OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page i Oxford Handbook of Oncology OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page ii Dose schedules are being continually revised and new side effects recognized. Oxford Uni- v ersity Press makes no representation, express or implied, that the drug dosages in this boo k are correct. For these reasons the reader is strongly urged to consult the pharmaceutical company \200\231s printed instructions before administering any of the drugs recommended i n this book. OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page iii Oxford Handbook of Oncology Jim Cassidy Professor of Oncology, Institute of Medical Sciences, Aberdeen Donald Bissett C onsultant Clinical Oncologist, Aberdeen Royal In \201rmary, Aberdeen and Roy AJ Spence OBE Consultant Surgeon, Belfast City Hospital; Honorary Professor, Queen \200\231s University, Belfast; Honorary Professor University of Ulster 1 OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page iv 1 Great Clarendon Street, Oxford OX2 6DP Oxford University Press is a department of the University of Oxford. It furthers the Univer sity s objective of excellence in research, scholarship, and education by publishing worldw ide in Oxford New York Athens Auckland Bangkok Buenos Aires Cape Town Chennai Dar es Salaam Delhi Hong Kong Istanbul Karachi Kolkata Kuala Lumpur Madrid Melbourne Mexico City Mumbai Nairobi S o Paulo Shanghai Taipei Tokyo Toronto and an associated company in Berlin Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries Published in the United States by Oxford University Press Inc., New York Oxford University Press, 2002 The moral rights of the author have been asserted Database right Oxford University Press (maker) First published 2002 All rights reserved. No part of this publication may be reproduced, stored in a retrieval s ystem, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, or under terms agreed with t he appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, a t the address above You must not circulate this book in any other binding or cover and you must impose this sam e condition on any acquirer A catalog record for this title is available from the British Library Library of Congress Cataloging in Publication Data (Data available) ISBN 0 19 263035 0 10 9 8 7 6 5 4 3 2 1 Typeset by EXPO Holdings, Malaysia Printed in Great Britain on acid-free paper by The Bath Press, Avon OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page v Preface Cancer is a word that describes a large number of related diseases. It will affect about on e in three of the Western population. The disease requires expertise from many disciplines if it is to be cured or ade- quately palliated. Much has been written about cancer. This is daunt- ing for the student, trainee, or other professional involved with cancer patients. This book is designed as a primer for those who are involved with cancer patients or the st udy of cancer. It is intended to supply suffi- cient background knowledge to allow the read er to seek more detailed information from the numerous textbooks and web resources in oncol ogy. As such, it is deliberately not all-inclusive. It does cover the principles of oncolog y and the common cancers as well as the com- plex clinical pictures that cancer can produce . We are very grateful to the long list of contributors who took time to give insight into th eir own specialist areas. Special thanks should to go to Roy Spence \200\223 who, in footb all terms, \200\230came into the team from the bench and scored the winning goal! \200\231 . I hope you enjoy this Handbook and it inspires you to learn more about this most fascinating disease. J.C. OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page vi This page intentionally left blank OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page vii Contents Preface v List of contributors ix Abbreviations xvii Part 1 Background 1 Multidisciplinary approach to cancer 2 2 Epidemiology of cancer 3 3 Biology of cancer 11 4 Pathology of cancer 37 5 Etiology of cancer 49 6 Staging of cancer 63 Part 2 Principles of treatment 7 Surgical oncology 83 8 Principles of radiation oncology 93 9 Principles of chemotherapy 1 35 10 Hormone therapy 181 11 Immunotherapy of cancer 189 Part 3 Principles of prevention and care 12 Cancer prevention and screening 207 13 Clinical trials 221 14 Principles of palliative c are 227 15 Psychosocial aspects of cancer 249 Part 4 Speci \201c types of cancer 16 Thoracic cancer 261 17 Breast cancer 295 18 Colorectal cancer 323 19 Anal cancer 339 OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page viii CONTENTS viii 20 Upper gastrointestinal cancer 349 21 Endocrine cancers 375 22 Genitourinary cancers 389 23 Gynecological cancer 417 24 Head and neck cancer 443 25 Tumors of the central nervous sy stem 469 