Supportive Oncology: (Expert Consult - Online and Print)

Supportive Oncology

Supportive Oncology Mellar P. Davis

MD, FCCP

Professor of Medicine Cleveland Clinic Lerner School of Medicine Case Western Reserve University Clinical Fellowship Director Palliative Medicine and Supportive Oncology Services Division of Solid Tumor Taussig Cancer Institute Cleveland Clinic Foundation Cleveland, Ohio

Petra Ch. Feyer

MD, PhD

Professor of Radiation Oncology Director, Clinic of Radiation Oncology Vivantes Clinics Berlin Neukoelln Berlin, Germany

Petra Ortner

PharmD, PhD

German Supportive Care in Cancer Group (ASORS) Pomme-med Medical Communication Munich, Germany

Camilla Zimmermann

MD, PhD, FRCPC

Head, Palliative Care Program Medical Director Lederman Palliative Care Centre Department of Psychosocial Oncology and Palliative Care Princess Margaret Hospital Associate Professor of Medicine Division of Medical Oncology and Hematology University of Toronto Scientist, Campbell Family Cancer Research Institute Ontario Cancer Institute Toronto, Ontario, Canada

1600 John F. Kennedy Blvd. Ste. 1800 Philadelphia, PA 19103-2899 SUPPORTIVE ONCOLOGY     ISBN: 978-1-4377-1015-1 Copyright © 2011 by Saunders, an imprint of Elsevier Inc. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher's permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. International Standard Book Number 978-1-4377-1015-1

Acquisitions Editor: Pamela Hetherington Publishing Services Manager: Patricia Tannian Team Manager: Radhika Pallamparthy Senior Project Manager: Claire Kramer Project Manager: Jayavel Radhakrishnan Designer: Louis Forgione

Printed in the United States of America Last digit is the print number:  9  8  7  6  5  4  3  2  1

We dedicate this book to our families in gratitude for their love and support: To my wife, Deborah, and my children Luke, Amanda, Meghan, Jessamyn, Emelin, and Lilian—Mellar Davis To Otto Josef — Petra Feyer To my daughter, Eva, and to my mother, Rose-Marie—Petra Ortner To my husband, Richard, and my children, Erica, Hendrik, and Karl—Camilla Zimmermann

Contributors 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 Duke University Medical Center Durham, North Carolina

Douglas G. Adler, MD

Associate Professor of Medicine Director of Therapeutic Endoscopy Gastroenterology and Hepatology University of Utah School of Medicine Huntsman Cancer Center Salt Lake City, Utah

Yesne Alici, MD

Attending Psychiatrist Geriatric Services Unit Central Regional Hospital Butner, North Carolina

Eugene Balagula, MD

Clinical Research Fellow Department of Dermatology Memorial Sloan-Kettering Cancer Center New York, New York

Chief, Psychiatry Service Vice Chairman Department of Psychiatry and Behavioral Sciences Memorial Sloan-Kettering Cancer Center New York, New York

Michael T. Brennan, DDS, MHS Associate Chairman Department of Oral Medicine Carolinas Medical Center Charlotte, North Carolina

Eduardo Bruera, MD

F.T. McGraw Chair in the Treatment of Cancer Medical Director Department of Palliative Care and Rehabilitation Medicine MD Anderson Cancer Center Houston, Texas

Resident Department of Radiation Oncology University of Toronto Princess Margaret Hospital Toronto, Ontario, Canada

Joseph R. Carver, MD

Doctoral Fellow Psychosocial Oncology and Palliative Care Princess Margaret Hospital University Health Network Toronto, Ontario, Canada

Director Cardiology Fellows Practice Chief of Staff Abramson Cancer Center Clinical Professor University of Pennsylvania Philadelphia, Pennsylvania

Julie R. Brahmer, MD, MSc

Harvey M. Chochinov, MD, PhD

Virginia Boquiren, MSc

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland

Consultant Assistant Professor Division of Respiratory and Critical Care Medicine Department of Medicine National University Heathcare System Singapore

Maureen E. Clark, MS

Raimundo Correa, MD

Amanda Caissie, MD, PhD

Palliative Care King's College London London, United Kingdom Assistant Medical Director Palliative Care Unit University Medical Center Freiburg Freiburg, Germany

Ai-Ping Chua, MMED (Int Med), MBBS

Robert Buckman, PhD, MB

Gerhild Becker, MD, MSc

Nikhil Banerjee, MD

Professor Department of Radiation Oncology University of Toronto Senior Scientist Sunnybrook Research Institute Chair of Rapid Response Radiotherapy Program and Bone Metastases Site Group Odette Cancer Centre Sunnybrook Health Sciences Centre Toronto, Ontario, Canada

Department of Oncology Haukeland University Hospital Bergen, Norway

University of Utah Salt Lake City, Utah

Johns Hopkins Hospital Baltimore, Maryland

Edward Chow, PhD, MSc, MBBS

Associate Director Center for Psycho-oncology and Palliative Care Research Dana-Farber Cancer Institute Boston, Massachusetts

Marianne Brydøy, MD

Medical Oncologist Princess Margaret Hospital Professor University of Toronto Toronto, Ontario, Canada Adjunct Professor MD Anderson Cancer Center University of Texas Austin, Texas

Ani Balmanoukian, MD

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William Breitbart, MD

Distinguished Professor Department of Psychiatry University of Manitoba Winnipeg, Manitoba, Canada

Department of Oncology Princess Margaret Hospital University of Toronto Toronto, Ontario, Canada

Kerry S. Courneya, PhD

Professor and Canada Research Chair in Physical Activity and Cancer Faculty of Physical Education and Recreation University of Alberta Edmonton, Alberta, Canada

David C. Currow, MD

Professor Palliative and Supportive Services Flinders University Chief Executive Officer Cancer Australia Adelaide, Australia

Shalini Dalal, MD

Assistant Professor Department of Palliative Care and Rehabilitation Medicine MD Anderson Cancer Center Houston, Texas

Contributors Mellar P. Davis, MD, FCCP

Professor of Medicine Cleveland Clinic Lerner School of Medicine Case Western Reserve University Clinical Fellowship Director Palliative Medicine and Supportive Oncology Services Division of Solid Tumor Taussig Cancer Institute Cleveland Clinic Foundation Cleveland, Ohio

Maike de Wit, MD, PhD

Professor, Medical Oncology Director, Clinic Hematology and Oncology Vivantes Clinics Berlin Neukoelln Berlin, Germany

Haryana Dhillon, PhD, MA(psych), BSc

Centre for Medical Psychology and Evidencebased Decision-making Central Clinical School Sydney Medical School and School of Psychology Faculty of Science University of Sydney Sydney, Australia

Mario Dicato, MD

Department of Hematology-Oncology Centre Hospitalier de Luxembourg Luxembourg, Luxembourg

Ingo J. Diel, MD, PhD

Institute for Gynecological Oncology Mannheim, Germany

Jason E. Dodge, MD, MEd

Gynecologic Oncologist Assistant Professor Department of OB/GYN Division of Gynecologic Oncology University of Toronto Princess Margaret Hospital University Health Network Toronto, Ontario, Canada

Matthew Doolittle, MD

Fellow in Psychosomatic Medicine Memorial Sloan-Kettering Cancer Center New York, New York

Wolfgang Dörr, DVM, PhD

Department for Radiotherapy and Radiation Oncology Medical Faculty Carl Gustav Carus Technical University of Dresden Dresden, Germany

Geoffrey P. Dunn, MD

Department of Surgery Palliative Care Consultation Service Hamot Medical Center Erie, Pennsylvania

Alexandra M. Easson, MSc, MD

Assistant Professor Department of Surgery University of Toronto General Surgery and Surgical Oncology Mount Sinai Hospital Princess Margaret Hospital Toronto, Ontario, Canada

Edzard K. Ernst, MD, PhD

Department of Complementary Medicine Peninsula Medical School University of Exeter Exeter, United Kingdom

Petra Ch. Feyer, MD, PhD

Professor of Radiation Oncology Director, Clinic of Radiation Oncology Vivantes Clinics Berlin Neukoelln Berlin, Germany

David R. Fogelman, MD

Assistant Professor Department of Gastrointestinal Medical Oncology Division of Cancer Medicine MD Anderson Cancer Center Houston, Texas

Sophie D. Fosså, MD

National Resource Center for Late Effects Department of Oncology Oslo University Hospital Montebello Oslo, Norway

Orit Freedman, MD, MSc

Medical Oncologist Durham Regional Cancer Centre Toronto, Ontario, Canada

Debra L. Friedman, MD, MS

Associate Professor of Pediatrics E. Bronson Ingram Chair in Pediatric Oncology Department of Pediatrics Vanderbilt University School of Medicine Nashville, Tennessee

Surafel Gebreselassie, MD

Department of Nephrology and Hypertension Cleveland Clinic Cleveland, Ohio

Thomas R. Gildea, MD, MS

Head Section of Bronchoscopy Respiratory Institute Department of Pulmonary Allergy and Critical Care Medicine and Transplant Center Cleveland Clinic Cleveland, Ohio

Marc Giovannini, MD, PhD Department of Paediatrics San Paolo Hospital University of Milan Milan, Italy

Paul A. Glare, MD

Chief, Pain and Palliative Care Service Memorial Sloan-Kettering Cancer Center New York, New York

Arin K. Greene, MD, MMSc

Department of Plastic and Oral Surgery Co-Director Lymphedema Program Children's Hospital Boston; Assistant Professor of Surgery Harvard Medical School Boston, Massachusetts

Janet R. Hardy, BSc, MD

Director of Palliative and Supportive Care Mater Health Services Brisbane, Australia

Daniel B. Hinshaw, MD

Section of Geriatrics and Palliative Care Program VA Ann Arbor Health Care System and Palliative Medicine Clinic University of Michigan Geriatrics Center Professor of Surgery University of Michigan Medical School Ann Arbor, Michigan

Ulrike Hoeller, MD

Associate Professor, Radiation Oncology Ambulatory Health Center of the Charité Berlin, Germany

Juliet Hou, MD

Department of Physical Medicine and Rehabilitation Cleveland Clinic Cleveland, Ohio

Lynn Jedlicka, MD

Department of Physical Medicine and Rehabilitation Cleveland Clinic Cleveland, Ohio

Siri Beier Jensen, DDS, PhD

Department of Oral Medicine, Clinical Oral Physiology, Oral Pathology and Anatomy Institute of Odontology Faculty of Health Sciences University of Copenhagen Copenhagen, Denmark

Katherine T. Johnston, MD, MA, MSc

Instructor of Medicine Harvard Medical School Beth Israel Deaconess Medical Center Breast Care Center and Women's Health Boston, Massachusetts

Jason M. Jones, MD

Department of Oncology Mayo Clinic Rochester, Minnesota

Karin Jordan, MD, PhD

Associate Professor, University of Halle/Saale Department of Oncology and Hematology Halle, Germany

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Contributors Karunakaravel Karuppasamy, MSc, MBBS Department of Radiology Cleveland Clinic Cleveland, Ohio

Raghid Kikano, MD, MS

Fellow Department of Neuroradiology University of Chicago Chicago, Illinois

Kenneth L. Kirsh, PhD

Assistant Professor in Pharmacy Practice and Science University of Kentucky College of Pharmacy Lexington, Kentucky

Cecilie Kiserud, MD

National Resource Center for Late Effects Department of Oncology Oslo University Hospital Montebello Oslo, Norway Buskerud University College Institute of Health Drammen, Norway

David W. Kissane, MD, MPM

Jimmie C. Holland Chair of Psycho-oncology Attending Psychiatrist and Chairman Department of Psychiatry and Behavioral Sciences Memorial Sloan-Kettering Cancer Center Professor of Psychiatry Weill Medical College of Cornell University New York, New York

Małgorzata Krajnik, MD

Department and Chair of Palliative Medicine Nicolaus Copernicus University in Torun Collegium Medicum Bydgoszcz, Poland

Christof Kramm, MD

University of Children's Hospital Department of Pediatrics and Adolescent Medicine Martin-Luther-University Halle-Wittenberg Halle, Germany

Sheldon Kwok, MD

Odette Cancer Centre Sunnybrook Health Sciences Centre Toronto, Ontario, Canada

Mario E. Lacouture, MD

Dermatology Service Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York

Abraham Levitin, MD

viii

Staff, Interventional Radiology Department of Radiology Cleveland Clinic Cleveland, Ohio

Madeline Li, MD, PhD

Psychiatrist Psychosocial Oncology and Palliative Care Princess Margaret Hospital University Health Network Assistant Professor Department of Psychiatry University of Toronto Toronto, Ontario, Canada

S. Lawrence Librach, MD, CCFP

Director Temmy Latner Centre for Palliative Care Mount Sinai Hospital, Toronto Professor and Head Division of Palliative Care Department of Family and Community Medicine University of Toronto Toronto, Ontario, Canada

Wendy G. Lichtenthal, PhD

Instructor Department of Psychiatry and Behavioral Sciences Memorial Sloan-Kettering Cancer Center New York, New York

Isador Lieberman, MD

Professor of Surgery Department of Orthopaedic Surgery Cleveland Clinic Foundation Cleveland, Ohio

Vernon W. H. Lin, MD

Department of Physical Medicine and Rehabilitation Cleveland Clinic Cleveland, Ohio

Hartmut Link, MD, PhD

Professor, Medical Oncology Director, Department of Internal Medicine, Hematology Oncology Westpfalz-Klinikum Kaiserslautern, Germany

Christopher Lo, PhD

Assistant Professor of Psychiatry University of Toronto Psychologist Department of Psychosocial Oncology and Palliative Care Princess Margaret Hospital University Health Network Toronto, Ontario, Canada

César V. Lopes, MD, PhD

Santa Casa Hospital Paoli-Calmettes Institute Porto Alegre, Rio Grande do Sul, Brazil

Charles L. Loprinzi, MD

Regis Professor of Breast Cancer Research Mayo Clinic Rochester, Minnesota

Amy E. Lowery, PhD

Chief Postdoctoral Research Fellow Department of Psychiatry and Behavioral Sciences Memorial Sloan-Kettering Cancer Center New York, New York

Robert Mader, MD

Division of Oncology Department of Medicine Medical University of Vienna Vienna, Austria

Henriette Magelssen, MD

National Resource Center for Late Effects Department of Oncology Oslo University Hospital Montebello Oslo, Norway

Vincent Maida, MD, MSc, BSc Assistant Professor University of Toronto Toronto, Ontario, Canada Clinical Assistant Professor McMaster University Hamilton, Ontario, Canada Division of Palliative Medicine William Osler Health System Toronto, Ontario, Canada

H. A. Marsman, MD

Department of Surgical Oncology Erasmus University Medical Center Daniel den Hoed Cancer Center Rotterdam, The Netherlands

Susan E. McClement, RN, PhD

Associate Professor Faculty of Nursing University of Manitoba Research Associate Manitoba Palliative Care Research Unit CancerCare Manitoba Winnipeg, Manitoba, Canada

Erin L. McGowan, PhD, MSc, BSc

Post-Doctoral Fellow, Kinesiology Canadian Cancer Society Research Institute University of Alberta Edmonton, Alberta, Canada

Daniel J. Moskovic, MD, MA, MBA Scott Department of Urology Baylor College of Medicine Houston, Texas Columbia University New York, New York

Marissa Newman, MD

Department of Dermatology Memorial Sloan-Kettering Cancer Center New York, New York

Contributors Tanya Nikolova, MD

Chief Fellow Pain and Palliative Care Service Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York

Jan Oldenburg, MD, PhD

National Resource Center for Late Effects Department of Oncology Oslo University Hospital Montebello Oslo, Norway

Petra Ortner, PharmD,

PhD

German Supportive Care in Cancer Group (ASORS) Pomme-med Medical Communication Munich, Germany

Dierdre R. Pachman, MD Department of Oncology Mayo Clinic Rochester, Minnesota

Jocelyn Pang, MD

Odette Cancer Centre Sunnybrook Health Sciences Centre Toronto, Ontario, Canada

Steven D. Passik, PhD

Associate Attending Psychologist Memorial Sloan-Kettering Cancer Center Associate Professor of Psychology Weill College of Medicine Cornell University Medical Center New York, New York

Timothy M. Pawlik, MD, MPH, FACS

Associate Professor of Surgery and Oncology Hepatobiliary Surgery Program Director Director Johns Hopkins Medicine Liver Tumor Center Multi-Disciplinary Clinic Co-Director of Center for Surgical Trials and Outcomes Research Johns Hopkins Hospital Baltimore, Maryland

Júlio C. Pereira-Lima, MD, PhD

Serviço de Endoscopia Digestiva Santa Casa de Caridade de Bagé Bagé, Rio Grande do Sul, Brazil

Douglas E. Peterson, DMD, PhD

Professor Oral Medicine Department of Oral Health and Diagnostic Sciences School of Dental Medicine Chair, Head and Neck Cancer and Oral Oncology Neag Comprehensive Cancer Center University of Connecticut Health Center Farmington, Connecticut

Barbara F. Piper, DNSc, RN, AOCN

Professor and Chair of Nursing Research Scottsdale Healthcare/University of Arizona Scottsdale, Arizona

Laurent Plawny, MD

Department of Hematology-Oncology Centre Hospitalier de Luxembourg Luxembourg, Luxembourg

Kathy Pope, MBBS (Hons)

Consultant Radiation Oncologist Division of Radiation Oncology Peter MacCallum Cancer Centre Melbourne, Victoria, Australia; Clinical/Research Fellow Palliative Radiation Oncology Program University of Toronto Division of Radiation Oncology Radiation Medicine Program Princess Margaret Hospital Toronto, Ontario, Canada

Jennifer Potter, MD

Director Women's Health Center Beth Israel Deaconess Medical Center Women's Health Program Fenway Health Associate Professor of Medicine Harvard Medical School Boston, Massachusetts

Holly G. Prigerson, PhD

Director Center for Psycho-oncology and Palliative Care Research Dana-Farber Cancer Institute Associate Professor of Psychiatry Brigham & Women's Hospital Harvard Medical School Boston, Massachusetts

Carla I. Ripamonti, MD

Head Supportive Care in Cancer Unit IRCCS Foundation National Cancer Institute Milano, Italy

Lizbeth Robles, MD

Resident Department of Neurology Cleveland Clinic Cleveland, Ohio

Gary Rodin, MD

Professor of Psychiatry University of Toronto University Health Network/University of Toronto Chair Psychosocial Oncology and Palliative Care Head Department of Psychosocial Oncology and Palliative Care Princess Margaret Hospital Toronto, Ontario, Canada

Lisa Ruppert, MD

The Rehabilitation Medicine Service Department of Neurology Memorial Sloan-Kettering Cancer Center New York, New York

Brenda M. Sabo, RN, BA, MA, PhD

Assistant Professor Dalhousie University School of Nursing Advance Practice Nurse Psychosocial Oncology Team Nova Scotia Cancer Centre Capital District Health Authority Halifax, Nova Scotia, Canada

Nadia Salvo, MD

Odette Cancer Centre Sunnybrook Health Sciences Centre Toronto, Ontario, Canada

Jose Fernando Santacruz, MD

Staff Physician Pulmonary, Critical Care Medicine, and Interventional Pulmonology Oncology Consultants International Cancer Center Houston, Texas

Josée Savard, PhD

Professor School of Psychology Université Laval Laval University Cancer Research Center Quebec City, Quebec, Canada

Carolyn C. Schook, BA

Harvard Medical School Children's Hospital Boston Boston, Massachusetts

Dale R. Shepard, MD, PhD

Associate Staff Solid Tumor Oncology Co-Director Taussig Oncology Program for Seniors (TOPS) Cleveland Clinic Taussig Cancer Institute Assistant Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University Cleveland, Ohio

Heather L. Shepherd, PhD, BA (Hons)

NHMRC Public Health Postdoctoral Research Fellow School of Public Health and Community Medicine University of New South Wales, Australia Centre for Medical Psychology and Evidence-based Decision-Making (CeMPED) School of Public Health University of Sydney Sydney, Australia

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Contributors Sumner A. Slavin, MD

Associate Clinical Professor Plastic Surgery Harvard Medical School Beth Israel Deaconess Medical Center Boston, Massachusetts

Martin L. Smith, STD

Director of Clinical Ethics Department of Bioethics Cleveland Clinic Cleveland, Ohio

Fred K. L. Spijkervet, DDS, PhD

Department of Oral and Maxillofacial Surgery University Hospital Groningen Groningen, The Netherlands

Glen H. J. Stevens, DO, PhD

Section Head Adult Neuro-Oncology Brain Tumor and Neuro-Oncology Center Neurologic Institute Cleveland Clinic Cleveland, Ohio

Michael D. Stubblefield, MD

Assistant Attending Physiatrist Rehabilitation Medicine Service Memorial Sloan-Kettering Cancer Center Assistant Professor of Rehabilitation Medicine Department of Physical Medicine and Rehabilitation Weill Medical College of Cornell University New York, New York

Nigel P. Sykes, MA

Consultant in Palliative Medicine St. Christopher's Hospice Honorary Senior Lecturer in Palliative Medicine King's College University of London London, United Kingdom

x

Matthew Tam, MD

The Radiology Academy Norfolk and Norwich University Hospital Norwich, United Kingdom

Martin H. N. Tattersall, MD, MSc Professor of Cancer Medicine Sydney Medical School University of Sydney Clinical Academic Sydney Cancer Centre Royal Prince Alfred Hospital Sydney, Australia

Mary L. S. Vachon, PhD, RN

Psychotherapist in Private Practice Professor Department of Psychiatry Dalla Lana School of Public Health University of Toronto Clinical Consultant Wellspring Toronto, Ontario, Canada

A. E. van der Pool, MD

Department of Surgical Oncology Erasmus University Medical Center Daniel den Hoed Cancer Center Rotterdam, The Netherlands

T. M. van Gulik, MD

Department of Surgery Academic Medical Center Amsterdam, The Netherlands

Janette Vardy, PhD, BMed (Hons) Sydney Cancer Centre University of Sydney Sydney, Australia Researcher-Clinician Cancer Institute NSW Eveleigh, Australia

Cornelis Verhoef, MD, PhD

Surgeon Department of Surgical Oncology Daniel den Hoed Cancer Center Erasmus Medical Center Rotterdam, The Netherlands

Arjan Vissink, DMD, MD, PhD

Department of Oral and Maxillofacial Surgery University Medical Center Groningen Groningen, The Netherlands

Hans-Heinrich Wolf, MD

Associate Professor, University Hospital Department of Oncology, Hematology, and Hemostaseology Halle, Germany

Rebecca K. S. Wong, MSc, MB, ChB Professor Department of Radiation Oncology University of Toronto Princess Margaret Hospital Toronto, Ontario, Canada

Camilla Zimmermann, MD, PhD, FRCPC

Head Palliative Care Program Medical Director Lederman Palliative Care Centre Department of Psychosocial Oncology and Palliative Care Princess Margaret Hospital Associate Professor of Medicine Division of Medical Oncology and Hematology University of Toronto Scientist Campbell Family Cancer Research Institute Ontario Cancer Institute Toronto, Ontario, Canada

Zbigniew Zylicz, MD

Consultant in Palliative Medicine Dove House Hospice Hull, United Kingdom

Foreword The new specialty of medical oncology emerged in the aftermath of World War II. Since then, it has expanded rapidly around the world as a vibrant and important area of specialist medicine. By definition, it often involves the care of people with cancer that recurred after definitive primary therapy or that presented de novo with metastatic disease. Because of advances in therapy and prevention, death from cancer in industrialized countries has declined, even as incidence has continued to increase. The latter is partly due to aging of the population; cancer is, in part, a disease of the aging process. In addition, lifestyle choices have a significant impact. Development of medical oncology was driven by the belief that cancer could be cured even when metastatic. Dramatic improvements in mortality (particularly pediatric oncology) have been obtained in some diseases. Over the same time frame, there have been dramatic improvements in medical technology with benefits in common structural complications of metastatic cancer. Examples include stenting techniques for gastrointestinal malignancies and sophisticated approaches to management of pleural effusions. Surgical oncology, oncology nursing, psychosocial oncology, and multidisciplinary care have also emerged as new allied areas of endeavor. It is still true that in most patients who are referred to a medical oncologist, death is a frequent (although not always explicitly recognized) outcome. Unfortunately, most common solid tumors remain incurable once they metastasize. In medical oncology, an early commitment was made to structured investigation of new therapies. The vehicle for this this has been through clinical trials. This discipline has made a major impact on diseases such as breast cancer and multiple myeloma. There has been some debate that other advances in imaging and laboratory medicine have contributed to the apparent increased duration of survival (because of earlier diagnosis). Nevertheless, there seems little doubt that the systematic use of clinical trials has been of therapeutic benefit for many patients and has improved clinical care. An important part of clinical trial methodology is the assessment of therapeutic toxicity. This allows the medical oncologist to carefully balance the potential benefits of therapy against its adverse effects. Therefore, we have come to realize that chemotherapy and radiation therapy are often blunt instruments. They can be associated with significant, sometimes life-threatening morbidity. Some of these effects are nonspecific, and others are particular to the therapeutic modality or specific drug used. Certain levels of morbidity have been considered acceptable (or inevitable) and part of the price for attempting to cure a

catastrophic illness. Examples include the complications associated with certain high-dose chemotherapy regimens for breast cancer and those seen in patients after bone marrow transplant. The morbidity experienced during active treatment includes significant psychological and physical symptoms, emotional and financial distress, family dysfunction, and work and career disruption. In addition, such toxicities may be prolonged in nature beyond the treatment time frame and may be responsible for significant long-term morbidity or development of new diseases. Among those who survive cancer, there are significant effects on quality of life and residual issues, such as sexual dysfunction, that disrupt life long after cancer has been cured. In addition, the response rates to many common therapies are still disappointing, toxicity is notable, and nonresponders are often exposed to significant morbidity without any therapeutic benefit. As the field of medical oncology progressed, certain common complications of cancer therapy, such as infections, were identified as requiring systematic attention. Later, the problems of nausea and vomiting associated with cis-platinum chemotherapy arose as another challenge. It was quickly realized that sophisticated management of these and the many other complications of therapeutic intervention was important in themselves as clinical challenges. Better management would also allow regimens to be administered most effectively. It also became apparent that the benefits to the patient were additive by improved quality of life, reduced hospitalization, and mitigated emotional and physical distress. In addition to the practical clinical benefits, a rigorous approach to the investigation and management of these common problems required significant academic endeavor. This field is now what is known as Supportive Oncology. This major new book about supportive oncology is a timely recognition of the practical relevance, academic rigor, and increasing sophistication of the field. Supportive oncology is now recognized as an important part of practice in all areas of clinical oncology, with many benefits to the millions of people around the world in whom cancer is diagnosed every year. It can also rightly be seen as a sister specialty to another modern development, Palliative Medicine. Modern care of the cancer patient is a multidisciplinary endeavor, and everyone involved in the field will benefit from access to the wisdom and ­perspectives of this exciting new book. T. Declan Walsh, MD

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Preface We are pleased to present this first edition of Supportive Oncology. The aim of supportive oncology is to minimize the physical, psychosocial, and spiritual suffering caused by ­cancer and the adverse effects of its treatment to ensure the highest possible quality of life for patients and their families. We believe that this book fulfills a unique need by providing a guide to supportive oncology throughout the cancer trajectory, from diagnosis to survivorship or bereavement. The book is based on an integrative model of care. We posit that supportive, rehabilitative, and palliative care measures should accompany patients throughout their course of disease and should be taken into account in the treatment goal in every situation, from diagnosis until cure or death. A well-defined integrative supportive care model should be included in every treatment protocol for cancer care. Supportive measures should be tailored to the special treatment or illness situation and must also reflect the wishes and needs of the patient. This book is a collaborative venture including not only ­oncologists, but also palliative care physicians, nurses, ­pharmacists, psychologists, and psychiatrists. It is also an international collaboration, with editors from the United States, Canada, and Germany and contributors from across the globe. We are fortunate to have the contribution of many international experts in their respective fields and are grateful for their excellent contributions to this book. This book is intended as a comprehensive resource for all oncology practitioners to assist in the management of physical and psychosocial symptoms and concerns throughout the illness trajectory. It is a useful resource for medical, radiation, and surgical oncologists; palliative medicine specialists; and

oncology nurses. In addition, this book serves as a guide to supportive oncology for primary care practitioners and other health care workers seeking detailed, practical information on the supportive management of patients with cancer. The fifty-nine chapters are organized into six sections: management of treatment-related adverse effects, management of tumor-related symptoms, management of complications in the palliative setting, rehabilitation and survivorship, communication and decision making, and psychosocial oncology. The organization of the book reflects the fact that supportive oncology encompasses symptoms and complications related to treatment, as well as those arising as a consequence of the malignancy. The section on rehabilitation and survivorship acknowledges the reality that cancer care continues after the cancer has been cured and addresses the important aspects of late effects of treatment, as well as ongoing recovery and rehabilitation The section on communication addresses decision making and supportive processes throughout the cancer trajectory. The psychosocial care not only of patients but also of professional caregivers is highlighted in the final section. We wish to express our sincere gratitude to all the contributors to this book. We also extend our thanks to the editorial staff at Elsevier, particularly Pamela Hetherington, who guided us through this project with patience and perseverance. Mellar P. Davis Petra Ch. Feyer Petra Ortner Camilla Zimmermann

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1

Chemotherapy extravasations (cutaneous and mucosal) Maike de Wit and Robert Mader

Prevalence and pathophysiology  2

Other pharmaceutical interventions  6

Definition  2

Quality control and quality assurance  7

Risk factors  3

Open questions  7

Risk factors associated with the individual patient  3

Summary for daily practice  8

Risk factors associated with the drug  3 Risk factors associated with the medical staff  3 Risk caused by the intravenous access  4 Diagnosis  4 Differential diagnosis  4 Flare reaction  4 Recall phenomenon  5 Photosensitivity  5

Although intravenous drug administration is a basic requisite and daily routine for every physician, extravasation has been observed with a variety of agents, including electrolyte solutions, contrast media, blood products such as red blood cells, heparins, phenytoin, and cytotoxics. The incidence and extent of injury are functions of localization, extravasating substance, absolute amount and concentration of the drug, and remedial action. Every physician should be aware of specific problems associated with different administration sites such as the back of the hand or foot and the inside of the elbow.

Interventions  5 General nonpharmacologic management  5 Pharmacologic management  5 Amsacrine, mitomycin c, mitoxantrone, dactinomycin  5 Vinca alkaloids and etoposide  5 Cisplatinum  5 Anthracyclines  6 Specific measures  6 Dry cold  6 Dry heat  6 Antidota  6 Dimethylsulfoxide (DMSO)  6 Hyaluronidase  6 2

Dexrazoxane, the first approved antidote  6

PREVALENCE AND PATHOPHYSIOLOGY Accidental extravasation of cytotoxic agents is a relatively rare complication, with an incidence varying between 0%, 1%, and 5%.1–3 In a recent survey of the MD Anderson Institute, 44 extravasations were observed in 40 to 60,000 chemotherapies during the same time period. Twelve extravasations included doxorubicin, and 10 of them needed surgical intervention.4 Because of smaller vessels and more complicated venous access, extravasation is more common among children and is observed in up to 11%.5 Obviously, only incidents identified by staff or patient are included.

DEFINITION Extravasation is the process of unintentional instillation of a given infusion or injection, passing out of a vessel into ­surrounding tissue such as subcutaneous fat, underlying connective tissue, or muscle. Consequences depend on local drug effects and have been shown to be especially disastrous for some anticancer cytostatic agents, causing severe tissue damage within hours, days, or even months.

Chemotherapy extravasations (cutaneous and mucosal)

RISK FACTORS The multiple risk factors can be divided in patient related, drug related, medical staff related (iatrogenic), or related to the intravenous access.

RISK FACTORS ASSOCIATED WITH THE INDIVIDUAL PATIENT Frequency and extent of damage vary with different locations. Peripheral veins at the back of the hand, the dorsum of the foot, or the inside of an elbow are more vulnerable. If veins have been used several times already, 6 or if they are small and fragile7 or are located near nerves, tendons, and arteries (e.g., of the hand), problems occur more frequently. Older patients and patients with sclerosis or smaller vessels suffer more damage from extravasations. The same is true for patients with higher venous pressure following thrombosis, 8 right cardiac insufficiency,7 mediastinal tumors,9 or a vena cava superior syndrome due to other reasons. Extremities with lymph edema following lymphadenectomy,10 radiotherapy,11 or problems like thrombophlebitis, venous spasms, or generalized vascular diseases like Raynaud's syndrome 7 hinder uncomplicated intravenous drug application. Patients with neurologic deficits like reduced sensitivity due to diabetes or ­chemotherapy-induced polyneuropathy 11 may report extravasation too late, and this results in more extensive tissue damage. The probability of extravasation, attitudes that can help to avoid them, and signs and symptoms of early detection of an extravasation should be completely explained to the patient. Informed patients are more compliant, usually keep their arms immobilized to avoid extravasation, and inform nurses earlier, thus reducing the amount of extravasated drug. Restless patients with neurologic disorders or lack of understanding such as children,12 psychotic patients, or patients with dementia suffer more problems related to intravenous access.

RISK FACTORS ASSOCIATED WITH THE DRUG Tissue injury is caused by the drug itself (e.g., with anthracycline extravasation),13,14 but sometimes it is caused by additives like solvents.15 Cytotoxic agents are divided into three groups according to the damage potential of the respective drug: vesicant, irritant, or nontoxic (Table 1-1). For grading, only low-level evidence, mostly based on case reports and new drugs, has to be observed carefully. Additional risk arises from osmolarity and pH value (e.g., undiluted 5-fluorouracil) as alkaline infusion (pH 9). Larger amounts of cytotoxic extravasation, longer exposure,16 or hypersensitivity exponentiates tissue reaction.

RISK FACTORS ASSOCIATED WITH THE MEDICAL STAFF Because intravenous devices are associated with a risk of extravasation, chemotherapy should be administered by experienced staff only. Insufficient puncture skills lead to higher

Table 1-1  Graduation of necrotizing potential High risk of ulceration (vesicans) Amsacrine Carmustine1 Cisplatin (concentration >0.4 mg/ml) Dactinomycin Daunorubicin Docetaxel1 Doxorubicin Epirubicin Idarubicin Mitomycin C Mitoxantrone Oxaliplatin1 Paclitaxel1 Vinblastine Vincristine Vindesin Vinflunin* Vinorelbine

Irritating; rarely necrotizing (irritans)

Low/No risk of inflammation

Bendamustine Busulfan Carboplatin1 Cisplatin 10%), have been performed to overcome the painful feeling of tightness in the extremity. This approach is not recommended generally, but it can be useful in special cases, such as with extravasation of a highly vesicant compound at the dorsum of the hand or from a central venous device.

PHARMACOLOGIC MANAGEMENT AMSACRINE, MITOMYCIN C, MITOXANTRONE, DACTINOMYCIN Extravasation of these substances demands immediate dry local cooling for at least 1 hour and continuation for some days several times daily, 15 minutes each time. Topical use of dimethylsulfoxide (DMSO) 99% 4 to 6 times daily is recommended for at least 7 days. Experience with dexrazoxane has not been reported with these cytotoxic agents.

VINCA ALKALOIDS AND ETOPOSIDE Perilesional hyaluronidase is injected subcutaneously or intradermally (1500 IU/ml in 10 ml NaCl), starting from the periphery and moving toward the center.54 Specific measures include dry heat (no hot humidity!) for 1 hour the first time, then 4 times daily for 20 minutes each time.

CISPLATINUM The toxicity of cisplatinum varies with concentration. Concentrations exceeding 0.4 mg/ml require specific management involving dry local cooling for at least 1 hour. This

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should be continued several (4 to 6) times daily for 15 minutes each time (e.g., DMSO 99% 4 to 6 times daily for at least 7 days).55,56

ANTHRACYCLINES Anthracycline extravasation may lead to progressive destruction of tissues such as nerves, vessels, tendons, and muscles, causing pain for a long time and possible permanent functional defects. Sometimes chemotherapy has to be interrupted, and hospitalization is necessary. Immediate pain, edema, and erythema are followed by vesication and induration with atrophic skin and ulceration 1 to 4 weeks later. The ulceration keeps growing for months, showing few tendencies toward spontaneous recovery but with the potential to destroy underlying structures. In addition, pain contractures, dystrophy, and functional loss of the extremity may follow. Small extravasations are often observed, leading to slowly growing ulcerations and the possible need for more aggressive strategies. Overall, surgical intervention is necessary during follow-up in 35% to 40% of cases. On the other hand, surgical results are best for excisions made within 8 hours but not later than 1 week after extravasation. The need for wide margins free of anthracyclines can be verified by fluorescence microscopy, especially before skin transplantation. Small uncontrolled series support conservative therapy but do not provide histologic verification. Although several therapeutic interventions have been tested in the past, the standard procedure so far consists of cooling in combination with topical DMSO 99%. In 2006, dexrazoxane (Savene) was the first approved antidote for treatment of anthracycline extravasation. Approval of dexrazoxane (Savene) was based on two series that reported a 98% success rate (i.e., in 54 cases of anthracycline extravasation confirmed by fluorescence microscopy, one surgical intervention was necessary). Chemotherapy was not delayed. Dexrazoxane must be infused as soon as possible, but not later than 6 hours after extravasation, using a new intravenous access. Local cooling has to be stopped at least 15 minutes before the first infusion and should not be initiated again. Application of DMSO in combination with dexrazoxane has not been approved. For 3 consecutive days, dexrazoxane is infused daily: 1000 mg/m2 on days 1 and 2, and 500 mg/m2 on the third day, for a maximum overall dose of 2000 mg each day.57,58 Upon reviewing the data on more than 100 extravasations with anthracyclines, the authors determined that around 40% of extravasations are discovered only one or several days after the event itself. In these cases, the use of topical cooling combined with DMSO is still recommended.

SPECIFIC MEASURES Immediate action is essential. Application of local warmth and cold is decided according to the cytotoxic agent. With most cytotoxic agents, low temperature slows diffusion and is beneficial, whereas with vinca alkaloids, cooling is never indicated because dry heat favors systemic resorption of vinca alkaloids.

Dry cold Use with anthracyclines (if not using dexrazoxane), cisplatinum, amsacrine, mitomycin C 6 l Initial duration of 1 hour, with topical cooling with cold packs l

Several times daily 15 minutes each time, with topical cooling for at least 1 week l Including DMSO, with the exception of liposomal daunorubicin and liposomal doxorubicin l Do not use DMSO when giving dexrazoxane. l

Dry heat l l l l

Vinca alkaloids Initial duration 1 hour with hot packs Several times daily at 15 minutes each for at least 1 week Do not use with DMSO.

ANTIDOTA

Dimethylsulfoxide (DMSO) The 99% solution enhances permeability of the skin, leading to better systemic absorption (application over 8 days every 8 hours with stippling and air drying). DMSO is a solvent that is not approved for use as medicine in humans.

Hyaluronidase The enzyme hyaluronidase loosens the structure of connective tissue. The exposed region is injected around the paravasate lesion with 10 ml of 1500 IU/ml hyaluronidase. The burning pain that results is alleviated with local anesthetics. Consideration of pain against benefit favors the treatment. With vinca alkaloids, hyaluronidase is combined with dry heat, but not with taxanes.

Dexrazoxane, the first approved antidote The registration of dexrazoxane as a novel antidote to anthracyclines was a consequence of its effective performance in preclinical and clinical studies. Clinical data obtained in registration trials were convincing, with a single patient requiring surgical intervention, while 53 recruited patients with histologically verified extravasation recovered completely with conservative management only.58 Nevertheless, several issues have not been addressed in these studies. First of all, it is not clear how the effectiveness of dexrazoxane compares with that of the highly established clinical use of DMSO/topical cooling, although the latter has not been approved for treatment of human patients. This reliable procedure has been tested in a prospective clinical trial under very similar circumstances (equal numbers of patients and very similar success rates), clearly proving that DMSO/topical cooling is an effective antidote for the management of anthracycline extravasation.59 The serious flaw in the dexrazoxane study design indicates that we have lost an opportunity to directly compare the effectiveness of the two antidotes. Other factors associated with the use of dexrazoxane include (1) that IV dexrazoxane is an invasive procedure requiring hospitalization over 3 days, and (2) that a higher rate of side effects is seen with dexrazoxane (elevation of liver enzymes and bilirubin) when compared with DMSO/ cooling.

OTHER PHARMACEUTICAL INTERVENTIONS Use of steroids is debatable; natrium thiosulfate and bicarbonate are no longer recommended.

Chemotherapy extravasations (cutaneous and mucosal)

Quality control and quality assurance Although extravasation of cytotoxic agents is one of the rarer complications of chemotherapy, severe complications may result, particularly after extravasation of vesicants. Prevention and appropriate management are therefore essential to avoid sequelae. In this regard, quality control and quality assurance contribute to both prevention and extravasation management and should be implemented in all oncologic centers. The following issues related to quality of care are considered to be essential: information and education for patients, training for medical and nursing staff, an emergency number for consulting an experienced physician, interdisciplinary cooperation, implementation of guidelines, documentation of all extravasation events (even if only suspected), and knowledge management. Regular training sessions help to raise sensitivity and awareness among medical and nursing staff. At the same time, they impart the knowledge necessary to promptly deliver an appropriate intervention in an emergency situation. To support therapeutic staff members of the hospital, an experienced physician should be appointed as emergency consultant in case of extravasation. His responsibilities should include management of acute situations (“first aid”) with information, communication, supervision of patient documentation, and coordination of the rescue procedure. The hospital pharmacy should provide an extravasation kit. It is highly recommended that guidelines be established and regularly updated to provide scientifically based recommendations with a focus on clinical practice. Deviations from these guidelines require sound reasoning and appropriate documentation. Besides the usefulness of standardized procedures (SOPs) in emergency situations, it is increasingly important to be prepared for questions of legal liability. Guidelines should include a registry of relevant substances, risk factors, prophylaxis, symptoms, and general and special therapeutic measures, as well as components of an extravasation kit (Table 1-2) and an extravasation report form. Standardized patient documentation is crucial for evaluating outcomes and should include the following: description of events, amount and concentration of extravasated substance, symptoms, measures taken, further developments/sequelae, aftercare, and outcomes (templates may be retrieved from <www.extravasation.at>). Because almost no prospective clinical studies on extravasation of cytotoxic drugs have been

Table 1-2  Table with overview for orientation • Drugs and necrotizing risk (grades 1 to 3) • General procedures • Drug-specific procedures • Cold-hot packs (Cold/Hot 10 × 26) • At least two • Swabs, sterile, minimum two sets with four swabs each • DMSO (e.g., dimethylsulfoxide 99% [Merck Art. Nr. 16743]) • Hyaluronidase (HYLASE 150 IE) 10 amp • Dexrazoxane 500 mg (10 vials) (Savene 10 vials with 500 mg and three bags Savene diluent) should be available on demand at the pharmacy or another central point within 4 hours to be administered within 6 hours. • Extravasation report form

conducted, our current knowledge is based primarily on lowlevel evidence. As long as this unsatisfactory situation persists, knowledge management is essential to gain experience and to share information.60

Open questions In terms of extravasation, the focus should be on preventive measures proposed as a catalogue of the most important questions that should be asked before therapy is initiated. This checklist includes questions about the vascular condition of a patient, hyposensitivities or hypersensitivities, previous therapies, polyneuropathy or medications reducing perception, patient compliance, and others. Knowledge of these risk factors provides the basis for preventive measures and contributes to early detection, thus warranting our full attention. The type of damage associated with novel cytotoxic agents usually requires an experienced clinician to determine its final classification. It may take years to obtain sufficient clinical information to properly assess cutaneous and tissue toxicity. Even after years of clinical use, some antineoplastic agents (e.g., busulfan, estramustine) are not conclusively classified. Although much pharmaceutical knowledge is available, it is not possible to extrapolate tissue toxicity on the basis of physicalchemical attributes. One possible approach would be to evaluate acute tissue toxicity, including vesicant potential, during the approval procedure of a novel substance, as has already been envisaged by the guidelines of the European Agency for the Evaluation of Medicinal Products (EMEA). From a clinical perspective, it would be helpful to explicitly define these requirements for extravasation by testing local and cutaneous tolerance. This information should be included in the summary of the product characteristics to inform physicians about the tissue toxicity of newly approved compounds, even before their first use. Extravasations are not always noticed instantly. According to the literature, the delay is often longer than 5 days, thus raising the following question: How much time may lapse before antidotes are no longer effective? Antidotes have been tested immediately following the extravasation event, but animal studies have shown that the efficacy of dexrazoxane against anthracyclines persists for at least 3 hours after extravasation and is clearly reduced against daunorubicin after 6 hours. Even smaller time windows seem to apply to the antidote hyaluronidase. For this reason, informing patients, in addition to regular monitoring of the infusion, is of such crucial importance: Early detection is the key when time is critical. Pathologic changes that occur in damaged tissue have not yet been sufficiently characterized. This lack of knowledge explains the ongoing discussion about the use of corticosteroids. Although we know that inflammation is not the prevailing process after extravasation, the literature still proposes the use of corticosteroids. The evidence needed can be achieved through cooperation with pathologists and examination of human tissue samples. New therapeutic developments will change the pharmacologic landscape fundamentally over the next 15 years. In addition to antihormonal substances, which most often are given orally, molecular and targeted therapies will complement and substitute for traditional cytotoxic agents. These compounds hardly possess vesicant potential—most probably, not even irritant effects. Today's trend toward peroral formulations will increase (e.g., cytotoxic agents like vinorelbine or ­temozolomide; 7

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oral tyrosine kinase inhibitors such as lapatinib, ­erlotinib, sorafenib, and others). Potentially toxic local taxanes such as paclitaxel will be used in polymer-bound form with reduced local toxicity, similar to the liposomal formulations of daunorubicin, doxorubicin, and vincristine. Monoclonal humanized antibodies are used increasingly often in oncology (e.g., rituximab, trastuzumab, bevacizumab, cetuximab). Thanks to these molecular therapeutic drugs, extravasation may become a less dreaded complication of chemotherapy. Notwithstanding, we should not forget that cytotoxic drugs will certainly remain the cornerstone of cancer therapy in less developed countries

and will continue to do serve this purpose in our hospitals for the upcoming years.

SUMMARY FOR DAILY PRACTICE Prophylaxis of extravasation is essential, as are instruction of patients, guidelines for physicians, and immediate action in cases of extravasation. If you have doubts or lack experience, do not lose time; get a specialist involved immediately. Appropriate and quick initiation of treatment is crucial.

REFERENCES

8

1. Laughlin RA, Landeen JM, Habal MB. The management of inadvertent subcutaneous Adriamycin infiltration. Am J Surg. 1979;137:408–412. 2. Cox K, Stuart-Harris R, Abdini G, et al. The management of cytotoxic-drug extravasation: guidelines drawn up by a working party for the Clinical Oncological Society of Australia. Med J Aust. 1988;148:185–189. 3. Barlock AL, Howser DM, Hubbard SM. Nursing management of Adriamycin extravasation. Am J Nurs. 1979;79:94–96. 4. Langstein HN, Duman H, Seelig D, et al. Retrospective study of the management of chemotherapeutic extravasation injury. Ann Plast Surg. 2002;49:369–374. 5. Brown AS, Hoelzer DJ, Piercy SA. Skin necrosis from extravasation of intravenous fluids in children. Plast Reconstr Surg. 1979;64:145–150. 6. Linder RM, Upton J. Prevention of extravasation injuries secondary to doxorubicin. Postgrad Med. 1985;77:105. 7. Ignoffo RJ, Friedman MA. Therapy of local toxicities caused by extravasation of cancer chemotherapeutic drugs. Cancer Treat Rev. 1980;7:17–27. 8. Larson DL. Treatment of tissue extravasation by antitumor agents. Cancer. 1982;49:1796–1799. 9. Jordan K, Grothe W, Schmoll HJ. Extravasation of chemotherapeutic agents: prevention and therapy. Dtsche Med Wochenschr. 2005;130:33–37. 10. Bowers DG, Lynch JB. Adriamycin extravasation. Plast Reconstr Surg. 1978;61:86–92. 11. Mullin S, Beckwith MC, Tyler LS. Prevention and management of antineoplastic extravasation injury. Hosp Pharm. 2000;35:57–76. 12. Upton J, Mulliken JB, Murray JE. Major intravenous extravasation injuries. Am J Surg. 1979;137:497–506. 13. Richardson DS, Johnson SA. Anthracyclines in haematology: preclinical studies, toxicity and delivery systems. Blood Rev. 1997;11:201–223. 14. Cox RF. Managing skin damage induced by doxorubicin hydrochloride and daunorubicin hydrochloride. Am J Hosp Pharm. 1984;41:2410–2414. 1 5. Larson DL. Treatment of tissue extravasation by anti-tumor agents. Cancer. 1982;49:1796–1799. 16. Reilly JJ, Neifeld JP, Rosenberg SA. Clinical course and management of accidental Adriamycin extravasation. Cancer. 1977;40:2053–2056. 17. Preuss P, Partoft S. Cytostatic extravasations. Ann Plast Surg. 1987;19:323–329. 18. Linder RM, Upton J, Osteen R. Management of extensive doxorubicin hydrochloride extravasation injuries. J Hand Surg (Am). 1983;8:32–38.

