Skeel’s Handbook of Cancer Therapy [9th ed.] 9781496305558

Table of contents :
Title Page......Page 3
Copyright......Page 4
Dedication......Page 5
Contributors......Page 6
Preface......Page 18
Contents......Page 20
1. Biologic and Pharmacologic Basis of Cancer Chemotherapy......Page 23
2. Biologic Basis of Molecular Targeted Therapy......Page 38
3. Principles of Cancer Immunotherapy......Page 81
4. Systematic Assessment of the Patient With Cancer and Consequences of Treatment......Page 96
5. Selection of Treatment for the Patient With Cancer......Page 113
6. Carcinomas of the Head and Neck......Page 119
7. Carcinoma of the Lung......Page 140
8. Carcinomas of the Gastrointestinal Tract......Page 173
9. Carcinomas of the Pancreas, Liver, Gallbladder, and Bile Ducts......Page 211
10. Carcinoma of the Breast......Page 237
11. Gynecologic Cancer......Page 272
12. Urologic and Male Genital Cancers......Page 314
13. Kidney Cancer......Page 335
14. Endocrine Cancers......Page 350
15. Melanomas and Other Cutaneous Malignancies......Page 371
16. Primary and Metastatic Brain Tumors......Page 398
17. Soft-Tissue Sarcomas......Page 419
18. Bone Sarcomas......Page 434
19. Acute Leukemias......Page 449
20. Chronic Leukemias......Page 501
21. Myeloproliferative Neoplasms and Myelodysplastic Syndromes......Page 530
22. Hodgkin Lymphoma......Page 563
23. Non-Hodgkin Lymphoma......Page 577
24. Multiple Myeloma, Other Plasma Cell Disorders, and Primary Amyloidosis......Page 619
25. Metastatic Cancer of Unknown Origin......Page 649
26. Side Effects of Chemotherapy......Page 656
27. Side Effects of Immune Therapy......Page 681
28. Classification, Use, and Toxicity of Clinically Useful Chemotherapy and Molecular Targeted Therapy......Page 691
Index......Page 874

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NINTH EDITION

Skeel’s Handbook of Cancer Therapy Samir N. Khleif, MD Director Georgia Cancer Center Immuno-Oncology Therapeutics Program Professor of Medicine Professor of Biochemistry and Molecular Biology Medical College of Georgia Professor of Graduate Studies Augusta University Augusta, Georgia

Olivier Rixe, MD, PhD Professor Division of Hematology-Oncology The Dana Wood Endowed Chair in Cancer Therapeutics and Early Phase Clinical Research University of New Mexico Comprehensive Cancer Center Albuquerque, New Mexico

Roland T. Skeel, MD Professor and Interim Chair Department of Medicine Division of Hematology-Oncology University of Toledo College of Medicine and Life Sciences Attending Physician University of Toledo Medical Center Toledo, Ohio

Acquisitions Editor: Julie Goolsby Senior Product Development Editor: Emilie Moyer Senior Editorial Assistant: Brian Convery Production Project Manager: Priscilla Crater Design Coordinator: Holly McLaughlin Manufacturing Coordinator: Beth Welsh Marketing Manager: Rachel Mante Leung Prepress Vendor: S4Carlisle Publishing Services Ninth Edition Copyright © 2016 Wolters Kluwer. Copyright © 2011 Wolters Kluwer Health / Lippincott Williams & Wilkins. Copyright © 2007 Lippincott Williams & Wilkins, a Wolters Kluwer business. Copyright © 2003, 1999 by Lippincott Williams & Wilkins. Copyright © 1995 by Lippincott-Raven Publishers. Copyright © 1991, 1987, 1982 by Little, Brown & Company. Previously titled “Handbook of Cancer Chemotherapy” edited by Roland T. Skeel, All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at [email protected], or via our website at lww.com (products and services). 9 8 7 6 5 4 3 2 1 Library of Congress Cataloging-in-Publication Data Names: Khleif, Samir N., editor. | Rixe, Olivier, editor. | Skeel, Roland T., editor. Title: Skeel’s handbook of cancer therapy/[edited by] Samir N. Khleif, Olivier Rixe, Roland T. Skeel. Other titles: Handbook of cancer chemotherapy. Description: Ninth edition. | Philadelphia: Wolters Kluwer Health, 2016. | Preceded by Handbook of cancer chemotherapy/edited by Roland T. Skeel, Samir N. Khleif. Eighth edition. 2011. | Includes bibliographical references and index. Identifiers: LCCN 2015051073 | 9781496305558 | 9781496353399 Subjects: | MESH: Neoplasms—therapy | Antineoplastic Agents—administration & dosage | Handbooks Classification: LCC RC271.C5 | NLM QZ 39 | DDC 616.99/4061—dc23 LC record available at http://lccn.loc.gov/2015051073 This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any warranties as to accuracy, comprehensiveness, or currency of the content of this work. This work is no substitute for individual patient assessment based on healthcare professionals’ examination of each patient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data, and other factors unique to the patient. The publisher does not provide medical advice or guidance, and this work is merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this work, including all medical judgments, and for any resulting diagnosis and treatments. Given continuous, rapid advances in medical science and health information, independent professional verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made, and healthcare professionals should consult a variety of sources. When prescribing medication, healthcare professionals are advised to consult the product information sheet (the manufacturer’s package insert) accompanying each drug to verify, among other things, conditions of use, warnings, and side effects and identify any changes in dosage schedule or contraindications, particularly if the medication to be administered is new, infrequently used, or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work. LWW.com

To May, Zein, Noor, and Farah (SK) To Sophie, Lea, Jeanne, Martin, and Eliott (OR) and Kristie, Joy, Kristi, Erika, Brian, Josh, Ali, and Jessica (RS) and to all our patients.

CONTRIBUTORS

Olivia Bally, MD Associate Professor Department of Medical Oncology Centre Léon Bérard Université Claude Bernard Lyon I Lyon, France

Rachid Baz, MD Associate Member Department of Malignant Hematology H. Lee Moffitt Cancer Center and Research Institute Associate Professor Department of Oncologic Sciences University of South Florida Tampa, Florida

Al B. Benson III, MD Professor of Medicine Division of Hematology-Oncology Associate Director for Cooperative Groups Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago, Illinois

Michael J. Birrer, MD, PhD Professor Department of Medicine Harvard Medical School Physician Division of Hematology-Oncology Massachusetts General Hospital Boston, Massachusetts

Jean-Yves Blay, MD, PhD Professor of Medicine Department of Medical Oncology

Centre Léon Bérard Université Claude Bernard Lyon 1 Lyon, France

Jad Chahoud, MD Resident Physician Department of Internal Medicine The University of Texas Health Science Center at Houston McGovern Medical School Houston, Texas

Shruti Chaturvedi, MBBS Clinical Fellow Vanderbilt University Nashville, Tennessee

Bruce D. Cheson, MD, FACP, FAAAS, FASCO Professor of Medicine and Deputy Chief Division of Hematology-Oncology Head of Hematology Georgetown University Hospital Lombardi Comprehensive Cancer Center Washington, District of Columbia

Muhammad O. Chohan, MD Director Neurosurgical Oncology Department of Neurosurgery Co-leader Neuro-Oncology Multidisciplinary Program University of New Mexico Comprehensive Cancer Center Albuquerque, New Mexico

Jean-Michel Coindre, MD Professor Department of Pathology Institut Bergonié Bordeaux, France

Marcela G. del Carmen, MD, MPH Professor Division of Gynecologic Oncology Department of Obstetrics and Gynecology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts

Jaydira del Rivero, MD Medical Oncology Fellow Adult Clinical Endocrinology National Cancer Institute National Institutes of Health Bethesda, Maryland

Don S. Dizon, MD, FACP Associate Professor of Medicine Harvard Medical School Clinical Co-Director Gynecologic Oncology Director The Oncology Sexual Health Clinica Massachusetts General Hospital Cancer Center Boston, Massachusetts

Robert Dreicer, MD, MS, FACP, FASCO Section Head Medical Oncology Deputy Director University of Virginia Cancer Center Associate Director for Clinical Research Professor of Medicine and Urology University of Virginia School of Medicine Charlottesville, Virginia

Robert A. Figlin, MD, FACP Professor of Medicine and Biomedical Sciences Steven Spielberg Family Chair in Hematology Oncology Director Division of Hematology-Oncology

Deputy Director, Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center Los Angeles, California

Antonio Tito Fojo, MD, PhD Medical Oncology Branch and Affiliates Head Experimental Therapeutics Section Senior Investigator Center for Cancer Research National Cancer Institute Bethesda, Maryland

Olga Frankfurt, MD Associate Professor in Medicine Division of Hematology-Oncology Northwestern University Feinberg School of Medicine Chicago, Illinois

Gregory N. Gan, MD, PhD Assistant Professor Director of Basic Research in Radiation Oncology Division of Medical Oncology Section of Radiation Oncology University of New Mexico Comprehensive Cancer Center Albuquerque, New Mexico

Guillermo Garcia-Manero, MD Professor Chief Section of MDS Deputy Chair Translational Research Department of Leukemia The University of Texas MD Anderson Cancer Center Houston, Texas

David E. Gerber, MD Associate Professor Division of Hematology-Oncology Department of Internal Medicine

Harold C. Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center Dallas, Texas

David M.J. Hoffman, MD, FACP Associate Clinical Professor of Medicine University of California Clinical Associate Professor of Medicine Cedars Sinai Medical Center Los Angeles, California

Clifford A. Hudis, MD, FACP Chief Breast Medicine Service Department of Medicine Vice President for Government Relations and Chief Advocacy Officer Memorial Sloan Kettering Cancer Center Professor of Medicine Weill Cornell Medical College New York, New York

Mohamad A. Hussein, MD, MB, BCh Professor of Medicine and Oncology University of South Florida Morsani College of Medicine Tampa, Florida

Elias Jabbour, MD Associate Professor Department of Leukemia The University of Texas MD Anderson Cancer Center Houston, Texas

John E. Janik, MD Director Immune Therapy Clinical Trials Program Leader Melanoma Multi-Disciplinary Clinic Professor of Medicine Georgia Cancer Center Augusta University

Augusta, Georgia

Hagop M. Kantarjian, MD Professor Department of Leukemia Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, Texas

Timothy J. Kennedy, MD, MBA Associate Professor Department of Surgery Rutgers Cancer Institute of New Jersey Chief of Gastrointestinal Surgical Oncology Rutgers Cancer Institute of New Jersey Robert Wood Johnson Hospital New Brunswick, New Jersey

Samir N. Khleif, MD Director Georgia Cancer Center Immuno-Oncology Therapeutics Program Professor of Medicine Professor of Biochemistry and Molecular Biology Medical College of Georgia Professor of Graduate Studies Augusta University Augusta, Georgia

Sheetal M. Kircher, MD Assistant Professor in Medicine Division of Hematology-Oncology Northwestern University Feinberg School of Medicine Chicago, Illinois

Ashwin Kishtagari, MD Resident Department of Internal Medicine Mount Sinai St. Luke’s–Roosevelt Hospital New York, New York

Ragini Kudchadkar, MD Assistant Professor Division of Hematology-Oncology Winship Cancer Institute Emory University Atlanta, Georgia

Rekha A. Kumbla, MD Hematology-Oncology Fellow Division of Hematology-Oncology Samuel Oschin Comprehensive Cancer Cedars Sinai Medical Center Los Angeles, California

Paul R. Kunk, MD Hematology Oncology Fellow Division of Hematology Oncology Department of Medicine University of Virginia Health System Charlottesville, Virginia

Catherine Lai, MD, MPH Faculty Lymphoid Malignancies Branch Center for Cancer Research National Cancer Institute Bethesda, Maryland

Steven K. Libutti, MD, FACS Director Montefiore Einstein Center for Cancer Care Vice-Chairman Department of Surgery The Marvin L. Gliedman, MD Distinguished Surgeon Professor of Surgery and Genetics Montefiore Medical Center and Albert Einstein College of Medicine Bronx, New York

Christophe Massard, MD, PhD Medical Oncologist

Senior Consultant Department of Medical Oncology and Drug Development Department (DITEP) Head of Inpatient Unit (SITEP) Chairman of Early Drug Development Tumor Board Gustave Roussy Cancer Campus Villejuif, France

David S. Morgan, MD Associate Professor of Medicine Division of Hematology-Oncology Vanderbilt University Medical Center Nashville, Tennessee

Frank E. Mott, MD, FACP Professor of Medicine Division of Hematology-Oncology Georgia Cancer Center Augusta University Augusta, Georgia

Lorraine C. Pelosof, MD, PhD Assistant Professor Attending Physician Division of Hematology-Oncology University of Texas Southwestern Medical Center Dallas, Texas

Osama E. Rahma, MD Assistant Professor of Medicine Division of Hematology-Oncology Department of Medicine University of Virginia Health System Charlottesville, Virginia

J. Alejandro Rauh-Hain, MD Instructor Division of Gynecologic Oncology Vincent Obstetrics and Gynecology Massachusetts General Hospital Harvard Medical School

Boston, Massachusetts

Olivier Rixe, MD, PhD Professor Division of Hematology-Oncology The Dana Wood Endowed Chair in Cancer Therapeutics and Early Phase Clinical Research University of New Mexico Comprehensive Cancer Center Albuquerque, New Mexico

Mark Roschewski, MD Staff Clinician Lymphoid Malignancies Branch Center for Cancer Research National Cancer Institute Bethesda, Maryland

Ibrahim Ebada Sadek, MD Second Year Fellow Division of Hematology-Oncology Augusta University Augusta, Georgia

Joan H. Schiller, MD Professor and Chief Division of Hematology-Oncology Harold C. Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center Dallas, Texas

Josh David Simmons, MD Hematology/Oncology Fellow Department of Internal Medicine Division of Hematology-Oncology Medical College of Georgia Georgia Regents University Augusta, Georgia

Roland T. Skeel, MD Professor and Interim Chair Department of Medicine

Division of Hematology-Oncology University of Toledo College of Medicine and Life Sciences Attending Physician University of Toledo Medical Center Toledo, Ohio

Lillian M. Smyth, MD Advanced Medical Oncology Fellow Breast Medicine Service Memorial Sloan Kettering Cancer Center New York, New York

Mario Sznol, MD Professor Section of Medical Oncology Department of Internal Medicine Yale University Yale–New Haven Hospital New Haven, Connecticut

Martin S. Tallman, MD Chief of Leukemia Service Memorial Sloan Kettering Cancer Center Professor of Medicine Weill Cornell Medical College New York, New York

Janelle M. Tipton, MSN, RN, AOCN Oncology Clinical Nurse Specialist Infusion Center Director Eleanor N. Dana Cancer Center University of Toledo Medical Center Volunteer Faculty Colleges of Medicine and Nursing University of Toledo Toledo, Ohio

Anis Toumeh, MD Medical Oncologist Central Care Cancer Center

Attending Physician Southwest Medial Center Liberal, Kansas

Chaitra Ujjani, MD Assistant Professor Division of Hematology-Oncology Department of Medicine Lombardi Comprehensive Cancer Center Medstar Georgetown University Hospital Washington, District of Columbia

Srdan Verstovsek, MD, PhD Professor of Medicine Director Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms Department of Leukemia The University of Texas MD Anderson Cancer Center Houston, Texas

Jeffrey S. Weber, MD, PhD Deputy Director Laura and Isaac Perlmutter Cancer Center Professor of Medicine New York University Langone Medical Center New York, New York

Wyndham H. Wilson, MD, PhD Senior Investigator Lymphoid Malignancies Branch Head Lymphoma Therapeutics Section National Institutes of Health National Cancer Institute Bethesda, Maryland

Jessica Yarber, MD Hematology and Oncology Fellow Division of Hematology-Oncology McGaw Medical Center of Northwestern University

Chicago, Illinois

PREFACE

Since the last edition of this book, many new significant advances have occurred in the systemic treatment of cancer, and they have occurred at a pace that has never been seen since 1982, when this Handbook was first published. This has led to major additions to the book and some changes to the way information is being presented. The recent immunotherapy revolution and the advances in oncology genomics and in molecular targeted therapy are reflected in this current edition in both the general sections and the disease-specific chapters. The rapid expansion of these new agents has resulted from the explosion of biologic insights into the etiology and behavior of cancer that have taken place over the last quarter century. These drugs have clearly changed the face of cancer treatment and are rapidly becoming integrated into cancer therapeutics and treatment strategies for many cancers. Because of the importance of this new class of agents, we have added a new chapter entitled “Biologic Basis of Molecular Targeted Therapy.” In this chapter, we give a brief overview of the molecular basis for the activity of these agents and the relevant pathways they target in order to provide the reader with the basic knowledge and understanding of the rationale for the use of such agents in the treatment of cancer. These major developments in the field of oncology, as reflected in the book, led us to change the name from Handbook of Cancer Chemotherapy to Handbook of Cancer Therapy. This book has been one of the leading handbooks in cancer treatment for more than three decades and has been one of the best-selling books in its category. It has been translated into several languages and is used by all levels of physicians, nurses, and allied health professionals who provide care to cancer patients. The champion behind this great effort has been Dr. Roland T. Skeel. For over five decades, Roland has been one of the best and most skillful clinicians who have ever existed and, most importantly, is an amazingly compassionate human being. Dr. Skeel is a true professor and an incredible educator. The Handbook is an example of his commitment to disseminating the knowledge of oncology and the skills of healing art. In recognition of Dr. Skeel’s contributions, we decided to name this book, starting with its 9th edition, Skeel’s Handbook of Cancer Therapy. As with previous editions, several new authors have been added to keep the information fresh and timely. As done previously, primary indications, usual dosage and schedule, special precautions, and expected toxici-ties have been added for the new drugs and biologic agents that oncologists have begun to use in the past five years, and new data have been added to the information for many of the older agents. To facilitate easy access to this practical information, we have kept the section containing an alphabetical listing for all drugs used in practice at the end of the Handbook. In addition, each of the chapters dealing with specific cancer sites has been revised to reflect current best medical practice, including the use of molecular targeted therapy, and to point the way toward future advances.

Cure of cancer with less toxic systemic treatment has been a long-term aspiration for many people: those engaged in basic cancer research, physicians who are daily faced with anxious patients who have cancer, and others in the health profession. It has also been a fervent hope for patients and their families. Although cure is possible for some common tumors, particularly when there is only micrometastasis, and for some more advanced tumors such as lymphomas, for most patients chemotherapy remains palliative, at best. When curing and minimizing the cancer can no longer be achieved, then expert, compassionate supportive care becomes the essential and appropriate focus of the oncology team. The section on supportive care has been updated to highlight those issues and pharmacologic agents that are most essential to the daily care of patients with cancer. The Handbook continues to be a practical pocket or desk reference, with a wide range of information for oncology specialists, non oncology physicians, house officers, oncology nurses, pharmacists, and medical and pharmacy students. It can even be read and understood by many patients and their families who want to be able to find practical information about their cancer and its treatment. Unlike many other books, Skeel’s Handbook combines in one place the most current rationale and the specific details necessary to safely administer pharmacologic therapy for most adult cancer patients. Progress is always slower than patients, physicians, and basic scientists would like. Current research that joins the expertise and discoveries of the basic scientist, systematic investigation through clinical trials by the clinician, and their interaction in “translational” research continues to offer a realistic expectation of accelerated progress in the control of cancer in the decades ahead. Samir N. Khleif, MD Olivier Rixe, MD

CONTENTS

Contributors Preface SECTION I: BASIC PRINCIPLES AND CONSIDERATIONS OF RATIONAL CHEMOTHERAPY AND MOLECULAR TARGETED THERAPY 1 2 3 4 5

Biologic and Pharmacologic Basis of Cancer Chemotherapy Roland T. Skeel

Biologic Basis of Molecular Targeted Therapy Osama E. Rahma, Paul R. Kunk, and Samir N. Khleif

Principles of Cancer Immunotherapy Mario Sznol

Systematic Assessment of the Patient With Cancer and Consequences of Treatment Roland T. Skeel

Selection of Treatment for the Patient With Cancer Roland T. Skeel

SECTION II: MEDICAL THERAPIES OF HUMAN CANCER 6 7 8 9 10 11

Carcinomas of the Head and Neck Frank E. Mott, Ibrahim Ebada Sadek, and Josh David Simmons

Carcinoma of the Lung Lorraine C. Pelosof, David E. Gerber, and Joan H. Schiller

Carcinomas of the Gastrointestinal Tract Jessica Yarber, Sheetal M. Kircher, and Al B. Benson III

Carcinomas of the Pancreas, Liver, Gallbladder, and Bile Ducts Timothy J. Kennedy and Steven K. Libutti

Carcinoma of the Breast Lillian M. Smyth and Clifford A. Hudis

Gynecologic Cancer J. Alejandro Rauh-Hain, Marcela G. del Carmen, Don S. Dizon, and Michael J. Birrer

Urologic and Male Genital Cancers Robert Dreicer

12 13 14 15 16 17 18 19 20 21 22 23 24 25

Kidney Cancer David M.J. Hoffman, Rekha A. Kumbla, and Robert A. Figlin

Endocrine Cancers Jaydira del Rivero and Antonio Tito Fojo

Melanomas and Other Cutaneous Malignancies Ragini Kudchadkar and Jeffrey S. Weber

Primary and Metastatic Brain Tumors Muhammad O. Chohan, Gregory N. Gan, and Olivier Rixe

Soft-Tissue Sarcomas Jean-Yves Blay, Olivia Bally, and Jean-Michel Coindre

Bone Sarcomas Jean-Yves Blay and Olivia Bally

Acute Leukemias Ashwin Kishtagari, Olga Frankfurt, and Martin S. Tallman

Chronic Leukemias Chaitra Ujjani and Bruce D. Cheson

Myeloproliferative Neoplasms and Myelodysplastic Syndromes Jad Chahoud, Srdan Verstovsek, Guillermo Garcia-Manero, Hagop M. Kantarjian, and Elias Jabbour

Hodgkin Lymphoma Shruti Chaturvedi and David S. Morgan

Non-Hodgkin Lymphoma Catherine Lai, Mark Roschewski, and Wyndham H. Wilson

Multiple Myeloma, Other Plasma Cell Disorders, and Primary Amyloidosis Rachid Baz and Mohamad A. Hussein

Metastatic Cancer of Unknown Origin Christophe Massard

SECTION III: SUPPORTIVE CARE OF PATIENTS WITH CANCER 26 27

Side Effects of Chemotherapy Janelle M. Tipton

Side Effects of Immune Therapy John E. Janik

SECTION IV: CHEMOTHERAPEUTIC AND MOLECULAR TARGETED AGENTS

AND THEIR USE

28

Classification, Use, and Toxicity of Clinically Useful Chemotherapy and Molecular Targeted Therapy Anis Toumeh and Roland T. Skeel

Index

SECTION I: BASIC PRINCIPLES AND CONSIDERATIONS OF RATIONAL CHEMOTHERAPY AND MOLECULAR TARGETED THERAPY

I. GENERAL MECHANISMS BY WHICH CHEMOTHERAPEUTIC AGENTS CONTROL CANCER The purpose of treating cancer with chemotherapeutic agents, whether traditional or targeted, is to prevent cancer cells from multiplying, invading, metastasizing, and ultimately killing the patient. Most traditional chemotherapeutic agents appear to exert their effect primarily on cell proliferation. Because cell multiplication is a characteristic of many normal cells as well as cancer cells, most nontargeted cancer chemotherapeutic agents also have toxic effects on many normal cells, particularly those with a rapid rate of turnover, such as bone marrow and mucous membrane cells. The goal in selecting an effective drug in this category, therefore, is to find an agent that has a marked growthinhibitory or controlling effect on the cancer cell and a minimal toxic effect on the host. In the most effective chemotherapeutic regimens, the drugs are capable not only of inhibiting but also of completely eradicating all neoplastic cells while sufficiently preserving normal marrow and other target organs to permit the patient to return to normal, or at least satisfactory, function, duration, and quality of life. Inhibition of cell multiplication and tumor growth can take place at several levels within the cell and its environment: ■ Macromolecular synthesis and function ■ Cytoplasmic organization and signal transduction ■ Cell membrane and associated cell surface receptor synthesis, expression, and function ■ Environment of cancer cell growth A. Classic chemotherapy agents Most traditional chemotherapy agents (not including immunotherapeutic agents, other biologic response modifiers, and molecular targeted therapies) appear to have their

primary effect on either macromolecular synthesis or its function.1 This effect means that they interfere with the synthesis of DNA, RNA, or proteins or with the appropriate functioning of the preformed molecule. When interference in macromolecular synthesis or function in the neoplastic cell population is sufficiently great, a proportion of the cells die. Some cells die because of the direct effect of the chemotherapeutic agent. In other instances, the chemotherapy may trigger differentiation, senescence, or apoptosis, the cell’s own mechanism of programmed death. Cell death may or may not take place at the time of exposure to the drug. Often, a cell must undergo several divisions before the lethal event that took place earlier finally results in the death of the cell. Clinical responses may thus be delayed even when the treatment has effectively put the tumor cells into a death spiral. Because only a proportion of the cells die as a result of a given treatment, repeated doses of chemotherapy must be used to continue to reduce the cell number (Fig. 1.1). In an ideal system, each time the dose is repeated, the same proportion of cells—not the same absolute number—is killed. In the example shown in Figure 1.1, 99.9% (3 logs) of the cancer cells are killed with each treatment, and there is a 10-fold (1-log) growth between treatments, for a net reduction of 2 logs with each treatment. Starting at 1010 cells (about 10 g or 10 cm3 leukemia cells), it would take five treatments to reach fewer than 100, or 1, cell. Such a model makes certain assumptions that rarely are strictly true in clinical practice2,3: ■ All cells in a tumor population are equally sensitive to a drug. ■ Drug accessibility and cell sensitivity are independent of the location of the cells within the host and of local host factors such as blood supply and surrounding fibrosis. ■ Cell sensitivity does not change during the course of therapy. The lack of curability of most initially sensitive tumors is probably a reflection of the degree to which these assumptions do not hold true.

FIGURE 1.1 The effect of chemotherapy on cancer cell numbers. In an ideal system, chemotherapy kills a constant proportion of the remaining cancer cells with each dose. Between doses, cell regrowth occurs. When therapy is successful, cell killing is greater than cell growth. B. Biologic response modifiers and molecular targeted therapy There are intricate interrelated mechanisms within individual cells and cell populations that promote or suppress cell proliferation, facilitate invasion or metastasis when the cell is malignant, lead to cell differentiation, promote (relative) cell immortality, or set the cell on the path to inevitable death (apoptosis). These activities are controlled in large part by normal genes and, in the case of cancer by mutated constitutive genes, cancer promoter genes, tumor suppressor genes, and their products. Included in these products are a host of cell growth factors that control the machinery of the cell. Some of these factors that affect normal cell growth have been biosynthesized and are now used to enhance the production of normal cells (e.g., epoetin- α and filgrastim) and to treat cancer (e.g., interferon). The recent expansion of our understanding of the biologic control of normal cells and tumor growth at the molecular level has begun to offer improved therapy for many

types of cancer, such as melanoma and kidney cancer that formerly were quite resistant to traditional chemotherapy, and has helped to explain differences in response among cancers, formerly thought to be similar such as diffuse large cell lymphoma. New discoveries in cancer cell biology have provided insights into apoptosis, cell cycling control, angiogenesis, metastasis, cell signal transduction, cell surface receptors, differentiation, and growth factor modulation. New drugs in clinical trials have been designed to block growth factor receptors, prevent oncogene activity, block the cell cycle, restore apoptosis, inhibit blockade of immune recognition and control, inhibit angiogenesis, restore lost function of tumor suppressor genes, and selectively kill tumors containing abnormal genes. Further understanding of each of these holds a great potential for providing powerful and more selective means to control neoplastic cell growth and have already led to more effective cancer treatments in the past decade.4 The fundamental principles related to this group of antineoplastic agents are discussed in Chapter 2. II. TUMOR CELL KINETICS AND CHEMOTHERAPY5 Cancer cells, unlike other body cells, are characterized by a growth process whereby their sensitivity to normal controlling factors has been partially or completely lost. As a result of this uncontrolled growth, it was once thought that all cancer cells grew or multiplied faster than normal cells and that this growth rate was primarily responsible for the sensitivity of cancer cells to chemotherapy. Now it is known that most cancer cells grow less rapidly than the more active normal cells such as bone marrow. Thus, although the growth rate of many cancers may be faster than that of normal surrounding tissues, growth rate alone cannot explain the greater sensitivity of cancer cells to chemotherapy. A. Tumor growth. The growth of a tumor depends on several interrelated factors.6 1. Cell cycle time or the average time for a cell that has just completed mitosis to grow, redivide, and again pass through mitosis determines the maximum growth rate of a tumor, but probably does not determine drug sensitivity. The relative proportion of cell cycle time taken up by the DNA synthesis phase may relate to the drug sensitivity of some types (synthesis phase–specific) of chemotherapeutic agents. 2. Growth fraction or the fraction of cells undergoing cell division contains the portion of cells that are sensitive to drugs whose major effect is exerted on cells that are dividing actively. If the growth fraction approaches 1 and the cell death rate is low, the tumor-doubling time approximates the cell cycle time. 3. Total number of cells in the population (determined at some arbitrary time at which the growth measurement is started) is clinically important because it is an index of how advanced the cancer is; it frequently correlates with normal organ dysfunction. As the total number of cells increases, so does the number of resistant cells, which in turn leads to decreased curability. Large tumors may also have greater compromise of blood supply and oxygenation, which can impair drug delivery to the tumor cells as well as impair sensitivity to both chemotherapy and radiotherapy.

4. Intrinsic cell death rate of tumors is difficult to measure in patients, but probably makes a major and positive contribution by slowing the growth rate of many solid tumors. B. Cell cycle The cell cycle7 of cancer cells is qualitatively the same as that of normal cells (Fig. 1.2). Each cell begins its growth during a postmitotic period, a phase called G1, during which enzymes necessary for DNA production, other proteins, and RNA are produced. G1 is followed by a period of DNA synthesis (S phase), in which essentially all DNA synthesis for a given cycle takes place. When DNA synthesis is complete, the cell enters a premitotic period (G2), during which further protein and RNA synthesis occurs. This gap is followed immediately by mitosis, at the end of which actual physical division takes place, two daughter cells are formed, and each cell again enters G1. G1 phase is in equilibrium with a resting state called G0. Cells in G0 are relatively inactive with respect to macromolecular synthesis and are consequently insensitive to many traditional chemotherapeutic agents, particularly those that affect macromolecular synthesis.

FIGURE 1.2 Cell cycle time for human tissues has a wide range (16 to 260 hours), with marked differences among normal and tumor tissues. Normal marrow and gastrointestinal lining cells have cell cycle times of 24 to 48 hours. Representative durations and the kinetic or synthetic activity are indicated for each phase. C. Phase and cell cycle specificity Most classic chemotherapeutic agents can be grouped according to whether they depend on cells being in cycle (i.e., not in G0) or, if they depend on the cell being in cycle, whether their activity is greater when the cell is in a specific phase of the cycle. Most agents cannot be assigned to one category exclusively. Nonetheless, these classifications can be helpful for understanding drug activity. 1. Phase-specific drugs. (see) Table 1.1. a. Implications of phase-specific drugs 1) Limitation to single-exposure cell kill. With a phase-specific agent, there is

a limit to the number of cells that can be killed with a single instantaneous (or very short) drug exposure because only those cells in the sensitive phase are killed. A higher dose kills no more cells. 2) Increasing cell kill by prolonged exposure. To kill more cells requires either prolonged exposure to, or repeated doses of, the drug to allow more cells to enter the sensitive phase of the cycle. Theoretically, all cells could be killed if the blood level or, more importantly, the intracellular concentration of the drug remained sufficiently high while all cells in the target population passed through one complete cell cycle. This theory assumes that the drug does not prevent the passage of cells from one (insensitive) phase to another (sensitive) phase. TABLE

1.1

Examples of Cell Cycle Phase–Specific Chemotherapeutic Agents

3) Recruitment. A higher number of cells could be killed by a phase-specific drug if the proportion of cells in the sensitive phase could be increased (recruited).

b. Cytarabine. One of the best examples of a phase-specific agent is cytarabine (ara-C), which is an inhibitor of DNA synthesis and thus is active only in the synthesis phase (at standard doses). When used in doses of 100 to 200 mg/m2 daily (i.e., not “high-dose ara-C”), ara-C is rapidly deaminated in vivo to an inactive compound, ara-U, and rapid injections result in very short effective levels of ara-C. As a result, single doses of ara-C are nontoxic to the normal hematopoietic system and are generally ineffective for treating leukemia. If the drug is given as a daily rapid injection, some patients with leukemia respond well but not nearly as well as when ara-C is given every 12 hours (or by continuous infusion). The apparent reason for the greater effectiveness of the 12hour schedule is that the synthesis phase (DNA synthesis) of human acute myelogenous leukemia cells lasts about 18 to 20 hours. If the drug is given every 24 hours, some cells that have not entered the synthesis phase when the drug is first administered will not be sensitive to its effect. Therefore, these cells can pass all the way through the synthesis phase before the next dose is administered and will completely escape any cytotoxic effect. However, when the drug is given every 12 hours, no cell that is “in cycle” will be able to escape exposure to ara-C because none will be able to get through one complete synthesis phase without the drug being present.8 If all cells were in active cycle, that is, if none were resting in a prolonged G1 or G0 phase, it would be theoretically possible to kill any cells in a population by a continuous or scheduled exposure equivalent to one complete cell cycle. Experiments with patients who have acute leukemia have shown that if tritiated thymidine is used to label cells as they enter DNA synthesis, it may be 7 to 10 days before the maximum number of leukemia cells have passed through the synthesis phase. This means that, barring permutations caused by ara-C or other drugs, for ara-C to have a maximum effect on the leukemia, the repeated exposure must be continued for a 7- to 10-day period. Clinically, continuous infusion or administration of ara-C every 12 hours for 7 days appears to be most effective for treating patients with newly diagnosed acute myelogenous leukemia. However, even with such prolonged exposure, it appears that a few of the cells do not pass through the synthesis phase and escape total cell kill, thus evading cure of the patient. 2. Cell cycle–specific drugs. Agents that are effective while cells are actively in cycle but that are not dependent on the cell being in a particular phase are called cell cycle–specific (or phase-nonspecific) drugs. This group includes most of the alkylating agents, the antitumor antibiotics, and some miscellaneous agents, examples of which are shown in Table 1.2. Some agents in this group are not totally phase-nonspecific; they may have greater activity in one phase than in another, but not to the degree of the phase-specific agents. Many agents also appear to have some activity in cells that are not in cycle, although not as much as when the cells are

rapidly dividing. TABLE

1.2

Examples of Cell Cycle–Specific and Cell Cycle–Nonspecific Chemotherapeutic

Agents

Class

Type

Characteristic Agents

Cell Cycle–Specific





Alkylating agent

Nitrogen mustard

Chlorambucil, cyclophosphamidemelphalan



Alkyl sulfonate

Busulfan



Triazene

Dacarbazine



Metal salt

Cisplatin, carboplatin

Natural product

Antibiotic

Dactinomycin, daunorubicin, doxorubicin, idarubicin

Cell Cycle–Nonspecific





Alkylating agent

Nitrogen mustard

Mechlorethamine



Nitrosourea

Carmustine, lomustine

3. Cell cycle–nonspecific drugs. A third group of drugs appears to be effective whether cancer cells are in cycle or are resting. In this respect, these agents are similar to photon irradiation; that is, both types of therapy are effective irrespective of whether or not the cancer cell is in cycle. Drugs in this category are called cell cycle–nonspecific drugs and include mechlorethamine (nitrogen mustard) and the nitrosoureas (see Table 1.2). D. Changes in tumor cell kinetics and therapy implications As cancer cells grow from a few cells to a lethal tumor burden, certain changes occur in the growth rate of the population and affect the strategies of chemotherapy. These changes have been determined by observing the characteristics of experimental tumors in animals and neoplastic cells growing in tissue culture. Such model systems readily permit accurate cell number determinations to be made and growth rates to be determined. (Because tumor cells cannot be injected or implanted into humans and permitted to grow, studies of growth rates of intact tumors in humans must be limited largely to observing the growth rate of macroscopic tumors.) 1. Stages of tumor growth. Immediately after inoculation of a tissue culture or an experimental animal with tumor cells, there is a lag phase, during which there is little tumor growth; presumably, the cells in this phase are becoming accustomed to the new environment and are preparing to enter into cycle. The lag phase is followed by a period of rapid growth called the log phase, during which there are repeated doublings of the cell number. In populations in which the growth fraction approaches 100% and the cell death rate is low, the population doubles within a period

approximating the cell cycle time. As the cell number or tumor size becomes macroscopic, the doubling time of the tumor cell population becomes prolonged and levels off (plateau phase). Most clinically measurable human cancers are probably in the plateau phase, which may account, in part, for the slow doubling time observed in many human cancers (30 to 300 days). Because the rate of change in the slope of the growth curve during the premeasurable period is unknown for most human cancers, extrapolation from two points when the mass is measurable to estimate the onset of the growth of the malignancy is subject to considerable error. The prolongation in tumor-doubling time in the plateau phase may be due to a smaller growth fraction, a change in the cell cycle time, an increased intrinsic death rate (predominantly apoptosis, which is a programmed and highly orchestrated cell death that occurs both naturally and under the influence of many types of chemotherapy), or a combination of these factors. Factors responsible for these changes include decreased nutrients or growth promotion factors, increased inhibitory metabolites or inhibitory growth factors, and inhibition of growth by other cell-cell interactions. In the intact host, new blood vessel formation is a critical determinant of these factors. 2. Growth rate and effectiveness of chemotherapy. Traditional chemotherapeutic agents are most effective during the period of logarithmic growth. As might be expected, this result is particularly true for the antimetabolites, which are largely synthetic phase–specific. As a result, when human tumors become macroscopic, the effectiveness of many chemotherapeutic agents is reduced because only part of the cell population is dividing actively. Theoretically, if the cell population could be reduced sufficiently by other means such as surgery or radiotherapy, chemotherapy would be more effective because a higher fraction of the remaining cells would be in logarithmic growth. The validity of this theoretical premise is supported by the varying degrees of success of surgery plus chemotherapy or radiotherapy plus chemotherapy in the treatment of breast cancer, colon cancer, Wilms tumor, ovarian cancer, small-cell anaplastic cell carcinoma of the lung, non–small-cell carcinoma of the lung, head and neck cancers, and osteosarcomas. III. COMBINATION CHEMOTHERAPY Combinations of drugs are frequently more effective in producing responses and prolonging life than are the same drugs used sequentially. Combinations are likely to be more effective than single agents for several reasons.9 A. Reasons for effectiveness of combinations 1. Prevention of resistant clones. If 1 in 105 cells is resistant to drug A and 1 in 105 cells is resistant to drug B, it is likely that treating a macroscopic tumor (which generally would have more than 109 cells) with either agent alone would result in several clones of cells that are resistant to that drug. If, after treatment with drug A, a resistant clone has grown to macroscopic size (if the same mutant frequency persists

for drug B), resistance to that agent will also emerge. If both drugs are used at the outset of therapy or in close sequence, however, the likelihood of a cell being resistant to both drugs (excluding, for a moment, the situation of pleiotropic drug resistance) is only 1 in 1010. Thus, the combination confers considerable advantage against the emergence of resistant clones. Compounding the problem of preexisting resistant clones is the resistance that develops through spontaneous mutation in the absence of drug exposure. The use of multiple drugs with independent mechanisms of action or alternating non–cross-resistant combinations (as well as the use of surgery or radiotherapy to eliminate macroscopic tumor) theoretically minimizes the chances for outgrowth of resistant clones and increases the likelihood of remission or cure. 2. Cytotoxicity to resting and dividing cells. The combination of a drug that is cell cycle–specific (phase-nonspecific) or cell cycle–nonspecific with a drug that is cell cycle phase–specific can kill cells that are dividing slowly as well as those that are dividing actively. The use of cell cycle–nonspecific drugs can also help recruit cells into a more actively dividing state, which results in their being more sensitive to the cell cycle phase–specific agents. 3. Biochemical enhancement of effect a. Combinations of individually effective drugs that affect different biochemical pathways or steps in a single pathway can enhance each other. This may apply to some newer agents whereby blocking more than one molecular target in the interacting signal transduction pathways may magnify the interference of cell proliferation compared with that seen with either agent alone. While this principle may apply equally well to targeted agents as traditional agents, in either circumstance toxicity may be enhanced as well. b. Combinations of an active agent with an inactive agent can potentially result in beneficial effects by several mechanisms, but with the exception of cooperative inhibition described in what follows, have limited clinical utility. 1) An intracellular increase in the drug or its active metabolites, by either increasing influx or decreasing efflux (e.g., calcium channel inhibitors with multiple agents affected by multidrug resistance [MDR] due to Pglycoprotein overexpression) 2) Reduced metabolic inactivation of the drug (e.g., inhibition of cytidine deaminase inactivation of ara-C with tetrahydrouridine) 3) Cooperative inhibition of a single enzyme or reaction (e.g., leucovorin enhancement of fluorouracil inhibition of thymidylate synthetase) 4) Enhancement of drug action by inhibition of competing metabolites (e.g., Nphosphonacetyl-L-aspartic acid inhibition of de novo pyrimidine synthesis with resultant increased incorporation of 5-fluorouridine triphosphate into RNA) 4. Sanctuary access. Combinations can be used to provide access to sanctuary sites

for reasons such as drug solubility or affinity of specific tissues for a particular drug type. 5. Rescue. Combinations can be used in which one agent rescues the host from the toxic effects of another drug (e.g., “leucovorin rescue” or glucarpidase (carboxypeptidase g2) administration after high-dose methotrexate). B. Principles of agent selection When selecting appropriate agents for use in a combination, the following principles should be observed. 1. Choose individually active drugs. Do not use a combination in which one agent is inactive when used alone unless there is a clear, specific biochemical or pharmacologic reason to do so (e.g., high-dose methotrexate followed by leucovorin rescue or leucovorin followed by fluorouracil). This principle may not be applicable to the combined use of chemotherapeutic agents with biologic response modifiers or molecular targeted agents because the cooperativity of chemotherapy and these drugs may not depend on the independent cytotoxic effect of these nonclassic agents. 2. When possible, choose drugs in which the dose-limiting toxicities differ qualitatively or in time of occurrence. Often, however, two or more agents that have marrow toxicity must be used, and the selection of a safe dose of each is critical. As a starting point, two cytotoxic drugs in combination can usually be given at twothirds of the dose used when the drugs are given alone. Whenever a new drug combination is tried, a careful evaluation of both expected and unanticipated toxicities must be carried out. Unexpected results such as the increased cardiotoxicity of the combination of trastuzumab with doxorubicin may occur, and this latter case has precluded the use of these agents together. 3. Select agents for a combination for which there is a biochemical or pharmacologic rationale. Preferably, this rationale has been tested in an animal tumor system or other appropriate model system, and the combination has been found to be better than either agent alone. 4. Be cautious when attempting to improve on a successful two-drug combination by adding a third, fourth, or fifth drug simultaneously. Although this approach may be beneficial, two undesirable results may be seen, as follows: ■ An intolerable level of toxicity that leads to excessive morbidity and mortality. ■ Unchanged or reduced antitumor effect because of the necessity to reduce the dose of the most effective drugs to a level below which antitumor responses are not seen, despite the theoretical advantages of the combination. Therefore, the addition of each new agent to a combination must be considered carefully, the principles of combination therapy closely followed, and controlled clinical trials carried out to compare the efficacy and toxicity of any new regimen with a more established (standard) treatment program. C. Clinical effectiveness of combinations

Combinations of drugs have been clearly demonstrated to be better than single agents for treating many, but not all, human cancers. The survival benefit of combinations of drugs compared with that of the same drugs used sequentially has been marked in diseases such as acute lymphocytic and acute nonlymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphomas with more aggressive behavior (intermediate- and high-grade), breast carcinoma, anaplastic small-cell carcinoma of the lung, colorectal carcinoma, ovarian carcinoma, and testicular carcinoma. The benefit is less marked in cancers such as non–small-cell carcinoma of the lung, non-Hodgkin lymphomas with favorable prognoses, head and neck carcinomas, carcinoma of the pancreas, and melanoma, although reports exist for each of these tumors in which combinations are better in one respect or another than single agents. It is critical to evaluate the evidence for each cancer type, stage, prior therapy, and patient status prior to making a decision what if any therapy to propose. IV. RESISTANCE TO ANTINEOPLASTIC AGENTS Resistance to antineoplastic chemotherapy is a combined characteristic of a specific drug, a specific tumor, and a specific host whereby the drug is ineffective in controlling the tumor without excessive toxicity. Resistance of a tumor to a drug is the reciprocal of selectivity of that drug for that tumor. The problem for the medical oncologist is not simply to find an agent that is cytotoxic but to find one that selectively kills neoplastic cells while preserving the essential host cells and their function. Were it not for the problem of resistance of human cancer to antineoplastic agents or, conversely, the lack of selectivity of those agents, cancer chemotherapy would be similar to antibacterial chemotherapy in which complete eradication of infection is regularly observed. Such a utopian state of cancer chemotherapy has not yet been achieved for most human cancers. The problem of resistance, including ways to overcome or even exploit it, remains an area of major interest for the oncologist, pharmacologist, and cell biologist. This reductionist description glosses over the fact that each of these factors is a consequence of the complex genetic characteristics and changes of the cancer cell as it evolves. Resistance to antineoplastic chemotherapeutic agents may be either natural or acquired. Natural resistance refers to the initial unresponsiveness of a tumor to a given drug, and acquired resistance refers to the unresponsiveness that emerges after initially successful treatment. There are three basic categories of resistance to chemotherapy: kinetic, biochemical, and pharmacologic. A. Cell kinetics and resistance Resistance based on cell population kinetics relates to cycle and phase specificity, growth fractions and the implications of these factors for responsiveness to specific agents, and schedules of drug administration. A particular problem with many human tumors is that they are in a plateau growth phase with a small growth fraction. This factor renders many of the cells insensitive to the antimetabolites and relatively unresponsive to many of the other chemotherapeutic agents. Strategies to overcome

resistance due to cell kinetics include the following: ■ Reducing tumor bulk with surgery or radiotherapy ■ Using combinations to include drugs that affect resting populations (with many G0 cells) ■ Scheduling of drugs to prevent phase escape or to synchronize cell populations and increase cell kill B. Biochemical causes of resistance Resistance can occur for biochemical reasons including the inability of a tumor to convert a drug to its active form, the ability of a tumor to inactivate a drug, or the location of a tumor at a site where substrates are present that bypass an otherwise lethal blockade. How cells become resistant is only partially understood. There can be decreased drug uptake by the cell, increased efflux, changes in the levels or structure of the intracellular target, reduced intracellular activation or increased inactivation of the drug, or increased rate of repair of damaged DNA. In one pre–B-cell leukemia cell line, bcl-2 overexpression or decreased expression of the homolog bax renders cells resistant to several chemotherapeutic agents. Because bcl-2 blocks apoptosis, it has been proposed that its overexpression blocks chemotherapy-induced apoptosis. The interrelationship between mutations of p53, overexpression of HER2, and similar changes in a host of other oncogenes and tumor suppressor genes and resistance to the cytotoxic effects of radiotherapy and chemotherapeutic, hormonal, and biologic agents, when better understood, may further our understanding of resistance and provide new therapeutic strategies. MDR,10 also called pleiotropic drug resistance, is a phenomenon whereby treatment with one agent confers resistance not only to that drug and others of its class but also to several other unrelated agents. MDR is commonly mediated by an enhanced energydependent drug efflux mechanism that results in lower intracellular drug concentrations. With this type of MDR, overexpression of a membrane transport protein called Pglycoprotein (“P” meaning pleiotropic or permeability) is observed commonly.11 Other MDR proteins are the MDR protein found in human lung cancer lines and the lung resistance protein. These proteins appear to have differing expression in different sets of neoplasms. Drugs that are effective in reversing resistance to P-glycoprotein do not reverse these latter MDR proteins. Combination chemotherapy can overcome biochemical resistance by increasing the amount of active drug intracellularly as a result of biochemical interactions or effects on drug transport across the cell membrane. Calcium channel blockers, antiarrhythmics, cyclosporine A analogs (e.g., PSC-833, a nonimmunosuppressive derivative of cyclosporine D), and other agents have been found to modulate the P-glycoprotein MDR effect in vitro, but limited beneficial effects have been observed clinically. The use of a second agent to rescue normal cells may also permit the use of high doses of the first agent, which can overcome the resistance caused by a low rate of conversion to the active metabolite or a high rate of inactivation. Another way to

overcome resistance is to follow marrow-lethal doses of chemotherapy by posttherapy infusion of stem cells obtained from the peripheral blood or bone marrow. This technique is effective for the treatment of some patients with lymphoma, leukemia, multiple myeloma, and a few other cancers. A more widely applicable technique is to combine higher or more frequent doses of chemotherapy with granulocyte colonystimulating factor or granulocyte-macrophage colony-stimulating factor. These and other marrow-protective and marrow-stimulating agents are being used increasingly and may enhance the effectiveness of chemotherapy in the treatment of several types of cancer. C. Pharmacologic causes of resistance Dosing of drugs based on body surface area has been used traditionally to account for drug distribution and glomerular filtration rate differences among individuals of different height and weight. This does not take into account potential differences in absorption, distribution, metabolism, and excretion that may occur depending on the route of administration, body composition, pharmacogenomics (relating to the cancer cell), and pharmacogenetics (relating to host genetic differences, including single nucleotide polymorphisms). Apparent resistance to cancer chemotherapy can result from poor tumor blood supply, poor or erratic absorption, increased excretion or catabolism, and drug interactions, all leading to inadequate blood levels of the drug. Strictly speaking, this result is not true tumor cell resistance; but to the degree that the clinician does not appreciate the insufficient blood levels, resistance appears to be present. The variation from patient to patient at the highest tolerated dose has led to dose modification schemes that permit dose escalation when the toxicities of the chemotherapy regimen are minimal or nonexistent, as well as dose reduction when toxicities are great. This regulation is particularly important for some chemotherapeutic agents for which the dose-response curve is steep or for patients who have genetically altered drug metabolism, such as can occur with irinotecan. Selection of the appropriate dose on the basis of predicted pharmacologic behavior is essential for some agents not only to avoid serious toxicity but also to optimize effectiveness. This has been applied successfully to dose selection of carboplatin by predicting the time × concentration product (area under the curve [AUC]) on the basis of the individual patient’s creatinine clearance. True pharmacologic resistance is caused by the poor transport of agents into certain body tissues and tumor cells. For example, the central nervous system (CNS) is a site that many drugs do not reach well. Several drug characteristics favor transport into the CNS, including high lipid solubility and low molecular weight. For tumors that originate in the CNS or metastasize there, the drugs of choice should be those that achieve effective antitumor concentration in the brain tissue and that are also effective against the tumor cell type being treated. D. Nonselectivity and resistance Nonselectivity is not a mechanism for resistance but rather an acknowledgment that for most cancers and most drugs, the reasons for resistance and selectivity are only

partially understood. Given a limited understanding of the biochemical differences between normal and malignant cells prior to the last 10 years, it is gratifying that chemotherapy has been as successful as frequently as it has. With the burgeoning of knowledge about the cancer cell, there is reason to hope that in 20 years, we will view current chemotherapy regimens as a fledgling—if not crude—beginning and will have found many more tumor molecular target–directed agents that have a high potential for curing the human cancers that now resist effective treatment.

References 1. Goetz MP. Clinical pharmacology. In: Loprinzi CL, ed. ASCO-SEP: medical oncology self-evaluation program. 4th ed. Alexandria: American Society of Clinical Oncology; 2015:61–70. 2. Goldie JH, Coldman AJ. A mathematical model for relating drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep. 1979;63:1727–1733. 3. Goldie JH. Drug resistance. In: Perry MC, ed. The chemotherapy source book. Baltimore: Williams & Wilkins; 1992:54–66. 4. Adjei AA, Hidalgo M. Intracellular signal transduction pathway proteins as targets for cancer therapy. J Clin Oncol. 2005;23:5386–5403. 5. Schabel FM Jr. The use of tumor growth kinetics in planning “curative” chemotherapy of advanced solid tumors. Cancer Res. 1969;29:2384–2398. 6. Slingerland JM, Tannock IF. Cell proliferation and cell death. In: Tannock IF, Hill RP, eds. The basic science of oncology. New York: McGraw-Hill; 1998:134–165. 7. Baserga R. The cell cycle. N Engl J Med. 1981;304:453–459. 8. Clarkson B, Fried J, Strife A, et al. Studies of cellular proliferation in human leukemia. 3. Behavior of leukemic cells in three adults with acute leukemia given continuous infusions of 3H-thymidine for 8 or 10 days. Cancer. 1970;25:1237–1260. 9. Friedland ML. Combination chemotherapy. In: Perry MC, ed. The chemotherapy source book. Baltimore: Williams & Wilkins; 1996:63–78. 10. Baguley BC, Holdaway KM, Fray LM. Design of DNA intercalators to overcome topoisomerase II-mediated multi-drug resistance. J Natl Cancer Inst. 1990;82:398–402. 11. Endicott JA, Ling U. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem. 1989;58:137–171.

I. INTRODUCTION Molecular targeted therapy (MTT) is a new approach to cancer treatment that resulted from the plethora of molecular and biologic discoveries into the etiology of cancer over the last quarter of a century. Several agents have been approved by the U.S. Food and Drug Administration (FDA) for clinical use and have replaced traditional chemotherapy in the treatment of some cancers. Many more are currently being tested in clinical trials, and their widespread integration into the mainstream for cancer treatment is expected to increase at an accelerated pace during the next decade. Agents in this type of therapy are vastly different from the traditional chemotherapeutic agents that constitute the majority of therapy described throughout the chapters of this book. These drugs are designed with the intention to specifically target molecules that are uniquely or abnormally expressed within cancer cells while sparing normal cells. In this chapter, we discuss drugs that are already available for clinical use and provide a brief description of the mechanism of action of these agents, the pathways they target, and some of their clinical uses. This chapter also addresses promising agents currently in clinical trials that may be available soon in the clinic. A. Characteristics of MTT The ideal molecule for targeted therapy should have the following characteristics: ■ Uniquely expressed in cancer cells but not in normal cells. ■ Important for the maintenance of the malignant phenotype; therefore, once the targeted molecule has been effectively disabled, the cancer cell will not be able to develop resistance against the therapeutic agent by suppressing its function or expelling the targeted molecule from the cell. The degree to which target molecules do not embody these characteristics coupled with nonspecificity of the therapeutic agent determines the limitations of the current targets and agents. B. Classification and type of MTT The classification of MTT is a moving target. In this chapter, we classify MTT based on the targeting strategy of each molecule. There are two targeting strategies for MTT. 1. Function-directed therapy This therapeutic strategy is intended to restore the normal function or abrogate the abnormal function of the defective molecule or a pathway in the tumor cell. This is

accomplished by the following: ■ Reconstituting the normal molecule ■ Inhibiting the production of a defective molecule ■ Aborting, altering, or reversing a newly acquired function by targeting the defective molecule, its function, and its downstream effect Agents under this category are classified based on the mechanism of action and subclassified based on the known affected targeted pathway. 2. Phenotype-directed therapy This is a therapeutic strategy that is intended to target the unique phenotype of the cancer cell where killing the cell is more dependent on nonspecific mechanisms rather than targeting a specific pathway. Accordingly, agents under this category are classified based on the type of therapy and subclassified based on the targeted pathway or molecule. Table 2.1 summarizes the classification and FDA-approved indications of molecular-targeted agents. II. FUNCTION-DIRECTED THERAPY Agents under this category target specific cellular pathways (e.g., signal transduction pathways, angiogenesis, protein degradation, etc.). A. Cell signaling–targeted therapy Signal transduction pathways are crucial for delivering messages from the extracellular environment into the nucleus and enabling the cell to carry on cellular processes including survival, proliferation, and differentiation. These signals are initiated from the cell surface by the interaction of molecules (ligands) such as hormones, cytokines, and growth factors with cell receptors. Cell receptors, in turn, transfer the signal through a network of molecules to the nucleus, which leads to the transcription of new molecules responsible for engineering the desired outcome. In cancer cells, these pathways are found to be altered through the mutation of some of their components. This leads to the functional dysregulation of the affected pathways resulting in uncontrolled proliferation and inhibition of apoptosis. Accordingly, targeting the components of these pathways is a prime goal for the development of MTT. The components of these pathways include the following: ■ The ligand ■ The receptors for these ligands, the majority of which are receptor kinases ■ The cascade of proteins that form these pathways, the majority of which are protein kinases TABLE

2.1

Classification and FDA-Approved Indications of Molecular-Targeted Agents

Accordingly, strategies targeting signal transduction pathways include the following: ■ Blocking the ligand-receptor interaction. This leads to the prevention of the initiation of the signal and can be accomplished by either blocking circulating ligands or blocking ligand binding to the extracellular domain of the receptor. ■ Inhibition of receptor kinases. This leads to the prevention of phosphorylation of the intracellular kinase domain of the receptor, resulting in the abortion of protein cascade in the cell signaling pathways. ■ Inhibition of intracellular signaling proteins. 1. Blocking of the ligand-receptor binding Blocking receptors and ligand-receptor interaction is currently achieved by utilizing specific monoclonal antibodies (MoAbs) directed against the ligand or the receptor.

MoAbs are biologic agents designed with the intention to specifically target soluble proteins or membrane proteins with an extracellular domain. The MoAbs can exert their antitumor effect through multiple potential mechanisms including blocking the targeted receptor or ligand and preventing its function in transmitting signals to the nucleus, activating antibody-dependent cellular cytotoxicity, or helping to internalize the receptor and hence deliver toxic agents into the cells. The MoAb technology has considerably improved in the last decade by humanizing these agents partially in chimeric or fully humanized constructs. Substituting the murine Fc portion of the MoAb with a human equivalent leads to a significant decrease in the generation of a human anti-mouse antibody (HAMA) immune reaction. Although generation of human anti-chimeric antibodies (HACAs) may still occur for those MoAbs, it does not occur with fully humanized MoAbs. This technology to humanize MoAbs has made these molecules more usable in the treatment of cancer, particularly when repetitive dosing is required. 2. Epidermal growth factor receptor family Epidermal growth factor receptors (EGFRs) are a small family of proteins belonging to the larger receptor tyrosine kinase (RTK) family. The EGFR family includes at least four described receptors: EGFR1, HER-2-neu (erbB2), HER3 (erbB3), and HER4 (erbB4). These receptors are glycoproteins consisting of three domains: an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain with a tyrosine kinase activity. Binding of the ligands to the receptor leads to the activation of the intracellular tyrosine kinase and the phosphorylation of the receptor, which, in turn, leads to activation of the downstream signal transduction pathway. The activation of this pathway promotes cell activation, proliferation, and enhanced survival. Agents have been developed against the receptors EGFR1 and HER-2-neu. 3. EGFR1-targeted therapy EGFR1 was the first member of the EGFR family to be identified. It is activated by binding to epidermal growth factor (EGF) and to transforming growth factor-α (TGF-α). EGFR1 is found to be overexpressed in many cancers, including 50% to 70% of colon, lung, and breast cancers. Several antibodies targeting EGFR have been approved by the FDA. a. Cetuximab (Erbitux) is a humanized immunoglobulin-G1 (IgG1) chimeric MoAb that binds to the external ligand-binding domain of EGFR1. It also binds with much lower affinity to EGF and TGF-α. The combination of cetuximab and irinotecan was found to improve disease response rate (RR) and progression-free survival (PFS) over the use of cetuximab alone in patients with metastatic colorectal carcinoma (CRC) who have previously failed irinotecan therapy. Recent studies have shown an improved PFS by 1.4 months and median overall survival (OS) by 4 months in patients with KRAS wild-type (WT) metastatic CRC with the addition of cetuximab to either FOLFIRI (folinic acid, fluorouracil

[5-FU], and irinotecan) or FOLFOX (folinic acid, 5-FU, and oxaliplatin). An increased RR was also observed in this patient population (46% vs. 38% in all patients, 57% vs. 39% in patients with KRAS-WT). Additionally, cetuximab has been studied in patients with metastatic CRC previously treated with irinotecan, with an improved OS of 1.5 months in all patients and 3.6 months in patients with KRAS-WT. These studies have led to its approval in the first-line setting for patients with KRAS-WT metastatic CRC in combination with FOLFIRI, patients who failed both irinotecan- and oxaliplatin-based chemotherapy regimens as a single agent, and patients who are refractory or intolerant to irinotecan-based chemotherapy in combination with irinotecan. Recently, the combination of cetuximab and FOLFIRI in patients with untreated KRAS-WT metastatic CRC was compared to FOLFIRI plus bevacizumab and showed an improved rate of carcinoembryonic antigen (CEA) decline, which correlated with an improved OS, favoring the cetuximab arm. Cetuximab is also approved for the treatment of squamous cell carcinoma of head and neck (SCCHN). It has been shown to improve local-regional control by 9.5 months and OS by 19.7 months in patients with stage III or IV previously untreated SCCHN when combined with radiation therapy (RT) compared to RT alone. It was also shown to improve RR (35.6% vs. 19.5%), PFS by 2.2 months, and OS by 2.7 months in patients with stage III or IV SCCHN when combined with 5-FU and either carboplatin or cisplatin. Additionally, cetuximab alone showed a RR of 13% with duration of response of 5.8 months in patients with recurrent or metastatic SCCHN who progressed within 30 days of a platinum agent. These studies have led to its approval as a first line in combination with either radiation or platinum-based therapy and 5-FU in patients with recurrent, locally advanced, or metastatic SCCHN and as a second line in SCCHN patients who progressed on a platinum agent. Common adverse effects include rash and diarrhea. Although very uncommon, cardiac arrest and myocardial infarction (MI) were reported among the serious side effects. b. Panitumumab (Vectibix) is a fully humanized MoAb that binds to EGFR1 with higher affinity than cetuximab. A randomized phase III study demonstrated that patients with refractory EGFR-expressing metastatic CRC treated with panitumumab plus best supportive care (BSC) had a better PFS compared to patients who received BSC alone. The patients who benefited from the treatment were those with tumors that did not express KRAS mutations. Therefore, panitumumab was approved by the FDA as a monotherapy for chemotherapyrefractory KRAS-WT metastatic CRC. It was also shown to improve PFS by 1.6 months and OS by 4.4 months in combination with FOLFOX in patients with untreated KRAS-WT metastatic CRC compared to FOLFOX alone. Importantly, it was found to be noninferior to cetuximab in patients with metastatic CRC previously treated with FOLFOX or FOLFIRI. It was also studied in patients with

metastatic SCCHN in combination with cisplatin and 5-FU compared to chemotherapy alone and had a nonsignificant trend toward improved OS and modest, but significant, improvement in PFS of 1.2 months. Other diseases with promising results using panitumumab include non–small-cell lung cancer (NSCLC) and renal cancer. Common adverse effects include rash, peripheral edema, fatigue, and diarrhea. Serious toxicity, including bronchospasm, has been reported only rarely. 4. HER-2-neu (HER2, erbB2)-targeted therapy HER2 is the second member of the EGFR family. This receptor has the same basic structure as the other family members; however, no conjugate ligand has been identified for HER2. There have been no mutations identified in the HER2 gene in human cancers, yet it is overexpressed in many epithelial cancers, including colon, pancreas, genitourinary, and breast cancers. HER2 signals through the phosphoinositide-3 kinase (PI3K)/Akt and mitogen-activated protein (MAP) kinase pathways, and HER2 overexpression leads to inhibition of apoptosis and increase in cell proliferation. a. Trastuzumab (Herceptin) was one of the first MTTs to be introduced in the clinic. It is a humanized (chimeric) MoAb that binds to HER2. Although the mechanism of action of trastuzumab is not entirely clear, it is believed to act through one or more of the following mechanisms: inhibiting the tyrosine kinase signaling of the receptor, activating antibody-dependent cellular cytotoxicity, inducing apoptosis, inducing G1 arrest by modulating the cyclin-dependent kinases, inhibiting angiogenesis, and enhancing chemotherapy-induced cytotoxicity. The FDA approved trastuzumab in 1998 for use in patients with metastatic breast cancer overexpressing HER2 protein. In a large, multicenter phase III study in patients with metastatic breast cancer overexpressing HER2, it was demonstrated that trastuzumab, when used as a first-line therapy in combination with chemotherapy (with either the combination of anthracyclines and cyclophosphamide or paclitaxel as a single agent), can significantly increase both the duration of response and OS.1 Trastuzumab is currently used in three settings for patients with breast cancer overexpressing HER2: as a first-line therapy in combination with paclitaxel; as a second-line monotherapy in patients who have received at least one prior chemotherapy regimen; or in an adjuvant setting in combination with doxorubicin, cyclophosphamide, and paclitaxel. It is also approved for patients with metastatic HER2+ gastric or gastroesophageal junction (GEJ) adenocarcinoma. This is based on an improved OS of 4.8 months when used in combination with cisplatin and either capecitabine or 5-FU compared to chemotherapy alone. Patients with HER2− disease showed no benefit when treated with trastuzumab. Common adverse effects are asthenia, rash, and diarrhea. Serious side effects are ventricular dysrhythmia, decreased left ventricular ejection fraction (LVEF), and thromboembolism.

b. Pertuzumab (Perjeta) is a fully humanized MoAb directed against the extracellular domain of HER2. It prevents dimerization of the HER2 receptor that is necessary for its activity and is a potential mechanism of resistance to trastuzumab. When combined with trastuzumab and docetaxel in patients with untreated metastatic HER2+ breast cancer, pertuzumab improved RR from 12.5% to 20.2%, median PFS by 6.3 months, and median OS by 15.7 months.2 This led to its FDA-approval for untreated HER2+ breast cancer in combination with trastuzumab and docetaxel. It has also been studied in the neoadjuvant setting and showed an improved pathologic complete response (pCR) rate of 46% when combined with docetaxel and trastuzumab (compared to 29% for docetaxel and trastuzumab). Common side effects include diarrhea, nausea, rash, and peripheral neuropathy. Serious effects include febrile neutropenia, severe diarrhea, and left ventricular dysfunction. Importantly, the combination of pertuzumab and trastuzumab does not seem to increase cardiotoxicity compared to trastuzumab alone. 5. Vascular endothelial growth factor Vascular endothelial growth factor (VEGF) family of proteins is one of the specific positive regulators of angiogenesis. It is composed of five different growth factors: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor. Of these, VEGF-A exerts the most influence on the angiogenesis process. The VEGF proteins bind to three tyrosine kinase receptors: VEGF receptor 1 (VEGFR-1/FLT-1), VEGFR-2 (kinase insert domain receptor/fetal liver kinase 1, FLK-1), and VEGFR3 (FLT-1). VEGFR-2, through its interaction with VEGF, is thought to be the main mediator of tumor-associated angiogenesis and metastatic processes, whereas VEGFR-1 plays a role in hematopoiesis. The VEGF-A is expressed or overexpressed in many tumors, including lung, breast, and ovarian cancer tumors, as well as gastrointestinal stromal tumors (GISTs) and renal cell carcinoma (RCC). Accordingly, targeting these molecules to block tumor-associated angiogenesis constitutes a logical therapeutic strategy to control cancer. Both antibodies and small molecules have been developed as targeted therapies utilizing this pathway. Here, we discuss the antibodies. The small molecules are discussed later in the chapter. a. Bevacizumab (Avastin) is a humanized murine anti-VEGF MoAb. It functions by blocking VEGF-A binding to its receptors (VEGFR), thereby inhibiting the tumorinduced angiogenesis process. Given the ubiquitous nature of angiogenesis in cancer, bevacizumab is used in many cancers, including colon, lung, glioblastoma, RCC, ovarian, and uterine cancers. Bevacizumab was found to improve RR, PFS, and OS when combined with first-line chemotherapy of FOLFOX or FOLFIRI in patients with metastatic CRC. Even in patients with metastatic CRC who received bevacizumab in the first-line setting, its addition to second-line chemotherapy showed an improved PFS of 1.7 months compared to second-line chemotherapy alone. However, bevacizumab use in the adjuvant

setting did not improve OS. These studies have led to its approval for metastatic CRC as a first-line treatment in combination with FOLFOX or FOLFIRI and as a second-line treatment with similar regimens, but not in the adjuvant setting. In previously untreated patients with metastatic, recurrent, or locally advanced nonsquamous NSCLC, bevacizumab plus paclitaxel and carboplatin (PC) was shown to improve OS by 2 months compared to PC alone.3 A similar study combining bevacizumab with gemcitabine and cisplatin failed to show an improvement in PFS or OS. This led to its approval for patients with previously untreated metastatic, recurrent, or locally advanced nonsquamous NSCLC in combination with PC. Squamous-type histology was excluded from these studies given an unacceptably high risk of massive hemoptysis with bevacizumab use. Bevacizumab is also approved for the use in patients with glioblastoma previously treated with either temozolomide or irinotecan with radiation. This was based on an improvement of RR of 26% and 20%, respectively, on two separate studies but with no survival advantage. Bevacizumab is also approved for the use in patients with previously untreated metastatic RCC in combination with interferon (IFN)-α2a, based on improvement of 18% in RR and 4.8 months in PFS with no difference in OS. Recently, bevacizumab was also studied in both cervical and ovarian cancer patients. Patients with refractory metastatic cervical cancer following initial chemotherapy received bevacizumab in combination with paclitaxel and cisplatin or paclitaxel and topotecan. Bevacizumab with either chemotherapy doublet improved RR by 11% and OS by 3.9 months. Patients with platinum-resistant, recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer had an improved PFS of 6.8 months when received bevacizumab in combination with paclitaxel, doxorubicin, or topotecan, compared to 3.4 months with chemotherapeutic agent alone. Accordingly, bevacizumab was approved in combination with chemotherapy in patients with persistent, recurrent or metastatic cervical cancer and patients with platinumresistant, recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer. Bevacizumab was approved by the FDA in 2008 for use as a first-line therapy in combination with paclitaxel in patients with metastatic HER2− breast cancer, based on an improvement in PFS of 5.9 months in patients receiving the combination compared to those receiving paclitaxel alone. However, the FDA Oncology Drugs Advisory Committee recommended that approval be withdrawn based on the new trials that did not show any improvement in OS and minimal improvement in PFS. Serious adverse effects include arterial and venous thrombosis, hypertension (HTN), gastrointestinal perforation, and delayed wound healing following surgery. Up to 31% of patients with squamous cell lung cancer (SCLC) were found to have serious or fatal pulmonary hemorrhage, restricting its use in this patient population. b. Ramucirumab (Cyramza) is a recombinant human IgG1 MoAb against VEGFR-2

that is approved in multiple settings. In patients with locally advanced or metastatic gastric or GEJ adenocarcinoma previously treated with either platinum-based or 5-FU-based regimen, ramucirumab showed an improvement of PFS by 0.8 months and OS by 1.4 months compared to placebo. In the same patient population, ramucirumab was combined with paclitaxel and compared to placebo in combination with paclitaxel. This study showed that ramucirumab improved RR by 12%, PFS by 1.5 months, and OS by 2.2 months. These studies had led to its approval in these disease settings. In addition, ramucirumab is approved for patients with locally advanced or metastatic NSCLC after progression on a platinum-based regimen. This was based on a phase III study comparing it in combination with docetaxel to docetaxel in combination with placebo showing an improvement of PFS by 1.5 months, with a nonsignificant trend toward improved OS. Recently, ramucirumab was approved in patients with metastatic colorectal cancer after 5-FU-, oxaliplatin-, bevacizumab-based chemotherapy failure, based on improved OS by 1.6 months and PFS by 1.2 months compared to placebo. Common adverse effects include HTN and diarrhea when used as a single agent. When used in combination with a taxane, adverse effects include neutropenia, neuropathy, and fatigue. Serious effects are similar to those of bevacizumab. c. Axitinib (Inlyta) is a small-molecule tyrosine kinase inhibitor (TKI) that inhibits VEGFR-1–3 in addition to platelet-derived growth factor receptor (PDGFR) and c-KIT. It is approved for patients with metastatic RCC after progression on at least one prior therapy (including sunitinib, temsirolimus, bevacizumab, or cytokines). In this patient population, it was shown to improve PFS by 2 months compared to sorafenib with added OS benefit. It has also been studied in the firstline setting compared to sorafenib in patients with untreated metastatic RCC and showed a nonsignificant trend toward improved PFS and RR. Common adverse effects include diarrhea, HTN, fatigue, hand-foot syndrome, constipation, and weight loss. Serious effects are similar to those of bevacizumab. d. Ziv-aflibercept (Zaltrap) is a recombinant fusion protein composed of VEGFbinding portions from the extracellular domains of human VEGFR-1 and -2 fused with the Fc portion of the human IgG1. It has been shown to effectively bind to VEGF-A and VEGF-B. This binding inhibits the proliferation of endothelial cells and in turn angiogenesis. It is approved in combination with FOLFIRI for patients with metastatic CRC that is resistant or refractory to an oxaliplatin-containing regimen. This is based on a large phase III clinical trial that showed an improved RR of 20% when combined with FOLFIRI (vs. 11% for FOLFIRI plus placebo), PFS of 6.9 months (vs. 4.6 months), and OS of 13.5 months (vs. 12 months).4 Common adverse effects include leukopenia, diarrhea, stomatitis, fatigue, and HTN. Serious effects include arterial thrombosis, severe HTN, and gastrointestinal fistula formation.

e. Lenvatinib (Lenvima) is an oral TKI of VEGFR-1–3, and also has activity against PDGFR, c-KIT, RET, and fibroblast growth factor (FGF). It is approved for patients with locally recurrent or metastatic, progressive, radioactive iodine– refractory differentiated thyroid cancer, based on improved RR by 63% and PFS by 14.7 months compared to placebo. Common adverse effects include fatigue, diarrhea, weight loss, nausea, and hand-foot syndrome. Serious adverse effects include HTN, decreased LVEF, arterial thrombosis, hepatotoxicity, QT prolongation, rare gastrointestinal perforation, kidney injury, hypocalcemia, and hemorrhage. f. Nintedanib (Ofev) is an orally available multiple kinase inhibitor of VEGFR, PDGFR, and FGF receptor (FGFR). It is currently approved in the United States for treatment of patients with idiopathic pulmonary fibrosis and used in Europe for patients with locally advanced or metastatic lung adenocarcinoma previously treated with chemotherapy. This is based on an improved OS by 2.3 months when combined with docetaxel compared to docetaxel alone. g. Brivanib is a humanized MoAb against VEGFR-2 that also has activity against PDGFR and FGF. It was compared to sorafenib in patients with untreated advanced hepatocellular carcinoma (HCC) in a recent phase III trial, but did not show a survival benefit. In another phase III trial, brivanib was shown to have an improved RR of 10% versus 2% for BSC in HCC patients who failed sorafenib. h. Telatinib is an oral TKI that targets VEGFR-2 and -3 in addition to PDGFR and KIT. In a phase II trial treating patients with advanced gastric adenocarcinoma, it had an RR of 66% when combined with capecitabine in the first-line setting. It was reportedly well tolerated, and additional studies are ongoing. i. Cediranib is an inhibitor of VEGFR that showed clinical response in NSCLC, RCC, and CRC in early phase I trials. In a recent phase II trial, it showed an improved PFS by 8.5 months when combined with olaparib (a poly(ADP-ribose) polymerase [PARP] inhibitor discussed later) versus olaparib alone in patients with recurrent platinum-sensitive high-grade serous ovarian cancer. It was also studied in a phase II trial in patients with NSCLC, but did not show an improvement in PFS or OS. It is currently being investigated in patients with glioblastoma. j. Dovitnib is an oral TKI of VEGFR and FGFR. It has been studied in the third-line setting for patients with metastatic RCC and found to be noninferior to sorafenib in terms of PFS. In patients with advanced GIST who were intolerant or resistant to imatinib, dovitinib showed a disease control rate at 12 weeks of 53%, with no difference in PFS compared to historical control patients treated with sunitinib. 6. Insulin-like growth factor type I receptor Insulin-like growth factor type I receptor (IGF-1R) is an RTK belonging to the insulin-like growth factor (IGF) receptor family, which is composed of three transmembrane proteins and binds to IGF-1 and -2. It is overexpressed in many

tumors, including melanoma, colon, pancreas, prostate, and kidney tumors. IGF-1R overexpression in cancer cells is an important factor for their proliferation, transformation, and metastasis. Therefore, IGF-1R became an attractive target for cancer therapy, although no IGF-1R-targeted agents are currently approved for use. a. Cixutumumab is a fully humanized MoAb IgG1 against IGF-1R that has shown to be safe and active in multiple phase II trials in a variety of cancers, including adrenocortical carcinoma, thymoma, and bone and soft-tissue sarcomas. Cixutumumab is currently being investigated in several phase III trials. b. Linsitinib is an oral small molecule that inhibits IGF-1R. In a recent phase III study in patients with locally advanced or metastatic adrenocortical carcinoma, it did not show any improvement in PFS or OS compared to placebo. Additional studies are ongoing. c. Ganitumab is a fully human MoAb that targets IGF-1R. Ganitumab was found to be promising in initial trials, but a recent phase III trial in patients with metastatic pancreatic cancer showed no benefit compared to gemcitabine alone. It is now being investigated in patients with metastatic Ewing sarcoma. 7. Inhibition of receptor tyrosine kinases Kinases are enzymes that have the ability of attaching a phosphate moiety to another protein. This occurs on a side chain of a serine, threonine, or tyrosine moiety, and the side chain that becomes phosphorylated is used to classify these kinases. The phosphorylation of proteins regulates the behavior of the molecules, including protein-binding activity, enzymatic activity, trafficking within the cell, or degradation. As a consequence, the phosphorylation process is a crucial biochemical reaction involved with controlling the behavior of a cell. Their critical role in cancer is shown by the observation that mutations in these kinases may lead to drastic outcomes, including uncontrolled proliferation. Receptor serine/threonine kinases are discussed later in this chapter; here, we discuss RTKs. RTKs are a family of proteins sharing several structural and functional features. These kinases are glycoprotein receptors with extracellular, transmembrane, and intracellular domains. While the transmembrane domain acts as an anchor for the receptor within the membrane of the cell, the extracellular domain contains a binding site for a specific multipeptide ligand. On receptor-ligand binding, signaling events specific to the receptor are initiated. The cytoplasmic domain contains a catalytic tyrosine kinase region and a regulatory region, which are integral to the transmission of downstream signals to the nucleus. Autophosphorylation of the receptor’s kinase region initiates a signal transduction cascade leading to cell proliferation, survival/apoptosis, migration, adhesion, and promotion of angiogenesis. Some of the subfamilies in this group of RTKs include PDGFR, EGFR, VEGFR, and FGFR. These RTKs are overexpressed or mutated in many human cancers. Therefore, targeting the activity of RTKs is an attractive strategy for cancer therapy and is currently achieved by small molecules. A few small molecules have already been

introduced into the clinical practice, and many more are currently in clinical trials. Here, we discuss some of these molecules. 8. EGFR, VEGFR, PDGFR, and/or FGF a. Erlotinib (Tarceva) is an oral small molecule that is a reversible kinase inhibitor of EGFR and acts by competing with ATP in binding the intracellular domain of the tyrosine kinase region. It blocks the signal transduction of the EGFR, leading to the inhibition of the downstream effect of the pathway, including cell propagation and survival, as well as angiogenesis. Erlotinib is a highly selective inhibitor of the EGFR tyrosine kinase region, as concentrations of more than 1,000-fold are required for the inhibition of other tyrosine kinases. Erlotinib has been studied in a variety of settings for patients with NSCLC and pancreatic cancer. In previously untreated patients with metastatic NSCLC with exon 19 deletions or exon 21 substitution mutations (L858R), it was superior to standard chemotherapy with improved RR (65% vs. 16%) and PFS (10.4 vs. 5.2 months).5 In patients with metastatic NSCLC who responded to first-line platinum-based chemotherapy, erlotinib maintenance until progression improved OS by 1 month compared to placebo, although the benefit was greater if tumor samples were positive for EGFR by immunohistochemistry (IHC) and had adenocarcinoma histology. Erlotinib has also been shown to be effective in patients with locally advanced or metastatic NSCLC who failed at least one chemotherapy regimen, showing an improved RR of 9% (vs. 1% with placebo) and OS by 2 months compared to placebo. However, studies combining erlotinib with platinum-based chemotherapy in similar patient population did not show a clinical benefit. Accordingly, these studies have led to its approval as a first line for patients with metastatic NSCLC with EGFR exon 19 deletions or exon 21 substitution mutations (L858R), as a second line after progressing on a platinum doublet, and as a maintenance following first-line platinum-based chemotherapy. In pancreatic cancer, the addition of erlotinib to gemcitabine was found to improve median survival by 13.8 days over gemcitabine alone, with an increase in 1-year survival from 19% to 24%. Despite this limited improvement in OS, erlotinib is FDAapproved for patients with locally advanced or metastatic pancreatic cancer in combination with gemcitabine. The most common toxicities include skin rash and diarrhea. MI and interstitial lung disease are reported among the serious side effects. b. Gefitinib (Iressa) is an oral small molecule designed to effectively inhibit the tyrosine kinase activity of EGFR. This compound initially showed an effect in randomized phase II trials with symptomatic improvement in advanced NSCLC (with RR around 15%). However, further placebo-controlled phase III studies showed no survival benefit as a frontline. Therefore, the FDA changed the labeling to limit its use to patients with locally advanced or metastatic NSCLC who have previously benefited from the drug or to patients who are already

receiving the agent and have demonstrated benefit. As a first-line therapy in NSCLC, gefitinib in combination with platinum-based chemotherapy showed no benefit. Gefitinib can cause rash and diarrhea. Serious adverse effects include interstitial lung disease and hemorrhage. c. Afatinib (Gilotrif) is an oral small molecule that competitively inhibits ATP at the kinase domain of EGFR, HER2, and HER4, as well as irreversibly blocks its autophosphorylation. It has been found to be particularly active in NSCLC patients with EGFR exon 19 deletions and exon 21 substitution mutations (L858R). Afatinib is approved for patients with untreated metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 substitution mutations (L858R). This is based on a large phase III trial comparing afatinib to pemetrexed and cisplatin in NSCLC patients with EGFR mutation. Afatinib improved RR by 31% and PFS by 4.2 months, but no benefit in OS was demonstrated. The main benefit was observed in patients with exon 19 deletions or exon 21 (L858R) substitution mutations. The 11% of patients with other EGFR mutations did not achieve a benefit with afatinib. Adverse effects include diarrhea, rash, stomatitis, pruritus, and dry skin. Serious effects include interstitial lung disease, severe diarrhea leading to dehydration, and hepatotoxicity. d. Sunitinib (Sutent) is a competitive inhibitor of ATP that leads to the inhibition of the phosphorylation of the kinase and inhibition of further downstream signal transduction in multiple RTKs. It functions as an inhibitor to a closely related family of RTKs, including PDGFR-α and -β, VEGFR, stem cell factor receptor KIT, FMS-like tyrosine kinase-3 receptor, and the RET oncoprotein. Accordingly, the sunitinib antitumor effect is multifactorial. It inhibits cell proliferation and has an antiangiogenesis effect. The antiangiogenesis effect of sunitinib is through the inhibition of both VEGFR and PDGFR, which is important for the recruitment of pericytes. By inhibiting both VEGFR and PDGFR, sunitinib possesses a stronger inhibiting effect on angiogenesis cells than those agents targeting VEGF alone. Since angiogenesis is the hallmark of RCC and RCC has been demonstrated to overexpress VEGF and PDGF, it is not surprising that sunitinib plays a major therapeutic role in this disease. A multinational phase III clinical trial comparing sunitinib to IFN-α as a first-line treatment in advanced RCC showed a major advantage in OS of 11 months versus 5 months,6 which had led to its approval as a first-line therapy for this indication. KIT and PDGFR play an important role in the development of GIST. More than 85% of GISTs possess activating mutations of the KIT kinase, and another 5% are associated with mutation in the PDGFR. In patients with GIST who progressed through imatinib, sunitinib showed PFS of 24.1 weeks (vs. 6 weeks with placebo) and time to progression (TTP) of 27.3 weeks (vs. 6.4 weeks with placebo). As a result, sunitinib is approved for patients with GIST whose disease has progressed on or unable to tolerate treatment with imatinib. Sunitinib is also approved for patients with locally

advanced or metastatic pancreatic neuroendocrine tumors, based on an increased PFS of 11.4 months compared to 5.5 months with placebo. Common side effects are rash, neutropenia, lymphopenia, thrombocytopenia, and increased transaminases. Serious side effects are HTN, left ventricular dysfunction, prolonged QT, and severe hypothyroidism. e. Lapatinib ditosylate (Tykerb) is an HER2 RTK inhibitor. It is FDA-approved in combination with capecitabine for patients with advanced, refractory HER2+ breast cancer who failed prior therapy including anthracycline, taxane, and trastuzumab and in combination with letrozole as a first-line therapy in patients with hormone receptor–positive metastatic breast cancer. When lapatinib was combined with capecitabine in a phase III, open-label, randomized trial, patients with HER2+, refractory, locally advanced or metastatic breast cancer had a longer time to disease progression compared with capecitabine alone (27.1 vs. 18.6 weeks) and a nonsignificant trend toward longer OS.7 Similar outcomes were found combining lapatinib with letrozole in patients with hormone receptor– positive metastatic breast cancer who had not received prior therapy for metastatic disease, showing PFS of 35.4 months with the combination versus 13 months with letrozole and placebo. Importantly, these outcomes were not found in patients with HER2− disease. Common adverse effects are diarrhea, anemia, and rash. Severe side effects are hand-foot syndrome and severe hepatotoxicity. f. Pazopanib (Votrient) is a TKI of VEGFR, PDGFR, and c-KIT. Pazopanib is FDAapproved for patients with advanced RCC. Pazopanib provided objective RRs of 30% and PFS of 9.2 months in patients with advanced RCC who were previously untreated or who received only cytokine therapy, compared to 3% and 4.2 months, respectively, for placebo. It has also been compared to sunitinib in this patient population and showed an improved RR (31% vs. 25%), but no differences in PFS or OS. It is also approved for patients with metastatic softtissue sarcomas after chemotherapy or who are unfit for chemotherapy, based on improved PFS of 3 months compared to placebo. This improvement was greater in patients with synovial sarcoma. Pazopanib is better tolerated than sunitinib in patients with metastatic RCC. Adverse effects include diarrhea, HTN, and nausea. Noted serious side effects are hepatotoxicity, hemorrhage, MI, and QT prolongation. g. Vandetanib (Zactima) is a multi-TKI of EGFR, VEGFR-2, and RET gene, which is associated with hereditary and sporadic medullary thyroid cancer. Vandetanib demonstrated an improvement in median PFS compared to placebo in unresectable locally advanced or metastatic medullary thyroid cancer with no survival benefit, which had led to its FDA-approval in this disease setting. In patients with advanced NSCLC, the addition of vandetanib to docetaxel resulted in a statistically significant improvement in PFS; however, in a more recent large multicenter study no benefit was found. Common side effects are fatigue,

headache, anorexia, nausea, vomiting, diarrhea, and myelosuppression. HTN and QT interval prolongation are occasional. h. Cabozantinib (Cometriq) is an oral small molecule that inhibits the tyrosine kinase activity of multiple kinases, including RET, MET, VEGFR-1–3, KIT, LFT3, and TIE-2. It is approved for patients with metastatic medullary thyroid cancer based on an improved PFS of 7.2 months compared to placebo and a RR of 27% (none with placebo). In this study, 25% of patients had received prior therapies, and 48% were reported to have a known RET mutation. Common adverse effects include diarrhea, stomatitis, hand-foot syndrome, elevated liver enzymes, neutropenia, and thrombocytopenia. Serious adverse effects include intestinal perforations, rare but fatal hemorrhage, arterial thrombosis, osteonecrosis, and HTN. i. Dacomitinib is an oral TKI that irreversibly inhibits EGFR and has shown activity in patients who developed resistance to other EGFR inhibitors. In a recent phase III trial in unselected patients with advanced or metastatic NSCLC treated with at least one chemotherapy regimen, dacomitinib was found not to be superior to erlotinib. In a more recent phase III trial in patients with untreated exon 19 or exon 21 mutated metastatic NSCLC, PFS at 4 months was 77%. Additional studies are ongoing. Adverse effects include diarrhea, rash, mucositis, dry skin, and nausea. j. Matuzumab is an EGFR inhibitor that was shown to have a RR of 5% and 24% rate of stable disease in patients with NSCLC previously treated with chemotherapy. In a recent phase II study, it was not shown to be effective in combination with chemotherapy in patients with advanced gastroesophageal carcinoma. k. Masitinib (Kinavet) is an orally available small molecule that has activity toward c-KIT and PDGFR. It is used for systemic mastocytosis in canines and now being investigated for the same disease in humans. In a phase II trial with symptomatic systemic or cutaneous mastocytosis, masitinib showed an RR of 56% with most responses lasting over 60 weeks. It is also being studied in patients with GIST. l. Midostaurin is a multitargeted kinase inhibitor with specific activity in D816V KIT mutation. In patients with aggressive systemic mastocytosis (ASM), it showed a RR of 73%. In a separate Italian study, it was used through compassionate use to treat seven patients with systemic mastocytosis. One patient had major response, but the remaining six had a partial response (PR). 9. Bruton tyrosine kinase Bruton tyrosine kinase (BTK) is a signaling molecule of the B-cell antigen receptor, and its inhibition results in decreased B-cell chemotaxis, adherence, and trafficking. Mutations in the gene causes the primary immunodeficiency disease X-linked agammaglobulinemia (also known as Bruton agammaglobulinemia), which results from decreased mature, circulating B-cells and subsequent decreased amount of

immunoglobulins. a. Ibrutinib (Imbruvica) is an oral small molecule that can inhibit BTK, which is an essential tyrosine kinase for B-cell maturation. It is approved for patients with mantle cell lymphoma (MCL) previously treated, including following stem cell transplant, based on an overall RR of 68%, 21% being complete responses (CRs). It has also been studied in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), with an overall RR of 71%, 26-month PFS rate of 75%, and OS rate of 83%. This response was not seen in patients with a mutated immunoglobulin variable-region heavy chain gene, but was maintained in patients with 11q or 17p mutations. Ibrutinib was compared to ofatumumab (discussed further later) in patients with previously treated CLL and demonstrated an improvement of PFS and OS. This led to its approval in patients with relapsed or refractory CLL.8 These outcomes were again preserved in patients with 17p deletions. More recently, it was studied in patients with previously treated Waldenstrom macroglobulinemia. This study showed an overall RR of 90.5%, with 73% being major responses, mainly in patients with MYD88 and CXCR4 mutations.9 Ibrutinib significantly decreased IgM levels while increasing hemoglobin and decreasing bone marrow involvement, resulting in a 2-year OS rate of 95.2%. Common adverse effects include neutropenia, diarrhea, thrombocytopenia, and fatigue. Serious adverse effects include rare cases of hemorrhage, severe myelosuppression, non-melanoma skin cancer, and renal failure. 10. Anaplastic lymphoma kinase Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is found to be mutated in a variety of cancers. ALK typically becomes activated by formation of a fusion gene with a constitutively active gene, gene amplification, or point mutations within the gene itself. The ALK gene, found on chromosome 2, is fused with the nucleophosmin (NPM) gene found on chromosome 5 to form a NPM-ALK fusion protein that is found in 60% of anaplastic large-cell lymphomas. Similarly, ALK may fuse with EML-4 to form an ELM-4-ALK fusion protein that is found in 3% to 5% of NSCLC (most of which are adenocarcinoma), and in 2% of colon, breast, and renal cancers. ALK amplification is found in 40% of neuroblastomas and 87% of inflammatory breast cancers. Overactivation of ALK can contribute to increased cell growth and survival, leading to malignant transformation. Accordingly, a class of inhibitors was created to target ALK. a. Crizotinib (Xalkori) is an oral TKI against ALK, c-MET, and ROS1. It was granted accelerated approval for patients with ALK+ locally advanced or metastatic NSCLC based on an overall RR of 50% to 61% with median duration of response of 42 to 48 months. There were 2 patients who achieved CRs and 69 patients with PRs. On the basis of two separate follow-up studies in patients with ALK+ metastatic NSCLC, it was subsequently granted regular approval.