26 Skin cancer 481 27 Hematological malignancies 489 28 Bone and soft tissue malig nancies 515 29 Cancer of unknown primary site 531 30 Paraneoplastic syndromes 543 31 AIDS-r elated malignances 559 Part 5 Emergencies in oncology 32 Spinal cord compression 573 33 Bone marrow suppression 583 34 Superior vena cava obstruc tion 591 35 Raised intracranial pressure 599 36 Stridor 605 37 Acute blood loss 611 38 Obst ruction 619 39 Biochemical crises 625 Part 6 The way forward 40 Novel therapeutic strategies 637 41 Gene therapy for cancer 655 Part 7 Appendices 1 NCIC common toxicity criteria (CTC) grading system 667 2 Nomogram for determination of bo dy surface area 681 Index 683 OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page ix List of contributors Dr F. Ahmed Aberdeen Royal In \201rmary, Aberdeen, UK J. W. Arndt Department of Diagnostic Radiology, Leiden University Hospital, Leiden, The Netherlands Dr Ahmed Awada Chemotherapy Unit, Jules Bardet Institute, Brussels, Belgium Professor Anne Barrett Professor of Radiation Oncology, Glasgow University and Beatson Onco logy Center, Western In \201rmary, Glasgow, UK Professor H. Bartelink The Netherlands Cancer Institute, The Netherlands Professor H. Bismuth University of South Paris, Paris, France Dr Bissett Aberdeen Royal In \201rmary, Aberdeen, UK Professor A. K. Burnett Department of Hematology, University Hospital of Wales, Cardiff Royal In \201rmary, Cardiff, UK Dr Sally Burtles Cancer Researc h Campaign, London, UK Professor Hilary Calvert Director of Oncology Research Unit, University of Newcastle-upon Tyne, Newcastle, UK Dr David Cameron Senior Lecturer in Medica l Oncology, Edinburgh University, Edinburgh, UK Dr Etienne Chatelut Pharmacology Laboratory, Institute Claudis Regard, Toulouse, France Dr John Chester ICRF Cancer Medical Research Unit, University of Leeds, Leeds, UK Dr John S. Cockburn Consultant Cardiothoracic Surgeon, Department of Cardiothoracic Surgery, Aberdeen Royal In \201rmary, Aberdeen, UK Professor Robert Coleman Cancer Research Center, YCR Department of Clinical Oncology, Western Park Hospital, Shef \201eld UK Professor Tim Cooke Department of Surgery, Royal In \201rmary, Glasgow, UK Professor Alan Craft Head of Department of Child Health, The Royal Victoria In \201rmary, Newcastle-upon-Tyne, Newcastle, UK Dr John Crown Department of Medical Oncology, St Vincent \200\231s Hospital, Dublin, Ireland OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page x LIST OF CONTRIBUTORS x Dr Dominic Culligan Consultant Hematologist and Honorary Senior Lecturer, Aberdeen Royal In \201rmary, Aberdeen, UK Dr David Cunningham Royal Marsden NHS Trust, Institute for Cancer Research, Sutton, Surrey, UK Dr Rosie Daniel Medical Director, Bristol Cancer Help Center, Clifton, Bristol, UK Dr Gedeske Daugaard Department of Oncology, Rigshospitalet, Blegdamsvejq, National Universi ty Hospital, Copenhagen, Denmark Dr Carol Davies Southampton General Hospital, Southampton, UK R. H. deBoer Royal Marsden Ho spital, Sutton, Surrey, UK Dr John Dewar Dundee University, Dundee, UK Professor S. Dische Center for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex, UK Dr David Dodds Beatson Oncology Center, Western In \201rmary, Glasgow, UK Dr. Sinead Donnelly Marie Curie Center, Glasgow, UK J. Doughty Department of Surgery, Glasg ow University, Glasgow, UK Dr. David Dunlop Beatson Oncology Center, Western In \201rmary, Glasgow, UK Professor L. Fallow \201eld Royal Free and UCL Medical School, London, UK Dr T. A. F. El-Maghraby Leiden University Hospital, Leiden, Netherlands Dr Marie Fallon Senior Lecturer in Palliative Care, Beatson Oncology Center, Western In \201rmary, Glasgow, UK; Senior Lecturer in Palliative Medicine, University of Glasgow, Glas gow, UK Paula Ganeh Department of Oncology, University of Birmingham, Birmingham, UK Professor Andrew Gesher MRC Toxicology Unit, University of Leicester, Leicester, UK Professor O. J. Garden University Department of Surgery, Edinburgh Royal In \201rmary, Edinburgh University, Edinburgh, UK Professor Fiona Gilbert Department of Radiology, Foresterhill House Annexe, Foresterhill, Aberdeen, UK Professor A. Goldstone Department of Hematology, University College Hospital, London, UK Dr Martin Gore Consultant in Medical Oncology, Royal Marsden Hospital, South Kensington, London, UK OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page xi LIST OF CONTRIBUTORS xi Dr John Graham Consultant in Clinical Oncology, Bristol Oncology Center, Bristol, UK Professor M. Greaves Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, UK Dr Anna Gregor Consultant in Clinical Oncology, Macmillan Lead Cancer Clinician, Western Ge neral Hospital, Edinburgh, UK Professor Neva Haites Department of Medical Genetics, University of Aberdeen, Aberdeen, UK Dr Adrian Harnett Consultant in Clinical Oncology, Beatson