Colorectal Cancer (2006)

Colorectal Cancer �� Edited by

Jim Cassidy

University of Glasgow Scotland, U.K.

Patrick Johnston Queen's University Belfast Belfast, Northern Ireland, U.K.

Eric Van Cutsem

University Hospital Gasthuisberg Leuven, Belgium

New York London

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Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016 © 2007 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid‑free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number‑10: 0‑8247‑2835‑1 (Hardcover) International Standard Book Number‑13: 978‑0‑8247‑2835‑9 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright. com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978‑750‑8400. CCC is a not‑for‑profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging‑in‑Publication Data Colorecal cancer / edited by Jim Cassidy, Patrick Johnston, Eric Van Cutsem. p. ; cm. Includes bibliographical references and index. ISBN‑13: 978‑0‑8247‑2835‑9 (alk. paper) ISBN‑10: 0‑8247‑2835‑1 alk. paper) 1. Colon (Anatomy)‑‑Cancer. 2. Rectum‑‑Cancer. I. Cassidy, Jim, 1958‑ II. Johnston, Patrick G., MD. III. Cutsem, Eric van. [DNLM: 1. Colorectal Neoplasms. WI 529 C71903 2006] RC280.C6C652 2006 616.99’4347‑‑dc22

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Dedication

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I would like to dedicate this book to Sandi. Jim Cassidy

Preface

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Colorectal cancer is a common disease in all developed nations of the World. Until about 10 to 15 years ago, it was largely a surgical disease, with chemotherapy or radiotherapy having little impact on survival. Few oncologists even treated the disease, and even fewer would admit to specialist interest in a disease that was considered ‘‘refractory.’’ We also had more knowledge of the underlying molecular events in this disease than in most other solid cancers of adults, but this had not been translated into any meaningful clinical interventions. However, the last two decades have seen advances in chemotherapy, radiotherapy, and use of molecular targeted agents that we could not have dreamed of 20 years ago. In the same timescale, we have made further and important advances in our knowledge and understanding of the genetics, molecular biology, and pathophysiology of this condition. This knowledge has been the driver for some of the clinical advances and promises to be important in the next generation of drugs that we hope will further improve outcomes. For example, it is not unreasonable to hypothesize that the prospect of chemopreventive agents for this disease can be realized within this generation. Our rapidly expanding knowledge base and the therapeutic advances based on it mean it is hard to keep up-to-date. This applies to both scientists trying to update therapy paradigms and clinicians trying to keep abreast of the molecular aspects. This book was designed to address these issues in a way that was accessible to the specialist as well as the generalist. This is important because some of the advances in colorectal cancer should be v

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applicable to other common malignancies that are currently regarded as ‘‘refractory.’’ The editorial team is currently based entirely in Europe, but all of us have the experience of practice in other nations and have been intimately involved in international research projects and clinical studies. We felt the time was ripe to produce a textbook that would update all aspects of our understanding in one publication. Thus, the goal was to produce a book that we would all like to own which would equip us enough to have informed discussion and conversation with experts within our own areas of expertise. This will be the key to making the molecular information that we are gaining at a frightening rate translate into clinical advances. We have collated contributions from world-class clinical and basic scientists in this book. Each was handpicked to represent their own disciplines and for their ability to describe complex issues in an understandable way. Each was tasked with producing text that was as comprehensive and up-to-date as possible in a rapidly moving field. There was a deliberate effort made to ‘‘globalize’’ the content of this book in order to maintain its relevance throughout a broad-based readership. The scope of the book encompasses risk factors, epidemiology, molecular pathogenesis, surgery, radiotherapy, chemotherapy, and even aspects of palliative care related to colorectal cancer. This text should serve as a useful and comprehensive reference for all who have an interest in colorectal cancer. In addition, it is designed so that the non-specialist can pick it up and access the topics that were of most interest to them without feeling overwhelmed. We thank our fellow editors and all the contributors for their diligence and help in the production of this book. Jim Cassidy Patrick Johnston Eric Van Cutsem

Contents

Preface . . . . v Contributors . . . . xiii 1. Genetic Susceptibility to Colorectal Cancer . . . . . . . . . . . . 1 Rebecca A. Barnetson and Malcolm G. Dunlop Introduction . . . . 1 Autosomal Dominant Disorders . . . . 2 Familial Adenomatous Polyposis . . . . 15 Other Defined Dominant Colorectal Cancer Susceptibility Syndromes . . . . 20 Autosomal Recessive Disorders . . . . 21 Low Penetrance Variants . . . . 24 Conclusions . . . . 30 References . . . . 31 2. Epidemiology of Colorectal Cancer . . . . . . . . . . . . . . . . . Julian Little and Linda Sharp Introduction . . . . 43 Descriptive Epidemiology of Colorectal Cancer . . . . 43 Groups at Increased Risk of Colorectal Cancer . . . . 46 Risk Factors for Colorectal Neoplasia . . . . 47 Conclusion . . . . 59 References . . . . 60 vii

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3. Colorectal Cancer Screening . . . . . . . . . . . . . . . . . . . . . . Robert J. C. Steele Introduction . . . . 77 Principles of Screening . . . . 78 Colorectal Cancer as a Suitable Target for Screening . . . . 80 Fecal Occult Blood Screening . . . . 82 Flexible Sigmoidoscopy . . . . 85 Colonoscopy . . . . 86 Radiology . . . . 88 Comparative Studies . . . . 88 Harm Caused by Screening . . . . 89 Economics of Screening . . . . 91 Novel Approaches to Screening . . . . 93 Conclusions . . . . 97 References . . . . 97 4. Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Christian Wittekind Introduction . . . . 103 Definition . . . . 103 Site Distribution . . . . 104 Gross Morphology . . . . 104 Histomorphology . . . . 105 Special Clinical Types of Colorectal Cancer . . . . 107 Classification of Anatomical Extent Before Treatment . . . . 110 Classification of Anatomical Extent After Treatment . . . . 113 Histological Grading of Tumor Regression . . . . 114 Prognostic Factors . . . . 114 The Histopathological Report . . . . 114 Quality Management Within Pathology Departments . . . . 116 Pathology Findings in Resection Specimens Indicative of Oncological Quality of Surgery . . . . 116 Quality Assurance of Clinical Trials on Adjuvant and Neoadjuvant Therapy: The Surgical Pathologist’s Point of View . . . . 119 Malignant Tumors Other than Carcinomas . . . . 120 References . . . . 121

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5. Familial Cancer Management . . . . . . . . . . . . . . . . . . . . Sabine Tejpar Introduction . . . . 125 Main Hereditary Colorectal Cancer Syndromes . . . . 127 Peutz–Jeghers Syndrome . . . . 139 Juvenile Polyposis . . . . 141 Cowden Syndrome or PTEN Hamartoma Syndrome . . . . 143 Familial Gastric Cancer . . . . 144 Familial Pancreatic Cancer . . . . 144 Hereditary Mixed Polyposis . . . . 144 Familial Colorectal Cancer . . . . 145 Aspects of Genetic Testing for GI Cancer Susceptibility . . . . 146 References . . . . 148 6. The Surgical Principles of Managing Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ian R. Daniels and Richard J. Heald Introduction . . . . 151 The ‘‘Embryological Approach’’ to Rectal Cancer . . . . 152 The Multidisciplinary Approach . . . . 152 The Principles of Rectal Cancer Excision: Total Mesorectal Excision . . . . 152 Recurrence and Survival . . . . 156 Applying the Principles of Total Mesorectal Excision to Colonic Cancer . . . . 158 Conclusion . . . . 159 References . . . . 159 7. Adjuvant Therapy for Colorectal Cancer . . . . . . . . . . . . Geoff Chong and David Cunningham Introduction . . . . 163 Adjuvant Therapy for Stage III Colorectal Cancer . . . . 164 Adjuvant Therapy for Stage II Colorectal Cancer . . . . 173 Newer Agents for Adjuvant Therapy . . . . 176 Prognostic Factors and Adjuvant Therapy . . . . 183

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Recommendations for Adjuvant Therapy . . . . 185 Conclusions . . . . 186 References . . . . 187 8. The Role of Radiotherapy in the Treatment of Rectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rob Glynne-Jones and Rob Hughes Background . . . . 195 Indications for Adjuvant Radiotherapy . . . . 197 Risk Factors for Local Recurrence . . . . 198 The Evidence Base for Adjuvant Radiotherapy in Resectable Rectal Cancer . . . . 201 The Rationale for Short Course Preoperative Radiotherapy . . . . 203 Short Course Preoperative Radiotherapy vs. Surgery Alone or Postoperative Radiotherapy . . . . 204 More Recent Trials Performed with Chemoradiation . . . . 205 Fixed/Unresectable Rectal Cancer . . . . 208 Intraoperative Radiotherapy . . . . 209 Early Rectal Cancer . . . . 209 Pretreatment Clinical Assessment . . . . 211 Radiotherapy Planning Techniques . . . . 212 Acute Toxicity and Supportive Care During Radiotherapy . . . . 214 Timing of Surgery Following Preoperative Radiotherapy . . . . 215 Surgical Complications . . . . 216 Late Effects . . . . 216 Conclusion . . . . 217 References . . . . 219 9. The Treatment of Metastatic Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eric Van Cutsem and Leonard Saltz Introduction . . . . 229 Cytotoxic Agents in Metastatic CRC . . . . 230

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Targeted Therapies for Metastatic CRC . . . . 236 References . . . . 244 10. Hepatic Directed Therapy . . . . . . . . . . . . . . . . . . . . . . Gregory D. Leonard and Nancy E. Kemeny Introduction . . . . 253 Hepatic Arterial Infusion Chemotherapy . . . . 254 Portal Vein Infusion Chemotherapy . . . . 271 Isolated Hepatic Perfusion Chemotherapy . . . . 272 Conclusion . . . . 274 References . . . . 275

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11. Pharmacogenomics of Colorectal Cancer . . . . . . . . . . . . 287 Patrick Johnston, Wendy L. Allen, and Howard L. McLeod Introduction . . . . 287 Loss of Heterozygosity . . . . 288 Microsatellite Instability . . . . 289 TGFb II Mutation . . . . 290 5-Fluorouracil . . . . 291 Oxaliplatin . . . . 296 Irinotecan . . . . 298 Novel Therapies . . . . 299 Vascular Endothelial Growth Factor . . . . 301 New Technologies . . . . 302 Conclusions . . . . 306 References . . . . 306 12. Drug Development for Advanced Colorectal Cancer in the United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 Igor Puzanov and Mace L. Rothenberg Introduction . . . . 317 Development of 5-FU and 5-FU/LV as First-Line Chemotherapy . . . . 318 Development of Capecitabine as an Oral Alternative to 5-FU . . . . 319 Development of Irinotecan as Second-Line Therapy . . . . 320 Integration of Irinotecan into Front-Line Chemotherapy . . . . 321 Oxaliplatin: Initial Data on Front-Line Therapy . . . . 322

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Oxaliplatin: Demonstration of Second-Line Efficacy . . . . 323 N9741: Comparison of First-Line Combination Regimens . . . . 324 Bevacizumab . . . . 325 Cetuximab . . . . 327 Regulatory Considerations of the U.S. FDA in the Approval of New Drugs for Treatment of Advanced Colorectal Cancer . . . . 328 Endpoints for New Drug Approval for Colorectal Cancer in the United States . . . . 329 How Will New Drugs be Developed for Colorectal Cancer in the Future? . . . . 331 References . . . . 333 Index . . . . 337

Contributors

Wendy L. Allen Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, Northern Ireland, U.K. Rebecca A. Barnetson Colon Cancer Genetics Group, University of Edinburgh, School of Molecular and Clinical Medicine and MRC Human Genetics Unit, Western General Hospital, Edinburgh, U.K. Geoff Chong Department of Medicine, Royal Marsden Hospital, Sutton, Surrey, U.K. David Cunningham Department of Medicine, Royal Marsden Hospital, Sutton, Surrey, U.K. Ian R. Daniels Pelican Cancer Foundation, North Hampshire Hospital, Basingstoke, U.K. Malcolm G. Dunlop Colon Cancer Genetics Group, University of Edinburgh, School of Molecular and Clinical Medicine and MRC Human Genetics Unit, Western General Hospital, Edinburgh, U.K. Rob Glynne-Jones Mount Vernon Centre for Cancer Treatment, Northwood, Middlesex, U.K. Richard J. Heald Pelican Cancer Foundation, North Hampshire Hospital, Basingstoke, U.K.