19. Lynch DJ, Key JC, White RR. Management and prevention of infiltration and extravasation injury. Surg Clin North Am. 1979;59:939–949. 20. MacCara ME. Extravasation: a hazard of intravenous therapy. Drug Intell Clin Pharm. 1983;17:713–717. 21. Anderson CM, Walters RS, Hortobagyi GN. Mediastinitis related to probable central vinblastine extravasation in a woman undergoing adjuvant chemotherapy for early breast cancer. Am J Clin Oncol. 1996;19:566–568. 22. Schummer W, Schummer C, Schelenz C. Case report: the malfunctioning implanted venous access device. Br J Nurs. 2003;12:210, 212–220. 23. Barutca S, Kadikoylu G, Bolaman Z, et al. Extravasation of paclitaxel into breast tissue from central catheter port. Support Care Cancer. 2002;10:563–565. 24. Ener RA, Meglathery SB, Styler M. Extravasation of systemic hemato-oncological therapies. Ann Oncol. 2004;15:858–862. 25. Gebarski SS, Gebarski KS. Chemotherapy port “Twiddler's syndrome.” A need for preinjection radiography. Cancer. 1984;54:38–39. 26. Hofer S, Schnabel K, Vogelbach P, et al. The “pinch off” syndrome: a complication of implantable catheter systems in the subclavian vein. Schweiz Med Wochenschr. 1997;127:1247–1250. 27. Aitken DR, Minton JP. The “pinch-off sign”: a warning of impending problems with permanent subclavian catheters. Am J Surg. 1984;148:633–636. 28. Hinke DH, Zandt-Stastny DA, Goodman LR, et al. Pinch-off syndrome: a complication of implantable subclavian venous access devices. Radiology. 1990;177:353–356. 29. D'Silva K, Dwivedi AJ, Shetty A, et al. Pinch-off syndrome: a rare complication of totally implantable venous devices. Breast J. 2005;11:83–84. 30. Biffi R, Orsi F, Grasso F, et al. Cenciarelli S, Andreoni B. Catheter rupture and distal embolisation: a rare complication of central venous ports. J Vasc Access. 2000;1:19–22. 31. Louie AC, Issell BF. Amsacrine (AMSA)—a clinical review. J Clin Oncol. 1985; 3:562–592. 32. Case Jr DC. Prevention of amsacrine-induced phlebitis with heparin. Clin Pharm. 1982; 1:490. 33. Weiss RB, Bruno S. Hypersensitivity reactions to cancer chemotherapeutic agents. Ann Intern Med. 1981;94:66–72. 34. Cornwell III GG, Pajak TF, McIntyre OR. Hypersensitivity reactions to IV melphalan during treatment of multiple myeloma: Cancer and Leukemia Group B experience. Cancer Treat Rep. 1979;63:399–403.

35. Haskell CM, Canellos GP, Leventhal BG, et al. Hansen HH. L-asparaginase toxicity. Cancer Res. 1969;29:974–975. 36. Markman M. Management of toxicities associated with the administration of taxanes. Expert Opin Drug Saf. 2003;2:141–146. 37. Vogelzang NJ. “Adriamycin flare”: a skin reaction resembling extravasation. Cancer Treat Rep. 1979;63:2067–2069. 38. Koppel RA, Boh EE. Cutaneous reactions to chemotherapeutic agents. Am J Med Sci. 2001;321:327–335. 39. Burdon J, Bell R, Sullivan J, et al. Adriamycininduced recall phenomenon 15 years after radiotherapy. JAMA. 1978;239:931. 40. Yeo W, Leung SF, Johnson PJ. Radiation-recall dermatitis with docetaxel: establishment of a requisite radiation threshold. Eur J Cancer. 1997;33:698–699. 41. Gabel C, Eifel PJ, Tornos C, et al. Radiation recall reaction to idarubicin resulting in vaginal necrosis. Gynecol Oncol. 1995;57:266–269. 42. McCarty MJ, Peake MF, Lillis P, et al. Paclitaxelinduced radiation recall dermatitis. Med Pediatr Oncol. 1996;27:185–186. 43. Fontana JA. Radiation recall associated with VP-16213 therapy. Cancer Treat Rep. 1979;63:224–225. 44. Castellano D, Hitt R, Cortes-Funes H, et al. Side effects of chemotherapy. Case 2. Radiation recall reaction induced by gemcitabine. J Clin Oncol. 2000;18:695–696. 45. Camidge DR. Methotrexate-induced radiation recall. Am J Clin Oncol. 2001;24:211–213. 46. Nemechek PM, Corder MC. Radiation recall associated with vinblastine in a patient treated for Kaposi sarcoma related to acquired immune deficiency syndrome. Cancer. 1992;70:1605–1606. 47. Kitani H, Kosaka T, Fujihara T, et al. The “recall effect” in radiotherapy: is subeffective, reparable damage involved? Int J Radiat Oncol Biol Phys. 1990;18:689–695. 48. Camidge R, Price A. Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol. 2001;59:237–245. 49. Iwamoto T, Hiraku Y, Okuda M, et al. Mechanism of UVA-dependent DNA damage induced by an antitumor drug dacarbazine in relation to its photogenotoxicity. Pharm Res. 2008;25: 598–604. 50. Douglas KT, Ratwatte HA, Thakrar N. Photoreactivity of bleomycin and its implications. Bull Cancer. 1983;70:372–380. 51. Goldfeder KL, Levin JM, Katz KA, et al. Ultraviolet recall reaction after total body irradiation, etoposide, and methotrexate therapy. J Am Acad Dermatol. 2007;56: 494–499.

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Chemotherapy extravasations (cutaneous and mucosal) 52. Pascu ML, Staicu A, Voicu L, et al. Methotrexate as a photosensitiser. Anticancer Res. 2004;24:2925–2930. 53. Ee HL, Yosipovitch G. Photo recall phenomenon: an adverse reaction to taxanes. Dermatology. 2003;207:196–198. 54. Bertelli G, Dini D, Forno GB, et al. Hyaluronidase as an antidote to extravasation of Vinca alkaloids: clinical results. J Cancer Res Clin Oncol. 1994;120: 505–506.

55. Dorr RT. Antidotes to vesicant chemotherapy extravasations. Blood Rev. 1990;4:41–60. 56. Louvet C, Bouleuc C, Droz JP. Tissue complications of cisplatin extravasation. Presse Med. 1989;18:725–726. 57. Jensen JN, Lock-Andersen J, Langer SW, et al. A promising antidote in the treatment of accidental extravasation of anthracyclines. Scand J Plast Reconstr Surg Hand Surg. 2003;37:174–175. 58. Mouridsen HT, Langer SW, Buter J, et al. Treatment of anthracycline extravasation

with Savene (dexrazoxane): results from two prospective clinical multicentre studies. Ann Oncol. 2007;18:546–550. 59. Bertelli G, Gozza A, Forno GB, et al. Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study. J Clin Oncol. 1995;13:2851–2855. 60. Mader I, Fürst-Weger PR, Mader RM, et al. Extravasation of cytotoxic agents. 2nd ed. New York: Springer; 2009.

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Allergic reactions to chemotherapy Dale R. Shepard

What is a systemic allergic reaction?  10 Types and mechanisms of allergic reactions  10 Agents associated with systemic allergic reactions  11 Cytotoxic chemotherapy  11

reactions, and are most likely to influence further use of the causative agent. These systemic allergic reactions will be the focus of this chapter. This chapter will describe the types and mechanisms of allergic reactions, the chemotherapeutic agents that most commonly cause allergic reactions, and the clinical manifestations of allergic reactions. The diagnosis, prevention, and management of allergic reactions will be reviewed.

Monoclonal antibodies  12 Diagnosis of systemic allergic reactions to chemotherapy  12 Prevention of systemic allergic reactions to chemotherapy  13 Skin testing  13 Premedications  13 Management of patients with allergic reactions to chemotherapy  13 Acute management  13 Further management  14 Desensitization  14 Conclusion  14

Infusion reactions are relatively common during administration of chemotherapy. Unfortunately, too little attention is often paid to whether these reactions are simple hypersensitivity reactions or more serious immune-mediated allergic reactions. Patients with apparent allergic reactions to chemotherapy must be evaluated very carefully so the cause of the reaction can be determined. If these reactions are not evaluated appropriately, a patient with a true allergy may be harmed by inadequate treatment of the reaction or by reexposure to the allergen, or an active regimen may be discontinued in a patient with a simple hypersensitivity reaction. Allergic reactions to chemotherapy can occur with both cytotoxic agents and monoclonal antibodies with systemic or cutaneous manifestations. Systemic allergic reactions to chemotherapy are more common than cutaneous reactions, are 10 most important to differentiate from benign ­hypersensitivity

WHAT IS A SYSTEMIC ALLERGIC REACTION? Reviewing the literature for trials, reviews, or guidelines pertaining to allergic reactions to chemotherapy is difficult because of the lack of standard terminology. Terms that occur frequently in the literature, although they usually are poorly defined, include hypersensitivity reaction, infusion reaction, allergic reaction, pseudoallergic reaction, standard infusion reaction, severe infusion reaction, anaphylactic reaction, and anaphylactoid reaction. Prevention, correct diagnosis, and management of allergic reactions to chemotherapy require an understanding of the distinctions between these terms and an ability to use them correctly when communicating with other clinicians. Hypersensitivity reaction, a term often used synonymously with infusion reaction, is a general term that is often used to describe an adverse reaction to a drug, which does not imply a mechanism. Infusion reactions can be characterized further as standard infusion reactions, severe infusion reactions, and anaphylactic or anaphylactoid reactions. Standard infusion reactions are not the result of an allergic mechanism, and anaphylactic reactions are immune mediated. Pseudoallergic reactions, also called anaphylactoid reactions, are not directly immune mediated, but may be severe. These reactions are due to indirect activation of the immune system by the drug or by an excipient. The National Cancer Institute (NCI) differentiates between infusion-related reactions, allergic reactions, and anaphylaxis in the Common Toxicity Criteria for Adverse Events (CTCAE), version 4 (Table 2-1).1

TYPES AND MECHANISMS OF ALLERGIC REACTIONS Allergic reactions historically have been divided into categories on the basis of their immunologic mechanisms via a classification system initially described by Gell and Coombs

Allergic reactions to chemotherapy

2

Table 2-1  Differences between hypersensitivity reactions and acute infusion reactions Grade Adverse event

1

2

3

4

5

Infusion-related reaction*

Mild transient reaction; infusion interruption not indicated; intervention not indicated

Therapy or infusion indicated but responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated for ≤24 hours

Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae

Life-threatening consequences; urgent intervention indicated

Death

Allergic reaction†

Transient flushing or rash, drug fever 90% without antiemetics)

Bortezomib

Paclitaxel

Carmustine, BCNU

Lomustine

Catumaxumab

Panitumumab

Cisplatin

Mechlorethamine

Cetuximab

Pegasparaginase

Cyclophosphamide (>1500 mg/m ) Pentostatin

Cytarabine (100 mg/m2)

Gemcitabine

Trastuzumab

Altretamine

Idarubicin

Ixabepilone

Azacitidine

Ifosfamide

Minimal (emesis risk 12 mg/m2)

Bleomycin

α-, β-, γ-Interferon

Clofarabine

Melphalan IV

Busulfan

Mercaptopurine

Cyclophosphamide (6), additional risk factors, such as a high degree of steatosis, should be ruled out. Vauthey et al24 found that grade 2 to 3 sinusoidal dilatation was associated with oxaliplatin-based CTx (19% vs. 2%; P < .001) but found no increase in postoperative morbidity or mortality. Aloia et al32 noted that patients with liver injury due to oxaliplatin-based chemotherapy required more perioperative blood transfusions than patients who received 5-FU. Perioperative blood transfusion has been shown to be a risk factor for poor outcomes following hepatic resection.34 Another study found that sinusoidal injury was associated with higher morbidity and longer hospital stay in patients undergoing major  hepatectomy, and that it resulted in an impaired liver functional reserve before hepatectomy.35 The association between postoperative morbidity and sinusoidal injury might be attributable to the intensive chemotherapy given in this study: 90 patients received an average of nine cycles, and 27% (24/90) received two different lines of chemotherapy. The link between sinusoidal injury and morbidity is still under debate.

A

Irinotecan C

Fig. 7-1  A, Right liver lobe. B, Left liver lobe. C, Ligamentum teres.

Irinotecan is a semisynthetic analog of the natural alkaloid camptothecin and is commonly used in combination with 5-fluorouacil and leucovorin. After administration, it is hydrolyzed into SN-38, a topoisomerase inhibitor, which prevents DNA replication and transcription. It is mainly used in patients with metastatic colorectal cancer and has shown 51 increased response rates (>50%) and improved survival.

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CV

CV

PT

SD

PT

S

PT

PT

A

PT

B

PT

Fig. 7-3  A, Normal liver parenchyma with portal tract (PT) and central vein (CV). No significant steatosis or sinusoidal dilatation of fibrosis is seen.B, Liver parenchyma after treatment with XELOX (capecitabine plus oxaliplatin); areas with sinusoidal dilatation (SD) are seen together with foci of steatosis (S).

However, an important downside of the use of irinotecan is the induction of chemotherapy-associated steatohepatitis (CASH). CASH is characterized by increased accumulation of hepatic fat in combination with hepatic inflammation following chemotherapy treatment. It is closely related to the upcoming Western disease known as nonalcoholic fatty liver disease (NAFLD), a condition inextricably associated with the current obesity epidemic. In NAFLD, simple steatosis can progress over time into nonalcoholic steatohepatitis. Although the exact mechanism is still under debate, a theory put forth to explain disease progression in NAFLD refers to the “two-hit” mechanism. The first hit is the unbridled hepatic fatty acid accumulation caused by a high caloric intake and insulin resistance. The second hit consists of increased oxidative stress response caused mainly by mitochondrial dysfunction through excessive microsomal and peroxisomal ω- and β-oxidation of fatty acids. This leads to activation of Kuppfer cells and a consequent inflammatory cascade. As was mentioned in a previous section, 5-FU, with or without LV, is the foundation to which other chemotherapy regimens are added. This regimen alone is already associated with steatosis induction caused by impaired mitochondrial function. In the FOLFIRI regimen, irinotecan is added to 5-FU and LV. In a small study by Fernandez et al,36 28% (4/14) of patients developed steatohepatitis following the FOLFIRI regimen. Lower rates of steatohepatitis were detected after FOLFIRI by Pawlik et al20: 2 of 55 (4%) patients. In a larger study, Vauthey et al24 showed that irinotecan treatment was associated with steatohepatitis in 20% (19/94) of patients. Furthermore, this study showed that a higher degree of steatohepatitis development occurred in obese (BMI > 25 kg/m2) patients (25%;15/61) as opposed to patients with a normal BMI (4 mg), although this is very uncommon.15 The acute peripheral neurotoxicity of vincristine is most likely related to inhibition of the axonal microtubule infrastructure (Fig. 8-2). Symptoms of toxicity include paresthesias of the distal extremities, numbness, and loss of ankle DTRs.16 These symptoms occur in a large majority (up to 70%) of patients treated with vincristine and present in a dose-dependent fashion. Once cumulative doses exceed the toxic threshold, symptoms appear soon after treatment. Cessation of treatment resolves the neuropathy in most cases; however, about 25% of patients experience worsening of symptoms when off therapy. A more worrisome peripheral complication is a collection of polyradicular findings similar to the Guillain-Barré syndrome. Although it occurs only on rare occasions, this complication can pose a diagnostic challenge to clinicians.17 The Guillain Barré–like syndrome has been shown to present progressively after cumulative doses of at least 4 mg of vincristine and is not regarded with the spectrum of acute or subacute toxicity. Vocal cord paralysis can present as an emergency requiring ventilatory support, although this rare complication has been reported in only a little more than 1% of children receiving vincristine therapy.18 An extremely rare multiple cranial and peripheral neuropathy within a few days of treatment can be fatal.19

SEMISYNTHETIC VINCA ALKALOIDS The semisynthetic vinca alkaloids, including vindesine and vinorelbine, are used in hematologic malignancies, as well as in breast and lung cancers. Vinorelbine holds a far lower risk of neurotoxicity as compared with vincristine.20 Peripheral neuropathy manifested by sensory changes and paresthesias will occur in 20% of patients, although significant symptoms appear in less than 1%. Additionally, constipation is frequently encountered and is believed to represent autonomic neuropathy. Both peripheral and autonomic neuropathies are readily reversible upon discontinuation of therapy. Similarly, vindesine can cause reversible peripheral and autonomic neuropathies at rates similar to vincristine neuropathies.21 In addition, vindesine has been found to induce a reversible Guillain 58 Barré–like syndrome.22

B Fig. 8-2  Cross sections of mictotubules in control (A) and vincristine-treated (B) rat nerves. Whereas neurofilaments were distributed throughout the axoplasmin control axons, there appeared to be more neurofilaments in many vincristinetreated axons. Neurofilaments in vincristine-treated axons also appeared to be abnormally clustered in the central portion of the axoplasm. In addition, many vincristine-treated unmyelinated axons were larger and more irregularly shaped compared with controls. (From Tanner KD, Levine JD, Topp KS. Microtubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat. J Comp Neurol 1998;395:481-2. Permission from www. copyright.com, academic subscription.)

ANTIMETABOLITES The antimetabolite class of chemotherapy includes agents that inhibit cellular metabolism at various points throughout the metabolic processes that are ongoing in the dividing cell. These drugs primarily interfere with processes involved in the synthesis and replication of DNA.

METHOTREXATE Methotrexate is a dihydrofolate reductase inhibitor that is used very commonly in hematologic and breast cancers. It is also used at high doses for central nervous system (CNS) lymphomas and intrathecally for acute lymphocytic leukemias. Debate has arisen over the pathogenesis of methotrexate-induced neurotoxicity, and it is unknown whether magnetic resonance imaging (MRI) changes precede symptoms or serve as evidence of irreversible damage. Intrathecal methotrexate administration has been associated with the development of aseptic meningitis, and a recent case ­description of ­methotrexate-induced

Acute neurotoxicity induced by common chemotherapies meningitis following intramuscular administration has been described.23 The symptoms present within a few hours of treatment and resolve within 72 hours. Other common complaints following intrathecal therapy include back pain, weakness, and sensory changes. These are precursory to the development of a rare but reversible transverse myelopathy.24 High doses of ­systemic methotrexate have been associated with subacute, reversible mental status changes and focal neurologic deficits in up to 15% of patients.25 Some of the damage induced by methotrexate therapy is irreversible, and more than 25% of patients show long-term cognitive and functional changes. Thus early recognition of toxicity is crucial in maintaining quality of life for these patients. A partially reversible lumbosacral radiculopathy has been reported on rare occasions.26 Symptoms of radiculopathy are progressive and often do not present immediately after treatment.

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20 days after therapy and result in a devastating demyelinating sensorimotor course. Patients may require mechanical ventilatory support, and the course can be fatal. More ­commonly, reversible sensory neuropathy (with or without neuropathic pain) will develop as the result of inhibition; this is followed by rebound overexpression of a specific capsaicin receptor on peripheral nerves.33

IFOSFAMIDE Ifosfamide is a nitrogen mustard alkylating agent used in the treatment of hematologic, gynecologic, urologic, and bone cancers. Transient central neurotoxicity has been observed in about 5% of children and presents as partial and generalized seizures.34 Reversible encephalopathy has been found to develop in the elderly, with men older than age 65 presenting with encephalopathic symptoms at a rate of up to 30%.35

5-FLUOROURACIL 5-Fluorouracil (5-FU) is an inhibitor of thymidylate synthase that prevents nucleotide synthesis and arrests cell division. This therapy is widely utilized for the treatment of gastrointestinal and head and neck tumors. Although rarely implicated in neurotoxicity, 5-FU has been associated with acute onset of encephalopathy, a cerebellar syndrome, seizures, or isolated cranial nerve deficits.27 Cerebellar (ataxia, slurred speech, nystagmus) or encephalopathic (cognition, confusion, sensation) changes manifest themselves within hours of chemotherapy and are reversible within days upon cessation of treatment. Either of these syndromes will present in fewer than 10% of patients, and rarely will a patient develop both conditions simultaneously. Although the mechanism of neurotoxicity is not entirely characterized, it is thought to be related to metabolic interference by 5-FU. Less acutely, a multifocal leukoencephalopathy has been described several days after therapy. Recent evidence indicates that susceptibility to 5-FU neurotoxicity may be related to genetic factors, although this concept is new and requires further development.28 It is known that patients with dihydropyrimidine dehydrogenase deficiency are at increased risk of developing 5-FU neurotoxicity, in addition to other 5-FU–mediated adverse events. Peripheral toxicity due to 5-FU is very rare, presenting with mild sensorimotor deficits that are reversible with cessation of therapy.29

CYTOSINE ARABINOSIDE (CYTARABINE, ARA-C) Cytarabine is a pyrimidine analog that inhibits DNA polymerase and is used primarily in hematologic cancers. Several case studies have documented aseptic meningitis after intrathecal cytarabine administration.30 This complication is largely reversible but can last for several weeks after therapy. Symptoms develop after a cumulative dose of about 20 mg. Seizures can also present in up to 20% of patients receiving intrathecal therapy. About 10% of patients will develop cerebellar dysfunction with high-dose cytarabine following cumulative doses of 36 mg/m2.31 Symptoms are largely reversible with cessation of therapy but occasionally (in 600 mg/m2) have been associated with a reversible encephalopathy (50% in 22 patients (55%) and less than 50% in 9 patients (22.5%), and with no stenosis in 9 patients.180,181 Key point: MR can improve outcomes in malignant disease, but the trade-off is increased risk of late cardiotoxicity.

HEART FAILURE Acute radiation-induced cardiotoxicity can cause perimyocarditis, ranging from asymptomatic decreases in measured LVEF to full-blown CHF with or without manifestations of pericarditis. In a study from 2003 that was previously referenced, Heidenreich and associates looked at myocardial disease in long-term Hodgkin's lymphoma (HL) survivors. They prospectively performed echocardiogram screening in 294 asymptomatic patients with a mean age of 42 ± 9 years who received a mean radiation dose of 43.3 Gy and were studied from 2 to 23 years (mean, 15 years) after treatment ­completion. Investigators found frequent abnormalities in left ventricular mass and systolic function. The prevalence of these abnormalities was greater than expected for a generally closely matched population. The incidence of all ­abnormalities increased as time from treatment completion elapsed. Radiation-induced myocardial disease differs from the predominantly systolic dysfunction associated with chemotherapy, with preponderance in late-onset disease for diastolic dysfunction and restrictive hemodynamics. Moderate techniques have reduced the risk of systolic dysfunction but have not changed the course of restrictive disease. In a group of 21 asymptomatic survivors treated with 20 to 70 cGy (mean, 35.9 Gy) before 1983, 57% had an abnormal LVEF by RNA 20 years after treatment completion (mean, 14.1 years) compared with the modern technique group, which evaluated 50 Hodgkin's lymphoma survivors (mean age, 35.1 years) 1 to 30 years after treatment (mean, 14.1 years); 4% had an abnormal LVEF by RNA, but 60% had RNA evidence of diastolic systolic dysfunction. Of Heidenrich's 294 patients, 26 (9%) had mild and 14 (5%) had moderate diastolic dysfunction.182 The use of modern techniques has led to a lower expected incidence of CT. Glanzmann et al reported their experience with 352 patients with the use of modern techniques; the incidence of acute pericarditis decreased from 20% to 2.5%. Giordano et al reviewed the risk of cardiac death after adjuvant radiotherapy for breast cancer and found a progressive decrease over time with the use of contemporary radiation delivery techniques.183–185 Key point: Radiation-induced myocardial disease is unusual with exposure less than 30 Gy, is increased with any anthracycline exposure, and has a predilection for diastolic dysfunction.

CORONARY ARTERY DISEASE Laboratory and clinical evidence supports the fact that MR can accelerate the development of coronary artery disease. Manifestations of CAD are unusual before 5 years from treatment completion. Hancock and associates at Stanford

Management of cardiac and pulmonary treatment–related side effects University reviewed the records of 635 patients younger than 21 years of age treated for Hodgkin's lymphoma between 1961 and 1991. After a mean follow-up of 10.3 years, 12 patients died of cardiac disease (relative risk [RR], 29.6; 95% confidence interval [CI], 16.0–49.3), including seven from acute myocardial infarction (AMI; RR, 41.5; 95% CI, 18.1–82.1), three from valvular heart disease, and two from radiation pericarditis/pancarditis. Death occurred 3 to 22 years after patients received 42 to 45 Gy to the mediastinum.186 The development of CAD differs from the development of atherosclerotic CAD in the lack of conventional risk factors for atherosclerosis seen in patients who have received MR. The clinical presentation of radiation-induced CAD is similar to that of CAD in the general population: It may be silent or may present with angina, ACS, myocardial infarction, or sudden death. The distribution of disease, however, is different and somewhat characteristic. It more commonly affects the ostial or proximal right coronary artery, the left anterior descending coronary artery, and the left main coronary artery, with relative sparing of the left circumflex system.187 The relative risk of right versus left chest radiation in females with breast cancer is controversial. Data from the early literature that was focused on women who were treated after mastectomy with adjuvant radiation suggested that those with left-sided breast cancer had an increased incidence of fatal cardiovascular disease compared with those with ­right-sided breast cancer.188–190 These studies, published before 1990, reflect pre-modern and modern radiation techniques. A preponderance of studies published after the institution of modern radiotherapy techniques show no increase in ischemic heart disease and no increased risk when treatment to the left versus the right breast is compared,191–195 and no difference in any other ­cardiac disease (valvular conduction or heart failure) with adjuvant radiotherapy for local stage I or II breast cancer after breast conservation surgery performed up to 15 years post treatment completion.192 Key point: Radiation-induced CAD may double the risk of death from CAD compared with the nonradiated population.

PERICARDITIS Pericardial disease is the most common manifestation of ­radiation-induced cardiotoxicity. During the delivery of radiation therapy, the pericardium can become inflamed and presents like typical acute pericarditis. Acute pericarditis that occurs during active radiation or within weeks of treatment completion is rare; incidence is probably less than 2%. Positional pleuritic chest pain is the hallmark feature of acute pericarditis that is often associated with dyspnea. Fever and other constitutional symptoms are less common. Cardiac auscultation reveals a typical three-component pericardial friction rub. Varying degrees of pericardial fluid may be present from asymptomatic effusions to acute pericardial tamponade. The ECG shows diffuse ST elevation with or without PR interval depression in acute pericarditis and may be completely normal other than sinus tachycardia. An echocardiogram confirms the presence or absence of pericardial fluid and measures systolic and diastolic left ventricular function. Similarly, radiation-induced late pericardial disease (within the first year post treatment completion) may be silent with the incidental discovery of an asymptomatic pericardial effusion, or it may present with hemodynamic compromise secondary to reduction in ventricular filling and cardiac output. The latter

9

can be due to pericardial fluid and can present as tamponade, may be purely constrictive without pericardial fluid, or may be caused by a combination of both—effusive constrictive pericarditis. All of the latter presentations are symptomatic with typical signs and symptoms. No evidence suggests that interventions can alter the course of hemodynamically inconsequential and clinically silent effusions. The literature reflecting pre-modern MR suggests that approximately 20% to 25% of those with late pericarditis progress to develop constrictive disease or acute tamponade 5 to 10 years after therapy. With modern techniques, the incidence of chronic pericardial disease is lower, with pericarditis occurring in less than 2% and chronic pericarditis in less than 5% of treated patients. Key point: The most frequent manifestation of radiationinduced pericardial disease is late-onset chronic pericarditis.

VALVULAR DISEASE The same process that can cause myocardial fibrosis is responsible for thickening and fibrosis that may occur on the cardiac valves. In the Heidenreich study, which used ­echocardiographic screening, the most common valvular abnormality was aortic regurgitation, with less frequent involvement of the mitral and tricuspid valves. Sixty percent of patients followed for 20 years or longer had at least mild aortic insufficiency. Of interest, only 5% of these patients were recognized to have an aortic insufficiency murmur on physical examination performed by an experienced cardiologist. Most patients present with asymptomatic murmurs without any hemodynamic consequence. Key point: Radiation-induced valvular disease is unusual before 10 years after treatment completion.

ARRHYTHMIAS The spectrum from simple isolated premature depolarizations to life-threatening arrhythmias and all forms of conduction disease may occur during treatment or years after treatment completion. A wide spectrum of abnormalities includes the development of sick sinus syndrome, all forms of atrioventricular block, and bundle branch block. Right bundle branch block is more commonly seen because of its anterior location in the heart. The frequency of serious conduction abnormalities in longterm asymptomatic survivors following MR is not known and is probably overstated in the literature, making causality a difficult assumption. A few prospective studies are reporting the incidence. Key point: Right bundle branch block is the most frequent conduction abnormality caused by MR.

DIAGNOSIS Diagnosis is based on clinical suspicion. At every ­encounter, questions about symptoms of cardiac disease and ­assessment of functional capacity are critical components. For the most part, until late in the progression of most cardiac disease related to radiation, physical findings are minimal. Although not generally used by cardiologists, assessment of functional capacity using the Karnofsky score or performance status is valuable. Typical physical findings of heart failure are uncommon; even edema is rare in the early stages of radiation-induced 83 heart failure.

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In appropriate patients with risk factors for CAD, we exclude ischemia as the cause of heart failure by a stress echocardiogram or an exercise nuclear perfusion study. Even though the incidence of CAD is increased in patients with prior MR, no evidence indicates that treatment of asymptomatic lesions favorably influences survival. We do not routinely screen patients for CAD in the absence of a change in functional capacity or with development of exercise-induced symptoms. We do, however, take an aggressive approach to risk factor management and target all patients who have had MR secondary prevention lipid values (i.e., an LDL 45). For most, statin therapy is employed because it is difficult to get to those target values by diet alone. Additional counseling regarding diet, weight, exercise, smoking, and substance abuse should be part of every evaluation of long-term survivors of MR. As a late complication of MR, constrictive pericarditis is suspected with a constellation of symptoms that include dyspnea, fatigue, and edema. Physical examination may show an inspiratory increase in jugular venous pressure (Kussmaul's sign) and a characteristic pericardial knock in diastole. The ECG may show low voltage and/or electrical alternans (beat-to-beat variation in total voltage). We confirm the diagnosis by echocardiography (showing characteristic pericardial thickening and restriction of filling with pronounced respiratory variation) and cardiac MRI with pericardial tagging. This combination of testing has been most valuable in defining anatomy for the surgeon if pericardiectomy is considered. All of these patients undergo right and left heart catheterization to confirm the diagnosis and exclude associated CAD that may need revascularization during open heart surgery. Of interest, because of the high incidence of hypothyroidism following MR, we check thyroid function in all patients who present with pericardial effusions. When a murmur suspected of arising from valvular disease is appreciated, we follow with a baseline echocardiogram to quantitate the degree of valvular stenosis/insufficiency and measure associated LV function. Symptoms of palpitation and dizziness are evaluated by ECG and longer-term ambulatory cardiac monitoring. Because the incidence of all CT tends to increase over time, we have been doing serial echocardiograms routinely at 5-year intervals even in asymptomatic patients. The latter is a ­recommendation and not an official guideline at this time. The American College of Radiology46 has developed appro­ priateness criteria for routine follow-up of asymptomatic patients who received MR.196 Key point: Hallmarks of radiation-induced CT include pericarditis, ostial or proximal CAD, aortic valve stenosis and insufficiency, and right bundle branch block

TREATMENT The general approach to the patient with radiation-induced heart disease is similar to that used for patients with cardiac disease that is unrelated to radiation. The medical management of pericardial disease, heart failure, arrhythmias, and coronary artery disease is virtually identical, regardless of the cause. When invasive procedures or surgery is contemplated, decisions may be tempered by the presence of scarring from 84 prior surgery and/or radiation and coagulopathy related to the

cancer and/or its treatment. For all, risk factor modification and reduction and the management of noncardiac comorbidity are essential starting points. The following represents some unique features related to radiation-induced cardiac disease by syndrome.

Pericardial disease When pericardial symptoms occur during treatment, the cause is more likely directly related to the tumor rather than to the treatment. Treatment in the absence of hemodynamic compromise is symptomatic with aspirin and/or NSAIDs. We try to avoid systemic steroids whenever possible because the latter tend to ultimately extend the course of the illness. As in acute idiopathic pericarditis, we use colchicine 0.6 mg twice daily for 6 to 12 weeks to help prevent recurrent pericarditis and the development of constrictive pericarditis. More common is the development of delayed pericarditis manifested by acute symptoms or asymptomatic pericardial effusions. In the absence of pericardial tamponade, symptomatic treatment is warranted, with careful monitoring of symptoms and physical examination to recognize the development of hemodynamically significant pericardial tamponade. In the presence of hemodynamic compromise, if an anterior window with clearance allows for safe percutaneous drainage, we first attempt pericardiocentesis in the Cath Lab to relieve the hemodynamic burden. Patients with recurrent effusions after drainage may require a pericardial window or a pericardiectomy. If no window for drainage is provided and if hemodynamic compromise occurs, we proceed with the surgical creation of a pericardial window. In the absence of significant restrictive cardiomyopathy, the treatment for documented constriction is surgical pericardiectomy. The presence of restrictive cardiac disease increases operative mortality to >50%, and long-term survival is ­limited by restrictive cardiomyopathy.

Heart failure We follow current guidelines for the treatment of heart failure in both asymptomatic and symptomatic patients. Because radiation-induced myocardial disease is more often manifested as diastolic dysfunction (impaired relaxation) or restrictive hemodynamics, medical management is more difficult than for purely garden-variety systolic heart failure. We use a combination of ACE inhibitors or ARBs and beta blockers, depending on the patient's major clinical presentation. Strict management of fluid status is critical with a narrow window of effectiveness: Over-diuresis leads to hypotension and renal insufficiency, and underdieresis leads to symptoms of congestion. The therapeutic window between these two points is often extremely narrow. For many patients, just managing fluid, blood pressure, and associated coronary disease and diabetes provides adequate treatment for heart failure. When ischemia is reversible and a component of ischemic cardiomyopathy is present, a role for revascularization may be identified. Small series case reports of cardiac transplantation for endstage CHF due to MR describe outcomes that are comparable with those of non–MR-induced disease.197

Management of cardiac and pulmonary treatment–related side effects

Valvular disease When radiation-induced valvular disease progresses to consideration of surgical correction, the decision process is not much different from that seen in “ordinary” valve disease. Additional consideration of altered chest anatomy caused by mediastinal disease, prior surgery, and radiation has an impact on the risks of the operation. In the absence of constrictive pericarditis or restrictive heart disease, risks and outcomes comparable to those seen without prior MR can be expected for mechanical valve replacement. Surgical repair of regurgitant valves has been reported to have technical feasibility but limited durability, with a percentage of patients requiring reoperation 3 to 5 years down the line.198,199

Coronary artery disease Medical management consisting of risk factor reduction, combined with a pharmacologic armamentarium that includes various combinations of nitrates, beta blockers, ACE inhibitors/ARBs, calcium blockers, and ranolazine, is the standard of care for radiation-induced CAD. More often than not, patients present with acute coronary syndromes that require revascularization. Percutaneous and operative revascularization can be done safely and effectively in this population. Specific risks regarding malignancy status, enhanced risk of thrombosis, and ability to institute and maintain long-term dual antiplatelet therapy may dictate the type of revascularization to be used, from balloon angioplasty to the choice between bare metal and drug-eluting stents to operative bypass surgery. In spite of prior exposure to radiation, the internal thoracic artery can be safely utilized for grafting.200,201 Early results of coronary artery bypass grafting for the ­treatment of MR-induced CAD are good. Late survival, however, is limited by malignancy (recurrent or second) and the development of heart failure. Many patients require concomitant or a later second valvular operation. Careful assessment of any valvular lesion is important during the initial coronary artery bypass grafting, as is careful follow-up.202 Key point: Radiation-induced CAD is marked by an ostial or proximal location of stenoses and sparing of the left ­circumflex coronary artery. The surgical approach to radiation-induced heart disease is complicated by fibrosis of mediastinal structures and association of multiple cardiac abnormalities that may need repair or may have an impact on ventricular function; early mortality is similar to that of a matched general population, with a higher rate of reexploration for postoperative bleeding, a  greater number of sternal wound infections, and a higher rate of sternal dehiscence. Late results differ by the more rapid development of new valve disease and the lack of long-term durability of valve repair. In general, to a greater extent than in the ­general population, more rigid individualized decision making is critical.203,204

Arrhythmias The treatment of arrhythmias for radiation-induced disease is identical to the standard approach to conduction disease and rhythm disturbances for non–radiation-induced disease.

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CAROTID DISEASE AND STROKE Carotid artery stenosis is a recognized complication of radiation treatment for head and neck tumors, with an increased incidence of carotid and/or subclavian artery atherosclerosis compared with the nonradiated population and an increased actuarial stroke rate. TIA/CVA may be asymptomatic or minimally symptomatic, and carotid bruits may be absent on examination. We recommend carotid duplex imaging at 5 years post treatment completion to establish a baseline. Subsequent monitoring interval and treatment options are driven by the imaging results. For all, we attempt to achieve secondary prevention levels for lipids because we consider MR another risk factor for atherosclerosis. For patients with any demonstrable disease, we recommend the addition of aspirin and a more intense serial monitoring schedule.205,206

SUPPORTIVE ONCOLOGY The presence of extracardiac abnormalities due to MR can complicate diagnosis and treatment. They include skeletal abnormalities and muscle wasting that can lead to hypoventilation, hypothyroidism whose lack of treatment or treatment has major cardiac effects, and pulmonary fibrosis with restrictive lung disease that can contribute to exert ional breathlessness. In summary, many of the features of radiation-induced cardio­toxicity mimic the natural history timelines and dose relationships of chemotherapy-induced cardiotoxicity. Radiationinduced disease differs by having a preponderance of diastolic as opposed to systolic dysfunction, development of valvular disease, late pericardial inflammation/fibrosis, conduction system disease, and coronary artery atherosclerosis.

RADIATION-INDUCED PULMONARY TOXICITY (PT) MR can cause acute pneumonitis and chronic fibrosis as manifestations of pulmonary toxicity. The cause of radiationinduced lung damage is multifactorial. Radiation can injure both capillary endothelial cells and type I cells, triggering the release of transcription factors (e.g., nuclear factor [NF]-κ B), cytokines, and growth factors that lead to localized or general inflammation and consolidation. The incidence and severity of radiation-induced PT are related to the volume of lung tissue radiated (minimal exposure of least 10% of the lung is required for the development of pneumonitis), the total dose of radiation, and the delivery technique used. Radiation pneumonitis is unusual when total exposure does not exceed 20 Gy, and its incidence increases progressively with higher doses; when 70 Gy is exceeded, the incidence is almost 100%. Delivering the total dose over more fractions also reduces the risk. The underlying disease that is being treated also plays a role: With all other factors being equal, the risk for pneumonitis is lower when Hodgkin's lymphoma or breast cancer is treated, rather than primary lung cancer. With modern techniques, the incidence of subacute pneumonitis is less than 3% in lymphoma and less than 1% for breast cancer compared with 5% to 20% for lung cancer. A higher percentage 85

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  Management of treatment-related adverse efects

of patients have asymptomatic changes in pulmonary function testing, and as more sophisticated imaging and testing are employed, the incidence of asymptomatic disease rises. Thus the true incidence of pulmonary toxicity is dependent on definition and diagnostic criteria: The more sensitive the technique, the higher the incidence that is reported.207–210 Other high-risk factors include any exposure to anthracycline chemotherapy, previous lung radiation, and steroid ­withdrawal. Increased age and/or underlying chronic obstructive lung disease does not increase risk, but disease may be more severe in the elderly and in patients with underlying parenchymal lung disease.211 Risk factors for MR-induced PT are listed in Table 9-10. Most patients who develop radiation pneumonitis have a self-limited course without long-term late consequences. The severity of illness is somewhat proportional to the time of onset, with early-appearing disease associated with a more aggressive course.212 Key point: The major manifestation of radiation-induced pulmonary toxicity is acute pneumonitis. Dyspnea, the most frequent presenting symptom, may be associated with cough and/or fever. These symptoms may be insidious and typically occur within months of treatment completion. Aside from hypersensitivity reactions, it is usual to find symptoms in the first month or beyond 8 months. Physical examination may be unremarkable or minimally abnormal with moist crackles, a pleural friction rub, or ­evidence of a pleural effusion. Most patients with acute pneumonitis have complete resolution of the process, become asymptomatic, and return to their baseline level; some develop a degree of ­fibrosis. In some cases, patients may present with late-onset progressive dyspnea due to radiation fibrosis, even in the absence of a history of an acute event. When fibrosis occurs, it generally evolves over several months and almost always stabilizes by 2 years. Similar to patients with acute ­pneumonitis, patients with fibrosis can be asymptomatic or may have varying degrees of dyspnea. At the worst end of the ­spectrum, patients may develop cor pulmonale and ­respiratory failure.213 Additional pulmonary complications of high-dose ­radiation, including bronchial stenosis, mediastinal fibrosis, and injury to the pulmonary veins, lymphatic system, and recurrent laryngeal nerve, have been reported.214 Diagnosis is based on clinical history and is confirmed by radiographic imaging. The chest x-ray may be normal or may present with nonspecific and nondiagnostic reticulonodular opacities to alveolar infiltrates. Fibrosis is recognized by

Table 9-10  Risk factors for radiation-induced pulmonary toxicity

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Patient related

Treatment related

Anthracycline exposure Preexisting lung disease Current smoking Oxygen use Cancer diagnosis (Lung cancer>breast cancer> HL) Steroid withdrawal

Total volume of lung at risk Radiation dose >2 Gy Fractionization Radiation quality Hilum/mediastinal structures included in field

HL, Hodgkin's lymphoma.

l­inear streaks, often with volume loss with or without a shift in ­mediastinal structures. One of the most characteristic features is that the area of fibrosis generally conforms to the field of radiation. Rarely, changes are seen in the contralateral lung. The latter may represent a hypersensitivity reaction to radiation. Computed tomography scans with and without contrast and positron emission tomography (PET) imaging may be more sensitive than a plain chest X-ray in making a diagnosis. Key point: The chest X-ray may be normal or may have nonspecific changes that limit its utility as a diagnostic tool for radiation-induced lung injury. Pulmonary function tests (PFTs) may show a decrease in lung volumes, diffusing capacity of carbon monoxide (DLCO), and arterial hypoxemia. In general, some recovery occurs in the first year after treatment completion.215 The role of plasma transforming growth factor (TGF)-β1 in predicting radiation-induced pulmonary toxicity has recently been reviewed.216 Key point: The hallmark symptom of radiation-induced pulmonary toxicity is dyspnea. Radiation-induced bronchiolitis obliterans with ­organized pneumonia (BOOP) has been reported. Similar to ­pneumonitis, dyspnea is the major symptom, and temperature elevation is common. The radiographic picture shows infiltrates that always extend beyond the radiation field, with an incidence up to 40% of contralateral lung involvement. This disease almost universally responds to steroids, and recurrence is often seen when steroids are tapered rapidly or are discontinued. This subject has recently been extensively reviewed.217 With interstitial pneumonitis, the differential diagnosis is between recurrent malignancy, lymphangitic spread of tumor, alveolar hemorrhage, and infection. In some cases, lung biopsy is needed to sort this out. Some researchers thought that biomarkers, including intercellular adhesion molecule-1 or TGF-β, may indicate a slightly higher risk of developing pulmonary toxicity. Corticosteroids (e.g., prednisone 1 mg/kg) are the cornerstone of treatment, although no controlled clinical trials have proved their benefit. Prophylactic steroids are not prophylactic and do not prevent the development of PT. Use of steroids for the treatment of radiation fibrosis is not indicated. Use of the protective agent amifostine to prevent lung injury has been controversial, with inconsistent results reported in major trials during radiation treatment.218 Guidelines have been generated for the use of amifostine during the course of radiation treatment.219

SUPPORTIVE ONCOLOGY Proactive recognition and treatment are provided for potential extrapulmonary complications of radiation, including esophagitis and aspiration pneumonia. Because esophageal injury frequently accompanies the pulmonary complications of radiation treatment, vigilance to the maintenance of caloric intake and constant reassessment of the ability to take oral medications are essential, especially for patients with comorbid conditions that require continuation of maintenance medication. For patients who have had head and neck radiation and are susceptible to recurrent bouts of aspiration pneumonia, aspiration should always be included in the differential diagnosis of a clinical picture that includes a pulmonary infiltrate, ­especially in a debilitated population.

Management of cardiac and pulmonary treatment–related side effects

CHEMOTHERAPY-ASSOCIATED PULMONARY TOXICITY Chemotherapy-induced pulmonary toxicity was first reported in the 1960s with busulfan, with subsequent recognition that lung injury is common to a wide variety of chemotherapy agents, with an incidence of up to 10%. Patients may present with acute or early lung injury during or soon after treatment or late after treatment completion. Diagnosis is often complicated and difficult because of the underlying cancer, the associated immunosuppression, similar presentation of infiltrates due to multiple causes, use of multimodality and multiagent chemotherapy, and lack of specific diagnostic criteria.220–224 Key point: Manifestations of chemotherapy-induced ­pulmonary toxicity involve the parenchyma (alveolar or interstitial disease), the airways (bronchospasm), the pleura (effusions), and the pulmonary circulation (hemorrhage or embolism) with asymptomatic changes on pulmonary ­function testing. A summary of chemotherapeutic agents that can cause PT is presented in Tables 9-11 and 9-12.

ACUTE LUNG INJURY Acute chemotherapy-induced PT is more common than late disease, and acute interstitial pneumonitis is the most common presentation. No universal mechanism of lung injury is known. It may be related to hypersensitivity, the generation of toxic metabolites, the induction of free radicals and/or genetic factors (gefitinib toxicity in the Japanese), and/or the presence of pretreatment pulmonary comorbidity.224–226 Similar to the anthracyclines and their associated cardiac toxicity, bleomycin (Blenoxane) is the “poster-child” and the best known and studied cause of chemotherapy-induced pulmonary toxicity. Bleomycin is an antineoplastic antibiotic effective in germ cell tumors, lymphomas, sarcomas, and carcinomas of the head and neck and esophagus. Its use is limited by its potential PT, which is fatal in 2% to 3% of treated patients.227–231 A specific entity, bleomycin-induced pneumonitis (BIP), is recognized. However, a wide range of pulmonary toxicity similar to chemotherapy-induced cardiotoxicity is associated with the pharmacologic treatment of cancer. The most important criteria for diagnosis include recognition of exposure and exclusion of progression of cancer, pulmonary infection, diffuse alveolar hemorrhage, pulmonary embolism, and nonpulmonary causes of interstitial edema that may occur with cardiac or renal failure. Progressive dyspnea is the most common presenting symptom, occurring in >90% of patients. Clinical presentation is similar to that seen in radiation-induced disease. Patients present with some combination of cough (50%), dyspnea, fever, and varying degrees of arterial hypoxemia. Pleural effusions may be associated, and patients may progress to respiratory failure and acute respiratory distress syndrome (ARDS) requiring mechanical ventilation. Timing of disease onset is unpredictable, and symptoms may occur with first dosing to anytime during treatment; similar to radiation-induced disease, prophylactic treatment with steroids may not prevent the development of toxicity. Key point: The major manifestation of chemotherapyinduced pulmonary toxicity is acute interstitial pneumonitis.

