JOURNAL TRANSCRIPT
Management of Gastric Cancer
Cancer Treatment and Research WILLIAM L . MCGUIRE, series editor Livingston, R . B . (ed): Lung Cancer 1. 1981. ISBN 90-247-2394-9 Humphrey G . B . , Dehner L . P . , Grindey G . B . , Acton R.T. (eds): Pediatric Oncology 1. ISBN 90-274-2408-2 DeCosse J.J., Sherlock P. (eds): Gastrointestinal Cancer 1. 1981. ISBN 90-247-2461-9 Bennett J . M . (ed): Lymphomas 1, including Hodgkin's Disease. 1981. ISBN 90-247-2479-1 Bloomfield C D . (ed): Adult Leukemias 1. 1982. ISBN 90-247-2478-3 Paulson D.F. (ed): Genitourinary Cancer 1.1982. ISBN 90-247-2480-5 Muggia F . M . (ed): Cancer Chemotherapy 1.1983. ISBN 90-247-2713-8 Humphrey G . B . , Grindey G . B . (eds): Pancreatic Tumors in Children. 1982. ISBN 90-247-2702-2 Costanzi J.J. (ed): Malignant Melanoma 1. 1983. ISBN 90-247-2706-5 Griffiths C.T., Fuller A . F . (eds): Gynecologic Oncology. 1983. ISBN 0-89838-555-5 Greco A . F . (ed): Biology and Management of Lung Cancer. 1983. ISBN 0-89838-554-7 Walker M . D . (ed): Oncology of the Nervous System. 1983. ISBN 0-89838-567-9 Higby D.J. (ed): Supportive Care in Cancer Therapy. 1983. ISBN 0-89838-569-5 Herberman R . B . (ed): Basic and Clinical Tumor Immunology. 1983. ISBN 0-89838-579-2 Baker L . H . (ed): Soft Tissue Sarcomas. 1983. ISBN 0-89838-584-9 Bennett J . M . (ed): Controversies in the Management of Lymphomas. 1983. ISBN 0-89838-586-5 Humphrey G . B . , Grindey G . B . (eds): Adrenal and Endocrine Tumors in Children. 1983. ISBN 0-89838-590-3 DeCosse J.J., Sherlock P. (eds): Clinical Management of Gastrointestinal Cancer. 1984. ISBN 0-89838-601-2 Catalona W.J., Ratliff T . L . (eds): Urologie Oncology. 1984. ISBN 0-89838-628-4 Santen R . J . , Manni A . (eds): Diagnosis and Management of Endocrine-Related Tumors. 1984. ISBN 0-89838-636-5 Costanzi J.J. (ed): Clinical Management of Malignant Melanoma. 1984. ISBN 0-89838-656-X Wolf G.T. (ed): Head and Neck Oncology. 1984. ISBN 0-89838-657-8 Alberts D.S., Surwit E. A . (eds): Ovarian Cancer. 1985. ISBN 0-89838-676-4 Muggia F . M . (ed): Experimental and Clinical Progress in Cancer Chemotherapy. 1985. ISBN 0-89838-679-9 Higby D.J. (ed): Issues in Supportive Care of Cancer Patient. 1986. ISBN 0-89838-816-3 Surwit E . A . , Alberts D.S. (eds): Cervix Cancer. 1987. ISBN 0-89838-822-8 Jacobs C. (ed): Cancers of the Head and Neck. 1987. ISBN 0-89838-825-2 MacDonald J.S. (ed): Gastrointestinal Oncology. 1987. ISBN 0-89838-829-5 Ratliff T . L . , Catalona W.J. (eds): Genitourinary Cancer. 1987. ISBN 0-89838-830-9 Nathanson L. (ed): Basic and Clinical Aspects of Malignant Melanoma. 1987. ISBN 0-89838-856-2 Muggia F . M . (ed): Concepts, Clinical Developments, and Therapeutic Advances in Cancer Chemotherapy. 1987. ISBN 0-89838-87^-5 Frankel A . E . (ed): Immunotoxins. 1988. ISBN 0-89838-984-4 Bennett J . M . , Foon K. A . (eds): Immunologic Approaches to the Classification and Management of Lymphomas and Leukemias. 1988. ISBN 0-89838-355-2 Osborne C . K . (ed): Endocrine Therapies in Breast and Prostate Cancer. 1988. ISBN 0-89838-365-X Lippman M . E . , Dickson R. (eds): Breast Cancer: Cellular and Molecular Biology. 