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Rob Hughes Mount Vernon Centre for Cancer Treatment, Northwood, Middlesex, U.K. Patrick Johnston Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, Northern Ireland, U.K. Nancy E. Kemeny Department of Gastrointestinal Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, U.S.A. Gregory D. Leonard Department of Gastrointestinal Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, U.S.A. Julian Little Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada Howard L. McLeod Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, U.S.A. Igor Puzanov Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A. Mace L. Rothenberg Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A. Leonard Saltz Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, U.S.A. Linda Sharp National Cancer Registry, Cork, Ireland Robert J. C. Steele Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K. Sabine Tejpar Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium Eric Van Cutsem Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium Christian Wittekind Institut fu¨r Pathologie des Universita¨tsklinikums Leipzig, Leipzig, Germany

1 Genetic Susceptibility to Colorectal Cancer Rebecca A. Barnetson and Malcolm G. Dunlop Colon Cancer Genetics Group, University of Edinburgh, School of Molecular and Clinical Medicine and MRC Human Genetics Unit, Western General Hospital, Edinburgh, U.K.

INTRODUCTION Research into the genetic basis of cancer will undoubtedly lead to new understanding about disease etiology, not only shedding new light on disorders with a predominantly genetic contribution but also those where gene– environment interactions play a main role. Such understanding will also have important implications for instigating preventative measures, including environmental risk factor avoidance, chemoprevention and refining surveillance strategies, removal of premalignant lesions, and targeting prophylactic surgery. Finally, insight into the heritable genetic defects that cause cancer could lead to the design of novel anticancer agents, as well as inform understanding the response to chemotherapy and the mechanisms of drug resistance. Hence, there are substantial potential benefits that could result from the current substantial research endeavor in the genetics of colorectal cancer. Heritable genetic defects make a major contribution to the overall incidence of colorectal cancer. Many studies have shown aggregation of colorectal cancer in families (1) and there is even evidence to suggest that almost all colorectal neoplasia has a heritable component (2). However, familial aggregation does not, in itself, prove a genetic etiology because environmental risk 1

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factors exposure is also frequently shared within families. However, twin studies comparing the incidence of colorectal cancer in monozygous and dizygous twins provide powerful evidence of a causal genetic involvement. From such twin data, it has been estimated that 35% of all colorectal cancer is attributable to genetic susceptibility (3). Despite this evidence for a substantial genetic contribution, only around 3% of the 32,000 incident cases arising annually in the United Kingdom are due to dominant syndromes for which the susceptibility gene responsible has been identified. The remainder are due to mutations in, as yet, undiscovered dominant genes with moderate to low penetrance, to recessive genetic traits, and to complex polygenic traits and multifactorial inheritance. Over recent years there have been considerable advances in understanding of the genetic basis of colorectal cancer in particular. The identification of a number of causative genes and the classification of the associated phenotype has meant that case-finding approaches can be set in place and surveillance instigated for at-risk relatives. It is now becoming possible to use genetic information clinically for prognosis as well as to tailor treatment and prophylaxis interventions. Indeed in some cases, the cancer risk is so high that prophylactic colectomy is merited. Here, we discuss hereditary colorectal cancer disorders that have been characterized to date and the implications for clinical practice. We also discuss low-penetrance alleles that, collectively, are likely to contribute more to overall colorectal cancer incidence than the known dominant disorders. Table 1 is a summary of the contribution of known genes to colorectal cancer incidence.

AUTOSOMAL DOMINANT DISORDERS HNPCC or Lynch Syndrome Hereditary nonpolyposis colon cancer (HNPCC) was one of the first disorders to be recognized as a hereditary cancer syndrome. First described in the 1890s by Aldred Warthin, who reported a high incidence of cancer of the colon and female organs in a seamstress’s family (4), the disease was further characterized by Henry Lynch in 1962, who was consulted by a patient who had a strong family history of colorectal and endometrial cancer, as well as several other cancer types (5). Segregation studies of other families with a predisposition to colon cancer strongly suggested an autosomal dominant pattern of inheritance. Further studies refined the definition of HNPCC and showed it was characterized by early age of cancer onset, a tendency for a greater proportion of tumors to be located in the proximal colon than in sporadic cancer, as well as a high frequency of synchronous and metachronous carcinomas (6). A typical HNPCC family is shown in Figure 1. Synchronous tumors are present in 5% to 20% of cases and metachronous tumors arise in 20% to 50% of cases (7). Despite the nomenclature, HNPCC

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Table 1 Relative Genetic Contribution of Genes Known to Predispose to Colorectal Cancer Gene Familial adenomatous polyposis HNPCC Rare dominant polyposis syndromes Peutz–Jegher’s syndrome Juvenile polyposis Multiple adenoma phenotype Familial Low-penetrance alleles

Gene–environment interactions

APC MMR STK11/LKB1 SMAD4, BMPR1A, PTEN MYH E-Cadherin, TGF-bRII, ?15q EpHx, GSTM1, GSTT1, NAT, CCND1 MTHFR, CYP1A1, CYP1A1 APCI1307K, APC-E1317Q, Hras APC-D1822V/fat (protective) MTHFR-A226V/folate

Contribution 0.07% 2.8% 1000 polyps), and almost all patients with these mutations who initially received colectomy and IRA required rectal excision due to rectal remnant polyposis and cancer concerns (119). Although there are descriptive and comparative studies that have described past practice, it is fair to say that there are no robust data with which to guide future surgical practice. Hence, all of the correlations discussed earlier should be taken with caution because of the lack of prospective randomized studies. Such studies are highly unlikely because of the rarity of FAP and the need for studies that last 25 years or more of follow-up. Hence patient involvement is important, with an honest appraisal of available information such that an informed choice can be made. This is particularly important because there are issues about undertaking major colorectal surgery that may have a detrimental effect on bowel function and on fertility, not to mention complications associated with any intra-abdominal operation, such as adhesions and bowel obstruction. Indeed, there is even conflicting evidence as to the relative benefits in terms of bowel function between colectomy and IRA and proctocolectomy with ileoanal

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pouch in FAP. By one measure, significantly better outcomes have been observed following ileorectal anastomosis compared to ileoanal pouch, whereas the same study groups’ quality of life using the SF-36 form showed no difference between ileorectal and ileoanal pouch patients (120,121). Another concern about pelvic surgery centers around the possibility of decreased fertility. Proctectomy requires more extensive pelvic dissection, whereas colectomy and IRA may minimize damage to Fallopian tubes. A recent study of Scandinavian polyposis registers concluded that patients undergoing ileorectal anastomosis retained fecundity in line with the general population but ileoanal pouch reduced fertility, with a cumulative chance of pregnancy of 48% at one year and 61% at two years (122). In summary, surgical practice and prophylaxis in FAP is largely empirical and guided mainly by clinician preference to date. However, as the strength of observational data increases, some reasonably well-supported guidelines are now possible. However, it is essential that patients are fully informed about the possible detriments of surgery as well as the substantial benefits in cancer prevention that can be achieved. Turcot’s Syndrome The hallmarks of this disorder are the development of tumors of the central nervous system, particularly cerebellar medulloblastomas or glioblastomas, and multiple colorectal adenomas. This is a rarer variant of FAP because in the majority of cases, the underlying molecular defect is a germline mutation in the APC gene (114). However, mutations have also been identified in the DNA mismatch repair genes, MLH1 and PMS2. It is unclear as to whether the syndrome is dominantly or recessively inherited. Turcot’s syndrome is best not considered a distinct syndrome but part of both FAP and HNPCC syndromes, depending on the underlying genetic defect. OTHER DEFINED DOMINANT COLORECTAL CANCER SUSCEPTIBILITY SYNDROMES Peutz–Jeghers Syndrome Peutz–Jeghers syndrome is characterized by multiple gastrointestinal hamartomatous polyps, and mucocutaneous melanin deposits are found on the lips, perioral and buccal regions, hands, and feet in 95% of cases. This is a rare disorder with an incidence of 1 in 120,000 (123) and is associated with low penetrance. Affected individuals have about a 50% increased chance of developing gastrointestinal carcinomas or tumors of the pancreas, ovaries, testes, breast, and uterus (124–126). Germline mutations have been identified in the serine threonine kinase gene, STK11/LKB1 at 19p13.3 in 20% to 63% of patients with this disorder (127). Large bowel surveillance is recommended three times yearly for affected individuals from age 18 years (127A).

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Juvenile Polyposis Juvenile polyposis (JPS) is characterized by the development of multiple hamartomatous polyps throughout the gastrointestinal tract, usually when aged less than 10 years. Affected patients have a high risk of developing gastrointestinal cancer (128,129) that ranges from 9% to 68% and is probably around 50%. Because it is rare, there are no reliable estimates of the frequency of JPS in the general population, but around 1:50,000 is a reasonable estimate based on population registry data. It is associated with incomplete penetrance for both polyposis and also colorectal cancer, and less than 0.1% of all cases of colorectal cancer are attributable to JPS (129a). Unlike Peutz–Jeghers syndrome, JPS exhibits genetic heterogeneity, with mutations in at least three genes being responsible. The molecular basis of JPS in around 50% of cases is germline mutation of SMAD4 (130,131). SMAD4 is a tumor suppressor encoding a protein involved in the transforming growth factor-b (TGF-b) signaling pathway, which is involved in the regulation of cell proliferation and differentiation (132). Consistent with this, sporadic colorectal carcinomas are frequently found to have mutations in SMAD4 or LOH at this chromosome region (133). A second locus has been identified and germline nonsense mutations identified in the bone morphogenic protein receptor 1A gene (BMPR1A/ALK3) and, like SMAD4, this gene is also part of the TGF-b superfamily (134). There are a minority of JPS cases that are due to germline mutations in the protein phosphotase gene PTEN (135). PTEN is also mutated in patients with Cowden disease, which is also characterized by the presence of multiple gastrointestinal hamartomatous polyps as well as benign and malignant neoplasms of the thyroid, breast, uterus, and skin, but there is not an increased risk of colorectal cancer. Hence, there is a possibility of misclassification and that PTEN mutations are not associated with an excess colorectal cancer risk. Estimates of cancer risk have wide confidence intervals but are around 50% lifetime risk, and so surveillance is important. Consideration should also be given to prophylactic colectomy, much in the same way as in FAP (83). Large bowel surveillance for at-risk individuals is recommended one to two times yearly from the age of 15 to 18 years or even before if the patient has presented with symptoms. Screening intervals could be extended at age 35 years in at-risk individuals. However, documented gene carriers or affected cases should be kept under surveillance until the age of 70 years and prophylactic surgery discussed.

AUTOSOMAL RECESSIVE DISORDERS To date there is one recessive colorectal cancer susceptibility syndrome, but it seems likely that others remain to be discovered. Detecting such recessive alleles poses particular practical problems because of the lack of clear

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Figure 6 Pedigree showing recessive inheritance of colorectal cancer.

family history in which to employ genetic approaches to gene identification, especially since colorectal cancer is so common in the general population. Hence it will be interesting to observe progress now that whole genome scanning approaches are being applied to detecting cancer susceptibility genes. These approaches allow the analysis to ignore presuppositions about the mode of inheritance. An example of a recessive colorectal cancer family is shown in Figure 6. MYH-Associated Polyposis In addition to the dominant inheritance of hundreds or thousands of polyps, another syndrome has recently become apparent in which there is a recessive mode of inheritance and a reduced number of adenomatous and of metaplastic/hyperplastic polyps, known as MYH-associated polyposis (MAP). Because many families have been included as FAP in genetic registries, the

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phenotype has not been fully described and is only now possible because of molecular testing of the underlying gene defects. Mutations were identified in the base excision repair (BER) gene, MYH, in around 25% of families that were originally categorized as FAP but with neither dominant transmission nor evidence of APC mutation (136–138). It is clear that the disorder is autosomal recessive because biallelic MYH mutations were required for the polyposis phenotype. Since transmission is as an autosomal recessive trait, this has substantial implications for genetic counseling, testing, and surveillance. MYH gene testing is now offered to patients with a phenotype resembling FAP when no clear evidence of vertical transmission is recorded and where no APC mutation is identified (138a). In addition to polyposis, recent studies have established that biallelic defects in BER genes predispose to colorectal cancer (139,140), with complete penetrance by age 60 years. However, it is not clear whether there is a heterozygous effect because very large numbers are required to show an effect. There is some supporting evidence that heterozygous mutations may be associated with a small excess risk of colorectal cancer (139,140), although the effect was only apparent for late onset disease and it is possible that some of the excess risk detected in heterozygotes is due to undetected variants on the other MYH allele. Indeed, data from mouse models suggest that on an ApcMin/þ background that monoallelic MYH inactivation does not increase tumor burden or the signature G:C to A:T transversions of the remaining Apc allele in the mouse tumors (141). Population frequency of heterozygous MYH mutations is around 0.6%, and the observed contribution to colorectal cancer is 2% for patients aged T:A mutations in colorectal tumors. Nat Genet 2002; 30:227–232. 137. Sampson JR, Dolwani S, Jones S, et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic