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Table 9-11  Chemotherapy-induced pulmonary toxicity by drug Type

Example

Parenchymal Interstitial pneumonitis

ARA-C, Bleomycin*, busulfan, chlorambucil, cyclophosphamide, doxorubicin, erlotinib, etoposide, fludarabine, FOLFIRI, FOLFOX, gefitinib, gemcitabine, ifosfamide, imatinib, irinotecan*, melphalan, methotrexate, mitomycin, oxaliplatin, procarbazine, rituximab, taxanes, vincristine/ vinblastine

Pneumonitis with fibrosis

BCNU (carmustine), CCNU (lomustine)

Airways Bronchospasm

Gemcitabine, methotrexate monoclonal antibodies, taxanes, trastuzumab, vinblastine

Pleura Effusion

Gemcitabine, docetaxel, fludarabine, imatinib, mitocycin, thalidomide

Circulation Noncardiac pulmonary edema

ARA-C, all trans-retinoic acid, cytoxan, gemcitabine, imatinib, immunomodulating drugs, monoclonal antibodies

Alveolar hemorrhage

Etoposide, gefitinib, gemcitabine

Veno-occlusive disease

Gemcitabine

Hemoptysis

Bevacizumab

Thromboembolic events

Thalidomide

*Dose dependent.

Table 9-12  Chemotherapy-induced pulmonary toxicity by timing of onset Time

Example

Early or Acute Immediate or days

Etoposide, methotrexate, procarbazine, rituximab, taxanes, vincristine/vinblastine

Subacute 1 month to 8 years

ARA-C, bleomycin, clorambucil, gemcitabine, melphalan

Late 10 or more years

BCNU, busulfan, cyclophosphamide,

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For simplicity, lung injury related to chemotherapy can be classified according to five syndromes defined by clinical presentation.

Interstitial lung disease The parenchymal manifestation of pulmonary toxicity is pneumonitis. This can be nonspecific, and may be due to hypersensitivity or allergy or alveolar hemorrhage. An illustrative example is the diffuse alveolar damage that occurs most commonly with bleomycin. The radiographic picture is not dissimilar from that seen with ARDS. It may also present with patchy/ground glass opacities. When bronchoalveolar lavage (BAL) yields a preponderance of eosinophils, and/or peripheral eosinophilia occurs, this interstitial pneumonitis is classified as eosinophilic pneumonia. Risk factors for BIP include the cumulative dose of bleomycin, the patient's age and smoking history, the presence of renal dysfunction, and concomitant use of supplemental oxygen. Prior MR also increases the risk. The reported incidence has varied from zero to 46% depending on the population studied and the criteria to make the diagnosis. BIP generally starts insidiously during treatment but can also develop up to 2 years after treatment completion. Most patients recover with discontinuation of bleomycin and/or steroid treatment. A minority of patients progress and develop pulmonary fibrosis. Another variation seen with methotrexate, cyclophosphamide, busulfan, and bleomycin is what used to be called organized pneumonia (BOOP). Currently, this entity is recognized as drug-induced organizing pneumonia. Its hallmark is the radiographic appearance of migratory opacities, often nodular and perilobular/perihilar, that change on serial imaging over weeks to months, often interspersed with a normal chest X-ray. Radiation recall pneumonitis is seen in patients who received prior chest radiation and following radiation develop symptoms of pneumonitis associated with radiographic infiltrates corresponding to the fields of prior radiation. This has been reported with gemcitabine, doxorubicin, carmustine, etoposide, paclitaxel, and trastuzumab.

HYPERSENSITIVITY PNEUMONITIS When symptoms occur during drug infusion or immediately after its completion and/or are accompanied by some combination of rash, urticaria, angioedema, changes in blood pressure, or bronchospasm, a hypersensitivity reaction should be suspected. This is often associated with diffuse interstitial edema or infiltrates. The taxanes are the most frequent culprits for this hypersensitivity reaction; this has been reported recently with the use of temozolomide.232 Muller and colleagues published a comprehensive review of chemotherapy-induced interstitial lung disease.233

Isolated bronchospasm Less common is isolated bronchospasm with evidence of airflow obstruction characterized by wheezing and prolonged expiration. This has been reported with gemcitabine, the taxanes, methotrexate, vinblastine, the immunomodulating drugs (interleukins and interferons), and most monoclonal antibodies. Treatment includes withdrawal of the offending agent and 88 use of bronchodilators.

Pulmonary edema This all-encompassing category is based on the ­development of interstitial edema that can be primarily cardiac or noncardiac (without elevation of left heart filling pressures). Noncardiogenic pulmonary edema occurs in a time frame that is closely related to administration; it is often preceded by self-limited dyspnea that may have occurred during previous exposure to the drug (previous cycles). Noncardiogenic ­pulmonary edema is due to an increase in capillary permeability. It is ­frequently associated with cytosine ­arabinoside (ARA-C)234 and with the use of all trans-retinoic acid ­(especially with a large number of circulating blasts). Early recognition and withdrawal of the offending drug or drugs are suggested as the most important steps toward successful management. Intravenous corticosteroids, diuretic therapy, and respiratory support with or without mechanical ventilation have been successfully employed.235

Pleural effusions The development of pleural fluid is most often a ­manifestation of metastatic disease. However, a primary pleural ­toxicity has been associated with several chemotherapy drugs ­(gemcitabine, docetaxel). Patients present with dyspnea that may be accompanied by pleuritic chest pain. Examination reveals marked dullness to percussion and decreased breath sounds and absent fremitus over the affected lung. A plain chest X-ray is often sufficient to make a diagnosis. Treatment consists of removing fluid to alleviate symptoms; a variety of longer-term solutions are available for recurrent accumulation of fluid, including chemical pleurodesis and the insertion of long-term ­indwelling drainage catheters.236

Asymptomatic decrease in pulmonary function testing Similar to that described with radiation, asymptomatic decreases in lung volumes and DLCO may occur. The incidence is unknown because of its clinically insignificant standing and the lack of a standardized and rigorous pursuit of this in patients without clinical symptoms.237

Diagnosis Chemotherapy-induced PT is almost always a diagnosis of exclusion. Physical examination may be unremarkable, crackles may be diffuse or localized, and pleural fluid may be evident. Clubbing almost never occurs even with profound hypoxemia. No specific radiologic pattern is known for parenchymal disease induced by chemotherapy. In fact, in the early stages, plain chest X-rays may be normal, and high-resolution computed tomography scanning may provide the first diagnostic clue. The benefit of computed tomography scanning is its virtual absence of risk compared with lung biopsy. However, because clinical presentations and radiographic patterns are often similar and nondiagnostic, bronchoscopy with BAL and/or open lung biopsy may be ­necessary to make a definitive diagnosis. Key point: Clinical presentation and plain chest radiography most often do not distinguish between drug-induced and other causes of pneumonitis.

Management of cardiac and pulmonary treatment–related side effects An echocardiogram may help to exclude a cardiac cause, especially when pulmonary edema is present; serologically, the measurements of BNP may also be useful. Key point: A normal BNP and a normal echocardiogram virtually exclude any cardiac causes.

Treatment Treatment is dictated by the diagnosis. The first step is when drug-induced pulmonary toxicity is suspected to stop the most likely offending drug. Assessment of hypoxemia dictates the use of supplemental oxygen or mechanical ventilation. Until a definitive diagnosis is made, empirical use of broadspectrum antibiotics until cultures are returned is the usual standard of care. In the absence of sepsis that dictates appropriate antibiotic use, a trial of high-dose steroids may be beneficial.

Supportive oncology It is essential to be overcautious and avoid iatrogenic fluid overload, especially when the patient presents with ­initial hypotension that may be initially managed with a fluid ­challenge. During the acute phase of chemotherapy-induced pulmonary injury, renal function may be temporarily compromised, which may contribute to fluid retention and higher drug levels. In addition to strict measurements of fluid intake and output, we recommend strict adherence to a policy of daily weights to help follow fluid status.

CHRONIC LUNG INJURY Less common than acute pneumonitis is the development of pulmonary fibrosis resulting in restrictive lung disease. The latter is defined by reductions in lung volumes, especially total lung capacity, with accompanying reductions in d­ iffusing capacity (DLCO). Symptoms consist of varying degrees of dyspnea that may occur insidiously and may progress over time, with or without a nonproductive cough. Physical examination may be unremarkable, or dry rales may be appreciated on lung auscultation. Imaging studies may show areas of fibrosis and/or a decrease in lung volume with a shift of mediastinal structures. PFTs typically show a restrictive pattern. The pathogenesis is most likely initial lung injury followed by ongoing inflammation with immune activation and the liberation of ­inflammatory cytokines, ultimately leading to fibrosis. Key point: Chronic chemotherapy-induced pulmonary fibrosis is less common than acute interstitial pneumonitis. Because this ends up being mainly a mechanical problem (i.e., a reduction in lung volume), supportive therapy and supplemental oxygen when indicated are limited management

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options. The value of long-term immunosuppression with steroids has not been proved. Infections should be aggressively treated in the early phases to avoid respiratory decompensation.238–240

Supportive oncology Pulmonary rehabilitation has a role in this population to maintain or improve functional capacity and to provide psychosocial support.

LUNG INJURY AFTER BONE MARROW TRANSPLANTATION The range of pulmonary toxicity after bone marrow transplant is similar to that described for chemotherapy in general. In addition, consideration of graft-versus-host disease (GVHD) is always a possibility. In-depth reviews of this subject have been published.241,242

CLINICAL PEARLS Chemotherapy- and radiation therapy–induced pulmonary injury may be insidious or may present with severe and ­rapidly fatal pulmonary decompensation. n The presentation of various possible syndromes is generally similar in spite of multiple pathophysiologic entities, and the diagnosis is almost always one of exclusion. n Because most of these patients are immunocompromised, opportunistic infections are always in the background. n

SUMMARY Current treatment of cancer with multimodality therapies that include chemotherapy and radiation has been effective in curing many cancers and has converted others to chronic diseases. This has created a group of long-term survivors that numbers hundreds of thousands, whose ranks continue to swell. The downside of this miraculous increase in cure and survival is the potential for acute and chronic cardiac and ­pulmonary ­toxicity. As treatments continue to be more effective, the potential risk for late toxicity increases in proportions that make diagnostic and management knowledge essential for most caregivers in the future. Successful management of this population requires a team approach that includes physicians of many specialties, as well as nursing and support personnel.

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202. Handa N, McGregor CGA, Danielson GK, et al. Coronary artery bypass grafting in patients with previous mediastinal radiation therapy. J Thorac Cardiovasc Surg. 1999;117:1136–1143. 203. Tamura A, Takahara Y, Mogi K, et al. Radiationinduced valvular disease is the logical consequence of irradiation. Gen Thorac Cardiovasc Surg. 2007;55:53–56. 204. Chang ASY, Smedira NG, Chang CL, et al. Cardiac surgery after mediastinal radiation: extent of exposure influences outcome. J Thorac Cardiovasc Surg. 2007;133:404–413. 205. De Bruin ML, Dorresteijn LD, van't Veer MB, et al. Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma. J Natl Cancer Inst. 2009;101:928–937. 206. Morris B, Partap S, Yeom K, et al. Cerebrovascular disease in childhood cancer survivors. A Children's Oncology Group Report. Neurology. 2009;73:1906–1913. 207. Yorke ED, Jackson A, Rosenszweig KE, et al. Dosevolume factors contributing to the incidence of radiation pneumonitis in no small cell cancer patients treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Phys. 2002;54:329–339. 208. Abratt RP, Ong FT, Morgan GW, et al. Pulmonary complications of radiation therapy. Clin Chest Med. 2004;25:167–177. 209. Brady LW, Germon PA, Cander L. The effects of radiation therapy on pulmonary function in carcinoma of the lung. Radiology. 1965;85:130–134. 210. Marks LB. The pulmonary effects of thoracic irradiation. Oncology. 1994;8:89–100. 211. McDonald S, Rubin P, Phillips TL, et al. Injury to the lung from cancer therapy: clinical syndromes, measurable endpoints, and potential scoring systems. Int J Radiat Oncol Biol Phys. 1995;31:1187–1203. 212. Garipagalou M, Munley MT, Hollis D, et al. The effect of patient specific factors on radiation induced lung injury. Int J Radiat Oncol Biol Phys. 1999;45:3331–3338. 213. Roach M, Grandara DR, You HS, et al. Radiation pneumonitis following combined modality therapy for lung cancer: analysis of prognostic factors. J Clin Oncol. 1995;13:2606–2612. 214. Dechambre S, Dorzee J, Fastrez J, et al. Bronchial stenosis and sclerosing mediastinitis: an uncommon complication of external thoracic radiotherapy. Eur Respir J. 1998;11:1188–1190. 215. Hirsch A, Vander els N, Strauss DJ, et al. Effect of ABVD chemotherapy with and without mantle or mediastinal radiation on pulmonary function in early stage Hodgkin's disease. J Clin Oncol. 1996;14:1297–1305. 216. Zhao L, Sheldon K, Chen M, et al. The predictive role of plasma TGF-β1 during radiation therapy for radiation-induced lung toxicity deserves further study in patients with non-small cell lung cancer. Lung Cancer. 2008;59:232–239. 217. Yahalon J, Portlock CS. Long-term cardiac and pulmonary complications of cancer therapy. Hematol Oncol Clin North Am. 2008;22:305–318. 218. Mao J, Oluwatoyosi A, Fatunase, et al. Cytoprotection for radiation-associated normal tissue injury. Radiat Oncol Adv. 2008;139:302–322. 219. Hensley ML, Hagerty KL, Kewalramani T, et al. American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol. 2009;27:127–145. 220. Limper AH. Chemotherapy-induced lung disease. Clin Chest Med. 2004;25:53–64.

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221. Vahid B, Marik PE. Pulmonary complications of novel antineoplastic agents for solid tumors. Chest. 2008;133:528–538. 222. Dimopoulou I, Bamias A, Lyberpoulos P, et al. Pulmonary toxicity from novel antineoplastic agents. Ann Oncol. 2005;17:373–379. 223. Shimura T, Kuse N, Yoshinto T, et al. Clinical features of interstitial lung disease induced by standard chemotherapy (FOLFOX or FOLFARI) for colo-rectal cancer. Ann Oncol. 2010; March. 224. Liu V, White DA, Zakowski MF, et al. Pulmonary toxicity associated with erlotinib. Chest. 2009;132:1042–1044. 225. Camus P, Fanton A, Bonniaud P, et al. Interstitial lung disease induced by drugs and radiation. Respiration. 2004;71:301–326. 226. Takano T, Ohe Y, Kusumoto M, et al. Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced nonsmall cell lung cancer treated with gefitinib. Lung Cancer. 2004;45:93–104. 227. Kudoh S, Kato H, Nishiwaki Y, et al. Interstitial ling disease in Japanese patients with lung cancer: a cohort and nested case-control study. Am J Respir Crit Care Med. 2008;177:1348–1357. 228. White DA, Stover DE. Severe bleomycin-induced pneumonitis: clinical features and response to corticosteroids. Chest. 1984;86:723–728.

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229. Maher J, Daly PA. Severe bleomycin lung toxicity: reversal with high dose corticosteroids. Thorax. 1993;48:92–94. 230. Sleijfer S. Bleomycin-induced pneumonitis. Chest. 2001;120:617–624. 231. Simpson AB, Paul J, Graham J, et al. Fatal bleomycin pulmonary toxicity in the west of Scotland 1991–95: a review of patients with germ cell tumours. Br J Cancer. 1998;78:1061–1066. 232. Koschel D, Handzhiev S, Leucht V, et al. Hypersensitivity pneumonitis associated with the use of temzolomide. Eur Respir J. 2009;33:931–934. 233. Muller NL, White DA, Gemma A. Diagnosis and management of drug-associated interstitial lung disease. Brit J Cancer. 2004;91(suppl 2):524–530. 234. Hupt HM, Hutchins GM, Moore GW. Ara-C lung: noncardiogenic pulmonary edema complicating cytosine arabinoside therapy of leukemia. Am J Med. 1981;70:256–261. 235. Briasoulis E, Pavlidis N. Noncardiogenic pulmonary edema: an unusual and serious complication of anticancer therapy. Oncologist. 2001;6:153–161. 236. Antony VB, Loddenkemper R, Astoul P, et al. Management of malignant pleural effusions. Eur Respir J. 2001;18:402–419.

237. Dimopoulou I, Galani H, Dafni U, et al. A prospective study of pulmonary function in patients treated with paclitaxel and carboplatin. Cancer. 2002;94:452–458. 238. O'Driscoll BR, Hasleton PS, Taylor PM, et al. Active lung fibrosis up to 17 years after chemotherapy with carmustine (BCNU) in childhood. N Engl J Med. 1990;323:378–382. 239. Alvarado CS, Boat TF, Newman AJ. Lateonset pulmonary fibrosis and chest deformity in two children treated with cyclophosphamide. J Pediatr. 1978;92:443–446. 240. Codling BW, Chakera TM. Pulmonary fibrosis following therapy with melphalan for multiple myeloma. J Clin Pathol. 1972;25:668–673. 241. Chan CK, Hayland RH, Hutcheon MA. Pulmonary complications following bone marrow transplantation. Clin Chest Med. 1990;11:323–332. 242. Wah TM, Moss HA, Robertson RJ, et al. Pulmonary complications following bone marrow transplantation. Br J Radiol. 2003;76:373–379.

Gonadal function after cancer treatment

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Jan Oldenburg, Cecilie Kiserud, Henriette Magelssen, Marianne Brydøy, and Sophie D. Fosså

Normal gonadal function  95 Males  95 Females  96 Gonadal function and cancer  96 Posttreatment gonadal function  96 Males  96 Chemotherapy  96 Radiotherapy  97 Surgery  98 Hormonal Cancer Treatment  98 Females  98 Chemotherapy  98 Radiotherapy  98 Surgery  99 Hormonal Cancer Treatment  99 Effects of gonadotoxicity on the offspring  99 Prevention of gonadal dysfunction  99 Males  99 Females  99 Conclusions  100

Human gonads (i.e., testicles and ovaries) are endocrine organs containing our germ cells. Cancer and its treatment may compromise both endocrine function and chances to generate and foster healthy offspring. In general, cancer is more common in elderly patients for whom fertility preservation might no longer be an issue, whereas younger patients might base their preferred treatment option on in-depth counseling about the risk of infertility.1

Gonadotoxicity is an unintended complication of cancer treatment, but in cases of hormone-driven cancers (e.g., those of the breast or of the prostate), complete disruption of endocrine function may be unavoidable. Principally, reduced endocrine gonadal function may be caused by insufficiency of the gonad (i.e., primary hypogonadism) or by insufficient hormonal stimulation (i.e., secondary hypogonadism). In this chapter, we provide an overview of different aspects of gonadal toxicity in cancer treatment.

NORMAL GONADAL FUNCTION MALES The two main functions of the testicles are production of sperm and production of testosterone (i.e., endocrine and exocrine). Gonadotropin-releasing hormone (GnRH) is produced in the hypothalamus, and its oscillating levels stimulate the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the anterior pituitary gland and their release to the bloodstream. Sperm cells (spermatozoa) are continuously produced by the testicular germinal epithelium, and maturation of spermatogonias to mature sperm cells takes approximately 70 days. New cycles of spermatogenesis are initiated at regular time intervals (every 2–3 weeks) before the previous ones are completed. FSH and testosterone stimulate the Sertoli cells to provide hormonal and nutritional support for spermatogenesis.2,3 Sertoli cells, regulated by FSH and spermatogenic status, secrete inhibin B, which limits FSH secretion through a negative feedback mechanism.4 In the adult, serum inhibin B levels correlate with total sperm count and testicular volume. Therefore, both FSH and inhibin B are considered useful markers of spermatogenesis. Spermatogenesis is usually evaluated by semen analyses, but in some cases, a testicular biopsy may be required. Testosterone production, the principal testicular endocrine function, is prone to an age-related decrease. Testosterone is mostly bound to circulating plasma proteins: 40% to 50% is loosely bound to albumin, 50% to 60% is bound tightly to sexual hormone–binding globulin (SHBG), and only 1% to 2% represents free testosterone. The latter and the ­albumin-bound testosterone fraction form the effective pool ­determining the biological activity of testosterone. Because the amount 95

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of SHBG increases by age, the decrease in free serum testosterone is more pronounced than the total testosterone concentration.5

FEMALES Female germ cells, as opposed to their male counterparts, do not proliferate post partum. At birth, the ovaries contain 1 to 2 million primordial follicles, most of which are destined to regression by a process called follicular atresia. From menarche to menopause, only 400 to 500 of the remaining 400,000 follicles are progressively released, whereas roughly 1000 per month are lost by apoptosis. By the age of 50, about 1000 remain; thus chances of natural conception are markedly reduced already, some years before menopause. Each oocyte remains in meiotic division from birth to ovulation. Interplay of a follicular two-cell system regulates the generation of steroidal hormones and follicular growth. LH and FSH stimulate cells of the theca and granulosa to produce and secrete estrogen, whereas initiation of follicular maturation is promoted by paracrine growth factors. A growth-stimulated follicle develops over a 3-month period until the time of degeneration or ovulation. Reduced numbers of follicles increase the risk of premature ovarian failure (POF), defined as menopause before 40 years of age in combination with low estrogen levels. A low oocyte reserve may decrease the chance of subsequent conception, despite a normal menstrual cycle.6 The number of remaining oocytes determines the tolerance of the ovaries toward an injury, ranging from continuously normal function to immediate loss of function. Even before the occurrence of POF, periods of transient amenorrhea may alternate with periods of apparently normal function. Menopause (i.e., the end of menstruation) defines the end of reproductive capability, but female fertility begins to decline already by the age of 30 years. The trend in the Western world to postpone pregnancy to the 30s contributes to the increasing demand for assisted reproduction techniques. For many women, the time required for diagnosis and treatment of their malignancy and subsequent recovery can reduce the chances of motherhood, because already by the age of 40 years, natural and artificial conception may be hampered by decreasing follicle numbers and oocyte quality. Simultaneously with lower chances of pregnancy, the risks of aneuploidy and abortion are increased.

GONADAL FUNCTION AND CANCER Cancer itself, and sometimes susceptibility to develop a malignancy, may impair gonadal function. Occult ovarian dysfunction may be associated with BRCA mutations.7 Thus, women with BRCA-associated breast cancer may experience a higher infertility risk already, before undergoing cancer treatment.7 Men requiring artificial reproduction techniques are estimated to have an almost 20 times higher incidence of testicular cancer as compared with men without infertility problems.8 For men with testicular cancer and Hodgkin's lymphoma, reduced spermatogenesis as compared with the general population before the time of diagnosis has been 96 reported.9,10

In testicular cancer patients, Skakkebaek et al hypothesize a testicular dysgenesis syndrome, comprising low sperm count, hypospadias, and cryptorchidism.11 The association between decreased male fertility and testicular cancer is well documented,12 and about half of patients diagnosed with testicular cancer have reduced spermatogenesis after orchiectomy before receiving additional treatment.13 Furthermore, biopsies have revealed that 24% of patients with unilateral testicular cancer probably have irreversibly impaired spermatogenesis in the contralateral testicle.14

POSTTREATMENT GONADAL FUNCTION Cancer treatment is changing over time, and evaluation of its gonadotoxic effects, particularly on the parenthood rate, requires sufficiently long follow-up. Therefore, published observations related to these topics often pertain to yesterday's treatment and do not take into account risk-adapted treatment options attempted today, particularly in the youngest patients.

MALES

Chemotherapy Gonadotoxic effects of cytostatic drugs hinge on several factors, among them the type of chemotherapy, the cumulative doses, the time since treatment, and the pretreatment fertility of the patient.6 Alkylating agents (cyclophosphamide, ifosfamide, chlorambucil, nitrosoureas, melphalan, busulfan, and procarbazine) are the most gonadotoxic cytostatic drugs (Table 10-1). The so-called “blood–testis barrier” refers to an intratubular nutritional germ cell compartment formed by Sertoli cells. However, blood vessels at that site are permeable, and cytostatic drugs reach intratubular cells (i.e., Leydig and Sertoli

Table 10-1  Expected gonadotoxicity of chemotherapy regimens High

Medium

Low

Unknown

procarbazine cyclophosphamide nitrogen mustard chlorambucil mechlorethamine ifosfamide busulfan MOPP MVPP ChlVPP MOPP/ABVD COPP/ABVD COPP HDT

cisplatin carboplatin oxaliplatin BEP CHOP

methotrexate Adriamycin prednisolone doxorubicin vincristine vinblastine 5-FU bleomycin ABVD

trastuzumab (herceptin) docetaxel (taxaner) monoclonal antibodies

ABVD, Doxorubicin, bleomycin, vinblastine, dacarbazine; BEP, bleomycin, etoposide, cisplatin; ChlVPP, chlorambucil, vinblastine, prednisolone, procarbazine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; CMF, cyclophosphamide, methotrexate, 5-FU; COPP, cyclophosphamide, vincristine, procarbazine, prednisolone; FEC, cyclophosphamide, epirubicin, 5-FU; 5-FU, 5-fluorouracil; HDT, highdose chemotherapy with autologous stem cell support; MOPP, nitrogen mustard, vincristine, procarbazine, prednisolone; MVPP, mustine, vinblastine, procarbazine, prednisolone.

Gonadal function after cancer treatment

100

80 Fatherhood %

cells) and may affect spermatogonia. Consequently, sperm production is reduced after many types of chemotherapy. However, because late-stage germ cells are less sensitive to cytotoxic treatment than early-stage germ cells, it may take weeks until an effect on spermatogenesis is observable by sperm counts. Recovery of spermatogenesis relies on the ability of spermatogonial stem cells to survive drug toxicity and to retain the potential to differentiate to spermatocytes. In unilaterally orchiectomized long-term survivors of testicular cancer, the prevalence of primary hypogonadism, as defined by LH levels > 12 IU/l and/or testosterone < 8 nmol/l, increases with treatment intensity.15 Hypogonadism was observed in 19% and 27% of testicular cancer (TC) survivors after ≤ 850 mg and > 850 mg cisplatin, respectively, as compared with 9% of those who underwent surgery only (Fig. 10-1). Almost one third of male lymphoma survivors are hypogonadal, with risk increasing by age >50 years, with treatment with alkylating agents, and with high-dose chemotherapy with autologous stem cell support.16 Sperm production recovers in approximately 80% of TC patients after cisplatin-based chemotherapy within 2 years after treatment.17 Among TC survivors attempting fatherhood, the likelihood of succeeding correlates with treatment intensity: Those requiring chemotherapy have inferior fatherhood rates compared with those who were cured by surveillance, retroperitoneal lymph node dissection, or radiotherapy only (Fig. 10-2).18 Elevated FSH was reported in roughly one third of males treated for early-stage Hodgkin's lymphoma (HL).19 The ­probability of elevated FSH increased after treatment with alkylating agents, with age over 50 years at treatment, and with stage II versus stage I disease. After treatment with CHOP ­(cyclophosphamide, hydroxydaunorubicin, Oncovin [vincristine], and prednisone/prednisolone)-like ­chemotherapy

10

60

40 Surveillance, n=52 RPLND, n=81 RT, n=201 Cis ≤ 850 mg, n=81 Cis > 850 mg, n=37

20

0 0

5 10 15 20 Years from orchiectomy to first born child

Fig. 10-2  Actuarial posttreatment fatherhood rates for testicular cancer survivors attempting conception by natural means according to treatment groups (P < .001, two-sided log-rank test). cis, Cisplatin; RPLND, retroperitoneal lymph node dissection; RT, radiotherapy. Vertical bars indicate 95% confidence intervals. (Redrawn from Brydoy M, Fossa SD, Klepp O, Bremnes RM, Wist EA, Wentzel-Larsen T, et al. Paternity following treatment for testicular cancer. J Natl Cancer Inst 2005;97:1580–1588.)

for non-Hodgkin's lymphoma, spermatogenesis is reported to recover in about two thirds of patients,20 whereas approximately 80% of TC patients will have sperm production after cisplatin-based chemotherapy within 2 years after treatment.17 High-dose chemotherapy with stem cell support will render most patients infertile.21

30 70

25 20 303 15

433

10 229 5

190

0 1 Controls

2 Surgery only

3 Rad. only

4 Chem+ ≤ 850

5 Chem+ > 850

Fig. 10-1  Percentage of testicular cancer survivors (TCSs) with hypogonadism as defined by serum testosterone 12 IU/l. Controls, Age-matched males from the normal population; Surgery only, TCSs treated by surgery only; Rad. only, TCSs treated by radiotherapy only; Chem+ ≤850 mg/>850 mg, TCSs treated by chemotherapy with a cumulative cisplatin dose ≤850 mg/>850 mg. (Data from Nord et al [2003],15 with permission by the authors.)

Radiotherapy The gonadotoxic effect of radiation therapy depends on dose, fractionation, and site of radiotherapy. Cranial radiation in doses of 40 to 70 Gy (e.g., for brain tumor) may cause hypogonadotropic hypogonadism (secondary hypogonadism) and is seen in up to 61% of patients.21a,21b Sperm cells are highly ­radiosensitive and may be damaged by direct or scattered ­radiation to the testicles. The latter effect is observed, for example, in radiotherapy for prostate, bladder, or rectal cancer, with irradiation given in doses of 0.4% to 18.7% of the target dose during treatment.22–24 The testicles, as opposed to most other organs, appear to tolerate single doses of radiation better than fractionated radiotherapy. The lowest sperm counts after radiotherapy are usually observed 4 to 6 months after treatment. Duration of oligozoospermia depends on the applied dose, and recovery of spermatogenesis can be expected 9 to 18 months after unfractionated radiation doses of 1 Gy or less to the testicles, 30 months after doses of 2 to 3 Gy, and 5 years or longer after doses of 4 Gy and above, whereas radiation doses of 4 Gy and above may result in permanent azoospermia.25,26 However, recovery of spermatogenesis is reported in 15% of patients receiving single doses of 8 Gy as total body irradiation before 97

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bone marrow transplantation,27 and recovery from azoospermia has been observed as long as 9 years after treatment.27 Pelvic radiotherapy with 46 to 50 Gy for rectal cancer results in testicular doses between 3.7 and 13.7 Gy and causes a 100% increase in serum FSH, a 70% increase in LH, and a 25% reduction in testosterone levels among men with a median age of 65 years.28 Thus, irradiation of the prostate is more often associated with hypogonadism than with radical prostatectomy.29 External beam radiotherapy with 70 Gy, as opposed to surgery, led to a decline of total and free testosterone levels by 27.3% and 31.6%, respectively, and LH and FSH increased by roughly 50% and 100%, respectively. The effect on gonadotropin levels was most significant in men older than 70 years. Scatter radiation is increased when inguinal lymph nodes are included in the radiation field for prostate cancer; the resulting decreased testosterone values may actually unfold a therapeutic effect.30 Radiotherapy for prostate, bladder, or rectal cancer may result in scattered irradiation in doses of 0.4% to 18.7 % of the target dose during treatment.22–24 However, most men in their middle and late 60s do not attempt to achieve fatherhood, and impaired spermatogenesis is usually not considered a problem for most of these patients. Some gonadotoxic effects of radiotherapy cannot be assessed by sperm count or hormone levels. DNA integrity of sperm may be compromised after irradiation: Ståhl et al31 demonstrated DNA damage in 38% of normospermic testicular cancer patients 1 to 2 years after irradiation of infradiaphragmatic para-aortic and ipsilateral iliac lymph nodes (i.e., so-called hockey stick field) as compared with 7% in healthy controls. The radiotherapy dose of 25.2 Gy was applied in 14 fractions, and the contralateral testicle, shielded by lead, probably did not receive more than 0.5 Gy (i.e., 80%) risk at age > 40 years, medium risk for women in their 30s, and low risk (75% of the cortex is lost.29 Surgeons who are considering surgical repair screen painful bone lesions with plain ­radiographs for this reason. Bone scans have high sensitivity but low specificity for bone metastases. Positivity is dependent on reactive bone around metastases. Bone scans do not reveal pure osteolytic lesions (as occur with multiple myeloma).29 Only one third of bone metastases imaged by bone scans are painful. The distribution using technetium 99 is as follows: 39% vertebral; 38% rib and sternum; 12% pelvis, and 10% skull and long bones. Osteolytic lesions appear as “cold spots.”29 Scans are positive for nonmalignant reasons in 23% to 30% of individuals with metastatic cancer. Super scans reveal red marrow extension to juxta-articular areas. The super scans appear “normal,” except there is an absence of kidney shadows and diffuse juxta-articular uptake is

13

noted.29 Bone scans can appear to worsen with response to chemotherapy (called “flare”) in prostate and breast cancer, which can persist for 6 months. Treating oncologists can be misled by bone scans during this time. Screening of asymptomatic individuals with early-stage cancer with bone scans has a low yield (50 years and without a history of cancer, is 9%.30 In this situation, it is better to obtain plain radiographs followed by computed tomography (CT) scans or magnetic resonance imaging (MRI). Bone scans can be positive 3 to 18 months before metastases are visualized on plain radiographs.31

CT SCANS Computed tomography imaging is guided by symptoms and plain radiographs.31 CT scanning is more cumbersome, is not portable, and gives only limited views of the bone. CT scans clarify bone scan–positive lesions in individuals unable to undergo MRI, or who are intolerant of MRI procedures because of claustrophobia. CT scans are combined with myelography to image spinal cord compression.31,32 CT scans will differentiate ­vertebral hemangiomas from metastases and will detect bone marrow metastases independent of bone destruction (differences of >20 Hounsfield units compared to normal fatty marrow).31,32

MRI Magnetic resonance imaging detects skeletal metastases with greater sensitivity and specificity than bone scans but provides limited views of the bone. Bone scans detect only one third to two thirds of lesions found on MRI.31,32 Skeletal metastases have low signal on T1-weighted images (marrow has high signal on T1 images) and high signal on T2-weighted images caused by water content found in metastases.31,32 A rim of bright T2 signal may be found around metastases (halo sign). Fat suppression T1-weighted images differentiate localized fatty deposits in bone and bone marrow from metastases.31,32 MRI differentiates bone edema, degeneration, and inflammation from metastases and visualizes bone marrow metastases.31,32 Gadolinium-enhanced MRI is important when imaging spinal soft tissues, epidural space, and spinal canal, but is not needed for bone images.31,32 Short-tau inversion recovery (STIR) sequences and coronal and axial views help clarify the locations and extent of metastases. MRI is the image modality of choice for vertebral metastases.29 MRI, like bone scans, is subject to super scan artifact from diffuse bone marrow and bone metastases.31 Malignant fractures in contrast to osteoporotic fractures have diminished T1 sequences and are associated with pedicle and posterior vertebral body involvement and epidural or paraspinal masses.29

LIVER METASTASES Each imaging modality has size limitations; lesions 250 mg every 4 hours.41 Transient flares of pain on ATC opioids are managed by “rescue” doses of the same potent opioid if at all possible. Several recommendations have been made for rescue: (1) the 4-hourly dose as the rescue dose every 1 to 2 hours as needed38; (2) 10% to 20% of the daily morphine dose (or equivalent)39; or (3) 50% of the 4-hourly dose given every 2 hours.42 Pain flares are volitional incident, nonvolitional incident, spontaneous, or end-of-dose failure. End-of-dose failure is managed by increasing the ATC opioid dose.43 Some consider end-of-dose failure to be an indicator of suboptimal ATC doses, and not of breakthrough pain. Transdermal fentanyl is increasingly being used for cancer pain. The initial dose is 12 μ per hour, which is equivalent to 30 mg of oral morphine per day.44 Transdermal fentanyl generic patches are commercially available as matrix and reservoir patches. Systematic experimental and clinical evidence of bioequivalence between the different patches is not established. Single case reports have described respiratory depression when matrix patches using the same dose are switched for reservoir patches.44 Time to maximum concentration after placement of a transdermal patch ranges between 12 and 40 hours. Patches should not be changed more frequently than every 48 hours during titration. Oral morphine and transmucosal or transbuccal fentanyl is used for rescue.45 Alternatively, intravenous or subcutaneous fentanyl is titrated to pain response and the effective dose converted to transdermal fentanyl using a 1:1 ratio. Dermal absorption is highly variable between individuals, so doses will need to be adjusted after conversion.45 Pain flares often peak within 2 to 5 minutes of onset and resolve within 30 to 60 minutes. Half of pain flares are spontaneous.46,47 Volitional incident and procedural pain may be treated preemptively. Onset and offset of most pain flares do not match the onset of oral opioid analgesia (≥30 minutes). The opioid dose needed to relieve pain flares poorly corresponds to the effective ATC dose, particularly when transmucosal or transbuccal fentanyl is used.48–50 Particular opioid formulations have been developed that bypass hepatic clearance, have a rapid onset and offset of action, and are relatively easy to administer, with high patient acceptance (Tables 13-2 and 13-3).43

OPIOID TITRATION If pain is uncontrolled with ATC opioid doses and breakthrough (rescue) doses, ATC and rescue doses over the last 24 hours are summed and increased by 30% to 50%. For ­example, an individual on sustained-released morphine 60 mg

Cancer pain

Table 13-2*  Opioid formulations for pain flares48 Transmucosal fentanyl   ACTIQ (Cephalon Inc., Frazer, PA, USA) Transbuccal fentanyl   Fentora (Cephalon Inc., Frazer, PA, USA)   Abstral (Prostakan, Galashiels, UK) Intranasal fentanyl   Instranyl (Nycomed, Zurich, Switzerland)   Nasalfent (Archimedes Pharma, Reading UK) *Rescue doses are titrated to response after chronic pain is under control.49

Table 13-3  Recommendations for managing cancer-related breakthrough pain47,49,50 Assess for presence and severity of pain flares. Consider treating the underlying mechanism. • Single-fraction radiation, bisphosphonates, and radioisotopes for bone pain • Kyphoplasty for vertebral fractures Use avoidance treatment of precipitating factors. Preemptively treat volitional incident pain and procedural pain. Use nonopioid analgesics. • NSAIDs for bone pain • Gabapentin, pregabalin for neuropathic spontaneous pain • Ketamine rescue for spinal analgesia • Anticholinergics for colic from bowel obstruction Maximize ATC opioid dose, particularly for end-of-dose failure. Use interventional techniques. • Neurolytic blocks • Regional anesthesia Use behavioral modalities, imagery, and mind/body techniques with analgesics. Assess breakthrough pain response with each change in analgesics.

every 12 hours and 20 mg of immediate-release morphine every 4 hours who has taken four rescue doses over 24 hours has a baseline pain >7 (NRS), and the summed dose is 120 mg + 80 mg, or 200 mg. The dose is increased by 30%, or 260 mg. The adjusted dose should then be sustained-release morphine 130 mg every 12 hours with rescue dose adjusted to 30 mg to 45 mg every 1 to 2 hours as needed.43 If pain is controlled but more than four rescue doses are needed to control chronic pain, the rescue doses are added to the ATC dose unless the pain is predominantly incident pain. If chronic pain is controlled but pain flares remain severe, the rescue dose is increased incrementally (by 30%–50%) for pain control. Alternatively, transmucosal, transbuccal, or intranasal fentanyl is used and titrated to response.48

ACUTE PAIN DOSING STRATEGY Severe and rapidly changing pain is not to be treated the same way that chronic pain is treated. Morphine is given at a dose of 1 mg to 2 mg intravenously every 1 to 2 minutes until significant

13

pain reduction is achieved.51 Responses are generally seen within 30 to 60 minutes. Alternatively, 1.5 mg is given every 10 minutes, or 10 mg to 15 mg every 15 minutes. This should be done by a physician at the bedside. Naloxone should be available for potential overdose.51 Pain assessment is done frequently; significant pain response, but not total analgesia, is the goal. Alternative opioids include hydromorphone 0.2 mg or fentanyl 20 μ every 1 to 2 minutes in place of morphine.51 Maintenance doses after titration are one third to one fourth of the effective dose given as an hourly continuous dose. Alternatively, the effective dose is converted to oral equivalent morphine equivalents (by multiplying by 3) and is given every 4 hours ATC. The chronic opioid dose before titration in opioid-tolerant individuals will have to be added to the effective dose to avoid a relapse of pain. Naloxone hydrochloride reverses opioid-induced respiratory depression at small doses (40 μ–100 μ) and should be given intravenously until the level of consciousness improves and spontaneous respirations are >10 per minute.52–55 Naloxone can be given subcutaneously and intranasally to reverse opioid toxicity. Continuous infusion may be needed in those on sustained-release morphine, transdermal fentanyl, or methadone.52–55

OPIOID POORLY RESPONSIVE PAIN Unrelieved chronic pain and concurrent dose-limiting side effects (delirium, hallucinations, myoclonus, nausea, or vomiting) are managed in three different ways: (1) opioid switch, (2) opioid route conversion, or (3) the addition of an adjuvant analgesic and opioid reduction (30%–50%).56–59 Several factors predict for opioid responsiveness. Neuropathic pain, breakthrough pain, opioid tolerance, and young age predict for less opioid responsiveness.59

OPIOID ROTATION Opioid switches or rotations reduce pain and opioid side effects in part because of lack of cross-tolerance between opioids.56 Disadvantages or pitfalls to rotation are that opioid conversion tables are largely based on single-dose studies, availability of certain opioid formulations is limited, potential drug interactions may occur with the second opioid, and treatment expenses are increased.58 Wide variability in ­equivalence is seen between individuals, and therefore wide confidence intervals with ratios56 (Tables 13-4 and 13-5).

OPIOID ROUTE CONVERSION Route conversions for uncontrolled pain and side effects are usually epidural or intrathecal.60-64 Conversions from oral to parenteral morphine may improve pain control and reduce side effects, but the usual reason is mucositis, dysphagia, nausea, vomiting, enteric fistula, or bowel obstruction due to the number of tablets or the need for rapid opioid titration.65 Epidural opioids are usually initiated when opioid rotation and adjuvants have failed to reduce pain or are limited by side effects.65 Epidural opioid analgesia should not be selected solely because systemic opioids have failed to relieve pain. Low doses of opioid will reduce pain via the ­epidural route in those experiencing intractable opioid side effects with 129

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Table 13-4  Equianalgesic table60,61

Table 13-6  Indications for Epidural Analgesia65

Opioid

Oral

Parenteral

Morphine

30

10

Hydromorphone

6

2–3

Fentanyl

1:70–100

Oxycodone

20–30

Methadone

4:1 (morphine 90 mg300 mg–1000 mg/day)

Equivalents have a clinical context such as organ function, medication, and individual genetic constitution, which governs opioid metabolism and opioid receptor activation.56,62,63 Equianalgesic ratios are not bidirectional equivalents. Rotations are usually “stop-start,” in which the first opioid is stopped while the second is started.

Table 13-5  Guidelines for Opioid Rotation56,62,63 • Be sure the patient was compliant with the ATC and rescue doses. • Be sure there is no other cause for symptoms that mimic opioid toxicity (hypercalcemia, brain metastases). • Consider route conversion or the addition of adjuvant analgesic as an alternative to opioid rotation. • Assess the clinical context of the patient (organ function, age, comedications, reasons for rotation, previous opioid response, comorbidities). • When rotating for opioid toxicity, a 30% to 50% dose reduction in the opioid equivalent should be the initial dose. • When rotating predominantly for pain, the initial opioid dose is the equivalent. • Individuals who are frail, elderly, or on high opioid doses and who are experiencing toxicity should have opioid rotations at a 50% reduction of equivalence. • Rotations to methadone should be performed with extreme care by using an experienced prescriber and a linear equivalent ratio (see Table 14-4) or 10% of the total daily oral morphine dose, up to 30 mg at the single maximum dose, every 3 hours orally as needed.

s­ ystemic opioids.65 Ranking order for responsive pains with epidural analgesia is as follows: somatic continuous pain, visceral continuous pain, somatic intermittent, neuropathic intermittent or continuous, and cutanous (cancer or fistula).65 Epidural opioids are used for individuals who have 1 month or less to survive.65 Indications and contraindications for epidural analgesia are outlined in Tables 13-6 and 13-7. Individuals who undergo spinal analgesia are opioid tolerant, thus combinations of opioids and local anesthetics are frequently needed to improve pain control.65–68 Metastatic vertebral metastases account for one of the most severe pain 130 syndromes. Vertebral body metastases involve the posterior

• Short life expectancy (usually ≤1 month) • Pain scores >6 (NRS) after opioid titration, rotation, and systemic adjuvants with limited side effects or intolerance • Neuropathic and somatic pain • Continuous plus intermittent or intermittent pain • Patient acceptance • Adequate community resources and support systems to maintain epidural analgesia at home

Table 13-7  Contraindications to Epidural Analgesia65 • Patient refusal • Lack of community support system or adequate informal caregivers • Platelet counts 30 minutes at least 3 nights per week 2. Sleep efficiency (total sleep time/total time spent in bed × 100) 30) at the time of administration.45 It is interesting to note that one small (N = 35) study demonstrated that a substantial proportion— 80%—of girls treated for childhood leukemia before the onset of menarche subsequently progressed through puberty normally; however, follow-up was insufficient to allow conclusions about the impact of treatment on later fertility.46 Other intriguing studies have demonstrated a higher incidence of CIA in women treated during the follicular phase of their menstrual cycle,47 as well as possible protective effects of coadministration of oral contraceptives48 or gonadotropin-releasing hormone (GnRH) agonists49 before and during ­chemotherapy; these findings warrant further study. In summary, because of the high likelihood of ovarian damage, all women of repro-

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ductive age should be informed of the possibility of CIA before beginning treatment, and options for fertility preservation should be discussed (please see the following section on Fertility After Cancer). In addition, because a significant minority of patients will eventually resume menstruation and be fertile after treatment, it is important to provide appropriate contraceptive counseling. Schwarz et al. provide an excellent recent review on this topic.50 In men, the most frequent chemotherapeutic culprits are high-dose alkylating agents and cyclophosphamide, which impair sexual function via direct injury to the testes. Cyclophosphamide causes the most sexual dysfunction due to damage to the Leydig cells, with consequent reduced production of testosterone and hypogonadism.51,52 Alkylating agents are more likely to damage seminiferous tubules and to limit sperm production without affecting testosterone production. Hormonal cancer therapies can exert unfavorable effects on sexual function in women by precipitating menopause altogether (e.g., lupron, tamoxifen) or by magnifying the effects of preexisting menopause-related hypoestrogenemia (e.g., tamoxifen, aromatase inhibitors).53 In addition, we have recently observed a very high frequency of vulvar lichen sclerosus in women in our practice who are taking aromatase inhibitors, which is not surprising because vulvar estrogen receptor expression and levels appear to be linked to the etiopathology of this entity54: Routine vulvar inspection is therefore a critical aspect of surveillance in patients on these medications. In men, hormonal cancer therapies cause sexual difficulties via effects on testosterone. Hormonal therapies are most commonly used in advanced prostate cancer for androgen deprivation therapy (ADT); however, ADT is now being increasingly used for short periods of time in men with early-stage disease. The most common form of ADT used in up to 90% of men is medical castration with a GnRH agonist—either leuprolide or goserelin. These agents lower testosterone levels significantly within 1 month, resulting in a decline in libido, erectile dysfunction, decreased size of the penis and/or testes, vasomotor changes, labile mood, fatigue, gynecomastia, and diminished self-image and quality of life.55 Although these adverse effects can occur after any form of treatment for prostate cancer, symptoms are frequently particularly severe in men using ADT56 and are exacerbated in men who are obese or of older age.57 Patients should always be counseled that recovery of sexual function after cessation of therapy is possible but is not guaranteed.58 Alternative regimens using antiandrogen monotherapy, such as bicalutamide without the addition of a GnRH agonist,59 or cyclic GnRH agonists with temporary withdrawal periods after an initial induction phase60 cause significantly less sexual dysfunction and fewer hot flashes, but without clear equality in disease control and survival. Until survival outcomes are more fully understood, these options remain controversial. Estrogens are sometimes used to complement ADT in men with prostate cancer; use of estrogens in men is associated with lethargy, poor libido, and erectile dysfunction.61 Immune-mediated cancer therapies can also affect sexual function in several ways. Immunocompromised patients are at increased risk for a number of infections, including candidiasis, which can be associated with vulvovaginal discomfort and pain on penetration. Bone marrow transplantation for ­hematologic malignancies frequently results in clinically manifest graft-versus-host disease (GVHD), which, in women, can 595

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result in a dry, thin, and painful vulvovaginal mucosa that is prone to scarring and stenosis.62 A recent case series suggests that vulvovaginal GVHD is relatively common, with typical cutaneous and soft tissue changes seen in 17 of 44 (39%) consecutive autologous bone marrow transplant recipients.63 These numbers suggest that routine perineal inspection should be the standard of care in women following transplantation. Because of the emphasis that the traditional medical model places on nature over nurture and the human tendency to seek quick pharmacologic fixes for our woes, we find that it is easy to fall into the trap of concentrating mainly on the physical effects of cancer treatment, rather than considering cancer’s numerous and equally important psychological and interpersonal effects. To avoid making this mistake, we find it helpful when evaluating patients to refer to a biopsychosocial model of sexual function (Fig. 57-3) that contains all of these features. Specific questions that delve into each of these key areas are presented later, in the section on history taking. 6. If sex was important before cancer, it generally remains important after cancer. Whether or not their lives are affected by cancer, some individuals and couples choose not to be sexually active and are content with that status. For example, 1% of respondents in a survey of the general population in the United Kingdom indicated that they were asexual (defined as having no sexual attraction to a person of either sex)64; approximately 20% to 30% of couples in committed relationships in another general population survey65 were estimated to be sexually abstinent (defined as engaging in sexual activity fewer than 10 times per year). Abstinence after a cancer diagnosis may not pose a

Relational-Interpersonal Factors: Partner availability Partner response to stress/couple coping style Satisfaction with non-sexual aspects of relationship Unresolved conflicts in the relationship Discrepant levels of sexual desire Inadequate stimulation/poor technical skill Excessive focus on vaginal intercourse (heterosexual couples) Excessive goal (orgasm) orientation Coincident sexual problems in partner Not making time

problem at all for individuals and couples such as these, and it is important to respect their choice. On the other hand, available evidence suggests that sexual activity is a priority for many people whose lives are affected by cancer: Some previously sexually active couples continue to have sex throughout the cancer experience, and most couples recommence or try to recommence sexual activity relatively early during the recovery period, usually in the first few months after treatment ends.66,67 Accordingly, cancer survivors and their partners typically have many questions about sex that deserve careful consideration (Table 57-2). Accurate information about what practices are safe during treatment (e.g., during chemotherapy and radiation administration in the setting of neutropenia and thrombocytopenia) and about what to expect and how to respond to changes in sexual function after ­treatment is ­crucial for these couples. 7. Adjustment and adaptation are heavily influenced by life stage and by both individual and couple coping responses. Acceptance of and successful adaptation to the physical changes associated with cancer treatment are influenced by each individual’s and couple’s psychological maturity and coping style, and also by the life phase during which cancer strikes. Significant changes in sexual function occur across the life cycle in association with acute stressors such as illness and the physiologic changes that come with major transitions such as puberty, pregnancy, breastfeeding, menopause, and senescence. Cancer treatment frequently causes an ­acceleration of the physiologic changes associated with aging. Careful explanation of this reality can help to normalize changes and facilitate adaptation, particularly for older individuals and couples

Psychosocial Factors

Relationalinterpersonal Factors

Biological Factors

Psychosocial Factors: Depression/anxiety/grief Meaning of loss of reproductive capacity Concurrent life stressors (e.g. financial) Response to stress/individual coping style Self-acceptance (identity/orientation) Self-esteem/self-efficacy Body image Perfectionism (performance anxiety) Attachment issues Past experiences Abuse/trauma history Sexual inexperience Cultural beliefs and prohibitions

Biological Factors: Aging Menopausal status Stage of cancer Type of cancer (site) Specific treatments (surgery, chemo, RT, hormones) Cormorbid illnesses (esp. vascular, neuromuscular) Functional status/Disability/Injury Prescription and non-prescription meds/substances

596

Fig. 57-3  Psychosocial and relational elements of the biopsychosocial model.

