Cancer Chemotherapy in Clinical Practice

Cancer Chemotherapy in Clinical Practice

Cancer Chemotherapy in Clinical Practice Terry Priestman

Terry Priestman, MD, FRCP, FRCR New Cross Hospital Wolverhampton UK British Library Cataloguing in Publication Data Priestman, Terry J. Cancer chemotherapy in clinical practice 1. Cancer - Chemotherapy I. Title 616.9 94061 Library of Congress Control Number: 2007936871 ISBN: 978-1-84628-989-7 e-isbn: 978-1-84628-991-0 Printed on acid-free paper Springer-Verlag London Limited 2008 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. 987654321 Springer Science+Business Media springer.com

Preface This book is intended as a basic overview of the drug treatment of cancer for junior doctors and specialist nurses who come into contact with people having chemotherapy as part of their day-today work. The aim is to provide a context to those treatments, explaining what the drugs are, how they work, some of their more likely side effects, how they are used in the treatment of the commoner cancers and what therapeutic results might be expected. The first use of the word chemotherapy is credited to Paul Ehrlich (1854 1915), who used it to describe the arsenical compounds he developed to treat syphilis. Nowadays when people talk about chemotherapy, as part of cancer treatment, they are usually referring to the use of cytotoxic drugs. Cytotoxics have dominated systemic cancer therapy for the last 50 years, and their use has resulted in enormous improvements in outcome. But they are only one component of the drug treatment of malignancy. Hormonal therapies are another major contributor to increased cure rates and survival times, and the last decade has seen an explosion of entirely new types of drugs for cancer treatment. The latter are mainly drugs specifically targeted against cancer cells (whereas cytotoxics affect both normal and malignant cells). These newer compounds have sometimes been popularly termed magic bullets, which again takes us back to Ehrlich, as this was another phrase he used to describe his treatments. The aim of this text is to cover all these different elements of systemic therapy, giving an explanation of their various modes of action, their side effects and their place in the everyday treatment of common cancers, with the hope of offering a simple overview of an increasingly complex, diverse, and incredibly exciting area of modern-day medicine. While some cytotoxic and hormonal agents have been in common use for more than 50 years, many of the treatments described in this book have only appeared in the last 5 years, and others remain prospects for the future. The recent rapid

vi PREFACE expansion of therapeutic options for systemic cancer treatment, with drugs having a range of new lines of attack on the process of cancer growth, has meant that there is no universally agreed system for classifying these therapies. Because some of the newer agents only affect cancer cells, and cause relatively little damage to normal tissue (in contrast to the established cytotoxic drugs), they have been called targeted therapies. Another phrase that is used is biological therapies or biological response modifiers ; some authorities restrict this to describing the cytokines, whilst others use it to embrace a far wider range of compounds, including all the monoclonal antibodies. As a result the current terminology can be confusing and is still evolving. I have adopted the approach of trying to show how all these different options we now have for attacking cancer relate to the basic process of tumour growth and development. Details of specific drug doses and treatment schedules are deliberately not given. This is partly because there is often considerable variation from hospital to hospital on the precise dosage and timing of treatment, even with standard therapies. But also the prescription of most of the drugs described in this book is restricted to experienced specialist clinicians and would not normally be the responsibility of more junior doctors. So whilst it is important to be aware of what the drugs are and why they are being used, it is not anticipated that the readers of this book would be involved in either the choice treatment or its prescription. Throughout the text I have used the approved (nonproprietary) names of the drugs. The UK proprietary (trade) names are given in Appendix 1. A current complication of cancer chemotherapy in the UK is the drug approval process. Once a new agent has gained its commercial product licence it may be prescribed. However, until the drug has been approved by the National Institute for Health and Clinical Excellence (NICE), in England and Wales, and the Scottish Medicines Consortium, in Scotland it will not be available on the National Health Service (NHS). This system, designed to ensure cost effectiveness of therapeutic innovations, is not without its critics not least because the two authorities sometimes reach different decisions! However, it does mean that at the time of writing some of the newer drugs mentioned in the text either are still awaiting approval or, for the present at least, have failed to gain approval. Because this is a constantly changing situation and because most of the readers of this book would not be directly involved in selecting treatments, I have specifically

PREFACE vii avoided commenting on the availability, or otherwise, of drugs on the NHS. Throughout the text I have given suggestions for further reading, citing articles which cover individual topics in more depth. In addition there are three textbooks which give more detailed accounts of almost all the subjects I have covered, and which provide excellent references. They are Cancer Chemotherapy and Biotherapy, 4th edition, Chabner BA, Longo DL, eds, Lippincott, Williams and Wilkins, 2006; Cancer: Principles and Practice of Oncology, 7th edition, DeVita DT, Hellman S, Rosenberg SA, eds, Lippincott Williams & Wilkins, 2005; The Oxford Textbook of Oncology, 2nd edition, Souhami RL, Tannock I, Hohenberger P, Horiot J-C, eds, Oxford University Press, 2002. Terry Priestman May 2007

Contents Preface... v 1. The Theoretical Basis of Cancer Chemotherapy... 1 Historical Introduction... 1 In the Beginning: Genes... 3 Growth Factors and Receptors... 5 Steroid Receptors and Endocrine Therapy... 5 Tyrosine Kinase Genes... 10 Cytokines... 15 CD Protein Targeted Monoclonal Antibodies... 15 Signal Transduction... 16 Proteasome Inhibition... 16 Mitosis: Cytotoxic Drugs... 17 Tumour Kinetics: Adjuvant Therapy... 28 Gene Analysis and Treatment Selection... 31 Bisphosphonates... 32 Chemoprevention... 33 2. Some Practical Aspects of Cancer Chemotherapy.. 35 Drug Dosing... 35 Drug Delivery... 36 Infusion Pumps... 39 Side Effects of Cancer Chemotherapy... 41 Side Effects of Hormonal Treatment... 70 Side Effects of Targeted Therapies... 74

x CONTENTS 3. Chemotherapy in the Management of Cancer... 78 Breast Cancer... 78 Lung Cancer... 82 Mesothelioma... 85 Urological Cancer... 86 Gastrointestinal Cancer... 93 Gynaecological Cancer... 98 Brain Tumours... 102 Head and Neck Cancer... 104 Skin Cancer... 105 Soft-Tissue Sarcomas... 106 Primary Bone Sarcomas... 108 Haematological Cancer... 109 Appendix I...121 Appendix II...123 Index... 126