MEDICINE MEDICINE MEDICINE ClinicalMEDICINE Trials in Ovarian Cancer MEDICINE MEDICINE CHRISTINE S. WALSH MEDICINE MEDICINE MEDICINE White logos Clinical Trials in Ovarian Cancer —-1 —0 —+1 5510-66190_ch00_3P.indd10-66190_ch00_3P.indd i 111/8/161/8/16 77:46:46 PMPM -1— 0— +1— 5510-66190_ch00_3P.indd10-66190_ch00_3P.indd iiii 111/8/161/8/16 77:46:46 PMPM Clinical Trials in Ovarian Cancer Christine S. Walsh, MD, MS Rutgers University Press Medicine New Brunswick, Camden, and Newark, New Jersey, and London —-1 —0 —+1 5510-66190_ch00_3P.indd10-66190_ch00_3P.indd iiiiii 111/8/161/8/16 77:46:46 PMPM Kel McGowan Executive Editor for Clinical Health and Medicine This publication was supported in part by the Eleanor J. and Jason F. Dreibelbis Fund. Library of Congress Cataloging- in- Publication Data Names: Walsh, Christine S., 1972– author. Title: Clinical trials in ovarian cancer / Christine S. Walsh. Description: New Brunswick, New Jersey : Rutgers University Press, [2017] | Includes bibliographical references and index. Identifi ers: LCCN 2016032168 | ISBN 9780813586472 (hardcover : alk. paper) | ISBN 9780813586489 (ePub) | ISBN 9780813586496 (PDF) Subjects: | MESH: Ovarian Neoplasms— therapy | Clinical Trials, Phase III as Topic Classifi cation: LCC RC280.O8 | NLM WP 322 | DDC 616.99/465— dc23 LC rec ord available at https:// lccn . loc . gov / 2016032168 A British Cataloging- in- Publication rec ord for this book is available from the British Library. Copyright © 2017 by Christine Walsh All rights reserved No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, or by any information storage and retrieval system, without written permission from the publisher. Please contact Rutgers University Press, 106 Somerset Street, New Brunswick, NJ 08901. The only exception to this prohibition is “fair use” as defi ned by U.S. copyright law. -1— Visit our website: www . rutgersuniversitypress . org 0— Manufactured in the United States of Amer i ca +1— 5510-66190_ch00_3P.indd10-66190_ch00_3P.indd iviv 111/8/161/8/16 77:46:46 PMPM This book is dedicated to all women with ovarian cancer and to the health care professionals and scientists who partner with these women to improve outcomes through the identifi cation of better treatment strategies through the clinical trials pro cess. —-1 —0 —+1 5510-66190_ch00_3P.indd10-66190_ch00_3P.indd v 111/8/161/8/16 77:46:46 PMPM -1— 0— +1— 5510-66190_ch00_3P.indd10-66190_ch00_3P.indd vivi 111/8/161/8/16 77:46:46 PMPM Contents List of Tables ix Preface and Acknowl edgments xi 1 Early Stage Epithelial Ovarian Cancer 1 GOG 7601 (Young, NEJM 1990) 1 GOG 7602 (Young, NEJM 1990) 5 GICOG Trials (Bolis, Ann Oncol 1995) 9 GOG 95 (Young, JCO 2003) 15 ICON1/ACTION Combined Analy sis (Trimbos, JNCI 2003) 19 ACTION (Trimbos, JNCI 2003; Trimbos, JNCI 2010) 24 ICON1 (Colombo, JNCI 2003) 32 GOG 157 (Bell, Gynecol Oncol 2006) 37 GOG 157 Exploratory Analy sis (Chan, Gynecol Oncol 2010) 43 2 Advanced Stage Epithelial Ovarian Cancer: Adjuvant Chemotherapy 46 GOG 47 (Omura, Cancer 1986) 46 GOG 52 (Omura, JCO 1989) 50 GOG 97 (McGuire, JCO 1995) 53 GOG 111 (McGuire, NEJM 1996) 57 GOG 104 (Alberts, NEJM 1996) 62 ICON2 (Lancet 1998) 66 GOG 132 (Muggia, JCO 2000) 70 Danish Netherlands Trial (Neijt, JCO 2000) 75 OV-10 (Piccart, JNCI 2000) 80 GOG 114 (Markman, JCO 2001) 86 ICON3 (Lancet 2002) 90 —-1 GOG 158 (Ozols, JCO 2003) 95 —0 —+1 vii 5510-66190_ch00_3P.indd10-66190_ch00_3P.indd viivii 111/8/161/8/16 77:46:46 PMPM viii Contents AGO/OVAR-3 (du Bois, JNCI 2003) 100 SCOTROC— Scottish Randomised Trial in Ovarian Cancer (Vasey, JNCI 2004) 105 GOG 172 (Armstrong, NEJM 2006) 109 GOG 182/ICON5 (Bookman, JCO 2009) 114 JGOG 3016 (Katsumata, Lancet 2009; Katsumata, Lancet Oncol 2013) 119 MITO-2 (Pignata, Oncology 2009; Pignata, JCO 2011) 126 AGO- OVAR9 (du Bois, JCO 2010) 132 OV16 (Hoskins, JNCI 2010) 137 ICON7 (Perren, NEJM 2011; Oza, Lancet Oncol 2015) 145 GOG 218 (Burger, NEJM 2011) 151 MITO-7 (Pignata, Lancel Oncol 2014) 157 3 Advanced Stage Epithelial Ovarian Cancer: Timing of Surgery and Interval Cytoreduction 162 EORTC- GCG 55865 (van der Burg, NEJM 1995) 162 GOG 152 (Rose, NEJM 2004) 168 EORTC 55971 (Vergote, NEJM 2010) 174 CHORUS (Kehoe, Lancet 2015) 178 4 Epithelial Ovarian Cancer: Maintenance Therapy 186 GOG 178/SWOG 9701 (Markman, JCO 2003) 186 GOG 175 (Mannel, Gynecol Oncol 2011) 193 5 Recurrent Epithelial Ovarian Cancer 200 Topotecan Versus Paclitaxel (ten Bokkel, JCO 1997) 200 Doxil Study 30-49 (Gordon, JCO 2001; Gordon, Gyn