The MASCC Textbook of Cancer Supportive Care and Survivorship

Ian N. Olver Editor

The MASCC Textbook of Cancer Supportive Care and Survivorship

Editor Ian N. Olver MD PhD Clinical Professor University of Sydney Medical School Chief Executive Officer Cancer Council Australia Surry Hills, Sydney NSW 2010 Australia [email protected]

ISBN 978-1-4419-1224-4 e-ISBN 978-1-4419-1225-1 DOI 10.1007/978-1-4419-1225-1 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2010935191 © Multinational Association for Supportive Care in Cancer Society 2011 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Preface

The Multinational Association of Supportive Care in Cancer (MASCC) has as its underlying principle that “Supportive Care Makes Excellent Cancer Care Possible.” This international group attracts a multidisciplinary group of support care practitioners and researchers to its annual symposia. Over the years it has expanded to having 17 study groups led by key professionals in their fields. More recent developments have seen a focus on survivorship. The groups have not only provided education, networking and the promotion of research but have produced guidelines and research and teaching tools. With all of that expertise across the world, what better organisation could there be to produce a book on supportive care and survivorship, which spans the management of symptoms and the control of the side effects of treatment? The result is a textbook with authorship by experts from 17 countries. The authors are MASCC members and their colleagues, all of whom have volunteered their time and expertise to produce this comprehensive text. The topics range from management of broad general symptoms such as pain and fatigue to the very specific details of toxicities affecting the eye. Special consideration is given to children and the elderly, to rehabilitation and to palliative care. The ongoing issues of survivorship embrace the physical, the psychosocial and the spiritual. As such this book will be a resource for people from a broad range of disciplines. I am most grateful to the Board of MASCC for giving me the opportunity of participating in this exciting project and to work with so many talented experts across the world. Surry Hills NSW, Australia

Ian N. Olver

v

Contents

Preface................................................................................................................................

v

Contributors......................................................................................................................

xi

Part I: Introduction   1. Cancer Symptoms and Side Effects of Treatment................................................. Ian N. Olver

3

Part II: General Symptoms   2. Cancer Pain............................................................................................................... 11 Mellar P. Davis   3. Cancer-Related Fatigue............................................................................................ 23 Barbara F. Piper, Karin Olson, and Carina Lundh Hagelin   4. Palliative Care: End-of-Life Symptoms.................................................................. 33 Paul Glare, Tanya Nikolova, and Nessa Coyle   5. Supportive Care in Elderly Cancer Patients.......................................................... 45 Matti S. Aapro   6. Supportive Care in Paediatric Oncology................................................................ 49 Marianne D. van de Wetering and Wim J. E. Tissing   7. Quality-of-Life Assessment: The Challenge of Incorporating Quality-of-Life and Patient-Reported Outcomes into Investigative Trials and Clinical Practice........................................................ 63 Richard J. Gralla and Patricia J. Hollen Part III: Cardiovascular   8. Cardiac Toxicities of Cancer Therapies: Challenges for Patients and Survivors of Cancer........................................................................................... 73 Winson Y. Cheung   9. Malignant Pericardial Effusion and Cardiac Tamponade (Cardiac and Pericardial Symptoms)...................................................................... 83 Marek Svoboda 10. The Vena Cava Syndrome........................................................................................ 93 Mario Dicato and Vincent Lens

vii

viii

Part IV: Respiratory 11. Pulmonary Toxicity of Therapy............................................................................... 99 Andriani G. Charpidou and Kostas K. Syrigos 12. Management of Respiratory Symptoms in People with Cancer........................... 107 David C. Currow and Amy P. Abernethy Part V: Endocrine and Metabolic 13. Endocrine and Metabolic Symptoms of Cancer and Its Treatment..................... 117 Rony Dev Part VI: Reproductive 14. Sexual Problems in Patients with Cancer............................................................... 127 Andreas Meißner, Charalampos Mamoulakis, Grada J. Veldink, and Jean J. M. C. H. de la Rosette 15. Sterility, Infertility, and Teratogenicity................................................................... 133 Hele Everaus 16. Menopause Symptoms.............................................................................................. 145 Debra L. Barton and Sherry L. Wolf Part VII: Hematological and Cardiac 17. Preserving Cardiac Health in the Breast Cancer Patient Treated with Anthracyclines.................................................................................... 161 Neville Davidson 18. Thrombosis and Bleeding in Cancer Patients........................................................ 171 Wolfgang Korte 19. Lymphedema Care.................................................................................................... 179 Andrea M. Steely and Patricia O’Brien Part VIII: Infections in Cancer 20. Infections and Cancer............................................................................................... 195 Bernardo L. Rapoport and Ronald Feld Part IX: Gastrointestinal 21. Cancer Cachexia and Anorexia............................................................................... 205 Neil MacDonald and Vickie Baracos 22. Xerostomia and Dental Problems in the Head and Neck Radiation Patient...................................................................................................... 213 Arjan Vissink, Fred K. L. Spijkervert, and Michael T. Brennan 23. Dysphagia, Reflux, and Hiccups.............................................................................. 223 Amy A. Shorthouse and Rebecca K. S. Wong 24. Nausea and Vomiting................................................................................................ 231 Ian N. Olver 25. Mucositis (Oral and Gastrointestinal).................................................................... 241 Rajesh V. Lalla and Dorothy M. K. Keefe

Contents

Contents

ix

26. Diarrhea, Constipation, and Obstruction in Cancer Management...................... 249 Lowell B. Anthony 27. Ascites......................................................................................................................... 261 Rohit Joshi 28. Hepatotoxicity and Hepatic Dysfunction................................................................ 267 Ahmet Taner Sümbül and Özgür Özyilkan Part X: Urogenital 29. Urological Symptoms and Side Effects of Treatment............................................ 281 Ehtesham Abdi 30. Gynecological Symptoms.......................................................................................... 301 Stefan Starup Jeppesen and Jørn Herrstedt Part XI: Neurologic and Muscular 31. Central Nervous System Symptoms: Headache, Seizures, Encephalopathy, and Memory Impairment........................................................... 313 Roxana S. Dronca, Charles L. Loprinzi, and Daniel H. Lachance 32. Neuromuscular Disease and Spinal Cord Compression........................................ 321 Roxana S. Dronca, Charles L. Loprinzi, and Daniel H. Lachance 33. Eye Symptoms and Toxicities of Systemic Chemotherapy.................................... 333 April Teitelbaum Part XII: Skin 34. Extravasation............................................................................................................. 351 Lisa Schulmeister 35. Dermatologic Toxicities............................................................................................ 361 Eugene Balagula and Mario E. Lacouture 36. Chemotherapy-Induced Alopecia: Overview and Methodology for Characterizing Hair Changes and Regrowth.................... 381 Elise A. Olsen Part XIII: Rehabilitation 37. Rehabilitation in Cancer.......................................................................................... 389 Martin R. Chasen and Paul B. Jacobsen Part XIV: Survivorship 38. Oral Health and Survivorship: Late Effects of Cancer and Cancer Therapy................................................................................................. 399 Joel B. Epstein and Barbara E. Murphy 39. Survivorship: Psychosocial, Physical Issues, and Insomnia.................................. 407 Melissa Y. Carpentier, Tammy Weitzmann, Ziv Amir, Grace E. Dean, and Ian N. Olver 40. Spiritual Issues in Supportive Cancer Care........................................................... 419 Antonella Surbone, Tatsuya Konishi, and Lea Baider Index................................................................................................................................... 427

Contributors

Matti S. Aapro, MD Clinique de Genolier, Multidisciplinary Oncology Institute, 1 route du Muids, 1272, Genolier, Switzerland Ehtesham Abdi, MBBS, FRACP, FACP Department of Medical Oncology, Cancer and Aged Care, Griffith University, The Tweed Hospital, Tweed Heads, NSW, 2485, Australia Amy P. Abernethy, MD Associate Professor of Medicine, Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Director, Duke Cancer Care Research Program, Durham, NC 27710, USA Ziv Amir, PhD, MSc, BSc Director, MacMillan Research Unit, University of Manchester, School of Nursing, Midwifery and Social Work, Oxford Road, M13 9PL, Manchester, UK Lowell B. Anthony, MD, FACP LSUHSC New Orleans, Professor of Medicine, Department of Medicine, Ochsner Kenner Medical Center, 200 West Esplanade, Ste 200, Kenner, LA 70065, USA Lea Baider, PhD Professor, Director, Department of Psycho-oncology, Sharett Institute of Oncology and Radiotherapy, Hadassah University Hospital, 91120 Jerusalem, Israel Eugene Balagula, MD Clinical Research Fellow, Department of Dermatology, Memorial Sloan Kettering Cancer Center, New York, NY 10022, USA Vicki Baracos, BSc, PhD Professor, Department of Oncology, University of Alberta, Cross Cancer Instutute, Edmonton, AB, 7Y1C2, Canada Debra L. Barton, RN, PhD, AOCN, FAAN Department of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Michael T. Brennan, DDs, MHS Associate Chairman, Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC 28203, USA Melissa Y. Carpentier, PhD Department of Oral Medicine Pediatrics, Indiana University School of Medicine, 401 West 10th St., Suite 1001, Indianapolis, IN 46202, USA

xi

xii

Andriani G. Charpidou, MD Chest Physician, Clinical Research Fellow, Oncology Unit, GPP, University of Athens Medical School, Athens, 11527 Greece Martin R. Chasen, MBChB, FCP(SA), MPhil(Pall Med) Division of Palliative Care, University of Ottawa; Palliative Rehabilitation, Élisabeth Bruyère Hospital, Ottawa, ON, Canada Winson Y. Cheung, MD, MPH, FRCPC British Columbia Cancer Agency, Division of Medical Oncology, 600 W. 10th Avenue, 4th Floor, Vancouver, BC, Canada V5Z 4E6 Nessa Coyle, MP, PhD Nurse Practitioner, Memorial Sloan Kettering Cancer Center, New York, NY 15021, USA David C. Currow, MPH, FRACP Palliative and Supportive Services, Flinders University, Adelaide 5041, South Australia Neville Davidson, FRCP, FRCR Department of Oncology Research, Broomfield Hospital, Ground Floor, West Wing 2, Court Road, Chelmsford CM1 7ET, Essex, UK Mellar P. Davis, MD, FCCP The Cleveland Clinic, 9500 Euclid Avenue R35, Cleveland, OH 44195, USA Grace E. Dean, PhD, RN Assistant Professor, University of Buffalo, School of Nursing, Buffalo, NY 14214, USA Rony Dev, DO Department of Palliative Care and Rehabilitation Medicine, University of Texas MD Anderson Cancer Center, Symptom Control and Palliative Medicine, Houston, TX 77030, USA Mario Dicato, MD Cancer Research Foundation – Luxembourg, Centre Hospitalier de Luxembourg, 1, rue Wieseck, L-8269, Mamer, Luxembourg Roxana S. Dronca, MD Department of Oncology/Hematology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55901, USA Joel B. Epstein, DMD, MSD, FRCD, FDS RCS(Ed) Department of Oral Medicine and Diagnostic Sciences, College of Dentistry and Head and Neck Surgery/Otolaryngology, 801 S. Paulina St, Chicago, 60612, IL, USA Hele Everaus, MD, PhD Department of Hematology-Oncology, Tartu University Hospital, Tartu 51014, Estonia Ronald Feld, BSc, Phm MD, FRCPC, FACP Professor of Medicine, University of Toronto; Staff Physician, Division of Hematology and Oncology, Princess Margaret Hospital, Toronto, M5G 2M9 Ontario, Canada Paul Glare, MBBS, FRACP, FACP Pain & Palliative Care Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA Richard J. Gralla, MD Division of Medical Oncology and Hematology, Hofstra North Shore-LIJ School of Medicine, Lake Success, NY 11042, USA

Contributors

xiii

Contributors

Carina Lundh Hagelin, RN, PhD Department of Oncology and Pathology, Division of Clinical Cancer Epidemiology, Karolinska Institutet and Sophiahemmet University College, Stockholm, 114 86, Sweden Jørn Herrstedt, MD Department of Oncology, Odense University Hospital, DK-5000 Odense C, Denmark Patricia J. Hollen, PhD, RN, FAAN Professor of Oncology Nursing, Boyd School of Nursing, Professor of Pediatrics, School of Medicine, Charlottesville, VA 22903, USA Paul B. Jacobsen, PhD Professor and Chair, Department of Health Outcomes & Behavior, Moffitt Cancer Center & Research Institution, Tampa, FL 33612, USA Stefan Starup Jeppesen, MD Department of Oncology, Odense University Hospital, DK-5000 Odense, Denmark Rohit Joshi, MD Medical Oncology, Christian Medical College & Hospital, Ludhiana 141012, Punjab, India Dorothy M. K. Keefe, MBBS, MD Cancer Council Professor of Cancer Medicine, University of Adelaide; Clinical Director, CNAHC and Royal Adelaide Hospital Cancer Services, Royal Adelaide Cancer Centre, Adelaide 5000, Australia Tatsuya Konishi Director of Spiritual Care, Higashi Sapporo Hospital, Sapporo, Hokkaido 060-003, Japan Wolfgang Korte, MD, PhD Institute for Clinical Chemistry and Hematology, Kantonsspital St. Gallen, St. Gallen and University of Bern, Bern, Switzerland Daniel H. Lachance, MD Consultant and Assistant Professor of Neurology, Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA Mario E. Lacouture, MD Department of Dermatology, Memorial Sloan Kettering Cancer Center, 160 East 53rd Street, New York 10022, USA Rajesh V. Lalla, DDS, PhD, CCRP Section of Oral Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA Vincent Lens, MD Department of Radiology, Centre Hospitalier de Luxembourg, L- 1210, Luxembourg Charles L. Loprinzi, MD Director, North Central Cancer Center, Treatment Group Cancer Control Program, Co-Director, Mayo Cancer Center, Cancer Prevention and Control Program, Rochester, MN 55905, USA Neil MacDonald, CM, MD, FRCP(Can), FRCP(Edin) Department of Oncology, McGill University, Montreal, QC, Canada H2W 1S6 Andreas Meißner, MD Academic Medical Center, Department of Urology, University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands

xiv

Charalampos Mamoilakis, MD, PhD, MSc Academic Medical Center, University of Amsterdam, Department of Urology, Amsterdam, 1105 AZ, The Netherlands Barbara E. Murphy, MD Associate Professor, Department of Internal Medicine, Vanderbilt University, Nashville, TN 37232, USA Barbara F. Piper, DNSc, RN, AOCN, FAAN Scottsdale Healthcare/University of Arizona, 10684 N. 113th Street, 85259-4034 Scottsdale, AZ, USA Patricia O’Brien, MD, PT Clinical Associate Professor, Fletcher Allen Health Care, Department of Hematology/ Oncology, Burlington, VT 05405, USA Elise A. Olsen, MD Duke University Medical Center, Box 3294, Durham, NC 27710, USA Karin Olson, BScN, MHSc, PhD University of Alberta, Edmonton, AB, T6G 2G3, Canada Ian N. Olver, MD PhD Clinical Professor, University of Sydney Medical School, Chief Executive Officer, Cancer Council Australia, Surry Hills, Sydney NSW 2010, Australia Özgür Özyilkan, MD Professor, Department of Medical Oncology, Baskent University School of Medicine, Adana, 01120, Turkey Tanya Nikolova, MD Pain & Pallative Care Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065 USA Bernardo L. Rapoport, MD Department of Medical Oncology, The Medical Oncology Centre of Rosebank, Johannesburg 2196, South Africa Jean J. M. C. H. de la Rosette, MD, PhD Academic Medical Center, University of Amsterdam, Department of Urology, Amsterdam, 1105 AZ, The Netherlands Lisa Schulmeister, RN, MN, APRN-BC, OCN, FAAN 282 Orchard Road, River Ridge, LA 70123, USA Amy A. Shorthouse, B.Med(Hons), BSc, FRANZCR Radiation Medicine Program, Princess Margaret Hospital, Toronto, ON, Canada M5G2M9 Fred K. L. Spijkervert, DDS, PhD Associate Professor of Oral and Maxillofacial Surgery and Vice Program Chair, Department of Oral and Maxillofacial Surgery, University Medical Center Gronigen, Gronigen, 9700 RB, The Netherlands Andrea M. Steely, BA, MA Department of Hematology and Oncology, University of Vermont College of Medicine, 89 Beaumont Ave., Burlington, VT 05405, USA Ahmet Taner Sümbül, MD Department of Medical Oncology, Baskent University School of Medicine, Baskent Universitesi Adana Hastanesi Kisla Yerleskesi Tibbi Onkoloji BD Kazim Karabekir cadYuregir, Adana, 01120, Turkey

Contributors

xv

Contributors

Antonella Surbone, MD, PhD, FACP Department of Medicine, Division of Medical Oncology, New York University Medical School, 550 First Ave BCD 556 New York, NY 10016 USA Marek Svoboda, PhD, MD Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Center, Zluty kopec 7, Brno 65653, Czech Republic Kostas K. Syrigos, MD, PhD Sotiria General Hospital, Oncology Unit, GPP, Athens School of Medicine, Athens 11527, Greece April Teitelbaum, MD, MS AHT BioPharma Advisory Services, 3525A Del Mar Heights #312, San Diego, CA 92130, USA Wim J. E. Tissing MD, PhD Pediatric Oncologist, University Medical Center Groningen, Department of Pediatric Oncology/Hematology, Groningen 9700 RB, The Netherlands Grada J. Veldink Academic Medical Center, University of Amsterdam, Department of Policlinic Surgery and Urology, Amsterdam 1105 AZ, The Netherlands Arjan Vissink, DDS, MD, PhD Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, Groningen, 9700 RB, The Netherlands Tammy Weitzman, LICSW Clinical Social Worker, Bone Marow Transplant Program, Dana Farber/Brigham and Women’s Cancer Center, Boston, MA 02115, USA Marianne D. van de Wetering, PhD, FCP(SA), MMed(SA) Department of Pediatric Oncology, Emma Children’s Hospital/Academic Medical Center, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands Sherry L. Wolf, RN, MS, AOCNS Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA Rebecca K. S. Wong, MBChB, MSc, FRCP Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario M5G2M9, Canada

