluconazole 150 mg once per week for 6 months.
Ibrexafungerp (2nd line)	Two tablets 150 mg twice in one day (po)
Topical azole therapy	Daily for 7 to 14 days. If recurrent infection, topical azole for 10 -14 days or oral azole followed by topical azole, 6 months
Boric acid (1st line treatment for C.glabrata)	Intravaginal – 600 mg capsule once daily at night for 14 days
Flucytosine	16% topical cream, 5 g nightly for 14 days
Other azole agents	Clotrimazole, Miconazole or Terconazole for 7-14 days
Chronic Mucocutaneous Candidiasis
Oral azoles	Fluconazole, Itraconazole, Voriconazole or Posaconazole (see above “ oesophageal candidiasis”).
Candidemia and Invasive Candidiasis
Caspofungin	70 mg loading dose, then 50 mg IV daily
Micafungin	100 mg IV daily
Anidulafungin	200 mg loading dose, then 100 mg IV daily
Amphotericin B (lipid formulation)	3 to 5 mg/kg IV daily
Voriconazole	400 mg orally (or 6 mg/kg IV) twice daily for two doses then 200 to 300 mg orally (or 3 to 4 mg/kg IV) twice daily
Chronic Disseminated Candidiasis (Hepatosplenic Candidiasis)
Caspofungin	70 mg loading dose, then 50 mg IV daily for at least two weeks
Anidulafungin	200 mg loading dose, then 100 mg intravenously (IV) daily for at least two weeks
Micafungin	100 mg IV daily for at least two weeks
Fluconazole	400 mg [6 mg/kg] orally once daily for at least two weeks
Amphotericin B deoxycholate	3 to 5 mg/kg IV daily
Adjuvant glucocorticoids	Prednisone 0.5 to 1 mg/kg orally daily) for a few weeks as a tapering dose, in conjunction with antifungal therapy

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Therapeutic Strategy Evidence

Level Grade PMID Nº

Esophageal candidiasis

Symptomatic patients require systemic antifungal therapy as initial therapy. [2, 14]

The initial treatment with fluconazole is considered first -line treatment and should be maintained for 14 to 21 days and, in refractory disease, extended to 28 days. [2, 15]

Intravenous therapy may be initially required in severely ill patients with no oral route available. [2]

In fluconazole-refractory infections, a non-albicans spp. infection or drug resistance may be considered, fluconazole dose may be increased and an endoscopy to obtain cultures and culture-targeted therapy should be performed. [2, 16]

In recurrent disease, suppressive therapy is not recommended by routine. [2, 14]

Vulvovaginal Candidiasis

Either topical antimycotic drugs or oral fluconazole are recommended as first -line treatment, but oral fluconazole is the preferred first-line treatment [2]

Chronic Mucocutaneous Candidiasis

Both antifungal therapy and endocrine and autoimmune diseases’ treatment is mandatory.

Azole treatment (fluconazole) is usually effective but chronic suppressive therapy is often required to prevent recurrences. [2, 17]

If drug resistance occurs, dose may be escalated or either another azole agent or amphotericin should be considered[2, 18]

Candidemia and Invasive Candidiasis

Antifungal therapy, targeted source control, and central venous catheter removal (if present) are mandatory. [2]

Prompt initial monotherapy with echinocandins, azoles, or amphotericin B is mandatory and susceptibility testing should be performed. [2]

Echinocandin is recommended as first-line treatment for both neutropenic and non-neutropenic patients with candidemia. Combination therapy was proven non beneficial. [2]

In non-neutropenic patients with no fluconazole -resistant Candida spp. oral fluconazole is considered an alternative agent. Otherwise, lipid formulations of amphotericin B may be considered. [2]

In neutropenic patients, lipidic amphotericin B is an alternative to echinocandin. Given the increased prevalence of non-

albicans infections, oral azole agents are not recommended as initial therapy. [2, 19]

When clinically stable, with fluconazole -susceptible Candida spp isolated and negative repeated blood cultures, the switch to oral fluconazole after 5-7 days and then a targeted step-down therapy should be performed. [2, 19]

Optimal therapy duration for candidemia is not well established. At least 2 weeks of therapy after negative blood cultures is recommended in cases of candidemia with no metastatic complications, and symptoms due to both candidemia and neutropenia should be solved. If metastatic foci of infection are present, extend therapy and consulta with an infectious disease specialist. [2]

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Chronic disseminated candidiasis (hepatosplenic candidiasis)

The optimal approach to treatment is uncertain. Glucocorticoids should be considered in case of persistent fever under appropriate antifungal therapy. [2]

Follow-up CT scan should be performed every 2 -3 months. Therapy should be maintained until lesions’ persistent resolution or calcification (about 6 months). Alkaline phosphatase should not be used alone to follow-up. [2, 20]

As initial treatment it is recommended, for at least 2 weeks, an echinocandin or a lipid formulation of amphotericin B. Since clinical improvement is observed (usually in 2-8 weeks), a step-down to oral fluconazole should be considered. [2]

Management should not delay treatment of the underlying malignancy. To prevent relapse after a chemotherapy treatment, fluconazole should be initiated or restarted for subsequent periods of immunosuppression. [2, 20, 21]

ASPERGILLOSIS Etiology

- Aspergillosis consists of an invasive mold infection due to either allergy, airway or pulmonary invasion, skin infection, or extrapulmonary dissemination promoted by Aspergillus spp., mainly A. fumigatus, A. flavus, A. niger, and A. terreus, usually acquired by spore inhalation and most seen in immunosuppressed individuals (hematologic cancer therapy or hematopoietic cell or solid organ transplantation). [1, 22]
- Risk factors: severe and prolonged neutropenia, high-dose glucocorticoids exposure, and comorbidities and therapies that compromise pulmonary and systemic immune responses [1]
- Invasive aspergillosis usually affects lungs or sinuses, and less frequently disseminates to gastrointestinal tract or directly inoculates into the skin. [22] Since Aspergilus spp. are Angio invasive, thrombosis, infarction and endocarditis are commonly seen. [1]

Symptoms, signs, and diagnosis

B1 Pulmonary aspergillosis

- Manifestations may vary from fever, chest pain, dyspnoea, or cough to haemoptysis. In neutropenic patients a classic presentation triad may be seen fever, pleuritic chest pain, and haemoptysis. [23]
- Diagnosis requires imaging, with chest radiograph and a CT scan as mandatory. The patient usually presents with single or multiple nodular lesions (most frequently with multiple small nodules), either with or without cavitation, patchy or segmental consolidation, or peri bronchial infiltrates that may have a tree-in-bud pattern. Sometimes, biopsy and/or culture are necessary. [22, 23]
- CT pulmonary angiography is useful to distinguish invasive mold infections from other possible causes of pulmonary infiltrates, by detecting the signs of angioinvasion. [22, 24]

B2. Cutaneous aspergillosis

- It may be either due to direct inoculation (frequently resulting from trauma) or a result from contiguous infection or bloodborne spread, as most seen in hematologic cancer patients and hematopoietic cell transplant recipients. [22, 25]
- Diagnosis requires a skin biopsy, obtained from the core of the lesion, reaching subcutaneous fat, thus allowing to visualize the blood vessels invasion by hyphae. [22, 25]

B3. Disseminated infection

- Disseminated aspergillosis is seen after Angio invasive disease establishment, with Aspergillus spp. most spread to the skin, brain, eyes, liver, and kidneys. These cases are related to a poor prognosis. [22]

Evidence Level Grade PMID Nº

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Pharmacotherapy

Prompt therapy with voriconazole is considered as first-line treatment. [22]

Amphotericin B and other oral azoles are considered an equally effective second-line treatment when voriconazole is not tolerated. Alternatively, combined therapy with echinocandins may be considered. [22, 26]

Azoles should be avoided in patients under chemotherapy, giving preference to a non-interacting antifungal agent. [22]

In cases of severe, refractory or progressive disease, a CT -guided biopsy should be performed and antifungal therapy adjusted case-to-case and combination therapy with an azole agent (voriconazole preferably) plus echinocandin is preferred. If possible, immunosuppression should also be reduced. [22, 27]

Therapy duration depends on location of the infection and patient’s comorbidities, current other treatments, and response

to given antifungal therapy. Usually maintained for at least 6-12 weeks, but it can be extended for months or even years. [22]

Surgical approach (debridement of necrotic tissue) may be considered as adjunctive therapy in severe cases of localized disease. [1, 22]

Posology

A day of 6 mg/kg IV every 12 hours and then reduced to 4 mg/kg IV every 12 hours. or 200 mg orally every 12 hours. In cases of disease progression dose increment to 4 mg/kg (or 300 mg) orally every 12 hours is recommended.

A loading dose of 372 mg of isavuconazonium sulphate (equivalent to 200 mg of

isavuconazole base) every 8 hours for 48 hours, orally or IV administration. Then 372 mg once daily orally or IV, 12-24 hours after the last loading dose.

A loading dose of 300 mg twice daily on the first day and then a 300 mg daily, either IV or orally delayed-release formulations.

3 to 5 mg/kg IV daily

70 mg loading dose, then 50 mg IV daily

100-150 mg IV daily. No loading dose required.

200 mg loading dose, then 100 mg intravenously (IV) daily


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Cryptococcus neoformans is the main responsible for infection, usually by inhalation into the lungs. [1]
Meningoencephalitis and disseminated disease are relatively rare but may occur in cancer patients. [1]
Main risk factors: lymphopenia, chemotherapy, and corticotherapy for less than a month before diagnosis. Although lymphoma or chronic lymphocytic leukaemia patients are at greater risk, in general, individuals with hematologic malignancies have lower risk for infection given antifungal prophylaxis. [1]

Symptoms, signs, and diagnosis

C1. PNEUMONIA

Lung is the primary site of infection, since after inhaling cryptococcal basidiospore or poorly encapsulated yeasts they cause focal pneumonitis, either symptomatic (< 40%) or not. Infection is usually due to latent infection reactivation, with granulomatous complexes leading to active infection. [1, 28, 29]
Most common manifestations range from asymptomatic to chest pain, fever, dyspnoea, or acute respiratory failure and acute respiratory distress syndrome (ARDS). [28, 30]
Diagnosis requires histology and fungal culture from sputum, bronchoalveolar lavage or affected tissue specimens (by fine needle aspiration or open lung biopsy), where encapsulated yeasts are identified. Also, a chest radiography should be obtained, where we frequently may find single or multiple noncalcified nodular formations, consolidation areas, reticular pattern, ground glass opacities, cavitations, and less commonly, even pleural effusion. Serum cryptococcal antigen should be performed in all patients. If positive, it usually implies the presence of extrapulmonary disease. [1, 28]

C2. CENTRAL NERVOUS SYSTEM CRYPTOCOCCOSIS

Meningoencephalitis is the main presentation (rarely meningitis alone or with cryptococcoma). It results from the haematological dissemination of inhaled Cryptococcus neoformans. [1, 28]
Clinical manifestations may vary from an indolent course, with fever and headache (may occur months before diagnosis), to nausea, vomiting, dizziness, somnolence, irritability, confusion, memory loss, or photophobia, as disease progresses. [1]
Diagnosis consists of India ink examination, serum cryptococcal antigen, and culture from cerebrospinal fluid (CSF) or extra neural sample. Routine lumbar puncture to evaluate for cryptococcal meningoencephalitis is generally not necessary. When performed, an elevated opening pressure (> 200 mmH2O), high cell count (20-200 cells/uL), low glucose levels, high protein concentrations and leucocytosis (lymphocyte predominance) are usually seen. [1, 28]

C3. Disseminated cryptococcosis

Disseminated disease mainly to the liver, prostate, eyes, skin (in 15%, most affecting face, neck, and scalp), and bone (<10%), is rare, but increasing due to use of antifungal prophylaxis. [1, 28, 31]

Evidence Level Grade PMID Nº

Drug	Posology
Extraneural Cryptococcosis
Fluconazole	Daily 400 mg po (6 mg/kg) for 6-12 months
Itraconazole	Loading dose of 200 mg orally 3 times daily for 3days and then reduced to a twice daily regimen
Voriconazole	Loading dose of 6 mg/kg IV twice daily or 400 mg po twice daily for 1 day, then reduced to half (200 mg po twice daily)
Posaconazole	Loading dose of 300 mg po twice daily for 1 day, and then just once daily
Isavuconazole	200 mg 3 times per day for 2 days, then reduced to once daily
Meningoencephalitis and disseminated cryptococcosis

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Evidence Level Grade PMID Nº

Fluctosine

100 mg/kg/day po divided in 4 daily doses, requiring adjustment to renal function

Echinocandin

Liposomal amphotericin B 3 -4 mg/kg or amphotericin B lipid complex 5 mg/kg or

Deoxycholate 0.7-1.0 mg/Kg IV daily

Fluconazole

Daily 800 mg po twice a day

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D.HISTOPLASMOSIS Etiology

Extra neural Cryptococcosis

Fluconazole is recommended as first-line treatment. [28]

Asymptomatic patients with incidental diagnosis, negative cultures and low cryptococcal antig en titters may not require antifungal therapy. [28]

Pleural effusions rarely require drainage and surgical excision of infected pulmonary tissue may be indicated when mass effect situations occur. [28]

Meningoencephalitis and disseminated cryptococcosis

Combined induction therapy with amphotericin B plus flucytosine for at least 2 weeks is recommended as initial treatment, and in some cases, extended to 4-6 weeks. [28]

In patients presenting with neurological complications, an alternative consisting of amphotericin B plus fluconazole for at least 2 weeks may be considered. [28]

If there are no neurologic complications, lumbar puncture should be repeated after 2 weeks of treatment, thus addressing the response to initial therapy. Serum cryptococcal antigen re-evaluation is not recommended. [28]

Maintenance therapy with fluconazole (400-800 mg po daily) is recommended for at least 6 -18 months and intracranial pressure must be closely monitored. [28]

Histoplasma capsulatum is the endemic microorganism, mainly seen in contaminated soil, responsible for histoplasmosis. [1]
Pulmonary histoplasmosis is the main presentation of the disease. Although usually asymptomatic, it may evolve to severe disease, thus becoming a common hospitalization cause especially in immunosuppressed patients, particularly in those with hematologic cancer. [1, 32]
Symptoms, signs, and diagnosis
Patients with symptomatic pulmonary disease may present fever, chills, headache, myalgias, anorexia, cough, and/or chest pain, usually 2-4 weeks after exposure. [32, 33]
Consider diagnosis in presence of either pneumonia plus a mediastinal or hilar lymphadenopathy, mediastinal or hilar mass, pulmonary nodular formations, lung cavitations, pericarditis associated with mediastinal lymphadenopathy, pulmonary manifestations and concomitant arthritis or arthralgia plus erythema nodosum, dysphagia secondary to oesophageal narrowing, and/or superior vena cava syndrome or other mediastinal structures’ obstruction. [32, 34]
Common extrapulmonary presentation are rheumatologic symptoms, arthritis, and pericarditis. [35, 36]
In acute disseminated disease patients may experience fever, fatigue and weight loss, and other symptoms related to the affected site. Diarrhoea and/or dyspnoea, and hepatosplenomegaly, and pancytopenia may be seen. Shock, respiratory distress, hepatic and renal failure, obtundation, and coagulopathy also occur in severely ill patients. [32, 34]
Diagnosis requires biopsy and fungi staining (granulomas are most identified), cultures of sputum and bronchoalveolar lavage (usually performed in cases of chronic pulmonary histoplasmosis), antigen detection enzyme immunoassay (EIA) and/or Histoplasma-specific antibodies’ serology. [32, 37]
A CT scan may be performed to better characterize lesions and exclude other suspected pathologies. [32]

Drug	Posology
Amphotericin B	Liposomal amphotericin B (AmBisome) 3 mg/kg/day IV (or 5 mg if CNS infection) or Amphotericin B lipid complex (Abelcet) 5 mg/kg/day IV or Amphotericin B deoxycholate 0.7 to 1 mg/kg/day IV
Itraconazole	Loading dose of 200 mg po 3 times daily for the first 3 days and then a maintenance reduced to twice daily and maintained for 6-12 weeks (in mild -moderate pulmonary disease) or at least 12 weeks (in severe pulmonary or disseminated disease)
Methylprednisolone	0.5-1.0 mg/kg/day IV for 1-2 weeks (plus amphotericin B)

Therapeutic Strategy

Mild to moderate pulmonary disease (particularly if symptomatic for less than a month ) usually dismisses treatment. Otherwise, monotherapy with itraconazole may be considered for 6-12 weeks. [1, 32]

In cases of extrapulmonary disease consider nonsteroidal anti-inflammatory therapy and prednisone (0.5-1 mg/Kg/day) if there is no response to initial treatment. [32]

In severe pulmonary or disseminated disease treatment is mandatory: amphotericin B for 1 -2 weeks followed by itraconazole (making up at least 12 weeks of treatment) is the recommended first-line therapy. Methylprednisolone may be used initially with amphotericin B. [1, 32]

Echinocandins should not be used given H. capsulatum non-susceptibility. [32, 37]

E.COCCIDIOIDOMYCOSIS

Etiology

Dimorphic fungi from Coccidioides genus, mainly C. immitis, may be inhaled from the environment and cause pulmonary infection, then progress to disseminated disease in immunosuppressed patients. [1, 38]

Symptoms, signs, and diagnosis

- In pulmonary disease, the most common symptoms are fever, hypoxemia, chest pain and cough, usually 7-21 days after exposure. Extrapulmonary manifestations (not meaning disseminated disease) may occur, affecting skin, bone, and joints. Thus, patients may present with erythema nodosum, erythema multiforme, toxic erythema and/or symmetric arthralgias (mostly affecting ankles, knees, and wrists). [1, 38, 39]
- Patients with coccidioidal meningitidis may present with persistent, progressive worsening and/or unusual severity headache (in 75% of cases), often associated with nausea and vomiting, blurry vision, and mental status alterations. [38-40]
- Diagnosis requires chest radiography and CT scan (diffuse pulmonary infiltrates), an EIA serologic test (sometimes negative), and in some cases also culture from lung, CSF, or other tissue sample.

Evidence Level Grade PMID Nº

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Pharmacotherapy

Drug	Posology
Fluconazole	In non-meningeal disease: 400 mg (in mild to moderate disease) or 400-800 mg PO daily (in severe disease) In meningeal disease: 400 -1200 mg PO daily (usually 800 mg) or up than 1200 mg daily (in some severely ill patients); then reduced to 800 mg daily (as clinical stability is verified)
Itraconazole	200 mg PO twice daily (in mild to severe disease) or three times daily (in meningeal disease)
Amphotericin B	Lipid formulation at 3 -5 mg/kg daily or deoxycholate formulation at 0.5 mg/kg daily (in severe disease, prior to azoles)

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Asymptomatic primary pneumonia does not require antifungal therapy by routine. [38]

In cases of severe infection or mild to moderate infection with high risk for complicated disease, treatment with either oral fluconazole or itraconazole should be initiated and maintained for at least 6-12 weeks. [38]

Suppressive therapy may be considered in selected patients. [38]

In cases of severe disease with respiratory compromise treatment should include amphotericin B prior to oral azole therapy and maintained for at least 12-24 weeks. [38]

Monitoring for complications and/or relapse should be perfo rmed at regular time intervals (every 12 weeks). Since clinical, radiographic, and serologic improvement is achieved, fluconazole may be maintained at 400 mg or reduced to 200 mg daily. [38]

In extra thoracic nonmeningeal disease surgical debridement or stabilization may be considered as adjunctive treatment in particular cases. [38]

In meningeal coccidioidomycosis an oral h igh-dose fluconazole regimen is the first -line treatment. Itraconazole is considered as alternative. [38]

Treatment for meningeal disease may be prolonged ad eternum , given the potentially fatal relapses described after treatment discontinuation. Usually oral fluconazole 400 -800 mg daily (preferred regimen) or itraconazole 200 mg 2 -3

times daily. [38]

In persistent disease, the switch from fluconazole to itraconazole is recommended. [38]

Management of intracranial pressure based on medical therapy and lumbar punctures is mandatory. If a hydrocephalus occurs, consider a shunt for decompression. [38, 40]

F.FUSARIOSIS

Etiology

- Fusarium spp. occurring in both soil and air, are responsible for broad-spectrum human infections, ranging from skin and nail infections to invasive and disseminated disease, those most seen in severely immunocompromised individuals, usually by Angio invasive behaviour. [1, 41]
- Fusarium solani is the agent most frequently isolated (about 50%). Others include F. moniliforme, F. oxysporum, and F. dimerum. [1, 41]

Symptoms, signs, and diagnosis

- Clinical presentation: most commonly, persistent fever, refractory to antibacterial and antifungal empiric treatment, established in a profound and prolonged neutropenia background. Patients may also present with sinusitis and rhino cerebral infection, pneumonia, cellulitis, metastatic skin lesion, endophthalmitis, myositis, arthritis, and central nervous system infection. [1, 41-43]



Disseminated disease is the most common presentation in immunocompromised individuals (about 70% of cases) and it relates to poor prognosis (60-80% of

mortality rate. [1, 41]

- Diagnosis is confirmed when isolating Fusarium spp. in culture of samples from the affected sites (positive in 50-70% of cases), especially in patients presenting with skin lesions. Biopsy is mandatory in all these patients to confirm diagnosis. Study should be complemented with blood culture and/or sputum fungal stain and culture. Also, an image study with radiograph and CT scan of paranasal sinuses and chest must be performed to address for disease extent. If positive findings are observed, bronchoscopy with bronchoalveolar lavage and even lung biopsy are recommended (if possible). [1, 41, 43]

Pharmacoterapy

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Drug	Posology
Disseminated disease
Amphotericin B	Lipid formulation at 3-5 mg/kg IV once daily
Voriconazole	6 mg/kg IV every 12 hours for 2 doses, then reduced to 4 mg/kg IV every 12 hours. A switch to 200-300 mg po twice daily should be made after significant response to initial therapy regimen
Posaconazole	300 mg po once daily

Therapeutic Strategy

Evidence Level Grade PMID Nº

Disseminated disease

Optimal treatment remains unclear but it is recommended amphotericin B (lipid formulation) as first -line treatment, and triazole agents (especially voriconazole), either in monotherapy or combined therapy regimens, as alternative. [1, 41]

The duration of treatment is not well established. It depends on neutropenia resolution, initial therapy response, immune system status, and infection’s site and extent. [1, 41]

Surgical debridement of infected tissues or foreign bodies should be performed. [1, 41]

Adjunctive immunotherapy with granulocyte or granulocyte-macrophage colony-stimulating factors may be considered [1, 41]

G.TRICHOSPORONOSIS AND BLASTOMYCOSIS

Etiology

Trichosporon spp., mostly T. asahi (beigelii), and Blastoschizomyces capitatus are related fungi present in soil and fresh water and responsible for rare invasive and disseminated human infections, most seen in immunocompromised patients. Frequency of these high-mortality rate diseases is increasing. [1, 44, 45]
Risk factors: immunocompromising disease (namely hematologic malignancies and neutropenia) and/or therapy, extensive burns, intravenous catheters, therapy with steroids, and heart valve surgery. [1]

Symptoms, signs, and diagnosis

Invasive infection may be either localized (lungs, skin, heart valves, central nervous system, peritoneum, and surgical wounds) or disseminated (most prevalent). The last, usually presents with acute febrile disease having rapidly progression to multiorgan failure. Skin lesions are usually erythematous papules, sometimes bullae, on trunk and extremities, that can develop central necrosis (similar appearance to eschars). Individuals presenting with CNS infection may experience headache, nausea, vomiting, and fever. [1, 44-46]
Diagnosis requires cultures of blood (commonly positive), urine, sputum, cerebrospinal fluid, and tissue may be performed. Culture and histopathology of skin lesions, chest radiographs (with an alveolar-patterned diffuse infiltrates, lobar or reticulonodular infiltrates, and/or cavitation), and echocardiography (large and bulky vegetations) may also contribute to establish the diagnosis. [1, 44, 45]

Pharmacoterapy

Drug	Posology
Invasive or disseminated disease
Voriconazole	In combination with Amphotericin B: 6 mg/kg IV every 12 hours for 2 doses, then reduced to 4 mg/kg IV twice daily In monotherapy: 200-400 mg po twice daily
Itraconazole	200 mg po 2-3 times per day
Amphotericin B	Lipid formulation at 3-5 mg/kg IV daily or Amphotericin B deoxycholate at 0.7-1.0 mg/kg IV daily

Therapeutic strategy

Evidence Level Grade PMID Nº

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Invasive or disseminated disease

Combined treatment with an azole agent (preferably voriconazole or itraconazole) plus amphotericin B is recommended as first-line therapy for severe blastomycosis. For mild to moderate disease itraconazole alone is suggested. [44]

Azoles are considered the first -line treatment for trichosporonosis. Echinocandins are ineffective against Trichosporon spp. thus contraindicated. [45]

Serum voriconazole concentration must be evaluated (4-7 days after initiate therapy) to access the optimal drug dose. [44]

The duration of treatment is not well established , but at least 6 -12 months is suggested. A prompt antifungal therapy adjustment to the resistance pattern of the isolated agent is mandatory. If patient is stable or improving under azole, switch to oral formulation. [44]

Etiology

Scedosporium spp. are opportunistic agents found in both soil and polluted water, increasingly responsible for infection in immunocompromised individuals (namely pneumonia, keratitis, endophthalmitis, central nervous system infection, soft tissue infection, and disseminated disease). [47, 48]

Symptoms, signs, and diagnosis

Clinical manifestations in patients presenting with:
- Lung disease: fever, cough, sputum production, pleuritic chest pain, tachypnoea, and malaise.
- Brain abscess: headache, confusion, disorientation, agitation, cognitive decline, progressive lethargy, hemiparesis, and seizures.
- Disseminated disease: mostly shock and multiorgan failure. [47]
Diagnosis requires (1) histopathologic examination showing tissue invasion with positive culture, or (2) histopathologic examination identifying fungi combined with a positive DNA polymerase chain reaction or gene sequencing, if cultures are negative, or (3) clinical and imaging established infection combined to a positive culture. [47, 49-52]
Since Scedosporium spp. have similar appearance to other fungi on histology examination, diagnosis is confirmed by culture. Is also allows to perform a susceptibility test to antifungal agents. [47]

Pharmacoterapy

Drug	Posology
Voriconazole	6 mg/kg IV every 12 hours for 2 doses, then reduced to 4 mg/kg IV every 12 hours. A switch to 200 -300 mg po twice daily should be made after significant response to initial therapy regimen

Monotherapy with voriconazole is considered as firstline treatment (is the-most active agent against S.apiospermum)and other oral azoles are known as alternative.[53, 54]

Adjunctive surgical debridement or immunomodulatory therapies may be required[.47]


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Therapeutic Strategy

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I.PNEUMOCYSTOSIS	2	C	16988
Etiology

The ascomycetous fungus Pneumocystis jirovecii, previously considered a protozoa microorganism), is responsible for a life-threatening pneumonia in immunocompromised patients that may acquire the infection by from immunocompetent individuals by means of person-to-person spread.[55-58]

Symptoms, signs, and diagnosis

Patients may present with fulminant respiratory failure plus with fever and dry cough. [55, 59, 60]
Diagnosis usually requires chest radiograph and CT scan, microscopy dye-based staining examination, Pneumocystis identification in culture, fluorescent antibody or polymerase chain reaction (PCR)-based assays of respiratory specimens. [59-62]

staining,

Drug	Posology
Trimethoprim- sulfamethoxazole (TMP-SMX)	15-20 mg/kg/day IV or orally daily, divided for 3 or 4 doses.
Clindamycin plus Primaquine	Clindamycin 900 mg IV every 8/8h or 600 mg IV every 6/6h or 600 mg po 3 times daily or 450 mg po 4 times daily plus Primaquine 30 mg (base) orally once daily
Trimethoprin plus Dapsone	TMP 5 mg/kg orally three times daily plus Dapsone 100 mg orally once per day
Atovaquone	750 mg orally twice daily (taken with food)
Pentamidine	4 mg/kg IV once daily

Therapeutic Strategy

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TMP-SMX is recommended as first -line treatment. In case of severe allergy, intolerance, or non -response, where desensitization is not possible, alternative therapies may be considered depending on disease severity. [62, 63]

For mild disease, atovaquone (preferred), clindamycin plus primaquine, or trimethoprim plus dapsone may be considered. [62, 63]

For moderate disease, clindamycin plus primaquine (preferred), or trimethoprim plus dapsone, are considered as viable options. [62, 63]

For severe disease, either clindamycin plus primaquine (preferred), or IV pentamidine are recommended. [62, 63]

Duration of treatment is not well established but it is recommended at least a 21 -day course, and some clinical improvement should be seen at the 7th day. [62, 63]

In moderate to severe disease, adjunctive glucocorticoid therapy may be useful. [62-64]

Referenc

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[7] J. D. Sobel, “Vulvovaginal candidosis,” Lancet, vol. 369, no. 9577, pp. 1961-1971, 2007, doi: 10.1016/S0140-6736(07)60917-9.

M. R. Anderson, K. Klink, and A. Cohrssen, “Evaluation of vaginal complaints,” JAMA, vol. 291, no. 11, pp. 1368-1379, 2004, doi: 10.1001/jama.291.11.1368.
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M. Thaler, B. Pastakia , T. H. Shawker , and e. al, “Hepatic candidiasis in cancer patients: the evolving picture of the syndrome,” Annals of Internal Medicine, vol. 108, no. 1, pp. 88-100, 1988, doi: 10.7326/0003-4819-108-1-88.
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E. K. Spanakis, G. Aperis, and E. Mylonakis, “New agents for the treatment of fungal infections: clinical efficacy and gaps in coverage,” Clinical Infectious Diseases, vol. 43, no. 8, pp. 1060-1068, 2006, doi: 10.1086/507891.
J. A. Sangeorzan, S. F. Bradley, X. He , and e. al, “Epidemiology of oral candidiasis in HIV-infected patients: colonization, infection, treatment, and emergence of fluconazole resistance,” The American Journal of Medicine, vol. 97, no. 4, pp. 339-346, 1994, doi: 10.1016/0002-9343(94)90300-x.
E. S. Husebye, J. Perheentupa, R. Rautemaa, and e. al, “Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I,” Journal of Internal Medicine, vol. 265, no. 5, pp. 514-529, 2009, doi: 10.1111/j.1365-2796.2009.02090.x.
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American Journal of Medicine, vol. 91, no. 2, pp. 142-150, 1991, doi: 10.1016/0002-9343(91)90006-j.

L.-M. Poon, H.-Y. Chia, L.-K. Tan , and e. al, “Successful intensive chemotherapy followed by autologous hematopoietic cell transplantation in a patient with acute myeloid leukemia and hepatosplenic candidiasis: case report and review of literature,” Transplant Infectious Disease, vol. 11, no. 2, pp. 160-166, 2009, doi: 10.1111/j.1399- 3062.2009.00363.x.
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M. Stanzani, G. Battista, C. Sassi, and e. al, “Computed tomographic pulmonary angiography for diagnosis of invasive mold diseases in patients with hematological malignancies,” Clinical Infectious Diseases, vol. 54, no. 5, pp. 610-616, 2012, doi: 10.1093/cid/cir861.
J. A. van Burik, R. Colven, and D. H. Spach, “Cutaneous aspergillosis,” Journal of Clinical Microbiology, vol. 36, no. 11, pp. 3115-3121, 1998, doi: 10.1128/JCM.36.11.3115- 3121.1998.
J. A. Maertens, G. Rahav, D.-G. Lee, and e. al, “Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: a phase 3, randomised, controlled, non- inferiority trial,” Lancet, vol. 397, no. 10273, 2021, doi: 10.1016/S0140-6736(21)00219-1.
K. A. Marr, H. T. Schlamm, R. Herbrecht, and e. al, “Combination antifungal therapy for invasive aspergillosis: a randomized trial,” Annals of Internal Medicine, vol. 162, no. 2, pp. 81-89, 2015, doi: 10.7326/M13-2508

Evidence Level Grade PMID Nº

J. R. Perfect, W. E. Dismukes , F. Dromer, and e. al, “Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america,” Clinical Infectious Diseases – IDSAGuideline, vol. 50, no. 3, pp. 291-322, 2010, doi: 10.1086/649858.
R. Velagapudi, Y.-P. Hsueh, S. Geunes-Boyer, and e. al, “Spores as infectious propagules of Cryptococcus neoformans,” Infection and Immunity, vol. 77, no. 10, pp. 4345-4355, 2009, doi: 10.1128/IAI.00542-09.
R. M. Shirley and J. W. Baddley, “Cryptococcal lung disease,” Current Opinion in Pulmonary Medicine, vol. 15, no. 3, pp. 254-260, 2009, doi: 10.1097/MCP.0b013e328329268d.
Y.-G. Ding and H. Fang, “Edematous Erythema, Subcutaneous Plaques, and Severe Pain in the Lower Extremities in an Immunocompromised Patient,” JAMA, vol. 309, no. 15, pp. 1632-1633, 2013, doi: 10.1001/jama.2013.3740.
L. J. Wheat, A. G. Freifeld, M. B. Kleiman, and e. al, “Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: 2007 Update by the Infectious Diseases Society of America,” Clinical Infectious Diseases – IDSAGuideline, vol. 45, no. 7, pp. 807-825, 2007, doi: 10.1086/521259.
A. L. Brodsky , M. B. Gregg , M. S. Loewenstein, and e. al, “Outbreak of histoplasmosis associated with the 1970 Earth Day activities,” American Journal of Medicine, vol. 54, no. 3, pp. 333-342, 1973, doi: 10.1016/0002-9343(73)90028-4.
L. J. Wheat, D. Conces , S. D. Allen, and e. al, “Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management,” Seminars in Respiratory and Critical Care Medicine, vol. 25, no. 2, pp. 129-144, 2004, doi: 10.1055/s-2004-824898.
L. J. Wheat, L. Stein, B. C. Corya, and e. al, “Pericarditis as a manifestation of histoplasmosis during two large urban outbreaks,” Medicine (Baltimore), vol. 62, no. 2, pp. 110- 119, 1983, doi: 10.1097/00005792-198303000-00004.
J. Rosenthal , K. D. Brandt , L. J. Wheat , and e. al, “Rheumatologic manifestations of histoplasmosis in the recent Indianapolis epidemic,” Arthritis and Rheumatism, vol. 26, no. 9, pp. 1065-1070, 1983, doi: 10.1002/art.1780260902.
C. A. Hage , J. A. Ribes , N. L. Wengenack, and e. al, “A multicenter evaluation of tests for diagnosis of histoplasmosis,” Clinical Infectious Diseases, vol. 53, no. 5, pp. 448-454, 2011, doi: 10.1093/cid/cir435.
J. N. Galgiani, N. M. Ampel, J. E. Blair, and e. al, “2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis,”

Clinical Infectious Diseases – IDSAGuideline, vol. 63, no. 6, 2016, doi: 10.1093/cid/ciw360.

N. F. Crum, E. R. Lederman, C. M. Stafford, and e. al, “Coccidioidomycosis: A Descriptive Survey of a Reemerging Disease. Clinical Characteristics and Current Controversies,” Medicine (Baltimore), vol. 83, no. 3, pp. 149-175, 2004, doi: 10.1097/01.md.0000126762.91040.fd
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S. R. Lockhart, R. Bialek, C. C. Kibbler, and e. al, “Molecular Techniques for Genus and Species Determination of Fungi From Fresh and Paraffin-Embedded Formalin-Fixed Tissue in the Revised EORTC/MSGERC Definitions of Invasive Fungal Infection,” Clinical Infectious Diseases, vol. 72, 2, pp. S109-S113, 2021, doi: 10.1093/cid/ciaa1836.

Evidence Level Grade PMID Nº

1. BONE METASTASIS

Authors: Ricardo Roque, Carolina Trabulo and Alícia Oliveira

Introduction

Bone is the third most common organ affected by metastases, after the lung and liver.

Bone metastases are a common manifestation of distant relapse from many types of solid and haematological cancers, especially those arising in the lung, breast, prostate and multiple myeloma[1], This entity represents a prominent source of morbidity [2,3] for the cancer patient.

This chapter pretends to summarize this problematic.

Symptoms

Bone pain
- Difficult to localize, worse at night and with weight-bearing, not relieved by immobility. May be associated with weight loss or a mass around the area of concern.
- The most common cause of cancer-related pain and is suggestive of bone metastases (BM) in cancer patients
- Has an inflammatory component – effect of inflammatory cytokines, periosteal irritation, and nerve rots stimulation – and a mechanical one – caused by the

Evidence Level Grade PMID Nº

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structural alterations in the bone, producing movement-related pain.

Impaired mobility: due to the pain, direct (tumour or metastasis involvement) or indirect (for example, due to fractures) radiculopathy, and skeletal deformities.
Pathological fractures
- Present in 10 to 30% of all cancer patients. Higher risk rises from prolonged metastatic involvement of the bone.
- Primarily affecting proximal parts of long bones, mostly the femur, but also the ribs and vertebrae, with the potential to induce kyphoscoliosis, restrictive lung
- disease, and spinal cord compression. patients (60%).

– Most cases occur in breast cancer (BC)

They can also be atraumatic.

Spinal cord compression (SCC)
- Due to vertebral collapse or metastasis extension to the vertebral canal.
- Considered an oncological emergency.
- Presents as back pain, progressing to lower limb weakness, and sensory and autonomic alterations, depending on the level of the lesion.
Myelophthisis
- direct infiltration of the bone marrow by cancer cells, causing mainly anaemia.
- Pancytopenia can occur.
Hypercalcemia and related symptoms
- Is a metabolic complication and an oncological emergency. Can also occur without concomitant bone metastases.
- Osteolytic lesions (in 10-30% of the cases) and diffuse humoral mediated osteolysis (by parathyroid hormone-related peptide, for example) are among the main causes.
Skeletal related events (SREs)
- It represents a group of skeletal complications or symptoms related to BM.
- Composite clinical parameter used as an endpoint in clinical trials.
- It includes pathological fractures; spinal cord compression; hypercalcemia; bone-related pain, and the need for radiation or surgery to treat pain, fractures, or cord
- compression. patients’ survival and quality of life, causing loss of mobility and social functioning, with increasing health costs.

SREs worsen

Etiology

Bone is the third most frequent location for metastases and most cases of BM occur in BC and prostate cancers (PC).
The cancer spread to the bone occurs mainly through the venous system. BM are usually multiple and affect mostly the axial skeleton – mostly the vertebra, followed by the femur, pelvis, ribs, sternum, humerus and finally skull.
They are a consequence of the interaction between receptors in tumour cells and the stroma and matrix of the bone.
BM can be classified into 3 types:

– Osteolytic: it mainly consists of osteoclastic mediated bone destruction. The activation of the signalling pathway of the receptor activator of NF-kappaB (RANK) and its ligand (RANKL) stimulates the production of parathyroid hormone-related peptide (PTHrP), leading to bone reabsorption. It is a consequence of:

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- - Hematologic cancers, like multiple myeloma (MM), non-Hodgkin lymphoma, or Langerhans-cell histiocytosis.
  - Solid cancers, like renal cell carcinoma, melanoma, non-small cell lung cancer, thyroid cancer, the great majority of BC and few cases of PC.

– Osteoblastic (or sclerotic): it’s characterized by excess bone deposition. In PC, multiple growth factors, like transforming growth factor-β (TGF-β) or bone morphogenetic protein (BMP), are released from cancer cells stimulating bone formation. These lesions are a consequence of:

- - Hematologic cancers, like Hodgkin lymphoma or medulloblastoma.
  - Solid cancers, like carcinoid and small cell lung cancers, PC, and fewer cases of BC.

-Mixed: more commonly found in solid tumours, like breast, gastrointestinal and squamous cancers. Two presentations are possible:

- - Both osteoblastic and osteolytic lesions are present in a cancer patient.
  - One bone metastasis has a mixture of the two components.

Diagnostic Studies

The diagnostic approach to BM may vary with the type of tumour, but also with the available imaging modalities. Ageneral diagnostic approach to BM can be seen in chart 1.

Blood workout: to access the bone metabolism; serum calcium and albumin (for further calcium correction), phosphorus, 25-hydroxyvitamin-D, alkaline phosphatase, and parathyroid hormone (PTH). Other bone biomarkers can be studied, but no blood or urine biomarkers have an established role in BM diagnosis or follow-up.
Radiographs of the skeleton: cheap and accessible, but with low sensitivity (SS up to 50%). Mostly capable of detecting lesions of the bone cortex and with size greater than 1 to 2 cm.
Bone scintigraphy (BS) and Computerized Tomography (CT): accessing skeletal vascularization and osteoblastic activity, BS with Technetium 99m-methyl diphosphonate (99mTc MDP) reflects the bone metabolism, presenting higher SS (86%) but lower specificity (SP of 81%). For Multiple Myeloma it is less sensitive and, therefore, less used. On the other hand, the SP of CT is higher and equivalent to magnetic resonance imaging (MRI) and positron emission tomography (PET). CT’s high anatomic resolution allows for a good definition of soft tissue metastatic extension and guidance for biopsies. However, it requires high cortical destruction for the diagnosis, lowering its SS (73%). The utilization of Single Photon Emission Computed Tomography (SPECT) joins the best of BS and CT, with high SS and SP, but is less available.
Magnetic resonance imaging (MRI): has a high SP (95%), being able to detect lesions in early states and intra-medullary. This anatomical image technique is highly sensitive (91%), however, the SS drops when applied to the whole body. It is required for the diagnosis of medullary compression and the best method to study vertebral BM and for soft-tissue changes.
Positron emission tomography (PET) with Fluorodeoxyglucose (FDG): is an overall very sensitive (90%) and specific (97%) functional imaging. SS can reach 94% when PET is used together with CT (PET-CT), adding anatomical definition. FDG-PET-CT is also the most accurate way of accessing treatment response of hypermetabolic bone metastasis through the widely accepted PET Response Criteria in Solid Tumours (PERCIST). However, some studies show that PET is less sensitive for diagnosing and following slow-growing and osteoblastic metastases, like in PC. Regarding agents used as tracers, 18F-sodium fluoride is more accurate in studying bone metastases but less available. In studying specific cancers, like prostate or neuroendocrine tumours, tracers can be combined with tumour-specific targets, like prostate-specific membrane antigen (gallium-68-anti-PSMA) or somatostatin receptors (gallium-68-DOTATATE), respectively.
Biopsy: CT-guided biopsy is recommended in diseases affecting only the bone. In bone lesions of patients with cancer of unknown origin, it can be also performed. In the presence of other metastases, it is preferable that the biopsy is performed in visceral metastases due to the lack of biomarkers in bone samples.

Level Grade PMID Nº

28584570

21887484

27752772

24782453

Chart 1: Algorithm for the Diagnosis of Bone Metastases

Treatment Treatment Options

The treatment of BM depends on the type of the primary cancer but rarely has a curative intention. Multiple strategies can be applied with the objective of preventing disease

progression or SREs, relieving the symptoms, and improving quality of life. The following treatment options can be applied to the treatment of BM arising from solid neoplasms, as illustrated in figure 1.

Level Grade PMID Nº

24782453

27663933

Level	Grade	PMID Nº
I	A	29397209 17416863
I	A	29397209
I	A	29397209
		19546803
II	A	16153729 12569144
		27315664
II	A	24094630 22300568
II II	B B	27663933 24369114 24094630
		34126044
II	A	28598293
		27663933
III	B	24782453
		22420969
II	B	31794625 34194637
III	B	31794625
		27524407
		24782453

Radiotherapy (RT)

RT in uncomplicated BM and localized disease is effective for palliation and pain relief (overall response of up to 80%), in the form of local external beam RT (EBRT).

– Multiple (MF) or single fraction (SF) RT have the same effect in pain control, with similar toxicity and complication rates (pathological fracture and spinal cord compression).

– A higher relapse of symptoms is seen with SFRT.

– SFRT is more cost -effective and has no disadvantage in the impact on quality of life when compared with MFRT. SFRT is also easier and more convenient for patients, especially the ones under palliative treatment and/or with limited life expectancy.

– EBRT can be used to retreat patients with peripheral or vertebral BM, when pain has recurred, adhering to the dosing limitations of the irradiated tissues, 4 weeks or more after the initial treatment.

– Retreatment with SF is as effective as with MF

– Previous response or absence of it may not dictate the response to RT retreatment

Studies regarding stereotactic body radiotherapy (SRBT) application for pain control in BM are lacking and this

treatment is not yet recommended in the clinical setting. This more expensive and less available method, may in the future replace EBRT in the treatment of vertebral BM.

RT should also be administered for the treatment of spinal cord compression (SCC) or spine instability due to vertebral metastases, independently of the pre-existing surgical treatment.

oIn non-operated patients for SCC, SF is non-inferior to MF. However, MF seems preferable in distal spine lesions due to bladder toxicity.

MFRT is also advised to be used after surgery in the treatment of pathological or impending fractures of the extremities. RT alone can be used as a palliative measure for pain control, for patents non -eligible for surgery.

Radionuclides

The use of systemic radionuclides allows more targeted delivery of radiation when compared to ERBT. It’s an evolving therapy, and nowadays it is being studied to target direct cell surface markers, like PSMA in PSMA -positive PC. However, this treatment modality is only available for a few types of cancers and its clinical application can be limited by secondary effects. For instance, strontium-89,

rhenium-186, and samarium -153 are efficient in palliating osteoblastic metastases, however with i mportant clinical limitations due to myelosuppression.

Systemic radioactive iodine-131 (131I) is the first line of treatment for iodine avid BM of thyroid cancer, with effect in overall survival (OS), especially in smaller BM and when in combination with other non-iodine dependent treatments

Radium-223 (223Ra) has been shown to improve OS and delay SRE in metastatic castration-resistant PC. 223Ra is restricted to those already treated with at least two lines of systemic treatment or ineligible for them, as a single agent and with previous or concomitant use of bone- targeted therapies, in patients that only have BM (BTA).

II A

34503240

31017051

23863050

32593798

Level Grade PMID Nº I A 25223925

Surgery

Surgical treatment is efficient to palliate the pain and reinstate function in patients with BM.

Pathological fracture: Pathological fracture stabilization and severe pain are indications for surgery. An intra-lesion approach is usually sufficient with an intramedullary nail, plate, or with (endo) prosthesis, for long bones fractures. Each bone and body area has its surgical specificities.

oIf BM of kidney and thyroid, embolization before surgery is advised.

In SCC, surgery preceding RT, may improve function. Laminectomy and spinal fixation by posteriorapproach is the most common procedure. Benefits may not apply to patients with radiosensitive tumors, total paraplegia for more than 48 hours or multiple areas of SCC.

For impending fractures, prophylactic bone stabilization is indicated if there is a high risk of fracture, using surgical approaches with adequate recovery times and durability for the expected patient survival.

-High-risk fractures can be defined using Mirels’ scoring system or radiological parameters for long bones (lytic destruction of >50% of the cortex, lesions >30 mm in greatest dimension, and continued

pain with weight-bearing after RT).

Bone-Targeted Agents (BTAs)

BTAs act as inhibitors of bone reabsorption and the currently available ones are bisphosphonates (BPs) and denosumab. BPs ind uce osteoclast cell death, while denosumab (a monoclonal antibody) blocks the interaction between RANK and RANKL, inhibiting bone reabsorption. Recent preclinical studies have shown that these BTAs may present concomitant antitumor effects. Both can cause

hypocalcaemia and osteonecrosis of the jaw (ONJ), but the risk is higher with denosumab. BPs are associated with nephrotoxici ty. A table with the Usual Doses of Bone-Targeted Agents for the Treatment of Bone Metastases is present in table 2.

BTAs have a marginal and controversial role in treating BM associated pain

BTAs are efficient in preventing SREs in patients with BM, independently of the nature of the BM (osteolytic or osteoblastic).

-Denosumab has a slightly higher efficiency in preventing SRE and a more convenient administration, however, it is a more expensive treatment.

-Bps are a more cost-effective alternative

24782453

III B

28461940

III B 28461940

27843593

16112300

20606090

24782453

III B

28461940

24782453

I A

28461940

24782453

32905286

12076438

29253322

31014505

26718881

33270906

29253322

31014505

33270906

24782453

31014505

24782453

23870108

30382484

30937279

30236112

I A

Adequate calcium and vitamin D supplementation should be provided to correct and/or maintain the levels of these elements and prevent BTAs’ associated hypocalcaemia. The calcium requirements vary between different

populations, increasing in the elderly.

Calcium and vitamin D levels should be measured previously to BTA treatment and monitored frequently in the first months.

Dental evaluation and oral invasive procedures should be performed before treatments with BTAs to prevent ONJ. If they are performed meanwhile, treatment must be stopped.

Bisphosphonates (BPs):

oIn MM and BC, parenteral (iv) zoledronate is the most effective BP in preventing SREs while being the only efficient in PC patients. It is also effective in the BM of other solid neoplasms.

oIn BC patients, ibandronate offers an intravenous and oral route of administration with a similar time to first SRE, but pamidronate is an inferior option.

oIn MM, all BPs (zoledronate, pamidronate, ibandronate, or clodronate) have been shown to affect equally the rates of pathological vertebral fractures, SREs, and pain . However, there is evidence supporting the superiority of zoledronate in preventing SREs and increasing overall and

progression-free survivals.

Denosumab:

oIn both BC and PC, denosumab showed superiority to zoledronate in preventing SREs.

oIn other solid tumours and MM, denosumab was not inferior to zoledronate.

oIn MM patients, due to kidney compromise, denosumab may have a favourable safety profile, mainly in patients with creatine clearance between 30-60 ml/min.

oDiscontinuation of denosumab may lead to a increased bone reabsorption with vertebral fractures.

Switching to a BP may prevent this event.

In BM prevention, only BPs are recommended (namely zoledronate, clodronate, and ibandronate) in the setting of early-stage BC, because they have been shown to improve survival and reduce tumour spread, treatment – induced bone loss, and cancer recurrence in the bone.

oBPs as prevention treatment are only indicated in early -stage postmenopausal (naturally or due to ovarian suppression treatment with gonadotropin -releasing hormone (GnRH) analogues) BC patients at high risk for recurrence.

oDenosumab is not a valid option in this context

oBTAs are not an accepted preventive strategy in other solid tumours.

24782453

18647964

III B

24782453

30937279

14534891

24332514

I	A	24166910
		12915606
		29253322
		24844358
		23995858
		24782453
I	A	21353695 26693901
		21060033
		29429912

24782453

IV B

29105841

24782453

26211824

I A 31693129

25035292

31806543

Figure 1: Treatment options for BM by type of cancer and treatment outcome

ERBT: external beam radiotherapy; SRBT: stereotactic body radiotherapy; BPs: bisphosphonates; SREs: skeletal-related events; BC: breast cancer; PC: prostate cancer; TC: thyroid cancer; AST: all solid tumours; MM: multiple myeloma

Therapeutic Strategy ^Evidence

Level Grade PMID Nº

Radiotherapy

SFRT with an 8-Gy dose is effective and recommended (instead of MFRT) in some clinical guidelines for reducing bone pain, in uncomplicated and not previously irradiated bone metastases of any location.

oMFRT is as effective in reducing bone pain in the following schemes: 20 Gy/5 fractions, 24 Gy/6 fractions, and 30 Gy/10 fractions

In retreatment of patients, both SF with 8-Gy or 20 Gy in 5 fractions are efficient, however, toxicity risks, cost, and patient convenience or option should be accounted for.

In SCC, for patients with a good prognosis and/or after surgery, and also patients with distal lesions of the spine independently of the prognosis, MFRT is preferable and a dose of 30 Gy in 10 fractions could be considered

– For patients with a worse prognosis, not candidates for surgery, palliative RT with an 8-Gy SF should be given

SRBT 24Gy/2 fractions can be used to control vertebral BM associated pain, with tolerability, in selected patients (with ECOG performance status superior to 2, expected survival of more than 3 months, and no more

than three consecutive spinal segments affected in the radiotherapy treatment volume site), with higher efficiency in pain control than 20 Gy/5 MFRT.

Antiemetic treatment (like 5-HT3-receptor antagonist and dexamethasone) should be provided to minimize nausea and vomiting, mainly in patients receiving RT in anatomic regions of moderate to high emetic risk.

Radionuclides

131I activity should be administered empirically (100-200 mCi) or determined by dosimetry, in the treatment of iodine avid BM of thyroid carcinoma.

223Ra has shown to be effective in treating BM of castration -resistant PC when injected at 50 kBq/kg every 4 weeks.

Surgery

The surgical treatment for BM or its complications should be individualized, accounting for the bone characteristics, affected body site, the patient survival, and functional status. An orthopaedic surgical team should be consulted.

Bone-Targeted Agents (BTAs)

It’s widely accepted to initiate BTAs as soon as the first BM is found, independently of patients’ symptoms.

However, there is no evidence to support this practice or to define which patients benefit from early BTAs.

29397209

I	A	28629871
I	A	29397209
II	B	24369114
		24782453
II	C	22420969
		31794625
		24782453
I	B	22420969
		31794625
II	C	34126044
II	B	27664248 30607675
III	B	26462967
II	B	23863050

III B

24782453

28461940

V D 24782453

31014505

In PC, BTAs should only be applied for the treatment of BM in castration-resistant tumours.
In MM, BTAs should be started at diagnosis.

Zoledronate is administered at 4 mg intravenously every 3 to 4 weeks and can be used to treat BM from solid

tumours and MM. Alternative BPs, doses, routes of administration and other pertinent information can be found in table 1.

oA less intensive schedule of zoledronate every 12 weeks is non-inferior and can be administered in PC,

BC and MM patients. Caution is advised with this scheme, due to lack of follow -up data and non-reduction of adverse effects.

Denosumab in a subcutaneous dose of 120 mg every 3 to 4 weeks is preferred to treat BM in PC and BC, and an

alternative to zoledronate in MM and other solid tumours.

Dose reduction (every 12 weeks) of pamidronate (in BC) and denosumab (in BC and PC) can be considered,

however, clear evidence to support this strategy is still lacking.

Treatment should be maintained indefinitely or interrupted after 2 years in patients in remission or with good

prognosis (like oligometastatic disease) or perceived low risk of complications.

Intravenous zoledronate (4 mg each 6 months) or d aily oral ibandronate or clodronate should be administered to

postmenopausal (naturally or induced) early -stage BC patients, at the beginning of neoadjuvant chemotherapy or as soon as possible in those with high recurrence risk but not receiving chemotherapy. oTreatment duration varies between 2 to 5 years but is still not well defined.

Vitamin D and Calcium Supplementation

Vitamin D deficiency should be corrected with a loading dose of 25 -50 000 IU of oral vitamin D3 weekly for 4 -8

weeks (ergocalciferol, cholecalciferol, alfacalcidol or calcitriol).

Maintenance treatment should be with 800 – 2000 IU of oral vitamin D3.
In addition to dietary calcium, calcium supplementation should allow for a total intake of 1000 to 1200 mg of calcium per day.