Oncology Center, Western In \201rmary, Glasgow, UK Dr Mark Harrison Consultant Oncologist, Mount Vernon Cancer Center, Middlesex, UK Professor G. Hawksworth Department of Medicine and Therapeutics, University of Aberdeen, Ab erdeen, UK Professor Alan Horwich Head of Clinical Laboratories, Royal Marsden NHS Trust, Institute for Cancer Research, Sutton, Surrey, UK Dr Grahame Howard Honorary Senior Lecturer, Directorate of Clinical Oncology and Hematology, Western General Hospital, Edinburgh, UK Dr Robin Hunter Christie Hospital, National Health Service Trust, Manchester, UK Dr N. D. James Institute for Cancer Studies, Birmingham University, Birmingham, UK Dr Roger James Kent Cancer Center, Maidstone, Kent, UK Dr Anthony Jeliffe 152 Harley Street , London, UK Dr Jonathan Joffee Macmillan Consultant in Medical Oncology, Greenlea Oncology Unit, Hudders \201eld Royal In \201rmary, Hudders \201eld, UK Lucie Jones Department of Oncology, University of Birmingham, Birmingham, UK Dr Ian Judson Reader in Clinical Pharmacology, Royal Marsden NHS Trust, Institute for Cance r Research, Sutton, Surrey, UK Dr Nicol Keith CRC Department of Medical Oncology, Beatson Oncology Center, Western In \201rmary, Glasgow, UK Professor David Kerr Professor of Clinical Oncology, CRC Institute for Cancer Studies, Univ ersity of Birmingham, Birmingham, UK Professor Henry Kitchener Academic Unit of Obstetrics, Gynecology & Reproductive Health, St Mary \200\231s Hospital, Manchester, UK Dr Robin Leake Division of Biochemistry and Molecular Biology, University of Glasgow, Glasgow, UK OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page xii LIST OF CONTRIBUTORS xii Dr Mike Lind The University of Hull School of Medicine, Academic Department of Oncology, Princess Royal Hospital, Hull, UK Professor Julian Little Department of Epidemiology, Aberdeen University, Aberdeen, UK Professor Valerie Lund Professor Rhinology, University College London Medical School and Ro yal National ENT Hospital, London, UK Dr Fergus Macbeth Clinical Effectiveness Support Unit, University Hospital of Wales and Lla ndough Hospital NHS Trust, Penarth, UK Dr A. McDonald Aberdeen Royal In \201rmary, Aberdeen, UK Dr D. Machin MRC Cancer Trials Of \201ce, Cambridge, UK Professor Rona MacKie Department of Dermatology, University of Glasgow, Glasgow, UK Professor J. MacVie Cancer Research Campaign, London, UK Mr Pietro E. Majno Department of S urgery, H pital Cantonal, Geneva, Switzerland Dr S. G. Martin University of Nottingham, CRC Department of Clinical Oncology, City Hospital, Nottingham, UK Dr Dynes McConnell Aberdeen Royal In \201rmary, Aberdeen, UK Dr John McLelland, Department of Radiotherapy, Aberdeen Royal In \201rmary, Aberdeen, UK Dr Howard McLeod Washington University, St Louis, USA Dr Stuart McNee Radiotherapy Physics Department, Beatson Oncology Center, Western In \201rmary, Glasgow, UK Professor W. R. Miller Professor of Experimental Oncology, Edinburgh Breast Unit Research G roup, The University of Edinburgh, The Paderewski Building, Western General Hospital, Edinb urgh, UK Dr Christopher Mitchell The John Radcliffe Hospital, Oxford, UK Dr Nicole Moreland London, UK Dr Graeme Murray Department of Pathology, University of Aberdeen, Aberdeen, UK Professor J. P. Neoptolemos Department of Surgery, Royal Liverpool University Hospital, Liverpool, UK Dr Don Newling Academisch Ziekenhuis, Vrije Universiteit, The Netherlands Dr M. C. Nicolson Aberdeen Royal In \201rmary, Aberdeen, UK Professor John Northover Consu ltant Surgeon, St Mark \200\231s Hospital, Harrow, Middlesex, London, UK OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page xiii LIST OF CONTRIBUTORS xiii Professor P. J. O \200\231Dwyer Department of Surgery, Western In \201rmary, Glasgow, UK Dr. K. Oberg Department of Internal Medicine, University Hospital, Uppsala, Sweden Professor Jan Olofsson Department of Otolaryngology, University of Bergen, Haukeland University Hospital, Bergen, Norway Dr. Daniel Palmer Department of Oncology, University of Birmingham, Birmingham UK Dr H. Pandha Department of Cellular and Molecular Sciences, Division of Oncology, St George \200\231s Hospital Medical School, London, UK M. K. B. Parmar Cancer Division, MRC Clinical Trials Unit, Cambridge, UK Professor Pauwels Department of Diagnostic Radiology, Leiden University Hospital, Leiden, Netherlands Dr Martine Piccart Head, Chemotherapy Uni, Institute Jules Bordet, Brussels, Belgium Professor Ross Pinkerton CRC Professor of Pediatric Oncology, Children \200\231s Department , Institute of Cancer Research and The Royal Marsden Hospital, Sutton, Surrey, UK Dr P. N. Plowman Radiotherapy and Clinical Oncology Department, St Bartholomew \200\231s Ho spital, London, UK Professor B. Ponder Department of Oncology, University of Cambridge, Cambridge, UK Dr Graeme Poston Consultant Surgical Oncologist, The