Part I

Introduction

Chapter 1

Cancer Symptoms and Side Effects of Treatment Ian N. Olver

This is a book to cover the management of the symptoms of cancer and side effects of cancer treatment. The symptoms discussed range from general symptoms to organ-specific symptoms and cover all stages of cancer from the presenting symptoms of the cancer to symptoms that arise in the terminal phase of the illness which require palliation, or symptoms and late effects of treatment which persist post-treatment into the survivorship phase. The authors discuss the management of symptoms which apply to both adults and children. One unique aspect of this handbook is that it covers the whole patient journey including survivorship. This includes both the late effects of treatment and the psychosocial issues to be managed post-treatment. There is also specifically a section on rehabilitation and another on palliative care. The authors are members of MASCC (Multinational Association for Supportive Care in Cancer), a multidisciplinary international organisation whose focus is on supportive care and whose membership includes many of the world leaders in that field. The organisation regularly publishes guidelines in symptom control in order to encourage evidencebased practice. The target audience is the health professional who manages cancer. This includes those from the primary specialties of surgery, radiation oncology, medical oncology, palliative care and rehabilitation medicine as well as from allied disciplines of psychology, social work, physiotherapy, occupational therapy and pharmacy as well as specialist and general nurses. General practitioners who manage many of the symptoms and side effects after treatment will find it a useful reference. The book will also be a helpful resource for medical and allied health students. Finally, with the increasing sophistication of consumers, some will benefit from the greater detail provided in this book if they wish to research beyond traditional resources for patients and carers. I.N. Olver (*) University of Sydney Medical School, Sydney, NSW, Australia and Cancer Council Australia, GPO Box 4708, Level 1, 120 Chalmers Street, Surry Hills NSW 2010, Sydney, NSW 2001, Australia e-mail: [email protected]

The Symptoms of Cancer It is important to become familiar with the symptoms of ­cancer when it presents and when it recurs, to aid in prompt diagnosis, but also to know when the symptoms are not ­typical of cancer and other diagnoses must be considered (Table 1.1). The differential diagnosis of the symptoms of cancer includes the side effects of treatment, which can occur at the time of treatment or later, other drugs given to patients including those for symptom control and unrelated illnesses. Symptoms also have both a physical and psychological dimension and so cannot be isolated from the other experiences of the patient with a diagnosis of cancer. A common feature of cancer-related symptoms is persistence [1]. In the absence of treatment, a cancer-related symptom will persist and often worsen as the cancer progresses. For example, a pain due to an acute back injury or a cough due to an infection would be expected to improve over time because the underlying problem may improve, but that is not the pattern expected if the same symptoms are due to cancer. Some of the physical symptoms of cancer are general and so this book contains chapters which describe symptoms such as fatigue, insomnia, anorexia, cachexia, delirium, fever and pruritus. Some common symptoms such as pain can be associated with multiple organ systems. There are many symptoms specific to organ systems when the cancer directly affects them either as the site of the primary or due to secondary spread. All the major organ systems, cardiovascular, respiratory, gastrointestinal, urogenital and neurological are associated with specific symptoms. For example, the headache associated with primary or secondary cerebral malignancy is usually due to raised intracranial pressure and so is worst in the morning and progresses over several weeks [2]. Paraneoplastic symptoms are distant effects associated with cancer but not directly due to local pressure from the primary or from metastatic disease. They can be associated with any organ system but are commonly endocrine, neurological, haematological, renal or dermatological. Sometimes a rash, for example, may be the initial manifestation of an

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_1, © Multinational Association for Supportive Care in Cancer Society 2011

3

4

I.N. Olver Table 1.1  How cancers present Found by screening or incidentally when asymptomatic Local presentations   Lump   Bleeding   Organ specific, e.g. pain, cough Systemic symptoms   Weight loss   Fatigue   Fever and sweats Medical emergency   Spinal cord compression   Superior vena caval obstruction   Bowel obstruction   Hypercalcaemia

internal malignancy [3]. Unfortunately, the paraneoplastic symptom may not resolve with successful treatment of the underlying malignancy. More generally, the symptoms due to the damage done by a tumour, for example nerve compression, may not reverse if the cancer is treated because the cancer may have caused irreversible cell death. Rehabilitation of the patient with cancer then parallels that which would be employed following other causes of the symptoms in the above example, that is vascular accidents or trauma [4]. Cancers often have predictable patterns of spread which will direct where to look for secondary spread, but will also predict from where symptoms are likely to arise. For example, breast cancer spreads first to the liver, lung, bones and brain [5]. Lung cancer spreads to the liver, brain and bones while colorectal cancer secondaries are most likely to be found in the liver and lungs [6, 7]. Prostate cancer will often cause most of its metastatic symptoms by spreading to the bones, but a subset of prostate cancers spread to soft tissues, often initially to lymph nodes [8]. Conversely, symptoms presenting because of secondaries can provide clues as to the primary sites of the cancer. For example, secondaries in the bone are most likely from prostate, breast, lung, thyroid, adrenal, and renal cancers or myeloma.

The Side Effects of Treatment It is perhaps easiest to group the side effects of cancer treatment depending on their temporal relationship to the treatment. With surgery, chemotherapy and radiotherapy side effects can be acute at the time of the treatment or late, coming sometimes years after the therapy. This can be illustrated by considering chemotherapy toxicities. The immediate toxicities of chemotherapy would include extravasation injury as it is being administered or an acute hypersensitivity reaction [9, 10]. A few hours later side

effects like emesis can occur, but even that has an acute phase spanning the first 24 h and a delayed phase which starts at the end of the first day and can continue for a week [11]. Furthermore, uncontrolled emesis following chemotherapy can establish a learned response where anticipatory emesis can occur prior to subsequent cycles of therapy. In 10–15 days after chemotherapy, in tissues with constant turnover such as the bone marrow, the mucosa or the hair follicles, the dividing cells that were meant to replace mature cells which had completed their life cycle in those tissues do not do so, because they had been destroyed by the chemotherapy, and so myelosuppression, mucositis and alopecia results [12–14]. The stem cells will be stimulated to produce replacements eventually, but the patient needs the symptoms managed in the interim. Next come symptoms that are often delayed by weeks or months, and these are the organ toxicities. Often these are due to cumulative damage from each cycle of chemotherapy. These include cardiotoxicity, pulmonary toxicity, neurotoxicity, nephrotoxicity and hepatic toxicity [15–18]. A good example is the cardiotoxicity associated with the anthracylines [19]. Every dose damages the myocardium until finally sufficient damage is done to manifest itself as a reduction in the ejection fraction. This becomes more likely with cumulative doses in excess of 500  mg/m2, but this varies between patients and depends on factors such as whether there is underlying cardiac disease or whether other cardiotoxic drugs are being administered, including other anti-­ cancer agents such as the targeted therapy, trastuzumab. Toxicities such as this are detailed in the chapters on the side effects associated with various organs. Months to years after the chemotherapy come the late effects. These include organ damage such as encephalopathy, sterility, or the most unfortunate late effect of the treatment, a second cancer [20–22]. Similar temporal relationships between the treatment and side effects are described for radiation therapy. Here the acute effects within the radiation field are most often due to direct cell death which leaves depleted stem cells and progenitor cells and results in denuded tissue, which recovers over time [23]. More general effects such as somnolence and fatigue are due to the release of cytokines by radiation. Subacute effects, are exemplified by pneumonitis when the lung is irradiated, or L’Hermitte’s syndrome following radiation to the spine, and occur between 6 weeks and 3 months. Their aetiology is uncertain, but they recover [24]. Late effects which occur months or years after treatment in tissues such as the brain, do not recover. Stem cells are depleted and the microvasculature is damaged, but also collagen is deposited secondary to activation by the radiation of a series of cytokines, ultimately resulting in fibrosis [25]. With the increasing use of multimodality treatment the propensity for different treatments to interact and worsen the

1  Cancer Symptoms and Side Effects of Treatment

side effects in tissues, must be considered. Including the heart in a radiation field may increase the propensity for later cardiotoxic drugs to exacerbate the damage done. Some drugs, such as gemcitabine will also cause recall reactions of the radiation reaction in a previous field [26].

Differential Diagnoses The importance of knowing the symptoms of cancers and the side effects of therapy has a practical significance because they form part of the differential diagnosis of a symptom cluster in a patient. Consider, for example, a patient receiving chemotherapy for a metastatic cancer who develops a non-specific symptom, such as somnolence, and on examination is dehydrated. This could be due to progressive disease, perhaps with the development of cerebral secondaries or worsening hepatic disease where nausea may decrease the oral intake. Alternately a patient who becomes neutropenic on treatment may develop sepsis with a fever causing somnolence and dehydration. This requires immediate treatment with broad spectrum antibiotics to avoid septic shock. Other medication which a patient is ­taking should be scrutinised. The same symptoms of somnolence and dry mouth would fit with the side effects of morphine. Paraneoplastic syndromes may also need to be considered with particular malignancies. For example non-small cell lung cancer or squamous cell carcinoma of the head and neck may be associated with secretion of a parathyroid-like hormone causing hypercalcaemia which could manifest itself with both of these symptoms. Note also that the hypercalcaemia could be from progression of bone metastases. The importance of considering hypercalcaemia, for example, is that even if the underlying cause is difficult to treat, the symptoms may respond quickly to rehydration and bisphosphonates. It is also important that not every symptom reported by a patient with cancer is automatically considered as due to the cancer or its treatment. Patients may be more susceptible to infections spreading through a community, or can develop common conditions like acute appendicitis. Also, given that the majority of cancers occur in older people, underlying heart or renal problems may be the problem. Separate consideration is given to managing cancers in the elderly where the goals of treatment may be modified by the prognosis of an underlying illness. However, symptom control will always be foremost.

5

Often, anti-cancer treatment is very good for palliating symptoms. When treated with full doses with curative intent, a partial response to radiotherapy or chemotherapy may not translate into a survival advantage but will often shrink a tumour enough to relieve symptoms by taking the pressure off a nerve root, or relieving the obstruction of a hollow viscus or duct. The use of anti-cancer treatment for palliation requires a balance between the likely efficacy and toxicity of the treatment and the possible duration of each. Reducing the toxicity of a therapy may mean reducing the dose or duration of therapy, to treat with palliative intent. Often, a single fraction of radiation can provide excellent relief from the pain of bone metastases, for example [27]. Substituting drug regimens can also alleviate side effects. An early example was the decrease in secondary leukaemia after the successful treatment of Hodgkin disease when ABVD (Doxorubicin, Bleomycin, Vinblastine, dacarbazine) was substituted for MOPP (Nitrogen Mustard, Vincristine, Procarbazine, Prednisone) [28]. More recently, the targeted therapies such as Trastuzumab, used in breast cancer, have a much improved toxicity profile as compared to conventional cytotoxic drugs because they spare normal tissues and therefore are better candidates for palliation [29]. The specialty of palliative care uses supportive care drugs to relieve symptoms. Near the end of life, for example, it is said that just four drugs, morphine, midazolam, haloperidol and atropine can alleviate the majority of symptoms. However, symptom control is also required during times when patients are being treated with anti-cancer therapy often since the effects of treatment may take weeks to manifest themselves. My ideal model of multidisciplinary care for symptom control is parallel care, where the palliative care physicians join oncologists on rounds to help with symptom control and also learn when anti-cancer therapies are best used to alleviate symptoms (Fig. 1.1). The other advantage of this model is that as anti-cancer treatment becomes less relevant, a gradual transition can be made to palliative care without an abrupt change. Patients will have been used to seeing the palliative care team during the time when the treatment was primarily directed at shrinking the cancer and the palliative care team will just become progressively more involved with the patients’ management as symptom control becomes the major focus of care.

Parallel Care Cancer is increasingly being treated by multidisciplinary teams because of the need for multimodality treatment.

Fig. 1.1  Parallel care

6

Quality of Life and Spiritual Well-Being To achieve the optimum quality of life the balance between the efficacy and toxicity of a drug must be optimised, whether it is an anti-cancer or supportive care drug. Scales of measure­ ment of quality of life can range from simple measures of performance status, which equates to the ability to ­perform the tasks of daily living, to validated scales which measure many domains of life’s quality [30]. Often in deciding the balance, physical symptoms predominate but psychosocial issues are being increasingly recognised as having a major impact on well-being [31]. Spiritual well-being has also shown to impact independently on quality of life. In one study which compared spiritual well-being as measured by the FACIT-Sp scale to quality of life, a hierarchical multiple regression showed spiritual well-being to be a significant, unique contributor to quality of life beyond the core domains of physical, social/family, and emotional well-being [32].

Survivorship Survivorship has several definitions ranging from surviving from the time of diagnosis to survivorship beginning at the time that a complete remission has been achieved [33]. It encompasses issues of adjusting to life with the experience of cancer and its treatment. There may be physical sequelae of the cancer, or late effects of treatment, or distress with anxiety and depression. There may be constant underlying concerns about recurrence of the cancer, particularly after the cessation of active treatment and less frequent monitoring. This is a time of change and relationships can be under stress and previous employment not as satisfying as the patients’ priorities have changed. It is recognised that survivorship issues may require management by a multidisciplinary team of health professionals. Recognising the problems and providing ongoing information and support as well as managing physical symptoms and treating psychological problems may all be required.

Conclusions After the diagnosis of cancer, supportive care is an ongoing need. Symptoms will arise from the cancer or its recurrence and side effects will occur in relation to the treatments offered. Supportive care encompasses managing the ­physical, psychosocial and spiritual needs of patients at the time of

I.N. Olver

d­ iagnosis, through treatment and once the patients have ­survived the cancer, or at the time when the end of life is approaching. Children and the elderly have special supportive care needs. The carers and families of patients will also be impacted by a relative or close friend’s diagnosis of cancer and will require support as well. Symptoms can arise from a number of causes which constitute a differential diagnosis. Once the cause of symptoms has been identified a multidisciplinary team of oncologists, allied health practitioners and palliative care specialists will all work together within a patients’ social support structure to maximise the patient’s quality of life for as long as possible. This book encompasses the many facets of that support.

References 1. Ramos M, Arranz M, Taltavull M, March S, Cabeza E, Esteva M. Factors triggering medical consultation for symptoms of colorectal cancer and perceptions surrounding diagnosis. Eur J Cancer Care (Engl). 2010;19:192–199. 2. Dexter AJ, Cheong J. Neurosurgical involvement with cancer patients. In Robotin M, Olver I, Girgis A, eds. When Cancer Crosses Disciplines. London: Imperial College Press 2009:343–365. 3. Pipkin CA, Lio PA. Cutaneous manifestations of internal malignancies: An overview. Dermatol Clin. 2008;26:1–15. 4. Fattal C, Gault D, Leblond C et  al. Metastatic paraplegia: care ­management characteristics within a rehabilitation centre. Spinal Cord. 2009;47:115–121. 5. Park YH, Lee S, Cho EY et al. Patterns of relapse and metastatic spread in HER2-overexpressing breast cancer according to estrogen receptor status. Cancer Chemother Pharmacol. 2010;66:507–516. 6. Beckles MA, Spiro SG, Colice GL, Rudd RM. Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests and paraneoplastic syndromes. Chest. 2003;123:97S–104S. 7. Giess CS, Schwartz LH, Bach AM, Gollub MJ, Panicek DM. Patterns of neoplastic spread in colorectal cancer: implications for surveillance CT studies. Am J Roentgenol. 1998;170:987–991. 8. Long MA, Husband JE. Features of unusual metastases form ­prostate cancer. Br J Radiol. 1999;72:933–941. 9. Goolsby TV, Lombardo FA. Extravasation of chemotherapeutic agents: prevention and treatment. Semin Oncol. 2006;33:139–143. 10. Lee C, Gianos M, Klaustermeyer WB. Diagnosis and management of hypersensitivity reactions related to common cancer chemo­ therapy agents. Ann Allergy Asthma Immunol. 2009;102:187–179. 11. Olver IN. Prevention of chemotherapy-induced nausea and ­vomiting: Focus on fosaprepitant. Ther Clin Risk Manag. 2008; 4(2):1–6. 12. Heuser M, Ganser A, Bokemeyer C. Neutropenia: Review of ­current guidelines. Semin Oncol. 2007;44:148–156. 13. Keefe DM, Schubert MM, Elting LS, Sonis ST et  al; Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer. 2007;109:820–831. 14. Lemieux J, Maunsell E, Provencher L. Chemotherapy-induced ­alopecia and effects on quality of life among women with breast cancer: a literature review. Psychooncology. 2008;17:317–328. 15. Vahid B, Marik PE. Pulmonary complications of novel antineoplastic agents for solid tumours. Chest. 2008;133:528–538.

1  Cancer Symptoms and Side Effects of Treatment 16. Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. J Periph Nerv Syst. 2008;13:27–46. 17. Darmon M, Ciroldi M, Thiery G, Schlemmer B, Azoulay E. Clinical review: Specific aspects of acute renal failure in cancer patients. Crit Care. 2006;10:211 (doi:1186/cc4907). 18. King PD, Perry MC. Hepatotoxicity of chemotherapy. Oncologist. 2001;6:162–167. 19. Bird BR, Swain SM. Cardiac toxicity in breast cancer survivors: Review of potential cardiac problems. Clin Cancer Res. 2008;14:14–24. 20. Hildebrand J. Neurologic complications of cancer chemotherapy. Curr Opin Oncol. 2006;18:321–324. 21. Meirow D, Schiff E. Appraisal of chemotherapy effects on reproductive outcome according to animal studies and clinical data. J Natl Cancer Inst Monogr. 2005;34:21–25. 22. Travis B, Rabkin CS, Brown LM et al. Cancer survivorship-genetic susceptibility and second primary cancers: research strategies and recommendations. J Natl Cancer Inst. 2006;98:15–25. 23. Fiorino C, Rancati T, Valdaqni R. Predictive models of toxicity in external radiotherapy: dosimetric issues. Cancer. 2009;115: 3135–3140. 24. Kempster PA, Rollison RD. The Lhermitte phenomenon: variant forms and their significance. J Clin Neurosci. 2008;15:379–381. 25. Enami B, Lyman J, Brown A et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21:109–122. 26. Friedlander PA, Bansal R, Schwartz L, Wagman R, Posner P, Kemeny N. Gemcitabine-related radiation recall preferentially

7 involves internal tissue and organs. Cancer. 2004;100: 1793–1799. 27. Kaasa S, Brenne E, Lund JA et al. Prospective randomised multicentre trial on a single fraction radiotherapy (8Gy x 1) versus multiple fractions (3Gy x 10) in the treatment of painful bone metastases. Radiother Oncol. 2006;79:278–284. 28. Brusamolino E, Baio A, Orlandi E et al. Long-term events in adult patients with clinical stage 1A-11A nonbulky Hodgkin’s ­lymphoma treated with four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine and adjuvant radiotherapy: a single institution experience. Clin Cancer Res. 2006;12:6487–6493. 29. Brufsky A. Trastuzumab-based therapy for patients with ­HER2-positive breast cancer: form early scientific development to foundation care. Am J Clin Oncol. 2010;33:186–195. 30. Bailey LJ, Sanson-Fisher R, Aranda S, D’Este C, Sharkey K, Schofield P. Quality of life research: types of publication output over time for cancer patients, a systematic review. Eur J Cancer. 2009;Oct 14 [Epub ahead of print]. 31. Cimprich B, Janz NK, Northouse L, Wren PA, Given B, Given CW. Taking CHAGE: A self-management program for women following breast cancer treatment. Psychooncology. 2005;14:704–717. 32. Whitford HS, Olver IN, Peterson MJ. Spirituality as a core domain in the assessment of quality of life in oncology. Psychooncology. 2008;17:1121–1128. 33. Little M, Sayers EJ, Paul K, Jordens CFC. On surviving cancer. J R Soc Med. 2000;93:501–503.