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G:C–>T:A mutations Inherited variants of MYH associated with somatic G:C– >T:A mutations in colorectal tumors. Lancet 2003; 362:39–41. 138. Sieber OM, Lipton L, Crabtree M, et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 2003; 348:791–799. 138a.http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id¼608456. 139. Croitoru ME, Cleary SP, Di Nicola N, et al. Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. J Natl Cancer Inst 2004; 96:1631–1634. 140. Farrington SM, Tenesa A, Barnetson R, et al. Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Am J Hum Genet 2005; 77:112–119. 141. Sieber OM, Howarth KM, Thirlwell C, et al. Myh deficiency enhances intestinal tumorigenesis in multiple intestinal neoplasia (ApcMin/þ) mice. Cancer Res 2004; 64:8876–8881. 142. Gu Y, Parker A, Wilson TM, Bai H, Chang DY, Lu AL. Human MutY homolog, a DNA glycosylase involved in base excision repair, physically and functionally interacts with mismatch repair proteins human MutS homolog 2/ human MutS homolog 6. J Biol Chem 2002; 277:11135–11142. 143. Chmiel NH, Livingston AL, David SS. Insight into the functional consequences of inherited variants of the hMYH adenine glycosylase associated with colorectal cancer: complementation assays with hMYH variants and pre-steady-state kinetics of the corresponding mutated E.coli enzymes. J Mol Biol 2003; 327:431–443. 144. Hirano S, Tominaga Y, Ichinoe A, et al. Mutator phenotype of MUTYH-null mouse embryonic stem cells. J Biol Chem 2003; 278:38121–38124. 145. Jaeger EE, Woodford-Richens KL, Lockett M, et al. An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome. Am J Hum Genet 2003; 72:1261–1267. 146. Kemp Z, Thirlwell C, Sieber O, Silver A, Tomlinson I. An update on the genetics of colorectal cancer. Hum Mol Genet 2004; 13 Spec No 2:R177–R185. 147. Laken SJ, Petersen GM, Gruber SB, et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet 1997; 17:79–83. 148. Lamlum H, Al Tassan N, Jaeger E, et al. Germline APC variants in patients with multiple colorectal adenomas, with evidence for the particular importance of E1317Q. Hum Mol Genet 2000; 9:2215–2221. 149. Hahnloser D, Petersen GM, Rabe K, et al. The APC E1317Q variant in adenomatous polyps and colorectal cancers. Cancer Epidemiol Biomarkers Prev 2003; 12:1023–1028. 150. Slattery ML, Samowitz W, Ballard L, Schaffer D, Leppert M, Potter JD. A molecular variant of the APC gene at codon 1822: its association with diet, lifestyle, and risk of colon cancer. Cancer Res 2001; 61:1000–1004. 151. Lipkin SM, Rozek LS, Rennert G, et al. The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer. Nat Genet 2004; 36:694–699. 152. Kong S, Wei Q, Amos CI, et al. Cyclin D1 polymorphism and increased risk of colorectal cancer at young age. J Natl Cancer Inst 2001; 93:1106–1108.

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153. Le Marchand L, Seifried A, Lum-Jones A, Donlon T, Wilkens LR. Association of the cyclin D1 A870G polymorphism with advanced colorectal cancer. JAMA 2003; 290:2843–2848. 154. Grieu F, Malaney S, Ward R, Joseph D, Iacopetta B. Lack of association between CCND1 G870A polymorphism and the risk of breast and colorectal cancers. Anticancer Res 2003; 23:4257–4259. 155. Sharp L, Little J. Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol 2004; 159:423–443. 156. Ewart-Toland A, Briassouli P, de Koning JP, et al. Identification of Stk6/ STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human. Nat Genet 2003; 34:403–412. 157. Ewart-Toland A, Dai Q, Gao YT, et al. Aurora-A/STK15 Tþ91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types. Carcinogenesis 2005; 26:1368–1373. 158. Laiho P, Hienonen T, Karhu A, et al. Genome-wide allelotyping of 104 Finnish colorectal cancers reveals an excess of allelic imbalance in chromosome 20q in familial cases. Oncogene 2003; 22:2206–2214. 159. Slattery ML, Samowtiz W, Ma K, et al. CYP1A1, cigarette smoking, and colon and rectal cancer. Am J Epidemiol 2004; 160:842–852. 160. Meijers-Heijboer H, Wijnen J, Vasen H, et al. The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet 2003; 72:1308–1314. 161. Kilpivaara O, Laiho P, Aaltonen LA, Nevanlinna H. CHEK2 1100delC and colorectal cancer. J Med Genet 2003; 40:e110. 162. de Jong MM, Nolte IM, Te Meerman GJ, et al. Colorectal cancer and the CHEK2 1100delC mutation. Genes Chromosomes Cancer 2005; 43:377–382. 163. Kaklamani VG, Hou N, Bian Y, et al. TGFBR16A and cancer risk: a metaanalysis of seven case-control studies. J Clin Oncol 2003; 21:3236–3243. 164. Cui H, Cruz-Correa M, Giardiello FM, et al. Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 2003; 299:1753–1755. 165. Sakatani T, Kaneda A, Iacobuzio-Donahue CA, et al. Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science 2005; 307:1976–1978. 166. Slattery ML, Sweeney C, Murtaugh M, et al. Associations between apoE genotype and colon and rectal cancer. Carcinogenesis 2005; 26:1422–1429.

2 Epidemiology of Colorectal Cancer Julian Little Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada

Linda Sharp National Cancer Registry, Cork, Ireland

INTRODUCTION Cancer of the large bowel is a major health problem. Worldwide each year, over 900,000 new cases are diagnosed, and almost 500,000 people die from the disease (1). About two-thirds of the incident cases occur in developed countries, where colorectal cancer is the third most common cancer in men and second most common in women (2). In developing countries, it is the fifth most common cancer in both sexes. Relatively few colorectal cancers occur in persons younger than 40. Rates increase rapidly with age thereafter, more markedly for colon than for rectal cancer (3). The burden of colorectal cancer is, therefore, expected to increase in the future as a result of population aging and increased life expectancy. This is particularly true for developing countries. DESCRIPTIVE EPIDEMIOLOGY OF COLORECTAL CANCER International Variations in Incidence After allowing for differences between the age structures of populations, there are substantial variations in incidence internationally (Fig. 1). In men, for the period 1993–1997, the highest rates, of 45 per 100,000 and 43

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Figure 1 Age-standardized (world) incidence rates of colorectal cancer per 100,000 population: males and females, 1993–1997. Source: From Ref. 3.

above, occurred in Australia, New Zealand, parts of Japan (Miyagi), and parts of western Europe (Saarland, Germany; Bas-Rhin, France; northeast Italy) (3). Rates in the range of 35 to 45 per 100,000 were observed in the rest of western Europe, the United States, Canada, Hong Kong, and in Israeli Jews. In eastern Europe incidence was somewhat lower—around 25 to 35 per 100,000. Incidence rates of less than 15 per 100,000 occurred in Africa, India, Thailand, and Vietnam, and parts of the Middle East. For women, the geographical pattern was similar, but the age-standardized rates were about 60% to 80% of those in men. Time Trends in Incidence In 1971, Haenszel and Correa noted that colon cancer incidence was slowly increasing (4). Since then, moderate increases in colorectal cancer incidence is observed in many populations, although the timing and the magnitude of the increases have differed between populations (5). Rates have risen both in populations that, in earlier decades, had intermediate or high rates of colorectal cancer—such as Sweden, Denmark, Spain, Italy, Australia, New Zealand, Britain, and the United States—and in those that had low rates—such as

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Japan (6–15). Although the general pattern is similar, the magnitude of the increase differed between populations, as did the timing. In most, the increase was either more pronounced in men than women or observed only in men. While these trends are in part an artifact of improvements in the efficiency of cancer registration and increased detection rates resulting from the introduction of newer diagnostic tools, this seems unlikely to be the full explanation. The different patterns in males and females indicate strong sex-specific cohort effects, most likely associated with changes in exposures to environmental and lifestyle risk factors for the disease. Subsite of Tumor Between 60% and 70% of large bowel cancers occur in the colon (16). In western European and U.S. data, tumors of the right (proximal) colon are overrepresented among women (6). This is partly a function of age, because right tumors are more common among older persons and there are greater numbers of women in the older age groups than men. Tumors of the right colon have been reported to have become more common over the past 30 years (17–20). However, these observations are difficult to interpret for a number of reasons including different data categorizations and methods of statistical analysis, selection bias, population aging, and increasing use of colonoscopy and flexible sigmoidoscopy (5). It is, therefore, not at all clear whether the underlying incidence of right colon tumors is truly increasing. Variations in Incidence Within Countries Ethnic Origin In the United States in the period 1973–1997, the incidence and mortality due to large bowel cancer was higher in blacks than in other ethnic groups (15). The incidence in blacks in the United States is substantially higher than in Africa (3). In England and Wales in the period 1970–1985, the death rate due to large bowel cancer in people born in the Caribbean and East Africa was about half that of those born in England and Wales (21). Nevertheless, this would suggest a higher incidence than in the populations from which they originated. Death rates from the disease in those born in West Africa were similar to those born in England and Wales. These data from the United Kingdom contrasts with those from the United States, but there are differences in the pattern and circumstances of settlement and study period. As regards other ethnic groups in the United States, in men in the period 1973–1997, the incidence was lower in Asian/Pacific Islanders than in white males, and lower again in Hispanic and Native Americans and Alaskan Natives than in Asian/Pacific Islanders (15). Among women incidence rates were similar for Asian/Pacific Islanders, Hispanics and Native Americans, and Alaskans, and were lower than the levels observed in white and black women.

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In addition to levels of incidence varying by ethnic group, there are some differences in time trends. In the United States while incidence has been declining in the white population since the mid-1980s, this trend has not been seen in the black population (15). Socioeconomic Status In most countries, the risk of colon cancer has been found to be higher in those with higher socioeconomic status (22). This has been observed in both men and women, both for incidence and mortality, and for diverse measures of socioeconomic status. The increase in risk with increasing socioeconomic status contrasts with most other types of cancer. No consistent association between cancer of the rectum and socioeconomic status has been observed. Survival and Mortality: International Variations and Time Trends In developed countries, colorectal cancer death rates have declined steadily over the past 20 to 30 years (23). This is due, at least in part, to declining proportions of patients presenting with more advanced disease over time (24,25), and most likely a consequence of increased availability and use of sigmoidoscopy, colonoscopy and, possibly, fecal occult blood (FOB) testing. The extent of disease at diagnosis is a strong predictor of survival for both colon and rectal tumors. USA Surveillance, Epidemiology and End Results (SEER) Program data for patients diagnosed with colon cancer in 1992–1997 show five-year relative survival of 91% for those whose disease was localized at diagnosis, 67% for those presenting with regional spread, and 9% for those with distant metastasis (15). For rectal cancer the corresponding figures were 87%, 57%, and 8%. Of all those for whom the extent of disease was known, 39% had localized disease, 40% regional spread, and 21% distant metastasis. In most of western and northern Europe, survival is lower than in the United States (26). This difference may be heavily influenced by a higher proportion of colorectal cancers that are adenocarcinomas in polyps diagnosed in the United States than in Europe (27). GROUPS AT INCREASED RISK OF COLORECTAL CANCER Several groups have an increased risk of developing colorectal cancer: those with inflammatory bowel disease or colorectal polyps, individuals in families affected by the autosomal dominant conditions hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP), and individuals who have a family history of colorectal neoplasia but are not part of families affected by HNPCC or FAP families. The risk of cancer in patients with longstanding ulcerative colitis or Crohn’s disease is hard to quantify, but is thought to be similar for patients

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with the two conditions (28). A meta-analysis of 116 studies estimated that the cumulative probability of cancer in a patient with ulcerative colitis was 2% by 10 years, 8% by 20 years, and 18% by 30 years (29). Studies have shown that adenomatous polyps left in situ progress from adenoma to cancer [reviewed in (30)]. These observations, coupled with indirect evidence, support the view that most colorectal carcinomas develop from adenomas. Although these lesions are usually removed when detected, the risk for recurrence three years after colonoscopic polypectomy is 30% to 40% (31,32). Investigation of factors related to occurrence and recurrence of polyps may provide information about the roles of exposures in the earlier stages of the adenoma–carcinoma sequence and, in turn, give clues as to likely routes for prevention of colorectal cancer. Adenoma recurrence is frequently used as a ‘‘model system’’ in intervention studies, the assumption being that an intervention that is effective in preventing recurrence in individuals with adenomas may also be effective in the prevention of colorectal cancer. Hyperplastic polyps also may exhibit malignant potential. These, and serrated adenomas, may be precursors of some right-sided colon cancers (33). Where pertinent, examples of studies of adenoma occurrence or recurrence are discussed later in this chapter. Fewer than 10% of incident colorectal cancers are due to HNPCC and FAP (34). Excluding these syndromes, carcinomas and adenomas aggregate in families. Individuals who have a first-degree relative with colorectal cancer have around a twofold increased risk of developing the disease themselves (35–37). This pattern is probably not entirely explained by familial clustering of environmental factors (38). This points to the potential importance of genetic susceptibility factors, and the interaction of these with each other and with environmental factors, in causing the disease. Genetic susceptibility is discussed further later in this chapter. RISK FACTORS FOR COLORECTAL NEOPLASIA The classic studies of Japanese migrants to the United States conducted in the 1960s revealed the overwhelming importance of environmental factors in colorectal cancer etiology (39) and the discussion below relates primarily to such factors. The evidence is summarized in Table 1. Physical Activity More than 40 case–control or cohort studies of physical activity and the risk of colorectal cancers have been carried out (40). These provide consistent evidence that physical activity is associated with a reduced risk of colon cancer, with relative risks for the highest category of activity compared with the lowest in the range 0.4 to 0.9 (41). The relationship has been observed in women as well as men, in various ethnic groups, and in diverse geographical