Royal Liverpool University Hospitals, Liverpool, UK Professor Allan Price Western General Hospital, Edinburgh, UK Dr Pat Price Cancer Center, H ammersmith Hospital, London, UK; Reader in Clinical Oncology, Head of Cancer Therapeutics, Imperial College School of Medici ne, London, UK Dr Roy Rampling Reader and Honorary Consultant in Clinical Oncology, University of Glasgow, Glasgow, UK; Neuro-oncology unit, Beatson Oncology Center, Western In \201rmary, Glasgow, UK Dr A. T. Redpath Head of Radiotherapy Physics, Radiatio n Physics Department, Western General Hospital, Edinburgh, UK Dr N. S. Reed Consultant Clinical Oncologist, Beatson Oncology Center, Western In \201rmary, Glasgow, UK Professor F Rilke Instituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy Dr J. Trevor Roberts Consultant Clinical Oncologist and Clinical Director, Northern Center for Cancer Treatment, Newcastle General Hospital, Newcastle-upon-Tyne OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page xiv LIST OF CONTRIBUTORS xiv Professor Mikael Rorth Department of Oncology, Rigshospitalet, Blegdamsvejq, National University Hospital, Copenhagen, Denmark Dr Paul Ross Royal Marsden NHS Trust, Institute for Cancer Research, Sutton, Surrey, UK Dr G. J. S Rustin Director of Medical Oncology, Center for Cancer Treatment, Mount Vernon H ospital, Northwood, Middlesex, UK Professor M. I. Saunders Consultant, Center for Cancer Tr eatment, Mount Vernon Hospital, Northwood, Middlesex, UK Dr. Schoe \201eld Reader in Surgery, University Hospital Nottingham, Nottingham, UK Dr Michael Seckl Senior Lecturer, Department of Medical Oncology, Imperial College, London, UK; Trophoblastic Tumor Screening and Treatment Center, Department of Cancer Medicine, Charing Cross Hospital, London, UK Dr Matt Seymour ICRF Cancer Medical Research Unit, University of Leeds, Leeds, UK Dr Duncan Shaw Professor in Genetics, Department of Molecular and Cell Biology, University of Aberdeen Professor Karol Sikora Imperial College School of Medicine, London, UK Dr C. R. J. Singer Department of Hematology, Royal United Hospital, Bath Dr Ian Smith Head of Section of Medicine, Royal Marsden Hospital, Sutton, Surrey, UK Professor John Smyth Department of Oncology, Western General Hospital, Edinburgh, UK Dr Margaret Spittle Clinical Consultant Oncologist, Meyerstein Institute of Oncology, Middlesex Hospital, London Dr Davis Spooner Department of Oncology, Queen Elizabeth Hospital, Birmingham Karen Steadman Senior Registrar in Palliative Medicine, Countess Mountbatten House, Southampton Professor Gordon Steel Radiotherapy Research Unit, Institute of Cancer Research, Sutton, Surrey, UK Professor R. J. C. Steele Professor of Surgical Oncology, University of Dundee; Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, Dundee, UK Dr David Stevenson Department of Medical Genetics, Aberdeen University, Aberdeen, UK Professor W. P. Steward Professor of Oncology, University Department of Oncology, Leicester Royal In \201rmary, Leicester, UK OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page xv LIST OF CONTRIBUTORS xv Dr D. J. Sugarbaker Associate Professor of Surgery, Brigham and Women \200\231s Hospital, Harvard Medical School, USA Dr John Sweetenham University of Southampton, Southampton, UK Dr Paul Symonds Department of Oncology, Leicester Royal In \201rmary, Leicester, UK Professor Kostas Syrigos Head, Oncology Unit, Athens Medical School, Athens, Greece Professor Nick Thatcher Department of Medical Oncology, Christie Hospital, Manchester, UK Dr Eoin Tiernan Tor-na-dee Hospital, Aberdeen, UK Dr Chris Twelves Senior Lecturer in Medic al Oncology, CRC Department, Beatson Oncology Center, Western In \201rmary, Glasgow R. Valkema Department of Diagnostic Radiology, Leiden University Hospital, Leiden, Netherlands Professor A. J. van der Kogel Professor of Clinical Radiobiology, Institute of Radiotherapy , University Hospital Niymegen, The Netherlands Professor Veronesi Scienti \201c Director, Instituto Europeo di Oncologia, Milan, Italy Dr Jaap Verweij Rotterdam Cancer Institute (Daniel den hoed Kliniek), University Hospital, Rotterdam, The Netherlands Professor Jamie Weir Consultant Radiologist, Academic Department of Radiology, Aberdeen Royal In \201rmary, Aberdeen, UK Professor John Welsh Department of Palliative Medicine, Beatson Oncology Center, Western In \201rmary, Glasgow, UK Dr Tom Wheldon Department of Radiation Oncology, Cancer Research UK Beatson Laboratories, Glasgow, UK Mr S. J. Wigmore Department of Surgery, University of Edinburgh, Edinburgh, UK Professor P. Workman Center Director, CRC Center for Cancer Therapeutics, Institute of Canc er Research, Sutton, Surrey, UK Dr P. Wou CRC Department of Clinical Oncology, City Hospita l, Nottingham, UK OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page xvi This page intentionally left blank OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page xvii Abbreviations CH2-FH4 dUMP dTTP 10-CHO-FH4 10-formyl-tetrahydrofolate FudR DHPD FdUMP PALA HGPRT PRPP CDH P 5-10-methylene-tetrahydrofolate 2 \200 -deoxyuridine-5 \200 monophosphate 2 \200 -deoxythy midine-5 \200 monophosphate 5- \202uoro-2-deoxyuridine dihydropyrimidine dehydrogenase 5- \202uoro-2-deoxyuridine-5-m onophosphate N-(phosphonacetyl)-L-aspartate hypoxanthine-guanine phosphoribosyltransferase 5-phosphoribosylpyrophsophate 5-chloro-2, 4-dihydroxypyridine OHO-Prelims (i-xviii) 11/16/02 11:05 AM Page xviii This page intentionally left blank OHO-01(1-2) 11/16/02 11:06 AM Page 1 Part 1 Background 1 Multidisciplinary approach to cancer 2 2 Epidemiology of cancer 3 3 Biology of cancer 11 4 Pathology of cancer 37 5 Etiology of cancer 49 6 Staging of cancer 63 OHO-01(1-2) 11/16/02 11:06 AM Page 2 Chapter 1 Multidisciplinary approach to cancer Management of cancer involves a number of clinical disciplines. A straightforward presentat ion of a cancer can (and should) draw on these and other health care professionals. With the development of more effective additional therapies for cancer (radiotherapy, chemo therapy), the management of cancer has become increasingly complex. No single clinician has all the skills needed to treat all cancers. This has led to the development of multidiscip linary teams that deal with certain types of cancer. Many professions allied to medi- cine have major roles to play in these teams (e.g. physiotherapists, stoma nurses, counselors). The team may include individuals who are not directly involved in the treatment at presenta tion but have adjunctive roles at some stage in the course of the illness (e.g. palliative care). The composition of the team will vary considerably between institutions \200\224 and disease states. There must be a suf \201cient range of expertise to allow for informed di scussion of the management policy for individual patients. The team \200\231s various roles include: (cid:2) To plan diagnostic and staging procedures, primary treatment approach, an d any adjuvant therapy to be delivered pre- or post- operatively. (cid:2) To prepare patients physically and psychologically for anti-cancer therapy and subsequent follow-up. (cid:2) To provide information on treatment, prognosis, side-effects, and any other pertinent matters (e.g. stoma care). (cid:2) To ef \201ciently plan and deliver surgery, radiotherapy, and chemotherapy as appropriate. (cid:2) To aid rehabilitation from the illness. (cid:2) To provide appropriate follow-up ca re. (cid:2) To ensure the transition from curative to palliative care is appro- priately managed. Management within such a team structure results in better out- comes for patients. Studies demonstrate survival advantages but, equally importantly, patients also h ave functional, psychological, cosmetic, and quality of life bene \201ts. OHO-02(3-10) 11/16/02 11:06 AM Page 3 Chapter 2 Epidemiology of cancer Genetic factors 4 Environmental factors 4 Smoking 4 Alcohol 5 Diet 5 Infections 6 Solar exp osure 7 Other exposures 7 OHO-02(3-10) 11/16/02 11:06 AM Page 4 EPIDEMIOLOGY OF CANCER 4 Approximately 7.8 million cases of cancer were diagnosed worldwide in 1990. The number of n ew cases doubled between 1970 and 2001. Factors involved in the causation of cancer include the following. Genetic factors The majority of recognized carcinogens cause genetic mutations. Changes in gene expression in somatic cells, mostly due to mutation, are thought to be the basis for malignant transfo rmation; there may be one or more, rare, dominantly inherited susceptibilities to every typ e of cancer. The contribution made by these highly penetrant, domi- nant susceptibilities t o the total incidence of cancer has been estimat- ed at 2 \200\2235% of fatal cancers. Gene tic variation in susceptibility to cancer may also arise because of genetic polymorphism af fecting the absorption, transportation, metabolic activation, or detoxi \201cation of envi - ronmental carcinogens. A number of studies have suggested an inter- action between some g enetic polymorphisms and environmental carcinogens. Environmental factors The incidence of many types of cancer varies greatly between geo- graphical areas. There ar e changes of rates following migration between areas of contrasting incidence, changes in i ncidence over time, and variation within populations according to socio-economic status. Th us environmental factors appear to have a major role in the etiology of most types of cance r, accounting for over 80% of human cancer. Identi \201cation of the precise causes depend s on multi- disciplinary research, with analytical epidemiological studies an essential com ponent. Based on evidence from analytical studies, a number of estimates of the proportion of cancer attributable to speci \201c