	24782453
A	24590644
	18990168
A	30937279 32905286
	31079283
A	31475116 28030702
	24782453
	30937279

I	A	32905286
		26693901
II	B	33023785
V	F	24782453
		24782453
		26211824
I A		31693129
		31806543
		21987386

I A 30236112

24782453

Table 1: Usual Doses of Bone-Targeted Agents for the Treatment of Bone Metastases

Agent Indication Route CrCl

(ml/min)

Dose (mg)

Infusion Rate Schedule

			≥ 60	4
			50-59	3,5	≥ 15 min in 100ml of	every 12 w or
Zoledronated	ST and MM	iv	40-49	3,3	0,9% saline	every 3-4 wa
			30-39	3
			< 30		Use not recommended

oral

≥ 50

30-50

50 NA

daily

every 2 d

Ibandronatee,f BC

< 30 every w

≥ 50 6 ≥ 15 min

iv 30-50 4 ≥ 1hb

< 30 2

every 3-4 w

Pamidronateg

BC and MM

≥ 90

90-30

≥ 2h

≥ 4hc

every 3 – 4 w (consider every 12 w)

< 30

Use not recommended

Clodronateh

Osteolytic lesions of BC

oral

≥ 50 1600

30-50 1200

NA daily

and MM

10-30 800

< 10 Use not recommended

Denosumabi ST and MM sc any 120 NA every 4 w

Based on Southcott D et al. Practical update for the use of bone-targeted agents in patients with bone metastases from metastatic breast cancer or castration-resistant prostate cancer. 2020. PMID 32905286 CrCl: Creatinine Clearance; ST: Solid Tumors; MM: Multiple Myeloma; iv: intravenous; w: week(s); BC: Breast Cancer; d: day(s); NA: not applicable; sc: subcutaneous

a ESMO suggests monthly therapeutic zoledronate schedule for at least 3 to 6 months. For the preventive treatment in early-stage high-risk BC, zoledronate each 6 months is suggested. b Normal infusion volume of 100 ml of 0,9% saline. 500 ml should be used if Cr clearance < 50 ml/min.

c Infusion should be made in 250 ml of 0,9% saline or 500 ml in MM patients. In MM patients, infusion should be in ≥ 4h independently of Cr Clearance

d Drug information recovered from: Mylan. Zoledronic acid 4 mg/5 ml concentrate for solution for infusion SmPC. 2020. Available at: https://www.medicines.org.uk/emc/product/2597/smpc; e Drug information recovered from: Atnahs Pharma UK Ltd. Bondronat 6 mg concentrate for solution for infusion SmPC. 2019. Available at: https://www.medicines.org.uk/emc/product/9375/smpc; f Drug information recovered from: Atnahs Pharma UK Ltd. Bondronat 50 mg film -coated tablets SmPC. 2019. Available at: https://www.medicines.org.uk/emc/product/9373/smpc; g Drug information recovered from: Wockhardt UK Ltd. Disodium Pamidronate 15mg/ml Concentrate for Solution for Infusion SmpC. 2019. Available at: https://www.medicines.org.uk/emc/product/2279/smpc; h D rug information recovered from: Beacon Pharmaceuticals / Kent Pharma UK Ltd.

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PMID 31017051: Wu D, Gomes Lima CJ, Moreau SL, Kulkarni K, Zeymo A, Burman KD, Wartofsky L, Van Nostrand D. Improved Survival After Multimodal Approach with 131I Treatment in Patients with Bone Metastases Secondary to Differentiated Thyroid Cancer. Thyroid. 2019 Jul;29(7):971-978. doi: 10.1089/thy.2018.0582.
PMID 29110129: Mazziotti G, Formenti AM, Panarotto MB, Arvat E, Chiti A, Cuocolo A, Dottorini ME, Durante C, Agate L, Filetti S, Felicetti F, Filice A, Pace L, Pellegrino T, Rodari M, Salvatori M, Tranfaglia C, Versari A, Viola D, Frara S, Berruti A, Giustina A, Giubbini R. Real-life management and outcome of thyroid carcinoma-related bone metastases: results from a nationwide multicenter experience. Endocrine. 2018 Jan;59(1):90-101. doi: 10.1007/s12020-017-1455-6.
PMID 30738780: Smith M, Parker C, Saad F, Miller K, Tombal B, Ng QS, Boegemann M, Matveev V, Piulats JM, Zucca LE, Karyakin O, Kimura G, Matsubara N, Nahas WC, Nolè F, Rosenbaum E, Heidenreich A, Kakehi Y, Zhang A, Krissel H, Teufel M, Shen J, Wagner V, Higano C. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):408-419. doi: 10.1016/S1470-2045(18)30860-X. Erratum in: Lancet Oncol. 2019 Oct;20(10):e559.
PMID 23863050: Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall’Oglio M, Franzén L, Coleman R, Vogelzang NJ, O’Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland ØS, Sartor O; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23. doi: 10.1056/NEJMoa1213755.
PMID 32593798: Parker C, Castro E, Fizazi K, Heidenreich A, Ost P, Procopio G, Tombal B, Gillessen S; ESMO Guidelines Committee. Electronic address: [email protected]. Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020 Sep;31(9):1119-1134. doi: 10.1016/j.annonc.2020.06.011.
PMID 25223925: Wood TJ, Racano A, Yeung H, Farrokhyar F, Ghert M, Deheshi BM. Surgical management of bone metastases: quality of evidence and systematic review. Ann Surg Oncol. 2014 Dec;21(13):4081-9. doi: 10.1245/s10434-014-4002-1.
PMID 28461940: Willeumier JJ, van der Linden YM, van de Sande MAJ, Dijkstra PDS. Treatment of pathological fractures of the long bones. EFORT Open Rev. 2017 Mar 13;1(5):136-145. doi: 10.1302/2058-5241.1.000008.
PMID 27843593: Shibata H, Kato S, Sekine I, Abe K, Araki N, Iguchi H, Izumi T, Inaba Y, Osaka I, Kato S, Kawai A, Kinuya S, Kodaira M, Kobayashi E, Kobayashi T, Sato J, Shinohara N, Takahashi S, Takamatsu Y, Takayama K, Takayama K, Tateishi U, Nagakura H, Hosaka M, Morioka H, Moriya T, Yuasa T, Yurikusa T, Yomiya K, Yoshida M. Diagnosis and treatment of bone metastasis: comprehensive guideline of the Japanese Society of Medical Oncology, Japanese Orthopedic Association, Japanese Urological Association, and Japanese Society for Radiation Oncology. ESMO Open. 2016 Mar 16;1(2):e000037. doi: 10.1136/esmoopen-2016-000037.
PMID 16112300: Patchell RA, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ, Mohiuddin M, Young B. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005 Aug 20-26;366(9486):643-8. doi: 10.1016/S0140-6736(05)66954-1.
PMID 20606090: Rades D, Huttenlocher S, Dunst J, Bajrovic A, Karstens JH, Rudat V, Schild SE. Matched pair analysis comparing surgery followed by radiotherapy and radiotherapy alone for metastatic spinal cord compression. J Clin Oncol. 2010 Aug 1;28(22):3597-604. doi: 10.1200/JCO.2010.28.5635.
PMID 32905286: Southcott D, Awan A, Ghate K, Clemons M, Fernandes R. Practical update for the use of bone-targeted agents in patients with bone metastases from metastatic breast cancer or castration-resistant prostate cancer. Curr Oncol. 2020 Aug;27(4):220-224. doi: 10.3747/co.27.6631. Epub 2020 Aug 1.
PMID 12076438: Wong R, Wiffen PJ. Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database Syst Rev. 2002;2002(2):CD002068. doi: 10.1002/14651858.CD002068.
PMID 29253322: Mhaskar R, Kumar A, Miladinovic B, Djulbegovic B. Bisphosphonates in multiple myeloma: an updated network meta-analysis. Cochrane Database Syst Rev. 2017 Dec 18;12(12):CD003188. doi: 10.1002/14651858.CD003188.pub4.
PMID 31014505: Tesfamariam Y, Jakob T, Wöckel A, Adams A, Weigl A, Monsef I, Kuhr K, Skoetz N. Adjuvant bisphosphonates or RANK-ligand inhibitors for patients with breast cancer and bone metastases: Asystematic review and network meta-analysis. Crit Rev Oncol Hematol. 2019 May; 137:1-8. doi: 10.1016/j.critrevonc.2019.02.004.

Evidence Level Grade PMID Nº

1. PERSISTENT HICCUPS

Authors: Juan Carlos Samamé Pérez-Vargas and Grezia Siancas Gonzales

Definition

A common and usually benign condition, affecting almost everyone at some point in their life. It is the sound caused by the rapid flow of air to the lungs after a contracture of the intercostal and diaphragmatic muscles followed by laryngeal closure1. According to the duration time, it can be classified as prolonged (>48h) or persistent (>1 month)2.

Symptoms

Feeling of narrowing at the level of the throat, abdomen, or chest
Patients with hiccups for more than 48 hours may have other symptoms such as:
Fatigue3-4
Insomnia3-5
Slurred speech: due to prolonged and constant hiccups6
Weight Loss7
Neurological symptoms (headache8, ataxia9) should be a warning sign 9-10.

Aetiology

Usually associated with benign causes that usually last less than 48h: abdominal distension11, irritating foods or drinks (alcohol)12, stress.
Gastroesophageal reflux disease. 4-13-14
Pharyngitis, laryngitis15, foreign body
Associated with CNS: cerebral vascular disease11-16, tumours of the nervous system17, neuro- optic myelitis 18, multiple sclerosis, infections of the nervous system19-20.
Acute myocardial infarction21, pericarditis
Diaphragmatic Tumours 22, mediastinal, sphogphic23, gynaecological.
Associated with drugs such as chemotherapy (platinum´s)1-24-25, steroids (dexamethasone)25-26, opiods27-28, antidepressants29-30, anesthesia31.

Pharmacotherapy

Although hiccups usually resolve spontaneously and last a few minutes, in some patients it can last more than 48 hours and be called persistent, requiring pharmacological measures.

Evidence Level Grade PMID Nº

MEDICAMENT	DOSAGE
Baclofen	3 x 5–20 mg/day
Pregabalin	2 x 75–150 mg/ day
Gabapentin	3 x 300–600 mg/day
Metoclopramide	3 x 10 mg/day
Chlorpromazine	4x 25 – 50 mg/ day
Amitriptyline	1 x 25 –100 mg/ night

2 B	26307025
4	26307025
5	26307025
2 B	26307025
4	26307025
5	26307025

Therapeutic strategies

There are some patients who opt for non-pharmacological measures for the treatment of prolonged hiccups, either as a single therapy or as an adjunct to pharmacological measures.

Evidence Level Grade PMID Nº

Physical measures: breathing manoeuvres (holding breathing, Valsalva manoeuvre), vagal stimulation, nasopharyngeal stimulation

Acupuncture

Hypnosis

Neural block C3-C5

Vagal nerve stimulator

4	C 26307025
4	26307025
5	26307025
5	26307025
5	26307025

References

Chang FY, Lu CL. Hiccup: mystery, nature and treatment. J Neurogastroenterol Motil. 2012;18(2):123-130. doi:10.5056/jnm.2012.18.2.123
Bredenoord AJ. Management of belching, hiccups, and aerophagia. Clin Gastroenterol Hepatol. 2013 Jan;11(1):6-12. doi: 10.1016/j.cgh.2012.09.006. Epub 2012 Sep 13. PMID: 22982101.
Askenasy JJ. Sleep hiccup. Sleep 1988; 11:187-94
Rouse S, Wodziak M. Intractable Hiccups. Curr Neurol Neurosci Rep. 2018 Jun 22;18(8):51. doi: 10.1007/s11910-018-0856-0. PMID: 29934880.
Moretto EN, Wee B, Wiffen PJ, Murchison AG. Interventions for treating persistent and intractable hiccups in adults. Cochrane Database Syst Rev 2013;2013:CD008768.
Martinez Paredes JF, Thompson CC, Rutt AL. Laryngeal Manifestations of Intractable Singultus. Cureus. 2021;13(3):e13730. Published 2021 Mar 6. doi:10.7759/cureus.13730 7 . Prince G, Sergel M. Persistent hiccups as an atypical presenting complaint of COVID-19. Am J Emerg Med. 2020;38(7): 1546.e5-1546.e6. doi: 10.1016/j.ajem.2020.04.045
Chaudhry P, Friedman DI. Hiccups as a migraine aura. Cephalalgia. 2015 Aug;35(9):831-4. doi: 10.1177/0333102414560633. Epub 2014 Nov 21. PMID: 25416324.
Sampath V, Gowda MR, Vinay HR, Preethi S. Persistent hiccups (singultus) as the presenting symptom of lateral medullary syndrome. Indian J Psychol Med. 2014;36(3):341-343. doi:10.4103/0253- 7176.135397
Rajagopalan, V., SenGupta, D., Goyal, K., Dube, S. K., Bindra, A., & Kedia, S. (2021). Hiccups in neurocritical care. Journal of Neurocritical Care. https://doi.org/10.18700/jnc.200018
Steger M, Schneemann M, Fox M. Systemic review: the pathogenesis and pharmacological treatment of hiccups. Aliment Pharmacol Ther. 2015 Nov;42(9):1037-50. doi: 10.1111/apt.13374. Epub 2015 Aug 25. PMID: 26307025.
Takahashi T, Murata T, Omori M, Tagaya M, Wada Y. Successful treatment of intractable hiccups with serotonin (5-HT)1Areceptor agonist. J Neurol. 2004; 251:486–487.
Rey E, Elola-Olaso CM, Rodríguez-Artalejo F, Locke GR, 3rd, Díaz-Rubio M. Prevalence of atypical symptoms and their association with typical symptoms of gastroesophageal reflux in Spain. Eur J Gastroenterol Hepatol. 2006; 18:969–975.
Cabane J, Bizec JL, Derenne JP. Adiseased esophagus is frequently the cause of chronic hiccup. Aprospective study of 184 cases. Presse Med 2010; 39: e141–6.
Morinaka S. Herpes zoster laryngitis with intractable hiccups. Auris Nasus Larynx. 2009 Oct;36(5):606-8. doi: 10.1016/j.anl.2009.01.011. Epub 2009 Mar 4. PMID: 19264432.
Kolodzik, P. W., & Filers, M. A. (1991). Hiccups (Singultus): Review and approach to management. Annals of Emergency Medicine, 20(5), 565–573. doi:10.1016/s0196-0644(05)81620-8
Tay SS, Yadav RR. Novel use of baclofen in cancer patients for the treatment of hiccups. Ann Acad Med Singapore. 2010; 39:154.
Wang KC, Lee CL, Chen SY, Lin KH, Tsai CP. Prominent brainstem symptoms/signs in patients with neuromyelitis optica in a Taiwanese population. J Clin Neurosci. 2011; 18:1197–1200.
Sugimoto T, Takeda N, Yamakawa I, et al. Intractable hiccup associated with aseptic meningitis in a patient with systemic lupus erythematosus. Lupus. 2008; 17:152–153.
Brañuelas Quiroga J, Urbano García J, Bolaños Guedes J. Hiccups: a common problem with some unusual causes and cures [published correction appears in Br J Gen Pract.
Krysiak W, Szabowski S, Stepień M, Krzywkowska K, Krzywkowski A, Marciniak P. Hiccups as a myocardial ischemia symptom. Pol Arch Med Wewn. 2008; 118:148–151.
Porzio G, Aielli F, Verna L, Aloisi P, Galletti B, Ficorella C. Gabapentin in the treatment of hiccups in patients with advanced cancer: a 5-year experience. Clin Neuropharmacol. 2010; 33:179–180.
Khorakiwala T, Arain R, Mulsow J, Walsh TN. Hiccups: an unrecognized symptom of esophageal cancer? Am J Gastroenterol. 2008; 103:801.
Takiguchi Y, Watanabe R, Nagao R, Kuriyama T. Hiccups as an adverse reaction to cancer chemotherapy. J Natl Cancer Inst. 2002; 94:772.
Gilbar P, McPherson I. Severe hiccups during chemotherapy: corticosteroids the likely culprit. J Oncol Pharm Pract. 2009 Dec;15(4):233-6. doi: 10.1177/1078155209102336. PMID: 19276142.
Dickerman RD, Overby C, Eisenberg M, Hollis P, Levine M. The steroid-responsive hiccup reflex arc: competitive binding to the corticosteroid-receptor Neuro Endocrinol Lett. 2003; 24:167–169.
Ruan X, Couch JP, Shah R, Wang F, Liu HN. Persistent hiccup associated with intrathecal morphine infusion pump therapy. Am J Phys Med Rehabil. 2007 Dec;86(12):1019-22. doi: 10.1097/PHM.0b013e31815206c8. PMID: 18090443.
García M, Lertxundi U, Aguirre C. Tramadol-induced hiccups: a case–noncase study in the European pharmacovigilance database. Therapeutic Advances in Drug Safety. January 2021. doi:10.1177/20420986211021230
Kutuk MO, Tufan AE, Guler G, Yildirim V, Toros F. Persistent hiccups due to aripiprazole in an adolescent with obsessive compulsive disorder responding to dose reduction and rechallenge. Oxf Med Case Reports. 2016;2016(4):66-67. Published 2016 Apr 20. doi:10.1093/omcr/omw017
Bozhüyük, Erol & Poyraz, Cana & Poyraz, Burç & Ozdemir, Armagan & Savrun, Mert & Arikan, Mehmet. (2009). Persistent Hiccups with Fluvoxamine: a Case Report. Yeni Symposium. 47. 161-163.
Baraka A. Inhibition of hiccups by the laryngeal mask airway. Anaesthesia. 2004; 59:926.
1. CANNABIS IN CANCER PATIENT

Authors: Alejandro Jesús Bermejo Valdés, Alexander Ariel Padrón González and Jessica Archer Jiménez

Introduction

The pain-vomiting-anorexia triad in cancer patients

A current challenge in the treatment of cancer patients is the treatment of pain, nausea and vomiting associated with chemotherapy, and anorexia. The pain caused by cancer considerably affects the quality of life of patients and has great negative effects on the psychological coping of the patient with his illness. This is often worsened by intolerance to treatment with opioids and antiemetic’s that some patients present. While cancer alone is physically and psychologically detrimental, the triad of pain, vomiting, and anorexia makes it even worse.

Cannabis as therapy in cancer. Myth or Reality?

Before becoming illegal, various preparations of the Cannabis sativa plant, cannabis, were used for centuries. This plant contains cannabinoids as active ingredients, which act in a similar way to endocannabinoids (or endogenous cannabinoids) activating specific cannabinoid receptors. Examples of cannabinoid receptors are CB1, which is found predominantly in the central nervous system, and CB2, which is found predominantly in cells involved in immune function. (1)

Cannabinoids have been available as a drug for the treatment of pain in cancer patients and for chemotherapy-induced nausea and vomiting. The plant’s main bioactive cannabinoid is delta-9-tetrahydrocannabinol (THC). (1)

There are multiple studies to date on cancer and cannabis; however, it is still not clear regarding the pharmacological use of cannabinoids or synthetic derivatives if their beneficial effects really outweigh the adverse reactions. This is a topic that will require further in-depth study.

Studies

If we do not consider the adverse effects of the use of cannabinoids, we can ensure that there is efficacy in the use of cannabinoids in various symptoms typical of cancer patients. For example, cannabinoids have been shown to be effective in treating anorexia in cancer patients (2-4), vomiting (5,6) and nausea or vomiting resistant to usual antiemetic treatment (7), as well as have been shown to improve sleep disorders, pain (3,8,9) and mood, thus improving the patient’s quality of life(3). Even beneficial effects of cannabinoids have been shown in the treatment of uncontrolled pain or in people with intolerance to opioid therapy (10-12); in addition, there are data on the possibility of long-term use of cannabinoids without loss of the analgesic effect over time (13). In vitro and in vivo studies have shown that cannabinoids have anticancer properties against glioma cells (14,15), prostate cancer (16) and melanoma(17). Although these are studies that today need to be developed in more depth and be extended to clinical trials. However, not all studies are in favour of the efficiency of cannabinoid use in cancer patients. This is due to the fact that conclusions have been reached that claim to have insufficient data or that contradict the benefits of using cannabis in cancer patients to relieve pain (18), vomiting or nausea due to chemotherapy and resolve anorexia (19-21). In addition, if we focus on cannabis itself, we have data suggesting that there is clear evidence to associate cannabis use with psychotic states, affective and sleep disorders, anxiety, cognitive failure, cancer, cardiovascular, respiratory, and gastrointestinal disorders (22).

Evidence Level Grade PMID Nº

Cannabis use also implies a risk factor for motor vehicle collisions, intimate partner and child violence, and suicide (22), although the evidence is not so clear on this last aspect (23). For heavy users, case-control studies suggest a possible association of cannabis with respiratory and brain cancers (23). Overall, there are studies concluding that the evidence for medical cannabis requires more rigorous evaluation before considering it as a treatment option for many conditions, and the evidence needed to inform policy and treatment guidelines is currently insufficient for many conditions (24-26). Even studies with low risk of bias showed that, in adults with advanced cancer, the addition of cannabinoids to opioids did not reduce cancer pain (27). In general, none of the cannabinoids (dronabinol, nabilone, medical cannabis, or delta-9-tetrahydrocannabinol: cannabidiol spray) have shown benefit in treating cancer pain (28). Public perception of the efficacy, tolerability, and safety of cannabis-based medications in pain management and palliative medicine conflicts with the findings of systematic reviews and prospective observational studies conducted according to standards of medicine evidence-based (28).

There is also a lack of high-quality evidence to recommend the use of cannabinoids in the treatment of cachexia. Given the limited pharmacological options available for cachexia and the potential for cannabinoids to increase appetite and alter the immune system, more research is needed before clinical recommendations can be made on the pharmacological management of cachexia (29).

In conclusion, it is not yet possible to speak of enhancing or detrimental effects of cannabis on cancer, since there is a lack of scientific evidence in this regard. In the years to come, due to continued research on this topic, we will surely get out of this ambiguity and come to workable conclusions.

Diagnosis requires the combination of symptoms, physical examination, vaginal pH determination (usually normal) and microscopy examination.[7, 9]
Culture confirms the diagnosis but is only recommended when there is a typical presentation and negative microscopy, or in cases of persistent or recurrent infections presumably by non-albicans agents’ infection or azole resistance. If positive it overestimates prevalence when there is no clinical correlation.[7, 9]

Pharmacotherapy and Therapeutic Strategy

Data in favor of cannabis use in c ancer patients	Evidence
Data in favor of cannabis use in c ancer patients	Level	Grade	PMID Nº
Cannabinoid is effective in increasing appetite in cancer patients. However, it declines the quality of life, which may be due to the side effects of cannabinoid.	1	1B ↑↑, Strong recommendation; ⊕⊕⊕⊕ , high quality of the evidence)	PMID: 31341892
Moderate to high certainty evidence shows that non -inhaled medical cannabis or cannabinoids results in a small to very small improvement in pain relief, physical functioning, and sleep quality among patients with chronic pain, along with several transient adverse side effects, compared with placebo .	1	1B ↑↑, Strong recommendation; ⊕⊕⊕⊕ , high quality of the evidence)	PMID: 34497047
Superiority of the anti -emetic efficacy of cannabinoids was demonstrated through meta -analysis, but the adverse effects were more intense and occurred more often among patients who used cannabinoids.	1	1B ↑↑, Strong recommendation; ⊕⊕⊕⊕ , high quality of th e evidence)	PMID: 18625004
In preclinical (rodent) models substantial evidence supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.	3	2B ↑, Conditional recommendation; ⊕⊕⊕⊝ , moderate quality of the evidence)	PMID: 33729211
Cannabis -based medications may be useful for treating refractory chemotherapy -induced nausea and vomiting. However, methodological limitations of the trials limit the conclusions and further research reflecting current chemotherapy regimens and newer anti -emetic drugs is likely to modify these conclusions.	1	1B ↑↑, Strong recommendation; ⊕⊕⊕⊕ , high quality of the evidence)	PMID: 26561338

Positive effects reported by children and parents in 80% of the cases regarding nausea and vomit, sleep disorders, pain, appetite, and mood, improving thus patient quality of life. However, 14% of patients who smoked the extract reported throat burning, anxiety attacks, and stomach pain.	2	1B ↑↑, Strong recommendation; ⊕⊕⊕ ⊝, moderate quality of the evidence	PMID: 34037196
Cannabinoid type 2 receptor agonists significantly attenuated pain-associated behaviours in mouse cancer and visceral inflammation models. The evidence in animals supports the hypothesis of cannabinoid-induced analgesia.	2	1B ↑↑, Strong recommendation; ⊕⊕⊕⊕, high quality of the evidence)	PMID: 33729209
The use of cannabis and cannabinoids via certain administration routes could reduce different types of pain.	2	1B ↑↑, Strong recommendation; ⊕⊕⊕⊕, high quality of the evidence)	PMID: 31495691
Nabiximols, a mixture extracted from cannabis sativa plant material, had acceptable safety and tolerability with no drug- drug interaction identified. The observed survival differences support further exploration in an adequately powe red randomised controlled trial.	2	2B ↑, Conditional recommendation; ⊕⊕⊕⊝, moderate quality of the evidence)	PMID: 33623076
In a multicentre, randomised, double -blinded, placebo -controlled, phase II/III trial evaluate an oral delta-9- tetrahydrocannabinol: cannabidiol (THC: CBD ) cannabis extract for prevention of refractory chemotherapy -induced nausea and vomiting. The addition of oral THC: CBD to standard antiemetics was associated with less nausea and vomiting but additional side-effects. Most participants preferred THC: CBD to placebo.	2	2C ↑, Conditional recommendation; ⊕⊕⊝⊝, low quality of the evidence)	PMID: 32801017
Nabilone, a synthetic cannabinoid, is an adequate and safe therapeutic option to aid in the treatment of patients diagnosed with anorexia. Larger trials are necessary in order to draw robust conclusions in regard to its efficacy in lung cancer patients.	1	2B ↑, Conditional recommendation; ⊕⊕⊕⊝, moderate quality of the evidence)	PMID: 29550881
Prior Phase 2/3 studies found that cannabinoids might provide adjunctive analgesia in advanced cancer patients with uncontrolled pain. Nabiximols might have utility in patients with advanced cancer who receive a lower opioid dose, such as individuals with early intolerance to opioid therapy.	1	2B ↑, Conditional recommendation; ⊕⊕⊕⊝, moderate quality of the evidence)	PMID: 28923526
The THC: CBD Oro mucosal spray is cannabinoid formulation with a long-term use as spray and generally well tolerated, with no evidence of a loss of effect for the relief of cancer -related pain with long-term use. P atients who kept using the study medication did not seek to increase their dose of this or other pain-relieving medication over time, suggesting that the adjuvant use of cannabinoids in cancer-related pain could provide useful benefit.	2	2C ↑, Conditional recommendation; ⊕⊕⊝⊝, low quality of the evidence)	PMID: 23141881
Nabiximols, a cannabinoid formulation, may be a useful add-on analgesic for patients with opioid-refractory cancer pain. A randomized, double-blind, placebo-controlled, graded-dose study demonstrated efficacy and safety at low and medium doses	1	2B ↑, Conditional recommendation; ⊕⊕⊕⊝, moderate quality of the evidence)	PMID: 22483680

THC can improve taste and smell (chemosensory) perception as well as appetite, caloric intake, and quality of life (QOL) for cancer patients with chemosensory alterations.	1	2B ↑, Conditional recommendation; ⊕⊕⊕⊝, moderate quality of the evidence)	PMID: 21343383
THC: CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids.	1	1B ↑↑, Strong recommendation; ⊕⊕⊕⊕, high quality of the evidence)	PMID: 19896326
Cannabinoids possess anticancer potencies against glioma cellsin vitro and/or in vivo, however this effect varies with the combinations and dosages used. Studies so far were conducted on cells in culture and on mice as well as a small number of studies that were conducted on humans. Hence to have more accurate results, higher quality studies mainly including human clinical trials with larger sample sizes are necessitated urgently for Glioblastoma Multiforme treatment.	2	2B ↑, Conditional recommendation; ⊕⊕⊕⊝, moderate quality of the evidence)	PMID: 33812759
A retrospective review comparing nabilone, dronabinol, THC (delta-9-tetrahydrocannabinol), and delta 8-THC with other antiemetics used to manage chemotherapy-induced nausea and vomiting in paediatric patients showed that these drugs could also be used as adjuvant antiemetics. Ca ncer patients on highly emetogenic chemotherapy but with insufficiently effective standard antiemetic therapy can be given cannabis preparations containing similar amounts of tetrahydrocannabinol and can-nabidiol, which should be received in strict compliance with the professional guidelines for the treatment chemotherapy-induced nausea and vomiting.	2	2C ↑, Conditional recommendation; ⊕⊕⊝⊝, low quality of the evidence)	PMID: 33415919
Different studies have reported that the treatment of prostate cancers in in vivo/xenograft models with various cannabinoids decreased the size of the tumour, the outcomes of which depended on the dose and length of treatment. Within the limitation of these identified studies, cannabinoids were shown to reduce the size of prostate cancer tumours in animal models. However, further well-designed, and controlled animal studies are warranted to confirm these findings.	2	2C ↑, Conditional recommendation; ⊕⊕⊝⊝, low quality of the evidence)	PMID: 32872551
Cannabinoids, individually or combined, reduced tumour growth and promoted apoptosis and autophagy in melanoma cells. Further preclinical and animal studies are required to determine the un derlying mechanisms of cannabinoids – mediated inhibition of cancer-signalling pathways.	3	2C ↑, Conditional recommendation; ⊕⊕⊝⊝, low quality of the evidence)	PMID: 32839414
There was limited moderate-quality evidence that supports the use of cannabinoids as adjuvant to the standard of care in the treatment of brain and CNS tumours. There was very low -quality evidence suggesting that cannabinoids were associated with adult-onset gliomas. Further prospective clinical trials are necessary to adequately evaluate the impact of cannabinoids on CNS tumours, specifically on survival and quality of life.	1	2C ↑, Conditional recommendation; ⊕⊕⊝⊝, low quality of the evidence)	PMID: 32765889
There was conclusive or substantial evidence that Cannabis or cannabinoids are effective for the treatment of pain in adults; chemotherapy-induced nausea and vomiting and spasticity associated with multiple sclerosis. Moderate evidence was found for second ary sleep disturbances. The evidence supporting improvement in appetite, Tourette syndrome, anxiety, posttraumatic stress disorder, cancer, irritable bowel syndrome, epilepsy and a variety of neurodegenerative disorders was described as limited, insufficient, or absent.	3	2C ↑, Conditional recommendation; ⊕⊕⊝⊝, low quality of the evidence)	PMID: 29325791

This case series suggests that topical cannabinoids may be helpful for patients with chemotherapy -induced peripheral neuropathy.	3	2C ↑, Conditional recommendation; ⊕⊕⊝⊝, low quality of the evidence)	PMID: 34841942
Data against or with a neutral position regarding the use of cannabis in cancer patients
No convincing, unbiased, high-quality evidence was found suggesting that cannabinoids are of value for anorexia or cachexia in cancer.	1	2B ↑, Conditional recommendation; ⊕⊕⊕⊝, moderate quality of the evidence)	PMID: 29400010
Lack of quality research literature on this subject and thus were unable to demonstrate a clear therapeutic benefit for either general or specific use of phytochemicals in the management of cancer pain. This lack of data is especially apparent for psychotropic phytochemicals, such as the Cannabis plant (marihuana).	1	2B ↑, Conditional recommendation; ⊕⊕⊕⊝, moderate quality of the evidence)	PMID: 26576425
Megestrol acetate provided superior anorexia palliation among advanced cancer patients compared with delta-9- tetrahydrocannabinol alone. Combination therapy did not appear to confer additional benefit.	2	2C ↑, Conditional recommendation; ⊕⊕⊝⊝, low quality of the evidence)	PMID: 11786587
Evidence shows a clear association between cannabis use and psychosis, affective disorders, anxiety, sleep disorders, cognitive failures, respiratory adverse events, cancer, cardiovascular outcomes, and gastrointestinal disorders. Moreover, cannabis use is a risk factor for motor vehicle collision, suicidal behaviour and partner and child violence. Cannabis use is a risk factor for several medical conditions and negative social consequences. There is still little data on the dose – dependency of these effects; evidence that is essentialto define, from a public health perspective, what can be considered risky use of cannabis.	2	2B ↑, Conditional recommendation; ⊕⊕⊕⊝, moderate quality of the evidence)	PMID: 32165103
Incomplete evidence of the efficacy and safety of medical use of cannabis in oncological patients treated with chemotherapy. Furthermore, for many of the outcomes considered, the confidence in the estimate of the effect was again low or very low.	2	2B ↑, Conditional recommendation; ⊕⊕⊕⊝, moderate quality of the evidence)	PMID: 29119763
There is insufficient evidence, particularly because of the low number of studies, to assess whether the a-lcl ause mortality rate is elevated among cannabis users in the general population. Case-control studies suggest that some adverse health outcomes may be elevated among heavy cannabis users, namely, fatal motor vehicle accidents, and possibly respiratory and brain cancers. The evidence is as yet unclear as to whether regular cannabis use increases the risk of suicide.	2	2C ↑, Conditional recommendation; ⊕⊕⊝⊝, low quality of the evidence)	PMID: 20565525
The body of evidence for medical cannabis requires more rigorous evaluation before consideration as a treatment option for many conditions, and evidence necessary to inform policy and treatment guidelines is currently insufficient for many conditions.	2	2C ↑, Conditional recommendation; ⊕⊕⊝⊝, low quality of the evidence)	PMID: 34676348

There were consistent results that there was insufficient evidence of any cannabis-based medicine for pain in cancer.	1	2B ↑, Conditional recommendation; ⊕⊕⊕⊝, moderate quality of the evidence)	PMID: 29034533
Studies with a low risk of bias showed that for adults with advanced cancer, the addition of cannabinoids to opioids did not reduce cancer pain.	1	1B ↑↑, Strong recommendation; ⊕⊕⊕⊕, high quality of the evidence)	PMID: 31959586
Due to the sparse amount of data, it is not possible to recommend a favoured use of cannabis or cannabinoids at this point.	2	1B ↑↑, Strong recommendation; ⊕⊕⊕ ⊝, moderate quality of the evidence	PMID: 26809975
There is inadequate evidence for any benefit of cannabinoids (dronabinol, nabilone, medical cannabis, or THC: CBD spray) to treat cancer pain. Treatment with cannabis-based medicines is associated with central nervous and psychiatric side effects. The publ ic perception of the efficacy, tolerability, and safety of cannabis -based medicines in pain management and palliative medicine conflicts with the findings of systematic reviews and prospective observational studies conducted according to the standards of evidence-based medicine.	1	1B ↑↑, Strong recommendation; ⊕⊕⊕ ⊝, moderate quality of the evidence	PMID: 29017688
There is a lack of high -quality evidence to recommend the use of cannabinoids in the treatment of cachexia. Given the limited available pharmacological options for cachexia and the potential for cannabinoids to increase appetite and alter the immune system, further research is needed before clinical recommendations on the pharmacological management of cachexia can be made.	2	2C ↑, Conditional recommendation; ⊕⊕⊝⊝, low quality of the evidence)	PMID: PMC8713261

References

Abrams DI, Guzman M. Cannabis in cancer care. Clin Pharmacol Ther. 2015 Jun;97(6):575-86. doi: 10.1002/cpt.108. Epub 2015 Apr 17. PMID: 25777363.
Wang J, Wang Y, Tong M, Pan H, Li D. Medical Cannabinoids for Cancer Cachexia: A Systematic Review and Meta-Analysis. Biomed Res Int. 2019 Jun 23;2019:2864384. doi: 10.1155/2019/2864384. PMID: 31341892; PMCID: PMC6612387.
Lopes-Júnior LC, Urbano IR, Schuab SIPC, Pessanha RM, Rosa GS, Lima RAG. Effectiveness of complementary therapies for the management of symptom clusters in palliative care in pediatric oncology: a systematic review. Rev Esc Enferm USP. 2021 May 19;55:03709. English, Portuguese. doi: 10.1590/S1980-220X2020025103709. PMID: 34037196.
Brisbois TD, de Kock IH, Watanabe SM, Mirhosseini M, Lamoureux DC, Chasen M, MacDonald N, Baracos VE, Wismer WV. Delta-9-tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double-blind, placebo-controlled pilot trial. Ann Oncol. 2011 Sep;22(9):2086-2093. doi: 10.1093/annonc/mdq727. Epub 2011 Feb 22. PMID: 21343383.
Machado Rocha FC, Stéfano SC, De Cássia Haiek R, Rosa Oliveira LM, Da Silveira DX. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J Cancer Care (Engl). 2008 Sep;17(5):431-43. doi: 10.1111/j.1365-2354.2008.00917.x. Epub 2008 Jul 9. PMID: 18625004.
Grimison P, Mersiades A, Kirby A, Lintzeris N, Morton R, Haber P, Olver I, Walsh A, McGregor I, Cheung Y, Tognela A, Hahn C, Briscoe K, Aghmesheh M, Fox P, Abdi E, Clarke S, Della-Fiorentina S, Shannon J, Gedye C, Begbie S, Simes J, Stockler M. Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial. Ann Oncol. 2020 Nov;31(11):1553-1560. doi: 10.1016/j.annonc.2020.07.020. Epub 2020 Aug 13. PMID: 32801017.
Serafimovska T, Darkovska-Serafimovska M, Stefkov G, Arsova-Sarafinovska Z, Balkanov T. Pharmacotherapeutic Considerations for Use of Cannabinoids to Relieve Symptoms of Nausea and Vomiting Induced by Chemotherapy. Folia Med (Plovdiv). 2020 Dec 31;62(4):668-678. doi: 10.3897/folmed.62.e51478. PMID: 33415919.
Rabgay K, Waranuch N, Chaiyakunapruk N, Sawangjit R, Ingkaninan K, Dilokthornsakul P. The effects of cannabis, cannabinoids, and their administration routes on pain control efficacy and safety: A systematic review and network meta-analysis. J Am Pharm Assoc (2003). 2020 Jan-Feb;60(1):225-234.e6. doi: 10.1016/j.japh.2019.07.015. Epub 2019 Sep 5. PMID: 31495691.
Abrams DI. The therapeutic effects of Cannabis and cannabinoids: An update from the National Academies of Sciences, Engineering and Medicine report. Eur J Intern Med. 2018 Mar;49:7- 11. doi: 10.1016/j.ejim.2018.01.003. Epub 2018 Jan 9. PMID: 29325791.
Lichtman AH, Lux EA, McQuade R, Rossetti S, Sanchez R, Sun W, Wright S, Kornyeyeva E, Fallon MT. Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain. J Pain Symptom Manage. 2018 Feb;55(2):179-188.e1. doi: 10.1016/j.jpainsymman.2017.09.001. Epub 2017 Sep 18. PMID: 28923526.
Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012 May;13(5):438-49. doi: 10.1016/j.jpain.2012.01.003. Epub 2012 Apr 5. PMID: 22483680.
Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage. 2010 Feb;39(2):167-79. doi: 10.1016/j.jpainsymman.2009.06.008. Epub 2009 Nov 5. PMID: 19896326.
Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013 Aug;46(2):207-18. doi: 10.1016/j.jpainsymman.2012.07.014. Epub 2012 Nov 8. PMID: 23141881.
Kyriakou I, Yarandi N, Polycarpou E. Efficacy of cannabinoids against glioblastoma multiforme: A systematic review. Phytomedicine. 2021 Jul 15;88:153533. doi: 10.1016/j.phymed.2021.153533. Epub 2021 Mar 5. PMID: 33812759.
Rodriguez-Almaraz JE, Chang S, Clarke J, Oberheim-Bush NA, Taylor J, Buerki R, Berger M, Zablotska L, Lobach I, Butowski N. A systematic review and meta-analysis examining the effects of cannabis and its derivatives in adults with malignant CNS tumors. Neurooncol Pract. 2020 Jul;7(4):376-383. doi: 10.1093/nop/npaa013. Epub 2020 Apr 3. PMID: 32765889; PMCID: PMC7393278.
Singh K, Jamshidi N, Zomer R, Piva TJ, Mantri N. Cannabinoids and Prostate Cancer: A Systematic Review of Animal Studies. Int J Mol Sci. 2020 Aug 29;21(17):6265. doi: 10.3390/ijms21176265. PMID: 32872551; PMCID: PMC7503992.
Bachari A, Piva TJ, Salami SA, Jamshidi N, Mantri N. Roles of Cannabinoids in Melanoma: Evidence from In Vivo Studies. Int J Mol Sci. 2020 Aug 21;21(17):6040. doi: 10.3390/ijms21176040. PMID: 32839414; PMCID: PMC7503316.
Harrison AM, Heritier F, Childs BG, Bostwick JM, Dziadzko MA. Systematic Review of the Use of Phytochemicals for Management of Pain in Cancer Therapy. Biomed Res Int. 2015;2015:506327. doi: 10.1155/2015/506327. Epub 2015 Oct 20. PMID: 26576425; PMCID: PMC4630373.
Mücke M, Weier M, Carter C, Copeland J, Degenhardt L, Cuhls H, Radbruch L, Häuser W, Conrad R. Systematic review and meta-analysis of cannabinoids in palliative medicine. J Cachexia Sarcopenia Muscle. 2018 Apr;9(2):220-234. doi: 10.1002/jcsm.12273. Epub 2018 Feb 5. PMID: 29400010; PMCID: PMC5879974.
Jatoi A, Windschitl HE, Loprinzi CL, Sloan JA, Dakhil SR, Mailliard JA, Pundaleeka S, Kardinal CG, Fitch TR, Krook JE, Novotny PJ, Christensen B. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol. 2002 Jan 15;20(2):567-73. doi: 10.1200/JCO.2002.20.2.567. PMID: 11786587.
Amato L, Minozzi S, Mitrova Z, Parmelli E, Saulle R, Cruciani F, Vecchi S, Davoli M. Revisione sistematica sull’efficacia terapeutica e la sicurezza della cannabis per i pazienti affetti da sclerosi multipla, dolore neuropatico cronico e pazienti oncologici che assumono chemioterapie [Systematic review of safeness and therapeutic efficacy of cannabis in patients with multiple sclerosis, neuropathic pain, and in oncological patients treated with chemotherapy]. Epidemiol Prev. 2017 Sep-Dec;41(5-6):279-293. Italian. doi: 10.19191/EP17.5-6.AD01.069. PMID: 29119763.
Campeny E, López-Pelayo H, Nutt D, Blithikioti C, Oliveras C, Nuño L, Maldonado R, Florez G, Arias F, Fernández-Artamendi S, Villalbí JR, Sellarès J, Ballbè M, Rehm J, Balcells-Olivero MM, Gual A. The blind men and the elephant: Systematic review of systematic reviews of cannabis use related health harms. Eur Neuropsychopharmacol. 2020 Apr;33:1-35. doi: 10.1016/j.euroneuro.2020.02.003. Epub 2020 Mar 9. PMID: 32165103.
Calabria B, Degenhardt L, Hall W, Lynskey M. Does cannabis use increase the risk of death? Systematic review of epidemiological evidence on adverse effects of cannabis use. Drug Alcohol Rev. 2010 May;29(3):318-30. doi: 10.1111/j.1465-3362.2009.00149.x. PMID: 20565525.
Jugl S, Okpeku A, Costales B, Morris EJ, Alipour-Haris G, Hincapie-Castillo JM, Stetten NE, Sajdeya R, Keshwani S, Joseph V, Zhang Y, Shen Y, Adkins L, Winterstein AG, Goodin A. A Mapping Literature Review of Medical Cannabis Clinical Outcomes and Quality of Evidence in Approved Conditions in the USA from 2016 to 2019. Med Cannabis Cannabinoids. 2021 Feb 25;4(1):21-42. doi: 10.1159/000515069. PMID: 34676348; PMCID: PMC8525213.
Häuser W, Petzke F, Fitzcharles MA. Efficacy, tolerability and safety of cannabis-based medicines for chronic pain management – An overview of systematic reviews. Eur J Pain. 2018 Mar;22(3):455-470. doi: 10.1002/ejp.1118. Epub 2017 Oct 15. PMID: 29034533.
Mücke M, Carter C, Cuhls H, Prüß M, Radbruch L, Häuser W. Cannabinoide in der palliativen Versorgung : Systematische Übersicht und Metaanalyse der Wirksamkeit, Verträglichkeit und Sicherheit [Cannabinoids in palliative care: Systematic review and meta-analysis of efficacy, tolerability and safety]. Schmerz. 2016 Feb;30(1):25-36. German. doi: 10.1007/s00482-015-0085-2. PMID: 26809975.
Boland EG, Bennett MI, Allgar V, Boland JW. Cannabinoids for adult cancer-related pain: systematic review and meta-analysis. BMJ Support Palliat Care. 2020 Mar;10(1):14-24. doi: 10.1136/bmjspcare-2019-002032. Epub 2020 Jan 20. PMID: 31959586.
Häuser W, Fitzcharles MA, Radbruch L, Petzke F. Cannabinoids in Pain Management and Palliative Medicine. Dtsch Arztebl Int. 2017 Sep 22;114(38):627-634. doi: 10.3238/arztebl.2017.0627. PMID: 29017688; PMCID: PMC5645627.
Hammond S, Erridge S, Mangal N, Pacchetti B, Sodergren MH. The Effect of Cannabis-Based Medicine in the Treatment of Cachexia: A Systematic Review and Meta-Analysis. Cannabis Cannabinoid Res. 2021 Dec;6(6):474-487. doi: 10.1089/can.2021.0048. Epub 2021 Oct 18. PMID: 34664988; PMCID: PMC8713261.

CENTRAL VENOUS CATHETER

Authors: Alice Pimentel, Daniela Lira and Jessica Joana Noronha

The insertion of a central venous catheter (CVC) allows a reliable and safe venous access and is widely used in oncological patients specially for the administration of chemotherapy.

Defintion

ACVC consists in a catheter inserted in a venous great vessel usually percutaneously.1

Clasification

CVCs are classified according to2,3:

Duration of use: Short-term (≤ 14 days), mid-term (> 14 days to 3 months) and long-term (> 3 months)
Location of insertion: jugular, subclavian, femoral, brachial
Number of lumens: single, double, triple
Location of the catheter: non-implanted, tunneled, totally implanted

Catheters placed for chemotherapy regiments are usually single lumen, totally implanted, long-term and placed either on the jugular or subclavian vein.

Catheters used in cases of absence of peripheral venous access or transitory administration of parental nutrition are usually triple lumen, non-implanted, short-term, and placed on the jugular, subclavian or femoral vein.

Indications

Indications for a CVC include:

Impaired peripheral venous access
Locally aggressive infusion (chemotherapy regiments, total parenteral nutrition, vasopressors)
Hemodynamic monitoring
Extracorporeal therapies (hemodialysis)4

Evidence Level Grade PMID Nº

Contraindication Evidence

Relative contraindications for CVC placement include:

Coagulopathy and thrombocytopenia: should be corrected before if possible5
Hostile insertion site: another venous great vessel should be chosen

Technique

The preferred site for catheter placement is the right internal jugular vein followed by the right subclavian vein.6 Some of the basic steps include:

Local anaesthesia
Puncture guided by ultrasound7
Catheter placed using the Seldinger method
Confirmation of correct placement of the catheter’s tip under fluoroscopy

Complications

Complications of the procedure have been significantly reduced by the combined use of ultrasonographical guided vein puncture and fluoroscopy.8,9 Complications related to the technique depend on the site of placement and include pneumothorax, artery injury, venous air embolism and arrhytmia.10 Complications of CVC placement and their management are listed below:

Pneumothorax
- Occurs at the time of CVC insertion
- Caused by pleural punction

– Treatment: Chest tube

Artery injury
- Due to puncture of the artery instead of the targeted vein
- If not recognized immediately, life-threatening bleeding can occur

– Treatment: Removal of the needle and direct compression for 15 minutes11

Venous air embolism
- Rare
- Can occur at the time of CVC insertion, during catheter use or at removal

– Treatment: Supportive measures12

Arrythmia
- Caused by insertion of the guidewire or catheter into the right hearth

– Treatment: Withdrawal of the catheter a few centimetres till the tip is placed in the superior vena cava

Deep Vein Thrombosis13
- Common

– Treatment: Anticoagulation

Central vein stenosis14
- More common in left internal jugular and subclavian vein
- Should only be treated if symptomatic: Angioplasty
Catheter infection
- Local

Level Grade PMID Nº

Inflammation may be treated with local measures
If signs of infection, systemic antibiotics and catheter removal are needed15

-Systemic

Blood cultures should be taken
Treatment: systemic antibiotics and catheter removal16
Catheter malfunction17
- Due to mechanical obstruction (malposition) or thrombosis

-If malposition, catheter should be replaced

References

Evidence Level Grade PMID Nº

Mandolfo S, Acconcia P, Bucci R, Corradi B, Farina M, Rizzo MA, Stucchi A. Hemodialysis tunneled central venous catheters: five-year outcome analysis. J Vasc Access. 2014 Nov-Dec;15(6):461-5. doi: 10.5301
Van de Weerdt EK, Biemond BJ, Baake B, Vermin B, Binnekade JM, van Lienden KP, Vlaar APJ. Central venous catheter placement in coagulopathic patients: risk factors and incidence of bleeding

complications. Transfusion. 2017 Oct;57(10):2512-2525. doi: 10.1111/trf.14248.

Wang, Pei & Wang, Yufei & Qiao, Yingjin & Zhou, Sijie & Liang, Xianhui & Liu, Zhangsuo. (2016). A Retrospective Study of Preferable Alternative Route to Right Internal Jugular Vein for Placing Tunneled Dialysis Catheters: Right External Jugular Vein versus Left Internal Jugular Vein. PloS one. 11. e0146411.
Saugel B, Scheeren TWL, Teboul JL. Ultrasound-guided central venous catheter placement: a structured review and recommendations for clinical practice. Crit Care. 2017 Aug 28;21(1):225. doi:

10.1186

Agarwal AK, Haddad N, Boubes K. Avoiding problems in tunneled dialysis catheter placement. Semin Dial. 2019 Nov;32(6):535-540. doi: 10.1111
Stone MB, Nagdev A, Murphy MC, Sisson CA. Ultrasound detection of guidewire position during central venous catheterization. Am J Emerg Med. 2010 Jan;28(1):82-4. doi: 10.1016
Tripathi M, Dubey PK, Ambesh SP. Direction of the J-tip of the guidewire, in seldinger technique, is a significant factor in misplacement of subclavian vein catheter: a randomized, controlled study.

Anesth Analg. 2005 Jan;100(1):21-24. doi: 10.1213

Oliver WC Jr, Nuttall GA, Beynen FM, Raimundo HS, Abenstein JP, Arnold JJ. The incidence of artery puncture with central venous cannulation using a modified technique for detection and prevention of arterial cannulation. J Cardiothorac Vasc Anesth. 1997 Dec;11(7):851-5. doi: 10.1016/s1053-0770(97)90119-1.
McCarthy CJ, Behravesh S, Naidu SG, Oklu R. Air Embolism: Practical Tips for Prevention and Treatment. J Clin Med. 2016 Oct 31;5(11):93. doi: 10.3390/jcm5110093.
Johnson RR, Faustino EVS. Central venous catheter-associated deep vein thrombosis in critically ill pediatric patients: risk factors, prevention, and treatment. Curr Opin Pediatr. 2022 Jun 1;34(3):273-278. doi: 10.1097
Agarwal AK. Central vein stenosis: current concepts. Adv Chronic Kidney Dis. 2009 Sep;16(5):360-70. doi: 10.1053
Bell T, O’Grady NP. Prevention of Central Line-Associated Bloodstream Infections. Infect Dis Clin North Am. 2017 Sep;31(3):551-559. doi: 10.1016
Oliver MJ, Callery SM, Thorpe KE, Schwab SJ, Churchill DN. Risk of bacteremia from temporary hemodialysis catheters by site of insertion and duration of use: a prospective study. Kidney Int. 2000 Dec;58(6):2543-5. doi: 10.1046/j.1523-1755.2000.00439.x.
Schmidli J, Widmer MK, Basile C, de Donato G, Gallieni M, Gibbons CP, et al. Editor’s Choice – Vascular Access: 2018 Clinical Practice Guidelines of the European Society for Vascular Surgery

(ESVS). Eur J Vasc Endovasc Surg. 2018 Jun;55(6):757-818. doi: 10.1016/j.ejvs.2018.02.001

VACCINATION IN CANCER PATIENT

 Diagnosis requires the

Authors: Rita Antunes Santos, Teresa Fraga and Ana Carlota Caetano

Introduction

Patients with cancer are at increased risk of serious infections, although the degree of risk varies based on underlying malignancy and type of immunosuppressive treatments used [1]. Many of these infections are vaccine preventable.
Although immunization appears to be an obvious way to prevent infection, many patients with impaired immunity are unable to mount a protective immune response [2].
Moreover, immunization with live-virus vaccines may result in unrestrained proliferation of attenuated strains.
Treatment for many cancers has intensified greatly in the last years, resulting in improved patient outcomes, but few studies of immunity and vaccination have been published during this period.
The main goal of this chapter is to expose and discuss the most important aspects of vaccination in patients with cancer.

Inactivated vaccines[2,3]

Except for inactivated influenza vaccine, vaccination during chemotherapy or radiation therapy should be avoided because antibody responses are suboptimal.
Indicated inactivated vaccines should be given at least 2 weeks prior to chemotherapy or other immunosuppressive therapy, to maximize the immune response.
If other inactivated vaccines are given during chemotherapy, they should not be considered valid doses unless protective antibodies are documented.
In such patients, vaccines should be readministered after the recovery of immune competence.

Live attenuated vaccines [2,3]

Patients receiving chemotherapy or other immunosuppressive therapy should not receive live-virus vaccines (e.g., measles, mumps, and rubella; varicella/zoster) because of the risk of vaccine-derived infections.
Live attenuated vaccines should be administered at least 4 weeks prior to immunosuppressive therapy.

For both live or inactivated vaccines, immunization after chemotherapy should not occur until at least 3 months after the discontinuation of the immunosuppressive therapy. In patients receiving regimens that include anti–B-cell antibodies, vaccination should be delayed for at least 6 months after treatment [4].

Table 1 summarizes the main recommendations for vaccination in cancer patients.

Table 1. Vaccination recommendations in patients with cancer [1,5]

Evidence Level Grade PMID Nº

See Table 2 24311479

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Vaccines	Recommendations
Pneumococcal	Pneumococcal infections are an important cause of morbidity and mortality. Vaccine should be offered to all patients, prior to starting treatment (see Table 2).
Influenza inactivated	Adults with cancer should receive an inactivated influenza vaccine annually. Optimally administered at least two weeks before chemotherapy starts or following completion of chemotherapy. If not possible, immunization should occur about a week after the start of a chemotherapy cycle.
Td/Tdap	Td booster immunizations should be considered for all patients, prior to treatment. Adults who have not been vaccinated with the acellular pertussisvaccine should receive theTdap.
Hepatitis B	All patients should be screened for immunity and vaccinated if any risk factor for hepatitis B is identified.
Hepatitis A	Should be administered in patients who have any risk factors for developing hepatitis A. Hepatitis B and hepatitis A vaccines may be co-administered.
Hib	No specific recommendations for patients with cancer.
Meningococcus	No specific recommendations for patients with cancer.
Polio inactivated	No specific recommendations for patients with cancer.
HPV	Follow the general vaccination schedule.
MMR	Not recommended in immunocompromised patients.
Varicella/Zoster	Not recommended in immunocompromised patients.

IIb B

IIb C

24311479

I B 24311479

Table 2. Recommendations for pneumococcal vaccination in immunocompromised patients Evidence

Level Grade PMID Nº

Vaccination Status	Recommendations
Unvaccinated	A single dose of PCV13 should be given, followed by a single dose of PPSV23 at least 8 weeks later.
At least 1 dose of PPSV23 received	A single dose of PCV13 should be given if 1 or more years have passed after the last dose of PPSV23.
Additional doses of PPSV23 required	The first additional dose of PPSV23 should be given no sooner than 8 weeks after PCV13 and at least 5 years after the most recent dose of PPSV23.