Part II

General Symptoms

Chapter 2

Cancer Pain Mellar P. Davis

Introduction Cancer pain is a subjective sensation of tissue damage, which has an adverse influence on multiple domains in an ­individual’s life. Severe pain is associated with decreased function, increased interference with daily activities, depression, and anxiety. Pain is a major problem in 25–30% of individuals with newly diagnosed cancer and 70–80% with advanced cancer. Over 500,000 Americans die of cancer each year corres­ponding to 1,500 deaths per day [1]; therefore, cancer pain is a major problem that cancer specialists face. The lifetime probability of invasive cancer is 45% for men and 38% for women. Among men, prostate, lung, colon, and rectal cancers account for 50% of newly diagnosed cancers. Breast, lung, and colorectal cancers account for 50% of cancers in women. [1] As a result, bone and visceral pain are major pain subtypes clinicians need to manage. Over 20% of individuals who have cancer pain also have pains related to treatment [2]. Over 60% with chronic pain have breakthrough pain. Most chronic pain is moderate to severe (>7 on a numerical rating scale where 0 = no pain, 10 = severe pain). Many suffer pain for months. There are 22 commonly classified cancer pain syndromes. These syndromes involve bone and/or joint lesions in 41%, visceral metastases in 28%, soft tissue in 28%, and pain from peripheral nerve injury in 28% [2]. Individuals frequently experience two or more distinct cancer pain syndromes. Nociceptive pain accounts for 72%, visceral pain 35%, and neuropathic pain (mixed or purely neuropathic) is experienced by 48% of individuals [2]. Factors associated with the greatest chronic pain intensity are the presence of breakthrough pain, bone, and neuropathic pain. Individuals less than 60 years and

M.P. Davis (*) The Cleveland Clinic, 9500 Euclid Avenue R35, Cleveland, OH 44195, USA e-mail: [email protected]

those with poor performance score will experience severe pain more frequently [2].

Pain and Nociception Rene Descartes in the 1600s articulated the theory that pain is conveyed by special nerves to the brain [3]. Nerves carry information about tissue damage to the central nervous ­system (CNS). This is termed nociception, which involves transduction of the electrical signals to the dorsal horn of the spinal cord, transmission through the superficial layers of the dorsal horn, through the contralateral spinothalamic tract or the ipsilateral dorsal column (in case of visceral pain) to the cerebral pain matrix. Nociception is modulated or gated through the spinal cord, brainstem, and supraspinal sites. Individual genetic makeup, prior experiences, physiological status, appraisal of the meaning of pain, mood, and social cultural environment modulate the conversion of nociception to pain [4]. Nociceptive stimuli are capable of eliciting pain but are not equated with pain. Pain is defined as “sensory and emotional experience associated with actual or potential tissue damage” and not tissue damage per se. There is a poor correlation between the degree of tissue damage and pain severity [4]. Acute pain is of short duration and is associated with a high level of physical pathology. Chronic pain (by definition >3–6 months) has low physical pathology because chronic pain tends to be perpetuated by factors that are both pathogenetically and physically remote for the original cause [4]. The degree of tissue injury does not correlate well with the pain severity for two reasons: (1)  persistent pain alters the CNS, resulting in facilitatory pain transmission and modulation (neuroplasticity) [5, 6]; (2) affective and cognitive factors associated with unrelieved pain interact with tissue damage and contribute to persistent pain and illness behaviors [4]. Prolonged uncontrolled pain kills [7]. It is therefore important that clinicians manage cancer pain aggressively.

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_2, © Multinational Association for Supportive Care in Cancer Society 2011

11

12

The Anatomy of Pain Vanilloid, Sodium Channels, Acid-Sensing Channels Both A-delta (lightly myelinated) and C nerve fibers (unmyelinated) are “pain fibers,” which slowly conduct impulses; they have high thresholds and are often “silent” except with noxious stimuli (Fig. 2.1). Transient receptor potential vanilloid receptor-1 (TRPV-1) respond to heat and capsaicin (found in peppers) (Fig. 2.1) [8]. TPRV-1 receptors are activated by various kinases (protein kinase A, protein kinase C, phosphatidylinosital-3-kinase). These kinases are, in turn, activated by inflammation [9]. Certain sodium channels are also activated or modulated by nerve injury (Na1.3, Na 1.8, Na 1.9), which facilitates nociception. Neuropathic injury increases certain sodium channel expression, channel trafficking in axons, and channel phosphorylation. As a result, surviving sensory nerves develop increasing responsiveness. Certain adjuvants (lidocaine, bupivicaine, tricylic antidepressants, topiramate, lamotrigine, and carbamazepine) block sodium channels and reduce neuropathic pain [10, 11]. Metastases are frequently hypoxic in the center, resulting in an acidic environment. Osteoclasts stimulated by metastatic cells within the bone trabeculae require an acidic environment (pH 4–5) for osteolysis. Both stimulate acid-sensing ion channels (ASIC), which increase sensory afferent depolarization [12].

Fig. 2.1  Anatomy of pain

M.P. Davis

Bone Pain Bone pain has a unique spinal cord “signature,” which is a combination of neuropathic and inflammatory pain. Continuous pain in addition to activation of ASIC involves local production of prostaglandin and endothelin, which stimulates preand postsynaptic afferent nociceptors in marrow spaces. As tumor grows within marrow, it destroys medullary sensory afferents. TPRV-1 receptors are also activated. Bone destruction leads to mechanical instability and periosteum nerve impingement. In the dorsal horn, sensory neurons produce and express C-fos, and astrocytes around secondary sensory neurons are activated and multiple in numbers [12–14]. For this reason, nonsteroidal anti-inflammatory drugs (NSAIDS) and gabapentin (an anticonvulsant commonly used for ­neuropathic pain) reduce bone pain [15].

Other Allergic Medications Neurokinins such as substance P are released by peripheral and central sensory neurons and bind to NK-1 receptors. Substance P causes neurogenic inflammation, hyperalgesia, vascular changes (increased permeability and dilatation), and increases prostaglandin production. Bradykinin and certain cytokines (interleukin-1 and tumor necrosis factor alpha) induce hyperalgesia through production of

2  Cancer Pain

prostaglandins [16]. Nerve growth factors maintain and stimulate sensory nerve regeneration and are avidly taken up by membrane receptors. It also stimulates production of substance P [16].

Calcium Channels, NMDA Receptors Several types of calcium channels are present in sensory afferents, which facilitate conduction, transmission, and modulation of pain. N-type calcium channels contain alpha2 delta subunits that are targeted by gabapentinoids. N-methyld-asparate (NMDA) receptors require glutamate (released presynaptically) and glycine to be activated. Activation results in removal of magnesium from the center of the channel, which then allows calcium to enter. NMDA receptors are largely responsible for maintaining pain through “wind up” from repetitive stimulation of wide dynamic range neurons by primary afferents [16]. Increasing intracellular calcium leads to depolarization. NMDA receptors are noncompetitively blocked by ketamine. A common pathway to pain is by way of prostaglandin (PGE2) production. PGE2 binds to multiple receptors (EP1–EP4) to activate neurons. PGE2 alone does not produce pain but is necessary for induction of pain by other mediators, such as histamine and bradykinin. PGE2 amplifies pain. Prostaglandins are not stored (which differs from other mediators of pain) but are synthesized at the time of depolarization by membrane-bound prostaglandin synthase and cyclooxygenase [17]. Prostaglandin synthesis uses arachidonic acid mobilized from membranes. PGE2 is released and binds to multiple EP receptors both pre- and postsynaptic. Cyclooxygenase 1 and 2 are the important enzymes in PGE2 production and are amplified peripherally and centrally within neurons and glia with inflammatory and neuropathic pain. Both NK-1 receptors and NMDA receptors increase cyclooxygenase transcription in the spinal cord [17]. Central nervous system cyclooxygenase is much more responsive than peripheral mechanisms to NSAIDS [17]. NSAID levels are measurable in the CNS within 15–30 min of administration. Certain NSAIDS (ibuprofen, indomethacin, and ketoprofen) have CNS levels that exceed plasma levels [17]. CNS nociceptive transmission inhibition is one of the more important components to NSAID analgesia [18]. Cyclooxygenase 2 is not the only enzyme to be targeted by NSAIDS. Cyclooxygenase 1 in the brainstem (periaqueductal gray) controls A-delta and C fiber-evoked spinal nociception. Cyclooxygenase 1 blockade within the periaqueductal gray (PAG) is important to analgesia [19]. Hence, broad, nonselective NSAIDs should be used to treat cancer pain as there are no trials of cyclooxygenase 2 selective inhibitors in ­cancer pain.

13

Central Excitatory Mechanism Primary sensory afferents synapse on superficial laminae of the dorsal horn (lamina I and II). Secondary afferents cross over to the contralateral lateral funiculus and ascend as the spinothalamic tract. The spinothalamic tract projects to the brainstem, PAG, rostral ventromedial medullary (RVM), thalamus, nucleus tractus solitarius, and medullary reticular formation. These fibers contain substance P and NK-1 receptors [8]. In the deeper laminae of the dorsal horn reside wide dynamic range neurons that respond to a wide variety of painful stimuli. These secondary neurons are activated by repetitive release of substance P and glutamate from primary afferents. These neurons produce a prolonged amplified ­signal (wind-up) and increase synaptic transmission efficiency [8, 20]. Wide dynamic range neurons are blocked by inhibitory interneurons and monoamines (mainly norepinephrine) [9]. Wide dynamic range neurons also project to the thalamus by way of the spinothalamic tract. The gate control theory proposed by Melzack and Wall in 1965 involved a descending modulatory/facilitatory system that gated nociceptive transmission through the dorsal horn [21]. The descending limb of the spinobulbospinal loop arises from the PAG, and RVM modulate spinal cord neurotransmission. The locus coeruleus, which contains norepinephrine, is also involved in modulation along with the PAG and RVM. The descending limb facilitates or inhibits nociceptive traffic at the level of dorsal horn, and descends through the dorsal funiculus [9]. Descending facilitation leads to central hypersensitivity (allodynia) and hyperalgesia. This facilitation is mediated by a particular serotonin receptor (5HT3). This receptor is blocked by ondansetron. This may explain why selective serotonin reuptake inhibitors (SSRI’s) are less effective than tricyclic antidepressants (TCAs) and selective norepinephrine serotonin reuptake inhibitors (SNRIs) in treating central sensitization and neuropathic pain [9]. Paradoxically, 5HT3 receptors are needed for gabapentin to work optimally as an analgesic [5].

Cerebral Pain Matrix The cerebral cortex “pain matrix” consists of a cerebral ­cortex medial and lateral pain matrix system. The medial system (prefrontal cortex, insular cortex, cingulate gyrus, and amygdala) is involved in the affective and motivational response to pain. The lateral sensory cortex locates the site of pain. The medial system receives projections from the medial thalamus as well as ascending projections from the brain stem. The sensory cortex receives input from the ventrioposteriolateral thalamus. The spinothalamic tract

14

projections are devoid of motor neuron projections, which can be interrupted by anterolateral cordotomy without producing motor deficits [16].

Visceral Pain Visceral sensory afferents travel with abdominal sympathetic afferents arising from internal organs and converge on the celiac plexus within the abdomen or thoracic paravertebral sympathetics in the chest. In the pelvis, the sensory afferents ascend with parasympathetics. Visceral afferents converge with somatic sensory afferent neurons on the dorsal horn. For this reason, somatic referral pain frequently occurs with severe visceral pain. Pain from pancreatic cancer, as an example, is referred to the abdomen, back, or shoulder. Lung cancer will refer pain to the ear, mediastinum, or back [16]. Visceral afferents terminate in lamina I, IV, and ventral horn. Secondary visceral sensory afferents ascend in the dorsal column of the spinal cord rather than the lateral funiculus. Celiac, hypogastric, or splanchnic blocks effectively reduce visceral pain, as does medial myelotomy at the level of the cervical cord (where the dorsal column projections cross over to the contralateral side) [16].

Opioid Receptors In 1973, morphine was found to bind to particular sites within the brain called “morphine receptors” [22, 23]. Two years later, endogenous opiate peptides were discovered. Three major receptors have been described and are located on peripheral afferents, within the dorsal horn, visceral afferents, within the brain stem, and cerebral pain matrix [22]. Mu receptors are divided into high affinity (mu1) and low affinity (mu2) receptors. Mu2 receptors produce respiratory depression, pruritus, prolactin release, physical dependence, anorexia, and sedation, whereas mu1 receptors produce analgesia, euphoria, and serenity. Kappa receptors produce ­analgesia sedation, dyspnea, dysphoria, and respiratory depression. Both mu and kappa produce constipation by binding to receptors on enteral neurons [23]. The actions of delta receptors are not well known but are upregulated when mu receptors are activated and may facilitate pain control. Separate genes are responsible for each of the major opioid receptors; receptor subtypes are produced by mRNA splicing. Opioid receptors are found on pre- and postsynaptic A-delta and C fibers [22]. Activation results in inhibition of calcium channels, reduction in adenyl cyclase, and stimulation of inward rectifying potassium channels [23]. These three mechanisms prevent neuron depolarization and release of substance P

M.P. Davis

and glutamate. Opioids inhibit gamma aminobutyric acid release by inter­neurons and increase dopaminergic neurotramission and prolactin release. Opioids reduce gonadotropin release from the hypothalamus. This leads to reduced libido and impotence. The rewarding effects of opioids. Are due to release of dopamine in the nucleus accumbens. There are three majors types of opioids used to treat ­cancer pain: phenanthrenes (represented by morphine), phenylpiperidines (represented by fentanyl), and diphenyl heptanes (represented by methadone). Tramadol resembles venlafaxine; however, the metabolite, 0-desmethyl tramadol, is a mu ­agonist. Each opioid binds to receptors with different affinity, producing a different conformation, resulting in a different set of G protein interactions. Some opioids internalize receptors. Morphine causes receptor inactivation without internalization [24]. Opioid receptor affinity and opioid receptor activation are two different properties of opioid ligands. A ligand may poorly activate the receptor (low intrinsic efficacy) but have a high affinity for the receptor [22]. Differences in opioid responses between individuals are determined mainly by differences in opioid receptor pharmacodynamics rather than individual differences in opioid metabolism and clearance (pharmacokinetics) [25]. Low intrinsic efficacy opioids require more opioid receptors to be bound for the same degree of analgesia relative to high intrinsic efficacy opioids. As a result, a “ceiling effect” to analgesia occurs with low intrinsic efficacy opioids at high doses or high pain intensities, which alter equianalgesic ratios. This is one reason why morphine–methadone equivalents change with morphine doses [22]. Opioids have a log linear response with dose; doses are generally limited by side effects, not analgesia [22].

Opioid Tolerance Chronic opioid exposure leads to an “antiopioid” response, which lasts longer than analgesia. This antiopioid response causes a withdrawal syndrome when opioids are suddenly stopped. Opioid receptors activate various kinases, which in turn phosphorylate NMDA receptors rendering them active. Opioid receptor phosphorylation leads to receptor inactivation and internalization [24]. Go/i proteins switch to Gz ­proteins with analgesic tolerance causing activation of neurons. Receptor activation is curtailed through phosphorylation of certain regulatory proteins (RGS) [24, 26]. A change in opioids (opioid rotation) may reverse opioid tolerance and enhance pain control. In rare cases, opioid ligands facilitate pain that becomes neuropathic in character. Opioid dose titration will cause increasing pain. Dose reduction in this situation paradoxically reduces pain. The use of certain adjuvant drugs such as ketamine blocks opioid tolerance and facilitates pain control [5, 16, 26, 27].

15

2  Cancer Pain

Cancer Pain Assessment Pain is a multidimensional experience though most experts believe pain intensity is most important [28] (Table  2.1). Multidimensional pain questionnaires most frequently measure pain intensity, location, and relief; temporal pattern is often not included [28]. Paradoxically, temporal pattern is most important to opioid dosing strategies [29, 30]. Worst pain and average pain severity over 24  h correlates with interference with daily activities. Breakthrough pain episodes are also critical to assessment. Numerical rating scales (0 = no pain, 10 = severe pain) are preferred to 10 cm. visual analog scales. Verbal rating scales or even observations for pain behaviors are helpful in assessing the cognitively impaired and in those suffering from dementia [31]. Pain qualities are reported to be helpful in determining pain mechanisms. “Numbness,” “pins and needles,” and “burning” pain occurring within an area of sensory or motor deficit is usually neuropathic pain. Bone pain has an achelike quality and is worsened with movement. Hyperalgesia (increased sensitivity to touch) occurs with inflammatory, bone, or neuropathic pain [31]. Pain qualities contribute to pain interference independent of severity. Deep pain, sharp pain, sensitive, or itchiness qualities interfere with daily activity [32]. Multidimensional scales provide a more comprehensive pain assessment. However, certain tools such as the Brief Pain Inventory may not be sensitive to changes in pain over time. Unidimensional pain intensity scales are validated and sensitive to changes in pain [33]. Pain interference may improve before severity. Pain relief may be experienced while pain intensity is still moderate or severe [31]. Asking “do you think your analgesics need to be increased (or decreased)” allows patients to find their personal acceptable relief as they judge benefits and risks of opioids. Recall fades with time; pain diaries, which include intensity and opioid doses, recorded several times during the day are helpful between clinic visits [31] (Table 2.2).

Table 2.2  Five axes for classifying pain into syndromes I. Anatomical Region II. Organ system that is producing pain III. Temporal characteristics IV. Pain intensity and pain onset V. Proposed pain etiology Source: Data from refs. [28, 31, 33]

In those with cancer and reduced cognition a questionnaire with 13 or more items in a multidimensional scale will have a significant number of items left blank by individuals [34]. The Brief Pain Inventory is completed by 4) where needed in the last 24 h 10. Do not add adjuvants and rotate simultaneously. Do one at a time and assess analgesia before altering the strategy Source: Data from refs. [30, 46, 51]

19

2  Cancer Pain Table 2.4  Equianalgesia Opioid

Oral

Morphine 30 Hydromorphone 6 Oxycodone 20–30 Fentanyl 1:70 Methadone See Table 2.3 Buprenorphine Conversion similar to fentanyl Source: Data from refs. [49–51, 55, 56, 62]

Parenteral 10 2–3

Equianalgesia and Opioid Rotation Opioid route conversion and opioid switch is needed in 40% of individuals with advanced cancer at some time during the course of their illness [55] (Table  2.4). Equianalgesia is the ratio of doses for two opioids, which result in the same degree of pain relief. This should be determined at steady state; however, most equianalgesic tables use single dose comparisons (nonsteady state) and summed pain intensity differences. The study design for equivalents is usually crossover or parallel with intraindividual (crossover) or interindividual (parallel) comparisons [56]. Most individuals in rotation studies are relatively opioid naïve and not highly opioid tolerant, which is not the usual case when rotations are done for cancer pain. Populations from whom equivalents are determined differ from populations in whom opioid rotations are performed. There are large variations in equivalents between individuals such that published equivalents have large confidence intervals but are reported as single ratios. Factors that significantly alter equivalents are age, polypharmacy, organ function, and opioid tolerance [56]. Opioid rotations utilize equianalgesia, but tables for the purpose of improving analgesia and/or reducing side effects [49, 57]. Almost all rotations involve a “StopStart” strategy where the first opioid is discontinued and the second is started. A “partial” opioid rotation where another opioid as an “added on” has little clinical evidence and is likely to lead to dosing error and/or reduced patient compliance.

significantly reduces pain intensity, is then used as the 4 h dose by converting to oral morphine (parenteral dose ­multiply by 3) or continuous parental ­morphine by dividing the effective dose by 3 to 4 and using this dose as the hourly continuous dose. If individuals are on around-the-clock morphine, this will need to be added to the maintenance dose.