The first study showed an improved PFS of 7.7 months (vs. 3 months for pemetrexed or docetaxel) in patients who previously received a platinum-based chemotherapy regimen. The second study showed a similar improvement in PFS compared to chemotherapy (11 vs. 7 months) in previously untreated patients.10 Common adverse effects include vision changes, nausea, diarrhea, peripheral edema, and constipation. Serious adverse effects include pneumonitis, increased alanine transaminase (ALT) and bilirubin, and QT prolongation. b. Ceritinib (Zykadia) is an oral ALK TKI against IGF-1R, insulin receptor, and ROS1. It inhibits ALK autophosphorylation and downstream activation of signal transduction and activator of transcription 3 (STAT3) and is roughly 20 times more potent than crizotinib. It is approved in patients with ALK+ metastatic NSCLC who have progressed through or are intolerant to crizotinib, based on a RR of 43% to 55% and median duration of response of 7 months.11 In this study, 1% to 2% of patients had CRs while 40% to 50% of patients had PRs. Common adverse effects include diarrhea, increased aspartate transaminase AST, fatigue, and constipation. Serious adverse effects include pneumonitis, severe nausea and vomiting, hepatotoxicity, QT prolongation, bradycardia, and hyperglycemia. c. Alectinib is an ALK inhibitor that is still under investigation. It has been studied in patients with metastatic NSCLC previously untreated with an ALK inhibitor as well as those previously treated with crizotinib. In two separate studies, it showed a RR of 93% in patients without previous ALK inhibitor exposure and 55% in patients who were previously treated with crizotinib. Additional studies are ongoing. 11. Inhibition of intracellular signaling proteins and protein kinases This therapeutic strategy is directed against a group of proteins that function in a network of communicating cascades to transfer the signal from receptors into the nucleus to produce the intended biologic effect such as cell proliferation, apoptosis, and angiogenesis. When these proteins mutate, the pathways become unregulated, contributing to the malignant transformation of the cell. These proteins are either non-RTKs or serine/threonine kinases. The non-RTKs are cytoplasmic kinases. Many of these are attached to and closely linked to membrane receptors. They are usually activated by the binding of ligand to their associated receptors. Some of these kinases include Src, Abl, and Janus kinase (JAK). The serine/threonine kinases are intracellular kinases, and some play crucial roles in carcinogenesis. These kinases include Raf, kinases from the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway, and MAP kinases. Small molecules have been designed to block or reverse the effect of these pathways. In general, these molecules can target multiple proteins, including receptor kinases. They can, therefore, be classified as receptor kinase inhibitors. For simplicity, this chapter classifies these kinases based on their primary kinase or pathway effect and alludes to their other roles within the description of the drug.

12. BCR-ABL fusion protein The BCR-ABL fusion protein is the resultant product of the translocation between the BCR and ABL-1 genes. The ABL-1 gene encodes a non-RTK, while the BCR encodes a serine/threonine kinase. The product of the translocation encodes for a phosphorylated fusion protein that activates many pathways, including the RAS, PI3K, and STAT pathways, and results in malignant transformation. A few drugs are designed to target this molecule. a. Imatinib mesylate (Gleevec) is one of the first targeted therapy small molecules to enter into clinical practice. It is primarily a protein kinase inhibitor that is designed to inhibit BCR-ABL fusion tyrosine kinase. By inhibiting the BCR-ABL fusion tyrosine kinase, imatinib mesylate induces apoptosis in BCR-ABL– positive cells through binding to ABL-1 and competing with ATP, leading to inhibition of the active tyrosine kinase of the fusion protein. Imatinib has seven FDA-approved indications in both solid and hematologic cancers. Given its mechanism of action, it is active in any cancer with the BCR-ABL fusion tyrosine kinase (also known as the Philadelphia chromosome [Ph]), particularly BCRABL–positive chronic myelogenous leukemia (CML) and BCR-ABL–positive acute lymphocytic leukemia (ALL). Imatinib mesylate produces hematologic, cytogenetic, and molecular remissions that are often long-term and sustainable and have now been shown to be beneficial for up to 5 years of use. In patients with newly diagnosed chronic-phase CML, imatinib has an improved hematologic RR of 96.6% compared to 56.6% for IFN in combination with cytarabine (IFN + Ara).12 Of these responses, 85.2% of the imatinib responses were major (vs. 16.8% with IFN + Ara) and 73.1% were complete (vs. 6.3% with IFN + Ara). Similar RRs were found when studied in patients with accelerated phase and blast crisis, with 20% and 18%, respectively, returning to chronic phase and 16% and 2%, respectively, having a complete cytogenetic response with imatinib alone. In two separate studies, similar RRs were observed in untreated pediatrics patients (up to 20 years old) and patients resistant to IFN. Patients with chronic-phase Ph+ ALL have also been found to have a benefit from imatinib. Patients with previously untreated or relapsed/refractory Ph+ ALL have shown RRs similar to patients with CML. The current FDA-approved indications for imatinib include CML that is Ph+ whether newly diagnosed, in chronic phase, in accelerated phase or blast crisis, after failure of IFN-α therapy, or recurrence after stem cell transplant. It is also approved in Ph+ ALL that has recurred or is refractory (in adults) and as the first treatment (in children). Imatinib is also approved in patients with myelodysplastic/myeloproliferative syndromes (MDS/MPS) with PDGFR gene rearrangements. In a small phase II study of seven patients with MDS, 45% developed a complete hematologic response with 39% being a major cytogenetic response. In addition, imatinib mesylate inhibits the receptor kinases PDGF and

c-KIT, which are found to be mutated in a variety of cancers. Thus, imatinib was approved for patients with untreated ASM, having a complete hematologic RR of 100% in patients with a FIP1L1-PDGFR fusion kinase or CHIC2 deletion. This benefit was not seen in patients with the D816V c-KIT mutation, and these patients should not receive imatinib. Imatinib is not approved for the less aggressive forms of mastocytosis such as cutaneous, smoldering, or isolated bone marrow mastocytosis. Another cancer associated with c-KIT and PDGFR mutations is hypereosinophilic syndrome/chronic eosinophilic leukemia. In this patient population, imatinib has a 61% complete hematologic RR and a 13% partial RR. In patients with a FIP1L1-PDGFR fusion kinase, 100% had a CR. Imatinib is also approved for patients with dermatofibrosarcoma protuberans, which is characterized by a translocation involving the PDGFR and collagen type 1 genes. In patients with metastatic, locally recurrent, or locally advanced disease, 83% of patients responded to imatinib, with 39% CR and 44% PR. As c-KIT is mutated in 85% of GISTs, imatinib has been studied in patients with cKIT-positive GISTs. In patients with metastatic or unresectable c-KIT-positive GIST, PFS was found to be 20 months, OS was 50 months, and overall RR was around 50% with 5% of the responses being CRs. In the adjuvant setting, imatinib has also shown a survival benefit compared to placebo following resection of GIST with a 1-year relapse-free survival (RFS) rate of 98% versus 83% with placebo. This benefit extended to a 5-year RFS rate of 66% if imatinib is taken for 36 months (vs. 48% if taken for 12 months). Common adverse effects are edema, rash, diarrhea, vomiting, and night sweats. Serious side effects are congestive heart failure (CHF), cardiogenic shock and tamponade, severe anemia, thrombocytopenia, and febrile neutropenia. Clinically significant resistance to imatinib mesylate has been found to occur in patients who develop mutations within the kinase domain of the BCR-ABL proteins. Therefore, alternative BCR-ABL inhibitors have been developed. b. Dasatinib (Sprycel) is an oral inhibitor of multiple tyrosine kinases, including BCR-ABL, c-KIT, and PDGFR. In patients with chronic-phase CML who are resistant or intolerant to imatinib, 92% achieved complete hematologic responses with dasatinib, with 63% being major cytogenetic and 50% being complete cytogenetic responses. Similar RRs were found in patients with accelerated, myeloid blast or lymphoid blast CML as well as Ph+ ALL. Therefore, dasatinib was initially approved for patients with chronic, accelerated, or blast phase of CML who are intolerant or resistant to prior therapy with imatinib. Subsequently, dasatinib was also approved as a first-line therapy in CML based on a study that showed a superiority of dasatinib over imatinib in major molecular RR and complete cytogenetic RR at 12 months (46% vs. 28% and 77% vs. 66%, respectively).13 Dasatinib is also indicated in patients with Ph+ ALL who failed or are intolerant to prior therapy. Dasatinib

can cause edema, pleural effusions, ascites, and rash. Serious side effects include CHF, prolonged QT, anemia, thrombocytopenia, and neutropenia. c. Nilotinib (Tasigna) is another ABL kinase inhibitor. Similar to imatinib, it acts by competing with the ATP-binding site of BCR-ABL. Nilotinib differs from imatinib by having a higher binding activity to the ABL kinase site with higher inhibitory activity in imatinib-sensitive cell lines. Similar to dasatinib, nilotinib was found to induce both hematologic and cytogenetic responses in patients with Ph+ CML in chronic or accelerated phase who are resistant or intolerant to imatinib. Nilotinib was initially approved by the FDA in chronic- or accelerated-phase CML that is resistant or intolerant to imatinib. Also similar to dasatinib, nilotinib was subsequently approved as a first-line therapy in CML based on data demonstrating superiority over imatinib in complete cytogenetic RR at 12 months (80% vs. 65%) and major molecular RR (from 22% to 44%) and the time of progression to accelerated phase or blast crisis.14 Edema, rash, nausea, diarrhea, thrombocytopenia, and anemia are among the common side effects. Prolonged QT, torsade de pointes, and sudden death are among the serious side effects. d. Ponatinib (Iclusig) is a highly potent ABL kinase inhibitor with inhibitory effects on VEGFR, PDGFR, FGFR, KIT, and FLT3. It is specifically effective in patients with a T315I-mutated BCR-ABL kinase. It is approved for patients with all phases (chronic, accelerated, or blast) of CML as well as Ph+ ALL that relapsed or refractory to other TKIs. This is based on a large study showing a major cytogenetic RR of 54% (with 44% CRs) in patients in all phases of CML. This RR was improved to 49% (37% complete) in patients who were refractory or intolerant to prior TKIs and further increased to 70% (with 66% CRs) in patients with the T315I substitution mutation.15 In patients with Ph+ ALL who were resistant or intolerant to prior TKIs, major hematologic RR was 41%, with 34% having complete hematologic responses. Common adverse effects include HTN, rash, fatigue, fever, and pancytopenia. Serious adverse effects include decreased LVEF, pancreatitis, fatal hemorrhage, QT prolongation, arterial thrombosis, and hepatotoxicity. e. Bosutinib (Bosulif) is also a BCR-ABL kinase inhibitor and has activity against the Scr-family of kinases. Bosutinib was designed to inhibit imatinib-resistant forms of BCR-ABL that is expressed in murine myeloid cell lines and has been shown to block 16 of the 18 resistant forms. It is approved for patients with all phases of CML who are resistant or intolerant to imatinib and have failed combination TKIs (particularly imatinib followed by dasatinib and/or nilotinib). This is based on a major cytogenetic RR of 34% in patients with chronic-phase CML previously treated with imatinib alone and 29% in patients treated with combination TKIs. In patients with accelerated or blast phase, complete hematologic RRs were 30% and 15%, respectively. Bosutinib is not active in

patients with the highly resistant T315I mutation. Common adverse effects include diarrhea, nausea, thrombocytopenia, rash, and fever. Serious adverse effects include severe myelosuppression, hepatotoxicity, and peripheral edema. f. Navitoclax (ABT-263) is a BCL-2 inhibitor that has been studied in patients with SCLC that progressed after at least one prior chemotherapy regimen with 1 out of 29 patients achieving a PR for over 2 years. In a more recent phase II trial in similar patient population, single-agent navitoclax showed a PFS of 1.5 months and OS of 3.2 months, with 41% of patients developing grade 3 or 4 thrombocytopenia. g. ABT-199 (Venetoclax) is a BCL-2 inhibitor that was designed to reduce the degree of severe thrombocytopenia seen in earlier inhibitors in its class. It demonstrated significant anti-leukemia activity in early studies, with a RR of 77% in patients with relapsed or refractory CLL (23% with CRs). ABT-199 resulted in significant tumor lysis after a single dose in three patients with refractory CLL. Additional studies are ongoing. It is generally well tolerated with neutropenia, diarrhea, nausea, and fatigue but without severe thrombocytopenia. h. Quizartinib is an oral potent FLT3 kinase inhibitor that has shown activity in patients with FLT3-mutated acute myeloid leukemia (AML), which typically conveys an aggressive leukemia and is less likely to respond to standard chemotherapy. In a recent phase II trial, it had a 46% RR in patients with FLT3mutated AML, allowing 37% to proceed to stem cell transplant. Additional studies are ongoing. 13. Signal transduction and activator of transcription STAT proteins are a family of seven transcription factors that are active by a variety of extracellular ligand-receptor interactions and are involved in cell proliferation, differentiation, and apoptosis. Studies have suggested that STAT proteins, and STAT5 in particular, are involved in controlling cell cycle, cell survival, and angiogenesis. Several other mutated oncogenic proteins have been shown to lead to constitutive activation of STAT proteins, including BCR-ABL, FLT-3, ABL, and JAK2. This has made STAT inhibition a novel therapeutic strategy, with several investigational drugs currently under investigation. a. OBP-31121 is a novel STAT3 inhibitor that has been shown to have a significant antitumor effect against leukemia and lymphoma cell lines. Phase I clinical trials are ongoing in patients with both solid tumor and hematologic malignancies. b. ISIS-481464 (AZD-9150) is an antisense oligonucleotide targeting STAT3. It was recently studied in patients with variety of solid tumors and both Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), resulting in PRs in two patients with diffuse large B-cell lymphoma (DLBCL). Multiple studies are ongoing in patients with HCC, DLBCL, and other advanced lymphomas. 14. Janus kinase

The cytoplasmic Janus protein tyrosine kinases (JAK) are a family of signal transduction kinases that are essential for cellular survival, proliferation, and apoptosis. Activation of JAK has been shown to result in downstream activation of other pathways such as STAT, Raf, and the PI3K/Akt pathways. Thus, the JAK pathway has been targeted in a variety of malignancies. a. Ruxolitinib (Jakafi) is an oral small molecule that inhibits JAK1 and JAK2 and is FDA-approved for patients with untreated intermediate or high-risk myelofibrosis (MF). This is based on two separate phase III trials in patients with MF, mostly untreated but some had previously received hydroxyurea or steroids. In the first study, single-agent ruxolitinib resulted in a 42% reduction in spleen size compared to 1% with placebo. The second study showed similar splenic reduction (41% vs. 0% with placebo).16 Ruxolitinib has also been shown to improve patient’s symptoms. It is also approved for patients with polycythemia vera refractory or intolerant to hydroxyurea, based on an improved RR (spleen size and phlebotomy dependence) of 21% compared to 1% with placebo. Ruxolitinib has also been studied in patients with previously treated metastatic pancreatic cancer demonstrating an improved OS and PFS compared to placebo. Common adverse effects include mild thrombocytopenia, anemia, dizziness, and headache. Serious effects include thrombocytopenia and neutropenia. b. Pacritinib is an oral TKI with potent activity against JAK2 and Flt-3. It was granted Fast Track Designation by the FDA for patients with intermediate or high-risk MF. This was based on its use in this patient population showing a reduced spleen size by over 50% (31% by MRI, 42% by physical exam) and improved symptoms in over 50% of patients. Phase III trials are ongoing. 15. The RAF/MAP pathway The RAF is a family of serine/threonine kinases that includes ARAF, BRAF, and CRAF and is part of the RAS pathway. RAF is activated when RAS, in response to the activation of a RTK, recruits and phosphorylates RAF kinase at the membrane site. RAF, in turn, phosphorylates MEK that activates and phosphorylates ERK. Activated ERK enters the nucleus to activate other transcription factors, leading to cellular proliferation. Aberration in this pathway leads to deregulation of proliferation, resulting in transformation of the cell. BRAF has been found to be mutated in many tumors such as melanoma, thyroid, and colorectal cancers. Therefore, inhibition of this kinase is a desirable target in cancer treatment. a. Sorafenib (Nexavar) is a small molecular inhibitor of CRAF kinase that leads to the inhibition of the RAF/MEK/ERK signaling pathway. Sorafenib has also been found to be a strong inhibitor of both VEGFR-2 and PDGF kinase. In patients with metastatic or advanced RCC untreated or treated previously with IL-2 or IFN, sorafenib showed an improved PFS compared to placebo leading to its FDA-approval in advanced RCC. However, with only 2% radiologic RR, the

benefit reflected stable disease. Sorafenib is also approved for the treatment of patients with unresectable HCC after it was found to prolong the median survival by 2.8 months and the time to radiologic progression by 2.7 months compared to placebo.17 The majority of these patients had well-compensated, early cirrhosis, with 95% Child-Pugh class A cirrhosis. Sorafenib was also recently approved for patients with recurrent or metastatic, progressive, differentiated thyroid cancer after radioactive iodine, based on an improved RR of 12% (1% with placebo) and PFS of 10.8 months (5.8 months with placebo). Other clinical trials are ongoing to test the efficacy of sorafenib in other cancers. Common side effects are HTN, alopecia, hypophosphatemia, and diarrhea. Severe side effects are hand-foot syndrome, chronic heart failure, and MI. b. Trametinib (Mekinist) is an inhibitor of MAP kinase (MEK/MAPK/ERK kinase). MEK-1 and -2 are upregulated in different cancers, and they are involved in the activation of the RAS/RAF/MEK/ERK signaling pathway. Trametinib specifically inhibits MEK-1 and -2, resulting in an inhibition of growth factor– mediated cell signaling and proliferation. It is approved for patients with metastatic or unresectable melanoma with BRAFV600E or BRAFV600K point mutations based on improved PFS (by 3.3 months) and RR (by 14%) compared to chemotherapy of paclitaxel or dacarbazine.18 In a second trial, trametinib was combined with dabrafenib in patients with BRAFV600E- or BRAFV600K-mutated unresectable or metastatic melanoma who had received one prior chemotherapy regimen.19 This combination demonstrated an RR of 76% compared to 54% in patients who received dabrafenib alone, leading to its approval in this patient population. Common adverse effects include rash, diarrhea, and lymphedema. When combined with dabrafenib, additional adverse effects include fever, nausea, fatigue, and myalgia. Serious effects include decreased LVEF, venous thromboembolism (VTE), increased rate of basal cell carcinoma, and hemorrhage. c. Dabrafenib (Tafinlar) is a selective inhibitor of RAF kinases. It has more potency toward BRAF than CRAF and inhibits BRAF kinase activity 100-fold more than sorafenib. Thus, it may be promising in overcoming the resistance to BRAF inhibitors. It is approved for patients with untreated BRAFV600E- or BRAFV600K-mutated unresectable or metastatic melanoma. Compared to dacarbazine, dabrafenib improved RR by 35% (3% CR vs. none with dacarbazine) and PFS by 2.4 months. Dabrafenib is also approved for use with trametinib as described earlier. Common adverse effects are similar to those of trametinib in addition to alopecia and hand-foot syndrome. d. Vemurafenib (Zelboraf) is a selective inhibitor of the oncogenic V600E-mutant BRAF kinase. It is approved for patients with untreated BRAFV600E-mutated unresectable or metastatic melanoma based on an improved PFS of 3.7 months

and RR of 43% compared to dacarbazine.20 Common adverse effects include arthralgia, rash, alopecia, and fatigue. Serious adverse effects are QT prolongation, photosensitivity, rash, and increased incidence of cutaneous squamous cell carcinoma. e. Binimetinib (MEK-162) is an oral potent inhibitor of MEK-1 and -2. It is currently being studied in patients with NRAS-mutant unresectable or metastatic melanoma that have previously received immunotherapy. f. Regorafenib (Stivarga) is an oral multikinase inhibitor, including RET, VEGFR1–3, KIT, PDGFR, FGFR-1 and -2, RAF, BRAF, and TIE-2. It was recently approved for heavily pretreated patients with metastatic CRC. This is based on a study of patients with metastatic colorectal cancer previously treated with 5-FU-, oxaliplatin-, and irinotecan-based chemotherapies as well as bevacizumab. Most patients were also KRAS-WT and previously received panitumumab or cetuximab. In this patient population, regorafenib demonstrated an RR of 5%, an improved PFS by 0.3 months, and OS by 1.4 months compared to placebo. It is also approved for patients with advanced GIST who are refractory or intolerant to imatinib, based on an improved PFS of 4.8 months (compared to 0.9 months with placebo). Common adverse effects include fatigue, hand-foot syndrome, diarrhea, mucositis, and HTN. Serious effects include hepatotoxicity and rare but fatal hemorrhage. g. Tivantinib is a MET inhibitor that has shown activity in a variety of cancers including NSCLC, HCC, and gastric adenocarcinoma. In a recent phase II trial, patients with metastatic gastric cancer showed a PFS of 1.4 months and stable disease in 37% patients when used as a second or third line after chemotherapy. h. Pimasertib is a selective MEK-1 and MEK-2 inhibitor that has shown preclinical activity in lung and colorectal cancers. It is currently being studied in phase II trials in melanoma, lung, and colorectal cancers. i. Foretinib is a multikinase inhibitor of MET, VEGFR-2, and ROS1. ROS1 has been found to be overexpressed in a variety of tumors including lung adenocarcinoma, cholangiocarcinoma, gastric adenocarcinoma, and glioblastoma. Foretinib is currently being studied in patients with lung adenocarcinoma. j. Linifanib is an oral tyrosine kinase with activity against VEGFR and PDGFR. It showed an improved PFS of 2.9 months compared to placebo in patients with advanced nonsquamous NSCLC. It was also studied in patients with advanced HCC, but did not show a survival benefit compared to sorafenib. Common adverse effects include diarrhea, anemia, and HTN. Serious adverse effects include severe thrombocytopenia. k. Refametinib is a potent inhibitor of MEK-1 and MEK-2. In a recent phase II trial in patients with previously treated metastatic pancreatic cancer, the combination of refametinib and gemcitabine demonstrated a trend toward improved response,

PFS, and OS in the KRAS-WT subset of patients. 16. Aurora kinase Aurora kinases are a network of kinases involved in mitosis. Aurora kinase A, in particular, is essential for centrosome function and maturation, spindle assembly, chromosome alignment, and entry into mitosis. Inhibition of these kinases disrupts spindle formation and prevents entry into mitosis, leading to cell cycle arrest and apoptosis. Overexpression of these kinases has been found in gastric, breast, lung, and head and neck squamous cancers. a. Alisertib is an orally available selective aurora kinase A inhibitor that demonstrated a significant activity in preclinical studies. In a recent phase II trial in patients with previously treated malignancies, it is was found to have an RR of 18% in breast cancer, 21% in SCLC, 4% in NSCLC, 9% in SCCHN, and 9% in gastric cancer. Adverse effects include severe neutropenia, fatigue, alopecia, and diarrhea. Additional studies are ongoing in patients with breast, lung, and peripheral T-cell lymphomas. 17. PI3K, Akt, and mTOR pathway The PI3Ks are a family of lipid kinases divided into three classes based on their protein structure. Class I PI3K has been studied more closely due to the role it plays as a regulator of cell survival, proliferation, and differentiation. Class IA PI3Ks, composed of four subunits (p110α, β, γ, and δ), is recruited to the membrane upon the activation of RTKs. This leads to a signaling cascade that activates multiple downstream signaling pathways, including the Akt pathway. The mTOR pathway is downstream of the PI3K/Akt pathway and plays an important role in cell growth regulation and proliferation. The mTOR pathway is regulated by the PTEN tumorsuppressor gene, which encodes for a phosphatase that works as an on/off switch. The switch moves to “on” position when PI3K deposits a phosphate group on the D3 position of the inositol ring; when PTEN removes this same phosphate group, the switch moves to the “off” position. It has been found that genetic alterations in the PI3K pathways play an important role in different cancers, including breast, colon, and ovarian cancers. Therefore, a plethora of novel agents targeting the PI3K/Akt/mTOR pathways have recently been developed for treatment of cancer. Three of these agents are already approved by the FDA, and the rest are still under clinical trials and expected to reach the clinic in the next decade. a. Everolimus (Afinitor) is a kinase mTOR inhibitor. It is approved for patients with metastatic RCC previously treated with sunitinib, sorafenib, or both, based on an improvement of PFS by 3 months compared to placebo. Everolimus, in combination with exemestane, is also approved in postmenopausal women with hormone receptor–positive metastatic breast cancer after letrozole or anatrozole. This is based on an improved PFS of 7 months (vs. 3 months with placebo) and improved RR of 9.5% (vs. 0.4%), but no difference in OS. Everolimus has also been studied in combination with tamoxifen in postmenopausal women who have

previously been treated with an aromatase inhibitor and showed an improved TTP of 9 months compared to 5 months with placebo.21 Everolimus is also approved for patients with locally advanced, unresectable or metastatic pancreatic neuroendocrine tumors, based on an improved PFS of 11 months versus 4.6 months with placebo. It has also been studied in patients with advanced carcinoid tumors and, when combined with long-acting octreotide, it improved PFS to 16.4 months compared to 11.3 months with long-acting octreotide and placebo. Everolimus is also approved for patients with tuberous sclerosis complicated by unresectable subependymal giant cell astrocytoma based on reduction in tumor size by at least 30% in 75% of patients at 3 months compared to placebo. Everolimus showed a decreased seizure frequency and improved quality of life in these patients compared to placebo. Common side effects include rash, edema, and diarrhea. Serious side effects include pneumonitis, anemia, leukopenia, and neutropenia. b. Temsirolimus (Torisel) is a competitive inhibitor of the mTOR kinase. It is approved for patients with untreated advanced RCC, both clear cell and non– clear cell histology. In a phase III trial, patients with a poor prognosis and/or poor performance status were treated with either temsirolimus or IFN-α. Both PFS and OS were improved by 2.4 and 3.6 months, respectively, favoring temsirolimus.22 Common side effects include anemia and hyperlipidemia. Serious anaphylaxis was also reported. c. Idelalisib (Zydelig) is a potent inhibitor of PI3K-δ. Inhibiting PI3K-δ subsequently blocks cellular proliferation and induces apoptosis. It is currently approved for patients with relapsed CLL in combination with rituximab as well as relapsed follicular lymphoma and relapsed small lymphocytic lymphoma (SLL). In patients with relapsed CLL who were unable to tolerate additional chemotherapy after an average of three prior regimens, idelalisib plus rituximab improved PFS compared to placebo.23 In patients with relapsed follicular lymphoma after two previous therapies, idelalisib showed a RR of 54% with 8% having a CR, and median time to response of 1.9 months. Similar RRs were found in patients with relapsed SLL, although no CRs were observed. Common adverse effects include diarrhea, fever, fatigue, nausea, and rash. Serious adverse effects include anaphylaxis, colitis (with rare cases of perforation), pneumonitis, and neutropenia. d. Pilaralisib (XL147) is an orally available selective inhibitor of class I PI3K isoform. It was studied in a phase I trial in patients with solid tumors, primarily NSCLC, and found to be safe with some patients having stable disease. It was shown to have an overall RR of 6% in patients with advanced or recurrent endometrial cancer after at least one prior chemotherapy regimen. It is also being evaluated in combination with trastuzumab or paclitaxel and trastuzumab in patients with metastatic breast cancer who have progressed on a previous

trastuzumab-based regimen. The most common side effects are rash, diarrhea, and fatigue. e. XL765 is a selective inhibitor of mTOR and class I PI3K isoform. A phase II trial is ongoing to evaluate the safety and clinical efficacy of either XL147 or XL765 in combination with letrozole in patients with breast cancer that is ER+/PR+ and HER2− and refractory to a nonsteroidal aromatase inhibitor. It is also currently being studied in glioblastomas and NHL. f. Buparlisib is an inhibitor of PI3K and found to be safe and active in early studies treating breast cancer and glioblastomas. In a recent phase II trial, it provided stable disease without a survival benefit in patients with resectable and unresectable glioblastomas. Additional studies are ongoing. Adverse effects include asymptomatic lipase elevation, rash, hyperglycemia, and fatigue. g. MK2206 is an orally available inhibitor of Akt through a non-ATP–competitive inhibition mechanism leading to apoptosis. It has shown activity against nasopharyngeal carcinoma cell lines, and clinical trials are ongoing. 18. Hedgehog signaling pathway The hedgehog signaling pathway is essential for embryonic and limb development. It has been found to be important in cell signaling and migration during brain and limb development, in addition to stem cell migration. Its role in these processes is thought to convey the cancer cells ability to metastasize to distant organs. It has been found to be over-activated in multiple cancers such as lung, brain, prostate, and skin cancers. Inhibition of this pathway has been shown to inhibit proper formation of the brain, gastrointestinal system, and limbs in mouse models and represents a novel antineoplastic mechanism. a. Vismodegib (Erivedge) is an orally available hedgehog pathway inhibitor that is approved for patients with locally advanced or metastatic basal cell carcinoma. This is based on a RR of 10% in patients with metastatic disease and 27% in patients with locally advanced disease (13% of these patients had CR) and a median duration of response of 7.6 months in both groups.24 Vismodegib has also shown activity in combination with chemotherapy in a small set of 59 patients with untreated metastatic pancreatic cancer demonstrating 2% CR, 41% PR, and 43% stable disease. Common adverse effects include muscle spasms, alopecia, weight loss, diarrhea, and nausea. Patients who are treated with vismodegib should not donate blood or blood products due to the teratogenicity of this drug. b. Erismodegib (Sonidegib) is a hedgehog signaling pathway inhibitor being studied in a variety of cancers, including basal cell carcinoma. c. IPI-926 (Saridegib) is also a hedgehog signaling pathway inhibitor being studied in chondrosarcoma treatment. 19. Poly(ADP-ribose) polymerase (PARPS) PARPs are a family of proteins involved in DNA repair. Found in the nucleus, it surveys DNA for single-strand breaks and, once found, initiates a cascade of

proteins to repair the break. If unable to repair the damage, it can induce programmed cell death through a caspase-independent mechanism. Inhibition of PARP is thought to disrupt cellular homeostasis and lead to cell death. This mechanism is thought to be essential for the BRCA1/2 oncogenesis and thus multiple agents have been developed to target PARP. a. Olaparib (Lynparza) is an oral PARP inhibitor that showed initial activity in BRCA1/2 related cancers, including ovarian, breast, and prostate related cancers. It is currently approved for patients with BRCA-mutated advanced ovarian cancer previously treated with at least three chemotherapy regimens. This is based on an RR of 34% in this patient population, with 2% complete RR. Common adverse effects include anemia, nausea, fatigue, diarrhea, and headache. Serious adverse effects include an increased incidence of MDS and AML and rare but fatal pneumonitis. b. Iniparib is an irreversible PARP-1 inhibitor (although recent data suggest alternative mechanisms). It has been studied in combination with gemcitabine and carboplatin (GC) in patients with metastatic triple-negative breast cancer, showing an improved RR of 52% (vs. 32% with GC alone), PFS of 5.9 months (vs. 3.6 months), and OS of 12.3 months (vs. 7.7 months). These findings, however, were not replicated in a later phase III trial. Additional studies are ongoing. c. Niraparib is an orally available PARP-1 and PARP-2 inhibitor that showed promising preclinical activity. It is currently being studied in a phase III trial in patients with platinum-sensitive recurrent ovarian cancer. 20. Histone deacetylase Histone deacetylases (HDACs) are a family of proteins that catalyze the removal of acetyl groups from lysine groups on histones and non-histone proteins. The removal of the lysine group is necessary for DNA to properly coil around histone groups and condense chromatin. If blocked, chromatin relaxes and cannot proceed through the cell cycle and results in apoptosis. a. Panobinostat (Farydak) is a small molecule that is highly specific and sensitive for the HDAC. In preclinical studies, it was shown to be more cytotoxic to tumor cells than normal cells, likely a result of tumor cells reliance on frequent chromatin condensing for proliferation. It is approved in combination with bortezomib (Velcade) and dexamethasone (VD), in patients with multiple myeloma (MM) who have progressed through two prior therapies. The combination of panobinostat with VD improved RR from 41% to 55% and PFS by 4.8 months compared to placebo. It is also being studied in MDS, breast, and prostate cancers. Common adverse effects include diarrhea, fatigue, nausea, and pancytopenia. Serious adverse effects include rare but fatal hemorrhage, severe thrombocytopenia, and hepatotoxicity. b. Vorinostat (Zolinza) is an orally available small molecule that inhibits HDAC1–

3 and HDAC6. It is approved for patients with cutaneous T-cell lymphoma (CTCL) after at least two prior therapies. This is based on two separate trials in patients with CTCL refractory to two previous therapies, both showing a RR of around 30% with a median duration of response of around 3.5 months. Common adverse effects include diarrhea, fatigue, nausea, and thrombocytopenia. Serious effects include pulmonary emboli and anemia. c. Romidepsin (Istodax) is an infusional HDAC inhibitor with activity in patients with CTCL. It is approved for patients who have received at least one prior treatment, based on two studies showing a 35% RR and duration of response of 11 to 15 months. Common adverse effects include fatigue, nausea, decreased appetite, and weight loss. Serious effects include QT prolongation, leukopenia, and thrombocytopenia. d. Mocetinostat is an oral small molecule that selectively inhibits HDAC1–3 and HDAC11. In preclinical studies, it was shown to be active in AML, HL, and NHL. In a recent phase II trial, it was combined with azathioprine in mostly untreated patients with MDS and showed a RR of 80% with a complete bone marrow RR of 50%, even in patients with baseline marrow blast count over 10%. In another phase II trial in patients with relapsed or refractory HL, mocetinostat showed a RR of 35%. Additional trials are ongoing in MDS, AML, HL, and urothelial cancer. B. Angiogenesis-targeted therapy Angiogenesis is a biologic process that is crucial for the development of tumors. The process of angiogenesis starts by the release of VEGF. VEGF binds to receptors on the blood vessels’ endothelial cells, leading to their proliferation and immigration toward the source of the angiogenic signal. Tumors have exploited this physiologic process to provide the milieu to permit the growth of both primary and metastatic cancers. Although the antineoplastic effect of antiangiogenesis therapy is mediated through the effect on the environment for the cancer cell growth, the initial mechanism of current therapies is based on molecular targeting, which was previously described. 1. Trebananib is a potent inhibitor of angiopoetin-1 and -2, as well as TIE-2R, which has been shown to be important in cancer-related angiogenesis. In patients with recurrent epithelial ovarian cancer treated with at least three previous chemotherapy regimens, trebananib showed an improved PFS of 1.8 months but no improvement in OS. In this study, 17% of patients discontinued trebananib because of adverse effects, including edema, ascites, and neutropenia. C. Protein degradation–targeted therapy Protein degradation is one of the mechanisms by which cell function is regulated. The ubiquitin-proteasome pathway plays a very important role in this regard. The proteasome is a large complex of proteins that degrades other ubiquitinated proteins. It exerts its degradation capability through coordinated catalytic activities of its three proteolytic sites that leads to chymotryptic, tryptic, and postglutamyl peptide hydrolytic-

like activities. Many key proteins in the cell cycle, apoptotic, and angiogenesis pathways are regulated by degradation, including the p53, p21, and p27 (cell cycle regulatory) proteins; NF-κB, a key transcription factor that is activated by the proteasomes; and intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule (VCAM), and E-selectin (cell adhesion molecules). Drugs targeting degradation machinery in the cell include the following. 1. Bortezomib (Velcade) is a dipeptidyl boronic acid derivative that inhibits the 26S proteasome, which is the principal regulator of the intracellular protein degradation. Bortezomib is the first of its class to be approved for clinical use. Bortezomib can selectively inhibit the chymotryptic site of the proteasome. This leads to a selective inhibition of the degradation of proteins involved in cell proliferation and survival regulation; as a consequence, apoptosis is induced. Bortezomib has been found to be particularly effective in MM where it is approved as a first-line therapy. The addition of bortezomib to melphalan and prednisone (MP) improved RR to 71% (35% with MP alone), PFS to 18.3 months (14 months with MP), and OS (median not reached in 16.3 months in either group).25 It has also been shown to be effective in combination with several other agents in patients with untreated and pretreated MM, in addition to patients who had stem cell transplant. Bortezomib is also FDAapproved for patients with MCL who failed at least one prior therapy, based on an RR of 33% (8% complete) with median duration of response of 9.3 months (15.4 months for those with a CR). Bortezomib has also been studied in patients with relapsed or refractory peripheral T-cell lymphoma with an RR of 67% when used alone and a CR rate of 62% when combined with Cytoxan, hydroxydaunorubicin, Oncovin, and prednisone (CHOP). Additional studies in this patient population are ongoing. Common adverse effects include asthenia, HTN, rash, and diarrhea. Serious side effects include CHF, anemia, neutropenia, and thrombocytopenia. 2. Carfilzomib (Kyprolis) is the next generation of proteasome inhibitor with higher selectivity and specificity than bortezomib. It binds selectively to the N-terminal threonine active sites within the proteasome and is approved for patients with MM who have failed two prior therapies, including bortezomib and an immunomodulator. This is based on its overall RR of 23% and OS of 15.6 months (compared to 9 months for historical controls). In patients with MM previously treated with one to three previous regimens, carfilzomib with lenalidomide and dexamethasone (Rd) showed an impressive PFS of 26.3 months compared to 17.6 months with Rd alone. Common adverse effects include fatigue, anemia, thrombocytopenia, dyspnea, and diarrhea. D. Nonspecific immunomodulators Nonspecific immunomodulators are a family of medications that are derivatives of thalidomide by minor structural modifications. These modifications lead to the enhancement of drug efficacy and the improvement in the side effect profile, including the neurologic toxicity and prothrombotic effects of thalidomide. The mechanism of

action for this group of compounds is not clearly defined, but many pathways have been shown to be triggered by these medications, including caspase-8, proteasome, NF-κB, and the antiangiogenesis pathways. 1. Lenalidomide (Revlimid) is one of the new generations of nonspecific immunomodulators. In a randomized phase III study, when combined with dexamethasone, lenalidomide was found to be superior in CR, PFS, and OS to dexamethasone alone in patients with relapsed or refractory MM. When lenalidomide was combined with dexamethasone in patients with newly diagnosed MM in two separate studies, combined results showed 91% of patients achieved an objective response, including 11% with CR.26,27 Lenalidomide has also been studied in various combination with other active agents in myeloma in this patient population demonstrating improvement in RRs and PFS. A lower dose of lenalidomide is approved for patients with MDS with 5q deletion who are transfusion dependent, with 67% achieving transfusion independence (90% within 3 months). It is also approved for patients with relapsed MCL after two prior therapies including bortezomib, based on an RR of 28%, PFS of 4 months, and OS of 19 months. Common adverse effects include somnolence, constipation, neuropathy, edema, and rash. Serious side effects include atrial fibrillation, StevensJohnson syndrome, neutropenia, anemia, and thrombocytopenia. 2. Pomalidomide (Pomalyst) is an oral thalidomide analog that is an immunomodulatory agent with antineoplastic activity. It has shown to induce apoptosis in lenalidomide-resistant MM cell lines and provide synergy with dexamethasone. It is approved for patients with MM that has been refractory to at least two prior therapies, including lenalidomide and bortezomib. This is based on an overall RR of 33% and duration of response of 7.4 months when combined with low-dose dexamethasone. More recently, a higher dose of dexamethasone in combination with pomalidomide showed an improved PFS of 4 months compared to 1.9 months with low-dose dexamethasone. Common adverse effects include fatigue, neutropenia, anemia, diarrhea, nausea, neuropathy, and fever. Serious effects include VTE, leading to a recommendation to consider prophylactic anticoagulation when using this medication, and severe neutropenia. I. PHENOTYPE-TARGETED THERAPY As outlined previously, this is a therapeutic strategy that is intended to target the unique phenotype of the cancer cell where killing the cell is more dependent on direct induction of a cytotoxic effect rather than targeting a specific pathway, as discussed subsequently. These MoAbs may be used alone (unconjugated) or as a delivery system for cellular toxins, radionuclides, or chemotherapy (conjugated). Agents under this category are classified based on the type of therapy and subclassified based on the target pathway or molecule, if applicable. A. Unconjugated antibodies

1. Rituximab (Rituxan) is an IgG1-κ murine-human chimeric MoAb that is generated against the CD20 antigen. CD20 is expressed on the cell surface of B-cells and hence on the surface of B-cell lymphoma. Rituximab is used in a variety of clinical setting and FDA-approved in NHL and CLL. Several studies have shown improved RRs with rituximab (around 50%) in patients with a variety of NHL, in addition to improve survival in follicular lymphoma and DLBCL. In combination with cyclophosphamide, vincristine, and prednisone (CVP), PFS was improved by 12 months in patients with follicular lymphoma, and 2-year OS was improved by 10% to 20% when combined with CHOP in patients with DLBCL.28 Rituximab is also approved in combination with fludarabine and cyclophosphamide in previously untreated patients with CD20+ CLL, based on improved PFS of 5 to 8 months. Rituximab is also used for CD20+ HL and a variety of autoimmune diseases such as thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, granulomatosis with polyangiitis, posttransplant lymphoproliferative disease (PTLD), and chronic graft-versus-host disease (GVHD). Rituximab can cause HTN, nausea, vomiting, fever, chills, and lymphopenia. Cardiac arrhythmia, cardiogenic shock, Stevens-Johnson syndrome, toxic epidermal necrolysis, and tumor lysis syndrome are reported as serious side effects. As with any chimeric antibody, severe infusion reactions and anaphylaxis can occur. Reactivation of hepatitis B and progressive multifocal leukoencephalopathy (PML) are also rare but serious adverse effects. 2. Alemtuzumab (Campath) is a humanized IgG1-κ chimeric MoAb that is directed against CD52 cell surface glycoprotein. CD52 is expressed on the surface of normal and malignant B- and T-cells, natural killer cells, monocytes, and macrophages. Alemtuzumab is approved for untreated patients with B-cell CLL, based on improved PFS of 14.6 months versus 11.7 months with chlorambucil. In patients with B-cell CLL previously treated with fludarabine, alemtuzumab showed a 2% CR and 31% PR. Similar to rituximab, alemtuzumab is used in a variety of off-label settings, including T-cell prolymphocytic leukemia, CLL-related autoimmune cytopenias, GVHD, and relapsing multiple sclerosis. Common side effects are anemia, neutropenia, thrombocytopenia, rash, and diarrhea. Serious side effects are cardiac arrhythmia and cardiomyopathy. Patients who have recently been treated with this MoAb should not receive any live viral vaccines because of the severe immune suppression effect of the medication. 3. Ofatumumab (Arzerra) is a humanized IgG1-κ MoAb that binds to the CD20 molecule on B-lymphocytes, which leads to B-cell lysis. It is FDA-approved in combination with chlorambucil in patients with untreated CLL and in patients with refractory CLL. In patients with untreated CLL, ofatumumab in combination with chlorambucil showed an improved PFS of 22.4 months compared to 13.1 months with chlorambucil alone. In patients with CLL refractory to fludarabine and alemtuzumab, it was shown to have an RR of 50% as a single agent. Ofatumumab

can cause rash, neutropenia, anemia, diarrhea, and sepsis. 4. Blinatumomab (Blincyto) is a bispecific humanized antibody directed against CD19 B-cells and CD3 T-cells. It activates T-cells by connecting the CD3 receptors of Tcells to the CD19 receptor on benign and malignant B-cells, enhancing the T-cell recognition of malignant B-cells. This mechanism leads to increased production of cytokines resulting in malignant B-cell lysis. It is approved for patients with relapsed Ph− ALL or refractory B-precursor ALL, based on a minimal residual disease rate of 80% and a duration of response of 6.7 months.29 It is currently being studied in gastrointestinal and lung cancers. Common adverse effects include fever, headache, peripheral edema, hypokalemia, and constipation. Serious effects include febrile neutropenia, encephalopathy, and headache. 5. Epratuzumab is a humanized MoAb that binds to CD22 glycoprotein. CD22 is expressed on the cell surface of mature B-cells in follicular NHL. An overall RR of 88% (with a 42% CR rate) was achieved when epratuzumab was combined with rituximab in patients with untreated follicular lymphoma. It is also being studied in patients with lupus and ALL. 6. Elotuzumab is a humanized IgG1 MoAb targeting signaling lymphocytic activation molecule (SLAM7), which is found primarily on natural killer cells and myeloma cells but not on other normal cells. For this reason, it has been studied in MM, showing an RR of 92% and PFS of 33 months when used in combination with lenalidomide and dexamethasone in previously treated patients. On the basis of these data, it received a Breakthrough Therapy Designation by the FDA. It is currently being studied in the first-line setting for smoldering myeloma and relapsed or refractory MM. B. Conjugated antibodies 1. Cellular toxin-conjugated antibodies a. Gemtuzumab ozogamicin (Mylotarg) is a humanized IgG4-κ antibody directed against the CD33 antigen and conjugated with calicheamicin. Calicheamicin is a cytotoxic agent isolated from fermentation of the bacterium Micromonospora echinospora ssp. calichensis. The CD33 antigen is a sialic acid–dependent adhesion protein expressed on the surface of immature myelomonocytic cells and on the surface of leukemic blast cells but not on the surface of normal pluripotent hematopoietic stem cells. When this fusion antibody binds to the CD33 receptors, it is internalized into the cell, and the calicheamicin is cleaved and released. Calicheamicin binds to the minor grooves of the DNA, leading to DNA breaks and apoptosis. Gemtuzumab is indicated for the treatment of patients over 60 years old after the first relapse of myeloid leukemia expressing CD33 who are not candidates for chemotherapy. Gemtuzumab as a single agent may lead to 16% CR and 30% overall response with a median time to remission of 2 months. Follow-up trials, however, failed to show a clinical benefit, and it was subsequently removed from the US market. Gemtuzumab can cause fever,

shivering, and nausea. Side effects can also be severe, including myelosuppression, hemorrhage, disseminated intravascular coagulation, and hepatotoxicity. b. Ado-trastuzumab emtansine (T-DM1 or Kadcyla) is a humanized MoAb against HER2 that is conjugated to DM1, a maytansine derivative and microtubule inhibitor. Upon binding to the HER2 receptor, it undergoes internalization and lysosomal degradation releasing DM1, which disrupts microtubule networks resulting in cell cycle arrest and apoptosis. In a phase III trial, it was shown to increase PFS by 3.2 months when combined with lapatinib and capecitabine in patients with HER2+ metastatic breast cancer. It was also shown to have a partial RR of 39% in patients with metastatic breast cancer who previously received trastuzumab. This led to its approval in patients with previously treated HER2+ metastatic breast cancer. Common adverse effects include fatigue, nausea, thrombocytopenia, increased liver enzymes, and headache. Serious effects include pulmonary toxicity, severe thrombocytopenia, and neuropathy. c. Brentuximab vedotin (Adcetris) is a chimeric IgG1 antibody against CD30 that is conjugate to monomethyl auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 receptor, the drug is internalized and the antineoplastic agent MMAE is released to disrupt the microtubule network, which results in cell cycle arrest and apoptosis. It is approved for patients with relapsed HL following autologous stem cell transplant, based on an overall RR of 73%, with 32% being CRs.30 Further study has shown that in patients with relapsed CD30+ HL or anaplastic large-cell lymphoma, including 73% who had undergone autologous stem cell transplantation, 50% had a response, lasting an average of 9.7 months (with a 38% CR rate). It is also approved for patients with relapsed systemic anaplastic large-cell lymphoma, based on an overall RR of 86%, with 57% being CRs. Common adverse effects are neutropenia, peripheral neuropathy, fatigue, anemia, diarrhea, cough, and fever. Peripheral neuropathy and neutropenia may be severe in rare cases. d. Inotuzumab ozogamicin is a humanized MoAb directed against CD22 that is conjugated to an ozogamicin, a cytotoxic agent from the calicheamicin class. Since CD22 is expressed in 90% of B-cell malignancies, inotuzumab has been studied in patients with ALL with promising results. In a recent interim analysis of an ongoing phase III study in patients with relapsed or refractory CD22+ ALL, it was found to have a complete hematologic RR of 58%, with 19% being CRs, allowing 40% to undergo allogeneic stem cell transplant. It has also been studied in patients with relapsed or refractory NHL, but was unable to show a survival benefit and stopped early. Common adverse effects include bilirubin elevations, fever, and asymptomatic hypotension (all reversible after therapy). Serious effects are an increased rate of venoocclusive disease in 17% after stem cell transplantation.

2. Radioimmunoconjugate antibodies a. Ibritumomab tiuxetan (Zevalin, IDEC-Y2B8) is a murine anti-CD20 MoAb conjugated to tiuxetan that chelates to pure β-emitting yttrium-90. The mechanism of action includes antibody-mediated cytotoxicity and cellular-targeted radiotherapy (radioimmunotherapy [RIT]). It is approved for patients with CD20+ refractory follicular lymphoma, based on an RR of 83%, with 37% achieving a CR. Ibritumomab tiuxetan is also being used in patients with relapsed B-cell NHL following high-dose chemotherapy and autologous stem cell transplantation with promising results. It should be used with caution in patients with 25% or greater marrow involvement with lymphoma, prior external beam radiotherapy to 25% or greater of the bone marrow, or a history of HAMAs or HACAs. Neutropenia and thrombocytopenia are common and are related to the radionuclide dose. Low-grade nausea and vomiting are common. Infusion-related fever, chills, dizziness, asthenia, headache, back pain, arthralgia, and hypotension are occasional side effects. b. Iodine-131 (131I)-tositumomab (Bexxar) is a murine IgG2a anti-CD20 MoAb radiolabeled with 131I, an emitter of both β and γ radiation. The mechanism of action includes antibody-mediated cytotoxicity and cellular-targeted RIT. It is indicated as a monotherapy in patients with rituximab-refractory NHL that is chemotherapy refractory, CD20+, low grade, or transformed low grade. Furthermore, it was found that the combination of high-dose 131I-tositumomab and autologous hematopoietic stem cell transplantation is effective for relapsed B-cell NHL. 131I-tositumomab can cause HTN, shivering, and diarrhea. It must be used with caution in patients with 25% marrow involvement with lymphoma, prior external beam radiotherapy to 25% of the bone marrow, or a history of HAMAs or HACAs. 3. Immunotoxins These are recombinant proteins that are conjugated to cellular toxins and are designed to bind to specific proteins on the surface of cancer cells, internalized, and induce direct cytotoxic effect by releasing conjugated toxins intracellularly. a. Denileukin diftitox (Ontak) is a recombinant construct that includes a fragment of the IL-2 protein (Ala1–Thr133) linked to a fragment of the diphtheria toxin fragments A and B (Met1–Thr387). This construct is designed to bind to the CD25 component of the IL-2 receptor (IL-2R) on the surface of the targeted cells expressing the receptor. The complex becomes internalized into the cytoplasm and releases the toxin to exhibit its damaging effect. The high-affinity IL-2R is normally present on the activated T- and B-lymphocytes and activated macrophages. CTCL expresses high-affinity IL-2R and forms an appropriate target. A phase III randomized trial in patients with refractory CTCL compared denileukin diftitox to placebo and showed a median PFS over 2 years, 10% CR,

and 34% PR in patients who received denileukin diftitox, which is significantly better than placebo (median PFS of 4 months and overall response of 15.9%). This led to its approval for patients with persistent or recurrent CTCL expressing CD25. Denileukin diftitox can cause elevated liver transaminases, fever, nausea, edema, rash, and diarrhea. It can also cause serious capillary leak syndrome.

References 1. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–792. 2. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2positive metastatic breast cancer. N Engl J Med. 2015;372:724–734. 3. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–2550. 4. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30:3499–3506. 5. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as firstline treatment for European patients with advanced EGFR mutation-positive non-smallcell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–246. 6. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584–3590. 7. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733–2743. 8. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–223. 9. Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenstrom’s macroglobulinemia. N Engl J Med. 2015;372:1430–1440. 10. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALKpositive lung cancer. N Engl J Med. 2014;371:2167–2177. 11. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370:1189–1197. 12. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and lowdose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004. 13. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed

chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260–2270. 14. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251–2259. 15. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369:1783–1796. 16. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799–807. 17. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390. 18. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–114. 19. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–1703. 20. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–2516. 21. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormonereceptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–529. 22. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–2281. 23. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997–1007. 24. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal- cell carcinoma. N Engl J Med. 2012;366:2171–2179. 25. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906–917. 26. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123–2132. 27. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133–2142. 28. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002; 346:235–242. 29. Topp MS, Gokbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16:57–66. 30. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30:2183–2189.

I. INTRODUCTION Agents that produce anticancer activity through one or more components of the immune system play an important and, in some cases, a predominant role in the treatment of several malignancies. The broad relevance of antitumor immunity to cancer therapeutics is likely underappreciated. For example, components of the immune system may contribute to the overall activity of certain cytotoxic and molecular targeted agents, and also to the activity of therapeutic antibodies against cell surface receptors with oncogenic function.1–6 The graft-versus-tumor effect in allogeneic bone marrow transplant can be considered a form of cancer immunotherapy. This chapter reviews the principles of cancer treatment with agents whose principal activity is mediated by the cells of the immune system. II. ANTICANCER IMMUNE RESPONSES The majority of effective immunotherapies produce tumor regression through induction, expansion, or activation of T-lymphocytes (T-cells) that recognize tumor antigens. Through their T-cell receptors (TCR), T-cells recognize peptide fragments of proteins that are processed intracellularly, bound to major histocompatibility complex (MHC) molecules, and then brought to the cell surface. Studies in patients have shown that T-cell responses against peptides from mutated proteins (neoantigens), tissue differentiation proteins such as MART-1 in melanoma, or developmental proteins re-expressed during malignant transformation (e.g., NY-ESO-1) can mediate tumor regression.7–9 Naïve T-cells are first activated by interactions with professional antigen-presenting cells (APCs, also called dendritic cells) in lymph nodes. Once activated, T-cells differentiate into effector cells and long-lived memory cells. In addition to the signal received by the TCR, T-cell activation, differentiation, and function are controlled by multiple soluble cytokines (hormone-like substances) or cell surface ligands on other cells (including APC and tumor cells) interacting with receptors on the T-cell surface.10 Because the immune system must have the capacity to eliminate foreign invaders while limiting autoimmunity and tissue damage, multiple mechanisms exist not only to provide activation signals but also to delete, inhibit, or terminate immune responses. Multiple types of T-cells with multiple functions can be involved in the generation of an immune response, including regulatory T-cells (Tregs) that are capable of suppressing the function of effector cells. For T-cells to produce an antitumor response, they must migrate back to the tumor site where they produce cytokines or kill tumor cells directly following TCR binding to the tumor

peptide–MHC complexes.11 Anticancer T-cell responses can be enhanced by several types of interventions. The interventions can include providing the putative tumor antigen in the form of an optimized “vaccine”; providing signals that enhance APC function; providing cytokines that support T-cell expansion and function; administering antibodies that directly activate costimulatory receptors or block inhibitory receptors on T-cells; administering agents that inhibit other Tcell–suppressive mechanisms within the tumor microenvironment; infusing T-cells with natural or engineered recognition of tumor cells; or combining one or more of the possible immunomodulating strategies. The type of intervention necessary to produce effective antitumor immune responses is highly dependent on the nature of the tumor-host relationship in the individual patient, which can be influenced by many factors, including host genetic variations in immune response, the number and type of tumor mutations, prior exposures to foreign antigens, and possibly even by the microbiome. In a substantial number of patients, the immune system is able to mount a T-cell response against tumor antigens during the course of time in which the malignancy is evolving in the host. In fact, inflammation may promote tumor growth at the early stages of tumor development, and likely controls the developing cancer for a period of time until the tumor develops escape mechanisms.12 Consistent with the latter observations, multiple factors that are capable of suppressing effector tumor antigen-specific T-cells within the tumor microenvironment have been identified. One of the most important is induced by tumor-infiltrating T-cells mounting the anticancer response. Activated T-cells produce cytokines, particularly interferon-γ (IFN-γ), which induce PD-L1 expression by tumor cells, stromal cells, or other immune infiltrating cells. PD-L1 then binds to the inhibitory receptor PD-1 on the activated T-cells, suppressing their function.13 Chronic exposure of tumor-specific T-cells to tumor antigens either within the tumor or in draining lymph nodes produces further “exhaustion” of the T-cells, with diminished capacity to produce cytokines or to proliferate.14 The exhausted T-cells are characterized by expression of multiple other coinhibitory receptors. Other factors that could inhibit effector T-cells include Tregs, myeloid-derived suppressor cells, a subset of macrophages, or possibly other stromal cells such as vascular endothelium. Inhibition may require direct cell-cell contact or production of inhibitory substances (e.g., enzymes that deplete essential amino acids and/or produce inhibitory metabolites, or cytokines that inhibit or deviate Tcell function or contribute to formation of Tregs). While not yet proven, a subset of tumors containing minimal to no T-cell infiltrate may actively “exclude” T-cells from the microenvironment by mechanisms which remain to be defined. The targets for agents that modulate T-cell responses can be found on multiple types of immune cells that may have opposing functions, and the outcome of any specific intervention may be context dependent and thus vary on the basis of unknown factors. For example, interleukin-2 (IL-2) administered to enhance the function of effector T-cells can also expand a population of Tregs.15 Moreover, activating interventions (e.g., vaccines, cytokines, or agonist T-cell costimulatory antibodies) can induce counterregulatory

mechanisms that limit effector T-cell expansion and function, and the tumor-specific T-cells must still overcome induced and constitutive immunosuppressive mechanisms in the tumor microenvironment. The latter factors likely explain the relative lack of efficacy for multiple cytokines and cancer vaccines developed since the early 1980s. In contrast, antibody antagonists of PD-1 or one of its ligands PD-L1 are capable of producing substantial and durable tumor regression in a subset of patients across many different malignancies.16–20 The remarkable activity of PD-1/PD-L1 antagonists confirms that many patients have ongoing T-cell responses against their cancers at the time of presentation with advanced disease, and highlights the importance of blocking negative regulation of T-cell responses to enable their antitumor function, particularly within the tumor microenvironment. Currently, there are relatively few examples of effective anticancer immunotherapies that are T-cell independent or rely primarily on other components of the immune system. Natural killer (NK) cells, whose cytotoxic activity is controlled by activating and inhibitory receptors, may contribute to the graft-versus-leukemia effect when the recipient is lacking ligands for the donor killer–inhibitory receptors.21 Induced or passively transferred antibodies can produce antitumor activity by mediating antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytolysis (CDC). ADCC is triggered by binding of the Fc portion of the antibody with the Fc receptor on NK cells or myeloid-derived cells. The ability to induce ADCC depends on the IgG isotype and also on the type of Fc receptor, which may be either activating or inhibitory.22 Preclinical studies and some clinical correlative data suggest that ADCC may play a role in the antitumor activity of antibodies such as trastuzumab and rituximab. Currently only one antibody, targeted to the ganglioside GD-2 (ch14.18), is presumed to produce its anticancer effect primarily by ADCC. It was effective when used in combination with IL-2 and granulocytemacrophage colony-stimulating factor (GM-CSF) in neuroblastoma patients following autologous marrow transplant, suggesting that the antitumor activity mediated by ADCC would produce the greatest benefit in a minimal residual disease setting.23 III. TOXICITY AND MANAGEMENT OF TOXICITY Excluding hypersensitivity reactions or antibody infusion-related events, the toxicities of immunotherapies can be classified as follows: cytokine-induced, for example, after administration of IFN or IL-2 or after T-cell expansion and activation in adoptive cellular therapy; autoimmune-type reactions, usually observed after administration of immune checkpoint inhibitors; and on-target effects, by recognition of passively transferred antibodies or cells of their intended targets on normal tissues. In addition to the indicated supportive care for symptoms, management of toxicity depends on the cause and expected time course for reversibility, and will often involve steroids. Because of the broad applicability of immune checkpoint inhibitors, most physicians treating cancer patients will be required to manage the autoimmune-like reactions associated with their use. Currently, only anti-CTLA-4 and anti-PD-1 have been approved for cancer treatment indications around the world. Unlike cytokines, immune checkpoint

inhibitors rarely produce acute adverse events following the infusion. When adverse events occur, almost any organ system can be affected, but most common are skin, gastrointestinal tract, liver, and endocrine glands.16,24–26 In a subset of patients, adverse events can occur in multiple organ systems, either concurrently or serially. Adverse events induced by antiCTLA-4 are more frequent and can be more severe than by PD-1/PD-L1 antagonists. Within the dose range of 1 to 10 mg/kg, the toxicity of anti-CTLA-4 is dose-related; in contrast, for anti-PD-1 doses in the 0.3- to 10-mg/kg range, no clear dose-response relationship for toxicity is apparent.16,27 Preliminary data suggest that patients developing high-grade immune-related adverse events (irAEs) from anti-CTLA-4 can be treated safely with PD-1/PD-L1 antagonists once toxicities resolve to baseline.28 Because of the long half-life of the antibodies, combined effects could be observed if administered within a short interval of each other. Concurrent administration of 3 mg/kg of anti-CTLA-4 with 1 mg/kg of nivolumab produced a higher rate of grade III to IV irAEs compared to either agent alone, which in incidence and severity resembled the toxicity profile of ipilimumab administered alone at 10 mg/kg.29–31 Careful observation of patients, frequent communication between patients and medical staff, and prompt administration of steroids when indicated are necessary to prevent severe outcomes from irAEs. A few toxicities associated with immune checkpoint inhibitors may be life-threatening if not treated promptly (e.g., bowel perforation that results from ongoing colitis, or progressive pneumonitis). After the development of an irAE, an initial workup is required to exclude other potential causes, and supportive care measures should be initiated. Physicians must subsequently determine if and when to start steroids, the dose of steroids, route of administration, inpatient or outpatient management, and length of steroid therapy. In steroid-refractory toxicity, a second immunosuppressive agent may be required, such as anti–tumor necrosis factor (TNF) or mycophenolate mofetil. Algorithms have been developed and published for management of each of the most common irAEs. For severe toxicities, including grade III to IV colitis or diarrhea, high-dose steroids equivalent to 2 mg/kg of IV solumedrol are administered for approximately a week, and then tapered slowly over approximately 30 days. Although the management algorithms are useful, clinical judgment is still required, for example, in assessing the rate of improvement and deciding if escalation of measures is required. If symptoms worsen or the rate of improvement is too slow on the starting dose of steroids, options include administering even higher doses of steroids, in some cases up to a gram of solumedrol IV daily, or initiating treatment with a second immunosuppressive agent. Recurrence of symptoms during the steroid taper can be managed by re-escalation of the steroid dose until resolution of the irAE, followed by another period of steroid dose taper, or administration of a second immunosuppressive agent. Because of the potential liver toxicity of anti-TNF agents, mycophenolate is used as the second-line immunosuppressive for liver irAEs. For prolonged immunosuppression exceeding 4 to 6 weeks, administration of prophylactic antibiotics to prevent opportunistic infection should be considered. With few exceptions such as the endocrinopathies, irAEs fully reverse over time. Administration of

steroids or other immunosuppressive agents to prevent onset of toxicity would be expected to counteract the antitumor effect of immune checkpoint inhibitors. However, current data suggest that use of steroids or other immunosuppressive agents to manage an adverse event does not substantially affect tumor response or duration of response. In contrast to the immune checkpoint inhibitors, toxicities induced by cytokines or cytokines combined with cell therapies are generally managed with intensive supportive care, and steroids are administered only if the complications are immediately lifethreatening.32 The toxicities are almost always rapidly reversible over hours to days. Administration of T-cells modified with a chimeric antigen receptor targeting CD19 on Bcells produced severe toxicity during the period of T-cell activation and expansion. Studies correlated the severe toxicity to induced cytokines and particularly to high circulating levels of IL-6. Toxicity was reversed rapidly by administration of an anti-cytokine against IL-6 without affecting antitumor response.33 IV. RESPONSE KINETICS Studies of cytokines such as IL-2 provided strong proof of concept that immunotherapies could produce regression of advanced and large-volume metastatic disease.34–36 Moreover, in a subset of patients, complete regressions persisted for years without relapse, indicating that responses were durable and possibly curative. For cytokines such as IL-2, which is given weeks 1 and 3 in cycles of 8 to 12 weeks, tumor regression was usually observed at the 8- to 12-week staging scans. Most patients with evidence of tumor regression received a second “cycle” of treatment, and rarely a third. Regression could continue beyond the end of treatment, but near-maximal tumor regression was often observed on staging scans obtained 5 to 9 weeks after the second cycle. Most patients with stable disease at the end of the first cycle did not go on to achieve complete responses with additional cycles of treatment. The majority of partial responses were short-lived, and occasional mixed responses were observed, but there are no comprehensive data on outcome for treatment continued beyond mixed response. The benefit, if any, of cytokineinduced mixed or partial responses or stable disease cannot be determined. However, a small subset of patients experienced long-term disease-free survival after surgical removal of a residual, recurrent, or discordant progressing lesion following substantial regression of multiple other sites of disease. Cell therapies (e.g., melanoma tumor-infiltrating lymphocytes administered with systemic IL-2) are usually given for one cycle.37,38 Regression of disease is often observed at 4 weeks after treatment and can continue over time. The kinetics of tumor regression for immune checkpoint inhibitors depends on the individual agents and other factors that currently remained undefined. Treatment with anti-CTLA-4 is given every 3 weeks for a total of 4 doses, and tumor response is assessed at 12 weeks. A large fraction, possibly 50%, of objective responses to anti-CTLA-4 are achieved beyond the 12-week assessment.26 In contrast, anti-PD-1 as a single agent is administered every 2 to 3 weeks for at least 1 year and in some trials until disease progression. Most objective responses to

anti-PD-1 are evident at the first staging study at 8 to 12 weeks, although responses may improve over time.39–41 The optimal duration of therapy for single-agent anti-PD-1 has not been defined. For both anti-CTLA-4 and anti-PD-1, partial responses may persist for prolonged periods, despite discontinuation of treatment. Similar to IL-2, the durable responses observed with checkpoint inhibitors may result in cures. For example, 10-year follow-up data for patients with metastatic melanoma treated with anti-CTLA-4 show flat survival curves beyond year 3 for up to 10 years.42 Preliminary data suggest that certain combinations, such as anti-CTLA-4 with anti-PD-1, may accelerate the kinetics of response and also the extent of tumor regression.29 Unconventional response patterns are reported infrequently with cytokines or adoptive cell therapies. In contrast, unconventional tumor responses appear to occur more frequently following treatment with immune checkpoint inhibitors such as anti-CTLA-4 and anti-PD-1, and possibly confer clinical benefit similar to patients achieving objective responses by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.43 Recognition of the unconventional response patterns is important for optimal patient management and also to avoid underestimation of potential treatment effect in single-arm phase II trials. The most common, and most difficult to manage in the clinic, manifests as initial progression of existing lesions or new lesions, possibly concurrent with reduction or stability of other lesions, followed subsequently by overall tumor burden reduction or stability. Late overall tumor burden reduction will often be associated with stabilization or regression of the previously noted new or progressing lesions. In addition to systemic sites of disease, we and others have observed apparent disease progression in brain while other sites of disease were regressing, followed subsequently by regression of the new brain lesions, without the addition of radiation. Therefore, patients whose initial scans at 8 to 12 weeks show traditional disease progression by RECIST criteria, but do not experience deterioration in performance status, should not change treatment until a second scan 4 to 8 weeks later confirms continued increase in overall tumor burden. Other unconventional response patterns were observed during trials of the immune checkpoint inhibitors, including long periods of stable disease, long periods of stable disease followed by late regression, slow prolonged tumor regression, or regression of multiple sites of disease concurrent with one or a few discordant continuously progressive lesions. For a subset of patients with a small number of discordant progressing lesions, local surgery or radiation for the growing lesions produced long disease-free intervals. The rate of unconventional response patterns likely varies between diseases and agents, and is higher with anti-CTLA-4 compared to anti-PD-1. Overall 10% to 15% of all patients with metastatic melanoma treated with anti-CTLA-4 will develop an unconventional response. A special set of immunotherapy response criteria (iRC) were developed to capture data on unconventional antitumor responses in clinical trials.43 In general, most immunotherapies are administered for a defined period and then discontinued. The role of maintenance therapy with any of the current agents is unknown. Even for treatments currently given for long periods, such as anti-PD-1, treatment will be

discontinued in a subset including complete responders, patients with maximal response after a period of additional therapy, and in those with severe toxicity. Although many responses will persist possibly without relapse, a subset of responding patients who are off treatment will eventually develop progression of disease. In clinical studies, selected patients with relapse after clinical response to the various immunotherapies were offered re-treatment with the same agent. In melanoma or renal cell carcinoma patients treated with IL-2, re-treatment at relapse with high-dose IL-2 rarely produced a second objective response.44 In contrast, a relatively high rate of clinical activity was observed in relapsed patients who were re-treated with anti-CTLA-4 after achieving at least stable disease for 24 weeks, or a response by standard RECIST or iRC criteria.45 In the patients re-induced with anti-CTLA-4, clinical activity included prolonged stable disease or a second objective response, both of which could be equal to or more durable than the initial response. Although reported only as anecdotes, second responses were also observed among a small number of patients re-treated at relapse with anti-PD-1 or with the combination of anti-CTLA-4 and anti-PD-1.46 V. PREDICTIVE BIOMARKERS AND PATIENT SELECTION Multiple candidates for predictive biomarkers to immunotherapy have been explored in clinical trials.18,47–49 In peripheral blood, potential candidates included cell counts such as absolute lymphocyte counts; number or percentage of various immune cell subsets including Tregs and myeloid-derived suppressor cells; functional capacity of various lymphocyte populations; circulating markers of disease or inflammation such as lactate dehydrogenase (LDH) and C-reactive protein; panels of circulating growth factors, cytokines, and chemokines; and gene expression studies in peripheral blood mononuclear cells (PBMCs) or subsets of PBMC. Several prior studies also included assays for preexisting serologic or T-cell responses to tumor antigens.50 Assays for predictive biomarkers in tumor tissue are generally performed on fresh or archived biopsy samples.48,51 In clinical trials, investigators have measured the immune cell infiltrate, including phenotype, function (as assessed by proliferative markers, cytotoxic molecules, or cytokine production), and TCR diversity and clonality. Studies on the cellular infiltrates are performed by flow cytometry of dissociated specimens, or by immunohistochemistry, which can provide the spatial relationships between the immune cell infiltrate and tumor cells. In some studies, gene expression analyses of tumor biopsies and patterns of antigen neoepitopes derived from mutations (as detected by whole exome sequencing) were correlated with response and overall survival.52,53 Despite the substantial efforts, no predictive biomarker assays are currently approved for any immunotherapy, including cytokines, anti-CTLA-4, the prostate cancer vaccine sipuleucel-T, and the two anti-PD-1 antibodies, nivolumab and pembrolizumab. In clinical trials for the immune checkpoint inhibitors, selected assays appeared to enrich for response or better outcome in the biomarker-positive group, but tumor responses to therapy were consistently observed in a fraction of the biomarker-negative groups.18,30,54–56 The failure

to find highly sensitive and specific biomarkers reflects the complexity of the events required to produce tumor regression after an immune intervention, and also inherent problems with assay methodologies, particularly in tumor biopsies. Assays in tumor tissue can be confounded by the heterogeneity of tumors and the immune cell infiltrates, the dynamic nature of the assessed biomarkers, sampling errors related to use of core biopsies or fine-needle aspirates, and difficulties in determining appropriate positive and negative cutoffs for biomarkers with a broad range of expression. Although the clinical utility of the assessed predictive biomarkers remains unclear, studies conducted to date provide insight into factors required for response to immune interventions. As a general rule, tumors with inflammatory infiltrates or inflammatory gene signatures are more likely to respond to current immunotherapies.47,48,56,57 A preexisting Tcell infiltrate in tumor tissue may be most critical for agents that block immune checkpoints active within the tumor microenvironment (e.g., anti-PD-1 or anti-PD-L1). As expected, for PD-1/PD-L1 antagonists, most trials showed higher response rates in patients with tumors expressing PD-L1, and survival differences between PD-1/PD-L1 antagonists and control arms in randomized trials were greatest in the PD-L1-positive group.54,58 In contrast, addition of anti-CTLA-4 to anti-PD-1 produced the greatest effect in the PD-L1-“negative” group, possibly because anti-CTLA-4 promotes T-cell infiltration into the tumor microenvironment.30 Certain clinical features also provide insight into the biologic conditions required for response to immune interventions. Although exceptions are clearly seen, response to PD1/PD-L1 antagonists appears to be higher in diseases with a larger number of genetic mutations, which presumably lead to formation of either more or a unique set of neoantigens that can induce broad tumor-specific T-cell responses. Melanoma and lung cancer are among the tumor types that carry the highest rate of genetic mutations. In lung cancer, response rates to PD-1/PD-L1 antagonists were higher in prior smokers versus nonsmokers, consistent with expected higher rates of tumor genetic mutations in prior smokers.53 Other clinical features less consistently predict response to immunotherapies. In metastatic melanoma studies, high baseline LDH has been associated with lower response rates to high-dose IL-2, and possibly also predicts for lower response rates to immune checkpoint inhibitors.59 Higher tumor burdens (e.g., above the mean for the population of patients) may also be associated with lower response rates, but the lower response rates in the “high” tumor burden group are likely to remain clinically meaningful. Overall, high tumor burden should not preclude treatment with the most effective immunotherapies, including cytokines and the immune checkpoint inhibitors. In contrast, certain types of immunotherapies, for example, cancer vaccines used alone or antibodies that primarily act through ADCC, may be effective only in patients with low tumor burdens or micrometastatic disease. For example, in the analysis of a trial comparing talimogene laherparepvec, an oncolytic herpesvirus that is administered by intratumoral injection, to GM-CSF in metastatic melanoma, a survival advantage was observed in advanced stage III

and stage IV M1a patients (limited to lymph node and soft tissue disease), but not in patients with visceral metastases.60 With the most active immunotherapies, all sites of disease appear capable of responding, including brain metastases.61 Depending on the agent and disease type, lower response rates may be observed for patients with disease involvement of certain organs (e.g., the liver). Similar to tumor burden, site of disease should not preclude offering an immunotherapy. However, caution is warranted for patients in whom the occasional induced inflammatory response and surrounding edema in tumor may create local complications, such as in untreated brain metastases in potentially symptomatic locations or near the spinal cord. At this time, the impact of prior cytotoxic or targeted therapies, or abnormal organ function, on the activity or safety of immunotherapies remains unknown. We administered anti-PD-1 to a metastatic melanoma patient on renal hemodialysis and observed a clinical response without complications. On the basis of limited animal model data, patients on immunosuppressive agents have been excluded from treatment with immunotherapies. The activity and safety of immunotherapies, and particularly immune checkpoint inhibitors or cytokines, in patients with prior autoimmunity has not been studied in prospective trials. Of particular concern are patients with prior inflammatory bowel disease, and the potential for marked exacerbation of symptoms leading to gastrointestinal bleeding or perforation. Nevertheless, prior autoimmunity not requiring current immunosuppressive agents should be considered only a relative contraindication to immunotherapy, and therefore the risk/benefit ratio of treatment must be weighed in each individual patient. There are a few anecdotal reports of patients with renal or marrow allografts treated safely with IL-2, antiCTLA-4, or anti-PD-1.62,63 VI. CLINICAL ACTIVITY AND APPLICATION Prior to the development of the immune checkpoint PD-1/PD-L1 antagonists, there were relatively few approved indications for use of traditional immunotherapies. The most common indications for immunotherapy agents were high-dose IL-2 in the treatment of metastatic melanoma and renal cell carcinoma, high-dose IFN-α for the adjuvant treatment of resected primary and regional melanoma at high risk for systemic recurrence, antiCTLA-4 for the treatment of metastatic melanoma, sipuleucel-T for the treatment of metastatic hormone-resistant prostate cancer, and anti-GD-2 in combination with GM-CSF and IL-2 for neuroblastoma following autologous bone marrow transplant. In randomized studies, anti-PD-1 improved survival compared to ipilimumab in melanoma, and improved survival in both adenocarcinoma and squamous cell carcinoma of the lung compared to second-line treatment with docetaxel.64,65 Anti-PD-1 is currently approved for treatment of metastatic melanoma and metastatic non–small-cell lung cancer. Current phase II trials demonstrate activity of anti-PD-1 or anti-PD-L1 in a subset of patients with multiple malignancies, and phase III trials are ongoing. Regulatory approvals are expected for the PD-1/PD-L1 antagonists in multiple types of malignancies. The

remarkable activity of chimeric antigen receptor–modified T-cells against CD20 in B-cell malignancies will also change the standard of care for those diseases. The optimal sequencing and integration of immunotherapy with chemotherapy, radiation, or targeted therapies remain unclear. The pattern of use for an individual disease will depend on the immunotherapy agent, its expected activity, comorbid conditions, presentation of the disease, the activity and toxicity of other available therapeutics, and potential agonist and antagonist drug interactions, many of which remain undefined. For certain agents, such as vaccines and antibodies that act primarily through ADCC, the immunotherapies will be directed primarily at small-volume or minimal residual disease settings. The substantial activity of immune checkpoint inhibitors in advanced disease raises more difficult questions on sequencing and integration with other therapies. It appears likely that in certain settings, the superior activity, potential for durable response, and better toxicity profile of the immunotherapy will justify first-line use in metastatic disease. Although not proven in human settings, expansion of tumor-specific immune responses would likely enhance the activity of subsequent nonimmunotherapies. However, the reverse sequence could also be effective; nonimmunotherapies may reduce tumor bulk, release antigen, and reduce tumor immunosuppressive mechanisms and thus enhance the activity of concurrent or subsequently administered immunotherapy. For melanoma tumorinfiltrating lymphocytes (TIL), lymphodepletion with chemotherapy prior to cell transfer appears necessary to demonstrate optimal clinical activity, possibly due to removal of tumor immunosuppressive mechanisms and to the rise of circulating cytokines that support persistence of the transferred cells.38 Combinations of immunotherapies with each other or with other treatment modalities will play an increasingly important role in the treatment of malignancies. The combination of anti-CTLA-4 and anti-PD-1 improved response rate and progression-free survival compared to either agent alone in metastatic melanoma, but with higher rates of grade III to IV irAEs.30 Effects of the combination on lymphocyte and monocyte gene expression differed markedly from either agent alone.66 Multiple combinations are in clinical development. Although combinations of immunotherapy with chemotherapy or radiation therapy appear safe, the benefit of such combinations remains to be proven. Unexpected adverse interactions can also occur with specific combinations, for example, elevated liver function tests with vemurafenib and anti-CTLA-4.67 Adverse interactions may be specific to individual agents and may not extend to other agents in the same class. Although agents such as IL-2, anti-CTLA-4, and anti-PD-1 cause regression of advanced disease, which is easily assessed on imaging studies, other types of potentially beneficial clinical activity for these and other types of immunotherapies are not readily captured with standard clinical endpoints (e.g., RECIST criteria and progression-free survival). Progression-free survival may underestimate activity for agents producing a substantial number of unconventional responses. The studies of sipuleucel-T also demonstrated that survival could be increased for a patient population with metastatic disease, but without an effect on progression-free survival or traditional measures of tumor

clinical response.68,69 Optimal use of immunotherapies in the surgical adjuvant setting or after substantial tumor debulking with other agents also remains undefined. Multiple large randomized studies of cancer vaccines in the surgical adjuvant setting for melanoma were negative, although the results do not preclude success of newer vaccination approaches.70 Immunologic responses that cause cancer regression in advanced disease may not be sufficient or optimal in the surgical adjuvant setting; for example, induction of antibody responses against cell surface targets, which may have little activity in advanced disease, could play an important role in eliminating micrometastases. Anti-CTLA-4 improved survival in metastatic melanoma, and early analysis of a large adjuvant study shows a 25% reduction in the risk of progression at 3 years; the studies will not address if the treatment effect is larger in the adjuvant setting compared to advanced disease.71 Studies of PD1/PD-L1 antagonists in the adjuvant setting have only recently been initiated.