Onc 2004) 207 ICON4/AGO- OVAR 2.2 (Parmar, Lancet 2003) 217 AGO- OVAR, NCIC CTG, EORTC GCG Trial (Pfi sterer, JCO 2006) 222 Gemcitabine Versus PLD (Mutch, JCO 2007) 228 OVA-301 (Monk, JCO 2010) 235 CALYPSO (Pujade- Lauraine, JCO 2010) 242 OCEANS (Aghajanian, JCO 2012) 249 AURELIA (Pujade- Lauraine, JCO 2014) 256 Abbreviations 263 References 267 Index 295 -1— 0— +1— 5510-66190_ch00_3P.indd10-66190_ch00_3P.indd viiiviii 111/8/161/8/16 77:46:46 PMPM List of Tables 1.1 GOG 7601 4 1.2 GOG 7602 8 1.3 GICOG Trial 1 13 1.4 GICOG Trial 2 14 1.5 GOG 95 18 1.6 ICON1/ACTION Combined Analysis 22 1.7 ACTION 28 1.8 ACTION Long- Term Follow- up 31 1.9 ACTION Long- Term Follow-up, Grade 3 Tumors 31 1.10 ICON1 35 1.11 GOG 157 41 1.12 GOG 157 Exploratory Analy sis 45 2.1 GOG 47 49 2.2 GOG 52 52 2.3 GOG 97 56 2.4 GOG 111 61 2.5 GOG 104 65 2.6 ICON2 69 2.7 GOG 132 73 2.8 Danish Netherlands Trial 78 2.9 OV-10 84 2.10 GOG 114 89 2.11 ICON3 93 2.12 GOG 158 98 2.13 AGO/OVAR-3 104 2.14 SCOTROC 108 2.15 GOG 172 113 —-1 2.16 GOG 182/ICON5 118 —0 —+1 ix 5510-66190_ch00_3P.indd10-66190_ch00_3P.indd ixix 111/8/161/8/16 77:46:46 PMPM x List of Tables 2.17 JGOG 3016 124 2.18 MITO-2 130 2.19 AGO-OVAR9 136 2.20 OV16 143 2.21 ICON7 149 2.22 GOG 218 155 2.23 MITO-7 160 3.1 EORTC- GCG 55865 166 3.2 GOG 152 172 3.3 EORTC 55971 177 3.4 CHORUS 184 4.1 GOG 178/SWOG 9701 190 4.2 GOG 175 198 5.1 Topotecan Versus Paclitaxel 205 5.2 Doxil Study 30-49 213 5.3 ICON4/AGO- OVAR 2.2 221 5.4 AGO- OVAR, NCIC, CTG EORTC GCG Trial 226 5.5 Gemcitabine Versus PLD 232 5.6 OVA-301 240 5.7 CALYPSO 247 5.8 OCEANS 254 5.9 AURELIA 261 -1— 0— +1— 5510-66190_ch00_3P.indd10-66190_ch00_3P.indd x 111/8/161/8/16 77:46:46 PMPM Preface and Acknowl edgments I fi rst met Dana Dreibelbis at the 2014 Annual Meeting of the American Society of Clinical Oncology. Rutgers University Press offered me the opportunity to edit a short clinical book as part of a new publishing initia- tive. I immediately knew that I wanted to put together a book that summa- rizes the seminal clinical trials that have shaped the practice of gynecologic oncology. Clinical trials have been instrumental in creating our current clinical practice paradigms. A clinician taking care of a woman with gynecologic cancer needs to understand this history in order to deliver evidence- based care. In some cases, clinical trials fi ndings result in clear establishment of standard of care therapy. In other cases, optimal treatment regimens are not yet defi ned, but clinical trials provide data to inform the clinician regarding treatment options and ongoing controversies. The clinical trials history of any fi eld is vast, making it diffi cult and time- consuming for any individual to collect and synthesize. Currently, a textbook focused on clinical trials in gynecologic oncology does not exist. Clinical trials are discussed in general textbooks but often within lengthy chapters that cover many other topics. There is no standardized formatting and the reader must wade through the text in order to fi nd rel- evant information. The concept for this textbook is to provide a concise, user- friendly ref- erence that focuses solely on clinical trials in gynecologic oncology. The text is formatted in a standardized fashion so the reader can rapidly fi nd relevant information. The seminal phase III trials that have shaped the fi eld are outlined in a standard format to include the details on the ratio- —-1 nale for the trial, the patient population studied, treatment details of the —0 —+1 xi 5510-66190_ch00_3P.indd10-66190_ch00_3P.indd xixi 111/8/161/8/16 77:46:46 PMPM xii Preface and Acknowledgments experimental arms, assessments, endpoints, statistical considerations, results, conclusions and further commentary. Standardized tables high- light the salient and relevant results by summarizing patient characteristics, treatment delivery, effi cacy and toxicities from each seminal phase III trial. The full reference and PMID number are provided for each study so that the reader can easily fi nd the original text and reference for further reading. A list of the abbreviations used in the text is provided at the end of the book for the reader’s con ve nience. This text focuses on the seminal phase III clinical trials that have been conducted in patients with epithelial ovarian cancer and represents the fi rst in a series of books. Similar textbooks outlining clinical trials in other gynecologic malignancies such as uterine and cervical cancer are forth- coming.