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Table 1 Environmental Factors Associated with Colorectal Neoplasia Increasing risk Probable

Excess weight/BMI Alcohol

Possible

Tobacco smoking Insulin/hyperinsulinemia/ related factors

Reducing risk Physical activity Aspirin Hormone replacement therapy Vegetables Oral contraceptives Other NSAIDs Calcium Folate/folic acid

Abbreviations: BMI, body mass index; NSAIDs, nonsteroidal anti-inflammatory drugs.

areas. The association has been consistent in studies with widely different methods of assessing physical activity exposure, and persists after adjustment for other lifestyle factors. The data suggest that any activity is better than none (41) and that risk decreases in a dose–response fashion with increasing levels of activity (40). The volume of evidence specifically relating to cancer of the rectum is less substantial and suggests either a weak inverse association with higher levels of physical activity, or no association. The risk of adenomas is reduced among those reporting higher activity levels (42), and there is some suggestion that the relation may be stronger for adenomas with advanced features than for nonadvanced adenomas (43). Body Mass Index Excess weight raises the risk of developing colon cancer, with an increase of 15% in risk for an overweight person and 33% for an obese person (44). Similarly, the risk of adenomatous polyps is increased in individuals with a higher body mass index (45,46). There is little evidence of an association between weight and rectal cancer (42). Tobacco Smoking Tobacco smoking has consistently been found to be associated with an increased risk for adenomas and hyperplastic polyps (30,47–49). In the earlier studies of smoking and cancer, which mainly covered the 1950s and 1960s, there was no association between smoking and colorectal cancer, even among heavy smokers. In more recent studies, long-term smokers have been found to be at an elevated risk, with relative risks typically in the range of 1.5 to 3.0, following an induction period of 35 to 40 years (50). However, a recent review by the International Agency for Research on Cancer (IARC) concluded that it is possible that this association could be due to inadequate control of confounding (51).

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The aromatic amines, polycyclic aromatic hydrocarbons, and N-nitrosamines present in tobacco smoke are metabolized by a complex series of phase I and phase II activation and detoxification reactions. There is considerable interindividual variation in tobacco metabolism, and many of the genes controlling the production of the phase I and phase II enzymes are polymorphic. Several of these genes have been investigated in relation to colorectal neoplasia, with the most extensive evidence relating to the glutathionine-S-transferase genes GSTM1 and GSTT1, the cytochrome P450 1A1 gene CYP1A1, and the N-acteyltransferase genes NAT1 and NAT2. As regards GSTM1 and GSTT1, combined analysis of studies suggests that there is no association between the GSTM1 genotype alone and colorectal cancer (52–54), but that there may be a positive association with homozygosity for the GSTT1 deletion variant (52). However, for both polymorphisms, there is heterogeneity between studies, which is likely to be due in part to methodological differences (55), and in part to publication bias (56,57). On the basis of current evidence, it seems unlikely that either the GSTM1 or GSTT1 genotype strongly modifies the association between smoking and colorectal neoplasia (53,58–61), but most of the available studies have been hampered by a lack of statistical power to detect interactions. Studies of the CYP1A1 m1 and m2 polymorphisms and colorectal neoplasia have reported inconsistent results (62–69). In a large study, Slattery et al. found that presence of a CYP1A1 m1 or m2 variant allele modified the relationship between current smoking and colorectal cancer (69). No evidence of interaction between CYP1A1 genotype and smoking was found in two other studies, one of cancer and one of adenomas, but these were much smaller and so would have lacked statistical power to detect interactions (63,64). In a meta-analysis of 20 published case–control studies, the NAT2 genotype was not related to colon cancer risk (70). Similarly, pooled analysis of seven studies revealed no strong association between the NAT1 genotype and colorectal cancer (52). van der Hel et al. noted that cancer risk was raised in smokers who were imputed to be NAT2 rapid acetylators, compared to nonsmokers who were NAT2 slow acetylators (71). While this is compatible with the findings in a study of adenomas (72), other studies that have considered interactions between NAT1 or NAT2 and smoking have had inconsistent results (60,73–77). Exogenous Hormones The differences in the time trends in colorectal cancer in males and females (discussed earlier) could be explained by cohort effects in exposure to some sex-specific risk factor; one possibility that has been suggested is exposure to estrogens (19). There is, however, little evidence of an influence of endogenous hormones on the risk of colorectal cancer (78). In contrast, there is evidence that exogenous estrogens such as hormone replacement therapy (HRT), tamoxifen, or oral contraceptives might be associated with colorectal tumors.

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In two large randomized controlled trials of the possible health benefits of HRT in postmenopausal women (79,80), the incidence of colorectal cancer was reduced by about one-third [relative risk (RR) in meta-analysis 0.64, 95% confidence interval (CI) 0.45–0.92] (81). These results were consistent with those of more than 20 case–control and cohort studies (82). When colon and rectal tumors have been considered separately, there was no evidence of an association between HRT and rectal cancer (83). Interpretation of the results of observational studies has not been straightforward. In meta-analyses, there was significant heterogeneity in the magnitude of the effect between studies (78,83–85). While the RR appear to be lower for current than for past HRT users and there is an attenuation of the risk several years after stopping hormone use (85), there is a lack of information on the effect by hormone type, dose, and duration of use. There has also been concern that unidentified confounding or the ‘‘healthy user effect’’ may have influenced the observed effect (78), but the observation of a similar effect in the two randomized controlled trials (RCTs) makes this a less likely explanation for the association. A potential issue of concern is that in the Women’s Health Initiative trial the colorectal tumors diagnosed in the group on estrogen plus progestin HRT were more advanced and had a greater number of positive lymph nodes than those that developed in women in the placebo arm (86). If confirmed, this would have important implications for the potential role for HRT in colon cancer prevention, in addition to the concerns about the increased risk of breast cancer, strokes, and pulmonary embolism (79,81). Regarding the use of the oral contraceptive pill, a meta-analysis of eight case–control studies and four cohort studies conducted up to 2000 was consistent with a moderate inverse association with risk of colorectal cancer (RR ¼ 0.82, 95% CI 0.70–0.97) (87). The relation was evident for both colon and rectal tumors. However, there was significant heterogeneity between the studies and risk did not decrease with increased duration of use. Although available data are sparse, the risk of colorectal cancer may also be increased among women taking tamoxifen therapy (85). Aspirin and Other Nonsteroidal Anti-inflammatory Drugs The relationship between colorectal cancer and aspirin use has been assessed in more than 20 observational studies. These consistently show that aspirin use is associated with a reduction in the risk for colorectal cancer of approximately 40% to 50% (88–95). Similar results have been reported for adenomas (88,96–101). There have also been four randomized controlled trials of aspirin in the prevention of colorectal neoplasia (97,102–105). Three of these found that aspirin, in doses between 81 and 325 mg/day, reduced risk of recurrence of adenomas (97,104,105). While the fourth trial failed to observe an effect, it had not been designed to evaluate colorectal neoplasia

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as endpoints and had limited statistical power (102,103). Despite this body of evidence, issues relating to the effective dose and duration of treatment that would be necessary for prevention are still unclear. These gaps in knowledge are particularly important because of the toxic effects of aspirin, particularly at high doses. As regards other types of nonsteroidal anti-inflammatory drugs (NSAIDs), three small randomized clinical trials have shown that sulindac reduces the number and size of colorectal polyps in patients with FAP, confirming the results of studies of nonrandomized case series (88,106). However, in one trial in patients who were genotypically affected with FAP but were phenotypically unaffected, sulindac did not prevent the development of colorectal adenomas (107). In a small randomized trial, no regression of small adenomatous polyps in patients without FAP was observed (108). Celecoxib and rofecoxib specifically inhibit cyclooxygenase-2 (COX-2). Celecoxib has been found to reduce the number of colorectal adenomas in patients with FAP (109). In an analysis of data from a prescription drug database in the elderly in Que´bec (Canada), there was an inverse association between colorectal adenomas and use of rofecoxib for a period of at least 90 days (110). In a secondary analysis relating to colorectal cancer, there were inverse associations with use of rofecoxib and celecoxib. It is likely that aspirin, or other NSAID, prophylaxis might be of benefit to particular subgroups of the population, but these groups have not yet been identified. However, there is intriguing evidence that genetic variation may modify the effect of NSAIDs on the development of colorectal neoplasia. Martinez et al. investigated the joint effects of aspirin use and a polymorphism in the ornithine decarboxylase gene (ODC) on the risk for recurrence of colorectal adenomas (111). Overall, both aspirin use and homozygosity for a G to A substitution in intron 1 of ODC were associated with a reduced risk of adenoma recurrence. The joint effect of aspirin use and homozygosity for the intron 1 variant was greater than would be expected on the basis of either an additive or multiplicative effect. Polymorphic genes encoding the two isoforms of prostaglandin H synthase [also known as cyclooxygenase (COX)], which are inhibited by NSAIDs, have also been investigated. Lin et al. reported that risks of both adenomas and colorectal cancers were associated with a rare COX-2 variant in AfricanAmericans (112). Cox et al., in an analysis of eight of the more frequent COX-2 polymorphisms in a study in Spain, observed that two variants in the untranslated region of exon 10 were associated with an increased risk of colorectal cancer (113). The protective effect of NSAIDs was not observed in those with the exon 10 variants, but this was based on small numbers. In a single study, in persons who carried either of two variants of COX-1, NSAID use was not associated with the decrease in adenoma risk observed in those without the variants (114). Other studies suggest interactions between aspirin and variants of the genes coding for interleukins IL6 (115)

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and IL10 (116), the insulin receptor substrate 1 (IRS1) (117), the vitamin D receptor (VDR) (117), and the cyclin D1 gene (CCND1) (118). It will be important to determine whether these findings can be replicated (56,119), and whether they hold for different types of NSAIDs. Diet Diet has long been regarded as the most important environmental influence on colorectal cancer, and this is reflected in the volume of studies that have tested hypotheses about specific foods and nutrients. Virtually all of the studies have been observational and subject to three problems: (i) diet is related to other aspects of lifestyle, which may influence risk, (ii) people eat foods rather than nutrients, and (iii) misclassification of intake, both of the food group or nutrient being investigated, and of other food groups or nutrients that might confound the association could dilute or bias associations. In consequence, it has proved extremely difficult to identify the specific components of diet that influence risk. Vegetables and Fruit The comprehensive report of the World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) noted that of 21 case–control studies examining the association between vegetable and fruit consumption and colon cancer risk, 17 found some degree of reduced risk with higher consumption of at least one category of vegetable and fruit (120). Less consistent evidence was observed in the four cohort studies considered in the review. Of 10 case–control studies of rectal cancer in which statistical significance was reported, eight showed a significant inverse association with at least one category of vegetables and/or fruit, and the one cohort study in which rectal cancer risk was reported suggested an inverse relationship with consumption of green salad. On this basis, it was concluded that the evidence that diets rich in vegetables protect against cancers of the colon and rectum was convincing, however, no judgment was possible regarding the relationship with fruit. Recent evidence suggests the relation between vegetables and fruit and colorectal neoplasia is complex (121–123). For example, the association is much stronger in case–control than cohort studies (124), and case–control studies are potentially more susceptible to bias than cohort studies. Meat There have been two meta-analyses of meat consumption reported in the last few years, one based on cohort studies only (125), the other based on both case–control and cohort studies (126). The association between total meat consumption and colorectal cancer is inconsistent, and both meta-analyses show no statistically significant overall association. There is considerable