1988. ISBN 0-89838-368-4 Kamps W . A . , Humphrey G . B . , Poppema S. (eds): Hodgkin's Disease in Children: Controversies and Current Practice. 1988. ISBN 0-89838-372-2 Muggia F . M . (ed): Cancer Chemotherapy: Concepts, Clinical Investigations and Therapeutic Advances. 1988. ISBN 0-89838-381-1 Nathanson L . (ed): Malignant Melanoma: Biology, Diagnosis, and Therapy. 1988. ISBN 0-89838-384-6 Pinedo H . M . , Verweij J. (eds): Treatment of Soft Tissue Sarcomas. 1989. ISBN 0-89838-391-9 Hansen H . H . (ed): Basic and Clinical Concepts of Lung Cancer. 1989. ISBN 0-7923-0153-6 Lepor H . , Ratliff T . L . (eds): Urologie Oncology. 1989. ISBN 0-7923-0161-7 Benz C , Liu E . (eds): Oncogenes. 1989. ISBN 0-7923-0237-0 Ozols R.F. (ed): Drug Resistance in Cancer Therapy. 1989. ISBN 0-7923-0244-3 Surwit E . A . , Alberts D.S. (eds): Endometrial Cancer. 1989. ISBN 0-7923-0286-9 Champlin R. (ed): Bone Marrow Transplantation. 1990. ISBN O-7923-0612-O Goldenberg D . (ed): Cancer Imaging with Radiolabeled Antibodies. 1990. ISBN 0-7923-0613-7 Jacobs C. (ed): Carcinomas of the Head and Neck. 1990. ISBN 0-7923-0668-6 Lippman M . E . , Dickson R. (eds): Regulatory Mechanisms in Breast Cancer: Advances in Cellular and Molecular Biology of Breast Cancer. 1990. ISBN 0-7923-O86&-9 Nathanson, L. (ed): Malignant Melanoma: Genetics, Growth Factors, Metastases, and Antigens. 1991. ISBN 0-7923-0895-6 Sugarbaker, P . H . (ed): Management of Gastric Cancer. 1991. ISBN 0-7923-1102-7
Management of Gastric Cancer
edited by Paul H. Sugarbaker, M.D., FACS The Cancer Institute Washington Hospital Center Washington, D. C.
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
^
Library of Congress Cataloging-in-Publication Data Management of gastric cancer/edited by Paul H. Sugarbaker. p. cm. — (Cancer treatment and research; 55) Includes bibliographical references. Includes index. ISBN 978-1-4613-6731-4 ISBN 978-1-4615-3882-0 (eBook) DOI 10.1007/978-1-4615-3882-0 1. Stomach — Cancer. I. Sugarbaker, Paul H. II. Series: Cancer treatment and research; v. 55. [DNLM: 1. Stomach Neoplasms — therapy. Wl CA693 v. 55AVI 320 M266] RC280.S8M26 1991 616.99'433 — dc20 DNLM/DLC for Library of Congress 90-15651 CIP Copyright © 1991 by Springer Science+Business Media New York Originally published by Kluwer Academic Publishers in 1991 Softcover reprint of the hardcover 1st edition 1991 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 publisher, Springer Science+Business Media, LLC. Printed on acid-free paper.
Dedication This volume is dedicated to Karl and Inge Aigner of Trostberg, West Germany for their timeless efforts in bringing together from all over the world persons interested in Regional Cancer Therapy. Our patients, our practice, and our research projects have benefitted from this endeavor.
Table of Contents
Foreword to the Series Foreword List of Contributors Preface 1. Natural history of surgically treated gastric cancer KENNETH A. KERN
xi xiii xv xix 1
2. Pathology and cytology of gastric cancer BARRY M. SHMOOKLER and MELISSA K. BUICK
17
3. Rationale for the intraperitoneal approach to surgical adjuvant chemotherapy of gastric cancer HAROLD O. DOUGLASS, JR.