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I. ESTABLISHING THE DIAGNOSIS A. Pathologic diagnosis is critical Although it might seem obvious that the diagnosis of cancer must be firmly established before chemotherapy or any other treatment is administered, the critical nature of an accurate diagnosis warrants a reminder. As a rule, there must be cytologic or histologic evidence of neoplastic cells together with a clinical picture consistent with the diagnosis of the cancer under consideration. It is rarely acceptable to initiate treatment based solely on clinical examination, radiologic evidence, and nontissue laboratory evidence, such as tumor markers. Commonly, patients present to their physicians with a complaint such as a cough, bleeding, pain, or a lump; through a logical sequence of evaluation, the presence of cancer is revealed on a cytologic or histologic specimen. Less frequently, lesions are discovered fortuitously during routine examination, evaluation of an unrelated disorder, or systematic screening for cancer. With some types of cancer, pathologists can establish the diagnosis based on small amounts of material obtained from needle biopsies, aspirations, or tissue scrapings. Other cancers require larger pieces of tissue for special staining, immunohistologic evaluation, flow cytometry, examination by electron microscopy, or more sophisticated studies such as evaluation for genetic deletions, amplifications, or other mutations. It is often helpful to confer with the pathologist before obtaining a specimen to determine what kind and size of specimen is adequate to establish the complete diagnosis. When a tissue diagnosis of cancer is made by the pathologist, it is incumbent on the clinician to review the material with the pathologist. This practice is good medicine. It also allows the clinician to tell the patient that he or she has actually seen the cancer and to avoid administering chemotherapy without a firm pathologic diagnosis. In addition, the pathologist often gives a better consultation—not just a tissue diagnosis—when the clinician shows a personal interest. B. Pathologic and clinical diagnosis must be consistent Once the tissue diagnosis is established, the clinician must be certain that the pathologic diagnosis is consistent with the clinical findings. If the two are not consistent, a search must be made for additional information, clinical or pathologic that allows the clinician to make a unified diagnosis. A pathologic diagnosis, like a clinical diagnosis, is also an opinion with varying levels of certainty. The first part of the pathologic diagnosis—and

usually the easier part—is an opinion about whether the tissue examined is neoplastic. Because most pathologists rarely render a diagnosis of cancer unless the degree of certainty is high, a positive diagnosis of cancer is generally reliable. The clinician must be more cautious if the diagnosis rendered states that the tissue is “highly suggestive of” or “consistent with the diagnosis of” cancer. Absence of definitively diagnosed cancer in a specimen does not mean that cancer is not present, however; it means only that it could not be diagnosed on the tissue obtained, and clinical circumstances must establish if additional tissue sampling is necessary. A second part of the pathologist’s diagnosis is an opinion about the type of cancer and the tissue of origin. This determination is not necessary in all circumstances but is usually helpful and may be critical in selecting the most appropriate therapy and making a determination of prognosis, and will become more relevant with precision (personalized) cancer treatment. C. Treatment without a pathologic diagnosis There are rare circumstances in which treatment is undertaken before a pathologic diagnosis is established. Such circumstances are clearly exceptions, however, and involve less than 1% of all patients with cancer. Therapy is begun without a pathologic diagnosis only when the following conditions are met: ■ The clinical features strongly suggest the diagnosis of cancer, and the likelihood of a benign diagnosis is remote. ■ Withholding prompt treatment or carrying out the procedures required to establish the diagnosis would greatly increase a patient’s morbidity or risk of mortality. Two examples of such circumstances are (1) a primary tumor of the midbrain and (2) superior vena cava syndrome from a large mediastinal mass with no accessible supraclavicular nodes and no endobronchial disease found on bronchoscopy in the occasional patient in whom the risk of bleeding from mediastinoscopic biopsy is deemed greater than the risk of administering radiotherapy for a disease of uncertain nature. II. STAGING Once the diagnosis of cancer is firmly established, it is important to determine the anatomic extent or stage of the disease. The steps taken for staging vary considerably among cancers because of the differing natural histories of the tumors. A. Staging system criteria For most cancers, a system of staging has been established on the basis of the following factors: ■ Natural history and mode of spread of the cancer ■ Prognostic import of the staging parameters used ■ Value of the criteria used for decisions about therapy B. Staging and therapy decisions In the past, surgery and radiotherapy were used to treat patients with cancer in early stages, and chemotherapy was used when surgery and radiotherapy were no longer

effective or when the disease was in an advanced stage at presentation. In such circumstances, chemotherapy was only palliative (except for gestational choriocarcinoma), and in the absence of exquisitely sensitive tumors or strikingly potent drugs, the likelihood of increasing the survival was low. As knowledge has increased about the genetic determinants of cancer growth, tumor cell kinetics, and the development of resistance, the value of early intervention with chemotherapy has been transposed from animal models to human cancers. To plan this intervention and evaluate its effectiveness, careful staging has become increasingly important. Only when the exact extent of disease has been established can the most rational plan of treatment for the individual patient be devised, whether it is surgery, radiotherapy, chemotherapy, or molecular targeted therapy alone or in combination. Although no single staging system is universally used for all cancers, the system developed jointly by the American Joint Committee on Cancer and the TNM Committee of the International Union Against Cancer is most widely used for staging solid tumors.1 It is based on the status of the primary tumor (T), regional lymph nodes (N), and distant metastasis (M). For some cancers, tumor grade (G) is also taken into account. The stage of the tumor is based on a condensation of the total possible TNM and G categories to create stage groupings, usually stages 0, I, II, III, and IV, which are relatively homogeneous with respect to prognosis. III. PERFORMANCE STATUS The performance status refers to the level of activity of which a patient is capable. It is a measure independent from the anatomic extent or histologic characteristics of the cancer and of how much the cancer or comorbid conditions have affected the patient, and a prognostic indicator of how well the patient is likely to respond to treatment. A. Types of performance status scales Two performance status scales are in wide use: ■ The Karnofsky Performance Status Scale (Table 4.1) has 10 levels of activity. It has the advantage of allowing discrimination over a wide scale, but the disadvantages of being difficult to remember and perhaps of making discriminations that are not clinically useful. ■ The Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO)/Zubrod Performance Status Scale (Table 4.2) has the advantages of being easy to remember and making discriminations that are clinically useful. According to the criteria of each scale, patients who are fully active or have mild symptoms respond more frequently to treatment and survive longer than patients who are less active or have severe symptoms. A clear designation of the performance status distribution of patients in therapeutic clinical trials is thus critical in determining the comparability and generalizability of trials and the effectiveness of the treatments used.

TABLE

4.1

Karnofsky Performance Status Scale

Functional Capability

Level of Activity

Able to carry on normal activity; no special care needed

100%—Normal; no complaints, no evidence of disease 90%—Able to carry on normal activity; minor signs or symptoms of disease 80%—Normal activity with effort; some signs or symptoms of disease

Unable to work; able to live at home; cares for most personal needs; needs varying amount of assistance

70%—Cares for self; unable to carry on normal activity or to do active work 60%—Requires occasional assistance but is able to care for most of own needs 50%—Requires considerable assistance and frequent medical care

Unable to care for self; requires equivalent of institutional or hospital care

40%—Disabled; requires special medical care and assistance 30%—Severely disabled; hospitalization indicated, although death not imminent 20%—Very sick; hospitalization necessary; active supportive treatment necessary 10%—Moribund; fatal processes progressing rapidly 0%—Dead

B. Use of performance status for choosing treatment In the individualization of therapy, the performance status is often a useful parameter to help the clinician decide whether the patient will benefit from treatment or will be made worse. For example, unless there is some reason to expect a dramatic response of a cancer to chemotherapy, treatment may be withheld from many patients with an ECOG Performance Status Scale score of 3 or 4, particularly those with solid tumors, because responses to therapy are infrequent and toxic effects of the treatment are likely to be great. TABLE

4.2

ECOG/WHO/Zubrod Performance Status Scale

Grade

Level of Activity

0

Fully active; able to carry on all predisease performance without restriction (Karnofsky 90%–100%)

1

Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature such as light housework or office work (Karnofsky 70%–80%)

2

Ambulatory and capable of all self-care but unable to carry out any work activities; up and about >50% of waking hours (Karnofsky 50%–60%)

3

Capable of only limited self-care; confined to bed or chair >50% of waking hours (Karnofsky 30%–40%)

4

Completely disabled; cannot carry on any self-care; totally confined to bed or chair (Karnofsky 10%–20%)

C. Quality of life A related but partially independent measure of performance status can be determined on the basis of patients’ own perceptions of their quality of life (QOL). QOL evaluations have been shown to be independent predictors of tumor response and survival in some cancers, and they are important components in a comprehensive assessment of response to therapy. For some cancers, improvement in QOL measures early in the course of treatment is the most reliable predictor of survival time. IV. RESPONSE TO THERAPY Response to therapy may be measured by survival (with or without disease), objective change in tumor size or in tumor product (e.g., immunoglobulin in myeloma), and subjective change.2 A. Survival One goal of cancer therapy is to allow patients to live as long and with the same QOL as they would have if they did not have the cancer. If this goal is achieved, it can be said that the patient is cured of the cancer (though biologically, the cancer may still be present). From a practical standpoint, we do not wait to see if patients live a normal lifespan before saying that a given treatment is capable of achieving a cure, but we follow a cohort of patients to see if their survival within a given timespan is different from that in a comparable cohort without the cancer. For the evaluation of response to adjuvant therapy (additional treatment after surgery or radiotherapy that is given to treat potential nonmeasurable, micrometastatic disease), survival analysis (rather than tumor response) must be used as the definitive objective measure of antineoplastic effect. With neoadjuvant therapy (chemotherapy or biologic therapy given as initial treatment before surgery or radiotherapy), tumor response and resectability are also partial determinants of effectiveness. B. Definitions The overall survival rate is used to describe the percentage of people in a cohort who are alive for a specified period of time after diagnosis or initiation of a given treatment. The median survival time is the time after either diagnosis or treatment at which half of the patients with a given disease are still alive. Disease-free survival, the length of time after treatment for a specific disease during which a patient survives with no sign of the disease, is often a useful comparator in clinical studies of adjuvant therapy, as return of disease most often represents loss of curability. Progression-free survival (PFS) is the length of time during and after treatment in which a patient is living with a disease that does not get worse. It is used primarily in studies of metastatic or unresectable disease. C. Other considerations It is, of course, possible that a patient may be cured of the cancer that was treated but dies early owing to complications associated with the treatment, including second cancers. Even with complications (unless they are acute ones such as bleeding or infection), survival of patients who have been cured of the cancer is likely to be longer

than if the treatment had not been given, though shorter than if the patient had never had the cancer. If cure is not possible, the reduced goal is to allow the patient to live longer than if the therapy under consideration were not given. It is important for physicians to know if, and with what likelihood, any given treatment will result in a longer life. Such information helps physicians to choose whether to recommend treatment and the patient to decide whether to undertake the recommended treatment program. It is important to learn from the patient what his or her goals of therapy are and to have a frank discussion about whether those goals are realistic. This can avoid unnecessary surprises and anger at some later time, which can occur when the patient has set a goal that is not realistic and the physician has not discussed what may or may not reasonably be expected as a consequence of therapy. D. Objective response Although survival is important to the individual patient, it is determined not only by the initial treatment undertaken but also by biologic determinants of the patient’s individual cancer and subsequent treatment; thus, survival does not give an early measurement of a given treatment effectiveness. Tumor regression, on the other hand, when measurable, frequently occurs early in the course of effective treatment and is therefore a readily used determinant of treatment benefit. Tumor regression can be determined by a decrease in size of a tumor or the reduction of tumor products. 1. Tumor size. When tumor size is measured, responses are usually classified by the Response Evaluation Criteria in Solid Tumors (RECIST) methodology first published in 2000 and revised in 2008 (RECIST 1.1), reported by Eisenhauer et al.3 in the European Journal of Cancer in 2009, and available online at http://www.eortc.be/recist/documents/RECISTGuidelines.pdf, and for the iPad from the APP Store (RECIST 1.1) a. Baseline lesions are characterized as “measurable” or “nonmeasurable.” To be measurable, non–lymph node lesions must be 20 mm or more in longest diameter and measurable by calipers using conventional techniques, or 10 mm or more in longest diameter using computed tomography (CT). On CT scan, lymph nodes must be more than or equal to 15 mm for target lesions or 10 to 15 mm in short axis for nontarget lesions. Smaller lesions and truly nonmeasurable lesions are designated nonmeasurable. To assess response, all measurable lesions up to a maximum of two per organ and five in total are designated as “target” lesions and measured at baseline. Except for lymph nodes, only the longest diameter of each lesion is measured. The sum of the longest diameters of all target lesions is designated the “baseline sum longest diameter.” There are a variety of lesions in cancer that cannot be measured. These include blastic and sclerotic metastatic lesions to the bone, effusions, lymphangitic disease of the lung or skin, and lesions that have necrotic or cystic centers. Bone lesions are measurable only if they include an identifiable soft-

tissue component, which constitutes the measureable lesion. b. Response categories are based on measurement of target lesions. 1) Complete response (CR) is the disappearance of all target lesions. If lymph nodes are included in target lesions, each node must achieve a short axis of less than 10 mm. 2) Partial response (PR) is a decrease of at least 30% in sum of the longest diameters of target lesions, using as reference the baseline sum of the longest diameters. 3) Stable disease (SD) is when there is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). 4) Progressive disease is an increase of 20% or more in the sum of the longest diameters of target lesions, taking as reference the smallest sum’s longest diameter recorded since the treatment started or the appearance of one or more new lesions. The sum must also demonstrate an absolute increase of at least 5 mm. While the fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan cannot be used to determine measureable disease, if there is negative FDG-PET at baseline with a positive FDG-PET at followup, this is a sign of PD, based on a new lesion. 5) Inevaluable for response is a category used where there is early death by reason of malignancy or toxicity, tumor assessments were not repeated, and so on. c. Time to progression based on response criteria is an additional indicator that is often used, similar to PFS. It takes into account the fact that from the patient’s perspective, CR, PR, and SD may be meaningless distinctions so long as the tumor is not causing symptoms or impairment of function. It also takes into account that some agents result in disease stability for a substantial period, despite failure to produce measurable disease shrinkage. This is particularly true for biologic targeted agents where it has been shown that time to progression for some cancers is substantially prolonged, despite no measurable reduction in tumor size; in other cases, such as with ipilimumab, responses may be delayed for months. Time to progression can also be used as an indicator of disease status Time to progression can also be used as an indicator of disease status when there was no measurable disease at the outset of therapy or when the therapeutic modalities were not comparable. For example, if one wanted to compare the results of surgery alone with those of chemotherapy alone, time to progression from the onset of treatment would allow a valid comparison of the effectiveness of the treatments, whereas the traditional tumor response criteria would not. Time to progression thus places each of the agents or modalities on an even basis. d. Survival curves. If survival curves of patient populations having different categories of response are compared, those patients with a CR frequently

survive longer than those with a lesser response. If a sizable number of CRs occur with a treatment regimen, the survival rate of patients treated with that regimen is likely to be significantly greater than that of patients who are untreated. When the number of complete responders in a population rises to about 50%, the possibility of cure for a small number of patients begins to appear. With increasing percentages of complete responders, the frequency of cures is likely to increase correspondingly. Although patients who have PR to a treatment usually survive longer than those who have SD or PD, it is often not easy to demonstrate that the overall survival of the treated population is better than that of a comparable untreated group. In part, this difficulty may be due to a phenomenon of small numbers. If only 15% to 20% of a population respond to therapy, the median survival rate may not change at all, and the numbers may not be high enough to demonstrate a significant difference in survival duration of the longest surviving 5% to 10% of patients (the “tail” of the curves) of the treated and untreated populations. It is also possible that the patients who achieve a PR to therapy are those who have less aggressive disease at the outset of treatment and thus will survive longer than the nonresponders, regardless of therapy. These caveats notwithstanding, most clinicians and patients welcome even a PR as a sign that offers hope for longer survival and improved QOL. 2. Tumor products. For many cancers, objective tumor size changes are difficult or impossible to document. For some of these neoplasms, tumor products (hormones, antigens, antibodies) may be measurable and may provide a good, objective way to evaluate tumor response. Two examples of such markers that closely reflect tumor cell mass are the abnormal immunoglobulins (M proteins) produced in multiple myeloma and the human chorionic gonadotropin produced in choriocarcinoma and testicular cancer. Other markers such as prostate-specific antigen or carcinoembryonic antigen are not quite as reliable, but are nonetheless helpful measures of response of the tumor to therapy. In some cancers, reduction in the number of circulating tumor cells is also an indicator of response to therapy. 3. Evaluable disease. Other objective changes may occur, but are not easily quantifiable. When these changes are not easily measurable, they may be termed evaluable. For example, neurologic changes secondary to primary brain tumors cannot be measured with a caliper, but they can be evaluated using neurologic testing. An arbitrary system of grading the degree of severity of neurologic deficit can be devised to permit surrogate evaluation of tumor response. Evaluable disease is not a category of the RECIST criteria. 4. Performance status changes may also be used as a measure of objective change; although in some respects, the performance status is as representative of subjective aspects as it is of the objective status of the disease. E. Subjective change and QOL considerations

A subjective change is one that is perceived by the patient but not necessarily by the physician or others around the patient. Subjective improvement and an acceptable QOL are often of far greater importance to the patient than objective improvement: If the cancer shrinks, but the patient feels worse than before treatment, he or she is not likely to believe that the treatment was worthwhile. It is not valid to look at subjective change in isolation, however, because temporary worsening in the perceived state of wellbeing may be necessary to achieve subsequent long-term improvement.4 This point is particularly well illustrated by the combined modality treatment in which chemotherapy is used to treat micrometastases after surgical removal of the macroscopic tumor. In such a circumstance, the patient is likely to feel entirely well after the primary surgical procedure, but the side effects of chemotherapy increase the symptoms and make the patient feel subjectively worse for the period of treatment. The patient should be encouraged to continue treatment, however, because if the chemotherapy treatment of the micrometastases is successful, he or she will be cured of the cancer and can be expected to have a normal or near-normal life expectancy rather than dying from recurrent disease. Most patients agree that the temporary subjective worsening is not only tolerable but well worth the price if cure of the cancer is a distinct possibility. This judgment depends on the severity and duration of symptoms, functional impairment, and perceptions of illness during the acute phase of the treatment; the expected benefit (increased likelihood of survival) anticipated as a result of the treatment; and the potential long-term adverse consequences of the treatment. In contrast, when chemotherapy is given with a palliative intent, patients (and less often physicians) may be unwilling to tolerate significant side effects or subjective worsening from treatment. Fortunately, subjective improvement often accompanies objective improvement, so those patients in whom there is measurable improvement of the cancer also feel better. The degree of subjective worsening that each patient is willing to tolerate varies, and the patient and physician together must discuss and evaluate whether the chemotherapy treatment program is worth continuing. Such discussions should include a clear presentation of the scientific facts that include objective survival and tumor response data together with whatever QOL information has been documented for the treatment proposed. Moreover, the expressed goals and desires and the social, economic, psychological, and spiritual situations of the patient and his or her family must be sensitively considered. A word of caution about discussions of response and survival is important. Patients can more easily understand the notion of response rates than survival probabilities. For example, a 50:50 chance of the cancer shrinking helps them to understand the goals and expectations of therapy and does not lead to undue anxiety over time. On the other hand, understanding and dealing with median or expected survival estimates is more problematic intellectually and even more difficult emotionally. It is therefore usually best to give the patient a range of expected survival rather than a discrete number. For example, the physician can say, “Some patients may have progression of their disease

and possibly die within 6 months, but others may go on feeling fairly well and functioning well for 2 or more years.” This helps the patient and family not to focus on a single number (“They said I had only 13 months to live”) and to avoid some of the feeling of impending doom. I. TOXICITY A. Factors affecting toxicity One of the characteristics that distinguishes cancer chemotherapeutic agents from most other drugs is the frequency and severity of anticipated side effects at usual therapeutic doses. Because of the severity of the side effects, it is critical to monitor the patient carefully for adverse reactions so that therapy can be modified before the toxicity becomes life-threatening. Most toxicity varies according to the following factors: ■ Specific agent ■ Dose ■ Schedule of administration, including infusion rate and frequency of dose and prior therapy with the same or other agents. ■ Route of administration ■ Predisposing factors in the patient, including genetic variants,* that may be known and predictive for toxicity or unknown and resulting in unexpected toxic effects B. Clinical testing of new drugs for toxicity Before the introduction of any agent into wide clinical use, the agent must undergo testing in carefully controlled clinical trials. The first set of clinical trials are called phase I trials. They are carried out with the express purpose of determining toxicity in humans and establishing the maximum tolerated dose; although with antineoplastic agents, they are done only in patients who might benefit from the drug. Such trials are undertaken only after extensive tests in animals have been completed. Much human toxicity is predicted by animal studies, but because of significant species differences, initial doses used in human studies are several times lower than doses at which toxicity is first seen in animals. Phase I trials are carried out using several schedules, and the dose is escalated in successive groups of patients once the toxicity of the prior dose has been established. At the completion of phase I trials, there is usually a great deal of information about the spectrum and anticipated severity of acute drug effects (toxicity). However, because patients in phase I trials often do not live long enough to undergo many months of treatment, chronic or cumulative effects may not be discovered. Discovery of these toxicities may occur only after widespread use of the drug in phase II trials (to establish the spectrum of effectiveness of the drug), in phase III trials (to compare the new drug or combination with standard therapy), or from postmarketing reports (when even larger numbers and less rigorously selected patients are treated). C. Common acute toxicities Some toxicities are relatively common among traditional cancer chemotherapeutic

agents. Common acute toxicities include the following: ■ Myelosuppression with leukopenia, thrombocytopenia, and anemia ■ Nausea, vomiting, and other gastrointestinal effects ■ Mucous membrane ulceration and cutaneous effects, including alopecia ■ Infusion reactions Some of these toxicities occur because of the cytotoxic effects of chemotherapy on rapidly dividing normal cells of the bone marrow and epithelium (e.g., mucous membranes, skin, and hair follicles) incidental to the mechanism of action of the drugs; others such as nausea and vomiting or infusion reactions are not related to the antineoplastic mechanism of action. D. Selective toxicities Other toxicities are less common and are specific to individual drugs or classes of drugs. Examples of drugs and their related toxicities include the following: ■ Anthracyclines and anthracenediones: irreversible cardiomyopathy ■ Asparaginase: anaphylaxis (allergic reaction), pancreatitis ■ Bleomycin: pulmonary fibrosis ■ Cisplatin: renal toxicity, neurotoxicity ■ Epidermal growth factor receptor inhibitors: acneiform rash ■ Fludarabine, cladribine, pentostatin, and temozolomide: prolonged suppression of cellular immunity with heightened risk of opportunistic infection ■ Ifosfamide and cyclophosphamide: hemorrhagic cystitis ■ Ifosfamide: central nervous system toxicity ■ Immune modulators, such as ipilimumab: a host of severe immune-mediated adverse reactions due to T-cell activation and proliferation. They may involve any organ system, but most common are the gastrointestinal tract, liver, skin, nervous system, and endocrine system ■ Mitomycin: hemolytic-uremic syndrome and other endothelial cell injury phenomena ■ Monoclonal antibodies (e.g., rituximab, trastuzumab): hypersensitivity reactions ■ Paclitaxel: neurotoxicity, acute hypersensitivity reactions (primarily from the vehicle) ■ Procarbazine: food and drug interactions ■ Trastuzumab: reversible cardiomyopathy ■ Vascular endothelial growth factor inhibitors: gastrointestinal perforation, impaired wound healing ■ Vinca alkaloids: neurotoxicity E. Recognition and evaluation of toxicity Anyone who administers chemotherapeutic agents must be familiar with the expected and the unusual toxicities of the agent the patient is receiving, be prepared to avert severe toxicity when possible, and be able to manage toxic complications when they cannot be avoided. The specific toxicities of commonly used individual

chemotherapeutic agents are detailed in Chapter 28. For the purpose of reporting toxicity in a uniform manner, criteria are often established to grade the severity of the toxicity. For many years, a simplified set of criteria was used by several National Cancer Institute (NCI)–supported clinical trial groups for the most common toxic manifestations. Although this document was helpful, it was, in many respects, incomplete. To address this issue, a new set of more comprehensive toxicity criteria, the Common Toxicity Criteria, was developed in 1999. A revised version of these criteria (Common Terminology Criteria for Adverse Events v3.0 [CTCAE]) was published in 2003 and updated again in 2009 (CTCAE v4.0) and is available online5 at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm or the latest version can be downloaded from http://evs.nci.nih.gov/ftp1/CTCAE/About.html. A host of other helpful information can be obtained online at http://ctep.cancer.gov/. All new clinical trials approved by the NCI Cancer Therapy Evaluation Program use these new toxicity criteria. Such standardization is important in the evaluation of the toxicity of cancer treatment. F. Acute toxicity management Prevention and treatment of bone marrow suppression can be partially achieved using filgrastim, sargramostim, epoetin-α, and oprelvekin. Management of nausea and vomiting, mucositis, and alopecia as well as diarrhea, nutrition problems, and drug extravasation are discussed in Chapter 26. Other acute toxicities are discussed with the individual drugs in Chapter 28. Long-term medical problems are a special issue and are highlighted in the subsequent section. VI. LATE PHYSICAL EFFECTS OF CANCER TREATMENT A. Late organ toxicities Late organ toxicities may be minimized by limiting doses when thresholds are known. In most instances, however, individual patient effects cannot be predicted.6–9 Treatment is primarily symptomatic. 1. Cardiac toxicity (e.g., congestive cardiomyopathy) is most commonly associated with high total doses of the anthracyclines (doxorubicin, daunorubicin, epirubicin). In addition, high-dose cyclophosphamide as used in transplantation regimens may contribute to congestive cardiomyopathy. When mediastinal irradiation is combined with these chemotherapeutic agents, cardiac toxicity may occur at lower doses. Although evaluation of ventricular ejection fraction with echocardiography or nuclear radiography studies has been useful for acutely monitoring the effects of these agents on the cardiac ejection fraction, studies have reported late onset of congestive heart failure during pregnancy or after the initiation of vigorous exercise programs in adults who were previously treated for cancer as children or young adults. The cardiac reserve in these previously treated cancer patients may be marginal. It is probable that there are some changes that take place even at low

doses, and it is only because of the great reserve in cardiac function that effects are not measurable until higher doses have been used. Mediastinal irradiation also accelerates atherogenesis and may lead to premature symptomatic coronary artery disease. Because of the large number of women with breast cancer who are treated with doxorubicin as part of an adjuvant chemotherapy regimen, this group is of special concern and warrants ongoing clinical follow-up. Many targeted agents, such as trastuzumab, are also associated with cardiac toxicity, but the mechanism of toxicity is different from that of the anthracyclines and often is at least partially reversible.10 Nonetheless, the adverse effect may limit the use and thus the efficacy of these agents. 2. Pulmonary toxicity has been classically associated with high doses of bleomycin (>400 U). However, a number of other agents have been associated with pulmonary fibrosis (e.g., alkylating agents, methotrexate, nitrosoureas). Premature respiratory insufficiency, especially with exertion, may become evident with aging. 3. Nephrotoxicity is a potential toxicity of several agents (e.g., cisplatin, methotrexate, nitrosoureas). These agents can be associated with both acute and chronic toxicities. Other nephrotoxic agents such as amphotericin or aminoglycosides may exacerbate the problem. Even usually benign agents such as the bisphosphonates or allopurinol may be a problem. Rarely, some patients may require hemodialysis as a result of chronic toxicity. 4. Neurotoxicity has been particularly associated with the vinca alkaloids, cisplatin, oxaliplatin, epipodophyllotoxins, taxanes, bortezomib, and ixabepilone. Peripheral neuropathy can cause considerable sensory and motor disability. Autonomic dysfunction may produce debilitating postural hypotension. Whole-brain irradiation, with or without chemotherapy, can be a cause of progressive dementia and dysfunction in some long-term survivors. This is particularly a problem for patients with primary brain tumors and for some patients with small-cell lung cancer who have received prophylactic therapy. Survivors of childhood leukemia have developed a variety of neuropsychological abnormalities related to central nervous system prophylaxis that included whole-brain irradiation.11 It has become evident over the years that some patients (up to one in five) who have received adjuvant chemotherapy for carcinoma of the breast also have measurable cognitive deficits such as difficulties with memory or concentration.12 This appears to be greater for women who have received high-dose chemotherapy than for those women who have received standard-dose chemotherapy; in both groups, the incidence is higher than in control groups. It is not uncommon for patients to refer to the effects of chemotherapy with complaints about memory being worse than it was, not being able to calculate numbers in their head, or just having “chemobrain.” Rarely patients may have severe, debilitating, idiosyncratic cognitive impairment or even fatal central nervous system damage subsequent to

chemotherapy. 5. Hematologic and immunologic impairment is usually acute and temporally related to the cancer treatment (e.g., chemotherapy or radiation therapy). In some instances, however, there can be persistent cytopenias, as with alkylating agents. Immunologic impairment is a long-term problem for patients with Hodgkin lymphoma, which may be due to the underlying disease as well as to the treatments that are used. Fludarabine, cladribine, and pentostatin, with or without rituximab, cause profound suppression of cluster of differentiation 4 (CD4) and CD8 lymphocytes and render treated patients susceptible to opportunistic infections for many months after treatment has been discontinued. Temozolomide causes CD4 lymphopenia and also carries a risk of opportunistic infection. Complete immunologic reconstitution may take 2 years after these therapies or marrow-ablative therapy requiring stem cell reconstitution. In some circumstances such as after stem cell transplant, revaccination is indicated. Patients who have undergone splenectomy are also at risk of overwhelming bacterial infections and must be given vaccination for both pneumococcal and haemophilus influenza infections prior to the spleen being removed. B. Second malignancies13 1. Acute myelogenous leukemia and myelodysplasia may occur secondary to combined modality treatment (e.g., radiation therapy and chemotherapy in Hodgkin lymphoma), prolonged therapy with alkylating agents or nitrosoureas, or other chemotherapy.14–18 In general, this form of treatment-related acute leukemia arises in the setting of myelodysplasia and is refractory even to intensive treatment. Treatment with the epipodophyllotoxins also has been associated with the development of acute nonlymphocytic leukemia. This may be the result of a specific gene rearrangement between chromosome 9 and chromosome 11 that creates a new cancer-causing oncogene: ALL-1/AF-9. The peak time of occurrence of secondary acute leukemia in patients with Hodgkin lymphoma is 5 to 7 years after treatment, with an actuarial risk of 6% to 12% by 15 years. Thus, a slowly developing anemia in a survivor of Hodgkin lymphoma should alert the clinician to the possibility of a secondary myelodysplasia or leukemia. Fortunately, the risk of secondary leukemias in women treated with standard adjuvant therapy for breast cancer (e.g., cyclophosphamide and doxorubicin) is only modestly higher (excess absolute risk of 2 to 5 per 100,000 person years) than that in the general population. 2. Solid tumors and other malignancies are seen with increased frequency in survivors who have been treated with chemotherapy or radiation therapy.19 NonHodgkin lymphomas have been reported as a late complication in patients treated for Hodgkin lymphoma or multiple myeloma. Patients treated with long-term cyclophosphamide are at risk of bladder cancer. Patients who have received mantle irradiation for Hodgkin lymphoma have an increased risk of breast cancer, thyroid

cancer, osteosarcoma, bronchogenic carcinoma, colon cancer, and mesothelioma. In these cases, the second neoplasm is usually in the irradiated field. In general, the risk of solid tumors begins to increase during the second decade of survival after Hodgkin lymphoma. As a result, young women who have received mantle irradiation for Hodgkin lymphoma should be screened more carefully for breast cancer, starting at an age earlier than what is advised in standard screening recommendations. Patients treated with molecular targeted agents such as dabrafenib may develop squamous cell carcinomas of the skin as well as noncutaneous malignancies. C. Other sequelae 1. Endocrine problems may result from cancer treatment. Patients receiving radiation therapy to the head and neck region may develop subclinical or clinical hypothyroidism. This is a particular risk in patients receiving mantle irradiation for Hodgkin lymphoma. Biennial assessment of thyroid-stimulating hormone should be undertaken in these patients. Thyroid replacement therapy should be given if the thyroid-stimulating hormone level rises in order to decrease the risk of thyroid cancer. Short stature may be a result of pituitary irradiation and growth hormone deficiency. 2. Premature menopause may occur in women who have received certain chemotherapeutic agents (e.g., alkylating agents, procarbazine) or abdominal and pelvic irradiation. The risk is age-related, with women older than 30 years at the time of treatment having the greatest risk of treatment-induced amenorrhea and menopause. Early hormone replacement therapy should be considered in such women, if not otherwise contraindicated, to reduce the risk of accelerated osteoporosis and premature heart disease from estrogen deficiency. 3. Gonadal failure or dysfunction can lead to infertility in both male and female cancer survivors during their peak reproductive years.20 Azoospermia is common, but the condition may improve over time after the completion of therapy. Retroperitoneal lymph node dissection in testicular cancer may produce infertility due to retrograde ejaculation. Psychological counseling should be provided to these patients to help them adjust to these long-term sequelae of therapy. Cryopreservation of sperm before treatment should be considered in men. For women, there are limited means available to preserve ova or protect against ovarian failure associated with treatment. Abdominal irradiation in young girls can lead to future pregnancy loss due to decreased uterine capacity. 4. The musculoskeletal system can be affected by radiation therapy, especially in children and young adults. Radiation may injure the growth plates of long bones and lead to muscle atrophy. Short stature may be a result of direct injury to bone. Aromatase inhibitors increase bone loss and can contribute to pathologic osteoporotic fractures. 5. Psychological and social concerns can be severe as patients who have had cancer often carry an ongoing sense of vulnerability and frequent worry of the cancer

returning. Changes in body image and sexual function can lead to difficulty with marriage and other relationships. Survivors may also suffer from discrimination on the job and find it difficult or impossible to get insurance, despite having been cured from their cancer.

Acknowledgments The author is indebted to Dr. Patricia A. Ganz, who contributed to previous editions of this chapter. Most of the section on the late consequences of cancer treatment in this revision of the handbook represents Dr. Ganz’s work.

References 1. Edge S, Byrd DR, Compton CC, et al., eds. AJCC cancer staging manual. 7th ed. New York: Springer; 2010. 2. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–655. 3. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247. Retrieved from http://www.eortc.be/recist/documents/RECISTGuidelines.pdf 4. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy (FACT) scale: development and validation of the general measure. J Clin Oncol. 1993;11:570–579. 5. Cancer Therapy Evaluation Program. Common Terminology Criteria For Adverse Events (CTCAE) v4.0, 2009. Retrieved from http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 6. Centers for Disease Control and Prevention. A national action plan for cancer survivorship: advancing public health strategies. Atlanta: Centers for Disease Control and Prevention; 2004. 7. Ganz PA. Late effects of cancer in adult survivors: what are they and what is the oncologist’s role in follow-up and prevention? Alexandria: American Society of Clinical Oncology; 2005:724–730. 8. National Cancer Institute. Survivorship. Retrieved from http://www.cancer.gov/cancertopics/coping/survivorship 9. Rowland JH, Hewitt M, Ganz PA. Cancer survivorship: a new challenge in delivering quality cancer care. J Clin Oncol. 2006;24:5101–5104. 10. Bhave M, Akhter N, Rosen ST. Cardiovascular toxicity of biologic agents for cancer therapy. Oncology. 2014;28:482–490. 11. Hudson MM, Mertens AC, Yasui Y, et al. Health status of adults who are long-term childhood cancer survivors: a report from the Childhood Cancer Survivor Study. JAMA. 2003;290:1583–1592.

12. Schagen SB, van Dam FS, Muller MJ, et al. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer. 1999;85:640–650. 13. Neglia JP, Friedman DL, Yasui Y, et al. Second malignant neoplasms in five-year survivors of childhood cancer: Childhood Cancer Survivor Study. J Natl Cancer Inst. 2001;93:618–629. 14. Curtis RE, Boice J-D Jr, Stovall M, et al. Risk of leukemia after chemotherapy and radiation treatment for breast cancer. N Engl J Med. 1992;326:1745–1751. 15. Howard RA, Gilbert ES, Chen BE, et al. Leukemia following breast cancer: an international population based study of 376,825 women. Breast Cancer Res Treat. 2007;105:359–368. 16. Pedersen-Bjergaard J, Sigsgaard TC, Nielsen D, et al. Acute monocytic or myelomonocytic leukemia with balanced chromosome translocations to band 11q23 after therapy with 4-epidoxorubicin and cisplatin or cyclophosphamide for breast cancer. J Clin Oncol. 1992;10:1444–1451. 17. Pui CH, Ribeiro RC, Hancock ML, et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med. 1991;325:1682–1687. 18. Tallman MS, Gray R, Bennett JM, et al. Leukemogenic potential of adjuvant chemotherapy for early-stage breast cancer: the Eastern Cooperative Oncology Group experience. J Clin Oncol. 1995;13:1557–1563. 19. van Leeuwen FE, Klokman JW, Hagenbeek A, et al. Second cancer risk following Hodgkin’s disease: a 20-year follow-up study. J Clin Oncol. 1994;12:312–325. 20. Nieman CL, Kazer R, Brannigan RE, et al. Cancer survivors and infertility: a review of a new problem and novel answers. J Support Oncol. 2006;4:171–178.

*An example is homozygosity for the UGT1A1*28 allele, a variation of a uridine diphosphate

glucuronosyltransferase gene and its corresponding enzyme (UGT1A1), which is responsible for glucuronidation of bilirubin and involved in deactivation of Sn-38, a toxic active metabolite of irinotecan.

I. SETTING TREATMENT GOALS A. Patient perspective Although patients most often come to the physician looking for medical perspective on what can be done about their cancer, it is critical that physicians and other health-care professionals remember that unless we know what the patient’s goals are, our ideas and our plans of therapy may not address the patient’s needs. As a consequence, it is critical for the physician to ask the patient to share in setting treatment goals because it is the patient who must undergo the rigors of treatment and be willing to abide by its consequences. Whereas the physician’s medical recommendations most commonly are accepted, some patients reject them as inappropriate for a variety of reasons. Some ask the physician for another recommendation, and others seek the opinion of a second physician. The physician must clearly present the reasons for the treatment recommendations and why those recommendations seem to be the best ways to achieve the treatment objective. The physician has the obligation to make a treatment recommendation, but the patient always has the right to reject that advice without fear that the physician will be upset, dislike the patient, or refuse to continue to give the patient care. B. Medical perspective Before a physician decides on a course of treatment to recommend for a patient with cancer, an achievable medical goal of treatment must be clearly defined. If the goal is to cure the patient of cancer, the strategy of therapy is likely to be different from the strategy chosen if the purpose is to prolong life or to relieve symptoms. To propose the goal of therapy, the physician must be: ■ Familiar with the natural history and behavior of the cancer to be treated. ■ Knowledgeable about the principles and practice of therapy for each of the treatment modalities that may be effective in that cancer. ■ Well-grounded in the ethical principles of the treatment of patients with cancer. ■ Familiar with the theory and use of antineoplastic agents. ■ Informed about the particular therapy for the cancer in question. ■ Aware of the patient’s individual circumstances, including stage of disease, performance status, social situation, psychological status, and concurrent illnesses. Armed with this information and with the treatment goals in mind, the physician can develop a course of treatment and make a recommendation to the patient.

Components of the treatment plan include the following: ■ Should the cancer be treated at all? If so, is the treatment to be designed for cure, prolongation of life, or palliation of symptoms? ■ How aggressive should the therapy be to achieve the defined objective? ■ Which modalities of therapy will be used and in what sequence? ■ How will the treatment efficacy be determined? ■ What are the criteria for deciding the duration of therapy? II. CHOICE OF CANCER TREATMENT MODALITY A. Surgery The oldest, most established, and still most effective way to cure most cancers is surgery. Surgery is selected as the treatment if the cancer is limited to one area and if it is anticipated that all cancer cells can be removed without unduly compromising vital structures. If it is believed that the patient can survive the operation and return to a worthwhile life, surgery is recommended. Surgery is not recommended if the risk of surgery is greater than the risk of the cancer; if metastasis always occurs despite complete removal of the primary tumor; or if the patient will be left so debilitated, disfigured, or otherwise impaired that although cured of cancer he or she feels that life is not worthwhile. If metastasis regularly (or always) occurs despite complete removal of the primary tumor, the benefits of removal of the gross tumor should be clearly defined before surgery is undertaken. Most commonly, surgery is reserved for treatment of the primary neoplasm; at times it may be used effectively to remove isolated metastases (e.g., in lung, brain, or liver) with curative intent. Surgery is also used palliatively, such as for decompression of the brain in patients with glioma or biliary bypass in patients with carcinoma of the pancreas. In nearly all nonhematologic cancers, a surgeon should be consulted to determine the role of surgery in the optimal treatment of the patient. B. Radiotherapy Radiotherapy is used for the treatment of local or regional disease when surgery cannot completely remove the cancer or when it would unduly disrupt normal structures or functions. In the treatment of some cancers, radiotherapy is as effective as surgery for eradicating the tumor. In this circumstance, factors such as the anticipated side effects of the treatment, the expertise and experience of local oncologists, and the preference of the patient may influence the choice of treatment. One determinant of the appropriateness of radiotherapy is the inherent sensitivity of the cancer to ionizing radiation. Some kinds of cancer (e.g., lymphomas and seminomas) are highly sensitive to radiotherapy. Other kinds (e.g., melanomas and sarcomas) tend to be less sensitive. Such considerations do not preclude the use of radiotherapy, however, and it is helpful to obtain the evaluation of the radiation oncologist before initiating treatment so that treatment planning can take into consideration the possible contribution of this modality.

Although radiotherapy is frequently used as the primary or curative mode of therapy, it is also well suited to palliative management of problems such as bone metastases, superior vena cava syndrome, and local nodal metastases. C. Chemotherapy As its primary role, chemotherapy treats disease that is no longer confined to anatomic one site or region and has spread systemically. In the earliest days of chemotherapy, this interpretation directed its use to diseases that regularly presented in a disseminated form (e.g., leukemia) or after disease recurred following primary management with surgery or radiotherapy. It is now understood that widespread systemic micrometastases commonly occur early in cancer. These metastases are associated with certain predictive factors such as the axillary node metastases of carcinoma of the breast and the large tumor size and poorly differentiated histologic features of sarcomas or the genetic profile of the cancer. Therefore, chemotherapy is now applied earlier to treat systemic disease. When this treatment is used for micrometastases, the response of an individual patient cannot be measured unless the chemotherapy is used as a neoadjuvant, that is, before surgery or radiotherapy. In that case, tumor response may predict more important endpoints such as time to treatment failure and survival. More commonly, when the chemotherapy is used as an adjuvant after removal of visible disease, the effectiveness of therapy must be determined by comparing the survival (or disease-free survival) of patients who receive therapy with that of similar (control) patients who do not receive therapy for the micrometastases. Chemotherapy also has a role in the treatment of localized or regional disease. D. Biologic response modifiers and molecular targeted therapy It has long intrigued cancer biologists that cancer does not occur randomly but preferentially selects specific populations: the young, the elderly, the immunosuppressed (predominantly certain types of cancer), and those with a strong family history of cancer. These observations have led cancer biologists to postulate that some kind of biologic control over or proclivity toward the emergence of cancer exists, which some people have and others do not, at least at the time the cancer becomes established. One prime candidate for the mechanism of biologic control of cancer has been immunity. That immunity plays some role in controlling the development of cancer has been clearly demonstrated in animal models and a few, though not most, human neoplasms. Other biologic factors, including those controlled by oncogenes and tumor suppressor genes and their protein products that affect the cancer cell directly or its environment, are becoming better defined and are even more important than classic immunity in the development of cancer. In an attempt to exploit and enhance the biologic control that is presumed to exist to some degree in everyone, or to counteract cancer-promoting factors that facilitate cancer growth, invasion, and metastases, a variety of agents called biologic response modifiers and molecular targeted therapy have been used in the treatment of cancer. Two classes of biologic response modifiers, the interferons and lymphokines (of which

interleukin-2 is an example), have been studied for many years, and there is evidence of their modest activity in some types of cancer. Related, but separate, are the molecular targeted agents discussed in Chapter 2 that inhibit the activity of abnormally expressed protein products such as the constitutively activated Bcr-Abl tyrosine kinase in chronic myelogenous leukemia or other unique features, such as the interaction between immune mechanisms and the cancer cell. This area of intensive research (as well as Wall Street interest) has begun to reach fruition, including those previously refractory to conventional chemotherapy such as renal cell carcinoma, and is expected to provide an increasingly important, though expensive, contribution to effective cancer therapy. E. Combined-modality therapy Alone, surgery, radiotherapy, biotherapy, and chemotherapy are not appropriate for the treatment of all cancers. Frequently, patients present with cancer in which there is a bulky primary lesion, macroscopically evident regional disease, and presumed microscopic or submicroscopic systemic disease. For this reason, oncologists have turned to a multidisciplinary approach to the treatment of cancer, selecting two or more modalities of therapy for sequential or simultaneous use. This approach requires close cooperation among the surgical oncologist, radiation oncologist, and medical oncologist to provide the patient with the best overall treatment plan. Although combined-modality therapy is neither effective nor desirable for all kinds or stages of cancers, the regular practice of a multidisciplinary approach provides the best opportunity to exploit the advantages of each mode of treatment. “Tumor Boards” often serve as the format for ensuring that patients will regularly have the benefit of various treatment perspectives. III. PALLIATIVE CARE The medical oncologist, who is also an internist, is often seen as the coordinator of cancer treatment. In this role, although the focus is on the cancer, the broader perspective of the oncologist as a coordinator of the patient’s care—in partnership with the patient—should not become obscured. Decisions about what therapy to use and how aggressively to treat the cancer are critically important to medically sound patient care. Decisions about when to stop active cancer treatment are also vitally important and may be among the most difficult responsibilities for the oncologist.1 It is critical that oncologists, who provide and profit from therapy, recognize the inherent conflict of interest in their dual role as caregivers and drug salespersons. Quality of life is often enhanced in patients responding to chemotherapy and other cancer treatments; it just as surely deteriorates more rapidly when the tumor does not respond to therapy and the patient experiences the toxicity of treatment along with the pain, fatigue, cachexia, and other symptoms of the cancer. For the 50% of patients with cancer who are not cured, the decision to stop antineoplastic therapy is just as important as the selection of chemotherapy regimens earlier in the disease. There comes a time when the best advice a physician can give is for the patient to forgo additional chemotherapy or any other active cancer treatment.2

The introduction and rapid acceptance of hospice programs throughout the United States during the last 35 years reflect the need for this kind of care.3,4 Hospice programs have effectively addressed the special physical, psychological, social, and spiritual needs of patients approaching the end of life and have provided the unique skills required to maintain the best possible quality of life as long as possible. More recently, acute care hospitals have recognized that they, too, have patients who are at the end of life and need a special focus on the palliative aspects of their care. Yet too often, physicians are reluctant to “give up” and are unable to recognize or to accept when the patient will be helped more by an acknowledgment that active cancer therapy will not improve survival or enhance quality of life. Oncologists and others caring for patients with cancer who have been trained as acute care physicians can learn specific techniques to enhance the quality of life from those who are expert in palliative care. There is some evidence that early palliative care integrated with standard oncologic care improves quality of life and mood and is associated with a longer survival, compared with giving standard care alone.5 Comfort at the end of life is also improved when there is a focus on palliative care. For example, consider the quality of death in hospitalized patients given “maintenance” intravenous hydration with that of hospice home care patients offered oral fluids and mouth care to assuage thirst. The former method may result in an overhydrated, edematous patient who dies with an uncomfortablesounding “death rattle” that is disconcerting to family and staff; the latter usually results in a visibly more comfortable patient who is more likely to die with less edema and without as much apparent respiratory distress. Legitimate questions also can be raised about medical costs toward the end of life that are incurred when physicians give “futile” and “marginal” care.6,7 Development of guidelines by physicians and hospitals that define futile care, along with thoughtful consideration of when the therapy offered patients has marginal value, may enable physicians to improve the quality of life for patients and at the same time hold down one component of the rising spiral of health-care costs.8,9

References 1. Brody H, Campbell ML, Faber-Langendoen K, et al. Withdrawing intensive lifesustaining treatment—recommendations for compassionate clinical management. N Engl J Med. 1997;336:652–657. 2. Skeel RT. Measurement of quality of life outcomes. In: Berger AM, Portnoy JL, Weissman DE, eds. Principles and practice of palliative care and supportive oncology. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2002:1107–1122. 3. Byock I. Palliative care and oncology: growing better together. J Clin Oncol. 2009;27:170–171. 4. Ferris FD, Bruera E, Cherny N, et al. Palliative cancer care a decade later: accomplishments, the need, next steps—from the American Society of Clinical Oncology.

J Clin Oncol. 2009;27:3052–3058. 5. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733–742. 6. Hillner BE, Smith TJ. Efficacy does not necessarily translate to cost effectiveness: a case study in the challenges associated with 21st-century cancer drug pricing. J Clin Oncol. 2009;27:2111–2113. 7. Meropol NJ, Schulman KA. Cost of cancer care: issues and implications. J Clin Oncol. 2007;25:180–186. 8. Jacobson M, O’Malley AJ, Earle CC, et al. Does reimbursement influence chemotherapy treatment for cancer patients? Health Aff. 2006;25:437–443. 9. Kantarjian HM, Fojo T, Mathisen M, et al. Cancer drugs in the United States: Justum Pretium—the just price. J Clin Oncol. 2013;31:3600–3604.

SECTION II: MEDICAL THERAPIES OF HUMAN CANCER

I. INTRODUCTION Data from the National Cancer Institute’s SEER (Surveillance, Epidemiology, and End Results) program estimate more than 1.6 million new cancer cases in 2014. Cancers of the head and neck (HNCs) account for 55,000 or 3.3% of those. The majority of HNCs are in the oral cavity and pharynx (oropharyngeal cancers [OPCs]) accounting for 42,000, with cancers of the larynx the next most common with 12,600.1 The common anatomic sites of HNCs include the oral cavity, nasal cavity, and pharyngeal cavity with subsites defined for nasopharynx, oropharynx, and hypopharynx, and the laryngeal-epiglottic region (considered part of the hypopharynx) (Fig. 6.1). Brain tumors and other cancers of the central nervous system, head and neck lymphomas, and thyroid cancers are considered separately. The commonly associated causes of squamous cell carcinoma of the head and neck (HNSCC) have been tobacco use in all forms and excessive alcohol consumption. In addition, some viral etiologies have been defined including the Epstein-Barr virus (EBV) and its association with nasopharyngeal carcinomas (NPCs)2; and, in recent years, the human papillomavirus (HPV) and its correlation with OPCs, especially the base of tongue and tonsillar regions.3,4 Eighty to ninety percent are squamous cell histology, with the remainder composed of adenocarcinoma, mucoepidermoid, and adenoid cystic histologies; these latter types are seen mostly in salivary glands. A. Presenting symptoms Presenting symptoms in HNC vary depending on the primary site and can be sometimes vague and confused with benign etiologies such as sinusitis or infectious pharyngitis. A heightened level of suspicion, especially in a patient with obvious risk factors such as smoking, is warranted. Vocal hoarseness is a common complaint in patients with laryngeal cancer. Ear pain or persistent nasal congestion could indicate a nasopharyngeal tumor. Other suspicious symptoms include oral pain, nonhealing ulcerative lesions, dysphagia, odynophagia, hemoptysis, epistaxis, headaches,

nonhealing dental infections, and a nonpainful neck mass. More advanced disease may also be associated with systemic symptoms such as anorexia and weight loss, fatigue, and even neurocognitive changes.

FIGURE 6.1 Anatomic divisions of the head and neck. Percentages indicate the relative frequencies of carcinoma in these regions. B. Evaluation Patients who are ultimately diagnosed with HNC will often present initially to a primary care physician, a dentist, or directly to an otolaryngologist, so an awareness of the possibility of cancer is important on the part of these providers. A careful history may help point to the primary site and suggest involved structures. A thorough head and neck evaluation will include an assessment of the primary site and the extent of nodal disease. Neck masses need careful assessment and often will require either fine-needle aspiration (FNA) or a core-needle biopsy to determine cancer and to provide adequate tissue for additional studies such as immunohistochemistry for HPV. An endoscopic examination is usually performed on initial evaluation by an otolaryngologist to identify and/or confirm the primary site. Most patients with laryngeal or pharyngeal tumors will undergo direct laryngoscopy with biopsy to determine the extent of disease and to rule out a second primary tumor. Imaging studies are considered a standard component of the workup in patients with locally advanced disease. The purpose of radiographic studies is to clearly define the extent of local disease, to identify nodal spread, and to rule out metastatic disease or a second primary tumor. Computed tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET) scans may each contribute unique clinical information; it is therefore important to discuss the appropriate radiographic evaluation with the radiologist in order to optimize the staging workup and to provide clinicians with the information needed for treatment planning. A

cohesive multidisciplinary team is essential to the proper evaluation and treatment planning for these patients. The HNC team consists of members representing all facets of the patient’s care and needs. This includes otolaryngologists with extensive training and expertise in HNC surgery, medical oncologists, radiation oncologists with expertise in complex radiotherapy protocols, pathologists, radiologists and nuclear medicine radiologists, dieticians, speech pathologists, oral surgeons and oral medicine specialists, psychooncologists and social workers, nurse navigators, and research coordinators. It is essential that all members of this complex team work seamlessly; this is often best accomplished in a multidisciplinary clinic setting with patient case discussion at tumor board conferences attended by all of the aforementioned members. C. Pathology Over 80% of HNCs are squamous cell carcinomas, typically showing areas of keratinization; however, basaloid (“jigsaw pattern”) features are more characteristic of HPV-associated squamous cell cancers. The remainder is composed of adenocarcinoma, mucoepidermoid, and adenoid cystic histologies; these latter types are seen mostly in salivary glands. D. Staging Treatment of HNC is based on primary tumor location and stage. Once a tissue diagnosis of HNC is obtained, a workup is undertaken to determine the clinical and/or pathologic stage of the tumor. This includes endoscopic evaluation of the throat, hypopharynx and larynx, and possibly the bronchial and esophageal areas; CT/MRI/PET imaging modalities; and biochemical assessment with complete blood counts, liver and kidney functions, and thyroid status. Tissue sampling of suspect areas is critical not only for histology and immunohistochemical (IHC) analysis but also for staging. Staging is based on the tumor, node, and metastasis (TNM) system defined in the American Joint Committee on Cancer (AJCC) staging system.5 Approximately one-third of patients present with localized disease (stages I and II); half present with locoregional disease (stages III and IV with nodal metastases); only about 10% present with distant metastatic disease. Early-stage or localized disease is often treated with a single modality, surgery or radiation therapy with an 80% to 90% long-term (5 years) survival. Locoregional disease (stages III, IVA, and IVB) is treated with multimodality therapy including various combinations and sequences of surgery, radiation therapy, and chemotherapy. Long-term survival for this group of patients is approximately 40%. Patients with recurrent disease can occasionally be “salvaged” with surgery (approximately 15% of patients); however, many of these patients as well as those with distant metastases are incurable and are usually managed with either palliative chemotherapy or supportive care. E. Treatment 1. Pretreatment assessment Even though HNC is usually confined to the head and neck area, a complete history

and physical examination is critical as these patients often have comorbidities that affect their treatment. Tobacco, alcohol, and other substance abuse need to be identified and discussed. Patients who continue to smoke during radiation therapy do poorly and have increased mucositis; therefore, a robust smoking cessation program is important. Other comorbidities such as cerebrovascular disease, cardiovascular disease, renal insufficiency, chronic obstructive pulmonary disease (COPD), and alcohol-related disorders are frequently present and need to be managed. An accurate medication history is important; antihypertensives, diuretics, and antihyperglycemic agents may need adjustment or even discontinuation during treatment. Nephrotoxic agents (drugs and contrast for imaging studies) can be harmful in the midst of dehydration. Depression and suicide are not uncommon in HNC patients, thus initial and ongoing screening for mood disorders is appropriate, and psychosocial oncology support is important. Social workers are helpful in dealing with patients who have poor support systems and lower socioeconomic status. It is also recommended that all patients undergo an upfront evaluation by oral health specialists to assess for any necessary dental extractions prior to radiotherapy as well as recommendations for oral health care during treatment, such as fluoride trays, rinses, and other preventive measures. Speech pathology assessment and evaluation before treatment can identify potential dysphagia risks and provide advice for swallowing mechanics to minimize aspiration risks and reduce long-term gastrostomy tube dependence. Dietary assessment and determination of nutritional support requirements such as gastrostomy tube placements are important. All chemotherapy agents may impair fertility either temporarily or permanently, so fertility preservation methods should be addressed where appropriate. Baseline assessment of bone marrow, liver, and renal function as well as audiograms may be indicated due to potential toxicities with chemotherapy agents, including cisplatin, 5-flourouracil, taxanes, and other drugs. 2. Localized disease Node-negative HNC can be managed with surgery alone in most cases, especially for small (T1–T2) tumors that are easily accessible. Radiation therapy is an acceptable alternative for patients who are poor surgical candidates. Chemotherapy has little role in this setting. Surgery is performed with curative intent with the aim to remove all disease with clear surgical margins. Neck dissections, either ipsilaterally or bilaterally, are determined on the basis of the primary tumor size and/or location, but are not routine in T1–T2, N0 tumors. Transoral robotic surgery (TORS) is an emerging technique that can be utilized in certain situations. Reconstructive measures are rarely needed for these early-stage tumors, but microvascular tissue “flaps” are occasionally needed to rebuild structural defects depending on site of the primary tumor and extent of surgery necessary. Radiation therapy as a single modality has evolved over the past four decades

with the development of intensity-modulated radiation therapy (IMRT), which has been shown to be useful in reducing long-term toxicity in oropharyngeal cancer, paranasal sinus cancer, and NPC. The use of altered fractionation schema and the incorporation of brachytherapy implants and stereotactic body radiation therapy (SBRT) have also been developed. Three-dimensional planning and improved understanding of tissue tolerance and physics of radiation have improved the delivery of higher doses, as much as 70 to 74 Gy in many cases. Careful treatment planning with pretreatment CT or PET imaging in the treatment position improves tumor delivery and takes into account moving structures affected by swallowing, breathing, and postural changes).6,7 Dental extractions, prior to treatment, to remove any teeth in the treatment field reduce the risk of mandibular osteonecrosis, but can delay the start of radiation by 2 to 4 weeks. Hyperfractionated or accelerated radiation protocols have shown a 10% to 15% improved locoregional control in phase II trials and a trend toward improved disease-free survival and overall survival in phase III trials. Acute toxicity (mucositis) was worse, but, at 2 years follow-up, late toxicity (xerostomia) was no different. A simultaneous integrated boost (SIB) technique, which utilizes “dose painting” with higher doses to the gross sites of tumor and lower doses to subclinical disease, is commonly used with conventional (five fractions/week) and accelerated (six fractions/week) schedules.8,9 3. Locoregional disease Locoregionally advanced (LRA) disease is defined as stages III to IVB disease of the head and neck. This includes newly diagnosed patients with a T3–T4 primary tumor, advanced or unresectable nodal disease, patients with recurrent/persistent disease, and/or patients with advanced disease who are unfit for surgery. Despite the disease being advanced, these patients can still be treated with curative intent. An exception would be if the patient has previously received radiotherapy and is deemed surgically unresectable, treatment would then be directed toward palliation. As mentioned previously, treatment usually involves input from a specialized multidisciplinary team and can involve options such as surgery, chemotherapy, and/or radiotherapy. The majority of patients with LRA disease are treated with definitive concurrent chemoradiotherapy in efforts to preserve the function of involved organs. Functional organ preservation approaches may not be appropriate in all situations, and surgical resection may be preferred if the tumor has already destroyed organ function, especially with laryngeal cancer. Other treatment options can include upfront surgery with postoperative radiotherapy or chemoradiotherapy, induction chemotherapy followed by chemoradiation, or salvage surgery after chemoradiotherapy. The decision on which combination would be optimal is made keeping multiple factors in mind, specifically, the patient’s age, performance status, comorbidities, size/location of primary tumor, organ function, nodal status, and patient preferences. Other factors should be considered as well especially those

affecting adherence, including patient motivation, psychosocial issues, family support, and travel distance. Select patients will undergo primary therapy with surgical resection depending on the size, location, and extent of local invasion. This depends on the experience and technology available at the specific treating institution. Areas that are more approachable, such as the oral cavity, are more amenable to surgical resection. Technological advances, such as TORS and TOLM (transoral laser microsurgery), now allow for increasing accessibility to the oropharynx, hypopharynx, and larynx permitting organ-preserving surgery. Postoperative radiation is often incorpora ted after surgery to eliminate residual disease in cases with pathology showing high-risk disease (e.g., close margins, perineural invasion, lymphovascular invasion, or multiple positive nodes/nodal sites). Consideration of chemoradiotherapy should be discussed with an experienced multidisciplinary team for patients with high-risk features. Studies show that chemoradiotherapy is warranted for evidence of extracapsular extension or positive margins after surgery showing improved locoregional control and disease-free survival compared to radiotherapy alone.10,11 HNCs commonly metastasize to the cervical lymph nodes. Metastases can be clinically occult, but once locoregionally advanced, the prognosis is markedly affected. If a surgical strategy is employed upfront, after resection of the primary tumor, the surgeon will consider either a selective or a comprehensive neck dissection depending on the amount of clinically evident disease in the neck. For patients with no, or limited, evidence of cervical lymph node extension, a selective neck dissection will be considered. This method depends on the location of the primary tumor as to which levels of lymph nodes will be removed. Oftentimes for tumors of the oral cavity, a selective lymph node dissection will involve the lymph nodes above the omohyoid in levels I to III and occasionally the superior region of level IV. For tumors arising in the pharynx/larynx, dissections will often involve lymph node levels II to IV and occasionally VI when deemed appropriate. When disease in the neck is extensive, including bulky disease, multiple nodal regions, or bilateral neck disease, a comprehensive neck dissection is usually employed. This is a more extensive surgery involving the removal of lymph nodes in levels I to V, and the term encompasses either the removal or the sparing of nonnodal structures such as the sternocleidomastoid muscle, spinal accessory nerve, and jugular vein. In the majority of patients with LRA disease, surgery is not indicated. This decision is based on the location of the primary tumor, extent of local invasion, and/or nodal involvement. These patients will be treated with either concurrent chemoradiotherapy or induction chemotherapy followed by chemoradiotherapy with efforts to preserve organ function. Combined modality treatment with chemotherapy and radiation is based on results of multiple randomized trials and meta-analyses.12– 16 This approach came into favor with the results of the Veterans Affairs Laryngeal Study Group proving that combined modality treatment with sequential

chemotherapy and radiation was equivalent in overall survival as compared to surgical resection with postoperative radiation.12 The long-term follow-up of the pivotal RTOG 91-11 trial proved that concomitant high-dose cisplatin with radiotherapy was similar in efficacy for laryngeal-free survival as compared to sequential chemotherapy followed by radiation. In this case, concurrent chemoradiation did show an improvement in locoregional control and larynx preservation, making this the new standard of care for LRA disease.13–15 Carboplatin is not as directly cytotoxic to tumor cells as cisplatin, but its effectiveness as a radiosensitizer is still in question. One trial suggests that carboplatin is not as effective as high-dose cisplatin with radiotherapy, but others argue that weekly carboplatin with radiation may be a reasonable option for patients with underlying renal dysfunction.17,18 Carboplatin has also been studied in combination with other agents such as 5-fluorouracil and paclitaxel. Some patients may not be able to tolerate platinum-based chemotherapy in general due to multiple factors. This group of patients may benefit from the addition of cetuximab, a monoclonal antibody (MoAb) inhibiting the epidermal growth factor receptor, in combination with radiotherapy as compared to radiation alone.19 Elderly or poorly functioning patients may consider radiation alone for palliation of symptoms. Induction chemotherapy is still quite controversial as to its efficacy when compared to concurrent chemoradiotherapy. The TAX 323, TAX 324, and GORTEC trials established TPF (docetaxel (Taxotere), cisplatin, 5-flourouracil) as a more active regimen when compared to PF (cisplatin, 5-fluorouracil) as induction therapy prior to concurrent chemoradiotherapy; significantly improving survival, local control, and laryngeal preservation.18,20,21 However, these trials did not compare induction chemotherapy followed by chemoradiation versus chemoradiation alone. Trials that have evaluated this have shown mixed results.16,21–27 A recent phase II Italian study favored sequential therapy with higher complete response rate and better progression-free survival, but still no difference in overall survival.25 This led to a phase III trial with a 2 × 2 design comparing induction therapy with TPF versus no induction therapy followed by concurrent chemoradiation with either cisplatin-fluorouracil or cetuximab. At a follow-up of 33 months, the induction regimen showed statistically better progression-free survival and overall survival.28 This is a significant result as this is the first randomized trial to show improvement in overall survival; however, the 2 × 2 design of the trial makes extrapolation to clinical practice controversial at present and further follow-up as well as additional phase III trials will be needed to confirm. Induction therapy is still useful in a select group of healthy individuals at high risk of both locoregional recurrence and distant metastatic disease, specifically the subgroup of patients with bulky tumors/lymph nodes and low level nodal disease. Induction chemotherapy does come with the risk of increased toxicity leaving up to 25% of patients unable to finish full sequential therapy with combined chemoradiation, significantly increasing the risk of local

relapse. Therefore, this question still remains unanswered and requires further evaluation for a definitive solution. Close follow-up with clinical examination and endoscopy is important after initial therapy with nonsurgical treatment. Post treatment imaging can be helpful in guiding further care if necessary. CT, MRI, or PET imaging modalities can be used in this situation. If PET imaging is selected, it should be done at least 12 weeks after the completion of therapy to reduce the rate of false-positive findings. If imaging shows no further evidence of malignancy, typically these patients are monitored closely. If imaging shows residual disease, salvage surgery is indicated. Oftentimes imaging may not be clear-cut and further close observation is indicated to evaluate for progressive nodal disease. 4. Metastatic and/or recurrent disease About 15% of HNC patients who develop local recurrence can be managed surgically; however, most patients will not be candidates for surgery due to prior treatment considerations (surgery and/or radiation effects), location/extent of the tumor, comorbidities (which may have eliminated surgery as an option with the initial diagnosis), or declining health and functional status. These patients are often managed palliative, either with a chemotherapy regimen or with supportive care alone. For many years, dogma has held that once radiated, further radiation was not possible. But studies in which re-irradiation is given to twice the expected tissue tolerance with minimal toxicity, resulting in disease control and good outcomes, have challenged the previous perceptions.29,30 Selection is important: tissue health, prior response to radiation, and durable radiation responses of a year or more have been shown to be good criteria for re-irradiation. For patients with recurrent HNC who meet these criteria, 50% to 75% may be able to receive more radiation therapy.8 Most patients with metastatic disease will not be candidates for local therapies such as surgery or radiation other than for palliative intent to relieve pain, and so on. Systemic therapy with chemotherapy will be the mainstay of treatment. The decision of whether or not to recommend chemotherapy requires assessment of the patient’s performance status, comorbidities, prior treatment(s) response and duration of response, and potential toxicities of the regimen being considered. If patients have poor performance status (Eastern Cooperative Oncology Group [ECOG], 3 to 4), are cachectic, and had less than 3 to 6 months of durable response from their prior treatment, they are unlikely to benefit from cytotoxic chemotherapy of any kind and should have serious discussion about supportive care and hospice referral. For those who are candidates for systemic therapy, options include monotherapy or combination regimens, with the decision based on potential toxicities and ability to tolerate. The specific chemotherapy agents are discussed later in this chapter, but

several points can be made here. Although response rates may be higher for combination regimens, in most cases the survival is not significantly different. Single-agent regimens such as cetuximab, weekly docetaxel or methotrexate, and oral capecitabine are all options to consider. Cost and convenience are factors as well. Monotherapy with cetuximab produces response rates of 13%.31 Combination chemotherapy for fit patients is usually platinum-based. The EXTREME trial demonstrated a survival advantage (Hazard ratio [HR], 0.797) for the addition of cetuximab to the combination of either cisplatin or carboplatin with infusional 5fluorouracil.32 5. Nasopharyngeal carcinoma NPC has a high prevalence in China, Southeast Asia, and North Africa, but is uncommon in other parts of the world. In low-risk areas such as the United States, NPC has a bimodal age distribution with peak incidence occurring between the ages of 15 and 25 years, and again between the ages of 56 and 79 years. Risk factors for the development of NPC include infection with EBV, environmental factors, and genetic predisposition. In the low-risk areas, the early peak in incidence is thought to be due to genetic susceptibility in conjunction with exposure to EBV and/or other environmental contacts; however, more traditional risk factors such as tobacco and alcohol use may play a role. Not all people with EBV infection develop NPC, thus other factors are implicated. NPC is commonly classified using the World Health Organization system. The first is a World Health Organization classification. This classifies NPC as keratinizing, nonkeratinizing well-differentiated, and nonkeratinizing undifferentiated. The keratinizing subtype is most common in the low-risk and older patients, whereas undifferentiated histologies are more common in the high-risk areas. 6. HPV-associated oropharyngeal carcinoma The incidence of OPCs, especially the base of tongue and tonsillar regions, has been increasing, and a causal relationship between the HPV and OPCs has been known for some time.3 The vast majority of cases within the United States are associated with serotype 16. The HPV-associated cancers present with a different clinical phenotype compared with the non-HPV counterparts. Patients are minimal or nonsmokers, non–alcohol abusing, and typically present at a younger age, and, while men are still more likely to be affected, the number of women with HPV-associated cancer is increasing more than that of HPV-negative counterparts. Histologically, these tumors are more likely to show basaloid squamous features (“jigsaw puzzle” appearance) with minimal to no keratinization; it is important to distinguish tonsillar cancers with a basaloid appearance from “basaloid squamous cancers,” which are an aggressive subtype thought to have a poor outcome. HPV can be demonstrated with IHC techniques for the p16 protein expression or by the more sensitive reverse transcriptase–polymerase chain reaction (RT-PCR) for the HPV-16/18 DNA. The use of p16 as a surrogate marker is supported by the fact that OPCs have a higher

likelihood of being HPV-positive compared to other anatomic sites of the head and neck; thus, it is considered a reliable diagnostic option.33 HPV-positive patients tend to have better prognosis than non-HPV patients; however, smoking appears to mitigate this advantage. Because of the better prognosis, studies of “de-intensified” regimens with shorter or fewer cycles of chemotherapy and altered fractionations of radiotherapy have been conducted and seem to support equivalent outcomes for less intense treatment.34 Randomized trials are stratifying patients into risk groups based on tumor size, surgical margins, number of lymph nodes involved, and presence of nodal extracapsular spread (ECS). 7. Organ preservation The concept of organ preservation is often applied to cancers of the larynx and the base of tongue in which nonsurgical approaches are initially recommended in an effort to preserve the function of these sites. In most cases, treatment consists of concurrent chemotherapy and radiation (discussed in the section on definitive concurrent chemoradiotherapy). Studies have demonstrated acceptable organ preservation and survival rates. Patients who fail can be salvaged with surgery; however, newer treatment modalities and re-irradiation principles have enabled patients to still be treated nonsurgically in the recurrent setting with potential success and continued delay of organ removal. F. Chemotherapy agents Chemotherapy for HNC consists of either single-agent therapy, usually cisplatin and often in combination with radiotherapy, or combination therapies, often cisplatin-based and usually for advanced or recurrent disease. Chemotherapy response, as in most cancers, is predicted by tumor stage, prior treatments, and the patient’s performance status and comorbidities. 1. Cisplatin cis-Diammino platinum or cisplatin is one of the most commonly used agents in HNC therapy, either as a single agent concurrent with radiation therapy or in combination with other chemotherapy agents. It intercalates with tumor DNA, creating DNA adducts that disrupt normal helical function. It can be a very toxic drug, particularly causing acute and delayed nausea and vomiting, and renal and ototoxicities; however, with careful supportive care, many of these toxicities can be ameliorated. Regimens giving cisplatin at a lower dose weekly during radiation are better tolerated and managed with outcomes similar to the higher dose regimens given every 3 weeks. Acute and delayed nausea and vomiting can be managed with 5-HT3 receptor antagonists and neurokinin-1 receptor antagonists as well as vigorous hydration with adequate potassium and magnesium replacement, which can protect against renal toxicities. The use of mannitol, a common practice for many years, may not be necessary with adequate hydration protocols and, in fact, may even be associated with a higher incidence of renal toxicity.35 2. Carboplatin

Carboplatin differs from cisplatin in that it contains a bidentate dicarboxylate (CBDCA) ligand in place of the two-chloride ligand. Its mechanism of action is similar to cisplatin; however, it is easier to administer than cisplatin because there is no requirement for forced hydration and less nausea and vomiting, renal toxicity, ototoxicity, and neuropathy. Response rates comparable to single-agent cisplatin are reported, but myelosuppression, in particular thrombocytopenia, can be doselimiting. Allergic reactions may occur in patients, particularly after multiple cycles. 3. Paclitaxel Paclitaxel as a single agent given either every 3 weeks (175 to 250 mg/m2) or weekly (50 to 120 mg/m2) is another option with comparable response rates. Toxicities include alopecia, neutropenia, neuropathy, and allergic reactions. The latter can be mitigated by premedicating with steroids, H1 and H2 blockers. 4. Docetaxel Docetaxel can also be dosed every 3 weeks (75 to 100 mg/m2) or weekly (15 to 40 mg/m2). Neuropathy may be lower than with paclitaxel, but asthenia may be greater with the high-dose regimen. Tissue edema may occur with higher doses; thus, steroid prophylaxis is indicated. 5. Methotrexate Methotrexate is an older antimetabolite and antifolate drug that has largely been replaced by platinum- and/or taxane-based regimens; however, it still has singleagent activity and is reasonably well tolerated, making it an option in the palliative setting. 6. Cetuximab Epidermal growth factor receptors are overexpressed in 90% of HNCs. Cetuximab is a MoAb that binds to epidermal growth factor receptors, thus blocking the proliferative signal. Cetuximab has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic disease and unresectable disease that failed prior platinum-based therapy and as a radiation-sensitizing agent. The standard regimen begins with a loading dose of cetuximab 400 mg/m2 IV given over 2 hours followed by weekly doses of 250 mg/m2 IV over 1 hour. Responses of up to 10% have been observed among patients with metastatic or recurrent disease. Skin rash, hypomagnesemia, and diarrhea are the common side effects. Anaphylactic reactions, although uncommon, may be severe, especially with hypokalemia or hypomagnesemia. Of note, anaphylactic reactions are more common in areas of the southeastern United States, where rates are as high as 20%. 7. Fluorouracil Fluorouracil is well tolerated and has comparable activity to cisplatin and other single agents. It is most often given as a 4- or 5-day continuous infusion. The drug is a vascular irritant at high concentrations and therefore, for prolonged infusions, a central venous catheter or access device is customary. Although suitable for use as a single agent, it is most often used in combination with other drugs. Common

toxicities are mucositis, palmar-plantar erythrodysesthesia (“hand-foot syndrome”), diarrhea, and rarely cardiotoxicity. Administration requires a port and an ambulatory pump. 8. Capecitabine Capecitabine is a prodrug that is converted enzymatically to fluorouracil. It is administered orally, which is more convenient. It has similar toxicity as infusional fluorouracil, but is usually reserved for palliative settings. Other chemotherapeutic agents that are less frequently used include ifosfamide, bleomycin, gemcitabine, and anthracyclines such as doxorubicin and mitoxantrone. As single agents, these all have minimal response rates and have, for the most part, been replaced by newer agents. G. New agents The discovery of the presence of epidermal growth factor receptors led to targeted therapies and cetuximab is one such agent (discussed previously). The EXTREME trial, which combined cetuximab with cisplatin and infusional fluorouracil, demonstrated improved response and survival compared to cisplatin and infusional fluorouracil alone.32 Panitumumab is another MoAb targeting the epidermal growth factor receptor. In the SPECTRUM trial, panitumumab combined with cisplatin and infusional fluorouracil demonstrated similar results with significantly prolonged progression-free survival compared to cisplatin and infusional fluorouracil alone with similar toxicity profile as the EXTREME trial.36 Another emerging approach in many cancers including HNC is to target the immune system, specifically the program death (PD) ligands 1 and 2 (PD-L1 and PD-L2). MoAbs formed from highly selective, humanized MoAbs designed to block PD-1 interaction with its ligands PD-L1 and PD-L2, reactivate the immune system to target the tumor. Phase I and II trials have demonstrated activity of these compounds in both HPV-associated and non-HPV–associated HNC. Results showed a best overall response rate of 20% in previously treated patients.37 1. Radiosensitizing chemotherapy The concurrent administration of chemotherapy and radiation has improved outcomes in locally advanced NPCs, advanced unresectable cancers, organ preservation in locally advanced larynx and base of tongue cancers, and in high-risk postoperative patients (positive margins and/or ECS nodal disease). Concurrent chemoradiotherapy results in a 4% to 8% absolute improvement in survival or a 12% to 19% reduction in the risk of death. Thus, concurrent chemoradiation is accepted as a standard option for these patients. High-dose cisplatin (100 mg/m2 on days 1, 22, and 43 concurrent with radiation) has been the most studied regimen and remains the reference standard. Other single-agent regimens such as weekly lowdose cisplatin, weekly cetuximab, and taxanes have been studied as well as combination regimens with cisplatin or carboplatin plus a second agent such as fluorouracil or a taxane.38 No comparative data to date have been done to show

combination regimens better than single-agent cisplatin; however, phase III cooperative group trials through RTOG are underway. Concurrent therapy does enhance toxicities, and careful pretreatment evaluation of the patient is critical. 2. Combination chemotherapy Combination chemotherapy regimens as the sole treatment modality are mainly used in the recurrent or metastatic setting in cases where surgery or radiation therapy is not possible. Median survival of metastatic or recurrent HNC is short (6 to 9 months), and treatment in this setting is palliative at best. The results of the EXTREME trial are discussed elsewhere. Common combination regimens are shown in Table 6.1. 3. Second-line therapy For patients who are a candidate for second-line cytotoxic chemotherapy, the choice of agent is based on prior treatment history and the overall condition of the patient. Cetuximab is approved by the FDA for second-line therapy in patients with recurrent or metastatic HNC with response rate of 11%. Similar targeted agents including gefitinib, sunitinib, erlotinib, and lapatinib have been tested in patients with advanced HNC, but have no clinically significant activity.39–43 Current trials are investigating immune targeted therapies with anti-PD-L1 and anti-PD-L2 agents in the second- and even third-line treatment of these patients. H. Palliative/supportive care Palliative care has been defined by various organizations and the definition has evolved over recent years. The Center to Advance Palliative Care defines palliative care as specialized medical care for people with serious illnesses, focusing on providing patients with relief from the symptoms, pain, and stress of a serious illness—whatever the diagnosis with a goal to improve quality of life for both the patient and the family.44 The National Cancer Institute defines palliative care as care given to improve the quality of life of patients who have a serious or life-threatening disease, where the goal is to prevent or treat as early as possible the symptoms of a disease, side effects caused by treatment of a disease, and psychological, social, and spiritual problems related to a disease or its treatment.45 Data have shown that integrating palliative care early along with the standard-of-care treatment results in better quality of life, better survival, and less cost than standard of care alone.46,47 A truly multidisciplinary team is necessary for the care of these patients. Treatment of HNC is time-intensive, complex, and fraught with complications. It requires a compliant and willing patient as well as a dedicated support system. The support system is composed of the patient’s caregivers, usually defined as a network of family and friends, and the health-care team. Prior to initiating therapy, it is important to inform the patient and caregivers about anticipated treatment toxicities and their potential impact on the patient’s ability to conduct routine activities of daily living. Working with the health-care team, the patient must identify the individuals who will provide support if and when it becomes necessary. Specific issues that should be

discussed include the following: (1) insurance coverage (including dental and pharmacy); (2) living situation (homeless, living alone, or living with others); (3) social supports (ability and willingness of caregivers to provide physical and emotional support); (4) financial issues (with specific discussion of ability to pay for household expenses during treatment); and (5) work issues (impact of cancer on work status of patient and caregivers). It is important to identify patients with critically limited resources in order to plan adequately for their ongoing care and to guide treatment decisions. Use of a validated psychosocial distress screening tool can be very helpful in this area. The health-care team should be composed of physicians, nursing staff, nutritionists, speech and swallowing therapists, physical therapists, psycho-oncologists and palliative care experts, and social workers who are trained to deal with the unique challenges faced by HNC patients and their caregivers. Because patient support needs change dramatically over time, frequent and ongoing assessment is required. TABLE

6.1

Response Rate for Combination Chemotherapy Agents in Recurrent HNC

Agent

Approximate Response Rate

Cisplatin/fluorouracil

25%–40%

Carboplatin/fluorouracil

26%

Cisplatin/paclitaxel

28%–35%

Cisplatin/docetaxel

42%

Cisplatin/cetuximab

26%

Methotrexate/bleomycin/cisplatin

48%

In NPC Gemcitabine/paclitaxel

41%

HNC, head and neck cancer; NPC, nasopharyngeal carcinoma.