Sexuality and intimacy after cancer

Table 57-2  Common questions survivors have about sex Did sexual activity cause my cancer? Will sexual activity spread the cancer to my partner? Will my partner lose hair if we have sex during treatment? How long should I wait to have sex after (surgery, chemo, radiation)? What level should my (platelets, absolute neutrophil count) be? Can I get pregnant while receiving (chemo, radiation)? How will I know if I can still have children after treatment? Will sex feel different while I’m having treatment? If I’m too tired or too sick, how do I let my partner know I still care? Ever since treatment ended, I just don’t seem to be interested anymore, and my vagina feels sore. What can I do? Adapted from www.stjude.org.

who have weathered the impact of some age-related physical changes already, and in whom the incremental impact of cancer treatment therefore tends to be less severe and abrupt. For example, it can be helpful to explain to a couple that because of treatment-associated changes in genital sensitivity and responsiveness, it is expected that the patient will require more intense and prolonged genital stimulation to achieve orgasm, and that this change is not a manifestation of diminished affection for his or her partner. Younger individuals generally require significant support because it can be extremely daunting to face the challenges of embracing and exploring one’s sexuality for the first time in the context of heightened body image concerns and the uncertainty and fear that surround when and how to divulge a history of cancer to prospective partners. Coping response has an enormous impact on the intensity and duration of sexual difficulties that patients and/or their partners experience after cancer. As shown in Figure 57-4, people tend to develop fairly stereotypical reactions (e.g., the fight-or-flight response) in response to stress, in which exposure to the stressor leads to a cascade of emotions (e.g., fear), automatic thoughts (e.g., I’ve got to get away), and physical sensations (e.g., elevated heart rate) and/or ­behaviors (e.g., person runs away). Although the original intent of this type of cascade is generally adaptive (i.e., the goal is to achieve safety and security), the individual is often less well served when automatisms become too deeply ingrained over time. Consider the hypothetical reactions of two different cancer survivors to

Stressful situation

Automatic thoughts Moods/ feelings

Physical symptoms Behaviors Fig. 57-4  Impact of individual coping response.

57

the emotional and physical losses associated with cancer treatment. Both women start with a feeling of sadness related to the losses they have experienced (“I miss my old body and sex life”). For one woman, this feeling of sadness immediately triggers a cascade of negative thoughts (“I look really ugly,” “No one will ever want me”), which, when coupled with maladaptive physical responses to stress, result in preoccupation or withdrawal and avoidance of intimacy and sexual activity, and ultimately culminate in increased isolation and loneliness. The other woman, who has more highly developed coping skills, is able to transition quickly from a place of sadness into a proactive position with a positive thought (“I need to learn my new body”); this cognitive framing permits her to research and experiment with ways to manage her symptoms and to seek connection and strengthen relationships with others. Although not pictured here, it is easy to imagine how ever more complicated these cascades would become if the reactions of each woman’s partner were included. Fortunately, patients and their partners can be taught to recognize and replace negative with positive thoughts, thereby learning how to choose courses of action that facilitate more favorable outcomes. As shown in Figure 57-5, coping in couples can be greatly enhanced when a stressor is perceived as a dyadic stress, and the couple coordinates their efforts to find a shared solution. 8. Although pharmacologic treatments can be helpful, the most successful interventions include attention to ­psychological and couples issues and lifestyle and behavioral change. Given the inherent complexity of sexual function and the need to explore all aspects of the biopsychosocial model when evaluating patients who present with sexual difficulties, it should not be surprising that the most effective interventions are also multimodal and include attention to individual and couples counseling and lifestyle and behavioral change, in addition to pharmacologic manipulation. In discussing the need for attention to each of these areas, we find it helpful to review the ­concept of a “sexual tipping point” when counseling patients (Fig. 57-6). According to this model, the degree of sexual responsiveness that a person experiences at any one point in time is a product of all of the excitatory psychological, interpersonal, cultural, and physiologic factors that act to “turn on” the system at that time balanced against all of the psychological, interpersonal, cultural, and physiologic influences that act to “turn off” the system. An excess of excitatory influences results in faster and/or greater sexual response (e.g., “hot”), whereas a preponderance of inhibitory influences results in slower and/ or less intense response (e.g., “not”).68 Optimal results can be achieved only by concentrating on all areas that are amenable to improvement, rather than focusing solely on pharmacologic intervention. For patients and their partners who remain unconvinced, it is helpful to point out that the positive effects of counseling and lifestyle change reach far beyond the realm of sexual function (e.g., improved communication enhances overall relationship satisfaction, weight loss reduces the risks for diabetes and cardiovascular disease). Moreover, in contradistinction to medications, behavioral and counseling techniques are far less likely to be associated with undesirable side effects. 9. Successful intervention has a positive impact on quality of life (QOL) and overall functioning. Sexual function is an important predictor of QOL. Erectile dysfunction has a significant impact on QOL, for example, in one study of men with erectile dysfunction, the strongest 597

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“I miss my old body and sex life”

Fig. 57-5  Modulation of coping in couples.

“I look really ugly” “No one will ever want me”

“I need to learn my new body” “I am still desirable”

Physical effects of treatment Physical reactions to stress (Insomnia, palpitations, fatigue)

Physical effects of treatment

Preoccupation or withdrawal Avoidance of sexual activity

Active management of symptoms Research and experimentation

Increased isolation and loneliness

Outreach and connection

Sexual response “at rest” is balanced within a normal range, which is subsequently influenced by numerous mental and physical factors, which may vary within and between experiences. “At Rest” A Variable Neutral Range

Fig. 57-6  Concept of the “sexual tipping point.” (Redrawn from Perelman MA. Clinical application of CNS-acting agents in FSD. J Sex Med 2007;4[suppl 4]:280–290.)

+ Physiological & Organic Factors

– Physiological & Organic Factors

+ Psychosocial-Cultural Factors

– Psychosocial-Cultural Factors

“Turn On”

“Turn Off”

Excite (+) Faster & Greater Sexual Response “Hot”

predictor of better QOL was better sexual functioning, followed by more positive beliefs about the effects of erectile dysfunction on masculinity.69 In another study, which evaluated satisfaction with outcome among 1201 men treated for prostate cancer and 625 spouses, sexual difficulties resulting from cancer treatment were significantly associated with reduced satisfaction and reduced QOL in both groups, highlighting the fact that sexual problems after cancer affect not only the survivor, but also the partner.70 Fortunately, although the field is young, a growing body of literature is beginning to show that interventions that prevent sexual side effects of treatment or that help to restore sexual function after treatment 598 have a positive impact on QOL and overall functioning.71

The Sexual Tipping Point®

Inhibit (–) Slower & Less Sexual Response “Not”

Dynamic Process

PREVALENCE AND PREDICTORS OF SEXUAL DIFFICULTIES AFTER CANCER Most of the research on sexual difficulties in female cancer survivors done to date has focused on “reproductive” cancers: An estimated 50% of women with breast cancer and 80% of women with gynecologic cancers experience problems, especially during the first 12 to 18 months after treatment.72,73 However, many women whose cancers affect geographic sites other than the breasts or genitalia also appear to experience dramatic changes in sexual function after treatment, with one comparative review demonstrating 84% versus 76% prevalence of sexual difficulties in women with “reproductive”

Sexuality and intimacy after cancer ­versus “nonreproductive” cancer sites.74 This is likely a result of treatment effects on psychosocial parameters, as well as systemically mediated effects on neurobiological mechanisms of sexual response, as discussed previously. For many women, sexual difficulties can persist for years, despite improvements in mood and overall adjustment; therefore it is important to ascertain the presence of problems and to initiate interventions promptly. Early intervention can be facilitated by identification of various predisposing factors, which include poor perceived health, poor body image, vaginal dryness, urinary incontinence, poor dyadic adjustment, a history of preexisting sexual problems, and having a partner with sexual problems.75–77 For the aforementioned reasons, younger women are especially vulnerable.78 Single women in particular experience significant anxiety regarding when to discuss their cancer history with prospective partners and frequently express the fear that they will be found sexually undesirable, will be rejected outright, or perhaps will never find another partner. Impaired sexual function is also documented in men with a variety of cancers, including prostate, testicular, rectal, bladder, penile, and hematologic malignancies. Difficulties reported include decreased interest in sex and overall dissatisfaction with the frequency and quality of sexual activity.79 Careful assessment of sexual function before treatment is important to understanding the late and long-term effects of treatment. In one study with rigorous presurgical assessment of sexual function, 50% of men were found to have erectile dysfunction before radical surgery for prostate cancer, which also was associated with depression and fear of the proposed procedure.80 Surveys demonstrate that treatment for prostate cancer disrupts marital and sexual happiness in 10% to 20% of patients.81 Disturbances in sexual function and relationships are compounded by cultural norms and perceptions of masculinity, which decrease the likelihood that men will seek help when needed.82 Predictors of impaired sexual function in men vary according to cancer diagnosis, strength of the partnered relationship before cancer, and treatments received. However, the greatest predictor of sexual function after cancer therapy is pretherapy sexual function.80 With controls for type of cancer and pretreatment sexual function level, predictors include (1) patient age, (2) difference in age between the survivor and his partner,84 (3) preservation of penis size,85 (4) early use of a vacuum erection device after prostatectomy,86 (5) poorer ­psychological function,87 and (6) lack of a spouse.87 In addition to having an impact on the patient, cancer subjects the patient’s partner to considerable stress, which may manifest as heightened anxiety, depression, feelings of being unprepared to help, fear of recurrence and eventual death of the spouse, and somatic preoccupations. Limited literature suggests that spouses may keep these fears to themselves, hoping to spare their loved one from additional burden or worry.89 When queried specifically, many spouses express specific concerns regarding sexual intimacy; although the incidence and origin of diagnosable sexual dysfunction in partners of female cancer survivors are not known, a high proportion—78% of partners in one study—reported adverse effects on their own sexual functioning.90 These results point to the importance of open communication between partners, particularly given the fact that emotional support provided by either partner to the other plays a critical role in each person’s adjustment.91 Fortunately, coping with cancer tends to strengthen relationships overall. For example, 282 couples

57

affected by breast cancer were surveyed in one study: In 42% of the couples, both partners reported that cancer “brought us closer”; in 14% both partners believed there was “no effect,” in 6% one partner reported feeling “distanced,” and in 1% both partners reported being “distanced.”92

HOW TO TAKE A SEXUAL HISTORY FROM PATIENTS AND THEIR PARTNERS The most important things clinicians can do to make a difference are to take a thorough sexual history and to be prepared to respond proactively when patients and their partners express concerns. Because talking about sex is something many clinicians feel uneasy about, and because it is an area in which most have had limited opportunity to practice their skills, several authors have proposed communication models to ease discussion. These include the P-LI-SS-IT model (Permission, Limited Information, Specific Suggestions, Intensive Therapy)93; the ALARM model (Activity, Libido, Arousal, Resolution, Medical)94; the BETTER model (Bring up, Explain, Tell, Time, Educate, Record)95; and the 5 A’s model (Ask, Advise, Assess, Assist, Arrange follow-up).96 The latter two models were designed specifically for use with cancer survivors. Rather than enumerating the specifics of each of these models, we would like to highlight several key themes: the importance of asking cancer survivors about sex; providing education about basic sexual function and common changes caused by cancer treatment; suggesting strategies to enhance sexual satisfaction in the face of these changes; and facilitating further workup and referral when requested to do so. We would like to emphasize the importance of scrupulously remembering to involve both patients and partners; to initiate discussion before, during, and after treatment; to ask questions about multiple dimensions (e.g., all domains of sexual response, everything in the biopsychosocial model); and to be mindful of cultural context (e.g., in some cultures, patients will discuss intimate topics only with a same-gender clinician). Several brief questionnaires about sexual function have been validated in different populations of cancer survivors, including the UCLA Prostate Cancer Index,97 the 5-item version of the International Index of Erectile Function,98 and the Female Sexual Function Index.99 For clinicians who have the time and are so inclined, use of these instruments may be helpful both during the initial evaluation and subsequently during follow-up, to ascertain benefits achieved using various interventions. However, it is important to note that the questions asked in these measures may not be apropos to all patients, for example, all of the female sexual function measures that have been reviewed to date were developed and tested in heterosexual or presumed heterosexual populations, and therefore may not be applicable to lesbians, who do not participate in vaginal intercourse.100 Fortunately, ongoing work is being done to develop a more apropos and psychometrically robust measure of sexual function for use in oncology settings, and we are hopeful that an improved assessment tool will be available in the near future.101 With or without the use of formal ­assessment tools, we believe strongly that all clinicians can learn to take a thorough sexual history in a sensitive manner, and that increased comfort and skill will inevitably accrue over time and with greater practice. Table 57-3 presents a list 599 of questions that can be used as a starting point.

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Table 57-3  Questions to ask when patients and partners present with sexual concerns Begin With General Opening Questions • Are you satisfied with your sexual life? • Are there things about your (or your partner’s) sexual function you wish you could change? • Has cancer treatment affected your sexual function (self-image, comfort showing your body to your partner, interest in sex, responsiveness to sexual stimulation) in any way? • Did you experience any problems with sexual intimacy before cancer? Determine Affected Functional Domains • Desire: Do you notice a change in your interest in sex? • Arousal: Do you become sufficiently lubricated (women)? Do you have difficulty obtaining or maintaining erections (men)? • Orgasm: Are you able to reach orgasm? • Comfort/Pain: Do you experience any discomfort or pain during sex? Evaluate Distress and Expectations • How have these changes affected you? Your partner? Your relationship? • Are you interested in trying to change the current situation? • Have you tried any interventions already? If so, what were the results? Evaluate Relationship Quality • How would you describe the overall quality of your relationship? • Do you feel comfortable talking with your partner about the kinds of stimulation you enjoy? • If you do talk about sex with your partner, have you found her/him to be responsive? Ask Specific Questions About Each Affected Sexual Domain Questions about Desire • What was your highest ever level of desire (grade on a 0–10 point scale)? How about now? • Can you identify any inhibiting feelings or thoughts that interfere with your level of desire? • Do you participate in sexual activities even though your level of desire has changed? If so, what motivates you? • Do you experience spontaneous sexual thoughts or fantasies? • Are you “turned on” by erotic descriptions in books or sex scenes in movies? • Do you find your partner (or other people) attractive? • How often do you masturbate? Questions About Arousal • (For women): Is dryness a problem? Have you tried using lubricants? Which ones? Are they helpful? • (For men): Do you experience any difficulty achieving or maintaining an erection? Do you have erections at night, or do you ever wake up with an erection? Is your penis firm enough to go inside your partner? • Do you experience pleasurable sensations when you masturbate? • What types of sexual activities do you and your partner engage in? Do you experience pleasurable sensations during these activities? • Can you identify any distracting feelings or thoughts that seem to inhibit these sensations? • Have you had any negative experiences that might be interfering with your enjoyment now, such as being sexually abused, raped, or coerced into having sex? Questions About Orgasm (For women): • Have you ever had an orgasm? • If not…Are you familiar with female genital structures, such as the clitoris? Are you aware that most women need clitoral stimulation to become fully aroused? • What kinds of sexual activities do you participate in? Do they involve stimulation of the clitoris? • If so…When did you notice a change? What happens exactly? Are you ever able to achieve orgasm? Does it take longer? Do some kinds of stimulation work better than others? • Can you identify any distracting feelings or thoughts that seem to interfere with orgasm? • Do you expect to have an orgasm every time you have sex? Do you ever feel satisfied without reaching climax? (For men): • What happens during orgasm? • Has the character, color, amount, or consistency of your semen changed? Questions About Pain/Discomfort • Do you experience any discomfort during sexual activity?

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Table 57-3  Questions to ask when patients and partners present with sexual concerns—cont'd • If so, when did it start? Does it occur every time you have sex or just sometimes? Is it related to how turned on you are feeling or how much foreplay you’ve had? • What does the discomfort feel like? Where do you feel it exactly? At what point during sexual activity does it occur? • (For women): On the outside skin of the vulva as soon as it is touched? At or just inside the vaginal opening at the time of penetration? Deep inside the vagina or in the pelvis? At the time of or following orgasm? • (For men): Have you been able to identify any triggers? Does anything (e.g., trying different sexual positions, using more lubricant) make it feel better? • (For women): Have you experienced pain in the past when using tampons or with speculum insertion during pelvic examination? (symptoms of vaginismus) • (For men): Do you experience penile curvature or pain with erection (symptoms of Peyronie’s disease)? Do you have pain during ejaculation?

PHYSICAL EXAMINATION Few studies have evaluated the reliability and reducibility of the physical examination to diagnose sexual problems; however, abnormal findings may be discovered that suggest specific causes, or that guide treatment (Table 57-4). It is reasonable to palpate the thyroid in all survivors with diminished libido, because hypothyroidism can be a side effect of various cancer treatments and may affect sexual function adversely. Breasts and liver should be examined when hormonal (especially systemic hormonal) treatments are being considered, because of possible toxicities. A careful genital examination should be performed in all patients, especially in those with decreased arousal (erectile dysfunction in men; reduced genital sensation and/or lubrication in women), anorgasmia, or sexual pain. The pelvic examination can be especially challenging in some women, especially those with a past history of abuse, severe postmenopausal atrophy, and/or vaginal stenosis related to pelvic irradiation. Simple measures can help reduce anxiety and discomfort and maximize a woman’s sense of control, including the presence of a support person/ chaperone; a contract to stop the examination if requested by the patient; the use of a very small and narrow speculum; and adequate lubrication with a water-based gel, which has been shown not to interfere with cytology or culture results.102,103 In our clinical experience, use of lidocaine jelly as the lubricant may also ease a challenging pelvic examination significantly. Inspection of male genitalia should begin with assessment of the Tanner staging of hair distribution. Male pubic hair should be dense and in a rhomboid or diamond-shaped pattern at maturity. A level inconsistent with maturity level could indicate a clinically important loss of testosterone. Testicular examination by palpation is an important next step to investigate for atrophy (if testosterone production has been affected by chemotherapy, radiation, or other secondary causes) or masses (signifying concern for additional cancers). Mature male testicular size ranges from 4 to 7 cm in length. Additionally, a complete male examination includes inspection and palpation of the chest for evidence of gynecomastia (glandular breast tissue over the pectoralis muscle), which is caused by a relative imbalance in testosterone. Gynecomastia should be distinguished from pseudogynecomastia (excess adiposity in the chest) and breast cancer, which often manifests as a firm eccentric mass lateral to the nipple. If the tissue type is not obvious after completion of the examination, diag-

nostic imaging should be performed. The cause of confirmed gynecomastia should be determined to rule out hypogonadism (primary or secondary), hyperthyroidism, hyperprolactinemia, and adrenocortical or germ cell testicular tumors, as well as liver or kidney failure. Gynecomastia is a common side effect of many medications and chemotherapeutic agents. The integrity of pelvic blood vessels and nerves should be assessed in patients with arousal problems. Blood pressure and peripheral pulses provide an assessment of overall cardiovascular function. Hair distribution on the lower legs can signify arterial insufficiency or peripheral vascular disease, which could be confirmed by the additional assessment of ankle-brachial index. If evidence of peripheral vascular disease is present in the lower extremities, vascular disease is likely to be a factor limiting arterial flow to the genitalia and impairing arousal. The integrity of sacral neurologic outflow can be assessed via digital rectal examination and assessment of anal sphincter tone and bulbocavernosus reflex. The Q-tip test is useful in determining the location and intensity of pain (graded from 1 to 10) in women with complaints of vulvar pain104; sensory testing has not been well published in men with pelvic pain syndromes. More sophisticated tests can provide additional functional information but are not generally necessary in the initial evaluation and usually fall in the province of the specialist. These tests include things such as nocturnal penile tumescence monitoring or duplex Doppler ultrasound of the cavernosal arteries in men, which may reveal arterial blockages amenable to surgical repair.105 In women, genital sensation can be measured using a device called a biothesiometer, and clitoral blood flow assessed using a vaginal photoplethysmograph. Ultrasound can be done to assess the integrity of pelvic structures in women with deep pelvic pain during sexual activity but is rarely needed.

LABORATORY AND OTHER TESTING Laboratory testing should be tailored to individual circumstances, with careful consideration given to cost and evidence of clinical usefulness. In noncancer patients with sexual difficulties, measurement of cardiovascular risk factors (lipids, glucose) and hormonal profiles have been recommended by expert consensus106; however, few data from randomized controlled trials (RCTs) support this approach. Appropriate laboratory testing is reasonable when hyperprolactinemia, 601

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Table 57-4  Physical examination in patients who report sexual problems Anatomic feature or examination maneuver

Possible source of sexual difficulty

Nongenital (female and male) Blood pressure

Atherosclerosis

Peripheral pulses Thyroid examination

Hypothyroidism

Breast examination

Hyperprolactinemia (nipple discharge)

Gynecomastia Musculoskeletal examination

Limited comfort and mobility

Neurologic examination

Neurologic impairment

Genital/perineal (female) Mons pubis

Low androgens (sparse pubic hair)

Vulvar skin inspection

Changes caused by infection (Candida, herpes), dermatitis (allergic, eczema, psoriasis), dermatoses (lichens)

Labia majora and minora

Atrophy, lesions, adhesions, fusion

Clitoris

Phimosis, adhesions, female genital

Circumcision Urethra

Infection, prolapse

Vaginal introitus

Atrophy, lesions, scarring, stricture

Vagina

Atrophy, lesions, stenosis, discharge

Valsalva

Cystocele, rectocele, uterine prolapse, urinary incontinence

Bimanual examination

Masses, tenderness

Vaginal and anal muscle contraction

Poor tone

Bulbocavernosus reflex

Pudendal neuropathy

Genital/perineal (male)

602

Mons pubis

Low androgens (sparse pubic hair)

Palpate penile shaft for plaque

Peyronie’s disease

Testicular size, consistency

Hypogonadism (testosterone deficiency)

Digital rectal examination

Prostate, anal tone

Bulbocavernosus reflex

Pudendal neuropathy

hypothyroidism, or anemia is suspected. Serum androgens are not diagnostically useful in women because there are no ­precise definitions of androgen deficiency, the “normal” ranges for serum androgens in women of different ages are poorly characterized, and two large population-based studies failed to show a correlation between low serum testosterone level and low sexual desire.107,108 Androgen testing should always be performed in a man with sexual difficulties. Testosterone is best checked in the morning around 8 am because of its diurnal variation. Appropriate morning levels should be in the range of 300 to 800 ng/dl. If borderline or lower than the normal range, a repeat testosterone level and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels should be checked to confirm the low level and assess for primary or secondary causes. Free testosterone levels are often unreliable and lead to false results but should be considered in obese and older men who may have impaired testosterone binding.109,110 If desired, a free level can be calculated with total testosterone, albumin, and sex hormone–binding globulin levels through the use of readily available online calculators. An appropriate evaluation should be performed in the setting of apparent vaginitis/cervicitis or penile discharge, or when male or female genital lesions are discovered, including selected tests for vaginitis and sexually transmitted infections and biopsy of suspicious lesions. Routine screening with clinical breast and prostate examinations, prostate-specific antigen (PSA), mammography, and Pap testing should follow usual age-, gender-, and risk-appropriate guidelines as outlined by the American Society of Clinical Oncology (ASCO)111 and the National Comprehensive Cancer Network (NCCN).112

INTERVENTIONS TO OPTIMIZE EMOTIONAL AND PHYSICAL INTIMACY Clinicians can do many things to help patients and their partners achieve and maintain optimal emotional and physical intimacy. In discussing potential interventions with patients, we find it helpful to keep several thoughts in mind: 1. Preparation and prevention are worth a pound of cure. Patients and their partners generally do better when they are apprised of potential hurdles that they may encounter before these challenges arise. The most effective ways to prevent emotional distance and problems with sexual function are to explicitly attend to communication and (for couples who want to be sexually active and for whom sexual activity is not clinical inadvisable) to continue regular sexual activity throughout the cancer experience. In women particularly, there is a certain “use it or lose it” aspect of sexual function, that is, ongoing sexual activity in and of itself tends to maintain vaginal lubrication and elasticity, even in the face of untreated postmenopausal estrogen decline. 2. Losses in function need to be acknowledged and grieved before it is possible to embrace the concept of change. It is therefore important for clinicians to listen empathically when patients and their partners express the multitude of emotions (e.g., sadness, anger, guilt) about the ways in which cancer has influenced their lives and their interactions with one another, and to help each partner support the other in dealing with these feelings.

Sexuality and intimacy after cancer 3. There is no such thing as “perfect” sexual function, and there are no “quick fixes.” Media hype about sex leads many patients and partners to believe that “good” sex requires rapid, multiple, and simultaneous orgasms, and that magic bullets (e.g., PDEIs) are available that can restore sexual function easily and completely when problems arise. Because this is seldom the case, it is important to help patients and their partners set reasonable expectations, and to point out that restoration and maintenance of emotional and sexual intimacy generally require substantial dedicated time and effort. 4. The complexity of human sexual response, which involves a dance between numerous excitatory and inhibitory influences, may be confusing and even overwhelming to patients and their partners, but it is important to point out that this complexity also means that many different pathways can usually be exploited to enhance pleasure. In our experience, taking the time to review the sexual tipping point diagram (see Fig. 57-6) and enumerating all of the opportunities for positive intervention facilitate better understanding and greater patience with the process of evaluation and treatment, and typically result in both parties becoming more readily engaged as active participants in their care.

EDUCATION, COUNSELING, AND LIFESTYLE CHANGE INTERVENTIONS Many patients and their partners are surprised by the extent to which their emotional reactions to the whole experience of cancer intrude during intimate moments, and by the degree to which physical changes associated with cancer treatment interfere with sexual functioning. Open discussion about the challenges cancer can pose to intimate relationships, including the need to manage numerous, powerful, conflicting and ever-changing emotions, as well as the need to adjust and adapt to physical changes that affect sexual function, helps prepare patients and their partners, so that these events do not arrive as a shock. Because the challenges cancer brings can be overwhelming, it is crucially important to offer patients and their partners a list of resources that they can use to achieve a greater understanding of and mastery over all of the changes they are experiencing, including books, websites, and referral to appropriate counseling services when additional support and guidance are needed. It is also beneficial to proactively and explicitly discuss various lifestyle strategies that patients and their partners can use to prevent sexual side effects of treatment or to ease adjustment to changes in sexual function when they occur. Table 57-5 lists helpful educational, counseling, and lifestyle interventions. The reader may also find it helpful to refer to Table 57-6 (“A Problem-Oriented Approach to Improving Sexual Function”) while reading this section and the following sections on pharmacologic strategies, mechanical devices, and surgical interventions to improve sexual function. Referral for counseling can help enhance general coping skills; alleviate depression, anxiety, and body image issues; and improve communication between patients and established or prospective partners. Counseling can be beneficial in many forms (e.g., individual, couples, groups), and when in-depth interventions are needed to address sexual communication and technique, dedicated sex therapy may be indicated. It is important to appreciate that body image, self-esteem,

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Table 57-5  Educational, counseling, and lifestyle interventions Sexuality education 1. Identify and address any misconceptions about sex. 2. Review sexual anatomy and physiology; expected changes with aging, menopause; and changes associated with specific cancer treatments. 3. Distinguish between lust and other motivations for initiating sexual activity or responding to a partner’s advances; identify and celebrate these motivations. 4. Discuss sexual techniques, including identification of both genital (e.g., the clitoris, in women) and nongenital erogenous zones; encourage exploration and experimentation. Referral for counseling and/or psychopharmacology consultation 1. Individual, couples, or group interventions. 2. Sex therapists have expertise providing counseling that focuses on the sexual aspect of relationships, using various behavioral techniques and homework assignments. AASECT provides a national listing of such therapists. 3. For patients with significant anxiety, depression, PTSD, or compulsive sexual behaviors, a combination of psychotherapy and medications may be appropriate. Lifestyle changes to enhance sexual satisfaction 1. Create opportunities for intimacy (make “dates,” eliminate distractions, create a conducive environment with candles, dimmed lighting, music, etc.). 2. Maximize comfort (encourage use of lubricants, experiment with position changes, strategic analgesic use, etc.). 3. Give permission to explore (masturbation, new positions, new techniques, sex toys, erotica, etc.). 4. Encourage weight loss and exercise.

and ­sexual responsiveness do not occur in isolation. Rather, patients’ self views are sculpted by the responses of the people with whom they interact: Positive messages and positive regard that they receive from the significant others in their lives can be profoundly healing.113 A recent review of couplebased interventions for enhancing women’s sexual adjustment and body image after cancer concluded that strategies that produce the strongest effects are couple-focused and include treatment components that (1) educate both partners about the women’s diagnosis and treatments, (2) promote couples’ mutual coping and support processes, and (3) include specific sexual therapy techniques to address sexual and body image concerns.114 In men with erectile dysfunction after cancer, both couples-based115 and group-based116 therapies have been shown useful in improving male distress and sexual function in both men and their partners; however, these study outcomes are affected by a high concurrent usage rate of pharmacologic therapies for erectile dysfunction. Therefore, whenever possible, we suggest exploiting the power of dyadic interventions with patients who have partners; for un-partnered individuals, group ­interventions may be particularly beneficial. Several other strategies may be beneficial in ­enhancing body image. Chemotherapy-induced hair loss is consistently ranked as one of the most distressing effects of ­cancer 603

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Table 57-6  A problem-oriented approach to improving sexual function Affected functional domain

Goal of treatment

Specific interventions

Desire

Address cognitive inhibitors

Stress reduction, work on body image, individual and couples therapy Maximize opportunities for closeness, exploit erotica, etc. Treat hypothyroidism, etc. Hormone therapy, bupropion, etc.

Optimize cognitive motivators Address biological inhibitors Consider biological motivators Arousal

Optimize sensory input Optimize blood flow Optimize lubrication Optimize muscle contraction Optimize positive cognitive feedback

Orgasm/Ejaculation

Reduce premature ejaculation Reduce latency to orgasm (frequently caused by SSRI antidepressants) Address concerns about retrograde ejaculation

Comfort/Pain

Address general comfort Assess specific issues (e.g., vaginal atrophy and stenosis in women)

Vibrators PDEIs, vacuum therapy devices, penile injections, penile implants Lubricants, vaginal estrogen Pelvic floor exercises Utilize sexual fantasies Desensitizing creams, stop/squeeze techniques, SSRIs, or PDEIs Switch to a less sex-negative medication, or add an antidote (see text) Reassure (not a harmful condition), remove potentially offending medications, trial of imipramine Strategic analgesic dosing, etc. Lubricants, vaginal estrogen, vaginal dilators

PDEIs, Phosphodiesterase inhibitors; SSRIs, selective serotonin reuptake inhibitors.

t­reatment and has a profoundly negative impact on body image in both women and men.117,118 Participation in programs such as the American Cancer Society’s Look Good… Feel Better program, which provides cosmetic makeovers and hair help, can enhance self-confidence and social comfort for patients whose appearance is altered by cancer treatment.119 For women who have undergone mastectomy without reconstruction and are bothered by the appearance of their surgical scar, consideration of various interventions, such as temporary or permanent postmastectomy tattooing or delayed surgical reconstruction, may be helpful. Both women and men who are distressed by the presence of a urostomy or colostomy bag may benefit from the use of a wide range of cleverly designed intimate lingerie in the bedroom. Obesity, weight gain, and physical activity also deserve close attention. Weight gain can be a complication of cancer treatment and is associated with negative effects on body image and sexual functioning among cancer survivors. Obesity after cancer diagnosis is associated with increased recurrence and/or poorer prognosis in breast, prostate, and colon cancer survivors.120–122 Although evidence to support the beneficial effects of weight reduction in this setting is limited, higher levels of posttreatment physical activity are associated with improved outcomes among breast and colon cancer survivors.123,124 Moreover, both moderate weight loss and regular physical activity reduce the risk of chronic health conditions other than cancer and are associated with improvements in body image and sexual satisfaction among overweight people in the general population.125,126 Therefore, cancer survivors should be encouraged to achieve and maintain a healthy weight and to engage in regular physical activity to improve their overall well-being and to enhance health outcomes. The 604 American Cancer Society (ACS) has published a useful set of

guidelines to help direct nutrition and physical activity during and after cancer treatment.127 Some cancer patients feel betrayed by their bodies after a cancer diagnosis; others experience their changed bodies as unfamiliar, strange, or alien. It can be difficult to engage in intimate sexual activities with a partner under these circumstances, and it is often helpful for patients to spend some time alone first, getting to know their new bodies and learning what locations and types of touch feel good. It is important to give patients explicit permission to explore masturbation; some may initially be reluctant to do so because of cultural constraints, and for those who are sexually inexperienced, it may be helpful to provide basic information about erogenous zones and sexual technique. Exploration of previously unappreciated nongenital erogenous areas (e.g., ears, breasts, neck, antecubital and popliteal fossae) should be encouraged. Patients can be assured that once they have learned about their own bodies, they can teach their partner what kinds of stimulation they enjoy. A wide variety of books can be recommended to provide guidance (see suggested resources). For patients who feel uncomfortable with erotic self-touch, simple body massage with a pleasantly scented lotion may ease adjustment to a changed body and eventually facilitate acceptance. For patients who have partners, it may be helpful to deliberately create opportunities for closeness, such as making dates to spend intimate time together, making sure there will be no distractions, and setting a relaxing and/or romantic mood by choosing a conducive setting, music, and/or candles. It is important to stress that physical intimacy encompasses far more than sexual activity: Snuggling, cuddling, and spooning are all to be cherished. Many survivors who experience loss of libido after cancer treatment express great concern that they will never be interested in having sex again. Although it

Sexuality and intimacy after cancer is important to acknowledge their loss, it is most helpful to point out that motivators other than lust (such as the desire to feel close to one’s partner) can lead people into participating in sex, and that once engaged in sexual activity, there are many ways to achieve satisfaction (e.g., if sufficient arousal results, orgasm may occur, or one may simply take pleasure in one’s partner’s enjoyment). This is an example of utilizing cognitive restructuring techniques (e.g., helping patients substitute productive for unproductive thoughts) to effect changes in behavior. For survivors whose instinct is to avoid recommencing genital stimulation because of performance anxiety, discomfort, or fear of discomfort, the use of nondemand, sensual touching exercises (“sensate focus exercises”) that focus on the pleasurable sensations associated with nongenital touch can be extremely helpful as a first step. Typically, these exercises begin with the least threatening types of touch, such as back rubs or foot massage, and can progress over time to nude, full-body caressing, including the genitals. As discussed earlier, patients who do not have partners often need help in planning how and when to discuss their cancer history with prospective partners, and may benefit from practicing these conversations using role-play exercises. Physical comfort during sexual activity may be an issue for many cancer survivors because of hypersensitivity to touch caused by scarring or neuropathy, lymphedema, or reduced mobility. Helpful suggestions include considering a warm bath before sexual activity, optimizing analgesic use, and experimenting with alternative sexual positions. For women with postmenopausal atrophic changes who experience discomfort during penetrative sexual activity, both vaginal moisturizers and sexual lubricants can be recommended. Vaginal moisturizers are used day-to-day to hydrate vulvar and vaginal cells and reduce mucosal fragility; lubricants are used during sexual activity to reduce friction and increase glide. Many different lubricants are available, including water-, oil-, and silicone-based options. Selection should be based on safety (only water-based lubricants should be used with latex safer sex barriers), palatability (some lubricants are designed to taste good—important if partners wish to engage in sequential oral and vaginal sex), and glide (oil- and silicone-based lubricants coat mucosal surfaces more effectively and are more long-lasting). In one small (N = 59) double-blind, randomized, crossover trial of Replens (a moisturizer) versus KY Jelly (a water-based lubricant), both products reduced vaginal dryness; however, a trend toward less dyspareunia was noted in the Replens group (P = .05).128 In our clinical experience, we find that daily use of a vaginal moisturizer plus use of a lubricant during sexual activity often results in greater comfort during penetration than use of either one alone. A small study (N = 15) in the general population indicated that Replens performs comparably to vaginal estrogen cream (discussed in the next section) in alleviating discomfort associated with vaginal dryness,129 and is therefore a good option for survivors in whom all estrogen therapies, including low-dose vaginal estrogen, are contraindicated. Although lifestyle recommendations and risk factor modifications are advised for all men with impaired erectile function,130,131 no study to date has examined the role of lifestyle changes in improving erectile function in male cancer survivors. It is recommended that all men limit or reduce factors known to exacerbate erectile function, such as obesity, lack of exercise, stress, and tobacco use. One RCT to date has

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assessed lifestyle modifications and erectile function in men. Esposito et al. examined 110 obese men with sexual dysfunction as determined by International Index of Erectile Function (IIEF) scores 4 weeks after start of therapy, before am dose

30 mg (60 tablets): $259.37

ache and flushing. Additional studies have examined specific predictors of success; factors that have been shown to decrease the effectiveness of PDEI therapy include poor level of sexual function before cancer treatment,170 older age, duration of time after cancer therapy before onset of PDEI use, androgen deprivation therapy for longer than 4 months, and radiation dose >85 Gy.171 Research demonstrates that simple maintenance of regular sexual activity tends to protect men from developing erectile dysfunction. For example, in one prospective 5-year study of 989 men aged 55 to 79 in the general population who had no impairment in sexual function at baseline (as defined by the IIEF inventory survey), those who reported sexual intercourse less than once per week were twice as likely to develop erectile dysfunction than those who reported sexual intercourse one time or more per week (incidence rate ratio, 2.2; 95% CI, 1.3%–3.8%).172 Frequent sexual activity is believed to exert its protective effect via maintenance of vascular endothelial function. Accordingly, recent trials have examined prophylactic therapies to maintain erectile function in men after treatment for cancer—a strategy termed “penile rehabilitation.” Results from one randomized, double-blind trial (subgroup analysis, N = 54) that examined the effects of nightly sildenafil after bilateral nerve-sparing radical retropubic prostatectomy (BNSRRP) on sexual function are illustrative. Although the placebo group experienced little to no improvement, the men who received prophylactic sildenafil nightly for 36 weeks after surgery demonstrated gradual dose-dependent improvement in erectile function. Up to one third of men receiving sildenafil demonstrated a return of nocturnal erections and erectile function (24% [4/17] of 50-mg sildenafil recipients,

Sexuality and intimacy after cancer 33% [6/18] of 100-mg sildenafil recipients, and 5% [1/19] placebo recipients).173 Additional randomized, controlled studies of daily prophylactic sildenafil therapy are needed before it can be considered safe and effective for daily use in men undergoing other surgical or radiation therapies for prostate cancer. Initiation of PDEIs in men with erectile dysfunction after cancer treatment should begin as soon as possible to have the most potent effect. In a study of 110 men found to have impaired sexual function (as measured by the IIEF scale) after radiation therapy for prostate cancer, men who started sildenafil therapy less than 1 year after completing therapy were 60% likely to have normalization sexual function scores, and men who started sildenafil more than 2 to 3 years after completion of radiation were only 26% likely to achieve normal scores.174 This potential loss of efficacy underscores the importance of talking about sexual function early on and offering effective options for treatment before it is too late to see physiologic improvement. We recommend following the same dosage guidelines for PDEIs in male noncancer survivors: Start with 50 mg sildenafil, 10 mg of vardenafil, or 10 mg of tadalafil, taken at least 30 minutes before desired activity. Both sildenafil and vardenafil have a mean duration of 4 hours, and tadalafil has a duration up to 36 hours175; all are considered equally effective in improving erectile function. Each should be used with caution or avoided in people using CYP3A4 inhibitors, which would prolong their duration of action. PDEIs are contraindicated in men with recent myocardial infarction/stroke, active coronary ischemia/congestive heart failure (CHF), hypotension, or taking nitrates. Men should be questioned about their exercise tolerance before starting therapy. An exercise tolerance level sufficient for sexual activity and orgasm is approximately 4 METS (metabolic equivalent of oxygen consumption)—the equivalent of walking up one flight of stairs, or walking 2 to 4 miles on a level surface without difficulty.176

Female Cancer Survivors PDEIs increase genital perfusion in women in a similar fashion; however, these agents have not been found to be as sexually beneficial as they are in men. One large, multicenter, placebo-controlled trial examined the efficacy of sildenafil, 10 to 100 mg, taken 1 hour before sexual activity in 577 ­estrogen-replete and 204 estrogen-deficient women with female sexual arousal disorder (FSAD).177 No increase in sexual arousal was observed in either treatment group at any treatment dose. This study has been criticized because less than half of the women studied had a primary diagnosis of FSAD; many also suffered from diminished sexual desire, which we would not expect to be improved by a medicine that causes vasodilation. Limited data suggest that PDEIs may be useful in treating women in the general population who have isolated FSAD. For example, in a subgroup analysis of women without concomitant HSDD during a randomized controlled trial of sildenafil 50 mg versus placebo in postmenopausal women with FSAD, significant improvements were seen in vaginal lubrication, genital sensation, and ability to achieve orgasm.178 On the basis of this preliminary information, we believe that PDEIs (off-label use) are worth a try in female cancer survivors in whom genital arousal difficulty predominates, as is sometimes the case among women who have undergone radical pelvic surgery with interruption of genital vascular and

57

nerve supply. As noted later, PDEIs may also be beneficial as antidotes to the sexual side effects of certain antidepressants. To our knowledge, no studies as yet have specifically ­examined the effects of PDEIs on genital arousal in female cancer survivors. If electing to prescribe PDEIs in this population, we recommend a starting dose of 50 mg sildenafil, or the equivalent, taken 1 hour before sexual activity. As in men, PDEIs are contraindicated in women with recent myocardial infarction/stroke, active coronary ischemia/CHF, or taking nitrates.

PROSTAGLANDIN E1 AGONISTS In men with insufficient erectile function after use of PDEIs and testosterone (when warranted), alprostadil offers a more effective option for both penile rehabilitation after cancer therapies and maintenance of erectile function throughout survivorship. Alprostadil is a prostaglandin E1 analog that causes vasodilation and smooth muscle relaxation, allowing blood flow and entrapment into the penis for erection to occur. It is administered as an intraurethral pellet suppository (Muse), or as an injection to the dorsolateral aspect of the proximal one third of the penile shaft. Multiple studies have examined the use of intraurethral or intracavernous injection of alprostadil after radical prostatectomy, and significant benefit was found.179–181 Overall, men who began to use alprostadil within 1 month of their surgery and continued use 3 times per week over a 6-month period were significantly more likely to achieve spontaneous erections at the completion of treatment. All of these studies were limited by no clear preoperative assessment of erectile function, short-term follow-up, and the fact that up to one third of the sample dropped out as the result of penile irritation or lack of initial success. Ongoing studies are needed, but current recommendations include considering alprostadil administration as second-line posttreatment therapy for men who fail to respond adequately to first-line treatment (PDEIs and testosterone in eligible candidates).182 When alprostadil suppositories are prescribed, the first dose must be given under clinical supervision to monitor for hypotension and severe side effects. Intracavernous injection therapy is considered the most effective nonsurgical treatment for erectile dysfunction. Injections can be prepared with alprostadil alone, or in combination with papaverine, an arterial vasodilator, and/or phentolamine, an alpha-1-receptor blocker. Although they are sometimes considered more effective, mixtures of these substances require the use of compounding pharmacies. Dosing and mixture should be based on individual effectiveness and side effects for each patient. Limitations include high risk of priapism, invasive approach and technique for the patient to learn, and the requirement that the first dose be administered under clinical supervision. It is also recommended that each patient be given a clear warning to monitor for an erection lasting longer than 4 hours, and a clear plan for how that will be managed with the clinician.183 To optimize the risks and benefits of therapy, we recommend that intracavernous injection therapies be prescribed in collaboration with a urology specialist. We are unaware of any studies that have examined the effectiveness of topical alprostadil in improving genital arousal in female cancer survivors specifically. However, in the general population, one RCT (N = 400 women aged 22–62) has shown significant improvement in several arousal parameters after application of a 900-μg alprostadil cream to the clitoris and 609

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anterior vaginal wall before intercourse184; a previous study showed that the most common adverse effect was a mild, ­transient genital burning sensation lasting 2.5 Gy to the testis, whereas in women, external beam radiation to any field that involves the ovaries has a >80% risk of causing amenorrhea. Women who have experienced total-body irradiation or uterine radiation are thought to be at increased risk for miscarriage, prematurity, and ­low-birthweight delivery.20

CHEMOTHERAPIES The most common cause of impaired fertility after cancer is exposure to chemotherapeutic agents. Any effect is dependent on dose, cycle number, and the age and pretreatment fertility function of the recipient. In women and men, the chemotherapeutic agents most likely to cause prolonged azoospermia or amenorrhea are alkylating agents, including cyclophosphamide, ifosfamide, nitrosoureas, chlorambucil, procarbazine, melphalan, and busulfan. Data on the degree to which fertility is impaired by specific chemotherapeutic regimens and dosages are outside the scope of this chapter but are nicely stratified in the ASCO guidelines.20 It is impossible to estimate the precise impact of various chemotherapeutic agents on gonadal function, as many studies report proxy outcomes, such as azo­ ospermia or amenorrhea, rather than actual conception rates or positive pregnancy outcomes. For example, many studies report on the likelihood of return to normal ­menstruation in women after receipt of chemotherapy, but resumption of cyclic menstruation does not indicate the degree of remaining 619

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Table 58-3  Fertility preservation methods Technique

Optimal timing with cancer therapies

Advantages

Considerations

• Outpatient procedure • ≈$1500 for three samples stored over 3 years

Males Sperm cryopreservation after masturbation

Before treatment (but may be performed after)

The most established technique Lowest cost No partner required at time of decision Ease of use at any age Fewer ethical concerns

Sperm cryopreservation after electroejaculation

Before treatment (but may be performed after)

Effective when nerve impairment • Outpatient surgical procedure is present • Requires some testicular function

Sperm cryopreservation after testicular sperm extraction

Before treatment (but may be performed after)

Effective in males with azoospermia

• Outpatient surgical procedure • Requires some testicular function

Embryo cryopreservation

Before treatment in women (but may be performed after)

Effective and well-established procedure

• Outpatient surgical procedure • Requires 10–14 days of ovarian stimulation from the beginning of the menstrual cycle • ≈$8000 per cycle; $350 per year storage fees • Partner or donor required at time of decision

Oocyte cryopreservation

Before treatment (but may be performed after)

No partner or donor needed at time of decision

• Experimental/Investigational • Outpatient surgical procedure • Live birth rate 3–4× lower than standard IVF

Ovarian tissue extraction ± transplantation

Before treatment

No partner or donor needed at time of decision

• Experimental/Investigational • Outpatient surgical procedure • Not suitable if ovarian cancer involvement possible

Females

IVF, In vitro fertilization.

ovarian reserve or the risk for early menopause. It is clearly important to review with patients limitations in our ability to predict fertility when attempting to select an optimal chemotherapeutic regimen.