41
4. Endoscopy in gastric malignancy JOHN D. MELLINGER and JEFFREY L. PONSKY
51
5. Surgical treatment of gastric cancer JOAN VIDAL-JOVE and PAUL H. SUGARBAKER
69
6. Staging of gastric cancer: clinical, surgical, and pathological HENNING ROHDE
91
7. Recent developments in diagnostic radiology of primary and recurrent gastric cancer ANN G. ARCHER and DAVID C. GRANT
107
8. In-vitro chemosensitivity testing of human gastric adenocarcinoma MINH VAN NGUYEN, GARY M. CLARK, DAVID MASCORRO, and DANIEL D. VON HOFF
133
vii
9. The rationale for early postoperative intraperitoneal chemotherapy for gastric cancer W.J. CUNLIFFE
143
10. Induction chemotherapy using intraarterial infusion FREDERICK O. STEPHENS
161
11. Treatment of gastric cancer E. MORENO GONZALEZ
171
12. Cancer of the cardia: The value of total extended esophagogastrectomy E. MORENO GONZALEZ
205
13. Radiation therapy for gastric carcinoma ROGER F. ANDERSON, JR., JUDY L. CHIN, KIN-SING AU, and JULIANA SIMMONS
247
14. Early postoperative intraperitoneal chemotherapy for gastric cancer WANSIK YU and PAUL H. SUGARBAKER
265
15. Early postoperative intraperitoneal adriamycin as an adjuvant treatment for advanced gastric cancer with lymph node or serosal invasion PAUL H. SUGARBAKER
277
16. Gastric cancer in Korea: Experience at the Seoul National University Hospital JAE-GAHB PARK, ADI F. GAZDAR, YONG-II KIM, BYUNG-IHN CHOI, IN-SUNG SONG, NOE-KYEONG KIM, SUNG-TAE OH, and JlN-POK KIM
285
17. New trends in therapy for gastric malignancy SHIGERU FUJIMOTO, JUNJI KASANUKI, SHO YOSHIDA, and KATSUJI OKUI
307
18. Tumor biology and quality of life in patients with gastric cancer ECKHARD RAU
325
19. The surgical treatment of gastric cancer with special reference to systematic lymph node dissection HAN J. BONENKAMP, MITSURU SASAKO, GERARDUS H.M. KAMPSCHOER, and CORNELIS J.H. VAN DE VELDE
339
viii
20. Celiac axis infusion (CAl) chemotherapy for advanced gastric cancer K.R. AIGNER, F. BENTHIN, and H. MULLER
357
21. New developments in the treatment of gastric carcinoma HANSJOCHEN WILKE, PETER PREUSSER, ULRICH FINK, WOLF ACHTERRATH, HAN-JOACHIM MAYER, MICHAEL STAHL, LUIGI LENAZ, JOCHEN MEYER, JURGEN R. SIEWERT, HEINZ GERLINGS, CLAUD H. KOHNE-WOMPNER, ANDREAS HARSTRICK, and HANS-JOACHIM SCHMOOL
363
Index
375
ix
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 oncology textbooks are generally out of date. Single papers in specialized journals are informative but seldom comprehensive; these are more often preliminary reports on a very limited number of patients. Certain general journals frequently publish good in-depth 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 that 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, and easily available on a single library shelf or by a single personal subscription. We have approached the problem in the following fashion: first, by dividing the oncology literature into specific subdivisions such as lung cancer, genitourinary cancer, pediatric oncology, etc.; and 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. Kluwer Academic publishers has made an equally major commitment to the rapid publication of high-quality books and to worldwide 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 xi
Foreword
Gastric cancer has been one of the great malignant scourges affecting mankind for as long as medical records have been kept. Until operative resection pioneered by Bilroth and others became available, no effective treatment was feasible and death from cancer was virtually inevitable. Even with resection by total gastrectomy, the chances of tumor eradication remained small. Over recent years, however, the situation has been changing. Some changes have resulted from better understanding of the disease, early detection, and better management techniques with applied clinical research, but the reasons for other changes are poorly understood. For example, the incidence of gastric cancer is decreasing, especially in westernized societies, where it has fallen from one of the most common cancers to no longer being in the top five causes of cancer death. Still it remains the number one killer of adult males in Japan and Korea. Whether the reduced incidence in western societies is a result of dietary changes or methods of food preservation, or some other reason, is as yet uncertain. Improvements in outcome have been reported from mass screening and early detection; more refined techniques of establishing early diagnosis, tumor type, and tumor extent; more radical surgical resection; and resection at earlier