1. Nutrition Due to the anatomic proximity to structures critical for normal alimentation, HNC and its treatment may have a dramatic impact on oral intake. Malnutrition is associated with impaired healing, increased toxicity of treatment, and decreased survival. Therefore, it is important to identify and treat nutritional deficiencies in a proactive and aggressive manner. At the time of diagnosis and periodically thereafter, patients should undergo a nutritional assessment by a dietician who is familiar with the issues facing HNC patients. A nutritional assessment should include a weight loss history, assessment of nutrient intake, and identification of barriers to adequate nutritional intake. Treatable causes of decreased caloric intake should be identified and appropriate interventions instituted. Ongoing monitoring and education is critical and should include routine

measurement of weight, assessment of hydration, and counseling by a certified dietician. Dieticians also ensure adequate nutrition as patients transition from an enteral to oral diet. Chronic xerostomia, which alters a patient’s ability to take in dry foods such as breads, requires management and education. Patients who are edentulous may have difficulty with intake of adequate protein. Dietary adaptations may predispose to long-term nutrient deficiencies that may impair overall health. 2. Mucositis Radiation therapy and select chemotherapy agents cause mucositis, a pan-tissue inflammation of the mucosa and underlying soft tissue. The classic mucosal manifestations are erythema, ulcer, and pseudomembrane formation. Mucositis associated with systemic chemotherapy is cyclic in nature. With chemotherapy regimens administered on a 3-week cycle, mucositis usually develops 7 to 10 days after administration and resolves 5 to 7 days later. Chemotherapy regimens administered weekly tend to have a slow escalation of mucosal symptoms over time, with resolution when chemotherapy is dose-reduced or held. Radiation-associated mucositis begins to develop 2 to 4 weeks after the initiation of therapy. Symptoms usually peak at 5 to 7 weeks, although occasionally patients will note worsening mucositis after the completion of therapy. Radiation-induced mucositis may take 4 to 12 weeks to resolve. Some patients have persistent symptomatic ulceration for protracted periods of time. It should be noted that the incidence of grade 3 to 4 mucositis increases from 25% to 35% with radiation alone to 40% to 100% with concurrent chemotherapy. Management of mucositis includes oral medicine experts and pain management. Early preventive measures with salt and soda rinses, viscous lidocaine-based solutions, and analgesics can reduce and ameliorate the severity of mucositis. 3. Dysphagia and aspiration Swallowing is a complex function that requires intact musculature, dentition, vasculature, and nervous system. Damage to any of these components may result in altered swallowing function. Thus, swallowing dysfunction is one of the common and devastating acute and late effects of therapy. Surgery-induced dysphagia is secondary to structural changes due to tissue extirpation and altered sensation from transected nerves. Acutely, radiation therapy–induced dysphagia is secondary to edema and painful mucositis. Over the long term, radiation therapy results in noncompliant fibrotic or contracted tissues that are unable to function normally. Of particular note, radiation may cause upper esophageal stricture formation. Strictureinduced dysphagia may be successfully treated with balloon dilation procedures. In order to maximize swallow function, it is important to involve speech and language pathologists (SLPs) at an early point in a patient’s treatment course. Health-care providers should also be aware of signs and symptoms that may indicate aspiration, which requires rapid referral and evaluation. These include coughing or throat clearing during or after swallow. Other indications for an SLP evaluation

include nasal regurgitation, drooling, pocketing food in the cheek, and food sticking in the throat. The role of the SLP includes (1) identifying swallowing abnormalities, (2) recommending further testing, (3) developing a treatment plan (including education and swallow therapy), (4) helping dieticians develop an adequate yet safe diet, and (5) ruling out significant aspiration. Common instrumental methods to assess swallow function include the modified barium swallow and the flexible endoscopic evaluation of swallowing safety. As noted previously, dysphagia may result in dietary adaptations and/or weight loss due to inadequate caloric intake. In addition, dysphagia may result in aspiration. Aspiration puts patients at risk for acute and long-term pulmonary toxicity. Acutely, aspiration may lead to pneumonia; in patients actively undergoing myelosuppressive chemotherapy, aspiration pneumonia is associated with a high rate of morbidity and mortality. Over the long term, aspiration may lead to pulmonary fibrosis and respiratory compromise. Of note, microaspiration can simulate pulmonary metastasis. 4. Xerostomia and oral care Poor oral health outcomes are one of the major late effects of HNC therapy. This is largely related to radiation-induced xerostomia. Initial dental evaluation is important for all patients undergoing therapy for HNC, particularly for those who will receive radiation therapy. Patients require extensive education regarding oral hygiene and preventive strategies to avoid radiation-induced dental caries. Oral hygiene should include the use of prescription-strength fluoride treatments because this agent has consistently demonstrated the ability to significantly reduce adverse late dental effects. In addition, patients undergoing radiation therapy should have extraction of nonviable teeth at least 10 to 14 days prior to initiation of therapy. This will allow adequate time for healing. As health-care providers, our role is to assess compliance with dental hygiene regimens and to refer to oral health specialists if problems are identified. 5. Lymphedema and fibrosis Surgery and radiation therapy can damage the soft tissues within the head and neck region with resulting lymphedema (swelling with lymphatic fluid) and fibrosis. In contemporary grading systems, lymphedema and fibrosis exist on a continuum with fibrosis, considered the end stage of tissue damage. Chronic inflammation may accompany lymphedema and fibrosis; damage may be ongoing and self-perpetuating, thus resulting in late toxicity. Generally, lymphedema and fibrosis may be characterized as involving external (neck and shoulders) or internal (pharynx and tongue) structures. Associated function loss may be severe. Early identification and treatment by certified physical therapists experienced in lymphedema and scar management is critical. Trismus is one of the most common and problematic manifestations of fibrosis. It is caused by surgery or radiation therapy involving the mandibular joint and muscles of mastication. It is characterized by a decrease in the

movement of the jaw, thus limiting the opening of the oral cavity. When trismus is severe, patients have difficulty with eating solid foods, dental hygiene, and procedures such as intubation. Trismus usually begins to develop within 1 year of the completion of therapy and is progressive in nature. Aggressive physical therapy may halt progression of symptoms; however, reversal of existing symptoms is limited. 6. Metabolic abnormalities HNC patients are subject to a number of metabolic abnormalities. First, radiation therapy to the thyroid gland can result in gradual loss of function. Estimated to occur in 25% to 50% of patients who receive doses above 6,000 cGy to the thyroid gland, hypothyroidism may develop years after the completion of therapy. Routine testing of thyroid function is recommended, particularly in patients with symptoms indicative of hypothyroidism. Patients with late-stage HNC may develop humoral hypercalcemia of malignancy. Although estimates vary widely, up to 23% of patients with advanced recurrent HNCs will manifest hypercalcemia before death. Standard treatment with hydration, saline diuresis, and bisphosphonate therapy are used. 7. Secondary cancer prevention and survivorship Some HNC patients are long-term survivors. HNC survivors with the traditional risk factors of smoking and drinking are at risk for the development of second primary cancers. The majority of second primary tumors involve the upper aerodigestive tract. It is hypothesized that this is related in part to a field cancerization effect of tobacco and alcohol exposure. Thus, smoking cessation and abstinence from alcohol are important adjuncts to the care of these patients. Although data are lacking, the widespread use of vaccination against HPV infections may lead to decreases in tumors associated with this virus. Chronic hypothyroidism and even thyroid cancer can occur and should be assessed in regular follow-up evaluations. Many of these issues can be managed in a survivorship program where attention to surveillance, second malignancies, chronic toxicities, and healthy lifestyle choices can be implemented.

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preservation. Ann Oncol. 2009;20(5):921–927. 19. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–578. 20. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357(17):1695–1704. 21. Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol. 2012;13(2):145–153. 22. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116–1127. 23. Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357(17):1705–1715. 24. Hitt R, Grau JJ, López-Pousa A, et al. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol. 2014;25(1):216–225. 25. Paccagnella A, Ghi MG, Loreggian L, et al. A Concomitant chemoradiotherapy versus induction docetaxel, cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: a phase II randomized study. Ann Oncol. 2012;21:1515–1522. 26. Cohen EE, Karrison TG, Kocherginsky M, et al. DeCIDE: a phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol. 2014;32(25):2735–2743. 27. Haddad R, O’Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol. 2013;14(3):257–264. 28. Ghi MG, Paccagnella A, Ferrari D, et al. Concomitant chemoradiation (CRT) or cetuximab/RT (CET/RT) versus induction docetaxel/cisplatin/5-fluorouracil (TPF) followed by CRT or CET/RT in patients with Locally Advanced Squamous Cell Carcinoma of Head and Neck (LASCCHN). A randomized phase III factorial study (NCT01086826). J Clin Oncol. 2014;32(15, suppl):Abstract 6004. Special issue on ASCO Annual Meeting. 29. Stevens KR, Britsch A, Moss WT. High-dose reirradiation of head and neck cancer with curative intent. Int J Radiat Oncol Biol Phys. 1994;29:687–698. 30. Weppelmann B, Wheeler RH, Peters GE, et al. Treatment of recurrent head and neck cancer with 5-fluorouracil, hydroxyurea, and reirradiation. Int J Radiat Oncol Biol Phys. 1992;22:1051–1056. 31. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to

respond to platinum-based therapy. J Clin Oncol. 2007;25:2171–2177. 32. Rivera F, García-Castaño A, Vega N, et al. Cetuximab in metastatic or recurrent head and neck cancer: the EXTREME trial. Expert Rev Anticancer Ther. 2009;9(10):1421–1428. 33. Chung CH, Zhang Q, Kong CS, et al. P16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinomas. J Clin Oncol. 2014;32(35):3930–3938. 34. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35. 35. Santoso JT, Lucci JA, Coleman RL, et al. Saline, mannitol, and furosemide hydration in acute cisplatin nephrotoxicity: a randomized trial. Cancer Chemother Pharmacol. 2003;52(1):13–18. 36. Vermorken JB, Stöhlmacher-Williams J, Davidenko I, et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol. 2013;14(8):697–710. 37. Mahoney KM, Atkins MB. Prognostic and predictive markers for the new immunotherapies. Oncology (Williston Park). 2014;28(suppl 3):39–48. 38. Jacobs C, Lyman G, Velez-García E, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol. 1992;10(2):257–263. 39. Cohen EE, Rosen F, Stadler WM, et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol. 2003;21(10):1980–1987. 40. Cohen EE, Kane MA, List MA, et al. Phase II trial of gefitinib 250 mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res. 2005;11(23):8418–8424. 41. Kirby AM, A’Hern RP, D’Ambrosio C, et al. Gefitinib (ZD1839, Iressa) as palliative treatment in recurrent or metastatic head and neck cancer. Br J Cancer. 2006; 94(5):631– 636. 42. Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol. 2009;27(11):1864–1871. 43. Soulieres D, Senzer NN, Vokes EE, et al. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol. 2004;22(1):77–85. 44. Center to Advance Palliative Care. What is palliative care? Retrieved from http://getpalliativecare.org. Published 2012. 45. National Cancer Institute. What is palliative care? Retrieved from http://www.cancer.gov/about-cancer/advanced-cancer/care-choices/palliative-care-factsheet#q1. Published 2014. 46. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with

metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733–742. 47. Zimmerman C, Swami N, Krzyzanowska M, et al. Early palliative care for patients with advanced cancer: a cluster-randomized controlled trial. Lancet. 2014;383:1721–1730.

I. INTRODUCTION Carcinoma of the lung is responsible for roughly 160,000 deaths each year in the United States. This represents one-fourth of all deaths due to cancer and more than the number of deaths due to breast, colon, and prostate cancers combined.1 Because early-stage lung tumors are often asymptomatic and, until recently, there has been no proven approach to radiographic screening, most patients are diagnosed with advanced-stage disease. Approximately 85% of cases are histologically classified as non–small-cell lung cancer (NSCLC), of which adenocarcinoma, squamous cell carcinoma, and large cell carcinoma are the primary subtypes. Small-cell lung cancer (SCLC) accounts for the remaining 15% of cases. The biology, staging, and treatment of SCLC differ substantially from NSCLC. Thus, these two groups are addressed in two separate sections. II. ETIOLOGY Lung cancer is predominantly a disease of smokers, although some studies suggest the rate of NSCLC is increasing in never smokers.2 Eighty-five percent of lung cancer occurs in active or former smokers, and an additional 5% of cases are estimated to occur as a consequence of passive exposure to tobacco smoke. Tobacco smoke causes an increased incidence of all four histologic types of lung cancer, although adenocarcinoma (particularly the adenocarcinoma in situ (AIS) variant) is also found in nonsmokers. Other risk factors for lung cancer include exposure to asbestos or radon. Familial factors such as polymorphisms in carcinogen-metabolizing hepatic enzyme systems may also play a role in determining an individual’s propensity to develop lung cancer.3 III. MOLECULAR BIOLOGY Numerous genetic changes have been associated with lung tumors. Most common among these include activation or overexpression of the myc family of oncogenes in SCLC and NSCLC and of the KRAS oncogene in NSCLC, particularly adenocarcinoma. Inactivation or deletion of the p53 and retinoblastoma tumor suppressor genes and a tumor suppressor gene on chromosome 3p (the FHIT gene) have been found in 50% to 90% of patients with SCLC. Abnormalities of p53 and 3p have been associated with 50% to 70% of cases of NSCLC. The KRAS mutation is more frequently found in smokers, those with adenocarcinoma, and those with poorly differentiated tumors. It is also associated with poor prognosis.4–6

Epidermal growth factor receptor (EGFR) is expressed or overexpressed in the majority of NSCLC tumors. Binding of ligand to the extracellular domain of EGFR causes receptor dimerization, which in turn activates an intracellular tyrosine kinase domain.7 Autophosphorylation of the receptor induces a cascade of signal transduction events leading to cell proliferation, inhibition of apoptosis, angiogenesis, and invasion, all resulting in tumor growth and spread. Tumors harboring activating EGFR gene mutations render the cancer highly dependent on EGFR for proliferation and survival. The most common activating mutations are found in exons 19 and 21, which result in in-frame deletions of amino acids 747 to 750 and L858R substitutions, respectively. Agents targeting mutated EGFR include tyrosine kinase inhibitors (TKIs), such as gefitinib,8 erlotinib,9 and afatinib.10 In NSCLC harboring EGFR gene mutation, these treatments often result in dramatic and sustained responses, with response rates exceeding 60% and median survival exceeding 2 years for stage IV cases. However, most patients often progress in about 9 months, and studies have shown that in about 50% of cases, this is due to a secondary mutation in exon 20, the T790M mutation.11 Drugs that target this mutation are currently being developed and one has recently gained FDA approval.12 KRAS and EGFR mutations are rarely found in the same tumor.13 Abnormalities in the anaplastic lymphoma kinase (ALK) gene have been identified in a subset of lung cancers. These gene rearrangements, which appear mutually exclusive with both EGFR and KRAS gene mutations, render cancers highly responsive to ALK inhibitors including crizotinib14 and ceritinib.15 Additional mutations found in smaller subsets (grade 3) versus 7.5% of patients treated with gemcitabine. 6) More recently, the preliminary results of the CONKO-005 trial were presented at the 2015 ASCO meeting. This study randomized 436 patients from 2008 through 2013 to 6 months of gemcitabine versus combination of gemcitabine and erlotinib following surgical resection of pancreatic adenocarcinoma. At a median follow-up of 41 months, there was no difference in disease-free survival (GemErlo 11.6 months, Gem 11.6 months; hazard ratio [HR] 0.89) or overall survival (median: GemErlo 24.6 months, Gem 26.5 months; HR 0.90). Similarly, there was no correlation between grade of rash and an improved disease-free survival in the GemErlo group. However, the overall survival curves do show a late divergence in favor of GemErlo (5-year survival, 28% vs. 19%) which will be followed further. 7) All of these trials show that in an acceptable candidate, chemotherapy improves survival and therefore adjuvant chemotherapy with 6 months of gemcitabine or 5-FU/leucovorin represents the standard of care. However, the addition of radiotherapy is still controversial. Additional retrospective data, phase II studies, and meta-analysis continue to provide evidence for and against chemoradiation in the adjuvant setting. At this time, no standardized regimen has been established for the adjuvant treatment of resected pancreatic cancer. 5-FU–based chemoradiation with additional gemcitabine chemotherapy as well as chemotherapy alone with gemcitabine, 5-FU, or capecitabine are listed in the guidelines for the adjuvant treatment of pancreatic cancer. 8) Currently, studies are underway looking at different approaches to improve outcomes in the adjuvant treatment of pancreatic cancer. These include combination of cytotoxic chemotherapeutic agents, the addition of targeted

agents, and immunotherapeutic approaches. ESPAC 4 is a large randomized phase III trial comparing the addition of capecitabine plus gemcitabine with gemcitabine alone. The trial is powered for an end point of overall survival with a target of 1,080 patients and will take several more years before results are available. RTOG 0848 is enrolling 952 patients randomized to gemcitabine alone compared with erlotinib and gemcitabine for 6 months; this will be followed by restaging and if no evidence of recurrence, patients will undergo second randomization with addition of chemoradiation versus no added therapy. 9) Given the significant survival advantage seen in metastatic pancreatic cancer with both FOLFIRINOX and the combination of gemcitabine and nabpaclitaxel compared with single-agent gemcitabine, both of these treatments are now being studied in the adjuvant setting. PRODIGE 24/ACCORD 24 is a phase III trial comparing adjuvant chemotherapy with gemcitabine versus modified FOLFIRINOX (omission of bolus 5-FU) to treat resected pancreatic adenocarcinoma. Estimated enrollment is 490 patients with primary outcome of disease-free survival at 3 years and began to accrue in January 2012. The APACT study is a phase III multicenter randomized study of nab-paclitaxel plus gemcitabine versus gemcitabine alone as adjuvant therapy in patients with surgically resected pancreatic adenocarcinoma. Estimated enrollment is 800 patients with primary outcome measure of disease-free survival and trial began accrual in March 2014. 10) Up to this point, no vaccine or immunotherapy has demonstrated significant improvement in overall survival in phase III clinical trials of resected pancreatic adenocarcinoma patients. However, using the concept of hyperacute rejection, a vaccine (algenpantucel-L) was recently studied with promising results in a phase II study. Therefore, a phase III trial was recently conducted, which randomized 722 patients with surgically resected pancreatic adenocarcinoma to standard of care treatment of gemcitabine with or without 5-FU–based chemoradiation and +/− HyperAcute pancreas immunotherapy (algenpantucel-L). This study has completed enrollment and results should be available in near future. 11) Currently, alternative adjuvant chemotherapy regimens (with or without radiotherapy) include the following a) Gemcitabine alone (1,000 mg/m2 on days 1, 8, and 15 with a 1-week break) or b) 5-FU 225 mg/m2 by continuous intravenous (IV) infusion throughout radiation therapy followed by four to six courses of bolus 5-FU weekly, or gemcitabine (1,000 mg/m2 on days 1, 8, and 15 with a 1-week break) or c) 5-FU 425 mg/m2 by IV push 1 hour after leucovorin 20 mg/m2 by IV push

daily for 4 days during the first week of radiation therapy and for 3 days during the fifth week of radiation therapy followed by four to six courses of bolus 5-FU weekly or gemcitabine (1,000 mg/m2 on days 1, 8, and 15 with a 1-week break) or d) Capecitabine 1,500 mg/m2 daily in divided doses with radiation therapy followed by four to six courses of bolus 5-FU weekly or gemcitabine (1,000 mg/m2 on days 1, 8, and 15 with a 1-week break). Capecitabine can be used in the chemotherapy-only part of the regimen as well, but there are no phase III data to confirm capecitabine in this setting. b. Neoadjuvant chemotherapy for resectable pancreatic adenocar-cinoma On the basis of the results of the many large phase III trials above, adjuvant chemotherapy provides a proven survival benefit compared with pancreatic resection alone. However, because of the significant morbidity associated with pancreatic surgery, many patients are not able to receive adjuvant therapy within the therapeutic window provided after surgery. Therefore, a neoadjuvant sequence of therapy provides a strong theoretical rationale to increase percentage of patients who see systemic treatment. To date there are no completed phase III trials studying role of neoadjuvant chemotherapy compared with adjuvant therapy. A small phase II prospective trial, evaluating neoadjuvant gemcitabine and cisplatin for resectable pancreatic cancer, demonstrated feasibility with favorable overall survival. However, results from meta-analysis have not shown benefit of neoadjuvant therapy over adjuvant therapy in terms of resectability or survival benefit. Recently, a multicenter U.S. phase II trial evaluating neoadjuvant and adjuvant gemcitabine and erlotinib (ACOSOG Z5041) completed recruitment of 123 patients but results are not yet available. Two phase III trials are currently underway in Europe that are studying the roles of neoadjuvant chemotherapy and neoadjuvant chemoradiation. The NEOPAC trial is a randomized multicenter phase III trial comparing adjuvant gemcitabine with neoadjuvant gemcitabine/oxaliplatin plus adjuvant gemcitabine in patients with resectable pancreatic cancer. This study completed enrollment of 310 patients and results should be available in near future. The NEOPA trial is a randomized multicenter phase III trial comparing neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy with upfront surgery and adjuvant chemotherapy in patients with resectable pancreatic cancer. This study is looking to enroll 410 patients and recently began recruiting patients. c. Borderline resectable pancreatic cancer Management of borderline resectable pancreatic cancer remains a challenging field without a defined approach and requires a multidisciplinary effort. This subgroup of patients with pancreatic cancer is potentially resectable if they have a good response with preoperative chemotherapy or combined chemotherapy with radiation. There are a number of phase II studies looking at gemcitabine-

based chemotherapy regimens and chemoradiation regimens for the neoadjuvant treatment of borderline resectable pancreatic cancer. However, there have been no phase III studies and there is no consensus among groups as to the preferred chemotherapeutic regimen or whether radiation should be utilized in the neoadjuvant setting. d. Localized unresectable carcinoma 1) Over two decades ago, a series of randomized trials conducted by the GITSG demonstrated superior survival of patients with localized but unresectable pancreatic cancer when treated with combined modality therapy compared with patients treated with radiation therapy or chemotherapy alone.7 Around the same time, the Eastern Cooperative Oncology Group (ECOG) randomly assigned patients with locally advanced gastric and pancreas cancers to receive 5-FU alone or in combination with radiation therapy; the study showed no improvement in progression-free or overall survival. The 2000 to 2001 FFCD/SFRO French study was a phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced pancreatic cancer. This trial demonstrated worse outcome with chemoradiotherapy (8.6 vs. 13 months; p = 0.03). 2) Subsequently, an ECOG trial compared gemcitabine alone with gemcitabine and radiotherapy in patients with locally advanced pancreatic cancer. Although this trial closed prematurely because of poor accrual, it was able to randomize 71 patients and found an improved survival with the addition of radiotherapy to gemcitabine (11.1 vs. 9.2 months; p = 0.017). The therapeutic strategy used by Group Cooperateur Multidisciplinaire en Oncologie (GERCOR) was to utilize systemic chemotherapy for 3 months alone and consider chemoradiation at investigator’s discretion if no evidence of progressive disease. On retrospective analysis, the group found that chemoradiation significantly improved survival compared with chemotherapy alone (overall survival 15 vs. 11.7 months; p = 0.009). This strategy was further evaluated in the international phase III LAP-07 study, with results presented at ASCO 2013 meeting but not yet published. This study demonstrated that the addition of radiation did not improve outcomes following 4 months of systemic therapy in patients with locally advanced pancreas adenocarcinoma. This study randomized 442 patients to receive gemcitabine alone or in combination with erlotinib for 4 months. Patients with controlled disease (269 patients) were then randomized to either 2 additional months of chemotherapy or 2 months of chemoradiation with 54 Gy of radiation therapy with capecitabine. The primary end point was overall survival after second randomization and no difference was found (16.5 months for chemotherapy arm and 15.3 months for chemoradiation arm).

3) Given the discrepant data on the benefit of radiation therapy for locally advanced pancreatic cancer and benefit of FOLFIRINOX in metastatic pancreatic cancer, a phase III study of modified FOLFIRINOX with or without radiation therapy in patients with locally advanced pancreatic cancer was launched in 2013. This study will randomize 172 patients to modified FOLFIRINOX alone or modified FOLFIRINOX with stereotactic body radiation therapy (SBRT). H. Chemotherapy for metastatic disease Patients with pancreatic cancer are often poor candidates for chemotherapy because of severe weight loss, poor performance status, severe pain, lack of measurable or evaluable disease, and presence of jaundice or hepatic involvement, which may interfere with clearance of therapeutic agents. The primary goals for advanced pancreatic cancer are palliation and improved survival. Randomized clinical trials have demonstrated survival and quality-of-life benefits to chemotherapy in selected patients with advanced pancreatic cancer compared with best supportive care alone. 1. Single agents A number of single agents have demonstrated clinical activity; however, no agent has demonstrated consistent complete or partial response rates greater than 20%. Gemcitabine has been accepted as first-line therapy for metastatic pancreatic cancer in patients with adequate performance status based on a phase III trial that compared bolus 5-FU with gemcitabine, with a primary end point being the “clinical benefit score.”8 Clinical benefit was defined as sustained (more than 4 weeks) improvement of one of the following parameters without worsening of any of the others: performance status, composite pain measurement (average pain intensity and narcotic analgesic use), and weight. The improvement in clinical benefit score in the gemcitabine and 5-FU arms were 23.8% and 4.8%, respectively (p = 0.0022). In addition, there was a significant improvement in median survival (5.65 vs. 4.41 months, p = 0.0025) and in survival at 12 months (18% vs. 2%). Therapy was generally well tolerated with a low incidence of grade 3 or 4 toxicities. The toxicities with gemcitabine include bone marrow suppression, lethargy, flulike syndrome, nausea and vomiting, and peripheral edema. 2. Combination chemotherapy a. For many years, despite promising phase II studies, the combination of gemcitabine with other cytotoxic drugs, including 5-FU, cisplatin, oxaliplatin, and irinotecan, had not been proven to be superior to gemcitabine alone in demonstrating a survival benefit. The first phase III trial to demonstrate a benefit with combination chemotherapy was the U.K. National Cancer Research Institute study. This study randomized 533 patients to higher doses of gemcitabine and capecitabine versus gemcitabine alone and identified a trend toward improved median overall survival (7.1 vs. 6.2 months, p = 0.077) and a statistically significant improvement in overall progression-free survival at 12 months

(13.9% vs. 8.4%, p = 0.004). A second phase III trial of 319 patients similarly showed a nonstatistically significant trend in median overall survival (8.4 vs. 7.2 months, p = 0.234) and 1-year survival rates (32% vs. 30%) in combination gemcitabine/capecitabine compared with gemcitabine alone. However, subgroup analysis showed that patients with a good performance status (KPS of 90 to 100) had a statistically improved median overall survival (10.1 vs. 7.4 months, p = 0.014) and progression-free survival (HR 0.69, p = 0.022) when treated with combination gemcitabine/capecitabine compared with gemcitabine alone. In addition, a meta-analysis of these randomized trials comparing combination gemcitabine/capecitabine with gemcitabine alone identified a significant survival benefit in favor of the gemcitabine/capecitabine combination (p = 0.02). b. The addition of platinum to gemcitabine failed to improve survival over gemcitabine alone in several phase III trials.9 The largest trial enrolled 400 patients randomized to gemcitabine with cisplatin versus gemcitabine alone and did not reveal any difference in median overall survival (8.3 vs. 7.2 months, p = 0.38) or progression-free survival (3.9 vs. 3.8 months, p = 0.80). However, a meta-analysis of five platinum-based randomized trials with a total of 623 patients did reveal a significant improvement in median overall survival (HR = 0.85; p = 0.01) for the combination over gemcitabine alone. A retrospective review from Johns Hopkins University evaluated 468 metastatic pancreatic cancer patients who received a cisplatin-based regimen. Patients with a strong family history of breast, ovarian, or pancreatic cancer had a median overall survival of 22.9 versus 6.3 months (p < 0.01) for patients with no strong family history of these cancers. The NCCN has endorsed the combination of a platinum analog with gemcitabine in the advanced setting, but generally for only patients with possible hereditary pancreatic cancer. c. A better understanding of the biology of cancer has led to the development of novel agents targeting pathways of cancer cell survival. Clinical trials have explored the combination of gemcitabine with a variety of biological “targeted” agents such as bevacizumab, cetuximab, and erlotinib over the past decade. Despite their promise in preclinical studies, most of these studies have not shown a survival advantage over standard monotherapy gemcitabine. Results of the Cancer and Leukemia Group B phase III trial, which evaluated gemcitabine plus bevacizumab (antivascular endothelial growth factor antibody) compared with gemcitabine plus placebo, and the Southwest Oncology Group phase III trial, which assessed gemcitabine plus cetuximab (targets epidermal growth factor receptor [EGFR]) versus gemcitabine alone, did not reveal any improvement in survival with the addition of the biologic agent. However, in a phase III trial of 569 patients with advanced or metastatic pancreatic cancer randomly assigned to receive either erlotinib (inhibitor of EGFR tyrosine kinase) plus gemcitabine or gemcitabine alone, patients in the erlotinib arm

showed statistically significant improvement in median and 1-year survival (6.24 vs. 5.91 months, p = 0.038, and 23% vs. 17%, respectively).10 There was a slight increase in incidence of grade 3 to 4 skin rash and diarrhea in the group receiving erlotinib, although there was no overall difference in quality of life between the two groups. On the basis of this study, the U.S. Food and Drug Administration approved erlotinib in combination with gemcitabine for first-line treatment of patients with locally advanced or metastatic pancreatic cancer. d. In 2011, combination chemotherapy in metastatic pancreatic cancer finally showed a meaningful survival benefit over single-agent gemcitabine. The ACCORD phase II/III trial studied 342 patients with previously untreated pancreatic cancer and randomized patient to FOLFIRINOX versus gemcitabine alone.11 Patients treated with FOLFIRINOX had a significantly improved median overall survival (11.1 vs. 6.8 months; p < 0.001) as well as improved progression-free survival (6.4 vs. 3.3 months; p < 0.001). A higher tumor response rate was also seen in the FOLFIRINOX arm (31.6% vs. 9.4%; p < 0.001). However, there was a significantly increased incidence of grade 3 and 4 toxicities in the FOLFIRINOX arm compared with gemcitabine. e. Nab-paclitaxel is the most recently approved first-line treatment for metastatic pancreatic cancer in combination with gemcitabine.12 Nanoparticle albuminbound paclitaxel (nab-paclitaxel) uses nanotechnology to combine human albumin with paclitaxel, which allows for delivery of an insoluble drug in the form of nanoparticles to the tumor, increasing the bioavailability of paclitaxel. In a phase III randomized multicenter trial (MPACT), 861 patients were randomized to receive gemcitabine plus nab-paclitaxel or gemcitabine alone. Median overall survival was improved (8.5 vs. 6.7 months, p < 0.001) as was progression-free survival (5.5 vs. 3.7 months, p < 0.001) in the gemcitabine plus nab-paclitaxel arm compared with gemcitabine alone. Tumor response rate was also significantly improved in the combination arm (23% vs. 7%, p < 0.001). As expected, patients treated with gemcitabine plus nab-paclitaxel combination had a higher incidence of myelosuppression and peripheral neuropathy. f. The new combination regimens of gemcitabine with nab-paclitaxel or FOLFIRINOX have emerged as new frontline options for patients with good performance status in the treatment of metastatic pancreatic cancer. 3. Current recommendations a. FOLFIRINOX ■ 5 FU 400 mg/m2 IV on day 1 followed by 2,400 mg/m2 continuous IV infusion over 46 hours, leucovorin 400 mg/m2 IV on day 1, irinotecan 180 mg/m2 IV on day 1, and oxaliplatin 85 mg/m2 IV on day 1 given every 14 days ■ Gemcitabine plus nab-paclitaxel. Gemcitabine 1,000 mg/m2 IV and nabpaclitaxel 125 mg/m2 IV weekly for 3 weeks with 1 week off

b. Gemcitabine plus erlotinib ■ Erlotinib 100 to 150 mg po daily plus gemcitabine 1,000 mg/m2 IV weekly for 3 weeks with a 1-week break c. Capecitabine and gemcitabine ■ Gemcitabine 1,000 mg/m2 IV weekly for 3 weeks with 1 week off and capecitabine 1,500 mg/m2 IV daily in twice-daily divided doses on days 1 to 14 every 21 days d. Capecitabine and oxaliplatin ■ Gemcitabine 1,000 mg/m2 IV weekly for 3 weeks with 1 week off plus oxaliplatin 130 mg/m2 on day 1 every 3 weeks e. Single-agent therapy with gemcitabine ■ Gemcitabine 1,000 mg/m2 IV weekly for 3 weeks with 1 week off 4. Second-line chemotherapy a. Nearly half of the patients with advanced pancreatic cancer who progress on frontline therapy are able to receive second-line therapy. In a phase III randomized trial, patients who had progressed on gemcitabine-based chemotherapy were randomized to best supportive care versus 5-FU, leucovorin, and oxaliplatin. This study was terminated early because of poor recruitment, but despite this the combination regimen showed a median survival of 4.82 versus 2.3 months (p = 0.008) and a median overall survival benefit of 9.1 versus 7.9 months (p = 0.031). More recently, the results of the CONKO-003 trial were published, which was a randomized phase III trial in which 168 patients with advanced pancreatic cancer who had progressed on gemcitabine were randomized to 5-FU/leucovorin (FF) versus oxaliplatin and 5-FU/leucovorin (OFF). Median overall survival was higher in the OFF group compared with FF alone (5.9 vs. 3.3 months, p = 0.010). On the basis of these trials, the NCCN recommends 5-FU plus oxaliplatin as second-line treatment in patients who progressed on gemcitabine-based therapy. However, recently the results of the recent phase III randomized PANCREOX trial showed that the addition of oxaliplatin to 5-FU/leucovorin in second-line treatment may be detrimental. This trial randomized 108 patients with advanced pancreatic cancer who progressed on gemcitabine-based treatment to receive second-line mFOLFOX6 or infusional 5-FU/LV. Median overall survival was worse in FOLFOX arm (6.1 vs. 9.9 months, p = 0.02). Furthermore, the addition of oxaliplatin resulted in increased toxicity with rates of grade 3/4 adverse events of 63% in FOLFOX arm and 11% in 5-FU/leucovorin. b. For patients who received FOLFIRINOX in the frontline setting, the second-line option is gemcitabine-based therapy, although there is no clear evidence to support this approach. There is no standard of care currently recommended for patients who progressed beyond two lines of therapy and therefore clinical trials are recommended for these patients.

c. Many clinical trials are currently in phase II/III development with different chemotherapeutic combinations. Recent results of the phase III NAPOLI-1 trial that looked at irinotecan encapsulated into liposomal-based nanoparticles (MM398) were recently released. This study randomized 417 patients with metastatic pancreatic cancer who progressed on gemcitabine-based regimens to MM-398 and 5-FU/leucovorin versus 5-FU/leucovorin. Median overall survival was improved with the combination therapy of MM-398 plus 5-FU/leucovorin compared with 5-FU/leucovorin (6.1 vs. 4.2 months, p = 0.012). II. PANCREATIC NEUROENDOCRINE TUMORS (PNETS) A. Epidemiology Neuroendocrine tumors (NETs) are a heterogeneous family of tumors with a wide and complex spectrum of clinical behavior. Pancreatic NETs (PNETs) are rare malignancies with an overall incidence in the United States of 0.32/100,000 people/year. Pancreatic NETs account for approximately 22% to 28% of all neuroendocrine tumors. The incidence of these tumors has been increasing over the past 30 years with no significant changes in survival. They account for less than 2% of all digestive malignant tumors and 1% of all endocrine tumors. These tumors cover a spectrum of neoplasms, many, but not all, of which originate from the pancreatic islets of Langerhans and are therefore are known as “islet cell tumors.” The peak incidence occurs between the ages of 70 and 79 years, with rates significantly increasing after 40 years of age. B. Presentation The majority of pancreatic neuroendocrine tumors are sporadic; however, they may arise as a result of familial syndromes such as MEN 1 syndrome, von Hippel-Lindau disease, and neurofibromatosis type I. PNETs have complex clinical behavior and clinical presentation depends on the ability of the tumor to secrete hormones and bioamines. They are broadly categorized into those with and those without a clinical syndrome and therefore have been termed “functional” or “nonfunctional.” Less than 50% of these tumors secrete one or more hormones excessively, which may cause clinical symptoms of excessive hormone release: most commonly, insulin or gastrin; less commonly, glucagon, serotonin, or adrenocorticotropic hormone; and rarely vasoactive intestinal peptides (VIPs), growth hormone–releasing hormone, or somatostatin. More than 50% are nonfunctional and are generally discovered through symptoms related to tumor burden itself or as incidental findings. Most neuroendocrine tumors (with the exception of insulinomas, of which 90% are benign) are malignant and have the ability to metastasize, most commonly to lymph nodes or the liver and less commonly to bone, lung, brain, or other organs. However, these tumors are usually slow growing with low mitotic activity and often have an insidious presentation. Management of PNETs depends on the pathologic differentiation, stage at diagnosis, and presence of symptoms related to hormone secretion. Somatostatin analogs are effectively used to

inhibit hormonal secretion and improve symptoms in about 75% of patients with functional tumors and carcinoid syndrome. C. Primary treatment 1. The majority of pancreatic neuroendocrine tumors are metastatic at the time of diagnosis and the liver is the predominant area of metastatic disease. In patients with localized well-differentiated PNETs, 5-year survival is 60% to 100%, while patients with well-to-moderately differentiated distant metastases have 5-year survival of 35% and poorly differentiated metastatic PNETs have less than 5% 5year survival. Surgical resection is the optimal treatment for pancreatic endocrine tumors and is the only curative option. However, since more than 50% of patients are metastatic at time of diagnosis, curative surgery is often not feasible. In these patients, palliative debulking surgery for the primary tumor and therapy directed to the liver are recommended. Before resection, the first goal of treatment must be to control endocrine syndromes. 2. The H+/K+-adenosine triphosphatase inhibitors omeprazole and lansoprazole successfully control gastric acid secretion in patients with gastrinoma. For patients with insulinoma, diazoxide, an insulin release inhibitor, is the therapy of choice for hypoglycemia when dietary measures fail. A diuretic should be given with diazoxide to prevent water retention. Octreotide acetate is a somatostatin analog that inhibits gut hormone secretion. It is generally useful for carcinoid and VIPoma syndromes and is possibly useful for controlling symptoms in patients with glucagonomas, gonadotrophic hormone–releasing tumors, and gastrinomas. In patients with unresectable insulinoma, it can reduce insulin secretion by 50% and return blood glucose levels to normal. However, it must be initiated cautiously in patients in the hospital because profound hypoglycemia may occur. The usual starting dose of octreotide is 50 μg subcutaneously twice a day; thereafter, the dose and frequency of injections can be increased to 100 μg three times a day. More recently, a long-acting preparation (octreotide LAR) has become available. The dose should be 20 to 30 mg intramuscularly monthly, depending on doses that the patient was requiring of the short-acting preparation. It is designed to provide the convenience of once-a-month or twice-a-month injections once a stable dose of the shorter-acting preparation is established. a. The treatment of pancreatic NETs is dependent upon grade and proliferation index. The WHO classification system of 2010 differentiates between the terms NET and neuroendocrine carcinoma (NEC). This classification system uses the proliferation index (Ki-67, MIB-1), angioinvasion, and mitoses as important factors to divide tumors into well-differentiated NETs (2% Ki-67 index or angioinvasive), and poorly differentiated NECs (>20% Ki-67 index). The European Neuroendocrine Tumor Society (ENETS) has proposed a grading system for these tumors (G1, G2, G3) on the basis of the mitotic count and the

Ki-67 index. G1 tumors exhibit Ki-67 in 20%. In general, G1 and G2 refer to welldifferentiated NETs and G3 refers to poorly differentiated NECs. b. Adjuvant therapy. Currently, no evidence exists to support the use of adjuvant therapy in cases of fully resected PNETs. Consideration should be given for surgically resected high-grade (G3) lesions given high risk of recurrence. Extrapolation from the adjuvant treatment of small cell lung cancer may be considered. 3. Management of locally advanced or metastatic islet cell tumors a. Surgical resection and somatostatin analogs Surgical resection is recommended for resectable locoregional recurrence. Patients with metastatic disease to the liver should be considered for surgical resection as well. However, for patients who are found to be unresectable and have symptomatic or clinically significant tumor burden, somatostatin analogs can be helpful in the management of symptomatic disease related to hormonal secretion.13 The most commonly utilized somatostatin analogs in clinical studies for PNETs are octreotide, lanreotide, and pasireotide. A phase III placebo– controlled randomized study comparing long-acting octreotide with placebo for the treatment of midgut neuroendocrine tumors demonstrated a 66% reduction in risk of disease progression.14 The PROMID study showed antitumor benefit in patients with functioning and nonfunctioning tumors treated with octreotide LAR. In an analysis of patients with nonfunctioning tumors, time to tumor progression for patients receiving octreotide LAR was 28.8 versus 5.9 months for those on placebo (HR = 0.25). For patients with functioning tumors, time to tumor progression for patients receiving octreotide LAR was 14.3 and 5.5 months for those on placebo (HR = 0.23). The utility of somatostatin analogs was recently validated by the CLARINET trial in which 204 advanced nonfunctioning G1 or G2 NET patients including PNETs were randomized to lanreotide versus placebo and showed a significant improvement in progression-free survival. 4. Standard chemotherapy a. PNETs are more responsive to systemic chemotherapy than non-PNETs, and chemotherapy is typically considered for patients with progressive disease (G3) and rapidly growing G1/G2 tumors. The systemic chemotherapeutic agents that have shown most benefit in PNETs are streptozocin, doxorubicin, 5-FU, and temozolomide. Streptozocin is the most active single agent, with a 50% response rate but has considerable renal and hematologic toxicity. The addition of other agents such as 5-FU and doxorubicin was associated with even higher response rates up to 70% and prolonged progression-free survival. The combination of streptozocin and doxorubicin was demonstrated to have a superior response rate (69%), median survival (26.5 months), and time to tumor progression (20 months) than the combination of streptozocin and 5-FU or single-agent

chlorozotocin in a North Central Cancer Treatment Group study.15 The dosing of this regimen was streptozocin 500 mg/m2 IV on days 1 to 5 and doxorubicin 50 mg/m2 IV on days 1 and 22; this regimen was repeated every 6 weeks. Toxicity from this regimen was common, with renal impairment occurring in about 30% of patients receiving a streptozotocin-based regimen; nausea and vomiting in about 60% of patients; and leukopenia in about 75%. A more recent phase III study comparing streptozotocin and 5-FU with doxorubicin and 5-FU demonstrated improved median survival in the streptozotocin/5-FU arm (24.3 vs. 15.7 months, p = 0.03). b. Another agent that has demonstrated efficacy against PNETs in phase II trials is temozolomide. A single-arm retrospective review investigating the use of oral temozolomide and capecitabine therapy observed a 70% objective response rate with a median progression-free survival of 18 months and an overall survival of 92% at 2 years. This combination has not been tested in a randomized phase III trial to date and it is unknown whether temozolomide monotherapy is as effective as the combination therapy. c. Platinum-based therapy remains the standard first-line option for patients with high-grade or G3 PNETs. Commonly used regimens include cisplatin + etoposide, carboplatin + etoposide, and carboplatin + paclitaxel. The combination of cisplatin and etoposide remains the standard of care for patients who have high-grade or G3 PNETs, with an observed 41.5% objective response with duration of response of 9.2 months. Currently there are no phase III trials that have investigated second-line chemotherapy for high-grade or G3 NETs. Temozolomide +/− capecitabine has demonstrated 33% response rate with a median response duration of 19 months in patients who received cisplatin/etoposide as first-line therapy. 5. Targeted therapies a. For cases with disease stabilization as primary goal, targeted therapy is a recommended treatment option. Recent investigations related to the molecular biology of PNETs have revealed elevated expression of several cellular growth factors and their receptors. Studies have particularly focused on the role of VEGF and mTOR pathways. Recent trials associated with targeted agents have indicated antitumor activity associated with bevacizumab and several tyrosine kinase inhibitors that inhibit VEGFR, as well as the mTOR inhibitor everolimus. These agents seem to be more effective in PNETs than in advanced gastrointestinal NETs. b. A recent phase III clinical trial (RADIANT-3) examined the use of everolimus (10 mg daily) in 410 patients with advanced low- or intermediate-grade PNETs and showed a progression-free survival of 11 months with everolimus versus 4.6 months with a placebo (HR 0.35; p < 0.001). The benefit from everolimus appeared to be primarily stable disease and minor tumor shrinkage. There was

no difference in overall survival between the two groups. Adverse events in >30% of patients included stomatitis, rash, diarrhea, fatigue, and infections. The grade 3 or 4 adverse events occurring in at least 5% of patients were anemia, hyperglycemia, and stomatitis. c. Another international phase III trial in patients with advanced well-differentiated PNETs comparing sunitinib (37.5 mg once a day) with placebo was closed prematurely after accruing 171 patients. Interim analysis revealed a significant difference in progression-free survival (11.4 vs. 5.5 months; HR 0.42; p < 0.001). Adverse events in >30% of patients included diarrhea, nausea, asthenia, vomiting, and fatigue. Grade 3 or 4 adverse events occurring in at least 5% of patients with sunitinib were diarrhea, asthenia, fatigue, neutropenia, abdominal pain, hypertension, and palmar-plantar erythrodysesthesia. d. Currently no data have been used to compare everolimus with sunitinib or to assess the sequencing of these agents. The choice of agent should be based on patient preference, comorbidities, toxicity profile, tolerance, and availability. 6. Radionuclides Peptide receptor radionuclide therapy delivers radioisotopes in a targeted fashion and is considered a standard approach among patients with octreotide avid disease. Studies have demonstrated a 36% partial response rate in nonfunctional PNETs 3 months after last administration. Grade 3 hematologic and renal toxicities are typically reported in 5% to 40% of patients. III. CARCINOMA OF THE BILE DUCTS (CHOLANGIOCARCINOMA) AND GALLBLADDER CARCINOMA A. Introduction Biliary tract cancers are invasive adenocarcinomas that arise from the epithelial lining of the gallbladder and intrahepatic (peripheral) and extrahepatic (hilar and distal biliary tree) bile ducts. Biliary tract cancers affect approximately 14,000 people in the United States annually. In 2015, there will be an estimated 10,910 new cases and 3,700 deaths in the United States. However, this figure does not include cases of intrahepatic biliary cancers, which are included with primary liver cancers in national databases. Although the incidence of extrahepatic cholangiocarcinoma has remained constant, the incidence of intrahepatic cholangiocarcinoma has increased markedly over the past two decades. B. Epidemiology and presentation The development of biliary tract cancers appears to be related to chronic inflammatory conditions, autoimmune disease, biliary calculi, several infectious agents, and certain carcinogens. Risk factors for gallbladder cancer, of which cholelithiasis is the most prevalent, are associated with the presence of chronic inflammation. Calcification of the gallbladder (porcelain gallbladder), a result of chronic inflammation, has also been associated with gallbladder cancer. No predisposing factors have been found in most

patients diagnosed with cholangiocarcinoma, although there is evidence that particular risk factors may be associated with the disease in some patients. These risk factors are associated with chronic inflammation and include cholelithiasis, ulcerative colitis, liver flukes, exposure to thorium oxide (Thorotrast), primary sclerosing cholangitis, and congenital anomalies such as choledochal cysts. Recently, intrahepatic cholangiocarcinoma has been associated with hepatitis C viral infection and may be partly responsible for an increased incidence of intrahepatic cholangiocarcinoma. Biliary tract cancers are usually diagnosed at a late stage because of the aggressive nature and rapid spreading of these tumors. Patients with gallbladder cancer can present with a clinical presentation that mimics biliary colic or chronic cholecystitis. Primary gallbladder malignancy is incidentally found in 0.4% to 2% of laparoscopic cholecystectomy specimens. Carcinoma of the gallbladder most commonly presents with pain, nausea and vomiting, and weight loss. Other possible clinical presentations of gallbladder cancer include a suspicious mass detected on ultrasound or jaundice. About one-third of patients present with jaundice, which is typically associated with advanced disease not amenable to surgical resection. Patients with intrahepatic cholangiocarcinoma are likely to present with nonspecific symptoms such as fever, weight loss, or abdominal pain; symptoms of biliary obstruction are uncommon. Alternatively, intrahepatic cholangiocarcinoma may be detected incidentally as an isolated intrahepatic mass on imaging. In contrast, patients with extrahepatic cholangiocarcinoma are more likely to present with jaundice with evidence of biliary obstruction on subsequent imaging. C. Natural history and pathogenesis Biliary tract malignancies are related anatomically and are characterized by local invasion, regional lymph node metastasis, vascular encasement, and distant metastasis. The only chance for cure of biliary tract cancers is complete surgical resection; however, only 10% of patients present with early-stage disease and are considered surgical candidates. The key prognostic factors are completeness of resection, lymph node status, and tumor differentiation. However, recurrence rates even in this group of resectable patients remains quite high and thus systemic chemotherapy in either the adjuvant or palliative setting is the mainstay of the treatment plan for almost all patients. Median overall survival in patients with unresectable or metastatic biliary tract cancer is less than 1 year. Gallbladder cancer appears to be the most aggressive of biliary tract cancers and has the shortest median survival. Although biliary tract cancers are similar in their aggressive course and resistance to chemotherapy, gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma have different molecular profiles and ideally should be studied independently. However, because of a relatively small number of patients, these diseases have been combined in most clinical trials analyzing systemic chemotherapy. D. Chemotherapy 1. The advantage of systemic chemotherapy over supportive care alone in improving

survival and quality of life was first suggested in an evaluation of 5-FU plus leucovorin and etoposide therapy versus best supportive care among a group of patients with pancreatic and biliary tract cancer.16 The overall survival in the chemotherapy group was 6 versus 2.5 months for the supportive care group but only 37/90 patients had biliary tract cancers. More recently, a randomized controlled phase II study randomized 81 patients with unresectable gallbladder cancer to either best supportive care versus 5-FU/leucovorin or GEMOX (gemcitabine and oxaliplatin). Median survival was 4.5 months in BSC arm, 4.6 months in 5FU/leucovorin arm, and 9.5 months in the GEMOX arm. 2. In 2010, the randomized phase III Advanced Biliary Cancer (ABC)-02 study was published and compared gemcitabine with gemcitabine and cisplatin.17 This study randomized 410 patients with locally advanced or metastatic intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, or ampullary carcinoma. The median overall survival was significantly longer in the patients treated with gemcitabine and cisplatin versus gemcitabine alone (11.7 vs. 8.1 months; HR 0.64; p < 0.001). Interestingly, the survival advantage seen with cisplatin and gemcitabine was achieved without an increase in grade 3 or 4 toxicity. Similar results were seen in a Japanese randomized phase II trial and in a pooled analysis of clinical trials. Patients with a good performance status (PS 0-1) seemed to have the most benefit while those with poor performance status (PS 2) and ampullary carcinoma had the smallest benefit. Therefore, the combination of gemcitabine and cisplatin (cisplatin, 25 mg/m2 of body surface area followed by gemcitabine, 1,000 mg/m2 on days 1 and 8 every 3 weeks) is the standard treatment for nonresectable cholangiocarcinoma in the first line. When contraindications exist for treatment with cisplatin such as renal insufficiency, cisplatin may be replaced with oxaliplatin. The combination of gemcitabine and oxaliplatin has demonstrated efficacy and safety in several phase II studies. Treatment with gemcitabine as a single agent is still considered appropriate for elderly patients and patients with comorbidities. Also those with a poor performance status may benefit from gemcitabine as symptom control was better in patients treated with gemcitabine than with best supportive care only. 3. In addition to gemcitabine-based chemotherapy, fluoropyrimidines have shown efficacy in treatment of cholangiocarcinoma. Combined treatment with gemcitabine plus 5-FU as well as gemcitabine plus capecitabine revealed response rates of 30% in multiple phase II randomized studies. Similar results have been seen in phase II randomized trials of platinum-based agents used in combination with 5-FU or capecitabine. The combination agents consistently demonstrated response rates and median survival times greater than 5-FU alone. 4. Currently, most ongoing trials in patients with advanced cholangiocarcinoma are looking to extend the benefit of gemcitabine and cisplatin, potentially by adding one or more targeted agents to the combination. The recently published phase II study BINGO randomized 150 patients to GEMOX with or without cetuximab and did not

reveal any benefit to the addition of cetuximab. There are numerous other phase II trials ongoing looking at role of VEGF inhibitors, MEK inhibitors, and multikinase inhibitors. 5. Other studies are trying to identify effective regimens for patients who have progressed on first-line chemotherapy. Currently, there are no randomized trials that have shown a benefit to second-line chemotherapy. Recently, the results of a large retrospective review of second-line chemotherapy outcomes for patients with advanced biliary tract cancers were published. The authors concluded that patients who obtained a second-line treatment had a survival benefit compared with those who received best supportive care. This study also provides a context for future clinical trials to improve upon the 2.8-month median progression-free survival that was observed. E. Current recommendations 1. Patients with a good performance status a. Gemcitabine/cisplatin ■ Cisplatin, 25 mg/m2 on day 1 with gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks or b. Gemcitabine/oxaliplatin (patients with contraindication to cisplatin, i.e., renal insufficiency). ■ Oxaliplatin 130 mg/m2 on day 1 with gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks or c. Gemcitabine/capecitabine ■ Capecitabine 1,500 mg/m2 daily in twice-daily divided doses on days 1 to 14 and gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks or d. Capecitabine with cisplatin or oxaliplatin ■ Capecitabine 1,500 mg/m2 daily in twice-daily divided doses on days 1 to 14 plus oxaliplatin 130 mg/m2 or cisplatin 25 mg/m2 on day 1 every 3 weeks or e. Fluorouracil with cisplatin or oxaliplatin ■ Leucovorin 400 mg/m2 IV infused over 2 hours prior to 5-FU plus 5-FU 400 mg/m2 IV bolus on day 1, followed by 2400 mg/m2 IV infused over 46 hours plus oxaliplatin 100 mg/m2 IV on day 1 every 2 weeks 2. Patients with lesser performance status Single-agent gemcitabine, capecitabine, or fluorouracil IV. PRIMARY CARCINOMA OF THE LIVER A. Epidemiology Hepatocellular carcinoma (HCC) accounts for 80% to 90% of primary liver cancer. Hepatocellular carcinoma is a major health problem worldwide with more than 750,000 cases diagnosed each year. It is the fifth most common cancer worldwide and the second most common cause of cancer-related death, with most cases occurring in

Asia. Although less common in the United States, the incidence is rising with an estimated 35,660 to be diagnosed in 2015 with an estimated 24,550 deaths (but this number also includes intrahepatic bile duct cancer as well). Ninety percent of primary cancers of the liver are HCC or hepatoma; the remaining cancers include cholangiocarcinomas (about 7%), hepatoblastomas, angiosarcomas, and other sarcomas. In the United States, the peak incidence is in the sixth decade of life, whereas in Asia and Africa it occurs much earlier in life. B. Etiology and risk factors The rates of HCC are two to four times higher in males than females. Eighty to ninety percent of cases of HCC develop in a cirrhotic liver, and cirrhosis is the strongest predisposing factor for HCC. Overall, 80% of cases of HCC are attributable to chronic infections with either hepatitis B or hepatitis C virus. Chronic hepatitis B viral infection is common in Asian and African countries and accounts for most cases of HCC. Chronic carriers of hepatitis B have a 100-fold relative risk for developing HCC with an annual incidence rate of 2% to 6% in cirrhotic patients. In contrast, chronic hepatitis C viral infection is more common in Western countries. Other causes of HCC include alcoholic liver cirrhosis, aflatoxin (a natural product of the Aspergillus fungus found in various grains), hereditary hemochromatosis, autoimmune hepatitis, α1-antitrypsin deficiency, and Wilson disease. The incidence of HCC is increasing in the United States, particularly among the population infected with the hepatitis C virus. Approximately 4 million people in the United States are chronically infected with hepatitis C virus, and the annual incidence among hepatitis C patients with hepatitis C–related cirrhosis is estimated to be between 2% and 8%. Approximately 1.5 million people are chronically infected with hepatitis B in the United States; the annual incidence of HCC in patients with hepatitis B–induced cirrhosis is 2.5%. In those carriers without cirrhosis, the annual incidence is 0.5%. C. Presenting signs and symptoms Patients with primary carcinoma of the liver commonly complain of right upper quadrant pain, abdominal distention, or weight loss. The pain is usually dull or aching but may be acute and radiate to the right shoulder. Fatigue, loss of appetite, and unexplained fever may occur. Patients with underlying cirrhosis may present with hepatic decompensation: new ascites, variceal bleeding, jaundice, or encephalopathy. Rarely, patients present with paraneoplastic syndromes. Erythrocytosis is the most common; hypercalcemia, hyperthyroidism, and carcinoid syndrome have also been described. Physical findings include nodular hepatomegaly with an arterial bruit and hepatic rub. Extrahepatic spread occurs in about 50% of patients during the course of the illness. Twenty percent of patients have lung metastases. D. Diagnostic evaluation and screening There are several published studies that have demonstrated reduction in HCC mortality with the utilization of screening programs for high-risk individuals such as those with cirrhosis or chronic hepatitis viral infections. Serum α-fetoprotein (AFP) and liver

ultrasound are the most widely used methods for screening for HCC. Most groups recommend periodic testing with AFP and ultrasonography every 6 to 12 months. Additional imaging is recommended in the setting of a rising serum AFP or following identification of a liver nodule on liver ultrasound. HCC lesions are characterized by arterial hypervascularity, deriving most of their blood supply from the hepatic artery. This is in contrast to surrounding liver, which receives most of its blood supply from the portal venous system. Therefore, the most commonly utilized tests for diagnostic imaging of HCC are triphasic helical CT or triphasic dynamic contrast-enhanced magnetic resonance imaging (MRI). CT or MRI for lesions greater than 2 cm demonstrating classic arterial enhancement is diagnostic for HCC. For lesions 1 to 2 cm in size, a classic arterial enhancement pattern on both CT and MRI is considered diagnostic for HCC. Liver lesions less than 1 cm should be followed closely with periodic repeat imaging. Liver lesions greater than 1 cm that do not demonstrate classic arterial enhancement should undergo tissue biopsy to confirm the diagnosis. E. Laboratory tests AFP is a tumor marker that is elevated in 60% to 70% of patients with HCC. Serum AFP is not a sensitive or specific test for HCC. However, results of AFP testing can be used in conjunction with imaging to guide management of patients with suspected AFP. An AFP greater than 200 in a patient with a liver lesion greater than 2 cm has a high predictive value for HCC and can be considered diagnostic even without the classic enhancement pattern on imaging. F. Staging and preoperative evaluation 1. Staging Patients diagnosed with HCC should undergo an extensive workup that includes determination of the etiology of underlying liver disease including hepatitis panel, assessment of other comorbidities, imaging studies to evaluate for metastatic disease (chest imaging and bone scan as most common sites for metastases are lung, bone, and abdominal lymph nodes), and evaluation of underlying hepatic function, including a determination of any evidence of portal hypertension. An effective staging system should incorporate tumor characteristics and underlying liver disease (Child-Pugh classification), as both of these factors impact choice of treatment and patient survival. A number of staging systems for patients with HCC have been devised. Some of the most commonly utilized include the Okuda staging system, Cancer of the Liver Italian Program score, Japanese Integrated Staging score, Chinese University Prognostic Index, simplified (Vauthey) staging for HCC, Izumi TNM modification, French classification system, and the Barcelona Clinic Liver Cancer staging classification. Each of these scoring systems has limitations, and therefore no one staging system has been universally accepted. Following workup, patients are stratified into one of the following groups: metastatic disease, locally advanced unresectable disease not amenable to transplantation, resectable or transplantable but performance status precludes operation, and resectable or

transplantable with appropriate performance status. 2. Preoperative evaluation The selection of patients with HCC for surgical resection incorporates information regarding tumor extent, severity of underlying liver disease, assessment of liver functional reserve, and general medical condition of the patient. The general criteria for unresectability of HCC includes large size of tumor with insufficient hepatic remnant after liver resection, multifocal bilobar lesions, extrahepatic tumor metastases, and tumor with main portal vein or hepatic vein/inferior vena cava involvement. In addition, resection is generally recommended only in the presence of preserved liver function with no evidence of portal hypertension. G. Primary therapy At presentation, only 25% of patients with HCC have potentially resectable lesions. Results of large retrospective studies have demonstrated 5-year survival of 50% to 70% in select patients undergoing liver resection for HCC in the setting of preserved liver function. However, the number of patients with HCC considered good candidates for resection in the United States is quite low because the majority of patients have underling child grade B or C cirrhosis. In addition, recurrence rates at 5 years following liver resection for HCC are quite high and approach 70%. Liver transplantation may permit resection of small tumors in patients with advanced cirrhosis, and survival is similar to or better than that seen after resection without transplantation. Patients with HCC who meet the Milan criteria for transplantation are those patients with one nodule less than 5 cm or two to three nodules that are less than 3 cm and no evidence of macrovascular involvement or extrahepatic disease. These select patients treated with liver transplantation have low recurrence rates with 5-year survival rates of greater than 75%. The main problem with transplantation is timely organ availability. Patients with localized disease who are not candidates for either resection or transplantation should be considered for ablative therapies or embolization. In addition, for patients awaiting liver transplantation, a number of studies have investigated the role of locoregional therapies in controlling disease as a bridge to transplantation. The locoregional therapies available include ablative therapies such as RFA, microwave ablation, cryoablation, or percutaneous ethanol injection and embolization therapies such as bland embolization, chemoembolization, drug-eluting beads, and radioembolization. Newer experimental techniques such as PHP may also have a role in this setting. H. Therapy of advanced HCC 1. The majority of patients diagnosed with HCC have advanced disease at presentation and are not candidates for surgery or locoregional therapies. Unfortunately, HCC is a relatively chemoresistant tumor and is highly resistant to cytotoxic chemotherapy. Clinical studies evaluating the use of cytotoxic chemotherapy such as doxorubicin have reported low response rates to therapy and evidence for a favorable impact on survival is lacking. Doxorubicin has been the most extensively studied chemotherapy

in this disease. At doses of 75 mg/m2 every 3 weeks, tumor shrinkage of at least 25% was reported in only 8% of patients and there is small survival benefit compared with best supportive care. In the past, this had been the standard treatment of unresectable HCC; however, the toxicities limited its use. In clinical practice, cumulative doses of more than 400 mg/m2 significantly increase risk of cardiac damage and cardiomyopathy. Neutropenia also occurs and can lead to sepsis in setting of biliary obstruction. 2. More recently, two phase III studies have found sorafenib to be beneficial in the treatment of patients with metastatic or locally advanced HCC. Sorafenib is an oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis. In a large multicenter, randomized, placebo-controlled phase III trial (SHARP), the efficacy of sorafenib versus placebo in patients with advanced HCC was evaluated.18 In this study, 602 patients with advanced measurable HCC, no prior systemic therapy, good performance status, and preserved liver function were randomized to either sorafenib 400 mg twice a day or placebo with best supportive care. Median survival was significantly longer in the sorafenib arm (10.7 vs. 7.9 months, HR = 0.69, p < 0.001). Another phase III trial with similar design, the AsiaPacific study, randomized 226 patients in a 2:1 fashion to either sorafenib or placebo. Patients in this study were Asian and tended to be younger, with underlying hepatitis B and a higher number of tumor sites compared with the SHARP trial. This study also demonstrated improved median survival in the sorafenib arm (6.5 vs. 4.2 months, HR = 0.68, p = 0.014). Overall, sorafenib is well tolerated with limited side effects, the most common being diarrhea, hypertension, and hand-foot skin reaction. As a result of these studies, sorafenib is now considered the standard of care for patients with advanced and metastatic HCC who are not candidates for curative or locoregional therapies, but at present only patients with good liver function have been rigorously studied. 3. Since the approval of sorafenib by the FDA in November 2007, multiple small molecule TKIs or monoclonal antibodies to VEGF have shown promising activity in phase II clinical trials but none of the therapies have been superior to sorafenib in the phase III setting. Currently there are multiple ongoing clinical trials looking at role of sorafenib in combination with liver-directed therapies such as SBRT, radiofrequecy ablation (RFA), and transarterial chemoembolization (TACE). There are also ongoing clinical trials looking at second-line therapies for patients who have progressed on sorafenib and have preserved adequate liver function. Agents such as regorafenib and c-met inhibitors are currently in phase III trials as potential second-line therapies. 4. Current recommendations a. Sorafenib Sorafenib 400 mg po twice daily.

References 1. Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer. 1987;59:2006–2010. 2. Klinkenbijl JH, Jeekel J, Shamoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999;230(6):776–782. 3. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350:1200– 1210. 4. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs. observation in patients undergoing curative-intent resection of pancreatic cancer; a randomized controlled trial. JAMA. 2007;297:267–277. 5. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299:1019–1026. 6. Neoptolemus JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized trial. JAMA. 2010;304:1073–1081. 7. Moertel CG, Frytak S, Hahn RG, et al. Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads–5-fluorouracil), and high dose radiation–5-fluorouracil. Gastrointestinal Tumor Study Group. Cancer. 1981;48:1705–1710. 8. Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–2413. 9. Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005;23(15):3509– 3516. 10. Moore MJ, Golstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Institute of Cancer Clinical Trials Group. J Clin Oncol. 2007;25:1960–1966. 11. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–1825. 12. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nabpaclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–1703. 13. Oberg K, Kvols L, Caplin M, et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004;15:966–973.

14. Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo controlled, double blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27:4656–4663. 15. Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin–doxorubicin, streptozocin– fluorouracil, or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992;326:519–523. 16. Glimelius B, Hoffman K, Sjoden PO, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996;7:593–600. 17. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273–1281. 18. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390.

I. NATURAL HISTORY AND MODES OF TREATMENT A. Epidemiology and risk factors Breast cancer, accounting for 25% of all cancers, remains the second most common cause of cancer worldwide, with an estimated 1.67 million new cancer cases diagnosed in 2012.1 It is by far the most common cancer in women, both in more and less economically developed regions, with slightly more cases in less developed (883,000 cases) than in more developed (794,000) regions.1 Incidence rates vary nearly fourfold across the world regions, with rates ranging from 27 per 100,000 in Middle Africa and Eastern Asia to 96 in Western Europe.1 The higher incidence of breast cancer in women in Western Europe and the United States is possibly associated with higher median population age, robust early detection programs, better control of other causes of early life mortality, and recent increases in obesity. It has been suggested that inflammation could play a role in the pathogenesis of breast and other cancers in obese and overweight patients.2–4 The rising breast cancer incidence in women of developing nations has also been attributed to “westernized” lifestyle changes including dietary changes, decreased exercise, and reproductive changes such as delayed childbearing, lower parity, and reduced breast-feeding.5,6 Breast cancer incidence has, however, declined in developed countries since 2003 and is associated with the marked decrease in the use of HRT among postmenopausal women following publication of the Women Health Initiative report that showed an increased breast cancer risk of about 10% for every 5 years of HRT use and even greater risk with combined estrogen/progesterone products than with estrogen therapy alone.7 Since 2004, overall breast cancer incidence rates have remained relatively stable.8 Breast cancer is less lethal than many other solid tumors and ranks as the fifth cause of death from cancer overall (522,000 deaths). It is, however, the most frequent cause of cancer death in women in less developed regions (324,000 deaths, 14.3% of total) but the second cause of cancer death in more developed regions (198,000 deaths, 15.4%) after lung cancer.1 The range in mortality rates between world regions is less than that for incidence because of the more favorable survival of breast cancer in (high incidence) developed regions, with rates ranging from 6 per 100,000 in Eastern Asia to 20 per 100,000 in Western Africa.1 Currently, more women survive because of earlier

diagnosis and better therapy,9 and the absolute number of deaths per year has been declining since about 1990 with a disease-specific mortality decrease of 2.2%/year since then, with a more prominent decline noted in women younger than 50 years (3.1%/year) than women 50 and older (1.9%/year).8 The incidence of breast cancer varies among different racial groups and ethnicities. Caucasian women in the United States are more likely to develop breast cancer compared with African American women for most age groups; however, African American women have a higher incidence rate before age 40 and are more likely to die from breast cancer at every age.10 This is confounded, however, by the general increase in cancer-related mortality for lower socioeconomic groups regardless of specific ethnicity. Although discrete causes of breast cancer cannot be identified in most individual women, many factors increase a woman’s risk of developing the disease. Among the strongest of the risk factors is family history, particularly if more than one family member has developed breast cancer at an early age.11 More precisely, genetic linkage analysis led to the discovery of dominant germ-line mutations in two tumor-suppressor genes, BRCA1 and BRCA2, localized to chromosomes 17 and 13, respectively, which are associated with a high risk of female breast cancer as well as ovarian cancer (BRCA1 and BRCA2), male breast cancer (BRCA2), and other cancers.12–17 Although these mutations account for less than 10% of all cases of breast cancer, together they account for about 45% of families with multiple cases of breast cancer and up to 90% of families with both breast and ovarian cancer.18,19 These mutations are present in less than 1% of the general population, but occur more often in certain ethnic groups such as those of Ashkenazi (Eastern European) Jewish descent.18 However, if a woman with breast cancer is below the age of 50 years and has any relative who developed breast cancer before she was 50 years old, her chance of having a mutation in BRCA1 or BRCA2 rises to as much as 25%.19 Other factors that increase her probability of a mutation include any relative with ovarian cancer or a personal history of bilateral breast cancer or ovarian cancer. Carriers of these mutations have up to a 70% lifetime risk of breast cancer, depending on familial history, perhaps the specific mutation, and other cellular genes that may modify penetrance.17 The 5-year survival rate of patients with either of the BRCA mutations is not significantly less than for other patients with breast cancer after adjusting for the specific subtypes of breast cancer carriers tend to develop. It is important to note that most patients with a family history of breast cancer do not have a defined inherited mutation and other, less common, causative mutations are sometimes seen.19,20 Rarer inherited conditions associated with increased breast cancer risk include Li-Fraumeni (germ-line mutations in p53) and Cowden syndromes (80% due to mutations in PTEN) and a number of more common genetic mutations. PALB2 (partner and localizer of BRCA2) has been previously identified as a moderate-risk

gene in breast cancer and germ-line loss-of-function PALB2 mutation carriers have a lifetime risk of breast cancer as high as the risk borne by BRCA2 mutation carriers.21,22 Beyond molecular testing for BRCA1/2, multiplex test panels are now commercially available, identifying both high- and moderate-penetrance genes for use in families who test negative for known familial cancer syndromes. However, a limited understanding of the risk associated with moderate-penetrance genes and the potential for detection of variants of uncertain clinical significance (VUCS) complicate the interpretation of test results. Comprehensive genetic counseling should be done prior to testing, to ensure test results appropriately modify the clinical care of these patients.23,24 Additional factors that increase breast cancer risk are early menarche, late menopause, nulliparity, late age at birth of first child, and prior benign breast disease (particularly if there is a high degree of benign epithelial atypia).25,26 Although breast cancer may occur among men, such cases represent less than 1% of all breast cancers. Male carriers of BRCA2 mutations have a 6% lifetime risk of breast cancer, significantly increasing their risk in comparison with the general population. B. Prevention The risk of hormone receptor–positive breast cancer can be reduced. At least three trials using selective estrogen receptor modulators (SERMs) have demonstrated that 3 to 5 years of preventive treatment with these agents reduces the rate of breast cancer development over the short term.27–30 Women at increased risk because of family history, age, and other risk factors, who are treated with the SERM tamoxifen, 20 mg/day, were found to have a 45% reduction in the rate of occurrence of invasive breast cancer compared with women treated with placebo. Noninvasive disease and preneoplastic breast lesions were also decreased. Raloxifene, 60 or 120 mg/day, also appears to reduce the risk of breast cancer in postmenopausal women (who had osteoporosis and a standard or reduced risk of breast cancer), with a relative risk of 0.26.31 Despite these benefits, SERMs are associated with an increased risk of both venous thromboembolism and endometrial cancer, although the risks with raloxifene appear to be lower than tamoxifen, which has been associated with an increased risk for endometrial cancer of 1.5 to 2 times that of untreated women.27 In addition, neither of these agents have demonstrated an improvement in survival when used for breast cancer prevention. In the Study of Tamoxifen against Raloxifene trial, these agents were compared and although there were no significant mortality differences, raloxifene was found to have 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer and less thromboembolic events).32 A meta-analysis of all nine prevention trials with tamoxifen, raloxifene, arzoxifene, and lasofoxifene showed an overall 38% reduction in breast cancer incidence.33 Indeed after 20 years of follow-up, the long-term benefits of 5 years of tamoxifen remain with a number needed to treat (NNT) of 22 to prevent one breast

cancer (95% CI, 19 to 26).34 These agents have similar but not identical toxicity profiles that may guide clinical decisions. Aromatase inhibitors (AIs) have also been shown to be beneficial as prevention in the postmenopausal population at high risk. Five years of exemestane significantly reduced the incidence of invasive breast cancers by 65% with only minimal changes in health-related quality of life and without serious toxic effects.35 Similarly, anastrozole was shown to reduce the risk of developing hormone receptor–positive invasive breast cancer and preinvasive cancers by 50%.36 There are several options in the management of women at very high risk because of family history or known gene mutations. Increased surveillance, through the addition of magnetic resonance imaging (MRI) screening on a yearly basis as a supplement to standard mammography, was effective in a high-risk population. In mutation carriers who are at risk for both breast and ovarian cancer, bilateral oophorectomy after childbearing age (before age 50 years but possibly as early as 35) has been recommended because of the inadequacy of screening tests for ovarian cancer and because it reduces the risk of both primary breast cancer by approximately 50% and the risk of ovarian cancer by approximately 80% and is associated with a lower all-cause mortality.37–39 Risk-reducing mastectomy is an effective option with a relative risk reduction of about 90%.37,40 Note that despite risk-reducing mastectomy, there is always a small risk of breast cancer in residual breast glandular tissue. SERMs may be useful in patients with BRCA1 and BRCA2 mutations as well. Analysis of blood samples of women who participated in the P-01 (tamoxifen) trial showed that mutation carriers also had a 47% lower risk of breast cancer.41,42 Tamoxifen has also been shown to reduce contralateral breast cancer incidence in this high-risk population.43 C. Detection, diagnosis, and pretreatment evaluation 1. Screening Because more lives can be saved if breast cancer is diagnosed at an early stage, many screening programs have been designed to detect small, early cancers. Monthly breast self-examination for all women after puberty and yearly breast examinations by a physician or other trained professional after a woman is 20 years of age is generally recommended, although evidence of effectiveness is limited. Mammography reduces breast cancer mortality by 25% to 30% in women older than 50 years.44 The benefit for women aged 40 to 50 years has been more difficult to demonstrate because the incidence of breast cancer is lower.45,46 Hence, more examinations are needed to find a cancer and save a life. However, additional benefits of early detection via mammography include the option for less disfiguring surgery, reduced utilization of radiation therapy, and decreased need for chemotherapy and other systemic treatments. Therefore, the absolute benefits extend beyond the simple end point of survival. As a result, mammography is recommended at age 40 years as a baseline, once every 1 to 2 years between the ages of 40 and 50

years (depending on risk factors and the recommending organization), and yearly after 50 years of age. An upper age of effectiveness is not established. For high-risk women and in family members of mutation-positive patients, annual mammography should be initiated 10 years earlier than the youngest diagnosed relative. Patients with Hodgkin lymphoma (regardless of a history of mantle field irradiation) should have a baseline mammogram by age 25. In BRCA1/BRCA2 mutation carriers, beginning at age 25, annual MRI of the breast in addition to annual mammography is recommended as its use has detected more interval and earlier stage cancers and has reduced the incidence of large or lymph node–positive breast cancers.47,48 Mammography has clearly led to the discovery of many earlier cancers and sharply increased the discovery of preinvasive cancers (ductal carcinoma in situ [DCIS]). These latter are not (yet) invasive and their treatment can be far less complicated than that of invasive breast cancer. Other screening modalities can include ultrasound, but it is more typically used diagnostically to evaluate palpable lesions. 2. Presenting signs and symptoms Although a large number of nonpalpable cancers are found by mammography, invasive breast cancer is still often discovered by a woman herself as an isolated, painless lump in the breast. If the mass has gone unnoticed, ignored, or neglected for a time (or if it is particularly rapidly growing or aggressive), there may be fixation to the skin or underlying chest wall, ulceration, pain, or inflammation. Some early lesions present with discharge or bleeding from the nipple. Occasionally, the primary lesion is not discovered, and the woman presents with symptoms of metastatic disease, such as pleural effusion, nodal disease, or bony metastases. About half of all lesions are in the upper outer quadrant of the breast (where most of the glandular tissue of the breast is). About 20% are central masses and 10% are in each of the other quadrants. Up to one-quarter of all women with breast cancer have axillary node metastasis at the time of diagnosis, although this is less common when the primary tumor has been detected by screening. 3. Staging. Carcinoma of the breast is staged according to the size and characteristics of the primary tumor (T), the involvement of regional lymph nodes (N), and the presence of metastatic disease (M). The TNM classification of breast cancer and stage grouping are used, which is published by the American Joint Commission on Cancer.49 Although preliminary staging is commonly done before surgery, definitive staging that can be used for prognostic and further treatment planning purposes usually must await postsurgical pathologic evaluation when the primary tumor size and the histologic involvement of the lymph nodes are established. In up to 30% of patients with palpable breast masses (not found by mammography) but without clinical evidence of axillary lymph node involvement, the histologic evaluation of the nodes reveals cancer. In patients with negative nodes by routine histologic evaluation, serial sectioning may reveal microscopic cancer deposits in additional patients. The principal changes in the new staging system take into consideration the

widespread use of immunohistochemical (IHC) and molecular biologic techniques that afford pathologists the ability to detect microscopic metastatic lesions down to the level of isolated tumor cells. It is not clear that there is prognostic value if cancer cells in nodes are detected by enhanced examination, and the current staging system designates nodes as pathologically negative if cells are identified by IHC alone and are in clusters of less than 0.2 mm. The identifier “(i)” is used to indicate isolated tumor cells such that pN0 (i+) indicates node-negative disease but the presence of such cells in the node. Similarly, “(mol +)” indicates that a molecular examination such as polymerase chain reaction has found evidence of malignant cells. D. Diagnostic evaluation 1. Before biopsy the woman should have a careful history, during which attention should be paid to risk factors, and a physical examination, with a focus not only on the involved breast but also on the opposite breast, all regional lymph node areas, the lungs, bone, and liver. This examination should be followed by bilateral mammography to help assess the extent of involvement and to look for additional ipsilateral or contralateral disease. 2. Excisional or core needle biopsy of the primary lesion is performed, and the specimen is given intact (not in formalin) to the pathologist, who can divide the specimen for histologic examination, hormone receptor assays, and HER2 testing (by immunohistochemistry examination or fluorescence in situ hybridization [FISH]). 3. After confirmation of the histology, the patient is evaluated for possible metastatic disease. It is important to emphasize that history and physical examination are the most critical components of this assessment. a. Typical studies include a complete blood count, and blood chemistry profile. b. Other studies that may be considered based on symptoms or signs or abnormal blood work, include radionuclide scan of the bones, skeletal survey (usually obtained only if the radionuclide scan is positive), and computed tomography (CT) scan of the liver (abdomen) and chest. PET CT is another option that may be helpful in the evaluation of locoregional disease. c. Histology About 75% to 90% of all breast cancers are infiltrating ductal carcinomas, and up to 10% are infiltrating lobular carcinomas; these two types have similar overall behavior but the latter tend to be hormone responsive and HER2negative. In addition, their patterns of metastatic spread can vary even if the overall risks of metastases are similar. The remainder of the histologic types of invasive breast carcinoma may have a somewhat better prognosis but are usually managed more according to the stage than to the histologic type. Microarray technology has added nuance to the traditional, histology-based categorization of breast cancer and supports the view that this is a disease with distinct subtypes.