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heterogeneity between the results of case–control studies (126). In the cohort studies in which a positive association was found, the possibility that confounding factors might account for the results could not be excluded (125). Data on red meat and processed meat suggest positive associations with the risk for colorectal cancer. However, the volume of evidence on these is substantially less than for total meat consumption, and it is possible that publication bias has favored positive results. Heterocyclic amines are generated during the cooking of red meat at high temperatures, and increased consumption of well-done red meat has been associated with increased risk of colorectal neoplasia in some studies (127,128). For the heterocylic amines to be carcinogenic they must be metabolized by enzymes including glutathione-S-transferase (GST), N-acetyltransferase 1 (NAT1), and N-acetyltransferase 2 (NAT2). This has prompted investigation of interactions between variants in phase I and phase II metabolism genes and meat intake with regard to risk of colorectal neoplasia. Ishibe et al. observed a sixfold increased risk of adenomas among rapid NAT1 acetylators (defined as those carrying the NAT1
10 allele) who were estimated, on the basis of reported meat intake, cooking methods and doneness level, to consume more than 27 ng/day of the heterocyclic amine MeIQx, whereas among slow acetylators the increase in risk was twofold (129). While other investigators have also reported patterns in risk suggestive of interactions between particular genetic variants and meat intake [e.g., Welfare et al. for NAT2; Gertig et al. for GSTM1 and GSTT1; Turner et al. for GSTT1 and GSTP1; Cortessis et al. for microsomal epoxide hydrolase (mEH) (59,73,130,131)], the direction of the associations have not always been consistent with the underlying hypotheses (55). Other studies have failed to find any evidence that the relationship between red meat intake and colorectal neoplasia is modified by genotype (76,128, 132,133). In addition to differences between studies in the genes and polymorphisms that have been investigated, and different approaches to statistical analysis and low statistical power, the difficulty of adequately assessing exposure to carcinogens in cooked red meats further complicates this area of research. Fat and Fiber The contrast between low colorectal cancer rates in sub-Saharan Africa and high rates in industrialized countries was the basis for the suggestion that diet, in particular one with high levels of fat and low levels of fiber, might have a key role in causing the disease. The results of epidemiological studies on macronutrients (fat, proteins, and carbohydrates) have been less consistent in establishing an associated risk of cancer than those on food groups (134). Although the hypothesis that high fat intake is a major risk factor of the diet of industrialized countries has been investigated in many epidemiological and laboratory studies, no

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clear relationship has been established with colorectal cancer (135). There is now increased emphasis on the effects of specific fatty acids (136). For example, in a single study, an intake of n-6 fatty acids above the median was associated with an increased risk of colon cancer in those who carried a variant of the promoter region of the COX-2 gene, but not in those who did not have the variant (137). As regards dietary fiber, in a large multicenter cohort study in Europe, a 40% reduction in risk of colorectal cancer among those with the highest dietary fiber intake was observed (138). In contrast, in large cohort studies in the United States and Finland, no association has been found (122, 139,140). Intervention studies examining the effect of bran and soluble fiber have not found any effect on adenoma recurrence, nor have trials of dietary modification to increase fiber and lower fat intake (141–143). The evaluation of the cancer–fiber relation is particularly challenging due to the varying composition of fiber from different sources and variations in assessment of intake (138,144). It has been suggested that higher levels of fat and lower levels of fiber might increase colorectal cancer risk by altering fecal characteristics. In particular, it has been postulated that development of colorectal neoplasia may be promoted either by a high fecal total bile acid concentration (145) or by an abnormal bile acid profile with a high ratio of lithocholic to deoxycholic acid (146–148). However, no consistent association between colorectal cancer and fecal bile acid concentrations has been observed (149–156). This inconsistency may be due in part to methodological factors such as selection bias and limited statistical power. It is also possible that fecal bile acid levels may have been affected by the presence of the tumor, either directly or indirectly; for example, as a result of changes in diet made because of symptoms or treatment. For this reason, colorectal adenomatous polyps have been investigated in some studies, however, the results have been inconclusive (150,152,157–159). Most of the studies have been based on small numbers of cases who have been ascertained as a result of symptoms. The factors causing the symptoms may have affected fecal constituents, including bile acids. In a study of asymptomatic subjects who had participated in FOB screening, no association between colorectal cancer and fecal bile acids was observed (160). Folate Vegetables, particularly green leafy vegetables, are a major source of folate. Folate is involved in the synthesis and methylation of DNA, and mechanisms have been postulated by which low folate status might increase the risk of malignancy [reviewed in (161)]. This has prompted considerable investigation of the role of folate, and its synthetic form folic acid in colorectal neoplasia. The majority of observational studies—either measuring blood folate or assessing intake—are compatible with an inverse association between

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folate level and risk of colon cancer and adenomas. Two of three prospective studies found an increased risk for colorectal cancer among people with reduced levels of serum or plasma folate (162–164), a short-term marker of folate intake. Two studies have reported an inverse association between red cell folate, a measure of folate status over a three- to four-month period, and adenoma risk (165,166). Almost all prospective studies of folate intake show an inverse association with risk of colon cancer (or colorectal cancer, where colon and rectal tumors have not been analyzed separately), with several reporting a dose–response relationship (162,164,167–173). While evidence from case–control studies is not as consistent, most have found at least a modest reduced risk of colon (or colorectal) cancer associated with higher intake, at least among subgroups (174–184). Moreover, use of dietary supplements containing folic acid has been related to lower risk of colon cancer in several studies and the association appears, albeit on limited evidence, to be stronger for longer periods of regular use, or for use of higher dose supplements (164,167,168,183,185,186). There appears to be no consistent association between folate and rectum cancer (162,170,172–175, 177,178,184). As regards adenomas, both cohort and case–control studies have reported risk of adenoma occurrence to be reduced among those with higher folate intake (165,178,187–192), but it is not currently clear whether dietary folate intake is associated with adenoma recurrence (193). Alcohol adversely affects the metabolism of folate (194), which has prompted interest in whether a composite dietary profile of lower folate and higher alcohol intake, together with low intakes of methionine and vitamins B6 and B12 (a ‘‘low methyl’’ diet) may be associated with colorectal neoplasia. Several studies suggest that persons with a low-methyl diet do indeed have higher risk for colon cancer than those with a high-methyl diet (162,167,169,172,180,184). Family history may impact on the folate–colon cancer relationship. Fuchs et al. found that a higher level of total folate intake had only a minimal protective effect on colon cancer risk among women without a family history of colorectal cancer in first-degree relatives but was associated with a substantial reduction in risk among women with a family history of the disease (195). Consistent with this, Slattery et al. observed a fivefold increased risk of colon cancer for a low-methyl diet among women who reported a first-degree family history of colorectal cancer, compared to a 1.5-fold risk among those without a family history (180). Many of the genes involved in the absorption, metabolism, and transport of folate contain common genetic variants (196). Several studies have investigated two common variants of the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR), C677T and A1298C, in relation to colorectal neoplasia. In most studies, these variants are associated with moderately reduced colorectal cancer risk (197–201). Findings from six studies of C677T and adenomatous polyps are inconsistent (192,197,202).

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In studies in which joint effects of MTHFR genotype and diet have been investigated, those homozygous for the C677T variant who had higher folate levels (or a high-methyl diet) had the lowest cancer risk (197). As yet, too few investigations on other polymorphisms in the folate pathway—such as variants of the gene coding for methionine synthase (MTR) (182,190,203,204) methionine synthase reductase (MTRR) (182), cystathione b-synthase (CBS) (182,205), or thymidylate synthase (TS) (206–210)—have been carried out to be conclusive. While the metabolism of any exposure is likely to depend on the balance between the relative activities of all the enzymes active within the metabolic pathway (211), to date joint effects of folate-pathway genes have only been little investigated (182,207). Carotenoids No consistent association between dietary carotenoids, or serum or plasma concentrations of beta-carotene, and colorectal cancer has been observed (212). None of the trials of beta-carotene supplementation suggests a decrease in the occurrence of colorectal cancer, and two randomized control trials provide evidence of a lack of efficacy of short-term supplementation of beta-carotene in preventing occurrence of colorectal adenomas (212). Calcium Several observational studies and three intervention trials have found a reduced risk of occurrence and recurrence of colorectal neoplasia associated with higher calcium intake, either from the diet or as supplements, but not all of the studies reached statistical significance (120,143,213–218). In a pooled analysis of 10 cohort studies of colorectal cancer, the relative risk for the highest versus lowest quintile of dietary intake was 0.86 (95% CI 0.78–0.95, p trend¼0.02); for total intake, combining dietary and supplemental sources, the relative risk was 0.78 (95% CI 0.69–0.88, p trend < 0.001) (219). It has been postulated that fecal calcium may protect against colorectal carcinogenesis (220), because calcium ions in the colon would also precipitate the bile acids as their calcium salts and so would modulate their toxicity (221). In a study of subjects participating in FOB screening, high levels of fecal calcium were associated with a reduced risk of both colorectal cancer and colorectal adenomas, but these associations were not statistically significant (160). Calcium homeostasis is maintained by vitamin D, in that the vitamin D metabolite 1–25(OH)2D3 mediates intestinal calcium absorption. Vitamin D mediates its effect through the vitamin D receptor (VDR). This has led to investigation of associations between polymorphisms in the VDR gene and colorectal neoplasia. The FokI polymorphism has been associated with risk of large adenomas and of colorectal cancer (222,223), but the direction of the relationship differed for the two types of neoplasm. Moreover, two

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other studies failed to find similar associations (224,225). However, the study of Slattery et al. did observe a relation between colon cancer and three other VDR polymorphisms (which are in linkage disequilibrium) (224). There is some evidence that the VDR genotype might modify the association between calcium intake and risk; three studies of adenomas and one of colorectal cancer found patterns consistent with an interaction (222,223,225,226). Alcohol In the WCRF/AICR report, an association was noted between colon cancer and alcohol intake in four out of five general population cohort studies, in three out of three cohort studies on rectal cancer, and two out of three cohort studies that did not distinguish between colon and rectal cancer (120). In 9 out of 18 case–control studies of colon cancer and 9 out of 17 case–control studies of rectal cancer, there was a positive association with alcohol intake. In a meta-analysis of studies published in the period 1966–1998 there was significant heterogeneity in the colon cancer–alcohol relationship between the cohort and case–control studies included (227). For the studies of rectal cancer, there was significant heterogeneity by study quality and gender. In a pooled analysis of eight cohort studies in five countries in North America and Europe, a small increase in risk (RR 1.23, 95% CI 1.07–1.42) of colorectal cancer associated with a reported intake of 30 g/day or more was observed (228). Alcohol is metabolized to the carcinogen acetaldehyde by oxidation by the enzyme alcohol dehydrogenase (ADH) and is subsequently detoxified into acetate by aldehyde dehydrogenase (ALDH). The ADH isoenzymes involved in these reactions include subunits encoded by the ADH3 gene, which is polymorphic. Two studies of adenomas have reported patterns consistent with an interaction between ADH3 genotype and alcohol intake (202,229). Among subjects in the male Health Professional Follow-up Study (HPFS), high consumers of alcohol with the slow catabolism genotype (
2/
2) had a substantially increased risk of disease [odds ratio (OR) > 30 g/day and
2/
2 vs. 5 g/day and
1/
1 ¼ 2.94, 95% CI 1.24–6.92] compared to those who consumed low levels of alcohol per day and carried the fast alcohol catabolism genotype (ADH3
1/
1). Those who consumed high quantities of alcohol but had the fast catabolism genotype had only minimally increased risk (OR > 30 g/day and
1/
1 vs.  5 g/day and
1/
1 ¼ 1.27, 95% CI 0.63–2.53) (202). The pattern of interaction described in the other study, from the Netherlands (229), was very similar to the HPFS result, and the relationship was apparent in both male and female subjects. Because of the link between alcohol and folate metabolism, Giovannucci et al. investigated, in the HPFS, whether ADH3 acted together with alcohol and folate intake to influence disease risk. Individuals with high alcohol and low folate and the slow catabolism genotype were at particularly high risk compared to fast catabolizers with low alcohol and high folate

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intake (OR ¼ 17.1, 95% CI 2.13–137.0: p interaction ¼ 0.006), although the result was based on small numbers in the high alcohol/low folate/slow catabolism group (202). This study, along with three others of cancer and one of adenomas, has explored interactions between alcohol intake and the MTHFR genotype (192,199–202). Giovannucci et al. described a borderline significant interaction where the presence of the 677 TT genotype did not affect adenoma risk among persons consuming low amounts of alcohol (OR TT and 5 g/day vs. CC/CT and 5 g/day ¼ 0.79, 95% CI 0.42–1.49), but was associated with increased risk among those with a high alcohol intake (OR TT and >30 g/day vs. CC/CT and 5 g/day ¼ 3.52, 95% CI 1.41–8.78: p interaction ¼ 0.009) (202). Yin et al., in a study of 685 colorectal cancer cases and 778 controls in Japan, observed a similar pattern of risk for the A1298C polymorphism, but not for C677T (201). The other studies of MTHFR, alcohol, and colorectal neoplasia, all of which were smaller than the HPFS and the study of Yin et al., had inconsistent results (192,199,200). Insulin, Hyperinsulinemia, and Insulin-Like Growth Factors The similarity of risk factors for colon cancer and diabetes, and the observation that insulin promotes the growth of colon cells in vitro and colon tumors in vivo (230,231), prompted suggestions that hyperinsulinemia and insulin resistance may lead to colorectal cancer through growth-promoting effects of elevated levels of insulin, glucose, or triglycerides (232,233). While several strands of epidemiological evidence support the hypothesis, inconsistencies remain and a number of areas require clarification. Moderately increased risks of colorectal cancer and adenomas have been associated with type 2 diabetes (234–238), although the studies are not entirely consistent (239). Individuals with several risk factors consistent with insulin resistance syndrome (e.g., high systolic blood pressure, high BMI, etc.) were found to have an increased risk of death from colorectal cancer in two studies (240,241). Hyperglycemia has been associated with risk; higher fasting and nonfasting blood glucose levels are associated with an increased risk of colorectal cancer (incidence and mortality), carcinoma in situ, and adenomas (236,240–244). Two prospective studies observed a modest relationship between plasma insulin levels and colorectal cancer incidence, but a third study was negative (243,245,246). In two prospective studies from the United States, an increased concentration of plasma C-peptide, an indicator of insulin secretion, was associated with a significantly raised colorectal cancer risk (247,248). Two large studies have found an approximately two- to threefold increased risk of colorectal cancer associated with being in the highest, compared to the lowest, quintile of dietary glycemic load (249,250). A single study of adenomas, however, found no evidence that glycemic load or glycemic index of the diet were related to risk (251).