stages of disease. A most exciting potential for improvement has come with clinical studies using combinations of treatment modalities. The most promising of these is the use of regional chemotherapy, either given by intraarterial or intraperitoneal delivery, or both, with operative surgery and possibly combined with radiotherapy or immunotherapy. Keeping up with these remarkable changes has been difficult, and to date there has been no one source collating this diverse but exciting information. Dr. Sugarbaker has accepted the challenge of gathering contributions from most authoritative international experts in the many changing aspects, especially in management of this disease. Together with the important contributions of his own department, he has compiled this comprehensive volume to xiii
provide all readers a better understanding of the present and future potential for improved management of gastric cancer. Professor F.O. Stephens, M.D., M.S., F.R.C.S., F.R.A.C.S. Department of Surgery The University of Sydney
xiv
List of Contributors
ACHTERRATH, Wolf, M.D., Division of Hematology/Oncology, Hanover University Medical School, Konstanty-Gutschow-Str. 8, 3000 Hannover 61, FRG AIGNER, K.R., M.D., Department of Surgery, KKH Trostberg, Seiger Thoehe, 8223 Trostberg, FRG ANDERSON, Roger F., Jr., M.D., Department of Radiation Oncology, Rex Cancer Center, 4420 Lake Boone Trail, Raleigh, NC 27607, USA ARCHER, Ann G., M.D., Department of Radiology, The Washington Hospital Center, 110 Irving Street, N.W., Washington, DC 20010, USA AU, Kin-Sing, M.D., Radiation Oncology, The Washington Hospital Center, 110 Irving Street, N.W., Washington, DC 20010, USA BENTHIN, F., M.D., Department of Surgery, KKH Trostberg, Siegerthoehe 1, 8223 Trostberg, FRG BONENKAMP, Han J., M.D., Department of Surgery, University Hospital, P.O. Box 9600,2300 RC Leiden, The Netherlands BUICK, Melissa K., M.D., Director of Cytopathology, Department of Pathology, The Washington Hospital Center, 110 Irving Street, N.W., Washington, DC 20010, USA CHIN, Judy L., M.D., Richmond Radiation Oncology Center, 5711 Staples Mill Road, Richmond, VA 23228, USA CHOI, Byung-Ihn. M.D., Department of Radiology, Seoul National University Hospital, Seoul, 110-744, Korea CLARK, Gary M., Ph.D., The University of Texas Health, Science Center at San Antonio, Department of Internal Medicine, Division of Oncology, San Antonio, TX 78284, USA CUNLIFFE, W.J., M.D., FRCS, Consulting Surgeon in Gastroenterology, and Surgical Oncology, The Queen Elizabeth Hospital, Gateshead, Tyne & Wear NE9 6SX, England DOUGLASS, Harold 0., Jr, M.D., FACS, Chief, Gastrointestinal Oncology, Associate Chief, Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA FINK, Ulrich, M.D., Division of Hematology/Oncology, Hannover Univerxv
sity Medical School, Konstanty-Gutschow-Str. 8,3000 Hannover 61, FRG FUJIMOTO, Shigeru, M.D., First Department of Surgery, School of Medicine, Chiba University, 1-8-1, Inohana, Chiba 280, Japan GAZDAR, Adi F., M.D., NCI-Navy Medical Oncology Branch, National Naval Medical Center, 8901 Wisconsin Avenue, Rockville Pike, MD 20814, USA GERLINGS, Heinz, M.D., Division of Hematology/Oncology, Hanover University Medical School, Konstanty-Gutschow-Str. 8, 3000 Hannover 61, FRG GRANT, David c., M.D., Department of Radiology, The Washington Hospital Center, 110 Irving Street, N.W., Washington, DC 20010, USA HARSTRICK, Andreas, M.D., Division of Hematology/Oncology, Hanover University Medical School, Konstanty-Gutschow-Str. 8, 3000 Hannover 61, FRG KAMPSCHOER, Gerardus H.M., M.D., Department of Surgery, University Hospital, P.O. Box 9600, 2300 RC Leiden, The Netherlands KASANUKI, Junji, M.D., Second Department of Internal Medicine, School of Medicine, Chiba University, 1-8-1, Inohana, Chiba 280, Japan KERN, Kenneth A., M.D., Assistant Clinical Professor of Surgery, University of Connecticut School of Medicine, Farmington, CT 06032, Department of Surgery, Hartford Hospital, Hartford, CT 06106, USA KIM, Jin-Pok, M.D., Department of Surgery, Seoul National University Hospital, Seoul, 110-744, Korea KIM, Noe-Kyeong, M.D., Department ofInternal Medicine, Seoul National University Hospital, Seoul, 110-744, Korea KIM, Yong-II, M.D., Department of Pathology, Seoul National University Hospital, Seoul, 110-744 Korea KOHNE-WOMPNER, Claud H., M.D., Division of Hematology/Oncology Hannover University Medical School, Konstanty-Gutschow-Str. 8, 3000 Hannover 61, FRG LENAZ, Luigi, M.D., Division of Hematology/Oncology Hannover University Medical School Konstanty-Gutschow-Str. 