PCV13: pneumococcal conjugated vaccine; PPSV23: pneumococcal polysaccharide vaccine.

Splenectomised Patients

Anatomic or functional asplenia is frequently encountered in patients with cancer. They have an increased risk for fulminant bacteraemia caused by encapsulated bacteria, which is associated with a high mortality rate [9].
Patients should undergo vaccination at least 2 weeks prior to an elective splenectomy [1].
The current recommended vaccines immediately before or after splenectomy are [1]:
- Pneumococcus (see Table 2);
- Neisseria meningitidis (meningococcus) – revaccination every 5 years is recommended for previously vaccinated adults who remain at an increased risk for infection.
- Haemophilus influenzae type b.

Covid-19

It´s recommended that all individuals with active or prior cancer be fully vaccinated to prevent SARS-CoV-2 infection (Grade IB).
Patients participating in clinical trials of novel anticancer therapeutics should not be deprived of COVID-19 vaccination [10].
Immunocompromised patients may have attenuated immunogenicity to the COVID vaccines, but vaccination is still safe and highly recommended [11, 12]. None of these vaccines can cause SARS-CoV-2 infection, regardless of immunosuppression.
For those receiving immunosuppressivetherapy, the vaccination should be administeredbetween treatment cycles, when immunosuppressionfrom treatment is minimized [12,13].

– For those receiving continuous treatment with targeted agents, vaccination should be administered when it is available [12].

Given the potential for interference with interpretation of radiologic imaging (postvaccination axillary adenopathy), it should be scheduled prior to the first dose of an mRNA-based vaccine or four to six weeks following completion of the primary series.
According to the scientific and logistical complexity in the identification of people with cancer with insufficient or waning immunity, a ‘global’ strategy of a vaccine booster dose should be considered [13, 14].

Conclusions

- Patients with oncological diagnosis and undergoing chemotherapy have in general higher risk of infections, many of which can be prevented by vaccination.
- As cancer treatments improve, physicians are encouraged to discuss vaccination and other aspects of preventive medicine with their patients.
- Prospective-multicentre clinical trials need to be performed to better assess the safety and efficacy of vaccination, as well as to evaluate the immunogenicity in patients undergoing immunosuppressive therapy.

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References Evidence

Ariza-Heredia EJ, Chemaly RF. Practical review of immunizations in adult patients with cancer. Hum Vaccin Immunother. 2015;11(11):2606-2614.
Kroger A, Bahta L, Hunter P. General Best Practice Guidelines for Immunization. Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP).
Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014; 58:e44.
Berglund A, Willen L, Grodeberg L, et al. The response to vaccination against influenza A(H1N1) 2009, seasonal influenza and Streptococcus pneumoniae in adult outpatients with ongoing treatment for cancer with and without rituximab. Acta Incol 2014; 53:1212-20.
Hamarström V, Pauksen K, Svensson H, et al. Tetanus immunity in patients with hematological malignancies. Support Care Cancer 1998; 6:469.
Centers for Disease Control and Prevention (CDC). Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2012; 61:816.
Ortbals DW, Liebhaber H, Presant CA, Van Amburg AL 3rd, Lee JY. Influenza immunization of adult patients with malignant diseases. Ann Intern Med. 1977;87(5):552-557.
Meerveld-Eggink A, de Weerdt O, van der Velden AMT, et al. Response to influenza virus vaccination during chemotherapy in patients with breast cancer. Ann Oncol. 2011;22(9):2031-2035.
Di Sabatino A, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic states. Lancet 2011; 378:86-97;
Desai A, Gainor JF, Hegde A et al. COVID-19 vaccine guidance for patients with cancer participating in oncology clinical trials. Nat Rev Clin Oncol 2021; 18 (5): 313-319.
Shulman RM, Weinberg DS, Ross EA, et al. Adverse Events Reported by Patients With Cancer After Administration of a 2-Dose mRNA COVID-19 Vaccine. J Natl Compr Canc Netw 2022; 20:160.
https://www.nccn.org/docs/default-source/covid-19/2021_covid-19_vaccination_guidance_v5-0.pdf.
https://www.esmo.org/covid-19-and-cancer/covid-19-vaccination.
CDC – An Additional Dose of mRNA COVID-19 Vaccine Following a Primary Series in Immunocompromised People.

Level Grade PMID Nº

PATHOLOGIC BONE FRACTURES

Authors: André Ferreira, Flávia Fernandes and Susana Sarandao Sousa

Definition

Pathologic bone fractures represent a growing concern in the field of musculoskeletal oncology because they represent a prominent source of morbidity. Skeletal-related events (SREs) due to bone metastases include pain, pathologic fracture, hypercalcemia, and spinal cord compression.[1] Across a wide variety of tumours with bone involvement, the frequency of SREs can be reduced through use of osteoclast inhibitors (bone-modifying agents) such as bisphosphonates.[2] The incidence of pathologic fractures is rising, due to improved diagnosis and also treatment of metastatic disease that leads to prolonged survival. Therefore, proper diagnosis, staging and treatment of pathologic fractures are essential to improve patient outcomes.[3]

Symptoms and signs

Pathologic bone fractures can be preceded by lesions producing prodromal pain or can be indolent until the time of fracture. Other symptoms include ecchymoses, a soft tissue mass, oedema, inability to bear weight or neurological symptoms (weakness, numbness, and tingling).[2] Table 1 summarizes the clinical features of pathologic bone fractures.

Table 1. Clinical features of pathologic bone fractures

Pain

Inability to bear weight

Point tenderness

Ecchymosis or skin discoloration

Pain that radiates (with nerve involvement)

Oedema or joint effusion

Loss of bony or limb contour

Extremity shortening

Decreased range of motion

Open wound and bone exposure

Significantly diminished mobility

Soft tissue mass or swelli ng at the site of pain

Sensory disturbance of the distal extremity

Radiculopathy (vertebral compression fracture)

Etiology

Most neoplastic pathologic fractures are secondary to metastatic disease. [3] Primary bone sarcomas occur far less frequently and usually present as a solitary bone lesion. Bone is one of the most common sites of distant metastases from cancer and is particularly affected in multiple myeloma. [4] Among visceral cancers, breast, prostate, lung, thyroid, and kidney cancer account for 80% of all skeletal metastases, but almost all malignant tumours can spread to bone including uterine leiomyosarcoma and hepatocellular, biliary, and uterine carcinomas. The most common sites for skeletal metastases include spine column, proximal femur, and pelvis. Solid tumours usually cause predominantly osteoblastic metastases, whereas haematological malignancies cause predominantly osteolytic metastases.

Pathologic fractures can be also secondary to benign lesions like Paget disease, giant cell tumour of bone or haemangioma.

Prevention SREs in patients with bone metastases

In patients with bone metastases, bone-targeted agents (BTAs) are used to reduce the risk of SREs as well as to treat hypercalcaemia of malignancy. Multiple randomised clinical trials have clearly demonstrated that they are effective in reducing skeletal morbidity from metastatic cancer.[5]

Currently available BTAs – bisphosphonates and denosumab – are potent inhibitors of bone resorption. Bisphosphonates are analogues of pyrophosphate that concentrate in active bone remodelling sites. During bone resorption, active osteoclasts ingest the bisphosphonate by endocytosis and undergo cell death. Non-nitrogen-containing bisphosphonates (e.g., clodronate) act through cytotoxic effects on osteoclasts whereas nitrogen-containing bisphosphonates (e.g., pamidronate, ibandronate and zoledronate) have a direct apoptotic effect. Denosumab is a monoclonal antibody that binds avidly to RANKL, preventing its interaction with its receptor RANK and causing rapid suppression of bone resorption.[5]

BREAST CANCER: Bisphosphonates can reduce skeletal morbidity rate by more than one-third, increase the median time to the occurrence of the first SRE by almost 50% and reduce the proportion of patients having any SRE. In patients with bone metastases secondary to breast cancer, denosumab was statistically superior to zoledronate in delaying both the first and subsequent SREs and delayed worsening of bone pain.[5]

PROSTATE CANCER: Zoledronate is the only bisphosphonate to demonstrate a significant reduction in SRE in patients with castration-resistant prostate cancer (CRPC). In the randomised trial comparing denosumab to zoledronate in men with bone metastases from CRPC, denosumab delayed the time to first SRE and produced an 18% reduction in cumulative SREs over zoledronate. In men with bone metastases from hormone-naïve prostate cancer (HNPC), the addition of zoledronate did not significantly reduce the frequency of SREs and showed no evidence of survival improvement.[5]

MULTIPLE MYELOMA: BTAs are an integral part of the treatment of multiple myeloma (MM). The Cochrane Myeloma Review Group concluded that both pamidronate and clodronate reduce the incidence of hypercalcaemia, pain index and number of vertebral fractures in MM patients. Denosumab was statistically noninferior to zoledronate in delaying time to first SRE and extended median progression-free survival by 10.7 months, although with no demonstrable overall survival benefit. Additionally, because Denosumab is not renally cleared, it has a better renal safety profile, especially in patients with creatinine clearance of 30-60 ml/min.[5]

Evidence Level Grade PMID Nº

Pharmacotherapy

	I	A	32801018
	I	A	32801018
	II	D	32801018
	I	B	32801018
	I	A	32801018
	III	A	32801018
	I	A	32801018
Therapeutic Strategy
	V	A	32801018
	IV	A	32801018
	III	B	32801018
	III	B	32801018
	I	A	32801018
	I	A	32801018
References [1] Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006 Oct 15;12(20 Pt 2):6243s-6249s.

It is recommended to start zoledronate or denosumab in all breast cancer patients with bone metastases, whether they are symptomatic or not.

Zoledronate or denosumab is recommended in patients with CRPC and bone metastases, whether they are symptomatic or not.

It is not recommended to start zoledronate or denosumab in patients with HNPC and bone metastases.

Zoledronate or denosumab is recommended in patients with advanced lung cancer, renal cancer, and other solid tumours with a life expectancy of ≥3 months and clinically significant bone metastases.

Zoledronate, pamidronate or denosumab should be initiated at diagnosis of multiple myeloma.

Patients should have a dental evaluation and, when feasible, complete invasive dental treatments before initiating a bone – targeted agent.

Correction of vitamin D deficiency and vitamin D supplementation with adequate intake of calcium throughout treatment to maintain normal serum calcium are recommended.

The investigation and management of patients with bone metastases/bone lesions should be discussed within a multidisciplinary team with links to all therapeutic modalities of relevance.

Structurally significant lesions in a long bone should be ev aluated by an orthopaedic surgeon to provide advice on suitability for surgery.

Prophylactic surgery for impending fracture is generally preferred to fixation after fracture.

Postoperative radiotherapy should follow orthopaedic fixation of a long bone or spinal decompression and/or stabilisation.

External beam radiotherapy remains the treatment of choice for localised moderate to severe bone pain due to bone metastases.

A single 8 -Gy fraction is recommended for painful uncomplicated bone metastases. The need of retreatment may be higher after single-fraction regimens, but a single fraction improves QoL.

Yu MH, Hoffe SE. Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults. In: Post TW, ed. UpToDate. UpToDate; 2021. Accessed December 7, 2021.

Available from: https://www.uptodate.com/contents/epidemiology-clinical-presentation-and-diagnosis-of-bone-metastasis-in-adults/

Rizzo SE, Kenan S. Pathologic Fractures. [Updated 2021 Jun 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559077/
Macedo F, Ladeira K, Pinho F, et al. Bone Metastases: An Overview. Oncol Rev. 2017;11(1):321. Published 2017 May 9. doi:10.4081/oncol.2017.321
Coleman R, Hadji P, Body JJ, et al. Bone health in cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2020 Dec;31(12):1650-1663

RISK OF SECOND IATROGENIC TUMORS (LONG SURVIVORS)

Authors: Lucrecia Ruiz Echeverria, Juan Pablo Fusco and Maria del Castillo

Introduction

Despite the success of the new advances in the treatment of cancer due resulted in improvement of prognosis even a cure of the disease, the cancer survivors remain at increased risk for life-threatening treatment-associated complications including major organ toxicity and the most serious; the secondary malignancies. Several large studies have shown that secondary malignancies are the leading cause of treatment-related premature mortality, that increased risk is worst in young adult and adolescent. (1,2)

It is necessary to underline that not all second tumours are due to prior oncologic therapy, several factors are associated as genetic predisposition, patient age, immunodeficiency, concomitant use of drugs, environmental and occupational risk factors and so on. But we must continue trying to characterize differences in the long-term, site-specific patterns of second malignancies to insights into mechanisms of carcinogenesis. The understanding of these factors should facilitate customization of screening and prevention strategies as well as the identification of high-risk patients.(3)

Evidence Level Grade PMID Nº

Figure 1: Etiology of iatrogenic tumours

Risk due Age of diagnosis

It has been observed that the diagnosis that the age at the time of diagnosis between 15 to 39 years increase significant risk of developing of several secondary cancers compared to the general population (4). Also, could be associated to hereditary syndrome or genetic predisposition and other factors as the initial cancer diagnosis, magnitude of the risks, the latency period, associated risk factors, modifying influences and treatment exposure. (5) The risk patterns by age include differences in

susceptibility of individual tissue/organ to carcinogenesis based on stage of development and level of tissue maturity, microenvironment, attained age, hormonal factors and immune function and lifestyle factors. (6) Although the most common secondary malignancies are breast cancer, thyroid, gastrointestinal cancer, genital cancers, and melanoma. Radiotherapy exposure is particularly associated with risk of secondary cancers. The risk factors were found to be older age at diagnosis, female sex, white race, advanced stage at first cancer diagnosis, and treatment with Radiotherapy. Another observation was that the cancer survivors diagnosed with second malignance’s seems to have a 7-fold increased mortality risk compared with those who did not develop them. (8)

Risk due Age of Chemotherapy agent

We don´t know exactly the mechanisms by which chemotherapy induces the development of second tumours. Not all second malignancies are related by cytotoxic agents, but certain chemotherapeutic agents had shown high oncogenic activity (9, 10, 11) :

1- Alkylating agents: mechlorethamine, chlorambucil, melphalan, busulfan, nitrosureas; carmustine, prednimustine, lomustine, semustine, dacarbazine, procarbazine, cyclophosphamide.

2.- Topoisomerase II inhibitors: non-intercalatin; etoposide, teniposide. Intercalatin: Adriamycin, epirubicin

Hormone therapy: tamoxifen
Platinum compounds: still not clear if has leukemogenicity activity alone or in association with others chemotherapy agents.

In general terms chemotherapy drugs has associated in the develop of acute myeloid leukaemia’s most often. Exceptions are bladder cancer and urinary tract carcinoma after cyclophosphamide-based chemotherapy and endometrial carcinoma after therapy with tamoxifen. (12)

The most reliable and widely studied mechanism of action by which antineoplastic agents can develop cancer are: (9,13, 14)

- Gene poly- morphism in drug-metabolizing enzymes, alterations in the mechanisms of DNArepair, Germline mutations in tumour-suppressor genes
- Concomitant administration of other cytostatic/cytotoxic and/or chemo-protective drugs,
- Variation of absorbing and distribution mechanism of the drugs: Interpatient variation in hepatic and renal function, Interindividual differences in drug absorption, distribution,

metabolism, and excretion

- Immunosuppression.

Alkylating agents transfer and/ or replace alkylating groups by the formation of covalent bonds with DNA interfering with cell replication. Hematopoietic precursors of the bone marrow lack enzymes with alkiltransferase activity, this explains why second tumours arising from alkylating agents are haematological. (15). Also Alkylating agent based has been associated with increased risk for secondary lung cancer in patients with diagnosis of Hodgkin Lymphoma at 40 years or younger, and the risk increased with number of cycles and cumulative doses. The risk was substantially higher in smoker’s patients (9,6% alone vs 63.3% due the combination of treatment and smoking). (16,17)

Topoisomerase I and II inhibitors damage occurs during the DNA duplication or mRNA transcription with subsequent translocations and cell death due to apoptosis or necrosis. (15) Secondary leukaemia related to chemotherapy with topoisomerase II inhibitors and alkylating agents has also been reported in testicular cancer survival. (18)

Risk due Radiotherapy

Despite the well-known beneficial effects of the oncological treatment with radiotherapy, there is a wide range of complications, the most fearsome of which is the oncologic potential of ionizing radiation, as widely analysed in nuclear catastrophes survivors. (19)

After entering the tissue, the radiation interacts with the tissue by delivering energy such could cause the irreparable damage to the DNAgiving rise to a neoblastic mutation, and ultimately a clinically evident tumour. (Table 1)

Evidence Level Grade PMID Nº

Time (latency)	Event	Effect
0	Irradiation
10 -15 second	Physical	Ionization -excitation
Minutes	Biochemical (macromolecules)	Enzymatic and DNA damage
Hours -Days	Genetic mutations, mitotic inhibition, activation of	Phenothypic and genotypic alteration, cell death,
	polymerase	damage repair,
Weeks – Months	Biological system changes	Alteration in organ function, death
Years	Expression of somatic and genetic mutations	Radio -induced tumors, hereditary diseases.

Table 1: Sequence of irradiation effects (20)

Special consideration by type of tumours

Colorectal Cancer Following Radiotherapy:

The radio induced neoplasm has a latency time of 5 -15 years after exposure and an onset site inside the irradiate field. The most affected are those patients who received high doses pelvic irradiation as Prostate cancer or cervical cancer in which the rectum receives high dose radiation. The increased risk in the rectum can be explained by the fact that rectum is so close to the prostate that the two structures receive almost the same dose of radiation. In recent years there is new techniques to protect the rectum and avoid more toxicities. (21)

Seminoma

Survivors of testicular cancer are also at significantly increased risk of developing secondary cancer, including contralateral testicular cancer, leukaemia, malignant mesothelioma, and cancers of the lung, colon, oesophagus, stomach, and pancreas. The treatments concerns of the radiation if lymph nodes of the lumbo aortic tract with extension to the homo or bilateral iliac station. The total dose of radiation is low (25-30 Gys). Nonetheless, the possibility of radio-induced second neoplasm is high since most patients are young and have long life expectancy. (22, 23)

Hodgkin´s disease

Even though the incidence of post irradiation sequalae is lower than in the past. However, radiotherapy for Hodgkin’s disease often requires high energy radiation (32-36 Gys) and the treatment of a large number of lymph nodes at different sites (cervical, axillary, mediastinal, hilar). Almost the 80% of the second tumours appear in previously irradiated sites, and the risk is about 13% at 15 years post treatment, increasing with increasing number of years of follow-up. (24). Women between ages 21 and 39 years are at an increased risk of developing secondary cancers, most frequently are breast, lung, thyroid, and gastrointestinal cancers. (25)

SURVIVORSHIP´S RISK IATROGENIC NEOPLASM DUE PREVIOUS EXPOSURE

Exposure	Recommendation
Total Body Irradiation (TBI)	Screening for secondary malignant neoplasms
Abdominal or Pelvic radiation	Colorectal cancer screening
Alkylating agents	Screening for treatment related AML (t-AML) or myelodysplasia
Anthracyclines	Screening for treatment related AML (t-AML) or myelodysplasia
Cisplatin / Carboplatin	Screening for treatment related AML (t-AML) or myelodysplasia
Epipodophyllotoxins	Screening for treatment related AML (t-AML) or myelodysplasia

(National Comprehensive Cancer Network – Nccn guidelines version 2.022)

Evidence Level Grade PMID Nº

References

Evidence Level Grade PMID Nº

ARTIFICIAL INTELLIGENCE FOR CLINICAL ONCOLOGY

Authors: Salvador Tortajada Velert, Francisco Javier Albiol Colomer and Alberto Albiol Colomer

Definition

Artificial Intelligence (AI) comprises a set of advanced mathematical and computational techniques that allow algorithms to be programmed automatically from data. AI is mainly based on machine learning (ML) tools. These are methods that are able to learn from a set of observations by minimising an error function, which allows them to recognise patterns in the data. These patterns are then represented in a model. Finally, this model can be applied to new observations to analyse, classify and predict events.

There are a wide variety of ML techniques, although they can be categorised into two types: supervised and unsupervised. The fundamental difference is that in supervised techniques the data are pre-annotated, allowing the model parameters to be adjusted based on this information. The two most common problems in supervised techniques are classification and regression. Classification discriminates between a set of classes. For example, making a differential diagnosis is a classification problem. Regression predicts data on a continuum. For example, patient survival or quality-adjusted life years. In unsupervised learning techniques, similarities between data are recorded for a problem whose answer is still being studied.

Generally, the use of ML techniques for all these problems requires that the data are well selected and well processed. Methodologically speaking, a correct selection of cases will reduce possible biases. In turn, a correct processing of the data will allow the extraction and selection of variables avoiding unnecessary noise.This preliminary stage of feature selection and extraction can take up about 80% of the development of AI models.

Finally, Deep Learning (DL) techniques are a subset of ML based on artificial neural networks. They are very powerful techniques in aspects related to processing, segmentation, and classification of unstructured data in general and medical imaging in particular. The great advantage of these techniques is their ability to include the feature extraction stage within the model itself thanks to their ability to include convolution layers to automatically encode the input information.

Clinical oncology applications

The goal of clinical oncology is to improve the patient’s quality of life and survival time by controlling the disease and minimising adverse ef fects to the patient. This requires individualised decisions to manage each case, because each tumour and the response to treatments may vary for each patient. In this sense, the adoption of AI tools, by conforming to the criteria of personalised medicine, can help reduce morbidity and mortality for each patient, while optimising healthcare costs.

Decision support tools existed before AI. Examples are the Nottingham Prognostic Index for breast cancer [1] or nomogram-based models [2-7]. The TNM cancer stratification system itself, which serves as a gold standard, is also a decision support system. The contribution of AI lies in its ability to find complex relationships between data to find new patterns, which is generally demonstrated by better results in terms of sensitivity and specificity.

The applications of AI in clinical oncology are multiple within the clinical patient pathways. Each AI application can be viewed as a mathematical optimisation problem of more or less complexity. It is important to understand that these applications should focus on concrete problems rather than a holistic approach, because this simplifies the development of AI models and facilitates the collection of data, which is often fragmented, heterogeneous and difficult to access for different ethical and legal reasons.

For decision support in clinical oncology, a solution can be applied in the stages of prevention, triage and screening (S), diagnosis (D), treatment (T) and follow-up (F) as shown in Figure 1.

It is also important to differentiate between AI applications that are part of software as a medical device, in which case they require certification, and applications that are not part of a medical device and therefore do not require such certification. The FDA defines a medical device as “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part or accessory […] intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body”. In cases where an application is not intended to be marketed and its purpose is scientific, it is not required to pass such a certification.

[1] https://www.fda.gov/industry/regulated-products/medical-device-overview#What%20is%20a%20medical%20device

Evidence Grade PMID Nº

Level

Screening

Automatic anomaly finding, detection of califications and soft-tissue tumors in FFDM.
Automatic lung lobe segmentation

cm Triage Transpara TM QuantX

Al- Rad Companion

Diagnosis

Patient characterization and classification tasks
Scoring findings of malignacy in regions of interest
Tissue analysis to provide histopathological diagnosis

Arterys Oncology DL Quantib Prostate

Treatment

Dose toxicity prediction
Prognosis prediction
QALY prediction

Follow-up

Risk of recurrence
Risk of readmission
Risk of one-year unplanned hospital admissions

Evidence Level Grade PMID Nº

Arterys MICA Profund QuantX

Kit-FFPE

PROView

A View LCS Koios DS

Genius Al Detection

- Automatic comparison of evolution of findings

Al-Rad Companion ClearView cCAD

Figure1. Different potential and actual applications of AI in clinical oncology for the four stages defined.

Methodologies for evaluating an AI tool

Artery Oncology DL Arterys MICA

A View LCS

Clinical decision support tools are consolidated when they are scientifically validated and demonstrate their usefulness over time. The emergence of AI as clinical decision support tools must also be validated and demonstrate their impact on daily clinical practice by improving patient health outcomes. To this end, some methodologies have been developed for the evaluation of predictive tools such as TRIPOD, STARD or PROBAST and are currently being extended to the evaluation of tools based on AI techniques.

The TRIPOD statement [8,9] presents a list of 22 elements to be considered when reporting and communicating in sufficient detail and clarity how the development, validation or update of a predictive model has been carried out.

The STARD statement [10,11] presents a list of 30 elements to consider when reporting and communicating diagnostic accuracy studies, such as sensitivity, specificity, predictive values and/or area under the ROC curve (AUC).

The PROBAST methodology [12,13], on the other hand, is a tool to assess the risk of bias in predictive modelling studies and its application to diagnostic and prognostic support. It is a tool that can be used as an adjunct to conduct systematic reviews involving the study of predictive models. It provides a list of 20 items related to participants, predictors, outcomes, and analysis to characterise the risk of bias.

Challenges

Despite the large number of studies and applications of AI to various problems in clinical oncology that have been developed over the last decades, it still seems necessary to demonstrate the clinical impact of these applications on a global level. Some developments have been used to provide software applications such as medical devices, certified by the FDA [14,15], with certain AI-based features to perform partial tasks under the responsibility of expert medical users. To achieve this clinical impact, systems employing AI need to be able to generate confidence in users, and this requires AI models to be reproducible and interpretable.

Currently, the most important challenge to achieving these goals is the quantity and quality of available data. Despite its growth and increasing availability, there remain limitations in quality, reliability, aggregation of sources and potential biases.

The above limitation directly impacts the next challenge: the generalisability of AI models. Generalisability is the ability of a predictive model to respond to new data with the expected Evidence

performance. In other words, situations where the training error is very low, but the generalisation error, the error made in predicting new data, is not low enough, must be avoided. This problem is in turn related to reproducibility and confidence in AI models.

Confidence also depends on the interpretability of the AI model’s responses. Its ability to explain why it suggests one decision or another. Some ML models can provide interpretable answers, but most DL models are still considered “black boxes” and the development of techniques to explain the decisions of these models has become a field of intense research.

Finally, in addition to the clinical validation that an AI-based model must pass, it is necessary to empirically demonstrate the relationship between the accuracy of AI models and their clinical utility, e.g. in terms of survival, quality of life, cost reduction, disease control or toxicity reduction, as well as their clinical acceptability by assessing their effects in terms of efficiency, user satisfaction or acceptance of AI recommendations.

FDA-Approved AI tools

	Information
	Intention	AI application	Clinical use	Clinical stage	Data type
Arterys Oncology D 2	Medical diagnostic application for 3D	Deep learning models for (semi-)	Thoracic,	D, F	CT, MR
Arterys Oncology D 2	visualisation, manipulation, registration, segmentation, and comparison of medical images from multiple imaging modalities. Designed to confirm the presence of lesions, their assessment, quantification, follow-up, and documentation.	automatic volumetric segmentation in lung and liver.	pneumological and hepatic
Arterys MICA3	Medical diagnostic application for displaying, processing and communicating DICOM and non-DICOM images, except mammograms. Allows filtering, digital manipulation and quantitative measurement of images. Includes the option to add Arterys Oncology DL.	Arterys Oncology DL	Radiology	D, F	CT, MR
cmTriage4	Patient prioritisation tool for triage and passive reporting from mammograms.	AI algorithm to analyse screening full-field digital mammograms (FFDM) and flag images with suspicious findings for further review.	Breast	S	FFDM 2D
ProFound™ AI Software V2.15	Computer-aided detection and diagnosis (CAD) software device for use by medical experts while reading digital breast tomosynthesis (DBT) scans from compatible systems. The system detects soft tissue densities, masses, anatomical distortions, asymmetries, and calcifications on 3D DBT slices.	AI algorithm that analyses the DBT and assigns a score on the certainty of malignancy of the findings in each detected region. The scores are shown to experts to assess the findings.	Breast	D	DBT 3D

(2)https://www.accessdata.fda.gov/cdrh_docs/pdf17/K173542.pdf (3)https://www.accessdata.fda.gov/cdrh_docs/pdf18/K182034.pdf (4)https://www.accessdata.fda.gov/cdrh_docs/pdf18/K183285.pdf (5) https://www.accessdata.fda.gov/cdrh_docs/pdf19/K191994.pdf

Level Grade PMID Nº

TransparaTM6	Concurrent help system for physicians interpreting screening mammograms from FFDM-compatible systems.	Image pre-processing and analysis with ML components trained to detect calcifications and soft tissue lesions to aid clinical decision making.	Breast	S	FFDM 2D
QuantX7	A computer-aided diagnostic device to assist radiologists in the assessment and characterisation of breast abnormalities using MR image data. The software automatically registers the images and segments and analyses user-selected regions of interest (ROIs). It is used for the evaluation of high-risk patients in screening and assessment of lesion extent.	An AI algorithm analyses the image features to obtain a score by comparison with a reference database of known anomalies.	Breast	S, D	MR
Pathwork Tissue of Origin Test Kit-FFPE8	Test kit based on the Affymetrix Pathchip microarray where each array contains 2000 human gene probes that the kit uses as markers to identify tissue origin. Each array has between 11 and 16 pairs of 25-base probes whose sequences match mRNA species found in human tissue.	Probe sets were selected using ML methods. The tissue under analysis is compared using similarity techniques to provide a histopathological diagnosis.	Tissue	D	Kit-FFPE
AI-Rad Companion (Pulmonary)9	Image processing software that provides quantitative and qualitative analysis of DICOM CT images to assist radiologists and emergency and specialty care physicians in the evaluation and assessment of lung disease.	Lung lobe segmentation is based on DL algorithms.	Thoracic, pneumological	S, D	CT
Quantib Prostate10	It is an image post-processing software that provides the user with the ability to view and edit prostate MRI images. It facilitates analysis and review of the study of MR data sets and provides additional statistical analysis.	Semi-automatic segmentation of anatomical structures and volume calculations together with tools for manual editing. PI-RADS category can be estimated automatically.	Prostate		MR
PROView11	A tool to assist in the review of magnetic resonance images of the prostate. Displays acquired and processed data for viewing and provides tools for prostate gland volume assessment and analysis of findings in patients with known or suspected prostate lesions.	Automatic prostate segmentation based on a DL model and PI-RADS category estimation.	Prostate		MR

Level Grade PMID Nº

Aview LCS 12	Tool for inspection, analysis, and documentation of thoracic CT images for characterisation of lung nodules in a single study or for evolution in several studies.	Automatic lung and lobe segmentation based on DL models.	Thoracic, pneumological	D, F	CT
Koios DS for Breast13	Tool designed to assist trained interpreting physicians in analysing breast ultrasound images of patients with soft tissue breast lesions who have been referred for further diagnostic ultrasound examination.	The system provides a generated categorical output that aligns with the sensitivity and specificity of the BI-RADS chosen by the radiologist using ML techniques.	Breast	D	Ultrasono-graphy
Genius AI Detection14	Detection and diagnostic support software compatible with digital breast tomosynthesis (DBT) systems to identify and mark regions of interest in soft tissue and calcifications.	Image processing features an ML model that helps detect, localise and characterise soft tissue densities and calcifications.	Breast	D	DBT 3D
ClearView cCAD15	Software application designed to assist medical experts in analysing breast ultrasound images. Allows automatic classification of shapes and orientations of user-selected regions of interest. Allows annotation of images following the BI- RADS classification.	The device uses multivariate pattern recognition methods to perform image characterisation and classification tasks.	Breast	D	Ultrasonography

References

https://www.accessdata.fda.gov/cdrh_docs/pdf19/K192287.pdf (7)https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN170022.pdf (8)https://www.accessdata.fda.gov/cdrh_docs/pdf9/K092967.pdf (9)https://www.accessdata.fda.gov/cdrh_docs/pdf18/K183271.pdf (10)https://www.accessdata.fda.gov/cdrh_docs/pdf20/K202501.pdf
1. https://www.accessdata.fda.gov/cdrh_docs/pdf19/K193306.pdf (12)https://www.accessdata.fda.gov/cdrh_docs/pdf20/K201710.pdf (13)https://www.accessdata.fda.gov/cdrh_docs/pdf19/K190442.pdf (14)https://www.accessdata.fda.gov/cdrh_docs/pdf20/K201019.pdf (15)https://www.accessdata.fda.gov/cdrh_docs/pdf16/K161959.pdf
  1. Lee, A.H.S., Ellis, I.O. The Nottingham Prognostic Index for Invasive Carcinoma of the Breast. Pathol. Oncol. Res. 14, 113–115 (2008).
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  3. Kattan MW, Yu C, Stephenson AJ, Sartor O, Tombal B. Clinicians versus nomogram: predicting future technetium-99m bone scan positivity in patients with rising prostate- specific antigen after radical prostatectomy for prostate cancer. Urology. 2013 May; 81(5):956–61. [PubMed: 23375915]
  4. Thompson AM, Turner RM, Hayen A, Aniss A, Jalaty S, Learoyd DL, et al. A preoperative nomogram for the prediction of ipsilateral central compartment lymph node metastases in papillary thyroid cancer. Thyroid. 2014 Apr; 24(4):675–82. [PubMed: 24083952]
  5. Gold JS, Gonen M, Gutierrez A, Broto JM, Garcia-del-Muro X, Smyrk TC, et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. The lancet oncology. 2009 Nov; 10(11):1045–52. [PubMed: 19793678]
  6. Kattan MW, Karpeh MS, Mazumdar M, Brennan MF. Postoperative nomogram for disease- specific survival after an R0 resection for gastric carcinoma. J Clin Oncol. 2003 Oct 1; 21(19): 3647–50. [PubMed: 14512396]
  7. Gorlia T, van den Bent MJ, Hegi ME, Mirimanoff RO, Weller M, Cairncross JG, et al. Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol. 2008 Jan; 9(1):29– 38. [PubMed: 18082451]
  8. Moons KG, Altman DG, Reitsma JB, Ioannidis JP, Macaskill P, Steyerberg EW, Vickers AJ, Ransohoff DF, Collins GS. Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD): Explanation and Elaboration. Ann Intern Med. 2015;162(1):W1-W73.
  9. Collins GS, Reitsma JB, Altman DG, Moons KG. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): The TRIPOD statement. Br J Cancer. 2015 Jan 6.
  10. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig L, LijmerJG Moher D, Rennie D, de Vet HCW, Kressel HY, Rifai N, Golub RM, Altman DG, Hooft L, Korevaar DA, Cohen JF,

For the STARD Group. STARD 2015: An Updated List of Essential Items for Reporting Diagnostic Accuracy Studies. BMJ. 2015;351:h5527. PMID

- 1. Cohen JF, Korevaar DA, Altman DG, Bruns DE, Gatsonis CA, Hooft L, Irwig L, Levine D, Reitsma JB, de Vet HCW, Bossuyt PMM. STARD 2015 guidelines for reporting diagnostic accuracy studies: explanation and elaboration. BMJ Open 2016;6:e 012799
  2. Wolff RF, Moons KGM, Riley RD, Whiting PF, Westwood M, Collins GS, Reitsma JB, Kleijnen J, Mallett S; PROBAST Group†. PROBAST: A Tool to Assess the Risk of Bias and Applicability of Prediction Model Studies. Ann Intern Med. 2019 Jan 1;170(1):51-58. doi: 10.7326/M18-1376. PMID: 30596875.
  3. Moons KGM, Wolff RF, Riley RD, Whiting PF, Westwood M, Collins GS, Reitsma JB, Kleijnen J, Mallett S. PROBAST: A Tool to Assess Risk of Bias and Applicability of Prediction Model Studies: Explanation and Elaboration. Ann Intern Med. 2019 Jan 1;170(1):W1-W33. doi: 10.7326/M18-1377. PMID: 30596876.
  4. Benjamens S, Dhunnoo P, Meskó B. The state of artificial intelligence-based FDA-approved medical devices and algorithms: an online database. NPJ Digit Med. 2020 Sep 11;3:118. doi: 10.1038/s41746-020-00324-0. PMID: 32984550; PMCID: PMC7486909.
  5. Kann BH, Hosny A, Aerts HJWL. Artificial intelligence for clinical oncology. Cancer Cell. 2021 Jul 12;39(7):916-927. doi: 10.1016/j.ccell.2021.04.002. Epub 2021 Apr 29. PMID: 33930310; PMCID: PMC8282694.

COMMUNICATION WITH CANCER PATIENT AND FAMILY

Authors: Sara Pereira Bravo and Paula Alexandra Sousa Mesquita

What is communication?

Communication involves both an exchange of information and a means of connection between two people or parties, two aspects deeply embodied by the relationship established between doctor and patient.

Patients with cancer desire information about their disease to make choices about treatment and, ultimately, to be able to live their lives more fully. Effective communication requires clinicians to convey information in a manner that patients can understand, manage emotional responses to the information provided and ultimately help patients make important decisions. [1]

Doctor-patient communication

Doctor-patient communication is defined by its bidirectional nature, with each participant giving and receiving information. Patients and their families are often greatly invested in their personal relationship with their doctors, with most patients looking to their clinician for guidance and support.

Frequently, the information that doctors share with patients is serious in nature and may evoke strong emotions from patients and caregivers.[1] As such, effective information exchange and a positive interpersonal relationship with the clinician are of fundamental importance to patients and family members. Moreover, these are intertwined; for instance, failure to provide needed information to a patient can damage this relationship, whereas excellent listening can foster it. [2]

Barriers to effective communication

Factors that hinder effective communication can be divided into two main groups: patient-led and physician-led reasons. On one hand, patients are often reluctant to disclose psychological problems of anxiety and depression, considering them to be understandable reactions and finding no purpose in mentioning them. On the other hand, health care professionals similarly experience feelings of avoidance; they too have fears and often lack communication skills and support. [3] There are several reasons why delivering bad news is an especially difficult task for doctors, irrespective of their age, speciality, or professional experience. These may be personal, social, professional, or legal/political.

Evidence Level Grade PMID Nº

Personal	Professional
Fear of own illness/death Fear of expressing own emotions Recent bereavement Identification with own experience Embarrassment/distress/discomfort	Lack of experience or training Fear of eliciting a difficult response Fear of being blamed by the patient or superiors Failure to provide cure Fear of causing pain/emotional damage Fear of destroying hope
Social	Political
Removal of death from home to institution makes death unacceptable and taboo Sickness stigmatized	Fear of litigation

Table 1 – Difficulties involved in breaking bad news [3]

How to deliver bad news?

The delivery of bad news is a routine but difficult task for many health professionals. Bad news has been defined as “any news that drastically and negatively alters the person’s view of her or his future” and may involve giving a terminal of life-changing prognosis (e.g., metastatic cancer or multiple sclerosis) or even news of a sudden loss of life, for example. The impact of such information will have not only medical but also physical, social, emotional, and occupational consequences.[5]

There are countless ways to deliver bad news, but most used method is the SPIKES protocol, a six-step protocol for disclosing unfavourable information to cancer patients about their illness. Not every episode of delivering bad news will require all the steps in SPIKES, but when they do, they are meant to follow each other in sequence.[5]

Each letter corresponds to a step, each of which is associated with specific skills.[5]

S – Setting

Arrange for some privacy.
Involve significant others.
Sit down.
Make connection and establish rapport with the patient.
Manage time constraints and interruptions.

P – Perception of condition/seriousness

Determine what the patient knows or suspects about the medical condition.
Listen to the patient’s level of comprehension.
Accept denial but do not confront at this stage.

I – Invitation from the patient to give information

Ask patient if he/she wishes to know the details of the medical condition and/or treatment.
Accept the patient’s right not to know.
Offer to answer any questions later if the patient so wishes.

K – Knowledge: giving medical facts

Use language intelligible to patient.
Consider educational level, socio-cultural background, and current emotional state.
Give information in small chunks.
Check whether the patient understands what you are conveying.
Respond to the patient’s reactions as they occur.
Present positive aspects first.
Give facts accurately about treatment options, prognosis, costs etc.

E – Explore emotions and sympathize

Prepare to give an empathetic response:

Identify emotion expressed by the patient (sadness, silence, shock etc.). 2.Identify cause/source of emotion.

3.Give the patient time express his or her feelings, then respond in a way that demonstrates you have recognized connection between 1 and 2.

S – Strategy and summary

Close the interview.
Ask whether they want to clarify anything else.
Offer agenda for the next meeting.

Communication with family

When cancer is diagnosed, it affects both the patient and the patient’s family. Throughout the cancer trajectory, open communication plays an important role for both patients and caregivers in their journey of coping with cancer. Open and constructive communication can reduce caregiver burden, promote intimacy between cancer patients and their family and caregivers, and improve the physical and mental health of patients and caregivers alike. Communication between cancer patients and family caregivers – including listening, talking, being respectful, and decision-making within the family – is an important part of managing family tensions and regulating healthy coping mechanisms [4]

To assist patients in breaking down barriers and discussing their illness openly, the physician can provide appropriate step-directed strategies, one of which is the GOALS program: [6]

Getting together. A special time and place should be chosen for this important conversation apart from the distractions of day-to-day life.
Opening. Those involved must agree that there is a need or wish to talk.
Acknowledging each other’s emotions. Understanding what the other person is feeling is crucial.
Learning about the disease and exchanging ideas.
Strategy. It’s important to make plans to meet again and to keep the discussion open.

It is crucial for physicians to be aware of how their attitudes toward death affect their communication with patients and their families during the delivery of bad news. They should be provided in-service professional education, and therapeutic support.

References

2022. [online] Available at: <https://www.cancer.gov/about-cancer/coping/adjusting-to-cancer/communication-hp-pdq%20Retrieved%20at%20July%2028>.
Mazor, K. M. et al. (2013). Patients’ and family members’ views on patient-centered communication during cancer care. Psycho–Oncology, 22(11), 2487-2495.
Maguire, P. (1999). Improving communication with cancer patients. European Journal of cancer, 35(14), 2058-2065.
Li, J. et al. (2020). Communication needs of cancer patients and/or caregivers: a critical literature review. Journal of oncology, 2020.
Baile, W. F., Buckman et al. (2000). SPIKES—a six-step protocol for delivering bad news: application to the patient with cancer. The oncologist, 5(4), 302-311.
J. DeNoon, D., 2022. Breaking the Bad News About Cancer to the Family. [online] WebMD. Available at: <https://www.webmd.com/cancer/news/20021022/breaking-bad-news-to-family>.

ADDRESSING MOURNING AT THE HEALTH CARE PROFESSIONAL

Authors: João Pedro de Sousa Lima and Susana Maria Sarandão de Sousa

Introduction

Terminology

Mourning, or grief, is a diverse psychological and physical response to bereavement (which is the term describing the loss of a significant other), separation or loss. It can be experienced immediately after the death, but also before (anticipatory grief) or delayed after a death. The term compassion fatigue (CF) refers to the exhaustion that arises from becoming too emotionally attached with the patients. Burnout may arise from cumulative and prolonged increase in stress2. Cumulative Loss happens when professionals don’t get the time to resolve the mourning issues of one patient before another patient dies. Prolonged Grief Disorder (PGD), or complicated grief, is a severe and protracted reaction to loss that manifests through extreme emotional distress and mental or functional impairment.

Background

Healthcare professionals are repeatedly exposed to suffering, loss, and death. However, grief in this group of people is still not well recognized and coping strategies for this category are often not addressed. Professionals who care for patients may experience grief during their illness due to many reasons. First, changing the treatment intent from radical to palliative or a sudden death may arise feelings of grief. Second, grief may arise because the patient reminded the healthcare provider of a family member or a significant other or simply because the professional felt an interpersonal closeness with the patient. Other reasons often referred are the death of younger patients or deaths of patients who were not cured by the standard treatment interventions or deaths that lacked the sense of dignity.

Clinical manifestations

The most common manifestations of grief are the feelings of helplessness, anxiety, fatigue, depression or sadness, loneliness, shock, numbness, anger, and disbelief. Physical manifestations are also common, such as weakness, headache, insomnia, shortness of breath, nausea or eating disorders, feeling of tightening of the chest and heightened sensations and a sense of depersonalization.

Treatment

There are currently many coping strategies directed for mourning experienced by patients and families, but health professionals need coping strategies of their own. Formal support is still lacking, and health care professionals are required to cope with occupational stress or grief by talking to colleagues or family members. The experience of mourning is considered to be dependent on an individual’s cultural norms, faith systems and life experiences. Therefore, an effective coping strategy should include finding balance, development of support systems and education in end-of-life care. Balance can be defined as the ability to find equilibrium between the stress of providing compassionate and quality care to dying patients and their families.

Organizational level support

The organization can and should provide education, training, opportunities for staff support and access to professional counselling when necessary.

Evidence Level Grade PMID Nº

32197009

22024306

23178352

19538808

12646826

28524889

7096935

DOI: 10.1016/S0820

-5930(09)60053-0

23178352 7096935

11902517

DOI: 10.1016/S0820

-5930(09)60053-0

19538808 12646826

20919512 22024306

28524889 21130937

DOI: 10.1016/S0820

-5930(09)60053-00

Ward level support

Colleagues are the primary support for healthcare professionals
Includes debriefing sessions, peer support, supervision, and education/training.

Self-care, self-awareness, and coping

Personal support has been related to characteristics such as “psychological strength”, “balance in mind and body”, and “responsibility for caring for one’s own feelings”.
Professionals should be encouraged to acquire self-care strategies as well as formal support to deal with grief experience. Professionals must recognize their grief reactions and symptoms and employ self-care strategies to deal with their various grief issues. Personal wellness strategies include cultivating relationships, endorse in personal reflection activities and spiritual practices, promote self-care practices such as exercise, nutrition and vacations and maintaining hobbies and personal interests such as reading, arts or community service.
Professionals need also to consider their personal strengths and limitations, to have self-knowledge and to remember why they chose to work with seriously ill patients.
Self-awareness also involves knowing when outside help is needed.

Interventions and treatments for grief

WHO published the “Guidelines for the Management of Conditions Specifically Related to Stress” in 2013, and regarding the topic “Bereavement: universally applied structured psychological interventions – adults”, the final recommendations are that “Structured psychological interventions should NOT be offered universally to (all) bereaved adults who do not meet the criteria for a mental disorder” (table 1.)

However, more recent data suggest psychological interventions that have shown positive results in adults experiencing mourning.

Psychodynamic and interpersonal treatments

Long-term and based on childhood experiences, object relations and unconscious conflicts as a framework for understanding a patient’s grief response.
Interpersonal therapy (IPT): manualized and time-limited, is focused on relational conflicts that cause symptoms of distress.

Cognitive behavioural therapy (CBT)
- Focuses on isolating and modifying automatic thoughts and negative beliefs which are often reinforced by maladaptive and/or avoidant behaviours.
- May be especially helpful when individuals are experiencing guilt or anger which may be caused by distorted cognitions regarding the circumstances of the death or the relationship with the deceased.
- It can also help the bereaved decrease their avoidance tendencies and return to day-to-day activities.
Group-oriented therapeutic approaches
- Participating individuals provide support to each other by sharing experiences, offering validation and normalization regarding emotions and behaviours related to coping with loss.
Internet-based therapy.
- Have demonstrated to be effective in reducing distress in the form of avoidance and depression
- Cheap, accessible in the comfort of home, anonymous and avoid medical settings that remind of the deceased’s treatment and death.
Combined psychopharmacological treatments
- Bereavement-related depression can be treated with combinations of psychotherapy and antidepressants, like the treatment of Major Depressive Disorder.

Evidence Level Grade PMID Nº

Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) have proved efficient in reducing depressive symptoms in the context of mourning.
The combination between psychotherapy and pharmacotherapy has shown to be successful. A double-blinded randomized control trial tested nortriptyline and interpersonal psychotherapy, showing decrease in depressive symptoms in 69% of treated patients following a median of 6.4 weeks of treatment, compared to 56% in nortriptyline alone and 29% in psychotherapy alone.

Treatment for PGD

When grief is prolonged, psychotherapeutic interventions are warranted.

1. Cognitive behavioural therapy – Explores how thought patterns influence an individual’s feelings and attitudes.
2. Cognitive restructuring – Focuses on identifying the negative thought patterns and replacing them with more positive ones
3. Exposure therapy – Confront with a traumatic event and learning how to process the emotions associated
4. Individual interpersonal therapy – Focuses on interpersonal issues that contribute to emotional distress

Table 1 – WHO “Guidelines for the Management of Conditions Specifically Related to Stress” (2013)

Structured psychological interventions should not be offered universally to (all) bereaved adults who do not meet the criteria for a mental disorder.

References

Barnes, S., Jordan, Z., & Broom, M. (2018). Health professionals’ experiences of grief associated with the death of pediatric patients: A qualitative systematic review protocol.

JBI Database of Systematic Reviews and Implementation Reports, 16(11), 2085–2091.

Kacel, E., Gao, X. and G. Prigerson, H. (2011) ‘Understanding Bereavement: What Every Oncology Practitioner Should Know’, J Support Oncol., 9(5), pp. 172–180. doi: 10.1016/j.suponc.2011.04.007.
Hildebrandt, L. (2012) ‘Providing Grief Resolution as an Oncology Nurse Fellowship As a Recruitment and Retention Strategy.’, Clinical Journal of Oncology Nursing, 16(12), pp. 601–606. doi: 10.1188/12.CJON.601-606.
Tofthagen CS, Kip K, Witt A, McMillan SC. Complicated Grief: Risk Factors, Interventions, and Resources for Oncology Nurses. Clin J Oncol Nurs. 2017 Jun 1;21(3):331-337. doi: 10.1188/17.CJON.331-337. PMID: 28524889.
Balch, C. M. and Shanafelt, T. (2010) ‘Combating stress and burnout in surgical practice: A review’, Advances in Surgery, 44(1), pp. 29–47. doi: 10.1016/j.yasu.2010.05.018.
Lerea, L. E. and LiMauro, B. F. (1982) ‘Grief among healthcare workers: Acomparative study’, Journals of Gerontology, 37(5), pp. 604–608. doi: 10.1093/geronj/37.5.604.
Lyckholm, L. (2001) ‘Dealing with stress, burnout, and grief in the practice of oncology’, Lancet Oncology, 2(12), pp. 750–755. doi: 10.1016/S1470-2045(01)00590-3.
M.L., M. et al. (2003) ‘Strategies for teaching loss, grief, and bereavement’, Nurse educator, 28(2), pp. 71–76. Available at:
Macaulay, J. (2005) ‘When Patients Die: Grief Amongst Health Care Professionals’, Canadian Journal of Medical Radiation Technology, 36(1), pp. 17–20. doi: 10.1016/s0820- 5930(09)60053-0.
Shimoinaba, K. et al. (2009) ‘Staff grief and support systems for Japanese health care professionals working in palliative care’, Palliative and Supportive Care, 7(2), pp. 245–252. doi: 10.1017/S1478951509000315.
Wittouck, C. et al. (2011) ‘The prevention and treatment of complicated grief: A meta-analysis’, Clinical Psychology Review, 31(1), pp. 69–78. doi: 10.1016/j.cpr.2010.09.005.
WHO (2013) ‘Guidelines for the Management of Conditions Specifically Related to Stress’, Assessment and Management of Conditions Specifically Related to Stress: mhGAP Intervention Guide Module (version 1.0), pp. 1–273. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24649518.

Evidence Level Grade PMID Nº

I B 24049868

COVID IN CANCER PATIENT

Authors: Fernanda Estevinho and Cándida Abreu

Definition

COVID-19 (coronavirus disease 2019) is a highly contagious infection caused by the virus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). Cancer patients may have increased risk of infection and worse prognosis 1,2.

COVID-19 was declared as a pandemic at 11th March 2020, by the World Health Organization 3.

Symptoms and signs

The clinical presentation in cancer patients is like that of patients without cancer. The spectrum of clinical manifestations is heterogeneous, and it may include fever, chills, myalgias, respiratory symptoms, sore throat, and/or loss of smell or taste1. Many patients have mild or no symptoms while others present with severe symptoms with development of respiratory failure, cytokine release syndrome, multi-organ failure and death4. Subgroups of patients with increased risk of severe disease have been identified and include advanced age and presence of comorbidities such as hypertension, chronic lung disease, diabetes, and cancer 4.

Mortality from COVID-19 has ranged between 5% and 61%4. A Systematic Review and Meta-analysis including 81 studies and 61,532 patients with cancer revealed that the relative risk (RR) of mortality from COVID-19 was higher among cancer patients than in patients without cancer. 9

After SARS-CoV-2 infection some patients have persistent symptoms and/or new symptoms, this entity is called long COVID5. Sequelae post-COVID-19 occur in up to 15% of cancer patients6.

Etiology

SARS-CoV-2 belongs to Coronaviridae family. SARS-CoV-2’s S protein binds to the ACE2 surface receptor of epithelial cells in the respiratory tree and it is cleaved by Transmembrane Serine Pro- tease 2 (TMPRSS2) and internalized4.Other proteases like cathepsin L (CTSL) protein cleave the S protein and release the RNAinto the cytoplasm 4.

The severe COVID-19 clinical syndrome, characterized by respiratory failure or death, has been attributed to a ”cytokine storm” or a ”bradykinin storm4. COVID-19-associated coagulopathy with symptomatic thrombotic events ranging from 9% to 21% has also been found4.

Among cancer patients with COVID-19, hematologic cancer and lung cancer patients have been associated with poorer outcomes4. Other poor prognosis factors in cancer patients are male sex, older age, comorbidities (like cardiovascular and respiratory comorbidities) poor general performance status and smoking4,7.

COVID 19 Clinical diagnostic

Complementary diagnostic tests (imaging, laboratory…) depend on the clinical presentation

SARS-CoV-2 diagnostic tests

Evidence Level Grade PMID Nº

Acute infectionNucleic acid amplification test (NAAT) with a sample collected from the upper respiratory tract (i.e., nasopharyngeal, nasal mid-turbinate, anterior nasal, or oropharyngeal); if NAATs are not available an antigen test may be used (AIII).

in intubated patients suspected to have COVID-19 if an initial upper respiratory tract sample is negative endotracheal aspirates are preferred over bronchial wash or bronchoalveolar lavage samples when collecting lower respiratory tract samples to establish a diagnosis (BII).

After acute infection

In asymptomatic persons

a NAAT should not be repeated (except for health care workers) within 90 days of a previous SARS-CoV-2 infection, even if the person has had a significant exposure to SARS- CoV-2 (AIII).

In symptomatic persons (suspected of reinfection)

consider using a NAAT for those who have recovered from a previous infection and who present with symptoms that are suggestive of SARS-CoV-2 infection if there is no alternative diagnosis (BIII).

