Basic Principles of Cancer Chemotherapy PDF
Preview Basic Principles of Cancer Chemotherapy
Basic Principles of Cancer Chcmotherapy Basic Principles of Cancer Chemotherapy c. Kenneth Cahnan, M.D., Ph.D., F.R.C.S., F.R.S.E. Cancer Research Campaign, ProfessorofOncology, The University ofGlasgow John F.Smyth,M.A., M.Sc., M.D., M.R.C.P. Imperial Cancer Research Fund, Professor of Medical Oncology, The University of Edinburgh Martin H. N. Tattersall, M.A., M.D., M.Sc., M.R.C.P., F.R.A.C.P. Director, Sydney Branch, Ludwig Institute for Cancer Research, and Professor of Cancer Medicine, The University of Sydney M © Kenneth C. CaIman, John F. Smyth and Martin H.N. Tattersall 1980 Softcover reprint ofthe hardcover 1st edition 1980978-0-333-21972-0 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission First published 1980 by THE MACMILLAN PRESS LTD London and Basingstoke Associated companies in Delhi Dublin Hong Kong Johannesburg Lagos Melboume New York Singapore and Tokyo Typeset in 10/12 Times Roman by STYLESET LIMITED . Salisbury . Wiltshire British Library Cataloguing in Publication Data CaIman, Kenneth Charles Basic principles of cancer chemotherapy. 1. Cancer - Chemotherapy I. Title 11. Smyth, John F III. Tattersall, Martin H N 616.9'94'061 RC271.C5 ISBN 978-0-333-30479-2 ISBN 978-1-349-86135-4 (eBook) DOI 10.1007/978-1-349-86135-4 This book is sold subject to the standard conditions of the Net Book Agreement Contents Foreword vii Preface and Acknowledgements ix l. Introduction 2. Tumour Biology in Relation to Chemotherapy 4 3. Basic Biochemistry 17 4. Clinical Pharmacology of Anti-Cancer Drugs 35 5. Mechanism of Action of Anti-Cancer Drugs 49 6. Principles of Chemotherapy 79 7. Drug Development and Screening 89 8. Staging, Evaluation of Treatment and Prognostic Factors 94 9. Complications of Cancer Chemotherapy 102 10. Hormones in Cancer Therapy 113 1l. Immunological Aspects of Cancer Chemotherapy 121 12. Drug Interactions in the Treatment of Neoplastic Disease 128 13. Growing Points 133 Appendix: Chemotherapeutic Agents in Cu"ent Use 138 Index 153 Foreword Cancer treatment involves fields of medicine which are undergoing profound change. Inevitably the management of the cancer patient is dictated by available therapy, so that surgery and, more recently, radiotherapy, have been long-standing bulwarks of the clinician. The dependence on local therapy and the absence of anything better was reflected in the attitude of hopelessness feIt by the clinician when faced by the patient with widespread disease. The fe ar of cancer engendered by this therapeutic impotence was surely communicated to patients and families alike, and many present-day misconceptions and lay beliefs undoubtedly had their origins in the desperate circumstances existing as little as thirty years ago. The advent of drugs active in certain cancers has not only made the treatment of patients with widespread disease a realistic possibility, but it has also placed the ability to administer anti-cancer therapy within the hands of all clinicians - a questionable advantage where no authoritative guidance to such therapy is available. Aspirations for cancer chemotherapy have grown with the appreciation that the majority of patients presenting with malignant disease have tumours which cannot be cured by local therapy alone. Unfortunately no drug is known which is capable of selective kill of the cancer cell without toxicity to normal tissues, so that a critical appraisal of treatment is essential. Much of the assessment of the benefits or otherwise of chemotherapy has been haphazard. The gradual development of clinical trials as the optimum vehicle for assessing the benefits of a particular form of chemotherapy has led to the recognition of favoured drug combinations for use in particular malignancies. The greater availability of anti cancer drugs, their toxicity, the complexity of their metabolism, interaction and administration, and the need for a more precise evaluation of their use, are all well recognised by the authors of this book. From its origins in the pioneer course of Basic Principles of Cancer Chemotherapy, the authors have sought to communicate current understanding of a complex field to those who will later be involved in the management of the cancer patient. In so specialised a field, it is inevitable that the administration of cancer chemotherapy will tend to be concentrated in the hands of those experienced in its administration. However, all clinicians should have an understanding of the treatments available to their patients and many will at some time be involved in the care of so comrnon a viii Foreword medical condition as cancer. This volume presents an excellent and informative review of the subject. Southampton, 1980 Professor J. M. A. Whitehouse Director C. R. C. and Wessex Regional Medical Oncology Unit Southampton General Hospital Preface and Acknowledgemel1ts The idea of this book grew out of an annual course entitled Basic Principles o[ Cancer Chemotherapy, organised by the authors and held in the Department of Oncology, University of Glasgow. This course was aimed at giving a basic back ground to the uses and mechanisms of actions of anti-cancer drugs. The principles behind the use of these drugs were described and an attempt was made to develop an understanding of the rational use of such agents. This book is directed at four groups of individuals. The first group comprises trainees in medical oncology who may wish to have abrief introduction to the principles behind the use of chemotherapeutic agents before developing their interest further. The second group comprises specialists in other areas of medical practice who may wish to understand more of the basis of anti-cancer drug action and rationale for using these agents. The third group comprises specialist nurse oncologists and pharmacists who are responsible for drug administration or counselling and who may wish to know more about the drugs themselves. The last group comprises interested senior medical students who may wish to read further into the subject of cancer chemotherapy. We should like to thank, specifically, Drs Stuart and Stockley who have con tributed the chapter on drug interactions (Chapter 12). We should also like to thank our respective secretaries