8,3000 Hannover 61, FRG MASCORRO, David, The University of Texas Health, Science Center at San Antonio, Department of Internal Medicine, Division of Oncology, San Antonio, TX 78284, USA MAYER, Han-Joachim, M.D., Division of Hematology/Oncology Hannover University Medical School, Konstanty-Gutschow-Str. 8, 3000 Hannover 61, FRG MELLINGER, John D., M.D., Department of Surgery, USAF Medical Center, Wright Patterson AFB, OH 45433, USA MEYER, Jochen, M.D., Division of Hematology/Oncology, Hannover University Medical School, Konstanty-Gutschow-Str. 8, 3000 Hannover 61, FRG MORENO-GONZALEZ, E. , M.D., FACS, Head of Department of General Surgery and Abdominal Organs Transplantation, Hospital '12 de Octubre', University of Madrid, Spain xvi
MULLER, H., M.D., Department of Surgery, KKH Trostberg, Siegerthoehe 1 8223 Trostberg, FRG VAN NGUYEN, Minh, M.D., The university of Texas Health, Science Center at San Antonio, Department of Internal Medicine, Division of Oncology San Antonio, TX 78284, USA OH, Sung-Tae, M.D., Department of Surgery, Seoul National University Hospital, Seoul, 110-744, Korea OKUI, Katsuji, M.D., First Department of Surgery, School of Medicine, Chiba University, 1-8-1, Inohana, Chiba 280, Japan PARK, Jae-Gahb, M.D., Department of Surgery, Seoul National University Hospital, Seoul, 110-744, Korea PONSKY, Jeffrey L., M.D., Director, Department of Surgery, Mount Sinai Medical Center, 1 Mount Sinai Drive, Cleveland, OH 44106-4198, USA PREUSSER, Peter, M.D., Division of Hematology/Oncology, Hannover University Medical School, Konstanty-Gutschow-Str. 8, 3000 Hannover 61, FRG RAU, Eckhard, M.D., Graf-Galen-Platz 7,5090 Leverkusen 1, FRG ROHDE, Henning M.D., Second Department of Surgery University of Cologne, Friesenplatz 17A, D-5000 Koln 1, FRG SASAKO, Mitsuru, M.D., Department of Surgery University Hospital, P.O. Box 9600,2300 RC Leiden, The Netherlands SCHMOOL, Hans-Joachim, M.D., Division of Hematology/Oncology, Hannover University Medical School, Konstanty-Gutschow-Str. 8, 3000 Hannover 61, FRG SHMOOKLER, Barry M., M.D., Director of Surgical Pathology, Department of Pathology, The Washington Hospital Center, 110 Irving St., N.W., Washington, DC 20010, USA SIEWERT, Jurgen R., M.D., Division of Hematology/Oncology, Hannover University Medical School, Konstanty-Gutschow-Str. 8, 3000 Hannover 61, FRG SIMMONS, Juliana, M.D., Chairman, Radiation Oncology, The Washington Hospital Center, 110 Irving Street, N.W., Washington, DC 20010, USA SONG, In-Sung, M.D., Department of Internal Medicine, Seoul National University Hospital, Seoul, 110-744, Korea STAHL, Michael, M.D., Division of Hematology/Oncology, Hannover University Medical School, Konstanty-Gutschow-Str. 8, 3000 Hannover 61, FRG STEPHENS, Frederick 0., M.D., M.S., FACS, FRCS, FRACS, Professor and Chairman of Department of Surgery, The University of Sydney, Sydney, New South Wales 2006, Australia SUGARBAKER, Paul H., M.D., FACS, Medical Director, The Cancer Institute, Washington Hospital Center, 110 Irving St., N.W., Washington, DC 20010, USA VAN DE VELDE, Cornelius J.H., M.D., Department of Surgery, University Hospital, P.O. Box 9600,2300 RC Leiden, The Netherlands xvii
VIDAL-JOVE, Joan, M.D., The Cancer Institute, Washington Hospital Center, 110 Irving Street, N.W., Washington, DC 20010, USA VON HOFF, Daniel D., M.D., FACP, The University of Texas Health, Science Center at San Antonio, Department of Internal Medicine, Division of Oncology, San Antonio, TX 78284, USA WILKE, Hansjochen, M.D., Abteilung Hamatologie/Onkologie, Medizinische Hochschule, Konstanty-Gutschow-Str. 8, 3000 Hannover 61, FRG YOSHIDA, Sho, M.D., Second Department of Internal Medicine, School of Medicine, Chiva University, 1-8-1, Inohana, Chiba 280, Japan YU, Wansik, M.D., Department of Surgery, Kyungpook National University, 52 Samduk-dong, 700-412, Taegu, Korea
xviii
Preface: Gastric cancer - therapeutic implications of new concepts of gastric tumor biology