OPTIONS FOR FERTILITY PRESERVATION BEFORE OR AFTER CANCER TREATMENT As previously noted, the best time to assess interest in fertility preservation is at the time of diagnosis or before initiation of treatment. For example, in women with breast cancer, an optimal 6-week window of opportunity exists after breast surgery and before chemotherapy administration, during which fertility preservation can be pursued without delaying cancer treatment. This time period can perhaps be extended further, as delays of up to 12 weeks between surgery and chemotherapy have not been shown to affect disease outcome.23 620 Multiple methods of preservation are available to both women

and men (Table 58-3), but the optimal methods by which to preserve ovarian and testicular tissue have not yet been delineated. Current studies are limited in size, lack randomization or adequate controls, use surrogate endpoints, and likely carry inherent bias caused by lack of referral or concern of physicians for recurrence potential. According to ASCO guidelines, anything other than sperm cryopreservation and embryo cryopreservation should be considered experimental.20 The availability and effectiveness of other preservation techniques remain in question, but this should not deter clinicians from referring patients to discuss all potential options with fertility preservation specialists.

FERTILITY OPTIONS FOR MEN WITH CANCER

Sperm cryopreservation

The ideal preservation technique for men is sperm cryopreservation. As stated previously, it should be offered to all men,24,25 has been proven effective,26 and has been shown to help men

Fertility assessment and preservation cope emotionally with the effects of treatment.27 The procedure involves extraction of sperm, through various methods, and exposure to cryopreservatives. The sperm retains much function and can be saved for thawing and future use with any fertilization procedure.

METHODS OF SPERM EXTRACTION Options for sperm extraction depend on the timing of the extraction and previous treatment for cancer. Whether sperm is extracted for immediate use with assisted reproductive technologies or cryopreservation, pregnancy success rates are similar.28 Before cancer treatment, a baseline functional appraisal can be obtained by collecting a semen sample via masturbation, with assessment of sperm count and motility. After treatment, remaining gonadal structure and function should be assessed. For men with at least one remaining testicle and with impairment of the nervous system (due to radiation, surgery, or chemotherapies), electroejaculation may be used. Electroejaculation is an operative procedure performed under anesthesia through direct electrical stimulation of the sympathetic nerves responsible for ejaculation.29 When successful, intraoperative ejaculation permits sperm collection for use with other reproductive technologies. For men with at least one testicle, testicular sperm extraction (TESE), the direct retrieval of sperm from the testes, is also effective. TESE involves a surgical procedure in which microdissection of the testes allows extraction of sperm from tubules most likely to be actively engaged in spermatogenesis.30 For later fertilization, any technique of sperm extraction can be combined with intracytoplasmic sperm injection (ICSI), or injection of a single live sperm into the center of an oocyte. Even in cases in which men have a preexisting diagnosis of azoospermia on assessment of ejaculate, TESE has been used successfully to extract sperm directly from the testicles before surgery or after chemotherapy. TESE plus ICSI is effective in producing live offspring in men with azoospermia, before or after chemotherapy.31,32

Treatment of retrograde ejaculation or anejaculation Retrograde ejaculation is considered highly treatable with removal of offending medications or, when due to nerve damage, through the use of medications such as imipramine 25 to 75 mg daily.33 For prompt restoration of fertility, referral to a specialist is often indicated. Sperm can be recovered from post-masturbation urine samples for use during assisted reproductive procedures. For men who are unable to achieve anterograde ejaculation with medications, electrovibration stimulation (EVS) can be used. EVS is performed by the affected patient by applying a specialized vibrator to the base of the penile surface. The vibrations initiate a reflex in the spinal cord that leads to anterograde ejaculation. The vibrator is applied for cycles of 3 minutes duration with 2 minutes of rest until anterograde ejaculation is achieved. EVS can be performed in a clinical setting, or within the privacy of one’s home, through the guidance of a clinician. Surgical options for management of retrograde ejaculation are also available but are rarely advised. For men with anejaculation, medical treatment can be attempted but is rarely successful because of the degree of nerve impairment. Most men with anejaculation seeking fertility require EVS for fertility assistance.33

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FERTILITY OPTIONS FOR WOMEN WITH CANCER

Embryo cryopreservation

Embryo cryopreservation is the most effective technique for fertility preservation in women. Because of its relatively high cost and the high rate of success of sperm cryopreservation options for men, embryo cryopreservation is reserved for use in preserving fertility in women before or after cancer. Embryo cryopreservation requires the presence of an available and willing partner or use of donor semen. The process involves oocyte retrieval from the woman and subsequent in vitro fertilization with her partner’s or donor sperm. The embryos are then exposed to cryoprotectants and are stored at subzero temperatures until desired for use. Upon making the decision to use the embryo, thawing takes place and arrangements are made for implantation. Survival rates per thawed embryo are estimated to be around 70% but vary considerably, depending on the conditions and the procedures performed.34,35 Rates of successful transfer and implantation can be as low as 10%.34,35 Despite these low numbers, cumulative pregnancy rates as high as 60% have been reported.35 Currently, few data inform the effectiveness of embryo cryopreservation with implantation and subsequent successful pregnancy outcome in cancer survivors specifically. Advantages of embryo cryopreservation include its relatively high success rate in the general population and the existence of well-tested protocols. Disadvantages include the need for a partner or donor gametes, as well as the potential exposure risk of ovarian stimulants needed for oocyte retrieval. Oocyte retrieval options for women with cancer who are considering embryo cryopreservation must be considered in the context of whether the tumor is estrogen sensitive. Conventional protocols of ovarian stimulants, such as clomiphene, interfere with the negative feedback mechanism of endogenous estrogens on the pituitary gland and hypothalamus.36 This cessation of feedback leads the pituitary gland to secrete follicle-stimulating hormone (FSH), which leads to ovarian follicle development and increased production of estrogen. Use of ovarian stimulants, such as clomiphene, or daily injections of FSH during the first 2 to 3 weeks of a menstrual cycle have been shown to increase serum estradiol levels in women up to 10-fold higher than normal cyclic levels. These high estradiol levels limit the safety of ovarian stimulation in women with estrogen-sensitive cancers.35 Newer regimens involve the use of selective estrogen receptor modulators (SERMs) such as tamoxifen, or aromatase inhibitors such as letrozole, as ovarian stimulants are also effective and are believed to be safer.37,38 Both tamoxifen and aromatase inhibitors are thought to work similarly to clomiphene, by interfering with negative feedback of endogenous estrogen on the pituitary gland and hypothalamus. Tamoxifen-based ovarian stimulation protocols result in lower serum estradiol levels than clomiphene or FSH stimulation (with a concomitant protective effect of blocking estrogen receptors on breast tissue), yet tamoxifen results in higher serum estradiol levels compared with aromatase inhibitors, such as letrozole. Despite the differences in serum estradiol levels produced by the use of tamoxifen or letrozole for ovarian stimulation, no study has documented a difference in cancer recurrence rates.39 For any female survivor considering embryo cryopreservation, an individualized approach is needed and will depend on whether 621

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she is awaiting or has already completed treatment, as well as the specific characteristics of her tumor type.40 As stated previously, when retrieval is planned during the time between surgical excision and initiation of chemotherapy, it is desirable to complete the retrieval process within 12 weeks to prevent potential adverse effects on cancer treatment.23 Clinicians referring patients for fertility preservation can provide introductory information about these options, while noting that the optimal approach will require a team approach in collaboration with oncology providers and a reproductive specialist.

Experimental techniques for fertility preservation For female cancer survivors who are not eligible for the fertility preservation procedures mentioned previously, a number of experimental procedures with limited efficacy are currently available. These techniques are not widely available and are most often applied in women who have not yet undergone exposure to cancer therapies. Experimental techniques include oocyte cryopreservation and ovarian tissue extraction. Oocyte cryopreservation is a technique in which no partner or donor sperm is needed. Oocytes are extracted via the same hormonal stimulation procedures described earlier in this chapter.35 Unfortunately, cryopreservation techniques have not progressed to the point where oocytes consistently retain an effective level of function; consequently, reproductive outcomes thus far are poor. Another option is cryopreservation of ovarian tissue with later transplantation. Through this procedure, ovarian tissue is extracted from a woman’s body and is cryopreserved and/or later transplanted to another part of her body.41 This technique is currently used in women who need radiation therapy for cervical cancer or lymphomas.42,43 Transplantation of a woman’s ovarian tissue into an area outside the radiation field, such as into her arm, permits the tissue to remain reproductively active and capable of producing oocytes for extraction at a later date.44,45 Currently, long-term data for ovarian tissue transplant are promising, and this procedure may become more effective with future research.46

Additional fertility sparing techniques Gonadal shielding is an option for women and men who need to have radiation therapy directed at pelvic organs. The shielding is used to decrease the dose of radiation delivered to reproductive organs. Research on the effectiveness of gonadal shielding is

limited to case series for both women and men. Limitations include the need for expertise to ensure that shielding does not magnify the doses delivered, and the fact that shielding techniques are feasible only with specific radiation fields and anatomy.19,20 For women with early-stage cervical cancer, hysterectomy is not necessarily required. Trachelectomy is useful for preserving fertility in women who are appropriate candidates. This procedure involves removal of the cervix with preservation of the uterus.19 In a retrospective review of 32 consecutive women with early-stage cervical cancer who opted for trachelectomy, after a median of 31 months’ follow-up, 24 women regained normal menstruation, six women attempted conception, three conceived, and one had cancer recurrence and death from recurrence.47 Trachelectomy is considered by ASCO to be a standard therapeutic option for appropriate candidates with early-stage cervical cancer. Finally, the use of gonadotropin-releasing hormone (GnRH) agonists to “protect” ovarian or testicular tissue during administration of chemotherapy or radiation therapy is widely studied but is still considered investigational.19 The medication is administered before the start of therapy and is continued through to completion. No studies to date have shown consistent effectiveness for fertility preservation in humans.48 Side effects of therapy include moderate to severe hot flashes estimated to occur in the majority of recipients and a transient rise in serum estrogen and testosterone levels, in women and men respectively, which may have a detrimental effect on hormonally sensitive cancers.

SUMMARY Studies show that patients and their partners frequently have many questions and fears about their reproductive capacity after cancer. They rarely spontaneously ask their clinicians about these concerns. A growing number of interventions are available to help interested survivors realize their parenting goals. Therefore, regardless of cancer type or the duration of time since treatment was received, clinicians need to ask all survivors of reproductive age about their desires regarding future childbearing. As noted in this chapter, clinicians can impart valuable information and offer resources to help survivors cope with the many difficult decisions that cancer and the possibility of childbearing present. This information and support are desired and highly valued by patients and their partners and may help them cope well throughout their cancer experience.

REFERENCES

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1. Bleyer A, Viny A, Barr RD. Cancer epidemiology in older adolescents and young adults 15 to 29 years: SEER incidence and survival, 1975–2000. Bethesda: National Cancer Institute; 2006. 2. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin. 2005;55:10–30. 3. Jones AL. Fertility and pregnancy after breast cancer. Breast. 2006;15(suppl 2):S41–S46. 4. Calhoun K, Hansen N. The effect of pregnancy on survival in women with a history of breast cancer. Breast Dis. 2005;23:81–86. 5. Madanat LM, Malila N, Dyba T, et al. Probability of parenthood after early onset

cancer: a population-based study. Int J Cancer. 2008;123:2891–2898. 6. Schover LR. Rates of postcancer parenthood. J Clin Oncol. 2009;27:321–322. 7. Schover LR. Motivation for parenthood after cancer: a review. J Natl Cancer Inst Monogr. 2005;34:2–5. 8. Schover LR, Rybicki LA, Martin BA, et al. Having children after cancer: a pilot survey of survivors' attitudes and experiences. Cancer. 1999;86:697–709. 9. Partridge AH. Fertility preservation: a vital survivorship issue for young women with breast cancer. J Clin Oncol. 2008;26:2612–2613.

10. Schover LR. Premature ovarian failure and its consequences: vasomotor symptoms, sexuality, and fertility. J Clin Oncol. 2008;26:753–758. 11. Thewes B, Meiser B, Taylor A, et al. Fertility- and menopause-related information needs of younger women with a diagnosis of early breast cancer. J Clin Oncol. 2005;23:5155–5165. 12. Peate M, Meiser B, Hickey M, et al. The fertilityrelated concerns, needs and preferences of younger women with breast cancer: a systematic review. Breast Cancer Res Treat. 2009;116:215–223. 13. Surbone A, Petrek JA. Childbearing issues in breast carcinoma survivors. Cancer. 1997;79:1271–1278.

Fertility assessment and preservation 14. Sutton R, Buzdar AU, Hortobagyi GN. Pregnancy and offspring after adjuvant chemotherapy in breast cancer patients. Cancer. 1990;65:847–850. 15. Berry DL, Theriault RL, Holmes FA, et al. Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol. 1999;17:855–861. 16. Schover LR, Brey K, Lictin A, et al. Oncologists' attitudes and practices regarding banking sperm before cancer treatment. J Clin Oncol. 2002;20:1890–1897. 17. Zapzalka DM, Redmon JB, Pryor JL. A survey of oncologists regarding sperm cryopreservation and assisted reproductive techniques for male cancer patients. Cancer. 1999;86:1812–1817. 18. Bober SL, Recklitis CJ, Campbell EG, et al. Caring for cancer survivors: a survey of primary care physicians. Cancer. 2009;115(18 suppl):4409–4418. 19. ASCO. Recommendations on fertility preservation in cancer patients: guideline summary. J Oncol Pract. 2006;2:143–146. 20. Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol. 2006;24:2917–2931. 21. Fertility guidelines address often-ignored treatment side effect. CA Cancer J Clin. 2006;56:251–253. 22. Ohl DA, Quallich SA, Sønksen J, et al. Anejaculation and retrograde ejaculation. Urol Clin North Am. 2008;35:211–220, viii. 23. Lohrisch C, Paltiel C, Gelmon K, et al. Impact on survival of time from definitive surgery to initiation of adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol. 2006;24:4888–4894. 24. Foley SJ, De Winter P, McFarlane JP, et al. Storage of sperm and embryos: cryopreservation of sperm should be offered to men with testicular cancer. BMJ. 1996;313:1078. 25. Lass A, Abusheikha N, Akagbosu F, et al. Cancer patients should be offered semen cryopreservation. BMJ. 1999;318:1556. 26. Neal MS, Nagel K, Duckworth J, et al. Effectiveness of sperm banking in adolescents and

young adults with cancer: a regional experience. Cancer. 2007;110:1125–1129. 27. Saito K, Suzuki K, Iwasaki A, et al. Sperm cryopreservation before cancer chemotherapy helps in the emotional battle against cancer. Cancer. 2005;104:521–524. 28. Schmidt KL, Larsen E, Bangsbøll S, et al. Assisted reproduction in male cancer survivors: fertility treatment and outcome in 67 couples. Hum Reprod. 2004;19:2806–2810. 29. Electroejaculation (EEJ). Fertil Steril. 2004;82(suppl 1):S204. 30. Tsujimura A. Microdissection testicular sperm extraction: prediction, outcome, and complications. Int J Urol. 2007;14:883–889. 31. Chan PT, Palermo GD, Veeck LL, et al. Testicular sperm extraction combined with intracytoplasmic sperm injection in the treatment of men with persistent azoospermia postchemotherapy. Cancer. 2001;92:1632–1637. 32. Descombe L, Chauleur C, Gentil-Perret A, et al. Testicular sperm extraction in a single cancerous testicle in patients with azoospermia: a case report. Fertil Steril. 2008;90:443, e1–4. 33. Kamischke A, Nieschlag E. Treatment of retrograde ejaculation and anejaculation. Hum Reprod Update. 1999;5:448–474. 34. Wang JX, Yap YY, Matthews CD. Frozen-thawed embryo transfer: influence of clinical factors on implantation rate and risk of multiple conception. Hum Reprod. 2001;16:2316–2319. 35. Sonmezer M, Oktay K. Fertility preservation in female patients. Hum Reprod Update. 2004;10:251–266. 36. Brown J, Farquhar C, Beck J, et al. Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database Syst Rev. 2009;(4): CD002249. 37. Azim AA, Costantini-Ferrando M, Oktay K. Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: a prospective controlled study. J Clin Oncol. 2008;26:2630–2635.

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38. Oktay K. Further evidence on the safety and success of ovarian stimulation with letrozole and tamoxifen in breast cancer patients undergoing in vitro fertilization to cryopreserve their embryos for fertility preservation. J Clin Oncol. 2005;23:3858–3859. 39. Oktay K, Buyuk E, Libertella N, et al. Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol. 2005;23:4347–4353. 40. Oktay K. An individualized approach to fertility preservation in women with cancer. J Support Oncol. 2006;4:181–182, 184. 41. Dobson R. Ovarian transplant raises hope for women facing cancer treatment. BMJ. 1999;319:871. 42. Clough KB, Goffinet F, Labib A, et al. Laparoscopic unilateral ovarian transposition prior to irradiation: prospective study of 20 cases. Cancer. 1996;77:2638–2645. 43. Pahisa J, Martínez-Román S, Martínez-Zamora MA, et al. Laparoscopic ovarian transposition in patients with early cervical cancer. Int J Gynecol Cancer. 2008;18:584–589. 44. Hilders CG, Baranski AG, Peters L, et al. Successful human ovarian autotransplantation to the upper arm. Cancer. 2004;101:2771–2778. 45. Oktay K. Successful human ovarian autotransplantation to the upper arm. Cancer. 2005;103:1982–1983 author reply 1983. 46. Kim SS, Lee WS, Chung MK, et al. Long-term ovarian function and fertility after heterotopic autotransplantation of cryobanked human ovarian tissue: 8-year experience in cancer patients. Fertil Steril. 2009;91:2349–2354. 47. Kim JH, Park JY, Kim DY, et al. Fertility-sparing laparoscopic radical trachelectomy for young women with early stage cervical cancer. BJOG. 2010;117:340–347. 48. Meistrich ML, Shetty G. Hormonal suppression for fertility preservation in males and females. Reproduction. 2008;136:691–701.

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Bereavement care Wendy G. Lichtenthal, Maureen E. Clark, and Holly G. Prigerson

Theories of grief and bereavement  625 Clinical presentations of grief  626 Anticipatory grief  626 Grief around the time of death  626 Acute grief following the death  627 Pathologic responses to bereavement  628 Prolonged grief disorder  628 Risk factors  629 Specific circumstances  629 Sudden death  629 Grief during childhood  630 Loss of a child  630 Interventions  630 Staff support  630 Individual psychotherapy  630 Supportive counseling  630 Psychodynamic and interpersonal psychotherapies  631 Cognitive-behavioral therapy  631 Group psychotherapy  632 Family therapy  632 Internet interventions  632 Combined psychopharmacologic approaches  632 Treatments for PGD  632 Conclusions  632 624

The practice of supportive oncology extends beyond the course of the patient’s illness to support family, significant others, and even professional providers of care. All witness grief in many forms, beginning with the multiple losses that cancer patients suffer before their death. The patient and family members may grieve the patient’s loss of physical capacity, important personal roles and activities, significant relationships, and even future plans as the patient’s health declines. Health care providers help optimize coping with these losses as the disease progresses. Through the development of trusting relationships with the patient and family over the course of the illness, practitioners are in a unique position to provide continuity of care from pre-bereavement to post-bereavement. By taking a family-centered approach during palliative care, clinicians can more readily facilitate bereavement care1 by helping the family to understand the dying process. This may provide surviving family members with a sense of predictability and comfort. Providers should be aware of risk factors for morbid bereavement outcomes, recognize the multiple presentations of grief, and be able to manage such expressions or make appropriate referrals when risk factors are apparent or clinical intervention seems necessary. Reactions to loss are described by many terms, which are often used interchangeably by clinicians, patients, and their families. The following are definitions that grief theorists maintain in the literature: Bereavement is the state of having experienced a loss resulting from death.2,3 n Grief is the distressing emotional response to any loss, including related feelings, cognitions, and behaviors.2 n Mourning is the process of adaptation to a loss, which includes expression of grief and behaviors influenced by culture, religion, and social events, such as grieving rituals.4 n Anticipatory grief is the distress and related emotions, cognitions, and behaviors that occur before an expected loss.4 n Pathologic grief is a severely distressing and disabling abnormal emotional response to loss that involves mental and/or physical dysfunction.5–8 n Disenfranchised grief occurs with losses that are not ­recognized by society, resulting in less social permission to express one’s grief.9 n

Bereavement care This chapter begins with a brief overview of theoretical models of bereavement that have influenced our understanding of the clinical presentation of grief. We then provide descriptions of various clinical presentations that may occur over the course of the palliative care and bereavement trajectory. We consider the reactions of specific populations, including parents who lose a child to cancer and children who lose a parent. Pathologic reactions to bereavement, such as prolonged grief disorder (PGD), and related risk factors are also discussed. Finally, we present a summary of grief interventions, including broad descriptions, indications, and, when available, ­efficacy data.

THEORIES OF GRIEF AND BEREAVEMENT By gaining an understanding of general bereavement ­theories, staff may be better able to comprehend and contextualize observed behaviors and make appropriate referrals when ­necessary. Theoretical models suggest adaptive tasks as well as potential preventive strategies and interventions (see references 2 and 10 for summaries). One of the most influential frameworks for understanding separation and loss is attachment theory. This model, advanced largely by Bowlby,11 focuses on the attachment that naturally occurs between social animals. It posits that children have an instinctual drive to bond with their caregivers, who provide safety and security, to survive. Reactions such as crying and searching when separated from an attachment figure serve the function of reuniting individuals. Studies of infants have distinguished secure from insecure attachment styles, which may be anxious, avoidant, or disorganized/hostile.12 Theorists believe that individuals internalize working models of these early attachments,11 and that having a more insecure attachment style increases one’s risk for separation distress and prolonged grief reactions.7,13 Adaptive grief reactions may involve continuing bonds to the deceased (i.e., maintaining connection to and the influence of the deceased in the survivor’s present-day life) as a healthy by-product of attachment and the grief process.10,14 Early relationships are also a focal point of psychodynamic theories. Freud argued that “grief work” is necessary for adaptation to bereavement.15 This process involves working through one’s emotions to loosen the bond to, and detach libido invested in, the deceased.2,10 Pathologic grief occurs when grief work is not accomplished.15 Although there has not been substantial empirical support of Freud’s hypotheses, some have argued that aspects of his contributions have validity and should not be completely dismissed.2,10 Object relations theory, rooted in psychodynamics, considers the influence of the initial separation between infant and mother, which is thought to serve as a template for reactions to subsequent separations.16 Yearning for the lost object and preserving rather than relinquishing ties are considered adaptive responses to these separations, including bereavement.10 Interpersonal theories of bereavement focus on the way interaction patterns and roles shape identity and self schemata, influencing how individuals grieve.17 Past experiences are believed to influence relationship patterns, including current interpersonal choices and behaviors. Interactions and relationship roles shape the individual’s identity and associated self schemata. Person schemata may be related to a lost

relationship, such as an “ambivalent” schema rooted in mixed feelings about the deceased.18 Horowitz described a treatment for stress responses to events such as bereavement that viewed these person schemata as modifiable once they are identified in current relationships.18 Several theories focus on the cognitive processes that are involved in adaptation to bereavement.3,19 Parkes proposed that death forces individuals to alter their assumptions about the world being safe and predictable so they can cope with life’s challenges.3 The psychosocial transitions necessary for adaptation to a loss involve accommodating the inevitability of death into one’s assumptive world.3,20 With a constructivist perspective, Neimeyer focused on a related adaptive task, “meaning reconstruction.”21 This process involves individuals making sense of and finding meaning in the loss by developing a coherent narrative about how the loss fits into their lives. According to cognitive stress theory, cognitive appraisals of a situation determine the extent to which the event is perceived as stressful, the manner in which an individual copes with the event, and its related physiologic impact.22 In addition to decreasing distress, making meaning of adverse life events such as bereavement can yield positive reactions, which can improve or maintain physical health. The social-functional perspective highlights the interpersonal benefits that these positive emotions can foster.2,10,23 Sociologic models of bereavement consider the impact of society on the individual’s grief and mourning process, including culture-specific rituals such as self-mutilation. Some cultural rituals support continuing, not severing, bonds with the deceased, for instance by revering and seeking spiritual guidance from deceased ancestors.10 The social constructionist perspective posits that the expression of grief, including the sanctioning of public and private grieving practices, is largely shaped by culture and social norms.24 Social support also plays a large role in facilitating the grieving process, providing an outlet for emotional expression, buffering against negative consequences of other stressful events, and reducing isolation of bereaved individuals. Family systems theorists propose that individual members of a bereaved family have reciprocal influences on the grief reactions of one another.25 Grief responses are affected by the role that the deceased individual played in the family system, as well as the family’s level of functioning before the loss.1 Poor communication, low cohesion, and increased conflict in the family have been associated with negative psychosocial outcomes during bereavement.1,26 The focus of cognitive-behavioral theory is on the interplay between grief-related emotions, thoughts, and behaviors, particularly those that are maladaptive and play a role in prolonged or severe grief responses.10,27,28 Distorted cognitions (e.g., unrealistic thoughts that one should have done more to care for the deceased) and associated feelings (e.g., guilt) can result in unhelpful ruminations about the deceased. Cognitivebehavioral theory also considers the role of avoidance of triggers of painful emotions, such as reminders of the deceased, in prolonging the course of grief. Avoidance can become negatively reinforcing and may reduce opportunities to process the loss and to engage in pleasurable, corrective experiences.28 One of the most widely accepted contemporary theories is Stroebe and Schut’s29 dual process model of coping. This theory proposes that engagement in both loss-oriented and restoration-oriented tasks is necessary for adaptive ­coping, highlighting the value of both approaching and avoiding

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the loss.10,29 Loss-oriented thoughts, emotions, and behaviors focus on the deceased, confronting the reality of the loss and processing positive and negative memories about the deceased, the relationship, and the future without him/ her. Restoration-oriented thoughts, emotions, and behaviors are those that involve restoring functioning through assimilation in the world without the deceased. Normal functioning is reestablished as the bereaved gradually resumes and develops valued activities and relationships. Oscillation between loss-oriented and restoration-oriented phases allows bereaved individuals to actively confront their grief for a time and then find respite from their pain as they attempt to reengage in life.2,10 Grief interventions have incorporated the dual process model into their theoretical rationales as a means of facilitating ­adaptive coping.26,27,30 All of the theories described previously may be considered within a biopsychosocial framework. In fact, initiatives to develop a neurobiopsychosocial model of grief have been advanced through the use of technology such as functional magnetic resonance imaging (fMRI).31 For example, a recent fMRI study gave participants a grief arousal task and found increased activity in the posterior cingulate cortex, a brain region believed to be involved in retrieval of emotion-laden episodic memories.32 The sheer number of theoretical models of bereavement developed suggests that grief is a complex process with numerous influences. Integration of biological, psychological, social, and behavioral viewpoints is critical to a comprehensive understanding of observed bereavement phenomena.2

CLINICAL PRESENTATIONS OF GRIEF Supportive care clinicians may witness grieving in numerous contexts, including the emergence of anticipatory grief as illness progresses, acute grief at the time of death, and, in some cases, prolonged grieving that does not dissipate over time.

ANTICIPATORY GRIEF The grief of cancer patients and their families may begin well before the patient’s death. In fact, both patients and family members may perceive the illness as fatal at the initial moment of diagnosis.4 Cognitive and emotional acceptance of a terminal prognosis is a dynamic process, waxing and waning as acknowledgment of the prognosis competes with a desire to maintain hope for a cure. Loved ones may present with unrealistic optimism, protest, anger, or heightened protectiveness of the patient. The challenge of accepting that the patient is going to die involves a complex interplay between one’s basic personality, the availability of social support, and one’s spiritual and existential views on life. A psychological process of adaptation evolves throughout the course of an illness.33,34 Achieving cognitive and emotional acceptance is important to bereavement care because of the role it can play in facilitating adjustment post loss.35 Without the ability or opportunity to come to terms with a patient’s prognosis, survivors are more at risk for a complicated course of bereavement and ­developing PGD after the patient dies.35 Anticipatory grieving may intensify when bad news or ­serious disease progression is communicated to the patient 626 and family. By using sensitive communication approaches,

providers can assist the family in processing clinical information and revising their expectations if necessary. This may allow loved ones the chance to mentally prepare for the loss. As additional losses associated with advanced illness occur, there may be opportunities for family members to express their attachment through acts of caregiving. Through these acts and through efforts to resolve any relationship issues, families may grow closer and more cohesive. However, families with greater dysfunction may experience more tension and conflict as some members react with denial, hostility, avoidance, or other maladaptive behaviors.26 Although some theorists have suggested that the presence of anticipatory grief diminishes the intensity of post-loss grief, studies in this area have yielded inconsistent findings. Intense anticipatory grief is a risk factor for clinical depression.36 These discrepancies may be due to variations in how anticipatory grief is operationally defined. The experience of grieving before the death should be distinguished from being prepared for the loss, which has been associated with the presence of PGD.37 Even when the course of illness is lengthy, survivors may perceive the death as sudden. Providers can help patients and families psychologically prepare for the patient’s death and foster positive emotions during stressful times by encouraging open communication and opportunities to say goodbye, allowing them to address unfinished business and express appreciation for one another.1

GRIEF AROUND THE TIME OF DEATH Family members at the patient’s bedside are often emotional and exceptionally attentive to details associated with the patient’s well-being. The final moments of the patient’s life often remain as vivid memories in the survivors’ minds long after the patient’s death. Even though many sources of distress may not be readily visible or easily articulated by patients, their influence on the end-of-life experience can be profound.38 Clinicians must exhibit the utmost respect and sensitivity at this time. Practitioners working at the patient’s bedside frequently have the opportunity to provide important consoling information, including reassurance about the patient’s comfort and clear explanations in layperson’s terms about the dying process, including the meaning of sounds, secretions, changes in breathing, and alterations in levels of consciousness. Providing family members with information about what to expect can be extremely helpful in preparing them for the death and reducing distress as they witness ­end-of-life symptoms. When death appears imminent, providers should contact family members who are not present. Relatives who cannot visit before the death occurs should be offered an opportunity to view the patient’s body and be given information about the sequence of events leading up to the death. Clinicians should take time to provide support and answer questions thoroughly. Culture may play a significant role in expressions of acute grief. Staff ought to respect and honor cultural and religious practices, including those related to autopsy and time alone with the patient. Providers may facilitate pastoral counseling and may wish to consult with a cultural intermediary to assist with sensitive and appropriate responses to a family’s practices and needs. Clinicians should make efforts to ­prevent disenfranchised grief,9 encouraging expression of ­sorrow for relationships that may not have been accepted and making

Bereavement care efforts not to minimize expected deaths. Families are often deeply appreciative when providers communicate their sympathy through a phone call or other personal channels. A letter of condolence can provide a grieving family with concrete expression of the provider’s care that may be reviewed in the future, while also providing a sense of closure for the professional.39 Support may also be offered through provision of prescriptions for anxiolytics or sleep aids, referrals for psychosocial services, and guidance about making funeral arrangements.

Hypothesized Grief Resolution Frequency1 Separation distress

Acceptance/ Recovery

Depression

Disbelief

Low 0

ACUTE GRIEF FOLLOWING THE DEATH The first empirical investigation of acute grief phenomena was conducted by Lindemann, who examined the reactions of bereaved relatives of individuals who perished in a 1942 Boston nightclub fire.40 Lindemann described acute grief as a characteristic syndrome of affective and somatic symptoms, such as sadness, anger, guilt, shortness of breath, and physical identification symptoms that the deceased experienced.40 Because these distressing symptoms may be intense and variable, even within a given family system, it is often difficult to distinguish between “normal” and pathologic responses during the first months of bereavement. Adaptive acute grief has characteristic emotions, cognitions, behaviors, and physical symptoms that come and go in waves. Emotional reactions include sadness, guilt, anger, distress, and anxiety.3,10 Initially, a profound sense of yearning occurs for the lost individual. When patients are significantly suffering as they approach death, surviving family members may, in parallel to their sadness, experience a sense of relief. They may also experience numbness or disbelief if the death was not expected to occur so soon, particularly if the death was sudden and due to disease-related complications. Grief-related thoughts range from purposeful reminiscing about the deceased to intrusive images and memories. The bereaved may anticipate the absence of the deceased in expected future life events (e.g., graduations, weddings). Behaviors include searching for the deceased, particularly when confronted with personal reminders of their loved one, and social withdrawal. Individuals may also seek support and comfort. Physical symptoms include difficulty sleeping, fatigue, anorexia, mild weight loss, numbness, restlessness, tension, tremors, and sometimes pain. Acute grief and its associated features may reflect difficulty in informational and emotional processing of the reality of the loss. Research has demonstrated that as grief decreases over time, acceptance increases.41 Grief at its height might reflect the emotional consequences of the inability to accept the loss and to continue wanting what one cannot have.41 Acceptance of the loss, by contrast, may represent emotional equanimity, that is, a sense of inner peace and tranquility that comes with relinquishing the struggle to regain what is lost or is being taken away as one rebuilds his/her life.42 Greater acceptance has been associated with less suffering, implying that benefits may be derived from promoting acceptance.42 Clinicians may be uniquely positioned to facilitate this process. For many years, the stage theory of grief resolution was widely accepted in the bereavement field. This theory proposed that “normal” or adaptive grief required consecutive passing through the stages of shock—yearning or angry protest to sad or depressed mood to, finally, acceptance of the loss.43,44 The top panel of Figure 59-1 illustrates this sequence.

59

1

2

3

4

5

6

Months from Loss Unadjusted Mean Grief Resolution Scores Frequency b

5

The first 6 months Acceptance

4 Yearning

3 2

Disbelief

Depressed Mood

Anger

1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months from Lossa

a: All of the lines start from 2 months after loss and end at 24 months b: 1=Less than once a month; 2=Monthly; 3=Weekly, 4=Daily; 5=Several times a day except for indicator of “depressed mood”

Fig. 59-1  Proposed grief resolution model and observed grief symptoms over time. (Redrawn from Pathologic grief: maladaptation to loss [Copyright 1993, American Psychiatric Publishing, Inc.].1)

To examine its validity, an empirical study of the stage theory was conducted with bereaved participants in the communitybased Yale Bereavement Study.45 Results showed that, rather than shock and disbelief, the most common initial grief symptom was yearning,45 as presented in the bottom panel of Figure 59-1. Participants were assessed between 2 and 24 months post loss, and it is possible that shock or other symptoms were elevated during the first 2 months, but were not captured in this investigation.45 A trajectory of gradual reductions in levels of shock, yearning, and sad mood represents the pattern of normal mourning. Anger levels remained low and relatively stable, and acceptance increased over time. When these grief indicators were rescaled and compared, their respective peak frequencies in the first 6 months post loss occurred in a sequence similar to the order of stages proposed by past bereavement theorists3,44 (see Fig. 59-1). The common contemporary perspective is that stages of grief overlap and intense emotions may wax and wane in the early phases of bereavement. Bereaved individuals may continue their bond to the deceased and reexperience grief symptoms intermittently throughout their lives.10 Bereavement theorists widely believe that adaptive coping involves the dynamic oscillation between confrontation of the loss and related emotions and reengagement in life without the 627

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deceased, as proposed by the dual process model of coping.29 Cultural sanctions may influence expressions of grief, including its duration. However, no absolute timeline exists for the adaptation process, as the duration and intensity of symptoms are often proportionate to the strength of the attachment to the deceased. The absence of grief symptoms may reflect, therefore, either a weak attachment to the deceased or coping with strong emotions through denial or dissociation. Although grief often does not completely “resolve,” studies suggest that 80% to 90% of bereaved individuals have largely begun to accept the death of their loved one and to adapt by 6 months after the loss.7 This adaptation is characterized by individuals’ ability to acknowledge the death and to begin to transform their relationship to the deceased. It also involves restoring functioning through reengagement in work, leisure, and creative activities and the development of new and existing personal relationships. As time passes, bereaved individuals are able to find meaning and purpose in their lives and to consider the future as fulfilling and satisfying.42 Although they may continue to grieve throughout their lives, particularly when reminders of the deceased or anniversaries present, the intensity and duration of their reactions will gradually diminish. In fact, resilience following bereavement is common.2,10,46

PATHOLOGIC RESPONSES TO BEREAVEMENT Intense distress and periods of sadness and anxiety are typical in the acute phase of grief. When bereavement-related psychological symptoms interact with an individual’s existing vulnerabilities, however, symptoms of depressive and anxiety disorders may emerge. In a longitudinal study of bereaved widows, Zisook and Schucter 47 found that 24% of their sample met criteria for major depression 2 months after their loss, with rates decreasing to 16% by 13 months post loss. Given that sadness is common during the early months of bereavement, the diagnosis of clinical depression becomes warranted when more pathologic features, such as profound loss of interest, pervasive sadness, psychomotor retardation, deep guilt, worthlessness, hopelessness, helplessness, loss of meaning, and/or suicidal ideation, are present.48 Neurovegetative depressive symptoms are less discriminatory. Anxiety disorders are also prevalent, and bereaved individuals may present with separation anxiety, generalized anxiety, phobic, and somatic symptoms. When family members witness circumstances that they perceive as traumatic, such as gross disfigurement, bedsores, foul odor, agitated confusion, or even an insufficient goodbye, symptoms of posttraumatic stress disorder (PTSD) may manifest. Individuals with a history of alcohol or other substance use, psychosis, or bipolar disorder are at increased risk of relapsing following bereavement. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)49 guidelines, clinicians should not make a diagnosis of an adjustment disorder if the clinical symptoms are due to the stress of bereavement.

PROLONGED GRIEF DISORDER Normatively, as bereaved individuals move toward acceptance of their loss and adaptation to life without the deceased, the 628 intensity and severity of grief symptoms dissipate over time.

However, approximately 10% to 20% exhibit a more prolonged and severe grief response.7,8 These individuals often seem “stuck” in their grief, with the acute, intense grief symptoms that are frequently observed immediately after a loss persisting over time. To assist clinicians in identifying these individuals, researchers have empirically derived diagnostic criteria of PGD, which is characterized by a cluster of symptoms that is distinct from symptoms of bereavement-related depression and anxiety.7,8 Although PGD may be comorbid with depression or anxiety, discriminating symptoms include intense yearning and longing for the deceased, preoccupying ruminations, intrusive painful thoughts, disbelief and trouble accepting the reality of the loss, and difficulty finding meaning and moving forward in their lives without their loved one. These are clinically distinct from symptoms of depression, such as depressed mood, psychomotor retardation, and changes in appetite or weight.50 Diagnoses of PGD and PTSD may co-occur, but PGD may manifest following traumatic or nontraumatic losses. In a study of bereaved individuals assessed for major depressive disorder, PTSD, and PGD, Barry et al.37 found that PGD was the most common disorder 4 and 9 months post loss, and that overlap between these diagnoses was modest. Silverman et al.51 similarly examined the prevalence of these mental disorders in a different cohort and found that PGD was most prevalent and had the lowest comorbidity rate. PGD has been associated with increased risk of negative mental and physical health outcomes, including cancer, hypertension, cardiac events, adverse health behaviors, hospitalization, depressive symptoms, functional impairment, and suicidal ideation.52–54 Bereavement experts have proposed that PGD, formerly referred to in the literature as complicated grief and traumatic grief, should be established as a distinct mental disorder in the next edition of the Diagnostic and Statistical Manual of Mental Disorders36 (i.e., DSM-V).8,50 The proposed diagnostic criteria8 are presented in Box 59-1. Note that a diagnosis of PGD should not be made until at least 6 months has elapsed since the death. This criterion is sensitive enough to identify individuals who might benefit from intervention because their grief is persisting, while attempting to avoid pathologizing the reactions of those individuals whose grief will resolve naturally with time.8 Typically, onset of symptoms occurs at the time of death, but delayed and chronic grief can also meet the 6-month timing criterion. Bereavement experts have described pathologic grief responses for decades. Many subtypes have been used to characterize grief pathology in the literature, including chronic grief, inhibited grief, and delayed grief.3,10 Despite a consensus that pathologic responses to bereavement exist, debates about whether symptoms of PGD should be established as a distinct mental disorder remain, as “normal” and abnormal grief responses are believed to fall on the same continuum. Pathologic symptoms consist of intensified and prolonged manifestations of acute grief symptoms. Advocates of establishing PGD as a mental disorder argue that doing so will allow consistent identification of individuals in need by researchers, clinicians, and even insurance companies, to facilitate the development and delivery of appropriate interventions.7,8,50 Detractors worry that PGD will result in stigmatization and potential medicalization of normal reactions to loss and will inhibit family members’ willingness to intervene.55

Bereavement care

BOX 59-1  Proposed Diagnostic Criteria for Prolonged Grief Disorder (PGD) A. Event Criterion: Bereavement (loss of a significant other). B. Separation Distress: The bereaved person experiences yearning (e.g., craving, pining, longing for the deceased; physical or emotional suffering as a result of the desired, but unfulfilled, reunion with the deceased) daily or to a disabling degree. C. Cognitive, Emotional, and Behavioral Symptoms: The bereaved person must have five (or more) of the following symptoms experienced daily or to a disabling degree: (1) Confusion about one’s role in life or diminished sense of self (i.e., feeling that a part of oneself has died) (2) Difficulty accepting the loss (3) Avoidance of reminders of the reality of the loss (4) Inability to trust others since the loss (5) Bitterness or anger related to the loss (6) Difficulty moving on with life (e.g., making new friends, pursuing interests) (7) Numbness (absence of emotion) since the loss (8) Feeling that life is unfulfilling, empty, and meaningless since the loss (9) Feeling stunned, dazed, or shocked by the loss D. Timing: Diagnosis should not be made until at least 6 months has elapsed since the death. E. Impairment: The disturbance causes clinically significant impairment in social, occupational, or other important areas of functioning (e.g., domestic responsibilities). F. Relation to Other Mental Disorders: The disturbance is not better accounted for by Major Depressive Disorder, Generalized Anxiety Disorder, or Posttraumatic Stress Disorder. Note: Proposed diagnostic criteria for PGD outlined by Prigerson HG, Horowitz MJ, Jacobs SC, et al.8

RISK FACTORS A majority of bereaved individuals will adapt over time to the death of a loved one from cancer without requiring intervention. When support resources are limited, it is particularly important to triage those at heightened risk for poor outcomes to psychosocial support services. Staff should hold a regular multidisciplinary death review to identify family members at risk for psychopathology.1,10 Table 59-1 presents common risk factors for negative bereavement outcomes. Individuals at risk for psychiatric disorders in general are vulnerable to the onset or recurrence of disturbances during bereavement. Studies of the causes of PGD have demonstrated the key role of early disturbances in secure attachment. Empirically identified risk factors include insecure attachment styles56,57; high marital dependency and close, security-enhancing relationships57,58; close kinship relationships to the deceased57,59; childhood separation anxiety13; childhood adversity51 (e.g., abuse, serious neglect, parent death); and controlling parents.60 PGD has also been associated with being African American,42 having lower perceived preparedness for the loss,37 and having lower levels of social support.61 Although peaceful acceptance of dying may reduce survivors’ risk for poor outcomes, clearly not all dying patients or bereaved

59

Table 59-1  Risk factors for pathologic grief outcomes Category

Description

Circumstances of death

• Perceived lack of preparedness for loss • Untimely within the life cycle (e.g., death of child) • Sudden and unexpected (e.g., death from septic neutropenia during chemotherapy) • Traumatic (e.g., shocking cachexia and debility) • Stigmatized (e.g., AIDS, suicide)

Personal vulnerability

• History of psychiatric disorder (e.g., clinical depression, separation anxiety) • Childhood adversity (e.g., abuse, neglect, controlling parenting) • Personality and coping style (e.g., intense worrier, low self-esteem) • Attachment style (e.g., insecure) • Cumulative experience of losses

Nature of the relationship to the deceased

• Overly dependent (e.g., securityenhancing relationship) • Ambivalent (e.g., angry and insecure with alcohol abuse, infidelity, gambling)

Family and social support

• Family dysfunction (e.g., poor cohesion and communication, high conflict) • Isolated (e.g., new migrant, new residential move) • Alienated (e.g., perception of low social support)

AIDS, Acquired immunodeficiency syndrome.

family members will be able to confront loss with peace and equanimity.35 However, clinicians may be ble to foster death acceptance and to provide support or referrals to those individuals who appear to be at greater risk for psychological distress and prolonged suffering.

SPECIFIC CIRCUMSTANCES SUDDEN DEATH Sudden death in oncology occurs in one quarter of patients, when infection, clots, or cardiac events interrupt the predicted cancer trajectory.62 Perceptions that a death was sudden are often due to the family member’s expectations about the amount of time they had left with the patient. These expectations might be based on the prognosis given or on the number of times the patient had near-fatal experiences but eventually recovered. Such experiences can reduce the family’s preparedness for the death actually occurring following an acute secondary condition, such as sepsis, pulmonary emboli, c­ ardiac events, or hemorrhage. Although families may have an intellectual understanding that the illness is terminal, they might still be unable to process this information on an emotional level. Emotional acceptance 629

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of a terminal prognosis is associated with feeling less terrified and more supported.63 Family members with greater acceptance that the patient is dying are more likely to feel prepared for the loss and less likely to experience negative bereavement outcomes.37 Improved quality of life among bereaved ­family members has also been associated with patients’ peaceful awareness of their prognosis, which is predictive of advance care planning, and greater mental and physical health in the last week of life.35 Conversely, those who experience the death as sudden or themselves as psychologically unprepared for the loss are at greater risk for PGD and depression, particularly when the death is perceived as violent.7,37 Clinicians should assess family members’ understanding of the circumstances surrounding the death and help the bereaved make sense of any aspects that were perplexing.

GRIEF DURING CHILDHOOD The grief reaction of a child who loses a parent or other attachment figure is dependent on his/her developmental stage.4,10 Children may not understand the irreversibility of death until they have developed the capacity for abstract thinking, which usually occurs around ages 8 to 10. Mourning can be facilitated and supported through open discussion of the death by the surviving parent and family. Clinicians can provide guidance to surviving parents by encouraging the child’s attendance at and participation in bereavement rituals and fostering emotional expression through family activities and creation of a memory book, to continue the child’s connection to the deceased.4,10

LOSS OF A CHILD The loss of a child to cancer is one of the most intense and prolonged types of bereavement.64 It often occurs after a lengthy battle with the illness and deep investment in providing care for the child. When caregiving for the child has long been the priority, parents may become disconnected from other relationships and roles that were meaningful. The intense pain of acute grief often deepens their sense of isolation. Parents may find solace in connecting with other bereaved parents through support groups. They may need additional assistance coping with guilt related to concerns that they could have done more to prevent the death. Finding ways to honor and memorialize their child’s life may help parents to move forward, and so staff should facilitate this when possible. Many aspects of parental grief that have been viewed as pathologic in other settings of bereavement (e.g., prolonged yearning) may, in fact, be typical of the experience of losing a child.64 Researchers have found heightened anxiety and depression among parents bereaved by cancer that persists 4 to 6 years after the loss.65 Among those parents with unresolved grief, poorer mental and physical health, increased health service use, and increased sick leave from work have been reported.66 The course of parental bereavement is highly individual, and many factors can influence it.67 Parents who appear to be at greater risk for poor adjustment are those who, before their loss, have difficulty accepting the possibility of death and have weak emotional bonds with others, and ­following their loss, have difficulties relating to others and redefining their identity and purpose in life.67 Clinicians can play an influential role in parents’ adjust630 ment to bereavement before the child’s death. Parents often do

not recognize their dying child’s poor prognosis, resulting in aggressive care at the end of life. Research suggests that parents who report the highest quality of care are those who feel most prepared for the end-of-life care period. Although providers may be reluctant to discuss the child’s prognosis because it is painful and difficult to predict, sensitive, open, clear, and supportive communication about how the end of the child’s life may unfold can be very helpful.68 Following the child’s death, providers should use the child’s name when speaking of him or her to the family and should offer to be available to answer questions if any arise over the course of the parents’ bereavement. Clinicians should recognize that they, themselves, often have strong emotional reactions to the death of a child and can benefit from outlets to express their own feelings.