About 15% of breast cancers are basal-like (basal epithelial subtype), with a relatively high concordance with the conventionally defined “triple negative” (hormone-receptor and HER2-negative) subset.50 Luminal tumors are generally hormone receptor–positive, but it is the luminal A subtype that is most clearly hormone responsive, and the luminal B subtype is clinically distinguished by either expression of HER2 or high proliferation rates.51 Basal-like tumors are seen in association with BRCA1 mutations and are more common in African American women.52 Each of these subtypes (luminal A, B, basal-like, HER2-positive, etc.) is associated with a distinct typical natural history in terms of time to develop distant metastases.53 E. Approach to therapy Many institutions have established multidisciplinary teams or centers to facilitate coordinated treatment planning. It may be useful in some settings to pursue this particular clinical care structure, but there are other reasonable strategies to employ in the development of an optimal care plan for individual patients. 1. Consultation with a surgeon, radiotherapist, and medical oncologist is generally required once the diagnosis of carcinoma is suspected or histologically confirmed or after definitive surgery has been accomplished. Multimodal therapy has had a profound impact on the outcome of breast cancer as it has allowed for organ preservation and improved disease-free survival (DFS) and overall survival. Any clinician treating patients for breast cancer should be very familiar with the roles and interventions offered by the other members of the team. It is also critical to have the patient (and her family if she desires) share in the therapy decisions after hearing the options, the relative advantages and disadvantages of each approach, and the recommendations of the consultants. The patient should be given an opportunity to hear why the recommended treatment is thought by the physicians to be best and to decide whether the treatment is appropriate for her. 2. Goals of therapy differ depending on the stage of disease being treated. 3. For early-stage invasive disease, the goal of therapy is to eradicate the primary tumor and to suppress the growth of or eliminate micrometastases, thereby preventing recurrence and death. In the postoperative setting, this is called adjuvant therapy. There are three broad classes of systemic adjuvant therapy: hormone therapy (tamoxifen or, in postmenopausal women, an aromatase inhibitor), chemotherapy (any of a large number of standard combination regimens), and HER2directed therapy (trastuzumab +/− pertuzumab for patients with HER2-positive tumors). These options are weighed and combined on an individualized basis based on careful risk-benefit analyses. Of course, while treating postoperative patients who may be cured by their surgery (and radiation therapy), we seek to avoid unnecessary short- and long-term drug-induced toxicities. Of particular concern is the increased incidence of second cancers (myelodysplasia and leukemias in particular with chemotherapy, and uterine cancer with tamoxifen) arising years after

the completion of therapy. Other risks can include osteoporosis with AIs and cardiac dysfunction following anthracycline or trastuzumab use. It is important to emphasize that despite these toxicities, overall survival has generally been improved in the patient populations treated with these modalities.54 However, one goal of ongoing investigational studies is to determine the minimum therapy that is effective for preventing the maximum number of recurrences in any given clinical situation. 4. For locally advanced disease defined as stage IIIA or T3–T4 disease or more, including inflammatory breast cancer, the goal of systemic therapy changes somewhat. In addition to critically important systemic control, there is the added potential benefit of local response facilitating less disfiguring surgery and, in some cases, any surgery. This is referred to as neoadjuvant or preoperative systemic therapy, and it specifically can reduce the size of an initially unresectable tumor or convert the planned surgical intervention from mastectomy to breast conservation. In the research setting, preoperative administration of systemic therapy allows the opportunity to test both the therapeutic efficacy of novel drugs and regimens as well as the ability to conduct correlative science studies, thereby potentially optimizing drug development. 5. For advanced (metastatic) disease the goal of therapy is to lengthen survival when possible and to palliate or limit symptoms and signs of the disease using therapy with an acceptable toxicity profile. In this setting, long-term toxicity is not usually of great importance, but short-term toxicity is a major focus for both physician and patient because the aim of therapy is to improve how the patient feels (quality of life) as well as to prolong survival. The general approach is to use hormone therapy if possible, anti-HER2 therapies when HER2 is amplified or overexpressed in the tumor, and chemotherapy as sequential single agents. There are a myriad of novel targeted therapies in development and an increasing number of treatments with proven impact on overall survival. 6. Surgery remains the most frequently used mode of primary therapy for the vast majority of women with breast cancer. Over the past half century, the extent of surgery has evolved toward less disfiguring procedures. Hence, breast conservation (lumpectomy) with radiation therapy and an examination of the sentinel nodes (or in some cases, an axillary node dissection) is now routine. Surgical margins should be free of tumor, but an exact definition of the safe width is not uniformly accepted. Complete axillary node dissection is unnecessary in most cases when a sentinel node procedure, performed by an experienced surgeon, reveals no cancer.55 Following breast conservation (and generally after the completion of chemotherapy), radiotherapy is delivered to control any microscopic cancer remaining in the breast. The decision to radiate nodal fields varies with the stage of the cancer. In terms of distant DFS and overall survival, appropriate candidates for breast conservation have the same outcomes as if they were treated with mastectomy.56 Therefore, many patients opt for breast-conserving surgery and radiotherapy over mastectomy. Apart

from patient preference, mastectomy is indicated when the tumor is too large or locally advanced to allow breast conservation (although preoperative systemic therapy can facilitate breast conservation in this situation), if the tumor is multicentric/multifocal, when the patient has a contraindication to radiation therapy, if it is an ipsilateral recurrence in a previously radiated breast (again, a contraindication to additional radiation therapy), or when margins free of tumor cannot be obtained. There remain wide geographic variations in the use of breast-conserving surgery throughout the United States and without obvious medical justification. For patients who have had mastectomy, reconstruction can be accomplished by several approaches and requires a skilled plastic surgeon. It may be done at the time of mastectomy or delayed for a period (usually 1 to 2 years). There is no evidence that any (or no) reconstructive approach has any impact on the natural history of breast cancer.57 7. Radiation therapy. The role of radiation therapy in the management of carcinoma of the breast has been expanded since the early 1970s. Radiotherapy is now commonly used in conjunction with breast conservation as part of the primary therapy. In this circumstance, the radiotherapy is commonly delivered to the entire breast with a boost of therapy to the tumor bed using external-beam therapy. More recently, shorter courses of external-beam radiation may be considered for treating the breast only.58 In addition, radiation therapy to only the affected part of the breast is now used in early-stage disease. Partial breast irradiation may be delivered by brachytherapy or focused external-beam treatment. Radiotherapy may also be employed following mastectomy in women who have a particularly high likelihood of local recurrence. When the risk of local recurrence is high, radiation therapy is associated with improved overall survival.59 Typically, postmastectomy radiation is indicated if the primary tumor is larger than 5 cm or if four or more positive lymph nodes were found in the axilla, although there is potential benefit on survival even in lower risk patients, such as those with one to three positive axillary lymph nodes.59 Following breast conservation, radiation may be omitted in patients older than 70 years of age with estrogen receptor–positive tumors smaller than 2 cm if they are treated with antiestrogen therapy.60 However, with longer follow-up, an increase in breast recurrences is found without radiation, but with no detectable impact on survival.60 Radiation therapy is generally administered after completion of cytotoxic therapy (when indicated). Radiation therapy is also helpful as adjunctive therapy for metastatic or locally advanced and unresectable disease. Local recurrences and isolated or specific (e.g., painful bone lesions particularly with impending fracture) distant metastases also are frequently treated successfully with radiotherapy. 8. Systemic therapy is used to reduce the likelihood of recurrence after local therapy for early-stage disease and to treat more advanced disease with or without distant metastasis. For operable (curable) breast cancer, The Early Breast Cancer Trialists’

Collaborative Group (EBCTCG) analysis of adjuvant therapy demonstrates a clear benefit of postoperative chemotherapy or hormonal therapy (including ovarian ablation in premenopausal women).54 Although the precise estimates of benefit vary with each half-decade review and update, in very general terms systemic therapy reduces the risk of recurrence by as much as 50%. Similarly, the odds of death are also reduced by as much as 30%. Similar proportional risk reductions are seen in node-positive as well as node-negative disease with the proviso that lower risk disease yields proportionately smaller absolute benefits for therapy.61 Historically, medical oncologists relied on node status, tumor size and grade, hormone receptor status, HER2 status, and perhaps DNA synthesis rate (percentage of cells in the synthesis phase), as well as any of a number of other factors to aid in determining risk for individual patients so that the oncologists could then estimate the benefits of specific systemic therapies and guide patients. More recently, commercially available tests (genomic assays) that provide prognosis, or more importantly, prediction of benefit for specific systemic therapies, have become available.62,63 As always, physiologic age of the patient and comorbid conditions are also important considerations in adjuvant therapy decisions. 9. Endocrine therapy includes surgical, radiotherapeutic, or drug-induced ablation or inhibition of ovarian function. It also includes antiestrogens (typically SERMs), AIs, progestins, androgens, and even corticosteroids. Tumors with no expression of either the estrogen or the progesterone receptor will generally not respond to hormone therapies, and the greater the expression of these receptors the greater the probability of benefit.64 However, there is no clear threshold (above zero) below which one can be certain that endocrine therapy will be ineffective.65 Similarly, when the estrogen receptor is detected, it is not clear that the level of the progesterone receptor is important. Variations in test quality and results remain important challenges in this area. A. Prognosis Breast cancer can vary from aggressive and rapidly fatal to relatively indolent disease with late-appearing metastasis. Molecular studies increasingly support the view that breast cancer is a collection of diseases rather than one single entity. At present, clinicians can use the following factors to provide crude estimates of the likelihood of relapse and survival, but this is an area where newer diagnostics may rapidly improve our current approach. 3. Stage. Axillary node involvement and the size of the primary tumor are major determinants of the likelihood of survival.66–68 a. Nodes. In the first National Surgical Adjuvant Breast and Bowel Project (NSABP) study, before the use of modern adjuvant therapy, 65% of all patients who underwent radical mastectomy survived 5 years, and 45% survived 10 years.69 When no axillary nodes were positive, the 5-year survival rate was nearly 80% and the 10-year survival rate 65%. If any axillary nodes were

positive, the 5-year survival rate was less than 50% and the 10-year survival rate 25%. If four or more nodes were positive, the 5-year survival rate was 30% and the 10-year survival rate less than 15%. Since that time (1975), there has been an improvement, with 5-year survival rates of 99% for stages I and II, 85% for stage III, and 25% for stage IV breast cancer.70 Lymph node involvement by conventional light microscopy remains the single most important prognostic factor in making survival predictions and treatment decisions. It is important to distinguish modern cases in which malignant cells are detected in lymph nodes using higher sensitivity techniques. Their prognosis is not as clearly established. a. Primary tumor Patients with large primary tumors generally face higher risks of relapse and death compared to patients with small tumors, irrespective of the nodal status, although patients with large primary tumors are more likely to have node involvement. Tumors that are fixed to the skin or to the chest wall have worsened prognoses compared to those that are not. Patients with inflammatory carcinomas have a particularly poor prognosis, with a median survival time of less than 2 years and a 5-year survival rate of approximately 30%.71,72 Neoadjuvant systemic therapy has improved the outcome significantly for this subset of patients by enabling local control surgery and improving long-term rates of relapse and death.73,74 2. Estrogen and progesterone receptors Although stage of disease is critical in determining the risk of recurrence, the timing of events is heavily influenced by tumor biology, particularly hormone receptor status. Patients with tumors that do not express estrogen or progesterone receptors (or do so at only very low levels) are much more likely to experience recurrence during the first few years after diagnosis than those who have receptor-positive disease.75 This observation is true for both premenopausal and postmenopausal patients within each major node group (zero, one to three, and four or more). Over decades, the risk of relapse and death is approximately the same but the distribution of these events is more even with hormone receptor–positive disease and skewed to the earlier years when the receptors are absent.75 3. HER2/neu gene amplification and overexpression of its transmembrane receptor is associated with impaired survival in early-stage breast cancer. Amplification (as is seen in 20% to 30% of early breast cancer) results in worse prognosis with earlier appearance of metastatic disease.76 However, it is now clear that this gene and receptor are predictive factors for response to HER2-directed therapies and as a result of which, outcomes for patients with HER2-positive disease may be superior to that of other subtypes. 4. Gene profiling There are several tools and assays using divergent technologies to provide more

precise individualized estimates of the risk of relapse (“prognosis”) and the benefits of specific treatments (“prediction”). The MammaPrint test (Agendia, Inc., Huntington Beach, CA) provides prognosis for node-negative breast cancer regardless of receptor status.77 The OncotypeDx (Genomic Health, Inc., Redwood City, CA) provides prognosis for node-negative, hormone receptor–positive breast cancer treated with tamoxifen and predicts the benefits of conventional combination chemotherapy as an additional treatment for this cohort.62,63 It may be similarly useful in hormone receptor–positive, node-positive disease. These technologies are based on our ability to determine gene expression on fresh frozen or paraffinembedded tissues. With regard to the OncotypeDx, the following are some considerations: ■ Patients with a result (recurrence score [RS]) of less than 18 (about 50% of patients in most series) are considered low risk and will probably not benefit from the addition of cytotoxic therapy to their hormonal manipulation. ■ Patients with an RS of greater than 30 have a high risk of systemic disease and will obtain the maximum benefit from chemotherapy. ■ Patients with an intermediate score (18 to 30) currently represent a decisionmaking dilemma and a large trial is under way to better define the value of chemotherapy in this patient population.78,79 5. Other prognostic factors are still undergoing study as to whether they can provide information as independent prognostic factors, particularly for node-negative cancers. In all cases, the key is whether or not they are reliable, validated, reproducible, and additive or supplemental in a meaningful way to the existing tools. 6. Adjuvant! Online is a Web-based decision-making tool (see www.adjuvantonline.com) that allows clinicians and patients to input key individual variables, model the impact of specific treatments, and display the benefits both numerically and graphically.80 There are well-recognized limits to this approach including its lack of inclusion of HER2 status, but it can be very useful in providing easily interpretable information and it has served as an early generation attempt to illustrate the approach to making adjuvant therapy recommendations. II. SYSTEMIC THERAPY OF BREAST CANCER A. Cytotoxic therapy As with other cancers, the basis for the effectiveness of cytotoxic drugs in the treatment of carcinoma of the breast is not completely understood. In general, a combination of two or more drugs is more effective in the adjuvant setting than single agents, and nearly all treatment programs use a variety of drugs either in concurrent combination or sequentially.81 In addition to their cytotoxic effects, chemotherapeutic agents may induce menopause in premenopausal women and this may represent an additional anticancer effect.82–85 1. Response to therapy

In the adjuvant setting, it is impossible to determine whether individual patients have responded to treatment for micrometastatic disease unless they relapse as there are no parameters to measure. Relapse means that treatment did not eradicate all disease, did not prevent the development of new disease, or only slowed the growth of microscopic metastases. Determination of the appropriate adjuvant therapy option for individuals must therefore depend on extrapolations from large randomized studies. 2. Treatment of early disease (adjuvant therapy) As discussed previously, standard treatment of early disease depends on a variety of factors; there is not yet a single agreed-on optimal chemotherapy regimen for any subset of women with breast cancer. Therefore, as a first priority, patients should be encouraged to participate in clinical trials. If none is available or the patient declines, Table 10.1 can be used as a guide for assessing risk. a. Choice of therapy Cytotoxic therapy is recommended for most otherwise healthy patients with hormone receptor–negative tumors that are 0.5 to 1 cm in size or greater, regardless of node status.87 Patients with HER2 overexpression or gene amplification generally receive chemotherapy and trastuzumab. Regardless of whether they receive cytotoxic therapy, most patients with hormone receptor– positive invasive cancer of any size should be treated with hormone therapy (tamoxifen if premenopausal and an aromatase inhibitor—alone or after tamoxifen—if postmenopausal). The goal of adjuvant chemotherapy is to decrease the risk of death and systemic disease. Because of the risks of competing causes of death, cytotoxic therapy is less commonly recommended in the adjuvant treatment of older women (based on physiologic and not solely on absolute chronologic age); for this subgroup particularly recommendations should be individualized considering comorbid conditions.88 The value of cytotoxic therapy when added to antiestrogen therapy in low-risk node-negative, hormone receptor–positive patients is partially addressed by the OncotypeDx discussed previously, although a number of additional tests may become available for this purpose. b. Traditional chemotherapy options Currently, a wide range of chemotherapy options exists, which generally developed as sequential experimental arms in lineages of clinical research. Although cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) remains an option for some low-risk patients, four cycles of dose-dense doxorubicin (Adriamycin) and cyclophosphamide (AC) with sequential paclitaxel delivered every other week (“dose-dense”) or weekly is a standard and NCCN “preferred” regimen, particularly for higher risk disease.88 Anthracyclines have been shown to have a moderate but significant advantage over CMF (recurrence rate ratio 0.89 [SE 0.03], 2p = 0.001; breast cancer death rate ratio 0.84 [0.03],

2p < 0.00001).54 The 2011 EBCTCG update showed a 2.8% absolute survival benefit with a taxane-plus-anthracycline-based regimen versus anthracyclinebased control regimens at 8 years.61 We highly recommend reviewing both the 2005 and 2011 EBCTCG update in Lancet for a better understanding of the evolution of breast cancer therapy.54,61 TABLE

10.1

Prognostic Factors for Assessing Risk of Recurrence of Breast Cancer

Value

Parameter

Nodal status

Risk increases with presence of metastasis and numbers of nodes involved

Tumor size

Risk increases with tumor size independent of nodal status

Estrogen and progesterone receptors

Positive receptors confer better prognosis

Age

Complex factor (biology chronology): Women aged 45–49 years have best prognosis, with increasing likelihood of deaths from breast cancer in older and younger age groups

Morphology

Higher nuclear grade, higher histologic grade, tumor necrosis, peritumoral lymphatic vessel invasion, increased microvessel density tumors have worse prognosis 86

DNA content and proliferative capacity

Tumors that are diploid and have low synthesis–phase fraction do better than those that are aneuploid or have a high synthesis–phase fraction (by flow cytometry)

HER2/neu (c-erbB-2)

Amplification is associated with earlier relapse and shorter survival. HER2/neu (c-erbB-2) testing by either FISH expressed as molecules/gene copy ratio (2.0 or more copies) or by IHC staining expressed as 0–3+, where 3+ correlates best with FISH positivity.

OncotypeDx Recurrence Score

Provides risk of recurrence (“prognosis”) and benefit of combination chemotherapy with CMF (and possibly cyclophosphamide, doxorubicin, and fluorouracil) (“prediction”) for hormone receptor–positive tumors

MammaPrint

Provides prognosis regardless of hormone receptor status

CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; FISH, fluorescent in situ hybridization; IHC, immunohistochemistry.

c. Addition of taxanes Multiple phase III trials have evaluated the addition of taxanes (paclitaxel or docetaxel) to chemotherapy regimens for early-stage breast cancer. Both the pivotal Cancer and Leukemia Group B protocol 9344 and the NSABP B28 trial supported the use of paclitaxel after AC for node-positive breast cancer regardless of receptor status, tamoxifen use, patient age, or the number of positive lymph nodes.89,90 Retrospective analysis suggests that the benefit is limited in patients with hormone receptor–positive, HER2-negative disease, but other studies have not been consistent in this regard. A slightly differently designed trial (Breast Cancer International Research Group 001) addressed the same question. In this trial, six cycles of concurrent docetaxel, doxorubicin, and cyclophosphamide (TAC) were compared to six cycles of fluorouracil,

doxorubicin, and cyclophosphamide (FAC) as adjuvant therapy for nodepositive patients. The study showed superiority of TAC in all patient groups.91 Similar findings were noted when epirubicin was used instead of doxorubicin. Three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by three cycles of docetaxel were found to be superior to six cycles of FEC in node-positive patients by the French Adjuvant Study Group.92 An overview [meta-analysis] of the available taxane studies showed a 3% absolute improvement in OS.93 a. Use of trastuzumab and pertuzumab in the adjuvant setting HER-neu–positive breast cancer accounts for 20% to 30% of all cases of breast cancer. In the absence of treatment, these patients have a higher risk of recurrence and earlier death, this is even true of small (T1a and T1b) HER2+ node-negative tumors.94 Trastuzumab prolongs survival in the metastatic setting and prevents recurrence and death in the adjuvant setting as well.95,96 The use of trastuzumab along with chemotherapy (a taxane was included in most of these trials) in high-risk node-negative as well as node-positive patients was associated with a 39% to 52% reduction in the risk of recurrence and significant improvements in survival.97–99 Adjuvant trastuzumab is recommended for a year and should be given concurrently with the taxane portion of adjuvant chemotherapy.100,101 Although an anthracycline-containing regimen— Doxorubicin/Cyclophosphamide/Paclitaxel/Trastuzumab (ACTH) remains the preferred choice for higher risk patients, trastuzumab may also be given with Taxotere/Carboplatin (TCH) with comparable efficacy and less cardiac toxicity and risk of secondary leukemia.96 A phase II study showed that node-negative HER2+ patients treated with adjuvant trastuzumab and paclitaxel alone can obtain excellent DFS (3-year DFS 98.7%) with minimal toxicity, offering a reasonable adjuvant strategy for low-risk stage I HER2+ tumors.102 Trastuzumab does not cross the blood-brain barrier, and the rates of recurrence in the brain, as opposed to all other sites, may not be reduced in the adjuvant setting. There are many active anti-HER2 agents either approved or in development for metastatic disease including trastuzumab-DM1, pertuzumab, neratinib, and several heat shock protein-90 inhibitors. Newer agents target signaling components downstream of HER2. Recently, pertuzumab, already shown to significantly prolong progressionfree survival (PFS) and overall survival in the metastatic setting, was also shown to increase pathologic complete response rates when administered with trastuzumab and a taxane preoperatively.103–106 The drug was granted accelerated approval for neoadjuvant use on this basis and an adjuvant trial was completed.107 Given its potential availability for patients with early-stage disease, the NCCN has endorsed conventional adjuvant use of pertuzumab even

while the results of the randomized adjuvant trial are pending.108 Lapatinib, a small molecule tyrosine kinase inhibitor was similarly active in the preoperative setting but did not add benefit to the standard adjuvant treatment of HER2positive breast cancer when tested in combination with trastuzumab in the phase III ALTTO trial.109 e. High-dose chemotherapy Dose escalation beyond “standard” dose levels, including those that require support with autologous bone marrow or peripheral blood progenitor cell reinfusion, has not been shown to offer advantage over conventional therapy and should not be offered.89,110 f. Dose and duration of chemotherapy More recently, six cycles of FEC were shown to be equivalent to four cycles of AC in terms of DFS and OS, but was associated with greater toxicity.111 Dosedense therapy, consisting of standard doses administered more frequently, was developed in recognition of the lack of benefit for higher dose regimens. It relies on the increased cytotoxicity of more frequent standard doses but generally requires growth factor support and has been shown to be superior in several randomized trials.112,113 For AC and paclitaxel, this is now a standard approach. At the same time, six cycles of standard regimens (AC or paclitaxel) have been shown to be no better than four, but more toxic.114 In the absence of targeted antiHER2 therapies, single-agent therapies have not been as effective as combinations.115 g. Some commonly used regimens (refer to previous discussion about choice of regimen based on nodal status) are as follows 1) AC plus taxane (dose-dense) ■ Doxorubicin 60 mg/m2 IV push through a rapidly running intravenous (IV) line. ■ Cyclophosphamide 600 mg/m2 IV. Repeat every 2 weeks with growth factor support. After four cycles, switch to paclitaxel 175 mg/m2 IV 3hour infusion every 2 weeks for four cycles. 2) Docetaxel and cyclophosphamide ■ Docetaxel 75 mg/m2 IV push through a rapidly running intravenous line. ■ Cyclophosphamide 600 mg/m2 IV. Repeat every 3 weeks. 3) FEC ■ Fluorouracil 500 mg/m2 IV on day 1. ■ Epirubicin 100 mg/m2 IV on day 1. ■ Cyclophosphamide 500 mg/m2 IV on day 1. Repeat cycle every 21 days. 4) TAC ■ Docetaxel 75 mg/m2 on day 1. ■ Doxorubicin 50 mg/m2 on day 1.

■ Cyclophosphamide 500 mg/m2 on day 1. Repeat cycle every 21 days. As mentioned previously, for patients with HER2-positive disease, trastuzumab may be added to a taxane after completion of four cycles of AC. Pertuzumab may be added for patients with presentations that would have qualified them for preoperative use. Options include the following: 1) Paclitaxel 80 mg/m2 weekly for 12 weeks given concurrently with trastuzumab 4 mg/m2 as an initial loading dose, followed by 2 mg/m2 weekly, which is continued for 52 weeks or 2) During the paclitaxel component of the dose-dense therapy using the same schedule of trastuzumab as previously mentioned or 3) Conventionally administered docetaxel (100 mg/m2 every 3 weeks for four cycles) with trastuzumab. Alternatively, adjunctive therapy for HER2-positive patients may begin with docetaxel 100 mg/m2 with carboplatin (area under the curve = 6) once every 3 weeks for six cycles with trastuzumab. In all cases, trastuzumab is generally administered with and after chemotherapy for one full year. h. Tips ■ Limit the number of cycles of doxorubicin in any combination regimen to six (300 to 360 mg/m2 or less) to limit enhanced cardiotoxicity from the combination. ■ Avoid concurrent administration of trastuzumab in combination with anthracyclines. ■ Monitor for peripheral neuropathy with taxanes, especially in diabetics and older patients. 3. Treatment of locally advanced disease (neoadjuvant therapy) For stage III or locally advanced disease, neoadjuvant (preoperative) chemotherapy is generally preferred. This strategy permits breast conservation in the group of operable stage III tumors and tests the disease biology of inoperable stage III disease, allowing better prognostication. This approach was not shown to improve survival116; however, the attainment of a pathologic complete response (pCR) to neoadjuvant chemotherapy is associated with a more favorable prognosis in the triple negative subgroup.117,118 The choice of therapy is as recommended for highrisk disease in the adjuvant setting and should consist of anthracycline- and taxanebased regimens.119 For HER2-positive patients, the addition of trastuzumab in this setting has been shown to improve pCR rates and reduce the risk of recurrence and death.120 In the phase III NeoALTTO study, the addition of lapatinib to trastuzumab and paclitaxel improved pCR rates.121 The combination of pertuzumab, trastuzumab, and docetaxel in the phase II Neosphere trial led to improved pCR rates.105 As mentioned

previously, these results combined with the survival advantage seen with pertuzumab in the metastatic setting led to its accelerated approval for use in the neoadjuvant setting.104,107 For the triple negative subgroup the addition of carboplatin to a taxane, and anthracycline regimen has been shown to significantly increase pCR rate but benefits for survival remain unknown.122,123 Postoperatively, the HER2-positive patients should complete a year of trastuzumab and the estrogen receptor–positive patients should begin standard adjuvant hormonal therapy. Radiation should be administered to the chest and supraclavicular region and internal mammary region if involved.88 4. Cytotoxic therapy of advanced (metastatic) disease Among the cytotoxic drugs, the most commonly used agents include doxorubicin, cyclophosphamide, methotrexate, fluorouracil, paclitaxel, docetaxel, albumin-bound paclitaxel, gemcitabine, capecitabine, vinorelbine, ixabepilone, and eribulin. Each of these agents has a response rate of 12% to 40% when used as a single agent (depending on the prior therapies and patient population). With very few exceptions, the data have not supported a survival advantage in the metastatic setting with combination chemotherapy, and toxicity is generally greater, so most patients are best palliated with sequential single agents.124 Cytotoxic chemotherapy is used as first-line treatment for advanced disease in patients with hormone receptor–negative disease. Its use in lieu of hormone therapy in patients with hormone receptor–positive disease when multiple organ systems are involved is controversial, as some clinicians believe it offers more rapid responses whereas endocrine therapy may offer longer disease stabilization. Cytotoxic chemotherapy produces clinical benefit (response and disease stabilization) in 60% to 80% of patients regardless of their estrogen receptor status. The responses to therapy at times are durable, but the median duration of treatment in most studies is less than 1 year. Clearly, improved survival is desirable, but the impact of many regimens on survival is modest. However, for patients with HER2-positive metastatic breast cancer, trastuzumab has improved survival, demonstrating that translational science can lead to therapeutic advances once the appropriate biologic target is identified. In support of this, the benefits of trastuzumab are limited to patients who are HER2 3+ positive by immunohistochemistry or those who are FISH positive. Continuing trastuzumab beyond progression has also been shown to be beneficial.125 Significant advances have been made for the HER2-positive patient population. Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has been shown in the phase III CLEOPATRA study to improve response rates, PFS, and overall survival when added to trastuzumab and docetaxel.103,104 Pertuzumab has been approved in the first-line setting and can also be combined with other active cytotoxics (paclitaxel, vinorelbine).126,127

Trastuzumab emtansine (T-DM1), an antibody-drug conjugate has shown improvement in RR, PFS, and OS with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane.128,129 Second-line chemotherapy is dependent on the specific prior treatments received by an individual patient. If the patient relapses while on treatment or within 6 months after finishing treatment for micrometastatic disease (adjuvant therapy), it is not likely that these drugs used in combination can be helpful in achieving a second remission. In addition, in selecting appropriate therapeutic approaches, the side effect profiles of the multiple treatment options should be considered in conjunction with patient-related considerations such as symptoms and residual toxicities from prior treatments. Effective individual drugs and regimens in addition to those used in the adjuvant setting include the following (Note: This is by no means an all-inclusive list. Regimens listed are commonly used in clinical practice): ■ Paclitaxel 150 to 175 mg/m2 IV over 3 hours every 3 weeks, or 80 mg/m2 over 1 hour weekly (the latter is generally preferred). ■ Docetaxel 60 to 100 mg/m2 IV over 1 hour every 3 weeks (premedication with oral corticosteroids such as dexamethasone 8 mg twice a day for 5 days starting 1 day prior to starting docetaxel is necessary to reduce the severity of fluid retention and hypersensitivity reactions). ■ Vinorelbine 20 to 30 mg/m2 IV over 6 to 10 minutes weekly. ■ Capecitabine 1,250 mg/m2 orally twice daily on days 1 to 14 followed by a 1week rest. Repeat cycle every 3 weeks. ■ Gemcitabine/paclitaxel ■ Gemcitabine 1,250 mg/m2 IV days 1 and 8 followed by a 1-week rest, plus ■ Paclitaxel 175 mg/m2 IV on day 1. Repeat every 3 weeks. ■ Nab-paclitaxel 260 mg/m2 IV over 30 minutes given every 3 weeks or 100 to 130 mg/m2 over 30 minutes weekly. ■ Weekly trastuzumab and paclitaxel (for HER2-positive disease) ■ Trastuzumab 4 mg/m2 IV as an initial loading dose, followed by 2 mg/m2 weekly with ■ Paclitaxel 200 mg/m2 IV every 3 weeks, or Nab-paclitaxel as discussed previously. ■ Lapatinib may be given at a dose of 1,250 mg orally once a day on days 1 to 21 continuously in combination with capecitabine 2,000 mg/m2/day on days 1 to 14 in patients with advanced, refractory HER2-positive breast cancer who have failed prior therapies including anthracyclines, taxanes, or trastuzumab. Lapatinib can also be given in combination with letrozole (2.5 mg daily) in postmenopausal, HER2-positive, hormone receptor–positive breast cancer at a

dose of 1,500 mg. 5. Dose modifications are regimen-specific. Readers must review the original source references for any regimen they administer. B. Endocrine (hormonal) therapy This therapy is effective because breast cancers retain hormone dependence. In premenopausal women, if breast cancer growth is supported by estrogen production from the ovary, antiestrogen therapy, and removal of endogenous estrogen by oophorectomy, or suppression of estrogen production using a luteinizing hormone– releasing hormone (LHRH) agonist, can result in regression of the cancer. Complicating the anticipated actions of SERMS are the presence of different classes of estrogen receptors, different ligands, many receptor-interacting proteins, a host of transcriptionactivating factors, and several response elements. In some tissues, this class of “antiestrogen” has estrogenic effects (i.e., bone). 1. Treatment of early disease (adjuvant therapy) Among the antihormonal drugs, the most commonly used agents are tamoxifen (a SERM), anastrozole, and letrozole and exemestane (AIs). Toremifene is an alternative to tamoxifen, but raloxifene is used for the treatment of osteopenia and as a chemopreventive and not as adjuvant therapy. The AIs (anastrozole, letrozole, and exemestane) block estrogen production at the cellular level by inhibiting reversibly or irreversibly to the aromatase enzyme (responsible for conversion of male hormones and other precursors to estrogen). Tamoxifen has been the traditional standard of care recommendation for premenopausal women with early-stage estrogen receptor–positive breast cancer. In postmenopausal women, AIs offer additional benefit to what was observed with 5 years of tamoxifen, with a comparative 5% absolute reduction in disease recurrence.130 Both the ATAC trial and the BIG 1–98 trials demonstrated an advantage to upfront use of an AI (anastrozole and letrozole, respectively) over tamoxifen therapy.131,132 Results of the IES study demonstrated a superior DFS with sequential therapy using exemestane following 2 to 3 years of tamoxifen to 5 years of tamoxifen alone.133,134 Fewer side effects are seen in this population with the use of AIs in comparison to tamoxifen. Letrozole after about 5 years of tamoxifen was also effective with modest improvements in DFS, DDFS, and OS.135 Importantly, the AIs offer lower incidence of venous thromboembolic events and endometrial carcinoma compared to tamoxifen but are associated with a higher incidence of osteoporosis and musculoskeletal complaints. Tamoxifen, 20 mg daily, is recommended in premenopausal women with hormone receptor–positive disease. Ten years of therapy has been shown to be superior to 5 years in reducing breast cancer recurrence and improving OS in both the ATLAS and aTTOM studies.136,137 In receptor-positive patients, its benefits are additive to those of chemotherapy (when used) and it has a relatively low risk in the adjuvant setting, and our current recommendations generally include tamoxifen

where it is indicated in addition to chemotherapy in Figure 10.1.

FIGURE 10.1 Systemic adjuvant therapy for breast cancer—suggested guidelines. a, Risk is determined by a balance of the prognostic factors listed in Table 10.1 (pt age, tumor size, grade, nodal status etc.), particularly inclusive of gene profiling (e.g., OncotypeDx) in ER/PR+ disease to more finely discern tumor biology and quantify inherent risk for recurrence; b, Adj Tx recommendation should be individualized, balancing comorbid conditions and individual pt tolerance for risk and toxicity associated with Adj Tx; c, CT to be considered for tumors >0.6 cm and recommended for >1 cm; d, Limited data to support use of Adj CT in those aged >70; e, TAM for premenopausal pts; AI for postmenopausal pts; AI+ OFS can be used for premenopausal pts deemed at high risk. CT, chemotherapy; ER, estrogen receptor; PR, progesterone receptor; TAM, tamoxifen; AI, Aromatase inhibitor; OFS, ovarian function suppression with an LHRH agonist or oophorectomy; LN, Lymph node ; TH, Taxol Herceptin; TCH, Taxotere Carboplatin Herceptin; ACTH, Adriamycin cyclophosphamide taxol Herceptin; P, Pertuzumab; CMF, Cyclophosphamide Methotrexate 5FU; TC, Taxotere Cyclophosphamide; Adj, Adjuvant; Tx, Treatment; Pts, patients. Tamoxifen and AIs (for postmenopausal patients) improve DFS and overall survival in most patients with estrogen receptor–positive tumors. Although the proportional reduction (about 25%) in death rate is similar for both high- and lowrisk patients (e.g., node-positive and node-negative), the absolute benefit is greater for those at higher risk of recurrence and death. The improvement in DFS is superior with all AIs, and there is an associated more significant reduction in contralateral breast cancer with these drugs in comparison to tamoxifen.131,132,138–140 Tamoxifen is metabolized by CYP2D6, and this activity can be inhibited by certain selective serotonin reuptake inhibitor antidepressants and by inherited variations in single nucleotide polymorphisms (SNPs).141 However, there is no prospective evidence that SNP testing can yet guide individual patients to better selection of hormone therapy and improved outcomes. 2. Ovarian suppression Suppression of ovarian (OS) estrogen production can be achieved by the administration of luteinizing hormone–releasing hormone (LHRH) agonists such as leuprolide, goserelin, and deslorelin or through ovarian ablation (OA) by surgical oophorectomy or radiation therapy. OS alone in premenopausal women reduces

breast cancer recurrence and improves survival.54,142,143 The benefit of adding OS to adjuvant chemotherapy and tamoxifen in this population has been less clear and may be more important in those aged under 40 years given they are more likely to regain ovarian function after chemotherapy.144–146 Given the demonstrated benefit of AIs over tamoxifen in the postmenopausal population,131,132 recent studies have asked the question whether premenopausal women rendered postmenopausal through OS could garner a similar superior benefit from AIs compared with tamoxifen. The joint analysis of the SOFT and TEXT trials showed that 5 years of exemestane plus OS significantly reduced recurrence compared with tamoxifen plus OS in premenopausal women.147 Consistent with previous studies, the addition of OS to tamoxifen did not provide a significant benefit in the overall study population. However, in those younger women who remained premenopausal after chemotherapy, the addition of OS improved disease outcomes, further improved with the use of exemestane instead of tamoxifen plus OS.148 The toxicities associated with this choice of therapy need to be balanced against breast cancer risk for the individual patient. 3. Treatment of advanced (metastatic) disease Hormonal therapy is indicated in women who have had a positive test for estrogen or progesterone receptors in their tumor tissue. This approach is not generally recommended for women who have previously been shown to be unresponsive to hormonal manipulation. It is also not appropriate therapy for women with visceral crises. For premenopausal women, oophorectomy still may be the treatment of choice. As previously mentioned, the LHRH analogs goserelin and leuprolide can achieve the equivalent of a medical oophorectomy. This treatment may then be combined with an AI or tamoxifen in such patients.149 For postmenopausal women, an AI should be used as the initial hormonal therapy. Responses to endocrine therapy tend to last longer than responses to cytotoxic chemotherapy, frequently lasting 12 to 24 months. Second-line hormonal manipulation (e.g., using fulvestrant, a selective estrogen receptor downregulator) is a reasonable option if the tempo of disease progression allows such. Sequential hormone manipulation may be most appropriate for patients with indolent hormone receptor–positive breast cancer, such as those with bone-dominant disease. In endocrine therapy in naïve patients there has been demonstrated benefit in PFS and OS for the combination of fulvestrant with an AI.150–152 Doses of commonly used drugs are as follows: ■ Tamoxifen 20 mg by mouth daily ■ Anastrozole 1 mg by mouth daily ■ Letrozole 2.5 mg by mouth daily ■ Exemestane 25 mg by mouth daily ■ Fulvestrant 500 mg intramuscularly (into buttock) monthly after loading with 500

mg on days 1 and 15 ■ Megestrol acetate 40 mg by mouth four times a day. Improved understanding of therapeutic resistance mechanisms has led to ongoing trials of several therapies that target the phosphoinositide-3-kinase (PI3K)Akt-mTOR pathway, an important signaling pathway implicated in endocrine therapy resistance.153,154 Everolimus, a rapamycin analog that inhibits mTOR is approved for use in combination with exemestane following progression on first- or secondline hormonal therapy. Despite a substantial improvement in PFS seen with the combination this did not translate into a statistically significant OS benefit.155,156 C. Complications of therapy A large range of possible side effects have been associated with treatments for breast cancer and vary extensively between agents and individuals. Acute toxicities are primarily hematologic and gastrointestinal. Subacute toxicities include alopecia, hemorrhagic cystitis, hypertension, edema, and neurologic abnormalities. Chronic or long-term toxicities may be cardiac, neoplastic, or neurologic. Premenopausal women need to be aware of menstrual irregularities, early menopause, and infertility as a consequence of chemotherapy and should be referred for consideration of fertility preservation when desired. Dose modifications for specific regimens must be based on the original sources. Readers are urged to review the original reports for any regimen they prescribe. In addition, because of individual differences, toxicities that are worse than expected may occur, and the responsible physician must always be alert to special circumstances that dictate further attenuation of the drug doses. The drug data listed in Chapter 28 should be consulted for the individual toxicities, precautions, and toxicity prevention measures for each drug. Like all therapeutic interventions, adjuvant tamoxifen therapy also has consequences. These include a twofold to fourfold increase in endometrial cancer, an increase in cataracts, and an increase in thromboembolic disease. Hot flashes are common but can be ameliorated in some women with venlafaxine 25 to 50 mg daily. While there is also reduction in the hot flashes from using a progestin, such as megestrol, 20 mg twice a day, the effect of the progestin on the risk of recurrence is not known. Adverse effects on vaginal mucosa may be ameliorated with minimal systemic estrogen effect by the estradiol vaginal ring or by an estradiol tablet administered intravaginally (Vagifem). Although fractures related to osteoporosis decrease with tamoxifen, there does not appear to be any reduction in cardiovascular events. AIs, on the other hand, may worsen osteoporosis despite an absence of increased fracture incidence in many trials. Caution and possibly anticoagulation should be exercised in treating women with Factor V Leiden who begin treatment with tamoxifen in the prevention or adjuvant setting. Bisphosphonates are commonly administered IV to all patients with bone metastases because of their role in reduction of skeletal events.88,157 Randomized studies in the adjuvant setting have demonstrated reductions in the risk of disease recurrence but no

impact on survival.158,159 IV bisphosphonate options include zoledronic acid 4 mg over 15 minutes or pamidronate 60 to 90 mg over 1 to 2 hours. An alternative option administered via the subcutaneous route is denosumab, a fully human monoclonal antibody against RANK-ligand, a mediator of osteoclast survival.160

Acknowledgments The authors are indebted to Drs. Iman Mohamed and Patrick Morris, who contributed to previous editions of this chapter. Several sections in this revision of the handbook represent their work.

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I. CERVICAL CANCER In the United States, the American Cancer Society (ACS) estimates approximately 12,000 women are diagnosed with cervical cancer each year and 4,000 die of disease. Among the gynecologic cancers it is the third most common diagnosis, but among women 20 to 39 years it is the second leading cause of death. As many as 300,000 women die globally each year as a result of cervical cancer. Historically a common disease, cervical cancer has become relatively rare in the developed world, thanks to successful screening with the Papanicolaou (Pap) test, which has allowed for early detection and therefore drastically reduced mortality rates. In developing countries, however, where access to effective and regular screening is not always available, the incidence of disease is much higher. The vast majority of cervical cancers are caused by human papillomavirus (HPV) infection. The development of an effective HPV vaccine has made the disease all the more preventable, and the mortality associated with cervical cancer in developed countries should decrease further in the coming decades. Still, global rates will remain high until both the vaccine and screening test are readily and consistently available in both resourcepoor and developed countries. A. Histology Cervical cancer is classified as squamous cell carcinoma (keratinizing, nonkeratinizing, verrucous): 80% to 85%; endometrioid and adenocarcinoma: 15%; and adenosquamous: 3% to 5%. B. Screening For asymptomatic women, preinvasive lesions are found only after abnormal routine screening Pap smear of the ecto-/endocervix (transformation zone) junction. Cervical cancer mortality has decreased in the United States by more than 70% since the Pap test was introduced in 1941. The Pap test is simple, safe, inexpensive, and well validated. Conventional cytology screening is reported to be 60% (30% to 87%) sensitive for dysplasia. Newer techniques using an ethanol medium (Sure-Path, BD Diagnostics, Franklin Lakes, NJ; Thin-Prep, Hologic, Bedford, MA; MonoPrep, MonoGen, Lincolnshire, IL) are as effective as conventional methods, are easier to read, and allow for sexually transmitted infection and HPV testing. Approximately 3.5 million women have an abnormal Pap smear every year in the United States. The American Congress of Obstetricians and Gynecologists (ACOG) and

ACS recommend that if a patient is exposed to diethylstilbestrol or is immunosuppressed (e.g., due to human immunodeficiency virus [HIV] infection), screening should be indefinite. In addition, HIV-positive women should be provided cervical cytology screening twice (every 6 months) within the first year after initial HIV diagnosis and, if both tests are normal, annual screening can be resumed thereafter. The older terminology (mild, moderate, severe dysplasia) was replaced with cervical intraepithelial neoplasia I to III, based on the replacement of each third of the epithelium. This has since been replaced by the present system of “abnormal squamous cells of unknown significance” (ASCUS), which represents two-thirds of all abnormal Pap smears, and squamous intraepithelial lesions (SILs), which can be further classified as low-grade SIL or high-grade SIL. An ASCUS Pap should trigger HPV testing. If positive, the patient should be referred for colposcopy. Women older than 40 years with normal endometrial cells on Pap smear require endometrial biopsy (EMB), although the yield of endometrial neoplasia is low. There is a clear correlation between cytologic diagnosis and histologic diagnosis at colposcopy in approximately half of patients. In the United States, both the United States Preventive Services Task Force (USPSTF) and the ACS recommend against routine yearly testing. Instead, the guidelines recommend testing every 3 years for women ages 21 to 65; routine cervical cancer screening for women below 21 and above 65 is no longer recommended. The two groups also introduced the option of a lengthened, 5-year screening interval for women ages 30 to 65 when screened with a combination of Pap testing and HPV testing.1 Cervical cancer in the absence of demonstrable HPV infection is extremely rare. Beyond the Pap test, HPV testing appears to be more sensitive and superior to standard Pap screening.2 C. Clinical disease and staging 1. Clinical presentation The most common symptoms of invasive cervical cancer are abnormal vaginal bleeding, either postcoital or intramenstrual, and vaginal discharge. Larger tumors may also interfere with urination and defecation and may be accompanied by pelvic pain. Locoregional disease can manifest as unilateral lower extremity swelling, back pain, neuropathic pain, and/or postobstructive renal failure. It should be noted that many women with cervical cancer do not present with any symptoms, but rather with disease detected during pelvic examination or screening procedures. The most common clinical sign of cervical cancer is an abnormal lesion on the cervix, usually detected by a physician during a pelvic exam. The exophytic lesion often presents as necrotic and friable. Involvement of surrounding tissues should be assessed, including the parametria, sidewalls, and uterosacral ligaments, as well as the superficial groin and femoral lymph nodes and the supraclavicular region. Infiltration of surrounding tissues is the most common reason to consider

chemoradiation therapy over surgery. 2. Diagnosis Once an abnormal cervical lesion has been assessed by a physician, a tissue biopsy should be performed to either confirm or rule out malignancy. The physician should make sure the biopsy is deep enough so as to include non-necrotic tissue, thus ensuring a diagnostically relevant sample. 3. Prognostic factors Stage, histologic grade and type, tumor size, depth of stromal invasion, involvement of parametrium, and lymphovascular space invasion (LVSI) all influence prognosis. Pelvic lymph node metastasis significantly decreases the survival rate of patients. In a report of whole-exome sequencing analysis of 115 cervical carcinoma normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumor-normal pairs was performed. Novel somatic mutations in 79 primary squamous cell carcinomas included recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%), and ERBB2 (6%). The authors also observed somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. In this study, squamous cell carcinomas had higher frequencies of somatic mutations in the Tp*C dinucleotide context than adenocarcinomas. Gene expression levels at HPV integration sites were significantly higher in tumors with HPV integration compared with expression of the same genes in tumors without viral integration at the same site.3 4. Staging Cervical cancer is staged clinically and includes palpation, colposcopy, cystoscopy, endocervical curettage, proctoscopy, hysteroscopy, intravenous (IV) urography, and radiograph. Many centers also use magnetic resonance imaging (MRI) to define the local extent of disease and positron emission tomography (PET)/computed tomography (CT) to determine if there is any metastatic spread. Postoperatively, pathologic staging does not change clinical International Federation of Gynecology and Obstetrics (FIGO) staging.4 5. Treatment Over the last decades, the management of cervical preinvasive and invasive disease has changed significantly. Colposcopy is being used with increasing frequency to treat preinvasive disease, surgery is preferred to radiation therapy for early-stage invasive disease, and adoption of chemoradiation therapy over radiation as primary or adjuvant therapy. 6. Dysplasia and in situ carcinoma Options for treatment include cervical conization (loop diathermy or cold knife) or hysterectomy. Lymphadenectomy is not required if stage IA-1 disease is demonstrated, as risk of metastases is very small (1%). If margins are positive, completion of hysterectomy might be required. For patients with positive excisional

margins, reexcision is recommended before offering hysterectomy for definitive treatment in order to rule out a more deeply invasive tumor that would require radical hysterectomy over simple or extrafascial hysterectomy. In patients with negative conization margins, careful follow-up is adequate. 7. Early-stage disease Early-stage disease can be treated with either chemoradiation or surgery. Surgery generally results in definitive treatment, an improvement in survival over primary radiotherapy (RT), and may provide a better quality of life. Retrospective data from case-control and nonrandomized studies showed that stage IB/IIA cancer of the cervix can be treated equally well with radical surgery and radical radiation therapy. A randomized controlled trial (RCT) of 343 patients with stage IB/IIA carcinoma cervix showed that these two modalities were equally effective in controlling the disease judged by the disease-free and total survival as well as by the relapse rates. This trial also conclusively showed that surgery has a survival advantage over radiation therapy for patients with adenocarcinoma cervix. However, surgery was associated with more serious adverse events (28% vs. 12%), and 64% of the surgical patients required postoperative radiation, likely associated with increased morbidity.5 Surgery should be considered in premenopausal women where ovarian function can be preserved, in patients with an undiagnosed pelvic mass, in patients with more risk of bowel toxicity from RT (adhesions because of pelvic inflammatory disease, endometriosis, inflammatory bowel disease, or in very thin women), or when compliance with the RT schedule may be difficult (with socially disadvantaged patients, for example). An important goal is to identify patients who would likely need RT and then avoid surgery; most clinicians now use PET/CT scans to screen for metastatic disease and MRI to evaluate the extent of local disease. This allows patients with more advanced disease to be triaged and treated with chemoradiation. Morbidly obese patients are typically not considered for standard surgery because of high surgical risk, though robotically assisted surgery may prove safer. Age does not appear to be a significant contraindication to radical hysterectomy. Treatment should be appropriately tailored in unusual circumstances such as pregnancy or patients with HIV. Lymphadenectomy is a standard part of surgical management of any early-stage disease being treated with radical hysterectomy. Sentinel node biopsy is still investigational. Retrospective analysis of lymph node debulking of palpable nodes prior to RT suggests a survival advantage in the prechemoradiation era, but is now more controversial with modern imaging (MRI and PET/CT) and chemoradiation. Based on a prospective study, the Gynecologic Oncology Group (GOG) defined an intermediate-risk group using various combinations of three factors (LVSI, deep stromal invasion, and tumor size). This approach resulted in the following “GOG criteria”: (a) positive capillary-LSVI, deep and middle third

penetration, and clinical tumor size of 2 cm; (b) superficial third penetration and clinical tumor size of 5 cm; and (c) negative capillary-lymphatic space involvement with middle or deep third penetration and clinical tumor size of 4 cm. In an RCT, in women with intermediate risk factors, adjuvant pelvic radiation following radical hysterectomy reduced the number of recurrences among women with stage IB cervical cancer.6 The role of chemoradiation in this population is currently being investigated. In contrast, adjuvant chemoradiation is necessary for women who have highrisk features after radical hysterectomy (positive lymph nodes, margins, or parametrium). A Southwest Oncology Group RCT in 243 women revealed that chemoradiation with cisplatin and 5-fluorouracil (5-FU) was significantly superior to RT alone (overall survival [OS] at 4 years of 81% with chemoradiation vs. 71% with RT), though it had more toxicity.7 If fertility preservation is desired, radical trachelectomy (removal of only the cervix and parametria) with concomitant lymphadenectomy for small (less than 2 cm) tumors may be considered. This procedure appears to be associated with retention of fertility (with up to 50% of patients becoming pregnant after radical trachelectomy) along with acceptable risk of recurrence in carefully selected patients. Tumor size is the single most important criterion in considering fertilitypreserving surgery, but other criteria, including grade, canal involvement, and LVSI, may be important.8 Patients being evaluated for radical trachelectomy should have pretreatment imaging studies including pelvic MRI and PET/CT to exclude extracervical disease. 8. Locally advanced disease (stage IIB–IVA) In 1999, the National Cancer Institute (NCI) released a clinical alert highlighting the survival advantage documented in five NCI-sponsored clinical trials evaluating the use of concurrent chemoradiation. A systematic review of 18 randomized trials revealed absolute benefit in progression-free survival (PFS) and OS of 16% (95% confidence interval 13% to 19%) and 12% (8% to 16%), respectively, but with twice the gastrointestinal (GI) toxicity. Late toxicity is anticipated to be less with concurrent chemotherapy because of the total lower dose of RT. Weekly cisplatin 40 mg/m2 during RT has been adopted as the preferred strategy because of its more favorable toxicity profile when compared with cisplatin and 5-FU. There has not been a direct comparison of cisplatin versus cisplatin and 5-FU, though many extrapolate their equivalence from GOG-120, which compared RT with cisplatin versus the combination of cisplatin, 5-FU, and hydroxyurea versus hydroxyurea alone in 526 patients with stages IIB, III, IVA cancer. In both groups who received radiation and cisplatin, the 3-year survival rate was 65% compared with 47% for women receiving radiation and hydroxyurea.9 Combining cisplatin with another agent improves response at the expense of considerably worse toxicity. In an international RCT of women with stages IIB and

III cervical cancer, the investigators compared standard concurrent weekly cisplatin and pelvic radiation with intensification of pelvic treatment with the addition of potentially radiosensitizing concurrent weekly gemcitabine and two further courses of adjuvant gemcitabine/cisplatin, a doublet with some independent systemic activity. Patients in the combination arm had a 9% improvement in PFS at the fixed time point of 3 years of follow-up.10 In addition, the International Gynecologic Cancer Intergroup is currently comparing standard therapy with concurrent weekly cisplatin and radiation with that same therapy followed by three additional courses of systemic adjuvant carboplatin and paclitaxel (OUTBACK trial). 9. Adenocarcinoma Adenocarcinoma is associated with a worse prognosis, although we do not stratify treatment based on histology. Therefore, these patients are typically the same as that for squamous cell carcinomas. 10. Neoadjuvant and adjuvant chemotherapy Primary chemotherapy (neoadjuvant) with combination platinum-based chemotherapy (cisplatin, vincristine, bleomycin) can have a very high response rate (90% in stage IB2) with consolidative adjuvant radiation.11 In parts of the world where access to radiotherapy is limited, neoadjuvant chemotherapy before surgical treatment is administered for locally advanced cervical cancer. However, there are no data that this approach is equally or more effective than primary chemoradiation. 11. Chemotherapy for recurrent and advanced-stage disease Three contemporary RCTs (GOG-204, GOG-240, and Japanese Clinical Oncology Group 0505 [JCOG-0505]) have investigated the optimal chemotherapy regimen in advanced and recurrent cervical cancer. GOG-204 was conducted to reconcile the relatively high overall response rate of 36% observed using the cisplatin-paclitaxel doublet in an earlier trial and the 2.9-month OS benefit attributed to the US Food and Drug Administration (FDA)–approved cisplatin-topotecan doublet. In GOG-204, a final definitive comparison of four cisplatin-based chemotherapy doublets was undertaken: cisplatin plus paclitaxel (standard arm), cisplatin plus vinorelbine, cisplatin plus gemcitabine, and cisplatin plus topotecan. Despite hope for progress with newer agents, no regimen outperformed the standard cisplatin-paclitaxel arm, in which a trend for improved response and survival rates was observed.12 The Japanese GOG reported that the more convenient and better-tolerated regimen of paclitaxel 175 mg/m2 over 3 hours with carboplatin at area under the serum concentration-time curve 5 every 21 days was not inferior to cisplatin plus paclitaxel. Thus, both the cisplatin and carboplatin combinations are acceptable with cisplatin having more renal, nerve, and intestinal toxicities but carboplatin having more marrow-related adverse events, especially thrombocytopenia. Finally, GOG-240 study used a 2 × 2 factorial design; patients were assigned to either of two chemotherapy regimens involving cisplatin plus paclitaxel or topotecan and paclitaxel, and then randomly assigned to receive 15 mg/kg of

bevacizumab or not. Treatment cycles were repeated every 21 days until disease progression, unacceptable toxicity, or complete response. More than 70% of patients in both groups had received prior platinum-based therapy. Importantly, in this trial the incorporation of bevacizumab showed a significantly improvement in the median OS as compared with chemotherapy alone (17.0 vs. 13.3 months). These data have led to the FDA approval of bevacizumab plus chemotherapy for these patients (Table 11.1).13 12. Novel biologics There is a desperate need for more effective therapy for recurrent cervical cancer. Agents that target the vascular endothelial growth factor, epidermal growth factor, and HER2/neu receptors are currently in clinical trial and look promising. However, there are no targeted treatments (beyond bevacizumab) that have a role in the current treatment of cervical cancer. TABLE

11.1

Gynecologic Oncology Group (GOG) 240 Bevacizumab Arm Regimens

1. Bevacizumab 15 m/kg IV every 3 weeks and cisplatin 50 mg/m2 plus paclitaxel 135 or 175 mg/m2 on day 1 2. Bevacizumab 15 mg/kg IV every 3 weeks and topotecan 0.75 mg/m2 days 1 to 3 plus paclitaxel 175 mg/m2 on day 1

13. Palliative care Supportive care, which addresses physical, psychological, social, and spiritual issues, is an essential part of the holistic care of patients as they approach the end of their life. Common medical problems include pain, nausea and vomiting, lymphedema, obstruction (genitourinary and GI), and fistulas, and require multiprofessional care. II. ENDOMETRIAL CANCER In the United States, endometrial cancer is the most common gynecologic malignancy. The ACS estimates that approximately 49,500 women are diagnosed with endometrial cancer every year in the United States, and 8,000 deaths attributable to the disease. The cancer typically presents at an early stage with vaginal bleeding in postmenopausal women. Because it usually presents while still confined to the uterus, it is often cured with surgery alone. Tamoxifen use is a significant risk factor for developing endometrial cancer. Given the continued and expanding use of tamoxifen in the prevention and treatment of breast cancer, a growing number of women have an increased risk of developing endometrial cancer. A. Histology Endometrial cancer includes epithelial endometrial carcinomas (95%) and mesenchymal tumors (5%). Two broad histologic categories of epithelial endometrial cancer have been described, termed types I and II carcinomas. They appear to have

different patterns of molecular alterations that underlie their pathogenesis and clinical outcomes. Type I endometrial cancers are associated with unopposed estrogen exposure and are often preceded by premalignant disease. They are usually early stage at diagnosis, low-grade tumors (predominantly of endometrioid histology), and carry a favorable prognosis. Obesity and family history remain two of the strongest risk factors for this type of endometrial cancer.14 In contrast, type II endometrial cancers represent estrogen-independent tumors and are associated with a more aggressive clinical course. Unlike type I tumors, there is no readily observed premalignant phase. Both clear cell and serous carcinoma and perhaps grade 3 endometrioid tumors comprise these histologic phenotypes. Some experts also classify uterine carcinosarcomas as a representative of type II histology. Mesenchymal tumors are composed of uterine sarcomas (leiomyosarcomas [LMS] and endometrial stromal sarcoma) and mixed epithelial/stromal tumors (carcinosarcomas and adenosarcomas). B. Screening Screening is not necessary for endometrial cancer as the disease typically presents early with postmenopausal vaginal bleeding and has a good prognosis. Although screening patients by ultrasound for thickened endometrial stripe has been evaluated, specifically for patients who are on tamoxifen, there is no clear survival advantage over clinical surveillance. By contrast, patients at higher-than-average risk of endometrial cancer because of a family history of colorectal cancer (Lynch II syndrome or hereditary nonpolyposis colorectal cancer syndrome) should undergo screening ultrasound and inoffice EMB starting at age 30 to 35 years or prophylactic hysterectomy and bilateral salpingo-oophorectomy (BSO) if fertility is no longer desirable.15 Lynch-associated endometrial cancer survivors should also undergo colorectal cancer screening. Family members who have not yet been diagnosed with any cancers should undergo screening for both endometrial cancer and colorectal cancer. Colorectal surveillance is the only surveillance protocol in Lynch syndrome proved to be effective. Regular colonoscopy every 3 years leads to a reduction of colon cancer-related mortality and also to a significant reduction of overall mortality in contrast with colon cancer screening in the general population. Women with Cowden syndrome, an autosomaldominant syndrome, are also associated with a 13% to 28% increased lifetime risk of developing endometrial cancer. Although there are no specific guidelines for endometrial screening in these patients, most advocate the same strategy used for women with Lynch II syndrome. C. Clinical disease 1. Clinical presentation The most common symptoms of endometrial cancer are abnormal vaginal bleeding and discharge. Because such bleeding can be caused by disorders other than cancer, special attention should be paid to women with abnormal bleeding who are either postmenopausal or women who are at high risk for endometrial cancer and are

above the age of 35 years. Metastatic intraperitoneal (IP) disease may also cause symptoms similar to those seen in advanced-stage ovarian cancer, including abdominal distention, pelvic pressure, and pelvic pain. In women with postmenopausal bleeding, a thickened endometrium on pelvic ultrasound is a sign of possible endometrial cancer and should be followed up with endometrial sampling. D. Diagnosis Definitive endometrial cancer diagnosis requires tissue sampling, which can be procured either via EMB or fractional dilation and curettage (D&C). EMB is the preferred method of evaluating abnormal uterine bleeding. It should be noted that EMB has proven more effective in postmenopausal, rather than premenopausal, women and is better at confirming the presence of cancer rather than its absence. In cases where outpatient EMB is not possible, or if abnormal bleeding persists despite negative biopsy, fractional D&C should be performed. E. Prognostic factors The 5-year survival rate for endometrial cancer is 83%, and tumor-related prognostic factors at diagnosis include histologic subtype, stage, grade, depth of myometrial invasion, and LVSI. The prognosis of type I carcinomas is more favorable than that of type II. The presence of certain molecular abnormalities also contributes to poor prognosis. One such abnormality is the overexpression of the epidermal growth factor receptor (EGFR). In endometrioid adenocarcinomas, overexpression of EGFR decreases the overall 5-year survival rate from 89% to 69%; in serous and clear cell, the presence of EGFR overexpression decreases the survival rate from 86% to 27%. Recently the results from The Cancer Genome Atlas’ (TCGA) analysis of 373 endometrial tumor samples utilizing array- and sequencing-based technologies have classified the disease into groups with differing prognoses. According to the study, some endometrial tumors with similar histologic features actually differ in their molecular profile and might benefit from different treatments. Uterine serous tumors and approximately 25% of high-grade endometrioid tumors had extensive copy number alterations, few DNA methylation changes, low estrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumors had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS and novel mutations in the SWI/SNF chromatin remodeling complex gene ARID5B. A subset of endometrioid tumors that were identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. With these results the authors classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy number low, and copy number high. The POLE group, with 17 tumors, or less than 10% of the cohort, was associated with the best prognosis in the study, while those in the high–copy number alterations had the worst outcomes.16 F. Staging

Endometrial cancer is surgically staged.4 Although historically this procedure has been carried out by laparotomy, laparoscopic management has increasingly been integrated into the forefront of surgical staging. The GOG performed a large prospective trial from 1996 to 2005 that included more than 2,600 women with clinically early-stage endometrial cancer. Women were randomized in a 2:1 ratio to laparoscopic versus open hysterectomy, BSO, and pelvic and aortic lymph node sampling. The first report from the study (Laparoscopic Surgery or Standard Surgery in Treating Patients with Endometrial Cancer or Cancer of the Uterus [LAP2]) confirmed the presumed short-term advantages of laparoscopy, including shorter hospital stays, fewer perioperative complications, reduced blood loss, and improved body image. Recurrence rates at 3 years after surgery were 11.39% in the laparoscopy group and 10.24% in the open surgery group (hazard ratio [HR] for laparoscopy 1.14; 95% CI, 0.92 to 1.46). Although the difference in 3-year survival was small, the trial was deemed inconclusive because laparoscopy could not be demonstrated with 95% confidence to have a HR below the predetermined threshold of 1.4 for noninferiority.17 As per FIGO recommendation, surgery for endometrial cancer includes, at the minimum, examination of the omentum, liver, adnexal surfaces, peritoneal cul-de-sac, and enlarged aortic and pelvic nodes, and total extrafascial hysterectomy with BSO. To complete the surgical staging of endometrial cancer, the removal of bilateral pelvic and paraaortic lymph nodes is also required. Many gynecologic oncologists have moved toward performing comprehensive surgical staging for nearly all patients with endometrial cancer. The rationale for uniform staging includes the lack of a patient population for whom nodal disease is so low that nodes should be omitted, the inaccuracy of preoperative or intraoperative assessments predicting the risk for nodal disease, the potential for therapeutic benefit in node-positive and -negative patients, and the lack of significant morbidity associated with the procedure. Postoperative adjuvant decisions are best made with the most complete information. If nodal assessment is the predominant factor by which to categorize patients into risk groups, routine nodal dissection is the best method by which to determine which few patients will require adjuvant therapy. It should be noted, however, that the role of complete lymphadenectomy is controversial after the publication of two negative randomized studies. A Study in the Treatment of Endometrial Cancer (ASTEC) randomized patients with endometrial cancer treated with hysterectomy to pelvic lymphadenectomy or not. Following surgery, patients with stages I and IIA diseases were then randomized again to observation or pelvic radiation therapy if they had grade 3, serous, or clear cell histology, more than 50% myometrial invasion, or endocervical glandular invasion (stage IIA). Treatment centers were also permitted to use vaginal cuff brachytherapy regardless of pelvic radiation assignment. The results show no evidence of benefit in terms of overall or recurrence-free survival for pelvic lymphadenectomy in women

with early endometrial cancer.18 A similar study was performed by Italian investigators (CONSORT trial). In this trial, 514 patients were assigned to hysterectomy with or without pelvic lymphadenectomy. Patients were required to have myometrial invasion, and patients with grade 1 tumors and less than 50% invasion were excluded. In the no-lymph nodissection (LND) group, 22% of patients had nodal dissections due to clinical suspicion with 14% of these cases, or 3% of the entire no-LND arm, having nodepositive disease. In the LND group, the median number of nodes removed was 26. Paraaortic dissection could be performed at the surgeon’s discretion and was done in 26% of cases. In the LND group, 13% were found to have positive nodes. Postoperative therapy was not protocol prescribed, but the use of radiation therapy was more common in the no-LND group (25% vs. 17%). The 5-year disease-free survival was 81% in both groups, and 5-year survival was 90% in the no-LND group versus 86% in the LND group (HR 1.2, p = 0.5). The authors concluded that pelvic lymphadenectomy could not be recommended as a routine procedure for therapeutic purposes.19 Although the new FIGO staging continues to require the collection of peritoneal cytology, positive pelvic washings are no longer formally considered part of the staging system, and consequently, do not alter staging. Positive cytology alone is generally not deemed to be a high-risk tumor criterion in the formulation of adjuvant treatment planning of patients with endometrial cancer. Treatment decisions in women with endometrial cancer should be based on extent of disease, as determined by staging, and final pathologic tumor features.4 G. Treatment 1. Surgery Surgical resection alone can be curative in many patients with endometrial cancer. ACOG recommends at least a total hysterectomy and BSO. The role of concomitant assessment of lymph nodes in all patients with endometrial cancer remains controversial. For patients with high-grade histologic subtypes of endometrial cancer, lymph node dissection at the time of hysterectomy and BSO is appropriate. For patients with low-grade tumors (grade 1 to 2) of endometrioid histology, lymphadenectomy should be based on other tumor risk factors, such as size of primary lesion, depth of myometrial invasion, and cervical stromal involvement. Laparoscopic surgery is associated with significantly shorter hospital stays and better quality of life. The use of robotically assisted laparoscopic hysterectomy has increased dramatically, especially in the obese patient population, and has resulted in significantly lower perioperative complications compared with abdominal surgery. However, whether robotic surgery is cost-effective has yet to be seen. Prophylactic total hysterectomy and BSO have been reported to prevent 100% of uterine cancers of women undergoing risk-reducing surgery for Lynch II syndrome or hereditary nonpolyposis colon cancer.

2. Radiotherapy Radiation is given adjuvantly to reduce the risk of local recurrence (brachytherapy to the vaginal vault postoperatively) to reduce the risk of a local recurrence, although a benefit in OS has not been shown. External-beam RT is indicated for completely resected, node-positive disease (stage IIIC) and is also considered for higher-risk patients (poor grade, or adverse histology, deep invasion, advanced age) with earlystage disease. In addition, brachytherapy is a reasonable and less toxic treatment. More extensive RT (extended field) may be indicated in carefully selected patients with small-volume residual disease, but the benefit has to be weighed against the risk of late complications.20 Two prospective randomized trials compared surgery alone to surgery and postoperative external-beam radiation in early-stage endometrial cancer. The first trial was conducted by the GOG (GOG 99) where 390 patients with stages IB and IIB endometrial cancers who underwent a total abdominal hysterectomy and BSO and pelvic/paraaortic lymph nodes sampling were randomized to observation (n = 202) or postoperative pelvic radiation (n = 190). With a median follow-up of 69 months, the 4-year survival rate was 92% in the irradiation arm, compared with 86% in the observation arm (p = 0.6). The 2-year estimated PFS rate was 97% versus 88% in favor of the irradiation arm (p = 0.007), with the greatest decrease seen in vaginal/pelvic recurrences.21 The second trial was the PORTEC study where 714 patients with stage IB grades 2, 3 and stage IC grades 1, 2 were randomized after total abdominal hysterectomy and BSO and no lymph nodes sampling to observation (n = 360) or pelvic radiation (n = 354). With a median follow-up of 52 months, the 5-year vaginal/pelvic recurrence rate was 4% in the radiation arm compared with 14% in the observation arm (p < 0.001). The corresponding 5-year survival rates were 81% and 85%, respectively (p = 0.37).22 In a follow-up study including 427 patients with higher-risk disease (age >60 years plus either grade 1 to 2 and outer 50% invasion, or grade 3 with inner 50% invasion, or stage IIA [1988 FIGO] disease), the PORTEC 2 study compared pelvic radiation therapy with vaginal brachytherapy. None of the patients underwent nodal assessment, and 5-year PFS (78% to 83%) and survival (80% to 85%) suggested that in this population vaginal brachytherapy was equivalent to pelvic radiation.23 Medically infirmed patients can be treated with primary RT with good clinical benefit, and radiation is very good palliation of symptomatic metastases (brain or bone metastases, pelvic pain, or bleeding). 3. Endocrine therapy Endocrine therapy has been used for patients with endometrial cancer, although it is limited to the treatment of metastatic or advanced disease.24 While it is most often administered to patients with a low- or intermediate-grade cancer, the predictive impact of hormone receptor status is not clear. For example, in one GOG trial that evaluated megestrol acetate alternating with tamoxifen in 56 women, the overall

response rate was 27% and OS was 14 months.25 Interestingly, patients with a grade 3 tumor had a 22% response rate. Progestins and tamoxifen as single agents are reasonable options as well; although data are far more limited, the aromatase inhibitors appear to have little activity in this disease with response rates less than 10% in two small trials. 4. Chemotherapy (Table 11.2) Increasingly, systemic therapy is being used earlier for patients with endometrial cancer. Adjuvant chemotherapy has been reported to increase 5-year survival rates (from 78% to 88%, HR 0.51, p = 0.02) in high-risk early-stage disease and is commonly recommended for deep-penetrative, node-positive, high-grade tumors. The data to support chemotherapy come from the GOG-122 trial, which included 396 patients with stage III and optimally debulked stage IV disease that were randomly assigned to treatment with whole abdomen radiation or to doxorubicincisplatin (AP) chemotherapy. There was significant improvement in both PFS (50% vs. 38%; p = 0.007) as well as OS (55% vs. 42%; p = 0.004), respectively, in favor of chemotherapy.26 The GOG conducted a randomized trial (GOG-163) for patients with primary stages III and IV or recurrent endometrial cancer with measurable disease comparing doxorubicin and cisplatin to doxorubicin with 24-hour paclitaxel and granulocyte colony-stimulating factor (G-CSF). There were no significant differences in response rate, PFS, or OS. The disadvantage of GOG-163 was the lack of platinum in the taxane-containing arm, however. The addition of a taxane was subsequently studied in GOG-177 evaluating doxorubicin with cisplatin as the standard arm versus paclitaxel, doxorubicin, and cisplatin (TAP regimen) and GCSF as the investigational regimen. Overall, TAP chemotherapy increased 12-month survival to 59% compared with 50% with doxorubicin and cisplatin with a HR of 0.75 (0.56 to 0.99). Although the TAP regimen produced an improvement in response rate and PFS, survival was minimally increased, and was associated with greater toxicity.27 TABLE

11.2

Chemotherapy Regimens for Endometrial Cancer

1. Doxorubicin and cisplatin

■ Doxorubicin 60 mg/m2 IV every 3 weeks ■ Cisplatin 50 mg/m2 IV every 3 weeks 2. Megestrol acetate 80 mg twice a day 3. Topotecan 1.2–1.5 mg/m2/day IV on days 1–5 every 3 weeks 4. TC

■ Carboplatin AUC 6 IV on day 1 ■ Paclitaxel 175 mg/m2 IV on day 1 every 3 weeks

5. TAP

■ Doxorubicin 45 mg/m2 IV on day 1 ■ Cisplatin 50 mg/m2 IV on day 1 ■ Paclitaxel 160 mg/m2 IV on day 2 AUC, area under the curve; IV, intravenous; TAP, paclitaxel, doxorubicin, and cisplatin; TC, carboplatin and paclitaxel.

