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1 Endocrine Management of Cancer 2 Contemporary Therapy Basil A. Stoll, London (Editor) Endocrine Management of Cancer 2 Contemporary Therapy 3 figures and 20 tables, 1988 KARGER Basel München Paris London New York NewDelhi Singapore - Tokyo Sydney Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Copyright 1988 by S. Karger AG, P.O. Box, CH009 Basel (Switzerland) Printed in Switzerland by Friedrich Reinhardt AG, Basel

2 ISBN (set) ISBN (v.2) Contents Contributors IX Preface XI The Role of Current Agents A. U. Buzdar 1 Progestins in Cancer Treatment l Pharmacology of Progestins 1 Breast Cancer 2 Endometrial Cancer 5 Epithelial Ovarian Cancer 7 Prostate Cancer 8 Mechanisms of Antitumor Activity 9 Future Directions 10 References 11 B.J.A. Furr, R.A. V. Milsted 2 LH-RH Analogues in Cancer Treatment 16 Pharmacology of LH-RH and Its Analogues 16 Formulation of LH-RH Analogues 17 Treatment of Prostate Cancer 18 Treatment of Advanced Breast Cancer 25 Treatment of Other Conditions 27 References 27 T..S. Bhatnagar, C. Nadjafi, R. Steiner 3 Aromatase Inhibitors in Cancer Treatment 30 Nonsteroidal Aromatase Inhibitors - Aminoglutethimide 30 Steroidal Aromatase Inhibitors 35 Conclusion 37 References 38 U. W. Tunn, A. Radlmaier, F. Neumann 4 Antiandrogens in Cancer Treatment 43 Pharmacology of Antiandrogens 43 Rationale of Androgen Deprivation in Prostatic Carcinoma 44 Contents VI

3 Clinical Experience with Antiandrogens 45 Side Effects of Antiandrogens 48 Combined Endocrine Therapy with LH-RH Analogues 48 Combined Chemo-Antiandrogen Therapy 49 Conclusion 51 References 51 V.C. Jordan 5 Antiestrogens in Cancer Treatment 57 Advanced Breast Cancer 57 Adjuvant Therapy 58 Prevention Therapy 60 Conclusions 61 References 62 New Aspects of Therapy M.J. Dunne, K. Kutz 6 Somatostatin Analogues in Cancer Treatment 65 Pharmacology and Physiology 65 Somatostatin Analogues 66 Sandostatin - Therapeutic Applications 67 Future Perspectives 75 Conclusion 75 References 76 B.A. Stoll 1 Combination Endocrine Therapy - Concurrent or Sequential?. 80 Endometrial Cancer - Concurrent or Sequential Therapy? 81 Prostatic Cancer - Concurrent or Sequential Therapy? 83 Breast Cancer - Concurrent Combination Therapy 85 Breast Cancer - Sequential Endocrine Therapy 87 Revised Approach to Endocrine Management 93 Conclusion 96 References 97 D. Rausch, D. T. Kiang 8 Interaction between Endocrine and Cytotoxic Therapy 102 Hypothetical Model 102 Status of Chemo-Endocrine Therapy 104

4 Interactions: Chemotherapeutic Effects on Endocrine Function 105 Interactions: Hormonal Effects on Chemotherapy Ill Cell Synchronization and Recruitment Regimens 113 Conclusion 114 References 115 Contents VII S. Kvinnsland, S. Gundersen 9 Prospects for Alternating Endocrine Therapy 119 Choice of Agents for Alternating Therapy 119 Clinical Forms of Alternating Therapy 122 References 124 R.D. Gambrell, Jr. 10 Hormonal Medication and Mitogenic Dangers 126 Epidemiologic Studies 126 Breast Cancer 127 Endometrial Cancer 134 Ovarian Cancer 136 Cervical Cancer 137 Hormones and Hepatic Tumors 138 Hormones and Pituitary Tumors 139 Malignant Melanoma, Sunlight and Oral Contraceptives 139 Diethylstilbestrol and Vaginal Cancer 139 References 140 K. Vallis, J. Waxman U Tumour Flare in Hormonal Therapy 144 Breast Cancer: Tamoxifen Therapy 144 Breast Cancer: Oestrogen Therapy 147 Breast Cancer: Androgen and Progestin Therapy 148 Prostatic Cancer: Gn-RH Agonist Therapy 149 Conclusion 150 References 151 Subject Index 153 Contents Vol. 1: Biological Bases Steroids, Mediators and Growth Factors