exposures have been made1,2. Smoking Tobacco smoking is the largest single avoidable cause of premature death and the most impor tant known carcinogen. Based on propor- OHO-02(3-10) 11/16/02 11:06 AM Page 5 ALCOHOL 5 tions of cancers of lung, larynx, oral cavity and pharynx, esophagus, pancreas, kidney, and bladder due to smoking, 15% (1.1 million new cases per year) of all cancer cases worldwide are attributed to smoking (25% of cases worldwide in men, 4% in women). Recent cohort studies show that smoking for 30 years or more increases the risk of colon ca ncer, with about 25% of cases being attributable to smoking. In addition, passive smoking m ay account for a small proportion of the cancer burden. In men from developed countries, th e tobacco burden has been estimated as 32% of all annu- al incident cases, whereas in those from developing countries, it has been estimated as 19%. In regions where men have smoked for several decades, 30 \200\22340% of all cancers are attributable to tobacco. In women fr om developed countries, 6% of all annual incident cases are accounted for by tobacco, in co ntrast with 2% in those from develop- ing countries. As a consequence of the massive rise in cigarette consumption over the last few decades in women and in developing countries, a substan- tial increase in the cancer burden is to be e xpected unless measures to control consumption are strengthened. Smoking cessation reduces the risk of cancer, but there has only been limited success in programs promoting cessation . Alcohol The main effect of alcohol is a joint effect with tobacco smoking in cancers of the oral ca vity, pharynx, larynx, and esophagus. Alcohol alone is implicated in cirrhosis (liver cance r) and may contribute to some cancers of the breast and large bowel. Diet High intake of vegetables and fruit show a consistent inverse relation- ship with cancer of the larynx, lung, esophagus, and stomach, and there is weaker evidence that this is the ca se also for cancer of the mouth and pharynx, pancreas, and cervix. High levels of vegetable consumption are associated with a reduced risk of colon cancer; high levels of meat consum ption appear to increase the risk of colon can- cer. Obesity in adult life is considered to be the main factor in endo- metrial cancer, probably increases the risk of post-menopausal breast cancer, and is associated with cancer of the kidney. Regular physical OHO-02(3-10) 11/16/02 11:06 AM Page 6 EPIDEMIOLOGY OF CANCER 6 activity is consistently associated with a reduced risk of colon cancer. Low levels of consumption of fruit and vegetables, high levels of meat consumption, obesity , and lack of regular physical activity tend to be aspects of a lifestyle more typical of d eveloped than of developing countries. In developing countries it has been estimated that 33 \200\22350% of nasopharyngeal cancer cases could be prevented by avoiding regular consumption of salt \201sh. Generalized diet ary de \201ciencies are associ- ated with increased risk of oesophageal cancer in areas of high inci- dence in developing countries. In randomized controlled trials in Linxian, Chin a, a combination of carotene, tocopherol, and sele- nium reduced mortality from cancer of a ll types and mortality from stomach cancer in particular3. Contamination of foods with a \202atoxins increases the risk of hepatocellular cancer; halving the median daily intake of a \202atoxin might reduce its incidence by 40% in Africa and Asia. Infections 16% of the worldwide incidence of cancer is due to infection. For developed countries, the proportion is 9%, and for developing coun- tries, 21%. Human papillomavirus (HPV) of any ty pe accounts for 82% of cervical cancers in developed countries and 91% in developing countr ies. The human papillomaviruses occur in 70 different types. The strongest evidence for car cinogeneity is for HPV types 16 and 18. 81% of cases of liver cancer are attributable to ch ronic infection with hepatitis B or hepatitis C. Strong evidence supports a causal relationship between chronic infec- tion with the bacteri um Helicobacter pylori and the development of gas- tric adenocarcinoma, and there is some e vidence for gastric lymphoma. 