INTERVENTIONS Research on grief interventions has yielded inconclusive findings, which, in large part, may be due to the inconsistent methodologic rigor of treatment outcome studies. Many studies have lacked adequate control groups, random assignment, treatment adherence monitoring, and standardized and blinded outcome assessments, and have had unexplained dropouts. A number of systematic reviews and meta-analyses of grief interventions have been conducted to determine which bereaved populations might benefit from psychotherapy and counseling.69–72 Table 59-2 presents a summary of these studies. With small to moderate effects for grief interventions, the research suggests that psychosocial treatment generally is not efficacious. Researchers have debated the meaning of these results. Some have argued that the effects are small because, for the majority of individuals, grief and related symptoms diminish naturally over time.72,73 Others have advocated cautious optimism about the utility of grief counseling.74 Although the results of grief intervention trials in general have been variable, interventions that target bereaved individuals at high risk for or exhibiting poorer adjustment have ­consistently demonstrated stronger effects.72

STAFF SUPPORT Families generally appreciate when oncology staff members connect with them following the patient’s death, particularly when close relationships have developed over the course of the patient’s care. Condolences may be offered over the telephone, through a sympathy card or personal visits, or by attending the funeral. Staff may also choose to hold an annual commemoration service for the deceased and include bereaved families in this ritual.

INDIVIDUAL PSYCHOTHERAPY

Supportive counseling

Support is a key component of many therapeutic approaches. Interventions that focus on support create a safe forum for emotional expression and time to focus on the loss, which can facilitate the natural adaptive grieving process.19 Providing validation and encouragement, supportive counselors also promote adaptation and restoration through discussion of future personal goals related to moving forward with life in the absence of the deceased.

Bereavement care

59

Table 59-2  Systematic reviews and meta-analyses of bereavement interventions

Authors

Number of studies included

Study characteristics

Effect size

Possible conclusions

Currier, Neimeyer, and Berman72

61

Randomized and nonrandomized studies No-intervention control group Participants did not choose study condition 48 peer-reviewed articles and 16 dissertations

0.16*

Generally, all participants (intervention and control) improved over time Clinical and self-referrals associated with better outcomes, although differences diminished at follow-up Age/sex of participants and timing of intervention did not appear to influence effects

Currier, Holland, and Neimeyer71

13

Controlled studies of interventions for children

0.14

Lack of support for efficacy of interventions Earlier intervention yielded stronger effects Targeting distressed associated with better outcomes

Allumbaugh and Hoyt69

35

Controlled and noncontrolled

0.43

Effects stronger for self-identified participants Low statistical power Moderating variables influence effects

Kato and Mann 70

13

Randomized controlled trials Treatment and control groups recruited similarly Post-loss interventions

0.11

Interventions may be ineffective Control groups also improve May need stronger dose of interventions Methodologic problems common

Fortner and Neimeyer84†

23

Randomized controlled trials

0.13

Greater effects with high-risk populations

Schut, Stroebe, van den Bout, and Terheggen85

16 primary; 7 secondary; 7 tertiary‡

Organized help Focused on treating grief Methodologically sound

Low to Modest effects

Strongest effects with individuals exhibiting psychopathology/pathologic grief Greater effects with self-referred

Jordan and Neimeyer73

4

Reviews and meta-analyses

N/A

Generally low efficacy of interventions Intervention may not be necessary for most bereaved Need to develop new approaches Need to improve study methods

*The effect size of d = 0.16 was for randomized studies at posttreatment; for nonrandomized studies (n = 12), the effect size was d = 0.51 at posttreatment. Tests of both effect size estimates were statistically significant. † From unpublished work of Fortner and Neimeyer (1999) as described by Neimeyer.84 ‡ Primary preventive interventions were open to all bereaved individuals. Secondary preventive interventions were open to high-risk individuals. Tertiary preventive interventions were open to individuals with complicated grief or other psychopathology.

Psychodynamic and interpersonal psychotherapies Psychodynamic approaches consider the influence that childhood experiences and internalized object relations may be playing in the patient’s unconscious conflicts and current related grief response. Psychotherapy is typically a longer-term process. There is a limited but growing evidence base for psychodynamic therapies, with the majority of trials focusing on supportive-expressive approaches.75 Individuals who struggle with unresolved issues influenced by early relationships and conflicts, including those related to attachment security, might benefit from a psychodynamic approach. Another treatment based on psychodynamic theory is interpersonal psychotherapy (IPT), a short-term (12 to 16 weeks) manualized approach that focuses on relationship problems that are believed to maintain symptoms. It was originally designed to treat depression but has been applied to treat a variety of disorders in several populations.76 IPT therapists choose a target area to focus on, which may include role disputes, role transitions, interpersonal deficits, or complicated grief. When

unresolved grief is targeted, patients work on reengaging in or developing relationships using strategies such as communication skill building. IPT is indicated for bereaved individuals exhibiting current interpersonal ­functioning issues.

Cognitive-behavioral therapy Cognitive-behavioral therapy (CBT) focuses on identifying and restructuring maladaptive thoughts and behaviors. For bereaved individuals, CBT approaches involve modification of dysfunctional thinking that prevents adaptive processing of the loss. Behavioral strategies include exposure to avoided thoughts and situations, as well as engagement in restorationoriented, pleasurable activities.28 CBT is indicated when individuals are struggling with excessive guilt and anger that may be fueled by cognitive distortions about, for example, the relationship to the deceased or circumstances surrounding the death. CBT also may be helpful for those avoiding reminders of the loss or avoiding resuming functional activities. For individuals suffering from severe depression following bereavement, research suggests that CBT is more effective than IPT.76 631

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GROUP PSYCHOTHERAPY

Treatments for PGD

Bereavement groups permit mutual support among individuals who have experienced similar types of losses. Members can provide validation to one another, while reducing the isolation that may occur during bereavement. Groups additionally facilitate emotional expression and processing and share effective coping strategies. In studies of short-term group psychotherapy for individuals with complicated grief (i.e., PGD), Piper and colleagues77–79 found that bereaved individuals were more likely to benefit from the treatment group if they had more social support; a history of mature relationships; and higher levels of extraversion, openness, and conscientiousness.

Symptoms of PGD can be resistant to traditional treatments for bereavement-related depression (e.g., IPT, antidepressants).7,50 Specific interventions designed to treat PGD have been developed. Shear et al.27 developed Complicated Grief Treatment (CGT), a 16-session manualized treatment that incorporates psychoeducation about the dual process model of bereavement coping with CBT approaches such as exposure to avoided loss-related thoughts, retelling the story of the death, imaginal conversations with the deceased, and development of personal goals to assist with restorative behaviors. An RCT comparing CGT to IPT found that a larger percentage of patients responded to CBT (51%) than to IPT (28%), and that the time to response for patients receiving CGT was more rapid.27 Boelen et al.83 compared a 12-session CBT intervention designed to treat PGD versus supportive counseling. They found that CBT was more efficacious in reducing PGD and other psychopathologic symptoms than the comparison arm. Greater benefits were found with exposure than with cognitive restructuring techniques, and when treatment began with exposure followed by cognitive restructuring, as opposed to when the order of these techniques was reversed.83

FAMILY THERAPY Using a family-centered approach throughout the course of cancer treatment and palliative care permits providers to identify those who might be at risk for poor psychological outcomes after death. Kissane et al.1,26 developed family-focused grief therapy (FFGT), a 6- to10-session preventive intervention designed to facilitate continuity of care. Families are screened to identify those with high conflict, low cohesion, and/or communication deficits while the patient is receiving palliative care. Therapy begins at this time and continues through bereavement, targeting dysfunctional families and “intermediate” families, who exhibit moderate challenges in their ability to relate effectively. Commencing therapy while the patient is still alive allows clinicians to understand the impact of the illness on the family and how it may affect their adjustment post loss. The goals of FFGT are to facilitate mutual support and the sharing of grief. A randomized controlled trial (RCT) of FFGT demonstrated significant reductions in distress among family members 13 months after the patient’s death.26,80 An ongoing RCT is comparing the dose intensity of 6 or 10 sessions of FFGT for high-risk families at Memorial Sloan-Kettering Cancer Center and other local institutions. By implementing routine screening of family functioning and interventions such as FFGT in oncology settings, more dysfunctional families can be identified, and morbid grief outcomes may be prevented.

INTERNET INTERVENTIONS Internet-based mental health interventions provide a promising vehicle to promote mental health and overcome barriers to accessing care by offering mental health information and homebased, self-help treatments to underserved populations.81 Selfdisclosure may be facilitated by the anonymity of the computer.82 It may also provide much needed assistance to grieving individuals who find it too painful to return to the institution where their loved one was treated. Internet delivery of more directive intervention approaches (e.g., CBT) may help reduce symptoms of psychiatric disorders such as PGD, depression, and PTSD.81

Combined psychopharmacologic approaches Bereavement-related mental disorders are wisely treated using appropriate combinations of standard psychopharmacologic and psychotherapeutic approaches.2,10 Anxiolytics and sleep aids may be particularly useful during the acute phase of bereavement. Selective serotonin and noradrenergic reuptake 632 inhibitors may be used to reduce depressive symptoms.

CONCLUSIONS Several theoretical models of bereavement have been proposed, each offering a unique perspective on the grieving experience of individuals who survive the loss of a loved one to cancer. These models are not mutually exclusive and can be integrated within a biopsychosocial framework to provide a comprehensive understanding of observed reactions and to develop effective interventions. Given the variety of disciplines and theoretical perspectives of grief, it is not surprising that a significant divide between clinical practice and research often exists in this field.2 Grief intervention research has been hindered by this and the challenges of recruiting and designing methodologically rigorous treatment outcome studies with vulnerable bereaved populations. Despite these issues, clinicians should make efforts to provide support to bereaved individuals through the application of, or referral for, empirically supported treatments. Controversial issues in the field of bereavement include whether it is appropriate to distinguish normal, or typical, grief from more pathologic reactions such as PGD. Efforts are being made to establish PGD as a mental disorder in DSM-V. Psychotherapy for grief should target those individuals who are at greatest risk and would likely benefit the most. Lower effect sizes observed in past grief intervention clinical trials were likely related to the inclusion of well-adjusted bereaved individuals whose grief dissipated naturally over time.72,85 By studying bereaved individuals who exhibit resilience after their loss,10,46 we can learn more about adaptive pathways that can be promoted through support and intervention. The importance of continuity of care for families from end of life through bereavement is gaining increasing recognition in palliative care. Oncology clinicians are uniquely positioned to facilitate this continuity, but there remains a great need to establish infrastructures that support these efforts within cancer treatment settings. Bereavement care begins before the patient’s death by screening for risk factors to identify family members who may be in need of continued support post loss, and by applying evidence-based interventions to reduce the suffering of those in greatest need.

Bereavement care

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 psychosocial oncology

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Index A

Abdominal vagal afferents, CINV with, 17 Ablative techniques, malignant dysphagia treatment with, 173 Acetabular fracture, risk assessment for bone metastases, 294–295 Acneiform rash, 115–117, 116t, 117f Activities of daily living, lymphedema management with, 215 Activity level, cancer-related fatigue associated with, 142–143 Acupuncture, 465–466, 465t background on, 465–466 clinical evidence for, 466, 466t definition of, 465 hot flashes management with, 227–228 xerostomia management with, 238 Acute delayed reaction, radiotherapy-induced, 37 Acute phase protein response (APPR), 152 Acute phase response, bisphosphonates with, 248 Acute stress disorder (ASD), 530 Acyclovir, dosage for, 30t Addiction, 568. See also Substance abuse Adipose tissue loss, 156, 156f Adjectival scale, 178 Adjustment disorder, 529 Adnexae, late effects of chemotherapy/radiation with, 432 Advance directives, 513 framework for, 515 overcoming barriers to completion of, 514–515 timing for discussion of, 515, 515t Airway obstruction, supportive interventions for, 384 Airway stents malignant central airway obstruction treated with, 320–321 metallic, 321, 321f, 322f silicone, 320–321, 321f Alcohol consumption, CINV risk with, 20t Alemtuzumab cardiotoxicity with, 70t emetogenic risk with, 19t inflammation risk with extravasation of, 3t Alendronate diarrhea with, 249t necrosis with, 249t ONJ with, 249, 249t side effects of, 249t Alkylating agents cardiotoxicity with, 70t cisplatin nephrotoxicity with treatment using, 46–47 diagnostic features with, 46 treatment strategies for, 46–47 role in secondary cancers of, 458 Alkylators, pulmonary complications with, 311–312 Allergic reactions, chemotherapy agents associated with, 11–12 cytotoxic chemotherapeutic agents, 11–12 monoclonal antibodies, 12 classification of, 12t Page numbers followed by b indicate boxes; f, indicate figures; t, indicate tables.

Allergic reactions, chemotherapy (Continued) definition, 10–11 diagnosis of, 12–13, 13t management of patients with, 13–14 acute management, 13–14 desensitization, 14 mechanisms of, 10–11 prevention of, 13 premedications for, 13 skin testing for, 13 types of, 10–11 Allopurinol, itch caused by, 206t Altretamine, emetogenic risk with, 19t Amikacin dosage for, 28t serum concentrations target for, 30t Aminoglycosides, serum concentrations target for, 30t Amiodarone, itch caused by, 206t Amitriptyline, itch caused by, 206t Amoxicillin, dosage for, 28t Amphotericin B lipid complex, dosage for, 30t Ampicillin, itch caused by, 206t Amsacrine extravasation of, 5 ulceration with extravasation of, 3t Anaphylactic reaction. See Allergic reactions, chemotherapy Anaphylactoid reaction, 10, 11t. See also Allergic reactions, chemotherapy Anemia cancer-related fatigue associated with, 141 radiotherapy-induced, 41 Angiotensin, late treatment effects modulated by, 435–436 Angular cheilitis, 233, 235f Anorexia CACS with, 159–160 cannabinoids for, 160 corticosteroids for, 160 dronabinol for, 160 megestrol acetate for, 160 Anorexia-cachexia syndrome, prognostic assessment with, 475 Anthracyclines cardiotoxicity with, 70t extravasation of, 6 pulmonary complications with, 312 Anticholinergics, nausea with, 334 Anticipatory grief, 626 Anticonvulsants, hot flashes management with, 225–226 Antidepressants. See also Tricyclic/heterocyclic antidepressants citalopram, 225 desvenlafaxine, 224 fluoxetine, 225 hot flashes with, 223–225 neurotoxicity treatment with, 64 novel, 536–537 paroxetine, 224 strategies to minimize antidepressant-induced dysfunction, 610 venlafaxine, 224 Antiemetic drugs 5-HT3-receptor antagonist, 18–19, 21t antihistamines, 20 benzodiazepines, 20, 168, 267, 550

Antiemetic drugs (Continued) cannabinoids, 20 CINV treated with, 18–22, 21t dopamine-receptor antagonist, 20 nausea with, 334 NK-1-receptor antagonist, 19–20, 21t olanzapine, 20 steroids, 19, 21t Antiepileptics, neurotoxicity treatment with, 64 Antihistamines, CINV treated with, 20 Antihistaminic agents efficacy for advanced cancer of, 266 nausea treatment with, 266 pharmacology of, 266 Anti-infection drugs, 28t Antimetabolites arrhythmias with, 79 cardiotoxicity with, 70t cisplatin nephrotoxicity with treatment using, 47 diagnostic features with, 47 treatment strategies for, 47 neurotoxicity with, 58–59 pulmonary complications with, 311 Antimicrobial therapy, neutropenic patients additional treatment options for, 29, 32t assessment of, 29 continuation of, 29 definitions for, 24 duration of, 29 follow-up for, 29 pathogen identification for, 25–27, 26t clinical-chemical diagnosis in, 27 clinically documented infection, 26 diagnosis after 72-96 hours therapy in, 27 infections, 25–27 microbiologically documented infection, 26–27 unexplained fever, 25 patients with pulmonary infiltrate, 28b risk classification for, 25t, 28 groups in, 24–25, 25t treatment of high-risk patients, 28, 31t treatment of intermediate-risk patients, 28, 31t treatment of low-risk patients, 25t, 26t, 28, 28t therapeutic concepts for, 27–29 when to start, 27 Antipsychotic medications, delirium management with, 548–550, 549t Antitumor antibiotics, cisplatin nephrotoxicity with treatment using, 47 Anxiety, 529 acute stress disorder, 530 adjustment disorder with, 529 continuum of distress with, 528–530 generalized anxiety disorder, 530, 537 mixed anxiety and depressive symptoms, 530–538 anxiety disorders, 533 assessment, 533–535, 542t causes, 530, 531f depressive disorders, 533 distress screening, 534–535 epidemiology, 533 interventions, 535–538 pharmacologic interventions, 536–538 psychological interventions, 535–536

635

index Anxiety (Continued) risk and resilience factors, 532–533 trajectory of distress response, 530–532, 531f panic attacks, 537 panic disorder, 529–530 pharmacologic interventions for, 536–538 phobias, 529–530 posttraumatic stress disorder, 530, 537 treatment-related anxiety, 537 APC. See Argon plasma coagulation Appetite regulation advanced cancer, implications of, 152–154 cannabinoids for, 160 corticosteroids for, 160 dronabinol for, 160 interactions between immune/neural/endocrine systems in, 154f megestrol acetate for, 160 neuropeptides involved in, 153t stress' effect on, 152–154 theoretical model of hypothalamic regulation of, 153f APPR. See Acute phase protein response Aprepitant, recommended dose for, 21t Argon plasma coagulation (APC), 319 Aromatase inhibitors, arterial thromboembolism with, 79 Aromatherapy, 465t, 466 background on, 466 clinical evidence for, 466 definition of, 466 Arrhythmias, cardiotoxicity with, 79–81, 80t antimetabolites, 79 arsenic trioxide in treatment of, 80 drugs in treatment of, 80–81 gemcitabine, 79 histone deacetylase inhibitors, 79–80 5-hydroxytryptamine 3 receptor antagonists in treatment of, 81 taxanes, 80 Arsenic trioxide arrhythmia treatment with, 80 cardiotoxicity with, 70t Ascites diagnosis of, 363–364, 363t management of symptomatic, 366–367 nonpharmacologic management of, 365–366 peritoneovenous shunts in, 366 permanent drains in, 366, 367f therapeutic paracentesis in, 365–366 pathophysiology of, 362–363 pharmacologic management of, 364–365 chemotherapy in, 364 diet in, 364 diuretic therapy in, 364 immunotherapy in, 365 intraperitoneal radiotherapy in, 364 other pharmacologic approaches in, 365 prevalence of, 362–363 supportive interventions for, 384 treatment of, 364 ASD. See Acute stress disorder Asparaginase emetogenic risk with, 19t inflammation risk with extravasation of, 3t Aspirin, itch caused by, 206t Atelectasis, malignant pleural effusions caused by, 355t Atenolol, itch caused by, 206t Atypical pneumonias, malignant pleural effusions caused by, 355t Autonomic neuropathy, 288t, 290 Azacytidine emetogenic risk with, 19t 636 inflammation risk with extravasation of, 3t

B

Bacterial pneumonia, malignant pleural effusions caused by, 355t Balloon tracheoplasty/bronchoplasty, malignant central airway obstruction treated with, 320 Behavioral modifications, hot flashes management with, 228–229 hypnosis in, 228 paced respirations in, 228 physical measures in, 228–229 Bellergal, hot flashes management with, 226 Bendamustine emetogenic risk with, 19t irritation with extravasation of, 3t Benzodiazepines CINV treated with, 20 delirium management with, 550 dyspnea intervention with, 168 nausea treatment with, 267 Bereavement clinical presentations of, 626–629 acute grief following the death, 627–628, 627f anticipatory grief, 626 pathologic responses to bereavement, 628 prolonged grief disorder, 628, 629b risk factors, 629, 629t time of death grief, 626–627 interventions for, 630, 631t specific circumstances with, 629–630 grief during childhood, 630 loss of a child, 630 sudden death, 629–630 staff support for, 630–632 cognitive-behavioral therapy, 631 combined psychopharmacologic approaches, 632 family therapy, 632 group psychotherapy, 632 individual psychotherapy, 630–631 internet interventions, 632 interpersonal psychotherapy, 631 psychodynamic psychotherapy, 631 supportive counseling, 630 theories of, 625–626 Bevacizumab cardiotoxicity with, 70t chemotherapy with, 52–53 cisplatin nephrotoxicity with treatment using, 46 heart failure associated with, 71t hypertension with, 75 inflammation risk with extravasation of, 3t thromboembolism with, 77 Bexarotene arterial thromboembolism with, 79 cardiotoxicity with, 70t Biopsychosocial model, 556, 556t elements of, 596f Bisphosphonates bone metastases treatment with, 244–249, 245f anti-osteolytic treatment in, 245–248, 246f clodronate in, 246, 246f ibandronate in, 246, 247f pamidronate in, 246, 246f zoledronate in, 246–248, 247f, 248f cancer pain adjuvant management with, 132 side effects of, 248–249, 248t, 249t acute phase response, 248 diarrhea, 249t gastrointestinal, 248 necrosis, 249t osteonecroses of jaw, 249, 249t renal toxicity, 249 treatment–induced osteoporosis treatment with, 442–443, 442f, 443f

Black cohosh, hot flashes management with, 227 Bladder, radiotherapy-induced adverse events for, 40 management of, 40 pathophysiology of, 40 prevention of, 40 symptoms of, 40 Bleeding, malignant wounds with, 348 Bleomycin inflammation risk with extravasation of, 3t itch caused by, 206t pulmonary complications with, 310–311, 311f Blue liver syndrome, 51, 52f BMD. See Bone mineral density Bone, late effects of chemotherapy/radiation with, 434 Bone health bone metabolism with, 438–439 hormones' stimulating effect on in, 438 loss of bone mineral density in, 438, 439f osteoclasts and osteoblasts in, 438, 439f risk factors for osteoporosis in, 439t total estrogen deprivation with, 440–442, 441f anastrozole in, 440–441, 441f exemestane in, 441f, 442 letrozole in, 441–442, 441f treatment options for osteoporosis, 442–446, 442t antibodies against RANKL, 444, 445f bisphosphonates, 442–443, 442f, 443f denosumab, 444–446, 445f, 446f prophylaxis, 442–443, 442f, 443f tumor/tumor treatment with, 439–440, 440f, 440t Bone marrow radiotherapy-induced adverse events for, 41 anemia, 41 leukopenia, 41 transplant, lung injury after, 89 Bone metastases, 243–249 destruction of bones by, 244, 244f pathogenesis of, 244 supportive interventions for, 388, 388f treatment with bisphosphonates for, 244–249, 245f anti-osteolytic treatment in, 245–248, 246f clodronate in, 246, 246f ibandronate in, 246, 247f pamidronate in, 246, 246f side effects of, 248–249, 248t, 249t zoledronate in, 246–248, 247f, 248f Bone metastases complications clinical features of, 294 compression fractures, 297–300, 298f radiotherapy for, 299 stereotactic spinal radiotherapy, 299–300, 301f surgery for, 299 vertebral augmentation for, 297–299, 299f, 300f epidemiology of, 293 fracture risk assessment with, 294–295, 294t, 295t acetabular fracture risk, 294–295 long bone fracture risk, 294–295 vertebral fracture risk, 295, 295f impending long bone fractures, 295–297 prophylactic surgery for, 297, 297f, 298f radiotherapy for, 296 long bone fracture, 293 management of, 295, 296t pathophysiology of, 293–294 spinal cord compression, 293, 300–304 combined radiotherapy and surgery for, 302–303, 303f, 303t combined radiotherapy/surgery v. radiotherapy alone for, 304

Index Bone metastases complications (Continued) radiotherapy dose fractionation for, 302–303, 304t radiotherapy for, 301–302 surgery for, 301, 302f spinal cord compression outcomes in, 304–306, 305f, 305t multidisciplinary opinion for management of, 306 supportive measures for, 306 vertebral fracture, 293 Bone mineral density (BMD) osteoprotection of, 443f risedronate improves, 443f Bone pain, 125 Bortezomib cardiotoxicity with, 70t emetogenic risk with, 19t inflammation risk with extravasation of, 3t neuromuscular complications of cancer with, 286t, 287 Bowel and bladder problems, last days of life pain with, 402 Brachial plexopathy, neuromuscular complications of cancer with, 284–285, 284f Brachioradial pruritus, 205 Brachytherapy, malignant central airway obstruction with, 322 Brain, radiotherapy-induced adverse events for, 36–38 acute delayed reaction, 37 edema, 37 hypopituitarism, 37–38 management of, 37 necrosis, 37 neurocognitive function, 37 pathophysiology of, 36–37 prevention of, 38 somnolence syndrome, 37 symptomatic epilepsy, 37 symptoms of, 37 Brain metastases, cancer rehabilitation complicated by, 408 Breast cancer cognitive function with cytokines in survivors of, 451t exercise interventions for, 406–407 hereditary, 457t risedronate for bone mineral density in, 443f Breast carcinoma bone metastases with, 243–249 destruction of bones by, 244, 244f pathogenesis of, 244 treatment with bisphosphonates for, 244–249, 245f skeletal metastases with, 249–255 clinical studies with denosumab for, 252–255 development of antibodies against RANKL, 251–252 Bronchospasm, isolated, pulmonary toxicity with, 88 Buccal mucosa dry/pale, xerostomia with, 233, 233f hyperkeratinized, xerostomia with, 233, 233f Bulk-forming agents, 183 Busulfan, irritation with extravasation of, 3t Butorphanol, itch caused by, 206t

C

Cachexia. See also Cancer anorexia-cachexia syndrome primary, 151 secondary, 151 starvation v., 151t

CACS. See Cancer anorexia-cachexia syndrome CALM therapy, 563–564, 564t Cancer anorexia-cachexia syndrome (CACS) assessment of, 156–158 decision-making process for, 158, 158f enteral or parenteral nutrition's role in, 160–161 exercise for, 160 individualized multimodal treatment plan for, 158–160, 159f mechanisms of, 151–156 acute phase protein response, 152 adipose tissue loss, 156, 156f skeletal muscle loss, 154–156, 155f monitoring response to therapy in, 161 multidimensional assessment for, 158, 158f nutritional assessment for, 156–158 anthropometrics, 157 body composition assessment, 157 comprehensive assessment, 157 laboratory assessment, 157 Malnutrition Screening Tool, 156–157 symptom assessment, 157 validated nutrition assessment tools, 157–158 nutritional intervention for, 158–159 assessment of current intake, 158 barriers to nutritional intake, 158 dietary recommendations, 159 energy/protein requirements calculation, 159 stress' effect on appetite regulation with, 152–154 implications in advanced cancer, 152–154 interactions between immune/neural/ endocrine systems in, 154f neuropeptides involved in, 153t theoretical model of hypothalamic regulation of, 153f symptom management for, 159–160 anorexia, 159–160 constipation, 159 depression, 160 early satiety, 159 mucositis, 160 nausea, 159 odynophagia, 160 xerostomia, 160 theoretical model for the pathogenesis of, 152f therapies directed at underlying mechanisms of, 160 Cancer pain acute pain dosing strategy for, 129 adjuvant medications/interventions, 132 bisphosphonates, 132 radioisotopes, 132 anatomy for, 123–126 cerebral pain matrix, 126 N -methyl- D -aspartate (NMDA) receptors, 123–124 opioids, 124–125 prostaglandins, 123 second order neurons, 126 somatic pain pathways, 124f synaptic nociceptive receptors/transmitters, 123f assessment of, 126–127 CT scan for, 127 expert opinion of, 127t liver metastases imaging for, 127–128 lung metastases imaging for, 128 MRI for, 127 skeletal metastases imaging for, 127 bone pain, 125 epidural analgesia contraindications for, 130t indications for, 130t

Cancer pain (*Continued) image-guided therapies for, 133 interventional approaches therapies for, 133 management of, 128 opioid formulations for pain flares in, 129t recommendations breakthrough pain in, 129t neuropathic pain, 125–126 opioid poorly responsive pain with, 129–132 adjuvant analgesics, 131–132, 131t, 132t corticosteroids, 131 NSAID, 131 opioid rotation for, 129, 130t opioid route conversion, 129–130 opioid titration for, 128–129 pancreatic, 386 substance abuse in patients with, 570–571, 571f visceral pain, 125, 125f Cancer rehabilitation, 406–413, 407f lymphedema with, 410–411 medical complications with, 411, 412t musculoskeletal complications of, 410 neuromuscular complications of, 408–410 brain metastases, 408 cancer-related fatigue, 409–410 Lambert-Eaton myasthenic syndrome, 409 myopathy, 409 neuropathy, 409 plexopathy, 409 radiation myelopathy, 409 pain in, 411–412 principles of, 407–408, 408f palliative rehabilitation in, 408 preventive rehabilitation in, 407 restorative rehabilitation in, 407 supportive rehabilitation in, 407–408 radiation-related injuries with, 412–413 rehabilitation team for, 406–407 Cancer treatment–induced bone loss (CTIBL), 442f Cancer-related fatigue (CRF) activity level contributing to, 142–143 exercise barriers with, 142–143, 142t patient/family education for, 142 provider assessment for, 142 treatment for, 143 anemia contributing to, 141 patient/family education for, 141 provider assessment for, 141 treatment for, 141 barriers to assessment/management with, 139, 139t cancer rehabilitation complicated by, 409–410 cognitive impairment with, 145 comorbidity contributing to, 141–142 patient/family education for, 141 provider assessment for, 141 treatment for, 142 definitions with, 137–138 case definitions, 138 impact on functioning in, 137–138 subjective perception in, 137–138 emotional distress contributing to, 143 patient/family education for, 143 provider assessment for, 143 treatment for, 143 future directions for, 147 incidence of, 137 chemotherapy with, 137 other forms of treatment with, 137 radiation therapy with, 137 types/stages of cancer with, 137 nutrition contributing to, 143–144 patient/family education for, 144 provider assessment for, 144 treatment for, 144

637

index Cancer-related fatigue (CRF) (Continued) pain contributing to, 144 patient/family education for, 144, 145t provider assessment for, 144 treatment for, 144 prevalence of, 137 provider assessment for, 139–140 baseline assessment, 140 differential diagnosis, 140 focused workup, 140 significance of, 137 sleep disturbances with, 145–147 patient/family education for, 146, 146t provider assessment for, 145 treatment for, 146–147 symptom clusters with, 144–145 syndrome criteria for, 138 treatment for, 140 fatigue as the sixth vital sign in, 140 general educational strategies in, 140 patient/family education in, 140 provider education in, 140 treatment principles for provider with, 140–144 underlying mechanisms of, 138 web-based resources for, 147 Cannabinoids CINV treated with, 20 nausea treatment with, 267 Capecitabine cardiotoxicity with, 70t, 74 emetic risk with, 20t hand foot syndrome with, 118 Captopril, itch caused by, 206t Carboplatin emetogenic risk with, 19t irritation with extravasation of, 3t neurotoxicity with, 57 Carcinoma. See also Breast carcinoma malignant pleural effusions caused by, 355t Cardiotoxicity (CT), 68–89 acute, 69 arrhythmias from, 79–81, 80t antimetabolites, 79 arsenic trioxide in treatment of, 80 drugs in treatment of, 80–81 gemcitabine, 79 histone deacetylase inhibitors, 79–80 5-hydroxytryptamine 3 receptor antagonists in treatment of, 81 taxanes, 80 carotid disease from, 85 supportive oncology for, 85 chemotherapy-related, 69, 70t chest pain from, 73–75 capecitabine, 74 cisplatin, 74 cytokines, 74 diagnosis of, 75 fluorouracil, 73–74 interferons, 74 interleukin, 74–75 monoclonal antibodies, 75 supportive oncology for, 75 systemic first dose infusion reactions for, 74–75 treatment of, 75 vinca alkaloids, 74 complementary and alternative medicine for, 69t heart failure from, 69–73 cyclophosphamide associated with, 71 diagnosis of, 72 drugs associated with, 71t epidermal growth factor receptor associated 638 with, 72

Cardiotoxicity (CT) (Continued) ifosfamide associated with, 71 imatinib associated with, 71 prevention of, 73, 73t sorafenib associated with, 72 sunitinib associated with, 72 supportive oncology with, 73 transmembrane receptor inhibitors associated with, 72 treatment of, 72–73 tyrosine kinase inhibitor associated with, 72 hypertension from, 75–76 bevacizumab, 75 diagnosis of, 76 epidermal growth factor receptor associated with, 76 sorafenib associated with, 76 sunitinib associated with, 76 supportive oncology for, 76 transmembrane receptor inhibitors associated with, 76 treatment of, 76 tyrosine kinase inhibitor associated with, 76 incidence of, 68, 69t ischemia from, 73–75 capecitabine, 74 cisplatin, 74 cytokines, 74 diagnosis of, 75 fluorouracil, 73–74 interferons, 74 interleukin, 74–75 monoclonal antibodies, 75 supportive oncology for, 75 systemic first dose infusion reactions for, 74–75 treatment of, 75 vinca alkaloids, 74 radiation-induced, 81–85 arrhythmias with, 83, 85 coronary artery disease with, 82–83, 85 diagnosis of, 83–84 heart failure with, 82, 84 pericardial disease with, 83, 84 risk factors for, 82t spectrum of, 82t treatment of, 84–85 valvular disease with, 83 subacute, 69 supportive oncology care for, 68–69 thromboembolism, arterial, from, 79 aromatase inhibitors, 79 bexarotene, 79 lipids, 79 retinoids, 79 tamoxifen inhibitors, 79 thromboembolism, arterial and venous, from, 76–79 bevacizumab, 77 cisplatin, 77 diagnosis of, 78–79 immunomodulating agents, 77–78 lenalidomide, 77 pomalidomide, 77 thalidomide, 77 treatment of, 78–79 VEGF, 78 thromboembolism, venous, from diagnosis of, 78 prevention of, 78 treatment of, 79 tumor lysis syndrome from, 81 diagnosis of, 81 supportive oncology for, 81 treatment of, 81

Caregivers. See Professionals caregivers Carmustine cisplatin nephrotoxicity with treatment using, 47 emetogenic risk with, 19t ulceration with extravasation of, 3t Carotid disease cardiotoxicity with, 85 supportive oncology for, 85 Cartilage, late effects of chemotherapy/radiation with, 434 CAS. See Constipation Assessment Scale CASH. See Chemotherapy-associated steatohepatitis Caspofungin, dosage for, 30t Catheter, indwelling, pleural effusions management with, 356–357 Catheter-related infection (CRI), 371–373 blood cultures in diagnosis of, 372 diagnosis of, 372 epidemiology of, 371 management of, 372–373 microbiological diagnosis after catheter removal, 372 pathogens of, 371–372 prophylaxis of, 373 risk factors for, 371 Catumaxumab, emetogenic risk with, 19t CBT. See Cognitive-behavioral therapy CDI. See Clinically documented infection CDP. See Complex decongestive physiotherapy Cecostomy tubes, malignant bowel obstruction treatment with, 336–337, 337t Cefalexin, dosage for, 28t Cefepime, dosage for, 28t Cefixime, dosage for, 28t Cefotaxime, dosage for, 28t Ceftazidime, dosage for, 28t Ceftriaxone, dosage for, 28t Cefuroxime-Axetil, dosage for, 28t Central pruritic neuropathic syndromes, 205–207 drug-induced itch with, 205–206, 206t opioid-induced pruritus with, 206–207 spinal opioids, 206 systemic opioids, 206–207 Central venous catheter (CVC), 369 thrombosis with, 280 Central venous lines (CVL), 369 infectious complications with, 371–373 blood cultures in diagnosis of, 372 diagnosis of, 372 epidemiology of, 371 management of, 372–373 microbiological diagnosis after catheter removal, 372 pathogens of, 371–372 prophylaxis of, 373 risk factors for, 371 mechanical complications with, 369–370, 370f thrombotic complications with, 370–371 Cephalosporins, itch caused by, 206t Cerebral pain matrix, cancer pain with, 126 Cetuximab cardiotoxicity with, 70t chemotherapy with, 53–54 emetogenic risk with, 19t CHALLENGE. See Colon Health and Life-Long Exercise Change Charles procedure, lymphedema management with, 217t, 218 Cheiralgia paresthetica, 205 Chemoreceptor trigger zone, CINV with, 17 Chemotherapy ascites management with, 364 cancer-related fatigue with, 137

Index Chemotherapy (Continued) cardiotoxicity with, 69, 70t cisplatin nephrotoxicity with, 44–47 cisplatin-containing, 22 colorectal liver metastases, 49–54 bevacizumab in, 52–53 cetuximab in, 53–54 complete response to, 50 5-fluorouracil/leucovorin in, 50–51 irinotecan in, 51–52 oxaliplatin in, 51, 51f, 52f regimens, 49–50 response to, 50–54 emetogenicity of high, 21, 22t low, 21, 22t minimal, 21, 22t moderate, 21, 22t female gonadal function in, 96t, 98 fertility, impact of treatments on, 619–620 high-dose, 22 kidney/liver toxicities with, 44–47 male gonadal function in, 96–97, 96t, 97f mucositis with, 107 multiple-day (cisplatin-containing), 22 pericardial effusion management with, 359 pulmonary toxicity with, 87–89, 87t role in secondary cancers of, 458 alkylating agents, 458 topoisomerase agents, 458 Chemotherapy extravasations daily practice with, 8 definition, 2 diagnosis of, 4–5 flare reaction in, 4 photosensitivity in, 5 recall phenomenon in, 5 differential diagnosis of, 4–5 local cutaneous hypersensitivity reaction, 4 local hypersensitivity, 4 thrombophlebitis, 4 interventions for, 5 nonpharmacologic management of, 5 pathophysiology of, 2 pharmacologic management of, 5–8 amsacrine in, 5 anthracycline in, 6 antidota for, 6 cisplatinum in, 5–6 dactinomycin in, 5 dexrazoxane for, 6 dimethylsulfoxide for, 6 dry cold for, 6 dry heat for, 6 etoposide in, 5 hyaluronidase for, 6 mitomycin C in, 5 mitoxantrone in, 5 natrium thiosulfate for, 6 open questions with, 7–8 quality control with, 7, 7t specific measures for, 6 steroids for, 6 vinca alkaloids in, 5 prevalence of, 2 risk factors for, 3–4 drug associated, 3, 3t intravenous access caused, 4 medical staff associated, 3 patient associated, 3 Chemotherapy-associated steatohepatitis (CASH), 52 Chemotherapy-induced nausea and vomiting (CINV) antiemetic drugs for, 18–22, 21t 5-HT3-receptor antagonist, 18–19, 21t

Chemotherapy-induced nausea and vomiting (CINV) (Continued) antihistamines, 20 benzodiazepines, 20 cannabinoids, 20 dopamine-receptor antagonist, 20 NK-1-receptor antagonist, 19–20, 21t olanzapine, 20 steroids, 19, 21t antiemetic prophylaxis of, 21, 22t classification of, 17–18 high-dose chemotherapy with, 22 mechanisms of, 17 abdominal vagal afferents, 17 chemoreceptor trigger zone, 17 neurotransmitters, 17 multiple-day cisplatin therapy with, 22 pathophysiology of, 17–18, 17f, 18f prevention, acute nausea/emesis (within 24 hours), 21 highly emetogenic chemotherapy, 21 low emetogenic chemotherapy, 21 minimal emetogenic chemotherapy, 21 moderately emetogenic chemotherapy, 21 prevention, delayed nausea/emesis (2-5 days after), 21 highly emetogenic chemotherapy, 21 low/minimal emetogenic chemotherapy, 21 moderately emetogenic chemotherapy, 21 risk factors associated with, 18 emetic risk, 20t emetogenic risk, 19t patient characteristics, 20t therapy against anticipatory nausea/vomiting for, 22 treatment approach for, 22 Chemotherapy-induced neuropathy, 286, 286t Chemotherapy-induced neurotoxicity, 56–60 antimetabolites with, 58–59 cytarabine arabinoside, 59 5-fluorouracil, 59 ifosfamide, 59 methotrexate, 58–59 diagnosis of, 56, 60 nitrosoureas with, 60 occurrence of, 56 patient identification with risk of, 60–61, 61t platinum compounds with, 56–57 carboplatin, 57 cisplatin, 57, 57f oxaliplatin, 57 prevention of, 61–64, 62t taxane with, 59–60 docetaxel, 59–60, 60f paclitaxel, 59, 60f treatment of, 61–64 antidepressants for, 64 antiepileptics for, 64 calcium for, 61–62 glutamine/glutamate for, 63 glutathione for, 62–63 magnesium for, 61–62 N -acetylcysteine for, 63 stop-and-go strategies for, 62 vitamin E for, 63–64 vinca alkaloids with, 58 semisynthetic vinca alkaloids, 58 vincristine, 58, 58f Chemotherapy-induced peripheral neuropathy (CIPN), 64 Chemotherapy-related lung toxicity, 309–310 Chest, supportive interventions for, 382 Chest pain cardiotoxicity with, 73–75 capecitabine, 74 cisplatin, 74

Chest pain (Continued) diagnosis of, 75 fluorouracil, 73–74 supportive oncology for, 75 treatment of, 75 vinca alkaloids, 74 systemic first dose infusion reactions with, 74–75 cytokines, 74 interferons, 74 interleukin, 74–75 monoclonal antibodies, 75 Chest radiograph (CXR). See Chest X-ray Chest X-ray, malignant central airway obstruction in, 314–315, 315f Childhood Cancer Survivor Study (CCSS), 457 Chloride channel activators, 183 Chlorpromazine pharmacokinetics of, 261t terminal agitation, medications for, 403t Cholestasis, itch of, 203–204 treatment for bile drainage, 203 miscellaneous, 204 opioid agonists/antagonists, 203 rifampicin, 203 serotonin reuptake antagonists, 203–204 serotonin reuptake inhibitors, 203 what does not work, 204 when a patient cannot swallow, 204 Cholinesterase inhibitors, delirium management with, 550 Chronic lung injury, pulmonary toxicity with, 89 Chylothorax, malignant pleural effusions caused by, 355t CINV. See Chemotherapy-induced nausea and vomiting CIPN. See Chemotherapy-induced peripheral neuropathy Ciprofloxacin, dosage for, 28t Circadian rhythm sleep disorders, 193 Cisapride, pharmacokinetics of, 261t Cisplatin cardiotoxicity with, 70t, 74 emetogenic risk with, 19t irritation/ulceration with extravasation of, 3t neuromuscular complications of cancer with, 286–287 neuropathy, genetic predisposition of, 61t neurotoxicity with, 57, 57f thromboembolism with, 77 Cisplatin nephrotoxicity, 44–47 diagnosis for, 44 mechanism of hypomagnesemia in, 45f mechanism of renal injury with, 44–45 prevention of, 46–47 treatment for, 46–47 alkylating agents in, 46–47 antimetabolites in, 47 antitumor antibiotics in, 47 bevacizumab in, 46 carmustine in, 47 gemcitabine in, 47 ifosfamide in, 46–47 immune modulators in, 47 interferon in, 47 interleukin-2 in, 47 lenalidomide in, 47 methotrexate nephrotoxicity in, 47 mithracycline in, 47 mitomycin C in, 47 nitrosoureas in, 47 streptozocin in, 47 VEGF inhibition in, 46

639

index Cisplatin-containing chemotherapy, 22 Cisplatinum, extravasation of, 5–6 Citalopram, hot flashes management with, 225 Cladribine, inflammation risk with extravasation of, 3t Clindamycin, dosage for, 28t Clinically documented infection (CDI), 26 Clodronate bone metastases treatment with, 246, 246f diarrhea with, 249t necrosis with, 249t ONJ with, 249, 249t side effects of, 249t Clofarabine emetogenic risk with, 19t inflammation risk with extravasation of, 3t Clonidine hot flashes management with, 226 itch caused by, 206t Code status, 515–516, 516b Cognitive function cognitive domains affected in cancer with, 449 cytokines in breast cancer survivors associated with, 451t dose response to chemotherapy for, 449 duration of impairment to, 449 hormone therapy for impairment of, 452–453 imaging/electrophysiologic studies for, 451–452, 452f incidence of impairment to, 448–449 interventions after cancer treatment for impairment of, 453 mechanisms of impairment in, 450–451, 451f, 451t self-reported, 449–450 Cognitive restructuring, insomnia management with, 196, 196t Cognitive-behavioral therapy (CBT), 558, 559t accessibility of, insomnia comorbid with cancer, 197 bereavement support with, 631 description of components in, 195–197, 196t efficacy of, 195f insomnia comorbid with cancer, 194–195 insomnia with, 194–197 primary insomnia with, 194 Colchicine, itch caused by, 206t Colistin, itch caused by, 206t Collagen vascular disease, pericardial effusion caused by, 357t Colon cancer, 333b, 457t Colon Health and Life-Long Exercise Change (CHALLENGE), 421 Colorectal cancer, exercise interventions for, 417–418 Colorectal liver metastases, 49 chemotherapy for, 49–54 bevacizumab in, 52–53 cetuximab in, 53–54 complete response to, 50 5-fluorouracil/leucovorin in, 50–51 irinotecan in, 51–52 oxaliplatin in, 51, 51f, 52f regimens, 49–50 response to, 50–54 Colorectal obstruction, stents for palliative treatment of, 379–380, 379f Colorectal stents, malignant bowel obstruction treatment with, 335–336, 337t, 338f Combination nonoperative therapy, lymphedema management with, 215t, 216–217 640 Common Toxicity Criteria for Adverse Events (CTCAE), 10, 11t

Communicating difficult news supportively bad news, 485–487 blaming messenger, 485–486 challenges to sense of invulnerability, 487 dealing with hope, 486–487 feelings in sympathy, 486 feelings of professional failure, 486 medico-legal factors, 486 “sorry” word, 486 strong emotions, 486 ethics/politics of truth telling, 487–488 need for strategies, not scripts with, 485–492 practicalities of breaking bad news, 492 SPIKES strategy for breaking bad news, 488–492, 488t guidelines for giving medical facts in, 490t optimizing setting of interview in, 489t suggested phrases for assessing perception in, 489t suggested phrases for invitation to share in, 490t Compassion fatigue, 578 Complementary therapies acupuncture, 465–466, 465t background on, 465–466 clinical evidence for, 466, 466t definition of, 465 aromatherapy, 465t, 466 background on, 466 clinical evidence for, 466 definition of, 466 herbal medicine, 465t, 466–467 background on, 466 clinical evidence for, 467 definition of, 466 homeopathy, 465t background on, 467 clinical evidence for, 467 definition of, 467 hypnotherapy, 465t, 467 background on, 467 clinical evidence for, 467 definition of, 467 imagery, 465t, 467 background on, 467 clinical evidence for, 467 definition of, 467 massage, 465t, 467–468 background on, 467–468 clinical evidence for, 468 definition of, 467 music therapy, 465t, 468 background on, 468 clinical evidence for, 468 definition of, 468 reflexology, 465t, 468 background on, 468 clinical evidence for, 468 definition of, 468 relaxation therapy, 465t, 468 background on, 468 clinical evidence for, 468 definition of, 468 spiritual healing, 465t, 468–469 background on, 469 clinical evidence for, 469 definition of, 468 tai chi, 465t, 469 background on, 469 clinical evidence for, 469 definition of, 469 Complex decongestive physiotherapy (CDP), lymphedema management with, 215t, 216–217 Complex physical therapy (CPT), lymphedema management with, 215t, 216–217