On the basis of GOG 209, carboplatin and paclitaxel are now the more routinely administered regimen. In this trial, almost 1,300 women with recurrent or advanced endometrial cancer (including stage III disease) were randomly assigned to TAP or carboplatin plus paclitaxel. As presented at the 2012 Society of Gynecologic Oncologists Annual Meeting, women who were treated with carboplatin and paclitaxel had a similar overall response rate to those treated with TAP (51% in both arms). In addition, survival results were no different (PFS, 13 months in each arm; OS 37 vs. 40 months, respectively). However, carboplatin and paclitaxel were significantly more tolerable. Recurrent disease (especially ER/PR-negative disease) is often treated with further palliative chemotherapy. However, response rates are very low and benefit is rarely durable.28 5. Uterine papillary serous carcinoma All uterine papillary serous carcinomas are typically treated with chemotherapy after initial surgery, although patients with a serous carcinoma limited to a uterine polyp may not require adjuvant chemotherapy. 6. Novel biologics Multiple molecular pathways of cellular proliferation have been identified, and several targets within these pathways have been explored. A growing understanding of the underlying molecular biology of endometrial cancer has established the mammalian target of rapamycin, angiogenesis, and the EGFR family as relevant therapeutic targets. In addition, a subgroup of tumors have overexpression or amplification of HER2/neu; however, the role of HER2-directed therapies remains unclear and use of these drugs should be considered investigational. The limited efficacy of systemic therapy for patients with advanced or recurrent disease has led to the initiation of several clinical trials that have tested targeted approaches against the key drivers of these pathways. Unfortunately, even though there is an initial response with these therapies, some epithelial tumors have intrinsic mutations that make them primarily resistant or eventually resistant during the course of the treatment. The mutations give the tumor the ability to bypass the blockage of one pathway and, since most pathways are redundant, tumors are still able to grow. 7. Multimodality therapy GOG-122 (doxorubicin-cisplatin vs. whole-abdominal irradiation) changed the landscape of endometrial cancer treatment with proof that chemotherapy improved

survival compared with radiation alone for stages III and IV disease. These patients need tailored multimodality therapy; however, the sequence and schedule are not optimally defined. Therapy most commonly consists of surgery, followed by chemotherapy and tailored RT. 8. Follow-up Surveillance requires a pelvic exam every 3 months in the first 2 years to detect a potentially curable local recurrence, and supportive care should address functional, psychological, social, and spiritual issues. III. UTERINE SARCOMAS A. Histology Endometrial stromal sarcomas (ESSs) and undifferentiated endometrial sarcomas are rare forms of uterine sarcomas. ESSs, whose cells resemble endometrial stromal cells, are of low grade. Other uterine sarcomas include LMS. B. Uterine leiomyosarcomas Uterine LMS are rare aggressive tumors, with high recurrence rates, even when confined to the uterine corpus at the time of diagnosis. These tumors are large myometrial masses, which typically spread hematogenously. Patients present with vague symptoms similar to those of patients with leiomyomas. Most patients are diagnosed with LMS postoperatively. In the presence of metastatic disease, complete surgical cytoreduction should be attempted when feasible. Lymphadenectomy should be performed only in patients with nodes suspected of harboring metastatic disease and as part of a cytoreductive effort. There are conflicting data to support adjuvant chemotherapy or radiation therapy for early-stage disease. Patients with advanced-stage disease should receive gemcitabine and docetaxel adjuvant chemotherapy. Patients with recurrent disease are candidates for a wide variety of second-line treatments, of which many are investigational. Although prognosis remains dismal, ongoing studies are investigating the role of advanced imaging, multimodality treatment, prognostic nomograms, and unique biomedical pathways to increase understanding of LMS and improve therapeutic options for patients. C. Endometrial stromal sarcoma ESSs are a specific histologic subtype within the larger group of mesenchymal tumors of the uterine corpus. The most common symptom experienced by women with ESS is abnormal vaginal bleeding. ESS tumors are almost always of low grade and on gross examination usually present as a single mass. They can occur in sites other than the uterus, including the ovary, fallopian tube, cervix, vagina, vulva, pelvis, abdomen, retroperitoneum, placenta, sciatic nerve, or round ligament. ESS can be mistaken for endometrial stromal nodules; two distinguishing characteristics are infiltrating margins with or without angioinvasion, both of which are found in sarcomas but are absent in nodules. A definitive diagnosis of ESS is not possible from endometrial curettage

specimens alone, and a full hysterectomy is required. Undifferentiated endometrial sarcomas are marked by extensive cytologic atypia to the point where they can no longer be recognized as arising from the endometrial stroma. Grossly, these tumors resemble undifferentiated mesenchymal tumors and mimic high-grade sarcomas in behavior. Stage and grade for all three types are important when considering a patient’s prognosis. ESS has a good prognosis, in part due to its low-grade characteristics, and most are cured surgically. However, low-grade ESS behaves aggressively if the following characteristics are present: high expression of androgen receptors or low expression of estrogen receptors. ESS is typically treated with surgery and possible hormonal therapy, including progestins or aromatase inhibitors. The relapse rate for ESS is 62%. Recurrence commonly includes pulmonary metastases and responds to hormonal therapy. In patients with recurrent or metastatic endometrial stromal sarcoma who have developed progression of disease after hormone therapy, chemotherapy with agents such as ifosfamide or doxorubicin may be indicated. Chemotherapy may also be indicated for patients with undifferentiated endometrial sarcoma tumors, although no studies to date have been able to show a definite benefit associated with the use of adjuvant chemotherapy. Active agents include ifosfamide, doxorubicin, gemcitabine, docetaxel, liposomal doxorubicin, and paclitaxel. Although, the response rate with these agents is low.29 IV. OVARIAN CANCER Ovarian cancer is a relatively rare disease, with an incidence of about 1 in 70 women. In the United States, according to the ACS, there are approximately 22,000 new cases of ovarian cancer every year and 14,000 deaths attributable to the disease. As early-stage ovarian cancer is rarely symptomatic, and due to the fact that there are no effective screening protocols, patients with ovarian cancer typically present with advanced-stage disease (stages III to IV). These tumors can be chemotherapy sensitive, enabling many patients to live for years with their disease. However, cure rates remain low. Five-year survival rates for women with advanced disease range from 20% to 40%; however, for women who are diagnosed when the disease is confined to the ovary, cure rates are approximately 70% to 90%.30 The cause of epithelial ovarian cancer remains unknown, but theories relate it to incessant ovulation or abnormalities in the fallopian tube fimbria. A. Histology Epithelial ovarian carcinomas are classified as serous (70%), endometrioid (20%), clear cell (1,000) and platelet count >50,000/µL Cycles should be repeated every 28 days

A-MVAC (accelerated or dose dense)

Methotrexate 30 mg/m2 IV on day 1 ■ Vinblastine 3 mg/m2 IV on day 1 ■ Doxorubicin 30 mg/m2 IV on day 1 ■ Cisplatin 70 mg/m2 IV on day 1 ■ Pegfilgrastin 24–48 hours after chemotherapy Vinblastine, doxorubicin and cisplatin may be given day 1 or 2 Cycle is repeated every 14 days

Gemcitabine/cisplatin

■ Gemcitabine 1,000 mg/m2 days 1, 8, and 15 ■ Cisplatin 70 mg/m2 on day 2 Give gemcitabine on days 8 and 15 if white blood cell count >2,000/µL (ANC >1,000) and platelet count >50,000/µL Cycles should be repeated every 28 days

b. Bladder-sparing therapy External-beam radiation therapy is widely used in parts of the world as the standard curative-intent local therapy, with recent level I evidence demonstrating an improvement in survival in those patients receiving chemo-radiotherapy versus radiotherapy alone.11 Patients who undergo radiotherapy do require ongoing bladder surveillance with periodic cystoscopic evaluations. Chemotherapy and radiation can be offered to patients with MIBC who desire bladder preservation or are not candidates for radical cystectomy. Cisplatin chemotherapy concurrent with radiation increases local control. Approximately 30% of patients are free of recurrence 5 years after combined modality therapy for muscle-invasive disease. Salvage cystectomy has been used in some patients who do not achieve a complete response or recur after a bladder-sparing approach. There have been no randomized trials comparing bladder preservation therapy with radical cystectomy. Local symptoms from radiation including urinary frequency, incontinence, and proctitis usually resolve, but can persist in some patients. Candidates for a bladder-sparing approach are patients with favorable tumors (e.g., no involvement of the trigone or ureter) or patients who are unfit for radical cystectomy due to comorbidities. 3. Renal pelvis urothelial cancers The management of transitional cell cancer of the renal pelvis is primarily surgical

with nephroureterectomy the procedure of choice, and the role of perioperative chemotherapy in this setting is the subject of ongoing clinical trials. 4. Metastatic urothelial cancer The prognosis for locally advanced and metastatic urothelial bladder cancer has changed little over the past 30 years. In the untreated metastatic settings, favorable prognostic factors include good performance status, the absence of visceral metastases, and normal albumin and hemoglobin values.12 Randomized trials of cisplatin-based combination regimens have demonstrated the ability to cure a small subset of patients ranging from 5% to 15%.13,14 C. Systemic therapy regimens and evaluation of response 1. Initial therapy As noted above, the MVAC (standard/dose dense) and GC regimens are the most widely used in the management of advanced urothelial cancers (Table 12.1). Although cisplatin is the most active single agent in advanced urothelial cancers many patients as a consequence of the disease or other comorbidities are not appropriate candidates for cisplatin-based regimens.15 Agents such as carboplatin, docetaxel, paclitaxel, and gemcitabine as single agents and in combination have demonstrated overt antitumor activity, but none have demonstrated curative potential. Cisplatin-based multiagent chemotherapy produces median progression-free and overall survival rates in the 7-to-8-month and 14-to-15-month ranges, respectively.8 The toxicity of these regimens can be substantial and patient selection in regard to medical comorbidities and performance status is important. Response to chemotherapy is monitored by periodic assessment of tumor responses typically with CT imaging, with the expectation that most patients who will respond will do so within the first one or two cycles of treatment. 2. Salvage therapy Patients with disease progression following initial platinum-based chemotherapy currently have very poor outcomes with no established standard of care. Antitumor activity has been demonstrated with a large number of chemotherapeutic agents primarily in phase II studies but to date, no evidence of improved survival has been demonstrated.16 Goals of therapy need to be carefully reviewed with patients before initiating therapy. Enrolling fit patients onto next-generation clinical trials should be a primary consideration for those patients desiring additional therapy. 3. Next-generation therapeutics Recently, next-generation immunomodulatory (anti-PD1/PDL1) agents have demonstrated significant activity in advanced urothelial cancer. Several phase II trials have demonstrated objective response rates in the 30 to 40 range with subsets of patients having sustained responses with a good safety profile. Phase III studies to define the role of these agents are underway.17 D. Nontransitional cell histologies

Management of the non-TCC histologies, typically adenocarcinoma, squamous cell, or small cell carcinomas, is challenging. Primary adenocarcinomas and squamous cancers of the bladder are managed surgically, as there is no defined role for chemotherapy in the neoadjuvant or adjuvant settings. Patients with metastatic disease should be considered for phase I studies, as there is no evidence of meaningful response rates to standard chemotherapeutic agents. Neuroendocrine tumors of the bladder are usually treated similar to small cell lung cancer with cisplatin and etoposide chemotherapy and bladder radiotherapy or cystectomy in selected patients with bladder-confined disease. Subsets of these patients with clinically organ-confined disease may be long-term survivors; however, patients with metastatic disease have similar outcomes to patients with extensive small cell lung cancer, demonstrating a relatively high response rate to chemotherapy, but very poor survival rates. II. PROSTATE CANCER A. General considerations and staging Carcinoma of the prostate is the second most common cancer in the United States after non-melanoma skin cancer. Following the introduction of prostate-specific antigen (PSA) into clinical practice in the late 1980s a significant increase in prostate cancer diagnoses as a consequence of a broadly applied screening paradigm led to a dramatic increase in the number of men with low-grade and low-stage disease undergoing curative-intent therapy with surgery or radiotherapy. Large randomized prostate cancer screening trials from the United States and Europe have reported mixed results, leading to much more nuanced recommendations for prostate cancer screening from major medical societies in the United States18–21 Active surveillance (AS) as a management strategy for low-risk patients and recent developments in genomic- based diagnostics may improve our ability to risk-stratify patients to enable curative-intent therapy for patients at risk of dying from prostate cancer while minimizing the side effects of therapy for those patients destined to die with, but not of prostate cancer.22,23 Definitive pathologic staging of prostate cancer requires surgical excision of the prostate and regional nodes, whereas clinical staging of prostate cancer uses pretreatment clinical parameters to predict the extent of disease and the patient’s prognosis as well as to inform the therapeutic decision process. Pretreatment modalities used to predict disease extent in prostate cancer patients include the digital rectal exam, prostate cancer features obtained from needle biopsy, PSA, and imaging with prostate MRI. Pathologic staging more accurately estimates disease burden and is more useful than clinical staging for outcome prediction. The most important pathologic criteria in the assessment of a radical prostatectomy specimen are tumor grade, the presence or absence of seminal vesicle invasion and extracapsular disease, surgical margin status, and pelvic lymph node involvement. The most commonly used staging for prostate cancer is the TNM system.2 B. Clinically organ-confined disease

As a consequence of widespread prostate cancer screening, the potential for clinical understaging, and the heterogeneity of prostate cancer, the therapeutic decision process for men with localized prostate cancer is complex. The guiding principal of disease management should be to offer curative-intent therapy to men who need to be cured and to avoid the side effects of the intervention in men who are not destined to die of prostate cancer.24 Our ability to make risk-based therapeutic recommendations can be refined by using available clinical and pathologic criteria to provide insight into the clinical behavior of patients with newly diagnosed prostate cancer. A number of prostate cancer risk classification systems are in broad use such as those promulgated by the National Comprehensive Cancer Network (NCCN), which stratify men into very low, low, intermediate, high, or very high-risk groups using clinical parameters including T stage, Gleason score, PSA values, and number of positive biopsy cores involved.25 1. Active surveillance As many men with low-risk prostate cancer may not in fact need therapy, AS is a management strategy that delays curative treatment until it is warranted on the basis of defined indicators of disease progression. AS is increasingly being considered for subsets of patients with favorable disease features such as those with very low NCCN risk criteria defined as T1c, Gleason ≤6, PSA 10 × upper limit of normal. Patients with nonseminoma without mediastinal primary or nonpulmonary visceral metastasis ■ Have a good prognosis with the AFP 1 cm should be evaluated, since they have a greater potential to be clinically significant cancers, and neck ultrasound is an important supplemental approach. Occasionally, thyroid nodules 1 cm, taking into considering that with DTC the incidence of disease in the contralateral lobe is 20% to 87%. It is also recommended in lesions that extend beyond the thyroid, or in patients with prior exposure to ionizing radiation to the head/neck area. Further, total thyroidectomy is conducive to RAI surveillance, and simplifies follow-up in patients with high-risk disease. Total thyroidectomy with modified neck dissection is often preferred for those who have lateral cervical lymph node involvement. Unilateral lobectomy with en bloc resection of tumor maybe considered for a DTC 4 cm even in the absence of other concerning features. Treatment with RAI (131I) is usually recommended for patients with DTC and known postoperative residual disease, patients with distant metastases, and/or patients with locally invasive lesions. For patients with nodal metastases that are not large enough to excise, a dose of 100 to 175 mCi of RAI is commonly given. Locally invasive cancer that is not completely resected is often treated with 150 to 200 mCi of RAI while patients with distant metastasis are treated with 200 to 250 or even 300 mCi. The potential exception to this schema

is lung metastasis; a dose of up to 80 mCi of RA whole body retention by dosimetry at 48 hours is generally used to avoid radiation-induced pulmonary fibrosis or empiric treatment with 100 to 200 mCi. Effective and safe use of RAI treatment requires that tumor cells are capable of concentrating iodide (i.e., DTC), and appropriate patient preparation to raise TSH levels by either temporarily withholding thyroid hormone replacement or via administration of recombinant TSH. In the former situation, because of its long half-life, T4 is discontinued and T3 is initiated for a period of 6 weeks prior to the scan, with all thyroid medication withheld in the 2-week period prior to RAI administration. Ideally, a TSH level of 25 to 30 μm/mL is required for successful ablation or radiotherapy. Alternatively, recombinant TSH can be used to stimulate thyroid cell uptake of RAI in the absence of T4 withdrawal; this approach maintains better quality of life but adds considerably to expense. A low iodine diet is also required for RAI efficacy, as dietary iodine can compete with RAI for uptake in normal thyrocytes and tumor and thereby reduce RAI therapeutic efficacy. Compliance with a low iodine diet is assessed via measurement of 24-hour urinary iodine excretion. Patients receiving high dose RAI (150 to 300 mCi) must be treated at centers with special lead-lined containment rooms, with monitoring of treated patients to assure compliance with environmental radiation safety regulations and patient and population safety. The duration of hospitalization depends on the dose given, the post-therapy method of transportation home, and contact of patient with the general public. Potential side effects of RAI include temporary bone marrow suppression (this can last weeks or even months with repeated high RAI dosage), transient nausea, sialoadenitis/dry mouth (with possible permanent cessation of salivary flow), skin reaction over the tissue concentrating the radioiodine, and pulmonary fibrosis. The use of very high cumulative RAI doses (usually when approaching 1,000 mCi) has also rarely been associated with acute myelogenous leukemia, as well as rarely with bladder and breast cancers. Scintigraphy should be performed 4 to 10 days after RAI therapy to assess uptake of RAI by tumor and to detect residual carcinoma perhaps not otherwise seen using other imaging approaches. d. Radiotherapy—local approaches including external beam radiotherapy. External beam radiation therapy in DTC is used infrequently except as a palliative treatment for locally advanced, unresectable disease in the neck that does not concentrate iodine. External beam radiotherapy is also used for localized painful bony metastasis, for other local disease that could lead to fractures, neurological or compressive symptoms that are not amenable to surgery; for example, vertebral, CNS, or pelvic metastases, or subcarinal lymph nodes. Stereotactic radiosurgical approaches are also used in patients with recurrent cancer at previously irradiated sites and when tumors are proximal to

critical radiation-sensitive tumors. e. Systemic therapies. Several putative VEGFR inhibitors have been shown to have activity in well-differentiated thyroid cancers and two—sorafenib and lenvatinib—have received Food and Drug Administration (FDA) approval on the basis of randomized phase III trials. Sorafenib is an inhibitor of several protein tyrosine kinases (VEGFR and PDGFR) and some intracellular serine/threonine kinases (e.g., C-Raf, wild-type and mutant B-Raf). Safety and effectiveness were established in a randomized trial involving 417 participants with locally recurrent or metastatic, progressive DTC that had not responded to RAI treatment. The sorafenib dose was 400 mg twice a day. The median progression-free survival (PFS) was 10.8 months with sorafenib compared with 5.8 months with placebo (p < 0.0001). Partial responses were observed in 12.2% of patients receiving sorafenib compared with 0.5% in the placebo arm (p < 0.0001). The most common side effects with sorafenib were diarrhea, fatigue, alopecia, hand-foot skin reaction, rash, weight loss, anorexia, nausea, gastrointestinal and abdominal pains, and hypertension. TSH, a potential promoter of thyroid cancer, may increase while on sorafenib, requiring adjustment of replacement therapy. Lenvatinib is an inhibitor of the VEGF receptor 2 (VEGFR2). The approval of lenvatinib was based on a multicenter, double- blind, placebo-controlled trial that enrolled 392 patients with locally recurrent or metastatic RAI-refractory DTC and radiographic evidence of progression within 12 months prior to randomization. Patients received lenvatinib 24 mg orally per day. Median PFS was 18.3 months in the lenvatinib arm and 3.6 months in the placebo arm (p < 0.0001). Objective response rates were 65% and 2% in the lenvatinib and placebo arms, respectively. No statistically significant difference in overall survival between the two arms was demonstrated. The most common adverse reactions were hypertension, fatigue, diarrhea, arthralgia/myalgia, anorexia, weight loss, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. Adverse reactions led to dose reductions in 68% of patients receiving lenvatinib and 18% of patients discontinued lenvatinib for adverse reactions. Thus, it is not clear whether the recommended dose will be tolerable, and the extent of efficacy thus remains uncertain. 2. Medullary thyroid cancer6,7,15 a. Surgery. In patients with MTC, total thyroidectomy with central lymph node dissection is recommended. Patients with FMTC syndromes should undergo early prophylactic thyroidectomy. b. Radiotherapy. External beam radiation can be used for residual or recurrent disease; however, the survival benefit is still unclear. As MTC does not uptake iodine, RAI has no role. c. Systemic therapies. As with WDTC several putative VEGFR inhibitors have

been shown to have activity in MTC with FDA approval granted to two inhibitors that also have activity against the RET tyrosine kinase. Approval of the first, vandetanib, was based on an international multicenter randomized double-blind trial in patients with unresectable locally advanced or metastatic MTC. An improvement in PFS was observed with vandetanib compared with placebo (HR = 0.35; p < 0.0001). The overall response rate (ORR) was 44% with vandetanib, compared with 1% placebo. The most common (at least 20%) grade 1 to 4 adverse reactions included diarrhea/colitis, rash, dermatitis acneiform, nausea, hypertension, headache, fatigue, decreased appetite, and abdominal pain. The recommended daily dose of vandetanib is 300 mg orally. Cabozantinib, the second drug, inhibits the activity of multiple tyrosine kinases, including RET, MET, and VEGF receptor 2 and its approval was based on an international, multicenter, randomized (2:1), placebo-controlled trial enrolling 330 patients with metastatic MTC. Patients were required to have progressive disease within 14 months prior to entry. The estimated median PFS was 11.2 and 4.0 months for the cabozantinib and placebo arms, respectively (p < 0.0001). The ORR was significantly higher with cabozantinib (27% vs. 0%; p < 0.0001) and all were partial responses. The median response duration was 14.7 months (95% CI, 11.1 to 19.3).No statistically significant difference in overall survival was observed. Adverse reactions observed in ≥25% of cabozantinib-treated patients were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, anorexia, nausea, fatigue, oral pain, hair color changes (hypopigmentation/graying), dysgeusia, hypertension, abdominal pain, and constipation. While the recommended dose and schedule for cabozantinib is 140 mg orally once daily, dose reduction was required in 79% of patients again raising questions as to the actual efficacy of a tolerable dose. 3. Anaplastic thyroid cancer16 a. Surgery. Surgical resection does not improve local control or survival in patients and most of the time the treatment is palliative. A total lobectomy or total or near-total thyroidectomy with a therapeutic lymph node dissection should be performed in patients with intrathyroidal ATC. If there is extrathyroidal invasion, an en bloc resection should be considered if grossly negative margins could be achieved. If surgery is performed, it should be followed by locoregional radiotherapy usually within 2 to 3 weeks after surgery. Local control is desirable in patients with ATC because of the likelihood of asphyxia from the rapidly enlarging tumor. b. Radiotherapy. Radiotherapy has an established role in the locoregional treatment of ATC. In patients with resectable disease and no distant metastases, locoregional radiation should be considered (with or without systemic therapy) and in patients with unresectable locoregional disease, radiation therapy can achieve long-term local control. Furthermore, treatment with external beam

radiotherapy, with systemic therapy, appears to achieve local control in twothirds of patients with ATC; however, almost all subsequently die of distant metastases. c. Systemic therapies for ATC. About 60% of all ATCs are unresectable or metastatic at the time of presentation and chemotherapy has offered little in improving survival in these patients. Even if a patient with advanced ATC responds to chemotherapy, a prolongation of the median survival time by several months is generally all that can be achieved. In terms of single-agent chemotherapy, there are two classes of cytotoxic agents with the greatest evidence in support of efficacy: anthracyclines (e.g., doxorubicin) and taxanes (e.g., paclitaxel), each with response rates in advanced disease as high as 50%. Improved survival may be achieved in patients with advanced disease who respond to these agents. Furthermore, there is accumulating rationale that the use of these agents in combination with radiation therapy in the adjuvant setting may also extend survival. Combination chemotherapy has been used in ATC, but it is uncertain whether multiagent therapy impacts survival more than single-agent therapies. Since there is no systemic therapy (cytotoxic, novel, targeted) of proven benefit in terms of improved survival and/or quality of life in advanced ATC, novel therapeutic approaches should be strongly considered. A number of novel agents have been preliminarily studied in ATC such as fosbretabulin assessed in phase II trial with increased overall survival in some patients. Tyrosine-kinase inhibitors (TKIs) such as sorafenib, axitinib, gefitinib have been studied with no evidence of RECIST response; however, a limited number of patients were reported to have stable disease. Ongoing studies are examining the use of MAPK and B-Raf inhibitors alone or in combination in patients with ATC whose tumors harbor B-Raf mutations. Some responses have been observed. II. ADRENOCORTICAL CARCINOMA A. Incidence and etiology17 Adrenocortical cancer (ACC) is a rare malignancy that presents many management challenges and requires a multidisciplinary approach to treatment. Across the world, the incidence of ACC is estimated at 1.5 to 2/million/year. While strides have been made in the management of these patients, ACC remains a difficult to treat disease, with a 5-year survival of 10% to 25% and an average survival from diagnosis of about 14.5 months. The majority of ACCs are sporadic without identifiable risk factors. However, a small percentage occurs in association with certain genetic syndromes including the Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, MEN-1, and familial adenomatous polyposis. B. Clinical manifestations18,19 Among patients with a diagnosis of ACC, approximately 50% present with biochemical evidence of hormone excess including 10% to 20% who present with Cushing

syndrome. The remaining present with less florid manifestations such as hirsutism in females and gynecomastia in males, or have no overt clinical symptoms. Several recent reviews provide in-depth summaries. While the diagnosis is obvious in a patient presenting with systemic or biochemical manifestations of endocrine hypersecretion, patients can also present without symptoms or only vague symptoms, or with local symptoms from a large, locally invasive primary tumor. C. Evaluation and workup19,20 A history, physical examination, and blood and urine studies to determine if the tumor is functional should be part of the initial evaluation, followed by either a CT or a magnetic resonance (MR) study. Both CT and MR can differentiate benign adenomas from malignant lesions and help establish the diagnosis, and can also guide management. Because ACCs have lower lipid content than adenomas, they usually have higher density values on CT scans; while on magnetic resonance imaging (MRI) they are usually iso-intense with liver on T1 images, and have intermediate-to-high intensity on T2 images. Attributes of an MRI include its superiority in identifying liver metastases and the extent of vascular invasion, especially the inferior vena cava (IVC), thus providing valuable information prior to surgery and for monitoring disease response in the liver. An 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) should not be used as the primary modality nor can it be considered definitive in discriminating benign from malignant adrenal masses, nor a primary adrenal tumor from other from other tumors with high metabolic activity. However, in a patient in whom a surgical intervention is planned, FDG-PET can help assess extent of disease and ensure all disease has been identified and that surgery should proceed as planned. D. The role of a biopsy21 For most patients presenting with an adrenal mass that is suspicious for malignancy, surgery and not a biopsy should be performed. While a risk of seeding tumor, and difficulty differentiating benign from malignant in a small biopsy sample are often cited as reasons, the most important reason is that a biopsy rarely if ever changes management. It is prudent to proceed to surgery without a prior biopsy in a patient (1) with either Cushing syndrome or biochemical evidence of hormone excess, where there is no doubt as to the diagnosis of ACC or (2) without evidence of hormone production but with an isolated adrenal mass found during evaluation or incidentally on an imaging scan. In the latter, surgical resection is both a diagnostic and a therapeutic intervention. A biopsy should only be performed only if (1) disease elsewhere suggests a primary location other than adrenal, or (2) widespread metastases make surgical resection unlikely to be beneficial. E. Pathology22,23 In 1984, Weiss first proposed a set of criteria to help distinguish a small ACC without local spread or distant metastases from a benign adenoma. He reported nine criteria he felt were most useful and today a malignancy is presumed if three or more criteria are identified in the tumor. The nine properties, now often referred to as the “Weiss

criteria,” include (1) nuclear grade III/IV; (2) mitotic rate greater than 5 per 50 highpower fields (HPFs); (3) atypical mitoses; (4) tumors with 25% or less clear cells; (5) diffuse architecture; (6) microscopic necrosis; (7) venous invasion; (8) sinusoidal invasion; and (9) capsular invasion. Despite the recognized value of the Weiss criteria in discriminating a small adenoma from a small carcinoma, their prognostic value in larger tumors has not been established. Although the nine properties often cluster, whether a greater number of criteria are associated with a worse prognosis is not clear. Indeed, the prognostic value of pathologic findings other than mitotic rate remains unconfirmed. Indeed, in 42 patients with a diagnosis of ACC, Weiss and colleagues found a strong statistical association with outcome only for mitotic rate; with tumor weight greater than 250 g, size greater than 10 cm, atypical mitoses, and capsular invasion demonstrating marginal associations with poor survival (p < 0.06). A recent study that attempted to simplify histopathologic classification of ACCs confirmed the importance of mitotic rate. F. Management of ACC24 Approaches used in the management of ACC include surgical resection, oral mitotane, intravenous chemotherapy, and palliative radiation. While the fact that it is a rare disease and that data from controlled trials is generally lacking, this does not mean there is no evidence nor does it mean anything is an option. For patients whose disease progresses after commonly used approaches, referral to a clinical trial must be seen as the best option. 1. Surgical resection24–28 Because surgery remains the only proven curative option for a patient with ACC, it must always be aggressively pursued at presentation and at relapse. At presentation less than complete resections should not be entertained given that survival is less than 1 year in patients who undergo incomplete resection. At the time of presentation, an experienced oncologic surgeon, not a general surgeon, should perform an open procedure. A laparoscopic approach should never be used. While such an approach may appear attractive to a surgeon and even more so to a patient who sees a short hospital stay and quick recovery as ideal, intraoperative tumor spill rates as high as 50% should discourage any approach other than an open resection. Not everyone agrees. A study summarizing outcomes in 152 ACC patients concluded that for localized ACCs ≤10 cm in diameter, laparoscopic adrenalectomy was not inferior to open adrenalectomy. However, extensive preselection occurred, laparoscopy resection was attempted in only 23%, and one-third of the latter were converted to open resections. Furthermore, these results in specialized tertiary referral centers have very limited-to-no applicability in the general community. In addition to a high likelihood of peritoneal seeding, laparoscopic resections have been reported to have a higher incidence of positive margins and more rapid recurrence. Given our still limited systemic chemotherapy options, an earlier peritoneal recurrence not amenable to surgical resection is a

serious adverse event that should be avoided, as should any recurrence. Finally, a systematic review of laparoscopic surgery for different cancers concluded, “There is no prospective randomized series to guide or endorse the use of laparoscopic resection for adrenocortical carcinoma or malignant pheochromocytoma,” a conclusion with which we agree. At the time of relapse, an aggressive surgical posture may emerge as the preferred option in selected patients. While metastasectomy of defined disease is likely to be of value, it must be recognized that all or the majority of studies addressing this approach have an inherent bias: those undergoing surgery likely have more limited disease, a better performance status, and possibly tumors whose biology might be considered “more indolent.” But the fact these recurrences are often aggressive and if left unattended would likely lead to death suggest that carefully planned metastasectomies might benefit patients without evidence of widespread recurrence. It is likely the literature will eventually validate this approach. 2. Mitotane 29,30 The use of mitotane as an anticancer agent for ACCs dates back to the 1960s when the insecticide, DDT, was identified as an adrenolytic agent. The enthusiasm for mitotane during that time—an era when assessment of an agent’s activity was much less precise with quantitation of tumor relying on physical examination and clinical presentation—seems in retrospect to have been not well founded. As a potent inhibitor of adrenal hormone synthesis it is likely that investigators’ assessments of mitotane’s antitumor effects were likely influenced by improved symptoms of hormone hypersecretion that were erroneously thought to represent tumor reduction. Indeed, although mitotane is approved for “the treatment of inoperable adrenal cortical carcinoma of both functional and nonfunctional types,” its clinical utility and value is primarily as an antihormonal agent and only marginally as a tumoricidal agent. Mitotane’s most valuable attribute is its ability to impair hormone synthesis by cells of adrenal origin and to modify the peripheral metabolism of steroids. Thus mitotane is indispensable in patients with hormone-producing tumors and it must be started as soon as possible and continue indefinitely. Indeed, in a patient with excess hormone production, mitotane should be continued even in the face progression on imaging studies—not as an anticancer agent but as an antihormonal agent to which other therapies may be added. Whether mitotane should be used as an adjuvant therapy has not been resolved, although most physicians who treat patients with ACCs used it albeit variably. Several small and one large retrospective studies suggest mitotane given as an adjuvant therapy and continued indefinitely, can at a minimum delay and possibly prevent a recurrence of disease. Ongoing studies are attempting to begin to better define those who may experience benefit. Identifying those who will benefit is important since mitotane is well tolerated by only a fraction of patients, with the

majority finding it a difficult therapy that impacts the quality of their lives. Administering mitotane to all patients after an initial resection means that as many as 35% to 40% of patients incur toxicities without benefit given that they have been cured by surgery. Whereas patients who present with large tumors, uncertain margins, and many of the histopathology findings described by Weiss as well as a Ki67 index higher than 10% to 15% should receive mitotane indefinitely. The decision made in other cases will be more nuanced. Thus, pending an accurate predictor of recurrence, clinical judgment based on experience is paramount. Finally, as regards the administration of mitotane, many recommendations including those in the current package insert (http://packageinserts.bms.com/pi/pi_lysodren.pdf) are impractical and likely to lead to its discontinuation. One should recognize that aggressive administration of mitotane has never been shown to lead to a rapid response and that mitotane’s effect comes only with time. Consequently, an aggressive administration schedule invariably leads to intolerance and discontinuation. Especially in a patient in whom it is given as an adjuvant where no disease is visibly present, an aggressive schedule that aims to reach a “threshold level” is unfounded. Mitotane as a therapy should be viewed a marathon not a sprint and its administration adjusted accordingly. A starting dose of 1 to 2 g/day should be gradually advanced to a maximum of 4 to 6 g/day over 2 to 3 months, with further adjustments guided by serum levels. Replacement steroids can be started with the initiation of mitotane or when clinical and laboratory parameters indicate the emergence of adrenal insufficiency. Both hydrocortisone and fludrocortisone should be given. It is important that patients receiving mitotane for prolonged periods of time be instructed to wear a bracelet labeled adrenal insufficiency and that this be worn for up to a year after mitotane is discontinued, since it takes many months for mitotane to be eliminated from the body. 3. Systemic chemotherapy31 There is very little clinical data to guide the practicing oncologist on what a patient with adrenocortical cancer should receive, but it is sufficient that it should not be disregarded, nor discarded in favor of a “novel targeted therapy,” none of which have been proven of efficacy to date. In the case of ACC, assessment of response rate has been the principal mode of evaluation with PFS quantitated in a few studies. The FIRM-ACT trial (First International Randomized trial in locally advanced and Metastatic Adrenocortical Carcinoma Treatment) was a randomized international trial that compared the two therapeutic regimens that had emerged as the preferred options for ACC: A combination of etoposide, doxorubicin, and cisplatin (EDP) with mitotane and single-agent streptozocin also in combination with mitotane. The study found a significantly better response rate (23.2% vs. 9.2%, p < 0.001) and PFS (5.0 vs. 2.1 months; hazard ratio, 0.55; p < 0.001) with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar

rates of toxic events. There was no significant difference in overall survival, possibly because crossover was allowed. The investigators noted “the tumor response in our study compares favorably with the results obtained with novel therapies …” although “the poor overall survival rates … confirm … the need for improved treatment options,” emphasizing both the value, albeit limited, of these regimens and the need for better therapies. Importantly, given that among the 185 patients who received EDP-mitotane as second-line therapy, the median PFS was essentially unchanged at 5.6 months despite a median of 2.1 months of streptozocin, one could argue that in a patient with a good performance status and a modest amount of disease, there exists a window to enroll in an experimental regimen and this should be encouraged. We would also note that the FIRM-ACT study found similar results for EDP plus mitotane and streptozocin with mitotane as first- or second-line therapies suggesting they are not cross-resistant and thus they may be administered in succession if a response is not achieved with the first regimen. One should emphasize that the efficacy of EDP versus a simpler regimen has never been addressed. An unproven alternative that can be considered in patients with severe hormonal excess who may be receiving full doses of ketoconazole is cisplatin at a dose of 40 mg/m2 administered weekly. This allows one to achieve a higher dose intensity with cisplatin, the drug many would agree is the most active in ACC. Finally, although many patients with ACC have undergone a nephrectomy, one cannot recommend that carboplatin be substituted for cisplatin given that in other cancers the activity profiles of these two agents have been dissimilar, and the data in ACC is largely with cisplatin. 4. Radiation therapy32 While there is no definitive data, the use of palliative radiation therapy can be beneficial for patients with metastatic disease. However, the use of radiation therapy nor following primary surgery is not supported. Given it is unlikely radiation therapy after a primary surgery has the potential to eradicate microscopic disease, the benefit remains uncertain while risk is guaranteed. The latter includes not only the well-known acute complications of radiation therapy but also the real possibility that a salvage surgery that may be the only curative option will be made more difficult. Postsurgical radiation should only be considered in a patient with known positive margins after surgery performed by a highly qualified surgical oncologist and only if a re-operation is deemed not possible. 5. Interventional radiology as a treatment modality33 Given the undisputed value of surgery as the only curative modality in the management of ACC, less invasive options including radiofrequency ablation (RFA) and cryoablation have emerged as potential surgical adjuncts or as stand-alone modalities in patients who have suffered a recurrence. But just as partial surgical resections to “debulk” disease should never be performed, an RFA or cryoablation that does not eradicate the tumor also should not be done. The value of embolization

to reduce tumor size and reduce vascular supply making a subsequent surgical intervention is established, albeit not with randomized data. The combination of RFA or cryoablation with embolization, either bland or with chemotherapy-loaded beads, needs formal evaluation, but offers promise. 6. Management of hormonal excess and deficiency34 In the preoperative setting, a patient’s hormonal status should be assessed carefully since a functioning tumor can suppress corticotropin (ACTH) and this can be complicated by involution of the contralateral adrenal. Keeping this in mind is important to ensure that in the postsurgical period any needed steroid replacement is administered once the hormone-producing tumor is removed. In patients with hormonal excess, the need for aggressive and sustained attention to this problem must be recognized. Looking to chemotherapy to solve the problem of hormonal excess is a flawed strategy since chemotherapy only benefits a minority of patients leaving a majority increasingly debilitated by the continued and increasing hormonal excess. Consequently, in addition to mitotane, identified earlier as the cornerstone for managing hormonal excess, ketoconazole, metyrapone, and etomidate, should be added singly or in combination to mitotane. The management must be proactive and forward thinking since what is felt adequate for today’s tumor burden will be insufficient for the larger quantity of tumor that will inevitably occur in a short time. G. A multidisciplinary approach to managing patients with ACC Managing patients with ACC requires a multidisciplinary approach involving medical, surgical, and radiation oncologists, interventional radiologists, and endocrinologists. As we have noted given that the only curative option is surgery, it must always be aggressively considered both at presentation and at relapse. However, in patients with rapid recurrences or widespread metastases, a trial of chemotherapy should be given. Given the rarity of achieving a long-lasting compete response with chemotherapy, in this setting chemotherapy is used to address metastatic disease, for example, in the lungs, and with the hope of improving the possibility of a surgical option by shrinking a tumor mass and possibly helping sterilize microscopic disease. H. Conclusion In the management of ACC, a multidisciplinary effort is mandatory. Surgery remains the cornerstone both at the time of presentation and when a limited recurrence occurs. In the latter, RFA and cryoablation may be of value. Chemotherapy can benefit many patients but new paradigms are needed. Referral to a clinical trial is strongly recommended. Radiation therapy should be reserved for palliation. Patients whose tumors are producing excess hormones should have this complication managed aggressively since it can have a great effect on the quality of their life. III. PHEOCHROMOCYTOMA AND PARAGANGLIOMA A. Description and diagnosis35–40

Pheochromocytomas and paragangliomas are rare neuroendocrine tumors that arise from chromaffin cells. Pheochromocytomas account for 90% of cases and arise in the adrenal glands, whereas paragangliomas, the extra-adrenal counterpart of pheochromocytomas, arise from ganglia along the sympathetic and parasympathetic chain (e.g., carotid body/skull base, urinary bladder, heart, organ of Zuckerkandl). Most pheochromocytomas represent sporadic tumors and 15% of these are associated with somatic mutations. However, about 35% are familial in origin and harbor germline mutations in susceptibility genes. The number of genes associated with susceptibility to pheochromocytoma/paraganglioma was recently increased to 19, and includes the von Hippel-Lindau (VHL) tumor suppressor gene, the rearranged during transfection (RET) proto-oncogene, the neurofibromatosis type 1 (NF1) tumor suppressor gene, the genes encoding the four succinate dehydrogenase complex (SDH) subunits (SDHA, -B, -C, D), and the gene encoding the enzyme responsible for flavination of the SDHA subunit (SDHAF2). Additionally, new susceptibility genes, transmembrane protein 127 (TMEM127), MYC-associated factor X (MAX), and hypoxia-inducible factor 2α (HIF2A), have been identified. Others include the kinesin family member 1B, transcript variant β (KIF1Bβ), prolyl hydroxylase 1 and 2 (PHD1/EGLN2 and PHD2/EGLN1), Harvey rat sarcoma viral oncogene (H-RAS), Kirsten rat sarcoma viral oncogene (KRAS), isocitrate dehydrogenase 1 (IDH1), fumarate hydratase (FH) and BRCA1associated protein-1 (BAP1). Finally, germline mutations in malate dehydrogenase 2 (MDH2) and somatic mutations in alpha thalassemia/mental retardation syndrome Xlinked (ATRX) genes were identified in pheochromocytoma/paraganglioma. Sporadic pheochromocytomas are usually unicentric and unilateral while familial pheochromocytomas are often multicentric and bilateral. Despite this low incidence, pheochromocytoma must always be considered because they can be cured in about 90% cases, whereas if left untreated, could be fatal. The incidence of malignancy is about 10%, with metastases the only definite proof of malignancy, as there are no definitive histopathologic criteria for malignancy. Oncologists must read the literature carefully given that descriptions of benign and malignant are often combined. The overall 5-year survival rate for patients with malignant pheochromocytoma is 36% to 44%. About 50% or more of SDHB mutation carriers will develop malignant paragangliomas, and up to 60% of patients with a malignant paraganglioma harbor a SDHB mutation. Pheochromocytomas are usually diagnosed on the basis of the measurement of plasma or urinary metanephrines and methoxytyramine since 30% do not secrete catecholamines. Imaging modalities employed include CT and MRI. 123I-MIBG scintigraphy has limited sensitivity but is of value in deciding if 131I-MIBG therapy is an option. B. Management of pheochromocytomas and paragangliomas41,42 1. Surgery Surgery, remains the only curative treatment option with

pheochromocytoma/paraganglioma. Minimally invasive adrenalectomy is recommended for most adrenal pheochromocytomas and open resection for large or invasive tumors to ensure complete resection and avoid local recurrence. Patients with hormone secreting tumors should undergo preoperative blockade for 7 to 14 days with α-adrenergic receptor blockers such as phenoxybenzamine, doxazosin to prevent perioperative cardiovascular complications. Many patients require the addition of β-blockers, which are indicated for persistent tachycardia; however, to prevent hypertensive crisis secondary to unopposed vasoconstriction, β-blockers should not be given before α-antagonists. In patients in whom elevated blood pressure and arrhythmia cannot be controlled with α- and β-blockade, α-methylpara-tyrosine (metyrosine, Demser) a competitive inhibitor of tyrosine hydroxylase can be used. Importantly, normal postoperative biochemical test results do not exclude microscopic disease. Long-term periodic follow-up is recommended especially important if the tumors harbor mutations of disease-causing genes. 2. Radiation therapy For patients whose tumors are positive 123I-MIBG scintigraphy, 131I-MIBG therapy can be a valuable treatment modality. However, this approach has bone marrow toxicity so it is best used in the context of a clinical trial. External beam radiotherapy, Gamma Knife, and CyberKnife stereotactic approaches can provide local control in focally symptomatic or threatening metastases. 3. Chemotherapy Because of its rarity clinical data on the efficacy of chemotherapy is very limited. Single agents and multidrug regimens in limited numbers of patients have been reported with variable results. A combination of cyclophosphamide, vincristine, and dacarbazine (CVD) is the most active chemotherapy regimen, producing remissions of moderate duration in symptomatic patients. In 18 patients with a diagnosis of pheochromocytoma/paraganglioma treated with CVD, 2 (11%) and 8 (44%) achieved complete or partial responses, respectively, with amelioration of symptoms related to catecholamine excess and objective improvements in blood pressure. CVD was well tolerated with only grade I/II toxicities (38).

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21. Williams AR, Hammer GD, Else T. Transcutaneous biopsy of adrenocortical carcinoma is rarely helpful in diagnosis, potentially harmful, but does not affect patient outcome. Eur J Endocrinol. 2014;170:829–835. 22. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol. 1984;8:163–169. 23. Lau SK, Weiss LM. The Weiss system for evaluating adrenocortical neoplasms: 25 years later. Hum Pathol. 2009;40:757–768. 24. Pommier RF, Brennan MF. An eleven-year experience with adrenocortical carcinoma. Surgery. 1992;112:963–970. 25. Leboulleux S, Deandreis D, Al Ghuzlan A, et al. Adrenocortical carcinoma: is the surgical approach a risk factor of peritoneal carcinomatosis? Eur J Endocrinol. 2010;162:1147–1153. 26. Miller BS, Ammori JB, Gauger PG, et al. Laparoscopic resection is inappropriate in patients with known or suspected adrenocortical carcinoma. World J Surg. 2010;34:1380–1385. 27. Brix D, Allolio B, Fenske W, et al. Laparoscopic versus open adrenalectomy for adrenocortical carcinoma: surgical and oncologic outcome in 152 patients. Eur Urol. 2010;58:609–615. 28. Bellantone R, Ferrante A, Boscherini M, et al. Role of reoperation in recurrence of adrenal cortical carcinoma: results from 188 cases collected in the Italian National Registry for Adrenal Cortical Carcinoma. Surgery. 1997;122:1212–1218. 29. Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007;356:2372–2380. 30. Huang H, Fojo T. Adjuvant mitotane for adrenocortical cancer—a recurring controversy. J Clin Endocrinol Metab. 2008;93:3730–3732. 31. Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. FIRM-ACT Study Group. N Engl J Med. 2012;366:2189– 2197. 32. Fassnacht M, Hahner S, Polat B, et al. Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma. J Clin Endocrinol Metab. 2006;91:4501–4504. 33. Wood BJ, Abraham J, Hvizda JL, et al. Radiofrequency ablation of adrenal tumors and adrenocortical carcinoma metastases. Cancer. 2003;97:554–560. 34. Veytsman I, Nieman L, Fojo T. Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J Clin Oncol. 2009;27:4619–4629. 35. Lenders JW, Eisenhofer G, Mannelli M, et al. Phaeochromocytoma. Lancet. 2005;366:665–675. 36. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA. 2002;287:1427–1434. 37. Manger WM, Gifford RW. Pheochromocytoma. J Clin Hypertens. 2002;4:62–72.

38. Lodish MB, Adams KT, Huynh TT. Succinate dehydrogenase gene mutations are strongly associated with paraganglioma of the organ of Zuckerkandl. Endocr Relat Cancer. 2010;17:581–588. 39. Amar L, Bertherat J, Baudin E, et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol. 2005;23:8812–8818. 40. Favier J, Gimenez-Roqueplo AP. Genetics of paragangliomas and pheochromocytomas. Med Sci. 2012;28:625–632. 41. Pacak K, Del Rivero J. Pheochromocytoma. Endotext [Internet]. South Dartmouth: MDText.com, Inc.; 2000–2013. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK278970/ 42. Martucci V, Pacak K. Pheochormoyctoma and paragnglioma: diagnosis, genetics, management and treatment. Curr Probl Cancer. 2014;38:7–41.

I. INTRODUCTION More than two million Americans were diagnosed with skin cancer in 2014, making it the most common malignancy in the United States and accounting for considerable morbidity. Most of the skin cancers are basal or squamous cell in origin with approximately 80% of these representing basal cell carcinomas (BCCs). Of these nonmelanoma skin cancers, most are curable but still approximately 2,000 people die each year from squamous cell carcinoma (SCC) or BCC.1 Melanoma accounted for approximately 76,100 cases and was responsible for an estimated 9,710 deaths in 2014, which far surpasses the number of deaths due to all other skin malignancies combined.2 Melanoma continues to increase in incidence at a higher rate than any other cancer in the United States, except for non–smallcell lung cancer in women. Approximately 5,120 cases of nonepithelial skin cancer cases with 3,270 deaths were diagnosed in 2014.1 These less common tumors of the skin include Merkel cell cancer, Kaposi sarcoma (see Chapter 25), and mycosis fungoides (MF). II. MELANOMA A. Natural history 1. Etiology and epidemiology Melanoma arises from pigment-producing melanocytes that migrate to the skin and eye from the neural crest during embryologic development. Approximately 5% of melanoma occurs in noncutaneous sites such as the eye and mucous membranes of the oropharynx, sinuses, vagina, and anus.3 Patients can present with regional lymph node involvement or distant metastatic disease without any primary being identified. This occurs in approximately 5% of patients. Melanoma occurs more commonly in men than women and has a peak age at incidence of approximately 50 years. Owing to the young age of many melanoma patients, this disease takes a striking toll in terms of the average number of years of life lost per patient in the United States. The incidence of the disease has increased in the United States to the point where melanoma is now the sixth most common cancer in men or women. The substantial increase in incidence is presumably due to increased exposure to sunlight (primarily ultraviolet B radiation), with the greatest risk of melanoma felt to be in those who have intermittent intense sun exposure, particularly in fair-skinned, light-haired individuals with red and blonde hair, and blue or green eyes. The cultural emphasis

on sun-tanned skin as an indicator of physical health and beauty has played a major role in this increase. Depletion of the ozone layer may contribute as well. Sunny parts of the United States have the highest incidence of the disease, especially California, Florida, Arizona, and Texas, which include three of the four most populous states in the United States. One particular melanoma subtype, lentigo maligna melanoma, which often occurs on the face, may be more closely associated with long-term occupational sun exposure and is seen in farmers and other outdoor workers. Patient education in prevention, including use of sun-protective clothing, performing outdoor activities at times other than the brightest sunlit hours of the day, use of topical sunscreens, refraining from use of sun-tan parlors, use of skin selfexamination, and avoiding sun-tanning (“tanned skin = damaged skin”), should be emphasized. Individuals with xeroderma pigmentosa, an autosomal-recessive disorder, typically incur multiple basal and squamous skin cancers and melanoma because their skin lacks the ability to repair damage induced by ultraviolet radiation. 2. Precursor lesions, genetics, and familial melanoma Melanomas arise not only from sporadic or familial atypical nevi but also from other congenital and acquired nevi; however, approximately half of cutaneous melanomas arise without a clear-cut precursor lesion. Individuals who have more than 20 benign nevi are at increased risk for melanoma. Approximately 10% of patients with melanoma have a family history of this cancer. Careful surveillance should be carried out in patients with these risk factors. Suspicious-appearing lesions or lesions that appear to have changed coloration, shape, height, or have bled should be excised. The familial atypical multiple mole melanoma syndrome is characterized by a young mean age at diagnosis (34 years) and multiple lesions. The most common germline mutation seen in familial melanoma occurs in the tumor suppressor gene CDKN2A. CDKN2A, PTEN, NRAS, and BRAF mutations have also been seen in nonfamilial melanoma.4,5 3. Types and appearance of primary lesions Clinical features, classically known as “ABCDE,” that raise suspicion for melanoma include: ■ Asymmetry of a lesion ■ Borders that are irregular ■ Color that is multihued ■ Diameter greater than 6 mm (i.e., “larger than the diameter of a pencil eraser”) ■ Evolution indicating a changing lesion Other characteristics of concern include history of recent growth, change in pigmentation, ulceration, itching, or bleeding. Any pigmented lesion that returns after excision should be reevaluated with biopsy. Nonpigmented skin lesions that behave like melanoma should be examined with immunohistochemical stains S-100 and HMB-45 as 1% to 2% of melanomas are amelanotic.3 There are four clinical types of primary cutaneous melanoma.3 Superficial

spreading melanoma is the most common type, accounting for 70% of melanomas. It is commonly found on the trunks of men and lower extremities of women. Nodular melanoma comprises 10% to 15% of melanomas and has an early vertical growth phase. It is commonly found on the trunks of men. Those lesions associated with intermittent sun exposure are often (50% to 60%) BRAF mutated but C-KIT wild type. Lentigo malignant melanoma accounts for approximately 10% of cases. It is characterized by flat, large (1 to 5 cm) lesions located on the arms, hands, and face of the elderly (median age 70 years) in particular and is known for a relatively longer radial phase. Acral lentiginous melanoma is seen in approximately 3% to 5% of cases and occurs primarily on the palmar surfaces of the hands, plantar surfaces of the feet, and under nails on the digits. This melanoma subtype is most commonly seen in individuals with darker-pigmented skin and is felt not to be as closely related to sun exposure as the other subtypes. Mutations in exons 9 and 11 of the CKIT gene are more commonly observed in acral lentiginous and mucosal melanomas than other subtypes, but still only occur in about 20% to 30% of these cases.4 In general, melanoma is felt to show two distinct growth phases: an initial radial phase during which the melanoma enlarges in a horizontal/superficial pattern above the basal lamina of the skin, followed eventually by a vertical growth phase characterized by invasion deeply with exposure to lymphatic vessels and the vasculature. It is during the vertical growth phase that metastases are felt to be most likely to occur (Table 15.1). TABLE

15.1

Clark Levels of Invasion

Level

Description

I

Limited to the epidermis

II

Invades papillary dermis

III

Extends to papillary–reticular dermal junction

IV

Invades reticular dermis

V

Invades subcutaneous fat

4. Patterns of metastases Melanoma has a proclivity for direct nodal spread presumably through the lymphatics, but a significant proportion of lesions exhibit hematogenous spread as well. Common sites of metastases include lung, liver, bone, subcutaneous areas, and, primarily in late stages, brain. However, melanoma can spread to virtually any site and can imitate virtually any solid malignancy in its pattern of spread. Following diagnosis, approximately 25% of patients will develop visceral metastases. An

additional 15% may develop disease limited to lymph nodes. Patients who present with lymph nodal or metastatic involvement without any obvious primary site may have undergone spontaneous remission of the primary, a phenomenon that may be attributable to some degree of immune system involvement. Interestingly, those patients may have a better outcome than similarly staged patients with known primaries. Patients with “cancer of unknown primary” should have their biopsy material analyzed with the immunohistochemical stains S-100 and HMB-45 to consider the possibility of melanoma. 5. Ocular melanoma Ocular melanoma is the most common malignancy of the eye in adults. It may occur in any eye structure that contains melanocytes, although uveal tract sites predominate, followed by choroid, ciliary body, and iris in decreasing frequency. Standard therapy may consist of either enucleation (often utilizing a “no touch” technique) or brachytherapy with radioisotopes such as iodine-125. A recently published large randomized study of those two treatments revealed that for primary uveal tumors less than 5 mm in depth, the outcome for survival was identical. This tumor metastasizes most frequently to the liver and appears to be less sensitive to both biologic agents and chemotherapy than is cutaneous melanoma. B. Staging Melanoma is staged according to the American Joint Committee on Cancer staging system.6 All patients should have a careful history and physical examination with special attention to the skin including scalp, mucous membranes, and regional lymph nodes. Pathology report should include thickness of the primary lesion, presence of absence of ulceration, number of mitoses per millimeter squared, and presence of lymphatic invasion.2,7,8 Laboratory studies should include complete blood count, blood urea nitrogen, serum creatinine, liver panel, alkaline phosphatase, and serum lactate dehydrogenase at baseline. A baseline chest radiograph is obtained to evaluate for pulmonary lesions. A computed tomography (CT) scan can be considered if clinically warranted. Elevation of liver function tests warrants further imaging of the liver, most typically with CT. Unexplained bone pain should also be evaluated with CT or magnetic resonance imaging. Primary lesions equal to or thicker than 1.0 mm are at higher risk of regional lymph node involvement; therefore, the use of sentinel node mapping is recommended for lesions between 0.76 and 1 mm and above. Important recent additions to the staging criteria include the concept of nodal disease burden, especially at the time of the sentinel node biopsy, and the presence or absence of mitoses in the primary lesion, which is a very significant negative prognostic factor.7,8 C. Surgical treatment The standard treatment for skin lesions suspected of being melanoma is excisional biopsy rather than incisional or “shave” biopsies. A subsequent wide and deep excision is required to provide adequate tumor-free margins as melanoma has a known propensity for local recurrences. While there is some variation in recommendations,

most experts would advocate a 1-cm tumor-free margin for melanomas less than 1 mm in thickness and 1- to 2-cm margins for deeper primary lesions if technically possible, following current National Comprehensive Cancer Network guidelines.9 Additionally, for primary lesions of at least 1 mm, sentinel node mapping is recommended. Lymph node “drainage areas” are assessed via a specific lymph node (sentinel node[s]— sometimes more than one) into which lymph-borne metastases generally first occur.10 The absence of tumor involvement in the lymph node is associated with a reduced risk of nodal spread and systemic relapse in general and eliminates the need for subsequent dissection of that nodal basin.11,12 In the recent Multi-Center Sentinel Lymph Node Trials 1, 1,347 patients with primary melanomas of 1.2 to 3.5 mm, felt to be at intermediate risk of recurrence, were randomly allocated to receive either observation or a sentinel node biopsy, with completion of lymphadenectomy if the sentinel node was positive and observation only if negative.13 A delayed lymph node dissection was performed in case of nodal recurrence in either group. Preliminary results from that trial suggest that there was no survival advantage for the performance of a sentinel lymph node biopsy in this risk group, although it reduced the relative risk of recurrence at any site by 26%, reduced the absolute chance of recurrence locoregionally from 15.6% to 3.4%, and confirmed that those with a positive sentinel node had a worse outcome than those with a negative sentinel node biopsy. D. Adjuvant therapy Eastern Cooperative Oncology Group (ECOG) protocol E1684 was a large randomized adjuvant trial of interferon (IFN)-α2b in patients with deep primary lesions (>4 mm thick) or regional lymph node involvement that showed statistically significant improvement in overall survival in the treated group compared with the observation group.14 The regimen used was IFN 20 million IU/m2 intravenously (IV) 5 days/week for 4 weeks (as a “loading phase”) followed by 10 million IU/m2 subcutaneously (SC) 3 days/week for 48 weeks as a maintenance phase. Toxicity was significant, but qualityof-life analysis demonstrated overall benefit. The follow-up study of observation versus the same IFN regimen versus a lower-dose regimen, ECOG 1690, also showed a significant disease-free survival advantage over the observation arm but not a benefit in overall survival for the high-dose regimen.15 The difference between these two studies may be that patients on the observation arm in the subsequent trial (1,690) may have been treated with immunotherapy (including IFN or interleukin [IL]-2) at the time of relapse. The final published randomized adjuvant study of high-dose IFN compared with a vaccine demonstrated a benefit in terms of relapse-free and overall survival for the IFN arm.16 A phase II study that evaluated a month of high-dose IFN versus the standard 1 year of drug for high-risk resected melanoma patients pioneered in ECOG 1684 suggested that the 1-month regimen was inferior.17 One month of high-dose IFN was also compared with chemotherapy for resected mucosal melanoma patients, with no advantage for the IFN cohort.18 Several recent meta-analyses of randomized trials of

high-dose IFN have shown that while there is a statistically significant and consistent advantage in relapse-free survival, the benefit for overall survival is very modest, at 2% to 3%.19,20 Nonetheless, given that patients with deep cutaneous primaries and/or lymph node involvement are at high risk for metastatic recurrence and that the majority of patients who suffer metastatic relapse will die of their disease, it is reasonable to treat such high-risk patients with either adjuvant high-dose IFN or to consider entrance into a clinical trial. While predictive biomarkers for the utility of adjuvant IFN are sought after and have not been clearly defined, the onset of vitiligo is often associated with a favorable outcome, as are other manifestations of autoimmunity, although their assessment is complicated by lead-time bias.21 This is because patients that appear to benefit from treatment will stay on therapy longer, increasing the likelihood of developing vitiligo. Peginterferon, which prolongs the half-life of the drug, allowing it to be delivered weekly, has been tested in several adjuvant trials in resected melanoma. In patients whose lesions were detected at sentinel node biopsy, there was an advantage in disease-free survival for peginterferon. In long-term follow-up of an EORTC randomized trial of peginterferon compared with placebo in patients with stage III resected disease, patients with ulcerated primary lesions that had nodal disease proven only by a sentinel lymph node biopsy had clear prolongation of survival with peginterferon.22,23 Ipilimumab, a CTLA-4-blocking human antibody, has been tested in a randomized phase III trial compared with placebo in patients with resected stage III melanoma. There was an increase in relapse-free survival for patients receiving up to 3 years of ipilimumab at 10 mg/kg compared with those receiving placebo, albeit at the cost of significantly increased side effects, chiefly so-called immune related adverse events.24 Chemotherapy as a single adjuvant modality has not been shown to be more beneficial than observation alone, and high-dose IFN with chemotherapy confers no difference in relapse-free or overall survival compared with the single-agent arms.25 Biochemotherapy was also compared with IFN in the adjuvant setting, though improvement was seen in relapse-free survival, no improvement was seen in overall survival plus there was increased toxicity in the biochemotherapy arm.26 Given the current data, IFN or observation remains the standard adjuvant option in the United States. Ongoing studies of ipilimumab and nivolumab hope to change this standard in the future. E. Therapy of metastases 1. General considerations about systemic therapy a. Patient selection While melanoma is considered relatively resistant to chemotherapy, certain favorable prognostic factors do lend themselves to longer survivals with singleagent or multiagent chemotherapy, high-dose IL-2, or even newer approved agents like ipilimumab, pembrolizumab, or nivolumab. These include ECOG performance status 0 or 1; subcutaneous, lymph node, or pulmonary metastasis

with normal lactate dehydrogenase (M1a or M1b disease); no prior chemotherapy; normal marrow, renal, and hepatic function; and absence of central nervous system (CNS) metastases. The biologic basis for these findings has not been fully elucidated. When reviewing potential therapy for stage IV melanoma patients, patient characteristics as well as the natural history of their metastatic disease must be considered. Surgical resection should be considered for one or even multiple sites of metastases that are resectable with a reasonable surgical procedure associated with modest morbidity. Failing that, for unresectable disease, an evaluation should be made whether the patient has indolent disease, suggesting that immunotherapy with frontline ipilimumab, or second-line pembrolizumab or nivolumab might be more appropriate, or more aggressive disease, indicating that other approaches are warranted, particularly a BRAF plus MEK combination if the patient’s tumor has a BRAF V600 mutation. While a clinical trial should generally be a first consideration for treatment-naïve or second-line patients with metastatic disease, high-dose IL-2 could also be considered in any line of therapy for the subset of patients that qualify for that rigorous therapy (Table 15.2). TABLE

15.2 Stage

Approximate Survival in Melanoma Based on Stage Grouping TNM (Pathologic)

Five-Year Survival (%)

IA

T1a

95

IB

T1b T2a

90 89

IIA

T2b T3a

77

IIB

T3b T4a

65

IIC

T4b

45

IIIA

N1a N2a

53 49

IIIB

N1b N2b

51 46

IIIC

N3

27

IV

M1a

19

M

98% 5-year OS in patients with 100% EOR based on volumetric analysis. Seven out of 8 studies with nonvolumetric assessment of EOR also confirmed a similar advantage of GTR on 5-OS. The 10-year OS in this series was 76% after GTR and 49% after STR, while MPFS was 12.5 and 7 years, respectively. Another series of 216 patients with a mean follow-up of 4.4 years showed that predicted OS was negatively influenced by a minimal residual tumor volume (as small as 10 cm3). The obvious caveat is that OS is not a valid tool in assessing outcomes in LGG because survival is often long. Therefore, achieving maximal survival with good quality of life (QoL) depends on the balance between decreasing oncologic burden (EOR) and respecting functional surgical boundaries. Data from three prospective randomized clinical trials in adults with LGG provide guidelines for the timing of radiation as well as the appropriate postoperative dose to use. The EORTC 22845 study demonstrated that the use of immediate versus delayed postoperative radiotherapy in patients improved median PFS (5.3 vs. 3.4 years), but did not affect median OS (7.4 vs. 7.2 years). Furthermore, there was no difference in the rate of malignant transformation between groups. However, this study observed that the use of immediate radiotherapy improved 1-year seizure control rates. Therefore, radiotherapy should be used for symptomatic patients as it can improve patient overall QoL.7,8 EORTC 22844 and INT/NCCTG both examined the use of high- versus lower-dose radiation regimens, and found that radiation doses of 45 to 54 Gy resulted in similar outcomes compared with higher doses (59 to 65 Gy) and were associated with improved tolerance without a decrement in OS when using the lower dose.9,10 Acceptable postoperative radiation doses for LGG range between 50.4 and 54 Gy, although a retrospective analysis by Shaw et al.11 suggested that postoperative radiation doses >53 compared with those 150 mg/dL with cryoprecipitate and fresh frozen plasma ■ Maintain platelet count ≥50,000/μL with platelet transfusions three or four times a day if necessary ■ Avoid central line placement ■ Avoid aminocaproic acid

APL, acute promyelocytic leukemia; ATRA, all-trans-retinoic acid; DIC, disseminated intravascular coagulation.

TABLE

19.13

Therapeutic Recommendations for APL

Induction recommendations ■ Induction therapy should consist of the administration of concomitant ATRA and anthracycline-based chemotherapy ■ On the basis of the available data, induction therapy should not be modified due to the presence of features such as secondary chromosomal abnormalities, FLT3 mutations, CD56 expression, and BCR3 PML-RARα isoform. ■ ATRA 45 mg/m2/day by mouth is divided into two doses with food given every day until CR (no longer than 90 days) plus an anthracycline, either DNR 50–60 mg/m2/day for 3 days or idarubicin 12 mg/m2 every other day for four doses. In the modified regimen used by the PETHEMA group, the fourth dose of idarubicin was omitted in patients older than 70 years of age. ■ It appears reasonable to initiate treatment with ATRA first for 2–3 days in patients with clinical evidence of bleeding to ameliorate the coagulopathy before initiating anthracycline-based therapy, provided the WBC count is not high (10,000/μL) younger than 60 years should receive at least one cycle of intermediate- and HiDAC: ■ Idarubicin 5 mg/m2/day × 4; Ara-C 1,000 mg/m2/day × 4; ATRA 45 mg/m2/day × 15 (consolidation #1) ■ Mitoxantrone 10 mg/m2/day × 5; ATRA 45 mg/m2/day × 15 (consolidation #2) ■ Idarubicin 12 mg/m2/day × 1; Ara-C 150 mg/m2/day/8 hours × 4; ATRA 45 mg/m2/day × 15 (consolidation #3) Arsenic can be considered for two cycles as an early consolidation followed by two courses of anthracycline and ATRA as given in the North American C9710 Intergroup trial ■ Arsenic therapy should be considered in the context of a clinical trial or for the patients not fit to receive chemotherapy. Maintenance recommendations ■ ATRA 45 mg/m2/day by mouth, divided into two doses with food for 15 days every 3 months (or 7 days on/7 days off plus 6mercaptopurine 90–100 mg/m2/day plus MTX 10–15 mg/m2/week all for 2 years), or ■ ATRA 45 mg/m2/day by mouth divided into two doses with food for 1 year, or ■ ATRA 45 mg/m2/day divided into two doses with food for 15 days every 3 months for 2 years. ■ Because early treatment intervention in patients with evidence of MRD results in better outcome than treatment in hematologic relapse, follow-up of PCR for PML-RARα every 3 months for up to 3 years is recommended for high-risk patients. Patients with lowand intermediate-risk disease can be monitored much less frequently or perhaps not at all (standard-risk disease).

APL, acute promyelocytic leukemia; Ara-C, cytarabine; ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CR, complete response; DNR, daunorubicin; IV, intravenous; MRD, minimal residual disease; PCR, polymerase chain reaction; PML, promyelocytic leukemia; RARα, retinoic acid receptor α; RT, reverse transcription; WBC, white blood cell.

2. Consolidation High rates of molecular remissions (approximately 95%) after at least two cycles of postinduction anthracycline-based chemotherapy have led to the adoption of this strategy as the standard for consolidation. Whereas a benefit from the addition of ATRA to consolidation chemotherapy has not been demonstrated in randomized trials. However, historical comparison of consecutive trials carried out independently by GIMEMA and PETHEMA groups showed a statistically significant improvement in outcome with the addition of ATRA to chemotherapy in consolidation. There is no consensus whether a specific chemotherapy regimen is optimal in consolidation. The focus of past research efforts has been to develop risk-adapted strategies to provide more intensive treatment in high-risk patients while minimizing toxicities in low-risk patients. A cooperative group multicenter studies done separately by PETHEMA (LPA2005) and GIMEMA (AIDA2000) administered cytarabine in high-risk patients only and reported an improved incidence of relapse compared with historical controls. However, this improved outcome is likely related to the use of ATRA in consolidation as the historical comparator received chemotherapy without ATRA. With the discovery of ATO, first-line ATRA-based consolidation regimens using ATO as a substitute for chemotherapy were developed. The North American Intergroup has shown in a randomized trial (C9710) that adding ATO to consolidation significantly improved DFS and OS in all risk groups.14 Subsequently, studies omitting chemotherapy and using only ATRA and ATO for consolidation reported excellent outcomes with 3-year OS of 85%. As mentioned above, randomized prospective data from a phase III trial demonstrated that ATRA/ATO after ATRA/ATO induction achieves excellent outcomes in low-risk patients.10 Therefore, in patients presenting with a WBC of ≤10,000/μl who do not have contraindications to ATO, a non–chemotherapy-based consolidation approach (as with induction) can be considered the new standard of care. In high-risk patients, ATRA/ATO combined with idarubicin for induction followed by ATRA/ATO consolidation without chemotherapy has demonstrated very favorable results and is commonly considered regimen of choice in these patients. Alternatively, a course of ATRA and idarubicin alone (without ATO) for induction followed by ​intermediate-dose cytarabine as the first consolidation is also an effective treatment strategy and can be used in high-risk ​patients. Although cytarabine appears to benefit high-risk ​patients when incorporated into ATRA and anthracycline-based regimens, its role in combination with ATO, if any, is unknown. 3. The role of HSCT Because of the high cure rates with ATRA/ATO and chemotherapy combinations, there is no role for a routine use of HSCT for patients with APL in molecular remission after consolidation chemotherapy. 4. Maintenance

Prolonged maintenance therapy is typically included in modern APL treatment protocols, although its importance remains controversial. Traditionally, consolidation has been followed by 2 years of maintenance therapy with ATRA, 6MP, and methotrexate. Now that ATO is being used in induction and/or consolidation, need for maintenance has been questioned. The results of recent studies showed no advantage of maintenance therapy in patients who achieved complete molecular remission after consolidation, especially for standard-risk patients. Therapeutic recommendations for APL outside of clinical trials are given in Table 19.13. D. APL differentiation syndrome APL differentiation syndrome (DS) (formerly retinoic acid syndrome [RAS]) is the main life-threatening complication of therapy with differentiating agents (ATRA and/or ATO) that manifests as unexplained fever, hypotension, respiratory distress with pulmonary infiltrates, pericardial and pleural effusions, peripheral edema, weight gain, and acute renal failure. Typically, DS occurs between the second day and the third week of ATRA and/or ATO therapy, with the incidence between 5% and 27% and a mortality rate (for those who develop DS) between 5% and 29%. Early recognition and prompt initiation of corticosteroids are key to managing this complication. Although a rising WBC count may be a risk factor for DS, it may occur with a WBC count below 5,000/ μL. Regardless of the WBC count or the risk of neutropenic sepsis, at the first sign of DS, dexamethasone (10 mg IV twice a day) should be initiated. If the symptoms are mild, ATRA may be continued concomitantly with steroids under careful observation. However, if the symptoms are severe or do not respond to steroid therapy, ATRA should be temporarily discontinued. For induction regimens that include both ATRA and ATO, prophylaxis with prednisone (0.5 mg/kg/day) can be given from day 1 through completion of induction therapy. It is recommended that the prophylaxis regimen follow the specific protocol used. If a patient develops DS, it is recommended that treatment be changed from prednisone to dexamethasone 10 mg twice a day until acute DS resolves. The patient may then be returned to the previous prednisone dose. E. Relapsed APL Approximately 10% to 20% of patients treated with a combination of ATRA and chemotherapy eventually relapse. Although second remissions with standard therapy are common, particularly if the last exposure to ATRA occurred more than 6 to 12 months prior to relapse, they are not durable. Several clinical trials show that ATO has remarkable activity in this patient population, leading to its FDA approval in this setting. Preclinical mechanisms of action of ATO include apoptosis and APL cell differentiation. Chinese investigators demonstrated CR rates of at least 85% and 2-year DFS of 40% in patients with relapsed APL. A U.S. multicenter study of ATO for induction and consolidation therapy for relapsed APL confirmed the high CR and longterm survival rates, and most importantly, an 85% rate of molecular remission after the completion of the consolidation therapy.

Two studies conducted in the pre-ATO era suggested a benefit for preemptive therapy at the development of the molecular relapse compared with treatment initiated at the time of frank hematologic relapse. Although the benefit of early intervention with ATO-based therapy remains to be proven, the high risk of hemorrhagic death and development of APL MRD associated with overt disease argues strongly in favor of an early intervention. Hence, molecular monitoring of MRD every 3 months for 3 years is recommended particularly for high-risk patients (Table 19.14). F. Early death rate Early death, and not relapse, has emerged as the single most important limitation of cure for the majority of APL patients. This is related to the characteristic bleeding diathesis. Current recommendations are that when a diagnosis of APL is suspected on the basis of clinical presentation and/or morphology, the disease should be treated as a medical emergency. Urgent administration of ATRA should be initiated with aggressive supportive measures including blood product support with platelets and cryoprecipitate while the genetic diagnosis is rapidly established.15 TABLE

19.14

Recommendations for Relapsed APL

■ For patients with confirmed molecular relapse (two successive PCR-positive results, demonstrating stable or rising PML-RARα transcript levels), preemptive therapy must be initiated to prevent frank relapse. ■ ATRA and chemotherapy combination may be used as a salvage regimen; however, ATO-based regimens are considered the first option in the setting of relapsed APL. ■ ATO ■ Induction: 0.15 mg/kg IV over 2 hours daily until bone marrow remission occurs, up to cumulative maximum of 60 doses. Bone marrow biopsy should be obtained on or before day 28 of therapy, and subsequently weekly until CR. ■ Consolidation: start 3–4 weeks after completing the induction therapy at 0.15 mg/kg IV over 2 hours daily or 5/7 days, for a cumulative total of 25 doses. ■ Maintain potassium >4 mEq/L and magnesium >1.8 mg/dL. ■ Frequent EKG monitoring for prolonged QTc interval assessment. ■ Monitor WBC count and for signs of APL differentiation syndrome. Institute steroids (dexamethasone 10 mg IV twice a day) at the earliest suggestion of the APL differentiation syndrome. ■ HSCT. Patient should be referred for the evaluation for the HSCT ■ Allogeneic-HSCT if fails to achieve a molecular remission ■ Autologous-HSCT if in molecular remission. ■ For patients in whom HSCT is not feasible, repeated cycles of ATO with or without ATRA with or without chemotherapy should be considered.

APL, acute promyelocytic leukemia; ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CR, complete response; EKG, electrocardiogram; HSCT, hematopoietic stem cell transplantation; IV, intravenously; PCR, polymerase chain reaction; WBC, white blood cell.

G. HSCT in relapsed APL Despite the high initial CR rates in relapsed disease, many patients relapse following ATO-based treatment. Results of retrospective studies have demonstrated that HSCT may be an effective option at this point or on achievement of second CR following ATO therapy. Auto-HSCT is associated with lower ​transplant-related mortality and is a reasonable option for patients in molecular remission and prolonged (greater than 1

year) first CR. Allo-HSCT is associated with a higher rate of transplant-related mortality but offers greater antileukemic activity due to the GVL effect. It could be recommended for patients who fail to achieve a complete molecular remission or those with short CR duration. Table 19.14 gives recommendations for treatment of relapsed APL. VI. THERAPY FOR ADULT ALL Over the last 40 years, significant advances have been made in the management of adult ALL. Current therapeutic strategies incorporate a more intensive induction and postremission regimens and take into account biologic and clinical features of the disease. Despite an excellent initial response to therapy (CR 80% to 90%), the overall long-term DFS is 40% to 50% in adult patients with ALL. Most chemotherapeutic regimens for ALL have been developed as complete programs without testing the contributions of the individual components, and they have not been compared with one another in a rigorous prospective randomized fashion. All patients undergoing therapy for ALL should be enrolled in clinical trials. The goals of intensified therapy are to eliminate leukemia cells, as determined by light microscopy and flow cytometry, prior to the emergence of drug-resistant clones, to restore normal hematopoiesis and to provide adequate chemoprophylaxis for the sanctuary sites such as the CNS. A typical ALL regimen consists of induction, ​consolidation/intensification, and maintenance; CNS prophylaxis is usually administered during induction and consolidation. Recent data from clinical trials demonstrate that young adults who were treated on adult protocols fared significantly worse than the same age group treated on pediatric protocols. This superior outcome has been attributed to the more intensive treatment on pediatric protocols, which includes high-dose steroids and L-Asp as well as better adherence to the therapy by patients, parents, and doctors. Currently, clinical trials evaluating the pediatric-type therapy in adult patients up to the age of 40 years are ongoing. A. Induction The addition of an anthracycline to the standard pediatric ALL induction regimen of vincristine, prednisone, and L-Asp increased CR rates in adults from 50–60% to 70%– 90%, and median duration of the disease remission to approximately 18 months. In some studies, dexamethasone has been substituted for prednisone because of its higher in vitro activity and better CNS penetration. However, findings of a small, randomized study showed that an augmented dose of prednisone produced results comparable to those achieved with dexamethasone in the context of intensive chemotherapy. Although L-Asp proved to be of value in the preanthracycline era, and in pediatric trials produced better survival when administered during induction and/or postinduction phases, its role in anthracycline-based adult programs is evolving. Given the significant toxicity of L-Asp, many investigators do not recommend its use in older patients; however, incorporation of L-Asp in intensive regimens for young adults is actively

investigated. The newer PEGylated form of L-Asp (peg-asp) has a prolonged half-life and has been FDA-approved for pediatric ALL. The CALGB 9511 trial substituted pegasp for native asparaginase and demonstrated CR rate of 76%, median OS of 22 months, and DFS at 7.5 years of 21%. Attempts to further improve the outcome of patients with ALL led to the incorporation of agents such as cytarabine, cyclophosphamide, etoposide, mitoxantrone, and MTX in induction and postinduction therapy. It is unclear whether intensification with additional agents or using multiple phases of induction therapy improved CR rates in the unselected patients; however, it may benefit certain subgroups. In a double blind, randomized trial conducted by CALGB, administration of G-CSF shortened the duration of neutropenia from 29 days in the placebo group to 16 days in G-CSF group. The CR rates were higher with G-CSF (90% vs. 81%), whereas induction mortality was higher in the placebo group (11% vs. 4%).16 B. Consolidation (intensification) therapy This typically includes three to eight cycles of non–cross-​resistant drugs administered after the remission induction. As mentioned previously, no randomized studies have compared the plethora of existing regimens (Linker trial, French LALA-94 trial, CALGB 8811 study, the MRC UKALL XA, GIMEMA ALL 0288 trial, the PETHEMA ALL-89 randomized trial, hyper-​cyclophosphamide, vincristine, doxorubicin, and dexamethasone [CVAD], or R-hyper-CVAD). C. Maintenance The benefit of maintenance therapy in adult patients with ALL has not been proven in randomized clinical trials, but is considered routine practice for most subtypes of ALL. In patients with low-risk disease, who enjoy outcomes similar to pediatric patients, maintenance therapy appears to be justified. Considering that more than half of the highrisk patients relapse while undergoing maintenance therapy, alternative strategies of eradicating MRD are urgently needed. The utility of maintenance therapy has been questioned for patients with T-cell ALL, and it is not given for patients with mature Bcell ALL or those with Philadelphia (Ph) chromosome–positive disease. The traditional maintenance regimen is given for approximately 2 years and includes daily doses of 6-mercaptopurine, weekly doses of MTX, and monthly doses of vincristine and prednisone. Dose intensification or extension of maintenance beyond 3 years does not appear to be of benefit, whereas its omission has been associated with shorter DFS. D. Recommendations for the therapeutic regimens for pre–B- and T-cell lineage ALL Although T-cell ALL previously had a poor prognosis with standard induction and maintenance chemotherapy, with the advent of more intensive chemotherapy regimens, response rates and long-term DFS are comparable to those for precursor B-cell ALL. A response rate of 100% and a projected long-term DFS of 59% were demonstrated by the regimen devised by Linker and colleagues in 2002 for T-cell ALL. The CALGB 8811 protocol produced a 100% CR rate with a 63% 3-year RFS for a similar group of

patients. Precursor B-cell and T-cell ALL are treated with similar regimens in most contemporary protocols. 1. Berlin-Frankfurt-Muenster (BFM)-like regimens (MRC/ECOG) The MRC UKALL XII/ECOG E2993 treatment regimen should be considered for patients regardless of age who are thought to be able to withstand the rigors of an intensive program.17 a. Induction (Consisting of two phases): 1) Phase I, weeks 1 to 4. ■ Vincristine1 1.4 mg/m2 (maximum 2 mg) IV push on days 1, 8, 15, and 22, and ■ Prednisone 60 mg/m2 by mouth on days 1 to 28 ​(followed by rapid taper over 7 days), and ■ DNR23 60 mg/m2 IV push on days 1, 8, 15, and 22, and ■ L-Asp 10,000 U IV (or intramuscularly) once daily on days 17 to 28. 2) Phase II, weeks 5 to 8, should be postponed until the total WBC exceeds 3 × 103/μL. ■ Cyclophosphamide 650 mg/m2 IV on days 1, 15, and 29, and ■ Cytarabine 75 mg/m2 IV on days 1 to 4, 8 to 11, 15 to 18, and 22 to 25, and ■ 6-Mercaptopurine 60 mg/m2 by mouth once daily on days 1 to 28. Direct Bilirubin

Dose of Vincristine to Give

Dose of DNR to Give

2–3 mg/dL

100% calculated

50% calculated

>3 mg/dL

50% calculated

25% calculated

b. CNS treatment and prophylaxis If CNS leukemia is present at diagnosis, MTX IT or via an Ommaya reservoir is given weekly until blasts are cleared from the CNS fluid. Additionally, 24 Gy cranial irradiation and 12 Gy to the spinal cord are administered concurrently with phase II induction. If CNS leukemia is not present at diagnosis, MTX 12.5 mg IT on day 15 in phase I and MTX 12.5 mg IT on days 1, 8, 15, and 22 in phase II are given. c. Intensification therapy begins 4 weeks after induction phase II and should be postponed until the WBC is greater than 3 × 103/μL. ■ MTX 3 g/m2 IV on days 1, 8, and 22 ■ Leucovorin rescue starting at 24 hours 10 mg/m2 by mouth or IV every 6 hours × 12 or until the serum MTX concentration is less than 5 × 10−8 M, and ■ L-Asp 10,000 U on days 2, 9, and 23.

d. Consolidation therapy (for patients not proceeding to ​allo-HSCT). Given after intensification when the WBC is higher than 3,000/μL and the platelet count is higher than 100,000/μL. 1) Cycle I consolidation ■ Cytarabine 75 mg/m2 IV on days 1 to 5, and ■ Vincristine 2 mg IV on days 1, 8, 15, and 22, and ■ Dexamethasone 10 mg/m2 by mouth on days 1 to 28, and ■ Etoposide 100 mg/m2 IV on days 1 to 5. 2) Cycle II consolidation (begins 4 weeks from day 1 of first cycle or when WBC exceeds 3,000/μL) ■ Cytarabine 75 mg/m2 IV on days 1 to 5, and ■ Etoposide 100 mg/m2 IV on days 1 to 5. 3) Cycle III consolidation (begins 4 weeks from day 1 of second cycle or when WBC exceeds 3,000/μL) ■ DNR 25 mg/m2 IV on days 1, 8, 15, and 22, and ■ Cyclophosphamide 650 mg/m2 IV on day 29, and ■ Cytarabine 75 mg/m2 IV on days 31 to 34 and 38 to 41, and ■ 6-Thioguanine 60 mg/m2 by mouth on days 29 to 42. 4) Cycle IV consolidation (begins 8 weeks from day 1 of third cycle or when WBC exceeds 3,000/μL). ■ Cytarabine 75 mg/m2 IV on days 1 to 5, and ■ Etoposide 100 mg/m2 IV on days 1 to 5. e. Maintenance for adult ALL by MTX- and 6-mercaptopurine-based therapy Pulses of vincristine and prednisone are given as “reinforcement” because they have relatively little toxicity. Maintenance therapy should be continued for 2.5 years from start of intensification. ■ 6-Mercaptopurine 75 mg/m2/day by mouth, and ■ Vincristine 2 mg IV every 3 months, and ■ Prednisone 60 mg/m2 by mouth for 5 days every 3 months with vincristine, and ■ MTX 20 mg/m2 by mouth or IV once per week for 2.5 years. 2. CALGB 8811 consists of a five-drug combination devised to achieve more rapid cytoreduction during the induction phase. For B-​cell–lineage ALL, it produced an 82% CR rate with 41% DFS at 36 months. Patients in remission receive multiagent consolidation treatment, CNS prophylaxis, late intensification, and maintenance chemotherapy for a total of 24 months. CALGB 8811 should be considered for patients, regardless of age, who are thought to be able to withstand the rigors of an intensive program. a. Induction for patients 60 years or younger ■ Cyclophosphamide 1,200 mg/m2 IV on day 1, and

■ DNR 45 mg/m2 IV on days 1, 2, and 3, and ■ Vincristine 2 mg IV on days 1, 8, 15, and 22, and ■ Prednisone 60 mg/m2/day by mouth on days 1 to 21, and ■ L-Asp 6,000 IU/m2 SC on days 5, 8, 11, 15, 18, and 22. b. Induction for patients older than 60 years ■ Cyclophosphamide 800 mg/m2 on day 1, and ■ DNR 30 mg/m2 on days 1, 2, and 3, and ■ Prednisone 60 mg/m2/day on days 1 to 7. c. Early intensification (two cycles) ■ IT MTX 15 mg on day 1, and ■ Cyclophosphamide 1,000 mg/m2 IV on day 1, and ■ 6-Mercaptopurine 60 mg/m2/day by mouth on days 1 to 14, and ■ Cytarabine 75 mg/m2/day SC on days 1 to 4 and 8 to 11, and ■ Vincristine 2 mg IV on days 15 and 22, and ■ L-Asp 6,000 U/m2 SC on days 15, 18, 22, and 25. d. CNS prophylaxis and interim maintenance ■ Cranial irradiation 2,400 cGy on days 1 to 12, and ■ IT MTX5 15 mg on days 1, 8, 15, 22, and 29, and ■ 6-Mercaptopurine 60 mg/m2/day by mouth on days 1 to 70, and ■ MTX 20 mg/m2 by mouth on days 36, 43, 50, 57, and 64. e. Late intensification ■ Doxorubicin 30 mg/m2 IV on days 1, 8, and 15, and ■ Vincristine 2 mg IV on days 1, 8, and 15, and ■ Dexamethasone 10 mg/m2/day by mouth on days 1 to 14, and ■ Cyclophosphamide 1,000 mg/m2 IV on day 29, and ■ 6-Thioguanine 60 mg/m2/day by mouth on days 29 to 42, and ■ Cytarabine 75 mg/m2/day SC on days 29 to 32 and 36 to 39. f. Prolonged maintenance (monthly until 24 months from diagnosis) ■ Vincristine 2 mg IV on day 1, and ■ Prednisone 60 mg/m2/day by mouth on days 1 to 5, and ■ MTX 20 mg/m2 by mouth on days 1, 8, 15, and 22, and ■ 6-Mercaptopurine 60 mg/m2/day by mouth on days 1 to 28. 3. Other vincristine, prednisolone, and daunorubicin (VPD)-based regimens A number of variations on the basic VPD program have been described. VPD should be used for patients who are thought not to be able to tolerate a more intensive chemotherapy program. Some options are shown in parentheses. a. Induction ■ Vincristine 2 mg IV on days 1, 8, 15, (22), and ■ Prednisone 40 or 60 mg/m2 by mouth on days 1 to 28 or days 1 to 35,

followed by rapid taper over 7 days, and ■ DNR 45 mg/m2 IV on days 1 to 3, and ■ L-Asp 500 IU/kg (18,500 IU/m2) IV on days 22 to 32. b. CNS prophylaxis is given as six doses of IT MTX and whole-brain irradiation starting on approximately day 36. c. Maintenance is usually started once the marrow suppression and the oral toxicity of the CNS prophylaxis have cleared. Maintenance may be given in a pulse or a continuous manner. Although allopurinol is usually not needed after remission is achieved, the dose of 6-mercaptopurine should be decreased by 75% when given concomitantly with allopurinol. d. Pulse maintenance is an 8-week cycle consisting of three courses of MTX and 6-mercaptopurine given every 2 weeks, followed by a 2-week pulse of vincristine and prednisone. ■ MTX 7.5 mg/m2 by mouth on days 1 to 5 during weeks 1, 3, and 5, and ■ 6-Mercaptopurine 200 mg/m2 by mouth on days 1 to 5 during weeks 1, 3, and 5, and ■ Vincristine 2 mg IV on day 1 during weeks 7 and 8, and ■ Prednisone 40 mg/m2 by mouth on days 1 to 7 during weeks 7 and 8. Oral MTX should be taken in a single daily dose because splitting the daily dose significantly increases the mucositis. Approximately three doses of IT MTX are needed once maintenance has started. The schedule should be coordinated so that the IT MTX is given on day 1 of the 5 scheduled days of oral MTX. On those days when IT MTX is given, the oral MTX is not given. Pulse maintenance is given for 3 years. Dose adjustments for hematologic toxicity from the MTX and 6mercaptopurine should be made on the basis of blood cell counts obtained before the start of each course. Dose

ANC (/μL)

Platelets (/μL)

100%

≥2,000

≥100,000

75%

1,500–1,999

75,000–99,999

50%

1,000–1,499

50,000–74,999

0%

55% prolymphocytes). The immunophenotype is different from CLL; the cells are positive for CD19, CD20, and CD24, and strongly express CD22, surface immunoglobulins, and FMC7. Less than a third express CD5 or CD23. What was formerly called T-CLL or chronic T-cell lymphocytosis was renamed in the World Health Organization classification as T-PLL. T-PLL has a median age of diagnosis of 65 years and is associated with a light male predominance. There is a younger variant

(median age of 30 years) that is associated with ataxia telangiectasia. Patients with TPLL present similarly to B-PLL but may also have skin infiltration and serous effusions. Patients with PLL tend to respond poorly to either single-agent or combination chemotherapy, with ORRs of less than 25% and rare CRs. The median survival for de novo PLL is 3 years, and it is less than a year for T-PLL. Small series and anecdotal cases suggest activity for nucleoside analogs and alemtuzumab in PLL. Allogeneic stem-cell transplantation should be considered for younger patients whose disease is responsive to induction therapy. B. Hairy cell leukemia (HCL) HCL is diagnosed in about 600 to 800 new patients each year in the United States. The median age at presentation is 52 years and there is a strong male predominance. Patients generally present with symptoms referable to cytopenias. The most common signs include palpable splenomegaly (72% to 86%), hepatomegaly (13% to 20%), hairy cells in the peripheral blood (85% to 89%), thrombocytopenia (less than 100,000/μL: 53%), anemia (hemoglobin less than 12/dL: 71% to 77%), and neutropenia (absolute neutrophil count less than 500/μL: 32% to 39%). The lymphocytes in the peripheral blood generally have an eccentric, spongiform, kidney-shaped nucleus, with characteristic filamentous cytoplasmic projections. The malignant cells express the Bcell antigens CD19, CD20, as well as the monocyte antigen CD11c, and specifically CD103. Bone marrow biopsy is generally required to confirm the diagnosis, as the aspirate is often not obtainable. Treatment is indicated in the setting of massive or progressive splenomegaly, worsening blood counts, recurrent infections, greater than 20,000 hairy cells/μL of peripheral blood, or bulky lymphadenopathy. Until the early 1980s, splenectomy was the standard treatment for HCL. Splenectomy is now reserved for the rare patient who is refractory to treatment and has splenomegaly that is either symptomatic or is resulting in cytopenias. Purine analogs and, more recently, monoclonal antibodies are the current standard for the treatment HCL. C. Pentostatin The nucleoside analog, pentostatin (21-deoxycoformycin, DCF), is typically administered at doses of 4 mg/m2 IV every other week for 4 to 6 months. It has demonstrated ORR of 79% to 100% with a CR of 76% to 89% in previously untreated patients.86,87 Responses appear to be durable as long-term follow-up indicated an estimated 10-year OS of 81%.88 D. Cladribine Using a 7-day continuous infusion or a 2-hour infusion for 5 to 7 days, cladribine (CdA) achieves responses in 80% to more than 90% of patients, including 65% to 80% CRs.89,90 These responses tend to be durable. One study reported a 12-year PFS of 54% and OS of 87%.90 In many cases, relapse is characterized only by an increase in bone marrow hairy cells, with no indication for treatment. Most patients who require retreatment achieve a second durable response.

The results with DCF are equivalent to those with CdA. The shorter duration of treatment makes CdA somewhat more attractive, although it may be associated with greater neurotoxicity and myelosuppression. E. Rituximab Rituximab has also shown promise for patients with HCL who fail purine analog therapy: ORR 50 to 80.91,92 It has been studied both sequentially and concurrently with pentostatin and CdA, demonstrating promising activity in relapsed and refractory disease.93 When administered following CdA in previously untreated patients, the CR was 100% and the median CR duration had not been reached.94 Other biologic therapies include the immunoconjugates against CD22 and CD25, which are strongly expressed in classic HCL and have shown promise in relapsed and refractory setting.95 BL22, a recombinant anti-CD22 immunotoxin, produced durable responses in up to 77% (CR 47%) of relapsed and refractory patients in the phase II setting, whereas the higher-affinity moxetumomab pasudotox is now being studied in a single-arm phase III trial for a better assessment of efficacy (NCT01829711). The BRAF V600E mutation, present in most patients, has also become a popular target given the availability of vemurafenib. Numerous case reports have indicated activity in patients with chemotherapy-resistant disease.96,97 Vemurafenib is currently under phase II investigation in the relapsed and refractory setting (NCT01711632), as is ibrutinib (NCT01841723).