60% of cases of gastric cancer in developed countries, and 53 % in devel- oping countries, may be attributable to Helicobacter pylori. Epstein \200\223Barr virus may account for up to 60% of Hodgkin \200\231s disease in develo ped countries, and 80% in developing countries. The virus accounts for over 90% of cases of Burkitt \200\231s lymphoma in sub-Saharan Africa, just over 80% in north Africa and the Mi ddle East, just under 50% in Latin America and the Caribbean, and less than a fourth of cas es elsewhere. There is greater uncertainty about the role of the virus in other types of no n-Hodgkin \200\231s lymphoma and nasopharyngeal carcinoma. Other infections considered to be carcinogenic include: (cid:2) Schistosomiasis haematobium and bladder cancer (attributable pro- portion in develo ping countries 8%, in developed countries 0%). OHO-02(3-10) 11/16/02 11:06 AM Page 7 OTHER EXPOSURES 7 (cid:2) Human T-cell lymphotrophic virus and acute T-cell leukemia/ lymphoma (attributable proportion worldwide 1%). (cid:2) HIV and Kaposi \200\231s sarcoma. (cid:2) HIV and non-Hodgkin \200\231s lymphomas. (cid:2) Opisthorchis viverrini and Clonorchis sinenis and cholangio- carcinoma. Solar exposure The 1996 Harvard Report on Cancer Prevention concluded that over 90% of malignant melanoma is attributable to solar radiation. Malignant melanoma accounted for just over 1% of the wo rld cancer burden in 1985. Uncertainties remain, even though it is widely assumed that expo sure to solar radiation also accounts for the great majority of cases of basal cell and squ amous cell carcinoma. Other exposures Other exposures account for 5% or less of the cancer burden. Occupational exposures have be en linked with lung, bladder, and haematopoietic malignancies. Breast cancer has consistent ly been associated with early age at menarche, late age at \201rst birth, and late age at menopause with relative risks of the order of 2.0 or less. Parity is associated inversely with endometrial and ovarian cancer. Although most types of cancer are more common in urban than in rural areas, few causal link s with environmental pollutants have been \201rmly established. It has been estimated tha t 1% of lung cancer deaths in the US are attributable to air pollution. While exposure to i onizing radiation at doses of 500 \200\2232000 mSv is known to be carcinogenic, exposures o f this magnitude are unusual \200\224about 1% of the deaths of the Japanese atomic bomb sur vivors could be attributed to radiation. The average per capita dose from all sources of io nizing radiation is about 3.4 mSv per year, of which about 88% is from natural sources and the remainder primarily from medical exposures. Extrapolation from data on people exposed t o doses of 500 mSv or more suggests that 1 \200\2233% of all cancers might be attributable to radiation arising largely from natural sources. No clear association with exposure to ex tremely low frequency magnetic \201elds has been established. O H O Table 2.1 Estimates of the proportion of cancer attributable to speci \201c exposures 0 2 Exposure Estimates (%) ( 3 USA Best estimate USA Nordic countries Men Women Worldwide 1 0 Range ) Tobacco Passive smoking Alcohol consumption Diet Obesity Food additives Sedentary lifestyle Infections Sexual behavior Occupation Perinatal factors/growth Reproductive factors Enviro nmental pollution Industrial products Man-made ionizing radiation Random Solar and ultravio let radiation Medicines and procedures Socio-economic status Geographical factors Family hi story of cancer 30 (25 \200\22340) 15 30 19 <1 2 ? <1 9 <1 2 ? 1 1 1 3 35 <1 (2 \200\2234) (10 \200\22370) ( \200\2235a \200\2232) 3 30 / 1 6 / 30 \200\22340 0 1 5 5 2 1 2b 3b 16 10 1 4 (1 \200\223?) (1) (2 \200\2238) 1 : 0 5 5 3 2 3 <1 6 A 6 2 <1 (0 \200\22312) (1 \200\2235) (<1 \200\2232) M P a g 2 <1 4 2 <1 5 e 2 8 (0.5 \200\2233) 1 3 5 1 1 3 (2 \200\2234) a Allows for protective effect of preservatives b Infection with human papillomavirus or He licobacter pylori ? No precise data available OHO-02(3-10) 11/16/02 11:06 AM Page 9 OTHER EXPOSURES 9 Some pharmaceutical agents (e.g. immunosuppressive agents, anti-neoplastic drugs, and hormo nal preparations) are human carcinogens. 1 Doll, R. and Peto, R. (1981) The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. Journal of the National Cancer Institute 66, 1191 \200\223308. 2 Parkin, D.M., Pisani, P., Lopez, A.D., and Masuyer, E. (1994) At least one in seven cases of cancer is caused by smoking. Global estimates for 1985. International Journal of Cancer 59, 494 \200\223504. 3 Blot, W.J., Li, J.Y., Taylor, P.R., Guo, W., Dawsey, S., Wang, G.Q., et al. (1993) Nutrit ion intervention trials in Linxian, China: supplementation with speci \201c vitamin/minera l combinations, cancer incidence, and disease-speci \201c mortality in the general populat ion. Journal of the National Cancer Institute 85, 1483 \200\22392. OHO-02(3-10) 11/16/02 11:06 AM Page 10 This page intentionally left blank OHO-03(11-36) 11/16/02 10:44 AM Page 11 Chapter 3 Biology of cancer The role of genetics 13 Molecular biology techniques 15 Cell cycle and its regulation 21 Gr owth of cancer 25 Oncogenes and tumor suppressor genes 27 Cytogenetics and cancer 32 OHO-03(11-36) 11/16/02 10:44 AM Page 12 BIOLOGY OF CANCER 12 Molecular biology is an approach to understanding how organisms work by studying the molecu les \200\224in particular nucleic acids that encode genetic information and proteins that p rocess this informa- tion and carry