SARS-CoV-2 serologic (antibody) testing:

- should not be done as the sole basis for diagnosis of acute SARS-CoV-2 infection (AIII).
- no recommendation for or against to assess for immunity, to guide COVID-19 vaccines or anti SARS-CoV-2 monoclonal antibodies

Pharmacotherapy and therapeutic strategy

Evidence Level Grade PMID Nº

A 2a 35172054

A 2a 34937145

C 3 33972947

C 2a 34914868

A I 33043231

32678530

A 2a-3

34824060

B I 32678530

B 2a

No differences from no cancer patients. ICU admission may be needed.
Non- severe Covid-19 at highest risk of hospitalizationand no need of supplemental oxygen(one of them)
Nirmatrelvir/ritonavir (Paxlovid®)
Remdesivir
Bebtelovimab
Molnupiravir
	Hospitalized but does not require supplemental oxygen
Anticoagulation therapy: Prophylactic dose of heparin (if without evidence of venous thromboembolism) Administer for the duration of the hospital stay
Against: dexamethasone or other corticosteroids Note: Corticosteroids that are prescribed for an underlying condition should be continued
Hospitalized and require supplemental oxygen (one of the following options):
A) Dexamethasone DEX 6 mg IV or PO once daily for up to 10 days or until hospital discharge
B) Remdesivir (for patients with minimal supplemental oxygen)
C) Dexamethasone plus remdesivir
Add a second immunomodulatory drug IF patients with rapid increasing oxygen needs and systemic inflammation: Baracitinib (or instead tofacitinib– PMID 34133856) or Tocilizumab IV (or instead sarilumab IV– PMID 33631065)
Anticoagulation therapy: IF not pregnant and D-dimer levels higher than upper limit of normal and not atincreased bleeding risk: a Therapeutic dose of heparin (low-molecular-weight heparinpreferred, alternative unfractionated heparin) Administer: 14 days or until hospital discharge, unless a diagnosis of VTE or anotherindication for anticoagulation For others: Prophylactic dose of heparin(if not contra-indicated) for the duration of the hospital stay
Hospitalized and require oxygen through a high-flow device or non-invasive ventilation(one of the following):
A) Dexamethasone DEX 6 mg IV or PO once daily for up to 10 days or until hospital discharge

C 2a

A I

35045989

34111274

34508656

34768455

34649864

33043231

32678530

Evidence Level Grade PMID Nº

B) Dexamethasone plus remdesivir

Add a second immunomodulatory drug IFpatients with rapid increasing oxygen needs and systemic inflammation:

Baracitinib (or instead tofacitinib– PMID 34133856) or Tocilizumab IV (or instead sarilumab IV– PMID 33631065)

Anticoagulation therapy:

Prophylactic dose of heparin (if not contra-indicated) for the duration of the hospitalstays

Hospitalized and require mechanical ventilation or ECMO (extra corporal membrane oxygenation)

Dexamethasone

DEX 6 mg IV or PO once daily for up to 10 days or until hospital discharge

For patients who are within 24h of UCI admission:

Dexamethasone plus tocilizumab IV(or instead sarilumab IV– PMID 33631065)

Anticoagulation therapy: Prophylactic dose of heparin (if without evidence of venous thromboembolism)

If patient is started on therapeutic heparin before transfer to ICU switch to a prophylactic dose of heparin, unless there is a non Covid-19 reason (ECMO; continuous renal replacement therapy, thrombosis)

B 2b 34111274

C 2a 34508656

Contraindications for the use of therapeutic anticoagulation: platelet count < 50×10)/L, Hgb <8g/dL, need for dual antiplatelet therapy, bleeding within the last 30 days that required an emergency visit or hospitalization, a history of bleeding disorder or an inherited or active acquired bleeding disorder. Rate of recommendation: A – strong; B – moderate; C – weak.

Rating of evidence: I – one or more randomized trials without major limitations; 2a – other randomized trials or subgroup analysis of randomized trials. 2b – nonrandomized trials or observational cohort studies; 3 – expert opinion

Pharmacotherapy

C 2a

A I

34768455

33043231

34768455

33043231

34351722

Preferred Therapy options

Nirmatrelvir/riton avir (Paxlovid®)

Orally bioavailable protease inhibitor that is active against MPRO, a viral protease that plays an essential role in viral replication by cleaving the 2 viral polyproteins.1 It has demonstrated antiviral activity against all coronaviruses that are known to infect humans. 2

For outpatients with no need of oxygen therapy, within 7 days of symptom onset in high risk of hospitalization patients; preferred treatment option Every 12hours (Nirmatrelvir 300mg/ritonavir 100 mg) for 5 days

eGFR ≥30 to <60mL/min: nirmatrelvir 150mg with ritonavir 100mg twice daily for 5 days eGFR < 30 mL/min and severe hepatic impairment (Child-Pugh Class C):

not recommended because possible dangerous drug interactions

recommendation to children, breastfeeding, and pregnant women: currently uncertain

Remdesivir

A nucleotide prodrug of an adenosine analogue

IV infusion daily for 3 days, 200mg IV on Day 1, 100mg IV once daily on Days 2 and 3. administered early from symptom onset (within 7 days of symptom onset) with monitoring (feasibility challenges) – ambulatory patients

IV infusion daily for 5 days or until hospital discharge, 200mg IV on Day 1, 100mg IV once daily on Days 2 -5 Evidence suggests that the benefit is greatest when the drug is given within 10 days of symptom onset.

On mechanical ventilation or ECMO: 10 days of remdesivir (low certainty of evidence)

Clinical trials: have not demonstrated a mortality benefit for remdesivir; a large, placebo -controlled trial, showed that remdesivir reduced time to clinical recovery in hospitalized patients


Dexamethasone	DEX 6 mg IV or PO once daily for up to 10 days or until hospital discharge
Baracitinib	An oral JAK inhibitor that is selective for JAK1 and JAK2; dose is dependent on eGFR; duration of therapy is up to 14 days or until hospital discharge eGFR ≥60 mL/min/1.73 m 2: Baracitinib 4 mg PO once daily; eGFR 30 to <60mL/min/1.73m2: Baracitinib 2mg PO once daily; eGFR 15 to <30mL/min/1.73m2: Baracitinib 1mg PO once daily; eGFR <15mL/min/1.73m2 is not recommended
Tocilizumab	An IL-6 inhibiting monoclonal antibody; 8 mg/kg actual body weight (up to 800 mg) administered as a single IV dose. In clinical trials, a third of the participants received a second dose of tocilizumab 8 hours after the first dose if no clinical improvement was observed
	Alternative therapy options
Tofacitinib	A first-generation selective oral JAK1/3 inhibitor with less inhibition of JAK2; 10 mg PO twice daily for up to 14 days or until hospital discharge; eGFR<60mL7Min/1.73m2: Tofacitinib 5mg PO twice daily)
Sarilumab	A human monoclonal antibody medication against the interleukin-6 receptor. Use the single-dose, prefilled syringe (not the prefilled pen) for SUBQ injection. Reconstitute sarilumab 400 mg in 100 cc 0.9% NaCl and administer as an IV infusion over 1 hour.)
Bebtelovimab	A recombinant neutralizing human mAb that binds to the spike protein of SARS -CoV-2. In vitro data suggest that bebtelovimab has activity against a broad range of SARS-CoV-2 variants, including the Omicron variant and its BA.1, BA.1.1, and BA.2 subvariants . Bebtelovimab is active in vitro against all circulating Omicron sub- variants, but there are no clinical efficacy data from placebo -controlled trials that evaluated their use in patients who are at high risk of progressing to severe COVID -19. Therefore, should be used only when the preferred treatment options are not available, feasible to use, or clinically appropriate. Single IV infusion, BEB 175 mg as a single IV injection, administered over ≥30 seconds. Patients should be observed for ≥1 hour after inje ction.
Molnupiravir	The oral prodrug of beta-D-N4-hydroxycytidine (NHC) Oral 800mg twice daily for 5 days, administered early from symptom onset Concerns about mutagenicity. ONLY when ritonavir -boosted nirmatrelvir (Paxlovid) and remdesivir are not av3 ailable, feasible to use, or clinically appropriate reduced the rate of hospitalization or death by 30% compared to placebo in no hospitalized patients with COVID-19.
Molnupiravir	The oral prodrug of beta-D-N4-hydroxycytidine (NHC) Oral 800mg twice daily for 5 days, administered early from symptom onset Concerns about mutagenicity. ONLY when ritonavir -boosted nirmatrelvir (Paxlovid) and remdesivir are not available, feasible to use, or clinically appropriate reduced the rate of hospitalization or death by 30% compared to placebo in no hospitalized patients with COVID-19.³
	Against use
	Chloroquine/hydroxychloroquine with or without azithromycin (AI) Lopinavir/ritonavir (AIII) Anticoagulants and antiplatelet therapy (AIIa) Sotrovimab (substantially decreased in vitro activity against the Omicron BA.2 subvariant)

1- Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH. An overview of severe acute respiratory syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: peptidomimetics and small molecule chemotherapy. J Med Chem. 2016;59(14):6595-6628. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26878082.

1. Owen DR, Allerton CMN, Anderson AS, et al. An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19. Science. 2021;374(6575):1586-1593. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/34726479

1. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for molnupiravir. 2022. Available at: https://www.fda.gov/media/155054/download.

Relevant published studies

•Apooled analysis of Fifty-two studies, including 18,650 cancer patients with COVID-19 shown a probability of death of 25.6% (95% CI: 22.0%-29.5%; I2 = 48.9%)(8).

•A Systematic Review and Meta-analysis including 81 studies and 61,532 patients with cancer revealed that the relative risk (RR) of mortality from COVID-19 was higher among

cancer patients than in patients without cancer, RR 1.69 (95%CI, 1.46-1.95; P < .001; I2 = 51.0%)9. There was an increased risk of mortality in lung cancer (RR, 1.68; 95%CI, 1.45-1.94; P < .001; I2 = 32.9%), and hematologic cancer (RR, 1.42; 95%CI, 1.31-1.54; P < .001; I2 = 6.8%). Lower risk of death was registered in breast cancer patients (RR, 0.51; 95%CI, 0.36-0.71; P < .001; I2 = 86.2%) and gynecological cancer patients(RR, 0.76; 95%CI, 0.62-0.93; P = .009; I2 = 0%)9. Chemotherapy was associated with the highest overall mortality of 30% (95%CI,25%-36%; I2 = 86.97%; range, 10%-100%), while endocrine therapy had the lowest 11% (95%CI, 6%-16%; I2 = 70.68%; range, 0%-27%)(9).

•COVID-19 and Cancer Consortium (CCC19) registry data through 31/12/2021 included 11,417 patients and showed that 55% required hospitalization, 15% were admitted to

ICU, and 30-day mortality was 12%10. Higher mortality was observed if: advanced age, male (14%), black race (14%), smoking (14%), DM (16%), pulmonary comorbidity (17%), cardiovascular comorbidity (19%), renal (21%) %), co-infection 25%, fungal co-infection (35%), ECOG2+ (31%), initial presentation with severe COVID19 (48%); active/progressing cancer (26%) or if systemic cancer therapy performed 1-3 months before COVID-19 diagnosis (17%) (l0).

•TERAVOLT (The Thoracic Centres International COVID-19 Collaboration) registry revealed a 24.2-33% mortality in patients with thoracic malignancies during the initial COVID

waves(11). From January 14, 2022, through February 4, 2022, there were included 346 patients, 86% had NSCLC (Non-Small Cell Lung Cancer), and overall mortality was 3.2% (11).

•An N3C-vaccinated population (N3C -National COVID Cohort Collaborative) analysis showed that cancer patients (with solid or hematologic malignancies) had significantly

higher risks for breakthrough infection (odds ratios [ORs] = 1.12, 95% CI, 1.01 to 1.23 and 4.64, 95% CI, 3.98 to 5.38) and severe outcomes (ORs = 1.33, 95% CI, 1.09 to 1.62 and 1.45, 95% CI, 1.08 to 1.95) adjusting for age, sex, race/ethnicity, smoking status, vaccine type, and vaccination date 12. The risk is higher for patients with hematologic malignancies compared with solid tumours. After second vaccine dose administration cancer patients had reduced risk of breakthrough infection (OR = 0.04; 95% CI, 0.04 to 0.05)(12).

•A systematic review and meta-analysis including 64 studies and a total of 10,511 patients showed an overall seroconversion rate of 78% (95% CI: 73-82%)(13). The

seroconversion rate was higher in solid tumours (93%, 95%CI: 91-95) compared to haematological tumours, (74%, 95%CI: 68-80) 13. For patients with solid tumours:

there were no significant differences in the seroconversion rate according to the primary tumour (lung versus non-lung) or cancer stage(13). Patients undergoing chemotherapy

had a numerically lower seroconversion rate compared to patients treated with immune checkpoint inhibitors, endocrine therapy and targeted therapy( 1)3. In haematological cancer patients, the seroconversion rate was lower in patients with CLL (Chronic Lymphocytic Leukaemia), Non-Hodgkin Lymphoma, patients treated with anti-CD20, immunomodulatory agents or other immunotherapies(13). The humoral response was lower in patients with lymphopenia: 50% (95% CI: 25-75), elderly patients with haematological tumours: 59% (95%CI:47-70%), hypogammaglobulinemia: 36% (95% CI: 19-57%)(14). There was a tendency for a lower humoral response: in men and Asians; adenovirus vaccines (28%; 95%CI:19-40%) versus mRNAvaccine (79%; 95% CI:74-83%)(14).

•The SerOzNET study evaluated patient-reported toxicity and quality of life after the SARS-CoV-2 vaccine. In the total population (n=495) the incidence of any adverse event was

high (70-100%). However, the presence of severe adverse events (adults: 5-7%) and treatment interruptions (adults: 1-4%) were infrequent and quality of life was not affected(15).

References

Bakouny, Z., Hawley, J. E., Choueiri, T. K., Peters, S., Rini, B. I., Warner, J. L., & Painter, C. A. (2020). COVID-19 and Cancer: Current Challenges and Perspectives. Cancer cell, 38(5), 629–646. https://doi.org/10.1016/j.ccell.2020.09.018. PMID: 33049215.
Grivas, P., Khaki, A. R., Wise-Draper, T. M., French, B., Hennessy, C., Hsu, C. Y., Shyr, Y., Li, X., Choueiri, T. K., Painter, C. A., Peters, S., Rini, B. I., Thompson, M. A., et al. (2021). Association of clinical factors and recent anticancer therapy with COVID-19 severity among patients with cancer: a report from the COVID-19 and Cancer Consortium. Annals of oncology : official journal of the European Society for Medical Oncology, 32(6), 787–800. https://doi.org/10.1016/j.annonc.2021.02.024. PMID: 33746047.
World Health Organization, 2020. WHO Director-General’s opening remarks at the media briefing on COVID-19 – 11 March 2020. [online] Who.int. Available at: <https://www.who.int/director- general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19 11-march-2020> [Accessed 31 May 2022].
Curigliano G, Banerjee S, Cervantes A, Garassino MC, Garrido P, Girard N, Haanen J, Jordan K, Lordick F, Machiels JP, Michielin O, Peters S, Tabernero J, Douillard JY, Pentheroudakis G; Panel members (2022). Managing cancer patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus. Ann Oncol. Oct;31(10):1320-1335. doi: 10.1016/j.annonc.2020.07.010. Epub 2020 Jul 31. PMID: 32745693; PMCID: PMC7836806.
Sharafeldin N, Madhira V, Song Q, Bates B, Mitra AK, Liu F, Bergquist T, Su J, Hsu F, Topaloglu U(2022). Long COVID-19 in patients with cancer: Report from the National COVID Cohort Collaborative (N3C). J Clin Oncol 40, 2022 (suppl 16; abstr 1540).
Pinato, D. J., Tabernero, J., Bower, M., Scotti, L., Patel, M., Colomba, E., Dolly, S., Loizidou, A., Chester, J., Mukherjee, U., Zambelli, A., Dalla Pria, A., Aguilar-Company, J., Ottaviani, D., Chowdhury, A., Merry, E., Salazar, R., Bertuzzi, A., Brunet, J., Lambertini, M., OnCovid study group (2021). Prevalence and impact of COVID-19 sequelae on treatment and survival of patients with cancer who recovered from SARS-CoV-2 infection: evidence from the OnCovid retrospective, multicentre registry study. The Lancet. Oncology, 22(12), 1669–1680. https://doi.org/10.1016/S1470-2045(21)00573-8
Passaro A, Bestvina C, Velez Velez M, Garassino MC, Garon E, Peters S. Severity of COVID-19 in patients with lung cancer: evidence and challenges. J Immunother Cancer. 2021 Mar;9(3):e002266. doi: 10.1136/jitc-2020-002266. PMID: 33737345; PMCID: PMC7978268.
Saini, K. S., Tagliamento, M., Lambertini, M., McNally, R., Romano, M., Leone, M., Curigliano, G., & de Azambuja, E. (2020). Mortality in patients with cancer and coronavirus disease 2019: A systematic review and pooled analysis of 52 studies. European journal of cancer (Oxford, England : 1990), 139, 43–50. https://doi.org/10.1016/j.ejca.2020.08.011.
Khoury, E., Nevitt, S., Madsen, W. R., Turtle, L., Davies, G., Palmieri, C. (2022). Differences in Outcomes and Factors Associated With Mortality Among Patients With SARS-CoV-2 Infection and Cancer Compared With Those Without Cancer: ASystematic Review and Meta-analysis. JAMAnetwork open, 5(5), e2210880. https://doi.org/10.1001/jamanetworkopen.2022.10880.
Shah DP, Shah P, Warner JL, Batist G, Friese CR, Griffiths EA, Hwang C, Vieira K, McKay RR, Mesa RA, Puc M, Robilotti EM, Ruiz-Garcia E, Portuguese AJ, Schmidt AL, Weissmann LB, Wise-Draper TM, Barnholtz-Sloan J, Peters S, Grivas P(2022). An update on the overall epidemiology, clinical characteristics, and outcomes from the COVID-19 and Cancer Consortium (CCC19). J Clin Oncol 40, 2022 (suppl 16; abstr 10565).
Bestvina, C. M., Whisenant, J. G., Torri, V., Cortellini, A., Wakelee, H., Peters, S., Roca, E., De Toma, A., Hirsch, F. R., Mamdani, H., Halmos, B., Arrieta, O., Metivier, A. C., Fidler, M. J., Rogado, J., Presley, C. J., Mascaux, C., Genova, C., Blaquier, J. B., Addeo, A., Finocchiaro , Khan H, Mazieres J, Floriana Morgillo 24 , Jair Bar 25 , Avinash Aujayeb 26 , Giannis Mountzios 27 , Vieri Scotti 28 , Federica Grosso, Erica Geraedts 30 , Ardak N Zhumagaliyeva 31 , Leora Horn 2 , Marina Chiara Garassino 1 , Javier Baena 32 , TERAVOLT study groupTERAVOLT study group (2022). COVID-19 Outcomes, Patient Vaccination Status, and Cancer-Related Delays during the Omicron Wave: A Brief Report from the TERAVOLT Analysis. JTO clinical and research reports, 100335. Advance online publication. https://doi.org/10.1016/j.jtocrr.2022.100335
Song, Q., Bates, B., Shao, Y. R., Hsu, F. C., Liu, F., Madhira, V., Mitra, A. K., Bergquist, T., Kavuluru, R., Li, X., Sharafeldin, N., Su, J., & Topaloglu, U. (2022). Risk and Outcome of Breakthrough COVID-19 Infections in Vaccinated Patients With Cancer: Real-World Evidence From the National COVID Cohort Collaborative. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 40(13), 1414–1427. https://doi.org/10.1200/JCO.21.02419.
Marta GN, Spilleboudt C, Martins-Branco D, Vuger AT, Debien V, Ameye L, Brandão M, Punie K, Loizidou A, Willard-Gallo K, Awada A, Piccart-Gebhart MJ, Azambuja E (2022). Impact of cancer diagnosis, stage, and systemic therapies on immunogenicity after COVID-19 vaccination in patients with cancer: Asystematic review and metaanalysis. J Clin Oncol 40, 2022 (suppl 16; abstr 1537).
Martins-Branco D, Loizidou A, Marta GN, Vuger AT, Debien V, Ameye L, Brandão M, Punie K, Spilleboudt C, Willard-Gallo K, Awada A, Piccart-Gebhart MJ, Azambuja E (2022). Demographic and laboratory determinants of humoral immune responses and impact of different anti-SARS-CoV-2 vaccine platforms in patients with cancer: A systematic review and meta-analysis. J Clin Oncol 40, 2022 (suppl 16; abstr 1543).
Body A, Wakefield C, Luong VTT, Donoghoe M, Bolanos NAF, Anazodo A, Ho C, Grech L, Ahern ES, Segelov E (2022). Patient-reported toxicity and quality of life following Sars-CoV-2 vaccination in adults and children with cancer. J Clin Oncol 40, 2022 (suppl 16; abstr LBA12068).

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AUTHORS

Adrián Pablo Huñis Alberto Albiol Colomer Alberto Alves Alejandro Bermejo

Alejandra Giménez-Ortiz Alexander Ariel Padrón González Alexandre Sarmento

Alice Pimentel Alicia Oliveira Alexandra Guedes Ana Barbosa

Ana Carolina Vasques Ana Carlota Caetano Ana Catarina Brás

Ana Filipa Coroado da Silva Ferreira Ana Isabel Paiva Santos

Ana Leonor Matos Ana María Comín Orce Ana Sofia Montez André Ferreira

André da Silva Ribeiro Andre Oliveira

Andreia do Carmo Lopes Ana Joaquim

Ana Teijo Quintans Andre Coutinho Andreia Silva Andrés Beltrán Giner André Pires

Beatriz Alonso de Castro Belén López Roldán Bárbara Castro

Bárbara Lima Bárbara Paracana Bernardo Santos Bruno Pereira

Bruno Moura Fernandes Candida Abreu

Carmen Salvador Coloma Carolina Carvalho Carolina Mazeda

Carlos Manuel Oliveira Soares da Costa Carolina Nunes Capucho Luzia Pereira Carlos Rabaça

Carlota Sofia Vieira Baptista Carolina Trabulo

Catarina Almeida Catarina Martins Silva Cecília Caramujo de Sá Clara Maria Dias Pinto Cláudia Sá

Cláudia Salgado Claudia Rosado Claudio Avila Andrade Claudia Matos

David Gomes Daniela Meireles Daniela Lira

Daniela Ribeiro Alves Delfim D. Duarte Diana Borges Duarte Diana Cardoso Simão Diana Correia

Diana Neto da Silva

Diana Pessoa Diogo Abreu

Diogo Augusto Ribeiro Soares* Diogo Lima Lopes

Duarte Vieira e Brito Pedro Duarte Domingues Ema da Silva Neto Fernanda Estevinho Filipa Ferreira

Filipa Pontes Flávia Fernandes

Francisco Garcia Navalón Gloria Ortega Pérez Grezia Siancas Gonzáles Gonçalo Durão Carvalho Guillermo Estrada Riolobos Henrique Costa

Helena Guedes Helena Sousa

Inês da Conceição Félix Pinto Inês Fernandes Santos

Inês Cunha

Inês Ferreira Gomes Ines Gois

Inês Leão Ines Pinheiro Inês Pintor

Inmaculada Soler-Ferrero Irene Rojo

Iria Parajó Vázquez Isa Peixoto

Isabel C. G. Fernandes

Isabel Domingues Isis Alonso

Jéssica Sobreiros Krowicki Jessica Archer Jiménez Joaquín Mosquera Martínez José García González Jose Mazarico

Joana Cruz Monteiro Joana Albuquerque Joana Marinho

Joana Duarte Albuquerque Joana Ferreira Mendes Joana Graça

Joana Liz Pimenta Joana Mendonça Joana Guimarães Joana Noronha Joana Providência João Boavida Ferreira João Barbosa Martins João Faia

Joao Faustino João Fonseca João Oliveira

Joao Paulo Gonçalves Vilas-Boas Jorge Moreira

Jorge Ricardo Sousa Rodrigues Jose Miguel Martins

José Pedro Leão Mendes

José Pedro Portela Cidade Silva João Pedro Lima

Juan Carlos Mellídez

Juan Carlos Samamé Pérez-Vargas Juan Pablo Fusco

Kiko Albiol

Lara Otero Plaza

Laura Martins Sobral Falcão Baptista Lúcia Borges

Lucrecia Ruiz Echevarría Luísa Leal da Costa Leonor Fernandes Leonor Naia

Luis Moreno Sánchez Mafalda Miranda Baleiras Mafalda Costa

Manuel Fernandez Bruno Marcos Dumont Bonfim Santos Mariana Malheiro Rodrigues Maria Menezes

Maria João Ramos Mariana Rebordão Pires Mariana Sardinha Maria Teresa Neves Marta Baptista Freitas Marta Riquito

Marta Teijo Quintáns

Martín-Igor Gómez-Randulfe Márcia Alves

Marcos Pantarotto

Margarida Batista Caldeira Massas Margarida Bettencourt

Maria del Castillo Maria Ribeiro Gomes María Rodríguez Plá

Maria Joao de Sousa Mariana Estevam Mariana Teixeira Marília Ferreira Marina Meri Abad

Marina Veloso Gonçalves Marisa Carvalho Couto Maria Madalena Machete Mário Lourenço

Martín Igor Gómez-Randulfe Rodríguez Michele Ghidini

Miguel Barbosa Mónica Mata Patricio Natacha Mourão

Nuno de Almeida Cordeiro Nuno Figueiredo

Oscar Alonso Casado

Paula Alexandra Sousa Mesquita Paulo Vilas-Boas

Paula Castilho

Patricia Cordeiro González Patricia Garrido

Patricia Chow Liu Pedro Bernardo Santos Pedro Marílio Cardoso

Pedro Miguel Antunes Meireles Pedro Simões

Rafael Matias

Raquel Barroso Varela Raquel Borrego

Raquel Margarida Gomes Martins Raquel Monteiro Vieira

Raquel Pereira Raquel Romao Rehab Ahmed Hamdy Ricardo Pinto

Rita Freitas

Rita Isabel Cebolais Bizarro Ricardo Godinho

Ricardo Roque Ricardo Prat Acín Rita Antunes Santos Rita Sousa

Ritu Dave

Rodrigo dos Santos Vicente Rosario Garcia Campelo Rui Dinis

Salvador Gámez Casado Salvador Tortajada Veler Sara Bravo

Sandra Custódio Sandra Silva

Santiago González Moreno Sara Couto Gonçalves Sara Cerejeira

Sara Gabriela Esteves Ferreira Sara Encinas

Sérgio Costa Monteiro Sergio Pascual Solaz Sara Marques Zorro Sofia Amorim

Sofia Durão Sofía Silva Díaz Sofia Pedrosa

Sofia Viamonte

Soraia Marques Carvalho Susana Sarandao

Tânia Duarte

Telma Amorim Santos Teresa Fraga

Teresa Padrão Teresa Puértolas Tiago Rabadão Tiago Valente Tomás Dinis Valter Duarte

Víctor Sacristán Santos

INDEX

Oncologic Pain
1. NEUROPATHIC PAIN. pgs.9
2. SOMATIC PAIN. pgs.13
3. VISCERAL PAIN. pgs.18
4. IRRUPTIVE PAIN. pgs.25
5. BONE PAIN. pgs.33
Emesis
1. CANCER-ASSOCIATED EMESIS. pgs. 36
2. IATROGENIC EMESIS. pgs. 39
Oncologic Emergencies
1. SPINAL COMPRESSION SYNDROME. pgs. 46
2. SUPERIOR VENA CAVA SYNDROM. pgs. 49
3. TUMOR HYPERCALCEMIA . pgs. 52
4. ENDOCRANIAL HYPERTENSION. pgs. 58
5. ACUTE BLEEDING. pgs. 64
6. INFUSION REACTIONS. pgs. 67
7. EMERGENCY KIT. pgs. 72
Immunotherapy-Associated Toxicity
IMMUNOTHERAPY-ASSOCIATED TOXICITY. pgs. 75
Neurological alterations
1. ENCEPHALOPATHIES. pgs. 88
2. WAKEFULNESS-SLEEP RHYTHM DISTURBANCES. pgs. 90
3. INSOMNIA. pgs. 92
4. MYELOPATHIES. pgs. 97
5. PERIPHERAL AND CRANIAL NERVE NEUROPATHY. pgs. 98
6. DELIRIUM IN CANCER PATIENT. pgs.105
Endocrinological alterations
1. HYPOPHYSITIS. pgs. 109
2. DIABETES. pgs. 113
3. THYROID ALTERATIONS. pgs. 117
4. ADRENAL ALTERATIONS. pgs. 124
5. CARCINOID SYNDROME. pgs. 127
Ophthalmologic disorders
1. ECTROPION – ENTROPION. pgs. 130
Constitutional
1. CANCER RELATED AND IATROGENIC ASTHENIA. pgs. 243
2. ANOREXIA CACHEXIA (FALTA CACHEXIA). pgs. 246
Nutrition in cancer patients
1. NUTRITIONAL RISK PATIENT. pgs. 249
2. MALNUTRITION IN CANCER PATIENT. pgs.254
Genito-urinary disorders
1. IATROGENIC MENOPAUSE. pgs. 260
2. ERECTILE DYSFUNCTION. pgs. 266
3. DYSPAREUNIA AND DECREASED FEMALE LUBRIFICATION.

pgs. 276

1. RADIATION THERAPY INDUCED CYSTITIS. pgs. 279

Hematological alterations
1. ANEMIA. pgs. 290
2. THROMBOCYTOPENIA. pgs. 295
3. LEUCOPENIA. pgs. 301
4. FEBRILE NEUTROPENIC SYNDROME. pgs. 306
5. BLOOD HYPER VISCOSITY. pgs. 308
Skin disorders
1. RADIATION THERAPY EPITELITIS. pgs. 313
2. ALOPECIA AND OTHER HAIR IATROGENIC DISORDERS. pgs.318
3. SKIN HYPERSENSITIVITY. pgs. 326
4. PHOTOSENSITIZATION. pgs. 336
5. HAND-FOOT ERYTRHODYSESTESIA. pgs. 339
6. UNGUAL ALTERATIONS. pgs. 346
7. SKIN TOXICITY INDUCED BY TARGETED THERAPIES. pgs. 348
Metabolic disorders
1. DEHYDRATION. pgs. 358
2. TUMOR LYSIS SYNDROME. pgs. 360
3. SODIUM METABOLISM. pgs. 365
4. POTASSIUM METABOLISM. pgs. 368
5. MAGNESIUM METABOLISM. pgs. 373
6. CALCIUM METABOLISM. pgs. 378
Kidney disorders
1. PROTEINURIA/NEPHROTIC SYNDROME. pgs.381
2. NEFROTOXICITY. pgs. 386
3. KERATITIS / KERATO-CONJUNCTIVITES SICCA . pgs. 131
4. CONJUNCTIVITIS. pgs. 133
Oropharyngeal disorders
1. OROPHARYNGEAL CANDIDIASIS. pgs. 135
2. STOMATITIS/MUCOSITIS. pgs. 137
3. XEROSTOMIA. pgs. 142
Gastrointestinal disorders
1. DIARRHEA. pgs. 145
2. INTESTINAL OCCLUSION. pgs. 149
3. CONSTIPATION. pgs. 154
4. COLITIS. pgs. 159
5. POST-RADIATION THERAPY PROCTITIS. pgs. 164
Hepato-Biliary disorders
1. LIVER FAILURE AND CHEMOTHERAPY. pgs. 167
2. HEPATIC ENCEFALOPATHY. pgs. 172
3. BILIARY OBSTRUCTION. pgs. 178
Cardiovascular disorders
1. HIGH BLOOD PRESSURE. pgs. 181
2. CONGESTIVE HEARTH FAILURE. pgs. 185
3. PERICARDIAL EFFUSION. pgs. 190
Respiratory disorders
1. PULMONARY FIBROSIS. pgs. 192
2. PNEUMONITIS. pgs. 197
3. PLEURAL EFFUSION. pgs. 201
4. BRONCHIAL HYPERSECRETION. pgs. 207
5. HEMOPTYSIS. pgs. 210
Rheumatological alterations
1. BONE DISORDERS. pgs. 216
2. CHEMOTHERAPYS AND HORMONTHERAPY ASSOCIATED RHEUMATIC COMPLICATIONS. pgs. 220
3. PARANEOPLASTIC RHEUMATIC MANIFESTATIONS. pgs. 224
4. MALIGNANT DISEASES WITH MUSCULOSKELETAL MANIFESTATIONS. pgs. 230
5. AUTOANTIBODIES ASSOCIATED TO RHEUMATIC DISEASE IN

CANCER PATIENTS. pgs. 234

1. IMMUNE CHECKPOINT INHIBITOR ASSOCIATED RHEUMATIC CONDITIONS. pgs. 235
2. RADIOTHERAPY TREATMENT ASSOCIATED RHEUMATIC

COMPLICATIONS. pgs. 241

1. Kidney Function Assessment. pgs. 390
2. KIDNEY DISORDERS: RENAL FUNCTION EVALUATION. pgs. 395

Clotting disorders
1. PULMONARY THROMBOEMBOLISM. pgs. 407
2. DEEP VEIN THROMBOSIS. pgs. 411
3. COAGULOPATHY. pgs.418
4. DISSEMINATED INTRAVASCULAR COAGULOPATHY. pgs. 424
5. BLEEDING IN CANCER PATIENT. pgs. 427
Sedation
1. SEDATION IN CANCER PANTIENT. pgs. 431
Prosthesis and endoprosthesis
1. MANAGEMENT OF OBSTRUCTIVE COLON CANCER. SELF-EXPANDING METALLIC STENT VERSUS EMERGENCY SURGERY. pgs. 435
Surgical Complications
1. SEROMAS, BRUISES. pgs. 440
2. LYMPHEDEMA. pgs. 442
3. FISTULA. pgs. 450
Exercice in cancer patients
1. EXERCISE IN CANCER PATIENT. pgs. 452
Other
1. FUNGAL INFECTIONS. pgs. 457
2. BONE METASTASIS. pgs. 473
3. PERSISTENT HICCUPS. pgs. 485
4. CANNABIS IN CANCER PATIENT. pgs. 487
5. CENTRAL VENOUS CATHETER. pgs. 494
6. VACCINATION IN CANCER PATIENT . pgs. 496
7. PATHOLOGIC BONE FRACTURES. pgs. 499
8. RISK OF SECOND IATROGENIC TUMORS (LONG SURVIVORS). pgs. 502
9. ARTIFICIAL INTELLIGENCE AND SYMPTOMS ASSOCIATED WITH CANCER AND ITS TREATMENTS. pgs. 506
10. COMMUNICATION WITH CANCER PATIENT AND FAMILY. pgs. 511
11. ADDRESSING MOURNING AT THE HEALTH CARE PROFESSIONAL. pgs. 514
12. COVID IN CANCER PATIENT. pgs. 517

Supportive care is an essential and inseparable part of the therapeutic approach to cancer patients.

INTERNATIONAL GROUP FOR SUPPORTIVE CANCER CARE STUDY publishes the “IOC 2022” as a guide to help professionals.

a quick impression and certainty of each of the treatments and strategies presented. The GRADE and OXFORD scales have been used for the levels of evidence.

GRADE SYSTEM (ADAPTED)

LEVEL OF EVIDENCE
Level 1	Evidence obtained from a Systematic Review or all Relevant Randomized Control Trials
Level 2a	Evidence obtained from at least one properly deigned Randomized Control Trial
Level 3a	Evidence obtained from well-designed Pseudo-Randomised Control Trials (alternative allocation or some other method)
Level 3b	Evidence obtained from Comparative Studies (including systematic review of such studies) with concurrent controls an allocation is nor tandomised Cohort Studies, Case Control Studies, Interrupted Time Series with a Control Group
Level 4	Evidence obtainded Case-Series-Either Post Test or Pre -Tests and Post Test
Level 5	Evidence obtained from Expert Opinion Without Critical Appraisal, or Based on Physiology, Based on Bench Resears Baed on Historically Based Clinic Principles

GRADE OF RECOMENDATION
QUALITY OF EVIDENCE	DEFINITION
High	Further research is very unlikely to change our confidence in the estimate off effect: Several high-quality studies with consistent results In special cases: one large, high quality multi center trial
Moderate	Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate One high-quality study Several studies with some limitations
Low	Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate One or more studies with severe limitations
Very Low	Any estimate of effect is very uncertain Expert opinion No direct research evidences One or more studies with very severe limitations

Oxford Center for Evidence-Based-Medicine Hierarchy (adapted)

Adapted from: “levels of Evidence (Oxford Centre for Evidence-based Medicine-March 2009)

The toxicity grades follow the CTCAE v5.0 classification.

We would like to thank all the authors for their work and dedication to this project. Without the effort of all of them it would not have been possible.

Level	Rec.	Therapy/Prevention, Etiology/Harm
1a	A	Systematic Review (with homogeneity) of randomized controlled trials
1b	A	Individual Randomized Controlled Trial (with narrow confidence interval)
1c	A	All or none
2a	B	Systematic Review (with homogeneity) of cohort studies
2b	B	Individual cohort study (including lox quality Randomized Controlled Trial
2c	B	“outcomes” research; Ecological studies
3a	B	Systematic Review (with homogeneity) of case control studies
3b	B	Individual case-control study
4	C	Case-series (and poor-quality cohort and case-control studies)
5	D	Expert opinion

Dr. Juan Carlos Mellídez – Coordinator

Javier Cortés

ONCOLOGIC PAIN

NEUROPATHIC PAIN

Authors: Adrián Pablo Huñis, Sara Zorro and José Pedro Cidade. . Evidence

Definition

Neuropathic or neurogenic pain (NP) is defined by the International Association for the Study of Pain (IASP) as pain initiated or caused by a lesion or dysfunction of the nervous system .
What differentiates NP from other types of pain is its poor response to cyclooxygenase-2 inhibitors and opioids. At any stage of life, NP is more common in women than in men . Approximately 70% of the patients have chronic NP .

Symptoms

Symptoms are very varied. Pain can be associated to sensory abnormalities (paraesthesia, allodynia, dysesthesia, hyperalgesia) and have different characteristics (burning, tingling, shooting, stabbing, cramping, electric shock-like pains, etc.) (Table 1)(Jensen et al. 2001).

Table1: Sensory abnormalities and characteristics of neuropathic pain

Level Grade PMID Nº

16827265

18439759

18003941

11698022

Dysesthesia

Unpleasant abnormal sensations:

Burning sensation
Sunburn-like
Skin tingles

Etiology

Paraesthesia

Abnormal sensations that are not unpleasant:

Pins and needles
Electric-like
Numb but achy
Like feet in ice water

Allodynia

Pain due to a stimulus that does not normally provoke pain.

Hyperalgesia

Increased pain from a stimulus that normally provokes pain.

- Increased firing of stimuli by the primary afferent nociceptor as result of an abnormal amount of sodium channels in damaged peripheral nerves causing ectopic discharges.
- Decreased inhibition of neuronal activity in central structures due to loss of inhibitory neurons.
- Altered central processing (central sensitization) so that the input of sensory impulses is amplified and sustained.

28205574

30586071

12707429

12620591

21356652

29056655

33671327

32584191

33858611

Diagnostic Studies

Screening Tools

- The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) contains ﬁve symptom items and two clinical examination items. It has also been validated as a self- report tool, the S-LANSS. Compared to clinical diagnosis, its sensitivity and speciﬁcity range 82–91% and 80–94%, respectively .
- The Neuropathic Pain Questionnaire (NPQ) contains 12. It demonstrated 66% sensitivity and 74% speciﬁcity, compared to clinical diagnosis in the validation sample.
- The Douleur Neuropathique in 4 questions (DN4) contains seven items related to symptoms and three related to clinical examination. A total score >=4 out of 10 suggests NP. It showed 83% sensitivity and 90% speciﬁcity when compared to clinical diagnosis in the development study.
- Pain DETECT was developed and validated in German and is available in several other languages. It is a self-report questionnaire with nine items. It correctly classiﬁes 83% of patients to their diagnostic group with 85% sensitivity and 80% speciﬁcity .

Assessment Questionnaires

- The Neuropathic Pain Symptom Inventory (NPSI) was originally validated in French and has been submitted to linguistic validation in 50 other languages. It is recommended to evaluate treatment e ects on neuropathic symptoms or their combination –.

Neurophysiology

- The trigeminal reﬂexes mediated by Aβ ﬁbres are useful in the diagnosis of trigeminal pain disorders. They are abnormal in patients with structural damage, in conditions such as trigeminal neuropathy (TN) and postherpetic neuropathy (PHN), and normal in patients with classic trigeminal neuralgia.
- Laser-evoked potentials are useful for assessing function of the Aδ ﬁbre pathways in patients with NP .

Skin Biopsy

- Small ﬁbres dysfunction.

Pain Scales

- Pain scales such as the Numerical Rating Scale (NRS), Verbal Rating Scale (VRS), or Visual Analogue Scale (VAS) are useful tools to assess the intensity of pain and treatment effect .

11698022

16091164

20298428

I High 11323136 15772908

20298428

20851519

I High 12966256 20298428

20851519

I High 15733628 20298428

20851519

I High 17022849 24200014

20298428

I High 15030944 31431674

20298428

I High 16401867 30860637

18721143 18716236

I High 20298428 23040705

28106318

I High 34335876 33802768

20642627

I High 20851519 22588748

21621130 29794282

First Line Treatment
- Multidisciplinary care in conjunction with gabapentinoids, tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), are the first-line agents for treating neuropathic pain. A four to six-week trial is recommended with at least two reviews to assess effectiveness .
Second Line Treatment
- Tramadol, a weak u-opioid agonist and inhibitor of serotonin and norepinephrine reuptake, is considered second-line treatment in most guidelines but first-line in cancer- related neuropathic pain.
- Tapentadol is a strong analgesic with a dual mechanism of action that combines μ-opioid receptor agonism (MOR) and norepinephrine reuptake inhibition (NRI). Experimental and clinical evidence indicates that its NRI component may become predominant in NP conditions. It proved to be effective in the treatment of diabetic peripheral neuropathy (DPN).
- Lidocaine 5% works by decreasing ectopic firing of peripheral nerves. It is recommended for the treatment of focal neuropathic pain such as PHN. Safety and tolerability are excellent.
- Capsaicin 8% patches acts through binding to the TRPV1 receptor located on the Aδ and C-nerve fibres. This results in release of substance P and depolarization of the nerve. Long-term exposure causes overstimulation, depletion of substance P, desensitization of the nerve, and reversible nerve degeneration. It is recommended for the treatment of PHN and HIV peripheral neuropathy .
Third Line Treatment
- Strong opioids (particularly oxycodone and morphine) have weak recommendations for use and are recommended as third line. Prescription of opioids should be strictly monitored particularly for patients requiring high dosages .
- Botulinum toxin (BoNT) is a potent neurotoxin produced by Clostridium botulinum, which blocks acetylcholine release at neuromuscular junctions causing muscle relaxation. The mechanism of action of BoNT in NP is related to the inhibition of the release of neurotransmitters and neuropeptides involved in pain mechanisms and inflammation (substance P, CGRP, glutamate). BoNT/A seems helpful in TN, PHN, painful diabetic neuropathy (PDN), occipital neuralgia, post-surgical pain and in SCI-related pain. However, ore studies are needed to confirm the efficacy, tolerability, and dose of BoNT.
- Oro mucosal cannabinoids are prepared from extracts of the plant cannabis sativa . Delta-9-tetrahydrocannabinol (THC), a partial agonist of cannabinoid type 1 (CB1) and type 2 (CB2) receptors, mimics the effects of endogenous cannabinoids. Activation of cannabinoid receptors by endogenous or extraneously administered cannabinoids has multiple analgesia-associated effects mediated by the peripheral and central nervous systems . The quantity and quality of evidence are such that cannabis-based medicines may be reasonably considered for chronic neuropathic pain . Patients must be kept under close clinical surveillance, mainly because of negative results, potential misuse, abuse, diversion, and long-term mental health risks.
Fourth Line Treatment
- For those patients with neuropathic pain who are unable to achieve an acceptable quality of life, neurostimulation is a treatment option .

20402746 31152178

20194146 25575710

25479151

17177582

20402746

31152178

25479151

29737410

31190965

25575710

31152178

28530786

25575710

25479151

28837075

32104061

30074291

31152178

· GABAPENTINOIDS

Gabapentin:

Level Grade PMID Nº

31152178

· TOPICALS (FOCAL NEUROPATHIC PAIN)

5% lidocaine:

Level Grade PMID Nº

31152178

Dose: Slow titration up to 600mg 8h/8h, until max daily dose of 3600mg.
Cautions: Reduce dose for renal impairment.

Pregabalin:

Dose: Start at 150mg 12h/12h or 8h/8h, until max daily dose of 600mg.
Cautions: Reduce dose for renal impairment.

· ANTIDEPRESSANT AGENTS

Nortriptyline (TCA):

Dose: Start at 10–25mg before bed, until max daily dose of 150 mg.
Cautions: Autonomic neuropathy, urinary retention, glaucoma.

Amitriptyline (TCA):

I High 25575710

29737410

31152178

I High 29737410

I High 31152178

Most useful for postherpetic neuralgia. I
Dose: Available in cream or patch. Apply to site of pain 12 hours on, 12 hours off, until max of three patches at one time.
Cautions: Virtually has no systemic side effects.

8% capsaicin:

Most useful for postherpetic neuralgia (PHN). I
Dose: Apply for 60 minutes under supervision of a physician.
Cautions: Avoid in diabetic peripheral neuropathy. Is painful on initial application, and its efficacy depends on regular consistent use.

Low 20194146

25479151

20402746

25575710

31152178

High 20194146

25479151

20402746

25575710

- Dose: Start at 10–25mg before bed, until max daily dose of 150 mg. I
- Cautions: More likely to produce drowsiness and anticholinergic side effects.

Mod. 31152178

25575710

WEAK μ-OPIOID AGONISTS AND SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS

Taking SNRI, SSRI, MAOI, and/or tramadol.

Duloxetine (SNRI):

- In the management of chemotherapy-induced painful peripheral neuropathy I showed a significant reduction in pain intensity relative to placebo.
- Dose: Start at 30mg daily, until max daily dose of 60mg.
- Cautions: Renal or liver disease.

Venlafaxine (SNRI):

- Has shown efficacy in trials involving painful diabetic neuropathy and mixed I painful polyneuropathy.
- Dose: Start at 3mg daily, until max daily dose of 60 mg.
- Cautions: Renal or liver disease.

High 31152178

23549581

High 31152178

23549581

Tramadol:

- Most useful for postherpetic neuralgia. I
- Dose: Start at 50mg immediate release from two to four times a day, until max daily dose of 400mg.
- Cautions: Seizure disorder. Taking SNRI, SSRI, TCA, and/or MAOI. Reduce dose for renal impairment.

Tapentadol:

- Some efficacy in DPN. I
Dose: Start with 50mg every 12h, until max of 300–450 mg/day.
Cautions: Constipation.

31152178

Mode 20194146

rate 25479151

20402746

25575710

31152178

Low 20194146

21162697

25575710

31190965

· STRONG OPIOIDS

Morphine:

Level Grade PMID Nº

28530786

CANNABINOIDS

Tetrahydro-cannabinol/cannabidiol:

Level Grade PMID Nº

25575710

- Dose: Start with 15mg every 12h, until max of 120 mg every 12h.
- Cautions: Constipation requiring laxatives. Monitor for addiction.

Oxycodone:

- Dose: Start with 10 mg every 12h, until max of 20–60 mg every 12h.
- Cautions: Constipation requiring laxatives. Monitor for addiction.

I Mod. 21621130

23549581

28530786

I Mod. 21621130

23549581

Dose: Start with 0.25–0.5mg at night; increase weekly by 0.5 mg/day. I
Cautions: Causes positive urine drug testing for cannabinoids. Monitor application site (oral mucosa).

Nabilone:

Dose: Start with 1–2 sprays every 4h, max 4 sprays on day 1; titrate slowly. I
Cautions: Does not test positive for cannabinoids on routine urine drug testing.

Mod. 25479151

32104061

30074291

25575710

Mod. 25479151

32104061

30074291

SOMATIC PAIN

Authors: Helena Isabel Poças da Silva e Sousa and Margarida Bettencourt.

Definition1

Somatic pain is a type of nociceptive pain, typically described as well localized (distribution of the somatic enervation), as aching, stabbing, or pressure. It is defined as a pain resulting from the reduced irritability threshold in nociceptors located in superficial (cutaneous pain from skin cancer) or deep structures (muscles, bone marrow infiltration).

Symptoms2,3,4

Musculoskeletal pain – Pain caused by metastasis to the bone is the most common source of moderate and severe cancer pain
Referred pain
BTcP – transient pain exacerbation that can occur in patients with stable and adequately controlled background pain.

Etiology2

Pain syndromes are divided into those arising from

A direct effect of a neoplasm on nearby tissues and structures (85%) – invasion of the skin, connective tissue, bone, or joints
side effect of a treatment (17%) – mucositis resulting from radiation or chemotherapy, postsurgical incisional pain or spasm of muscle from tissue damage
pain due to disease progression (9%),
and pain from other causes not related to malignancy.

Studies5,6

Assess the components of the pain.

Observation of pain-related behaviours and discomfort is indicated in patients with cognitive impairment to assess the presence of pain [V, C]

Evidence

Level Grade PMID Nº

Description of the pain quality.

Presence of trigger factors and signs and symptoms associated with the pain; Presence of relieving factors.
Use of analgesics and their efficacy and tolerability.
Impact in the patient daily life.

The assessment of all components of suffering, such as psychosocial distress, should be considered and evaluated [II, B]

Treatment7, 8, 9, 10, 11, 2

A comprehensive and holistic approach to the treatment of cancer pain is a standard of care. This would include pharmacologic as well as nonpharmacologic modalities. Many chronic pain syndromes are mixed, thus requiring a combination of treatment approaches and medications targeting a variety of nociceptor sites. The WHO proposes a strategy for cancer pain treatment based on a sequential three-step analgesic ladder, from non-opioids to weak opioids to strong opioids, according to pain intensity.

Treatment strategy

Step I – mild pain

Non-opioids

Evidence

Level Grade PMID Nº

30052758

- Paracetamol (acetaminophen): analgesic and antipyretic. It has hepatic and renal toxicity. It was insufficient evidence to support use of paracetamol in combination with step 3 opioids
- Nonsteroidal anti-inflammatory drugs [NSAIDs] – side effect profile problematic in high-risk groups – gastrointestinal bleeding, vascular risks and nephrotoxicity. There is no significant evidence to support or refute the use of NSAIDs alone or in combination with opioids for mild to moderate pain.

Asystematic review of the safety and efficacy of NSAIDs in cancer pain found NSAIDs to be approximately equivalent to 5 to 10mg intramuscular morphine.

- Adjuvant analgesics work at different levels to relieve pain.

Step II – moderate pain

“Weak” opioids“

For mild to moderate pain, weak opioids such as tramadol, dihydrocodeine and codeine can be given in combination with non-opioid analgesics.

- Tramadol – Up to 10% of patients are slow metabolizers and derive a weaker analgesic effect.

In the dose 100 mg causes similar analgesia to 10 mg of morphine when the drugs are given orally. Advertencies:

1. Side effects: dizziness, nausea, vomiting and constipation
2. Affects serotonin metabolism or availability, potentially leading to serotonin toxicity (particularly in the elderly), and can lower seizure thresholds
- Codeine – has no or little analgesic effect until metabolised to morphine, mainly via CYP2D6 (ineffective in poor metabolisers).

After oral administration, 60 mg DHC analgesic activity is similar to 10 mg of morphine. Prescribed as both an analgesic and an antitussive agent. Advertencies:

Side effects: nausea, vomiting and constipation.
Hypersensitivity, asthma, DPOC, respiratory depression.
Low metabolizers with 5 to 10% of patients having no clinical benefit.

Step III – severe pain

Low-dose formulations of strong opioids

There is no evidence of increase in adverse effects from the use of low-dose strong opioids instead of the standard step 2 approach with weak opioids

I C 30052758

I C 32119322 28220448

19117155 21448038

22126843 29432225

I C 30052758

21448038

I C 28326952 10388250

3 C 30052758

3 C 28220448 21448038

20935619 22300860

20946274

30052758

20946274

31166900

2 C 30052758

Level Grade PMID Nº

Morphine is the opioid of first choice for moderate to severe cancer pain. I

The average relative potency ratio of oral to i.v. morphine is between 1:2 and 1:3. 2

The average relative potency ratio of oral to s.c. morphine is between 1:2 and 1:3. 4

M6G is an active metabolite that contributes significantly to morphine’s analgesic effects, whereas M3G is inactive as an analgesic, but may cause paradoxical central neuroexcitatory effects.

Large presystemic elimination (in gut wall and liver). Advertencies:

1. adjustment of doses is required in renal dysfunction.Drug interactions: Ranitidine, rifampicin, valspodar. 2

Oxycodone – The analgesic effect seems to have less individual variability compared to codeine. There is a lack of good evidence to support the use of oxycodone over morphine. Compared with morphine showed less sedation, delirium, vomit and itching, and less constipation in the association with naloxone.

It is extensively metabolized to nor oxycodone, oxymorphone, and their glucuronides. Nor oxycodone is reported to be a considerably weaker analgesic than oxycodone.

Hydrocodone – some patients are slow or fast metabolizers causing problems of variability with analgesic efficacy and toxicity. Hydrocodone is commonly combined with paracetamol, limiting the maximum allowable dose that can be administered.
Hydromorphone – rapid onset and increased potency (high lipophilicity). Unlike other opioids, hepatic metabolism is independent of the CYP450 isoenzymes. The renally excreted metabolite hydromorphone-3-glucuronide can accumulate (excitatory neurotoxic effects including myoclonus and restlessness). It absorbed in colon.
Hydromorphone – rapid onset and increased potency (high lipophilicity). Unlike other opioids, hepatic metabolism is independent of the CYP450 isoenzymes. The renally excreted metabolite hydromorphone-3-glucuronide can accumulate (excitatory neurotoxic effects including myoclonus and restlessness). It absorbed in colon.

Very little data on potential interactions. 4

Without immunosuppressor effect. 2a

Fentanyl – much rapid onset and greater potency due to its lipophilicity (can be administered intravenous, subcutaneous, as well as intrathecally). Transdermal patch is frequently used when cannot be administered orally – The t.d. route is usually contraindicated during the titration phase, in opioid-naive patients or to control BTcP.

Safe to use in hepatic insufficiency. Advertencies:

Buprenorphine – In some trials, intramuscular buprenorphine is 25 times more potent than intramuscular morphine, and sublingual buprenorphine is 15 times more potent than intramuscular morphine.

Advertencies:

Risk of prolonged QT with doses >20mcg/h.
Precaution in respiratory disease, hypothyroidism, mixedeme, Addison Disease, central nervous system disease
Is not expected to cause significant alteration of other drugs’ metabolism because of the low plasma concentrations reached after transdermal application. Fentanyl TD and buprenorphine TD can be useful in patients with nausea, vomiting, problems with swallowing, constipation and poor compliance.

Fentanyl and buprenorphine (via the t.d. or i.v. route) are the safest opioids in patients with chronic kidney disease stages 4 or 5 (estimated glomerular filtration rate < 30 3

mL/min)

Tapentadol – it is a more potent mu-receptor agonist and a noradrenaline reuptake inhibitor, although a much weaker serotonin reuptake inhibitor – better adverse effect profile (because it has low plasma protein binding activity and is not metabolized by the CYP system). It proved non-inferior to standard opioids like morphine or oxycodone in the management of moderate-to-severe cancer pain.

Proved efficacy in nociceptive and neuropathic pain.

A 30052758

C 30052758

28220448 21448038

B 18503626

31166900

18503626

28220448 21448038

32302346

28220448 21448038

32302346

18503626

32302346 18503626

30052758

32302346

32302346 18503626

28220448 32909847

16010532 18503626

30052758 22300860

28220448

B 30052758

28220448 31190966

34471056

31166900

Advertencies:

1. Nausea, vomiting, somnolence, and dizziness
2. Should not be associated with buprenorphine, SSRI (associated with serotoninergic syndrome), cetoconazol or fluconazole (excretion inhibition of Tapentadol)
Methadone – treatment of complex pain associated with advanced cancer and neuropathic pain syndromes in which conventional opioids were no longer effective. Its big concern is the individual variability in metabolism and the difficulty in titrating the correct dose.

Adverse effects: myoclonus, sedation, confusion, nausea and vomiting.