Patient-Controlled Analgesia In the 1960s, analgesic responses to small intravenous doses of morphine by patient demand was found to be superior to intramuscular opioids given at a fixed dose as needed [58]. The experience with patient-controlled analgesia (PCA) taught us: (1) small increases in opioid serum levels can dramatically reduce pain; (2) there is a minimally effective analgesic concentration, which varied considerably among ­individuals; (3) there is no single effective analgesic serum concentration of morphine. Two prerequisites are needed for effective PCA: (1) individualized titration to pain relief and (2) maintenance of plasma opioid concentrations by demand only (opioid naïve) or continuous plus demand (in opioid tolerant individuals) dosing. For PCA to be successful, the demand dose should produce appreciable analgesia with a single activation [58]. Demand doses too low frustrate patients and demand doses too high (or activation frequency or intervals too short) lead to delayed opioid toxicity. A large number of PCA strategies have been published; in the opioid naïve, 1–4 mg at a 5–60 min lockout interval, and in the opioid ­tolerant, continuous morphine plus 1–20 mg of morphine at 20–60 min intervals. Some strategies use 25–50% of the hourly morphine dose as the demand, or 10% of the total daily morphine dose converted to parenteral equivalents as the demand dose [59]. In general, lockout intervals are ­longer if continuous ­morphine infusion is used.

Acute Pain

Spinal Analgesia

Severe acute or crescendo pain usually arises from complications related to cancer (bone fracture, perforated bowel). Strategies for managing pain are distinct from those used to treat chronic pain [29]. Morphine 1–2 mg every 1–2 min, fentanyl 20  mcg/min or hydromorphone 0.2  mg/min intravenously until pain control is an effective titration strategy [29]. This requires bedside titration by physicians with assessment of pain intensity every 1–2 min and a respite every 10 min. Alternatively, 1.5 mg of morphine can be given every 10 min or 10–20  mg every 15  min. The goal is significant but not complete pain relief with titration. The morphine dose which

Intrathecal and epidural opioid analgesia are effective in ­managing continuous deep somatic pain unresponsive to ­systemic opioids or in individuals experiencing dose limiting toxicity from systemic opioids [54]. Cutaneous pain and pain from intestinal obstruction are not responsive to spinal ­opioids. Sixty to 80% will experience relief. Adjuvant analgesics such as bupivicaine, clonidine, or the calcium channel blocker ziconotide are frequently needed to improve pain control. Spinal opioid rotation (morphine to hydromorphone or fentanyl) may improve pain that is not responsive to morphine [54]. Epidural opioids are used in those with only a

20

few weeks to survive, whereas intrathecal opioids are preferred in those expected to survive months. In general, 1% or less of the oral morphine dose is needed for effective spinal analgesia. Certain side effects related to the opioid (nausea, ­vomiting, sedation); pruritus, urinary retention, hypogonadotropic hypogonadism are more frequent with spinal opioids than systemic opioids. Clonidine and ziconotide may produce orthostatic hypotension. Major motor weakness can develop from a hematoma at the catheter insertion site or with high doses of bupivicaine [54].

Opioid Overdose Respiratory depression occurs with opioid overdose. Tachypnea and dyspnea with sedation is usually not due to opioids. Overdose will reduce the respiratory rate and tidal volume leading to carbon dioxide retention. Opioid overdose is almost always accompanied by reduced consciousness and pupillary miosis. Dilated fixed pupils or unequal pupils are indications that the cause of reduced consciousness is the result of a stroke, hypoxia, or mass lesion rather than opioid. Individuals on stable doses of morphine for weeks may develop signs and symptoms of overdose from radiation induced pain response, progressive renal failure, drug interactions, or sepsis, which alters morphine or morphine 6-glucuronide clearance. To manage opioid overdose, dilute a 1 ml (0.4 mg) ampoule of naloxone to 10 mg of saline or glucose and give 1 ml intravenously every 2–3 min until the respiratory frequency increases to 10 per minute and sedation resolves. The goal is to reverse respiratory depression, not analgesia [38, 48]. The half-life of naloxone is 30 min, so repeat doses or continuous infusion may be necessary to reverse respiratory depression with methadone, transdermal fentanyl, or sustained release morphine.

M.P. Davis

choices. Sublingual methadone is relatively well absorbed and has a quicker onset to analgesia than oral morphine [52].

Adjuvant Analgesics NSAIDs are technically analgesics rather than adjuvant medications. The addition of NSAIDs to morphine improves analgesia, and may reduce side effects by reducing morphine requirements by 30% [60, 61]. Adjuvant analgesics are added to improve pain control or to allow for opioid dose reduction in those with inadequately controlled pain and opioid side effects (Table 2.5). This strategy is effective and an alternative to opioid rotation and route switch. A listing of adjuvant analgesics is provided on Table 2.5. Corticosteroids (dexamethasone 2–16  mg/day) reduce headaches from increased intracranial pressure, pain from soft tissue infiltration, nerve compression, or hepatomegaly [45]. Bisphosphonates (pamidronate 60–90  mg or zolendronate 4  mg monthly) relieve pain from bone metastases. Tricyclic antidepressants, gabapentin, pregabalin, duloxetine, and venlafaxine are equally effective in relieving neuropathic pain as determined by the NNT. However, the gabapentinoids are better tolerated and have fewer drug interactions. Two or three adjuvant analgesics may be needed for neuropathic pain [45]. Transdermal lidocaine is effective for mononeuropathies and postherpetic neuralgia. Transdermal lidocaine is not absorbed to any great extent, and is particularly safe in the elderly or for those on multiple psychotropic medications. Ketamine is a NMDA receptor antagonist, which is analgesic at subanesthetic doses [62]. Ketamine reverses morphine tolerance and can be used for breakthrough pain for those on systemic or spinal opioids. Oral doses are 25–50 mg three to four times daily or 0.1–0.5 mg/kg/h as a continuous infusion. Strontium-89 chloride and samarium-153 are absorbed in Table 2.5  Adjuvant analgesic and nonopioid analgesics

Pain Management in the Actively Dying Delirium occurs in 80% of those actively dying and so pain assessment will depend on non-verbal cues. Terminal restlessness is often related to delirium, fecal impaction, urinary retention, or poorly controlled pain. Opioid dosing should not be interrupted; rescue doses are used as a trial to see if restlessness improves, once sure that urinary retention or fecal impaction are not a problem. Oral intake may be a problem such that an alternative route  is frequently necessary. Conversion to rectal opioids (morphine, hydromorphone, oxycodone, and methadone) is 1  to 1. Sublingual morphine and oxycodone are poorly absorbed and have a delayed onset to action, so are not good

Drug Acetaminophen Ibuprofen Naproxen Ketorolac Etodolac Amitriptyline Nortriptyline Gabapentin Pregabalin Carbamazepine

Caution/side effects

Hepatotoxicity GI, renal toxicity GI, renal toxicity GI, renal toxicity GI, renal toxicity Sedation, cardiac Sedation Sedation Sedation Sedation, myelosuppression Duloxetine Headache, dizziness, sleepiness Venlafaxine Headache, dizziness, sleepiness Source: Data from ref. [50]

Maximum dose/day 4,000 mg 3 × 800 mg 3 × 500 mg 45 mg × 6 (sc/IV) 1,200 mg 50–225 mg 50–225 mg 3,600 mg 600 mg 1,600 mg 120 mg 225 mg

2  Cancer Pain

areas of high bone turnover and will reduce pain from diffuse bone metastases over several weeks to months. Delayed myelosuppression limits repeated dosing. Baclofen reduces muscle spasm pain secondary to spinal cord compression, as  does low doses of diazepam [63]. Methylphenidate improves opioid-induced somnolence as well as depression. Doses are 5–10 mg in the morning and at noon. Octreotide and anticholinergic medications reduce painful colic from malignant bowel obstruction [63].

Nondrug Treatment for Cancer Pain Transcutaneous electrical nerve stimulation, acupuncture, single fracture radiation, and vertebral kyphoplasty can relieve poorly controlled pain [45, 53]. Hypnoses reduce procedural pain and mucositis. Cordotomy or rhizotomy, celiac or splanchnic blocks reduce morphine requirements and pain in those whose pain is not responding to opioids or who develop dose-limiting opioid toxicity [53].

Conclusion Cancer pain is a composite of acute and chronic pain, which is tumor- or treatment-related in etiology. Individuals with cancer generally experience more than one pain during the course of their illness. Assessment is the key to effective management. The World Health Organization 3-step ladder and five principles form the foundation for medically managing cancer pain. Dosing strategies take into account pain intensity and temporal pattern to sculpt opioid doses to individual needs. Opioid rotation, route change, or the addition of adjuvant analgesics successfully relieves opioid poorly responsive pain.

References 1. Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2008. CA Cancer J Clin 2008, 58:71–96. 2. Caraceni A, Portenoy RK, a working group of the IASP Task Force on Cancer Pain. An International survey of cancer pain characteristics and syndromes. Pain 1999, 82:263–74. 3. Soderlund V. Radiological diagnosis of skeletal metastases. Eur Radiol 1996, 6:587–95. 4. Turk DC. Remember distinction between malignant and benign pain? Well forget it. Clin J Pain 2002, 18(2):75–6. 5. Dickenson AH, Bee LA, Suzuki R. Pains, gains, and midbrains. Proc Natl Acad Sci USA 2005, 102(50):17885–6. 6. Iannetti GD, Zambreanu L, Wise RG, et  al. Pharmacological ­modulation of pain-related brain activity during normal and central

21 sensitization states in humans. Proc Natl Acad Sci USA 2005, 102(50):18195–200. 7. Liebeskind JC. Pain can kill. Pain 1991, 44(1):3–4. 8. Harvey VL, Dickenson AH. Mechanisms of pain in nonmalignant disease. Curr Opin Support Palliat Care 2008, 2:133–9. 9. D’Mello R, Dickenson AH. Spinal cord mechanisms of pain. Br J Anaesth 2008, 101:8–16. 10. Aurilio C, Pota V, Pace AC, et al. Ionic channels and neuropathic pain: physiopathology and applications. J Cell Physiol 2007, 215:8–14. 11. Rogers M, Tang L, Madge DJ, et al. The role of sodium channels in neuropathic pain. Semin Cell Dev Biol 2006, 17:571–81. 12. Luger NM, Mach DB, Sevcik MA, et al. Bone cancer pain: from model to mechanism to therapy. J Pain Symptom Manage 2005, 29(5S):S32–46. 13. Honore P, Rogers SD, Schwel MJ, et al. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 2000, 98(3):585–9. 14. Luger NM, Sabino MC, Schwei MJ, et  al. Efficacy of systemic ­morphine suggests a fundamental difference in the mechanisms that generate bone cancer vs inflammatory pain. Pain 2002, 99(3): 397–406. 15. Caraceni A, Zecca E, Martini C, et al. Gabapentin for breakthrough pain due to bone metastases. Palliat Med 2008, 22:392–3. 16. Regan JM, Peng P, Chan VWS. Neurophysiology of cancer pain: from the laboratory to the clinic. Curr Rev Pain 1999, 3:214–25. 17. Burian M, Geisslinger G. COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at center and peripheral sites. Pharmacol Ther 2005, 107:139–54. 18. McCormack K. The spinal actions of nonsteroidal anti-­inflammatory drugs and the dissociation between their anti-inflammatory and analgesic effects. Drugs 1994, 47(5):28–45. 19. Leith JL, Wilson AW, Donaldson LF, et  al. Cyclooxygenase1-derived prostaglandins in the periaqueductal gray differentially controls C-versus A-fiber-evoked spinal nociception. J Neurosci 2007, 27(42):11296–305. 20. Murakami M, Kudo I. Prostaglandin E synthase: a novel drug target for inflammation and cancer. Curr Pharm Des 2006, 12:943–54. 21. Melzack R, Wall PD. Pain mechanisms. Science 1965, 150(699): 971–9. 22. Pasternak GW. Molecular biology of opioid analgesia. J Pain Symptom Manage 2005, 29(5S):S2–9. 23. Trescot AM, Datta S, Lee M, et  al. Opioid pharmacology. Pain Physician 2008, 11:S133–53. 24. Law PY, Loh HH. Regulation of opioid receptor activities. J Pharmacol Exp Ther 1999, 289:607–24. 25. Snyder SH. Opioid receptor revisited. Anesthesiology 2007, 107:659–61. 26. Garzon J, Rodriguez-Munoz M, Sanchez-Blazquez P. Do pharmaceutical approaches that prevent opioid tolerance target different elements in the same regulatory machinery? Curr Drug Abuse Rev 2008, 1:222–38. 27. Pelissier T, Laurido C, Kramer V, et al. Antinociceptive interactions of ketamine with morphine or methadone in mononeuropathic rats. Eur J Pharmacol 2003, 477:23–28. 28. Hermstad MJ, Gibbins J, Caraceni A, et al. Pain assessment tools in palliative care: an urgent need for consensus. Palliat Med 2008, 22:895–903. 29. Davis MP, Weissman DE, Arnold RM. Opioid dose titration for severe cancer pain: a systematic evidence-based review. J Palliat Med 2004, 7(3):462–8. 30. Walsh D, Rivera NI, Davis MP, et al. Strategies for pain management: Cleveland Clinic Foundation guidelines for opioid dosing for cancer pain. Support Cancer Ther 2004, 1(3):157–64. 31. Anderson KO. Assessment tools for the evaluation of pain in the oncology patient. Curr Pain Headache Rep 2007, 11:259–64.

22 32. Jensen MP, Dworkin RH, Gammaitoni AR, et al. Do pain qualities and spatial characteristics make independent contributions to interference with physical and emotional functioning? J Pain 2006, 7(9):644–53. 33. Caraceni A, Cherny N, Fainsinger R, et al. Pain measurement tools and methods in clinical research in palliative care: recommendations of an expert working group of the European Association of Palliative Care. J Pain Symptom Manage 2002, 23(3):239–55. 34. Radbruch L, Sabatowski R, Loick G, et al. Cognitive impairment and its influence on pain and symptom assessment in a palliative care unit: development of a minimal documentation system. Palliat Med 2000, 14:266–76. 35. Twycross R, Harcourt J, Bergl S. A survey of pain in patients with advanced cancer. J Pain Symptom Manage 1996, 12(5):273–82. 36. Farrar JT, Berlin JA, Strom BL. Clinically important changes in acute pain outcome measures: a validation study. J Pain Symptom Manage 2003, 25(5):406–11. 37. Turk DC, Dworkin RH, McDermott MP, et al. Analyzing multiple endpoints in clinical trials of pain treatments: IMMPACT recommendations. Pain 2008, 139:485–93. 38. Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain 2008, 9(2):105–121. 39. Rosenthal DI. Radiological diagnosis of bone metastases. Cancer 1997, 80:1595–607. 40. White AP, Kwon BK, Linskog DM, et al. Metastatic disease of the spine. J Am Acad Orthop Surg 2006, 14:587–8. 41. Mahfouz AE, Hamm B, Mathieu D. Imaging of metastases to the liver. Eur Radiol 1996, 6:607–14. 42. Pfister DG, Johnson DH, Azzoli C, et  al. American Society of Clinical Oncology treatment of nonresectable non-small-cell lung cancer guidelines: update 2003. J Clin Oncol 2004, 22(2): 330–53. 43. Gould MK, Kuschner WG, Rydzak CE, et al. Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a metaanalysis. Ann Intern Med 2003, 139(11):879–92. 44. Silvestri GA, Gould MK, Margolis ML, et al. Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 2007, 132(3 Suppl):178S–201 45. Fallon M, Hanks G, Cherny N. Principles of cancer pain. BMJ 2006, 332:1022–4. 46. Hanks GW, de Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001, 84(5):587–93.

M.P. Davis 47. Jost L. Management of cancer pain: ESMO clinical recommendations. Ann Oncol 2007, 18:92–94. 48. Krakowski I, Theobald S, Balp L, et  al. Summary version of the standards, options and recommendations for the use of analgesia for the treatment of nociceptive pain in adults with cancer (update 2002). Br J Cancer 2003, 89(Suppl 1):S67–72. 49. Mercandante S. Opioid rotation for cancer pain. Rationale and ­clinical aspects. Cancer 1999:86:1856–66. 50. Gralow I. Cancer pain: an update of pharmacological approaches in pain therapy. Curr Opin Anaesthesiol 2002, 15:555–61. 51. Davis MP, Lasheen W, Gamier P. Practical guide to opioids and their complications in managing cancer pain. What oncologists need to know. Oncology 2007, 21(10):1229–38. 52. Hagen NA, Biondo P, Stiles C. Assessment and management of breakthrough pain in cancer patients: current approaches and emerging research. Curr Pain Headache Rep 2008, 12:241–8. 53. Carr DB, Goudas LC, Balk EM, et al. Evidence report on the treatment of pain in cancer patients. Evidence report on the treatment of pain in cancer patients. J Natl Cancer Inst Monogr 2004, 32:23–31. 54. Newsome S, Frawley BK, Argoff CE. Intrathecal analgesia for refractory cancer pain. Curr Pain Headache Rep 2008, 12:249–56. 55. Shaheen PE, Walsh D, Lasheen W, et  al. Opioid equianalgesic tables: are they all equally dangerous? J Pain Symptom Manage 2009, 38(3):409–17. 56. Knotkova H, Fine PG, Portenoy RK. Opioid rotation: the science and limitations of the equianalgesic dose table. J Pain Symptom Manage 2009, 38(3):426–39. 57. Miller L, Shaw JS, Whiting EM. The contribution of intrinsic activity to the action of opioids in vitro. Br J Pharmac 1986, 87:595–601. 58. Grass JA. Patient-controlled analgesia. Anesth Analg 2005, 101: S44–61. 59. Davis MP. Patient-controlled analgesia chapter 24. Opioids in Cancer Pain, Oxford University Press, (Oxford UK) 2009, 367–84. 60. Elia N, Lysakowski C, Tramer MR. Does multimodal analgesia with acetaminophen, nonsteroidal anti-inflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Anesthesiology 2005, 103:1296–304. 61. Marret E, Kurdi O, Zufferey P, et al. Effects of nonsteroidal antiinflammatory drugs on patient-controlled analgesia morphine side effects. Anesthesiology 2005, 102:1249–60. 62. Grond S, Radbruch L, Lehmann KA. Clinical pharmacokinetics of transdermal opioids. Clin Pharmacokinet 2000, 38(1):59–89. 63. Pharo GH, Zhou L. Controlling cancer pain with pharmacotherapy. J Am Osteopath Assoc 2007, 107(Suppl 7):ES22–32.