Compression fractures, 297–300, 298f radiotherapy for, 299 stereotactic spinal radiotherapy, 299–300, 301f surgery for, 299 vertebral augmentation for, 297–299, 299f, 300f Computed tomography (CT) cancer pain assessment with, 127 malignant bowel obstruction diagnosis with, 329, 330f malignant central airway obstruction in, 315 Congenital lymphedema, 212t Constipation CACS with, 159 causes of, 180–181 factors arising from cancer, 181 factors not directly from cancer, 181–182 definition, 177 diagnosis, 177–178 adjectival scale, 178 Constipation Assessment Scale, 178 PAC-QOL, 178 PAC-SYM, 178 patient's complaint of problem, 177 stool formation in, 178, 178f visual analog scale, 178 normal intestinal physiology and, 179–180 intestinal fluid handling in, 179–180 neural control of intestinal activity in, 179 patterns of intestinal motility in, 179 opioid-induced, 184 pathophysiology of, 179 prevalence of, 179 treatment for, 182–184, 183f rectal laxatives, 184 softening laxatives, 182–184 stimulant laxatives, 182 Constipation Assessment Scale (CAS), 178 Constrictive pericarditis, malignant pleural effusions caused by, 355t Corticosteroids cancer pain poorly responsive to opioids with, 131 efficacy for nausea of, 267 nausea treatment with, 266–267 nausea with, 334 pharmacology of, 267 Coumarins, itch caused by, 206t Counseling. See also Psychotherapy sexuality after cancer helped by, 603–606, 603t supportive, 557–558 Couples therapy, 561–562 CPT. See Complex physical therapy CRF. See Cancer-related fatigue CRI. See Catheter-related infection Cryotherapy, malignant central airway obstruction treated with, 319 CT. See Cardiotoxicity; Computed tomography CTCAE. See Common Toxicity Criteria for Adverse Events CTIBL. See Cancer treatment–induced bone loss CVC. See Central venous catheter CVL. See Central venous lines Cyclizine nausea treatment with, 266 pharmacokinetics of, 261t Cyclophosphamide cardiotoxicity with, 70t emetic risk with, 20t emetogenic risk with, 19t heart failure associated with, 71, 71t inflammation risk with extravasation of, 3t CYP2D6. See Cytochrome P450 enzyme

Index Cytarabine cardiotoxicity with, 70t emetogenic risk with, 19t hand foot syndrome with, 118 inflammation risk with extravasation of, 3t neuromuscular complications of cancer with, 287 Cytarabine arabinoside, neurotoxicity with, 59 Cytochrome P450 enzyme (CYP2D6), hot flashes management with, 225 Cytokines, cardiotoxicity with, 70t, 74 Cytoreduction, supportive interventions for, 384–385, 385f Cytotoxic chemotherapeutic agents, 11–12

D

Dacarbazine, emetogenic risk with, 19t Dacarbazine, irritation with extravasation of, 3t Dactinomycin emetogenic risk with, 19t extravasation of, 5 ulceration with extravasation of, 3t Daunorubicin cardiotoxicity with, 70t emetogenic risk with, 19t ulceration with extravasation of, 3t DCBE. See Double-contrast barium esophagrams Death acute grief following, 627–628, 627f sudden, 629–630 Decision support tools (DST), 509, 510t Decision-making capacity (DMC) assessing, 495 assessing adolescents for, 494 decision making for patients lacking, 494 described/distinguished, 494 responsibility for assessing, 495–496 sliding scale for, 496 standardized tools for assessing, 496–497 triggers for, 494–495 Decitabine, inflammation risk with extravasation of, 3t Decongestive lymphatic therapy (DLT), 215t, 216–217 Deep vein thrombosis (DVT), 274 diagnosis of, 277–278, 279f Delirium assessment of, 545–546 differential diagnosis, 545–546 interference of delirium with, 546 causes of, 546–547, 546t clinical features of, 542–543, 542t controversies in management of terminal, 551 diagnostic criteria for, 543–544 experience of, 544–545 management in advanced patients of, 548–550 antipsychotic medications in, 548–550, 549t benzodiazepines in, 550 cholinesterase inhibitors in, 550 dexmedetomidine in, 550 nonpharmacologic interventions in, 548 pharmacologic interventions in, 548–550 psychostimulants in, 550 pathophysiology of, 542 prevalence of, 541–542 prevention of, 551–552 prognosis with, 550–551 prognostic assessment with, 475–476 reversibility of, 546–547 subtypes of, 543–544 Denosumab adverse events with, 254t bone metastases treatment with, 254

Denosumab (Continued) breast cancer treatment with, 253, 253f, 254f, 254t clinical studies with, 252–255 multiple myeloma treatment with, 254 solid tumors treatment with, 254 treatment–induced osteoporosis treatment with, 444–446, 445f, 446f Dental decay, xerostomia with, 233, 234f Dependence, 568 Depomedroxyprogesterone (DMPA), hot flashes management with, 223 Depression adjustment disorder with, 529 CACS with, 160 continuum of distress with, 528–530 depressive disorders, 529 major depressive disorder, 529 mixed anxiety and depressive symptoms, 530–538 anxiety disorders, 533 assessment, 533–535, 542t causes, 530, 531f depressive disorders, 533 distress screening, 534–535 epidemiology, 533 interventions, 535–538 pharmacologic interventions, 536–538 psychological interventions, 535–536 risk and resilience factors, 532–533 trajectory of distress response, 530–532, 531f pharmacologic interventions for, 536–538 augmenting agents, 537 monoamine oxidase inhibitors, 536 novel antidepressants, 536–537 selective serotonin reuptake inhibitors, 536 tricyclic/heterocyclic antidepressants, 536 subthreshold mood disorders, 528–530 Dermatologic adverse events acneiform rash, 115–117, 116t, 117f dry skin, 116t grading of, 115 hand foot syndrome, 118, 118f, 118t maculopapular rash, 116t, 118 morbilliform eruption, 116t, 118 nail toxicity, 119–120 nail discoloration, 116t nail loss, 116t nail ridging, 116t onycholysis, 119–120, 119f paronychia, 119 palmar-plantar erythrodysesthesia syndrome, 116t papulopustular rash, 115–117, 117f pathophysiology of, 115 photosensitivity, 116t pruritus, 116t, 119, 119f Stevens Johnson syndrome, 118–119 terminology criteria for, 116t toxic epidermal necrolysis, 118–119 xerosis, 119, 119f Desensitization, allergy management with, 14 Desvenlafaxine, hot flashes management with, 224 Dexamethasone itch caused by, 206t pharmacokinetics of, 261t recommended dose for, 21t Dexmedetomidine, delirium management with, 550 Dexrazoxane, chemotherapy extravasations management with, 6 Diarrhea, bisphosphonates with, 249t Diazoxide, itch caused by, 206t Diet. See also Nutrition ascites management with, 364 recommendations for CACS intervention, 159

Dignity therapy, 560, 561t Dimethylsulfoxide, chemotherapy extravasations management with, 6 Distal obstruction, stents for palliative treatment of, 377–378, 377f Diuretic therapy, ascites management with, 364 DLT. See Decongestive lymphatic therapy DMC. See Decision-making capacity DMPA. See Depomedroxyprogesterone Dobutamine, itch caused by, 206t Docetaxel cardiotoxicity with, 70t emetogenic risk with, 19t hand foot syndrome with, 118 neuropathy, genetic predisposition of, 61t neurotoxicity with, 59–60, 60f ulceration with extravasation of, 3t Dolasetron pharmacokinetics of, 261t recommended dose for, 21t Domperidone, pharmacokinetics of, 261t Dopamine, CINV with, 17 Dopamine receptor antagonists CINV treated with, 20 efficacy for advanced cancer of, 266 nausea treatment with, 265–266 pharmacology of, 265–266 Double-contrast barium esophagrams (DCBE), 171–172 Doxorubicin cardiotoxicity with, 70t emetogenic risk with, 19t hand foot syndrome with, 118 ulceration with extravasation of, 3t Drainage/exudation, malignant wounds with, 348 Draining percutaneous endoscopic gastrostomy tubes (PEG tubes), nausea treatment with, 268–269 Dressler’s syndrome. See Myocardial infarction Dry skin (Xerosis), 116t, 119, 119f, 202–203 DSS. See Dysphagia scoring system DST. See Decision support tools Durable power of attorney, 514 DVT. See Deep vein thrombosis Dysphagia scoring system (DSS), 171, 172t Dyspnea assessing, 165–166 interventions for, 166–168 current therapeutic options, 168 medical gases, 166–167 nonpharmacologic, 167 pharmacologic, 167–168 magnitude of, 164–165 mechanisms of, 165 nonpharmacologic interventions for, 167 breathing techniques, 167 caregivers and breathlessness, 167 emotional/social support, 167 improving service delivery, 167 pharmacologic interventions for, 167–168 benzodiazepines, 168 inhaled furosemide, 168 promethazine, 168 psychotropic medications, 168 selective serotonin reuptake inhibitors, 168 systemic opioids, 168 prognostic assessment with, 475 severity of, 164–165

E

Early satiety, CACS with, 159 EBV. See Epstein-Barr virus Echoendoscopically guided hepaticogastrostomy for biliary drainage, stents for palliative treatment of, 378, 379f

641

index Edema pulmonary, 88 radiotherapy-induced, 37 systemic, 214t EGD. See Esophagogastroduodenoscopy EGFR. See Epidermal growth factor receptor Electrocautery, malignant central airway obstruction treated with, 318, 319f Electronic medical records (EMR), 343 Electrostimulation, xerostomia management with, 238 Emesis. See also Chemotherapy-induced nausea and vomiting radiotherapy-induced, 35, 41t Emotional distress, cancer-related fatigue associated with, 143 EMR. See Electronic medical records Enalapril, itch caused by, 206t Endobronchial microdebrider, malignant central airway obstruction treated with, 320 End-of-life planning advance directives, 513 framework for, 515 overcoming barriers to completion of, 514–515 timing for discussion of, 515, 515t code status, 515–516, 516b discussing, 513 durable power of attorney, 514 hospice and palliative care definitions of, 516–518 discussing, 516 referral to specialized, 518 treatment transitions/goals of, 516–518, 517b living will, 514 supporting hope in, 518–519, 519b Endoscopic retrograde cholangiopancreatography (ERCP), stents for palliative treatment of, 377 Endoscopy, malignant central airway obstruction in, 315–316, 318 Enteropathy, radiotherapy-induced adverse events for, 39 management of, 39 pathophysiology of, 39 prevention of, 39 symptoms of, 39 EORTC QLQ-C30. See European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Epidermal growth factor receptor (EGFR) heart failure with, 72 hypertension associated with, 76 Epidural analgesia contraindications for, 130t indications for, 130t Epilepsy, radiotherapy-induced, 37 Epilithones, cardiotoxicity with, 70t Epirubicin cardiotoxicity with, 70t emetogenic risk with, 19t ulceration with extravasation of, 3t Epithelones, neuromuscular complications of cancer with, 287 Epstein-Barr virus (EBV), 460 EPUAP. See European Pressure Ulcer Advisory Panel ERCP. See Endoscopic retrograde cholangiopancreatography Esophageal cancer, stents for palliative treatment of, 375–376, 376f Esophageal perforation, malignant pleural effusions caused by, 355t 642 Esophageal stents, malignant dysphagia treatment with, 173–175, 174f

Esophagogastroduodenoscopy (EGD), 172 Esophagus late effects of chemotherapy/radiation with, 432 radiotherapy-induced adverse events for, 38–39 management of, 38–39 pathophysiology of, 38 prevention of, 39 symptoms of, 38–39 Estrogen therapy, hot flashes management with, 223 Estrogens, itch caused by, 206t Etidronate diarrhea with, 249t necrosis with, 249t ONJ with, 249, 249t side effects of, 249t Etoposide emetic risk with, 20t extravasation of, 5 irritation with extravasation of, 3t neuromuscular complications of cancer with, 287 Etoposide IV, emetogenic risk with, 19t Etoposide phosphate, inflammation risk with extravasation of, 3t European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), 393–394, 394f European Pressure Ulcer Advisory Panel (EPUAP), 343 Everolimus, emetic risk with, 20t Exercise, CACS with, 160 Exercise interventions, supportive oncology breast cancer with, 417 cancer survivors behavior change for, 422–425 clinical implications for, 421–422 colorectal cancer with, 417–418 disease endpoints with, 420–422, 421f future directions in, 425–426 lung cancer with, 418–420 lymphoma cancer with, 418, 420f other cancers with, 420 physical activity motivation for, 422–425 adherence barriers and motives in, 424 adherence determinants in, 423–424 behavior change interventions, 424–425 determinants in, 422–423 exercise barriers and motives in, 424 participation barriers and motives in, 424 participation determinants in, 423 prevalence in, 422 physical activity's effects on outcomes with, 415–417 cancer diagnoses targeted, 416f health outcomes targeted, 416f mean effect sizes by cancer phase, 416f prostate cancer with, 418, 419t Extravasations. See Chemotherapy extravasations Eye care, last days of life pain with, 402

F

FACT-G. See Functional Assessment of Cancer Therapy–General Family therapy, 562, 563t bereavement support with, 632 Fanconi's anemia, 457t Fatigue. See also Cancer-related fatigue CINV risk with, 20t compassion, 578 insomnia management with, 197

Feeding tubes, malignant esophageal dysphagia with, 172–173 Female gender, CINV risk with, 20t Female gonadal function chemotherapy for, 96t, 98 hormonal cancer treatment for, 99 normal, 96 posttreatment function in, 98–99 prevention of dysfunction in, 99–100 radiotherapy for, 98–99 surgery for, 99 Female sexual dysfunction, radiotherapyinduced, 40 Fentanyl, itch caused by, 206t Fertility care providers attitudes on, 618–619, 618t, 619t female preservation of, 621–622 additional fertility sparing techniques, 622 embryo cryopreservation, 621–622 experimental techniques, 622 impact of cancer and treatments on, 619–620 cancer type, 619 chemotherapies, 619–620 radiation therapies, 619 surgery, 619 male preservation of, 620–621 anejaculation treatment, 621 retrograde ejaculation treatment, 621 sperm cryopreservation, 620–621 sperm extraction, 621 options for preservation of, 620–622, 620t men with cancer, 620–621 women with cancer, 621–622 scope of the problem with, 617 survivors concerns with, 618 Fever antimicrobial therapy, when to start for, 27 definition, 24 risk groups for, 24–25, 25t unexplained, 25 Fever of unknown origin (FUO), 25 5-FU. See 5-fluorouracil 5-HT3-RA. See 5-HT3-receptor antagonists Flap transposition, lymphedema management with, 217t, 218 Flare reaction, extravasation diagnosis with, 4 Flaxseed, hot flashes management with, 227 Flucloxacillin, dosage for, 28t Fluconazole, dosage for, 30t Fludarabine emetic risk with, 20t inflammation risk with extravasation of, 3t Fluoroscopic/endoscopic procedures, malignant bowel obstruction treatment with, 335–337, 338f Fluorouracil, cardiotoxicity with, 70t 5-fluorouracil (5-FU) cardiotoxicity with, 73–74 chemotherapy with leucovorin combined with, 50–51 emetogenic risk with, 19t hand foot syndrome with, 118 hepatoxicity of, 50 neurotoxicity with, 59 Fluoxetine, hot flashes management with, 225 Folate antagonists, cardiotoxicity with, 70t Fondaparinux, VTE prevention with, 279 Food and fluid intake, last days of life pain with, 403 Fosaprepitant, recommended dose for, 21t Fotemustine, irritation with extravasation of, 3t Functional Assessment of Cancer Therapy– General (FACT-G), 393–394 Fungal infection, therapy strategy for patients with, 28b

Index FUO. See Fever of unknown origin Furosemide dyspnea intervention with, 168 itch caused by, 206t

G

Gabapentin, hot flashes management with, 225–226 GAD. See Generalized anxiety disorder Ganciclovir, dosage for, 30t Gastric electrical stimulation (GES), nausea treated with, 269–270 Gastric outlet obstruction (GOO), stents for palliative treatment of, 376, 376f Gastrointestinal adverse events assessment of, 109 clinical impact of, 102–103, 103f, 104f clinical practice guidelines for, 110t clinical translation for, 112–113 definition of, 103 economic impact of, 102–103, 104f future research directions for, 112–113 incidence of, 105–107 nutritional support for, 112 pathobiology of, 107–109, 108f, 109f risk of development of, 103–107 treatment of, 109–112 Gastrointestinal obstruction enteral stent placement for, 386–387 malnutrition treated by enteral tube placement in, 386 Gastrointestinal stenting, nausea treated with, 269 Gastrointestinal tract, late effects of chemotherapy/radiation with, 432 Gemcitabine arrhythmias with, 79 cardiotoxicity with, 70t cisplatin nephrotoxicity with treatment using, 47 diagnostic features with, 47 treatment strategies for, 47 emetogenic risk with, 19t irritation with extravasation of, 3t Gene therapy, xerostomia management with, 239 Generalized anxiety disorder (GAD), 530 pharmacologic interventions for, 537 Genitourinary hemorrhage, supportive interventions for, 387 Gentamicin dosage for, 28t serum concentrations target for, 30t GES. See Gastric electrical stimulation Global Wound Distress Score (GWDS), 343 Glutamine/glutamate neuropathy prevention in, 62t neurotoxicity treatment with, 63 Glutathione (GSH) neuropathy prevention in, 62t neurotoxicity treatment with, 62–63 Gold salts, itch caused by, 206t Gonadal function cancer with, 96 females chemotherapy for, 96t, 98 hormonal cancer treatment for, 99 normal, 96 posttreatment function in, 98–99 prevention of dysfunction in, 99–100 radiotherapy for, 98–99 surgery for, 99 males chemotherapy for, 96–97, 96t, 97f hormonal cancer treatment for, 98 normal, 95–96

Gonadal function (Continued) posttreatment function in, 96–98 prevention of dysfunction in, 99 radiotherapy for, 97–98 surgery for, 98 normal, 95–96 posttreatment, 96–99 prevention of dysfunction, 99 GOO. See Gastric outlet obstruction Granisetron pharmacokinetics of, 261t recommended dose for, 21t Grief. See also Bereavement anticipatory, 626 clinical presentations of, 626–629 theories of, 625–626 Group psychotherapy, bereavement support with, 632 GSH. See Glutathione GWDS. See Global Wound Distress Score

H

Haloperidol pharmacokinetics of, 261t terminal agitation, medications for, 403t Hand foot syndrome (HFS), 118, 118f, 118t preemptive strategies for, 118t HCT. See Hematopoietic cell transplantation Health-related quality of life (HRQoL), palliative surgery with, 393–394, 393f, 394t Healthy Exercise for Lymphoma Patients (HELP), 418, 420f Heart, late effects of chemotherapy/radiation with, 434 Heart failure, 69–73 chemotherapy drugs associated with, 71t chemotherapy-related cardiotoxicity with, 69–73 cyclophosphamide associated with, 71 diagnosis of, 72 drugs associated with, 71t epidermal growth factor receptor associated with, 72 ifosfamide associated with, 71 imatinib associated with, 71 malignant pleural effusions caused by, 355t prevention of, 73, 73t sorafenib associated with, 72 sunitinib associated with, 72 supportive oncology with, 73 transmembrane receptor inhibitors associated with, 72 treatment of, 72–73 tyrosine kinase inhibitor associated with, 72 HELP. See Healthy Exercise for Lymphoma Patients Hematology-oncology. See Thrombosis, cancer with Hematopoietic cell transplantation (HCT), mucositis incidence with, 105–107 Hematopoietic stem cell transplant, neuromuscular complications of cancer with, 286 Hemoptysis, supportive interventions for, 382, 383f Hemothorax, malignant pleural effusions caused by, 355t Heparins itch caused by, 206t low-molecular-weight, 278, 280 unfractionated, 278 Hepatic hydrothorax, malignant pleural effusions caused by, 355t Hepatic toxicity 5-FU, 50 chemotherapy for colorectal liver metastases with, 49–54 oxaliplatin, 51

Hepatobiliary cancer, supportive interventions for, 384 Herbal medicine, 465t, 466–467 background on, 466 clinical evidence for, 467 definition of, 466 Hereditary breast cancer, 457t Hereditary nonpolyposis, 457t Hexamethylmelamine, emetic risk with, 20t HFS. See Hand foot syndrome High-dose chemotherapy, 22 Highly emetogenic chemotherapy, 21, 22t High-resolution computed tomography (HRCT), 315 Histone deacetylase inhibitors, arrhythmias with, 79–80 HIV. See Human deficiency virus Homeopathy, 465t background on, 467 clinical evidence for, 467 definition of, 467 Hormonal cancer treatment female, 99 male gonadal function in, 98 Hormone therapy cognitive impairment with, 452–453 hot flashes management with, 223 depomedroxyprogesterone in, 223 estrogen therapy in, 223 progesterone analogs in, 223 progesterone cream in, 223 Hospice and palliative care definitions of, 516–518 discussing, 516 referral to specialized, 518 treatment transitions/goals of, 516–518, 517b Hot flashes anticonvulsants for, 225–226 gabapentin, 225–226 pregabalin, 226 antidepressants for citalopram, 225 desvenlafaxine, 224 fluoxetine, 225 paroxetine, 224 venlafaxine, 224 behavioral modifications for, 228–229 hypnosis, 228 paced respirations, 228 physical measures, 228–229 centrally acting medications for, 226 Bellergal, 226 clonidine, 226 evaluation of, 223 hormonal therapy for, 223 depomedroxyprogesterone (DMPA), 223 estrogen therapy, 223 progesterone analogs, 223 progesterone cream, 223 measurement of, 223 model of pathways involved in, 222f nonhormonal agents for, 223–227 anticonvulsants, 225–226 black cohosh, 227 centrally acting medications, 226 complimentary agents, 226–227 CYP2D6, 225 flaxseed, 227 newer antidepressants, 223–225 phytoestrogens, 227 red clover isoflavone extract, 227 soy, 227 SSRI, 225 vitamin E, 226–227

643

index Hot flashes (Continued) nonpharmacologic management of, 227–228 acupuncture, 227–228 stellate ganglion block, 228 pathophysiology of, 222, 222f pharmacologic management of, 223–228 prevalence of, 221 recommendations for, 229 thermoregulatory zone with, 222 treatment algorithm for, 228f HPV. See Human papillomavirus HRCT. See High-resolution computed tomography HRQoL. See Health-related quality of life Human deficiency virus (HIV), 460 Human papillomavirus (HPV), 460 Hyaluronidase, chemotherapy extravasations management with, 6 Hydrochlorothiazide, itch caused by, 206t Hydronephrosis, supportive interventions for, 387 5-hydroxytryptamine 3 receptor antagonists, arrhythmia treatment with, 81 Hyoscine butylbromide, pharmacokinetics of, 261t Hyoscine hydrobromide, pharmacokinetics of, 261t Hyoscyamine, nausea treatment with, 267 Hyperbaric oxygen treatment, xerostomia management with, 238 Hyperemesis gravidarum, CINV risk with, 20t Hypersensitivity pneumonitis, pulmonary toxicity with, 88 Hypersensitivity reaction, 10, 11t. See also Allergic reactions, chemotherapy Hypertension, cardiotoxicity with, 75–76 bevacizumab, 75 diagnosis of, 76 epidermal growth factor receptor associated with, 76 sorafenib associated with, 76 sunitinib associated with, 76 supportive oncology for, 76 transmembrane receptor inhibitors associated with, 76 treatment of, 76 tyrosine kinase inhibitor associated with, 76 Hypnosis, hot flashes management with, 228 Hypnotherapy, 465t, 467 background on, 467 clinical evidence for, 467 definition of, 467 Hypoalbuminemia, malignant pleural effusions caused by, 355t Hypogonadism, treatment-related, 440t Hypopituitarism, radiotherapy-induced, 37–38 Hyposalivation moderate, 238 severe, 238 slight, 238 treatment recommendations for, 238

I

Ibandronate bone metastases treatment with, 246, 247f diarrhea with, 249t necrosis with, 249t ONJ with, 249, 249t side effects of, 249t ICCTF. See International Cognition and Cancer Task Force Idarubicin cardiotoxicity with, 70t emetogenic risk with, 19t 644 ulceration with extravasation of, 3t

Ifosfamide cardiotoxicity with, 70t cisplatin nephrotoxicity with treatment using, 46–47 diagnostic features with, 46 treatment strategies for, 46–47 emetogenic risk with, 19t heart failure with, 71 inflammation risk with extravasation of, 3t neuromuscular complications of cancer with, 287 neurotoxicity with, 59 IGF-1. See Insulin-like growth factor 1 Imagery, 465t, 467 background on, 467 clinical evidence for, 467 definition of, 467 Imatinib cardiotoxicity with, 70t emetic risk with, 20t heart failure associated with, 71, 71t Imipramine, itch caused by, 206t Immunomodulating agents cardiotoxicity with, 70t cisplatin nephrotoxicity with treatment using, 47 thromboembolism with, 77–78 Immunotherapy, ascites management with, 365 IMRT. See Intensity-modulated radiotherapy Individual psychotherapy, bereavement support with, 630–631 Indwelling catheter, pleural effusions management with, 356–357 Infections. See also Catheter-related infection anti-infection drugs for, 28t antimicrobial therapy, when to start for, 27 clinically documented, 26 fungal, therapy strategy for, 28b microbiologically documented, 26–27 pathogen identification for, 25–27 risk groups for, 24–25, 25t, 26t secondary cancers with, 460 unexplained fever with, 25 Inferior vena cava filters, VTE treatment with, 280 Inflammatory demyelinating polyneuropathy, 288t, 290 Infusion reaction. See Allergic reactions, chemotherapy Insomnia cognitive-behavioral therapy for, 194–197 accessibility of, 197 description of components in, 195–197, 196t efficacy of, 195f insomnia comorbid with cancer, 194–195 primary insomnia, 194 diagnosis of, 188t, 192–193 differential diagnosis of, 192–193 circadian rhythm sleep disorders in, 193 narcolepsy in, 193 parasomnias in, 193 sleep apnea in, 192–193 sleep-related movement disorders in, 193 nonpharmacologic management of, 194–197 cognitive restructuring, 196, 196t cognitive-behavioral therapy, 194–197 fatigue management, 197 relaxation, 197 sleep hygiene, 197 sleep restriction, 195–196 stimulus control therapy, 195 objective measures of, 188–189 pathophysiology of, 189–192, 189f perpetuating factors for, 189f, 191–192, 191f, 195f pharmacologic management of, 193–194 available medications, 193

Insomnia (Continued) efficacy, 193–194 frequency of use, 193 limitations, 194 precipitating factors for, 189f, 190–191 predisposing factors for, 189–190, 189f, 190t prevalence of, 187–189 risk factors for, 190t subjective measures of, 187–188 cross-sectional studies, 187–188 longitudinal studies, 187–188, 188t Insulin, itch caused by, 206t Insulin-like growth factor 1 (IGF-1), radiation injury reduction with pretreatment of, 237 Intensity-modulated radiotherapy (IMRT), 235–236 Interferon cardiotoxicity with, 70t, 74 cisplatin nephrotoxicity with treatment using, 47 Interleukin, cardiotoxicity with, 70t, 74–75 Interleukin-2, cisplatin nephrotoxicity with treatment using, 47 Intermittent oxaliplatin strategy, neuropathy prevention with, 62t International Cognition and Cancer Task Force (ICCTF), 454 Interpersonal psychotherapy, 558–559 bereavement support with, 631 Interstitial lung disease, pulmonary toxicity with, 88 Intimacy. See Sexuality/intimacy after cancer Intraperitoneal radiotherapy, ascites management with, 364 Intrapleural therapy, pleural effusions management with, 356 Intravenous access. See also Central venous lines extravasation risk with, 4 Irinotecan CASH with, 52 chemotherapy with, 51–52 emetogenic risk with, 19t inflammation risk with extravasation of, 3t Isaac's syndrome. See Neuromyotonia Ischemia cardiotoxicity with, 73–75 capecitabine, 74 cisplatin, 74 diagnosis of, 75 fluorouracil, 73–74 supportive oncology for, 75 treatment of, 75 vinca alkaloids, 74 systemic first dose infusion reactions with, 74–75 cytokines, 74 interferons, 74 interleukin, 74–75 monoclonal antibodies, 75 Isotretinoin, itch caused by, 206t Itch (Prurigo, Pruritus) central pruritic neuropathic syndromes, 205–207 drug-induced itch with, 205–206, 206t opioid-induced pruritus with, 206–207 pruritus induced by systemic opioids with, 206–207 spinal opioids with, 206 classification of, 200–201 mixed pruritus, 200–201 neuropathic itch, 200–201 pruritoceptive itch, 200–201 psychogenic itch, 200–201 epidemiology in malignant diseases of, 201, 202t itch of cholestasis treatments bile drainage, 203

Index Itch (Prurigo, Pruritus) (Continued) miscellaneous, 204 opioid agonists/antagonists, 203 rifampicin, 203 serotonin reuptake antagonists, 203–204 serotonin reuptake inhibitors, 203 what does not work, 204 when a patient cannot swallow, 204 malignant wounds with, 348 neurophysiology of chronic, 202, 202f pruritic syndromes with malignant disease, 202–205 brachioradial pruritus, 205 cheiralgia paresthetica, 205 dry skin (xerosis), 202–203 itch of cholestasis, 203–204 neuropathic itch, 200–201, 204–205 notalgia paresthetica, 205 paraneoplastic pruritus, 204 post-herpetic itch, 205 trigeminal trophic syndrome, 205 uremic pruritus, 204 Itraconazole, dosage for, 30t Ixabepilone cardiotoxicity with, 70t emetogenic risk with, 19t

K

Keratinocyte growth factor (KGF), radiation injury reduction with pretreatment of, 237 Ketoconazole, itch caused by, 206t KGF. See Keratinocyte growth factor Kidney, chemotherapy toxicity of cisplatin nephrotoxicity with, 44–47 diagnosis for, 44 mechanism of hypomagnesemia in, 45f mechanism of renal injury with, 44–45 prevention of, 46–47 treatment for, 46–47 alkylating agents (ifosfamide), 46–47 antimetabolites, 47 antitumor antibiotics, 47 bevacizumab, 46 carmustine, 47 gemcitabine, 47 immune modulators, 47 interferon, 47 interleukin-2, 47 lenalidomide, 47 methotrexate nephrotoxicity, 47 mithracycline, 47 mitomycin C, 47 nitrosoureas, 47 streptozocin, 47 VEGF inhibition, 46

L

LACE. See Life After Cancer Epidemiological study Lambert-Eaton myasthenic syndrome (LEMS), 287–288, 288t, 289f cancer rehabilitation complicated by, 409 Lapatinib emetic risk with, 20t heart failure associated with, 71t Laptinib, cardiotoxicity with, 70t Laser photoresection/endoscopy, malignant central airway obstruction treated with, 318 Last days of life crises at, 400 determine when someone is entering, 399–400

Last days of life (Continued) managing symptoms with, 400–401 essential medications and equipment for, 400, 401t general approaches, 400 reviewing medications, 400–401 pain at, 401–403 bowel and bladder problems, 402 eye care, 402 food and fluid intake, 403 oral care, 402 respiratory symptoms, 401–402 retained respiratory secretions, 402, 402t seizures, 402–403 skin care, 402 terminal agitation, 403, 403t patient death after, 404 sedation at, 403 setting of, 398–400 24-Hour access to team for, 399 advance care planning for, 398–399 care provider acceptance for, 400 careful documentation for, 399 communication for, 399 delineation of goals for, 398, 399t delineation of rites and rituals for, 399 interprofessional team approach to, 399 Late effects, chemotherapy/radiation amelioration of, 434 consequential, 431, 431f documentation on, 431–432 classification systems used for, 432 in individual organs, 432–434 adnexae, 432 bone, 434 cartilage, 434 esophagus, 432 gastrointestinal tract, 432 heart, 434 liver, 432–433 nervous system, 433 oral cavity, 432 respiratory tract, 433–434 sense organs, 434 skin, 432 urinary tract, 433 pathogenesis of, 430–431, 430f symptomatic treatment of, 434–436 antiinflammatory strategies in, 435 antioxidative approaches in, 435 biology-based prophylactic/therapeutic approach in, 434–435, 435f growth factor signaling in, 435 modulation of angiotensin in, 435–436 time course for, 431–432 Laxatives rectal, 184 softening, 182–184 stimulant, 182 LEMS. See Lambert-Eaton myasthenic syndrome Lenalidomide cardiotoxicity with, 70t cisplatin nephrotoxicity with treatment using, 47 emetic risk with, 20t thromboembolism with, 77 Leptomeningeal carcinomatosis, neuromuscular complications of cancer with, 285 Leucovorin, chemotherapy with 5-fluorouracil combined with, 50–51 Leukemia, malignant pleural effusions caused by, 355t Leukopenia, radiotherapy-induced, 41 Levofloxacin, dosage for, 28t Levomepromazine, pharmacokinetics of, 261t

Life After Cancer Epidemiological study (LACE), 421 Li-Fraumeni syndrome, 457t Light's criteria, 355 Linezolid, dosage for, 28t Lipedema, 214t Lipids, arterial thromboembolism with, 79 Liposomal daunorubicin, irritation with extravasation of, 3t Liposomal doxorubicin, irritation with extravasation of, 3t Liver. See also Colorectal liver metastases; Kidney, chemotherapy toxicity of blue liver syndrome of, 51, 52f cancer pain with metastases of, 127–128 late effects of chemotherapy/radiation with, 432–433 nonalcoholic fatty liver disease with, 52 Living will, 514 LMWH. See Low-molecular-weight heparins Lomustine, emetogenic risk with, 19t Long bone fractures bone metastases with, 293 impending, 295–297 prophylactic surgery for, 297, 297f, 298f radiotherapy for, 296 risk assessment for bone metastases, 294–295 Lorazepam, terminal agitation, medications for, 403t Loss of a child, bereavement with, 630 Low emetogenic chemotherapy, 21, 22t Low-molecular-weight heparins (LMWH) tumor progression with, 280 VTE prevention with, 278 Lumbosacral plexopathy neuromuscular complications of cancer with, 285 radiation-induced, 285 Lung cancer pain with metastases of, 128 radiotherapy-induced adverse events for, 38 management of, 38 pathophysiology of, 38 prevention of, 38 symptoms of, 38 Lung cancer exercise interventions for, 418–420 supportive interventions for, 383–384 Lung injury acute, pulmonary toxicity with, 87–89 bone marrow transplant with, 89 chronic, 89 radiation-induced, 322–323 Lung toxicity, chemotherapy-related, 309–310 LVA. See Lymphatico-venous anastomoses Lymphatico-venous anastomoses (LVA), lymphedema management with, 217, 217t Lymphedema cancer rehabilitation with, 410–411 classification, 212t clinical monitoring of, 215 congenital, 212t definition, 211 diagnosis of, 213–215 differential diagnosis, 214–215, 214t imaging in, 214 patient history in, 213–214, 214f physical examination in, 213–214, 214f management of, 215 morbidity with, 213 nonoperative management of, 215–217, 215t activities of daily living, 215 combination nonoperative therapy, 215t, 216–217

645

index Lymphedema (Continued) complex decongestive physiotherapy, 215t, 216–217 complex physical therapy, 215t, 216–217 decongestive lymphatic therapy, 215t, 216–217 elevation, 215t exercise, 215t manual lymphatic drainage, 215t, 216–217 massage therapy, 216 pharmacotherapy, 217 pneumatic compression, 215t, 216, 216f, 216t static compression, 215–216, 215t operative management of, 217–218, 217t Charles procedure, 217t, 218 excisional procedures, 217t, 218 flap transposition, 217t, 218 lymphatico-venous anastomoses, 217, 217t microsurgery, 217 other procedures, 218 physiologic procedures, 217–218, 217t staged subcutaneous excision, 217t, 218 suction-assisted lipectomy, 217t, 218 pathophysiology of, 213–215 praecox, 212t prevalence of, 211–213, 212f, 213f secondary, 212f, 213f tarda, 212t Lymphoma cancer, exercise interventions for, 418, 420f malignant pleural effusions caused by, 355t

M

Macrogols, 183 Maculopapular rash, 116t, 118 Magnetic resonance imaging (MRI) cancer pain assessment with, 127 malignant bowel obstruction diagnosis with, 329 Major depressive disorder (MDD), 529 diagnostic complexity in cancer of, 529 Male gonadal function chemotherapy for, 96–97, 96t, 97f hormonal cancer treatment for, 98 normal, 95–96 posttreatment function in, 96–98 prevention of dysfunction in, 99 radiotherapy for, 97–98 surgery for, 98 Male sexual dysfunction, radiotherapy-induced, 41 Malignant bile duct obstruction, stents for palliative treatment of, 377 Malignant bowel obstruction (MBO) classification of causes of, 327f clinical manifestations of, 328, 328t definition, 327 diagnosis of, 329–330 clinical history in, 329–330, 329t CT scan in, 329, 330f investigations in, 329–330 magnetic resonance imaging in, 329 physical examination in, 329–330 X-rays of the abdomen in, 329, 329f further research for, 338–339 pathophysiology of, 327–328, 327f, 328f treatment of, 330–338 cecostomy tubes in, 336–337, 337t colorectal stents in, 335–336, 337t, 338f conservative (best supportive care) for, 330–331, 332t, 333b fluoroscopic/endoscopic procedures for, 335–337, 338f interventional procedures for, 334–337, 646 334t

Malignant bowel obstruction (MBO) (Continued) nasogastric tubes in, 331 nausea, management of, 333–334 nonpharmacologic treatment for, 331–333 nutritional considerations in, 331–333 oral intake restriction with, 331 pain management with, 333 pharmacologic treatment in, 333–334 surgical procedures for, 337–338 venting gastrostomy in, 335, 336t vomiting, management of, 333–334 Malignant central airway obstruction, 312–322 brachytherapy for, 322 chest X-ray for, 314–315, 315f CT scan for, 315 diagnosis of, 314 differential diagnosis of, 316 endoscopy for, 315–316 epidemiology of, 312–313, 313f, 314f etiology of, 313 imaging for, 314–316 management of, 316–322, 317f nonthermal therapies for, 320–321 airway stents, 320–321, 321f, 322f balloon tracheoplasty/bronchoplasty, 320 endobronchial microdebrider, 320 rigid bronchoscopic debulking, 320 physical examination for, 314 pulmonary function tests for, 316 radiation therapies for, 322 symptoms of, 314 thermal therapies for, 318–320 argon plasma coagulation (APC), 319 cryotherapy, 319 electrocautery, 318, 319f laser photoresection/endoscopy, 318 photodynamic therapy (PDT), 319–320 Malignant esophageal dysphagia, 171–175 anatomic structures involved in, 171 diagnosis of, 171–172 DCBE in, 171–172 EGD in, 172 dysphagia scoring system (DSS), 171, 172t endoscopic treatment options for, 173–175 ablative techniques, 173 esophageal stents, 173–175, 174f nutrition for, 172–173 feeding tubes, 172–173 Malignant peripheral nerve sheath tumors (MPNST), 285 Malignant pleural effusions, 354–357, 355t causes of, 355t clinical manifestations of, 354–355 diagnosis of, 355 diagnostic criteria in, 355–356 Light's criteria in, 355 evaluation of, 355 management of, 355–357 indwelling catheter in, 356–357 intrapleural therapy in, 356 pleurectomy in, 357 pleurodesis in, 356 shunt in, 357 thoracentesis in, 355–356 video-assisted thoracic surgery in, 356 pathophysiology of, 354 Malignant spinal cord compression (MSCC), 293 Malignant wounds, 343–349 bleeding with, 348 cosmetic/esthetic concerns with, 348 drainage/exudation of, 348 elements of, 346t epidemiology of, 343–344 itching with, 348 management of, 346

Malignant wounds (Continued) odor with, 348 pain with, 347–348 pathophysiology of, 343–344 prevention of, 346 prognosis for, 348–349 wound palliation with, 347–348 Malnutrition, enteral tube placement for, 386 Malnutrition Screening Tool (MST), 156–157 Manual lymphatic drainage (MLD), lymphedema management with, 215t, 216–217 MAOI. See Monoamine oxidase inhibitors Marijuana, nausea treatment with, 267 MASCC. See Multinational Association for Supportive Care in Cancer Massage, 465t, 467–468 background on, 467–468 clinical evidence for, 468 definition of, 467 lymphedema management with, 216 MBO. See Malignant bowel obstruction MDCT. See Multidetector computed tomography MDD. See Major depressive disorder MDI. See Microbiologically documented infection Meaning-centered therapy, 560–562, 561t couples therapy, 561–562 family therapy, 562, 563t Mechanical prophylaxis, VTE prevention with, 279 Mechlorethamine, emetogenic risk with, 19t Melphalan, irritation with extravasation of, 3t Melphalan IV, emetogenic risk with, 19t Meropenem, dosage for, 28t Mesothelioma, malignant pleural effusions caused by, 355t Metallic stents, 321, 321f, 322f Methotrexate cardiotoxicity with, 70t emetogenic risk with, 19t hand foot syndrome with, 118 inflammation risk with extravasation of, 3t neurotoxicity with, 58–59 Methotrexate nephrotoxicity, 47 diagnostic features with, 47 treatment strategies for, 47 Methotrimeprazine, terminal agitation, medications for, 403t Metoclopramide, pharmacokinetics of, 261t Metronidazole dosage for, 28t itch caused by, 206t Mezlocillin, dosage for, 28t MG. See Myasthenia gravis Miconazole, itch caused by, 206t Microbiologically documented infection (MDI), 26–27 Microdebrider, malignant central airway obstruction treated with, 320 Microtubule-targeting agents, cardiotoxicity with, 70t Midazolam, terminal agitation, medications for, 403t Minimal emetogenic chemotherapy, 21, 22t Mithracycline, cisplatin nephrotoxicity with treatment using, 47 Mitomycin C cisplatin nephrotoxicity with treatment using, 47 extravasation of, 5 ulceration with extravasation of, 3t Mitoxantrone cardiotoxicity with, 70t emetogenic risk with, 19t extravasation of, 5 ulceration with extravasation of, 3t

Index Mixed pruritus, 200–201 MLD. See Manual lymphatic drainage Moderate hyposalivation, 238 Moderately emetogenic chemotherapy, 21, 22t Monoamine oxidase inhibitors (MAOI), depression intervention with, 536 Monoclonal antibodies, 12 cardiotoxicity with, 70t, 75 Morbilliform eruption, 116t, 118 Morphine, itch caused by, 206t Motor neuron disease, 290 MPNST. See Malignant peripheral nerve sheath tumors MRI. See Magnetic resonance imaging MSCC. See Malignant spinal cord compression MST. See Malnutrition Screening Tool Mucositis assessment of, 109 OMAS scale, 108b, 109 WHO scale, 109, 109b CACS with, 160 clinical impact of, 102–103, 103f, 104f clinical practice guidelines for, 110t clinical translation for, 112–113 definition of, 103 economic impact of, 102–103, 104f example of oral, 103f future research directions for, 112–113 gastrointestinal, 103f incidence of, 103–107, 105f, 105t chemotherapy associated, 107 HCT patients, 105–107 head/neck radiation associated, 104–105 nutritional support for, 112 pathobiology of, 107–109, 108f, 109f risk of development of, 103–107, 104f, 105t, 107b, 108b treatment of, 109–112, 110t, 112t Multidetector computed tomography (MDCT), 315 Multinational Association for Supportive Care in Cancer (MASCC), risk index established by, 25, 25t Multiple myeloma, denosumab for, 254 Multiple-day (cisplatin-containing) chemotherapy, 22 Music therapy, 465t, 468 background on, 468 clinical evidence for, 468 definition of, 468 Myasthenia gravis (MG), 288, 288t Myocardial infarction (Dressler’s syndrome), pericardial effusion caused by, 357t Myopathy, 289 cancer rehabilitation complicated by, 409 radiation-induced, 285 steroid-induced, 286 Myxedema, pericardial effusion caused by, 357t

N

N -acetylcysteine, neurotoxicity treatment with, 63 NAFLD. See Nonalcoholic fatty liver disease Nail toxicity, 119–120 nail discoloration, 116t nail loss, 116t nail ridging, 116t onycholysis, 119–120, 119f paronychia, 119 Narcolepsy, insomnia differential diagnosis with, 193 Narrative therapies, 560 Nasogastric tubes, malignant bowel obstruction treatment with, 331

National Pressure Ulcer Advisory Panel (NPUAP), 343, 344t National Surgical Adjuvant Breast and Bowel Project (NSABP), 251 Natrium thiosulfate, chemotherapy extravasations management with, 6 Nausea. See also Chemotherapy-induced nausea and vomiting anticholinergic for, 334 antiemetics for, 334 assessment of, 260–261, 261t barriers to, 260 outcomes to, 260–261 symptom clusters, 261 CACS with, 159 causes of, 259, 260t characteristics of, 259 corticosteroids for, 334 definitions in advanced cancer of, 258–259 drugs for treating, 263–267 5-HT3 receptor antagonists, 264–265 antihistaminic agents, 266 benzodiazepines, 267 cannabinoids, 267 corticosteroids, 266–267 cyclizine, 266 dopamine receptor antagonists, 265–266 hyoscyamine, 267 marijuana, 267 neurokinin-1 antagonists (NK-1 antagonists), 267 novel prokinetic agents, 267 octreotide, 267 prokinetic agents, 263 promethazine, 266 endoscopic techniques for, 269 gastric electrical stimulation for, 269–270 gastrointestinal stenting for, 269 incidence of, 259 malignant bowel obstruction treatment with, 333–334 nonsurgical procedures for, 268–270 octreotide for, 333 other modes of nausea control for, 268–270 PEG tubes for, 268–269 pharmacologic approaches to, 261–267 mechanistic v. empirical, 261–262 receptor site affinities of antiemetics in, 262t prevalence of, 259 prokinetic agents for, 263, 334 efficacy for advanced cancer of, 263 pharmacology of, 261t, 263 proton pump inhibitors for, 334 radiotherapy-induced, 41 Necrosis bisphosphonates with, 249t radiotherapy-induced, 37 Nelarabine, inflammation risk with extravasation of, 3t Nephrotic syndrome, malignant pleural effusions caused by, 355t Nervous system late effects of chemotherapy/radiation with, 433 paraneoplastic disorders with peripheral, 289–290 Netilmicin dosage for, 28t serum concentrations target for, 30t Neurocognitive dysfunction, radiotherapyinduced, 37 Neurokinin-1 antagonists (NK-1 antagonists), nausea treatment with, 267 Neuromuscular complications direct effects of cancer in, 284–285 brachial plexopathy, 284–285, 284f

Neuromuscular complications (Continued) leptomeningeal carcinomatosis, 285 lumbosacral plexopathy, 285 peripheral neuropathy, 285 plexopathies, 284–285 polyradiculopathy carcinomatosis, 285 effects of cancer treatment on, 285–287 bortezomib, 286t, 287 chemotherapy-induced neuropathy, 286, 286t cisplatin, 286–287 cytarabine, 287 epithelones, 287 etoposide, 287 hematopoietic stem cell transplant, 286 ifosfamide, 287 radiation-induced brachial plexopathy, 285 radiation-induced lumbosacral plexopathy, 285 radiation-induced myopathy, 285 radiation-induced nerve tumors, 285 steroid-induced myopathy, 286 suramin, 286t, 287 surgery related neuropathy, 285 taxanes, 286t, 287 thalidomide, 286t, 287 vinca alkaloids, 286, 286t neuromuscular hyperactivity, 288–289 myopathies, 289 neuromyotonia, 288–289, 288t stiff person syndrome, 288t, 289 paraneoplastic disorders affecting peripheral nervous system, 289–290 autonomic neuropathy, 288t, 290 inflammatory demyelinating polyneuropathy, 288t, 290 motor neuron disease, 290 sensorimotor polyneuropathy, 288t, 289 sensory neuronopathy, 288t, 289 vasculitic neuropathy, 288t, 289–290 physical activity with, 290 remote (paraneoplastic) effects of cancer in, 287–288 Lambert-Eaton myasthenic syndrome, 287–288, 288t, 289f Myasthenia gravis, 288, 288t neuromuscular junction affected disorders, 287–288 paraneoplastic disorders, 287–288 Neuromuscular hyperactivity, 288–289 Neuromuscular junction affected disorders, 287–288 Neuromyotonia (Isaac's syndrome), 288–289, 288t Neuropathic itch, 200–201, 204–205 Neuropathic pain, 125–126 Neuropathy cancer rehabilitation complicated by, 409 chemotherapy-induced, 286, 286t Neurotransmitters CINV with, 17 dopamine, 17 serotonin, 17 substance P, 17 Neutropenia antimicrobial therapy for additional treatment options for, 29, 32t assessment of, 29 concepts in, 27–29 continuation of, 29 duration of, 29 follow-up for, 29 patients with pulmonary infiltrate, 28b when to start, 27 definition, 24 pathogen identification for, 25–27, 26t clinical-chemical diagnosis in, 27 clinically documented infection, 26