Gastric cancer is a devastating disease, with a dismal prognosis when the diagnosis is made from symptoms. At the time that symptoms send a patient to the physician, the disease usually shows an aggressive biology, with local infiltration and lymphatic invasion. Unfortunately, many of the effective remedies for gastric irritation also mask the early symptoms caused by gastric cancer. Advances have been made in Japan and Korea with early endoscopic diagnosis. These efforts have not been realized in the United States or Europe. In the western world, the diagnosis of this disease is almost always made at an advanced stage. One is left with treatment of advanced cancer as the only effective means of reducing mortality. It is possible that new and more effective treatments are becoming available. A more generous removal of the primary tumor and its draining lymph nodes may provide improved local control. A new understanding of the mechanisms of intraabdominal tumor spread suggests that induction (preoperative) chemotherapy may go far to shrink cancer prior to its surgical removal and thereby reduce tumor spread related to surgical trauma. Induction chemotherapy may be effective because it downstages the malignancy and, for a limited time period, reduces its ability to metastasize or implant. Intraperitoneal chemotherapy may result in reduced local-regional recurrence resulting from the dissemination of cancer cells related to surgical trauma. Careful natural history studies have made it clear that regional cancer recurrence is a prominent part of surgical treatment failure. Surprisingly, new combinations of systemic chemotherapy have recently shown unusually high response rates and may be expected to deal effectively with systemic micrometastases. These preoperative and perioperative treatments can be collectively referred to as neoadjuvant therapy (Table 1). The time has come to collectively reevaluate the treatments available for gastric cancer: (1) More aggressive surgical techniques to cytoreduce this malignancy more effectively than in the past, (2) induction chemotherapy designed to shrink the tumor prior to its surgical removal, (3) early postoperative intraperitoneal chemotherapies to eliminate local-regional cancer spread, and (4) systemic chemotherapy to reduce the subsequent progression P. Sugarbaker (ed), MANAGEMENT OF GASTRIC CANCER. Copyright © 1991. Kluwer Academic Publishers, Boston. All rights reserved. ISBN 0-7923-1102-7.
xix
Table 1. Neoadjuvant therapy Preoperative • Induction IA chemotherapy • Induction IV chemotherapy • Induction IP chemotherapy • External beam radiotherapy Perioperative • EPIC • Intraoperative radiotherapy • Interstitial radiotherapy
of micro metastatic disease. Can survival benefits be achieved? We hope that an organized utilization of this book will result in an optimal plan of attack on this dreaded malignancy. Prominent in our current thinking about the optimal use of chemotherapy is the concept of dose intensity, that is, the maximal amount of antitumor effects are given over the most restricted time period. The oncologist theorizes that this strategy will eliminate the maximal amount of cancer and prevent the development of drug resistance. A fundamental concept presented by this text is dose intensity. However, the strategy involves more than vigorous utilization of systemic chemotherapy. The goal is multimodality dose intensity. Surgery, radiation, and chemotherapy are coming together as a well-orchestrated single event. Can this concept of multimodality dose intensity be developed so that improved survival and quality of life are achieved? To explore the proper strategy whereby cancer chemotherapy is combined with surgery, it may be of value to review the success story surgery has had with infectious disease. Few surgeons overlook the remarkable improvements in the postoperative course of patients recovering from surgical procedures involving the alimentary tract. With proper mechanical preparation of the intestinal lumen and high-dose perioperative antibiotics, infection rates now approach those of clean cases. Are there analogies from the use of antibiotics with gastrointestinal surgery that can lead to an improved utilization of cancer chemotherapy in gastric cancer surgery? There are, I suggest, two essential requirements of an optimal bowel preparation. First, the bowel lumen must be purged of all particulate matter just prior to the surgical procedure. Second, high tissue levels of antibiotics must be maintained during the procedure and in the early postoperative period. I would hypothesize that the mechanical cleansing of the bowel minimizes the amount of bacterial contamination that can occur. Then, properly timed antibiotics present in and around the operative site can effectively suppress the proliferation of organisms disseminated within the operative field. How many bacterial prophylaxis be considered to relate to the treatment of gastric cancer? Unprepared bowel may result in bacteria or fungus dissemination into the abdomen and seriously jeopardize the operative event because of intraabdominal infection. Similarly, tumor cells disseminated from
