Gynecologic Oncology Cancer Treatment and Research WILLIAM L. MCGUIRE, series editor 1. R. B. Livingston, ed., Lung Cancer 1. 1981. ISBN 90-247-2394-9. 2. G. B. Humphrey, L. P. Dehner, G. B. Grindey and R. T. Acton, eds., Pediatric Oncology 1. 1981. ISBN 90-247-2408-2. 3. J.J. DeCosse and P. Sherlock, eds., Gastrointestinal Cancer 1. 1981. ISBN 90-247-2461-9. 4. J.M. Bennett, ed., Lymphomas 1, including Hodgkin's Disease. 1981. ISBN 90-247-2479- 1. 5. C.D. Bloomfield, ed., Adult Leukemias 1. 1982. ISBN 90-247-2478-3. 6. D. F. Paulson, Genitourinary Cancer 1. 1982. ISBN 90-247-2480-5. 7. F.M. Muggia, ed., Cancer Chemotherapy 1. 1982. ISBN 90-247-2713-8. 8. G. B. Humphrey and G. B. Grindey, eds., Pancreatic Tumours in Children. 1982. ISBN 90- 247-2702-2. 9. John J. Costanzi, ed., Malignant Melanoma 1. 1982. ISBN 90-247-2706-5. Gynecologic Oncology edited by c. THOMAS GRIFFITHS, M.D. Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA ARLAN F. FULLER, Jr., M.D. Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA 1983 MARTINUS NIJHOFF PUBLISHERS a member of the KLUWER ACADEMIC PUBLISHERS GROUP BOSTON / THE HAGUE / DORDRECHT / LANCASTER Distributors for the United States and Canada: Kluwer Boston, Inc., 190 Old Derby Street, Hingham, MA 02043, USA for all other countries: Kluwer Academic Publishers Group, Distribution Center, P.O.Box 322,3300 AH Dordrecht, The Netherlands Library of Congress Cataloging in Publication Data Main entry under title: Gynecologic oncology. (Cancer treatment and research ; v. 10) 1. Reproductive organs, Female--Cancer. I. Griffiths, C. Thomas. II. Fuller, Arlan F. III. Series. [DNLM: 1. Genital neoplasms, Female. WI CA693 v. 10 / WP 145 G99651] lU'\2lfO.C5G886 1983 616.99'465 82-14491 ISBN-13: 978-1-4613-3854-3 e-ISBN-13: 978-1-4613-3852-9 DOl: 10.1007/978-1-4613-3852-9 Copyright © 1983 by Martinus Nijhoff Publishers, Boston. Softcover reprint of the hardcover I st edition 1983 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publishers, Martinus Nijhoff Publishers, 190 Old Derby Street, Hingham, MA 02043, USA. Contents Foreword to the Series vii Preface ix List of Contributors xiii 1. Evidence for a Viral Etiology of Squamous Cell Carcinoma of the Cervix ........................ . LAURE AURELIAN 2. Tumor Markers in Gynecologic Malignancies 63 JOHN R. VAN NAGELL 3. Hormonal Receptors in Endometrial and Ovarian Neoplasia 81 GEORGE S. RICHARDSON and DAVID T. MACLAUGHLIN 4. Germ Cell Tumors of the Ovary: Pathology, Behavior and Treat- ment ................ . 103 ROBERT J. KURMAN and EDMUND S. PETRILLI 5. Treatment of Advanced Trophoblastic Disease . . 155 RICHARD H. J. BEGENT and KENNETH D. BAGSHA WE 6. The Immunobiology of Ovarian Carcinoma . . 187 ROBERT C. BAST Jr. and ROBERT C. KNAPP 7. Lymph Node Metastases from Gynecologic Cancer - Biological Concepts and Therapeutic Implications . . . . . . . . . . . 227 ARLAN F. FULLER Jr. 8. Radiation Therapy of Ovarian Carcinoma 263 ALON J. DEMBO and RAYMOND S. BUSH vi 9. Heavy Particle Radiation Therapy in Gynecological Malignan- cies . . . . . . . . . . . . . . . . . . . . . . . .. 299 ROBERT D. HILGERS, STEVEN E. BUSH and FRANCISCO AMPUERO 10. Growth of Gynecologic Neoplasms in Tissue Culture and as Heterografts ...................... 313 CHARLES E. WELANDER and JOHN L. LEWIS Jr. 11. Clinical Trials in Gynecologic Oncology: Cooperative Group Research . . . . . . . . . . . . . . . . . . . . . 343 GEORGE C. LEWIS Jr., JOHN BLESSING and JOHN R. KELLNER Subject Index ... 385 Foreword to the Series Where do you begin to look for a recent, authoritative article on the diagnosis or management of a particular malignancy? The few general onco logy textbooks are generally out of date. Single papers in specialized journals are informative but seldom comprehensive; these are more often prelimi nary reports on a very limited number of patients. Certain general journals frequently publish good indepth reviews of cancer topics, and published symposium lectures are often the best overviews available. Unfortunately, these reviews and supplements appear sporadically, and the reader can never be sure when a topic of special interest will be covered. Cancer Treatment and Research is a series of authoritative volumes which aim to meet this need. It is an attempt to establish a critical mass of oncology literature covering virtually all oncology topics, revised frequently to keep the coverage up to date, easily available on a single library shelf or by a single personal subscription. We have approached the problem