Chapter 3

Cancer-Related Fatigue Barbara F. Piper, Karin Olson, and Carina Lundh Hagelin

Introduction and Significance Cancer-related fatigue (CRF) is one of the most common and distressing symptoms experienced by cancer patients [1, 2] and often is more distressing than pain, nausea, or vomiting [3]. CRF may be dose-limiting, may compromise the timing and frequency of treatments [2], and may also affect treatment adherence and survival [4]. Despite its frequency and negative impact, CRF remains underreported, underdiagnosed, and undertreated [1].

Prevalence Rates Approximately 70–100% of cancer patients experience CRF at some time during diagnosis and treatment [1]. Prevalence rates vary from 25 to 99% [5, 6] depending on the type of treatment, dose and route of administration, type and stage of cancer, and the method and timing used to assess CRF [7]. In patients receiving chemotherapy (CT), 80–90% report CRF, and its prevalence rates and patterns over time may vary with the specific CT agent, its route of administration, and the frequency and density of treatment cycles. Less is known about CRF’s prevalence rates and patterns prediagnosis [2] and in patients receiving oral or targeted CT agents [7]. Few studies have examined fatigue in surgically treated or hospitalized cancer patients. One study reported an increase in

B.F. Piper () Scottsdale Healthcare/University of Arizona, 10684 N. 113th Street, 85259-4034 Scottsdale, AZ, USA e-mail: [email protected] K. Olson University of Alberta, Edmonton, AB, T6G 2G3, Canada C.L. Hagelin Department of Oncology and Pathology, Division of Clinical Cancer Epidemiology, Karolinska Institutet and Sophiahemmet University College, Stockholm, 114 86, Sweden

fatigue in cancer patients associated with a longer period of hospitalization [8]. During radiation therapy (RT), CRF is an almost universal occurrence with 70–100% of patients experiencing a gradually increasing, cumulative pattern of CRF over time that peaks and plateaus usually at 4–6 weeks and gradually declines thereafter over time. Patients need to be forewarned about the possibility of experiencing this type of CRF pattern, as they may feel that their disease is getting worse instead of better, and may fear that their treatment is not working [1, 7]. Increased CRF may be reported when different therapies such as RT and CT are used in combination [9]. In patients treated with biologic-response modifiers or biotherapy, such as interleukin-2 and interferon-a, CRF can be dose-limiting [7]. A prevalence rate of 70% is reported with interferon [10]. Fatigue in cancer patients receiving ­hormonal therapy has not been well studied [10, 11]. Increased levels of CRF are reported by patients with advanced malignancies [12, 13], and in those who have other illnesses or comorbidities [14]. In patients with metastatic disease, for example, fatigue prevalence rates may exceed 75% [1, 7].

Definition(s) Many definitions for CRF exist in the literature [7]. The most common definition used in practice settings, at least in the United States (US), is the National Comprehensive Cancer Network’s (NCCN) CRF definition: CRF is a distressing persistent subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity that interferes with usual functioning [1]. There is an emerging consensus for clinicians and researchers to begin to use a “case definition” for CRF to better enable comparisons across studies and populations to be made [7, 15]. For example, using a “cut score” of ³4 on a 0–10 numeric rating scale (NRS) during the past week where “0” = no fatigue, and “10” = worst fatigue, and using established

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_3, © Multinational Association for Supportive Care in Cancer Society 2011

23

24

severity levels of 0 = none, 1–3 = mild, 4–6 = moderate, and 7–10 = severe [16, 17] is recommended by several investigators for clinical and research purposes [1, 18, 19]. In 1998, the first attempt to develop a case definition was proposed that included a set of diagnostic criteria for the syndrome of CRF [20]. These criteria were to be included in the United States version of the World Health Organization’s International Classification of Diseases-10 Clinical Modification (WHO ICD-10-CM) but were never submitted to the Center for Disease Control and Prevention (CDC) (D. Pickett, personal communication, December 8, 2008). At a recent international CRF consensus conference [21], it was acknowledged that these syndrome criteria unfortunately were not developed based on a broad range of evidence [7]. They were designed to classify CT “cases” who were receiving every 2 week dosing cycles of CT; and may have “set the bar too high” for a CRF case definition, as many patients with CRF did not fit these criteria. Thus, prevalence rates were far lower than expected. At that same CRF consensus conference, it was concluded that there were probably different phenotypes [22] or manifestations for CRF across the illness and treatment trajectories (i.e., active treatment, survivorship, and palliative end-of-life care) that require more study [7]. This conclusion was reached, in part, because symptoms such as weakness that can be reported as part of the CRF experience, may more commonly occur in palliative care patients with advanced or incurable malignancies [12], who also may be experiencing anorexia, weight loss, and the loss of muscle mass. Whereas, weakness is not a common occurrence or descriptor of CRF in earlier stage patients, such as women undergoing treatment for breast cancer, or men receiving hormonal ablation therapy [7, 23].

Underlying Mechanisms Despite the prevalence of CRF, little is known about CRF’s underlying mechanisms. Recently, two investigative teams working independently from one another have integrated a variety of seemingly disparate underlying mechanisms based on emerging evidence from several studies into over-arching integrated conceptual frameworks based on stressors, such as pain, cancer, its treatments, and other comorbidities including psychological stress, that activate inflammation [22, 24]. Cytokines released as part of the innate inflammatory immune response to these stressors, alter the sleep–wake cycle. This, in turn, contributes to the disruption in the neuroendocrine system especially in the HPA-axis and its related glucocorticoids [22]. This interaction results in unrestrained inflammation and increased release of proinflammatory cytokines, which interact with central nervous system (CNS) pathways that regulate behaviors. This leads to the pathophys-

B.F. Piper et al.

iological changes that underlie the behavioral manifestations of fatigue, depression, impaired sleep, and impaired cognitive function [22]. The model put forth by Olson et al. [24] also includes central and peripheral mechanisms for muscle fatigue. While more study is needed to validate these proposed models and their underlying assumptions and propositions, they both offer plausible explanations based on the evidence thus far about underlying mechanisms for CRF [7]. Both these models [22, 24] can be used to guide future studies investigating how CRF is related to other symptoms and behavioral alterations such as pain, insomnia, depression, and cognition [7, 25].

Assessment Barriers Despite the prevalence of CRF and the availability of guidelines such as the NCCN Evidence-Based Guidelines for CRF assessment and management [1] used in the US (www.nccn. org) and elsewhere, assessment is still not routinely performed in many institutions and oncology practice settings [18, 26, 27]. Numerous patient-, provider-, and systemrelated barriers hinder the translation of these guidelines into practice settings [18, 26]. In one study, the most frequent patient-related barrier was the patient’s belief that the physician would ask about CRF if it was important, followed by the patient’s desire to play the “good patient role” and not bring the subject up for discussion unless the physician did. Provider-and systems-related barriers included the lack of documentation in the medical record for guideline adherence and lack of supportive care referrals [7]. When the intervention phase of this study was implemented that included educational materials and teaching sessions for both patients and their providers [18], many of the patient-related barriers including the severity of CRF decreased over time compared to the usual care (control) group [18]. This suggests that many of the patient-related barriers to the assessment and management of CRF including its severity can be reduced by patient and provider education.

Screening The NCCN CRF Guidelines state that all patients must be assessed for the presence or absence of CRF at their first visit and at each subsequent visit. If CRF is present, the guidelines recommend that a simple 0–10 numeric rating scale (NRS) be used to assess CRF intensity (0 = no fatigue; 10 = worst fatigue you can imagine). Patients can be asked directly: “How would you rate your fatigue on a scale of

3  Cancer-Related Fatigue

0–10 over the past 7 days?” Mild fatigue is indicated by a 1–3 score, moderate fatigue by a 4–6 score, and severe fatigue by a 7–10 score [1]. For patients who are unable to assign a number to their fatigue, using the words “none, mild, moderate, and severe” is recommended [1]. As baseline CRF severity levels have been shown to be predictive of severity levels over time in patients undergoing treatment [28], it is important to assess and document these levels before patients begin treatment and to repeat and compare these screening assessments periodically over time during treatment [7]. Because CRF can persist for months, even years following treatment cessation, repeated assessments posttreatment are recommended [1, 2]. These assessments can be supplemented by having patients’ complete daily diaries prior to their next clinical visit [7].

Focused Workup For patients who are experiencing moderate to severe levels of CRF (4–10 on the 0–10 NRS), further assessment of CRF and its possible underlying causes is indicated. The NCCN guidelines recommend that this focused workup includes a more in-depth CRF symptom history [7]. Also included is an assessment of the patient’s current disease status, the type and length of cancer treatment planned as well as its potential to cause CRF [1]. It is important to evaluate whether CRF is due to disease recurrence or progression as treatment planning may be affected [7]. A review of systems is important as it serves to direct the physical examination and diagnostic testing.

Differential Diagnosis In making the differential diagnosis of CRF, it is important to distinguish CRF from other diagnoses such as depression [29] as the treatments may vary. It is essential to assess the presence of common contributing and treatable factors of CRF [1, 27]. These factors include anemia, comorbidities and medication side effects, activity levels and deconditioning, emotional distress (depression and/or anxiety), nutrition, pain, and sleep disturbance [1, 7].

Management

25

41% were not at all familiar with them [30]. In another survey conducted by the NCCN nationally of more than 1,000 oncology clinicians, roughly one third were not aware of the CRF guidelines, and 34% of oncology specialist physicians (N = 293/863) were unaware of the guidelines, compared to 17% of advanced practitioners and nurses (N = 27/157) [31]. These findings indicate that health-care providers might benefit from more information about the existence of these CRF evidence-based guidelines and assistance in how to translate and implement them in their practice settings. Patient and Family Education Patients and family members need to receive education about CRF before they even start treatment to better prepare them for how to manage it, should they experience it. There are now several studies that have evaluated nurse-led educational programs focused on CRF during treatment [18, 32–38]. All but one [36] demonstrated decreased fatigue in the experimental groups receiving the educational intervention [7]. The small sample size in this study may have affected its conflicting results [36, 39]. In two of these studies [18, 37, 40], the intervention effect on fatigue was maintained during the follow-up period [39]. Each of these studies used short educational interventions, consisting of three to four individual patient sessions lasting 10–60 min [39], and to a large extent, the same elements, such as information about CRF, self-care or coping skills, and activity management, such as learning how to balance activities and rest [39]. Patients need to be “coached” to treat CRF as the 6th vital sign (after temperature, pulse, respirations, blood pressure, and pain) [22, 27] and to bring up the subject of CRF for discussion themselves to their health-care provider, even if the provider does not do so on their own [7]. Energy Conservation and Distraction The NCCN Guidelines suggest that general educational strategies to manage CRF need to be included as well, such as energy conservation techniques [40] and distraction techniques such as games, music, reading, and socializing [1]. Energy conservation techniques use a common sense approach to help patients prioritize and pace activities, and to delegate less essential activities [1, 40]. Daily or weekly diaries can inform the patient about peak energy periods allowing them to plan their activities accordingly [1].

Provider Education Provider education about CRF is essential to effective CRF management. At one national meeting held in the US, approximately 50% of health-care providers (mostly nurses), were only somewhat familiar with the NCCN CRF Guidelines, and

General Treatment Principles Treatment must always be tailored to the patient [1], taking into account the patient’s disease and treatment status and

26

B.F. Piper et al.

goals of treatment [7]. Treatment planning also takes into account what is most likely the primary underlying cause of CRF and whether referrals to other health-care providers or supportive care disciplines are needed [1]. Treatment should be first directed to one or more of the common contributing and treatable factors associated with CRF [7]. By the time patients realize that the fatigue has become unusual for them, CRF most likely is multicausal, and will probably require multimodal combination therapies and referrals [7]. If none of these common contributing and treatable factors is present or the patient continues to have moderate to severe fatigue despite treatment, additional workup and treatment planning must occur [1]. Each of these common contributing factors is discussed in more depth in the following sections [7].

While more studies are clearly indicated in this area, there are a few studies in cancer that are beginning to report consistent and significant findings about how specific comorbidities such as arthritis [44] and an increase in the actual total number of comorbidities a patient has, can increase CRF severity [45]. The CRF guidelines recommend that each comorbidity be reviewed to determine whether any changes in the management of the comorbidity or its medications need to be made within the context of the patient’s CRF [1]. Referral to an internist or specialist, and/or consultation with a clinical pharmacist often is helpful [7]. Patients need to receive education that comorbidities and medications are one of the common contributing and treatable factors associated with CRF.

Anemia

Activity and Deconditioning

Decreased hematocrit [41] and hemoglobin levels are associated with CRF [41]. In one study, the degree of anemia (mild, moderate, severe) predicted fatigue severity (p 50% cases and >72 h beforehand in 80–90%), in contrast to adults. The catheters that are inserted are internal long-term catheters called port-a-caths or external long-term catheters such as the Broviac or Hickmann catheter. These catheters have many advantages for administering chemotherapy, blood products and fluids. Complications related to the long-term use of CVCs are minimised by recommended protocols for catheter-placement, dressing, care, administration of solutions and monitoring [36]. The two most important complications in CVCs are infections and thrombosis. Infections in CVCs in children with cancer occur in about 30% of patients, which is 2 infections per 1,000 catheter days for port-a-caths. In patients at high risk of infection such as bone marrow transplant patients, these numbers will be even higher. Infectious complications are those that result in infection of the bloodstream and/or device, the subcutaneous pocket, the tunnel or exit site. Treatment of the infected catheter can be successful in more than 80% of documented catheter-related infections. Usually these infections are caused by Gram-positive organisms (mainly coagulasenegative staphylococci). However, cover for Gram-negative organisms is necessary until an organism is identified. Treatment failures result from infections with multiple organisms: fungi, P. aeruginosae, resistant Gram-negative organisms and tunnel infections. Thus, in cases of persistent fever despite adequate antibiotics, removal of the catheter should be considered. In case of a Staphylococcus aureus infection, the treatment should be administered for at least 2–3 weeks if the catheter is left in place, as S. aureus is associated with a late complication rate of 6.1%. If the catheter is left in place, the systemic

M.D. van de Wetering and W.J.E. Tissing

antibiotics should be administered through the catheter. Cycling antibiotics through each lumen or placing concentrated antibiotics within the locked catheter hub (antibiotic-lock technique) is not widely validated yet for children so cannot be recommended [36]. Thrombosis is far less well documented, but it is thought that at least 50% of the children experience an episode of occlusion during the duration of the catheter for which intervention is needed. If the catheter is occluded, mechanical obstruction has to be ruled out. If this is not the case, causes could be the precipitation of drugs, the use of parenteral nutrition or the formation of a thrombus. In children, not many studies have been performed to establish the optimal management of thrombosis in CVCs. If the catheter is not needed anymore, then remove; otherwise, treat with lowmolecular-weight heparin for at least 3 months and measure anti-Xa concentration until it is in an adequate range (0.6– 1.0 U/ml) [37] (Fig. 6.3).

Vaccinations Children with cancer who receive high-dose chemotherapy (autologous or allogeneic bone marrow transplant) or patients with haematological malignancies (leukaemia and lymphoma) will not only become granulocytopenic but will also have low lymphocytes and therefore most likely lose their antibody response to their vaccinations that were administered prior to chemotherapy. Thus, these children need attention concerning the vaccinations needed during chemotherapy and reimmunisation schedules need to be given after chemotherapy [38]. Children on standard chemotherapy with an increased chance of lymphocyte dysfunction are reimmunised no sooner than 6 months after stopping chemotherapy. Allogeneic transplant children are revaccinated 12–18 months after BMT (according to the guidelines of the country they live in).

Immunisation During Chemotherapy Even if small children diagnosed with cancer have not completed their immunisation schedule, it should be clear that these children are NOT allowed live vaccines such as measles–mumps–rubella (MMR), oral polio (OPV), oral typhoid and yellow fever vaccine. In countries where tuberculosis is prevalent, the BCG vaccination is not allowed to be administered. Killed or inactivated vaccines do not represent a danger to the immunocompromised host, although it is well known that the immunogenic response to vaccinations is decreased during chemotherapy. However, this immunogenic response is not zero, which makes it possible

55

6  Supportive Care in Paediatric Oncology

Fig. 6.3  Algorithm for management of a central venous catheter obstruction. DVT deep vein thrombosis, MRI magnetic resonance imaging, MRA magnetic resonance angiography. (Reprinted from Baskin et al. [37], with permission from Elsevier.)

to vaccinate with certain vaccines, especially in areas where herd immunity is low. Certain conditions should be met which include an adequate number of lymphocytes (>1,000 × 109/L), an adequate number of granulocytes (>1,000 × 109/L) and no use of dexamethasone 14 days before the vaccine and 1 week after the vaccine. If herd immunity for measles is low, single-antigen measles vaccine should be given before starting chemotherapy with the understanding that this should be repeated after stopping chemotherapy. If herd immunity for polio is low, eIPV (enhanced inactivated polio vaccine) is recommended in the household contacts and for the immunocompromised patient. It is safe and can confer some degree of protection. DTP (Diphtheria–Tetanus–Pertussis) can be administered to the immunocompromised patient, including the use of acellular pertussis containing vaccines (DtaP). Haemophilus influenzae b conjugate Vaccine (Hib) should be administered in those situations where the risk of Haemophilus influenzae type b is high, in persons with anatomical or functional asplenia or additional sickle cell anaemia.

Hepatitis B vaccination should ideally be given after stopping chemotherapy, but in high-risk groups or areas it can be given to the immunocompromised with a lesser immunogenic response. The vaccine advised then is Recombivax HB 40 mg/ml. Periodic booster doses are usually necessary following successful immunisation, with the timing determined by serologic testing at 12 month intervals.

Special Vaccinations During Chemotherapy Influenza Vaccination A Cochrane systematic review [39] was published emphasising the paucity of data on this vaccine. Serological responses are generally lower than expected in healthy controls, and antibody levels considered protective in healthy individuals may not prevent clinical infection in those with malignant disease. There are no data on whether vaccination of peadiatric

56

M.D. van de Wetering and W.J.E. Tissing

cancer patients protects for clinical infection. The vaccine is well tolerated; therefore, it is not contraindicated. Most countries recommend yearly vaccination and to vaccinate household contacts, but to date there is no evidence that this will decrease complications due to influenza.

need to be revaccinated a year to 18 months after transplant, and the immunogenic response should be measured.