A different opioid should be considered in the absence of adequate analgesia (despite opioid dose escalation) or in the presence of unacceptable opioid side effects. Step IV – interventional approaches: nerve blocks, neurolytic blocks and intrathecal drug delivery	3	C	30052758
Interventional techniques include nerve blocks, neurolytic blocks (including spinal neurolytic blocks and cordotomy) and intrathecal (i.t.) drug delivery (spinal or epidural).
Employed to provide an immediate pain control after surgical procedures and to alleviate refractory chronic oncologic pain when oral analgesics fail to provide a satisfactory pain			30320541
relief, or when is hindered by debilitating adverse effects of the medications.
These interventional strategies are not appropriate in patients with infections, coagulopathy or very short life expectancy.
Intrathecal drug delivery	2	B	30052758
Intraspinal techniques (both epidural and intrathecal routes) should be considered when patient experiences pain in head and neck, upper and lower extremities, and trunk,
although it is more likely to be useful for pain below the diaphragm.
This form of pain relief includes percutaneous catheters, tunnelled catheters, and implantable programmable pumps.
When compared with epidural, i.t. drug delivery presents fewer catheter problems, smaller drug dose requirement and fewer adverse effects.
Peripheral nerve blocks – when pain occurs in the field of one or more peripheral nerves, or if pain is caused by complications such as pathological fracture or vascular			28265859
occlusion.
Used together with systemic combined analgesia.
Neurolytic blockade – limited to patients with short life expectancy (produce a block lasting 3– 6months).
It can be used for the sympathetic system for visceral pain as well as for spinal neurolytic purposes for somatic pain. Spinal neurolytic blocks are used when pain is localised to a
few dermatomes.
Spinal neurolytic blocks: for focal somatic pain in a small number of dermatomes.
Side effects of this neuroablative technique includes numbness or dysesthesia.
Cordotomy (also called spinothalamic tractotomy) should be considered in patients with poorly controlled cancer-related pain.	5	C	30052758
It results in selective reduction of pain and temperature perception on the contralateral side, up to several segments below the level of the disruption – via percutaneous, open,			28265859

Level Grade PMID Nº

31166900

32874036 32599153

32564328

endoscopic, or trans discal approach.

The use of open cordotomy has diminished significantly in recent years because of the advent of other less invasive approaches.

Other therapies

For advanced cancer patients with pain not fully alleviated by opioid therapy, the additive effect of different cannabis-based therapies to the ongoing opioid treatment remains 2 D unclear.

30320541

30052758

28934780

Farmacotherapy Level GradeEvidence

PMID Nº

Step I

Paracetamol: 500-1000mg (PO or IV). 4000mg/24h. It can be combined with codeine or tramadol (step II) 2 B
Metamizol: 500-2000 mg (PO or IM) each 8h; rectal route 1g/6-12h. 8000mg/24h.
Ibuprofen: 200-600mg/per os/6-8h. 1200mg/24h. I A
Cetorolac: 10-30mg/PO/6h; 10mg/IM/single dose; 30mg/rectal route/single dose. 40mg/24h. 1b A Cetorolac 10mg/IM/single dose is as effective as cetorolac 30mg/IM/single dose.
If CV risk factors, should be prescribed naproxen (1 g/24 h) or low dose ibuprofen (<1200 mg/24 h). If high risk of upper GI complications, NSAIDs should be avoided; for those in whom it is essential, celecoxib (200 mg/24 h) plus a proton pump inhibitor has been recommended.

WHO step II

Codeine: 30mg/PO/4-6h. Maximum dose 240mg/24h PO (because of association with paracetamol). If > 360mg/24h, should be done rotation to a strong opioid (step III) 2a B
Tramadol: prolonged release, 400mg/24h PO. IV dose is about 50% of the oral dose.

WHO step III

Morphine: PO treatment should be started with immediate release 5mg (if opioid naïve) or 10mg (if opioid tolerant). In PO treatment manutention the modified-release are I A preferred: start with 10-30mg in 12/12h. If IV, IM or SC route used: 10-20mg/mL. 60mg/24h PO, 30mg/24h SC.

Starting a low-dose strong opioid (e.g., ≤30 mg/day oral morphine) has been shown to give better pain relief than using weak opioids such as codeine

maintained for 24 h, then changed to oral or transdermal administration.

If the pain improves, the dose should be calculated for 24 h and divided into 4-6 h intervals.

Oxycodone: 30-40mg/24h PO.
Hydromorphone: initial dose of 4mg/24h and increment of 4-8mg/24h.
Oxycodone or hydromorphone, in both immediate-release and modified-release formulations for oral administration.

There are no differences between morphine, oxycodone, and hydromorphone. Treatment typically starts with immediate-release doses every 4 h.

Fentanyl TD: 600mcg/24h = 25 mcg/h patch. Effective systemic analgesic concentrations reached in 3-24h (steady state plasma concentrations 36-48h). Similar absorption in thorax, abdomen, and thigh (rotation of the region in each application).
Buprenorphine TD – 600 mcg/24 h = 25 mcg/h patch. Analgesic effect in 30 minutes. Similar absorption in thorax, abdomen, and thigh (rotation of the region in each application).
Tapentadol: prolonged release, start with 50mg 12/12h.

Doses of Tapentadol may be increased at least up to 400-500 mg/day, which corresponds to the range of 60-150 mg/day of oral morphine equivalents.

Methadone is available as a liquid suspension (5mg/ml) and oral tablet (5mg, 10mg) which is administered by oral, buccal, sublingual routes and less preferred being rectal, intravenous, subcutaneous, and intrathecal routes.
A different opioid should be considered in the absence of adequate analgesia (despite opioid dose escalation) or in the presence of unacceptable opioid side effects.
if despite opioid titration the patient experiences pain scoring >4 on an 11-point numeric rating scale and adverse drug reactions occur, namely nausea for >1 week or sedation for more than 2 to 3 days. If refractory obstipation occurs, rotation to fentanyl or methadone is explicitly recommended.
The SC route is simple and effective for the administration of morphine, diamorphine and hydromorphone and it should be the first-choice alternative route for patients unable to 3 B receive opioids by oral or TD routes.

2196536

15654708

9620101 31800611

29436434

31166900	29436434
	29436434
29436434	30052758
	29436434
30052758	28326952
	29436434
	31166900
30052758	28326952
22300860	28220448
	29436434
29436434	31166900
	31166900
30052758	22300860
32874036	32599153
	32564328
	30052758
	29563006
	30052758

IV infusion should be considered when SC administration is contraindicated (peripheral oedema, coagulation disorders, poor peripheral circulation and need for high volumes and doses).
IV administration is an option for opioid titration when rapid pain control is needed.

Fourth step WHO ladder: nerve blocks, neurolytic blocks and intrathecal drug delivery

Intrathecal drug delivery

Evidence Level Grade PMID Nº

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References

PMID: 31085106. Russo, M.M, Sundaramurthi, T. An Overview of Cancer Pain: Epidemiology and Pathophysiology. Semin Oncol Nurs, 2019. doi: 10.1016/j.soncn.2019.04.002.
PMID: 12703331. Burton AW. Acute, Chronic, and Cancer Pain: Clinical Management. Methods Mol Med. 2003. DOI: 10.1385/1-59259-379-8:267 3. PMID: 24799469
PMID: 30052758. Fallon M, Giusti R, Aielli F, Hoskin P, Rolke R, Sharma M, Ripamonti C.I. Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines. European Society for Medical Oncology, 2018. DOI: 10.1093/annonc/mdy152.
PMID: 31980005. Chapman, E.J., Edwards, Z., Boland, J.W., Maddocks, M., Fettes, L., Malia, C., Et al. Practice review: Evidence-based and effective management of pain in patients with advanced cancer. Palliat Med, 2020. doi: 10.1177/0269216319896955.
PMID: 21856077. Valente, M.A.F., Ribeiro, J.L.P., Jensen, M.P. Validity of four pain intensity rating scales. Pain, 2011. doi: 10.1016/j.pain.2011.07.005.
PMID: 28326952. Lara-Solares, Argelia; Olea, Marisol A.; Pinos, Amparito A.; et al. Latin-American guidelines for cancer pain management. Pain Manag. 2017. DOI: 10.2217/pmt-2017-0006.
PMID: 32119322. Anekar A, Cascella M. WHOAnalgesic Ladder. StatPearls, 2021.
PMID: 28265859. Candido, Kenneth; Kusperm Teresa M.; Knezevic, Nebojsa N. New Cancer Pain Treatment Options. Curr Pain Headache Rep. 2017. DOI: 10.1007/s11916-017-0613-0
PMID: 28220448. Liu, Weiyang C.; Zheng, Zhong X.; Tan, Kian H; Meredith, Gregory J. Multidimensional Treatment of Cancer Pain. Curr Oncol Rep. 2017. DOI: 10.1007/s11912-017-0570-0.
PMID: 7500538. Jadad AR, Browman GP. The WHO analgesic ladder for cancer pain management: Stepping up the quality of its evaluation. JAMA. 1995. Doi:10.1001/jama.1995.03530230056031

VISCERAL PAIN

Authors: Helena Isabel Poças da Silva e Sousa and Margarida Bettencourt. Evidence

Definition1, 2, 3

Visceral pain affects approximately 70% of patients with advanced cancer disease.
It is diffuse and poorly localized, often characterized by ill-defined deep, squeezing, or colicky sensations, includes the involvement of multiple luminal organs at once, with visceral differentiation often relying on the determination of associated pathology and changes in organ function.

Symptoms4, 5, 3

Visceral pain is often associated with dysautonomia including pallor, sweating, nausea or vomiting, and cardiovascular perturbations.
Acute pain syndromes – related directly to the cancer or to antineoplastic therapy, or to diagnostic or therapeutic interventions.
Breakthrough cancer pain (BTcP), defined as ‘a transitory flare of pain that occurs on a background of relatively well-controlled baseline pain’, requires careful assessment and appropriate management. Typical BTcP episodes are of moderate to severe intensity, rapid in onset (minutes) and of relatively short duration (median 30 minutes).

Level Grade PMID Nº

Etiology1, 3, 6, 7

Neoplasms generate visceral pain through numerous mechanisms including chemical release from cancer and immune cells, distension or obstruction of luminal organs, and direct nerve compression or infiltration.
Localization is challenging due to the low density of visceral sensory innervation and secondary hyperalgesia caused by referral to parietal somatic structures.
Mechanisms continue to be poorly understood but are generally thought to involve sensitization of primary sensory afferent innervating visceral organs, dysregulation of descending pathways that modulate spinal nociceptive transmission, and hyperexcitability of spinal ascending neurons that receive synaptic input from the viscera.

Studies 8, 9

Assess the components of the pain: Causes, onset, type, site, absence/presence of radiating pain, duration, intensity, relief and temporal patterns of the pain, number of BTcPs, pain syndrome, inferred pathophysiology, pain at rest and/or moving

The intensity of pain and the treatment outcomes should be assessed regularly and consistently using the VAS or NRS using the question: ‘What has been your worst pain in the last 24 hours?’ [V, D]
Observation of pain-related behaviours and discomfort is indicated in patients with cognitive impairment to assess the presence of pain [V, C]

Description of the pain quality:
- - Aching, throbbing, pressure: often associated with somatic pain in skin, muscle and bone
  - Aching, cramping, gnawing, sharp: often associated with visceral pain in organs or viscera
  - Shooting, sharp, stabbing, tingling, ringing: often associated with NP caused by nerve damage
Presence of trigger factors and signs and symptoms associated with the pain, Presence of relieving factors
Use of analgesics and their efficacy and tolerability
Impact in the patient daily life

The assessment of all components of suffering, such as psychosocial distress, should be considered and evaluated [II, B]

Evidence

Level Grade PMID Nº

1. Assess the components of the pain

Observation of pain-related behaviours and discomfort is indicated in patients with cognitive impairment to assess the presence of pain [V, C]

Evidence Level Grade PMID Nº

2. Description of the pain quality

Aching, throbbing, pressure: often associated with somatic pain in in skin, muscle, and bone.

Aching, cramping, gnawing, sharp: often associated with visceral pain in organs or viscera. Shooting, sharp, stabbing, tingling, ringing: often associated with NP caused by nerve damage

3. Presence of trigger factors and signs and symptoms associated with the pain; Presence of relieving factors

4. Use of analgesics and their efficacy and tolerability

5. Impact in the patient daily life

The assessment of all components of suffering, such as psychosocial distress, should be considered and evaluated [II, B]

Treatment 10, 11, 12, 13, 14, 15

A comprehensive and holistic approach to the treatment of cancer pain is a standard of care. This would include pharmacologic as well as nonpharmacologic modalities. Many chronic pain syndromes are mixed, thus requiring a combination of treatment approaches and medications targeting a variety of nociceptor sites. The WHO proposes a strategy for cancer pain treatment based on a sequential three-step analgesic ladder, from non-opioids to weak opioids to strong opioids, according to pain intensity.

Treatment strategy

Step I – mild pain

Non-opioids

Paracetamol (acetaminophen): analgesic and antipyretic. It has hepatic and renal toxicity. I There was insufficient evidence to support use of paracetamol in combination with step 3 opioids.
Nonsteroidal anti-inflammatory drugs [NSAIDs] – side effect profile problematic in high-risk groups – gastrointestinal bleeding, vascular risks and nephrotoxicity. There is no significant evidence to support or refute the use of NSAIDs alone or in combination with opioids for mild to moderate pain.

Asystematic review of the safety and efficacy of NSAIDs in cancer pain found NSAIDs to be approximately equivalent to 5 to 10mg intramuscular morphine. I

Adjuvant analgesics work at different levels to relieve pain.

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Step II – moderate pain

Weak” opioids

Evidence

Level Grade PMID Nº

For mild to moderate pain, weak opioids such as tramadol, dihydrocodeine and codeine can be given in combination with non-opioid analgesics. 3

Tramadol – Up to 10% of patients are slow metabolizers and derive a weaker analgesic effect.

In the dose 100 mg causes similar analgesia to 10 mg of morphine when the drugs are given orally. Advertencies:

1. Side effects: dizziness, nausea, vomiting and constipation
2. Affects serotonin metabolism or availability, potentially leading to serotonin toxicity (particularly in the elderly) and can lower seizure thresholds.
Codeine – has no or little analgesic effect until metabolised to morphine, mainly via CYP2D6 (ineffective in poor metabolisers).

After oral administration, 60 mg DHC analgesic activity is like 10 mg of morphine. Prescribed as both an analgesic and an antitussive agent. Advertencies:

Side effects: nausea, vomiting and constipation.
Hypersensitivity, asthma, DPOC, respiratory depression.
Low metabolizers with 5 to 10% of patients having no clinical benefit.

Step III – severe pain

Low-dose formulations of strong opioids. 2

There is no evidence of increase in adverse effects from the use of low-dose strong opioids instead of the standard step 2 approach with weak opioids

Morphine is the opioid of first choice for moderate to severe cancer pain. I

The average relative potency ratio of oral to IV morphine is between 1:2 and 1:3. 2

The average relative potency ratio of oral to SC morphine is between 1:2 and 1:3. 4

M6G is an active metabolite that contributes significantly to morphine’s analgesic effects, whereas M3G is inactive as an analgesic, but may cause paradoxical central neuroexcitatory effects.

Large presystemic elimination (in gut wall and liver). Advertencies:

Adjustment of doses is required in renal dysfunction.

Drug interactions: Ranitidine, rifampicin, valspodar. 2

Oxycodone – The analgesic effect seems to have less individual variability compared to codeine. There is a lack of good evidence to support the use of oxycodone over morphine.

Compared with morphine showed less sedation, delirium, vomit and itching, and less constipation in the association with naloxone.

It is extensively metabolized to nor oxycodone, oxymorphone, and their glucuronides. Nor oxycodone is reported to be a considerably weaker analgesic than oxycodone.

Hydrocodone – some patients are slow or fast metabolizers causing problems of variability with analgesic efficacy and toxicity. Hydrocodone is commonly combined with paracetamol, limiting the maximum allowable dose that can be administered.
Hydromorphone – rapid onset and increased potency (high lipophilicity). Unlike other opioids, hepatic metabolism is independent of the CYP450 isoenzymes. The renally excreted metabolite hydromorphone-3-glucuronide can accumulate (excitatory neurotoxic effects including myoclonus and restlessness).

It is absorbed in the colon.Very little data on potential interactions. 4

Without immunosuppressor effect. 2a

Fentanyl – much rapid onset and greater potency due to its lipophilicity (can be administered intravenous, subcutaneous, as well as intrathecally). Transdermal patch is frequently used when cannot be administered orally – The TD route is usually contraindicated during the titration phase, in opioid-naive patients or to control BTcP.

Safe to use in hepatic insufficiency.

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Advertencies:

1. Concomitant use with potent CYP P450 3A4 inhibitors (ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazodone) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.
Buprenorphine –In some trials, intramuscular buprenorphine is 25 times more potent than intramuscular morphine, and sublingual buprenorphine is 15 times more potent than intramuscular morphine.

Advertencies:

Risk of prolonged QT with doses >20mcg/h.
Precaution in respiratory disease, hypothyroidism, mixedeme, Addison Disease, central nervous system disease
Is not expected to cause significant alteration of other drugs’ metabolism because of the low plasma concentrations reached after transdermal application. Fentanyl TD and buprenorphine TD can be useful in patients with nausea, vomiting, problems with swallowing, constipation and poor compliance.

Level Grade PMID Nº

32302346 18503626

28220448 32909847

16010532 18503626

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Fentanyl and buprenorphine (via the t.d. or i.v. route) are the safest opioids in patients with chronic kidney disease stages 4 or 5 (estimated glomerular filtration rate < 30 mL/min)

Tapentadol – it is a more potent mu-receptor agonist and a noradrenaline reuptake inhibitor, although a much weaker serotonin reuptake inhibitor – better adverse effect profile 3

Proved efficacy in nociceptive and neuropathic pain. Advertencies:

Nausea, vomiting, somnolence, and dizziness
Should not be associated with buprenorphine, SSRI (associated with serotoninergic syndrome), cetoconazol or fluconazole (excretion inhibition of Tapentadol)

Methadone – treatment of complex pain associated with advanced cancer and neuropathic pain syndromes in which conventional opioids were no longer effective. Its big concern is the individual variability in metabolism and the difficulty in titrating the correct dose.

Adverse effects: myoclonus, sedation, confusion, nausea, and vomiting

A different opioid should be considered in the absence of adequate analgesia (despite opioid dose escalation) or in the presence of unacceptable opioid side effects. 3

Step IV – interventional approaches: nerve blocks, neurolytic blocks and intrathecal drug delivery

These interventional strategies are not appropriate in patients with infections, coagulopathy, or very short life expectancy.

- Intrathecal drug delivery

This form of pain relief includes percutaneous catheters, tunnelled catheters, and implantable programmable pumps.

When compared with epidural, i.t. drug delivery presents fewer catheter problems, smaller drug dose requirement and fewer adverse effects.

- Peripheral nerve blocks – when pain occurs in the field of one or more peripheral nerves, or if pain is caused by complications such as pathological fracture or vascular occlusion.

Used together with systemic combined analgesia.

- Neurolytic blockade– limited to patients with short life expectancy (produce a block lasting 3– 6months).

It can be used for the sympathetic system for visceral pain as well as for spinal neurolytic purposes for somatic pain. Spinal neurolytic blocks are used when pain is localised to a few dermatomes.

B 18503626

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Level Grade PMID Nº

Coeliac plexus block (CPB) is useful when pain is of visceral aetiology only, and due to cancer in the upper abdomen or pancreas. 2

The use of open cordotomy has diminished significantly in recent years because of the advent of other less invasive approaches.

Other therapies

For advanced cancer patients with pain not fully alleviated by opioid therapy, the additive effect of different cannabis-based therapies to the ongoing opioid treatment remains 2

unclear.

Farmacotherapy

Step I

Paracetamol: 500-1000mg (PO or IV). Maximum dose of 4000mg/24h. It can be combined with codeine or tramadol (step II) 2
Metamizol: 500-2000 mg (PO or IM) each 8h; rectal route 1g/6-12h. 8000mg/24h.
Ibuprofen: 200-600mg/per os/6-8h. 1200mg/24h (maximum dose). I
Cetorolac: 10-30mg/PO/6h; 10mg/IM/single dose; 30mg/rectal route/single dose. 40mg/24h (maximum dose). Ib Cetorolac 10mg/IM/single dose is as effective as cetorolac 30mg/IM/single dose.
If CV risk factors, should be prescribed naproxen (1 g/24 h) or low dose ibuprofen (<1200 mg/24 h). If high risk of upper GI complications, NSAIDs should be avoided; for those in whom it is essential, celecoxib (200 mg/24 h) plus a proton pump inhibitor has been recommended.

WHO step II

Codeine: 30mg/PO/4-6h. Maximum dose 240mg/24h PO (because of association with paracetamol). If > 360mg/24h, should be done rotation to a strong opioid (step III) 2a
Tramadol: prolonged release, 400mg/24h PO. IV dose is about 50% of the oral dose.

WHO step III

- Morphine: PO treatment should be started with immediate release 5mg (if opioid naïve) or 10mg (if opioid tolerant). In PO treatment manutention the modified-release are I

preferred: start with 10-30mg in 12/12h. If IV, IM or SC route used: 10-20mg/mL. 60mg/24h PO, 30mg/24h SC.

Starting a low-dose strong opioid (e.g., ≤30 mg/day oral morphine) has been shown to give better pain relief than using weak opioids such as codeine

The NCCN Guidelines (2015) recommend starting with immediate-release oral morphine or equivalents at 5–15 mg. If pain does not diminish or increases, the dose should be 2

increased by 50–100%; if pain decreases, but remains severe, the same dose should be repeated, up to a maximum of three doses. If pain decreases, the same dose should be

maintained for 24 h, then changed to oral or transdermal administration.

If the pain improves, the dose should be calculated for 24 h and divided into 4–6 h intervals.

Oxycodone: 30-40mg/24h PO.
Hydromorphone: initial dose of 4mg/24h and increment of 4-8mg/24h.
Oxycodone or hydromorphone, in both immediate-release and modified-release formulations for oral administration.

There are no differences between morphine, oxycodone, and hydromorphone. Treatment typically starts with immediate-release doses every 4 h.

Fentanyl TD: 600mcg/24h = 25 mcg/h patch. Effective systemic analgesic concentrations reached in 3-24h (steady state plasma concentrations 36-48h). Similar absorption in thorax, abdomen, and thigh (rotation of the region in each application).

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Level Grade PMID Nº

Buprenorphine TD – 600 mcg/24 h = 25 mcg/h patch. Analgesic effect in 30 minutes. Similar absorption in thorax, abdomen, and thigh (rotation of the region in each 2a application).
Tapentadol: prolonged release, start with 50mg 12/12h.

Doses of Tapentadol may be increased at least up to 400-500 mg/day, which corresponds to the range of 60-150 mg/day of oral morphine equivalents.

Methadone is available as a liquid suspension (5mg/ml) and oral tablet (5mg, 10mg) which is administered by oral, buccal, sublingual routes and less preferred being rectal, intravenous, subcutaneous, and intrathecal routes.
A different opioid should be considered in the absence of adequate analgesia (despite opioid dose escalation) or in the presence of unacceptable opioid side effects (namely nausea for >1 week or sedation for more than 2 to 3 days).

If refractory obstipation occurs, rotation to fentanyl or methadone is explicitly recommended.

The SC route is simple and effective for the administration of morphine, diamorphine and hydromorphone and it should be the first-choice alternative route for patients unable to 3 receive opioids by oral or TD routes.
IV infusion should be considered when SC administration is contraindicated (peripheral oedema, coagulation disorders, poor peripheral circulation and need for high volumes and doses).
IV administration is an option for opioid titration when rapid pain control is needed.

Fourth step WHO ladder: nerve blocks, neurolytic blocks and intrathecal drug delivery

Intrathecal drug delivery

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References

PMID: 30822530. Mercadante S.; Adile C.; Masedu F; Valenti M; Aielli F. Breakthrough Cancer Pain in Patients With Abdominal Visceral Cancer Pain. J Pain Symptom Manage, 2019. DOI: 10.1016/j.jpainsymman.2019.02.014
PMID 30379615. Grundy L; Erickson A; Brierley S.M. Visceral Pain. Annu Rev Physiol, 2019. DOI: 10.1146/annurev-physiol-020518-114525
PMID: 33961156. Hao D; Sidharthan S; Cotte J; Decker M; Orhurhu M.S.; Olatoye D; et al. Interventional Therapies for Pain in Cancer Patients: a Narrative Review. Curr Pain Headache Rep, 2021. doi: 10.1007/s11916-021-00963-2.
PMID: 29729775. Portenoy R.; Ahmed E. Cancer Pain Syndromes. Hematol Oncol Clin North Am, 2018. DOI: 10.1016/j.hoc.2018.01.002
PMID: 30052758. Fallon M, Giusti R, Aielli F, Hoskin P, Rolke R, Sharma M, Ripamonti C.I. Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines. European Society for Medical Oncology, 2018. DOI: 10.1093/annonc/mdy152.
PMID: 21243067. Wesselmann U; Baranowski A.P.; Borjesson M; Curran N.C; et al. EMERGING THERAPIES AND NOVEL APPROACHES TO VISCERAL PAIN. Drug Discov Today Ther Strateg, 2009. doi: 10.1016/j.ddstr.2009.05.001.
PMID: 30042373. Yam, Mun Fei; Loh, Yean Chun; Tan, Chu Shan; Adam, Siti K.; Manan, Nizar A.; Basir, Rusliza. General Pathways of Pain Sensation and the Major Neurotransmitters Involved in Pain Regulation. Int J Mol Sci. 2018. DOI: 10.3390/ijms19082164.
PMID: 31980005. Chapman, E.J., Edwards, Z., Boland, J.W., Maddocks, M., Fettes, L., Malia, C., Et al. Practice review: Evidence-based and effective management of pain in patients with advanced cancer. Palliat Med, 2020. doi: 10.1177/0269216319896955.
PMID: 21856077. Valente, M.A.F., Ribeiro, J.L.P., Jensen, M.P. Validity of four pain intensity rating scales. Pain, 2011. doi: 10.1016/j.pain.2011.07.005.
PMID: 28326952. Lara-Solares, Argelia; Olea, Marisol A.; Pinos, Amparito A.; et al. Latin-American guidelines for cancer pain management. Pain Manag. 2017. DOI: 10.2217/pmt-2017-0006.
PMID: 32119322. Anekar A, Cascella M. WHOAnalgesic Ladder. StatPearls, 2021.
PMID: 28265859. Candido, Kenneth; Kusperm Teresa M.; Knezevic, Nebojsa N. New Cancer Pain Treatment Options. Curr Pain Headache Rep. 2017. DOI: 10.1007/s11916-017-0613-0
PMID: 28220448. Liu, Weiyang C.; Zheng, Zhong X.; Tan, Kian H; Meredith, Gregory J. Multidimensional Treatment of Cancer Pain. Curr Oncol Rep. 2017. DOI: 10.1007/s11912-017-0570-0.
PMID: 7500538. Jadad AR, Browman GP. The WHO analgesic ladder for cancer pain management: Stepping up the quality of its evaluation. JAMA. 1995. Doi:10.1001/jama.1995.03530230056031
PMID: 12703331. Burton, AW. Acute, chronic, and cancer pain. Clinical management. Methods Mol Med. 2003. DOI: 10.1385/1-59259-379-8:267

IRRUPTIVE PAIN

Authors: Tomás Cabral Dinis, André Pires and Bruno Moura Fernandes.

Definition

BTcP is associated with poor overall pain control, negatively influencing the quality of life (QoL) of patients and their caregivers (7,12,13).

Symptoms and signs

BTcP can be considered when there are ≤4 episodes per day of well distinguished peaks from background pain intensity (≥7/10) (8,12). These episodes must be acute in onset (< 10 minutes to reach peak intensity) and of relatively short duration (~30 minutes) (2,7,10,12,13). A circadian variation in the occurrence of BTcP exists, with most patients experiencing it during the day (10,13). BTcP often occurs at the same location as the background pain and is referred to with similar qualitatively pain descriptors (10). It can also be described in more than one site, especially in patients with metastatic cancer (14).

Clinical algorithms have been proposed (7) and can be useful in day-to-day clinical practice (Figure 1).

Physical complications: immobility, insomnia
Psychological complications: anxiety, depression.
Social complications: changes in routine activity, unemployment, social isolation.

Etiology

Several classifications have been proposed. BTcP can be classified into (3,7,15):

Spontaneous pain (“idiopathic pain”): episodes are not related to an identifiable precipitant, being unpredictable in nature, requiring a preventive therapy rather than an as needed medication.
Incident pain (“precipitated pain”): episodes are related to an identifiable precipitant, and so are somewhat predictable in nature, giving patient the possibility to take an active role in their pain management:
- Volitional incident pain – is brought on by a voluntary act (e.g., walking in patients with skeletal pain, swallowing in patients with mucositis);
- Non-volitional incident pain – is brought on by an involuntary act (e.g., Valsalva maneuver caused by coughing or sneezing);
- Procedural pain – is related to a therapeutic intervention (e.g., wound dressing, radiotherapy positioning).

Evidence

Level Grade PMID Nº

Studies Level Grade PMID Nº

The assessment of BTcP should include evaluations of both background pain intensity and worst pain intensity. It should start by taking a detailed history focusing on (2,3,9,10,13,14):

Pain assessment:

Type and quality of pain.
Pain history (eg, onset, duration, course);
Pain intensity (ie, pain experienced at rest; with movement) using a verbal numerical scale or visual analogue scale.
Location(s).
Referral pattern.
Radiation of pain.
Associated factors that exacerbate or relieve the pain.
Current pain management plan.
Patient’s pain experience and response to current or prior pain therapies.
Breakthrough or episodic pain inadequately managed with existing pain regimen. Patient assessment:
Clinical situation by means of a thorough physical examination and review of appropriate laboratory and imaging studies.
Presence and intensity of signs, physical and/or emotional symptoms associated with cancer pain syndromes.
Impact of pain (ie, interference with activities such as work, sleep, and interpersonal interactions).
Presence of comorbidities (i.e., diabetic, renal and/or hepatic failure, etc.), alcohol and/or substance abuse.
Performance status.
Psychosocial factors (eg, patient distress, family/caregiver and other support, psychiatric history, risk factors for undertreatment of pain).
Other special issues relating to pain (eg, opiophobia, misconception related to pain treatment, meaning of pain for patient and family/caregiver; cultural beliefs toward pain, spiritual or religious considerations and existential suffering).

Therapeutic Strategy

Initially, cancer patients should have their chronic background pain appropriately controlled, which is conventionally considered to b≤4/10, on a numerical scale 0-10 (8).

There is strong evidence to support individualization of pain treatment due to individual differences in opioid receptors and opioid metabolism (10).

Short acting opioids (SAOs):

Short acting opioids (SAOs) have traditionally been the standard treatment approach for BTcP, with oral formulations of morphine being available (10,16).

If the pain score remains unchanged or is increased: further increase in opioid rescue dose by 50 to 100% is recommended.
If the pain is reduced but still inadequately controlled, the same opioid dose is repeated, and second reassessment should be performed (same time intervals as mentioned before).
If pain score remains unchanged upon reassessment after 2 to 3 cycles of the opioid, in patients with moderate to severe pain, changing the route of administration form p.o. to iv/sc should be considered.
If the pain score decreases to a level where it is adequately controlled, the current effective dose can be continued “as needed” over na initial 24h before proceeding to subsequent management strategies.

Rapid onset opioids (ROOs):

Fentanyl is metabolized by cytochrome enzymes, and any drug that induces or inhibits cytochrome P450 can affect its metabolic conversion (6,10,16).

Opioid-induced adverse effects:

The longer the duration of opioid therapy, the less frequent the adverse effects, fact that can be explainable by the tendency to develop tolerance with prolonged opioid use (12).

Level Grade PMID Nº

Therapeutic Strategy Level GradeEvidence

Fentanyl is metabolized by cytochrome enzymes, and any drug that induces or inhibits cytochrome P450 can affect its metabolic conversion (6,10,16).

Opioid-induced adverse effects:

Opioids AEs are formulation, route of administration and dose related. Most common AEs include nausea, dizziness, somnolence, and less frequently asthenia, constipation, confusion, insomnia, vomiting, peripheral oedema, diarrhoea, and dyspnoea (6,16).They´re also associated with impaired mental and/or physical ability to operate heavy machinery, and patients must be advised against it (19).

The longer the duration of opioid therapy, the less frequent the adverse effects, fact that can be explainable by the tendency to develop tolerance with prolonged opioid use (12).

Immediate-release opioids should be used to treat BTcP that is opioid-responsive and for which background cancer pain management has been optimised.(2,6) I A
Transmucosal fentanyl formulations (oral, buccal, sublingual, and intranasal) have a role in unpredictable and rapid-onset BTcP.(2) I A
There are indications for standard normal-release oral opioids (e.g., morphine) that include a slow-onset BTcP or a pre-emptive administration of oral opioids ~30 minutes 2 B before a predictable BTcP triggered by known events.(2)

Pharmacotherapy

PMID Nº

Breakthrough cancer pain

Short acting opioids (SAOs):

The effective dose of oral opioid preparations used to treat BTcP is calculated as a proportion of the daily dose of opioid a nalgesics administered at fixed intervals (15,17):

Opioid-naïve patients: 5-15mg p.o. or 2-5mg IV morphine sulphate or equivalent.

Note: A sc route of administration can be substituted for IV, but the time to peak effect is generally longer (~30min) (9);

Opioid-tolerant patients, a rescue dose equivalent to 10-20% of the total opioid taken in the previous 24h should be given, every hour as needed during severe exacerbations of pain (4,9).

Morphine sulphate:
- Sevredol® 10, 20mg (tablet).
- Oramorph® 20mg/mL (oral liquid).

Max. dose: –

Administration: oral. Pills can be smashed and swallowed but should not be chewed.

Onset of action: 30-45 minutes.

Bioavailability: 30%.

CI: acute respiratory depression; acute alcoholism; risk of paralytic ileus; raised intracranial pressure or head injury; phaeo chromocytoma.

Rapid onset opioids (ROOs):

Oral transmucosal fentanyl citrate (OTFC-):(15)

o Actiq® 200, 400, 600, 800µg (oral lozenge).

Max. dose: 1600 µg.

Max. frequency: 4 doses/24h (> 4h interval). Max. of 2 doses/episode.

Onset of action: 15 minutes.

Bioavailability: 50%

– Sublingual fentanyl (SLF):(19)

o Vellofent ® 133, 267, 400, 533, 800µg.

o Abstral® 100, 200, 300, 400, 600, 800µg.

Max. dose: 800 µg.

Max. frequency: 4 doses/24h (> 4h interval).

Administration: sublingual. Should not be chewed or swallowed. Prior oral hydration is recommended.

Onset of action: 6-10 minutes; If pain control is not achieved upon 15 -30 min of re-assessment, dose can be repeated without further adverse effects (4).

Bioavailability: 54-70%

– Fentanyl buccal tablet (FBT):(15,19)

o Breakyl® 200, 400, 600, 800, 1200µg (buccal film).

Max. dose: 1200 µg.

Max. frequency: 4 doses/24h (> 2h interval).

Administration: buccal. Should not be chewed or swallowed. Should not be used with more than 4 formulations simultaneously.

Onset of action: 10 minutes.

Bioavailability: 71%

– Intranasal fentanyl spray (INFS):(15)

o PecFent® 100, 200, 400, 800µg/spray.

o Instanyl® 50, 100, 200µg/spray (not available in Portugal).

Max. dose: 800µg/episode.

Max. frequency: 4 inhalations/24h (> 4h interval).

Administration: intranasal.

Onset of action: 5-10 minutes.

Bioavailability: 90-120%

Fentanyl specifications (regardless of route of administrations) (6,16):

I A

toxic psychosis; (patc hes:) increased serum levels in patients with fever >40 °C (104 °F).

Management of opioid-induced adverse eﬀects

Laxatives must be routinely prescribed for both the prophylaxis and the management of opioid -induced constipation (OIC). (2)

Naloxegol (peripherally acting μ -opioid receptor) has been shown to be highly eﬀective in OIC, but to date, there is no speciﬁc reported experience in the cancer population.(2)

Metoclopramide and antidopaminergic drugs should be recommended for treatment of opioid-related nausea/vomiting. (2)

receptor antagonists (e.g. naloxone) must be used promptly in the treatment of opioid-induced respiratory depression. (2)

2 B

1 B

Others

Figure 1. Clinical algorithm for the assessment of breakthrough cancer pain (BTcP). Adapted from (2)

= pain present for ≥ 12h/day

background pain?

Does the patient have

YES

Patient has BTcP.

during previous week (or would

YES NO be if not taking analgesia)

Does the patient have transient exacerbations of pain (≤ 4 /day)?

Patient does not have BTcP but does have uncontrolled background pain.

Is the background pain

adequately controlled (intensity of pain ≤ 4/10)?

Patient does not have BTcP.

Figure 2 . Clinical tools for pain assessment

S ite

O nset

C haracter

R adiation

A ssociated factors

T iming

E xacerbation/relieving factors

Clinical mnemonic on pain characteristics (14).

Numerical Rating Scale. Reprinted from (9).

The Faces Pain Rating Scale. Reprinted from (9).

Route of administration	Drug	Unit	Opioid equi-analgesic dose
Oral	Codeine	mg	60	90	180	210	Has a maximum dose*
	Tramadol		25	50	75	100	150	200	300	400	Has a maximum dose*
	Morphine		5	10	15	20	30	40	60	80	100	120	160	180	200	240	320
	Tapentadol							100	150	200	250	300	400	450	500
	Hydromorphone							8		16		24	32		40	48	64
Transdermal	Buprenorphine	μg/h							35		53	70	88	105		140
Transdermal	Fentanyl	μg/h					12,5		25		38	50	63	75		100	125
IV/s.c.	Morphine	mg			5		10		20		30	40	50	60		80	110
IV/s.c.	Tramadol	mg					100		200
* Maximum dose: 360mg (isolated) or 240mg (associated with paracetamol) ** Maximum dose: 400mg (adult); 300mg (elderly); 150mg (poor performance status, malnutrition)

Table 1: Opioid equi-analgesic conversion table. Adapted from (4,6).

References

Løhre ET, Klepstad P, Bennett MI, Brunelli C, Caraceni A, Fainsinger RL, et al. From “breakthrough” to “episodic” Cancer Pain? A European Association for Palliative Care Research Network Expert Delphi Survey Toward a Common Terminology and Classification of Transient Cancer Pain Exacerbations. Journal of Pain and Symptom Management. 2016 Jun 1;51(6):1013–9.
Fallon M, Giusti R, Aielli F, Hoskin P, Rolke R, Sharma M, et al. Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines. Annals of Oncology. 2018 Oct 1;29:iv166–91.
Mercadante S, Radbruch L, Caraceni A, Cherny N, Kaasa S, Nauck F, et al. Episodic (breakthrough) pain: Consensus conference of an expert working group of the European Association for Palliative Care. Cancer. 2002 Feb 1;94(3):832–9.
Ritto C, Rocha FD, Costa I, Diniz L, Raposo MB, Pina PR, et al. Manual de Dor Crónica. 2a ed. Lisboa; 2017.
Boceta J, de la Torre A, Samper D, Farto M, Sánchez-de la Rosa R. Consensus and controversies in the definition, assessment, treatment and monitoring of BTcP: results of a Delphi study. Clinical and Translational Oncology. 2016 Nov 1;18(11):1088–97.
WHO guidelines for the pharmacological and radiotherapeutic management of cancer pain in adults and adolescents. Geneva: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO.
Davies AN, Dickman A, Reid C, Stevens AM, Zeppetella G. The management of cancer-related breakthrough pain: Recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. Vol. 13, European Journal of Pain. 2009. p. 331–8.
Mercadante S, Valle A, Porzio G, Aielli F, Adile C, Ficorella C, et al. Relationship between background cancer pain, breakthrough pain, and analgesic treatment: A preliminary study for a better interpretation of epidemiological and clinical studies. Current Medical Research and Opinion. 2013 Jun;29(6):667–71.
Swarm RA, Youngwerth JM, Agne JL, Anghelescu DL, Are M, Buga S, et al. NCCN Guidelines Version 1.2022 Adult Cancer Pain Continue NCCN Guidelines Panel Disclosures [Internet]. 2022. Available from: https://www.nccn.org/home/member-
Løhre ET, Thronæs M, Klepstad P. Breakthrough cancer pain in 2020. Vol. 14, Current opinion in supportive and palliative care. NLM (Medline); 2020. p. 94–9.
Deandrea S, Corli O, Consonni D, Villani W, Greco MT, Apolone G. Prevalence of breakthrough cancer pain: A systematic review and a pooled analysis of published literature. Vol. 47, Journal of Pain and Symptom Management. Elsevier Inc.; 2014. p. 57–76.
Mercadante S, Lazzari M, Reale C, Cuomo A, Fusco F, Marchetti P, et al. Italian Oncological Pain Survey (IOPS): A multicentre Italian study of breakthrough pain performed in different settings. Clinical Journal of Pain. 2015 Mar 13;31(3):214–21.
Webber K, Davies AN, Zeppetella G, Cowie MR. Development and validation of the breakthrough pain assessment tool (BAT) in cancer patients. Journal of Pain and Symptom Management. 2014 Oct 1;48(4):619–31.
Caraceni A, Shkodra M. Cancer pain assessment and classification. Cancers. 2019 Apr 1;11(4).
Mercadante S. The use of rapid onset opioids for breakthrough cancer pain: The challenge of its dosing. Vol. 80, Critical Reviews in Oncology/Hematology. 2011. p. 460–5.
Capelas ML, Monteiro C, Simões C, Ferreira C, Pires C, Pereira C, et al. Dor irruptiva: consenso. 2nd ed. Laboratórios Angelini; 2018.
Shimoyama N, Gomyo I, Katakami N, Okada M, Yukitoshi N, Ohta E, et al. Efficacy and safety of sublingual fentanyl orally disintegrating tablet at doses determined by titration for the treatment of breakthrough pain in Japanese cancer patients: a multicenter, randomized, placebo-controlled, double-blind phase III trial. International Journal of Clinical Oncology. 2015 Feb 1;20(1):198–206.
Rauck R, Reynolds L, Geach J, Bull J, Stearns L, Scherlis M, et al. Efficacy and safety of fentanyl sublingual spray for the treatment of breakthrough cancer pain: A randomized, double-blind, placebo-controlled study. Current Medical Research and Opinion. 2012 May;28(5):859–70.
Garnock-Jones KP. Fentanyl Buccal Soluble Film: AReview in Breakthrough Cancer Pain. Vol. 36, Clinical Drug Investigation. Springer International Publishing; 2016. p. 413–9.

BONE PAIN

Author: Dr. Salvador Gámez Casado, Cláudia Franco de Sá and Carolina Trabulo.

Introduction

Etiology

Symptoms

Pain upon palpation is often found around metastatic bone lesions. If the tumour keeps growing within the bone usually leads to another type of cancer pain: breakthrough

In clinical practice, observations of patients with bone metastases reveal that breakthrough (episodic) pain often poses a greater therapeutic problem more than background pain.

Treatment

Evidence

Level Grade PMID Nº

Opioids therapy as the mainstay of cancer pain treatment to provide freedom from cancer pain I A
Bisphosphonates is a class of medication which may be used to treat pain and reduce morbidity associated with metastatic bone cancer lesions. I A Reduce tumour-induced bone destruction and bone cancer pain

Unwanted side effects (including induction of arthralgias and osteonecrosis of the jaw), Bisphosphonates increase the survival of patients with bone cancer

Evidence Level Grade PMID Nº

Monoclonal antibody therapy with specific affinity for RANKL has been proven to inhibit osteoclast genesis. The use of the MAb denosumab has been shown to not only reduce I B pain, but to also reduce tumour size and increase time to skeletal related events (which include fracture and pain) (11).
Radiotherapy is performed to control a bone affected from metastasis. Radiotherapy has been proven to provide tumour shrinkage, pain reliever, prevent pathological fractures I A

as well as spinal cord compression and delay neurological dysfunction.

Pharmacotherapy

The WHO’s approach to cancer pain treatment involves the use of a three-step ladder which provides a guideline for clinicians to treat patients who struggle from cancer pain syndromes.

Therapeutic Strategy

Invasive treatments

Surgery

It is indicated when the bone pain is uncontrolled, neurological compromise, risk of fracture or a consolidated fracture. I A

Radiotherapy

It is used to treat a vast of bone metastasis which cause pain and it is also used to avoid and treat spinal cord compression and pathological bone fractures. It is prescribed by a I A

radiation oncologist who will protect adjacent healthy organs from unwanted radiation.

The goals of radiotherapy are to improve quality of life, reduces analgesic requirements and maintain ameliorate skeletal function. This treatment is usually well tolerated and effective.
Pain flare is described as a temporary increase in bone pain at the treated metastatic site, during or shortly after radiotherapy completion. This is the reason it may be necessary to increase the analgesic/ anti-inflammatory medication during the radiotherapy treatment.
Single fraction radiotherapy schedule (8Gy in 1 fraction) is recommended as standard of care for treatment of a symptomatic and uncomplicated bone metastasis.
In case of spinal cord compression, it is necessary use corticosteroids because of the oedema caused by the compression and radiotherapy treatment. Usually, the scheme used is 20 Gy in 5 fractions or 30 Gy in 10 fractions.
Combined modality treatment, surgery, and radiotherapy, should be offered for fit and functional patients with spinal cord compression, while radiotherapy alone is best reserved for the unfit, already incapacitated patients with poor prognosis.

Non-invasive treatments I A

Bisphosphonates work by inhibiting the remodelling process at the site of the metastatic bone cancer lesion. By reducing both bone resorption and bone formation,

This class of medication is widely used due to the evidence of reducing the risk of fractures, hypercalcemia, and the need for palliative radiation.
Bisphosphonates are not recommended in patients with renal failure with clearance of creatinine < 30 ml/min and in case of use it is necessary adjustment of dose. The common adverse events are hypocalcaemia and osteonecrosis of the jaw. All patients must have supplements of calcium and vitamin D, unless they have hypercalcemia.

All patients must have supplements of calcium and vitamin D unless they have hypercalcemia.

28148890

26237249

28148890

WHO’s cancer paln treatment ladder Freedom from

cancer pain

Figure 1. WHO’s recommended three-step ladder approach to cancer pain treatment.

Non-opiold

+- adjuvant

2 Opioid for mild to moderate to pain

+- non-opiold

+- adjuvant

Opioid for moderate to

severe pain

+- non-opiold

+- adjuvant

References

Zajączkowska R, Kocot-Kępska M, Leppert W, Wordliczek J. Bone Pain in Cancer Patients: Mechanisms and Current Treatment. Int J Mol Sci. 2019 Nov 30; 20(23):6047. doi: 10.3390/ijms20236047. PMID: 31801267; PMCID: PMC6928918.
Falk S, Dickenson AH. Pain and nociception: mechanisms of cancer-induced bone pain. J Clin Oncol. 2014 Jun 1; 32(16):1647-54. doi: 10.1200/JCO.2013.51.7219. Epub 2014 May 5. PMID: 24799469.
Kane CM, Hoskin P, Bennett MI. Cancer induced bone pain. BMJ. 2015 Jan 29; 350:h315. doi: 10.1136/bmj.h315. PMID: 25633978.
Jimenez-Andrade JM, Mantyh WG, Bloom AP, Ferng AS, Geffre CP, Mantyh PW. Bone cancer pain. Ann N Y Acad Sci. 2010 Jun; 1198:173-81. doi: 10.1111/j.1749-6632.2009.05429.x. PMID: 20536932; PMCID: PMC5642911.
Figura, N.; Smith, J.; Yu, H. Mechanisms of, and Adjuvants for, Bone Pain. Hematol. Oncol. Clin. N. Am. 2018, 32, 447–458. doi: 10.1016/j.hoc.2018.01.006 ; PMID: 29729780
Mantyh, P. Bone cancer pain: Causes, consequences, and therapeutic opportunities. Pain 2013, 154, 54–62. doi: 10.1016/j.pain.2013.07.044; PMID: 23916671.
Li, B.T.; Wong, M.H.; Pavlakis, N. Treatment and prevention of bone metastases from breast cancer: A comprehensive review of evidence for clinical practice. J. Clin. Med. 2014, 3, 1–24. doi: 10.3390/jcm3010001; PMID: 26237249; PMCID: PMC4449670
Fleetwood–Walker, S.M.; Colvin, L.A.; Fallon, M. Translational medicine: Cancer pain mechanisms and management. Br. J. Anaesth. 2008, 101, 87–94. doi: DOI: 10.1093/bja/aen100; PMID: 18492671
Mantyh PW. Bone cancer pain: from mechanism to therapy. Curr Opin Support Palliat Care. 2014 Jun; 8(2):83-90. doi: 10.1097/SPC.0000000000000048. PMID: 24792411; PMCID: PMC4068714.
Lipton A. Emerging role of bisphosphonates in the clinic—antitumor activity and prevention of metastasis to bone. Cancer Treat Rev. 2008; 34 (Suppl 1): S25–S30.
Body JJ, et al. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin. Cancer Res. 2006; 12:1221–1228.
Francesca De Felice, Andrea Piccioli, Daniela Musio,Vincenzo Tombolini. The role of radiation therapy in bone metastases management. Oncotarget. 2017. Jan 26.doi:10.18632/oncotarget.14823; PMID: 28148890; PMCID: PMC5421962.

EMESIS

CANCER-ASSOCIATED EMESIS

Authors: Marina Meri Abad, Carolina Capucho Pereira and Ana Mafalda Baleiras

Symptoms and signs

Learning objectives

To recognize emesis as one of the most frequent and bothersome symptoms for cancer patients.
To understand that emesis is often multifactorial, and treatment should be directed at the underlying causes.

Introduction

Etiology

Evidence

Level Grade PMID Nº

vomiting are summarized in figure table 1.

Figure Table 1. Causes for cancer-related emesis.

Stimulus	Receptors involved	Causes
Vagal stimulation	Ach 5HT3	Visceral or serosal disease: Distention of the liver capsule, faecal impaction Gastroparesis (paraneoplastic visceral neuropahy and dyspepsia syndrome) Irritation of the digestive mucosa (drugs, infection, radiotherapy) Extrinsic compression of digestive structures Peritoneal irritation Mediastinal disease Cough
Direct stimulation of vomiting center	D2 Ach H1	Intracranial hypertension Meningeal irritation (infection, carcinomatosis) Brain radiotherapy Intracranial metastasis
Trigger zone stimulation	D2 5HT3 NK1	Drugs (opioids, antibiotics) Bacterial toxins Metabolic disorders: hypercalcemia, renal impairment, hypokalemia, hyponatremia

Studies Evidence

Complete patient examination should search for signs of intestinal obstruction, ascites and hepatomegaly, which may suggest gastric stasis. Rectal examination should be Level Grade PMID Nº

Pharmacotherapy

In the case of refractory symptoms, nasogastric tube placement can be useful to decompress the stomach and allow for drainage of gastric contents.

Table 2. Treatment for reversible causes of cancer-related emesis (sc: subcutaneous, SSRI: selective serotonin reuptake inhibitor, NSAID: nonsteroidal anti-inflammatory drug)

Cause

Triggers

Firstline

Secondline

Chemical

Drugs (opioids, digoxin, antibiotics, antifungals, iron, SSRIs, NSAIDs, dopamine agonists)

Chemotherapy

Metabolic (renal or liver failure, hypercalcaemia, hyponatraemia, ketoacidosis)

Toxins (ischaemic bowel, tumour products, infection)

Haloperidol 0.5-1.5 mg oral or sc, 3 times daily

Levomepromazine 3.125-6.25 mg oral or sc 3 times daily

Visceral or serosal

Bowel obstruction

Severe constipation or faecal impaction Liver capsule stretch

Ureteric distension Mesenteric metastases

Difficult expectoration or pharyngeal stimulation

Cyclizine 50 mg oral or sc 3 times daily

Levomepromazine 3.125-6.25 mg oral or sc 3 times daily

Evidence Level Grade PMID Nº

Gastric stasis	Drugs (opioids, tricyclics, phenothiazines, anticholinergics) Tumour ascites Hepatomegaly Autonomic dysfunction Tumour infiltration	Domperidone 10 mg oral 4 times daily before meals	Metoclopramide 10 mg 3 to 4 times daily before meals
Cranial	Raised intracranial pressure (tumour, bleed, infarction) Meningeal infiltration Radiotherapy	Cyclizine 50 mg oral or sc 3 times daily Add dexamethasone 8-16 mg oral or sc daily if raised intracranial pressure	Haloperidol 0.5-1.5 mg oral or sc, 3 times daily
Vestibular	Drugs (opioids) Motion sickness Base of skull tumour	Cyclizine 50 mg oral or sc 3 times daily	Levomepromazine 3.125-6.25 mg oral or sc 3 times daily
Cortical	Anxiety Pain	Lorazepam 0.5-1 mg sublingual 4 times daily as needed	Levomepromazine 3.125-6.25 mg oral or sc 3 times daily

Metoclopramide (1)
Dexamethasone (2)
Haloperidol (3)
Levosulpiride (4)
Tropiseron (5)

Therapeutic Strategy

Evaluation: anamnesis, physical exploration, review of medication.
Depending on clinical exploration: blood test (metabolic disorder); abdominal Rx (intestinal occlusion); abdominal CT scan (retroperitoneal disease); abdominal ultrasound (obstructive uropathy); cerebral CT scan (CNS lesions)
General measures: correction of diet; oral hygiene; quiet atmosphere; oral or parenteral hydration if required; parenteral administration of essential medication.
Etiological treatment: antitussives (cough); laxatives (constipation); corticoids (endocranial hypertension); CNS lesions (radiotherapy if indicated); correction of metabolic disorders; antibiotics (infection).
Antiemetic drugs: metoclopramide or domperidone (vagal stimulation); haloperidol (trigger center); dexamethasone (CNS stimulation). If there is no adequate control after first

Refelinreetnrecatemse:nt: Metroclopramie + dexamethasone (vagal stimulation); haloperidol + dexamethasone (trigger center and CNS stimulation).

II II II III II

III III

III

A 10908823

B 15471656

A 11503632

B 8537694

B 9740088

C 27664248 27896642

Bruera E, Belzile M, Neumann C, Harsanyi Z, Babul N, Darke A. A double-blind, crossover study of controlled-release metoclopramide and placebo for the chronic nausea and dyspepsia of advanced cancer. J Pain Symptom Manage. 2000 Jun;19(6):427–35.
Bruera E, Moyano JR, Sala R, Rico MA, Bosnjak S, Bertolino M, et al. Dexamethasone in addition to metoclopramide for chronic nausea in patients with advanced cancer: a randomized controlled trial. J Pain Symptom Manage. 2004 Oct;28(4):381–8.
Critchley P, Plach N, Grantham M, Marshall D, Taniguchi A, Latimer E, et al. Efficacy of haloperidol in the treatment of nausea and vomiting in the palliative patient: a systematic review. J Pain Symptom Manage. United States; 2001. p. 631–4.
Corli O, Cozzolino A, Battaiotto L. Effectiveness of levosulpiride versus metoclopramide for nausea and vomiting in advanced cancer patients: a double-blind, randomized, crossover study. J Pain Symptom Manage. 1995 Oct;10(7):521–6.
Mystakidou K, Befon S, Liossi C, Vlachos L. Comparison of the efficacy and safety of tropisetron, metoclopramide, and chlorpromazine in the treatment of emesis associated with far advanced cancer. Cancer. 1998 Sep;83(6):1214–23.
Collins E, Mather H. Nausea and vomiting in palliative care. BMJ 2015;351:h6249.
Leach C. Nausea and vomiting in palliative care. Clinical Medicine 2019 Vol 19, No 4: 299–301.