xx
Table 2. Similarities and differences with the use of antibiotics and neoadjuvant chemotherapy in gastrointestinal cancer surgery Similarities 1. Timing 2. Nature of drugs 3. Target of preoperative treatment 4. Target of perioperative treatment
5. Results Differences I. Source of contamination
Antibiotics Pre- and peri operative Broad spectrum Gross reduction of intra abdominal bacteria Operative site - spread of bacteria as a result of operative trauma Reduce intraabdominal infection Antibiotics Bacteria from bowel tumor
2. Treatment interval
48 hours
3. Route of drug delivery
Orally and intravenous
4. Result of nonuse
Intraabdominal and wound infection
5. Timing treatment failure
Second postoperative week
Chemotherapy Pre- and perioperative Multidrug Gross shrinkage of tumor Operative site - spread of cancer cells as a result of operative trauma Reduce intra abdominal cancer recurrence Chemotherapy Cancer cells from transected lymphatics and serosal invasion Maximal chemical cytoreduction may require 2-3 months Intraarterial and intraperitoneal Resection site recurrence, peritoneal carcinomatosis, wound seeding Second to third postoperative year
the primary cancer will jeopardize the success of a gastric cancer resection. But, rather than peritonitis occurring at 7-10 days postoperatively, cancer will recur 2-4 years later. Table 2 compares the prophylaxis of bacteriologic and cancer contamination occurring with surgical procedures for removal of a gastrointestinal malignancy. Mechanisms of local-regional cancer recurrence The growth patterns of primary gastrointestinal cancer place a majority of patients at great risk for disease recurrence within the abdomen. This tumor grows through the bowel wall early in its natural history, usually before symptoms occur. Not infrequently, for example, the only barrier between the free peritoneal cavity and malignant tissue is a single layer of mesothelium. This is a dangerous situation and is liable to frequently result in contamination of the peritoneal cavity with cancer cells. In almost every patient, exfoliated cancer cells are present in the gastric lumen. These tumor cells are often disseminated from the bowel lumen into the bowel anastomosis or free peritoneal cavity. Most surgeons use largevolume preoperative and intraoperative bowel irrigation to minimize the spill XXI
of exfoliated intraluminal cancer cells. However, other sources of tumor contamination exist. Probably the greatest source of malignant cells is transected lymphatic channels. This leakage of tumor cells from transected lymphatics may explain why local recurrence rates with gastrointestinal cancer double in patients with node-positive disease. It is naive of us to expect lymphatic channels to be free of cancer cells when lymph nodes are involved. How did the tumor cells skip from the primary tumor to the nodes in the first place? Another source of cancer spread not preventable by using current surgical techniques comes from tumor cells in venous blood lost from the specimen. No matter how meticulous the surgical technique, small-vessel bleeding from the specimen occurs throughout the operative event until the cancercontaining tissue is released and leaves the field. In a wide variety of malignancies treated by surgery, the prognosis diminishes if blood loss becomes excessive. The blood loss is, for the most part, venous bleeding from the specimen itself. The blood from the specimen will most likely be contaminated by cancer cells, especially if the resected malignancy must be extensively manipulated to complete the dissection. The tumor-contaminated blood will fix itself in tiny tissue crevices and eventually result in recurrence. This disease persistence will be most evident at the resection site, but may occur anywhere that blood clots accumulate. The possible causes of surgical treatment failure following the resection of gastric cancer are itemized in Table 3. Also an estimate of possible improvements in survival are included. Are there analogies from our success with bowel preparation that can be used to improve the results of surgery for gastrointestinal cancer? Table 3.
Biology of surgical treatment failures following resection of gastric cancer
+
Occult metastases: Liver and systemic sites
+
Occult metastasis in lymph nodes
+
Tumor emboli from transected lymphatics
+
Tumor emboli from serosal invasion
+
Tumor emboli in blood lost from specimen
Treatments
+
+
Systemic chemotherapy
Extended lymph node dissection
?