Varicella Zoster Vaccination

TLS is a set of complications that can arise from treatment of rapidly proliferating and drug-sensitive neoplasms. In children, it mostly occurs in Burkitt’s lymphoma, lymphoblastic lymphoma, acute lymphocytic leukaemia with hyperleukocytosis and T-cell ALL. The chance of developing a TLS in above-mentioned cancers in childhood is around 2–4%. In acute myeloid leukaemia, the chance of TLS is much less. In very rare cases, TLS has been reported in solid tumours such as neuroblastoma, medulloblastoma and germ cell tumours [41]. The metabolic disturbances include hyperuricaemia, hyperphosphatemia, hypocalcemia and hyperkalemia. Low-risk patients should be treated with allopurinol (100–200 mg/m2 2× dd) combined with hyperhydration (2–3 l/m2 per 24 h), No consensus has been reached as yet if one needs to alkalanize these patients (urinary pH 6.5–7.5). Urine output is extremely important and should be measured at 3 ml/kg/h. If not adequate, loop diuretics are administered, furosemide at 1 mg/kg/iv. High-risk patients (such as Burkitt’s lymphoma and ALL with hyperleucocytosis) should receive urate-oxidase Uricozyme® or the recombinant form rasburicase (Europe Fasturtec® and in the United States Elitek® ) at the dose of 0.20 mg/kg/day, infused over 30 min, administering the first dose at least 4 h before the start of tumour-specific therapy and continuing for at least 3–5 days. In these patients, concomitant use of allopurinol is not allowed, and alkalinisation of urine is not recommended [41]. In a randomised prospective multicentre trial, it was shown that the risk of developing renal complications requiring dialysis in patients treated on Rasburicase was 0.4%. Therefore, in the high-risk groups, this is the drug of choice [42]. Note that if Rasburicase is used, blood samples for uric acid measurement should be taken on ice, to prevent false low values. Depending on the risk of severe tumour lysis syndrome, once or twice daily blood should be drawn for levels of Potassium, Phosphate, Calcium, Uric Acid and Creatinine.

Although this is a live vaccine, it has been proven to be possible to administer safely during chemotherapy and raise an adequate immune response. As more complications of varicella zoster infection are seen in immunocompromised patients, it would be of great benefit if oncological patients with no detectable antibodies to VZV could receive the vaccine and seroconvert. It is, however, not yet routinely recommended. If considered appropriate to give the VZV vaccine, then chemotherapy should be suspended for 1 week before and 1 week after vaccination, and the patient should not be receiving steroids. Two doses are required [40]. Cases of vaccine-associated varicella have been reported and oral or intravenous acyclovir, as appropriate, should be used if the child develops a skin rash consistent with varicella. Seroconversion to VZV occurred in 82% of vaccinees after one dose and in 95% after two doses. In addition, the incidence of clinical reactivation in vaccinated children is lower than in unvaccinated leukaemic children. Therefore, varicella vaccine administered under these conditions might be beneficial to the leukaemic patient. Pneumococcal Vaccine This is recommended for use in persons >2 years of age with increased risk of pneumococcal disease, such as patients with splenic dysfunction or anatomical asplenia, Hodgkin disease with involvement of the spleen or after radiotherapy, to the spleen.

Immunisation Post-Chemotherapy Patients with haematological malignancies (leukaemia, lymphoma) after standard chemotherapy are recommended in most countries to be revaccinated 6 months post-chemotherapy. Most programmes recommend a booster dose for the routine childhood vaccines (Hib-conjugate, diphtheria/tetanus/acellular pertussis (DtaP), MMR, inactivated poliovirus (IPV) and meningococcal C conjugate), and in some countries the pneumococcus conjugate vaccine (PCV7) is included, although no studies have been done on the response to PCV7 after chemotherapy [38]. Those patients who have undergone an allogeneic bone marrow transplant or autologous BMT

Tumour Lysis Syndrome

Pain-Management Pain in children with cancer is mainly therapy- or procedurerelated. This is contrary to that in adult patients where pain is mainly tumour-related. Fortunately, children have a much better survival rate than the adult patients, and only 15% of patients have pain related to the tumour, either in the initial stage or in their palliative phase [43]. The first step in managing pain is to accurately assess the presence of pain. In children less than

57

6  Supportive Care in Paediatric Oncology

4 years old, the assessment relies on behavioural pain scales, where crying, posture and facial expression are tools used to assess pain. Over 4 years of age, different validated scales are used, for instance the FACES pain rating scale (see Fig. 6.4) [44] or the word graphic rating scale. It is extremely important that the pain is assessed at regular intervals over the day by parents or nursing staff, and the score found is acted on. Therapy-Related Pain or Tumor-Related Pain As in adults, the step ladder of the World Health Organisation is used as a guideline for the adequate treatment of pain. This recommends: Step 1: acetominophen (paracetamol). Step 2: mild opioid acetominophen (paracetamol) combined with step 1. Step 3: opioids (morphine 10  mg/kg/h continuous iv or sc) combined with step 1. The dose of morphine must be increased until adequate pain control is achieved.

If the patient does not achieve adequate pain control on the above step-wise approach, adjuvant therapy should be considered (See Table 6.1). Children need pain control most often less than 1 week, much shorter than the adult patient. This concerns mainly the therapy-related pain, which is given in an in-patient setting. Children should not suffer, so rather start too high on the WHO step ladder, than allowing these children to struggle up the ladder. In adults, step 1 also includes NSAID’s such as Ibuprofen and Naproxen. In children, thrombocytopenia is a frequent adverse effect of treatment. Since NSAIDs have the theoretical potential to increase the bleeding risk due to NSAID-induced thrombocytopathy, their usage is avoided. If a child needs step 3, morphine, most often this is administered intravenously when the pain is therapy-related because the duration will be short; mostly shorter than 1 week. If the child is in the palliative phase and should better be at home with adequate pain medication, Fentanyl patches are preferred together with rescue medication via the oral or rectal route.

Fig. 6.4  FACES Pain Rating Scale. (From Hockenberry MJ, Wilson D, Winkelstein ML: Wong’s Essentials of Pediatric Nursing, ed. 7, St. Louis, 2005, p. 1259. Used with permission. Copyright, Mosby.)

Table 6.1  Pain management Medication

Doses

Remarks Max. 4,000 mg/day

Naproxen (NSAID) Diclofenac

Oral 15 mg/kg/dose 4–6 per day Supp. 20–30 mg/kg/dose 2–4 per day Oral 5 mg/kg/dose 2–3× per day Oral 1–2 mg/kg/dose 3× per day

Step 2 Continue Medication step 1 Tramadol

>1 year 1–2 mg/kg/dose 3–4 per day orally or iv

Max. 400 mg/day Weak opioid

Oral 0.3–0.6 mg/kg/dose 2–3× per day 0.1–0.3 mg/kg/dose 4–6× per day 0.2–0.4 mg/kg/dose 4–6× per day i.v. start dose 0.01–0.03 mg/kg/h or 0.25 mg/kg/24 h Bolus 0.02 mg/kg/10 min. Infusion: 0.005 or 0.01 mg/kg/h iv Transdermal, change every 72 h Dose: 60–90 mg morphine oral per day ~ fentanyl 25 mg/h.

Antagonist: naloxone 0.1 mg/kg i.v. or i.m.

Step 1 Acetaminophen

Step 3 Continue Medication step 1 Morphine (MS Contin) Morphine solution Morphine supp Morphine i.v.   Morphine i.v. patient-controlled analgesia (PCA) Fentanyl patch: 25, 50, 75 en 100 mg/h

Adapted from van de Wetering [46], with permission of Oxford University Press

Cave thrombocytopathy

Need rescue medication; patient should have oral or suppository (rectal application of medication) morphine as rescue medication to administer if pain is present with the patch

58

M.D. van de Wetering and W.J.E. Tissing

Table 6.2  Adjuvant pharmacological therapy Group of drugs Example Dose

Indication

Anxiolytics

Muscle relaxant

Diazepam Oxazepam

0.1–0.2 mg/kg/dose 3–4× per day oral 6 years 2.5–15 mg/dose 3–4 per day oral Sedatives Nitrazepam 1–6 years 2.5–5 mg/dose 1× daily oral >6 years 5 mg/dose 1× daily oral Temazepam 10–20 mg 1 per day oral Anti-depressants Amitriptyline Start dose 0.2–0.5 mg/kg in 2 dd oral. Dose can be increased to 3 mg/kg/day Anti-epileptics Carbamazepine 1.5–3 mg/kg/dose increase to 2.5–5 mg/kg/dose 2–4× daily oral Gabapentin 5 mg/kg 1 dd, max 8–30 mg/kg in 3 dd oral Rivotril 0.05–0.1 mg/kg/dose apply mucosal Steroids Prednisone 1 mg/kg/day oral Dexamethasone 10 mg/m2/day oral Reprinted from van de Wetering [46], with permission of Oxford University Press

Special Pain Syndromes Vincristine-induced neuropathy is a special pain syndrome. Symptoms vary from a feeling of paresthesia underneath the feet to severe pain in the extremities. Regular opiates usually do not relieve optimally. Anti-epileptic drugs like gabapentin can be used, and sometimes a combination with other drugs is necessary. Mucositis: methotrexate and other chemotherapeutic drugs can induce oral mucositis. When the patient needs pain medication, the pain is usually of such a magnitude that morphine is needed; when possible, use PCA (patient-controlled analgesia). Beyond the use of pharmacologic and medical care, one needs to consider non-pharmacologic adjunctive therapy. Although much less evidence is available, it is well known that hypnosis, fantasy, art therapy, etc can help relieve anxiety and stress, and therefore, the experience of pain will hopefully be less severe [45] (Table 6.2).

Treatment of Pain Associated with Diagnostic Procedures The main goal during paediatric procedures is to make the child comfortable so that the child and parents will not dread the subsequent procedures. Since paediatric oncology patients frequently need invasive, painful procedures, it is of utmost importance that the child gets optimal pain management during the first of a series of procedures. Both pain and anxiety have to be managed to achieve adequate control. In general, one must achieve a situation in the treatment room where adequate staff will create a calm environment where the procedure can be performed rapidly and efficiently. Sedation is performed in many different ways. The American Academy of Pediatrics [47] and The American Society of Anesthesiology [48] have set up guidelines, but

Neuropathic pain Neuropathic pain and phantom pain

Intracranial raised pressure brain tumours And severe end stage tumours

these have to be individualised to the particular situation for that specific child. 1. For minor procedures such as venipunctures or access to subcutaneous reservoirs, topical anaesthetic cream can be used 1  h before the procedure (EMLA® or Rapydan®). 2. For procedures such as bone-marrow puncture, conscious sedation can be given. Usually, this consists of midazolam (Versed®) 0.15–0.03  mg/kg rectally 15  min before the procedure or 0.05 mg/kg/iv slowly, but if the iv route is followed, trained anaesthetic personnel should be available, as midazolam can give respiratory depression. In countries where anaesthetics can be given, it is preferred to do bone-marrow aspirations and lumbar punctures under general anaesthetic (Propofol). 3. Procedures such as bone-marrow trephine are always performed under general anaesthetic where airway patency, breathing and circulation can be assured. In all above steps, it is also important to help the child with non-pharmacologic methods in reducing stress and anxiety. Although the evidence available is poor, it is important to find a way to minimise stress and anxiety [45].

Anti-Emetics Nausea and vomiting (N + V) remain an important concern in cancer treatment. The American Society of Clinical Oncology has updated the guidelines in 2006 [49], and MASCC performed the latest update in 2008 [50] Both are for adult cancer patients. With the treatment given nowadays, adequate control is usually achieved, but these guidelines used in adult oncology cannot automatically be adjusted for children, as no adequate pharmacokinetic trials have been performed in children. First, it is important to assess with a validated nausea and

59

6  Supportive Care in Paediatric Oncology

vomiting tool how severe the score is for nausea and vomiting. This scale was developed and is called the PENAT score [51], and is comparable with the FACES pain rating scale for assessment of pain. It is extremely important that the N + V is assessed at regular intervals over the day by parents or nursing staff and that the score found is acted on, only then will it be possible to optimally manage N + V in the child with cancer. Chemotherapeutic agents are grouped in four classes: minimal emetogenic (10% reduction in left ventricular ejection fraction, when compared to those who received the conventional bolus treatment [8]. Interestingly, there was also a trend towards an increased rate of metastasis in the subset of individuals receiving infusion therapy. For this reason, in spite of possible cardioprotective effects from infusional delivery, anthracyclines are still typically administered by the bolus route. There are also ongoing efforts aimed at modifying the anthracycline molecule to minimize cardiotoxic effects, while maintaining its antitumor efficacy. A prime example of this strategy is the incorporation of anthracyclines into liposomes,

75

which has been shown in studies to have a similar efficacy as free, unbound anthracyclines. In addition, this formulation is appealing because it lowers the incidence of cardiac ­dysfunction and also permits substantially higher cumulative doses to be delivered [9]. Finally, the use of adjunctive cardioprotective agents, such as dexrazoxane, in conjunction with anthracyclines may reduce cardiotoxicity. Dexrazoxane is an EDTA-like chelator [10]. It can be used at the onset of anthracycline treatment or started only after a cumulative dose of 300 mg/m2 has been reached. In either scenario, it has been shown in randomized controlled trials to reduce the incidence of anthracyclineassociated heart failure [11]. Dexrazoxane is believed to prevent cardiac damage by binding to iron stores that are released from intracellular storage during oxidative stress. While this cardioprotective agent can be helpful, it is imperfect amidst concerns of its potential to interfere with cancer therapy, its apparent association with lower treatment response rates, and its possible exacerbation of anthracycline-induced myelosuppression [12]. Unfortunately, data in these areas have been inconsistent; thus, it is currently unclear whether the benefits of dexrazoxane truly outweigh its risks. At the present time, the American Society of Clinical Oncology endorses the use of dexrazoxane only for patients who have received a cumulative dose of doxorubicin ³300 mg/m2 or an equivalent dose of epirubicin for the treatment of metastatic disease. Given its potential detrimental impact on antitumor efficacy as well as on myelosuppression, dexrazoxane is not recommended for use in the adjuvant setting when the goal of therapy is cure. Of clinical relevance, the use of dexrazoxane never completely eliminates the risk of cardiotoxicity. As such, its use does not preclude the need for regular ­cardiac monitoring. Preliminary research points towards a possible benefit of administering b-blockers and ACE inhibitors with anthracyclines as a primary preventive measure against cardioto­xicity. In some of these prior studies, the prophylactic use of b-blockers, ACE inhibitors or both was associated with ­better preservation of left ventricular ejection fraction [13]. Definitive conclusions, however, are difficult to draw as data in this regard have been based on small retrospective studies and will require further prospective validation. Whether ­benefit from these agents is statistically and clinically ­significant remains to be seen.

Cardiac Monitoring Since methods to eliminate anthracycline-related cardiac ­dysfunction are not absolute, serial cardiac monitoring continues to be an important component in the ongoing management of anthracycline-treated patients so that the earliest possible

76 Table 8.1  Recommendations for cardiac monitoring in patients receiving anthracyclines A baseline assessment of left ventricular ejection fraction is recommended before starting treatment with an anthracycline Anthracyclines should not be administered if left ventricular ejection fraction is less than 30% If ejection fraction is between 30 and 50%, ejection fraction should be reevaluated prior to each dose of anthracycline Anthracyclines should be discontinued if there is cardiotoxicity, defined as an absolute decrease in ejection fraction by greater than 10% or a final ejection fraction of less than 30% Serial reassessments of ejection fraction should be performed once the cumulative dose threshold has been reached, and even sooner in patients with known heart disease, radiation exposure, or abnormal electrocardiographic results

evidence of cardiotoxicity can be detected. A variety of monitoring techniques have been employed; one set of proposed guidelines is shown in Table 8.1. Echocardiography is perhaps the most frequently used, noninvasive strategy for evaluating left ventricular ejection fraction. This modality is currently endorsed by the American College of Cardiology for monitoring anthracycline-induced cardiotoxicity. Owing to its widespread availability and its lack of radiation exposure, echocardiograms remain a popular standard. Disadvantages, however, include its poor reproducibility and variability in interpretation among clinicians. In addition, it can be occasionally difficult to accurately quantify the global ventricular function. A related approach is the use of multigated blood pool imaging, also known as the MUGA scan, which has become a well-regarded technique for monitoring cardiac dysfunction. This modality is sometimes preferred given its ability to detect cardiotoxicity at very early stages of dysfunction, even before the development of clinical symptoms of heart failure. Specifically, the MUGA scan can identify increased interstitial fibrosis of the heart by measuring subtle changes in systolic and diastolic function. As a result of such early detection, some cardiac abnormalities may be potentially reversible. A case in point: In a small study, patients who experienced an asymptomatic absolute decline in ejection fraction of 15% based on MUGA were discontinued on doxorubicin. Upon treatment cessation, none of the patients progressed to symptomatic heart failure when followed. In fact, repeat measurement of ejection fraction several months after stopping doxorubicin showed a modest improvement in ejection fraction in all patients [14]. There is also emerging interest in exploring newer approaches to cardiac monitoring. Cardiac magnetic resonance imaging, for instance, may be particularly useful for patients where there is significant concern about changes in cardiac structure (rather than function) induced by cancer drug exposure. Alternately, there is ongoing research to clarify the role of cardiac biomarkers, such as troponin and natriuretic

W.Y. Cheung

peptide. The hypothesis is that these biomarkers may provide earlier signs of cardiac damage than any other ­standard imaging techniques. In preliminary studies, elevations in troponin and natriuretic peptide were associated with the severity of myocardial damage secondary to anthracyclines, correlated with the degree of decrease in left ventricular ejection fraction, and were predictive of subsequent cardiac-related morbidity and mortality [15]. A related question that remains unanswered is whether elevations in these biomarkers predict response to conventional therapeutic agents for heart failure, such as b-blockers and ACE inhibitors. Overall, these early data are promising for identifying early anthracycline-related cardiotoxicity, but there is insufficient evidence to support their use at the present time. Finally, it is important to recognize that the “gold ­standard” of assessing anthracycline cardiotoxicity is the endomyocardial biopsy since this method allows for direct evaluation of both the presence and the degree of cardiac damage [16]. Characteristic features of chemotherapy-related injury include depletion of myofibrillary bundles, evidence of myofibrillar lysis, mitochondrial disruption, and intramyocyte vacuolization. Understandably, this procedure is invasive and itself carries the risk of complications, such as arrhythmias and bleeding. Furthermore, the interpretation of the biopsy specimens requires special expertise in histology and pathology. For these reasons, endomyocardial biopsy has typically been reserved for patients in whom a definitive diagnosis is required or for those whom noninvasive imaging modalities fail to ­provide adequate information regarding the cardiac functional status.