IATROGENIC EMESIS

Author: Helena Guedes, Sandra Custódio and Alexandra Guedes

Definition

Symptoms and signs

Gastrointestinal: gastric stasis (often induced by opioids and anticholinergics), pancreatic carcinoma, peritonitis, cholangitis, partial or complete bowel obstruction, malignant ascites, vesicular dysfunction, or other intra-abdominal causes.
Central nervous system: primary or metastatic brain tumor, intracranial hypertension.
Vestibular: labyrinthitis, Meniere’s disease, acoustic neuroma, primary or metastatic brain tumor.
Metabolic: hypercalcemia, hyperglycemia, hyponatremia, ketoacidosis.
Pharmacological: cytostatic drugs, opioids, diuretics, oral antidiabetics, antibiotics such as amoxicillin, metronidazole, trimethoprim.
Others: cough, pharyngeal irritation from infection/respiratory secretions, radiotherapy.

In most cases, the aetiology is multifactorial, and a thorough evaluation is necessary to correctly identify the contributing factors and decide upon the most appropriate intervention.

Types of nausea and/or vomiting: CINV is commonly classified as acute, delayed, anticipatory, breakthrough, or refractory.

ACUTE: usually occurs within few minutes to several hours after administration of certain anticancer agents and commonly resolves within the first 24 hours. The intensity of acute-onset emesis generally peaks after 5 to 6 hours. 13
DELAYED-ONSET: develops more than 24 hours after the anticancer agent administration.1,4
ANTICIPATORY: occurs before patients receive their next anticancer treatment. Because it is primarily considered a conditioned response, anticipatory emesis typically occurs after a previous negative experience with anticancer agents. Its incidence ranges from 18% to 57%, and nausea is more common than vomiting. 5
BREAKTHROUGH: occurs despite prophylactic antiemetic treatment and/or requires rescue with antiemetics. 6
REFRACTORY: occurs during subsequent treatment cycles after guideline directed prophylactic antiemetic agents have failed in earlier cycles.7 There are several factors that that contribute to the severity of CINV:
Individual patient variability: younger age, female gender, prior anticancer agents; history of little or no alcohol use, morning sickness, motion sickness, anxiety.
Chemotherapy drug’s emetogenic potential.

Chemotherapy agents are divided into four levels of emetogenicity according to the percentage of patients who experience acute emesis in the absence of antiemetic prophylaxis. 8

HIGH EMETIC RISK – more than 90% of patients experience acute emesis.
MODERATE EMETIC RISK – more than 30% to 90% of patients experience acute emesis.
LOW EMETIC RISK – 10% to 30% of patients experience acute emesis.
MINIMAL EMETIC RISK – fewer than 10% of patients experience acute emesis.

Evidence

Level Grade PMID Nº

Table 1 – Emetic Risk Groups – Single IV Agents

HIGH

Anthracycline/cyclophosphamide combination* Carmustine

Cisplatin

Cyclophosphamide > 1500 mg/m² Dacarbazine

Mechlorethamine Streptozocin

MODERATE

Alemtuzumab Azacitidine Bendamustine Carboplatin Clofarabine

Cyclophosphamide < 1500 mg/m²

Cytarabine > 1000 mg/m²

Daunorubicin Doxorubicin Epirubicin Idarubicin Ifosfamide

Irinotecan

Oxaliplatin Romidepsin Temozolomide** Thiotepa

Trabectedin

LOW

Aflibercept Belinostat Blinatumomab Bortezomib Brentuximab Cabazitaxel Carfilzomib Catumaxumab Cetuximab

Cytarabine < 1000 mg/m²

Docetaxel

Eribulin Etoposide

5-Fluorouracil Gemcitabine Ipilimumab Ixabepilone Methotrexate Mitomycin Mitoxantrone Nab- paclitaxel

Paclitaxel

Panitumumab Pemetrexed Pegylated liposomal doxorubicin Pertuzumab Temsirolimus Topotecan

Trastuzumab-emtansine

Vinflunine

MINIMAL

Bevacizumab Bleomycin Busulfan

2-Chlorodeoxyadenosine Cladribine

Fludarabine Nivolumab

Ofatumumab

Pembrolizumab Pixantrone Pralatrexate Rituximab Trastuzumab Vinblastine Vincristine

Vinorelbine

Evidence Level Grade PMID Nº

Table 2 – Emetic Risk Groups – Adults – Single Oral Agents.

HIGH

Hexamethylmelamine

Procarbazine

MODERATE

Bosutinib Ceritinib

Crizotinib

Cyclophosphamide Imatinib

Temozolomide

Vinorelbine

LOW

Afatinib Axatinib Capecitabine Dabrafenib Dasatinib Everolimus Etoposide

Fludarabine

Ibrutinib Idelalisib Lapatinib Lenalidomide Olaparib Nilotinib

Pazopanib

Ponatinib Regorafenib Sunitinib Tegafur Uracil Thalidomide Vandetanib

Vorinostat

MINIMAL

Chlorambucil Erlotinib Gefitinib Hydroxyurea

Melphalan

Methotrexate

L-Phenylalanine mustard Pomalidomide

Ruxolitinib

Sorafenib

6-Thioguanine Vemurafenib

Vismodegib

Pharmacotherapy

Table 3 – CINV Prophylaxis according to each drug’s emetogenic potential.

Evidence

Level Grade PMID Nº

	Drug	Dose on the day of treatment
	High Emetic	Risk: cisplatin and other agents; anthracyclines combined with cyclophosphamide
5-HT3 Receptor Antagonist	Ondansetron	Single 24 mg dose administered by tablets, successive dissolving tablets, or oral dissolving film applications before the start of chemotherapy or 8 mg or 0.15 mg/kg IV
	Granisetron	2 mg PO or 1 mg or 0.01 mg/kg IV or 1 transdermal patch or 10 mg subcutaneous
	Dolasetron	100 mg PO only
	Palonosetron	0.50 mg PO or 0.25 mg IV
	Tropisetron	5 mg PO or IV
	Ramosetron	12 mg PO or IV

Evidence Level Grade PMID Nº

	Drug	Dose on the day of treatment Dose(s) on Subsequent Days
Neurokinin – 1 – Receptor Antagonist	Aprepitant	125 mg PO or 130 mg IV	80 mg PO on days 2 and 3
	Fosaprepitant	150 mg IV
	Netupitant – Palonesetron	300 mg netupitant/ 0.5 mg palonosetron PO in single capsule
	Fosnetupitant – Palonosetron	235 mg fosnetupitant/ 0.25 mg palonosetron IV
	Rolapitant	180 mg PO
Corticosteroids	Dexamethasone	20 mg PO or IV	8 mg PO or IV twice daily on
		If aprepitant, netupita-nt palonosetron or fosnetupitant – palonosetron are used:
		12 mg PO or IV	8 mg PO or IV once daily on days 2-4
		If rolapitant is used:
		12 mg PO or IV	8 mg PO or IV twice daily on days 2 – 4
		If fosaprepitant is used:
		12 mg PO or IV	8 mg PO or IV on day 2; 8 mg PO or IV twice daily on days 3-4
Atypical antipsychotics	Olanzapine	5 or 10mg PO	5 or 10mg PO on days 2-4
Moderate Emetic Risk
5-Ht3 Receptor Antagonist		Refer to “High Emetic Risk: Cisplatin and other agents”
Corticosteroid	Dexamethasone	8 mg PO or IV	8 mg PO or IV on days 2-3
Low Emetic Risk
5-HT3 Receptor Antagonist		Refer to “High Emetic Risk: Cisplatin and other agents”
Corticosteroid	Dexamethasone	8 mg PO or IV

Table 4 – CINV prophylaxis in Advanced Cancer.

Evidence Level Grade PMID Nº

	Drug
First line agents	Metoclopramide
First line agents	Haloperidol
Second line agents	Methotrimeprazine
Second line agents	Olanzapin
Third line agents	Levosulpiride
Third line agents	Tropisetron

Therapeutic Strategy

II	A	34398289
II	A	34398289
II	B	34398289
II	B	34398289
III	B	34398289
II	B	34398289
I	A
I	B
I	A
II	B
II	B
II	B

Table 5 – Guideline recommendations for CINV prophylaxis.

Prevention of Acute Nausea and Vomiting Following Non-AC Chemotherapy of High Emetic Risk.

Prevention of Delayed Nausea and Vomiting Following Non-AC Chemotherapy of High Emetic Risk.

Prevention of Acute Nausea and Vomiting Following Anthracycline-Cyclophosphamide-Based Chemotherapy of High Emetic Risk.

Prevention of Delayed Nausea and Vomiting Following Anthracycline-Cyclophosphamide-Based Chemotherapy of High Emetic Risk.

Prevention of Acute and Delayed Nausea and Vomiting Following Non-AC and AC Chemotherapy of High Emetic Risk.

Prevention of Acute Nausea and Vomiting in Moderately Emetogenic Chemotherapy

For the prevention of acute nausea and vomiting in moderately emetogenic chemotherapy-treated patients, a 5-HT3 receptor antagonist plus dexamethasone is recommended.

Prevention of Delayed Nausea and Vomiting in Moderately Emetogenic Chemotherapy.

In patients receiving moderately emetogenic chemotherapy with known potential for delayed nausea and vomiting,the use of dexamethasone for days 2 to 3 can be considered

Prevention of Acute Nausea and Vomiting in Patients Receiving Carboplatin-Based Chemotherapy.

A combination of an NK1 receptor antagonist, 5-HT3 receptor antagonist, and dexamethasone is recommended for the prophylaxis of nausea and vomiting induced by carboplatin-based chemotherapy.

III C

II B

Prevention of Delayed Nausea and Vomiting in Patients Receiving Carboplatin-Based Chemotherapy.

Prevention of Acute Nausea and Vomiting in Patients Receiving Low Emetogenic.

Prevention of Acute Nausea and Vomiting in Patients Receiving Minimally Emetogenic Chemotherapy.

No antiemetic should be routinely administered before chemotherapy to patients without a history of nausea and vomiting.

Prevention of Delayed Nausea and Vomiting in Patients Receiving Minimally Emetogenic Chemotherapy.

No antiemetic should be administered for prevention of delayed nausea and vomiting induced by low or minimally emetogenic chemotherapy.

Prevention of Nausea and Vomiting in Patients Receiving Multiple-Day Cisplatin.

Prevention of Nausea and Vomiting in Patients Receiving High-Dose Chemotherapy.

For patients receiving high-dose chemotherapy for stem cell transplant, a combination of a 5-HT3 receptor antagonist with dexamethasone and NK1 receptor antagonist is recommended before chemotherapy.

Guideline for Breakthrough Nausea and Vomiting

The available evidence for breakthrough nausea and vomiting suggests the use of 10 mg PO olanzapine, daily for 3 days.

Prevention of Anticipatory Nausea and Vomiting.

The best approach for the prevention of anticipatory nausea and vomiting is the best possible control of acute and delayed nausea and vomiting.

*netupitant is administered with palonosetron as part of the fixed-dose combination agent NEPA.

ADDITIONAL RECOMMENDATIONS:

Antineoplastic Combinations: Adults treated with antineoplastic combinations should be offered antiemetics appropriate for the component antineoplastic agent of greatest emetic risk. 10
Adjunctive Drugs : Lorazepam is a useful adjunct to antiemetic drugs, but is not recommended as a single-agent antiemetic.10
Cannabinoids: Evidence remains insufficient for a recommendation regarding medical marijuana for the prevention of nausea and vomiting in patients with cancer receiving chemotherapy. 10 Complementary and Alternative Therapies: Evidence remains insufficient for a recommendation for or against the use of ginger, acupuncture/acupressure, and other complementary or alternative therapies for the prevention of nausea and vomiting in patients with cancer.
High Dose Chemotherapy with Stem Cell or Bone Marrow Transplant: Adult patients treated with high-dose chemotherapy and stem-cell or bone marrow transplantation should be offered a three drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone. A four-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, dexamethasone, and olanzapine may be offered to adults treated with high-dose chemotherapy and stem-cell or bone marrow transplantation.10
Breakthrough Nausea or Vomiting: Adults who experience nausea or vomiting despite optimal prophylaxis, and who did not receive olanzapine prophylactically, should be offered olanzapine in addition to continuing the standard antiemetic regimen. Adults who experience nausea or vomiting despite optimal prophylaxis, and who have already received olanzapine, may be offered a drug of a different class (e.g. an NK1 receptor antagonist, lorazepam or alprazolam, a dopamine receptor antagonist, dronabinol, or nabilone) in addition to continuing the standard antiemetic regimen.10
Anticipatory Nausea and Vomiting. Clinicians should use such regimens with initial antineoplastic treatment, rather than assessing the patient’s emetic response with less effective antiemetic treatment. If a patient experiences anticipatory emesis, clinicians may offer behaviour therapy with systematic desensitization. 10

Evidence Level Grade PMID Nº

II B

IV D

II B

II A

References: Level GradeEvidence

PMID Nº

National Comprehensive Cancer Network. NCCN.pdf. https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf (2022).
Herrstedt, J. Antiemetics: An update and the MASCC guidelines applied in clinical practice. Nat. Clin. Pract. Oncol. 5, 32–43 (2008).
Warr, D. G., Street, J. C. & Carides, A. D. Evaluation of risk factors predictive of nausea and vomiting with current standard-of-care antiemetic treatment: Analysis of phase 3 trial of aprepitant in patients receiving adriamycin-cyclophosphamide-based chemotherapy. Support. Care Cancer 19, 807–813 (2011).
Kris, M. G. et al. Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J. Clin. Oncol. 3, 1379–1384 (1985).
Moher, D., Arthur, A. Z. & Pater, J. L. Anticipatory nausea and/or vomiting. Cancer Treat. Rev. 11, 257–264 (1984).
Roila, F. et al. Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the 2004 Perugia International Antiemetic Consensus Conference. Ann. Oncol. 17, 20–28 (2006).
Navari, R. M. Management of chemotherapy-induced nausea and vomiting: Focus on newer agents and new uses for older agents. Drugs 73, 249–262 (2013).
Grunberg, S. M. et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity – State of the art. Support. Care Cancer 19, 2–6 (2011).
Aapro, M., Gralla, R. J., Roila, F., Herrstedt, J. & Molassiootis, A. MASCC / ESMO Antiemetic Guideline 2016 with Updates in 2019. Multinatl. Assoc. Support. Care Cancer 1–55 (2019).

ONCOLOGIC EMERGENCIES

SPINAL COMPRESSION SYNDROME

Authors: Teresa Fraga, Catarina Almeida and Diana Correia

Introduction [1]-[6]

- - Spinal Cord Compression (SCC) is an oncological emergency.
  - SCC is one of most common neurological complications in patients with cancer second only to brain metastases.
  - Up to 5% of cancers can complicate with SCC.
  - SCC can lead to extensive neurologic deficits when not promptly recognized and treated.
  - Lung, breast and prostate are the types of cancer most frequently associated with SCC, followed by multiple myeloma, renal cell carcinoma and non-Hodgkin lymphoma.
  - SCC can be the initial manifestation of a previously undiagnosed malignancy in around 20% of patients.• The most common site for compression is in the thoracic segment of the spine (~60% of all cases).
  - Survival in patients with multiple spinal metastases and cord compression is generally less than 6 months.

Etiology [1]-[6]

- - The mechanism of the compression is multifactorial.
  - Haematogenous vertebral corpus metastases are the most common mechanism in adults.
    - Epidural venous plexus obstruction may lead to vasogenic oedema of the white matter (early stages) and increase inflammatory reactions that result in hypoxic injury of the spinal cord. This injury induces the release of Vascular Endothelial Growth Factor (VEGF) which leads to more vascular permeability and interstitial oedema.
  - Other mechanisms include the local spread from a tumour near the spine and a direct metastasis to the epidural space (rare).
  - Early decompression increases the probability of recovery, with the opposite leading to irreversible spinal cord damage and debilitating sequelae.

Clinical Manifestations [1]-[6]

- - SCC arises in the thoracic segment of the spine in more than half of all cases (approximately 60%), and in the lumbosacral and cervical spine in 30% and 10% of cases, respectively.
  - In almost one third of all patients imaging of the entire spine reveals multiple levels of compression.
  - Key presenting features include back pain, motor weakness, sensory deficits, and bowel or bladder dysfunction.
  - Signs and symptoms vary according to pathophysiology (upper or lower motor lesion) and spinal location.
  - SCC usually presents with pain (back pain), which is reported in 80-95% of patients.
    - Pain is constant and it worsens at night and with the Valsalva manoeuvre (i.e.: coughing, sneezing).
    - Radicular pain may manifest in cases of advanced disease.
    - Back pain and tenderness in the site are typical and may precede neurologic features by several weeks.
  - Motor deficits are found in 35 to 75% of cancer patients.
  - Sensory loss is less common but can be found in 40-90% of cancer patients. The level of sensory deficit may correlate poorly with the level of the spine lesion.
  - Although rarely the presenting complaint, patients can also have autonomic deficits such as bowel or bladder dysfunction. These tend to occur later, along with worsening motor weakness, and are associated with a poorer functional outcome after treatment.

Evidence

Level Grade PMID Nº

Studies [1]-[6] Level GradeEvidence

PMID Nº

- - Gadolinium contrast-enhanced Magnetic Resonance Imaging (MRI) is the gold standard (sensitivity 93%, specificity 97%).
  - Since multilevel disease may be present and the symptoms may not correlate with the level of the lesion, the entire spine should be imaged with and without contrast.
  - Bone scan computed tomography (CT) and positron emission tomography (PET) are less useful.
  - CT is only recommended when MRI is contraindicated.

Differential Diagnosis [1]

- - Benign musculoskeletal diseases (muscle spasm, spinal stenosis, and intervertebral disc diseases).
  - Infectious diseases (spinal epidural abscess).
  - Radiation myelopathy and metastatic disease with vertebral metastases without SCC.
  - Brain metastases should be ruled out.

Therapeutic Strategy [1]-[7]

- - The goals of care consist of pain control and preservation of neurological function and performance status.
  - Prolonged loss of motor function cannot be restored by either surgery or radiation therapy (RT). The timeliness of treatment initiation influences the resulting outcomes in both RT and surgery with superior results if treatment starts within 48 hours of diagnosis.
  - Although this is a common complication in cancer patients, data from randomized controlled trials is scarce.
  - The treatments most commonly include the use of steroids, RT and surgery.
  - Surgery is indicated in patients with spinal instability or severe compression on MRI with neurologic deficits.
CORTICOSTEROIDS
- First-line treatment for most patients. I A
- Glucocorticoid (GC) therapy results in the downregulation of VEGF and prostaglandin E2, with a corresponding decrease in spinal cord oedema.
- GC reduce neurologic impairment and pain, however there is no consensus on the optimum loading and maintenance doses.
- Patients with paraparesis or paraplegia:

– High-dose” corticosteroid treatment (96 mg intravenous [i.v.] dexamethasone, followed by 24 mg qid for 3 days, and then tapered over 10 days)

- Patients with pain but minimal neurological dysfunction:

“Low-dose” corticosteroid treatment (10mg dexamethasone i.v. bolus, followed by 16mg id)

- Management decisions must be individualized and need to take into consideration: spinal stability, degree of neurologic compromise, radiosensitivity of the tumour, and the patient’s overall health status and goals of care.
SURGERY
- The Spinal Instability Neoplastic Score (SINS) is a classification that has been developed to determine whether surgery is appropriate to correct instability.
- Radiation is usually administered after surgical decompression.

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- Early surgical intervention in patients with metastatic spine lesions before the patients become non-ambulatory is supported by retrospective evidence that patients with preoperative ambulatory function are twice more likely to maintain the ability to walk after decompressive surgery.
- Surgical treatment resulted in a longer survival time, maintenance of continence, and a reduction in the need for corticosteroids and analgesics.
- Decompressive surgery followed by RT may have better outcomes than RT alone in selected patients, such as:
  - patients with radioresistant primary tumours – displacement of spinal cord on MRI – a single area of cord compression
  - loss of motor function less than 48 hours – estimated survival longer than three months

•Surgery is also an option for the treatment of spinal tumor Tumour? recurrence after RT.

RADIOTHERAPY
- Key factors in undergoing surgery before RT include spinal stability, presence of neurologic deficits, and patient prognosis.
- RT with or without surgery is the recommended treatment for SCC.
- Radiation can be given at previously treated sites if the prior dose was moderate. The cumulative amount is limited to avoid spinal cord damage.
- Treatment with either single fraction or multiple fractionated RT has shown equivalent efficacy.
- Single fraction of 8 Gy is as effective for bone metastases as more protracted schedules, with a shorter, more convenient delivery for patients with poor prognosis.
- Extended treatment and higher fractionated doses are used if longer survival is anticipated.
- Stereotactic body radiation therapy (SBRT) provides tumour control, pain relief, and minimal risk of radiation myelopathy but may not prevent progressive vertebral fracture and kyphosis.
  - Tumours such as melanoma, sarcoma, and renal cell carcinoma (resistant to standard fractionated RT) appear to respond as well to SBRT
  - The current evidence primarily supports the use of spine SBRT in spine metastases without cord compression.
  - SBRT can be utilized to manage residual tumour after decompressive surgery for SCC
INTERVENTIONAL THERAPY
- Percutaneous radiofrequency ablation (PRA) is a useful to reduce pain and related disability in patients with end-stage spinal metastases when there are no other options.
  - Lesions within 1 cm of the spinal cord are considered ineligible because of the risk of thermal injury to the spinal cord.

References

- [1] ESMO, ESMO Handbook of Oncological Emergencies. 2016.
- [2] J. Spring and L. Munshi, “Oncologic Emergencies: Traditional and Contemporary,” Crit. Care Clin., vol. 37, no. 1, pp. 85–103, 2021, doi: 10.1016/j.ccc.2020.08.004.
- [3] A. E. Ropper and A. H. Ropper, “Acute Spinal Cord Compression.,” N. Engl. J. Med., vol. 376, no. 14, pp. 1358–1369, 2017, doi: 10.1056/NEJMra1516539.
- [4] A. J. Lawton et al., “Assessment and management of patients with metastatic spinal cord compression: A multidisciplinary review,” J. Clin. Oncol., vol. 37, no. 1, pp. 61–71, 2019, doi: 10.1200/JCO.2018.78.1211.
- [5] E. S. C. Ribas and D. Schiff, “Spinal cord compression,” Curr. Treat. Options Neurol., vol. 14, no. 4, pp. 391–401, 2012, doi: 10.1007/s11940-012-0176-7.
- [6] T. R. Halfdanarson, W. J. Hogan, and T. J. Moynihan, “Oncologic emergencies: Diagnosis and treatment,” Mayo Clin. Proc., vol. 81, no. 6, pp. 835–848 2006, doi: 10.4065/81.6.835.
- [7] M. H. Suppli, “Approaches to radiotherapy in metastatic spinal cord compression,” Dan Med J., Apr;65(4):B5451, 2018, PMID: 29619931

III I

III

B 22547256

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16770986 29619931

B 22547256

29619931

C 22547256

SUPERIOR VENA CAVA SYNDROME

Authors: Inês Nobre-Góis, Marta Freitas and Helena Guedes

Definition

Superior vena cava (SVC) syndrome (SVCS) is a medical emergency resultant from the partial or complete obstruction of blood flow through the SVC.

Symptoms and Signs [1]-[3]

Most common presenting symptoms include:
- - Facial, neck and upper arms swelling and cyanosis.
  - Respiratory symptoms including dyspnoea, orthopnoea, cough, hoarseness, stridor and chest pain, aggravated if concomitant pleural effusion.
Less common presenting symptoms include:
- Neurologic manifestations due to cerebral oedema (including headache, confusion and visual disorders), potentially leading to life-threatening brainstem herniation.
The severity of symptoms depends on the grade of the SVC calibre reduction, the time course (and hence the possibility to recruit venous collaterals) and the probable association with acute thrombosis.
On physical examination there may be distension of neck and chest wall veins, facial and arm oedema and cyanosis, and facial plethora.

Etiology

Most frequent causes of SVCS include:

Intrathoracic malignancies (60 to 85% of all cases), causing direct SVC invasion or it’s extrinsic compression and potential subsequent thrombosis[4]-[6] .
- Bronchogenic carcinoma, including non-small cell lung cancer (approximately 50%) and small cell lung cancer (25 to 35%)[7]-[9] .
- Non-Hodgkin lymphoma (10 to 15%)[10] .
- Other less common: thymoma and other thymic neoplasms[11] , mesothelioma, germ cell neoplasms[12] and solid metastatic tumours[13].
Benign or non-malignant causes (15- 40% of all cases)[14]-[15] .
- Latrogenic thrombus formation or device-related SVCS with rising incidence, related to the increased use of intravascular devices (e.g.: pacemaker and implantable cardioverter-defibrillator (ICD) wires and intravascular catheters used for or chemotherapy or haemodialysis).
- Other benign conditions (e.g.: fibrosing mediastinitis, post-radiation fibrosis).

Studies

Upper body and vasculature imaging studies:[4],[16]-[8]

Chest X-Ray.

-May show enlarged superior mediastinum.

Contrast enhanced computed tomography (CT).
- Can demonstrate the site, level, and extent of venous obstruction, map collateral vessels, and often identify the underlying cause of venous blockage.
- Sensitivity of 96-98% and specificity of 97-99%.
Magnetic resonance (MRI).
- Can provide information complementary information to CT.
Ultrasound (US) of the jugular, subclavian, brachiocephalic and axillary veins .
- Can provide indirect findings to suggest SCV obstruction as SVC cannot be directly imaged by US.
- Can identify a luminal thrombus in the above-mentioned draining system.
Venography.
- Can be used as diagnostic and therapeutic strategy.

Evidence

Level Grade PMID Nº

Pharmacotherapy Level GradeEvidence

PMID Nº

Glucocorticoids, in known steroid-responsive malignancies (e.g.: lymphoma or thymoma)[10]. 2C

C	6368759
D	9135892
C	7234887
C	16502166
C	16502166
B	6368759
A	33357528
A	22319249
B	19620456
B	12555872
B	6368759
C	16429916
C	28979481

Glucocorticoids, in patients receiving Rt[19]. 2C
Diuretics and avoiding overhydration[20]. 2C
Thrombolytic techniques (mechanical preferable to pharmacological) in SVCS due to thrombus, or in selected cases after stenting[21]. 2C
Anticoagulation therapy in SVCS due to thrombus and after stenting[21]. 2C
Chemotherapy agents, for patients with chemo-sensitive tumours (e.g.: lymphoma, small cell lung cancer, germ cell tumours)[10]. 2C
Mechanical strategies (e.g.: head elevation to decrease the hydrostatic pressure in the head and neck)[22].
Patient stabilization in severe cases (ABC: airway, breathing and circulation)[23].
Endovascular treatment, including SVC stenting for recanalization[24]. 2A
Radiotherapy, as an alternative or complement to endovascular treatment strategies[25]. 2A
Chemotherapy, for patients with chemo-sensitive tumours[10]. 2C
Surgical venous bypass in highly selected patients[26]. IV
Removal of intravascular catheter in SVCS due to thrombus (if present and possible[27]. 3A

References

Drouin L, Pistorius MA, Lafforgue A, et al. [Upper-extremity venous thrombosis: A retrospective study about 160 cases]. La Revue de medecine interne. 2019;40(1):9-15. doi:10.1016/j.revmed.2018.07.012
Zimmerman S, Davis M. Rapid Fire: Superior Vena Cava Syndrome. Emerg Med Clin North Am. 2018;36(3):577-584. doi:10.1016/j.emc.2018.04.011
Carmo J, Santos A. Chronic Occlusion of the Superior Vena Cava. N Engl J Med. 2018;379(1):e2. doi:10.1056/NEJMicm1711273
Friedman T, Quencer KB, Kishore SA, Winokur RS, Madoff DC. Malignant Venous Obstruction: Superior Vena Cava Syndrome and Beyond. Semin Intervent Radiol. 2017;34(4):398-408. doi:10.1055/s-0037-1608863
Kalra M, Sen I, Gloviczki P. Endovenous and Operative Treatment of Superior Vena Cava Syndrome. Surg Clin North Am. 2018;98(2):321-335. doi:10.1016/j.suc.2017.11.013
García Mónaco R, Bertoni H, Pallota G, et al. Use of self-expanding vascular endoprostheses in superior vena cava syndrome. Eur J Cardiothorac Surg. 2003;24(2):208-211. doi:10.1016/s1010-7940(03)00293-8
Rice TW, Rodriguez RM, Light RW. The superior vena cava syndrome: clinical characteristics and evolving etiology. Medicine. 2006;85(1):37-42. doi:10.1097/01.md.0000198474.99876.f0
Yellin A, Rosen A, Reichert N, Lieberman Y. Superior vena cava syndrome. The myth–the facts. Am Rev Respir Dis. 1990;141(5 Pt 1):1114-1118. doi:10.1164/ajrccm/141.5_Pt_1.1114
Markman M. Diagnosis and management of superior vena cava syndrome. Cleve Clin J Med. 1999;66(1):59-61. doi:10.3949/ccjm.66.1.59
Perez-Soler R, McLaughlin P, Velasquez WS, et al. Clinical features and results of management of superior vena cava syndrome secondary to lymphoma. J Clin Oncol. 1984;2(4):260-266. doi:10.1200/JCO.1984.2.4.260
Dib HR, Friedman B, Khouli HI, Gerber DR, Weiss RL. Malignant thymoma. A complicated triad of SVC syndrome, cardiac tamponade, and DIC. Chest. 1994;105(3):941-942. doi:10.1378/chest.105.3.941
Holbert BL, Libshitz HI. Superior vena caval syndrome in primary mediastinal germ cell tumors. Can Assoc Radiol J. 1986;37(3):182-183.
Chen JC, Bongard F, Klein SR. Acontemporary perspective on superior vena cava syndrome. Am J Surg. 1990;160(2):207-211. doi:10.1016/s0002-9610(05)80308-3
Rozmus G, Daubert JP, Huang DT, Rosero S, Hall B, Francis C. Venous thrombosis and stenosis after implantation of pacemakers and defibrillators. J Interv Card Electrophysiol. 2005;13(1):9-19. doi:10.1007/s10840-005-1140-1
van Putten JW, Schlosser NJ, Vujaskovic Z, Leest AH, Groen HJ. Superior vena cava obstruction caused by radiation induced venous fibrosis. Thorax. 2000;55(3):245-246. doi:10.1136/thorax.55.3.245
de Potter B, Huyskens J, Hiddinga B, et al. Imaging of urgencies and emergencies in the lung cancer patient. Insights Imaging. 2018;9(4):463-476. doi:10.1007/s13244-018-0605- 6
Cansu A, Soyturk M, Ozturk MH, Kul S, Pulathan Z, Dinc H. Diagnostic value of color Doppler ultrasonography and MDCT angiography in complications of hemodialysis fistulas and grafts. Eur J Radiol. 2013;82(9):1436-1443. doi:10.1016/j.ejrad.2013.03.015
Ko SF, Huang CC, Ng SH, et al. MDCT angiography for evaluation of the complete vascular tree of hemodialysis fistulas. AJR Am J Roentgenol. 2005;185(5):1268-1274. doi:10.2214/AJR.04.1553
Ostler PJ, Clarke DP, Watkinson AF, Gaze MN. Superior vena cava obstruction: a modern management strategy. Clin Oncol (R Coll Radiol). 1997;9(2):83-89. doi:10.1016/s0936- 6555(05)80445-5
Schraufnagel DE, Hill R, Leech JA, Pare JA. Superior vena caval obstruction. Is it a medical emergency? Am J Med. 1981;70(6):1169-1174. doi:10.1016/0002-9343(81)90823-8
Uberoi R. Quality assurance guidelines for superior vena cava stenting in malignant disease. Cardiovasc Intervent Radiol. 29(3):319-322. doi:10.1007/s00270-005-0284-9
Azizi AH, Shafi I, Shah N, et al. Superior Vena Cava Syndrome. JACC Cardiovasc Interv. 2020;13(24):2896-2910. doi:10.1016/j.jcin.2020.08.038
Thim T, Krarup NHV, Grove EL, Rohde CV, Løfgren B. Initial assessment and treatment with the Airway, Breathing, Circulation, Disability, Exposure (ABCDE) approach. Int J Gen Med. 2012;5:117-121. doi:10.2147/IJGM.S28478
Lanciego C, Pangua C, Chacón JI, et al. Endovascular stenting as the first step in the overall management of malignant superior vena cava syndrome. AJR Am J Roentgenol. 2009;193(2):549-558. doi:10.2214/AJR.08.1904
Rowell NP, Gleeson F v. Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus: a systematic review. Clin Oncol (R Coll Radiol). 2002;14(5):338-351. doi:10.1053/clon.2002.0095
Messner GN, Azizzadeh A, Huynh TT, Estrera AL, Porat EE, Safi HJ. Superior vena caval bypass using the superficial femoral vein for treatment of superior vena cava syndrome. Tex Heart Inst J. 2005;32(4):605-606.
Wall C, Moore J, Thachil J. Catheter-related thrombosis: A practical approach. J Intensive Care Soc. 2016;17(2):160-167. doi:10.1177/1751143715618683

Others

- National Cancer Institute grading system (Common Terminology Criteria for Adverse Events [CTCAE]) to stratify SVCS occurring as an adverse event during cancer therapy

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Asymptomatic; incidental finding of SVC

Symptomatic;

medical intervention indicated

Severe symptoms; multimodality intervention

Life-threatening consequences;

Death

thrombosis

(eg, anticoagulation, radiation, or chemotherapy)

indicated (eg, anticoagulation, chemotherapy, radiation, stenting)

urgent multimodality intervention indicated (eg, lysis, thrombectomy, surgery)

Reproduced from: Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, November 27, 2017, National Institutes of Health, National Cancer Institute.

Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5×11.pdf

Evidence Level Grade PMID Nº

TUMOR HYPERCALCEMIA

Authors: Michele Ghidini, Patricia Chow Liu, Victor Sacristan Santos and Lara Otero Plaza

Definition

Hypercalcemia of malignancy (HCM) is one of the most common paraneoplastic syndromes. It constitutes the most frequent cause of hypercalcemia in hospitalized patients. Its incidence had decreased in the past years due to bisphosphonates usage in patients with bone metastases . It occurs in 20-30% of all cancer patients, and is specially found in breast, lung and kidney cancer as well as multiple myeloma. It often indicates a more advanced disease and thus, worse prognosis.

Symptoms (Feldenzer KL, 2018; Shane E, 2022)

Mild hypercalcemia [serum calcium <12 mg/dL (3 mmol/L)]: It can be either asymptomatic or with unspecific symptoms:

- Neurological: anxiety, depression and fatigue;
- Gastrointestinal: constipation, anorexia and abdominal pain;
- Renal: polyuria (caused by nephrogenic diabetes insipidus);
- Cardiovascular: shortened QT interval, depressed ST segment and prolonged PR and QRS. Moderate hypercalcemia [serum calcium of 12-14 mg/dL (3-3.5 mmol/L)]:
- Neurological: altered mental status and hyporeflexia;
- Gastrointestinal: nausea, vomiting and weight loss (chronic);
- Renal: dehydration, nephrolithiasis (chronic);
- Cardiovascular: symptoms and signs similar to that of mild hypercalcemia;
- Musculoskeletal: weakness, bone pain (rare).

Severe hypercalcemia [serum calcium >14 mg/dL (>3.5 mmol/L)]:

- Neurological: lethargy, confusion, stupor and coma;
- Gastrointestinal: pancreatitis and peptic ulcer disease (rare);
- Renal: acute kidney injury and renal failure;
- Cardiovascular: elevation ST segment, arrhythmias, ventricular tachycardia and cardiac arrest;
- Musculoskeletal: weakness, bone pain (rare).

Etiology (Horwitz MJ, 2022; Zagzag J, 2018)

HCM is caused by three mainly mechanisms:

- Humoral HCM (80%): Tumour production of parathyroid hormone-related protein (PTHrP) is the most frequent pathway. It is correlated with squamous cell malignancies (lung, head and neck), kidney, bladder, breast and ovarian cancer, and also with other non-solid tumours. PTHrP has a similar structure than PTH (parathyroid hormone). Moreover, because of this reason, PTHrP bonds to the same receptor as PTH (PTH-1) and it can develop some of PTH actions. On the one hand, osteoblasts are stimulated by PTHrP and they secrete the Receptor Activator for Nuclear Factor κ B Ligand (RANKL) so it bonds to its receptor (RANK) in the osteoclasts. This stimulates its maturation and ultimately the calcium resorption and its release into the blood stream. On the other hand, it promotes calcium reabsorption in the kidney. It is less common that PTHrP stimulates calcitriol production (an active metabolite of vitamin D) and so it doesn´t increase calcium intestinal absorption like PTH really does. Bringing all of these together, it leads to a higher calcium concentration in the bloodstream, which consequently contributes to HCM development.
- Osteolytic HCM (20%): Local induction of osteolysis is a more frequent cause of HCM in multiple myeloma and bone metastases due to solid tumours such as breast cancer. These tumours activate certain cytokines that promote osteoclast production and activity, leading to calcium release. Moreover, in breast cancer cells PTHrP is more commonly produced and so it leads to HCM development.
- Vitamin-D secreting (<1%): An extrarenal production of calcitriol is the cause of HCM in lymphomas. Its raise promotes intestinal and bone absorption of calcium and it also decrease its urinary excretion.

It has been described another infrequent HCM related mechanism: ectopic PTH secretion.

Evidence

Level Grade PMID Nº

Pharmacotherapy Level GradeEvidence

PMID Nº

SALINE HYDRATION
- Isotonic saline corrects possible volume depletion due to hypercalcemia-induced urinary salt wasting and, in some cases, vomiting. Hypovolemia exacerbates hypercalcemia I A by impairing the renal clearance of calcium.
- Saline therapy requires careful monitoring since it can lead to fluid overload in patients who cannot excrete the administered salt because of impaired renal function, which can be induced by hypercalcemia or heart failure.
- Patients often require 1 or 2 liters as an initial bolus and then a maintenance rate of 150 to 300 cm3/hour to maintain adequate urine output. Care must be taken to avoid volume overload, especially in patients with renal insufficiency or heart failure.
BIPHOSPHONATES (BPs)
- After initial resuscitation, the next step includes intravenous administration of bisphosphonates. Through direct mechanisms they induce osteoclast apoptosis, and through I A indirect mechanisms acting on the osteoblasts they can reduce osteoclastic bone resorption. BPs should be given within 48 hours of diagnosis, because it takes 2 to 4 days for

them to have effect and response to therapy can last for 1 to 3 weeks.

- The two most commonly used are pamidronate (60-90 mg intravenously over 2-6 hours) and zoledronic acid (4 mg intravenously over 15-30 minutes). Retreatment with zoledronic acid may be considered for persistent hypercalcemia, but no sooner than 7 days after the initial dose.
- Nephrotoxicity must be taken into account when prescribing BPs. Thus, dose reductions have to be made depending on the glomerular filtration rate (GFR 50-60 mL/min, 3.5mg; GFR 40-49mL/min, 3.3mg; and GFR 30-39 mL/min, 3.0 mg. Other side effects include flu-like symptoms (fever, arthralgias, myalgia, fatigue, bone pain), uveitis, hypocalcemia, hypophosphatemia and osteonecrosis of the jaw.
- Oral bisphosphonates are not efficacious in the setting of HCM. They don´t lead to serum concentrations that are high enough to deactivate osteoclasts.

GLUCOCORTICOIDS
- Corticosteroid administration results in decreased bone resorption via inhibition of osteoclast maturation. It also diminishes the number of calcitriol receptors present in bone. I B Glucocorticoids serve to impede intestinal calcium absorption and cause an increase in renal calcium excretion. They are usually given as hydrocortisone 200 to 400 mg/day intravenously for three to four days and then prednisone 10 to 20 mg/day for seven days, or prednisone 40 to 60 mg/day for 10 days. Dexamethasone can be also useful in a dose

of 0,1-0,22mg/kg subcutaneously or intravenously every 12 hours. The duration of response is uncertain.

DENOSUMAB
- Denosumab is a fully human monoclonal antibody that binds to RANKL to prevent ligand interaction with RANK receptors on precursor osteoclasts. It interferes with osteoclast maturation, function and survival and reduces bone resorption. Its dose is 120 mg subcutaneously every 4 weeks and it can have a loading dose on days 8 and 15.
- Due to the fact that denosumab, unlike bisphosphonates, is not cleared by the kidney, there is no restriction of its use in patients with chronic kidney disease. However, it can I B cause renal impairment in patients with GFR <30 ml/min or on hemodialysis.
- Denosumab can lead to hypocalcemia, especially in patients with vitamin D deficiency, and osteonecrosis of the jaw. Further side effects include bone pain, nausea, diarrhea, and shortness of breath.
CALCITONIN
- It reduces the serum calcium concentration by increasing renal calcium excretion and by decreasing bone resorption via interference with osteoclast function. Calcitonin (4-8 I B U/kg intramuscularly or subcutaneously every 12 hours) has a rapid onset of action, lowering serum calcium levels by a maximum of approximately 2 mg/dL (0.5 mmol/L) for up

to 72 hours, beginning within four to six hours. It´s especially useful as an initial strategy along with hydration while waiting for other treatments to take effect.

- The efficacy of calcitonin is limited to the first 48 hours, but it has mild side effects.

7342172

30240520

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26355578

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25128013

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30240520

DYALISIS
- Dialysis may be indicated in patients with severe malignancy-associated hypercalcemia and renal insufficiency or heart failure, in whom hydration cannot be safely II A administered. Renal replacement therapy with low or calcium-free dialysate is highly effective at restoring normal calcemia with reductions of 3–5 mg/dL achieved over a 3–4

hour. Hypophosphatemia induced by hemodialysis should be searched for and corrected as appropriate.

LOOP DIURETICS
- They are no longer a strong recommendation because of the electrolyte abnormalities that they could cause. IV D
- They may be useful to prevent fluid overload in patients with renal insufficiency or heart failure.
- Specially if furosemide is used, potassium and phosphorus need to be monitored and replaced.

Therapeutic Strategy

Indication of treatment is based on the severity of the hypercalcemia and the nature of associated symptoms.

MILD HYPERCALCEMIA

[serum calcium <12 mg/dL (3 mmol/L)]

Asymptomatic or mildly symptomatic: do not require immediate treatment.

- Avoid factors that aggravate hypercalcemia (e.g. thiazide diuretics, volume depletion, inactivity, high calcium diet).
- Adequate hydration (at least 6-8 glasses of water per day).
- Treat the underlying cause.

MODERATE HYPERCALCEMIA

[serum calcium of 12-14 mg/dL (3-3.5 mmol/L)]

- Chronic hypercalcemia: proceed as mild hypercalcemia (see “Mild hypercalcemia”).
- Acute hypercalcemia: proceed as severe hypercalcemia (see “Severe hypercalcemia”).

SEVERE HYPERCALCEMIA

[serum calcium >14 mg/dL (>3.5 mmol/L)]

- Require treatment regardless of symptoms.

VERY SEVERE

[serum calcium of 18 – 20 mg/dL (4.5 – 5 mmol/L)]

- Proceed as severe hypercalcemia (see “Severe hypercalcemia”).Dialysis may be indicated in patients with severe malignancy-associated hypercalcemia and renal insufficiency or heart failure, in whom hydration cannot be safely administered. Renal replacement therapy with low or calcium-free dialysate is highly effective at restoring normal calcemia with reductions of 3-5 mg/dL achieved over a 3-4 hour. Hypophosphatemia induced by hemodialysis should be searched for and corrected as appropriate.

SALINE HYDRATION I B

Initial rate: 200-300 mL/hour » adjust to maintain urine output at 100-150 mL/hour.
Onset of action: hours. Duration of action: during infusion.
Monitor for fluid overload if renal impairment or elderly
Loop diuretics rarely used and only if fluid overload develops; not effective for reducing serum calcium. Avoid thiazide diuretics.

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CALCITONIN

- Initial dose: 4 IU/kg SC or IM every 12 hours » 4-8 IU/kg every 6 hours. I B
- Onset of action: 4-6 hours. Efficacy limited to the first 48 hours.
- Monitor serum calcium in several hours.

BISPHOSPHONATES

- Zoledronic Acid: 4 mg IV diluted 100 mL over 15-30 minutes. I A
- Alternative: Pamidronate: 60-90 mg IV over 2-6 hours.
- Onset of action: 2-4 days. Duration of action: 1-3 weeks.
- Adjust to renal function. Monitor serum calcium response.

If refractory hypercalcemia or contraindication of BPs due to severe renal impairment. I B

Denosumab: 120 mg SC every week for 4 weeks » monthly.

- Onset of action: 4-10 days. Duration of action: 4-15 weeks. If hypercalcemia associated with excess of vitamin D

Glucocorticoids: I B

- e.g. Hydrocortisone 200-400 mg IV per day for 3-4 days and then Prednisone 10-20 mg per day for 7 days; Prednisone 40-60 mg per day for 10 days.
- Onset of action: 2-5 hours. Duration of action: days to weeks.

If hypercalcemia due to parathyroid carcinoma, in hemodialysis patients with an elevated calcium-phosphorous product and secondary hyperparathyroidism 2 B

Calcimimetics (cinacalcet)

- Onset of action: 2-3 days. Duration of action: during therapy.

In case of very severe hypercalcemia consider DIALYSIS. 2 A

- Onset of action: hours. Duration of action: during treatment.

Relevant published studies

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27170690

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26675713

References

Agraharkar, M. “Hypercalcemia treatment and management”. Medscape. Las updated Feb 17, 2021.
Austin LA, Heath H 3rd. Calcitonin: physiology and pathophysiology. N Engl J Med. 1981; 29;304:269-78. PubMed PMID: 7003392.
Carroll, F. and Schade, D. A Practical Approach to Hypercalcemia. Am Fam Physician. 2003;67:1959-1966. PubMed PMID: 12751658.
Cicci JD, Buie L, Bates J, et al. Denosumab for the management of hypercalcemia of malignancy in patients with multiple myeloma and renal dysfunction. Clin Lymphoma Myeloma Leuk. 2014;14:e207-11. PubMed PMID: 25128013.
Daniels E, Sakakeeny C. Hypercalcemia: Pathophysiology, Clinical Signs, and Emergent Treatment. JAm Anim Hosp Assoc. 2015;51:291-9. PubMed PMID: 26355578.
Diel IJ, Body J-J, Stopeck AT et al. The role of denosumab in the treatment of hypercalcaemia of malignancy in cancer patients with metastatic bone disease. Eur J Cancer 2015;51:1467-75. PubMed PMID: 25976743.
Feldenzer KL, Sarno J. Hypercalcemia of Malignancy. JAdv Pract Oncol. 2018;9:496-504. PubMed PMID: 31086686.
Goldner W. Cancer-Related Hypercalcemia. J Oncol Pract. 2016;12:426-32. PubMed PMID: 27170690.
Green, T. “Hypercalcemia in Emergency Medicine”. Medscape. Last updated: Apr 29, 2020.
Horwitz MJ. Hypercalcemia of malignancy: Mechanisms. In: Rosen CJ, Mulder JE, editors. UpToDate; 2022 [accessed 25-01-22]. Available in: https://www.uptodate.com/contents/hypercalcemia-of-malignancy-mechanisms
Hosking DJ, Cowley A, Bucknall CA. Rehydration in the treatment of severe hypercalcaemia. Q J Med. 1981;50:473-81. PubMed PMID: 7342172.
Jameson JL, Fauci AS, Kasper DL, et al. Eds. “Harrison’s Principles of Internal Medicine”. 20th ed. McGraw Hill; 2018.
LeGrand, S. B., Leskuski, D, Zama, I Narrative Review: Furosemide for Hypercalcemia: An Unproven yet Common Practice. Annals of Internal Medicine. 2008; 149,259. PubMed PMID: 18711156.
Martin M, Bell R, Bourgeois H et al. Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid. Clin Cancer Res. 2012 1;18:4841-9. PubMed PMID: 22893628.
Minisola, S., Pepe, J., Piemonte, S. et al. The diagnosis and management of hypercalcaemia. BMJ. 2015; 350:h2723. PubMed PMID: 26037642.
Paiva, P. and Pimentel, J. “Hipercalcemia”. In Carneiro, A., Neutel, E. Manual de procedimentos do curso de evidência na emergência, 2010. 3.ª ed. Porto: Editora Quadricor, Artes Gráficas, Lda.
Pecherstorfer M, Steinhauer EU, Rizzoli R et al. Efficacy and safety of ibandronate in the treatment of hypercalcemia of malignancy: a randomized multicentric comparison to pamidronate. Support Care Cancer. 2003;11:539-47. PubMed PMID: 12783289.
Rosen LS, Gordon D, Tchekmedyian S et al. Zoledronic Acid Versus Placebo in the Treatment of Skeletal Metastases in Patients With Lung Cancer and Other Solid Tumors: A Phase III, Double-Blind, Randomized Trial—The Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003;21:3150-7. PubMed PMID: 12915606.
- Rosen LS, Gordon D, Kaminski M. et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter comparative trial. Cancer 2003.;98:1735-44. PubMed PMID: 14534891.
- Rosen LS, Gordon D, Tchekmedyian S et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with non-small cell lung carcinoma and other solid tumors: a randomized phase III double blind placebo-controlled trial. Cancer. 2004;100:2613-21. PubMed PMID: 15197804.
- Schwarz, P., Body J.J., Cap J. et al. The PRIMARA study: a prospective, descriptive, observational study to review cinacalcet use in patients with primary hyperparathyroidism in clinical practice. Eur J Endocrinol. 2014;171:727-35. PubMed PMID: 25240499.
- Shane, E. and Berenson, J. “Treatment of hypercalcemia”. UpToDate. Last updated: Aug 06, 2020.
- Shane E. Clinical manifestations of hypercalcemia. In: Rosen CJ, Mulder JE, editors. UpToDate; 2022 [accessed 03-02-22]. Available in: https://www.uptodate.com/contents/clinical-manifestations-of-hypercalcemia.
- Sternlicht H, Glezerman IG. Hypercalcemia of malignancy and new treatment options. Ther Clin Risk Manag. 2015;11:1779-88. PubMed PMID: 26675713
- Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352:373-9. PubMed PMID: 15673803.
- Stopeck AT, Lipton A, Body J-J et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010;28:5132–9. PubMed PMID: 21060033.
- Suki, W.N., Yium J.J., Von Minden M., et al. Acute treatment of hypercalcemia with furosemide. N Engl J Med 1970.;283:836-40. PubMed PMID: 5458033.
- Thosani S, Hu MI. Denosumab: a new agent in the management of hypercalcemia of malignancy. Future Oncol. 2015;11:2865-71. PubMed PMID: 26403973.
- Zagzag J, Hu MI, Fisher SB, et al. Hypercalcemia and cancer: Differential diagnosis and treatment. CACancer J Clin. 2018;68:377-386. PubMed PMID: 30240520.
- Walsh, J., Gittoes, N., Selby, P. et al. Society for Endocrinology Emergency Guidance: Emergency management of acute hypercalcaemia in adult patients. Endocrine Connections. 2016; 5, G9–G11.

ENDOCRANIAL HYPERTENSION

Authors: Ricardo Prat Acín, Andrés Beltrán Giner and Alexandra Guedes

Definition

Elevated intracranial pressure (ICP) is a potentially devastating complication of neurologic injury. Elevated ICP may complicate, central nervous system (CNS) tumours, and derived hydrocephalus.

Brain parenchyma – 80 percent.
Cerebrospinal fluid (CSF) – 10 percent.
Blood – 10 percent.

The interrelationship between changes in the volume of intracranial contents and changes in ICP defines the compliance characteristics of the intracranial compartment.

Intracranial compliance can be modelled mathematically (as in other physiologic and mechanical systems) as the change in volume over the change in pressure (dV/dP).

Symptoms and signs

Evidence

Level Grade PMID Nº

15258230

15046669

The major causes of increased ICP include:

- Intracranial mass lesions (e.g., tumour, hematoma).
- Cerebral oedema .
- Increased CSF production (e.g., choroid plexus papilloma).
- Decreased CSF absorption (e.g., arachnoid granulation adhesions after tumoral bleeding meningitis)• Obstructive hydrocephalus.
- Obstruction of venous outflow .

Studies

ICP monitoring

Indications

In general, invasive monitoring of ICP is indicated in patients who are:

- Suspected to be at risk for elevated ICP.
- Comatose (Glasgow Coma Scale [GCS] <8).
- Diagnosed with a process that merits aggressive medical care.

Types of monitors

Waveform analysis

11889475

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1436417

1782538

9012577

Osmotic therapy and diuresis – With growing familiarity of use, hypertonic saline has increasingly been employed as a first-line agent, supplanting mannitol at numerous institutions.

III	B	18272864
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II	A	21942722
II	A	11889475
II	B	12576970
II	A	6415245
II	B	1907077
I	A	30883663
IV	C	6202480
I	A	30883663
I	A	19957014

Other agents – Furosemide, 0.5 to 1.0 mg/kg intravenously, may be given with mannitol to potentiate its effect. However, this effect can also exacerbate dehydration and hypokalaemia

Therapeutic Strategy

I	A	10961490
II	B	7490638
III	A	15259863

- A history that suggests elevated ICP (e.g., sudden severe headache suggesting tumoral haemorrhage).
- An examination that suggests elevated ICP (unilateral or bilaterally fixed and dilated pupil[s], decorticate or decerebrate posturing, bradycardia, hypertension and/or respiratory depression).
- AGlasgow Coma Scale (GCS) ≤8.
- Potentially confounding and reversible causes of depressed mental status, such as hypotension (systolic BP [SBP] <60 mmHg in adults), hypoxemia (PaO2 <60 mmHg), hypothermia (<36oC), or obvious intoxication, are absent.

In such patients, osmotic diuretics may be used urgently.

In addition, standard resuscitation techniques should be instituted as soon as possible:

- Head elevation.
- Hyperventilation to a PCO2 of 26 to 30 mmHg.
- Intravenous mannitol (1 to 1.5 g/kg).

I	A	31194438
III	A	1404521
II	A	338285171
I	A	31194438
II	B	3772451

Monitoring and the decision to treat – If a diagnosis of elevated ICP is suspected and an immediately treatable proximate cause is not present, then ICP monitoring should be instituted.

The goal of ICP monitoring and treatment should be to keep ICP <20 mmHg. Interventions should be utilized only when ICP is elevated above 20 mmHg for >5 to 10 minutes.

Hypertonic saline in bolus doses may acutely lower ICP, but further investigations are required to define a role, if any, for this approach in the management of elevated ICP.

Propofol has been utilized to good effect in this setting, as it is easily titrated and has a short half-life, thus permitting frequent neurologic reassessment.

V	D	3136668
I	B	1919695

decreasing metabolic demand can lower ICP by reducing blood flow.

II	B	848367
II	B	22381845
IV	C	8065488

Potential complications of surgery include herniation through the skull defect, spinal fluid leak, wound infection, and epidural and subdural hematoma.