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One mechanism by which raised insulin levels could affect cancer risk is by increasing the bioactivity of insulin-like growth factor-1 (IGF-1) and inhibiting production of two main binding proteins, IGFBP-1 and IGFBP-2 (252). IGF-1 has mitogenic effects on normal and neoplastic cells, inhibiting apoptosis and stimulating cell proliferation (252). Three prospective studies of colorectal cancer have observed a greater than twofold increased risk among those in the highest quantile of IGF-1, compared with those in the lowest (247,253,254). A further prospective study reported a positive relationship with colon cancer (OR highest vs. lowest quantile ¼ 2.66; p trend ¼ 0.03) and a negative one for rectal cancer (OR ¼ 0.33; p trend ¼ 0.09), although the result for rectal cancer did not reach statistical significance (255). Risk of intermediate/late-stage adenomas, but not early stage adenomas, has also been found to be positively related to IGF-1 levels (254). One prospective study observed an inverse relationship between IGFBP-1 and IGFBP-2 and colorectal cancer (247), but two others have been null (245,246). A genetic variant at position 1663 in the human growth hormone-1 gene (GH1) is thought to be associated with lower IGF-1 levels. In a single study, the variant A allele was related, in a dose–response fashion, to a reduced risk of both colorectal cancer and adenomas (256). Also in a single study, polymorphisms in the genes encoding the insulin receptor substrates (IRS-1, IRS-2) were associated with risk of colon, but not rectal, cancer (257). In the same study, variants in the IGF-1 and IGFBP3 genes were not independently related to cancer but did appear to act together with IRS-1 to influence risk. Although requiring confirmation, the findings suggest that combinations of polymorphisms in the insulin-related signaling pathway may be important in colon cancer etiology. CONCLUSION Colorectal cancer continues to pose a major public health problem, with almost a million new cases being diagnosed each year worldwide, and over half a million deaths. The numbers are likely to increase as a result of population aging and increased life expectancy, especially in developing countries. Evidence that physical activity, a lower body mass index, use of aspirin and other NSAIDs, a higher intake of vegetables, and use of exogenous hormones in women are associated with decreased risk strongly suggest that there is considerable potential for primary prevention through lifestyle modification and, possibly, chemoprevention. While there remain challenges with implementation of lifestyle modification, and in developing methods of chemoprevention in either the general population or high-risk groups that maximize benefits and minimize harms, it is important that the potential power of primary prevention is not overlooked in developing strategies and guidelines for control of the disease, which tend to focus on treatment and screening.

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An emerging theme is the investigation of associations with genetic polymorphisms, and interactions between these and established or putative risk factors. This is a challenging area of investigation. In many of the studies of gene–environment interaction and colorectal neoplasia that have been conducted to date, there has been limited statistical power to detect interaction. The methods used to test for the same putative interaction have differed between studies, making it difficult to integrate evidence across studies. It is important that evidence in these areas is synthesized and efforts made to minimize the likelihood of publication bias. Collaborative networks such as the Human Genome Epidemiology Network (258) should facilitate this.

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251. Oh K, Willett WC, Fuchs CS, Giovannucci E. Glycemic index, glycemic load, and carbohydrate intake in relation to risk of distal colorectal adenoma in women. Cancer Epidemiol Biomarkers Prev 2004; 13:1192–1198. 252. Kaaks R. Nutrition, insulin, IGF-1 metabolism and cancer risk: a summary of epidemiological evidence. Novart Found Symp 2004; 262:247–260. 253. Ma J, Pollak MN, Giovannucci E, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGFbinding protein-3. J Natl Cancer Inst 1999; 91:620–625. 254. Giovannucci E, Pollak MN, Platz EA, et al. A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal neoplasia in women. Cancer Epidemiol Biomarkers Prev 2000; 9:345–349. 255. Palmqvist R, Hallmans G, Rinaldi S, et al. Plasma insulin-like growth factor 1, insulin-like growth factor binding protein 3, and risk of colorectal cancer: a prospective study in northern Sweden. Gut 2002; 50:642–646. 256. Le Marchand L, Donlon T, Seifried A, Kaaks R, Rinaldi S, Wilkens LR. Association of a common polymorphism in the human GH1 gene with colorectal neoplasia. J Natl Cancer Inst 2002; 94:454–460. 257. Slattery ML, Samowitz W, Curtin K, et al. Associations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer. Cancer Epidemiol Biomarkers Prev 2004; 13:1206–1214. 258. HuGENet2: http://www.cdc.gov/genomics/hugenet/default.htm

3 Colorectal Cancer Screening Robert J. C. Steele Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K.

INTRODUCTION Colorectal cancer is a major problem worldwide, and the highest incidences are found in the most developed countries. In Europe, the incidence is currently very similar to that of lung and breast cancer (about 135,000 cases per year), and in the developed countries there are some 250,000 deaths attributable to the disease each year (1). The main symptoms of colorectal cancer consist of overt rectal bleeding, change of bowel habit, abdominal pain and anemia, and, unfortunately, a tumor giving rise to any of these symptoms is likely to be locally advanced. As a result symptomatic cancers are rarely early and, in the United Kingdom, only about 8% of colorectal cancers present at Dukes’ stage A with 25% having distant metastases at the time of diagnosis (2); in many instances ‘‘symptomatic’’ early cancer is probably discovered as a result of investigating symptoms arising from concurrent benign causes such as hemorrhoids or irritable bowel syndrome. It is well established that early-stage colorectal cancer carries a much better prognosis than does late-stage disease (3), but it is self-evident that relying purely on symptomatic presentation will never substantially increase the proportion of cancers treated early and thus with curative intent. The only reliable way to detect early disease consistently is to look for it actively in asymptomatic individuals; in other words to screen. Screening for colorectal cancer is now widespread throughout the developed world

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although very few countries have a systematic screening policy. In this chapter we shall first briefly consider the principles of screening and then look at colorectal cancer as a suitable target for screening. The evidence for the major screening modalities, cost-effectiveness issues, and future approaches using novel methods will then be examined. PRINCIPLES OF SCREENING Screening can be defined as a process whereby a test is applied to individuals with a view to identify unrecognized disease at an early stage when treatment will be more effective. It is often stated that the individuals to whom screening is applied are asymptomatic but experience shows that this is not necessarily the case; an invitation to be screened may be more readily accepted in a patient with unreported symptoms. Indeed, recent work has indicated that about 50% of subjects accepting an invitation to be screened for colorectal cancer have significant symptoms, although these symptoms are unrelated to the findings on screening colonoscopy (4). It is also very important to be clear about the purpose of screening in a particular context. If the aim is to reduce the burden of disease on a community the correct approach is population screening; this requires the use of a test that is associated with a high uptake and low cost. If, on the other hand, the aim is to respond to an individual’s request for information regarding their disease status, uptake is not an issue and the emphasis must be on a test of high sensitivity and specificity. In this chapter, the emphasis will be largely on population screening, but it must be recognized that case finding on an individual basis forms the foundation of screening in many countries. The principles underlying an effective screening intervention were developed by Wilson and Jungner in 1968 (5), and these are summarized in Table 1. The essence of these principles is that the target disease process should be a common problem that has a better outcome when treated at an early stage, and that the test employed is acceptable and sufficiently sensitive, specific, and inexpensive to be cost-effective. That screening is a useful strategy may seem obvious, but the process of screening is associated with inherent biases that inevitably make screendetected disease appear to have a better prognosis than symptomatic disease whether or not the screening process has had a true effect on outcome. These biases are three in number: length-time bias, lead-time bias, and volunteer bias. Length-time bias arises from the fact that intermittent screening tests will tend to pick up slow-growing, indolent disease that is likely to have a better prognosis than the rapidly advancing disease, which is more likely to appear with symptoms between screening intervals (Fig. 1). Leadtime bias arises from early diagnosis itself; this will always lead to an apparent improved duration of survival merely by shifting the point of diagnosis forward and not necessarily by improving survival (Fig. 2). Volunteer bias is

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Table 1 Principles of Screening The condition should be an important health problem There should be an accepted treatment for patients with recognized disease Facilities for diagnosis and treatment should be available There should be a recognizable latent or early symptomatic stage There should be a suitable test or examination The test should be acceptable to the population The natural history of the condition, including development for latent to declared disease, should be adequately understood There should be an agreed policy on whom to treat as patients The cost of case-finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole Case finding should be a continuing process and not a ‘‘once and for all’’ project Source: From Ref. 5.

created by the fact that screening invitations tend to be accepted by healthconscious individuals who are likely to have a better outcome for reasons other than early detection of the tumor. The collective effect of these biases is to exaggerate the beneficial effect of screening, and to ensure that screening is producing a real benefit it is essential to carry out population-based randomized trials in which the group randomized to screening is analyzed as a whole and includes those who refuse the invitation to be screened and those who develop cancers that are not detected by screening. Only if the disease-specific mortality in the whole of this group is significantly lower than in the randomly selected group that is not offered screening can we be sure that the screening process is producing a truly beneficial effect.

Figure 1 Length bias. Screening tests tend to detect slow-growing disease, whereas rapidly progressive disease tends to arise and present between screening intervals.

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Figure 2 Lead-time bias. Early diagnosis will always appear to lengthen survival whether or not it affects the rate of tumor growth.

Cost-effectiveness is a more arbitrary measure and is essentially dependent upon a society’s willingness to pay for prolonged high-quality survival. In screening cost-effectiveness can be calculated in purely monetary terms but it has to be remembered that screening produces morbidity both psychological and physical, and it is important that this is also factored into the equation when a cost-benefit analysis is carried out. The cost-effectiveness of colorectal cancer screening will be examined later in this chapter. COLORECTAL CANCER AS A SUITABLE TARGET FOR SCREENING Wilson and Jungner (5) stated that for screening to be successful: 1. the condition should be an important health problem 2. there should be an accepted treatment for patients with recognized disease 3. the natural history of the condition including development from latent to declared disease should be adequately understood 4. treatment of early-stage disease confers a benefit over treating the same disease at a later, symptomatic stage Using these criteria there is little doubt that colorectal cancer is a suitable candidate for screening. In the western world it is extremely common and there are well-established methods of diagnosis and treatment. Colonoscopy is the gold standard investigation for symptomatic patients and high-risk individuals, although, as will be discussed in detail, there is considerable debate as

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to whether it should be used as a primary screening tool in asymptomatic people. Barium enema is still widely employed, but the published evidence would indicate that this is an inferior method of investigation compared with colonoscopy (6), and most authorities would now recommend that it be supplemented by flexible sigmoidoscopy. The latest computed tomography (CT) technology and analytical software has resulted in the development of CT colography or ‘‘virtual colonoscopy,’’ and this is emerging as a highly sensitive and specific diagnostic modality for colorectal neoplasia, set to render barium enema obsolete and perhaps replace colonoscopy as a purely diagnostic procedure (7). Consensus regarding treatment protocols for colorectal cancer is also improving. Surgery is fairly well standardized, particularly for rectal cancer (8), although the role of laparoscopic surgery is still to be fully established (9). Adjuvant therapy, on the other hand, is a rapidly shifting area, and although chemotherapy for Dukes’ stage C disease is now widely accepted and backed up by high-quality randomized evidence, there is a great deal of debate around the ideal agents and the question of adjuvant radiotherapy for rectal cancer (10). This does not, however, detract from the basic principle that surgical excision is the only potentially curative approach in the majority of tumors, and that the earlier the tumor, the more likely it is to be successful. As far as natural history is concerned, the evidence for the adenoma– carcinoma sequence is strong although essentially circumstantial (Table 2), and it is now generally accepted that most, if not all, invasive cancers arise from preexisiting adenomas (11). This offers an opportunity to reduce the incidence of colorectal cancer if the screening process employed detects significant adenomas and allows for their removal. It is also well established that surgery for early-stage disease results in better outcomes than for latestage disease; the five-year survival for Dukes’ stage A in the United Kingdom

Table 2 Evidence Supporting the Adenoma–Carcinoma Sequence in Colorectal Cancer Adenomas and carcinomas are frequently contiguous The anatomical distribution of adenomas and carcinomas is similar Adenomas over 2 cm in diameter have a 50% risk of harboring invasive malignancy The prevalence of adenomas is similar to that of carcinomas, and the average age of adenoma patients is about five years younger In about one-third of all surgical specimens resected for carcinoma, synchronous adenomas will be found Familial adenomatous polyposis (FAP) is unequivocally premalignant Adenomas and carcinomas share similar patterns of chromosomal abnormality and genetic mutation There is indirect but strong evidence that colonoscopy and polypectomy are associated with a reduced incidence of carcinoma Source: From Ref. 11.