for the enormous amount of work involved in the retyping necessary for a book like this. Penultimately, we should like to thank our colleagues who have contributed ideas and the participants on the courses whose criticisms and comments have helped to shape this book. Finally, we acknowledge the help and advice of Professor J. M. A. Whitehouse and thank him for contributing the Foreword to this book. G/asgow, Edinburgh and Sydney, 1980 K.C.C. J. F. S. M.H.N.T. 1 Introduction The majority of patients with cancer present to their doctor when their disease has already spread. For these patients, surgical resection ofthe primary tumour or local radiotherapy may control the tumour, but cure of the metastatie disease by these treatments is impossible. Thus, for the majority of cancer patients, cure of the disease depends either upon earlier diagnosis - tumours being treated when local treatments may be curative - or upon the development of some systemic treatment to kill metastatic tumour cells. The origins of cancer chemotherapy can be traced to the 1860s, when potas sium arsenite was used in the treatment of leukaemia. The early results of cancer chemotherapy were not impressive, but, in 1941, oestrogens were shown to cause regression of metastatic prostatie cancer, and this was the first real evidence that cancer cells could be controlled by drug treatment. During the 1940s, a number of drugs, including androgens, actinomycin, nitrogen mustard, cortieosteroids and the antifolate, aminopterin, were shown to have useful anti-tumour effects and, in the last twenty-five years, cancer chemotherapy has evolved to become part of asound medical discipline with an important role in the control of cancer. The number of drugs with proven activity in advanced cancer has increased rapidly in the last twenty-five years. This change can be attributed in large part to the development of animal tumour model systems for screening drugs. When a drug is found to eradieate these animal tumours at doses that are not toxie to the normal tissues, a further series of tests is set up in dogs and monkeys to establish the maximum tolerated dose and to search for toxie effects. A drug that has passed through this screen is then assessed in man, initially in patients with advanced cancer and, subsequently, if activity is seen, in patients with cancers of different types and stages. When drugs were first used to treat cancer, it was never envisaged that they would be curative, and the original strategy was to use a drug known to be effec tive in the partieular tumour only when the disease was far advanced and causing symptoms. If the tumour failed to respond to the first drug, a second drug was tried, and so on. It was then realised that many drugs had a much more powerful effect against the cancer, and with less toxicity to the normal tissues, if large doses of drug were given intermittently rather than smaller doses continuaIly. This introduced the concept of high-dose intermittent chemotherapy, leaving 2 Basic Principles of Cancer Chemotherapy intervals between treatments for recovery of normal tissues. A further advance was the discovery that drug combinations were frequently more effective than single-drug treatments. Combination cancer chemotherapy was first used clinically in the early 1950s and the value of this approach has become apparent during the past ten years. Drugs were used at first for the treatment ofleukaemia andlymphoma because the established cancer treatment modalities of surgery and radiotherapy had little to offer. Occasional remissions were reported using single-agent treatment, but, with the introduction of pulsed combination chemotherapy during the 1960s, complete remissions were obtained frequently. As the outlook in leu kaemia and lymphoma improved due to drug treatment, interest in the role of chemotherapy in treatment of other cancers evolved. During the 1960s, chemotherapy was used in the treatment of testicular tumours, choriocarcinoma and certain children 's tumours. In choriocarcinoma and Burkitt's lymphoma (a lymphoma occurring most commonly in Africa), it was soon clear that chemotherapy was frequently curing patients. In some chil dren's tumours, most notably Wilms' tumour, chemotherapy quite often caused tumour regression and drug treatment was soon established as an important com ponent in treatment. Scientific and clinical interest in the use of drugs in cancer treatment was stimulated by these encouraging results, and the combined efforts of experi mental and clinical cancer chemotherapists during the last few years have expanded further the role of chemotherapy in cancer treatment. Our knowledge of tumour kinetics, tumour biology and the mechanism of action of anti-cancer drugs has also increased, and many cancer chemotherapy units now have pharmacologists, chemists and biochemists on their staff, reflecting the increased collaboration between clinicians and laboratory scientists. The majority of human cancers do not show the same degree of chemosensi tivity as choriocarcinoma and lymphoma, and the initial euphoria about the efficacy of cancer chemotherapy has been replaced by a more balanced appraisal of the contribution that chemotherapy can make towards cancer management. Experimental chemotherapists have identified situations where chemotherapy is more effective; for example, it has been shown that early drug treatment of animal tumours is frequently curative, whereas the same chemotherapy given to animals with more advanced disease is only palliative. It has also been shown that surgical resection of the primary tumour, followed by chemotherapy, might be a curative treatment in mice with locally advanced tumours when neither treatment given alone would be effective. This clear demonstration in animal tumours, that combined modality treatment was frequently more effec tive than either modality alone, prepared the way for the development of multi disciplinary approaches to clinical cancer treatment. In childhood cancer, this approach has been very successful; in Wilms' tumour, for example, before chemotherapy was used, only 20% of children were cured but, with the addition of modern chemotherapy, approximately 80% of these children are now cured.
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