References

PMID 15258230 Hadjikoutis S, Carroll C, Plant GT. Raised intracranial pressure presenting with spontaneous periorbital bruising: two case reports. J Neurol Neurosurg Psychiatry. 2004;75(8):1192-1193. doi:10.1136/jnnp.2003.016006
PMID 15046669 Binder DK, Lyon R, Manley GT. Transcranial motor evoked potential recording in a case of Kernohan’s notch syndrome: case report. Neurosurgery. 2004;54(4):999-1003. doi:10.1227/01.neu.0000115674.15497.09
PMID 11889475 Dennis LJ, Mayer SA. Diagnosis and management of increased intracranial pressure. Neurol India. 2001;49 Suppl 1:S37-S50.
PMID 3598682 Ostrup RC, Luerssen TG, Marshall LF, Zornow MH. Continuous monitoring of intracranial pressure with a miniaturized fiberoptic device. J Neurosurg. 1987;67(2):206-209. doi:10.3171/jns.1987.67.2.0206
PMID 1436417 Gambardella G, d’Avella D, Tomasello F. Monitoring of brain tissue pressure with a fiberoptic device. Neurosurgery. 1992;31(5):918-922. doi:10.1227/00006123-199211000-00014

I A

III B

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6856064

PMID 1782538 Hayashi M, Handa Y, Kobayashi H, Kawano H, Ishii H, Hirose S. Plateau-wave phenomenon (I). Correlation between the appearance of plateau waves and Level Grade PMID Nº

CSF circulation in patients with intracranial hypertension. Brain. 1991;114 ( Pt 6):2681-2691. doi:10.1093/brain/114.6.2681

PMID 9012577 Manno EM. Transcranial Doppler ultrasonography in the neurocritical care unit. Crit Care Clin. 1997;13(1):79-104. doi:10.1016/s0749-0704(05)70297-9
PMID 18272864 Koenig MA, Bryan M, Lewin JL 3rd, Mirski MA, Geocadin RG, Stevens RD. Reversal of transtentorial herniation with hypertonic saline. Neurology. 2008;70(13):1023-1029. doi:10.1212/01.wnl.0000304042.05557.60
PMID 21242790 Kamel H, Navi BB, Nakagawa K, Hemphill JC 3rd, Ko NU. Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: a meta- analysis of randomized clinical trials. Crit Care Med. 2011;39(3):554-559. doi:10.1097/CCM.0b013e318206b9be
PMID 21942722 Mortazavi MM, Romeo AK, Deep A, et al. Hypertonic saline for treating raised intracranial pressure: literature review with meta-analysis. J Neurosurg. 2012;116(1):210-221. doi:10.3171/2011.7.JNS102142
PMID 12576970 Polderman KH, van de Kraats G, Dixon JM, Vandertop WP, Girbes AR. Increases in spinal fluid osmolarity induced by mannitol. Crit Care Med. 2003;31(2):584-590. doi:10.1097/01.CCM.0000050287.68977.84
PMID 6415245 Pollay M, Fullenwider C, Roberts PA, Stevens FA. Effect of mannitol and furosemide on blood-brain osmotic gradient and intracranial pressure. J Neurosurg. 1983;59(6):945-950. doi:10.3171/jns.1983.59.6.0945
PMID 1907077 García-Sola R, Pulido P, Capilla P. The immediate and long-term effects of mannitol and glycerol. A comparative experimental study. Acta Neurochir (Wien). 1991;109(3-4):114-121. doi:10.1007/BF01403005
PMID 6202480 Gabor AJ, Brooks AG, Scobey RP, Parsons GH. Intracranial pressure during epileptic seizures. Electroencephalogr Clin Neurophysiol. 1984;57(6):497-506. doi:10.1016/0013-4694(84)90085-3
PMID 30883663 Chang, S. M., Messersmith, H., Ahluwalia, M., Andrews, D., Brastianos, P. K., Gaspar, L. E., Gatson, N. N., Jordan, J. T., Khasraw, M., Lassman, A. B., Maues, J., Mrugala, M., Raizer, J., Schiff, D., Stevens, G., Sumrall, A., Van den Bent, M., & Vogelbaum, M. A. (2019). Anticonvulsant prophylaxis and steroid use in adults with metastatic brain tumors: summary of SNO and ASCO endorsement of the Congress of Neurological Surgeons guidelines. Neuro-oncology, 21(4), 424–427. https://doi.org/10.1093/neuonc/noz034
PMID 19957014 Ryken, T. C., McDermott, M., Robinson, P. D., Ammirati, M., Andrews, D. W., Asher, A. L., Burri, S. H., Cobbs, C. S., Gaspar, L. E., Kondziolka, D., Linskey, M. E., Loeffler, J. S., Mehta, M. P., Mikkelsen, T., Olson, J. J., Paleologos, N. A., Patchell, R. A., & Kalkanis, S. N. (2010). The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline. Journal of neuro-oncology, 96(1), 103–114. https://doi.org/10.1007/s11060-009-0057-4
PMID 10961490 Procaccio, F., Stocchetti, N., Citerio, G., Berardino, M., Beretta, L., Della Corte, F., D’Avella, D., Brambilla, G. L., Delfini, R., Servadei, F., & Tomei, G. (2000). Guidelines for the treatment of adults with severe head trauma (part I). Initial assessment; evaluation and pre-hospital treatment; current criteria for hospital admission; systemic and cerebral monitoring. Journal of neurosurgical sciences, 44(1), 1–10.
PMID 15259863 Smith, E. R., & Madsen, J. R. (2004). Cerebral pathophysiology and critical care neurology: basic hemodynamic principles, cerebral perfusion, and intracranial pressure. Seminars in pediatric neurology, 11(2), 89–104. https://doi.org/10.1016/j.spen.2004.04.001
PMID 31194438 Munakomi, S., & M Das, J. (2022). Intracranial Pressure Monitoring. In StatPearls. StatPearls Publishing.
PMID: 1404521 Schmoker, J. D., Shackford, S. R., Wald, S. L., & Pietropaoli, J. A. (1992). An analysis of the relationship between fluid and sodium administration and intracranial pressure after head injury. The Journal of trauma, 33(3), 476–481. https://doi.org/10.1097/00005373-199209000-00024
PMID: 33828517 Musick, S., & Alberico, A. (2021). Neurologic Assessment of the Neurocritical Care Patient. Frontiers in neurology, 12, 588989. https://doi.org/10.3389/fneur.2021.588989
PMID 3772451 Rosner, M. J., & Coley, I. B. (1986). Cerebral perfusion pressure, intracranial pressure, and head elevation. Journal of neurosurgery, 65(5), 636–641. https://doi.org/10.3171/jns.1986.65.5.0636
PMID 1919695 Muizelaar, J. P., Marmarou, A., Ward, J. D., Kontos, H. A., Choi, S. C., Becker, D. P., Gruemer, H., & Young, H. F. (1991). Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial. Journal of neurosurgery, 75(5), 731–739. https://doi.org/10.3171/jns.1991.75.5.0731
PMID 6856064 Rea, G. L., & Rockswold, G. L. (1983). Barbiturate therapy in uncontrolled intracranial hypertension. Neurosurgery, 12(4), 401–404. https://doi.org/10.1227/00006123-198304000-00005
PMID 848367 James, H. E., Langfitt, T. W., Kumar, V. S., & Ghostine, S. Y. (1977). Treatment of intracranial hypertension. Analysis of 105 consecutive, continuous recordings of intracranial pressure. Acta neurochirurgica, 36(3-4), 189–200. https://doi.org/10.1007/BF01405391
PMID: 22381845 Di Rocco, F., Jucá, C. E., Zerah, M., & Sainte-Rose, C. (2013). Endoscopic third ventriculostomy and posterior fossa tumors. World neurosurgery, 79(2 Suppl), S18.e15–S18.e19. https://doi.org/10.1016/j.wneu.2012.02.018
PMID 8065488 Jourdan, C., Convert, J., Mottolese, C., Bachour, E., Gharbi, S., & Artru, F. (1993). Evaluation du bénéfice clinique de l’hémicraniectomie décompressive dans l’hypertension intracranienne non contrôlée par le traitement médical [Evaluation of the clinical benefit of decompression hemicraniectomy in intracranial hypertension not controlled by medical treatment]. Neuro-Chirurgie, 39(5), 304–310.

ACUTE BLEEDING

Authors: Teresa Puértolas Hernández, Ana María Comín Orce and Belén López Roldán

Symptoms Level GradeEvidence

PMID Nº

Acute bleeding is associated with symptoms such as dizziness, cold and clammy skin, hypotension, blanching, tachycardia, dyspnoea, and asthenia. (1)
Depending on the location of the bleeding we can also find:
- Haemoptysis. It consists of the emission of blood with expectoration from the trachea-bronchial tree or the lungs. Its magnitude can vary from blood streaks to massive haemoptysis (loss of 600 cc/day or more than 50-75 cc/hour or when appear signs and symptoms of hypovolemia or respiratory failure regardless of its amount)
- Upper gastrointestinal bleeding. It is the one that occurs between the oral cavity and Treize ligament. It appears like:
  - hematemesis or vomiting with fresh undigested blood
  - melaena or stools foul-smelling blackish, with digested or partially coagulated blood
  - haematochezia or bloody stools
- Low digestive bleeding. It manifests itself like a rectal bleeding or emission of red blood from the rectum.
- Intracranial bleeding is associated with some neurological deficit such as aphasia, hemiplegia, hemiparesis, instability, etc. Headache and vomiting usually also appear and in massive haemorrhages it can manifest with drowsiness, stupor and/or coma.
- Haematuria or bleeding in the urine. May associate pain if bleeding is with blood clots

Aetiology

Platelet alterations or thrombopenia: it is a decrease in the blood platelet count (less than 100,000 platelets/mm3). The risk of bleeding appears when the platelet count is less than 20,000 platelets/mm3. The causes can be:
- production deficit in the bone marrow due to infiltration by the tumour
- increased destruction by antibodies or chemotherapy
- a greater consumption by the formation of thrombus
- greater dilution in cases of extra fluid intake or mass transfusion
- platelet sequestration in the spleen due to splenomegaly and/or portal hypertension
Alterations in coagulation. Decreased or defective production of coagulation factors due to:

a )Liver failure, either due to metastasis or drugs: as most of the proteins involved in coagulation and fibrinolysis are synthesized in the liver, a decrease in their function will favour bleeding.

Fibrinolysis. We differentiate:

Vascular defects. Due to defects in the blood vessels causing petechiae, bruising and haematomas. Severe haemorrhages son rare, have been described in hereditary haemorrhagic telangiectasia, in cases where there is a deficit of vascular and perivascular collagen (Ehlers-Danlos syndrome) and in hereditary connective tissue disorders (Marfan syndrome)

Studies

The studies should focus on identifying the cause of the bleeding, so they depend on the source of bleeding.

In general, we can do:

History, blood pressure and exploration
Review concurrent medications, focused on non-steroidal anti-inflammatory drugs and/or anticoagulants.

– Analytics: Complete blood counts, coagulation profiles. Sometimes urinalysis or blood in the stool can be helpful.

Specific tests to focus on the origin of acute bleeding:

Brain CT or body CT, abdominal ultrasound.
Endoscopic studies such as gastroscopy, colonoscopy, bronchoscopy, cystoscopy, hysteroscopy.

– Angiography studies.

Pharmacotherapy

Level Grade PMID Nº

VITAMIN K (Fistomenadione). When there is a deficit of coagulation factors. 2B C

VASOPRESSIN/DESMOPRESSIN. Doses between 0.1- 0.4 mg continuous infusion. Useful in bleeding from tumours of the upper digestive tract. 2B C Vasoconstrictor effects on myocardium, mesenteric and cerebral circulation should be considered.
SOMATOSTATIN ANALOGUES. Dose in acute bleeding: a bolus of 50 microg intravenous or subcutaneous, followed by a continuous infusion of 50 microg/hour for 48h. 2B C

Used in upper gastrointestinal bleeding.

High doses may cause nausea, abdominal discomfort, and diarrhoea.

TRANEXAMIC ACID. The recommended intravenous dose is 10mg/kg 3-4 times daily, infused over one hour. 3 D
AMINOCAPROIC ACID. The dose is 4-5 g in 250 ml over one hour and thereafter 1g/h in 50 ml administered as an 8-hour continuous infusion until bleeding is controlled. 3 D
RADIOTHERAPY. It can be administered in different regimens: single doses of 8-10Gy, intermediate regimen of 4-8 Gy in 3-5 doses or long regimen of 30-45Gy in 10-15 sessions. 2B C Useful in haemoptysis due to lung cancer, in vaginal, skin, rectal and bladder bleeding and in head and neck, oesophageal and gastric tumours.

Therapeutic Strategy

- The probability of reversing or controlling bleeding depending on the underlying aetiology. – The risk-benefit depending on the tumour situation.
- The patient’s life expectancy and quality of life.

There are two lines of action:

SYSTEMIC TREATMENT:
- Stabilise the patient: fluids, volume expanders and blood components. Remove anti-inflammatory drugs and anticoagulants. – Vitamin K
- Vasopressin – Somatostatin analogues – Tranexamic acid – Symptomatic treatment of end-of-life patients
LOCAL INTERVENTION:
- Dressings, local compression, haemostatic agents, tamponades – Balloon catheters: Foley catheter or Sengstaken-Blakemore catheter
- Radiotherapy – Endoscopy – Transcutaneous arterial embolization – Surgery

PLASMA FLUIDS AND/OR EXPANDERS in case of haemodynamic instability. 2B B
BLOOD COMPONENTS OF: HEMATIA, PLATELETS OR FRESH PLASMA, depending on whether there is symptomatic anaemia, thrombocytopenia or if there is an alteration in 2A B platelet function respectively.
VITAMIN K, in cases where an elevated INR or prolongation of the prothrombin time is detected in the blood test. 2B C
VASOPRESIN, in bleeding from tumours of the upper digestive tract, vasopressin can stop bleeding in up to 50% of cases. Its vasoconstrictor effects on the myocardium, mesenteric

and cerebral circulation must be considered.

SOMATOSTATIN ANALOGUES are also used in upper gastrointestinal bleeding, although surgery would be more effective. 2B C
TRANEXAMIC ACID inhibits the lysis of fibrin clots. In vitro it is ten times more potent than amino caproic acid. 3 D
DRESSINGS, LOCAL COMPRESSION, TAMPONADE. They are useful in cases where there is superficial bleeding. Tamponades can be used in nosebleeds, vaginal or rectal 2A B bleeding, with different swabs, which can be coated with chemicals to facilitate haemostasis.

HEMOSTATIC AGENTS, applied to the area of superficial bleeding, such as epinephrine, thrombin/thromboplastin, prostaglandins E2 and F2, or silver nitrate among others.

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Level Grade PMID Nº

BALLON CATHETERS, such as Foley catheter or Sengstaken-Blakemore catheter in oesophageal bleeding. These are temporary measures because prolonged pressure can 3 D cause local ischaemia.
RADIOTHERAPY. It has been shown to be effective in haemoptysis due to lung cancer (up to 80%), rectal bleeding (controls up to 85%), haematuria in bladder cancer (controls up to 2B C

ENDOSCOPY. It can be useful in bleeding from the upper digestive tract, lung, and bladder. This technique can be used to cauterise bleeding vessels, either with argon, by placing

clips, with injection of epinephrine or sclerosing agents, or with laser. 2C C

TRANSCUTANEOUS ARTERIAL EMBOLISATION. For patients with tumours of the head and neck, pelvis, lung, and gastrointestinal tract. 2B B
SURGERY. This may be the last option for patients in whom previous treatments have failed. It consists of vessel ligation or resection of the bleeding tumour.

References

3.- Candice Johnstone, Shayna E. Rich. Bleeding in cancer patients and its treatment: a review. Ann Palliat Med 2018;7(2):265-273

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8.- Ker K, Edwards P, Perel P, et al. Effect of tranexamic acid on surgical bleeding: Systematic review and cumulative meta-analysis. BMJ 2012;344:e3054.

13.- Patsner B. Topical acetone for control of life-threatening vaginal hemorrhage from recurrent vaginal gynaecological cancer. Eur J Gynaecol Oncol 1993;1433-1435.

19.- Yan J, Milosevic M, Fyles A, et al. Ahypofractionated radiotherapy regimen (0-7-21) for advanced gynaecological cancer patients. Clin Oncol (R Coll Radiol) 2011;23:476-81.

23.- Delgal A, Cercueil JP, Koutlidis N, et al. Outcome of transcatheter arterial embolization for bladder and prostate hemorrhage. J Urol 2010;183:1947-53.

INFUSION REACTIONS

Authors: Inês Leão, Ema Neto and Pedro Simões

Definition

Table 1. NCI CTCAE v5.0 classification

Grade	Infusion-related reaction	Cytokine release syndrome	Allergic reaction	Anaphylaxis
1	Mild and transient reaction; infusion interruption or intervention not indicated.	Fever with/without constitutional symptoms.	Systemic intervention not indicated.
2	Therapy or infusion interruption indicated but responds promptly to symptomatic treatment; prophylactic medications indicated for <=24 hrs.	Hypotension responding to fluids; hypoxia responding to <40% O2.	Oral intervention indicated.
3	Prolonged (not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae.	Hypotension managed with one pressor; hypoxia requiring ≥40% O2.	Bronchospasm; hospitalization indicated for clinical sequelae; intravenous intervention indicated.	Symptomatic bronchospasm, with or without urticaria; parenteral intervention indicated; allergy-related oedema/angioedema; hypotension.
4	Life-threatening consequences: urgent intervention indicated.	Life-threatening consequences: urgent intervention indicated.	Life-threatening consequences: urgent intervention indicated.	Life-threatening consequences: urgent intervention indicated.
5	Death.	Death.	Death.	Death.

Symptoms

Evidence

Level Grade PMID Nº

Typical symptoms of IR include mucocutaneous manifestations (90% of patients), respiratory (40%), circulatory (30%–35%) or abdominal symptoms, that appears minutes to Level GradeEvidence

hours after exposure to the drug. The same drug might produce different clinical symptoms and signs in different individuals.

Mucocutaneous symptoms: flushing, urticaria, pruritus (see Chapter 91 Skin Hypersensitivity)
Upper airway symptoms: rhinorrhoea, coryza, sternutation
Lower airway symptoms: wheezing, dyspnoea, cough, chest tightness, oxygen desaturation
Gastrointestinal symptoms: nausea, vomiting, diarrhoea, abdominal cramps, bloating, reflux
Circulatory symptoms: tachycardia, syncope, hypertension, hypotension
Neuromuscular symptoms: numbness, weakness, seizures, unusual taste
Influenza-like symptoms: chills, fever, headache, myalgia, arthralgia, fatigue, diaphoresis

In non-immediate / delayed HSR other organs may be affected, and symptoms may include lymphadenopathy, hepatitis, renal failure, pneumonitis, anaemia, neutropenia, and thrombocytopenia.

Although their mechanism is due to the direct action of the chemotherapy agents, two specific syndromes can either appear in association or be confused with IR:

Acute laryngopharyngeal dysesthesia: sensation of dyspnoea, difficulty in swallowing or talking, jaw tightness, “tingling” / “itchy” sensation in the tongue and/or pharynx; occurs during or after oxaliplatin infusion, often related to cold air inhalation / cold beverage ingestion.
Irinotecan-related cholinergic syndrome: diarrhoea, emesis, diaphoresis, abdominal cramps, hyper lacrimation, rhinorrhoea; occurring within the first 24h of irinotecan administration.

Cytokine-Release Syndrome

Anaphylaxis

The diagnosis of anaphylaxis is purely clinical, and it is likely if at least one of the criteria summarized on Table 2 is fulfilled.

Table 2. Clinical criteria for diagnosing anaphylaxis.

Illness of acute onset (minutes to hours since exposure to trigger)with cutaneous / mucous involvement (e.g. hives, generalised pruritus, glossal / uvular

swelling) and at least one of:

Respiratory symptoms (e.g. dyspnoea, wheezing, stridor, hypoxaemia)
Reduced blood pressure or symptoms of end-organ dysfunction (e.g. hypotonia [collapse], syncope, incontinence)

Illness of acute onset with two or more of:

Cutaneous / mucous membranes involvement (see above)
Respiratory symptoms (see above)
Reduced blood pressure or symptoms of end-organ dysfunction (see above)
Persistent gastrointestinal symptoms (e.g. abdominal cramps, nausea and/or vomiting)

Reduced blood pressure of acute onset after exposure to known trigger for that patient (defined by a systolic blood pressure of < 90 mmHg or > 30%

decrease from baseline)

PMID Nº

Etiology

Treatment schemes combining different drugs are very common and it is crucial to recognise the features of an IR to determine which drug is most likely to have caused it and act accordingly.

Table 3. Characteristics of IRs with some drugs.

Evidence

Level Grade PMID Nº

Drug Incidence of IRs Onset Signs / Symptoms
Anthracyclines	7%–11% with PEGylated liposomal doxorubicin and daunorubicin.	Most IRs occur on the first infusion.	Chest pain, pruritus, syncope, flushing, chills, fever, urticaria, angioedema, rash, tachycardia, hypotension, dyspnoea, nausea, vomiting, headache, back pain.
Atezolizumab	1% – 2%	Most IRs occur on the first infusion.	Chills, itching, flushing, shortness of breath, swelling, dizziness, fever, pain.
Bevacizumab	IRs <3% during the first infusion. Severe in<1%.	Most IRs occur on the first infusion. The likelihood pf an IR declines with each subsequent course of therapy.	Dyspnoea, flushing, rash, blood pressure changes, chest pain, rigours, nausea, vomiting.
Bleomicine	1%	Immediate or delayed for several hours, usually after the first or second dose.	Hypotension, mental confusion, fever, chills, wheezing.
Carboplatin	12%	Highly variable (minutes to hours). The risk increases with cumulative doses. Highest incidence 8th course.	Rash, itching, erythema on palms and soles, abdominal cramps, facial oedema, bronchospasm, hypotension, tachycardia, dyspnoea, chest pain.
Cetuximab	90% on the first infusion. Severe 2%–5%.	Most IRs occur on the first infusion. The likelihood pf an IR declines with each subsequent course of therapy.	Flushing, rash, fever, urticaria, chills, bronchospasm, dyspnoea, nausea, vomiting, blood pressure changes, angina, myocardial infarction.
Daratumumab	IRs 40%–50%, most mild to moderate in severity. 82%–95% on the first infusion.	Most IRs occur on the first infusion. The likelihood pf an IR declines with each subsequent course of therapy.	Nasal congestion, chills, cough, allergic rhinitis, throat irritation, dyspnoea and nausea. Less frequent: bronchospasm, hypertension and hypoxia.
Daratumumab

Evidence

Level Grade PMID Nº

Docetaxel	30% IRs without premedication. 2% severe reactions with premedication.	First or second dose, within the first 10 min of infusion.	Hypotension, dyspnoea, bronchospasm, urticaria, skin reactions, angioedema, flushing, pruritus, tachycardia, chest or back pain.
Etoposide	Anaphylactic reactions 1%–3%.	Usually after first doses.	Hypotension, fever, chills, urticaria, bronchospasm, angioedema, chest discomfort.
Ipilimumab	2%–5%, the majority grade 2 IRs. More common after the first dose.	Most IRs occur on the first infusion.	Pruritus, maculopapular rash, cough, shortness of breath, chills, rigors, facial flushing, chest, abdominal or back pain.
Nivolumab	5%, including grade 3–4 IRs.		Facial flushing, hives, angioedema.
Oxaliplatin	HSR 0.5%–25%. Severe reactions <1%.	Within 60 min after the start of infusion (typically 5–10 min). Highest incidence seventh to eighth course.	Sweating, watering, pruritus, rash, back or chest pain, laryngospasm, dyspnoea, fever, urticaria, bronchospasm, hypotension.
Paclitaxel	30% IRs without premedication. Severe anaphylactic reactions in 2%–4%.	First or second dose, within the first 10 min of infusion.	Flushing, skin reactions, dyspnoea, Hypotension, tachycardia, bronchospasm, angioedema, urticaria.
Panitumumab	IRs in 4% of patients. Severe in<1%.	Most IRs occur on the first infusion. The likelihood pf an IR declines with each subsequent course of therapy.	Chills, dyspnoea, flushing, blood pressure changes, pyrexia, tachycardia, vomiting, anaphylaxis, angioedema, bronchospasm.
Pembrolizumab	3% IRs. Grade 3 <1%.		Pyrexia, chills.
Rituximab	77% on the first infusion. Severe reactions 10%.	Most IRs occur on the first infusion. The likelihood pf an IR declines with each subsequent course of therapy.	Fever, chills, rash, dyspnoea, hypotension, nausea, rhinitis, urticaria, pruritus, asthenia, angioedema, bronchospasm. May be associated with features of tumour lysis syndrome.
Trastuzumab	20%–40% on the first infusion. Severe reactions <1%.	Most IRs occur on the first infusion. The likelihood pf an IR declines with each subsequent course of therapy.	Chills, fever, blood pressure changes, bronchospasm, itching, dyspnoea, wheezing, arrhythmia, angioedema.

Studies

Blood tests may reflect the systemic inflammatory response, therefore helping on the diagnosis or its severity classification:

Haematology: leucocytosis may appear due to the systemic inflammatory response or treatment with glucocorticoids; anaemia, leukopenia, neutropenia, or thrombocytopenia may occur due to the underlying malignancy or its treatment.
Electrolytes: electrolyte abnormalities such as hypophosphatemia, hypokalaemia, or hyponatremia occur commonly in cytokine-release syndrome.
End-organ function: abnormalities of renal and/or liver function tests are common, especially in more severe cases.
Inflammation markers: nonspecific markers of inflammation like C-reactive protein or ferritin may be elevated.
Biochemical mediators released during the degranulation of mast cells and basophils: plasma histamine begins to rise within 5 min and remains elevated for 15-60min. Urinary histamine metabolites, may be found for up to 24h after onset of anaphylaxis. Serial measurements of tryptase levels 15 min to 3h after onset of an IR and their comparison to the baseline tryptase level after recovery.

– Normal levels of tryptase or histamine do not rule out the clinical diagnosis of anaphylaxis.

Therapeutic Strategy

Evidence

Level Grade PMID Nº

Before the administration of the drug: assess patient´s medical history and concomitant treatment. Ensure appropriate pre-medications. V C
Primary prophylaxis: Antihistamines (H1 / H2 antagonists) and / or glucocorticoids, if drugs with high incidence of infusion reactions (e.g. paclitaxel, docetaxel, cabazitaxel or asparaginase).

Acute management of IR

Stop the infusion and maintain i.v. access. V C
Vital signs, ABCs (airway, beathing, circulation) and consciousness.
If hypotension, place the patient in the trendelenburg position
If respiratory distress, the patient should be sitting up
If unconscious, place the patient in a recovery position
Oxygen if hypoxia.

HSR suspected / Cytokine-release: IV B

Grade 1: slow rate of infusion

Secondary prophylaxis: Antihistamines (H1 / H2 antagonists) and / or glucocorticoids.

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H1 antagonists: chlorpheniramine 10 mg i.v., dexchlorpheniramine 5 mg i.v., diphenhydramine 25-50 mg i.v., clemastine 2 mg i.v., cetirizine 10 mg i.v.
H2 antagonists: famotidine 20 mg i.v., ranitidine 50 mg i.v.

The combined use of H1 and H2 histamine blockers is superior to their use alone.

Glucocorticoids: methylprednisolone i.v. 1-2mg/kg (different protocols).
Adrenaline i.m. immediately at a dose of 0.01 mg/kg (maximum total dose of 0.5 mg) and can be repeated every 5-15 minutes.
Atropine 600 g i.v. (if bradicardia).

V C

I B

V C

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Glucagon 1–5 mg i.v. infusion over 5 min followed by an infusion 5–15 µg /min titrated to clinical response.	V	C	28881914

References

PMID 28881914: Roselló S, Blasco I, Fabregat LG, Cervantes A, Jordan K. Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Annals of Oncology. 2017 Jul 1;28:iv100–18. DOI: 10.1093/annonc/mdx216.
Castells MC, Matulonis UA, Horton TM. Infusion reactions to systemic chemotherapy. UpToDate, topic last updated January 19, 2021 [Internet]: https://www.uptodate.com/contents/infusion- reactions-to-systemic-chemotherapy
LaCasce AS, Castells MC, Burstein HJ, Meyerhardt. Infusion-related reaction to therapeutic monoclonal antibodies used for cancer therapy. UpToDate, topic last updated September 15, 2021 [Internet]: https://www.uptodate.com/contents/infusion-related-reactions-to-therapeutic-monoclonal-antibodies-used-for-cancer-therapy

EMERGENCY KIT

Authors: Joana Marinho, Tania Duarte and Ana Leonor Matos

Definition

Symptoms

Evidence

Level Grade PMID Nº

Most oncologic emergencies can be classified as metabolic, hematologic, structural, or treatment-related and symptoms can vary according to the aetiology and organ, or system involved.

Etiology

IV fluid challenge: 20-30 mL/Kg saline, dextrose 5%.
Adrenaline for anaphylaxis: Intramuscular (IM) adrenaline (0.5 mg (which is 0.5 mL of a 1 mg in 1 mL ampoule of adrenaline)) into the anterolateral thigh as soon as anaphylaxis is suspected. Repeat the IM adrenaline if there is no improvement in the patient’s condition after about 5 min.

Therapeutic Strategy

All hospital staff should be able to rapidly recognise cardiac arrest, call for help, start cardiopulmonary resuscitation (CPR), and defibrillate rapidly (<3 min) when appropriate.
European hospitals should adopt a standard “cardiac arrest call” telephone number (2222) .
Hospitals should have a resuscitation team that immediately responds to in hospital cardiac arrest (IHCA) or to patients who are critically ill or at risk of clinical deterioration.

Initial rescue should follow:

Airway:
- Ensure patient’s airway.
- Treat life-threatening hypoxia with 100% inspired oxygen. Once SpO2 can be measured reliably or arterial blood gas values are obtained, titrate the inspired oxygen to achieve an arterial oxygen saturation of 94-98% or PaO2 75-100kPa.
Breathing:
- Assess respiratory rate, accessory muscle use, ability to speak in full sentences, pulse oximetry, percussion and breath sounds, request chest X-ray.
- Consider non-invasive ventilation if respiratory distress and safe to do so.
- If an advanced airway is required, only rescuers with a high tracheal intubation success rate should use tracheal intubation.
Circulation:
- Assess heart rate and blood pressure, place the patient on a cardiac and oxygen saturation monitor and obtain ECG.
- Obtain intravenous (IV) access to enable drug delivery and blood collection.
- Consider IV fluids (crystalloids) and/or vasoactive drugs to support the circulation.
Disability:

-Check patient’s neurological status (Glasgow coma scale) and vital signs periodically.

Exposure:

-Maintain normothermia.

In the case of cardiac arrest
- Activate cardiac arrest protocol according to your institution (call 2222).
- Start CPR – Alternate 30 chest compressions to 2 ventilations. If you are unable to provide ventilations, give continuous chest compressions.
- Apply an Automated External Defibrillator and follow instructions.
- If an advanced airway is required, only rescuers with a high tracheal intubation success rate should use tracheal intubation.
- Follow existing protocols after resuscitation team arrives.
In case of suspected anaphylaxis
- Recognizing is essential, by the presence of airway (swelling), breathing (wheeze or persistent coughing), or circulation (hypotension) problems with or without skin and mucosal changes.

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- Identify and remove or stop the trigger.
- Give intramuscular (IM) adrenaline (0.5 mg (which is 0.5 mL of a 1 mg in 1 mL ampoule of adrenaline)) into the anterolateral thigh as soon as anaphylaxis is suspected. Repeat the IM adrenaline if there is no improvement in the patient’s condition after about 5 min.
- Stabilize and follow the previous outline (ABCD).
- Follow existing guidelines for the investigation and follow-up care of patients with suspected anaphylaxis.
In case of oncologic emergencies, it is important to exclude Hypo- Hyperkalaemia/ electrolyte disorders; Hypoxia, Hypovolemia, Hypothermia, Venous thromboembolism, cardiac tamponade, sepsis/infection, treatment-related causes such as hypersensitivity or infusion reactions/anaphylaxis.

References

Perkins GD, Graesner JT, Semeraro F, Olasveengen T, Soar J, Lott C, Van de Voorde P, Madar J, Zideman D, Mentzelopoulos S, Bossaert L, Greif R, Monsieurs K, Svavarsdóttir H, Nolan JP; European Resuscitation Council Guideline Collaborators. European Resuscitation Council Guidelines 2021: Executive summary. Resuscitation. 2021 Apr;161:1-60. Erratum in: Resuscitation. 2021 May 4;163:97-98. PMID: 33773824.
Lott C, Truhlář A, Alfonzo A, Barelli A, González-Salvado V, Hinkelbein J, Nolan JP, Paal P, Perkins GD, Thies KC, Yeung J, Zideman DA, Soar J; ERC Special Circumstances

Soar J, Berg KM, Andersen LW, Böttiger BW, Cacciola S, Callaway CW, Couper K, Cronberg T, D’Arrigo S, Deakin CD, Donnino MW, Drennan IR, Granfeldt A, Hoedemaekers

Soar J, Becker LB, Berg KM, Einav S, Ma Q, Olasveengen TM, Paal P, Parr MJA. Cardiopulmonary resuscitation in special circumstances. Lancet. 2021 Oct 2;398(10307):1257-

1268. doi: 10.1016/S0140-6736(21)01257-5. Epub 2021 Aug 26. PMID: 34454688.

Evidence Level Grade PMID Nº

IMMUNOTHERAPY-ASSOCIATED TOXICITIES

Authors: Marcos Pantarotto, Patricia Garrido and Claudia Matos.

Introduction Level GradeEvidence

PMID Nº

The use of immune-checkpoint inhibitors (ICI) started a new era of benefits for cancer patients. However, the diverse mechanism of action brought new challenges to oncologists, mainly associated with immune-related adverse events (irAEs), which are very different from the side effects caused by commonly used cytotoxic drugs.

Given the broad spectrum of clinical manifestations and syndromes related to immune modulation, we emphasize the importance of a multidisciplinary approach.

Infusional reactions

1. Incidence according to treatment modality:
  - For anti-CTLA4 only: 2-6%
  - For anti-PD(L)1 only: 4% (avelumab associated with higher incidence of infusion reaction: 21-29% with 0-3% grade ≥3)
2. Clinical Presentation:
  - Short-lived; time frame: from immediate up to 1h post-infusion.
  - Symptoms include chest tightness, cough, wheezing, back pain, tongue swelling, dizziness/syncope, rash, pruritus, fever, dyspnoea, angioedema, tachycardia, hypo or hypertension, flushing/headache, hypoxia, arthralgia/myalgia.
3. Classification (CTCAE) and management.

Grade 1		Grade 2	Grade 3 / Grade 4
Recommendation	Evaluate and monitor the patient. EKG as per clinical presentation.
ICI treatment	Hold infusion and resume when symptoms cease. Next cycle: consider premedication (H1 and H2 -blockers; acetaminophen).	Hold infusion and treat the reaction with supportive medications (including hydrocortisone, antihistamines, and beta-agonists). Resume with half -rate when symptoms cease. Consider premedication as for grade 1 reactions.	Hold infusion and treat the reaction (DO NOT DELAY epinephrin administration; life support measures as needed; consider treatment with hydrocortisone, antihistamines, and beta – agonists). Consider patient admission if there is no improvement or if the patient worsens after initial improvement
Other comments			Consider changing the ICI for another drug with a similar mechanism of action

Fatigue

1. Incidence according to treatment modality:
For anti-CTLA4 and anti-PD(L)1 combination: 36% (4% grade ≥ 3) – For anti-CTLA4 only: 25% (2% grade ≥ 3)
For anti-PD(L)1 only: 21% (1% grade ≥ 3)
1. Clinical Presentation:
  - Most likely to occur after the first month following initiation of ICI therapy.

Evidence Level Grade PMID Nº

- - Patients experiencing fatigue should be evaluated for conditions that may cause or contribute to fatigue. Laboratory tests should include complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone (TSH), free-T4 (fT4), morning cortisol, and adrenocorticotropic hormone (ACTH).
1. Classification (CTCAE) and management:

– Address any abnormality found. – Hold or consider discontinuing immunotherapy if grade 3, after ruling out reversible causes.

Gastrointestinal IrAEs

Diarrhoea and colitis

Incidence according to treatment modality:
- For anti-CTLA4 and anti-PD(L)1 combination: 44% (10% grade ≥ 3) – For anti-CTLA4 only: 36% (8% grade ≥ 3)
- For anti-PD(L)1 only: 11% (1% grade ≥ 3)
Clinical Presentation:

Diarrhoea must be closely followed by the oncologist. Severe diarrhoea can be, per se, clinically relevant, and its presence can also translate to the presence of colitis. Colitis is a potentially life-threatening adverse event related to immune therapy, as it may cause bowel perforation, ischemia with necrosis, haemorrhage, and megacolon.
Symptoms vary and include watery diarrhoea, abdominal pain/cramps, and fever. The presence of more than four bowel movements a day should prompt medical evaluation and the presence of blood or mucus in the stool.

Classification (CTCAE) and management:

Grade 1		Grade 2	Grade 3 / Grade 4
Recommendations	Loperamide/dietary modification; encourage hydration. If persistent, check lactoferrin/calprotectin on the stool (if positive, treat as grade 2)	Rule out infections; Consider abdominopelvic CT scan; Consider GI consultation (with endoscopic examination)	Rule out infections; Consider an abdominopelvic CT scan Consider GI consultation (with endoscopic examination)
ICI treatment	Consider holding ICI	Hold ICI; Start prednisone-equivalent (1-2mg/kg/day) If there is no improvement in 2 – 3 days, keep steroids and consider infliximab/vedolizumab	Discontinue anti-CTLA4 / Hold anti-PD(L)1. For grade 4 — permanently discontinue ICI; Patient admission; IV methylprednisolone 1-2mg/kg/day. If there is no improvement in 1-2 days, keep steroids and consider infliximab/vedolizumab
Steroids wean		Within 4 weeks	Within 4 weeks

If there is (a) no improvement with steroids, (b) recurrence after steroids tapering, or (c) ulcerative colitis: administer infliximab 5mg/kg IV at weeks 0, 2, 6.
In case of persistent symptoms after the second dose of infliximab, treatment should change to vedolizumab 300mg at weeks 0, 2, 6.
Infliximab/vedolizumab appears safe for patients with HIV, Hepatitis B, or tuberculosis, and administration should not be delayed. Nevertheless, patients should be tested for these conditions, and appropriate treatment should ensue as clinically indicated.

AST/ALT elevation

Incidence according to treatment modality:
- For anti-CTLA4 and anti-PD(L)1 combination: 19% (9% grade ≥ 3) – For anti-CTLA4 only: 5% (2% grade ≥ 3)
- For anti-PD(L)1 only: 5% (1% grade ≥ 3)
Clinical Presentation:

Evidence Level Grade PMID Nº

– Generally asymptomatic. Alanine or aspartate transaminase (ALT/AST) elevations typically are the initial manifestation of liver toxicity and manifest in 1-15 weeks after treatment.

Classification (CTCAE) and management:

Grade 1		Grade 2	Grade 3	Grade 4
Recommendations	Differential diagnosis: rule out virus infections, metastatic infiltration, drug toxicity, OTC medications/alcohol abuse. Provide abdominal CT scan	Differential diagnosis: rule out virus infections, metastatic infiltration, drug toxicity, OTC medications/alcohol abuse. Provide abdominal CT scan	Differential diagnosis: rule out virus infections, metastatic infiltration, drug toxicity, OTC medications/alcohol abuse. Provide abdominal CT scan Inpatient care / GI consultation	Differential diagnosis: rule out virus infections, metastatic infiltration, drug toxicity, OTC medications/alcohol abuse. Provide abdominal CT scan Inpatient care / GI consultation
ICI treatment	Consider holding ICI; Weekly check for AST/ALT values	Hold ICI; Weekly check for AST/ALT values; Consider prednisone – equivalent (0,5-1mg/kg/day) If there is no improvement in 3 days, treat as grade 3	Hold ICI; Start prednisone -equivalent (1-2mg/kg/day) If there is no improvement in 1- 2 days, add MMF If there is no improvement with MMF, consider ATG	Permanently discontinue ICI Start prednisone -equivalent (1-2mg/kg/day) If there is no improvement in 1- 2 days, add MMF If there is no improvement with MMF, consider ATG
Steroids wean		Within 4-6 weeks	Within 4-6 weeks	Within 4-6 weeks

ATG = antithymocyte globulin; MMF = mycophenolate mofetil; OTC = off the countyATG = antithymocyte globulin; MMF = mycophenolate mofetil; OTC = off the county

Laboratory evaluation for grade 2 toxicities should include AST/ALT, Alkaline phosphatase, coagulation tests, serum bilirubin, iron studies, hepatitis virus, autoimmune hepatitis panel (ANA; ANCA, AMA, ASMA);
Infliximab should not be used in patients with liver toxicity (GRADE 1). Tacrolimus and ATG should be considered instead.
If there is no improvement to grade ≤ 1 in 10-14 days of MMF, consider liver biopsy and rule out CMV infection.

Acute Pancreatitis Evidence

Clinical Presentation:
- The median time to amylase/lipase elevation is 9-20 weeks.
- ICI can cause elevation of amylase and lipase; nevertheless, pancreatitis is a rare irAE, with few cases reported in the literature. For the clinical diagnosis, consider the presence of compatible epigastric pain or radiographic changes (abdominal CT scan with IV contrast or cholangiopancreatography MRI), together with amylase/lipase elevation.
- Amylase/lipase elevations with no corresponding signs/symptoms of pancreatitis should be kept under surveillance.
Classification (CTCAE) and management:

Level Grade PMID Nº

Grade 2		Grade 3	Grade 4
Recommendations	Treat the patient for acute pancreatitis, with IV hydration as indicated. Exclude other causes, such as alcohol abuse, hyperlipemia, and cholelithiasis. Gastroenterology referral.
ICI treatment	Consider holding;	Hold ICI; Start prednisone-equivalent (0,5-1mg/kg/day)	Permanently discontinue. Start prednisone-equivalent (1-2mg/kg/day)
Steroids wean		After improvement to grade ≤ 1, taper over 4-6 weeks.

Cutaneous IrAEs

Rash

Incidence according to treatment modality:
- For anti-CTLA4 and anti-PD(L)1 combination: 41% (5% grade ≥ 3)
- For anti-CTLA4 only: 23% (1% grade ≥ 3)
- For anti-PD(L)1 only: 10% (1% grade ≥ 3)
Clinical Presentation
- Onset: 2-5 weeks; often with pruritus. Diverse presentations: acneiform, maculo-papular, papulopustular. CTCAE classification according to type of rash.
Classification (CTCAE) and management

Grade 1		Grade 2	Grade 3	Grade 4
Recommendations	Differential diagnosis: rule out virus infections, metastatic infiltration, drug toxicity, OTC medications/alcohol abuse. Provide abdominal CT scan		For grades 3/4: same as grades 1 / 2, additionally consider patient admission and GI consultation.
ICI treatment	Consider holding ICI. Weekly check for AST/ALT values	Hold ICI. Weekly check for AST/ALT values. Consider prednisone- equivalent (0,5-1mg/kg/day) If there is no improvement in 3 days, treat as grade 3	Hold ICI. Start prednisone-equivalent (1- 2mg/kg/day) If there is no improvement in 1 – 2 days, add MMF If no improvement with MMF, consider ATG	Permanently discontinue ICI Start prednisone -equivalent (1 – 2mg/kg/day) If there is no improvement in 1-2 days, add MMF If there is no improvement with MMF, consider ATG
Steroids wean	After improvement to grade ≤ 1, taper over 4-6 weeks.

Pruritus

Incidence according to treatment modality:
- For anti-CTLA4 and anti-PD(L)1 combination: 34% (2% grade ≥ 3) – For anti-CTLA4 only: 25% (1% grade ≥ 3)
- For anti-PD(L)1 only: 15% (0% grade ≥ 3)
Clinical presentation:
- May present with no skin lesion in 50% of cases.
- Special attention to the examination of the skin; the presence of bullous formation or mucosal involvement should raise concerns of a more severe process in development.
Classification (CTCAE) and management:

Evidence

Level Grade PMID Nº

Grade 1		Grade 2	Grade 3
Recommendations	Whole-body skin examination
ICI treatment	Continue ICI; Oral anti-H1 Topical Steroids	Continue ICI. Oral anti-H1 in association with gabapentin / high-potency topical steroids. Dermatology consultation.	Hold ICI. Systemic steroids indicated: prednisone-equivalent (0,5 – 1mg/kg/day) Associate gabapentin / other adjuvant treatment (as aprepitant) Dermatology consultation
Steroids wean			After improvement to grade ≤ 1, taper over 4-6 weeks.

Stevens-Johnson syndrome _Level _Grade^Evidence

PMID Nº

Urgent dermatologic consultation is warranted. Treatment involves steroids in immunosuppressive doses, eventually associated with IV immune-globulin.

Pulmonary adverse events

* Pneumonitis

Incidence and risk factors:
- Pneumonitis is the most common lung toxicity related to ICI, with an overall incidence of 2,7% (1% grade ≥3). There is no known risk factor for the development of this complication.
- For anti-CTLA4 and anti-PD(L)1 combination: 3,6% – For anti-PD(L)1 only: 1,3%
- Median time to onset: 2,8 months (9 days – 19,2 months). An earlier onset is seen in NSCLC patients (median 2,1 months) and with combination regimens (2,7 vs. 4,6 months), irrespective of dosage.
Clinical presentation:
- Patients can be asymptomatic but may develop progressive dyspnoea (53%) and cough (35%); more than half of the patients (58%) present with additional immune toxicity (e.g., rash and colitis). In asymptomatic or mildly symptomatic patients, severity can be assessed by resting oximetry and 6- minutes walking test plus respiratory function tests with pulmonary diffusing capacity.
- The differential diagnosis can be challenging in patients with previous respiratory comorbidities; perform a thoracic high-resolution CT scan with contrast in the presence of new or progressive respiratory symptoms. Bronchoscopy with BAL (bronchoalveolar lavage with a high percentage of lymphocytes and T-cell infiltrate) may be helpful to establish the differential diagnosis with infection, oncological progression, or inflammatory conditions, e.g., sarcoidosis, and is especially recommended in symptomatic patients. Alung biopsy (transbronchial per-endoscopy or video-assisted thoracoscopic surgery) can establish the diagnosis in selected cases.
Severity Grade and management pathway:

Grade 1		Grade 2	Grade 3 Grade 4
Recommendations	Referral to a pulmonologist. For grade ≥2 and steroids treatment, antibiotic prophylaxis with cotrimoxazole 480mg bid, 3 times/week, oral).
	Consider treatment delay;	Hold ICI Prednisolone 1mg/Kg/day oral	Permanently discontinue ICI Hospital admission
ICI treatment	Close follow – up (re-evaluate in 48h)	Antibiotic (if suspicion of infection) If there is no improv ement within 48h , treat as grade ≥3	Methylprednisolone 2-4mg/kg/day, i.v. Antibiotic (empiric) If not improving within 48h: Infliximab 5mg/kg or MMF (if concurrent hepatic toxicity) over at least 8 weeks
Steroids wean		Taper over 4 – 6 weeks

Re-challenge:

Other pulmonary toxicities Evidence

Level Grade PMID Nº

Sarcoid-like granulomas Tuberculosis

Time to onset: 9 months ICI treatment was not associated with TB development; however, the steroid used to manage irAEs and other underlying conditions (i.e., CPOD) can be a risk factor

Asymptomatic or cough, fatigue, dyspnoea (latent TB infection – IGRA test before ICI).

Micronodular opacities/GGO lesions resemble recurrence or disease Asymptomatic or cough, fatigue, dyspnoea progression with many organs involved (mainly lymph nodes, lungs, skin)

Micronodular opacities/GGO lesions resemble recurrence or disease

Diagnosis: bio psy with histological epithelioid non -necrotizing granulomas

Neurologic adverse events

Incidence:
- For anti-CTLA4 and anti-PD(L)1 combination: 12% – For anti-CTLA4 only: ≤4%
- For anti-PD(L)1 only: 6% – grade ≥ 3-4 is less than 1% in all treatments
Clinical presentation:
- Median time to onset: 4 weeks
- Usually nonspecific, with headache, seizures, focal neurological abnormalities, altered mental status, or PRES (with acute confusional state, drowsiness or sometimes stupor, visual impairment, seizures).
- The differential diagnosis is complex and includes disease progression, infection (especially viral – HSV), seizures, metabolic derangement, vitamin B12 deficiency, diabetic neuropathy, vasculitis – ANCA, paraneoplastic syndromes, and autoimmune encephalopathies.
Severity Grade and management pathway:
- Obtain a complete anamnesis and physical examination with a thorough neurologic exam.
- Baseline hematologic and biochemical panel (i.e., complete blood count, renal function test, electrolytes, C – reactive protein ± procalcitonin, calcium, liver function tests, thyroid panel)
- Evaluation, in most cases, with MRI brain and spine imaging, Nerve conduction studies and EMG (in cases with sensory symptoms or weakness), EEG (to rule out subclinical seizures)
- Lumbar puncture (LP) with opening pressure measurement and CSF analysis: cell count, protein, glucose, gram stain, culture, PCR for HSV or other viral infection, cytology, oligoclonal bands, autoimmune encephalopathy panel

Endocrine Evidence

Level Grade PMID Nº

Hypothyroidism

Incidence and risk factors:
- For anti-CTLA4 and anti-PD(L)1 combination: 15% (0-2% ≥ grade 3) – For anti-PD(L)1 only: 8%
- For anti-CTLA4 only: 3%
Clinical Presentation:

Diagnosis is based on plasma TSH assay since clinical signs are nonspecific. Routine monitoring of thyroid function is necessary during ICI treatment; TSH and fT4 should be tested every 4-6 weeks and should continue to be tested every 6-12 months following the conclusion of immunotherapy.
Symptoms vary and may include fatigue, weight gain, bradycardia, and constipation. III.Classification (CTCAE) and management:

	Elevated TSH and normal fT4	Elevated TSH and Low fT4
Recommendations	If there are no symptoms, repeat measure next visit. If symptomatic, consider thyroxine if TSH > 10 mIU/L	If there are no symptoms , repeat measure next visit ; If symptom atic, initiate thyroxin
ICI treatment	Continue
Steroids	Not usually recommended

Levothyroxine should be administered to patients with hypothyroidism at 0.5 – 1.5mcg/kg/day. In elderly patients or those with heart disease, start at lower doses.
Patients with hypothyroidism symptoms or elevated TSH and low fT4 should be tested for morning cortisol to identify possible concurrent adrenal insufficiency.

Hyperthyroidism

Incidence and risk factors:
- For anti-CTLA4 and anti-PD(L)1 combination: 8% – For anti-PD(L)1 only: 5% – For anti-CTLA4 only: 4%
Clinical Presentation:
- Except in severe cases of thyrotoxicosis, the diagnosis can be challenging. Routine monitoring of thyroid function follows the same recommendations as for hypothyroidism. Thyroid autoantibodies measurement can be helpful for differential diagnosis.
- Symptoms vary and may include fatigue, nervousness, weight loss, heat intolerance, fine tremor, and palpitations.
Classification (CTCAE) and management:

Low TSH	Elevated fT4	Low fT4
Recommendations	If there are no symptoms, repeat measure next visit. If there are symptoms of hyperthyroidism start beta blockers	Check morning cortisol (may indicate hypopituitarism)
ICI treatment	For symptomatic hyperthyroidism (grade ≥ 2) consider holdingICI and resuming after completion of workup and improvement of symptoms and fT4
Steroids	Not usually recommended

Consider treatment with beta-blockers (10-20 mg every 4-6 hours for symptoms as needed) until thyrotoxicosis resolves. Atenolol or metoprolol can be considered.
Thyrotoxicosis often evolves into hypothyroidism (50-90%), requiring treatment with thyroid hormone replacement.
Patients with low/normal TSH and low fT4 should be tested for ACTH levels and morning cortisol to identify possible Hypophysitis.
Patients with persistently low TSH and high fT4 should be evaluated for Graves’ disease (ICI thyrotoxicosis usually lasts 4-6 weeks).

Hypophysitis

Incidence and risk factors:
- For anti-CTLA4 and anti-PD(L)1 combination: 9-11% – For anti-CTLA4 only: 4% – For anti-PD(L)1 only: 1%
Clinical Presentation:
- ICI-induced Hypophysitis is most frequently manifested as secondary adrenal insufficiency due to ACTH deficiency and less commonly due to TSH, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) deficiency. ACTH, morning cortisol, TSH, fT4, FSH, LH, testosterone in males, and oestrogen in premenopausal females should be tested.
- Patients may present with different complaints, including fatigue, nausea/emesis, anorexia, dizziness, headache, and gonadotrophic deficiency (including loss of libido or erectile dysfunction).
- Headache and visual disturbances require immediate evaluation and differentiation with cerebral metastasis, leptomeningeal disease, or cerebrovascular disease. On brain MRI, pituitary enlargement and enhancement can be seen.
Classification (CTCAE) and management:

Management
Recommendations	Treat with hormone replacement if indicated: Steroid replacement (hydrocortisone 20 mg PO every AM and 10 mg PO every PM) if secondary adrenal insufficiency (low ACTH, low cortisol); an endocrinologist should guide further titration. In central hypothyroidism (low TSH, low fT4), proceed to thyroid hormone replacement Consider testosterone supplementation in males and oestrogen in premenopausal females if central hypogonadism (low LH, low FSH, low sex hormones).
ICI treatment	Hold if grade ≥ 2 until resolution and hormone replacement is initiated
Steroids	If acute severe symptoms such as optic chiasm compression or mass effec,t consider high dose steroids: prednison-e equivalent 1 mg/kg/day until symptoms resolve (1-2 weeks), then rapid taper to physiologic replacement

Renal IrAEs

Evidence Level Grade PMID Nº

Acute kidney injury

Incidence and risk factors:
- For anti-CTLA4 and anti-PD(L)1 combination: 5% (0-2% ≥ grade 3) – For anti-CTLA4 only: 2% – For anti-PD(L)1 only: 2%
Clinical Presentation:
- Patients with possible ICI-related AKI should have a urinalysis and quantification of proteinuria with a spot urine protein to creatinine ratio.
- In cases of potential ICI-related AKI, concomitant toxic medications (e.g., NSAIDs, proton pump inhibitors, and some antibiotics) should be discontinued. If an antibiotic is implicated and ongoing treatment of infection is required, an antibiotic from a different class should be used.
Classification (CTCAE) and management:

Grade 1 Grade 2 Grade 3 / Grade 4
Recommendations	Differential diagnosis: Review hydration status, medications, urine test/culture if urinary tract infection symptoms Renal ultrasound +/- doppler to exclude obstruction/clot Repeat creatinine weekly	Rule out other causes. Review creatinine in 48h-72h. Repeat creatinine/K+ every 48h Consider nephrologist consultation	Rule out other causes. Admit patient for monitoring and fluid balance. Grade 4: patients should be managed in a hospital where renal replacement therapy is available. Repeat creatinine every 24h. Consider nephrologist consultation
ICI treatment	Consider holding ICI	Hold ICI. Start prednisone-equivalent (0.5- 1mg/kg/day) If there is no improvement in 1 week, titrate steroids to 1- 2mg/kg/day	Hold ICI. Start prednisone -equivalent (1 – 2mg/kg/day)
Steroids wean		Within 2-4 weeks	Over ≥ 4 weeks

- Given the lack of specific clinical features for ICI-related AKI, renal biopsy should be considered when feasible in grade ≥ 2.
- Patients with glomerular disease should receive standard therapy for the underlying lesion.
- If sustained grade > 2 kidney injury after 4-6 weeks of steroids, consider adding azathioprine, cyclophosphamide, cyclosporine, infliximab, or mycophenolate mofetil.
- Patients with renal allografts may receive ICIs, but only after extensive counselling on the associated risks and high probability of rejection and subsequent dialysis dependence, particularly with anti-PD-(L)1 antibodies.