Prognosis and Management The short- and long-term prognosis of individuals affected by anthracycline-induced cardiac toxicities appears to depend heavily on the severity and stage of cardiac symptoms at the time when dysfunction is initially diagnosed. This observation further underscores the importance of prompt and early detection. Patients who manifest with clinical symptoms at diagnosis have a worse outcome when compared with those who present with an asymptomatic decrease in left ventricular ejection fraction. Currently, it is unclear whether patients with chemotherapy-associated cardiac dysfunction respond to similar medical therapy, such as b-blockers and ACE inhibitors, as those with heart failure from other causes, although preliminary data suggest that there is some benefit with this approach [13]. Likewise, it is uncertain if prophylactic use of such drugs will prevent the risk of developing treatment-related cardiac dysfunction. At least one study suggests that ACE

8  Cardiac Toxicities of Cancer Therapies: Challenges for Patients and Survivors of Cancer

inhibitors should be considered as first-line treatment for both asymptomatic left ventricular dysfunction and symptomatic heart failure. In this small series of women with metastatic breast cancer who received epirubicin, 7 of 8 women treated with ACE inhibitors had an increase in ejection fraction ³15% whereas only 1 of 33 women without ACE inhibitor therapy demonstrated a similar response [13]. Until more evidence becomes available, medical management of chemotherapy-related heart failure should incorporate the use of these medications. To this end, most experts also concur that for patients in whom anthracycline-induced cardiotoxicity is refractory to standard medical therapy, interventions such as cardiac resynchronization therapy should at the very least be considered.

77

e­ mbryonic cardiac development. It also participates in ­protecting the heart from potential cardiotoxins where studies show that HER-2 gene knockout mice are more likely to develop dilated cardiomyopathy and their myocytes demonstrate increased susceptibility to anthracycline-induced cell death [18]. In further support, serum HER-2 levels appear to be increased in patients with chronic heart failure with levels correlating inversely with left ventricular function [19]. The following section briefly reviews the clinical manifestations of trastuzumab cardiotoxicity, the guidelines for monitoring cardiac function during treatment, and the management of patients who experience cardiotoxicity as a result of trastuzumab exposure.

Risk Factors Trastuzumab Background Trastuzumab is a humanized monoclonal antibody that binds to HER-2 on the surface of breast cancer cells, and inhibits downstream signal transduction, thereby resulting in cellular growth inhibition. For the approximately 20–25% of the breast cancer patient population whose tumors overexpress HER-2, this molecularly targeted agent has quickly become an important component in the management of both locally advanced and metastatic disease. More recently, trastuzumab has also been integrated into many adjuvant chemotherapy regimens for the treatment of early stage, HER-2 overexpressing breast cancers due to the statistically significant survival benefit that has been demonstrated in several large randomized controlled trials. Importantly, these benefits must be carefully weighed against the added risk of cardiac toxicities from trastuzumab treatment. The precise mechanisms underlying trastuzumab-associated cardiac dysfunction are as yet unclear. Of note, considering that many patients who receive trastuzumab have also been previously treated with anthracyclines, it was once postulated that potentiation of prior anthracycline-induced cardiac damage was the most responsible factor. However, histopathological studies from endomyocardial biopsy specimens from individuals with trastuzumab-related cardiac dysfunction have refuted this hypothesis, since anthracycline-based structural changes were not always observed. Moreover, trastuzumab dysfunction can develop even in the setting of anthracycline-naïve patients. Preliminary studies indicate that trastuzumab cardiotoxicity may be directly related to HER-2 blockade [17]. Early animal models, for instance, suggest that HER-2 signaling is an important step in

The overall incidence of cardiac dysfunction from trastuzumab alone ranges between 3 and 8%, but the rate becomes significantly higher among individuals who receive trastuzumab concurrently with other potentially cardiotoxic agents, especially anthracyclines and taxanes [20]. In the pivotal phase III trial that evaluated the benefit of adding trastuzumab to conventional cytotoxic chemotherapy for metastatic breast cancer, the incidence of any cardiac dysfunction was 27% for trastuzumab plus adriamycin and cyclophosphamide (AC) vs. 8% for AC alone, and 13% for trastuzumab plus paclitaxel vs. 1% for paclitaxel alone [6]. As expected, the incidence of severe heart failure, consisting of either class III or IV symptoms, was substantially lower: 16% with trastuzumab plus AC vs. 4% for AC alone and 2% with trastuzumab plus paclitaxel vs. 1% for paclitaxel alone [6]. These findings resulted in the recommendation that concurrent delivery of anthracyclines and trastuzumab be generally avoided or used with great caution in favor of sequential therapy because of the increased risk of cardiotoxicity associated with concurrent administration. The precise mechanisms underlying the additive cardiotoxicity of anthracyclines and trastuzumab are unclear, but upregulation of HER-2 blockade by anthracyclines is thought to be at least partially responsible for this synergistic effect. Aside from concurrent anthracycline and taxane use, additional risk factors have been identified that may predispose individuals to a higher likelihood of developing trastuzumabrelated cardiotoxicity. In one series, prior chest irradiation, diabetes mellitus, valvular heart disease, and coronary artery disease were noted to increase the toxicity risk [21]. In the phase III trial by Slamon et al., advanced age was identified as the most significant risk factor [6]. Unfortunately, both of these analyses were based on a limited number of patients; as a result, their conclusions should be interpreted with caution.

78

Clinical Manifestations Unlike the adverse events observed with anthracyclines, ­trastuzumab-related cardiac toxicities tend to manifest as asymptomatic reductions in ejection fraction as opposed to overt heart failure. In further contrast, trastuzumab-­associated cardiac disease is not dependent on the cumulative dose of drug administered. It is commonly reversible with treatment cessation and frequently amenable to treatment rechallenge if cardiac function recovers after a planned treatment break. Because of these differences, chemotherapy-related ­cardiac abnormalities are categorized by some experts into Type I and Type II dysfunction [22]. The former “Type I” refers to anthracycline-associated injury, which results in permanent myocyte destruction and clinical heart failure. Conversely, the latter “Type II” refers to trastuzumab-associated damage, which is more often associated with transient loss of cardiac contractility and less likely to involve myocyte death or clinical heart failure. Owing to its somewhat transient nature, this form of dysfunction may be reversible.

Minimizing the Risk At least in the adjuvant setting, two approaches have been proposed as potential ways to lower the risk of trastuzumabrelated cardiotoxicity. First, most adjuvant breast cancer trials involving trastuzumab have administered the agent over the course of 12 months. In the important FinHer trial, however, an anthracycline and taxane-containing regimen was compared to the same chemotherapy regimen plus a 9-week course of trastuzumab [23]. There was a survival benefit, but no cardiac dysfunction was observed in the trastuzumab study arm, suggesting that a decrease in the duration of exposure to trastuzumab may confer substantially less cardiac risk. Certainly, these results are only hypothesis-generating, since longer follow-up and a larger number of patients are required to validate whether this approach leads to a better cardiac risk profile without unduly compromising the survival benefits seen with longer courses of trastuzumab. There is also increasing interest in integrating trastuzumab into noncardiotoxic, nonanthracycline containing adjuvant regimens. One example consists of docetaxel and carboplatin, plus trastuzumab. Indeed, early results from the BCIRG 006 trial, in which one of the three arms utilized a nonanthracycline containing adjuvant chemotherapy regimen, are promising with respect to lowering cardiac risk [24]. However, pressing questions remain in regards to the efficacy of nonanthracycline containing adjuvant regimens, and

W.Y. Cheung

these will need to be addressed in additional, longer follow-up of these study participants.

Cardiac Monitoring Heart function should always be evaluated prior to the instigation of trastuzumab therapy as well as regularly during treatment. Only patients with a normal baseline ejection fraction based on imaging, and neither symptoms nor signs of heart failure on history and physical examination, respectively, should be considered eligible for trastuzumab therapy. While the following are not absolute contraindications to therapy, special caution should be taken when patients with a prior history of hypertension, coronary artery disease, and valvular heart disease are receiving trastuzumab. Currently, there are no universal recommendations on the optimal methods or schedules for monitoring patients for trastuzumab cardiotoxicity. However, some early clinical guidelines have been proposed by several tertiary centers and major organizations. A set of proposed guidelines is outlined in Table 2. Briefly, the British Society of Echocardiography presently recommends that left ventricular ejection function be assessed before commencing trastuzumab therapy and then regularly at 3-month intervals during therapy. Likewise, guidelines from the Memorial Sloan Kettering Cancer Center suggest that heart rate and body weight be monitored weekly once treatment has started. As Table 8.2 illustrates, there are additional indications that should trigger a formal reassessment of left ventricular ejection fraction during trastuzumab therapy. Table 8.2  Recommendations for cardiac monitoring in patients receiving trastuzumab Asymptomatic patients If ejection fraction remains normal or decreases by less than 10%, continue with trastuzumab and repeat ejection fraction assessment in 3–4 weeks If ejection fraction decreases by 10–20% and overall ejection fraction is more than 40%, continue with trastuzumab and repeat ejection fraction assessment in 2 weeks If ejection fraction decreases by 20–30% or overall ejection fraction is less than 40%, hold trastuzumab and repeat ejection fraction assessment in 2 weeks Once held, trastuzumab can be resumed if overall ejection returns to more than 40%; otherwise, trastuzumab should be stopped Symptomatic patients If ejection fraction decreases by less than 10%, continue with trastuzumab, search for other causes of symptoms, and repeat ejection fraction assessment in 3–4 weeks If ejection fraction decreases by more than 10–20% and overall ejection is more than 50%, continue with trastuzumab and repeat ejection fraction assessment in 2 weeks If ejection fraction decreases by more than 20%, stop trastuzumab

8  Cardiac Toxicities of Cancer Therapies: Challenges for Patients and Survivors of Cancer

Prognosis and Management In contrast to anthracyclines, data indicate that trastuzumabrelated cardiac toxicities are frequently reversible in the majority of cases. Moreover, early evidence suggests that reintroduction of trastuzumab appears to be safe as long as cardiac abnormalities that develop while receiving the drug have resolved. In the phase III trial by Slamon et  al., for instance, 33 patients continued trastuzumab for a median of 26 weeks despite developing an asymptomatic decline in ejection fraction. The cardiac status of 85% improved or remained the same, while symptoms were reversible for 75% of those who received standard medical therapy for heart failure [6]. Similarly, in a retrospective review from MD Anderson Cancer Center, the majority of those who stopped trastuzumab after developing symptomatic heart failure recovered with appropriate medical therapy, which consisted of b-blockers and ACE inhibitors [21]. While recovery was not universal, treatment was reinitiated in more than half of patients who interrupted trastuzumab for either an asymptomatic or symptomatic cardiac event, of whom most remained free of subsequent cardiac problems.

Radiation Therapy Background Radiation therapy, which can be applied either by itself or in combination with systemic treatment agents, has contributed to significant improvements in the survival of patients with specific cancers, including the breast, Hodgkin disease, as well as malignancies involving the thorax (e.g., lung, esophagus). Such advances have resulted in a higher prevalence of cancer survivors, who are now at increased risk for late complications of radiation treatment, which can frequently involve the heart. Most of the data pertaining to the cardiovascular toxicities of radiation therapy are derived primarily from survivors of breast cancer and Hodgkin lymphoma, since these are diseases in which radiation is a frequent component of initial management and for which survival is often prolonged to a significant degree. Radiation, if administered in sufficiently high doses or large volumes, can potentially damage any and all aspects of the heart, including the pericardium, myocardium, heart valves, coronary blood vessels, and conduction system. Pericarditis is a common manifestation of acute radiation injury, while chronic pericardial disease, coronary artery ­disease, restrictive cardiomyopathy, valvular disease, and conduction abnormalities can present years or decades after

79

the original treatment. All of these conditions can potentially result in significant morbidity and mortality. The increasing recognition of radiation-induced cardiac toxicities has led to the development of improved radiotherapy techniques that aim to minimize the dose and volume of exposure to the heart. These contemporary measures appear to have drastically reduced the incidence of radiation-related cardiac complications, although there is still some residual risk.

Risk Factors Several factors increase the risk for developing radiationinduced cardiac toxicities. These include the total radiation dose administered, the dose per fraction, the volume of heart irradiated, and the concurrent delivery of cardiotoxic systemic therapeutic agents, such as anthracyclines and trastuzumab [25]. In breast cancer, for example, the older generation of radiation techniques used in the management of this disease has almost always involved irradiation to the chest wall and surrounding lymph nodes. This classically resulted in a relatively high dose of radiation being delivered to a substantial volume of the heart. There is abundant evidence that this form of radiation delivery was associated with excess cardiovascular morbidity and mortality. Modern techniques currently deliver much less radiation to the heart and appear to have reduced the number of cases and degree of associated cardiotoxicity. In many of these cases, however, longer follow-up is required to confirm these safety findings. Patient dependent factors, such as younger age at the time of initial radiation exposure and the presence of other personal risk factors for coronary heart disease, including hypertension, high serum cholesterol, and smoking history, may also increase the risk of radiation-associated cardiac dysfunction [25].

Clinical Manifestations The main mechanism for radiation-related cardiac toxicities involves radiation damage to coronary blood vessels. This injury is believed to subsequently lead to the production of reactive oxygen species that disrupts DNA strands, which then results in secondary inflammatory changes and ultimately fibrosis. The classic hallmarks of radiation-induced cardiotoxicity consist of diffuse fibrosis of the myocardium coupled with narrowing of arterial and capillary lumens [26]. The ratio of capillaries to cardiac myocytes decreases by 50%, which contributes to cell death, cardiac ischemia, and further fibrosis. Collagen replaces the normal adipose tissue

80

that usually forms around the outer layer of the heart, leading to pericardial fibrosis, effusion, and possibly tamponade. All of these changes can culminate in various forms of coronary artery diseases, valvular heart diseases, pericardial diseases, diastolic dysfunction, and dysrhythmias. There are subtle differences between chemotherapyrelated cardiac dysfunction and radiation-induced cardiac toxicities. First, irradiation causes fibrosis of the myocardium, which can lead to a restrictive cardiomyopathy. This appears to have a greater impact on diastolic rather than systolic cardiac function. This contrasts the general effects of anthracyclines, which predominantly causes systolic dysfunction. Second, radiotherapy (specifically mediastinal irradiation) has been associated with an increased risk of clinically significant valvular abnormalities. Of potential clinical importance, many of the common abnormalities found in mediastinal irradiated patients are slowly progressive and may necessitate lifelong follow-up, some of which may also require antibiotic prophylaxis for endocarditis. Third, radiation can cause fibrosis of the conduction pathways in the heart, potentially leading to life-threatening arrhythmias and conduction defects that develop years after initial radiation therapy. Examples of such dysfunction include bradycardia and sick sinus syndrome, as well as complete and lesser degrees of heart block.

Additional Aspects Unlike chemotherapy-induced cardiotoxicity, cardiac ­dysfunction related to radiation may be more challenging to  manage in part because of its diverse manifestations. Improvements in radiotherapeutic techniques have been the primary means of decreasing the cardiac risk by minimizing the amount of radiation received by the heart. It is noteworthy that cardiovascular complications still appear more ­frequently in patients with left-sided than right-sided tumors, providing some evidence that the risk associated with radiation has not been completely eliminated with the newer ­generation of methods for radiotherapy. Awareness of key factors that modify the risk of cardiovascular toxicity is another channel in which complications can be reduced. The size of the radiation field and the dose of exposure, for instance, determine the amount of incidental irradiation to the heart. Studies that compared breast cancer patients who received internal mammary lymph node irradiation were noted to have an increased risk of cardiovascular complications than those in whom the internal mammary lymph nodes were not included in the field [27]. Thus, radiation field and radiation dose are parameters that should be minimized, whenever possible. Care must also be taken to modify other risk factors for cardiovascular

W.Y. Cheung

disease, such as hypertension, hyperlipidemia, and ­smoking, as well as to adequately manage preexisting coronary artery disease, since all of these variables may increase and potentiate radiation-related cardiotoxicity. Special attention is further warranted when radiation is used in patients who have or will receive known cardiotoxic agents, such as anthracyclines and trastuzumab.

Nonanthracycline Agents 5-Fluorouracil 5-Fluorouracil is widely used in various chemotherapy ­regimens to fight a diverse array of cancers. Because of its frequent use, it is the second most common cause of chemotherapy-related cardiotoxicity after anthracyclines. The most frequent cardiac side effect from 5-fluorouracil is anginal chest pain. Myocardial infarction, acute pulmonary edema, and pericarditis can also occur, but these events are much rarer. The underlying mechanism for 5-flourouracil cardiotoxicity is thought to be due to coronary artery vasospasm. Its incidence is estimated to be around 8% [28]. The risk may be related to the mode of 5-flourouracil administration where infusional therapy is associated with a higher risk than bolus treatment. A prior history of coronary artery disease and concurrent use of cardiotoxic agents, including chemotherapy and radiation, also increase the risk. Fortunately, cardiac symptoms typically resolve with either the cessation of 5-flourouracil treatment or the instigation of standard antianginal medical therapy. Rechallenging patients who have previously experienced 5-fluoruracil related cardiac toxicities is somewhat controversial and generally not recommended. Alternately, if rechallenge is being considered, it should be done under cardiac monitoring and close observation by specialized medical personnel. Furthermore, symptomatic patients should ideally undergo stress testing or coronary angiography to rule out occult coronary ischemia.

Capecitabine Capecitabine is a flouropyrimidine that is metabolized by the enzyme thymidine phosphorylase to 5-flourouracil, which is the active anticancer form of the drug. Thus, the cardiac toxi­ city profile of capecitabine is very similar to that observed for 5-flourouracil [29]. Furthermore, patients who have a history of 5-flourouracil cardiotoxicity may also have a predisposition to capecitabine toxicity. The most frequent clinical

8  Cardiac Toxicities of Cancer Therapies: Challenges for Patients and Survivors of Cancer

manifestations include angina, arrhythmias, and myocardial infarction. It is presumed that the mechanism for cardiotoxicity is akin to that reported for 5-flourouracil, with coronary artery vasospasm being most responsible.

Taxanes For taxanes such as paclitaxel, mild bradycardia and heart blocks can occur, although these are usually relatively asymptomatic. Overall, the incidence of these events is very low, and thus routine cardiac monitoring is not required for typical patients without risk factors. It is important to note that the nanoparticle albumin-bound paclitaxel (e.g., nab-paclitaxel) bodes the same cardiac toxicity profile as the regular, nonalbumin-bound formulation. Similarly, conduction abnormalities and angina have been reported in users of docetaxel. Both paclitaxel and docetaxel also appear to potentiate the cardiotoxic effects of anthracyclines, as described previously [30].

Summary In summary, advances in early detection and treatment strategies have prolonged the natural history of many cancers and contributed to an increasing prevalence of cancer survivors. Some of these patients are now faced with the sequelae of early and late treatment-related toxicities, many of which involve the heart. Anthracyclines, trastuzumab, and radiation are increasingly incorporated into current treatment paradigms, but each agent is associated with a spectrum of ­cardiac side effects. As members of the cancer team, a basic awareness of the mechanisms, risk factors, management and prognosis of these various treatment-associated cardiac ­toxicities is important for addressing the specific needs and optimizing care for present and future cancer survivors.