10%
xxii
+
Induction chemotherapy + EPIC
+
Induction chemotherapy + EPIC
Possible Improvement in Survival 20% 10% Total = 40%
+
EPIC
?
The first goal of bowel preparation mentioned above involves minimizing the spill. For cancer surgery, minimizing the spill would require shrinking the primary tumor mass and eliminating cancer cells from lymphatics. This may be possible using the relevant arterial blood supply of the tumor as the route for chemotherapy administration. High local drug levels with surprisingly increased response rates of infused tumors have been achieved with this approach. However, rather than just starting the drugs a few hours before surgery, as with antibiotics, induction intraarterial chemotherapy needs two to three preoperative cycles to maximize tumor shrinkage. A second requirement for effective bacterial prophylaxis involves effective treatment of small amounts of bacterial contamination. Perioperative use of broad-spectrum antibiotics is required. Unfortunately, for cancer chemotherapy, reliable cancer control cannot be achieved with intravenous agents. To obtain the levels of drugs needed to destroy cancer cells in in-vitro assays, much greater exposure is needed. Intraperitoneal chemotherapy can be used in the early postoperative period and can provide the exposure required to prevent the regrowth of tumor on peritoneal surfaces. The regional treatment advantage of intraperitoneal drug administration has been repeatedly demonstrated. In order to prevent cancer cells from implanting in the resection site
!
Tumor Cell Entrapment Hypothesis Resection of Primary Tumor
Severed Lymphatic Channels
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Intraperitoneal Tumor Emboli H
G
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Fibrin Deposition
E
A L I N
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Spilled Venous Blood
Severed Interstitial Tissues
•
Inflammatory Cells
.
Growth Factors Tumor Cell Deposit
Figure 1. Fibrin entrapment hypothesis describes a mechanism for the high incidence of localregional cancer recurrence with resected gastric cancer.
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METASTATICALLY EFFICIENT 100 --SURGERY ------ SURGERY· NEOADJUVANT
SURVIVAL
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LOCAL DISEASE PROGRESSION
METASTATICALLY INEFFICIENT 100
--SURGERY - - - - -. SURGERY· NEOADJUVANT
,
SURVIVAL
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LOCAL DISEASE PROGRESSION Figure 2. Top, effects of preoperative chemotherapy. By downstaging the primary tumor, perioperative treatments may optimize the surgical event and thereby improve survival. This is only true if systemic metastases are present, that is, a metastatically inefficient cancer. Bottom: These treatments directed at the primary tumor are unlikely to diminish the incidence of systemic metastases. If advanced local disease has resulted in systemic spread, neoadjuvant chemotherapy may produce quality-of-life benefits but not improvements in survival.
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Table 4. Analogous strategies to reduce bacteriologic and cancer contamination
Bacteriologic
Oncologic
1. Sensitivity and resistance to antibiotics determined in vitro 2. Bowel purged preoperatively to remove gastrointestinal contents, which may otherwise cause gross contamination 3. Use antibiotics intensively during the operation and in the early postoperative period 4. For ultimate success, need host immune response to eliminate last few organisms. Prolonged systemic treatment needed in immune-suppressed host.
Sensitivity and resistance to chemotherapy determined in vitro Induction chemotherapy used to shrink tumor mass and thereby reduce gross tumor contamination Use chemotherapy intensively in the early postoperative period For ultimate success, need host immune response; systemic chemotherapy may reduce incidence of metastases from microemboli of cancer.
and on traumatized peritoneal surfaces, early postoperative intraperitoneal chemotherapy should be used (Figure 1). Induction intraarterial chemotherapy and early postoperative intraperitoneal chemotherapy do not exclude the use of systemic chemotherapy to eradicate micrometastasis in lungs and other sites. Rather, sequential treatment at all sites of surgical treatment failure should be used. Finally, the use of antibiotics to prevent infection usually requires broadspectrum coverage. Multiple cancer chemotherapy agents can be used. Alternatively, a chemotherapy resistance-sensitivity assay may be utilized to maximize responses. Table 4 presents parallels in bacteriologic and oncologic use of perioperative drugs. One must not be disappointed with this dose-intensive approach to gastric cancer if only small incremental improvements in survival occur. Even the most comprehensive dose-intensive regimen will have little, if any, effect on systemic disease, and unfortunately, systemic metastases are the cause of death in a majority of gastric cancer patients. Figure 2 presents my concept of survival improvements as a result of multimodality doseintensive treatments.
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Management of Gastric Cancer