Evidence Level Grade PMID Nº

References

Bae, S., Kim, Y.-J., Kim, M.-J., Kim, J. H., Yun, S.-C., Jung, J., Kim, M. J., Chong, Y. P., Kim, S.-H., Choi, S.-H., Kim, Y. S., & Lee, S.-O. (2021). Risk of tuberculosis in patients with cancer treated with immune checkpoint inhibitors: Anationwide observational study. Journal for Immunotherapy of Cancer, 9(9), e002960. https://doi.org/10.1136/jitc-2021-002960
Brahmer, J. R., Abu-Sbeih, H., Ascierto, P. A., Brufsky, J., Cappelli, L. C., Cortazar, F. B., Gerber, D. E., Hamad, L., Hansen, E., Johnson, D. B., Lacouture, M. E., Masters, G. A., Naidoo, J., Nanni, M., Perales, M.-A., Puzanov, I., Santomasso, B. D., Shanbhag, S. P., Sharma, R., … Ernstoff, M. S. (2021). Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. Journal for ImmunoTherapy of Cancer, 9(6), e002435. https://doi.org/10.1136/jitc-2021-002435
Delaunay, M., Prévot, G., Collot, S., Guilleminault, L., Didier, A., & Mazières, J. (2019). Management of pulmonary toxicity associated with immune checkpoint inhibitors. European Respiratory Review: An Official Journal of the European Respiratory Society, 28(154), 190012. https://doi.org/10.1183/16000617.0012-2019
Haanen, J. B. A. G., Carbonnel, F., Robert, C., Kerr, K. M., Peters, S., Larkin, J., & Jordan, K. (2017). Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 28, iv119–iv142. https://doi.org/10.1093/annonc/mdx225

Imoto, K., Kohjima, M., Hioki, T., Kurashige, T., Kurokawa, M., Tashiro, S., Suzuki, H., Kuwano, A., Tanaka, M., Okada, S., Kato, M., & Ogawa, Y. (2019). Clinical Features of Liver Injury Induced by Immune Checkpoint Inhibitors in Japanese Patients. Canadian Journal of Gastroenterology & Hepatology, 2019, 6391712. https://doi.org/10.1155/2019/6391712
Naidoo, J., Wang, X., Woo, K. M., Iyriboz, T., Halpenny, D., Cunningham, J., Chaft, J. E., Segal, N. H., Callahan, M. K., Lesokhin, A. M., Rosenberg, J., Voss, M. H., Rudin, C. M., Rizvi, H., Hou, X., Rodriguez, K., Albano, M., Gordon, R.-A., Leduc, C., … Hellmann, M. D. (2017). Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 35(7), 709–717. https://doi.org/10.1200/JCO.2016.68.2005
Schneider, B. J., Naidoo, J., Santomasso, B. D., Lacchetti, C., Adkins, S., Anadkat, M., Atkins, M. B., Brassil, K. J., Caterino, J. M., Chau, I., Davies, M. J., Ernstoff, M. S., Fecher, L., Ghosh, M., Jaiyesimi, I., Mammen, J. S., Naing, A., Nastoupil, L. J., Phillips, T., … Bollin, K. (2021). Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. Journal of Clinical Oncology, 39(36), 4073–4126. https://doi.org/10.1200/JCO.21.01440
Wright, J. J., Powers, A. C., & Johnson, D. B. (2021). Endocrine toxicities of immune checkpoint inhibitors. Nature Reviews. Endocrinology, 17(7), 389–399.
Yoo, M. J., Long, B., Brady, W. J., Holian, A., Sudhir, A., & Gottlieb, M. (2021). Immune checkpoint inhibitors: An emergency medicine focused review. The American Journal of Emergency Medicine, 50, 335–344.
Zivelonghi, C., & Zekeridou, A. (2021). Neurological complications of immune checkpoint inhibitor cancer immunotherapy. Journal of the Neurological Sciences, 424, 117424.

Annex A

CTCAE v5 grading for the disorders presented in this chapter

CTCAE term	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
		Therapy or infusion	Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae
		interruption indicated but
	Mild transient	responds promptly to
Infusion Related Reaction	reaction; infusion interruption not indicated; intervention	symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV		Life-threatening consequences; urgent intervention indicated	Death
	not indicated	fluids); prophylactic
		medications indicated for
		<=24 hrs

Fatigue	Fatigue relieved by rest	Fatigue not relieved by rest; limiting instrumental ADL	Fatigue not relieved by rest; limiting self-care ADL
Diarrhea	Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline	Increase of 4 6 stools per day over baseline; moderate increase in ostomy output compared to baseline; limiting instrumental ADL	Increase of >=7 stools per day over baseline; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL	Life-threatening consequences; urgent intervention indicated	Death
AST/ALT	> ULN – 3xULN if baseline was normal; 1.5 – 3x baseline is baseline was abnormal.	>3.0 – 5.0 x ULN if baseline was normal; >3.0 – 5.0 x baseline is baseline was abnormal.	>5.0 – 20.0 x ULN if baseline was normal; >5.0 – 20.0 x baseline is baseline was abnormal.	>20.0 x ULN if baseline was normal; >20 x baseline is baseline was abnormal.
Acute Pancreatitis		Enzyme elevation; radiologic findings only	Severe pain; vomitin; medical intervention indicated (e.g., analgesia, nutritional support)	Life-threatening consequences; urgent intervention indicated
Pruritus	Mild or localized; topical intervention indicated	Widespread and intermittent; skin changes from scratching (e.g., edema, papulation, excoriations, lichenification, oozing/crusts); oral intervention indicated; limiting instrumental ADL	Widespread and constant; limiting self care ADL or sleep; systemic corticosteroid or immunosuppressive therapy indicated		Death

Stevens-Johnson syndrome			Skin sloughing covering <10% BSA with associated signs (e.g., erythema, purpura, epidermal detachment, and mucous membrane detachment)	kin sloughing covering 10 – 30% BSA with associated signs (e.g., erythema, purpura, epidermal detachment and mucous membrane detachment)	Death
Pneumonitis	Asymptomatic; clinical or diagnostic observations only; intervention not indicate	Symptomatic; medical intervention indicated; limiting instrumental ADL	Severe symptoms; limiting self care ADL; oxygen indicated	Life-threatening respiratory compromise; urgent intervention indicated (e.g., tracheotomy or intubation)
Hypothyroidism / hyperthyroidism	Asymptomatic; clinical or diagnostic observations only; intervention not indicated	Symptomatic; thyroid replacement indicated; limiting instrumental ADL	Severe symptoms; limiting self care ADL; hospitalization indicated	Life-threatening consequences; urgent intervention indicated	Death
Hypophisitis	Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated	Moderate; minimal, local or noninvasive intervention indicated; limiting age- appropriate instrumental ADL	Severe or medically significant but not immediately life- threatening; hospitalization or prolongation of existing hospitalization indicated; limiting self care ADL	Life-threatening consequences; urgent intervention indicated
Hypophisitis					Death
Acute Kidney Injury			Hospitalization indicated	Life-threatening consequences; dialysis indicated	Death

Death

NEUROLOGICAL ALTERATIONS

ENCEPHALOPATHIES

Authors: Alexandra Guedes, Helena Guedes, Rafael Matias and Henrique Costa

Definition and Etiology

Encephalopathy refers to an acute cerebral dysfunction in the absence of primary structural brain disease and can lead to clinical delirium, decreased level of consciousness or even coma.

Symptoms

Symptoms may range from apathy, impaired attention, memory loss and temporospatial disorientation to agitation and psychosis. Patients may also suffer from headaches, nausea and vomiting, visual impairment, sleep disturbances, focal deficits, and seizures.

Etiology

In the cancer patient, four main etiological categories should be considered.

Metabolic. Metabolic derangements are the most common cause of altered levels of consciousness in cancer patients
Electrolyte disturbances such as hyponatremia (associated or not with the syndrome of inappropriate antidiuretic hormone secretion (SIADH)), hypercalcemia or hypomagnesemia place cancer patients at special risk for seizures.
Hypo- and hyperglycaemic syndromes, as well as renal and hepatic failure, are also possible causes for encephalopathy.
Nutritional deficiencies (especially folic acid and B-complex vitamins) are important in the oncological population, given the prevalence of malnutrition and chemotherapy induced nausea and vomiting.
Infectious. Infections are common in immunocompromised cancer patients. Seventy percent of patients with bacteraemia have neurological symptoms ranging from lethargy to coma and more than eighty percent have abnormalities on the electroencephalogram.
In a cancer patient presenting with fever, septic encephalopathy is one of the most common causes of CNS dysfunction
One must keep in mind that immunosuppressed cancer patients are susceptible to rare opportunistic infections with viruses (e.g., Herpes simplex (HSV) or JC virus reactivation resulting in progressive multifocal leukoencephalopathy), fungus (e.g., Cryptococcus spp or Aspergillus spp) or bacteria (e.g., Listeria spp or M. tuberculosis) causing meningoencephalitis.
Associated with treatment. Multiple treatment modalities can have neurologic complications, either from radiotherapy, surgical procedures, chemotherapy, or adjunctive medication.
Radiation-induced cognitive impairment represents a spectrum of severity; when administered to a large brain volume, radiation may cause acute encephalopathy within weeks to years. Acute injury develops during or immediately after radiation therapy, manifesting mainly by headache, nausea, and vomiting; it involves acute oedema, thus being steroid responsive. Early delayed injury occurs beyond a month and up to 6 months from completion of radiation therapy and fatigue or cognitive symptoms are more prominent. These changes are reversible, and improvement may also be seen with steroids. Late injury is associated with permanent irreversible leukoencephalopathy and cognitive impairment, resulting in severe dementia; very severe forms may be seen in patients treated with combination treatment such as methotrexate administered concomitantly with radiation. Nowadays, with WBRT being generally administered in fractions of ≤3 Gy, the risk has become very reduced.
Ifosfamide and high-dose methotrexate are both associated with a transient acute encephalopathy which resolves spontaneously within a few days.
Posterior reversible encephalopathy syndrome (PRES) is a clinic-radiological syndrome characterised by headache, seizures, altered mental status and visual impairment associated with the presence of white matter vasogenic oedema affecting the parieto-occipital lobes on RMN. Besides uncontrolled hypertension and preeclampsia/ eclampsia, several chemotherapy and immunosuppressant drugs have been implicated, including platinum-based agents, VEGF inhibitors or cyclosporine. If recognized and treated early, the clinical syndrome commonly resolves within 1-2 weeks.

Evidence Level Grade PMID Nº

-Finally, support therapies may also be associated with some degree of neurotoxicity. Opioids, for example, may cause neurological disturbances raging from mild confusion to Evidence

Diagnostic Approach

Acomprehensive initial evaluation should be carried out in order to identify possible precipitating factors.

Obtain the patient’s clinical history with corroboration from caretakers, medication review (check for recent changes in prescription), physical and neurological examination.
Biochemical blood work with renal function, electrolytes and hepatic panel with albumin and coagulation studies, glucose levels, thyroid function and vitamin status, namely B1, B12 and folate.
Ammonia levels if severe hepatic failure is suspected, although they can be within normal range.
Arterial blood gas analysis if there’s evidence of dyspnoea or abnormal chest exam.
In the presence of fever, look for white blood cell count, urinalysis and c-reactive protein and consider blood and urine cultures.
Rule out HIV infection.
All patients with suspected encephalitis require a lumbar puncture unless there is a significant contraindication (eg, risk of herniation on brain imaging); the analysis should include cell count and differential, protein, glucose, CSF/serum glucose ratio, albumin quotient, IgG index and synthesis rate, oligoclonal bands, broad viral studies including HSV1/2 PCR and varicella zoster virus (VZV) PCR and IgG/IgM and bacterial/fungal cultures when appropriate. Testing for neuronal autoantibodies associated with paraneoplastic autoimmune encephalopathy is recommended in case of high clinical suspicion, and these are tested in the patient’s serum and liquor. Keep in mind that its absence does not exclude the disease.
Being more accessible, order a head computed tomography scan (CT-scan) to quickly rule out space-occupying lesions and vascular complications, which may be part of the differential diagnosis. Perform Magnetic resonance imaging (MRI) to look for specific patterns. If PLE is suspected, look for signal hyperintensities on FLAIR or T2-weighted images in the medial temporal lobes; HSV encephalitis may have a similar appearance, but it characteristically spares the basal ganglia and frequently presents with haemorrhage. In PRES, both parietal-occipital lobes are characteristically enhanced. In cases of PCD, MRI may reveal cerebellar atrophy months after the symptom onset.
EEG to check for specific patterns of activity, especially in the presence of negative MRI findings or epileptic activity. Look for sharp and slow waves in PLE, triphasic waves in metabolic encephalopathies or delta brushes in NMDAR encephalitis.
If an autoimmune paraneoplastic syndrome is suspected at patient presentation, initial cancer screening with CT of the chest, abdomen and pelvis with contrast is a reasonable approach given its lower cost compared with FDG-PET.

Therapeutic Strategy

Level Grade PMID Nº

Medication or therapy withdrawal in patients undergoing treatment with drugs associated with encephalitis.

Bisphosphonates (such as i.v. zoledronic acid) to control severe hypercalcaemia.

Magnesium replacement is recommended for the management of hypomagnesaemia.

Methylene blue is not recommended for the prevention and treatment ofIfosfamide-induced acute encephalopathy.

In cases of PRES, cessation of anticancer therapy and adequate blood pressure control is paramount, with antiepileptic treatment in case of seizures.

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If there is no clinical, radiological or electrophysiological improvement by the end of the initial treatment cycle, add IVIG or plasma exchange.

Consider starting with a combination therapy from the beginning (as opposed to sequentially) in patients with severe initial presentation.

Pharmacotherapy for suspected autoimmune encephalitis

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Evidence Level Grade PMID Nº

Intravenous methylprednisolone: 1 g per day for 3 –7 days.

Intravenous Ig (IVIg): 2 g/kg over 2 –5 days.

Plasma exchange: 5 –10 sessions every other day.

References:

Jordan, B., Margulies, A., Cardoso, F., Cavaletti, G., Haugnes, H., Jahn, P., le Rhun, E., Preusser, M., Scotté, F., Taphoorn, M., & Jordan, K. (2020). Systemic anticancer therapy- induced peripheral and central neurotoxicity: ESMO–EONS–EANO Clinical Practice Guidelines for diagnosis, prevention, treatment and follow-up. Annals of Oncology, 31(10), 1306–1319. https://doi.org/10.1016/j.annonc.2020.07.003
Bush, S., Lawlor, P., Ryan, K., Centeno, C., Lucchesi, M., Kanji, S., Siddiqi, N., Morandi, A., Davis, D., Laurent, M., Schofield, N., Barallat, E., & Ripamonti, C. (2018). Delirium in adult cancer patients: ESMO Clinical Practice Guidelines. Annals of Oncology, 29, iv143–iv165. https://doi.org/10.1093/annonc/mdy147
Abboud, H., Probasco, J. C., Irani, S., Ances, B., Benavides, D. R., Bradshaw, M., Christo, P. P., Dale, R. C., Fernandez-Fournier, M., Flanagan, E. P., Gadoth, A., George, P., Grebenciucova, E., Jammoul, A., Lee, S. T., Li, Y., Matiello, M., Morse, A. M., Rae-Grant, A., Titulaer, M. J. (2021). Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. Journal of Neurology, Neurosurgery & Psychiatry, 92(7), 757–768. https://doi.org/10.1136/jnnp-2020-325300
Dalmau, J., & Rosenfeld, M. R. (2008). Paraneoplastic syndromes of the CNS. The Lancet Neurology, 7(4), 327–340. https://doi.org/10.1016/s1474-4422(08)70060-7
1. WAKEFULNESS-SLEEP RHYTHM DISTURBANCES

Authors: Sérgio Costa Monteiro and Andreia do Carmo Lopes

Definition

- - Circadian rhythm sleep-wake diseases are a class of sleep disorders caused by alterations of the circadian time-keeping system, its mechanisms, or a misalignment of the endogenous circadian rhythm and the external environmental. These are characterized by a desynchrony between the internal circadian timing system and desired sleep-wake times or an alteration in the timing system itself. (1,2)
  - The prevalence rates of nocturnal sleep-wake disturbances range from 31%–75% in cancer patients. (3)
  - In circadian rhythm sleep-wake disorders, the timing of primary sleep episode is either earlier or later than desired, irregular from day-to-day, and sleep occurs at the wrong circadian time. (4)
  - Pathophysiology: The suprachiasmatic nucleus (SCN) is a central circadian pacemaker. The disease can occur at the level of input to the SCN or within the SCN itself, resulting in reduced amplitude or mistiming of rhythms. (4)

Symptoms and signs Evidence

- - Insomnia.
  - Excessive sleepiness.

Etiology

- - Cancer related factors: Pain. Activity-rest. Hormone secretion. Cytokine production. Nervous central system tumors. Cancer treatments. (2, 5)
  - Predisposing factors: Female gender. Older age. Hyperarousability as a trait. Personal or family history. Mood or anxiety disorders. Poor sleep hygiene. Caffeine intake. Alcohol intake. Smoking. (2, 5)
  - Precipitant factors: Cancer treatments that alter levels of inflammatory cytokines or disrupt circadian rhythms or sleep-awake cycles. Side-effects of cancer treatment.
  - Menopausal symptoms. Hospitalization. Distress in response to cancer diagnosis. Co-occurring symptoms (e.g., pain or fatigue). Medications. (2, 5)
  - Perpetuating behavioural factors: Excessive daytime sleeping, long-term use of medications or use of inappropriate medications. Maladaptive cognitions. (2, 5)
  - Side effects of cancer treatment that affect the sleep-wake cycle include Pain. Anxiety. Night sweats/hot flashes. Gastrointestinal disturbances (e.g., incontinence, diarrhoea, constipation, or nausea). Genitourinary disturbances (e.g., incontinence, retention, or irritation). Respiratory disturbances. Fatigue. (2, 5)

Studies

- - Clinical interview: Surveys (Pittsburgh Sleep Quality Index. Epworth Sleepiness Scale. Insomnia. Severity Index. Stop-Bang. Brief Fatigue Inventory.). Characterization of sleep. Documentation of predisposing factors. Evaluation of emotional status. Assessment of exercise, activity levels and diet. Medical history. Current medication (e.g., Opiate. Sedative-hypnotics. Stimulant. Anti-epileptic.). (1,2,3)
  - Complete physical examination. (1,2,3)
  - Laboratorial studies: Anaemia. Hypothyroidism. Electrolyte abnormalities. Ferritin level. (1,2,3)
  - Collection of salivary dim light melatonin onset: Time-consuming. Expensive. Lacks established guidelines for normal values. (6,7)
  - Urinary 6-sulfatoxy melatonin (a metabolite of melatonin) measurement at 24 hours urine sample to assess circadian pattern. (8)

Diagnosis

- - Complaint of insomnia, excessive sleepiness, or both. (1,2,4)
  - Disruption of the normal circadian sleep-wake cycle. (1,2,4)
  - At least two of the following symptoms:
Decreased daytime performance. (1,2,4)
Altered appetite and gastrointestinal function. (1,2,4)
An increase in the nocturnal awakening. (1,2,4)
General malaise. (1,2,4)
- - Polysomnography and the multiple sleep latency test demonstrate loss of a normal sleep-wake pattern evidence. (2,4)

Pharmacotherapy

DRUG

POSOLOGY

Melatonin receptor agonist (MRA) a

Ramelteon Tasimelteon

–

8 mg

0.5-10 mg

Melatonin

2 mg

- - These agents do not treat difficulties staying asleep but also carry much less risk of cognitive/motor impairments and dependence. (3) Taken one hour prior to desired bedtime. (4)

Level Grade PMID Nº

–	–	–
IV	C	33582815
IV	C	33582815
IV	C	33582815

Therapeutic Strategy (4, 9, 10)

Bright light therapy

Exogenous melatonin

Chronotherapy

Motivational enhancement (to improve adherence)

Sleep hygiene

Hypnotic medication is not recommended

Encourage exercise on regular basis.

Encourage to have healthy dietary habits. Maintain a normal weight. Avoid alcohol (< 30 mL/day) and tobacco use.

References:

(1)Goldstein, C. Overview of circadian sleep-wake ehythm disorders. UpToDate. Literature review current through: Jul 2022. Topic last uptadet: May 12, 2022. Acessed August 08, 2022.

Duffy JF., et al.. (2021) Workshop report. Circadian rhythm sleep-wake disorders: gap and opportunities. Sleep. 44(5). (PMID 33582815)
Clark J., et al. (2004) Sleep-Wake Disturbances in People With Cancer Part II: Evaluating the Evidence for Clinical Decision Making. Oncology Nursing Forum. 31(4) (6)Pullman RE, et al. (2012) Laboratory validation of an in-home method for assessing circadian phase using dim light melatonin onset (DLMO). Sleep Medicine. 13(6):703-706 (7)Burgess HJ, et al. Home dim light melatonin onsets in delayed sleep phase disorder. Journal of Sleep Research. 25(3):314-317
Flynn-Evans EE, et al. (2014) Circadian Rhythm disorders and melatonin production in 127 blind women with and without light perception. Journal of Biological Rhytms. 29(3):215- 224.
Auger R., et al. (2015) Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015. An American Academy of Sleep Medicine Clinical Practice Guideline. Journal of Clinical Sleep Medicine. 11(10): 1199-1236. (PMID 26414986)
Morgenthaler TI., et al. (2007) Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 30(11): 1445-1459.

Evidence Level Grade PMID Nº

IV C 26414986

IV C 33582815

I C 26414986

IV C 33582815

INSOMNIA

Authors: Tânia Duarte and Luísa Leal da Costa

Definition

ISBN 9780415375306

Sleep is an essential circadian process for the physical and psychological recovery of individuals. Insomnia is a subjective experience that can be defined, based on the International Classification of Sleep Disorders, 3rdedition (ICSD-3), as difficulty in falling asleep (initial insomnia), difficulty in staying asleep with prolonged nocturnal awakenings (middle insomnia), early-morning awakening with the inability to resume sleep (terminal insomnia), or the complaint of non-restorative or poor-quality sleep. Cancer-related insomnia (CRI) occurs in 19% to 63% of patients and is twice as prevalent as in the general population.

23616275

26065120

24142594

Etiology

There are cancer-specific precipitating factors that lead to insomnia, whereas others may affect anyone in the healthy population. Etiologic factors in cancer-related insomnia are:

- Predisposing factors: older age, female, familial or personal history of insomnia, psychiatric disorders and/or hyperarousability trait.

ISBN 9780415375306

Evidence Level Grade PMID Nº

2414259

- Precipitating factors: bone marrow transplantation, psychiatric disorders, acute distress related to cancer/treatment, concomitant cancer symptoms (pain, fatigue, delirium), mutilating surgery (aesthetic or functional impairment), hospitalization, radiotherapy, chemotherapy, hormonal fluctuations, tumours that increase corticosteroid production, symptoms from tumour invasion and/or medications antidepressants (SSRIs), antiemetics (prochlorperazine, metoclopramide), corticosteroids (dexamethasone), hormonal therapy (tamoxifen, leuprolide), opioids, sedatives, hypnotics, neuroleptics, diet supplements (caffeine).
- Perpetuating factors: maladaptive behaviours (excessive amount of time spent in bed, irregular sleep-wake schedule, engaging in sleep interfering activities in the bedroom) and/or faulty beliefs and attitudes (unrealistic sleep expectations and faulty appraisals of sleep difficulties).

11157043

Symptoms

7ISBN 978-1-4419-1225-1

- The most common consequences of CRI are fatigue and excess daytime sleepiness. Other adverse outcomes of CRI include impaired cognitive and psychomotor skills, such as difficulties in sustained attention, working memory, memory retention, decision making and hand–eye coordination, secondary anxiety and depression. These can affect daytime function and quality of life, decreasing work productivity and increasing treatment costs and substance abuse.

24142594

33910162

Diagnostic/Assessment

ISBN 9780415375306

- Insomnia is a complex pathology. No single parameter has been validated for screening insomnia in the general population or in cancer patients. The nature, history and severity of CRI must be determined.

There are also two tools for objective sleep measurement: polysomnography (PSG) and actigraphy, although none of them has a good correlation with subjective measures.

Therapeutic Strategy

12,13Survivorship and Palliative Care Guidelines NCCN 2022

24142594

2748771

15157038

11438246

15376284

Assess for and treat contributing factors: pain, depression, anxiety, delirium, and nausea.

Based on evidence, Cognitive Behavioural Therapies for Insomnia (CBT-I) is the preferred first -line treatment for CRI.

Pharmacotherapy should only be used after all other methods have been deemed unsuccessful or have failed.

At end of life, assess patient´s desire to have insomnia and sedation treated .

2 A	23008320
2 A	23008320
2 A	23008320
2 A	32101021

Nonpharmacologic Treatments Evidence

Level Grade PMID Nº

12,13Survivorship and Palliative Care Guidelines NCCN 2022, 14PMID: 23008320

2 A 27136449

Therapy	Goal	Procedure
CBT-I	Combination of cognitive therapy, behavioural interventions (stimulus control therapy and sleep restriction therapy) and education (sleep hygiene), with or without relaxation therapy
Stimulus control therapy	Establish a regular sleep -wake rhythm	Go to bed when sleepy/tired, when unable to fall asleep get out of bed; wake up at the same time every morning; no napping during the day
Sleep restriction therapy	Improve sleep continuity and efficiency	Restrict the time in bed to sleep time, then gradually increasing time in bed as sleep efficiency improves
Sleep hygiene therapy	Change health practices and environmental factors that interfere with sleep	Keep a regular schedule; exercise regularly but not too late in the evening; do not eat heavy/spicy meal before bedtime; avoid stimulants or alcohol near bedtime; maintain a quiet and dark sleep environment
Cognitive therapy	Changing dysfunctional attitudes and beliefs about sleep	Identify sleep cognitive distortions; challenge validity of the sleep misconceptions; reframe dysfunctional cognition into more adaptive thoughts
Relaxation training	Reducing tension or levels of arousal interfering with sleep	Progressive muscle relaxation, guided imagery, abdominal breathing, hypnosis, biofeedback, meditation
Exercise/Yoga

26434673

2 A 23008320

21274408

31165647

32314110

Pharmacotherapy Evidence

Level Grade PMID Nº

12,13Survivorship and Palliative Care Guidelines NCCN 2022, 16PMID 27136449, 21PMID 28875581

Drug	Dose	Notes
Benzodiazepine Recep	tor Agonists
Zolpidem	5-15 mg PO at bedtime	Rapid onset of action; short -intermediate duration of action; helps with sleep initiation; short-term or periodic use
Zolpidem CR	12.5 mg PO at bedtime	Rapid onset of action; intermediate -long duration of action; indicated for sleep initiation and maintenance; short -term or periodic use
Benzodiazepines
Temazepam	7.5-30 mg PO at bedtime	Intermediate onset of action; intermediate duration of action; indicated for sleep initiation and maintenance; short -term or periodic use
Lorazepam	0.5-1 mg PO at bedtime	Intermediate onset of action; intermediate duration of action; indicated for sleep initiation and maintenance; short -term or periodic use
Antipsychotics
Quetiapine	12.5-25 mg PO	Indicated for patients with concomitant bipolar disorder or depression
Melatonin Receptor Agonist
Ramelteon	8 mg PO 30 min before bedtime	Rapid onset of action; short duration of action; helps with sleep initiation
Melatonin	3-20 mg PO 30 min before bedtime	Helps with sleep initiation and improves sleep quality
Antidepressants
Trazodone	25-150 mg PO	Onset of action: 0.5h -2h; duration of action: 8h; indicated for sleep maintenance; short-term use
Mirtazapine	7.5-30 mg PO	Onset of action: 1.2 -1.6h; duration of action: 20 -40h; indicated for patients with concomitant anxiety or anorexia
Doxepin	3-6 mg PO 30 min before bedtime	Indicated for sleep initiation and maintenance; short -term use

2	A
2	A
2	A
2	A
2	A	32314110
2	A	32314110
2	A	33910162
2	A	32314110
2	A	32314110
2	A	32314110

Evidence Level Grade PMID Nº

References:

Catane R et al. ESMO Handbooks: ESMO Handbook of Advanced Cancer Care (European Society for Medical Oncology Handbooks, Volume 1, CRC PRESS, 2005
Davis MP, Khoshknabi D, Walsh D, Lagman R, Platt A. Insomnia in patients with advanced cancer. Am J Hosp Palliat Care. 2014 Jun;31(4):365-73
Ito E, Inoue Y. The International Classification of Sleep Disorders, third edition. American Academy of Sleep Medicine. Nihon Rinsho. 2015 Jun;73(6):916-23. 4.Induru RR, Walsh D. Cancer-related insomnia. Am J Hosp Palliat Care. 2014 Nov;31(7):777-85
Savard J, Morin CM. Insomnia in the context of cancer: a review of a neglected problem. J Clin Oncol. 2001 Feb 1;19(3):895-908
Jafari-Koulaee A, Bagheri-Nesami M. The effect of melatonin on sleep quality and insomnia in patients with cancer: a systematic review study. Sleep Med. 2021 Jun;82:96- 103
Olver IN. The MASCC Textbook of Cancer Supportive Care and Survivorship, Multinational Association for Supportive Care in Cancer Society, 2011
Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213
Beck SL, Schwartz AL, Towsley G, Dudley W, Barsevick A. Psychometric evaluation of the Pittsburgh Sleep Quality Index in cancer patients. J Pain Symptom Manage. 2004 Feb;27(2):140-8
Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001 Jul;2(4):297-307 11.Savard MH, Savard J, Simard S, Ivers H. Empirical validation of the Insomnia Severity Index in cancer patients. Psychooncology. 2005 Jun;14(6):429-41 12.Sanft T et al. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines), Survivorship, 2022 Mar
Dans M et al. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines), Palliative Care, 2022 Mar
Pachman DR, Barton DL, Swetz KM, Loprinzi CL. Troublesome symptoms in cancer survivors: fatigue, insomnia, neuropathy, and pain. J Clin Oncol. 2012 Oct 20;30(30):3687-96
Nzwalo I, Aboim MA, Joaquim N, Marreiros A, Nzwalo H. Systematic Review of the Prevalence, Predictors, and Treatment of Insomnia in Palliative Care. Am J Hosp Palliat Care. 2020 Nov;37(11):957-969
Qaseem A et al. Clinical Guidelines Committee of the American College of Physicians. Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016 Jul 19;165(2):125-33
Johnson JA, Rash JA, Campbell TS, Savard J, Gehrman PR, Perlis M, Carlson LE, Garland SN. A systematic review and meta-analysis of randomized controlled trials of cognitive behavior therapy for insomnia (CBT-I) in cancer survivors. Sleep Med Rev. 2016 Jun;27:20-8. doi: 10.1016/j.smrv.2015.07.001. Epub 2015 Aug 1. PMID: 26434673. 18.Sprod LK, Palesh OG, Janelsins MC, Peppone LJ, Heckler CE, Adams MJ, Morrow GR, Mustian KM. Exercise, sleep quality, and mediators of sleep in breast and prostate cancer patients receiving radiation therapy. Community Oncol. 2010 Oct;7(10):463-471
Lin PJ et al. Influence of Yoga on Cancer-Related Fatigue and on Mediational Relationships Between Changes in Sleep and Cancer-Related Fatigue: A Nationwide, Multicenter Randomized Controlled Trial of Yoga in Cancer Survivors. Integr Cancer Ther. 2019 Jan-Dec;18:1534735419855134.
Kwak A, Jacobs J, Haggett D, Jimenez R, Peppercorn J. Evaluation and management of insomnia in women with breast cancer. Breast Cancer Res Treat. 2020 Jun;181(2):269-277
Riemann D et al. European guideline for the diagnosis and treatment of insomnia. J Sleep Res. 2017 Dec;26(6):675-700
1. MYELOPATHIES

Author: Marcos Dumont Bonfim Santos, Pedro Miguel Antunes Meireles and Tomás Dinis

Symptoms and signs

Back pain.
Motor findings (weakness; paraplegia)
Sensory findings
Sphincter dysfunction (bladder and bowel dysfunction)
Ataxia
Cauda equina syndrome daytime function and quality of life, decreasing work productivity and increasing treatment costs and substance abuse.

Etiology

Vascular: ischemic; haemorrhagic.
Previous treatment: radiation induced; chemotherapy (cytarabine, methotrexate, cisplatin, carmustine, thiotepa)
Infectious: Epstein-Barr virus, varicella zoster virus, cytomegalovirus, herpes simplex virus, huma herpesvirus 6.
Paraneoplastic
Primary spinal cord tumours
Secondary to cancer: metastatic (spinal cord compression, intramedullary; leptomeningeal, intravascular).

Studies

Myelopathies are neurological complications of cancer. Several causes may be associated, from metastatic neoplasms to infectious causes. The treatment decision must be individualized. Magnetic Resonance is an allied exam in the definition of severity and whenever possible it should be requested.
Assessment of cord instability, cancer histology, and radiosensitivity assessment will guide treatment decisions about initial surgery, radiation, and/or systemic therapy.
Radiosensitive tumours are lymphoma, myeloma, small cell lung cancer, germ cell tumours, prostate, and breast cancer. Radioresistant tumours are melanoma, renal cell carcinoma, non-small cell lung cancer, gastrointestinal cancers, and sarcoma.

Pharmacotherapy

Initial 10 mg intravenous bolus of dexamethasone followed by 16 mg daily.

Venous thromboembolism prophylaxis

Therapeutic Strategy

Evidence Level Grade PMID Nº

24142594

33910162

II	C	28437329
II	C	28574332

Surgery in case of patients with unstable spine and radioresistant tumours .

Radiotherapy (includes radiosensitive tumours ).

II	C	23709750
II	B	16112300
II	C	19520448

References: Evidence

The NOMS framework: approach to the treatment of spinal metastatic tumors.Laufer I, Rubin DG, Lis E, Cox BW, Stubblefield MD, Yamada Y, Bilsky MH.Oncologist. 2013;18(6):744. Epub 2013 May 24.

Effectiveness of radiation therapy without surgery in metastatic spinal cord compression: final results from a prospective trial.Maranzano E, Latini P .Int J Radiat Oncol Biol Phys. 1995;32(4):959.

Level Grade PMID Nº

5.5 PERIPHERAL AND CRANIAL NERVE NEUROPATHY

Authors: Ema Neto and Sandra Silva and Helena Guedes

Symptoms

Peripheral neuropathy: The most common manifestation is neuropathic pain that might be associated with balance disturbance, difficulty in fine motor skills and muscle weakness. Autonomic features (including mottled skin, sweating, redness and swelling) can also be present.
Cranial neuropathy: Less common. Clinical manifestations may suggest specific cranial nerves involvement. Can be associated with neuropathic pain and neurologic symptoms. Clinical manifestations that may elucidate for specific cranial nerve involvement include: 1) Oculomotor, trochlear or abducens nerve – Diplopia 2) Trigeminal nerve – Facial pain, paraesthesia, and numbness 3) Facial nerve – Weakness of upper face (i.e. difficulty closing the eye completely, decreased eyebrow raise) and the lower face facia

neuralgia, and malignant painful radiculopathy.

Etiology

Studies

Anamneses
1. Evaluate pre-existing neuropathy, neurological disease or muscle spasticity from disorders of the motor system
2. Evaluate the presence of conditions that predispose to neuropathy such as diabetes and/or a family or personal history of hereditary peripheral neuropathy
3. Collect information about cancer treatment history and comorbid conditions, psychosocial and psychiatric history (including substance use)
In case of painful neuropathy
1. Initial comprehensive pain assessment that should include pain descriptors, associated distress, functional impact, and related physical, psychological, social, spiritual factors and prior treatments for the pain.
2. Evaluate the probability of neuropathic pain – IASP – NeuPSIG grading system
3. Screening and assessment questionaries – LANSS, DN4, PDQ, NPS and NPSI
Physical exam including full neurological examination
Confirmatory tests (generally limited to specialist context) – electrophysiological studies, quantitative sensory testing (QST) and evaluation of intraepidermal nerve fibres (IENFs) via skin biopsy.
Other exams – particularly in case of cranial nerve involvement and neurologic symptoms – TC and MRI; lumbar puncture and liquor analysis; Neurology and/or Neurosurgery urgent evaluation (+++ if acute onset)

Evidence Level Grade PMID Nº

Therapeutic Strategy Evidence

Step 1 Evaluation and diagnosis

1.1. Evaluate pain and establish the diagnosis of peripheral or central neuropathy. If uncertain about the diagnosis, refer to a p ain specialist or neurologist

1. Identify and evaluate possible treatable causes of NP – high intracranial pressure, nerve compression, bone lesions, paraneoplastic syndrome – discuss the plan in a multidisciplinary team meeting or refer to urgent observation by the intervenient specialis t (surgeon, radio -oncologist, medical oncologist, other)
2. Identify relevant comorbidities ( e.g., cardiac, renal, or hepatic disease, depression, gait instability) that might be relieved or exacerbated by treatments, or that might require dose adjustment or additional monitoring of therapy.
3. Explain the diagnosis and treatment plan to the patient and stablish realistic expectations

Step 2 – Initiate Treatment

2.1 Initiate therapy for the primary cause of neuropathy, if appropriate – initiate treatment directed to cancer or its complications, including surgery, chemo and/or radiotherapy.

2.2. Initiate pharmacologic symptomatic treatment

2.2 Evaluate for non -pharmacologic treatments, and initiate if appropriate

Step 3 – Reassess symptoms and health -related quality of life frequently In case of neuropathic pain (NP):

3.1. If substantial pain relief ( e.g., average pain reduced to ≤ 3/10) and tolerable side effects – Continue treatment

1. If partial pain relief ( e.g., average pain remains 4/10) after an adequate trial – switch to an alternative first -line medication
2. If no or inadequate pain relief ( e.g., < 30% pain reduction) at target dose after an adequate trial – switch to an alternative first line medication;

Step 4 – If trials of first -line medications alone fail, consider second and third -line medications or referral to a specialist

neuropathic in nature, and poorly responsive to opioids alone.

Localized peripheral neuropathic pain – Consider initiate treatment with topical analgesics alone +/ – one of the first -line medications.

prevention of CIPN in patients with cancer

impairment during treatment. For patients with cancer experiencing painful CIPN, clinicians may offer Duloxetine.

compression.

Trigeminal and glossopharyngeal neuropathy – For patients with cancer experiencing painful neuropathy, first option is Carbamazepine.

IV	C	20402746
IV	C	20402746
IV	C	20402746
IV	C	20402746
II	B-C	17920770 30052758
II	B	32663120
II	B	32663120
II	A	30860637

Level Grade PMID Nº

Pharmacotherapy for neuropathic cancer pain (NCP) Evidence

Level Grade PMID Nº

Local analgesics Alone or in combination with systemic agents for focal peripheral neuropathy

First Line

– Lidocaine 5% Dose:1-3 plasters 12h/day.

Second – Line Capsaicin 8% Dose: 1 – 4 patches/ 3 months; Available in a limited number of pain units;

–

Botulinum toxin A Dose: 50 300 U/3 months; Available in a limited number of pain units;

Third Line Capsaicin ≤0,1% Topical application

Lidocaine i.v Dose: 3 – 7,5 mg/kg (usually 5mg/kg) over 30-60 minutes, once a week for 4 weeks;

Systemic analgesics

First-Line

Analgesic antidepressants Consider as first option in patients who suffer from depression; Duloxetine appears safer and more effective over TCA’s.

Amitriptyline, Imipramine

Serotonin – Norepinephrine Reuptake Inhibitors (SNRI’s)

Duloxetine

Duloxetina is preferable over Venlafaxine (more high-quality trials yielding positive results; Duloxetine is the only considered Venlafaxine a first line option in 2018 ESMO guidelines)

Analgesic antiepileptics Initial dose: 30 mg once daily; Increasing dose: 30mg per week, if tolerated; Target dose: 60- 120 mg once daily. First option in CIPN.

Gabapentin Initial dose: 37,5 mg once daily; Increasing dose: 37,5mg per week, if tolerated; Target dose: 75 – 225mg daily.

Pregabalin

Initial dose: 100-300mg once nightly; Increasing dose: Dose increments of 50-100% every 3 days and dose frequency to 2- times a day; Target dose: 900-3600 mg daily in divided doses 2-3 times a day.

Initial dose: 25 mg once nightly; Increasing dose: Dose increments of50-100% every 3 days and dose frequency to 2-3 times a day; Maximum dose: 600 mg daily in divided doses 2-3 times a day.

31390582

29929349

I-II B

I B

II C

I-II C

I A

32276788

31390582

30480345

32276788

17920770

25575710

32276788

25575710

32276788

30052758

31390582

30884837

32276788

17920770

32276788

31390582

30884837

32663120

30052758

31390582

I B-C

I A

30884837

32276788

32663120

32276788

31390582

30884837

32276788

17920770

30052758

31390582

32276788

Evidence Level Grade PMID Nº

I A-B

IV B

II B

II C

25575710

30480345

34295184

30480345

34295184

17920770

30052758

34295184

17920770

30052758

34295184

30052758

34295184

I C 30052758

34295184

II C

Second-Line

Weak Opioids

Tramadol Initial dose: 50 mg every 4 to 6 hours as needed Increasing dose: as needed and tolerated to 50 to 100 mg every 4 to h6ours; Maximum dose: 400 mg/day.

Combinations TCA/Duloxetine + Gabapentin TCA/Duloxetine + Opioids

II B

32276788

30052758

Evidence Level Grade PMID Nº

Dexamethasone

Carbamazepine

Intrathecal drug (i.t) delivery

doses and appropriate adjuvant analgesia and non-effective response to switching the opioid or the route of administration, as well as when side effects increase because of dose escalation.

II C

32276788

17920770

25575710

30052758

Recommendations against use of certain drugs

Ketamine There is a lack of evidence to support the routine use

Levetiracetam There are strong recommendations against the use Mexiletine

refractory cancer pain, in case-by-case basis.

II	B	30480345
		31390582
I	A	30860637
II	B	30052758
II	D	30052758
II	E	30052758
		32276788
		25575710
II	C	34295184

Moisset X, Bouhassira D, Avez Couturier J, Alchaar H, Conradi S, Delmotte MH, Lanteri-Minet M, Lefaucheur JP, Mick G, Piano V, Pickering G, Piquet E, Regis C, Salvat E, Attal

Edwards HL, Mulvey MR, Bennett MI. Cancer-Related Neuropathic Pain. Cancers (Basel). 2019 Mar 16;11(3):373. doi: 10.3390/cancers11030373. PMID: 30884837; PMCID: PMC6468770.

Neuropathic pain in adults: pharmacological management in non-specialist settings. London: National Institute for Health and Care Excellence (NICE); 2020 Sep 22. PMID: 31961628.

Level Grade PMID Nº

WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents. Geneva: World Health Organization; 2018. PMID: 30776210.

5.6 DELIRIUM IN CANCER PATIENT

Authors: Ribeiro Alves, João Fonseca, André da Silva Ribeiro and Inês Guimarães Rento

Definition and Etiology

Delirium is an acute and confusional state of mind and represents a sudden and significant decline from a previous level of functioning, most of the time when an external stressor is superior to the cerebral reservoir5.
It´s very important to distinguish delirium from dementia. The main difference is that the last one has a very slow cognitive decline. However, it is not infrequent the coexistence of both since a certain degree of dementia increases the risk of delirium5.
Delirium can affect any person of any age5.
This dysfunction seems to gain importance in Palliative Units despite many times being underdiagnosed. Palliative patients develop delirium throughout all hospital admission from 13–42% on admission to 88% in the last weeks–hours of life7.
The diagnosis is based on the clinical history (more often near the family) and the physical examination. Complementary exams will not diagnose this condition; however, they can help find the cause of delirium5.
Some scales can help with the recognition of delirium; the Confusion Assessment Method (CAM) is one of them. When well applied, this scale has a specificity of 99% and a sensibility of 82% in the diagnosis of delirium. It is now approved to be used in palliative care units4. .

Evidence Level Grade PMID Nº

Symptoms and signs

Abnormal attention or arousal is the cardinal feature and means distractibility, inability to focus, drowsiness or semi-consciousness5,6.
It is marked by sudden onset, a fluctuating course, inattention, and often abnormal level of consciousness5,6.
There are three types of delirium:
Hypoactive: more common; the patient presents somnolent.
Hyperactive: the patient presents agitated.
Mixed: fluctuation between hypoactive and hyperactive.
Sleep disturbances and disruption in the circadian circle, disorientation, memory deficit, disturbances in language, visuospatial ability, or perception are frequent2.
Other prodromal features include irritability, anxiety, and restlessness2.

Etiology

Acommon risk factor model for delirium distinguishes predisposing from precipitating factors5.
Predisposing factors are chronic conditions that increase the patient’s vulnerability to develop delirium; these predisposing factors include pre-existing cognitive impairment, multiple comorbid conditions, polypharmacy, impaired sensation or functional ability5.
Precipitating factors are acute conditions that start delirium5; The mnemonic PINCH ME can be used to remember the main causes of delirium, as seen in figure 1.
The more predisposing factors the fewer precipitating factors are needed to develop delirium.

P	Pain
I	Infection
N	Nutrition
C	Constipation
H	Hydration
M	Medication
E	Environment

Figure 1 Mnemonics for Delirium’s precipitating factors

Therapeutic Strategy Evidence

Level Grade PMID Nº

Treat the underlying cause for delirium

Optimize sleep-wake pattern

Patient orientation

Avoid sensory deprivation (by restoring a patient’s glasses or hearing aid)

Monitor hydration and nutrition

Monitor bladder and bowel function

Encourage mobility

Stop or reduce, if possible, a medication that might increase the risk of developing delirium such as tricyclic

antidepressants, anticholinergic medications, benzodiazepines, antihistamines andopioid analgesics.

I	A	30927352
IIb	C	7922932
IIb	C	7922932
IIb	C	7922932
IIb	C	7922932
IIb	C	7922932
IIb	C	7922932
IIb	C	7922932

Pharmacotherapy

Nonpharmacologic interventions and treatment of underlying conditions are initial steps to prevent and manage delirium. The use of this medication should be for a short period as adjunctive use while addressing underlying causes of severe symptoms and if distressing symptoms, such as agitation, anxiety, and combative behaviour, are present. The lowest possible dose is recommended for these individuals.

Medication	Posology	Observations
Risperidone	Oral: 0.5 mg/day in 2 divided doses;	These should be carefully used when the patient has prolonged QTc on ECG and Parkinson’s Disease (risk for EPE).
Quetiapine	Oral: Initial: 25 mg at bedtime; may increase the dose gradually (e.g., weekly) based on response and tolerability up to 75 mg twice daily
Olanzapine	Oral: Initial: 1.25 to 5 mg once daily; titrate daily based on symptoms in 2.5 to 5 mg increments up to 20 mg/day
Haloperidol	IV, IM or oral: Initial: 0.5 to 1 mg; if needed, may repeat every 30 minutes until calm. Maximum 5 mg/day

IIa A 30927352

IIb A 30927352

IIa A 30927352

Chlorpromazine

IV: 12.5 mg every 4-12 hour

Rectal: 25 mg every 4-12 hour

Indicated in terminal cancer

patients

Benzodiazepine

Should not be used in nonspecific delirium.

These may increase the risk

of delirium.

Diazepam: 5 to 10 mg IV every 5 to 10 minutes, until the appropriate level of sedation is achieved.
If diazepam is unavailable, we

favour Midazolam for rapid symptom control.

These should be used in alcohol withdrawal and benzodiazepines withdraw

References:

AGS/NIA Delirium Conference Writing Group, Planning Committee and Faculty. The American Geriatrics Society/National Institute on Aging Bedside-to-Bench Conference: Research Agenda on Delirium in Older Adults. JAm Geriatr Soc. 2015 May;63(5):843-52. doi: 10.1111/jgs.13406. Epub 2015 Mar 31. PMID: 25834932; PMCID: PMC5407494.
Bush SH, Tierney S, Lawlor PG. Clinical Assessment and Management of Delirium in the Palliative Care Setting. Drugs. 2017 Oct;77(15):1623-1643. doi: 10.1007/s40265-017- 0804-3. PMID: 28864877; PMCID: PMC5613058.
Clegg A, Young JB. Which medications to avoid in people at risk of delirium: a systematic review. Age Ageing. 2011 Jan;40(1):23-9. doi: 10.1093/ageing/afq140. Epub 2010 Nov 9. PMID: 21068014.
Cole MG, Primeau FJ, Bailey RF, Bonnycastle MJ, Masciarelli F, Engelsmann F, Pepin MJ, Ducic D. Systematic intervention for elderly inpatients with delirium: a randomized trial. CMAJ. 1994 Oct 1;151(7):965-70. PMID: 7922932; PMCID: PMC1337283.
Davis D, Searle SD, Tsui A. The Scottish Intercollegiate Guidelines Network: risk reduction and management of delirium. Age Ageing. 2019 Jul 1;48(4):485-488. doi: 10.1093/ageing/afz036. PMID: 30927352.
Hasuo H, Kanbara K, Fujii R, Uchitani K, Sakuma H, Fukunaga M. Factors Associated with the Effectiveness of Intravenous Administration of Chlorpromazine for Delirium in Patients with Terminal Cancer. J Palliat Med. 2018 Sep;21(9):1257-1264. doi: 10.1089/jpm.2017.0669. Epub 2018 May 14. PMID: 29757064.
Holbrook AM, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of benzodiazepine use in the treatment of acute alcohol withdrawal. CMAJ. 1999 Mar 9;160(5):649-55. PMID: 10101999; PMCID: PMC1230110.
Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med.

1990 Dec 15;113(12):941-8. doi: 10.7326/0003-4819-113-12-941. PMID: 2240918.

Mattison MLP. Delirium. Ann Intern Med. 2020 Oct 6;173(7):ITC49-ITC64. doi: 10.7326/AITC202010060. PMID: 33017552.
Trzepacz, Paula & Breitbart, William & Franklin, J. & Levenson, J. & Martini, R. & Wang, P.. (2006). Practice guideline for the treatment of patients with delirium. American Psychiatric Association Practice Guidelines for the Treatment of Psychiatric Disorders. 1-38.
Watt CL, Momoli F, Ansari MT, Sikora L, Bush SH, Hosie A, Kabir M, Rosenberg E, Kanji S, Lawlor PG. The incidence and prevalence of delirium across palliative care settings: A systematic review. Palliat Med. 2019 Sep;33(8):865-877. doi: 10.1177/0269216319854944. Epub 2019 Jun 11. PMID: 31184538; PMCID: PMC6691600.
Young J, Murthy L, Westby M, Akunne A, O’Mahony R; Guideline Development Group. Diagnosis, prevention, and management of delirium: summary of NICE guidance. BMJ.

2010 Jul 28;341:c3704. doi: 10.1136/bmj.c3704. PMID: 20667955.

Evidence Level Grade PMID Nº

IIa B 29757064

III A 21068014

I A 10101999

ENDOCRINOLOGICAL ALTERATIONS

HYPOPHYSITIS

Authors: Sara Gabriela Esteves Ferreira, Joana Guimarães and Márcia Alves

Definition

Symptoms and signs

As with other adverse events on patients with cancer therapy, the Common Terminology Criteria for Adverse Events (CTCAE) has been used to grade the severity of immunotherapy related Hypophysitis.

Grade 1	Grade 2
Absent or mild symptoms	Moderate symptoms
Tiredness, fatigue, weight loss, susceptibility to infection, normal BP with no postural drop
Grade 3		Grade 4	Grade 5
Severe, disabling or medically significant symptoms		Life – threatening consequences	Death
Hypotension (systolic BP <90 mmHg), postural h-ypotension (>20 mmHg drops in BP from standing to sitting), dizziness/collapse, hypovolemic shock, abdominal pain,tenderness or guarding, nausea, vomiting, tachycardia +/ cardiac arrythmias, fever confusion/delirium, coma, hyponatraemia, hyperkalaemia, hypoglycaemia, pre-renal/renal failure

Etiology

Studies

- 1. Biochemical testing: A biochemical profile should be obtained before institution of treatment with ICI, regularly during treatment and whenever there is suspicion of Hypophysitis – in patients with suggestive symptoms, hyponatremia, pituitary deficiency and/or abnormal pituitary imaging (Table 2). Of note, a decrease in TSH may precede immunotherapy associated Hypophysitis by several weeks, so a fall in TSH should prompt closer monitoring.

Baseline profile

Plasma sodium
TSH, free T4
08:00h serum cortisol (in the absence of treatment with corticosteroids)
LH, FSH and testosterone (in men)
LH, FSH and oestradiol (in pre-menopausal women with irregular periods, in the absence of other aetiologies)
FSH (in post-menopausal women)
In premenopausal women not taking hormonal contraceptives, the a ctivity of the gonadotropin axis should be evaluated by the regularity of cycles

Monitoring during treatment

Clinical monitoring for signs or symptoms of Hypophysitis.
Plasma sodium
TSH, free T4
08:00h serum cortisol
Testosterone (in men)
Patients with possible adrenal insufficiency (table 3) should be referred for dynamic testi ng under endocrine supervision

Suspicion of Hypophysitis

Blood electrolytes
TSH, free T4
Blood glucose
Prolactin
LH, FSH and oestradiol (in premenopausal women not taking oral contraceptives)
FSH (in postmenopausal women)
LH, FSH and total testosterone (in men)
08:00h ACTH and serum cortisol (in the absence of treatment with synthetic glucocorticoids)
In case of suspicion of acute adrenal insufficiency, plasma cortisol should be measured regardless of the time of day
In the presence of symptoms suggestive of DI, such as polyuria and polydipsia, plasma and urine osmolality should be assessed
Patients with suggestive MRI abnormalities should be subjected to weekly monitoring of 08:00h cortisol for 1 month

Serum cortisol	08:00 cortisol <7 ug/dL (<200 nmol/L) Random cortisol <3 ug/dL (<100 nmol/L)	Adrenal insufficiency likely Measure ACTH
	08:00 cortisol 7-16 ug/dL (200-450 nmol/L) Random cortisol 3-16 ug/dL (100-450 nmol/L)	Adrenal insufficiency possible Measure ACTH
	>16 ug/dL (>450 nmol/L)	Adrenal insufficiency unlikely
TSH	Within/below reference range, with free T4 below reference range	May indicate hypopituitarism Check cortisol

- 1. Imaging monitoring: Imaging studies are important to confirm the diagnosis, evaluate for mass effect and eliminate differential diagnosis, such as pituitary abscess, apoplexy, infiltrative disease, or metastasis. Pituitary MRI is the most sensitive imaging technique and should be performed as soon as possible. Changes in pituitary MRI can precede clinical and biochemical alterations by several weeks in up to 50% of these patients. Patients with an abnormal MRI suggestive of Hypophysitis should be subject to closer monitoring. It typically evolves to an early decrease in pituitary volume. Since these alterations are transient and not present in all patients, a normal MRI should not exclude the diagnosis of Hypophysitis. Imaging monitoring is advised in the first 3 months after diagnosis to rule out a differential diagnosis, since at this time point immunotherapy-related enlargement should be resolved.
  2. Histological testing: Diagnosis of immunotherapy induced Hypophysitis is presumptive and biopsy for histological confirmation can be dismissed in the absence of suspicion of other pituitary pathology, such as metastasis.

Pharmacotherapy

Corticosteroids
1. Patients with severe/life-threatening symptoms (CTCAE grade 3-4):
  1. Immediate bolus injection of 100mg hydrocortisone i.v. or i.m. followed by continuous intravenous infusion of 200mg hydrocortisone per 24h (alternatively, 50m hydrocortisone per i.v. or i.m. injection every 6h). Treatment initiation should not be delayed while waiting for laboratory results.