in the following fashion. First, by divid ing the oncology literature into specific subdivisions such as lung cancer, genitourinary cancer, pediatric oncology, etc. Second, by asking eminent authorities in each of these areas to edit a volume on the specific topic on an annual or biannual basis. Each topic and tumor type is covered in a volume appearing frequently and predictably, discussing current diagnosis, staging, markers, all forms of treatment modalities, basic biology, and more. In Cancer Treatment and Research, we have an outstanding group of editors, each having made a major commitment to bring to this new series the very best literature in his or her field. Martinus Nijhoff Publishers has made an equally major commitment to the rapid publication of high quality books, and world-wide distribution. Where can you go to find quickly a recent authoritative article on any major oncology problem? We hope that Cancer Treatment and Research provides an answer. WILLIAM L. MCGUIRE Series Editor Preface At the turn of the century gynecology had achieved independence from surgery in most medical schools; although gynecologists were surgeons, their interests were turning toward nonsurgical aspects of their specialty. In 1900, merely two years after the Curies' discovery, radium was first used as a treatment for carcinoma of the cervix. In that day cervical cancer claimed more women's lives than any other malignancy and was described by Wil liam P. Graves, the second professor of gynecology at Harvard as follows: 'Cancer of the cervix may rightly be termed of all tumors one of the most deadly and most ghastly. It kills by slow torture, causing in later stages months of agonizing pain and producing a discharge of such a foul and nauseating character as to repel proper medical assistance. Nurses declined to care for these cases, while many public hospitals closed their wards to them as patients.' In late twentieth century parlance the dramatic results of radium therapy would indeed have been called a 'breakthrough'? and radium techniques, later combined with external irradiation, were devel oped by gynecologists, no longer just surgeons. Pathology was the basic science of gynecology and gynecologists with a special interest in pathology served as pathologist to the departments of gynecology. As late as 1970 six months of the three-year residency program in obstetrics and gynecology at Harvard were devoted to formal training in pathology. After the observa tion in the early 1950s that nitrogen mustard could induce regression of ovarian cancers, clinical trials with this agent and its congeners were carried out by gynecologists. In 1961 Howard W. Jones, Jr. ofJohns Hopkins Medi cal School admonished gynecologists to become further involved in cancer chemotherapeutic research and then added a prophetic warning that 'a new specialty might arise which would include gynecological cancer in its ken.' As we entered the last quarter of the twentieth century gynecologic onco logy became formally recognized as a subspecialty of obstetrics and gyneco- x logy. At the same time, it became apparent that the era of multimodality expertise had waned; a gynecologic oncologist would function primarily as a surgeon but also as a consultant by virtue of erudition in the natural history of a particular class of diseases. The establishment and rapid growth of the specialties of radiation oncology and medical oncology had so expanded the therapeutic potential in gynecologic cancer that no one person or specialty could be qualified to undertake the broad range of complex therapies. In addition, a small but active group of pathologists had attained special know ledge through fellowship training in the field of gynecologic pathology. Only 202 gynecologists in the United States have been certified for special competence in gynecologic oncology. In order to maintain their identity, much less their visibility, gynecologic oncologists cannot function merely as surgical technicians. Expansion of their knowledge to include the latest developments in all phases of cancer research and treatment which pertain to the female genitalia has become even more important at a time when keeping abreast has become all the more difficult. With these thoughts in mind we designed this first volume in the series on gynecologic malignancies for the gynecologic oncologist in particular. We selected subjects for the chapters based upon our perception of need for scholarly reviews of certain complex, rapidly moving areas. Our