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is currently around 90% and for stage C 40% (12). It must be appreciated, however, that part of this observation may be accounted for by lead-time bias, and it is important to evaluate the evidence provided by populationbased randomized trials of screening as outlined earlier. FECAL OCCULT BLOOD SCREENING There are various methods of testing for blood in the feces but the method that has been employed in all the published population-based screening trials involves the use of guaiac. Guaiac tests, by detecting peroxidases, react to heme in its free form or bound to protein (globin, myoglobin, and some cytochromes), and do not detect the degradation products of heme that are formed in the intestine as these lack peroxidase activity (13). Heme enters the proximal gastrointestinal tract as hemoglobin or myoglobin in food or as red cells from bleeding lesions, and relatively little is absorbed by the small intestine. However, in the colon, heme is modified by the microflora so that it loses its peroxidase activity, and, as a result, guaiac tests are more sensitive for distal (colonic) than for proximal (gastric) bleeding pathology. Using an unrehydrated guaiac test the clinical sensitivity (proportion of subjects with the disease who have a positive test) for colorectal cancer is only around 50% in a population screening context; this figure is derived from the interval cancer rate found in the randomized trials and will be discussed later. The reason for the low sensitivity of this test is presumably related to the fact that cancers bleed intermittently. The specificity of this test (proportion of subjects without the disease who have a negative test) is about 98% but, as the majority of the population do not have colorectal cancer, this still translates into a high false-positive rate. This is caused by a combination of factors including dietary hemoglobin, myoglobin, and peroxidase. The sensitivity of the test can be improved by rehydration before testing but at the expense of decreasing the specificity and thereby increasing the false-positive rate. Specificity is harder to deal with, and although appropriate dietary restriction for weakly positive tests has been employed, a recent meta-analysis suggests that this approach is ineffective and therefore unnecessary (14). The other issue is that traces of an individual’s own blood can be found in the stool for reasons other than colorectal neoplasia. More recently immunological fecal occult blood (FOB) tests have been introduced, and as these are specific for human hemoglobin or its early degradation forms, they are again more likely to detect distal rather than proximal disease. These tests, which are based on a variety of methods including reverse passive hemagglutination (using chicken erythrocytes that have been coated in antihuman hemogloblin, which agglutinate in the presence of human hemoglobin) and immunochromatography, can be set to a wide range of analytical sensitivities thus varying the clinical sensitivity (13).

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Studies have demonstrated that such tests can be highly clinically sensitive for colorectal cancer, but any increase in sensitivity is balanced by a decrease in specificity (15). All the population-based trials that have been reported used the guaiacbased Hemoccult II test, and were carried out in Minnesota (U.S.A.) (16), Nottingham (England) (17), Funen (Denmark) (18), Bordeaux (France) (19) and Goteborg (Sweden) (20). The first was the Minnesota study where volunteers were randomized to no screening, biennial screening, or annual screening using rehydrated Hemoccult II without dietary restriction. All subjects who had a positive test underwent colonoscopy and were statistically significant, 21% and 33% reductions in colorectal cancer mortality were observed in the biennial and annual groups, respectively, after 18 years (21). It has to be appreciated, however, that 10% of all tests were positive and 38% of the annually screened group underwent colonoscopy at least once. Thus, screening with unrehydrated hemoccult resulted in a high rate of colonoscopy and the implications of this study for an unselected and nonvolunteer population are not entirely clear. It is of great interest, however, that long-term follow-up of the Minnesota study has indicated that after 18 years the incidence of colorectal cancer in the groups offered screening was signficantly less than that in the control group (22). The underlying reasons for this observation are not clear, but as the colonoscopy rate in the screened groups was so high, it is likely to be related to polypectomy. In the Nottingham study (17) approximately 150,000 unselected subjects were randomized by household. The screened group was offered biennial nonrehydrated Hemoccult II testing. Dietary restriction was not specified but if the individual returned a weakly positive test they were offered a retest with dietary restriction. This led to a much lower rate of test positivity than the Minnesota study with a 2% investigation following the first (prevalence) round and 1.2% in subsequent (incidence) rounds. Over five screening rounds only 4% of the population offered screening underwent colonoscopy. In the Nottingham study, uptake varied from round to round, but overall 60% of the group offered screening completed at least one test. Screen-detected cancers tended to be highly favorable, with 57% being diagnosed at stage A (including polyp cancers). There were, however, a substantial number of interval cancers, and indeed about 50% of the cancers arising among those who had accepted at least one invitation to be screened were not detected by the screening process. This suggests that, for the purposes of population screening, the Hemoccult II test is only about 50% sensitive. Nevertheless, when the group offered screening was compared with the control group after a median of 7.8 years of follow-up, a statistically significant 15% reduction of colorectal cancer mortality was seen, and at a median of 11 years this was maintained at 13% (23). An interesting side effect of the Nottingham screening study has been highlighted by the observation that in the control group the percentage of

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patients presenting with favorable stage rectal cancer (Dukes’ stage A) increased from 9% in the first half of the recruitment to 28% in the second half (24). This implies that the very existence of the screening program had an effect on the control group, presumably related to a heightened awareness of the significance of rectal bleeding among the general population and at primary-care level. Another encouraging finding was related to emergency presentation of colorectal cancer. Throughout the duration of the study, there were a total of 1962 cancers identified, and there were significantly fewer emergencies in the group offered screening (25), suggesting that a policy of screening should lead to a significant reduction in the emergency workload with favorable consequences for operative mortality. A Danish study carried out on the island of Funen that was almost identical in design to the Nottingham trial in all respects (other than for the use of dietary restriction from the outset) obtained very similar results (18). In this study 61,933 individuals were randomized either to be offered biennial screening or to form a control group. The uptake was higher than that in the Nottingham study with 67% completing the first screening round and with more than 90% accepting repeated screenings. The overall positivity rate was somewhat lower, however, being 1% following the first round and dropping to 0.8% in the second round. Interestingly, the Danish group found the positivity rate to increase with subsequent rounds and by round 5 it was 1.8%. As with the Nottingham study the stage at diagnosis of screen-detected cancers was extremely favorable, with 48% at stage A and only 8% with distant spread. Again, interval cancers were relatively common and making up approximately 30% of the cancers arising in the screening group. As might be expected the mortality reduction was also similar, with a statistically significant reduction of 18% after five rounds rising to 30% after seven rounds (26). In France the results of a population-based study using nonrehydrated hemoccult have recently been published (19). In this study small geographical areas were allocated either to screening or to no screening. This involved inviting 91,199 subjects between the ages of 50 and 74 years, and no dietary restriction was employed. Uptake in the first round was 52.8% and increased slightly in subsequent rounds. Positivity was 1.2% on the first round and 1.4% on average thereafter, and the overall colorectal cancer mortality reduction was 16%. In Sweden, all the 68,308 residents of Goteborg born between 1918 and 1931 were randomized into a control group or a group offered screening using the Hemoccult II FOB test (20). In the first round, uptake was 63% and dropped to 60% in later rounds. The positivity rate was 4.4% in the first round, and screen-detected cancers were found to be at a much more favorable stage than those arising in the control group. Unfortunately, mortality data are not available from this study. Thus there are five major studies investigating the role of guaiac-based FOB testing as a screening tool; four of these are randomized, four are truly

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population based, and four have reported mortality data. The message from these studies is remarkably uniform and it is clear that this approach can bring about a substantial reduction in deaths from colorectal cancer. A metaanalysis using data from all five studies has indicated a 16% reduction in colorectal cancer mortality in those offered screening, going up to a 23% reduction when adjusted for compliance (27). From an ideal perspective it can be argued that the test is insensitive, compliance is poor, and there has been educational ‘‘contamination’’ of the control groups that would tend to diminish the effect of screening. Despite this, however, the statistically significant effect is a very powerful indicator that the screening process is beneficial in colorectal cancer, even if the FOB test approach is not necessarily optimal. In the United Kingdom, when the National Screening Committee was considering a recommendation on colorectal cancer screening, it was decided that a demonstration pilot of FOB testing should be carried out to ensure that the results of the randomized trials could be reproduced in the U.K. National Health Service (28). This pilot was run in two areas, one in Scotland and one in England, and a total of 478,250 individuals were invited to take part over a two-year period to simulate the first round of a biennial screening program. Uptake was 56.8%, positivity was 1.9%, and 48% of all screen-detected cancers were at Dukes’ stage A with only 1% having metastasized by the time of diagnosis (29). The results of this pilot were independently evaluated and compared with the results in the Nottingham study (30). The similarities were striking and the clear implication is that a national screening program based on FOB test screening within the United Kingdom should bring about a useful reduction in colorectal cancer mortality. As a result of this pilot, the U.K. government has now given a firm commitment to develop a comprehensive colorectal cancer screening program (31,32). FLEXIBLE SIGMOIDOSCOPY The concept of using flexible sigmoidoscopy (examination of the distal colon and rectum with a 60-cm flexible instrument) is based on the assumptions that the majority of colorectal cancers are within reach of this instrument and that a finding of a distal significant adenoma is a marker for possible proximal cancer. It has been proposed that a single flexible sigmoidoscopy at around the age of 60 with removal of all small adenomas at the time of initial examination with colonoscopy reserved for those with high-risk polyps would be an effective intervention to reduce mortality from colorectal cancer and ultimately reduce the incidence of colorectal cancer by means of polypectomy (33). This hypothesis is being tested by two multicenter randomized controlled trials of identical design, one being carried out in the United Kingdom (34) and the other in Italy (35). In the U.K. trial, men and women

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aged 60 to 64 in fourteen centers were sent a questionnaire in the mail to ask if they would attend for flexible sigmoidoscopy screening if invited. Of 354,262 people sent this questionnaire 194,726 (55%) responded in the affirmative, and of these, 170,432 eligible subjects were randomized using a 2:1 ratio of controls to those invited for screening. The screening protocol involved a flexible sigmoidoscopy with removal of all small polyps seen at the time of sigmoidoscopy with colonoscopy reserved for those with high-risk polyps (three or more adenomas, an adenoma greater than 1 cm in diameter, a villous or severely dysplastic adenoma) or invasive cancers. Of the 57,254 individuals invited for screening 40,674 (71%) attended. It must be appreciated therefore that this study is essentially a volunteer study and the extrapolated population compliance was no more than 30%. Of those undergoing flexible sigmoidoscopy distal adenomas were found in 12.1% and distal cancer in 0.3%. In those that went to colonoscopy proximal adenomas were found in 18.8% and a proximal cancer in 0.4%. Of particular importance was the stage of diagnosis, and it was found that 62% of the cancers were Dukes’ stage A. In the SCORE trial (the Italian arm of the once only flexible sigmoidoscopy study), similar results were found. In this case 236,568 people aged between 55 and 64 were sent letters of invitation but only 56,532 (23.9%) indicated that they would be prepared to be screened, and of the 17,148 assigned to screening 9999 (58%) attended. Fifty-four individuals were found to have colorectal cancer and 54% of these were diagnosed at Dukes’ stage A. A further randomized trial as part of a study looking at prostate, lung, colorectal, and ovarian cancer screening in the United States has looked at flexible sigmoidoscopy as a screening modality (36). To date there have been no data on uptake compliance or pathology yield published from this study although it is of some interest that repeat flexible sigmoidoscopy three years after an initial examination revealed advanced adenoma or cancer in the distal colon. The authors suggest that this highlights the need for repeated flexible sigmoidoscopy rather than the once only approach advocated by the U.K. and Italian studies. Thus the randomized evidence related to flexible sigmoidoscopy screening indicates that, although flexible sigmoidoscopy is an effective means of detecting early disease and adenomas, it does tend to miss proximal disease and currently compliance rates are modest. This calls into question the use of flexible sigmoidoscopy as a population screening tool, and although the randomized trials are likely to indicate mortality reductions further work requires to be done to estimate true population compliance. COLONOSCOPY In many countries there is considerable interest in using colonoscopy as a screening tool. The advantages are obvious. It is highly accurate with a