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I. BCR-ABL1-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS A. Overview The myeloproliferative neoplasms (MPNs) are clonal disorders of pluripotent hematopoietic stem cells or of lineage-committed progenitor cells. MPNs are characterized by autonomous and sustained overproduction of morphologically and functionally mature granulocytes, erythrocytes, or platelets. Although one cellular element is most strikingly increased, it is not uncommon to have modest or even major elevations in other myeloid elements (e.g., thrombocytosis and leukocytosis in patients with polycythemia vera [PV]). Bone marrow (BM) aspirates and biopsy specimens typically show hyperplasia of all myeloid lineages (panmyelosis). Morphologic maturation and cellular function are essentially normal, although platelet dysfunction occasionally contributes to bleeding. The overproduction of blood elements in MPNs now appears related to “switched-on” tyrosine kinase signaling pathways. For chronic myelogenous leukemia (see Chapter 19), this arises from the t(9;22) translocation and the BCR-ABL1 gene product. On the other hand for the BCR-ABL1-negative MPNs, a single nucleotide mutation in the gene coding for JAK2, a tyrosine kinase normally activated by erythropoietin and other cytokines, plays an analogous role. This group of MPNs that encompasses PV, essential thrombocythemia (ET), both primary and secondary myelofibrosis (MF),1 is discussed in the first section of this chapter. The incidence of PV ranges from 0.4 to 2.8/100,000/year, ET 0.4 to 3.4/100,000/year, and primary myelofibrosis (PMF) 0.8 to 2.1/100,000/year. Ever since the observation of William Dameshek in 1951, that PV, ET, and PMF were a set of closely interrelated disorders, the understanding of the pathogenesis of classical MPNs has come a long way. This evolution has been marked by three major milestones that rendered MPNs among the best genetically characterized malignancies. The first finding was in 2005, with the detection of somatically acquired mutations of the gene JAK2 in the majority of patients with MPNs. The point mutation V617F in exon 14 of JAK2 is present in 74% to 97% of patients with PV, and in 30% to 65% of patients with ET or PMF. The second breakthrough occurred in 2006, with the detection of the myeloproliferative leukemia (MPL) virus oncogene mutations in 3% to 5% and 8% to 11% of nonmutated JAK2 ET and PMF, respectively. Lastly, the third milestone

was in 2013, when mutations in calreticulin (CALR) gene were observed in approximately 50% to 70% of patients with ET or PMF who do not carry a mutation in either the JAK2 or MPL gene.2 The above-mentioned genetic discoveries have rendered approximately 90% of patients with MPN carriers of a mutually exclusive mutation in only one of these three genes: JAK2, MPL, or CALR.3 Therefore, positivity for JAK2 V617F gives important diagnostic confirmation for MPNs, although a negative result is not basis for exclusion. Other discovered mutations are less specific to MPNs but are prognostically relevant, such as additional sex combs–like 1 (ASXL1) mutation. The prognostic value varies by mutation and can be summarized as follows; in ET, JAK2 mutations are associated with increased risk of thrombosis, while in PMF patients, type 1 or type 1–like CALR mutations are associated with superior survival, and ASXL1 mutations with inferior survival.3,4 Major MPN-related complications comprise thrombosis and leukemic or fibrotic transformation. The management of MPNs was also revolutionized with the discovery of these new mutations through the development of molecularly targeted therapy, including JAK inhibitors. JAK inhibitors have shown promising activity in controlling splenomegaly and constitutional symptoms in PMF and PV, which led to the recent approval of the JAK inhibitor ruxolitinib for use in hydroxyurea-resistant PV. In view of these changes, the next sections discuss the diagnosis, evolution, prognosis, and the recent therapeutic advances for PV, ET, and PMF. B. Polycythemia vera 1. Diagnosis In the golden era of disease description, around the end of the 19th century, Vaquez was the first to describe the idiopathic entity, PV (maladie de Vaquez). Later on, Osler established it as a new clinical entity distinguished from secondary and relative polycythemia. PV must be distinguished from relative or spurious polycythemia (normal red blood cell [RBC] mass, decreased plasma volume) and from secondary erythrocytosis (increased RBC mass due to hypoxia, carboxyhemoglobinemia, inappropriate erythropoietin syndromes with tumors or renal disease, etc.). PV is suspected in patients with hemoglobin levels greater than 18.5 g/dL in men or 16.5 g/dL in women or hemoglobin levels greater than 17 g/dL in men or 15 g/dL in women if associated with a documented and sustained increase of at least 2 g/dL from an individual’s baseline value. Diagnostic evaluation begins with peripheral JAK2 V617F mutation screen and measurement of serum erythropoietin levels. This is because JAK2 is present in 97% of patients with PV and is not associated with other causes of increased hemoglobin/hematocrit levels; similarly, a subnormal serum erythropoietin level is expected and encountered in more than 90% of patients with PV but not in secondary or apparent polycythemia. However, neither the absence of JAK2 nor the presence of a normal erythropoietin level rules out the diagnosis of PV.3

The presence of a JAK2 V617F in suspected PV is highly supportive of the diagnosis, regardless of the serum erythropoietin level. In the absence of a JAK2 V617F mutation, the serum erythropoietin level is useful to guide further evaluation. If the serum erythropoietin level is subnormal, a JAK2 exon 12 mutation screen should be performed. In the setting of a negative JAK2 mutation and a normal erythropoietin level, the diagnosis of PV is unlikely and evaluation should focus on secondary causes of erythrocytosis. The oldest PV diagnostic criteria was developed in the late 1960s by the French polycythemia vera study group (PVSG). This was prior to the general availability of assays for erythropoietin and JAK2 mutational analyses, and at a time when blood volume studies were readily available. Today this diagnostic tool has its advantages and limitations. The PVSG diagnostic criteria for PV require the presence of all three major criteria or the presence of the first two major criteria and any two minor criteria: a. Major criteria ■ Increased RBC mass: males: ≥36 mL/kg and females: ≥32 mL/kg ■ Arterial oxygen saturation ≥92% ■ Splenomegaly b. Minor criteria ■ Platelet count >400,000/μL ■ White blood cell (WBC) count >12,000/μL ■ Leukocyte alkaline phosphatase score>100 ■ Serum vitamin B12 > 900 pg/mL or serum unbound B12 binding capacity >2,200 pg/mL. The World Health Organization’s (WHO) revised diagnostic criteria were developed to surpass some of the limitations of the PVSG diagnostic criteria.1 The diagnosis of PV requires meeting either both major criteria and one minor criterion or the first major criterion and two minor criteria: a. Major criteria ■ Hemoglobin greater than 18.5 g/dL in men, 16.5 g/dL in women, or other evidence of increased RBC volume ■ Presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12 mutation b. Minor criteria ■ BM biopsy showing hypercellularity for age with trilineagemyeloproliferation ■ Serum erythropoietin level below the normal reference range ■ Endogenous erythroid colony formation in vitro1 The 2008 WHO diagnostic criteria for PV are currently under revision. Proposed changes in PV include lowering of the diagnostic hemoglobin/hematocrit level to 16.5 g/dL/49% in men and 16 g/dL/48% in women, in the presence of

consistent BM morphology, and the inclusion of BM morphology as a major criterion, along with JAK2 mutation screening. Even though WHO revised diagnostic criteria are the most used tool for diagnosing PV, two interesting discussion topics remain unanswered. The first is whether the use of hematocrit rather than hemoglobin as a measuring tool provides a greater predictive value of the RBC volume for diagnosis and evaluation of response to therapy. This position is defended by the clinicians using the revised British Committee for Standards in Hematology’s definition as an alternative definition based on hematocrit. The second diagnostic dilemma pertains to the masked PV phenomena described by Barbui et al., where patients present with normal hemoglobin but with suspicious features as an unexplained thrombosis or itching.5 The important message here for clinicians is to maintain a high degree of clinical vigilance in this subset of patients. Figure 21.1 proposes a potential algorithm to guide clinicians in the diagnosis of PV. 2. Aims of therapy PV is generally an indolent disorder with the decision to treat on the basis of risk stratification. In patients younger than 60 years, the median survival is approximately 24 years. Risk factors for survival comprise leukocytosis (leukocyte count >13,000/μL [to convert to ×109/L, multiply by 0.001]), thrombosis, advanced age (>70 years), and abnormal karyotype. The respective 10-year relative survival rates for patients with no risk factors, one, and two risk factors were 84%, 59% and 26% respectively.6 In contrast, low-risk patients (i.e., those with no history of thrombosis, age less than 60 years, or platelets below 1 × 106/μL) are usually treated with phlebotomy and/or aspirin (ASA). The goal of phlebotomy is to keep the hematocrit level below 45% in men and below 42% in women. Initially, phlebotomy is used to reduce hyperviscosity by decreasing the RBC mass, and subsequent phlebotomies help maintain the RBC mass in a normal range. For patients with high-risk features (i.e., history of thrombosis, or an age greater than 60 years), treatment consists of phlebotomy, ASA, and cytoreductive therapy. Control of hypertension and diabetes and avoidance of smoking are also important. Although PV patients generally benefit of good outcomes, the challenges of uncontrolled PV symptoms and refractory disease are imminent clinical problems. To address these challenges a PV management algorithm is proposed in Figure 21.2.

FIGURE 21.1 Proposed diagnostic algorithm for PV. BM, bone marrow; EPO, erythropoietin; PV, polycythemia vera. 3. Treatment regimens a. Phlebotomy Removal of 350 to 500 mL of blood every 2 to 4 days (less often in the elderly or in patients with cardiac disease) is the standard initial approach; the goal is getting the hematocrit to 40% to 45%. The blood count is then checked monthly, and phlebotomy is repeated as needed to maintain the hematocrit at no more than 45%. Rapid lowering of the hematocrit may also be achieved in emergency situations by erythropheresis. Elective surgery should be deferred until the hematocrit has been stable at no more than 45% for 2 to 4 months. Platelet function should be evaluated before surgery or invasive procedures.6 b. Antithrombotic therapy Concomitantly with phlebotomy, use of low-dose ASA is now widely regarded as standard therapy, following a large European study (European Collaboration on Low-Dose Aspirin in Polycythemia [ECLAP]) utilizing 100 mg ASA daily that showed an approximately 60% reduction in thrombotic events.7 Higher doses of ASA (325 mg daily) carry risk of bleeding, especially in patients with platelet counts greater than 1.5 × 106/μL, in whom acquired von Willebrand disease may be seen. The exact thrombogenic role of platelets in MPNs is not clear, but hydroxyurea and anagrelide have been shown to lower platelet counts and reduce the risk of thrombosis.6

FIGURE 21.2 Management approach for PV. *European Leukemia Net Definition of Resistance/Intolerance to hydroxyurea. ASA, aspirin; CV, cardiovascular; HCT, hematocrit; INFα, interferon α; Plt, platelet; PV, polycythemia vera; WBC, white blood cells. c. Myelosuppressive agents Myelosuppressive agents are indicated in conjunction with phlebotomy for persistent thrombocytosis, recurrent thrombosis, enlarging spleen, or similar problems. They may also reduce the risk of progression to MF compared with phlebotomy alone. Most alkylating agents carry a high risk of inducing a secondary myelodysplastic syndrome (MDS) or leukemia and should no longer be used.6 Currently recommended choices are as follows: 1) Hydroxyurea 10 to 30 mg/kg by mouth daily. Weekly blood cell counts are required initially, with dose adjustments to maintain the hematocrit at no more than 45%, the platelet count at 100,000 to 500,000/μL, and the WBC count at greater than 3,000/μL. Side effects are usually minimal, but longterm use may cause painful leg ulcers and aphthous stomatitis. For younger patients and cases difficult to control with hydroxyurea, acceptable alternatives include the following. 2) Interferon-α (IFN-α) is usually effective in controlling hematocrit, platelet count, and splenomegaly and in relieving pruritus. The starting dose is 1 to 3

× 106 U/m2 three times weekly (pegylated interferon once weekly may also be an option—see Section I.C.2.5.). Common side effects include myalgia, fever, and asthenia, usually controlled with acetaminophen. Leukemogenic effects are presumably absent, but high cost is a deterrent to long-term use. For high-risk patients during pregnancy IFN-α is the optimal choice of management. Quintás-Cardama et al. published the results of their phase II trial with pegylated-IFN-α-2a (PEG-IFN-α-2a) treatment in 43 PV patients.8 This study showed that after a median follow-up of 42 months, complete hematologic response (CHR) was achieved in 76% of patients with a median duration to complete response of 40 days. The same study also reported a complete molecular response (CMR) in 18%, partial molecular response (65 years, (2) presence of constitutional symptoms, (3) hemoglobin 25 × 109/L, and (5) circulating blasts ≥1%. The prognostic model stratifies patients into four risk categories as follows: low risk (0 points; median survival 11.3 years), intermediate-1 (1 point; median survival 7.9 years), intermediate-2 (2 points; median survival 4 years), and high risk (3 or more points; median survival, 2.3 years). The JAK2 V617F mutation is present in approximately 50% of patients with PMF, mutations in MPL are found in 5% to 10% of patients, and CALR mutations in an additional 25% to 40%. CALR mutations seem to confer a better prognosis for patients with PMF (median survival, 15.9 years), while triple-negative patients harbor the worst prognosis (median OS, 2.3 years).3,17 Apart from the three driver mutations, a number of other mutations have been found at much lower frequencies in PMF. Even though most of these mutations are relatively less frequent, mutations in ASXL1, SRSF2, and EZH2 have been shown to be independently associated with reduced survival and ASXL1, SRSF2, and IDH1/2 with increased risk of transformation to acute leukemia. In particular, ASXL1 appears to be the most detrimental in PMF, and was used in a recent trial to establish a mutation-enhanced international prognostic scoring system (MIPSS) for PMF in the goal to further stratify patients classified as low risk by standard criteria. This novel scoring system incorporates four clinical variables (age, hemoglobin, platelet count, constitutional symptoms) and four molecular variables (triple negativity, JAK2/MPL mutation, ASXL1 and SRSF2 mutations). This recent trial showed a better survival predictive value for the MIPSS in comparison with the IPSS and allowed the identification of a subgroup within the conventional IPSS stratification with less favorable prognosis. An abnormal karyotype is also demonstrable in approximately 50% and connotes shortened survival time. Although no specific cytogenetic changes for PMF have been described, common abnormalities are del(13q), del(20q), and trisomy 8 or 9. Other adverse prognostic factors include advanced age, anemia, WBC count of less than 4,000/μL or greater than 30,000/μL, thrombocytopenia, blasts in peripheral blood, and hypercatabolic symptoms (weight loss, night sweats, fever). Diseases causing secondary marrow fibrosis, such as metastatic carcinoma, hairy-cell leukemia, and granulomatous infections, must be excluded. Similar to ET, the presence of a JAK2 V617F, CLAR, or an MPL mutation can be helpful to rule out reactive marrow fibrosis. However, the absence of these molecular markers does not exclude the presence of an MPN. Therefore, causes of reactive marrow fibrosis must be excluded in cases where no clonal marker is found. Again, BM histology in combination with other clinical and laboratory features helps to establish the diagnosis of PMF. BCR–ABL should be performed to rule out the presence of CML

and criteria for another myeloid neoplasm should not be met. The minor criteria, which help to establish a diagnosis of PMF, include leukoerythroblastosis, increased serum lactate dehydrogenase, anemia, and palpable splenomegaly. Major causes of death in PMF include marrow failure, infection, portal hypertension, and leukemic transformation. Cases of MDS with marrow fibrosis are easily confused with PMF. Postpolycythemic MF is clinically indistinguishable but carries a poor prognosis, evolving to acute leukemia in 25% to 50% of patients (compared with 5% to 20% for de novo PMF). Acute megakaryoblastic leukemia (M7) may also present with a myelofibrotic picture and be confused with PMF. The diagnosis of PMF requires meeting all three major criteria and two minor criteria: a. Major criteria ■ Presence of megakaryocyte proliferation and atypia, accompanied by either reticulin or collagen fibrosis; or, in the absence of significant reticulin fibrosis, the megakaryocyte changes must be accompanied by an increased marrow cellularity characterized by granulocytic proliferation and often decreased erythropoiesis (i.e., prefibrotic cellular-phase disease). ■ Not meeting WHO criteria for PV, CML, MDS, or other myeloid disorders. ■ Demonstration of JAK2 V617F or other clonal marker (e.g., MPL W515K/L); or, in the absence of the above clonal markers no evidence of secondary BM fibrosis.1 b. Minor criteria ■ Leukoerythroblastosis ■ Increased serum lactate dehydrogenase level ■ Anemia ■ Palpable splenomegaly.1 2. Treatment regimens PMF has a much more aggressive course than ET and PV, and treatments include androgen preparations (e.g., fluoxymesterone or danazol), corticosteroids, erythropoietin, and lenalidomide (LEN). Splenectomy should be considered for patients with portal hypertension, to improve anemia (due to sequestration) or for symptomatic relief of abdominal pain or problems with alimentation. Radiation therapy may be beneficial for palliative relief; however, a significant increase in the risk of neutropenia and infection is seen. Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is considered the only curable treatment option for patients with PMF. This option should be considered in young patients with intermediate-/high-risk PMF. For patients older than 60 years, a reasonable option would be a reduced-intensity conditioning regimen.18 Studies assessing the efficacy of JAK kinase inhibitor combinations are ongoing and, in the setting of clinical benefit, may eventually change the course of the disease.19 Intervention is indicated in the following situations.

3. Anemia Androgens (e.g., testosterone enanthate 600 mg intramuscularly weekly or fluoxymesterone 10 mg by mouth two or three times a day for men; danazol 400 to 600 mg by mouth daily for women) are recommended and reduce transfusion requirements in 30% to 50% of patients. Corticosteroids (e.g., prednisone 40 mg/m2 by mouth daily) should be tried if overt hemolysis is present. Erythropoietin is helpful in a small percent of patients but requires large doses; response is unlikely if serum erythropoietin level is greater than 200 mU/mL. In limited studies, improvement in cytopenias or transfusion requirements has been reported in 20% to 50% of patients with PMF receiving low-dose thalidomide (50 mg/day) or LEN (5 to 10 mg/day). PMF patients routinely become transfusion-dependent; early institution of iron-chelating agents is advisable. 4. Splenomegaly Massive splenomegaly may lead to cytopenias, portal hypertension, variceal bleeding, abdominal pain, or compression of adjacent organs. Anorexia, fatigue, and hypercatabolic complaints may be prominent. The first option for control by myelosuppressive therapy is hydroxyurea, given as for PV. Melphalan (2.5 mg by mouth three times weekly, with escalations up to 2.5 mg daily as tolerated) and busulfan (2 mg/day in older patients) can also be considered. IFN-α produces responses in some cases as well.19 Radiation 50 to 200 cGy is effective in improving splenomegaly but causes cytopenias in 40% of patients. Radiation occasionally is indicated for extramedullary hematopoietic tumors causing compression syndromes or for bone pain. Splenectomy is indicated in carefully selected cases but carries significant perioperative mortality and morbidity from bleeding, sepsis, and postoperative thrombocytosis. 5. Curative intent Allo-HSCT from appropriately matched donors appears to be potentially curative, but transplant-related mortality is high in patients with PMF who are older than 45 years. Younger patients with expected survival of no more than 5 years may be reasonable candidates. Engraftment rates are equal to those in other hematologic disorders, and a “graft versus myelofibrosis” effect has been demonstrated. Encouraging early results with nonmyeloablative allo-HSCT suggest that this modality may be the most appropriate option and is feasible in older patients with PMF.18 6. Novel therapies a. JAK2 inhibitors The approval of ruxolitinib in the United States, Europe, and Canada has significantly changed the treatment landscape for PMF. Regulatory approval of ruxolitinib for PMF was based on the results of two pivotal phase III trials, where ruxolitinib showed significantly better reduction in spleen volume

maintained to week 48 of study (approximately 50% reduction by palpation and more than 35% by radiology).20,21 Ruxolitinib also significantly improved PMFrelated symptoms and quality of life in comparison with the best available therapy. Although ruxolitinib has not been shown to eliminate the malignant clone, long-term follow-up analyses have demonstrated that the effects of ruxolitinib are durable, associated with delay in transformation and survival benefit. However, all these are at the expense of thrombocytopenia and anemia as the most common toxicities associated with ruxolitinib.21,22 These toxicities can be managed with dose reduction as avoidance of treatment interruption is important for overall success since symptoms return to baseline within 7 to 10 days. Current recommendations are to use a starting dose of 20 mg BID in patients with platelets above 200 × 109/L, 15 mg BID in patients with platelets between 100 and 200 × 109/L, and 5 mg BID for patients with platelet counts below 100 × 109/L. The dose can then be modified as tolerated to a maximum dose of 25 mg BID. b. Ruxolitinib combinations therapy In the goal of optimizing PMF outcomes a multitude of drug combination with ruxolitinib is currently being tested. c. Ruxolitinib plus panobinostat In the setting of moderate- to high-risk PMF, a phase II trial used 15 mg BID and panobinostat 25 mg TIW/QOW, which resulted in substantial reductions in splenomegaly. However, the study did not report improvements in other symptoms. AEs were within the expected range. 7. Conventional drug therapy a. Hydroxyurea Prior to the approval of ruxolitinib for MF by the Food and Drug Administration (FDA) in 2011, cytoreductive drugs such as hydroxyurea were used to control hyperproliferation. However, the natural course of the disease remained undisturbed, hydroxyurea rarely induces complete spleen regression, and responses are rarely durable. b. Immunomodulatory drugs (IMiDs) These agents have engendered an interesting clinical activity in a subset of patients with PMF, including improvements in anemia, thrombocytopenia, and splenomegaly, thought to be due to their effect on BM environment. Thalidomide and LEN induced responses in 16% to 34% of patients. The combination of LEN and prednisone may be more effective and safer than single-agent IMiD therapy. New agents like pomalidomide are under study. II. MYELODYSPLASTIC SYNDROMES This is a diverse group of hematopoietic stem cell clonal neoplasms characterized by ineffective hematopoiesis and dysplastic morphologic changes in one or more lineages.

The disease occurs at a median age of 65 to 70 years, is the most frequent hematologic malignancy in the above-65 age group, and affects more than 30,000 cases annually in the United States. For the population above 60 years of age, the incidence is 1 in 500. Eighty percent of cases occur de novo and have no specific etiology or known cause. In the remaining 20% of cases, an association with prior chemotherapy use can be identified, most frequently high-dose alkylator or topoisomerase-II inhibitor-based regimens, or exposure to radiation. Whether a specific inciting cause can be identified or not, the pathophysiologic process of MDS is DNA damage in a pluripotential BM stem cell with a dynamic balance of secondary and associated changes in proliferation, differentiation, and apoptosis intrinsic cellular pathways along with extrinsic marrow microenvironment, angiogenic, cytokine, and immune effects. The global DNA hypomethylation with concurrent silenced hypermethylation of gene promoter region characteristic of MDS genome provides an epigenetic mechanism for controlling gene expression. The studies that have proven disease response to hypomethylating agents (HMAs) present added evidence of the role of DNA methylation in the pathogenesis of MDS. Clonal cytogenetic abnormalities can be identified in 40% to 50% of de novo cases, most typically a loss of chromosome material involving chromosomes 5, 7, 11, 20, or Y, or trisomy of chromosome 8. Cytogenetic abnormalities in chromosomes 5 or 7 will be identifiable in 95% of therapy-related cases, with half of the cases also having complex cytogenetic changes involving three or more chromosomes.23 A. Diagnosis The typical clinical picture is an elderly patient with macrocytic anemia, with or without thrombopenia and neutropenia. In addition to routine history and physical exam, the documentation of transfusion history is necessary on the initial evaluation. Initial diagnostic studies needed are complete blood count with differential and peripheral smear review, BM aspirate and biopsy with cytogenetics, reticulocyte count, serum erythropoietin level prior to transfusion, thyroid stimulating hormone (TSH) level, serum iron, total iron binding capacity, serum ferritin, B12 and folate levels, along with human immunodeficiency virus status if a clinical concern, and human leukocyte antigen (HLA) typing in young patients if a candidate for transplant or aggressive immunosuppressive therapy. There is no single diagnostic test, however. A confirmed diagnosis is made from the hematologic picture of cytopenias and dysplastic lineage morphology supported by associated marrow cytogenetic findings, if abnormal. The typical dysplastic features seen in the marrow and peripheral blood include megaloblastoid precursors, budding and irregular nuclear outline of normoblasts, hypochromia and basophilic stippling of RBCs, iron-laden sideroblasts, hyposegmentation (bilobed Pelger-Huet like forms are characteristic) and hypogranularity of neutrophils, hypolobar and/or micromegakaryocytes, and hypogranular platelets. Platelet and neutrophil functional abnormalities exist, further contributing to the symptomatic cytopenias. The BM is most often hypercellular (but 10% to 20% will be hypocellular) with a low reticulocyte count. Abnormal localization

of immature precursors is often seen on the marrow core biopsy. A variable number of myeloblasts will be seen from less than 5% up to 20%. Differential diagnosis includes B12 and folate deficiency, lead poisoning and alcohol abuse in patients with sideroblastic anemia, aplastic anemia in patients with hypoplastic marrows, PMF if marrow fibrosis is present, and paroxysmal nocturnal hemoglobinuria (PNH). Further personalized testing might be considered depending on the clinical presentation: (1) in case of suspicion of large granular lymphocytic leukemia or PNH, clone flow cytometry might be helpful to confirm MDS diagnosis; (2) in young patients or patients with family history of cytopenias, consider further genetic testing to rule out Fanconi anemia and dyskaretosiscongenita. B. Classification The French-American-British (FAB) classification for MDS put forth in 1982 continues to be useful (Table 21.1). More recently, the WHO classification of MDS was modified in 2008 to better correlate with more homogenous subsets and natural histories (Table 21.2). The major changes (1) lowered the percentage of marrow blasts to define fullblown AML at greater than or equal to 20%, removing refractory anemia with excess blasts (RAEB) in transformation as a category; (2) separated out the 5q– syndrome, given its different clinical picture and treatment; and (3) moved chronic myelomonocytic leukemia (CMML) to a separate category of myelodysplastic/myeloproliferative disease. TABLE

21.1

MDS Subtypes: FAB Classification

TABLE

21.2

2008 WHO Classification of MDS and Pertinent Features

Subtype

Blood

Bone Marrow

RCUD*

Single or bicytopenia

Dysplasia in ≥10% of one cell line, 11 ng/mL) drawn at the time of the reaction may be helpful in determining the indication for desensitization. If the serum tryptase level is elevated, a subsequent level is needed to screen for mastocytosis.8,11

TABLE

26.5

Sample Carboplatin Skin Testing Protocol

1. All patients receiving their sixth and subsequent doses of carboplatin will have skin test dosing. 2. The planned carboplatin dose is diluted in 50 mL of 0.9% sodium chloride. A 0.02-mL aliquot is withdrawn and administered intradermally. 3. Following the intradermal injection, the injection site is examined at 5, 15, and 30 minutes. 4. A positive skin test is a wheal of ≥5 mm in diameter, with surrounding redness. A strongly positive skin test was one with ≥1 cm in diameter. If a patient develops a positive skin test, the physician is notified. 5. If the skin test is negative, the patient is then pretreated for the carboplatin with antiemetics, dexamethasone, diphenhydramine, and famotidine. Thirty minutes after the premedications are given, the carboplatin is given.

Source: Patil SU, Long AA, Ling M, et al. A protocol for risk stratification of patients with carboplatin-induced hypersensitivity reactions. J Allergy Clin Immunol. 2012;129(2):443–447; Calado J, Picard M. Diagnostic tools for hypersensitivity to platinum drugs and taxanes: skin testing, specific IgE, and mast cell/basophil mediators. Curr Allergy Asthma Rep. 2014;14:451; and Blatman KS, Castells MC. Desensitizations for chemotherapy and monoclonal antibodies: indications and outcomes. Curr Allergy Rep. 2014;14:453.

4. Desensitization procedures Desensitization procedures for specific agents may be utilized in patients in which there is considerable benefit to the continuation of therapy. Desensitization may be utilized after HSRs to paclitaxel, platinum agents (cisplatin, carboplatin, oxaliplatin), and rituximab, and is documented in the literature; however, planning for the desensitization is necessary. Regimens including dexamethasone 20 mg orally at 36 and 12 hours before chemotherapy and the morning of chemotherapy have been studied. Other regimens have included loratadine or cetirizine 10 mg for days and hours preceding the desensitization. Other premedications such as oral acetylsalicylic acid 325 mg may be used, if the reaction included flushing. A full 30 minutes before the chemotherapy, other IV premedications such as dexamethasone 20 mg, diphenhydramine 50 mg, and a H2-histamine antagonist are given. For paclitaxel, the desensitization procedure continues with administration of a test dose of 2 mg in 100 mL of normal saline over 30 minutes. If there is no reaction, 10 mg in 100 mL of normal saline is given over 30 minutes, followed by the remaining full dose in 500 mL of normal saline over 3 hours if there is still no reaction.12 If a reaction is experienced, the usual diphenhydramine and methylprednisolone medications are given. C. Chemotherapy-induced nausea and vomiting (CINV) Nausea and vomiting continue to be some of the most feared side effects of chemotherapy. Nausea and vomiting can be distressing enough to the patient to cause extreme physiologic and psychological discomfort, culminating in withdrawal from therapy. With the advent of more effective antiemetic regimens in the last 20 years, many improvements in the prevention and control of nausea and vomiting have led to a better quality of life for patients receiving chemotherapy. The goal of therapy is to prevent the three phases of nausea and vomiting: that which occurs before the treatment is administered (anticipatory), that which follows within the first 24 hours after the

treatment (acute), and that which occurs more than 24 hours after the treatment (delayed). It is also important to assess nausea and vomiting separately because they are different events and may have different causes. Factors related to the chemotherapy that can affect the likelihood and severity of symptoms include the specific agents used, the doses of the drugs, and the schedule and route of administration. Other patient characteristics that may affect emesis include history of poor emetic control, history of alcoholism, age, gender, anxiety level, and history of motion sickness.1,13 1. Emetic potential To plan an effective approach to control nausea and vomiting, the chemotherapeutic agents are grouped according to their emetic potential (Table 26.6).14,15 This type of categorization is helpful in making decisions regarding possible antiemetics to be used and how aggressive the antiemetic regimen should be for patients receiving chemotherapy for the first time or in subsequent treatments. It is important to select appropriate antiemetics from the outset with the first cycle of therapy. Failure to control nausea and/or vomiting may result in a conditioned response and subsequent anticipatory nausea and vomiting. 2. Antiemetic drugs Agents that have been effective in preventing and treating nausea and vomiting (Table 26.7) come from various pharmacologic classes. They work through different mechanisms that may relate to the pathophysiologic processes causing nausea and vomiting. Within the last 20 years, it was discovered that agents that block predominately the serotonin 5-hydroxytryptamine subtype 3 (5-HT3) receptors, rather than the dopamine receptors, have greater efficacy in the prevention of nausea and vomiting. More recent research indicates that the tachykinins, including a peptide called substance P, play an important role in emesis. Substance P binds to the neurokinin type 1 (NK-1) receptor. Thus, the NK-1 receptor antagonists are now validated in their role in inhibiting nausea and vomiting with moderately and highly emetogenic chemotherapy. NK-1 receptor antagonists are thought to improve acute nausea and vomiting associated with chemotherapy when combined with standard regimens (i.e., dexamethasone and 5-HT3 receptor antagonists) and to have additional effect during the period of delayed nausea and vomiting, alone or in combination with dexamethasone. Netupitant is a new fixed-dose oral agent that combines netupitant, a new highly selective NK-1 receptor antagonist, and palonosetron, a serotonin 5-hydroxytryptamine receptor antagonist. This provides an oral option for CINV associated with highly and moderately emetogenic chemotherapy.16 Olanzapine has recently been incorporated into clinical practice guidelines, not only for breakthrough nausea and vomiting, but for the prevention of acute and delayed emesis. Olanzapine has been studied in combination with palonosetron and dexamethasone.15,17–20

TABLE

26.6

Emetogenic Potential for Commonly Used Intravenous and Oral

Chemotherapeutic Agents*

Highly Emetogenic Agents (≥75% Potential for Nausea, Vomiting, or Both)

Moderately Emetogenic Agents Mildly Emetogenic agents (50%–75% Potential for (25%–50% Potential for Nausea, Vomiting, or Both) Nausea, Vomiting, or Both)

■ IV: ■ Carmustine ■ Cisplatin ■ Cyclophosphamide (>1 g/m2) ■ Cytarabine (>1 g/m2) ■ Dacarbazine ■ Doxorubicin (≥60 mg/m2) ■ Epirubicin ■ Ifosfamide (>1.2 g/m2) ■ Methotrexate (>1 g/m2) ■ Mitomycin (>15 mg/m2) ■ Oxaliplatin ■ Oral: ■ Lomustine ■ Procarbazine ■ Temozolomide

■ Ado-trastuzumab emtansine ■ Asparaginase ■ Bevacizumab ■ IV: ■ Bleomycin ■ Arsenic trioxide ■ Bortezomib ■ Azacitidine ■ Capecitabine ■ Bendamustine ■ Cetuximab ■ Carboplatin ■ Cyclophosphamide (50%). Pleural effusion, hypoxia, wheezing, and asymptomatic auscultatory findings are occasional to common (8% to 20%). f. Renal. Renal failure is occasional.

ASPARAGINASE Other names. L-Asparaginase, Elspar, Kidrolase, pegaspargase, Oncaspar, Erwinaze (asparaginase Erwinia chrysanthemi). Mechanism of action. Hydrolysis of serum asparagine occurs, which deprives leukemia cells of the required amino acid and inhibits protein synthesis. Normal cells are spared because they generally have the ability to synthesize their own asparagine. Pegaspargase is a chemically modified formulation of asparaginase in which the L-asparaginase is covalently conjugated with monomethoxy polyethylene glycol (PEG). This modification increases its half-life in the plasma by a factor of 4 to about 5.7 days and reduces its recognition by the immune system, which allows the drug to be used in patients previously hypersensitive to native Lasparaginase. Primary indication. Acute lymphocytic leukemia, primarily for induction therapy. Usual dosage and schedule. All schedules are used in combination with other drugs. The schedules listed are only a few of many acceptable dosing schedules. 1. L-asparaginase. 6,000 IU/m2 SC on days 5, 8, 11, 15, and 22 of the treatment period. 2. L-asparaginase. 10,000 IU IV daily for 10 successive days beginning on day 17 of the treatment period. 3. Pegaspargase. 2,500 IU/m2 intramuscular (IM; or IV) once every 14 days, either for firstline acute lymphocytic leukemia or in patients who have developed hypersensitivity to native forms of asparaginase. For IM use, limit volume at single injection site to 2 mL. For IV administration, give over 1 to 2 hours in saline or normal saline with 5% dextrose. Special precautions. Asparaginase is contraindicated in patients with pancreatitis or a history of pancreatitis. Asparaginase is contraindicated in patients who have had significant hemorrhagic events associated with prior L-asparaginase therapy. Pegaspargase is also contraindicated in patients who have had previous serious allergic reactions, such as generalized urticaria, bronchospasm, laryngeal edema, hypotension, or other unacceptable adverse reactions to prior pegaspargase. Be prepared to treat anaphylaxis at each administration of the drug. Epinephrine, antihistamines, corticosteroids, and life-support equipment should be readily available. Giving concurrently with or immediately before vincristine may increase vincristine toxicity. The IM route is preferred for pegaspargase, because of a lower incidence of hepatotoxicity, coagulopathy, and GI and renal disorders compared with the IV route of

administration. Toxicity 1. Myelosuppression and other hematologic effects. Occasional myelosuppression. CNS thrombosis and other coagulopathies are uncommon. 2. Nausea, vomiting, and other GI effects. Occasional and usually mild. (see below for liver and pancreas effects.) 3. Mucocutaneous effects. No toxicity occurs except as a sign of hypersensitivity. 4. Anaphylaxis. Mild-to-severe hypersensitivity reactions, including anaphylaxis, occur in 20% to 30% of patients. Such reaction is less likely to occur during the first few days of treatment. It is particularly common with intermittent schedules or repeat cycles. If the patient develops hypersensitivity to the Escherichia coli–derived enzyme (Elspar), Erwinia-derived asparaginase may be safely substituted because the two enzyme preparations are not cross-reactive. Note that hypersensitivity may also develop to Erwinia-derived asparaginase, and continued preparedness to treat anaphylaxis must be maintained. If given IM, asparaginase should be given in an extremity so that a tourniquet can be applied to slow the systemic release of asparaginase should anaphylaxis occur. Approximately 30% of patients previously sensitive to L-asparaginase will have a hypersensitivity reaction to pegaspargase, while only 10% of those who were not hypersensitive to the native form will have a hypersensitivity reaction to the PEG-modified drug. 1. Miscellaneous effects a. Mild fever and malaise are common and occasionally progress to severe chills and malignant hyperthermia. b. Hepatotoxicity is common and occasionally severe. Abnormalities observed include elevations of serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase, and bilirubin; depressed levels of hepatic-derived clotting factors and albumin; and hepatocellular fatty metamorphosis. c. Renal failure is rare. d. Pancreatic endocrine and exocrine dysfunction, often with manifestations of pancreatitis, occasionally occurs. Nonketotic hyperglycemia is uncommon. e. CNS effects (depression, somnolence, fatigue, confusion, agitation, hallucinations, or coma) are seen occasionally. They are usually reversible following discontinuation of the drug.

AXITINIB Other name. Inlyta. Mechanism of action. Multi-receptor tyrosine kinases inhibitor, including vascular endothelial growth factor receptors VEGFR-1, VEGFR-2, and VEGFR-3, which results in decreased

angiogenesis, tumor growth, and cancer progression. Primary indications. Advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Usual dosage and schedule. 5 mg orally every 12 hours. A dose escalation to 7 mg twice daily may be used if treatment is well tolerated for at least 2 consecutive weeks with no grade 2 or higher adverse events and if patients remain normotensive and not receiving antihypertension medications. A second dose escalation to 10 mg twice daily under the same criteria can be done. The concomitant use of strong CYP3A4/5 inhibitors should be avoided. Starting dose should be decreased to 50% in patients with moderate (Child-Pugh B) hepatic impairment, while treatment should be avoided in patients with severe (Child-Pugh C) hepatic impairment. Special precautions 1. Axitinib can cause fetal harm if administered to a pregnant woman. 2. As with other agents with antiangiogenic effect, wound healing complications can occur, and thus, treatment should be held at least 24 hours prior to scheduled surgery. The decision to resume therapy after surgery should be based on clinical judgment of adequate wound healing. 3. GI fistula formation and perforations have been reported and can be fatal. 4. Hemorrhagic events including cerebral hemorrhage, hematuria, hemoptysis, lower GI hemorrhage, and melena are common, but severe reactions are rare and can be fatal. 5. Axitinib has not been studied in patients who have evidence of untreated brain metastasis. Toxicity 1. Myelosuppression and other hematologic effects. Leukopenia and thrombocytopenia are occasional. Anemia and lymphopenia are common. Polycythemia is rare. 2. Nausea, vomiting, and other GI effects. Diarrhea is common and occasionally severe. Nausea, vomiting, and constipation are common. Stomatitis, dysgeusia, dyspepsia, and abdominal pain are occasional. 3. Mucocutaneous effects. Palmar-plantar erythrodysesthesia syndrome is common and occasionally severe. Rash, pruritus, dry skin, and mucosal inflammation are occasional. Alopecia and erythema are uncommon. 4. Immunologic effects and infusion reactions. Not applicable. 5. Miscellaneous effects a. General. Fatigue, asthenia, and decreased appetite are common. Tinnitus is uncommon. b. Respiratory. Dysphonia is common. Cough and dyspnea are occasional. c. Cardiovascular. Treatment-related hypertension is common with median onset of 1 to 4 weeks. It can be severe in up to 16% of cases and rarely lead to hypertensive crisis. Arterial thromboembolic events including transient ischemic attacks, cerebrovascular accidents, myocardial infarctions, and retinal artery occlusions are uncommon, but can be fatal. Venous thromboembolic events including pulmonary embolism, deep vein thrombosis, retinal vein occlusion, and retinal vein thrombosis are uncommon and can

be fatal. d. Metabolic. Hypocalcemia, hyperglycemia, hypernatremia, and increase in lipase and amylase are common. Hyperkalemia, hypophosphatemia, hyponatremia, and hypoglycemia are occasional. e. Hepatic. Elevation in ALT, AST, or both are common, and periodic monitoring of liver function is recommended. f. Neurologic. Reversible posterior leukoencephalopathy syndrome (RPLS), which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances, and is diagnosed by MRI, is rare. Headache and dizziness are occasional. g. Endocrine. Hypothyroidism is common, while hyperthyroidism is rare. Monitoring of thyroid function should be done at baseline and periodically during treatment. h. Genitourinary. Proteinuria is occasional and uncommonly severe. Creatinine increase is common and rarely severe. i. Musculoskeletal and connective tissue. Arthralgia, myalgia, and pain in extremities are occasional.

AZACITIDINE Other name. Vidaza. Mechanism of action. Pyrimidine analog that inhibits methyltransferase, causing hypomethylation of DNA and thus, it is believed, results in cellular differentiation or apoptosis. May restore normal function of genes that are critical for the control of cellular differentiation and proliferation. Nonproliferating cells are relatively insensitive to azacitidine. Primary indication. Myelodysplastic syndrome (MDS). Usual dosage and schedule. 75 mg/m2 SC or IV daily for 7 days, repeated every 4 weeks. Dose may be increased to 100 mg/m2 if no toxicity other than nausea and vomiting. Therapy may be continued so long as the patient has improved from the drug. Toxicity 1. Myelosuppression and other hematologic effects. Neutropenia, thrombocytopenia, and anemia are common. Febrile neutropenia is four times as common as in patients receiving supportive care. Petechiae or ecchymosis are occasional. 2. Nausea, vomiting, and other GI effects. Anorexia, nausea, vomiting, and diarrhea or constipation are common. Abdominal pain is occasional. 3. Mucocutaneous effects. Pharyngitis and stomatitis—occasional. Skin rash is occasional, urticaria is occasional. Injection site pain is common. 4. Neurotoxicity. Insomnia is common. Lethargy, dizziness, or confusional state are occasional.

5. Miscellaneous effects a. Cardiorespiratory. Cough and dyspnea are common. Pulmonary edema—uncommon. Edema is occasional. Tachycardia or other more serious cardiac disorders—uncommon. b. Fever is common. c. Fatigue and weakness—common. d. Arthralgias and back pain are occasional. e. Hypokalemia—occasional.

BELINOSTAT Other name. Beleodaq. Mechanism of action. Histone deacetylase (HDAC) inhibitor. It causes accumulation of acetylated histones and other proteins, including cell cycle arrest and/or apoptosis of some transformed cells. It has preferential cytotoxicity toward tumor cells compared with normal cells. Primary indications. Relapsed or refractory peripheral T-cell lymphoma (PTCL). Usual dosage and schedule. The recommended dose is 1,000 mg/m2 IV on days 1 to 5 of each 21-day cycle. Cycles are continued until disease progression or intolerable toxicity. Dose modifications may be required for neutropenia and/or thrombocytopenia. All nonhematologic toxicities need to be of grade 2 or less prior to each treatment cycle. The starting dose should be reduced to 750 mg/m2 in patients known to be homozygous for the UGT1A1*28 allele. Special precautions. Belinostat can cause teratogenicity and/or embryo-fetal lethality. Patients with moderate-to-severe hepatic impairment (total bilirubin >1.5 times the ULN) were excluded from clinical trials and there is insufficient evidence to recommend a dose for those patients. Hepatic failure, tumor lysis syndrome in patients with bulky disease, ventricular fibrillation, and pneumonia can occur. Toxicity 1. Myelosuppression and other hematologic effects. Anemia is common. Thrombocytopenia is occasional. Leukopenia (neutropenia and lymphopenia) with serious or fatal infections including pneumonia and sepsis can also occur. 2. Nausea, vomiting, and other GI effects. Nausea, vomiting, constipation, and diarrhea are common. 3. Mucocutaneous effects. Rash and pruritus are common. Abdominal pain is occasional. 4. Immunologic effects and infusion reactions. Infusion site pain can occur in up to 14% of patients. 5. Miscellaneous effects a. Hepatic. Fatal hepatotoxicity and liver function abnormalities can occur. b. Pyrexia and fatigue are common. c. Neurologic. Headache and dizziness are occasional.

d. Respiratory. Cough and dyspnea are common. e. Cardiovascular. Peripheral edema is common. Prolonged QT interval and fatal ventricular fibrillation can occur.

BENDAMUSTINE Other names. Treanda, bendamustine hydrochloride. Mechanism of action. Bendamustine is an alkylating agent that is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring. It forms interstrand DNA crosslinks that lead to cell death in both resting and dividing cells, though the exact mechanism of cell death is not clear. Primary indications 1. Chronic lymphocytic leukemia (CLL) 2. Indolent B-cell non-Hodgkin lymphoma Usual dosage and schedule 1. CLL. 90 to 100 mg/m2 IV over 30 minutes on days 1 and 2 of a 28-day cycle, up to 6 cycles. 2. Non-Hodgkin lymphoma. 120 mg/m2 IV over 30 minutes on days 1 and 2 of a 21-day cycle, up to 8 cycles. Initiation of successive cycles of therapy is usually delayed until there is an absolute neutrophil count (ANC) ≥1 × 109/L and a platelet count ≥75 × 109/L. Dose reductions of 50% to 75% should be initiated for grade 3 to 4 hematologic or nonhematologic toxicity. Special precautions. Infusion reactions consisting of fever, chills, pruritis, and rash are common. Severe anaphylactic or anaphylactoid reactions, particularly in the second or subsequent cycles of therapy, may rarely occur. Antihistamines (e.g., diphenhydramine and cimetidine) and corticosteroids are commonly used to minimize the severity of infusion reactions. Tumor lysis syndrome has been observed, particularly in the first cycle of therapy. Toxic epidermal necrolysis has rarely occurred when bendamustine was given with rituximab. Stevens–Johnson syndrome has rarely occurred when bendamustine was administered concomitantly with allopurinol. The relationship of these severe reactions to bendamustine is not known. If severe skin reactions occur, bendamustine should be withheld or discontinued. Do not give if known hypersensitivity to bendamustine or mannitol. Bendamustine can cause fetal harm and must not be administered to pregnant women. Toxicity 1. Myelosuppression and other hematologic effects. Myelosuppression is common and in the higher dosage ranges is universal. Grade 3 to 4 leukopenia (both neutrophils and lymphocytes) is common. Grade 3 to 4 anemia and thrombocytopenia are occasional. Infections overall are occasional. Pneumonia and neutropenic sepsis are uncommon, but may be fatal.

2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are occasional to common and dose dependent, but rarely severe. Anorexia, dyspepsia, gastroesophageal reflux, upper abdominal pain, and distension are occasional. 3. Mucocutaneous effects. Skin rash and pruritis are occasional, including toxic skin reactions and bullous exanthema. 4. Immunologic effects and infusion reactions. Infusion reactions consisting of fever, chills, pruritis, and rash are common. Severe anaphylactic or anaphylactoid reactions, particularly in the second or subsequent cycles of therapy, are rare. Preventive measures, including antihistamines, and corticosteroids, should be given if grade 1 or 2 infusion reactions were experienced in a prior cycle. Bendamustine should generally not be repeated if patients have had a prior grade 3 or 4 infusion reaction. 5. Miscellaneous effects a. Fever (occasionally with chills) and fatigue are common; weakness and weight loss are occasional. b. Tumor lysis syndrome, including hyperuricemia, may occur, primarily with the first cycle of therapy, and lead to acute renal failure. With concomitant allopurinol, watch closely for severe skin reactions. c. Hypokalemia is only occasional, but may be severe. d. Cough, dyspnea, throat pain, wheezing, and nasal congestion are occasional to common. e. Hypotension is occasional.

BEVACIZUMAB Other name. Avastin. Mechanism of action. Binds VGEF and prevents interaction of VEGF with its receptors on the surface of endothelial cells. This in turn impairs endothelial cell proliferation and new blood vessel formation, impeding tumor growth and metastasis. Primary indications 1. Breast, colon, kidney, rectum, and nonsquamous NSCLC, usually with other agents. 2. Glioblastoma, alone or with other agents. 3. Ovarian, fallopian tube, or primary peritoneal cancer in the recurrent, platinum resistant setting. 4. Cervical cancer in combination with paclitaxel and cisplatin or paclitaxel and topotecan in persistent, recurrent or metastatic disease. Usual dosage and schedule 1. 5 to 10 mg/kg IV once every 2 weeks. 2. 15 mg/kg IV once every 3 weeks. Special precautions. GI perforation occurs in up to 4% of patients, and may have a fatal outcome. Impaired wound healing may rarely lead to anastomotic dehiscence. Bevacizumab

should not be initiated for at least 28 days following major surgery. The interval between termination of bevacizumab and subsequent surgery should take into account the accumulation ratio of 2.8 (with every 2-week dosing) and the half-life of approximately 20 days. Blood pressure monitoring is recommended every 2 to 3 weeks because of the risk of hypertension. RPLS has been reported rarely; if it occurs, therapy must be discontinued immediately and treatment for hypertension initiated if it is present. Urinary protein should be evaluated prior to each treatment with a urine dipstick, and if 2+ or greater, the patient should undergo further assessment to rule out severe proteinuria, such as with a urine protein-creatinine (UPC) ratio. Hold therapy if UPC >3.5. Toxicity 1. Myelosuppression and other hematologic effects. Leukopenia is common, but associated primarily with the cytotoxic agents used together with bevacizumab. Thrombocytopenia is uncommon. Minor bleeding, such as epistaxis, is common; severe hemorrhage is not, except for hemoptysis in patients with squamous cell carcinomas of the lung. Serious, and in some cases fatal, hemoptysis has occurred in NSCLC, with the highest risk appearing in patients with squamous cell histology; other severe or fatal hemorrhage, including CNS bleeding has occurred. Thromboembolic events are occasional and may be severe. 2. Nausea, vomiting, and other GI effects. Anorexia, nausea, vomiting, and constipation are common. Diarrhea is common, particularly when used with fluorouracil and irinotecan chemotherapy. Abdominal pain is common. GI hemorrhage is occasional; perforation is uncommon. 3. Mucocutaneous effects. Dry skin, skin discoloration, stomatitis, and exfoliative dermatitis are occasional to common. Alopecia, skin ulcers, and nail changes are uncommon. 4. Immunologic effects and infusion reactions. Infusion reactions with hypertension, wheezing, stridor, desaturation, chest pain, headaches, and diaphoresis are uncommon. Severe reactions are rare (0.2%). 5. Miscellaneous effects a. Fatigue, weakness, and headache—common b. Cardiovascular and respiratory—Hypertension is common and occasionally is severe (>200/110 mm Hg). Blood pressure >160/100 or rise of >30 mm Hg requires holding therapy, at least temporarily. Hypotension is occasional. Dyspnea is occasional. Congestive heart failure is uncommon, but risk with anthracyclines is increased (14%). Venous thromboembolic events are increased by about 15% compared with chemotherapy not containing bevacizumab. c. Neurologic—Dizziness is common. RPLS has been reported rarely (3.5 g/24 hours) is uncommon and rarely leads to nephrotic syndrome ( 1.5 ULN). Consider dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability. Special precautions. Cardiogenic shock, congestive heart failure, and respiratory insufficiency have been rarely observed. Anaphylaxis has also been observed. Patients with hepatic impairment should be monitored closely, as bortezomib is metabolized by liver enzymes. Consider acyclovir 400 mg b.i.d for Herpes zoster prophylaxis. Toxicity 1. Myelosuppression and other hematologic effects. Anemia, neutropenia, and thrombocytopenia are common; neutropenia is only occasionally severe (grade 3 or 4). Thrombocytopenia is severe in 30% of patients. Disseminated intravascular coagulation has been observed (rare to uncommon). 2. Nausea, vomiting, and other GI effects. Anorexia, nausea, vomiting, diarrhea, and constipation are common. Dehydration is a concern because of vomiting and diarrhea and may be seen occasionally. 3. Mucocutaneous effects. Rash is common (20%). 4. Neurotoxicity. Peripheral neuropathy is common, and occasionally (7%) severe. This is frequently manifest by paresthesias and dysesthesias. Headache is common. Neurotoxicity is often less with SC rather than IV administration. 5. Immunologic effects and infusion reactions. Hypersensitivity reactions have been seen, including anaphylactic reactions and immune complex mediated hypersensitivity (rare).

Tumor lysis syndrome may be seen in patients with a high tumor burden. Increased incidence of H. zoster compared with controls—occasional. 6. Miscellaneous effects a. Fatigue and weakness are common. b. Arthralgias, muscle cramps, and back pain are occasional. c. Fever is common. d. Cardiovascular. Hypotension is occasional, is seen throughout therapy, and may be orthostatic or not. Peripheral edema is common. Other cardiovascular events during treatment have included severe congestive heart failure, AV block, angina, atrial fibrillation, and flutter—these are probably uncommon to rare as a consequence of the drug. e. Infiltrative pulmonary disease—rare, but may be severe or fatal. f. Hepatitis and pancreatitis have been observed—probably rare.

BOSUTINIB Other name. Bosulif. Mechanism of action. A tyrosine kinase inhibitor that inhibits the Bcr-Abl kinase (including imatinib-resistant forms of Bcr-Abl) and the Src-family kinases including Src, Lyn, and Hck. Primary indications. Chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) CML with resistance or intolerance to prior therapy. Usual dosage and schedule. 500 mg orally once daily with food. If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. Dose escalation to 600 mg once daily can be considered in patients who do not reach complete hematologic response (CHR) by week 8 or a complete cytogenetic response (CCyR) by week 12, who did not have grade 3 or higher adverse reactions. Concomitant use of strong or moderate CYP3A inhibitors, strong or moderate CYP3A inducers, and/or P-gp substrates should be avoided. In patients with preexisting mild, moderate, and severe hepatic impairment, the recommended dose of Bosulif is 200 mg daily. Special precautions 1. Bosutinib can cause fetal harm if administered to a pregnant woman. 2. Fluid retention that may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema is common, but uncommonly severe and can be fatal, requiring dose interruptions, modifications, or even permanent discontinuation. 3. Hypersensitivity reactions have been reported in less than 10% of patients and anaphylactic shock occurred in less than 0.2% of treated patients. Toxicity 1. Myelosuppression and other hematologic effects. Anemia, leukopenia, and thrombocytopenia are common and can be severe. Febrile neutropenia can occur in less

than 10% of cases. CBC monitoring should be done at baseline, weekly for the first month and monthly thereafter. 2. Nausea, vomiting, and other GI effects. Abdominal pain, nausea, vomiting, and diarrhea are common. Diarrhea can be occasionally severe. These reactions can be managed using standards of care. Dose interruptions/adjustments may be indicated for severe reactions. Gastritis is occasional. Pancreatitis and GI hemorrhage are rare. 3. Mucocutaneous effects. Skin rash is common and occasionally severe. Pruritus is occasional. Erythema multiforme is rare. 4. Immunologic effects and infusion reactions. Upper and lower respiratory tract infections are occasional but rarely severe. 5. Miscellaneous effects a. General. Fatigue and pyrexia are common. Asthenia is occasional. Tinnitus has been reported in less than 10% of patients. b. Respiratory. Cough is common and dyspnea is occasional. c. Cardiovascular. QTc prolongation to more than 500 msec is rare, but caution should be used in patients with underlying cardiovascular disease and other risk factors for QTc prolongation. d. Metabolic. Hypophosphatemia and elevation in lipase level are occasional. Hyperkalemia as well as elevation in creatinine level and acute renal failure have been reported in less than 10% of patients, the latter of which may be related to dehydration rather than direct drug-related toxicity. e. Hepatic. Drug-induced liver injury is rare. Moderate elevations in ALT or AST (1 week). Cases of upper respiratory tract infections were reported in 47% of patients, all of which were mild. Cases of urinary tract infection, pyelonephritis, and septic shock were uncommonly reported. 2. Nausea, vomiting, and other GI effects. Abdominal pain, nausea, vomiting, diarrhea, and constipation are common but uncommonly severe. 3. Mucocutaneous effects. Rash and pruritus are common. Alopecia is occasional. Dry skin is uncommon. 4. Immunologic effects and infusion reactions. Infusion-related reactions (including chills, nausea, dyspnea, pruritus, pyrexia, cough, and anaphylaxis) have occurred. If an infusionrelated reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Premedication for subsequent infusions with acetaminophen, an antihistamine and a corticosteroid is recommended. Transient and persistent antibodies to the ADC can develop in 30% and 7%, respectively. A higher incidence of infusion-related reactions was observed in patients who developed persistently positive antibodies. Stevens–Johnson syndrome has been reported. 5. Miscellaneous effects a. General. Fatigue and pyrexia are common. Chills and night sweats are occasional. b. Respiratory. Cough is common. Dyspnea and oropharyngeal pain are occasional. Cases of pneumonitis, pulmonary embolism, and pneumothorax were reported in 2% of patients. c. Cardiovascular. Peripheral edema is uncommon. Supraventricular tachycardia was

reported in 3% of patients. d. Metabolic. Decreased weight and appetite are occasional. e. Neurologic. ADC-induced peripheral sensory and motor neuropathy is common and is cumulative. This can persist even after discontinuation of treatment. Headache is common and dizziness is occasional. f. Musculoskeletal and connective tissue. Arthralgia and myalgia are common. Back pain, pain in extremity, and muscle spasms are occasional. g. Psychiatric. Insomnia is occasional.

CABAZITAXEL Other name. Jevtana. Mechanism of action. Microtubule inhibitor binds to tubulin, which leads to the stabilization of microtubules, and the inhibition of mitotic and interphase cellular functions. Primary indication. Carcinoma of the prostate, metastatic, previously treated with a docetaxel-containing regimen. Usual dosage and schedule. 25 mg/m2 IV over 1 hour every 3 weeks in combination with prednisone 10 mg daily. Reduce dose to 20 mg/m2 if the patient experiences prolonged grade 3 or higher neutropenia, febrile neutropenia, or severe or persistent diarrhea. Special precautions. Hypersensitivity reactions can occur, and therefore patients should be premedicated with corticosteroids and histamine H1 and H2 antagonists. Should not be given to patients with hepatic impairment. Patients aged 65 years and older are more likely to experience adverse effects from cabazitaxel treatment. Because cabazitaxel is metabolized primarily through CYP3A, coadministration with strong CYP3A inhibitors should be avoided. Toxicity 1. Myelosuppression and other hematologic effects. Neutropenia, anemia, and thrombocytopenia are common. Grade 3 to 4 febrile neutropenia is occasional, but may be fatal. 2. Nausea, vomiting, and other GI effects. Nausea, vomiting, anorexia, diarrhea, and constipation are common, but infrequently (2% to 6%) severe. 3. Mucocutaneous effects. Alopecia is occasional. 4. Immunologic effects and infusion reactions. Hypersensitivity reactions are uncommon, but may occur within a few minutes following initiation of therapy; they may be associated with rash, erythema, hypotension, and bronchospasm. 5. Miscellaneous effects a. Fatigue and weakness are common. Fever is occasional. b. Renal failure is uncommon, but may be fatal (rare). Hematuria is occasional. c. Peripheral edema—occasional.

d. Cardiac arrhythmias and hypotension are uncommon. e. Back pain and arthralgias are occasional. f. Peripheral neuropathy and headache are occasional. g. Dyspnea and cough are occasional.

CABOZANTINIB Other name. Cometriq. Mechanism of action. Inhibits the tyrosine kinase activity of RET, MET, VEGFR-1 and 2, KIT, TRKB, FLT-3, AXL, and TIE-2, which are involved in oncogenesis, metastasis, tumor angiogenesis, and maintaining tumor microenvironment. Primary indications. Progressive, metastatic medullary thyroid cancer. Usual dosage and schedule. 140 mg orally daily. To be taken at least 2 hours after or 1 hour before a meal. Certain foods (grapefruit, grapefruits) or nutritional supplements known to inhibit cytochrome P450 should not be taken during treatment period. Missed doses can be taken up to 12 hours before the next dose. Special precautions. Cabozantinib can cause fetal harm if administered to a pregnant woman and can cause male infertility. Coadministration with substrates of P-glycoprotein can increase the plasma concentration of the latter. It is recommended not to coadminister cabozantinib with strong CYP3A4 inhibitors and/or inducers. If the use of a strong CYP3A4 inhibitor is required, the dose of cabozantinib should be decreased by 40 mg prior to initiation until 2 or 3 days after discontinuation of the strong inhibitor. If the use of a strong CYP3A4 inducer is required, the dose of cabozantinib should be increased by 40 mg prior to initiation until 2 or 3 days after discontinuation of the strong inducer. Moderate and severe hepatic impairment should preclude the use of cabozantinib. Dose interruptions are recommended for grade 4 hematologic toxicities, grade 3 or higher nonhematologic toxicities, and for intolerable grade 2 adverse reactions. Permanent discontinuation is required for: visceral perforations, fistulas formation, severe hemorrhage, serious arterial thromboembolic events, nephrotic syndrome, malignant hypertension and hypertensive crisis, osteonecrosis of the jaw, and RPLS. Toxicity 1. Myelosuppression and other hematologic effects. Neutropenia and thrombocytopenia are common, mostly grade 1 and 2. Lymphopenia is common with grade 3 toxicity occurring in up to 16% of patients. The incidence of serious (grade 3 or higher) hemorrhagic events was observed in 3% of patients treated with cabozantinib. These reactions can be fatal and permanent discontinuation of treatment is indicated. Cabozantinib can impair wound healing and cause healing complications. Withholding treatment at least 28 days prior to scheduled surgeries is recommended, and treatment resumption postsurgery is indicated after adequate wound healing. 2. Nausea, vomiting, and other GI effects. Serious GI perforations and fistulas (including

esophageal) and non-GI (tracheal) fistulas formation can occur in 3%, 1%, and 4%, respectively, and can be fatal. Abdominal pain, stomatitis, nausea, vomiting, diarrhea, and constipation are common. Diarrhea can be grade 3 or greater in 16% of cases. Dysphagia and dyspepsia are occasional. 3. Mucocutaneous effects. Palmar-plantar erythrodysesthesia syndrome (PPES) can occur in up to 50% of patients, with grade 3 or higher reported in 13% of cases. Rash, dry skin, and alopecia are common. Hyperkeratosis is occasional. Hair color changes (depigmentation/graying) can occur in up to 34% of patients. 4. Immunologic effects and infusion reactions. Not applicable. 5. Miscellaneous effects a. General. Decreased appetite, fatigue, asthenia, and weight loss are common. b. Respiratory. Dysphonia was reported in 20% of patients, all grade 1 or 2. c. Cardiovascular. Elevation in blood pressure is universal with most cases being pre- or stage I hypertension. Stage I or II hypertension can occur in up to 61% of patients. Mild cases can be managed with antihypertensive medications. More severe cases or those that are not adequately controlled with medications may require dose reduction/interruption and/or permanent discontinuation. Increased risk of both venous and arterial thromboembolic events have been reported; 6% and 2%, respectively. Permanent discontinuation is recommended in patients who develop treatment-related acute myocardial infarction or other serious thromboembolic complications. Although 10 to 15 msec increase in QTc interval was observed at 4 weeks after initiation of treatment, changes in wave form morphology or new rhythms were not observed and no patients had a QTc interval >500 msec. d. Metabolic. Electrolytes disturbances, including hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia are common. Grade 3 or higher hypocalcemia was observed in 12% of patients. e. Hepatic. Increase in AST, ALT, ALP, and total bilirubin is common but grade 3 or higher are uncommon. f. Neurologic. Dysgeusia and headache are common. Peripheral neuropathy is occasional. Although RPLS is rare (occurred in one patient across clinical trials), clinical suspicion is warranted in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental status, and evaluation with MRI is indicated to make the diagnosis. Permanent discontinuation of cabozantinib is recommended if the diagnosis is confirmed. g. Genitourinary. Nephrotic range proteinuria and nephrotic syndrome can occur. Regular monitoring of urine protein is recommended and permanent discontinuation is warranted in patients who develop nephrotic syndrome. h. Musculoskeletal and connective tissue. Musculoskeletal chest pain, arthralgia, and muscle spasms are occasional. Osteonecrosis of the jaw (ONJ) can occur and manifests as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, gingival ulceration or erosion, or slow healing after dental surgery. Periodic oral

examination is recommended. Treatment should be held for at least 28 days prior to scheduled surgery, if possible. i. Psychiatric. Grade 1 or 2 anxiety was reported in 9% of patients taking cabozantinib versus 2% of patients taking placebo.

CAPECITABINE Other name. Xeloda. Mechanism of action. An orally administered prodrug that is converted to fluorouracil intracellularly. When this is converted to the active nucleotide, 5-fluoro-2-deoxyuridine monophosphate, it inhibits the enzyme thymidylate synthetase and blocks DNA synthesis. The triphosphate may also be mistakenly incorporated into RNA, which interferes with RNA processing and protein synthesis. Primary indications 1. Metastatic breast cancer that is resistant to anthracycline- and paclitaxel-containing chemotherapy regimens. May also be used in patients in whom anthracyclines are contraindicated. 2. Colorectal (adjuvant or metastatic), small bowel, stomach, pancreas, and biliary carcinomas. Usual dosage and schedule. Generally taken with water, twice daily (about 12 hours between doses) within 30 minutes after a meal. Dose reductions are commonly required, by reducing the daily dose, the number of consecutive daily treatments, or both. 1. 1,000 to 1,250 mg/m2 orally twice daily for 2 weeks as a single agent, followed by a 1week rest, given as 3-week cycles. 2. 850 to 1,250 mg/m2 orally twice daily for 2 weeks when used in combination with other drugs, followed by a 1-week rest, given as 3-week cycles. 3. 800 mg/m2 orally twice daily 5 days per week during radiotherapy as a radiosensitizer. Special precautions. Increase in prothrombin time (PT) and International Normalized Ratio (INR) may be seen in patients previously stable on oral anticoagulants. Monitor PT/INR more frequently when patient is on capecitabine. Patients with moderate renal impairment (CCr 30 to 50 mL/minutes) require a 25% dosage reduction: Diarrhea may be severe and require fluid and electrolyte replacement. Incidence and severity may be worse in patients 80 years of age or older. Therapy may need to be interrupted and subsequent doses decreased for severe or repeated toxicity. Phenytoin levels should be monitored, as elevated levels may occur. Toxicity 1. Myelosuppression and other hematologic effects. Common, but when used as a single agent, these usually are mild to moderate with anemia predominating. Neutropenia is common when used in combination and may be associated with neutropenic fever. 2. Nausea, vomiting, and other GI effects. Both nausea (45%) and vomiting (35%) are

common, but usually not severe. Diarrhea is common (55%); in up to 15% of patients, it is severe to life-threatening. GI motility disorders, including ileus, may be seen, and necrotizing enterocolitis has been reported. Abdominal pain is occasional to common. Anorexia is occasional to common (26%). 3. Mucocutaneous effects. Hand-and-foot syndrome is common (54%) and may be severe. Dermatitis is also common (27%), as is stomatitis, but it is uncommon that these are severe. Eye irritation and increased lacrimation are occasional. 4. Miscellaneous effects a. Fatigue is common. b. Paresthesias are occasional. c. Hyperbilirubinemia is common (48%), but only occasionally severe or life-threatening. d. Fever is occasional. e. Headache or dizziness is occasional. f. Cardiotoxicity is possible as with any fluorinated pyrimidine.

CARBOPLATIN Other names. Paraplatin, CBDCA. Mechanism of action. Covalent binding to DNA. Primary indications. Ovarian, endometrial, breast, bladder, and lung cancers, and other cancers in which cisplatin is active. Usual dosage and schedule. AUC (area under the curve) dosing (Calvert formula) is generally preferred. 1. Target AUC is commonly 4 to 6, depending on previous treatment and other drugs to be used. Administration dose (mg) = (target AUC) × ([creatinine clearance] + 25). Administration dose is given by IV infusion over 15 to 60 minutes, and repeated every 4 weeks. 2. Higher doses up to 1,600 mg/m2 divided over several days have been used followed by stem cell rescue. Special precautions Much less renal toxicity than cisplatin, so there is no need for a vigorous hydration schedule or forced diuresis. If AUC dosing is not used, reduce dose to 250 mg/m2 for creatinine clearance of 41 to 59 mL/minute, reduce to 200 mg/m2 for clearance of 16 to 40 mL/minute. Anaphylactic-like reactions to carboplatin have been reported and may occur within minutes of carboplatin administration. Infusion reactions generally develop after several months of drug tolerance. Epinephrine, corticosteroids, antihistamines, and fluid administration for hypotension have been employed to alleviate symptoms. Toxicity 1. Myelosuppression and other hematologic effects. Anemia, granulocytopenia, and

thrombocytopenia are common and dose-limiting. Red blood cell transfusions or epoetin may be required. Thrombocytopenia may be delayed (days 18 to 28). 2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common, but vomiting (65%) is not as frequent or as severe as with cisplatin and can be controlled with combination antiemetic regimens. Liver function abnormalities are common. GI pain is occasional. 3. Mucocutaneous effects. Alopecia is uncommon. Mucositis is rare. 4. Immunologic effects and infusion reactions. Infusion reactions are occasional, but may be severe. These may include rash, urticaria, pruritus, and rarely bronchospasm and hypotension. Desensitization protocols may allow continued therapy with carboplatin, but should be carried out under close observation. See Special Precautions above. 5. Miscellaneous effects a. Peripheral neuropathies or central neurotoxicity are uncommon. b. Cardiovascular (cardiac failure, embolism, cerebrovascular accidents) are uncommon. c. Hemolytic-uremic syndrome is rare. d. Renal tubular abnormalities. Elevation in serum creatinine or blood urea nitrogen occurs occasionally. More common is electrolyte loss with decreases in serum sodium, potassium, calcium, and magnesium.

CARFILZOMIB Other name. Kyprolis. Mechanism of action. Irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome that mediates ubiquitinated protein degradation and plays an essential role in intracellular protein regulation and consequent cellular signal transduction pathways and cellular homeostasis. Primary indications 1. Multiple myeloma in combination with lenalidomide and dexamethasone in patients who have received one to three prior lines of prior therapy. 2. Multiple myeloma after receiving at least two prior therapies including an immunomodulatory agent and bortezomib, and have demonstrated disease progression on or within 60 days of the completion of the last therapy. Usual dosage and schedule 1. Cycle 1: 20 mg/m2 (maximum BSA of 2.2 m2) IV over 2 to 10 minutes on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. 2. If tolerated, the dose should be escalated to a target dose of 27 mg/m2 (maximum BSA of 2.2 m2) starting day 8 of cycle 1 and during the subsequent cycles. Hydrate prior to and subsequent to each dose to reduce risk of renal failure and tumor lysis syndrome. Premedicate with dexamethasone prior to all cycle 1 doses, during first

cycle of dose escalation, and if infusion reactions develop or reappear. Dose adjustments do not need to be made for weight changes of equal or less than 20%. Special precautions 1. No safe dose has been determined in patients with baseline hepatic impairment. 2. Can cause fetal harm if administered to a pregnant woman. 3. Cases of cardiac arrest, cardiogenic shock, congestive heart failure, pulmonary edema, pulmonary hypertension, and fatal hepatic failure have been observed. Anaphylaxis has also been observed. Consider acyclovir 400 mg b.i.d for H. zoster prophylaxis. Tumor lysis syndrome can rarely occur, especially in patients with high tumor burden. Toxicity 1. Myelosuppression and other hematologic effects. Anemia, neutropenia, and lymphopenia are common and occasionally severe. Thrombocytopenia is common and can be grade 4 in 10% of patients. Upper respiratory tract bacterial infections are common but mostly mild. Pneumonia is occasional and rarely fatal. 2. Nausea, vomiting, and other GI effects. Nausea, vomiting, diarrhea, and constipation are common and can be rarely severe. 3. Mucocutaneous effects. Not reported. 4. Immunologic effects and infusion reactions. Infusion reactions, characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions may happen immediately following or up to 24 hours after administration. Administer dexamethasone prior to each treatment to reduce the incidence and severity of reactions. H. zoster reactivation is uncommon but antiviral prophylaxis should be considered. 5. Miscellaneous effects. a. General. Fatigue, peripheral edema, and pyrexia are common. Chills and anorexia are occasional. b. Respiratory. Pulmonary arterial hypertension was reported in 2% of patients (grade 3 or greater in less than 1%). Dyspnea is common and rarely severe/fatal. Cough is common. c. Cardiovascular. Cardiac failure events (congestive heart failure, pulmonary edema, and decrease in ejection fraction) were reported in 7% of patients. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were excluded from the clinical trials. These patients may be at greater risk for cardiac complications. Hypertension is occasional and uncommonly severe. d. Metabolic. Hyponatremia, hypophosphatemia, hypercalcemia, hyperglycemia, hypokalemia, and hypomagnesemia are occasional. e. Hepatic. Elevation in AST/ALT and/or bilirubin levels is occasional. Dose adjustments/interruption may be recommended.

f. Neurologic. Peripheral sensory and motor neuropathy occurred in 14% of patients. Grade 3 or 4 toxicity is rare. Dizziness is occasional. Headache is common. g. Genitourinary. Increase in blood creatinine is common. Renal failure is occasional. These events are occasionally severe and rarely life-threatening. h. Musculoskeletal and connective tissue. Back pain and arthralgia are common. Muscle spasms, chest wall pain, and pain in extremity are occasional. i. Psychiatric. Insomnia is occasional.

CARMUSTINE Other names. BCNU, BiCNU, Gliadel wafer (surgically implantable, biodegradable polymer wafer that releases impregnated carmustine from the hydrophobic matrix after implantation.) Mechanism of action. Alkylation and carbamylation by carmustine metabolites interfere with the synthesis and function of DNA, RNA, and proteins. Carmustine is lipid soluble and easily enters the brain. Primary indications A. Systemic therapy: 1. Brain tumors 2. Hodgkin and non-Hodgkin lymphomas 3. Melanoma B. Implantable carmustine-impregnated wafer. Glioblastoma multiforme Usual dosage and schedule C. Systemic therapy: 1. 200 to 240 mg/m2 IV as a 30- to 45-minute infusion every 6 to 8 weeks. Dose often is divided and given over 2 to 3 days. Some recommend limiting the cumulative dose to 1,000 mg/m2 to limit pulmonary and renal toxicity. 2. Higher doses of up to 600 mg/m2 have been used with stem cell rescue (e.g., bone marrow or peripheral blood stem cell transplantation). D. Implantable carmustine-impregnated wafer. Up to 8 wafers, each containing 7.7 mg of carmustine, are applied to the resection cavity surface after removal of the tumor. Special precautions (systemic therapy). Because of delayed myelosuppression (3 to 6 weeks), do not administer drug more often than every 6 weeks. Await a return of normal platelet and granulocyte counts before repeating therapy. Amphotericin B may enhance the potential for renal toxicity, bronchospasm, and hypotension. Toxicity A. Systemic therapy: 1. Myelosuppression and other hematologic effects. Delayed and often biphasic, with the nadir at 3 to 6 weeks; it may be cumulative with successive doses. Recovery may be protracted for several months. High-dose therapy requires stem cell rescue.

2. Nausea, vomiting, and other GI effects. Begins 2 hours after therapy and lasts 4 to 6 hours—common. 3. Mucocutaneous effects a. Facial flushing and a burning sensation at the IV site may be due to alcohol used to reconstitute the drug; this is common with rapid injection. b. Hyperpigmentation of skin after accidental contact is common. 4. Miscellaneous effects a. Hepatotoxicity is uncommon but can be severe. b. Pulmonary fibrosis is uncommon at low doses, but its frequency increases at doses higher than 1,000 mg/m2. c. Secondary neoplasia is possible. d. Renal toxicity is uncommon at doses of less than 1,000 mg/m2. e. With high-dose therapy, encephalopathy, hepatotoxicity, and pulmonary toxicity are common and dose limiting. Hepatic veno-occlusive disease also occurs (occasional). B. Implantable carmustine-impregnated wafer: Limited toxicity beyond that expected from craniotomy is seen. Serious intracranial infection was seen in 4% of patients, compared with 1% of placebo-treated patients. Brain edema not responsive to steroids may also be seen in a similar percentage of patients. Abnormal wound healing may occur. Remnants of the wafer may be seen for many months after implantation.

CERITINIB Other name. Zykadia. Mechanism of action. Inhibitor of receptor tyrosine kinases including ALK, insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1. Among these, ceritinib is most active against ALK. Ceritinib inhibits autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALKdependent cancer cells. Primary indications. Locally advanced or metastatic anaplastic lymphoma kinase (ALK)positive NSCLC in patients who have progressed on or are intolerant of crizotinib. Usual dosage and schedule. 750 mg orally once daily on an empty stomach (i.e., do not administer within 2 hours of a meal). A recommended dose has not been determined for patients with moderate-to-severe hepatic impairment. Missed doses can be taken up to 12 hours before the next scheduled dose. Dose modifications/interruptions and/or permanent discontinuation may be warranted in hepatic dysfunction, pneumonitis and interstitial lung disease (ILD), QTc prolongation, and bradycardia. Special precautions 1. Concurrent use of strong CYP3A inhibitors should be avoided. If concomitant use of a

strong CYP3A inhibitor is unavoidable, reduce the dose by approximately one-third, rounded to the nearest 150-mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume treatment at the dose that was taken prior to initiating the strong CYP3A4 inhibitor. 2. Ceritinib can cause fetal harm if administered to a pregnant woman. 3. Cases of severe/fatal ILD/pneumonitis have been observed. Toxicity 1. Myelosuppression and other hematologic effects. Anemia is common and occasionally severe. 2. Nausea, vomiting, and other GI effects. Diarrhea, nausea, vomiting, constipation, abdominal pain, and esophageal disorder are common and occasionally severe, requiring dose interruptions/modifications and symptomatic management. 3. Mucocutaneous effects. Rash is common but rarely severe. 4. Immunologic effects and infusion reactions. Not applicable. 5. Miscellaneous effects a. General. Fatigue is common and occasionally severe. Decreased appetite is common. b. Respiratory. ILD or pneumonitis has been reported in 4% of patients and was severe in 3%. Permanent discontinuation is recommended upon diagnosis of any grade treatmentrelated pneumonitis. c. Cardiovascular. QTc interval prolongation can uncommonly occur and is concentration dependent. Periodic monitoring with electrocardiograms (ECGs) is recommended in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those who are taking medications that are known to prolong the QTc interval. Treatment interruption is indicated in patients who develop a QTc interval greater than 500 msec on at least two separate ECGs until the QTc interval is less than 481 msec or recovery to baseline if the QTc interval is greater than or equal to 481 msec. Dose resumption should be at a reduced dose. Permanent discontinuation is recommended in patients who develop QTc interval prolongation in combination with torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmias. Bradycardia is uncommon. In cases of symptomatic bradycardia that is not lifethreatening, withhold treatment until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, evaluate the use of concomitant medications, and adjust the dose. Permanent discontinuation is indicated for life-threatening bradycardia if no contributing concomitant medication is identified; however, if associated with a concomitant medication known to cause bradycardia or hypotension, withhold ceritinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if the concomitant medication can be adjusted or discontinued, resume at a reduced dose upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring. d. Elevations in ALT/AST and or bilirubin levels are common and can be severe in up to 27% of patients requiring dose interruptions/modifications. Regular monitoring of

hepatic function is recommended once a month and as clinically indicated. e. Neurologic. Neuropathy syndromes (comprised of paresthesia, muscular weakness, gait disturbance, peripheral neuropathy, hypoesthesia, peripheral sensory neuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, or polyneuropathy) can occur in up to 17% of patients. f. Endocrine. Hyperglycemia is common and occasionally severe. Hypophosphatemia and elevation in lipase level are common and occasionally severe. g. Genitourinary. Increase in creatinine level is common but uncommonly severe. h. Ophthalmic vision disorders (comprised of vision impairment, blurred vision, photopsia, accommodation disorder, presbyopia, or reduced visual acuity) can occur in 9% of patients.

CETUXIMAB Other names. EGFR antibody, C225, Erbitux. Mechanism of action. EGFR antibody that blocks the ligand-binding site and inhibits proliferation of cells. It is thought potentially most useful in those tumors that overexpress EGFR, but correlation with percent of positive cells or intensity of EGFR expression is weak. Primary indications 1. Carcinoma of head and neck, in combination with radiation therapy or as first-line therapy with platin-based therapy plus fluorouracil for recurrent locoregional advanced or metastatic disease, or after failure of platinum-based therapy. 2. Colon cancer when KRAS is wild-type either as a. First-line therapy in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin), or b. After failure of irinotecan and oxaliplatin-based regimens. Often-in combination with irinotecan or other cytotoxic regimens. 3. Lung cancer if EGFR amplification. Usual dosage and schedule. 400 mg/m2 IV loading dose administered over 2 hours on day 1. Then 250 mg/m2 IV maintenance doses administered over 1 hour weekly thereafter. May be administered in combination with other agents. Special precautions. Serious infusion reactions, some fatal, may occur (3% of patients). Onehour observation period is recommended following a cetuximab infusion. Cardiopulmonary arrest or sudden death has occurred in 2% of patients receiving cetuximab in combination with radiation therapy. Severe hypomagnesemia is seen in 10% to 15% of patients, and all patients should have magnesium levels monitored throughout the persistence of cetuximab (8 weeks). All patients with metastatic colorectal cancer who might be candidates for cetuximab should have their tumor tested for KRAS mutations. If KRAS mutation in codon 12 or 13 is detected, cetuximab should not be given, as the patient is unlikely to benefit.

Toxicity 1. Myelosuppression and other hematologic effects. Leukopenia and anemia are occasional. 2. Nausea, vomiting, and other GI effects. Anorexia, nausea, vomiting, diarrhea, and constipation are occasional. Abdominal pain is common. 3. Mucocutaneous effects. Acne-like rash is common (76%). Stomatitis is occasional when used alone, but universal when used in combination with radiation therapy. Severe radiation dermatitis may be seen when used concurrently with radiation therapy. 4. Miscellaneous effects a. Asthenia is common; headache and back pain are occasional. b. Weight loss, peripheral edema, and dehydration are occasional. c. Infusion reactions with allergic or hypersensitivity reactions, fever, chills, or dyspnea are occasional to common (approximately 20%), but may be severe. d. Human antichimeric antibodies (HACAs) are uncommon. e. Electrolyte depletion, particularly hypomagnesemia, occurs commonly. Hypomagnesemia is occasionally severe.

CHLORAMBUCIL Other name. Leukeran. Mechanism of action. Classic alkylating agent, with primary effect on preformed DNA. Primary indications 1. CLL 2. Low-grade non-Hodgkin lymphoma Usual dosage and schedule 1. Initially, 3 to 4 mg/m2 PO daily until a response is seen or cytopenias occur; then, if necessary, maintain with 1 to 2 mg/m2 PO daily. 2. 30 mg/m2 PO once every 2 weeks (with or without prednisone 80 mg/m2 PO on days 1 to 5). Special precautions. Increased toxicity may occur with prior barbiturate use. Toxicity 1. Myelosuppression and other hematologic effects. Dose-limiting and may be prolonged. 2. Nausea, vomiting, and other GI effects. May be seen with higher doses, but are uncommon. 3. Mucocutaneous effects. Rash is uncommon. 4. Miscellaneous effects a. Liver function abnormalities is rare. b. Secondary neoplasia is possible. c. Amenorrhea and azoospermia is common. d. Drug fever is uncommon.

e. Pulmonary fibrosis is rare. f. CNS effects including seizure and coma may be seen at very high doses (>100 mg/m2).