goal has been to synthesize all currently available information in selected areas in a manner that will enable the clinician to reconcile his clinical observations with related scientific observations. In a traditional sense we began with carcinoma of the cervix and some exciting new information brilliantly espoused by Aurelian that increases the probability of a viral etiology. We then turned to radiation therapy with chapters on irradiation for ovarian cancer by Dembo and Bush and on heavy particle therapy for gynecologic malignancy by Hilgers and associates. The former authors, having induced the revival of interest in radiotherapy for ovarian cancer whereas the latter authors introduce an altogether new biophysical approach to the deliverance of lethal radiation to the cancer cell. Recent advances in pathological research and their clinical application are demonstrated in the chapter on germ cell tumors of the ovary by Kurman and Petrilli. Utilizing immunoperoxidase histochemical techniques Robert Kurman in collaboration with Henry J. Norris at the Armed Forces Insti tute of Pathology established embryonal carcinoma of the ovary as a dis tinct entity and clearly defined the influence on prognosis of the histologic counterparts of mixed germ cell tumors of the ovary. Some newer biologic concepts of lymph node metastasis in gynecologic cancer, particularly as a manifestation of systemic disease, are presented by one of us (AFF Jr.). The victories of cancer chemotherapy are exemplified by accomplish- xi ments in the management of choriocarcinoma. Innovations in the treatment of advanced trophoblastic disease and its complications have come from the Charing Cross Hospital in London and Richard H.J. Begent and Kenneth D. Bagshawe ofthat institution have presented their approach to these diseases. Clinical trials by cooperative groups have become the means whereby the efficacy of rational chemotherapeutic regimens are evaluated. The scientific approach to group trials as well as the bureaucratic mechanisms involved in their conduct are described best by those qualified, George C. Lewis, Jr. and his associates at the Gynecologic Oncology Group headquarters. We have selected three areas of basis preclinical research in which clinical application has begun to emerge. The identification of estrogen and proges terone receptor proteins in the cytosol of endometrial carcinomas has been with us for some time and that of ovarian neoplasms only recently. Rele vance of this knowledge to treatment has been slowed by the infrequency of recurrent endometrial cancer wherein receptor status and endocrine respon siveness can be correlated. George. S. Richardson and David T. MacLaugh lin, have been active investigators in this field for more than a decade and have contributed a succinct' state of the art' review. Cell cultures of gyne cologic cancers have a long history dating from the successful passage of HeLa cells into immortality by George Gey in the late 1940s. Although cell cultures in soft agar for clonogenic assays of chemotherapeutic sensitivity have dominated the scene in recent years, other in vivo and in vitro tech niques need review. We have chosen two modem experts in gynecologic cancer cell culture, Charles E. Welander and John L. Lewis Jr. of Sloan Kettering Memorial Hospital to review this field. Finally, clinical applica bility of long-term studies of the immunobiology of ovarian carcinoma has now arrived. Clinical trials of immunodiagnostic techniques are underway and immunotherapy is now moving from nonspecific to specific immunos timulants. Robert C. Bast and Robert C. Knapp who have developed a monoclonal antibody to a purified ovarian cancer antigen have contributed a chapter on the immunobiology of ovarian carcinoma. The usefulness of tumor markers in monitoring therapy is well brought out in the chapters on germ cell tumors of the ovary, trophoblastic disease, and immunobiology, but we felt that for completeness a summary on tumor markers in gynecologic cancer in general was needed. John R. van N agell has contributed more than any other to the application of a broad range of oncofetal antigens and other biochemical markers to gynecologic cancer in general. Van Nagell's summary of this subject overlaps somewhat with the aforementioned chapters but we believe that the information presented is more complementary than repetitive. Accordingly these areas are cross referenced in the text. The selection of authors for this volume was easy. We simply asked those