5 1 Y.S. Cho-Chung: Models of Tumor Regression in Endocrine-Related Cancer 2 J.D. Simnett: Hormonal Regulation of Protein Synthesis and Cell Differentiation 3 M.J. Tisdale: Role of Intracellular Mediators in Hormonal Mechanisms 4 J.R. C. Sainsbury: Growth Factors and Their Receptors as Mediators of Response 5 R.A. Hawkins, W.R. Miller: Endogenous Sex Hormones in Cancer Development Factors in Hormonal Responsiveness 6 J. T. Hamm, J. C. Allegra: Loss of Hormonal Responsiveness in Cancer 7 H.S. Poulsen: In vitro Observations in Relation to Response 8 D.E. Merkel, C.K. Osborne: Steroid Receptors in Relation to Response 9 P. Davies: Steroid Metabolism in Tumours in Relation to Response 10 H.K. Adam: Pharmacokinetics of Agents in Relation to Response 11 J.T. Isaacs: Clonal Heterogeneity in Relation to Response Contributors Bhatnagar, A.S., PhD, Adjunct Associate Professor, Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebr., USA; and Research Department Pharmaceuticals Division, Ciba-Geigy AG, Basel, Switzerland Buzdar, A.U., MD, Professor of Medicine, Department of Medical Oncology, University of Texas, M.D. Anderson Hospital and Tumor Institute, Houston, Tex., USA Dunne, M.J., MB, BCh, MSc, MRCPath, Medical Advisor, Clinical Research Unit London, Sandoz Ltd., Honorary Research Fellow, Westminster Hospital, London, UK Furr, B. J.A., BSc, PhD, Head of Bioscience Research Department, ICI Pharmaceuticals Division, Macclesfield, UK Gambrell, R.D., Jr., MD, Clinical Professor, Department of Physiology and Endocrinology, Medical College of Georgia, Augusta, Ga., USA Gundersen, S., MD, Department of Oncology, Norwegian Radium Hospital, Oslo, Norway Jordan, V.C., PhD, DSc, Professor of Human Oncology and Pharmacology, University of Wisconsin, Clinical Cancer Center, Madison, Wise., USA Kiang, D.T., MD, PhD, Associate Professor of Medicine, Director, Breast Cancer Research Laboratories, Masonic Cancer Center, University of Minnesota, Minneapolis, Minn., USA Kutz, K., MD, Head of Department of Human Pharmacology, Clinical Research Department, Sandoz AG, Basel, Switzerland; and Professor of Internal Medicine, Faculty of Medicine, University of Bonn, Bonn, FRG Kvinnsland, S., MD, Professor, Department of Oncology, University of Trondheim,

6 Trondheim, Norway Milsted, R.A.V., MD, MSc, MRCP, Medical Adviser in Oncology, ICI Pharmaceuticals Division, Macclesfield; and Honorary Consultant in Medical Oncology, Withington Hospital, Manchester, UK Nadjafi, C., MD, Medical Department, Pharmaceuticals Division, Ciba-Geigy AG, Basel, Switzerland Neumann, F., MD, Professor and Director of Endocrine Pharmacology, Schering AG, Berlin Radlmeier, A., MD, Department of Clinical Research, Schering AG, Berlin Rausch, D., MD, Postdoctoral Associate, Division of Medical Oncology, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, Minn., USA Contributors X Steiner, R., MD, Research Department, Pharmaceuticals Division, Ciba-Geigy AG, Basel, Switzerland Stoll, B.A., FRCR, FFR, Honorary Consulting Physician to Oncology Departments, St. Thomas Hospital and Royal Free Hospital, London, UK Tunn, U.W., MD, Head of Urology, Stadtkrankenhaus Offenbach, Offenbach/Main, FRG Vallis, K., MRCP, Department of Clinical Oncology, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK Waxman, J., BSc, MD, MRCP, Senior Lecturer and Honorary Consultant, Department of Clinical Oncology, Royal Postgraduate Medical School, London, UK Preface The approach of this book differs from that of others on this topic. It is not divided into sections dealing separately with the endocrine management of cancers of the breast, prostate, uterus and so on, because such reviews can be found in specialist journals and books. Instead, the book discusses the clinical role and pharmacological characteristics of several new groups of hormone-modulating agents which have become commercially available in recent years. The new agents have come at a time of incredible advances in our knowledge of the molecular biology of the cancer cell and in our ability to recognize biological mechanisms which make tumours behave in a particular manner in the individual patient. Clinically, it is an ideal time to collate such knowledge because the new agents have now completed extensive clinical trials in cancers of the breast, prostate and endometrium especially. Many have yielded a significant degree and duration of tumour regression in patients with the advanced

7 disease, and evidence of delayed recurrence when used as adjuvant therapy in the high-risk patient after primary surgical treatment. Their ability to prolong survival has been less clearly proved. Combinations of endocrine agents or combination chemo-endocrine therapy have a greater potential to prolong remissions and thereby increase survival, but, in the past, selection of combinations was empirical. The introduction of biological assays of tumour receptors, and biological indices of tumour aggressiveness and tumour burden, should now permit more rational selection of suitable subsets of patients for such treatment. Metabolic disposition of agents in the body also needs to be considered in selecting patients for treatment. The book reviews the principles underlying the use of the new hormonemodulating agents in the treatment of breast, prostatic and uterine cancers. In this aim, the writers distinguish between the effects of an endocrine agent which are specific for a particular tumour, as distinct from those which may apply to all hormonally responsive tumours. This is an innovative approach, as the literature has previously made no attempts to establish parallels Preface XII between the tumours in their rates and duration of primary response, likelihood of response to secondary therapy, significance of flare, path to autonomy and so on. It is hoped that the insights into new agents and treatment approaches, together with an up-to-date account of the biological characteristics of tumours likely to respond, will lead clinicians to institute new clinical trials of hormonal modalities based upon rational, rather than empirical principles. London, 1988 Basil A. Stoll Consulting Physician, Oncology Department, St. Thomas Hospital, London