CISPLATIN Other names. cis-Diamminedichloroplatinum (II), DDP, CDDP, Platinol. Mechanism of action. Similar to alkylating agents with respect to binding and cross-linking strands of DNA. Primary indications. Usually used in combination with other cytotoxic drugs. 1. Testis, ovary, endometrial, cervical, bladder, head and neck, GI, and lung carcinomas. 2. Soft tissue and bone sarcomas. 3. Non-Hodgkin lymphoma. Usual dosage and schedule 1. 40 to 120 mg/m2 IV on day 1 as infusion every 3 weeks. 2. 15 to 20 mg/m2 IV on days 1 to 5 as infusion every 3 to 4 weeks. 3. 30 to 50 mg/m2 IV days 1, 8 every 4 weeks (in combination with other therapy). Special precautions. Do not administer if serum creatinine level is more than 1.5 mg/dL. Irreversible renal tubular damage may occur if vigorous diuresis is not maintained, particularly with higher doses (>40 mg/m2) and with additional concurrent nephrotoxic drugs, such as the aminoglycosides. At higher doses, diuresis with mannitol with or without furosemide plus vigorous hydration is mandatory. 1. An acceptable method for hydration in patients without cardiovascular impairment for cisplatin doses up to 80 mg/m2 is as follows. a. Have patient void, and begin infusion of 5% dextrose in half-normal saline with potassium chloride (KCl) 20 mEq/L and magnesium sulfate (MgSO4) 1 g/L (8 mEq/L); run at 500 mL/hour for 1.5 to 2.0 L. b. After 1 hour of infusion, give 12.5 g of mannitol by IV push. c. Immediately thereafter, start the cisplatin (mixed in normal saline at 1 mg/mL) and infuse over 1 hour through the sidearm of the IV, while continuing the hydration. d. Give additional mannitol (12.5 to 50.0 g) by IV push if necessary to maintain urinary output of 250 mL/hour over the duration of the hydration. If patient gets more than 1 L behind on urinary output or signs or symptoms of congestive heart failure develop, 40 mg of furosemide may be given. 2. For doses of more than 80 mg/m2, a more vigorous hydration is recommended. a. Have patient void, and begin infusion of 5% dextrose in half-normal saline with KCl 20 mEq/L and MgSO4 1 g/L (8 mEq/L); run at 500 mL/hour for 2.5 to 3.0 L. b. After 1 hour of infusion, give 25 g of mannitol by IV push. c. Continue hydration.

d. After 2 hours of hydration, if urinary output is at least 250 mL/hour, start the cisplatin (mixed in normal saline at 1 mg/mL) and infuse over 1 to 2 hours (1 mg/m2/minute) through the sidearm of the IV, while continuing the hydration. e. Give additional mannitol (12.5 to 50 g by IV push) if necessary to maintain urinary output of 250 mL/hour over the duration of the hydration. If patient gets more than 1 L behind on urinary output or signs or symptoms of congestive heart failure develop, 40 mg of furosemide may be given. 3. For patients with known or suspected cardiovascular impairment (ejection fraction 1.5 ULN), because of more profound neutropenia. Toxicity 1. Myelosuppression and other hematologic effects. Severe (grade 4) neutropenia is common and dose related. Many patients have neutropenic fever. 2. Nausea, vomiting, and other GI effects. Common, but brief; severe episodes are uncommon. 3. Mucocutaneous effects. Mild mucositis is common; severe mucositis is uncommon. Alopecia is common. Mild-to-moderate cutaneous reactions such as maculopapular eruptions are common; severe reactions, which may be associated with desquamation or bullous eruptions, occur only occasionally if systemic prophylaxis is used. Mild-tomoderate nail changes are common, but severe onycholysis is uncommon. 4. Immunologic effects and infusion reactions. Mild-to-moderate hypersensitivity reactions with flushing, hypotension (or rarely hypertension) with or without dyspnea, and drug fever are occasional with use of the prophylactic regimen recommended. Severe hypersensitivity reactions are uncommon. 5. Miscellaneous effects a. Fluid retention syndrome is common and cumulative (more commonly after four courses); can be reduced to occasional frequency (6%) by prophylactic steroids; may limit continuing therapy. May be associated with both pleural and pericardial effusions b. Neurologic. Mild and reversible dysesthesias or paresthesias are common; more severe sensory neuropathies are uncommon. c. Hepatic. Reversible increases in transaminase, alkaline phosphatase, and bilirubin. d. Local reactions. Reversible peripheral phlebitis. e. Mild diarrhea is common; severe diarrhea is rare. f. Fatigue, weakness (asthenia), and myalgia are common; arthralgia is occasional.

DOXORUBICIN Other names. ADR, Adriamycin, Rubex, hydroxydaunorubicin. Mechanism of action. DNA strand breakage mediated by anthracycline effects on topoisomerase II; DNA intercalation; DNA polymerase inhibition. Primary indications 1. Breast, bladder, liver, lung, prostate, stomach, and thyroid carcinomas. 2. Bone and soft tissue sarcomas.

3. Hodgkin and non-Hodgkin lymphomas. 4. Multiple myeloma 5. Wilms tumor, neuroblastoma, and rhabdomyosarcoma of childhood. Usual dosage and schedule 1. 60 to 75 mg/m2 IV every 3 weeks. (Or as 96-hour continuous infusion.) 2. 30 mg/m2 IV on days 1 and 8 every 4 weeks (in combination with other drugs). 3. 9 mg/m2 IV daily for 4 days as a continuous infusion (in myeloma). 4. 15 to 20 mg/m2 IV weekly. 5. 50 to 60 mg instilled into the bladder weekly for 4 weeks, then every 4 weeks for 6 cycles. Special precautions 1. Administer over several minutes into the sidearm of a running IV infusion (except when given as a continuous infusion), taking care to avoid extravasation. 2. Do not give if patient has significantly impaired cardiac function (ejection fraction 3 × ULN); monitor those with less liver impairment closely. Toxicity 1. Myelosuppression and other hematologic effects. Myelosuppression is not an effect of

erlotinib. Deep venous thrombosis—uncommon. Unexpected INR elevation may occur in patients taking warfarin. Microangiopathic hemolytic anemia with thrombocytopenia is rare. 2. Nausea, vomiting, and other GI effects. Anorexia, dyspepsia, nausea, vomiting, diarrhea (second most common reason for dose interruption), constipation, and abdominal pain are common. 3. Mucocutaneous effects. Rash is common (75%) and the most common reason for dose interruption; stomatitis is occasional to common (17%). Keratoconjunctivitis is occasional. 4. Miscellaneous effects a. Systemic. Fatigue, weight loss, edema are common; fever is common, occasionally with rigors. b. Hepatic. Transaminase elevations are common, and occasionally associated with increased bilirubin, but they are rarely life-threatening. c. Bone pain and myalgia are common. d. Dyspnea is common, cough is occasional. e. Anxiety, depression, headache, and neuropathy are occasional. f. Myocardial ischemia or infarction is uncommon. g. Cerebrovascular accidents are uncommon.

ETOPOSIDE Other names. Epipodophyllotoxin, VP-16, VP-16-213, VePesid, Etopophos (etoposide phosphate). Mechanism of action. Interaction with topoisomerase II produces single-strand breaks in DNA. Arrests cells in late S phase or G2 phase. Primary indications 1. Small cell anaplastic and NSCLC. 2. Stomach carcinoma. 3. Germ cell cancers. 4. Lymphomas. 5. Acute leukemia. 6. Neuroblastoma. Usual dosage and schedule 1. 120 mg/m2 IV on days 1 to 3 every 3 weeks. 2. 50 to 100 mg/m2 IV on days 1 to 5 every 2 to 4 weeks. 3. 125 to 140 mg/m2 IV on days 1, 3, and 5 every 3 to 5 weeks. 4. High-dose therapy (750 to 2,400 mg/m2) is investigational and should only be used with progenitor cell rescue (e.g., bone marrow or peripheral blood stem cell transplantation). Special precautions

1. Administer etoposide as a 30- to 60-minute infusion to avoid severe hypotension. Monitor blood pressure during infusion. Etoposide phosphate may be administered as a 5-minute bolus infusion. 2. Take care to avoid extravasation. 3. Etoposide must be diluted in 20 to 50 volumes (100 to 250 mL) of isotonic saline before use. Etoposide phosphate vials (100 mg) may be reconstituted in 5 to 10 mL (water, saline, or dextrose) to a concentration of 10 or 20 mg/mL. 4. Decrease dose by 50% for bilirubin levels of 1.5 to 3 mg/dL; decrease by 75% for bilirubin levels of 3 to 5 mg/dL; discontinue drug if bilirubin level is more than 5 mg/dL. 5. Decrease dose by 25% for creatinine clearance rate of less than 30 mL/minute. Toxicity 1. Myelosuppression and other hematologic effects. Dose-limiting leukopenia and less severe thrombocytopenia have a nadir at 16 days with recovery by days 20 to 22. 2. Nausea, vomiting, and other GI effects. Usually mild-to-moderate nausea and vomiting in about one-third of patients receiving standard doses; common with high-dose therapy. Anorexia is common. Diarrhea is uncommon. 3. Mucocutaneous effects a. Alopecia is common. b. Stomatitis is uncommon with standard doses; common with high-dose therapy. c. Painful rash may occur with high-dose therapy. d. Chemical phlebitis is occasional. 4. Miscellaneous effects a. Hepatotoxicity is rare. b. Peripheral neurotoxicity is rare. c. Allergic reaction is rare. d. Hemorrhagic cystitis may occur with high-dose therapy.

EVEROLIMUS Other name. Afinitor. Mechanism of action. Everolimus, after complexing with an intracellular protein, FKBP-12, is an inhibitor of the mammalian target of rapamycin (mTOR), a serine threonine kinase, the pathway of which is dysregulated in several human cancers. It also inhibits the expression of hypoxia-inducible factor (HIF-1) and the expression of vascular endothelial growth factor (VEGF). Mechanism is similar, if not identical, to temsirolimus. Primary indications 1. Advanced renal cell carcinoma. 2. In combination with exemestane in metastatic hormone receptor–positive breast cancer in postmenopausal women after failure of nonsteroidal aromatase inhibitors. 3. Subependymal giant cell astrocytoma (SEGA) in adults and children, which cannot be

totally resected. 4. Unresectable, locally advanced or metastatic pancreatic neuroendocrine tumors in adults. 5. Renal angiomyolipomas, associated with tuberous sclerosis complex, that do not require immediate surgery. Usual dosage and schedule 1. 10 mg PO once daily. 2. Reduce dose to 5 mg PO once daily for patients with Child-Pugh class B hepatic impairment or as needed to manage adverse drug reactions. 3. If strong inducers of CYP3A4 are required, increase daily dose in 5-mg increments to a maximum of 20 mg once daily. Special precautions. Coadministration of everolimus with strong or moderate inhibitors of CYP3A4 or the multidrug efflux pump PgP, such as ketoconazole, increases the AUC of everolimus by up to 15-fold and should be avoided. CYP3A4 inducers may decrease everolimus AUC, and increased doses may be required. Toxicity 1. Myelosuppression and other hematologic effects. Anemia and lymphopenia are common and occasionally severe. Thrombocytopenia and neutropenia occur only occasionally, and are rarely grade 3 or 4. Hemorrhage is uncommon. 2. Nausea, vomiting, and other GI effects. Diarrhea, nausea, and vomiting are common, but rarely severe. Abdominal pain is occasional. 3. Mucocutaneous effects. Mucositis is common (44%), but grade 3 or 4 ulceration is uncommon. Rash is common; pruritis and dry skin are occasional. Hand-foot syndrome is uncommon as are nail disorders and acneiform dermatitis. 4. Miscellaneous effects a. Noninfectious pneumonitis (a class effect of rapamycin derivatives) is occasional, but grade 3 or 4 reaction is uncommon. b. Infections, particularly with opportunistic infections are common, and may occasionally be severe. c. Metabolic changes. Elevations in lipids, glucose, creatinine, and transaminases and decreased phosphate are common. Except for glucose elevation, which is occasional, severe (grade 3 or 4) abnormalities of the other changes are uncommon to rare. d. Asthenia, fatigue, peripheral edema, fever, headache, cough, and dyspnea are common (15% to 30%), but severe episodes are uncommon to rare. Decreased weight is occasional. e. Cardiovascular. Hypertension, tachycardia, chest pain are uncommon, and congestive heart failure is rare. f. Nervous system. Insomnia, dizziness, and paresthesias are occasional to uncommon. g. Acute renal failure is rare.

EXEMESTANE Other name. Aromasin. Mechanism of action. Exemestane is an irreversible, steroidal aromatase inactivator that decreases estrogen biosynthesis by selective inhibition of aromatase (estrogen synthetase) in peripheral tissues. Primary indications 1. Carcinoma of the breast in postmenopausal women that has progressed following tamoxifen therapy. 2. Carcinoma of the breast as adjuvant treatment in postmenopausal women with estrogenreceptor positive breast cancer. Usual dosage and schedule. 25 mg PO once daily after meal. Special precautions. Potential hazard to fetus if given during pregnancy. Toxicity 1. Myelosuppression and other hematologic. No dose-related effect. Thromboembolic events are uncommon to rare. 2. Nausea, vomiting, and other GI. Nausea, vomiting, constipation, diarrhea are uncommon to occasional. 3. Mucocutaneous effects. Rash is uncommon. 4. Miscellaneous effects a. Fatigue is occasional. b. Musculoskeletal pain (arthralgia or bone) is occasional to common. c. Headache is occasional. d. Peripheral edema, weight gain are occasional (lower than with megestrol). e. Dyspnea and cough are uncommon to occasional. f. Hot flushes are occasional. g. Decreased bone mineral density with osteoporosis is occasional, and there is increased risk for fractures. h. Hypertension is occasional.

FLUDARABINE Other names. FAMP, Fludara, Oforta. Mechanism of action. A purine analog that causes inhibition of DNA polymerase alpha, ribonucleotide reductase, and DNA primase, thus inhibiting DNA synthesis. Primary indications 1. CLL (B-cell). 2. Macroglobulinemia.

3. Indolent lymphomas. 4. Acute leukemia (in combination). Usual dosage and schedule 1. 25 mg/m2 IV as a 30-minute infusion daily for 5 days. (Fludara). Other dose schedules, usually less intensive, have been used, often in combinations with other drugs. Repeat every 4 weeks. 2. 40 mg/m2 PO daily for 5 days. Repeat every 4 weeks. (Oforta). Special precautions. If there is the potential for tumor lysis syndrome, administer allopurinol and ensure good hydration and close clinical monitoring. Transfusion-associated graft versus host disease may be seen. Therefore, prior irradiation of blood products for transfusion in patients at risk is recommended. Sometimes fatal cases of autoimmune hemolytic anemia have been reported, and patients should be closely monitored for hemolysis, particularly if there is a prior history of autoimmune hemolysis or immune thrombocytopenia related to the CLL. Not recommended for use in combination with pentostatin because of high incidence of pulmonary toxicity. Adult patients with moderate impairment of renal function (creatinine clearance 30 to 70 mL/minute/1.73 m2) should have a 20% dose reduction of fludarabine. It should not be given to patients with severely impaired renal function (creatinine clearance less than 30 mL/minute/1.73 m2). Toxicity 1. Myelosuppression and other hematologic effects. Granulocytopenia and thrombocytopenia are common but appear to become less common in patients whose disease is responding. May progress to trilineage marrow hypoplasia. Infection, particularly pneumonia, is common during early courses and uncommon after the sixth course. Autoimmune hemolytic anemia and immune thrombocytopenia have been observed (probably rare). 2. Nausea, vomiting, and other GI effects. Nausea is occasional to common but not usually severe. Diarrhea is occasional. 3. Mucocutaneous effects. Occasional mucositis, rash, no alopecia. 4. Neurotoxicity. Uncommon at usual dosage. Somnolence or fatigue, paresthesias, and twitching of extremities may be seen. Severe neurologic symptoms, including visual disturbances, have been common at higher doses than those recommended. 5. Immune suppression. Common. Usually seen as a depression in CD4 and CD8 lymphocyte counts. Opportunistic infections may result, and many recommend pneumocystis pneumonia prophylaxis with trimethoprim-sulfamethoxazole until the CD4 lymphopenia resolves. 6. Miscellaneous effects a. Abnormal liver or renal function is rare. b. Cough, dyspnea, upper respiratory infections are occasional. c. Fever, infection, diaphoresis, headache are occasional. d. Allergic pneumonitis is occasional to uncommon. e. Edema is occasional.

f. Tumor lysis syndrome is uncommon.

FLUOROURACIL Other names. 5-FU, Adrucil, Efudex, Fluoroplex, 5-fluorouracil. Mechanism of action. A pyrimidine antimetabolite that, when converted to the active nucleotide, inhibits the enzyme thymidylate synthetase and thereby blocks DNA synthesis. Primary indications 1. Breast, colorectal, anal, stomach, pancreas, esophagus, liver, head and neck, and bladder carcinomas. 2. Actinic keratosis; basal and squamous cell carcinomas of skin (topically). Usual dosage and schedule 1. Systemic options (alternatives). Other schedules when in combinations, particularly with leucovorin. a. 500 mg/m2 IV on days 1 to 5 every 4 weeks. b. 450 to 600 mg/m2 IV weekly. c. 200 to 400 mg/m2 daily as a continuous IV infusion. d. 1,000 mg/m2 daily for 4 days as a continuous IV infusion every 3 to 4 weeks. 2. Intracavitary. 500 to 1,000 mg for pericardial effusion; 2,000 to 3,000 mg for pleural or peritoneal effusions. 3. Topically. Apply solution or cream twice daily. Use only 5% strength for carcinomas. Special precautions 1. Reduce dose in patients with compromised liver function. 2. Precipitation may occur if leucovorin and fluorouracil are mixed in the same bag. Toxicity 1. Myelosuppression and other hematologic effects. Dose-limiting with a nadir at 10 to 14 days after the last dose and recovery by 21 days. 2. Nausea, vomiting, and other GI effects. Nausea and vomiting may occur, but are not usually severe. Diarrhea is common with higher doses, continuous infusion, or when used in combination with leucovorin and irinotecan. Esophagitis and proctitis may also occur. 3. Mucocutaneous effects a. Stomatitis is an early sign of severe toxicity. It progresses from soreness and erythema to frank ulceration, which becomes hemorrhagic in a small number of patients. b. Partial alopecia is uncommon. c. Hyperpigmentation of skin over face, hands, and the veins used for infusion is occasional. d. Maculopapular rash is uncommon. e. Sun exposure tends to increase skin reactions.

f. “Hand-foot syndrome” with painful, erythematous desquamation and fissures of palms and soles is common with continuous infusion, occasional with other schedules or combinations. 4. Miscellaneous effects a. Neurotoxicity, including headache, minor visual disturbances, and cerebellar ataxia is rare. b. Increased lacrimation is uncommon. c. Cardiac toxicity, including arrhythmias, angina, ischemia, and sudden death is rare. May be more common with continuous infusion and previous history of coronary artery disease.

FLUTAMIDE Other name. Eulexin. Mechanism of action. Competitive inhibitor of androgens at the cellular androgen receptor in the prostate cancer cells. Primary indication. Carcinoma of the prostate, most often in combination with LHRH agonists. Usual dosage and schedule. 250 mg PO every 8 hours. Special precautions. Serum transaminase levels should be measured prior to starting treatment with flutamide. Flutamide is not recommended in patients whose serum transaminase values exceed twice the ULN. Toxicity 1. Myelosuppression and other hematologic effects. None. 2. Nausea, vomiting, and other GI effects. Nausea and vomiting are uncommon to occasional. Diarrhea, flatulence, and mild abdominal pain are occasional. 3. Mucocutaneous effects. Mild skin rash is occasional. 4. Miscellaneous effects a. Endocrine. Secondary pharmacologic effects, including breast tenderness, breast swelling, hot flashes, impotence, and loss of libido, are common but reversible after cessation of therapy. b. Hepatic. Elevated liver function tests are uncommon; liver failure is rare, but may be preceded by flulike symptoms or right upper quadrant pain and tenderness. c. Hypertension is occasional. d. Adverse cardiovascular events are similar to those seen with orchiectomy.

FULVESTRANT Other name. Faslodex.

Mechanism of action. An estrogen receptor antagonist that binds to the estrogen receptor in a competitive manner. It downregulates the estrogen receptor protein in human breast cancer cells. In vitro there is reversible inhibition the growth of tamoxifen-resistant as well as estrogen-sensitive human breast cancer cell lines. Primary indications Hormone receptor–positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. (There are no efficacy data for premenopausal women with advanced breast cancer.) Hormone receptor–positive metastatic breast cancer in postmenopausal women with disease progression following therapy with a third-generation aromatase inhibitor. Usual dosage and schedule 1. 500 mg IM as two concurrent 5-mL injections (50 mg/mL) into each buttock, repeated once monthly after loading on days 1, 15, and 29. 2. Reduce dose to 250 mg in patients with moderate hepatic impairment (Child-Pugh class B), using the same schedule as above. Special precautions. Safety has not been evaluated in patients with severe hepatic impairment. Toxicity 1. Myelosuppression and other hematologic effects. Anemia is rare. 2. Nausea, vomiting, and other GI effects. Nausea is common; vomiting, constipation, diarrhea, and anorexia are occasional. 3. Mucocutaneous effects. Rash and increased sweating are occasional. 4. Miscellaneous effects a. For the body as a whole, headache, back pain, abdominal pain, injection site pain, and pelvic pain are occasional. Occasional patients also experience a flulike syndrome or fever. b. Vasodilation and edema are occasional. c. Dizziness, insomnia, paresthesias, depression, and anxiety are uncommon to occasional. d. Pharyngitis, dyspnea, and increased cough are occasional. Gefitinib Other names. Iressa, ZD1839. Mechanism of action. Selectively inhibits tyrosine kinase activity of the EGFR. Epidermal growth factor receptor tyrosine kinase inhibition by gefitinib impairs epidermal growth factor– stimulated autophosphorylation and thus blocks growth signals within the cell. Primary indications 1. Advanced NSCLC that is EGFR mutation positive for exon 19 deletions or exon 21 substitution mutations. 2. Carcinoma of the lung as monotherapy for the continued treatment of patients with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel

chemotherapies who are benefiting or have benefited from its use. Usual dosage and schedule. 250 mg daily. (May require interruption for diarrhea or skin reactions.) Special precautions. Diarrhea or hepatic function abnormalities may be dose limiting and require discontinuation of the drug. Toxicity 1. Myelosuppression and other hematologic effects. Uncommon, except for anemia, which is occasional and not dose related. 2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are common. Diarrhea may be dose limiting. Anorexia, constipation, and abdominal pain are also common but usually not severe. 3. Mucocutaneous effects. Acne-like or folliculitis-type rash is common, usually appearing by day 14; frequency and severity are dose related. May be associated with dry skin and itching. Rash usually does not worsen with continued treatment and resolves within a week of discontinuation of the drug. Dry mouth and conjunctivitis are occasional. 4. Miscellaneous effects a. Dyspnea is occasional to common. b. Asthenia is common. c. Headache and somnolence are occasional. d. Hepatic: Elevated transaminases are occasional but may be severe (grade 3 or 4).

GEMCITABINE Other name. Gemzar. Mechanism of action. After being metabolized intracellularly to the active diphosphate and triphosphate nucleotides, gemcitabine, a cytidine analog, inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. Primary indications 1. Carcinoma of the pancreas, locally advanced or metastatic. 2. Non–small cell carcinomas of the lung. 3. Carcinomas breast, biliary tract, bladder, and ovary. 4. Non-Hodgkin lymphoma. 5. Soft tissue sarcoma. Usual dosage and schedule 1. 1,000 mg/m2 IV over 30 minutes once weekly for up to 7 weeks when used as a single agent. After 1 week of rest, subsequent cycles are given once weekly for 3 consecutive weeks out of 4. 2. 1,000 to 1,250 mg/m2 IV over 30 minutes once weekly for 2 or 3 successive weeks during

each 3- to 4-week cycle, when used in combination regimens. Special precautions. Prolongation of infusion time beyond 60 minutes increases toxicity. Toxicity 1. Myelosuppression and other hematologic effects. Dose-related and common. Overt hemolytic-uremic syndrome is rare, but milder cases with renal insufficiency may be more common. 2. Nausea and vomiting and other GI effects. Nausea and vomiting are common, but only occasionally severe. Diarrhea and constipation are occasional to common. 3. Mucocutaneous effects. Rash, alopecia, and mucositis are occasional. 4. Miscellaneous effects a. Hepatic. Transient elevations of serum transaminases and alkaline phosphatase are common. Serious hepatotoxicity is rare. b. Mild proteinuria and hematuria are common. c. Fever without documented infection is common. d. Neurotoxicity. Mild paresthesias are occasional. e. Dyspnea is occasional.

GLUCARPIDASE Other name. Voraxaze. Mechanism of action. A recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from folic acid and classical antifolates such as methotrexate. It converts methotrexate to its inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate providing an alternative nonrenal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment. Primary indications. The treatment of toxic plasma methotrexate concentrations (>1 µmol/L) in patients with delayed methotrexate clearance due to impaired renal function. Usual dosage and schedule. Single IV bolus injection of 50 U/kg over 5 minutes. Patients with preglucarpidase methotrexate concentrations >100 µmol/L could receive a second dose 48 hours after the first dose. Special precautions 1. Methotrexate concentrations within 48 hours following administration can only be reliably measured by a chromatographic method as DAMPA interferes with the measurement of methotrexate concentration using immunoassays resulting in an erroneous measurement, which overestimates the methotrexate concentration. 2. Leucovorin should not be administered within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase. The leucovorin dose should remain the same for the first 48 hours after the glucarpidase dose. Beyond 48 hours,

leucovorin dose is based on the measured methotrexate concentration and continued until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days. Toxicity Allergic reactions to the infusion that could include parethesias, flushing, hypotension, nausea and vomiting, tremor, headaches, blurry vision, diarrhea, throat irritation, and rash are all uncommon and mostly grade 1 or 2. Severe reactions are rare.

GONADOTROPIN-RELEASING HORMONE ANALOGS Other names. LHRH analogs, leuprolide (Eligard, Lupron, Lupron depot), goserelin (Zoladex depot), triptorelin pamoate (Trelstar depot). Mechanism of action. Initial release of FSH and LH from the anterior pituitary, followed by diminution of gonadotropin secretion owing to desensitization of the pituitary to gonadotropinreleasing hormone (GnRH) and consequent decrease in the respective gonadal hormones. May also have direct effects on cancer cells, at least in cancer of the breast, in which GnRHbinding sites have been demonstrated. Primary indications 1. Metastatic prostate carcinoma. 2. Breast carcinoma in premenopausal and perimenopausal women with metastatic disease (goserelin). Usual dosage and schedule 1. Leuprolide depot, 7.5 mg IM monthly, 22.5 mg IM every 3 months, or 30 mg IM every 4 months. 2. Goserelin depot, 3.6 mg SC every 4 weeks or 10.8 mg SC every 12 weeks. Use only 3.6 mg implant for breast carcinoma. 3. Triptorelin depot 3.75 mg IM monthly; triptorelin depot 22.5 mg IM every 6 months. Special precautions. Worsening of symptoms may occur during the first few weeks. Toxicity 1. Myelosuppression and other hematologic. Rare, if at all. 2. Nausea, vomiting, and other GI. Anorexia, nausea, vomiting, and constipation are uncommon. 3. Mucocutaneous effects. Erythema and ecchymosis at the injection site, rash, hair loss, and itching are uncommon. 4. Cardiovascular effects. Congestive heart failure, hypertension, and thrombotic episodes are uncommon. Peripheral edema is occasional. 5. Miscellaneous effects a. Central nervous system: dizziness, pain, headache, and paresthesias are uncommon.

b. Endocrine: hot flashes are common; decreased libido is common; gynecomastia with or without tenderness is uncommon; impotence is occasional to common. c. Bone pain, or “flare,” is common on initiation of therapy in patients with bony metastasis. This can be minimized by pretreating with flutamide or another androgen antagonist in men with prostate cancer. d. Hypersensitivity reactions with rare angioneurotic edema and anaphylaxis have been reported.

HYDROXYUREA Other names. Hydrea, Droxia. Mechanism of action. Interferes with DNA synthesis, at least in part by inhibiting the enzymatic conversion of ribonucleotides to deoxyribonucleotides. Primary indications 1. Head and neck carcinomas. 2. CML 3. ALL and AML with high blast counts. 4. Essential thrombocythemia. 5. Polycythemia rubra vera. 6. Prevention of retinoic acid syndrome in acute promyelocytic leukemia. 7. Sickle cell anemia with frequent painful crises. Usual dosage and schedule 1. 800 to 2,000 mg/m2 PO as a single or divided daily dose. Dose is adjusted up or down, depending on efficacy and tolerability. 2. 3,200 mg/m2 PO as a single dose every third day (not for leukemias). 3. Starting dose in sickle cell anemia is 15 mg/kg/day, with increments of 5 mg/kg every 12 weeks, so long as ANC is >2,000 cells/μL and platelets >80,000/μL. Special precautions. The daily dose must be adjusted for blood count trends. Be careful not to change dose too often, because there is a delay in response. Severe cutaneous vasculitic toxicities, including ulcers and gangrene, have been seen, particularly in association with current or prior interferon therapy. Toxic reactions may be greater in patients with impaired renal function, such as may be seen in elderly patients. Reduce doses by 50% if creatinine clearance less than 60 mL/minute. Toxicity 1. Myelosuppression and other hematologic. Occurs at doses of more than 1,600 mg/m2 daily by day 10. Recovery is usually prompt. Increased RBC mean corpuscular volume (MCV) is common. 2. Nausea, vomiting, and other GI. Nausea is common at high doses. Other GI symptoms are uncommon. Pancreatitis may be seen in patients with HIV disease being treated with

didanosine and other antiviral agents. 3. Mucocutaneous effects. Stomatitis is rare. Maculopapular rash may be seen. Inflammation of mucous membranes caused by radiation may be exaggerated. 4. Miscellaneous effects a. Temporary renal function impairment or dysuria is uncommon. b. CNS disturbances are rare. c. May be leukemogenic or teratogenic.

IBRUTINIB Other name. Imbruvica. Mechanism of action. Inhibitor of Bruton tyrosine kinase, which results in inhibition of signaling pathways necessary to malignant B-cells proliferation and survival. Primary indications 1. Mantle cell lymphoma (MCL) in patients who received at least one prior therapy. 2. CLL in patients who received at least one prior therapy. 3. CLL in patients who carry a deletion in chromosome 17 (17p del). 4. Waldenström macroglobulinemia (WM). Usual dosage and schedule 1. MCL—560 mg PO daily for MCL. 2. CLL and WM—420 mg PO daily. The dose is to be taken approximately at the same time daily with water. Dose interruption and/or reduction is indicated for grade 3 or greater hematologic and nonhematologic toxicities, and also for concomitant use of CYP3A inhibitors. Concomitant use with strong CYP3A inhibitors/inducers should be avoided. If a dose is missed, it can be taken as soon as possible with return to the same schedule the next day. Special precautions. Ibrutinib can cause fetal harm if administered to a pregnant woman. Use in patients with baseline impairment in liver function should be avoided as those with serum AST or ALT ≥3 times upper normal limit were excluded from clinical trials of ibrutinib. Grade 3 or higher bleeding events can occur in up to 5% with the dose of 560 mg daily. Withholding ibrutinib 3 to 7 days pre- and postsurgical procedures may be warranted, depending on the bleeding risk. Toxicity 1. Myelosuppression and other hematologic effects. Neutropenia and thrombocytopenia are common. Anemia is occasional. Bleeding events, including bruising, of any grade can occur in up to 48% of patients taking the 560 mg oral daily dose. Ibrutinib-induced lymphocytosis can result from redistribution of tissue-resident CLL cells into the blood with rapid shrinkage of the lymph nodes. This effect is transient in most patients lasting for about 8 months but can be prolonged for up to more than 12 months in some cases. This, however,

does not imply drug inactivity, and close monitoring for expected recovery should be undertaken unless other signs of disease progression are present. Grade 3 or greater infections can occur in up to 25% of patients and some cases can be fatal. Upper respiratory tract infections are more common. However, skin infections, urinary tract infections, and pneumonia can also occur. 2. Nausea, vomiting, and other GI effects. Diarrhea, constipation, nausea, vomiting, and abdominal pain are common. Dyspepsia is occasional. 3. Mucocutaneous effects. Rash is common. Stomatitis is occasional. 4. Immunologic effects and infusion reactions. Not applicable. 5. Miscellaneous effects a. Pyrexia is occasional. Peripheral edema is common. b. Neurologic. Peripheral sensory neuropathy is uncommon. Dizziness and headache are occasional. c. Renal toxicity. Increase in creatinine levels of up to 1.5 times the ULN—67%; 1.5 to 3 times the ULN 9%. d. Second primary malignancies. In patients with MCL treated with ibrutinib, other malignancies occurred in 5% of patients, including skin cancers (4%) and other carcinomas (1%). e. Musculoskeletal and connective tissue. Musculoskeletal pain is common. Muscles spasms and arthralgia are occasional. f. Respiratory. Dyspnea is common and cough is occasional. g. Cardiovascular. Increased risk of atrial fibrillation has been observed in 3% to 5% of patients.

IDARUBICIN Other names. 4-Demethoxydaunorubicin, IDA, Idamycin. Mechanism of action. DNA strand breakage mediated by anthracycline effects on topoisomerase II or free radicals; DNA intercalation; DNA polymerase inhibition. Primary indications 1. AML. 2. Blast crisis of CML. 3. ALL. Usual dosage and schedule. 12 to 13 mg/m2 IV daily for 3 days (usually in a combination with cytarabine) during induction; 10 to 12 mg/m2 IV daily for 2 days during consolidation. Special precautions. Administer over several minutes into the sidearm of a running IV infusion, taking care to avoid extravasation. Cardiac toxicity may be less than that with daunorubicin. Maximum dose not yet established. Cumulative doses >150 mg/m2 have been associated with decreased cardiac ejection fraction.

Toxicity 1. Myelosuppression and other hematologic effects. Universal and dose-limiting. 2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and anorexia, are common. Diarrhea is occasional to common. 3. Mucocutaneous effects. Alopecia is common; mucositis is common but usually not severe. 4. Miscellaneous effects a. Hepatic dysfunction. Common but usually not severe and not clearly due to the idarubicin. b. Renal effects. Common but usually not clinically significant. c. Cardiac effects. Uncommon during induction and consolidation (1% to 5%). d. Tissue damage is probable if infiltration occurs. e. Neurologic effects. Occasional.

IDELALISIB Other name. Zydelig. Mechanism of action. Inhibitor of PI3K-delta kinase. It induces apoptosis and inhibits proliferation in cell lines derived from malignant B cells and in primary tumor cells. Primary indications 1. Relapsed CLL, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other comorbidities. 2. Relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least two prior systemic therapies. 3. Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies. Usual dosage and schedule. 150 mg oral twice a day. Can be taken with or without food. Dose reduction and/or interruption may be indicated for severe or life-threatening adverse events. Permanent discontinuation is indicated with reoccurrence of severe or life-threatening adverse events and in patients with symptomatic pneumonitis of any severity. Should not be used with strong CYP3A inducers or with drugs that may cause liver toxicity. Close monitoring for toxicity is warranted when used with strong CYP3A inhibitors. This is also critical in patients with baseline hepatic impairment as those with serum AST or ALT greater than 2.5 ULN or bilirubin greater than 1.5 ULN were excluded from clinical studies. Special precautions. Idelalisib can cause fetal harm if administered to a pregnant woman. Fatal and/or serious hepatotoxicity, colitis, pneumonitis, and intestinal perforation can occur (up to 15% of patients), warrant special caution, and may require dose interruption or permanent discontinuation. Toxicity 1. Myelosuppression and other hematologic effects. Anemia and thrombocytopenia are

common. Neutropenia is common, with grade 3 or higher occurring in up to 31% of cases. Pneumonia was reported in 25% of cases. Other infections can occur, including upper respiratory tract and urinary tract infections. 2. Nausea, vomiting, and other GI effects. Nausea and diarrhea are common. Vomiting is occasional. Grade 3 or higher diarrhea or colitis can occur in up to 14% of cases and responds poorly to antimotility agents. This may warrant dose interruption and in some cases, corticosteroids use. Intestinal perforation can occur and warrants permanent discontinuation. 3. Mucocutaneous effects. Stomatitis is occasional. Rash is common. Severe (grade 3 or greater) cutaneous manifestations including rash, dermatitis, and even TEN are rare and warrant discontinuation of treatment. 4. Immunologic effects and infusion reactions. Serious allergic reactions including anaphylaxis are rare but warrant discontinuation of treatment and supportive care. 5. Miscellaneous effects a. Hepatic. Fatal and/or serious hepatotoxicity can occur in up to 14% of patients generally within the first 12 weeks and is reversible with dose interruption. Recurrent hepatotoxicity warrants permanent discontinuation. Monitor AST and ALT every 2 weeks for the first 3 months, then every 4 weeks for the next 3 months, then every 1 to 3 months thereafter. Monitor weekly if the ALT or AST rises above three times ULN until resolves, and withhold idelalisib if the ALT or AST rises above five times ULN, and continue to monitor the ALT/AST weekly until resolved. b. Pyrexia is occasional. Peripheral edema is common. Asthenia is occasional. c. Neurologic. Headache is occasional. d. Musculoskeletal and connective tissue. Arthralgia is occasional. e. Respiratory. Cough and dyspnea are common. Fatal and serious pneumonitis can occur. Patients with symptomatic pneumonitis secondary to idelalisib are treated with discontinuation of therapy and corticosteroids. f. Psychiatric. Insomnia is occasional.

IFOSFAMIDE Other name. Ifex. Mechanism of action. Metabolic activation by microsomal liver enzymes produces biologically active intermediates that attack nucleophilic sites, particularly on DNA. Primary indications 1. Testicular and lung cancers. 2. Bone and soft tissue sarcomas. 3. Lymphoma. Usual dosage and schedule 1. 1.2 g/m2 IV over 30 minutes or more daily for 5 consecutive days every 3 or 4 weeks,

usually with other agents. Mesna 120 mg/m2 is given just before ifosfamide, then mesna 1,200 mg/m2 as a daily continuous infusion is given until 16 hours after the last dose of ifosfamide. 2. 3.6 g/m2 IV daily as a 4-hour infusion for 2 consecutive days, usually with other agents. Mesna is given at a dose of 750 mg/m2 IV just prior to and at 4 and 8 hours after the start of the ifosfamide. Higher dosage schedules have been used experimentally with up to 14 g/m2 being used per course over a 6-day period, with equal or greater doses of mesna. Special precautions. Must be used with mesna to prevent hemorrhagic cystitis. Mesna dose is at least 20% of the ifosfamide dose (on a weight basis), administered just prior to (or mixed with) the ifosfamide dose and again at 4 and 8 hours after the ifosfamide to detoxify the urinary metabolites that cause the hemorrhagic cystitis. Higher doses of ifosfamide may require higher doses and longer durations of mesna. Neither mesna nor its only metabolite, mesna disulfide, affect ifosfamide or its antineoplastic metabolites. Mesna disulfide is reduced in the kidney to a free thiol compound, which then reacts chemically with urotoxic metabolites resulting in their detoxification. Vigorous hydration is also required with a minimum of 2 L of oral or IV hydration daily. Administer as a slow IV infusion over a period of at least 30 minutes. Toxicity 1. Myelosuppression and other hematologic effects. Myelosuppression is dose-limiting. Platelets are relatively spared. Granulocyte nadirs are commonly reached at 10 to 14 days, and recovery is seen by day 21. Thrombocytopenia may be seen with higher doses. 2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common without standard antiemetics. 3. Mucocutaneous effects. Alopecia is common; mucositis is rarely seen at standard doses; dermatitis is rare. 4. Hemorrhagic cystitis. Common and dose-limiting unless a uroprotective agent such as mesna is used. With mesna, the incidence of hemorrhagic cystitis is 5% to 10%, and gross hematuria is uncommon. Increasing the duration of mesna may alleviate the problem during subsequent cycles. 5. Miscellaneous effects a. CNS toxicity (somnolence, confusion, depressive psychosis, hallucinations, disorientation, and uncommonly seizures, cranial nerve dysfunction, or coma) is occasional with doses in lower range, more common with larger doses. b. Infertility is common in men and women, as with other alkylating agents. c. Renal impairment is occasional to common. Fanconi syndrome dependent on dose. May be severe acidosis. d. Liver dysfunction is uncommon. e. Phlebitis is uncommon. f. Fever is rare. g. Peripheral neuropathy with high-dose therapy is uncommon.

IMATINIB MESYLATE Other names. Gleevec, STI-571 (signal transduction inhibitor 571). Mechanism of action. Inhibitor of the constitutively activated Bcr-Abl tyrosine kinase that is created as a consequence of the (9;22) chromosomal translocation and is required for the transforming function and excess proliferation seen in CML. It also inhibits the RTKs for platelet-derived growth factor (PDGF), stem cell factor, and c-KIT, the latter of which is activated in gastrointestinal stromal tumors (GISTs). Primary indications 1. CML in chronic phase, accelerated or blast phase of the disease. 2. ALL, Philadelphia chromosome positive (Ph+). 3. GIST that is KIT+ (CD117), adjuvant and metastatic disease. 4. MDS or myeloproliferative diseases (MPD) with PDGF receptor gene rearrangements 5. Aggressive systemic mastocytosis (ASM) without D816V c-KIT mutation or with cKIT mutation status unknown. 6. Hypereosinophilic syndrome (HES) or chronic eosinophilic leukemia (CEL) with the FIP1L1-PDGFRα fusion kinase (CHIC2 deletion) (and also if fusion kinase negative or unknown.) 7. Dermatofibrosarcoma protuberans (DFSP). Usual dosage and schedule 1. 400 mg PO daily in the chronic phase of CML; MDS or MPD; or GISTs. Reduce to 300 mg/day with severe liver impairment or moderate renal impairment. 2. 600 mg PO daily in the accelerated phase or blast crisis of CML or Ph+ ALL. 3. 100 to 400 mg PO daily in ASM, HES, or CEL. 4. 800 mg PO daily in DFSP. Special precautions Use caution when giving to patients with cardiac disease, who have an increased likelihood of developing severe congestive heart failure, edema, and severe fluid retention. Risk particularly high in patients with high eosinophil counts who may develop cardiogenic shock. GI perforations have been reported, as have bullous dermatologic reactions. Patients who require anticoagulation should not receive warfarin. Imatinib is an inhibitor of and primarily metabolized by CYP3A4. Toxicity 1. Myelosuppression and other hematologic effects. Moderate neutropenia and thrombocytopenia are common in all phases, but severe neutropenia or thrombocytopenia is uncommon unless patients are in the accelerated phase or blast crisis of CML. 2. Nausea, vomiting and other GI effects. Nausea, vomiting, abdominal pain, and diarrhea are common, but it is uncommon that they are severe. 3. Mucocutaneous effects. Skin rash and nasopharyngitis are common; pruritis and petechiae

are occasional. Erythema multiforme and Stevens–Johnson syndrome have been reported. 4. Miscellaneous effects a. Fluid retention and edema are common. Pleural effusion and ascites are occasional. b. Musculoskeletal pain or cramps, arthralgia, headache, fever, and fatigue are common, but it is uncommon that they are severe or life-threatening. c. Dyspnea and cough are occasional. d. Hepatic. Elevated liver function tests are occasional. Rare cases of severe hepatotoxicity have been seen. e. Rise in serum creatinine and hypokalemia are occasional but rarely severe. f. Congestive heart failure is uncommon, but may lead to pulmonary edema and rarely pericardial effusion. It may be related to imatinib inhibition of Abl, which in turn may be related to mitochondrial function in the heart. g. Monitor TSH levels during imatinib treatment in patients who have had thyroidectomy and are on levothyroxine.

INTERFERON ALPHA Other names. Roferon-A (interferon α2a, recombinant alpha-A interferon), Intron A (interferon α2b, recombinant alpha-2 interferon), Sylatron (peginterferon α2b). Mechanism of action. Believed to involve direct inhibition of tumor cell growth and modulation of the immune response of the host, including activation of NK cells, modulation of antibody production, and induction of major histocompatibility antigens. Primary indications 1. Melanoma (both as adjuvant and metastatic disease therapy). 2. Renal cell carcinoma. 3. Multiple myeloma. 4. Kaposi sarcoma, HIV associated. 5. Non-Hodgkin lymphoma (low grade), mycosis fungoides. 6. Condyloma acuminatum (intralesional). 7. Chronic hepatitis B and C. Usual dosage and schedule 1. 3 to 10 million IU IM or SQ in various schedules. Daily dosing is often used for several weeks or months, followed by three times a week dosing. 2. As adjuvant therapy for high-risk melanoma, 20 million IU/m2 IV 5 consecutive days weekly for 4 weeks, then 10 million IU/m2 SQ three times weekly for 48 weeks. 3. For HIV-related Kaposi sarcoma, 1 to 5 million IU SC daily, with dose modifications based upon toxicity. 4. Investigationally, doses have been higher (up to 50 million IU/m2 per dose), usually IV at doses higher than 10 million IU/m2.

5. Peginterferon α2b—6 μg/kg/week SC for 8 weeks followed by 3 μg/kg/week SC for up to 5 years as adjuvant therapy for node positive melanoma after surgical resection. Special precautions May cause or aggravate life-threatening or fatal neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. Toxicity 1. Myelosuppression and other hematologic effects. Common but usually mild to moderate and transient, even with continued therapy. Higher doses may be associated (25% of patients receiving the recommended adjuvant therapy for melanoma) with granulocyte counts of 1 mm pathologic involvement of lymph nodes that have been resected. Usual dosage and schedule. 3 mg/kg IV over 90 minutes every 3 weeks × 4 doses. Discontinue if unable to complete full treatment course within 16 weeks from administration of first dose. Special precautions. Ipilimumab can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including TEN), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifest during treatment but may occur weeks to months after discontinuation of ipilimumab. Permanently discontinue ipilimumab and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. Toxicity 1. Myelosuppression and other hematologic effects. Anemia, leukopenia, and lymphopenia are common, but only occasionally grade 3 or more. Venous thrombosis is uncommon. 2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common, but usually not severe. Diarrhea is also common and occasionally severe (grade 3) and may be associated with colitis. 3. Mucocutaneous effects. Pruritis is common (>40%), as is skin rash. TEN—rare. 4. Immunologic effects and infusion reactions. Many of nonhematologic effects, particularly skin and GI, but also hepatic, neurologic, ocular (uveitis), endocrine, and other organ system reactions may be immunologic in etiology and require emergent treatment with corticosteroids. 5. Miscellaneous effects a. Fatigue is common and occasionally severe. b. Increased transaminases are common and occasionally (8%) grade 3 to 4. Significant rise in bilirubin may also be seen as well as pancreatitis. c. Endocrine: Adrenal insufficiency, hypothyroidism, and hypopituitarism are rare to uncommon, but may require emergent therapy.

d. Dyspnea is common. e. Pain is common. f. Confusion is occasional.

IRINOTECAN Other names. Camptosar, CPT-11, Onivyde (liposome formation). Mechanism of action. Irinotecan, a semisynthetic water soluble derivative of camptothecin, is a prodrug for the lipophilic metabolite SN-38, a potent inhibitor of topoisomerase I, an enzyme essential for effective replication and transcription. It binds to the topoisomerase I—DNA cleavable complex, preventing re-ligation after cleavage by topoisomerase I. The liposome form is irinotecan encapsulated in a lipid bilayer. Primary indications 1. Carcinoma of the colon or rectum, esophagus, or stomach. 2. Carcinoma of the lung. 3. Glioblastoma multiforme. 4. Pancreatic adenocarcinoma. Usual dosage and schedule 1. 80 to 125 mg/m2 IV over 90 minutes weekly for 4 weeks followed by a 2-week rest to complete one cycle when used either as a single agent or in combination with fluorouracil and leucovorin. 2. 180 mg/m2 IV over 90 minutes every 2 weeks when used with leucovorin (over 2 hours) plus bolus fluorouracil followed by a 22-hour infusion of fluorouracil. 3. The dose of the liposome injection is 70 mg/m2 IV infusion over 90 minutes every 2 weeks, and in those who are homozygous for the UGT1A1*28 allele, 50 mg/m2 IV infusion over 90 minutes every 2 weeks. It is to be given in combination with fluorouracil and leucovorin. (Pancreatic adenocarcinoma.) In patients being concurrently treated with enzyme-inducing antiepileptic drugs (EIAEDS), doses must be increased approximately fourfold. For severe or worse diarrhea (≥7 stools over pretreatment), doses should be held. When the diarrhea has improved (≤7 stools over pretreatment), treatment may be restarted with doses modified downward by 25 to 30 mg/m2 during the current and subsequent cycles if there was an increase in stools of 7/day to 9/day, and by 50 to 60 mg/m2 if there was an increase in stools of 10 or more. Doses are also held during treatment and reduced in the same and subsequent cycles for severe neutropenia (absolute neutrophil count [ANC] 2.5 ULN or bilirubin > 1 × ULN. Dose reductions required in patients with moderate hepatic impairment (AST or ALT > 2.5 ULN or bilirubin > 1.5 ULN). Toxicity 1. Myelosuppression and other hematologic effects. Severe (grade 3 to 4) neutropenia is common. Severe anemia and thrombocytopenia are only occasional. 2. Nausea, vomiting, and other GI effects. Anorexia, nausea, vomiting, and diarrhea are common, but it is uncommon that they are severe. Constipation and abdominal pain are occasional, but rarely severe. 3. Mucocutaneous effects. Mucositis is common, but it is uncommon that it is severe. Alopecia is common. Skin rash, nail disorders, palmar-plantar erythrodysesthesia, and pruritis are occasional. Hyperpigmentation and skin exfoliation are uncommon. 4. Immunologic effects and infusion reactions. 1% of patients may have hypersensitivity reactions. 5. Miscellaneous effects a. Neurologic. Peripheral neuropathy is common and cumulative and occasionally severe (grade 3 to 4). It is the most frequent toxicity responsible for drug discontinuation. Headache, dizziness, insomnia, and altered taste are occasional. b. Musculoskeletal. Myalgia and arthralgia are common. c. Fatigue and asthenia are common. Edema and fever are occasional. d. Cardiorespiratory. Use of ixabepilone in combination with capecitabine may increase cardiac adverse reactions such as myocardial ischemia or ventricular dysfunction (1% to 2%). Cough and dyspnea are occasional.

IXAZOMIB Other name. Ninlaro.

Mechanism of action. Reversible PI. It preferentially binds and inhibits the chymotrypsin-like activity of the β5 subunit of the 20S proteasome. Primary indications. In combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Usual dosage and schedule. 4 mg orally on days 1, 8, 15, of a 28-day cycle, at least 1 hour before or 2 hours after a meal. A missed dose should not be taken within 72 hours of the next scheduled dose and a double dose should not be taken to make up for the missed dose. Starting dose should be reduced to 3 mg in patients with moderate-to-severe hepatic impairment as well as in those with severe renal impairment and end stage renal disease (ESRD) requiring dialysis. Special precautions 1. Concomitant use with strong CYP3A inducers should be avoided. 2. Ixazomib can cause fetal harm if administered to a pregnant woman. Toxicity 1. Myelosuppression and other hematologic effects. Thrombocytopenia and neutropenia are common and can be severe in up to 26% of cases. 2. Nausea, vomiting, and other GI effects. Diarrhea is common and occasionally severe. Nausea, vomiting, and constipation are common, but uncommonly severe. 3. Mucocutaneous effects. Macular and maculopapular rash is common, but mostly mild. 4. Immunologic effects and infusion reactions. Upper respiratory tract infections occurred in 19% of patients and were rarely severe. 5. Miscellaneous effects a. Cardiovascular. Peripheral edema is common and mostly grade 1 or 2. b. Neurologic. Peripheral neuropathy, mainly sensory, is common but uncommonly severe. c. Musculoskeletal and connective tissue. Back pain is common, but rarely severe. d. Ophthalmic. Blurry vision, dry eyes, and conjunctivitis are occasional, but uncommonly severe. e. Other. The following serious adverse reactions have each been reported at a frequency of 1.5 × normal. 2. Use in early myeloma may preclude harvest of sufficient numbers of peripheral stem cells for autologous transplantation. Toxicity 1. Myelosuppression and other hematologic effects. Dose-limiting; nadir at days 14 to 21. 2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are uncommon at standard doses, but common with high-dose regimens. 3. Mucocutaneous effects. Alopecia, dermatitis, and stomatitis are uncommon at standard doses; alopecia and mucositis are common with high-dose regimens. 4. Miscellaneous effects

a. AML and MDS are rare, but well documented. b. Pulmonary fibrosis is rare.

MERCAPTOPURINE Other names. 6-Mercaptopurine, 6-MP, Purinethol. Mechanism of action. A purine antimetabolite that, when converted to the nucleotide, inhibits the formation of nucleotides necessary for DNA and RNA synthesis. Primary indication. ALL Usual dosage and schedule 1. 100 mg/m2 PO daily if used alone. 2. 50 to 90 mg/m2 PO daily if used with methotrexate or other cytotoxic drugs. Special precautions 1. Decrease dose by 75% when used concurrently with allopurinol. 2. Increase interval between doses or reduce dose in patients with renal failure. Toxicity 1. Myelosuppression and other hematologic effects. Common but mild at recommended doses. 2. Nausea, vomiting, and other GI effects. Nausea and vomiting are uncommon. Diarrhea is rare. 3. Mucocutaneous effects. Stomatitis may be seen with very large doses. Dry, scaling rash is uncommon. 4. Miscellaneous effects a. Intrahepatic cholestasis and mild focal centrilobular necrosis with jaundice are uncommon. b. Hyperuricemia with rapid leukemia cell lysis is common. c. Fever is uncommon.

MESNA Other name. Mesnex. Mechanism of action. Mesna disulfide is reduced in the kidney to a free thiol compound, which then reacts chemically with urotoxic metabolites of ifosfamide or cyclophosphamide resulting in their detoxification. Primary indication. Prophylaxis for ifosfamide (or high-dose cyclophosphamide)-induced hemorrhagic cystitis. Usual dosage and schedule. Mesna dose is at least 20% of the ifosfamide dose (on a weight

[mg] basis), administered just prior to (or mixed with) the ifosfamide dose and again at 4 and 8 hours after the ifosfamide to detoxify the urinary metabolites that cause the hemorrhagic cystitis. Higher doses of ifosfamide may require higher doses and longer durations of mesna. Special precautions. Contraindicated if patient is sensitive to thiol compounds. Does not prevent or ameliorate any adverse effects of ifosfamide or cyclophosphamide other than hemorrhagic cystitis. Neither mesna nor its only metabolite, mesna disulfide, affects ifosfamide, cyclophosphamide, or their antineoplastic metabolites. Toxicity 1. Myelosuppression and other hematologic effects. None. 2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are occasional. Nausea and vomiting more commonly from ifosfamide. 3. Mucocutaneous effects. Bad taste in the mouth is common. 4. Miscellaneous effects a. Headache, fatigue, limb pain are occasional. b. Hypotension or allergic reactions are uncommon to rare. c. Gives false-positive test for urinary ketones.

METHOTREXATE Other names. Amethopterin, MTX, Mexate, Folex, Trexall. Mechanism of action. Inhibition of dihydrofolate reductase, which results in a block of the reduction of dihydrofolate to tetrahydrofolate. This blockage in turn inhibits the formation of thymidylate and purines, and arrests DNA (predominantly), RNA, and protein synthesis. Primary indications 1. Breast, head and neck, gastric, and gestational trophoblastic carcinomas. 2. Osteosarcomas (high-dose methotrexate). 3. ALL. 4. Meningeal leukemia or carcinomatosis. 5. Non-Hodgkin lymphoma. Usual dosage and schedule 1. Gestational trophoblastic carcinoma. 15 to 30 mg PO or IM on days 1 to 5 every 2 weeks. 2. Other carcinomas. 40 to 80 mg/m2 IV or PO two to four times monthly with a 7- to 14-day interval between doses. 3. ALL. 15 to 20 mg/m2 PO or IV weekly (together with mercaptopurine). 4. Osteosarcoma. Up to 12 g/m2 with leucovorin rescue (high-dose methotrexate). This usage requires on-site monitoring of methotrexate levels and a high degree of expertise to administer safely. 5. Intrathecally. 12 mg/m2 (not >20 mg) twice weekly.

Special precautions 1. High-dose methotrexate (>80 mg/m2) should be administered only by individuals experienced in its use and at institutions where serum methotrexate levels can be readily measured. 2. Intrathecal methotrexate must be mixed in buffered physiologic solution containing no preservative. 3. Avoid, aspirin, sulfonamides, tetracycline, phenytoin, and other protein-bound drugs that may displace methotrexate and cause an increase in free drug. 4. Oral anticoagulants, for example, warfarin, may be potentiated by methotrexate; therefore, prothrombin times should be followed carefully. 5. Oral antibiotics may decrease methotrexate absorption; penicillin and NSAIDs decrease clearance of methotrexate. 6. Concomitant use of proton pump inhibitors with high-dose methotrexate may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, leading to methotrexate toxicities. 7. Monitor use with theophylline. 8. In patients with renal insufficiency it may be necessary to markedly reduce the dose or discontinue methotrexate therapy. 9. Do not give if patient has a significant effusion, because of “reservoir” effect. Toxicity 1. Myelosuppression and other hematologic effects. Occurs commonly, with nadir at 6 to 10 days after a single IV dose. Recovery is rapid. 2. Nausea, vomiting, and other GI effects. Occasional at standard doses. 3. Mucocutaneous effects a. Mild stomatitis is common and a sign that a maximum tolerated dose has been reached. Higher doses may result in confluent or hemorrhagic stomal ulcers and bloody diarrhea. This requires prompt leucovorin therapy to limit duration and severity. b. Erythematous rashes, urticaria, and skin pigment changes are uncommon. c. Mild alopecia is frequent. 1. Miscellaneous effects a. Acute hepatocellular injury is uncommon at standard doses. Hepatic fibrosis is uncommon but seen at low chronic doses. b. Pneumonitis is rare. Polyserositis is rare. c. Renal tubular necrosis is rare at standard doses. d. Convulsions and a Guillain-Barré–like syndrome following intrathecal therapy are uncommon.

MITOMYCIN Other names. Mitomycin C, Mutamycin.

Mechanism of action. Alkylation and cross-linking by mitomycin metabolites interfere with structure and function of DNA. Primary indications. Bladder (intravesical), esophagus, stomach, anal, and pancreas carcinomas. Usual dosage and schedule 1. 20 mg/m2 IV on day 1 every 4 to 6 weeks or 2. 2 mg/m2 IV on days 1 to 5 and 8 to 12 every 4 to 6 weeks. 3. 10 mg/m2 IV on day 1 every 8 weeks in combination with fluorouracil and doxorubicin for stomach and pancreatic carcinomas. 4. 30 to 40 mg instilled into the bladder weekly for 4 to 8 weeks, then monthly for 6 months. Special precautions. Administer as slow push or rapid infusion through the sidearm of a rapidly running IV infusion, taking care to avoid extravasation. Pulmonary, renal, and hematologic toxicity (microangiopathic anemia and thrombocytopenia) may result from endothelial cell damage. Toxicity 1. Myelosuppression and other hematologic effects. Myelosuppression is serious, cumulative, and dose-limiting. Nadir is reached usually by 4 weeks but may be delayed. Recovery is often prolonged over many weeks, and occasionally the cytopenia never disappears. Hemolytic-uremic syndrome—rare, but when it occurs, may be poorly responsive to plasmapheresis and other therapies. 2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common at higher doses, but severity is usually mild to moderate. 3. Mucocutaneous effects. Stomatitis and alopecia are common. 4. Miscellaneous effects a. Renal toxicity is uncommon. Hemolytic-uremic syndrome is rare. b. Pulmonary toxicity is uncommon, but may be severe. c. Fever is uncommon. d. Cellulitis at injection site if extravasation occurs is common. e. Secondary neoplasia is possible.

MITOTANE Other names. o, p’-DDD, Lysodren. Mechanism of action. Suppresses adrenal steroid production, modifies peripheral steroid metabolism, and is cytotoxic to adrenal cortical cells. Primary indication. Adrenocortical carcinoma. Usual dosage and schedule. Begin with 2 to 6 g PO daily in three or four divided doses and build to a maximum tolerated daily dose that is usually 8 to 10 g, although it may range from 2

to 16 g. Glucocorticoid and mineralocorticoid replacements during mitotane therapy are necessary to prevent hypoadrenalism. Cortisone acetate (25 mg PO in the a.m. and 12.5 mg PO in the p.m.) and fludrocortisone acetate (0.1 mg PO in the a.m.) are recommended. Special precautions. Patients who experience severe trauma, infection, or shock should be treated with supplemental corticosteroids. Because of the effect of mitotane on peripheral steroid metabolism, larger than usual replacement doses may be necessary. Toxicity 1. Myelosuppression and other hematologic effects. None. 2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and anorexia are common and may be dose-limiting. Diarrhea is occasional. 3. Mucocutaneous effects. Skin rash occurs occasionally. 4. CNS effects. Lethargy, sedation, vertigo, or dizziness in up to 40% of patients; may be dose-limiting. 5. Miscellaneous effects. Albuminuria, hemorrhagic cystitis, hypertension, orthostatic hypotension, and visual disturbances are uncommon.

MITOXANTRONE Other names. Novantrone, dihydroxyanthracenedione, DHAD, DHAQ. Mechanism of action. DNA strand breakage mediated by anthracenedione effects on topoisomerase II. Primary indications 1. AML. 2. Carcinoma of the breast or ovary. 3. Non-Hodgkin and Hodgkin lymphoma. Usual dosage and schedule 1. 12 to 14 mg/m2 IV as a 5- to 30-minute infusion once every 3 weeks for solid tumors. 2. 12 mg/m2 IV as a 5- to 30-minute infusion daily for 3 days for acute nonlymphocytic leukemia. Special precautions. Rarely causes extravasation injury if infiltrated. Cardiotoxicity probably less than with doxorubicin; but prior anthracycline, chest irradiation, or underlying cardiac disease increases the risk. Toxicity 1. Myelosuppression and other hematologic effects. Universal. 2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common, but less frequent and less severe than with doxorubicin. Diarrhea is uncommon. 3. Mucocutaneous effects. Alopecia is common, but its frequency and severity are less than with doxorubicin. Mucositis is occasional.

4. Miscellaneous effects a. Cardiac toxicity. Probably less than with doxorubicin; there is no clear maximum dose, though the risk appears to increase at 125 mg/m2 cumulative dose. b. Local erythema and swelling with transient blue discoloration if extravasated, but rarely leads to severe skin damage. c. Green or blue discoloration of urine. d. Phlebitis is uncommon.

NECITUMUMAB Other name. Portrazza. Mechanism of action. A recombinant human IgG1 monoclonal antibody that binds to the human EGFR and blocks the binding of EGFR to its ligands. Primary indications. In combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous NSCLC. Usual dosage and schedule. 800 mg administered as an IV infusion over 60 minutes on days 1 and 8 of each 3-week cycle prior to gemcitabine (days 1 and 8) and cisplatin (day 1) infusion. For patients who have experienced a previous grade 1 or 2 infusion-related reaction, premedicate with diphenhydramine hydrochloride (or equivalent) prior to all subsequent infusions. For patients who have experienced a second occurrence, premedicate for all subsequent infusions, with diphenhydramine hydrochloride (or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent) prior to each infusion. Special precautions 1. Cardiopulmonary arrest and sudden death was reported in 3% of patients. Severe electrolytes abnormalities can increase the risk. Close monitoring of serum electrolytes including magnesium, potassium, and calcium is critical prior to each infusion and correction of electrolytes abnormalities, if abnormal, is recommended until improved to grade 2 or less. Special attention needs to be directed toward patients with underlying coronary artery disease and other cardiopulmonary risk factors. 2. Venous and/or arterial thrombotic events including deep venous thrombosis and pulmonary emboli were occasionally reported. These are uncommonly severe but can be rarely fatal. 3. Necitumumab can cause fetal harm if administered to a pregnant woman. Toxicity 1. Myelosuppression and other hematologic effects. Not reported. 2. Nausea, vomiting, and other GI effects. Vomiting and diarrhea are common, but uncommonly severe. Stomatitis is occasional and uncommonly severe. 3. Mucocutaneous effects. Rash and dermatitis acneiform are common and occasionally severe. Dry skin and pruritus are occasionally, but rarely, severe. Withhold treatment for grade 3 rash or acneiform rash until symptoms resolve to grade ≤2, then resume at reduced

dose of 400 mg for at least one treatment cycle. If symptoms do not worsen, may increase dose to 600 mg and 800 mg in subsequent cycles. Permanently discontinue therapy if grade 3 rash or acneiform rash does not resolve to grade ≤2 within 6 weeks, reactions worsen or become intolerable at a dose of 400 mg, patient experiences grade 3 skin induration/fibrosis or grade 4 dermatologic toxicity. Paronychia are occasional but rarely severe. 4. Immunologic effects and infusion reactions. Infusion-related reactions are uncommon and rarely severe. 5. Miscellaneous effects a. Respiratory. Hemoptysis is occasional, but uncommonly severe. b. Metabolic. Hypomagnesemia is common and commonly severe. Hypokalemia, hypocalcemia, and hypophosphatemia are common and may be severe. c. Musculoskeletal and connective tissue. Muscle spasms are uncommon. d. Ophthalmic. Conjunctivitis is occasional, but rarely severe.

NELARABINE Other name. Arranon. Mechanism of action. Nelarabine is a prodrug of arabinofuranosylguanine (ara-G), a cytotoxic analog of deoxyguanosine. When converted to triphosphorylated ara-G, it is incorporated into DNA (preferentially into T cells), inducing fragmentation and apoptosis. Primary indications T-cell ALL and T-cell lymphoblastic lymphoma that have relapsed or are refractory to at least two prior chemotherapy regimens. Usual dosage and schedule Adults—1,500 mg/m2 IV over 2 hours on days 1, 3, and 5, repeated every 21 days. Children—650 mg/m2 IV over 1 hour daily for 5 consecutive days, repeated every 21 days. Special precautions. Close monitoring for neurologic events is recommended, owing to the possibility of severe neurologic complications of therapy. Prophylaxis against tumor lysis syndrome recommended. Toxicity 1. Myelosuppression and other hematologic effects. Anemia, neutropenia, and thrombocytopenia are common. Febrile neutropenia is occasional. 2. Nausea and vomiting and other GI effects. Nausea, vomiting, diarrhea, and constipation are common, but usually low grade. Abdominal pain is occasional. 3. Mucocutaneous effects. Stomatitis is occasional. 4. Neurologic effects a. Headache is occasional. b. Somnolence and confusion are occasional.

c. Peripheral neuropathy is occasional. May range from numbness and paresthesias to motor weakness and paralysis. d. Ataxia is occasional. e. Insomnia is occasional. f. Convulsions and coma are rare. g. Leukoencephalopathy and demyelination and ascending peripheral neuropathy are rare. 5. Miscellaneous effects a. Fatigue, weakness, and fever (occasionally with rigors) are common. b. Cough, dyspnea, pleural effusion are common to occasional. c. Abnormal liver function tests are occasional. d. Hypokalemia, hypomagnesemia, hypocalcemia, increased creatinine are occasional. e. Edema is occasional. f. Sinus tachycardia is occasional. g. Musculoskeletal pain is occasional.

NILOTINIB Other names. Tasigna, AMNI07. Mechanism of action. Selective inhibitor of the constitutively activated Bcr-Abl tyrosine kinase that is created as a consequence of the (9;22) chromosomal translocation and is required for the transforming function and excess proliferation seen in CML. In vitro, nilotinib is active against many Bcr-Abl mutations associated with imatinib resistance. Primary indications 1. CML (Philadelphia chromosome positive [Ph+])—in chronic, accelerated, or blastic phase —in newly diagnosed patients and in those resistant or intolerant of imatinib. 2. Investigational a. Ph+ ALL b. GI stromal tumor Usual dosage and schedule. 1. Newly diagnosed Ph+ CML-Chronic Phase: 300 mg orally twice daily. 2. Resistant or intolerant Ph+ CML-Chronic Phase and CML—Accelerated Phase: 400 mg orally twice daily. Lower doses recommended for hepatic impairment or for toxicity. Special precautions. Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. ECGs should be obtained to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter. Do not give if QTc >480 minutes/second. Toxicity

1. Myelosuppression and other hematologic effects. Thrombocytopenia and neutropenia are common. Anemia is occasional. 2. Nausea, vomiting, and other GI effects. Nausea and vomiting are occasional. 3. Mucocutaneous effects. Skin rash is common; alopecia, dry skin, and pruritis are occasional. 4. Miscellaneous effects. a. Abnormal liver function tests, including elevations in bilirubin (primarily unconjugated) are occasional. b. Increase in the corrected QT interval by 5 to 15 minutes/second has been seen and may result in sudden death—rare. c. Increase in lipase and amylase are uncommon. d. Grade 3 or 4 hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia are occasional to uncommon. e. Arthralgia, myalgia, muscle spasms, and bone pain are occasional. f. Fatigue and insomnia are common; fever and weakness are occasional. g. Peripheral edema is occasional. h. Cough and dyspnea are occasional.

NILUTAMIDE Other name. Nilandron. Mechanism of action. Competitive inhibitor of androgens at the cellular androgen receptor in prostate cancer cells. Complements surgical castration. Primary indications. Metastatic carcinoma of the prostate, in combination with surgical castration or LHRH agonist. Usual dosage and schedule. 300 mg PO once daily for 30 days, followed by 150 mg PO once daily thereafter. Special precautions. Should be restricted to patients with normal liver function test values. Because interstitial pneumonitis may occur, a routine chest radiograph should be obtained before therapy and any time that the patient reports new exertional dyspnea or worsening of preexisting dyspnea. Inhibits activity of liver cytochrome P450 isoenzymes and may delay elimination of drugs such as warfarin, phenytoin, and theophylline. Toxicity 1. Myelosuppression and other hematologic effects. None. 2. Nausea, vomiting, and other GI effects. Nausea, constipation, and anorexia are occasional to common. Vomiting is uncommon. 3. Mucocutaneous effects. Rash, dry skin, and sweating are uncommon. 4. Miscellaneous effects a. Hepatitis is rare (1%). Increased liver function test values are uncommon.

b. Interstitial pneumonitis with dyspnea is uncommon (2%). May be higher in patients with Asian ancestry. c. Inhibits activity of liver cytochrome P450 isoenzymes and may delay elimination of drugs such as warfarin, phenytoin, and theophylline. d. Hot flashes are common. e. Impaired adaptation to dark is common (57%). f. Cardiac and other lung disorders are uncommon.

NIVOLUMAB Other name. Opdivo. Mechanism of action. A fully human monoclonal IgG4 antibody that binds to the programmed death-1 (PD-1) receptor on T cells and blocks its interaction with its ligands PD-L1 and PDL2, both of which are upregulated in several tumor types and responsible for immune response inhibition. Primary indications 1. Alone or in combination with ipilimumab in patients with unresectable or metastatic melanoma with wild-type BRAF V600 mutation. 2. Unresectable or metastatic melanoma following progression on ipilimumab therapy or BRAF inhibitors (in tumors that harbor the BRAF V600 mutations). 3. Metastatic NSCLC for patients who have had tumor progression during or after treatment with platinum-based chemotherapy. 4. Metastatic renal cell carcinoma in patients who received prior antiangiogenic therapy. Usual dosage and schedule 1. 1 mg/kg IV over 60 minutes followed by ipilimumab on the same day, every 3 weeks for four doses. After four doses of the combination, give 3 mg/kg IV over 60 minutes every 2 weeks as a single agent until disease progression or unacceptable toxicity. 2. 3 mg/kg administered as an IV infusion over 60 minutes every 2 weeks until disease progression or intolerable toxicity. Special precautions. Nivolumab can cause fetal harm if administered to a pregnant woman. Immune-related adverse events (irAEs) including colitis, pneumonitis, hepatitis, hypophysitis, nephritis, thyroiditis, uveitis, optic neuritis, hemolytic anemia, pancreatitis, dermatitis, partial seizures, myositis, and arthritis can occur and require close monitoring and occasionally withholding treatment and steroid therapy (see below). Rare cases of autoimmune encephalitis as well as TEN have been described. Toxicity 1. Myelosuppression and other hematologic effects. Not reported. 2. Nausea, vomiting, and other GI effects. Not reported. 3. Mucocutaneous effects. Rash and pruritus are common, but rarely severe. Exfoliative

dermatitis, erythema multiforme, vitiligo, and psoriasis were reported in less than 10% of cases. 4. Immunologic effects and infusion reactions. Upper respiratory tract infections are occasional. a. Immune-mediated pneumonitis, which is defined as requiring the use of corticosteroids and no clear alternate etiology and can manifest with dyspnea, cough, or chest pain, has been reported in 3% to 4% of patients. For grade 2 reactions, withholding therapy in addition to administering systemic steroids (greater or equal to 40 mg of prednisone or equivalent per day followed by a taper for at least a month) is indicated until improvement to grade 1 or less. Permanent discontinuation is indicated for grade 3 or 4 reactions. Some cases can be fatal. b. Immune-mediated colitis, which is defined as requiring the use of corticosteroids and no clear alternate etiology and can present with abdominal pain, diarrhea, and/or hematochezia, occurs in 2% to 3% of patients. For grade 2 and 3 reactions, withholding therapy in addition to administering systemic steroids (greater or equal to 40 mg of prednisone or equivalent per day followed by a taper for at least a month) is indicated until improvement to grade 1 or less. Permanent discontinuation is indicated for grade 4 reactions. c. Immune-mediated hepatitis, which is defined as requiring the use of corticosteroids and no clear alternate etiology, was reported in about 1% of patients. For grade 2 or higher reactions, treatment with systemic steroids is indicated. Dose interruption and permanent discontinuation may be indicated for more severe reactions. d. Immune-mediated nephritis including autoimmune nephritis and interstitial nephritis with renal failure occurred in 25 × 109/L) are at higher risk and require appropriate prophylaxis with antihyperuricemic agents and hydration beginning 12 to 24 hours prior to the infusion of obinutuzumab. 5. The use in patients with creatinine clearance of 1 × ULN, or bilirubin >1.0 to 1.5 × ULN and any AST) and 10 mg in patients with moderate hepatic impairment (bilirubin > 1.5 to 3.0 × ULN, any AST). Should not be used in patients with severe hepatic impairment. Starting dose is 10 mg in patients using strong CYP3A inhibitors. Special precautions 1. Should not be used concomitantly with strong CYP3A inducers, sensitive CYP2D6 substrates, or antiarrhythmic drugs/QT-prolonging drug. 2. Panobinostat can cause fetal harm if administered to a pregnant woman. 3. Severe diarrhea, and severe and fatal cardiac events including ischemia and arrhythmias can occur and can be exacerbated by electrolytes abnormalities. Baseline ECG and serum electrolytes, including potassium and magnesium, should be checked and monitored periodically during treatment. Electrolytes abnormalities are to be corrected as indicated prior to and during therapy. Toxicity 1. Myelosuppression and other hematologic effects. Anemia, leukopenia, neutropenia, and lymphopenia are common and can be severe. Use of granulocyte-colony stimulating factor (G-CSF) may be warranted, especially in patients older than 65. Thrombocytopenia is universal and can be severe in two-thirds of patients. Fatal hemorrhage associated with grade 3 to 4 thrombocytopenia has occurred during treatment. Grade 3/4 hemorrhage has been reported in 4% of patients. 2. Nausea, vomiting, and other GI effects. Diarrhea is common and can be severe in 25% of cases. Nausea and vomiting are common and occasionally severe. Abdominal pain, dyspepsia, gastritis, abdominal distension, flatulence, and colitis have been reported in less than 10% of cases. 3. Mucocutaneous effects. Rash, erythema, cheilitis, and dry mouth are occasional. 4. Immunologic effects and infusion reactions. Serious infections are common, including pneumonia, bacterial infections, invasive fungal infections, and viral infections. Hepatitis B infection has been seen in less than 10% of patients. 5. Miscellaneous effects a. General. Fatigue and asthenia are common. Asthenia can be severe in up to 25% of patients. Pyrexia is common but uncommonly severe. Decrease or loss of appetite is common, but mostly mild. b. Respiratory. Cough, dyspnea, respiratory failure, rales, and wheezing were reported in less than 10% of cases. c. Cardiovascular. Arrhythmias occurred in 12% of patients, while cardiac ischemic events occurred in 4%. Treatment should not be initiated in patients with history of recent myocardial infarction or unstable angina. Electrocardiographic abnormalities such as ST-segment depression, T-wave abnormalities, or QT/QTc prolongation

occurred in 22% of patients. Treatment should not be started in patients with a QTc of >450 msec or clinically significant baseline ST-segment or T-wave abnormalities. Arrhythmias may be exacerbated by electrolyte abnormalities. If during treatment, the QTc increases to ≥480 msec, interrupt treatment. Correct any electrolyte abnormalities. If QT prolongation does not resolve, permanently discontinue treatment. Peripheral edema is common, but uncommonly severe. Hypertension and orthostatic hypotension were reported in less than 10% of patients. d. Metabolic. Hypokalemia and hypophosphatemia are common and can be severe in up to 20% of cases. Hyponatremia is common and occasionally severe. Hypermagnesemia, hyperphosphatemia, hypocalcemia are common, but uncommonly severe. Increased blood creatinine level is common, but uncommonly severe. Increased serum alkaline phosphatase can occur in less than 10% of patients. Cases of hypothyroidism were described in less than 10% of patients. Hyperglycemia, hyperuricemia, and hypomagnesemia can occur in less than 10% of cases. e. Hepatic. Elevations in aminotransferases, hypoalbuminemia, and increased total bilirubin are uncommon. f. Neurologic. Dizziness, headache, syncope, tremor, and dysgeusia can occur in less than 10% of patients. g. Musculoskeletal and connective tissue. Joints swelling can occur in less than 10% of cases. h. Renal. Renal failure and urinary incontinence can occur in less than 10% of cases.

PAZOPANIB Other name. Votrient. Mechanism of action. An oral multitargeted receptor tyrosine kinase inhibitor of VEGFR, PDGFR, fibroblast growth factor receptor, and c-KIT that blocks tumor growth and inhibits angiogenesis. Metabolized primarily by CYP3A4 and excreted in the stool. Primary indication 1. Advanced renal cell carcinoma. 2. Advanced soft tissue sarcoma with prior chemotherapy. 3. Carcinoma of the ovary. Usual dosage and schedule 1. 800 mg PO daily without food. 2. 200 mg PO daily without food, if moderate hepatic impairment. 3. 400 mg or less PO if strong inhibitors of CYP3A4 cannot be avoided. Special precautions. May cause severe liver toxicity; therefore, liver function tests should be monitored closely before and during treatment. Do not give pazopanib if severe hepatic impairment. Fatal hemorrhagic events have been seen, and use in patients with history of GI

hemorrhage, hemoptysis, or cerebral hemorrhage should be avoided. If possible, avoid use of strong inhibitors of CYP3A4, which may increase concentration of pazopanib. CYP3A4 inducers may decrease pazopanib concentrations. Toxicity 1. Myelosuppression and other hematologic effects. Neutropenia, thrombocytopenia, and lymphocytopenia are common, but rarely severe. Arterial thrombotic events have been observed and can be fatal. Fatal hemorrhagic events have also been observed. 2. Nausea, vomiting, and other GI effects. Diarrhea is common, as are nausea, vomiting, and anorexia. GI perforation has been observed, but is probably rare. Abdominal pain is occasional. 3. Mucocutaneous effects. Hair color change (de-pigmentation) is common. Hand-foot syndrome is occasional. Skin depigmentation is uncommon. 4. Immunologic effects and infusion reactions. None. 5. Miscellaneous effects a. Systemic effects. Fatigue, asthenia, and headache are occasional to common. b. Hepatic. ALT and AST elevations are common and occasionally (12%) severe. c. Cardiovascular. Hypertension is common, but grade 3 or 4 hypertension is uncommon. Prolonged QT intervals and torsades de pointes have been observed, but are rare. Chest pain is uncommon. d. Hyponatremia, hypomagnesemia, and hypophosphatemia. Occasional. e. Hypothyroidism. Occasional. f. Proteinuria. Occasional, but rarely severe.

PEMBROLIZUMAB Other name. Keytruda. Mechanism of action. A humanized monoclonal IgG4 antibody that binds to the programmed death-1 (PD-1) receptor on T cells and blocks its interaction with its ligands PD-L1 and PDL2, both of which are upregulated in several tumors and responsible for immune response inhibition. Primary indications 1. Unresectable or metastatic melanoma. 2. Metastatic NSCLC in patients whose tumors express programmed death ligand 1 (PD-L1) as determined by an FDA-approved test and who have had progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor alterations should have disease progression on and FDA-approved therapy for these aberrations prior to receiving pembrolizumab. Usual dosage and schedule. 2 mg/kg administered as an IV infusion over 30 minutes every 3 weeks until disease progression or intolerable toxicity.

Special precautions. Pembrolizumab can cause fetal harm if administered to a pregnant woman. Immune-related adverse events (irAEs) including colitis, pneumonitis, hepatitis, hypophysitis, nephritis, thyroiditis, uveitis, optic neuritis, hemolytic anemia, pancreatitis, dermatitis, partial seizures, myositis, and arthritis can occur, and require close monitoring and occasionally withholding treatment and steroids therapy (see below). Toxicity 1. Myelosuppression and other hematologic effects. Anemia is common and occasionally severe. Upper respiratory tract infections are occasional. 2. Nausea, vomiting, and other GI effects. Nausea, vomiting, constipation, and diarrhea are common and mostly mild. Abdominal pain is occasional. 3. Mucocutaneous effects. Rash and pruritus are common. Vitiligo is occasional. 4. Immunologic effects and infusion reactions. Upper respiratory tract infections are occasional; sepsis is uncommon to occasional. a. Immune-mediated pneumonitis is seen in 2% to 3% of patients. For grade 2 reactions, withholding therapy in addition to administering systemic steroids (greater than or equal to 40 mg of prednisone or equivalent per day followed by a taper for at least a month) is indicated until improvement to grade 1 or less. Permanent discontinuation is indicated for grade 3 or 4 reactions. b. Immune-mediated colitis occurred in 1% of patients. For grade 2 and 3 reactions, withholding therapy in addition to administering systemic steroids (greater than or equal to 40 mg of prednisone or equivalent per day followed by a taper for at least a month) is indicated until improvement to grade 1 or less. Permanent discontinuation is indicated for grade 4 reactions. c. Immune-mediated hepatitis is rare (500 msec and >60 msec change from pretreatment values. d. Hepatic. Elevations in ALT/AST, alkaline phosphatase, and/or bilirubin are uncommon, but monitoring of liver function is recommended during treatment. e. Neurologic. Headache is common. Dysgeusia is occasional. Peripheral sensory neuropathy and VIIth nerve palsy reported in