References 1. Elliot P. Pathogenesis of cardiotoxicity induced by anthracyclines. Semin Oncol 2006; 33: 2–7. 2. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003; 97: 2869–79. 3. Hershman DL, McBride RB, Eisenberger A, Tsai WY, Grann VR, Jacobson JS. Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin’s lymphoma. J Clin Oncol 2008; 26: 3159–65. 4. Shapiro CL, Hardenbergh PH, Gelman R, Blanks D, Hauptman P, Recht A, et al. Cardiac effects of adjuvant doxorubicin and ­radiation

81

therapy in breast cancer patients. J Clin Oncol 1998; 16: 3493–501. 5. Bria E, Giannarelli D, Felici A, Peters WP, Nistico C, Vanni B, et al. Taxanes with anthracyclines as first-line chemotherapy for metastatic breast carcinoma. Cancer 2005; 103: 672–9. 6. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783–92. 7. Nakamae H, Tsumura K, Terada Y, Nakane T, Nakamae M, Ohta K, et al. Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Cancer 2005; 104; 2492–8. 8. van Dalen EC, van der Pal HJ, Caron HN, Kremer LC. Different dosage schedules for reducing cardiotoxicity in cancer patients receiving anthracycline chemotherapy. Cochrane Database Syst Rev 2006; 4: CD005008. 9. Gabizon AA, Lyass O, Berry GJ, Wildgust M. Cardiac safety of pegylated liposomal doxorubicin (Doxil/Caelyx) demonstrated by endomyocardial biopsy in patients with advanced malignancies. Cancer Invest 2004; 22: 663–9. 10. Seifert CF, Nesser ME, Thompson DF. Dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity. Ann Pharmacother 1994; 28: 1063–72. 11. Dalen E, Caron H, Dickinson H, Kremer L. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 2005; 1: CD003917. 12. Swain SM, Whaley FS, Gerber MC, Weisberg S, York M, Spicer D, et al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 1997; 15: 1318–32. 13. Kalay N, Basar E, Ozdogru I, Er O, Cetinkaya Y, Dogan A, et al. Protective effects of carvedilol against anthracycline-induced ­cardiomyopathy. J Am Coll Cardiol 2006; 48: 2258–62. 14. Nousiainen T, Jantunen E, Vanninen E, Hartikainen J. Early decline in left ventricular ejection fraction predicts doxorubicin cardiotoxicity in lymphoma patients. Br J Cancer 2002; 86: 1697–700. 15. Kuittinen T, Husso-Saastamoinen M, Sipola P, Vuolteenaho O, ­Ala-Kopsala M, Nousiainen T, et  al. Very acute cardiac toxicity ­during BEAC chemotherapy in non-Hodgkin’s lymphoma patients undergoing autologous stem cell transplantation. Bone Marrow Transplant 2005; 36: 1077–82. 16. Cooper LT, Baughman KL, Feldman AM. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Circulation 2007; 116: 2216. 17. Ewer MS, Vooletich MT, Durand JB, Woods ML, Davis JR, Valero V, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 2005; 23: 7820–6. 18. Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, et  al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 2002; 8: 459–65. 19. Perik PJ, de Vries EG, Gietema JA, van der Graaf WT, Smilde TD, Sleijfer DT, et al. Serum HER2 levels are increased in patients with chronic heart failure. Eur J Heart Fail 2007; 9: 173–7. 20. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002; 20: 1215–21. 21. Guarneri V, Lenihan DJ, Valero V, Durand JB, Broglio K, Hess KR, et  al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the MD Anderson Cancer Center experience. J Clin Oncol 2006; 24: 4107–15. 22. Ewer M, Lippman S. Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol 2005; 23: 2900.

82 23. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006; 354: 809–20. 24. Robert NJ, Eiermann W, Pienkowski T. BCIRG 006: docetaxel and trastuzumab-based regimens improve DFS and OS over AC-T in node-positive and high risk node-negative HER2 positive early breast cancer patients: quality of life at 36 months follow-up. J Clin Oncol 2007; 25: 719. 25. Aleman BM, van den Belt-Dusebout AW, De Bruin ML, van’t Veer MB, Baaijens MH, de Boer JP, et al. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood 2007; 109: 1878–86. 26. Hardenberg PH, Munley MT, Hu C. Doxorubicin-based chemotherapy and radiation increase cardiac perfusion changes in patients treated for left-sided breast cancer. Int J Radiat Oncol Biol Phys 2001; 51: 158.

W.Y. Cheung 27. Hooning MJ, Botma A, Aleman BM, Baaijens MH, Bartelink H, Klijn JG, et  al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst 2007; 99: 365–75. 28. Akhtar SS, Salim KP, Bano ZA. Symptomatic cardiotoxicity with high-dose 5¢fluorouracil infusion: a prospective study. Oncology 1993; 50: 441–4. 29. Ng M, Cunningham D, Norman AR. The frequency and pattern of cardiotoxicity observed with capecitabine used in conjunction with oxaliplatin in patients treated for advanced colorectal cancer. Eur J Cancer 2005; 41: 1542–6. 30. Malhotra V, Dorr VJ, Lyss AP, Anderson CM, Westgate S, Reynolds M, et al. Neoadjuvant and adjuvant chemotherapy with doxorubicin and docetaxel in locally advanced breast cancer. Clin Breast cancer 2004; 5: 377–84.

Chapter 9

Malignant Pericardial Effusion and Cardiac Tamponade (Cardiac and Pericardial Symptoms) Marek Svoboda

Introduction The malignant pericardial effusion (PCE) and cardiac tamponade are known life-threatening complications in cancer patients. Early recognition and prompt treatment may dramatically relieve patients of symptoms and decrease a shortterm risk of death from the effusion. Although pericardial involvement by malignancy is the leading cause, other etiological factors need exclusion and the underlying medical status of a patient has to be considered before the final treatment strategy determination. An optimal management of the PCE improves the quality of life and increases the overall survival of cancer patients, especially those with diseases that are potentially responsive to current therapies [1–3].

Etiology and Pathogenesis of Pericardial Effusion Malignancy Pericardial involvement by malignancy is the leading cause of PCE and a cardiac tamponade in cancer patients. The prevalence of pericardial involvement varies from 2 to 65% in cancer patients’ autopsies. The tumors most frequently associated are lung cancer, breast cancer, melanoma, lymphomas, and leukemias, followed by unknown primary tumors, sarcomas, esophageal cancer, and ovarian cancer. Adenocarcinomas represent up to 70% of documented malignant effusions. A primary mesothelioma of the pericardium, an exceedingly rare tumor, comprises less than 1% of all mesothelioma cases [2, 4]. The pathologic cause of the effusive process often involves hematogeneous or lymphatic metastasis to the parietal pericardium, although direct invasion of the epicardial surface or M. Svoboda (*) Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Center, Zluty kopec 7, Brno 65653, Czech Republic e-mail: [email protected]

myocardium can also be present. Alternatively, the presence of mediastinal lymph node metastases may lead to disruption of homeostatic mechanisms of lymphatic drainage, resulting in the PCE [1].

Other Causes Although other causes of pericarditis and/or accumulation of an effusion were identified in less than 5% of PCE cases in cancer patients, they should be considered before the final treatment strategy is determined. A radiation induced pericarditis or a disruption of the lymphatic drainage is relatively the most common of these. Less frequent causes are drugs, bacterial and viral infections (especially HIV associated), thoracic surgery, percutaneous and endoscopic procedures, chronic renal failure (uremia), GVHD (graft-versus-host disease), and connective tissue diseases. An extrapericardial tamponade has rarely been reported and may be caused by pleural effusions or a dilated retrosternal gastric roll, when elevated pressures are transmitted to the pericardial space, resulting in an impaired cardiac filling and a tamponade-like physiology [3].

Radiation Therapy The PCE due to radiation was identified in only 3% of general clinical series, whereas it may be observed in as many as 30% of patients receiving mantle therapy for lymphomas or Hodgkin disease. An acute radiation pericarditis may occur weeks to months after radiotherapy and is usually self-limiting and often asymptomatic. However, a chronic effusive or a constrictive process may occur as many as 20 years after radiotherapy and can be insidious at the onset of tamponade, leading to death [2]. Presently, there is a concern about the occurrence of such complications after chemoradiotherapy, which is a widely used therapeutic strategy in many different types of solid tumors (esophageal and gastric cancer, lung cancer), although

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_9, © Multinational Association for Supportive Care in Cancer Society 2011

83

84

such treated patients may survive longer. For example, the risk of PCE is 5 times greater after induction with chemoradiotherapy than after a surgery alone in patients with a locally advanced esophageal cancer [5, 6]. In patients with an inoperable esophageal cancer treated with a definitive concurrent chemotherapy and radiation therapy, the crude rate of PCE was 27.7% and a median time of an onset of PCE was 5.3 months after radiotherapy. In multivariate analysis, a volume of pericardium receiving a dose greater than 30  Gy (V30) was selected as the only parameter significantly associated with risk of PCE [6].

Drugs There are many drugs capable of causing pericarditis, especially in the presence of pericardial abnormalities and prior or concurrent mediastinal radiation [7]. Doxorubicin, cyclophosphamide, BCNU, and gemcitabine are mentioned as the most important, but any cardiotoxic drugs may induce PCE, despite their cancer cell selectivity [3, 5, 8, 9]. Tyrosine kinase inhibitors can serve as an example. Despite the apparent selectivity of these agents, significant side effects can occur, including a serosal inflammation manifested by a pleural and/or PCE. The serosal inflammation is frequently associated with dasatinib therapy but is occurring less frequently during imatinib and nilotinib therapies. The pathogenesis is uncertain but may involve an inhibition of platelet-derived growth factor or an expansion of cytotoxic T and natural killer cells. The development of the serosal inflammation with dasatinib poses a significant challenge to physicians. It cannot be predicted, the time of onset is variable, and its management frequently requires repeat invasive procedures [10].

GVHD The PCE and the cardiac tamponade have been described in patients with a “GVHD” reaction in the posttransplant period. Rarely, the PCE may occur as an isolated GVHD manifestation [11].

Diagnosis The malignant PCE can be difficult to diagnose because its onset is often insidious, and its clinical manifestations may be attributed to a gradual deterioration in cardiopulmonary function in patients with an advanced state of the disease [1, 2]. The consequences of the PCE depend mainly on the rate of exudation, the compliance of the pericardium, and the

M. Svoboda

underlying medical status of a patient [12]. In one of the early clinicopathologic series, on one hand, 64% of patients with autopsy-proven pericardial metastases were asymptomatic and had a normal cardiac exam [2]. On the other hand, the cardiac tamponade was the immediate cause of death in about 85% of previously asymptomatic cancer patients [13].

Signs and Symptoms The majority of patients with PCEs are asymptomatic or demonstrating a gradual onset of symptoms rather than an acute tamponade. The most common presenting symptom is dyspnea followed by thoracic pain, orthopnea, dizziness, cough, and fatigue [1, 2]. Physical signs include tachycardia (a heart rate >90  beats/min), absolute or relative hypotension, tachypnea, pulsus paradoxus (inspiratory fall in systolic blood pressure >10 mmHg), jugular venous distension, and distant heart sounds. If the tamponade develops subacutely, peripheral edema, hepatomegaly, and ascites are frequently present [14].

Chest Imaging On a chest radiograph, any type of a large cardiac silhouette in a patient with clear lung fields should suggest the presence of a PCE [14]. On the one hand, a normal chest radiograph may be observed with rapidly accumulating or small ( 2 cm

Ultrasound-guided pericardiocentesis and placement of indwelling pericardial catheter

Intrapericardial instillation of agent with sclerosing and/or antineoplastic activity

Effective therapy

Pericardial fluid cytology

Yes Systemic anticancer therapy

No Rapid reaccumulation

No

Systemic anticancer therapy or mediastinal irradiation *

Yes Life expectancy > 6 months

Yes

No

Fig. 9.2  Algorithm for management of PCE in cancer patient

Repeating of pericardiocentesis and local therapy or percutaneous approaches of creating a pericardial window (Annotation: * see indication under Noninvasive Modalities )

Pericardial window

9  Malignant Pericardial Effusion and Cardiac Tamponade (Cardiac and Pericardial Symptoms)

recently been described as an alternative technique to create a pericardial window [17]. More aggressive surgical approaches involve anterolateral thoracotomy, thoracoscopy or videoassisted thoracoscopy (VATS) with removal of a portion of the parietal pericardium to form a pleuropericardial window and to allow drainage into the pleural space. These procedures are advocated by some who feel that there is a high incidence of recurrence after the subxiphoid pericardiotomy [2]. These techniques afford an excellent diagnostic yield due to improved visualization of intrathoracic disease, better exposure of the pericardium, and a potential to obtain more tissue for study. Disadvantages include the need for a general anesthesia and the occasional need for prolonged postoperative ventilatory support.

Initial Management of Pericardial Effusion – Percutaneous Approaches Percutaneous treatment of a PCE has undergone an evolution in recent years with the use of less invasive drainage techniques. Percutaneous needle puncture routes, ultrasound (echocardiography)-guided drainage, and percutaneous management of the pericardial fluid effusion (pericardial sclerosis and balloon pericardiotomy) can be performed under local anesthesia [3]. Limits of percutaneous paraxiphoid ultrasound-guided procedures include obese patients, patients with Morgagni hernias, narrow costal margins, or those who have had prior thoracic surgery, or patients presenting with bowel obstruction or severe ascites. A presence of hematoma within the pericardium, a minimal (diaphragmatic thickening less than 10 mm) or loculated posterior PCE represent contraindications to a percutaneous approach [3].

87

Indwelling Pericardial Catheter To drain a large PCE and/or for instillation of the sclerosing and/or cytostatic agents into the pericardial sac, the indwelling pericardial catheter (e.g., pigtail drain) is usually used. The catheter is inserted into the pericardial space by the Seldinger technique under local anesthesia and ultrasound control. Catheter specific complications are rare and include catheter occlusions and infections [3].

Balloon Pericardiotomy A subxiphoid approach is used to insert a pigtail pericardial drain. After drainage of the fluid, the pericardial space is delineated with contrast, and a 12 × 20  mm balloon angioplasty catheter is introduced into the pericardial space to form a pericardial stoma or window. Several inflations (usually 12–14 atmospheres for 60–80 s) are performed until waisting of the balloon by the pericardium disappears [18]. The exact mechanism by which the fluid is drained is unclear. The window appears to facilitate drainage into the peritoneal or pleural space, where the resorptive surface and function are greater than in the pericardium [18]. Intravenous antibiotics (e.g., flucloxacillin) are given as prophylaxis. This procedure is performed using local anesthesia, but opiate analgesia (i.v. morphine) before and during the procedure, often together with benzodiazepine sedation is given routinely for pain relief, as stretching of the pericardium is often painful. Subsequent studies have shown the efficacy of this therapy in larger series, in children and in nonmalignant conditions. Relative contraindications to the procedure include an INR >2 or platelet count 25% decline in LVEF from baseline) reduction in cardiac function compared with 36% for those 10 points or a fall below

Table 17.1  Methods of monitoring anthracycline-associated cardiotoxicity Method Benefits Endomyocardial biopsy

Provides histological evidence of cardiotoxicity

Radionuclide ventriculography

Well-established and well-validated method to determine ejection fraction Can also assess regional wall motion and diastolic function Provides a wide spectrum of information on cardiac morphology and function Does not expose patients to ionising radiation Reliably diagnoses left ventricular systolic and diastolic dysfunction More reliable than conventional Doppler Cardiac abnormalities that remain occult at rest can be detected

Echocardiography

Tissue Doppler imaging Stress testing

Biomarkers

MRI

Troponin is a highly specific and sensitive biomarker for the detection of myocardial damage Potentially useful screening tool Valuable tool to assess myocardial function and damage

CT

Image quality better than MRI

Scintigraphy

Sensitive method to detect myocyte damage in patients after doxorubicin therapy MRI magnetic resonance imaging, CT computed tomography Adapted from [12] with permission from Oxford University Press

Limitations Invasive Requires specialist input for performing the procedure and interpreting the findings Invasive – exposes patients to radiation which limits its repeatability Observer dependence LVEF measurements are not sensitive for the early detection of preclinical cardiac disease Both FS and LVEF depend on preload and afterload Data analysis can be time consuming

Not routinely performed Mixed reports on ability to enhance diagnostic sensitivity Data regarding clinical value are limited

High costs of repeated examinations Limited availability High radiation dose Limited availability Larger prospective trials required to ascertain potential role

166

the institutional lower limit of normal (60%) as indicative of anthracycline-associated cardiotoxicity [33–35]. The use of biomarkers, such as troponins and natriuretic peptides, might provide more detailed and useful information, particularly on early cardiac damage caused by anthracyclines [36, 37]; however, the use of such methods is still in its infancy.

N. Davidson

Liposomal Anthracyclines

An important step forward in reducing anthracycline-induced cardiotoxicity was accomplished by encapsulating the drug within a liposome. This significantly reduces its distribution volume, diminishing its diffusion in the body and consequently the toxicity for healthy tissues such as the heart, while increasing the accumulation of active drug at tumour sites [43]. There are two formulations of liposomal doxoruTherapeutic Modifications and Interventions bicin: non-pegylated and pegylated. Several clinical studies have shown them to have similar efficacy but less cardiac toxicity when compared with conventional doxorubicin as ACE Inhibitors and Beta-Blockers first-line treatment for metastatic breast cancer (Table 17.2) For patients at a heightened risk of cardiovascular dysfunc- [33–35, 44, 45]. In a phase III trial of 509 women with metastatic breast tion, it may be appropriate to treat them with ACE inhibitors and/or beta-blockers in order to prevent adverse cardiovascu- cancer, pegylated liposomal doxorubicin had comparable lar events associated with anthracycline treatment [12]. efficacy [median progression-free survival (PFS) 6.9 vs. 7.8 Preliminary evidence suggests that pretreatment with such months; hazard ratio (HR) 1.00] but significantly reduced agents can reduce or even prevent the fall in LVEF seen with cardiotoxicity compared with conventional doxorubicin (4% high-dose chemotherapy [38, 39]. Heart rate or rhythm-­ vs. 19%; P 65 and CHF [11, 12]. However, it is important to remember that years of age, prior adjuvant anthracycline, cardiac risk facACE inhibitors and beta-blockers do not prevent anthracy- tors) [34]. However, pegylated liposomal doxorubicin was cline-induced myocyte apoptosis, but simply improve the associated with a higher incidence of palmar-plantar erythrodysesthesia (PPE; hand-foot syndrome) than conventional heart’s compensatory mechanisms [40]. doxorubicin (48% vs. 2%, respectively) [34]. Non-pegylated liposomal doxorubicin has also been demonstrated to have similar efficacy and be significantly less Dose Limitation and Schedule Modification cardiotoxic than conventional doxorubicin, in both anthracyTo minimise the risk of cardiotoxicity and CHF, the recom- cline-naïve patients and those who have received prior adjumended cumulative dose thresholds for doxorubicin and epi- vant anthracycline therapy [33, 35, 44]. In two prospective, rubicin are set at 20%); however, it should be taken into account that any degree of loss is of greater consequence in patients with a premorbid BMI