647

index Neutropenia (Continued) diagnosis after 72-96 hours therapy in, 27 infections, 25–27 microbiologically documented infection, 26–27 unexplained fever, 25 risk classification for, 25t, 28 groups in, 24–25, 25t treatment of high-risk patients, 28, 31t treatment of intermediate-risk patients, 28, 31t treatment of low-risk patients, 25t, 26t, 28, 28t Niacin, itch caused by, 206t Nimustine, inflammation risk with extravasation of, 3t Nitrosoureas cisplatin nephrotoxicity with treatment using, 47 neurotoxicity with, 60 pulmonary complications with, 311–312 NK-1 antagonists. See Neurokinin-1 antagonists NK-1-receptor antagonist CINV treated with, 19–20, 21t recommended dose for, 21t NMDA. See N-methyl-D-aspartate N-methyl-D-aspartate (NMDA), receptors, 123–124 Nonalcoholic fatty liver disease (NAFLD), 52 Nonpolyposis, hereditary, 457t Nonsteroidal anti-inflammatory drugs (NSAID) cancer pain poorly responsive to opioids with, 131 itch caused by, 206t Notalgia paresthetica, 205 NPUAP. See National Pressure Ulcer Advisory Panel NSABP. See National Surgical Adjuvant Breast and Bowel Project NSAID. See Nonsteroidal anti-inflammatory drugs Nutrition CACS intervention with, 158–159 assessment of current intake, 158 barriers to nutritional intake, 158 dietary recommendations, 159 energy/protein requirements calculation, 159 CACS with assessment of, 156–158 anthropometrics, 157 body composition assessment, 157 comprehensive assessment, 157 laboratory assessment, 157 Malnutrition Screening Tool, 156–157 symptom assessment, 157 validated nutrition assessment tools, 157–158 CACS with enteral or parenteral, 160–161 cancer-related fatigue associated with, 143–144 malignant bowel obstruction treatment with, 331–333 malignant dysphagia with, 172–173 mucositis with support for, 112 oropharyngeal adverse events with support for, 112

O

Obstruction, supportive interventions for, 386 Octreotide nausea treatment with, 267 nausea with, 333 pharmacokinetics of, 261t Odor, malignant wounds with, 348 648 Odynophagia, CACS with, 160

Olanzapine CINV treated with, 20 pharmacokinetics of, 261t Ondansetron pharmacokinetics of, 261t recommended dose for, 21t ONJ. See Osteonecroses of jaw Onycholysis, 119–120, 119f Opioid agonists/antagonists, itch of cholestasis treatment with, 203 Opioid Risk Tool (ORT), 572, 572t Opioids cancer pain with, anatomy, 124–125 cancer pain with, poorly responsive to, 129–132 adjuvant analgesics, 131–132, 131t, 132t corticosteroids, 131 NSAID, 131 opioid rotation for, 129, 130t opioid route conversion, 129–130 constipation for, 184 dyspnea intervention with, 168 pain flares, formulations for, 129t pruritus induced by, 206–207 spinal opioids, 206 systemic opioids, 206–207 side effects with, 131t titration for cancer pain with, 128–129 Oral candidiasis mucocutaneous lesions on tongue with, 233, 235f red erythematous patches on oral mucosa, 233, 234f Oral care, last days of life pain with, 402 Oral cavity, late effects of chemotherapy/ radiation with, 432 Oral contraceptives, itch caused by, 206t Oral Mucositis Assessment Scale (OMAS), 108b, 109 Oropharyngeal adverse events assessment of, 108b, 109, 109b clinical impact of, 102–103, 103f, 104f clinical practice guidelines for, 110t clinical translation for, 112–113 definition of, 103 economic impact of, 102–103, 104f future research directions for, 112–113 incidence of, 103–107, 105t nutritional support for, 112 pathobiology of, 107–109, 108f, 109f risk of development of, 103–107, 104f, 105t, 107b, 108b treatment of, 109–112, 110t, 112t ORT. See Opioid Risk Tool Osmotic agents, 182–183 Osteoblasts, 438, 439f Osteoclasts, 438, 439f Osteonecroses of jaw (ONJ), bisphosphonates with, 249, 249t Osteoporosis, 438–439. See also Treatmentinduced osteoporosis hormones' stimulating effect on, 438 loss of bone mineral density in, 438, 439f osteoclasts and osteoblasts in, 438, 439f primary and secondary, 439t risk factors for, 439t Ovarian cancer, 333b Oxaliplatin cardiotoxicity with, 70t chemotherapy with, 51, 51f, 52f colorectal liver metastases with, 51f emetogenic risk with, 19t hepatoxicity of, 51 neuropathy, genetic predisposition of, 61t neurotoxicity with, 57 ulceration with extravasation of, 3t

P

Paced respirations, hot flashes management with, 228 Paclitaxel cardiotoxicity with, 70t emetogenic risk with, 19t neuropathy, genetic predisposition of, 61t neurotoxicity with, 59, 60f ulceration with extravasation of, 3t PAC-QOL (Patient Assessment of Constipation—Quality of Life), 178 PAC-SYM (Patient Assessment of Constipation—Symptoms), 178 Pain. See also Cancer pain bone, 125 cancer rehabilitation with, 411–412 cancer-related fatigue associated with, 144 chest cardiotoxicity with, 73–75 systemic first dose infusion reactions with, 74–75 CINV risk with, 20t last days of life, 401–403 malignant wounds with, 347–348 management, malignant bowel obstruction treatment with, 333 neuropathic, 125–126 pain flares, opioids for, 129t pancreatic cancer, 386 somatic pain pathways, 124f visceral, 125, 125f Palliative care ethical considerations for, 396 hospice and definitions of, 516–518 discussing, 516 referral to specialized, 518 treatment transitions/goals of, 516–518, 517b principles of, 391t Palliative Performance Scale (PPS), 477, 477t Palliative prognostic index (PPI), 477–478 calculating, 478t classification for survival prediction with, 477t survival curves of scores with, 478f Palliative prognostic score (PaP score), 476 calculating, 477t survival curves of scores with, 477f Palliative surgery defined, 391 ethical considerations for, 396 future of outcomes assessment in, 395–396 measurement of surgical outcomes with, 393–395, 393f EORTC QLQ-C30 for, 393–394, 394f FACT-G for, 393–394 HRQoL, 393–394, 393f, 394t palliative surgery outcome score for, 393–394 quality-of-life instruments for, 394t patient assessment for, 391–393 principles of, 391–393, 391t readiness of surgery for, 391 Palliative surgery outcome score (PSOS), 393–394 Palliative treatment, stents for colorectal obstruction with, 379–380, 379f distal obstruction with, 377–378, 377f echoendoscopically guided hepaticogastrostomy for biliary drainage with, 378, 379f endoscopic retrograde cholangiopancreatography with, 377 esophageal cancer with, 375–376, 376f gastric outlet obstruction with, 376, 376f malignant bile duct obstruction with, 377 pancreatic cancer with, 377f proximal biliary obstruction, 378, 378f

Index Palmar-plantar erythrodysesthesia syndrome, 116t Palonosetron pharmacokinetics of, 261t recommended dose for, 21t Pamidronate bone metastases treatment with, 246, 246f diarrhea with, 249t necrosis with, 249t ONJ with, 249, 249t side effects of, 249t Pancreatic cancer pain, supportive interventions for, 386 stents for palliative treatment of, 377f Panic attacks, pharmacologic interventions for, 537 Panic disorder, 529–530 Panitumumab, emetogenic risk with, 19t PaP score. See Palliative prognostic score Papulopustular rash, 115–117, 117f Paracentesis, ascites management with, 365–366 Paraneoplastic disorders, 287–288 peripheral nervous system affected by, 289–290 Paraneoplastic pruritus, 204 Parasomnias, insomnia differential diagnosis with, 193 Paronychia, 119 Paroxetine, hot flashes management with, 224 Patient Assessment of Constipation—Quality of Life. See PAC-QOL Patient Assessment of Constipation—Symptoms. See PAC-SYM PDEI. See Phosphodiesterase inhibitors PDT. See Photodynamic therapy PE. See Pulmonary embolism PEG tubes. See Draining percutaneous endoscopic gastrostomy tubes Pegasparaginase emetogenic risk with, 19t inflammation risk with extravasation of, 3t Pemetrexed cardiotoxicity with, 70t emetogenic risk with, 19t inflammation risk with extravasation of, 3t Pentostatin emetogenic risk with, 19t inflammation risk with extravasation of, 3t Percutaneous balloon pericardiotomy, 359 Pericardial effusion, 357–359, 357t causes/types of, 357t clinical manifestations of, 357–358 diagnosis of, 358 evaluation of, 358 management of, 358–359 chemotherapy in, 359 evaluation of pericardial fluid in, 358 pericardiocentesis in, 358 sclerosing therapy in, 359 surgical approaches in, 358–359 pathophysiology of, 357 percutaneous balloon pericardiotomy for, 359 Pericardiocentesis, pericardial effusion management with, 358 Peripheral neuropathy, neuromuscular complications of cancer with, 285 Peritoneovenous shunts, ascites management with, 366 Permanent drains, ascites management with, 366, 367f PFT. See Pulmonary function tests Phenolphthalein, itch caused by, 206t Phobias, 529–530 Phosphodiesterase inhibitors (PDEI), sexuality after cancer with, 608–609

Photochemotherapy (PUVA), itch caused by, 206t Photodynamic therapy (PDT), malignant central airway obstruction treated with, 319–320 Photosensitivity, 116t extravasation diagnosis with, 5 Physical activity motivation in cancer survivors with, 422–425 adherence barriers and motives in, 424 adherence determinants in, 423–424 behavior change interventions, 424–425 determinants in, 422–423 exercise barriers and motives in, 424 participation barriers and motives in, 424 participation determinants in, 423 prevalence in, 422 quality of life with, 414 cancer survivor studies on, 415–417, 416f supportive care outcomes with, 415–417 cancer diagnoses targeted, 416f health outcomes targeted, 416f mean effect sizes by cancer phase, 416f Phytoestrogens, hot flashes management with, 227 Pilocarpine, radiation injury reduction with, 236–237 Piperacillin, dosage for, 28t Platinum agents, cardiotoxicity with, 70t Platinum compounds, neurotoxicity with, 56–57 Pleural disease, supportive interventions for, 384 Pleural effusions, malignant, 354–357, 355t causes of, 355t clinical manifestations of, 354–355 diagnosis of, 355 diagnostic criteria in, 355–356 Light's criteria in, 355 evaluation of, 355 management of, 355–357 indwelling catheter in, 356–357 intrapleural therapy in, 356 pleurectomy in, 357 pleurodesis in, 356 shunt in, 357 thoracentesis in, 355–356 Video-assisted thoracic surgery (VATS) in, 356 pathophysiology of, 354 pulmonary toxicity with, 88 Pleurectomy, pleural effusions management with, 357 Pleurodesis, pleural effusions management with, 356 Plexopathy cancer rehabilitation complicated by, 409 neuromuscular complications of cancer with, 284–285 Pneumatic compression, lymphedema management with, 215t, 216, 216f, 216t Polymyxin B, itch caused by, 206t Polyradiculopathy carcinomatosis, neuromuscular complications of cancer with, 285 Pomalidomide cardiotoxicity with, 70t thromboembolism with, 77 Posaconazole, dosage for, 30t Post-herpetic itch, 205 Posttraumatic stress disorder (PTSD), 530 pharmacologic interventions for, 537 PPI. See Palliative prognostic index; Proton pump inhibitors PPS. See Palliative Performance Scale Pregabalin, hot flashes management with, 226

Pressure ulcers, 349–351 epidemiology of, 349, 349f management of, 350–351, 350f debridement in, 350 edge effect in, 351 infection/inflammation in, 350–351 moisture balance in, 351 pathophysiology of, 349, 349f prevention of, 349–350 mechanical loading and support surfaces in, 350 risk assessment in, 349 skin care in, 349 prognosis for, 351 Primary cachexia, 151 Probenecid, itch caused by, 206t Procarbazine, emetic risk with, 20t Prochlorperazine, pharmacokinetics of, 261t Proctitis, radiotherapy-induced, 39–40 management of, 39–40 prevention of, 40 symptoms of, 39–40 Professionals caregivers challenges of educating, 585b fertility, attitudes on, 618–619, 618t, 619t interventions to support, 583–585 educational interventions, 585 professional/organizational responsibilities, 585 self-awareness for self-care, 584–585 occupational health for, 579–583 compassion satisfaction with, 579–580 compassion with, 582 empathy with, 582 job engagement with, 580 positive emotion with, 580–581 religion with, 582–583, 583b resilience with, 580 spirituality with, 582–583, 583b vitality with, 580 occupational stress among, 575–579 burnout with, 576–579 community with, 577 compassion fatigue with, 578 emotion-work variables with, 578–579 fairness with, 577 moral distress with, 578–579 reward with, 577 values with, 577–578 vicarious traumatization with, 579 workload with, 576–577 Progestagens, itch caused by, 206t Progesterone analogs, hot flashes management with, 223 Progesterone cream, hot flashes management with, 223 Prognostic assessment challenges with, 473 clinical predictions of survival in, 473–474 accuracy of, 473–474 foreseeing and foretelling with, 474 need for models with, 474 communicating prognosis with, 481–482 definition of, 472–473 ethical issues with, 482 patient understanding of, 473 prediction factors, 474–476 anorexia-cachexia syndrome, 475 biological factors, 476 delirium, 475–476 dyspnea, 475 performance status, 475 prognostic tools and models, 476–481 limitations of models, 481 model for survival in radiotherapy clinic, 478–481, 479f, 479t, 480t

649

index Prognostic assessment (Continued) other models, 481 Palliative Performance Scale, 477, 477t palliative prognostic index, 477–478, 477t, 478f, 478t palliative prognostic score, 476, 477f, 477t Terminal Cancer Prognostic score, 481 Prokinetic agents efficacy for advanced cancer of, 263 nausea treatment with, 263, 334 pharmacology of, 261t, 263 Prolonged grief disorder (PGD), 628, 629b treatments for, 632 Promethazine dyspnea intervention with, 168 nausea treatment with, 266 pharmacokinetics of, 261t Prophylaxis catheter-related infection treated with, 373 treatment–induced osteoporosis treatment with, 442–443, 442f, 443f Prophylaxis, mechanical, VTE prevention with, 279 Propylthiouracil, itch caused by, 206t Prostaglandin E1 agonists, sexuality after cancer with, 609–610 Prostaglandins, cancer pain with, 123 Prostate cancer, exercise interventions for, 418, 419t Proteasome inhibitors, cardiotoxicity with, 70t Proton pump inhibitors (PPI), nausea with, 334 Proximal biliary obstruction, stents for palliative treatment of, 378, 378f Prurigo. See Itch Pruritic syndromes with malignant disease, 202–205 brachioradial pruritus, 205 cheiralgia paresthetica, 205 dry skin (xerosis), 202–203 itch of cholestasis, 203–204 neuropathic itch, 200–201, 204–205 notalgia paresthetica, 205 paraneoplastic pruritus, 204 post-herpetic itch, 205 trigeminal trophic syndrome, 205 uremic pruritus, 204 Pruritoceptive itch, 200–201 Pruritus, 116t, 119, 119f. See also Itch brachioradial, 205 mixed, 200–201 opioid-induced, 206–207 spinal opioids, 206 systemic opioids, 206–207 paraneoplastic, 204 uremic, 204 Pseudoallergic reaction. See Allergic reactions, chemotherapy PSOS. See Palliative surgery outcome score Psychodynamic psychotherapy, 559–560 bereavement support with, 631 Psychoeducational interventions, 557 Psychogenic itch, 200–201 Psychostimulants, delirium management with, 550 Psychotherapy biopsychosocial model in, 556, 556t collaborative team care models of support with, 562–565 CALM therapy, 563–564, 564t complementary approaches to, 564 effectiveness in supportive care of, 564–565 concerns with, 555–557 diagnoses with, 555–557 dignity therapy, 560, 561t interpersonal, 558–559 meaning-centered therapy, 560–562, 561t couples therapy, 561–562 650 family therapy, 562, 563t

Psychotherapy (Continued) models of, 557–558 cognitive-behavioral therapy, 558, 559t psychoeducational interventions, 557 supportive counseling, 557–558 supportive-expressive group therapy, 557–558 narrative therapies, 560 patient issues with, 555–557 psychodynamic, 559–560 Psychotropic medications, dyspnea intervention with, 168 PT. See Pulmonary toxicity PTSD. See Posttraumatic stress disorder Pulmonary complications alkylators leading to, 311–312 anthracyclines leading to, 312 antimetabolites leading to, 311 bleomycin leading to, 310–311, 311f chemotherapy-related lung toxicity, 309–310 malignant central airway obstruction, 312–322 chest X-ray for, 314–315, 315f CT scan for, 315 diagnosis of, 314 differential diagnosis of, 316 endoscopy for, 315–316 epidemiology of, 312–313, 313f, 314f etiology of, 313 imaging for, 314–316 management of, 316–322, 317f nonthermal therapies for, 320–321, 321f, 322f physical examination for, 314 pulmonary function tests for, 316 radiation therapies for, 322 symptoms of, 314 thermal therapies for, 318–320, 319f nitrosoureas leading to, 311–312 radiation-induced lung injury, 322–323 taxanes leading to, 312 Pulmonary edema, pulmonary toxicity with, 88 Pulmonary embolism (PE), 274 diagnosis of, 279f malignant pleural effusions caused by, 355t Pulmonary function tests (PFT), malignant central airway obstruction in, 316 Pulmonary infiltrate, therapy strategy for patients with, 28b Pulmonary toxicity (PT), 68–89 chemotherapy-induced, 87–89, 87t acute lung injury, 87–89 asymptomatic decrease in, 88 chronic lung injury, 89 diagnosis of, 88–89 hypersensitivity pneumonitis, 88 interstitial lung disease, 88 isolated bronchospasm, 88 pleural effusions, 88 pulmonary edema, 88 supportive oncology for, 89 treatment of, 89 complementary and alternative medicine for, 69t incidence of, 68, 69t radiation-induced, 85–86 risk factors for, 86t supportive oncology for, 86 supportive oncology care for, 68–69 PUVA. See Photochemotherapy

Q

QoL. See Quality of life QPL. See Question prompt lists

Quality of life (QoL). See also Health-related quality of life cancer survivor studies on, 415–417, 416f physical activity with, 414 Question prompt lists (QPL), 508–509, 509b Quinidine, itch caused by, 206t

R

Radiation myelopathy, cancer rehabilitation complicated by, 409 Radiation recall dermatitis, 36 prevention of, 36 Radiation therapy (RT). See also Radiotherapy cancer-related fatigue with, 137 malignant pleural effusions caused by, 355t role in secondary cancers of, 458–459 age at irradiation with, 458 delay from therapy to emergence of cancer in, 458 dosage in, 459 gender at irradiation with, 458 organs radiated with, 459 Radiation-induced brachial plexopathy, neuromuscular complications of cancer with, 285 Radiation-induced lumbosacral plexopathy, 285 Radiation-induced lung injury (RILI), 322–323 Radiation-induced myopathy, 285 Radiation-induced nerve tumors, 285 Radioimmunotherapy, cardiotoxicity with, 70t Radioisotopes, cancer pain adjuvant management with, 132 Radioprotection, 236 Radiotherapy compression fractures with, 299 fertility, impact of treatments on, 619 long bone fractures with, 296 radiation injury reduction with pilocarpine during, 236–237 stereotactic spinal, 299–300, 301f Radiotherapy-induced adverse events bladder, 40 management of, 40 pathophysiology of, 40 prevention of, 40 symptoms of, 40 bone marrow, 41 anemia, 41 leukopenia, 41 brain, 36–38 acute delayed reaction, 37 edema, 37 hypopituitarism, 37–38 management of, 37 necrosis, 37 neurocognitive function, 37 pathophysiology of, 36–37 prevention of, 38 somnolence syndrome, 37 symptomatic epilepsy, 37 symptoms of, 37 cardiotoxicity, 81–85 emesis, 35, 41t enteropathy, 39 management of, 39 pathophysiology of, 39 prevention of, 39 symptoms of, 39 esophagus, 38–39 management of, 38–39 pathophysiology of, 38 prevention of, 39 symptoms of, 38–39 female gonadal function in, 98–99 lung, 38

Index Radiotherapy-induced adverse events (Continued) management of, 38 pathophysiology of, 38 prevention of, 38 symptoms of, 38 male gonadal function in, 97–98 mucositis, 104–105 nausea, 41 pathophysiology/prevalence of, 35 acute effects, 35 late effects, 35 prevention of, 36 proctitis, 39–40 management of, 39–40 prevention of, 40 symptoms of, 39–40 pulmonary toxicity, 85–86 radiation recall dermatitis, 36 risk factors for, 35–36 dose, 35 drugs, 35 radiation technique, 35 radiosensitivity, 35–36 sexual function, 40–41 female, 40 male, 41 skin, 36 management of, 36 pathophysiology of, 36 symptoms of, 36 stomach, 39 management of, 39 symptoms of, 39 Raltitrexed, inflammation risk with extravasation of, 3t RANK. See Receptor activator of nuclear factor K-B RANKL. See RANK-ligand RANK-ligand (RANKL), 244 development of antibodies against, 251–252, 252f treatment–induced osteoporosis treatment with antibodies against, 444, 445f Recall phenomenon, extravasation diagnosis with, 5 Receptor activator of nuclear factor K-B (RANK), 244 5-HT3-receptor antagonists (5-HT3-RA) CINV treated with, 18–19, 21t efficacy for advanced cancer of, 265 nausea treatment with, 264–265 pharmacology of, 264–265 recommended dose for, 21t Rectal laxatives, constipation treatment with, 184 Red clover isoflavone extract, hot flashes management with, 227 Reflexology, 465t, 468 background on, 468 clinical evidence for, 468 definition of, 468 Relaxation therapy, 465t, 468 background on, 468 clinical evidence for, 468 definition of, 468 insomnia management with, 197 Renal toxicity, bisphosphonates with, 249 Renin-angiotensin system, late effects of chemotherapy/radiation with, 435–436 Respiratory symptoms, last days of life pain with, 401–402 Respiratory tract, late effects of chemotherapy/ radiation with, 433–434 Retained respiratory secretions, last days of life pain with, 402, 402t

Retinoblastoma, 457t Retinoids arterial thromboembolism with, 79 cardiotoxicity with, 70t Rifampicin, itch of cholestasis treatment with, 203 Rigid bronchoscopic debulking, malignant central airway obstruction treated with, 320 RILI. See Radiation-induced lung injury Risedronate bone mineral density improvement with, 443f diarrhea with, 249t necrosis with, 249t ONJ with, 249, 249t side effects of, 249t Rituximab cardiotoxicity with, 70t inflammation risk with extravasation of, 3t RT. See Radiation therapy

S

SAL. See Suction-assisted lipectomy Salivary gland dysfunction CACS with, 160 clinical examination of, 233–235 angular cheilitis, 233, 235f cracked lips, 233, 233f dental decay, 233, 234f dry surface of dorsum of tongue, 233, 233f dry/pale buccal mucosa, 233, 233f hyperkeratinized buccal mucosa, 233, 233f hyposalivation-related dental caries, 234f oral candidiasis, 233, 234f, 235f management of radiation-induced, 237–239 acupuncture in, 238 electrostimulation in, 238 gene therapy in, 239 gustatory stimulant in, 237, 237t healing injury to salivary gland tissue in, 239 hyperbaric oxygen treatment in, 238 insufficient effect of stimulation in, 238 new radiation techniques in, 239 pharmacologic sialagogues in, 237, 237t stem cell therapy in, 239 stimulation of residual function in, 237–238 tactile stimulant in, 237, 237t prevention of, 235–237 can radiation injury be reduced?, 235–237, 235f intensity-modulated radiotherapy in, 235–236 radiation injury to salivary gland tissue, 235–237 radiation injury reduction strategies for, 235–237 IGF-1 and KGF pretreatment, 237 pilocarpine during radiotherapy, 236–237 radioprotection, 236 surgical transfer of submandibular gland, 236 symptoms of, 232–233 treatment of, 235–237 treatment recommendations for, 238 moderate hyposalivation, 238 severe hyposalivation, 238 slight hyposalivation, 238 Sarcoidosis, malignant pleural effusions caused by, 355t Sclerosing therapy, pericardial effusion management with, 359 Secondary cachexia, 151

Secondary cancers in cancer survivors burden of disease with, 460–461 chronic health conditions, 460 Screening recommendations for survivorship care with, 461t survivorship clinics, 460–461 cancer syndromes with hereditary susceptibility to, 457t, 459–460 chemotherapy's role in, 458 alkylating agents, 458 topoisomerase agents, 458 genetic predisposition to, 459–460 incidence of, 456–457 in adult survivors, 456–457 in childhood survivors, 457, 457f multiple factors causing, 460 alcohol, 460 hormones, 460 immune suppression, 460 infection, 460 nutrition, 460 tobacco, 460 radiation therapy's role in, 458–459 age at irradiation with, 458 delay from therapy to emergence of cancer in, 458 dosage in, 459 gender at irradiation with, 458 organs radiated with, 459 risk factors in developing, 457t SEGT. See Supportive-expressive group therapy Seizures, last days of life pain with, 402–403 Selective serotonin reuptake inhibitors (SSRI) depression intervention with, 536 dyspnea intervention with, 168 hot flashes management with, 225 itch of cholestasis treatment with, 203 Self-expandable metal stents (SEMS), 375 Semisynthetic vinca alkaloids, neurotoxicity with, 58 SEMS. See Self-expandable metal stents Sense organs, late effects of chemotherapy/ radiation with, 434 Sensorimotor polyneuropathy, 288t, 289 Sensory neuronopathy, 288t, 289 Serotonin, CINV with, 17 Serotonin antagonists, pharmacokinetics of, 261t Serotonin reuptake antagonists, itch of cholestasis treatment with, 203–204 Severe hyposalivation, 238 Severe infusion reaction. See Allergic reactions, chemotherapy Sexual dysfunction, radiotherapy-induced, 40–41 female, 40 male, 41 Sexuality/intimacy after cancer conceptual framework for, 591–598 Basson’s integrated model of sexual response in, 592f common questions of survivors about sex in, 597t elements of biopsychosocial model in, 596f individual coping response in, 597f modulation of coping in couples in, 598f neurobiology of sexual response in, 591f sexual tipping point in, 598f treatment-associated with sexual difficulties in, 594t interventions for, 602–612 bupropion, 610 counseling, 603–606, 603t, 604t education, 603–606, 603t, 604t erectile dysfunction therapies, 610 female cancer survivors, 606–607, 609 hormonal therapies, 606–608 investigational medications of promise, 610

651

index Sexuality/intimacy after cancer (Continued) lifestyle change interventions, 603–606, 603t, 604t male cancer survivors, 607–609, 608t mechanical devices, 611 nonhormonal therapies, 608–610 pelvic floor physical therapy, 611 pharmacologic interventions, 606–610 phosphodiesterase inhibitors, 608–609 prostaglandin E1 agonists, 609–610 strategies to minimize antidepressantinduced dysfunction, 610 surgeries, 611–612 vaginal dilators, 611 predictors of difficulties with, 598–602 laboratory testing for, 601–602 other testing for, 601–602 physical examination for, 601, 602t taking sexual history for, 599, 600t prevalence of, 598–602 when/whom to refer for, 612 Shunt peritoneovenous, 366 pleural effusions management with, 357 Silicone stents, 320–321, 321f SJS. See Stevens Johnson syndrome Skeletal metastases, 249–255, 250f, 251f clinical studies with denosumab for, 252–255 treatment of bone metastases, 254 treatment of breast cancer, 253, 253f, 254f, 254t treatment of multiple myeloma, 254 treatment of solid tumors, 254 development of antibodies against RANKL, 251–252, 252f imaging of, 127 Skeletal muscle loss, 154–156, 155f Skin care, last days of life pain with, 402 late effects of chemotherapy/radiation with, 432 radiotherapy-induced adverse events for, 36 management of, 36 pathophysiology of, 36 symptoms of, 36 testing, allergic reaction prevention with, 13 Sleep apnea, insomnia differential diagnosis with, 192–193 Sleep hygiene, insomnia management with, 197 Sleep restriction, insomnia management with, 195–196 Sleep-related movement disorders, 193 Slight hyposalivation, 238 Softening laxatives bulk-forming agents, 183 chloride channel activators, 183 constipation treatment with, 182–184 macrogols, 183 osmotic agents, 182–183 surfactants, 183 Somatic pain pathways, cancer pain with, 124f Somnolence syndrome, radiotherapy-induced, 37 Sorafenib cardiotoxicity with, 70t heart failure with, 71t, 72 hypertension associated with, 76 Soy, hot flashes management with, 227 Spinal cord compression bone metastases with, 293, 300–304 combined radiotherapy and surgery for, 302–303, 303f, 303t combined radiotherapy/surgery v. radiotherapy alone for, 304 outcomes for, 304–306, 305f, 305t multidisciplinary opinion for management for, 306 652 supportive measures for, 306

Spinal cord compression (Continued) radiotherapy dose fractionation for, 302–303, 304t radiotherapy for, 301–302 surgery for, 301, 302f Spiritual healing, 465t, 468–469 background on, 469 clinical evidence for, 469 definition of, 468 Spirituality definition/discourse of, 521–522 providing spiritual care, 524–525 spiritual assessment, 522–523 spiritual care interventions, 523–524 SPS. See Stiff person syndrome SSRI. See Selective serotonin reuptake inhibitors Staged subcutaneous excision, lymphedema management with, 217t, 218 Standard infusion reaction. See Allergic reactions, chemotherapy Starvation, cachexia v., 151t Static compression, lymphedema management with, 215–216, 215t Stellate ganglion block, hot flashes management with, 228 Stem cell therapy, xerostomia management with, 239 Stents. See also Airway stents colorectal, 335–336, 337t, 338f palliative treatment using colorectal obstruction with, 379–380, 379f distal obstruction with, 377–378, 377f echoendoscopically guided hepaticogastrostomy for biliary drainage with, 378, 379f endoscopic retrograde cholangiopancreatography with, 377 esophageal cancer with, 375–376, 376f gastric outlet obstruction with, 376, 376f malignant bile duct obstruction with, 377 pancreatic cancer with, 377f proximal biliary obstruction, 378, 378f Stereotactic spinal radiotherapy, compression fractures with, 299–300, 301f Steroid-induced myopathy, neuromuscular complications of cancer with, 286 Steroids chemotherapy extravasations management with, 6 CINV treated with, 19, 21t recommended dose for, 21t Stevens Johnson syndrome (SJS), 118–119 Stiff person syndrome (SPS), 288t, 289 Stimulant laxatives, constipation treatment with, 182 Stimulus control therapy, insomnia management with, 195 Stomach, radiotherapy-induced adverse events for, 39 management of, 39 symptoms of, 39 Stool formation, constipation diagnosis with, 178, 178f Streptozocin cisplatin nephrotoxicity with treatment using, 47 irritation with extravasation of, 3t Streptozotocin, emetogenic risk with, 19t Submandibular gland, surgical transfer of, 236 Substance abuse addiction with, 568 assessment of, 571–572, 572t cancer pain v. nonmedical users, 570–571 cancer pain patients, 570–571, 571f nonmedical users, 571 clinical issues with, 569–570

Substance abuse (Continued) aberrant drug-related behaviors, 569–570, 569t comorbid psychiatric disorders, 569 drugs in medically ill populations, 569–570, 570f primary or secondary abuse, 570 dependence with, 568 errors in labeling with, 569 physical dependence with, 568–569 prevalence with, 567–568 tolerance with, 568 treatment modalities for, 572–573 pharmacologic approach, 573, 573t psychotherapeutic approach, 572–573 Substance P, CINV with, 17 Suction-assisted lipectomy (SAL), 217t, 218 Sulfonamides, itch caused by, 206t Sulfonylureas, itch caused by, 206t Sunitinib cardiotoxicity with, 70t emetic risk with, 20t heart failure with, 71t, 72 hypertension associated with, 76 Superior vena cava syndrome, supportive interventions for, 382–383, 383f Supportive counseling, 557–558 bereavement support with, 630 Supportive oncology airway obstruction treatment in, 384 ascites treatment in, 384 bone metastases treatment in, 388, 388f chest treatment in, 382 complementary therapies for acupuncture, 465–466, 465t aromatherapy, 465t, 466 herbal medicine, 465t, 466–467 homeopathy, 465t, 467 hypnotherapy, 465t, 467 imagery, 465t, 467 massage, 465t, 467–468 music therapy, 465t, 468 reflexology, 465t, 468 relaxation therapy, 465t, 468 spiritual healing, 465t, 468–469 tai chi, 465t, 469 cytoreduction treatment in, 384–385, 385f exercise interventions for breast cancer with, 417 cancer survivors behavior change for, 422–425 clinical implications for, 421–422 colorectal cancer with, 417–418 disease endpoints with, 420–422, 421f future directions in, 425–426 lung cancer with, 418–420 lymphoma cancer with, 418, 420f other cancers with, 420 physical activity motivation for, 422–425 physical activity's effects on outcomes with, 415–417 prostate cancer with, 418, 419t gastrointestinal obstruction treatment in enteral stent placement, 386–387 enteral tube placement for malnutrition, 386 genitourinary hemorrhage treatment in, 387 hemoptysis treatment in, 382, 383f hepatobiliary cancer treatment in, 384 hydronephrosis treatment in, 387 lung cancer treatment in, 383–384 obstruction treatment in, 386 pancreatic cancer pain treatment in, 386 pleural disease treatment in, 384 psychotherapy for, 555–557 spirituality in definition/discourse of, 521–522 providing spiritual care, 524–525

Index Supportive oncology (Continued) spiritual assessment, 522–523 spiritual care interventions, 523–524 superior vena cava syndrome treatment in, 382–383, 383f Supportive-expressive group therapy (SEGT), 557–558 Suramin itch caused by, 206t neuromuscular complications of cancer with, 286t, 287 Surfactants, 183 Surgery related neuropathy, 285 Symptomatic epilepsy, radiotherapy-induced, 37 Synaptic nociceptive receptors, cancer pain with, 123f Systemic edema, 214t

T

Tai chi, 465t, 469 background on, 469 clinical evidence for, 469 definition of, 469 Tamoxifen, cardiotoxicity with, 70t Tamoxifen inhibitors, arterial thromboembolism with, 79 Taxanes arrhythmias with, 80 cardiotoxicity with, 70t neuromuscular complications of cancer with, 286t, 287 neurotoxicity with, 59–60 pulmonary complications with, 312 TCA. See Tricyclic/heterocyclic antidepressants TCP score. See Terminal Cancer Prognostic score Teicoplanin, dosage for, 28t Temozolomide emetic risk with, 20t emetogenic risk with, 19t TEN. See Toxic epidermal necrolysis Teniposide emetogenic risk with, 19t irritation with extravasation of, 3t Terminal agitation, last days of life pain with, 403, 403t Terminal Cancer Prognostic score (TCP score), 481 Thalidomide cardiotoxicity with, 70t emetic risk with, 20t neuromuscular complications of cancer with, 286t, 287 thromboembolism with, 77 Therapeutic paracentesis, ascites management with, 365–366 Thermoregulatory zone, 222 Thiotepa emetogenic risk with, 19t inflammation risk with extravasation of, 3t Thoracentesis, pleural effusions management with, 355–356 Thromboembolism, arterial, cardiotoxicity with, 79 aromatase inhibitors, 79 bexarotene, 79 lipids, 79 retinoids, 79 tamoxifen inhibitors, 79 Thromboembolism, arterial and venous, cardiotoxicity with, 76–79 bevacizumab, 77 cisplatin, 77 diagnosis of, 78–79 immunomodulating agents, 77–78 lenalidomide, 77 pomalidomide, 77

Thromboembolism, arterial and venous, cardiotoxicity with (Continued) thalidomide, 77 treatment of, 78–79 VEGF, 78 Thromboembolism, venous, cardiotoxicity with diagnosis of, 78 prevention of, 78 treatment of, 79 Thrombophlebitis, 4 Thrombosis, cancer with, 274–281. See also Venous thromboembolism anticoagulation in patients with, 280–281 central venous catheter–related, 280 diagnosis of, 277–278, 279f epidemiology of, 276–278 LMWH and tumor progression with, 280 pathophysiology of, 274–276 host cells interaction in, 275 microparticles in, 275–276 pathways in myeloma in, 276 procoagulant activity of tumor cells in, 275, 275f risk assessment for, 276–278, 276t biomarkers in, 276–277 cancer-associated risk factors in, 276, 276t patient-associated risk factors in, 276 risk assessment model in, 277, 277t treatment-associated risk factors in, 276–277, 277t TKI. See Tyrosine kinase inhibitor Tobramycin dosage for, 28t serum concentrations target for, 30t Tolerance, 568 Topoisomerase agents, role in secondary cancers of, 458 Topotecan, emetogenic risk with, 19t Topotecan, inflammation risk with extravasation of, 3t Toronto Symptom Assessment System for Wounds (TSAS-W), 343, 345f Tositumomab, cardiotoxicity with, 70t Toxic epidermal necrolysis (TEN), 118–119 Trabectedin emetogenic risk with, 19t irritation with extravasation of, 3t Transmembrane receptor inhibitors heart failure with, 72 hypertension associated with, 76 Trastuzumab cardiotoxicity with, 70t emetogenic risk with, 19t heart failure associated with, 71t inflammation risk with extravasation of, 3t Trauma, pericardial effusion caused by, 357t Treatment options curative to palliative care transition discussion guidance, 501b defined, 501 factors affecting patient involvement, 505–506 clinician factors, 506 context, 505 cultural factors, 506 disease, 505 patient factors, 505–506 system factors, 505 measuring outcomes v. measuring process with, 507 patients’ recall of decision making, 507 preparing patients for cancer consultation, 508–509 consultation planning/coaching, 509 decision support tools, 509, 510t question prompt lists, 508–509, 509b shared decision making in, 502–504

Treatment options (Continued) benefits of, 503–504 competencies of patients for Informed, 504b, 505b current debate around, 503 doctors support of, 507–508, 508t improvement in discussion about treatment with, 504 measuring, 506–507 skills and competences required to practice, 504, 504b use by doctors of, 506 steps reach cancer care decision, 501–509 doctors’ acknowledgment of options, 502 involving patients in decisions, 504–505 patient awareness of choice, 502 patient information preferences, 504 patient involvement preferences, 505 recommendation: doctor's perspective, 502, 502b tools to monitor patient involvement, 504b, 506–507, 507f, 507t strategies to enhance discussion of, 508 what constitutes, 501 Treatment–induced osteoporosis bone metabolism with, 438–439 hormones' stimulating effect on in, 438 loss of bone mineral density in, 438, 439f osteoclasts and osteoblasts in, 438, 439f risk factors for osteoporosis in, 439t total estrogen deprivation with, 440–442, 441f anastrozole in, 440–441, 441f exemestane in, 441f, 442 letrozole in, 441–442, 441f treatment options for, 442–446, 442t antibodies against RANKL, 444, 445f bisphosphonates, 442–443, 442f, 443f candidates selection for, 443–444, 444f denosumab, 444–446, 445f, 446f prophylaxis, 442–443, 442f, 443f tumor/tumor treatment with, 439–440, 440f, 440t Treatment-related anxiety, pharmacologic interventions for, 537 Treatment-related hypogonadism, 440t Treosulfan emetogenic risk with, 19t irritation with extravasation of, 3t Tricyclic/heterocyclic antidepressants (TCA), depression intervention with, 536 Trigeminal trophic syndrome (TTS), 205 Tropisetron pharmacokinetics of, 261t recommended dose for, 21t TSAS-W. See Toronto Symptom Assessment System for Wounds TTS. See Trigeminal trophic syndrome Tuberculosis, pericardial effusion caused by, 357t Tumor lysis syndrome cardiotoxicity with, 81 diagnosis of, 81 supportive oncology for, 81 treatment of, 81 Tumors, radiation-induced nerve, 285 Tyrosine kinase inhibitor (TKI) cardiotoxicity with, 70t heart failure with, 72 hypertension associated with, 76

U

Unfractionated heparin, VTE prevention with, 278 Uremic pruritus, 204 Urinary tract, late effects of chemotherapy/ radiation with, 433

653

index V

Vancomycin dosage for, 28t serum concentrations target for, 30t VAS. See Visual analog scale Vascular endothelial growth factor (VEGF) cisplatin nephrotoxicity with treatment using inhibition if, 46 diagnostic features with, 46 thromboembolism with, 78 treatment strategies with, 46 Vasculitic neuropathy, 288t, 289–290 VATS. See Video-assisted thoracic surgery VEGF. See Vascular endothelial growth factor Venlafaxine, hot flashes management with, 224 Venous access systems infectious complications with, 371–373 blood cultures in diagnosis of, 372 diagnosis of, 372 epidemiology of, 371 management of, 372–373 microbiological diagnosis after catheter removal, 372 pathogens of, 371–372 prophylaxis of, 373 risk factors for, 371 mechanical complications with, 369–370, 370f thrombotic complications with, 370–371 Venous stasis, 214t Venous thromboembolism (VTE), 274–281 diagnosis of, 78, 277–278, 279f epidemiology of, 276–278 incidence of symptomatic, 277t pathophysiology of, 274–276 host cells interaction in, 275 microparticles in, 275–276 pathways in myeloma in, 276 procoagulant activity of tumor cells in, 275, 275f prevention of, 78, 278–279 fondaparinux in, 279 low-molecular-weight heparins in, 278 mechanical prophylaxis in, 279 new molecules in, 279 recommendations for, 279 unfractionated heparin in, 278 vitamin K antagonists in, 279 risk assessment for, 276–278, 276t biomarkers in, 276–277 cancer-associated risk factors in, 276, 276t patient-associated risk factors in, 276 risk assessment model in, 277, 277t treatment-associated risk factors in, 276–277, 277t treatment of, 79, 279–280 inferior vena cava filters, 280 initial treatment, 279–280, 280t long-term treatment, 280 recommendations for, 280 Venting gastrostomy, malignant bowel obstruction treatment with, 335, 336t Vertebral augmentation, compression fractures with, 297–299, 299f, 300f Vertebral fracture bone metastases with, 293 risk assessment for bone metastases, 295, 295f Vertebral metastases complications compression fractures, 297–300, 298f radiotherapy for, 299 stereotactic spinal radiotherapy, 299–300, 301f surgery for, 299 vertebral augmentation for, 297–299, 299f, 300f spinal cord compression, 300–304 654

Vertebral metastases complications (Continued) combined radiotherapy and surgery for, 302–303, 303f, 303t combined radiotherapy/surgery v. radiotherapy alone for, 304 radiotherapy dose fractionation for, 302–303, 304t radiotherapy for, 301–302 surgery for, 301, 302f Video-assisted thoracic surgery (VATS), pleural effusions management with, 356 Vinblastine, ulceration with extravasation of, 3t Vinca alkaloids cardiotoxicity with, 70t, 74 extravasation of, 5 neuromuscular complications of cancer with, 286, 286t neurotoxicity with, 58 Vincristine neurotoxicity with, 58, 58f ulceration with extravasation of, 3t Vindesin, ulceration with extravasation of, 3t Vinflunin, ulceration with extravasation of, 3t Vinflunine, cardiotoxicity with, 70t Vinorelbine emetic risk with, 20t ulceration with extravasation of, 3t Visceral pain, 125, 125f Visual analog scale (VAS), 178 Vitamin B complex, itch caused by, 206t Vitamin E hot flashes management with, 226–227 neurotoxicity treatment with, 63–64 Vitamin K antagonists (VKA), VTE prevention with, 279 VKA. See Vitamin K antagonists Vomiting. See also Chemotherapy-induced nausea and vomiting anticholinergic for, 334 antiemetics for, 334 assessment of, 260–261, 261t barriers to, 260 outcomes to, 260–261 symptom clusters, 261 causes of, 259, 260t characteristics of, 259 corticosteroids for, 334 definitions in advanced cancer of, 258–259 drugs for treating, 263–267 5-HT3 receptor antagonists, 264–265 antihistaminic agents, 266 benzodiazepines, 267 cannabinoids, 267 corticosteroids, 266–267 cyclizine, 266 dopamine receptor antagonists, 265–266 hyoscyamine, 267 marijuana, 267 neurokinin-1 antagonists (NK-1 antagonists), 267 novel prokinetic agents, 267 octreotide, 267 prokinetic agents, 263 promethazine, 266 endoscopic techniques for, 269 gastric electrical stimulation for, 269–270 gastrointestinal stenting for, 269 incidence of, 259 malignant bowel obstruction treatment with, 333–334 nonsurgical procedures for, 268–270 octreotide for, 333 other modes of nausea control for, 268–270 PEG tubes for, 268–269 pharmacologic approaches to, 261–267

Vomiting. See also Chemotherapy-induced nausea and vomiting (Continued) mechanistic v. empirical, 261–262 receptor site affinities of antiemetics in, 262t prevalence of, 259 prokinetic agents for, 263, 334 efficacy for advanced cancer of, 263 pharmacology of, 261t, 263 proton pump inhibitors for, 334 radiotherapy-induced, 35, 41t Voriconazole, dosage for, 30t VTE. See Venous thromboembolism

W

WAO. See World Allergy Organization Warfarin, itch caused by, 206t WEMR. See Wound electronic medical records World Allergy Organization (WAO), 10–11 World Health Organization (WHO), mucositis assessment scale by, 109, 109b Wound electronic medical records (WEMR), 343 Wounds assessment of, 343 Electronic medical records in, 343 European Pressure Ulcer Advisory Panel in, 343 Global Wound Distress Score in, 343 National Pressure Ulcer Advisory Panel in, 343, 344t Toronto Symptom Assessment System for Wounds in, 343, 345f wound electronic medical records in, 343 chronic, 342 malignant, 343–349 bleeding with, 348 cosmetic/esthetic concerns with, 348 drainage/exudation of, 348 elements of, 346t epidemiology of, 343–344 itching with, 348 management of, 346 odor with, 348 pain with, 347–348 pathophysiology of, 343–344 prevention of, 346 prognosis for, 348–349 wound palliation with, 347–348 management, 343 palliation, 343, 347–348 pressure ulcers, 349–351 epidemiology of, 349, 349f management of, 350–351, 350f pathophysiology of, 349, 349f prevention of, 349–350 prognosis for, 351

X

Xerosis. See Dry skin Xerostomia CACS with, 160 clinical examination of, 233–235 angular cheilitis, 233, 235f cracked lips, 233, 233f dental decay, 233, 234f dry surface of dorsum of tongue, 233, 233f dry/pale buccal mucosa, 233, 233f hyperkeratinized buccal mucosa, 233, 233f hyposalivation-related dental caries, 234f oral candidiasis, 233, 234f, 235f management of radiation-induced, 237–239 acupuncture in, 238 electrostimulation in, 238

Index Xerostomia (Continued) gene therapy in, 239 gustatory stimulant in, 237, 237t healing injury to salivary gland tissue in, 239 hyperbaric oxygen treatment in, 238 insufficient effect of stimulation in, 238 new radiation techniques in, 239 pharmacologic sialagogues in, 237, 237t stem cell therapy in, 239 stimulation of residual function in, 237–238 tactile stimulant in, 237, 237t prevention of, 235–237 can radiation injury be reduced?, 235–237, 235f

Xerostomia (Continued) intensity-modulated radiotherapy in, 235–236 radiation injury to salivary gland tissue, 235–237 radiation injury reduction strategies for, 235–237 IGF-1 and KGF pretreatment, 237 pilocarpine during radiotherapy, 236–237 radioprotection, 236 surgical transfer of submandibular gland, 236 symptoms of, 232–233 treatment of, 235–237 treatment recommendations for, 238 moderate hyposalivation, 238 severe hyposalivation, 238 slight hyposalivation, 238

X-rays of the abdomen, malignant bowel obstruction diagnosis with, 329, 329f

Z

Zoledronate adverse events with, 254t bone metastases treatment with, 246–248, 247f, 248f diarrhea with, 249t necrosis with, 249t ONJ with, 249, 249t side effects of, 249t Zoledronic acid, bone mineral density (BMD), 443f

655