out activities in cells. It is grounded in other scient i \201c \201elds, particularly biochemistry, chemistry, microbiology, genetics, and math /computer science. Molecular biology is a development of biochemistry, with less emphasis on the chemistry of biological molecules and more on how they function within cells and organisms. To study thi s, convenient biological systems are needed and microbiology plays a crucial role. Yeast an d bacteria are often used in experiments because they are simple, cheap, and ethically acce ptable. In cancer, there are two excellent recent examples of this: (cid:2) Understanding o f the cell cycle (work with yeast). (cid:2) Repair of damaged DNA (using the bacterium Esch erichia coli). Although humans and micro-organisms are a long way apart in evo- lutionary terms, their fun damental cellular processes are remarkably similar. OHO-03(11-36) 11/16/02 10:44 AM Page 13 THE ROLE OF GENETICS 13 The role of genetics Molecular biology relies heavily on genetics; traditionally many inter- esting properties o f organisms have been studied via their inheritance, so identifying the genes responsible. Once the genes are found, how they work can be investigated using molecular biology. In hum an genetics, much emphasis has been on what goes wrong \200\224i.e. the genetics of inherit ed disease. The full implications of this for cancer are now becoming clear, since most of these diseases carry a genetic predisposition of some kind. If these predisposing genes are identi \201ed, we have a new handle on some crucial aspects of the disease process; recen tly several cancer susceptibility genes have been isolated. The Human Genome Project (a mul ti-laboratory collaboration to identify the DNA sequence of all the genes in an organism) i s now complete; the task of identifying genes will become routine. Linking these genes with certainty to the risk of diseases such as cancer is still problematic: there are many othe r factors involved (e.g. environmental). The Human Genome Project has shown the DNA sequence for 30 000 genes. Most are novel with n o resemblance to a gene of known function. The amino-acid sequence of the protein product i s pre- dictable, but current methods do not lead to a prediction of the three- dimensional structure of the protein. Once possible, there will still be great dif \201culties in de \201ning the role of novel gene products in the organism \200\231s biology. Applications to health care (cid:2) Using genetically engineered vaccines, therapeutic proteins and hormones, antibodie s, etc. \200\224essentially existing therapies with improved products. Identifying new drug targets and therapeutic strategies. These will come from research into identi \201cation of genetic factors in disease and the development of methods for relating protein sequence (deduced from the DNA sequence) to the function of the protein and its role in pathology. (cid:2) (cid:2) Developing DNA (or derivatives) as drugs i.e. gene therapy. There have been promisi ng preliminary results with diseases such as cystic \201brosis, but there is still a long way to go before this becomes a general therapeutic method. The question of individual ris k modi \201cation according to genotype and attendant issues of privacy, right to know, co nsequences for those with a \201nancial stake in the individual \200\231s health, are imp ortant. Because genetic risk OHO-03(11-36) 11/16/02 10:44 AM Page 14 BIOLOGY OF CANCER 14 factors are already being identi \201ed, these are pressing issues which can only be resol ved by full and informed debate between the public, lawmakers, scientists, and clinicians. OHO-03(11-36) 11/16/02 10:44 AM Page 15 MOLECULAR BIOLOGY TECHNIQUES 15 Molecular biology techniques Scienti \201c advances All cancers arise as a result of changes in genes that regulate cel l growth and behavior; DNA research now offers the greatest potential for the development o f new cancer diagnostics and therapies. Molecular medicine is thus concerned with turning g enes into new therapeutic targets. Developing and applying molecular technologies is the ke y to a new understanding of cancer. Molecular techniques comprise two groups: lysate and analysis and in situ analysis. (cid:2) With lysate methods, tumor biopsies are homogenized and spatial r elationships between tumor cells are destroyed (Southern blot analysis and PCR). This leads to loss of information on hetero- geneity and small subpopulations and an averaging of cha nges. However, quantitation can be simpler and more accurate than in situ approaches. In si tu techniques such as \202uorescence in situ hybridization (FISH) allow the genetic make- up of individual cells within their histological context to be visualized. (cid:2) Genetic analysis Southern blot analysis Loss of genetic material from cancer cells is a classic marker for t