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specificity of virtually 100% and a very high sensitivity, although it has to be appreciated that sensitivity is not 100% as has been demonstrated by back-toback colonoscopy studies, which show that adenomas and occasionally carcinomas can be overlooked by even experienced colonoscopists (37). In addition, a recent study comparing state-of-the art CT colography with colonoscopy suggests that the sensitivity of colonoscopy for adenomatous polyps may be as low as 87.5% (7). Nevertheless colonoscopy is currently seen as the gold standard investigation for the colon and has the advantage of allowing immediate polypectomy with the potential for preventing colorectal cancer. Unfortunately there are no randomized trials of colonoscopy as a screening instrument and conclusions must necessarily be limited. One of the most influential studies in this area was the U.S. National Polyp Study that compared a cohort of subjects undergoing periodic colonoscopy with historical controls (38). In this study 1418 patients who had undergone total colonoscopy and removal of adenomas underwent subsequent colonoscopy during an average follow-up period of six years and the incidence of colorectal cancer in this group was compared with that in three reference groups including two cohorts in which polyps had not been removed. Ninety-seven percent of these subjects were followed up for a total of 8401 person years, and the majority (80%) had one or more follow-up colonoscopies. During this time five asymptomatic early-stage colorectal cancers were detected by colonoscopy and no symptomatic cancers were detected. When compared with the reference group this represented a much lower rate of diagnosis of colorectal cancer than would have been expected, and the conclusions were that colonoscopic surveillance in adenoma patients reduces the incidence of and subsequent mortality from colorectal cancer. Although a landmark study, the conclusions must be interpreted with caution as the comparison group was not derived from the same population as the cases and this is likely to have led to an overestimate of the efficacy of colonoscopy. In addition, it is difficult to extrapolate from polyp surveillance to screening asymptomatic populations. The most important study in the literature in terms of estimating the efficacy of screening colonoscopy is a case–control study conducted among U.S. military veterans (39). The study group consisted of 4411 veterans dying of colorectal cancer between 1998 and 1992. The control group was derived from living control patients and dead control patients without colorectal cancer matched by age, sex, and race to each case. Using this study design it was found that colonoscopy reduced death rates from colorectal cancer with an odds ratio of 0.41 (range 0.33–0.50). Further, comparison with the living control group revealed that the protective effects lasted for five years and that polypectomy was particularly protective. Similar results were found when the dead control group was employed. Again the study is far from perfect, particularly as the reasons for colonoscopy in the study group were varied and included investigation of symptomatic patients.

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There are, of course, abundant uncontrolled data on screening colonoscopy and perhaps the most useful study was carried out in 13 veterans affairs medical centers to determine the utility of colonoscopy in detecting colorectal neoplasia in asymptomatic individuals aged 50 to 75 (40). Of 17,732 potential subjects 3196 were included and 3121 underwent total colonoscopy. The mean age was 62.9 years and 96.8% were males. An adenoma of at least 10 mm diameter was detected in 7.9% and invasive cancer in 1%. Of 1765 subjects with no adenomas distal to the splenic flexure 48% had proximal adenomas or cancers. It can be concluded from this study that if colonoscopy was used as a screening tool in men aged between 50 and 75 the uptake would only be 20% and only 1% of colonoscopies would detect colorectal cancer. Thus, although colonoscopy is widely used to screen asymptomatic individuals on demand, it would seem very unlikely that it could ever be used as an effective population screening modality. This question will be considered further in the section on cost-effectiveness. RADIOLOGY There are no reliable data to support barium enema as a screening tool but the new technology of CT colography (virtual colonoscopy) shows distinct promise. The most exciting results to date come from the National Naval Medical Center in Bethesda where 1233 asymptomatic individuals with a mean age of 57.8 years underwent CT colography and colonoscopy on the same day (7). The sensitivities and the specificities of the two investigations were calculated on the basis of a final unblinded colonoscopy as the reference standard. It was found that the sensitivity of CT colography was 93.8% for adenomas of 10 mm in diameter or more, whereas the sensitivity of standard colonoscopy for the same lesions was only 87.5%. The specificity of CT colography was 96% for adenomas of 10 mm or more. It would seem therefore that CT colography has the appropriate sensitivity and specificity characteristics for a colorectal neoplasia screening tool but there are as yet no data with which to assess its performance or costeffectiveness in population screening. COMPARATIVE STUDIES There are very few studies that directly compare different screening methods and of those that exist all address the relative merits of FOB testing and flexible sigmoidoscopy. The Nottingham group carried out a randomized study comparing FOB testing with a combination of flexible sigmoidoscopy and FOB testing (41). The neoplasia yield in those undergoing the combined approach was four times greater than in those doing the FOB test alone, but while compliance with FOB testing was 50% in those offered both tests only 20% went on to have flexible sigmoidoscopy. In Sweden a group of

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6367 individuals aged between 55 and 56 were randomized to be offered screening with Hemoccult II or flexible sigmoidoscopy (42). Compliance with the FOB test screening was 59% and with flexible sigmoidoscopy 49%. Of those who attended for FOBT screening 4% had a positive test and 13% had a neoplastic lesion greater than 1 cm in the rectum or sigmoid colon; the corresponding rate in the flexible sigmoidoscopy group was 2.3%. Overall, 10 individuals were diagnosed with a neoplastic lesion in the FOBT group compared with 31 in the flexible sigmoidoscopy group. In the Norwegian Colorectal Cancer Prevention (NORCCAP) Screening Study (43) 20,780 individuals aged between 50 and 64 were randomized to be invited for flexible sigmoidoscopy only or a combination of flexible sigmoidoscopy and FOB testing. Compliance was 65% and overall 41 (0.3%) cases of colorectal cancer and 2208 (17%) adenomas were found. The diagnostic yields in the two groups were identical in terms of colorectal cancer or high-risk adenomas indicating that there was very little benefit in adding a FOB test to a screening flexible sigmoidoscopy. These studies indicate that while compliance with flexible sigmoidoscopy tends to be less than that for FOB testing, the sensitivity of flexible sigmoidoscopy is much higher. On the other hand it has to be remembered that all the randomized studies of FOB test screening were based on repeated testing, and in a nonrandomized study from Denmark comparing once only flexible sigmoidoscopy plus FOB testing with FOB testing alone over 16 years found that the FOB test screening program had a diagnostic yield at least as high as a single flexible sigmoidoscopy (44). To date, the evidence relating to the relative merits of an FOB test program and once only flexible sigmoidoscopy is not of particularly high quality, and this question can only be fully resolved by a randomized trial directly comparing these two modalities. HARM CAUSED BY SCREENING Screening comes at a cost, and the cost is not only financial but can also be measured in terms of morbidity and mortality. The question of financial cost is dealt with in the section on economics, but the other two issues are no less important. While performing an FOB test is unlikely to occasion physical morbidity and flexible sigmoidoscopy is very safe, the possibility of complications of the subsequent colonoscopy for those with a positive test and of surgery for those who are diagnosed with cancer must not be overlooked. In addition, false-negative results caused by the low sensitivity of the FOB test and the propensity of sigmoidoscopy to miss proximal cancers might falsely reassure individuals and lead to delayed cancer diagnosis and poorer outcome (‘‘certificate of health effect’’). The Nottingham group has addressed these issues by examining the investigation and treatment-related mortality and the stage at presentation

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of the interval cancers (45). There were no colonoscopy-related deaths and five deaths after surgery for screen-detected cancers; this represents a 2% operative mortality at a time when mortality after elective colorectal cancer surgery in the United Kingdom was estimated to be around 5% by a large national audit (46). Furthermore, the stage distribution of the interval cancers (cancers that were diagnosed after a negative FOB test or colonoscopy) was similar to that of the cancers in the control group, and the survival was significantly better than that for the control cancers—findings that are not consistent with an appreciable certificate of health effect. Nevertheless, these concerns have been highlighted by the finding that all-cause mortality is not affected by colorectal cancer screening and indeed, in the Nottingham study it was found to be increased in the group offered screening (47). However, colorectal cancer only accounts for around 2% of all deaths, and a 15% reduction in disease-specific death rate could only be expected to reduce all-cause mortality by 0.3%. To demonstrate a difference of this size with statistical power would require a trial too big to be feasible. Furthermore, unlike the difference in disease-specific mortality, the excess of all-cause deaths observed in the group offered screening was not statistically significant and therefore likely to represent a chance finding. Another important adverse effect of screening relates to psychological morbidity. In colorectal cancer screening there has been relatively little work done in this field, but there are two studies of note. In the Swedish randomized study of FOB test screening a questionnaire was administered to 2932 participants and it was found that 4.7% experienced worry from the invitation letter sufficient to influence daily life, and that this increased to 15% after a positive test (48). Worry decreased rapidly after the screening process was over, however, and at one year 96% declared that they had appreciated the opportunity to be screened. As part of the Nottingham trial a similar study was carried out using validated measures of psychiatric morbidity, and this was found to be highest in those with a positive test result, but in those with false-positive tests it fell the day after colonoscopy and remained low one month later (49). Thus it appears that the screening process does cause anxiety, but that is short lived. Finally, there is the issue of overinvestigation in the group with falsepositive tests. Despite the fact that the guaiac tests are very insensitive for upper gastrointestinal bleeding (q.v.), there is concern that ignoring a positive FOB test result in the face of a normal colonoscopy might be seen as negligent if significant upper gastrointestinal pathology is missed. To try to rationalize this fear the Nottingham group looked at a cohort of 283 FOB positive cases who had no neoplastic disease on colonoscopy (50). Fourteen (5%) of these underwent upper gastrointestinal endoscopy because of symptoms, and one was found to have gastric carcinoma. The rest, who were asymptomatic, were followed up for a median period of five years and only one, who had persistent symptoms after a previous partial gastrectomy, was subsequently

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diagnosed as having gastric cancer. Thus, the evidence supports a strategy of reassuring the majority of those who have a negative colonoscopy and reserving upper gastrointestinal endoscopy for those with relevant symptoms. ECONOMICS OF SCREENING Before deciding on a screening strategy, it is important to have information regarding cost-effectiveness. Unfortunately, however, there are no published data from the randomized controlled trials on the cost-effectiveness of colorectal cancer screening and the only approach is to use information provided by health economic models. In a recent study, 25 papers that were potentially relevant were identified although eight had to be excluded because the results were based on cost per cancer detected rather than cost per life year saved (51). Of the remaining papers the strategies assessed were yearly FOB testing, sigmoidoscopy every five years or colonoscopy every 10 years, or a combination of these strategies. It has to be stressed that there is no reliable information on biennial FOB testing or once only flexible sigmoidoscopy. This is unfortunate as these appear to be the most likely candidates for an effective population screening program. Overall, the models did not help to distinguish between the three approaches as the estimates of cost per life year saved were highly variable and overlapping (Fig. 3). The underlying reason for this huge variation is basically the lack of high-quality data on the efficacy of the different screening methods. As detailed earlier in this chapter, although we know a lot about the effect of FOB testing on colorectal cancer mortality from population-based randomized trials, we do not have the same level of information on flexible sigmoidoscopy and colonoscopy. Currently there are three randomized

Figure 3 Cost-effectiveness of fecal occult blood, sigmoidoscopy, and colonoscopy screening compared with no screening from 17 health economic papers. Abbreviation: FOB, fecal occult blood.

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trials of flexible sigmoidoscopy but none have reported mortality data. As far as colonoscopy is concerned most of the models utilize the U.S. National Polyp Study (38), which is severely limited in this context owing to the selection criteria and the historical controls. The single case–control study that evaluated the efficacy of lower gastrointestinal endoscopy (39) was rarely used in the health economic models evaluated. To compound these shortcomings none of the models have followed international recommendations with regard to the uncertainty of data (52). This is usually evaluated using sensitivity analysis where one parameter is varied over a specific range, and the effect this has on the model is expressed as a range of incremental cost-effectiveness ratios. This does not allow for the distribution of the statistical uncertainty and assumes that any value within the 95% confidence intervals is equally possible. This is inaccurate as it does not take into account all the uncertainty that can exist. In order to overcome these problems specific techniques were used (Monte Carlo simulations of a Markov model). In this approach it was assumed that individuals were screened from 45 to 75 years of age and yearly FOB testing, sigmoidoscopy every five years, and colonoscopy every 10 years were compared with one another. The assumptions made are given in Table 3. The first simulation compared yearly FOB testing with no screening and suggested that FOB screening costs 48,900 per life year saved. This does not take into account the uncertainty but if this is incorporated it is still 95% certain that an annual FOB test is cost-effective provided society is willing to pay 430,000 per life year saved (Fig. 4). As this is below the threshold that most countries are prepared to pay it is possible to say with a high degree of certainty that FOB test screening is cost-effective. On the basis of the result of the first model, sigmoidoscopy and colonoscopy were compared with FOB test screening. Sigmoidoscopy was estimated to cost 48,000 per life year saved, which is in fact cheaper than FOB test screening, but when uncertainty was incorporated into the model it was not even possible to be 80% certain that sigmoidoscopy is costeffective compared with FOB test screening no matter how much is paid for each life year saved (Fig. 5). This uncertainty is caused by the lack of data on mortality reduction brought about by flexible sigmoidoscopy and will be resolved when the results of the randomized trials are available. As far as colonoscopy is concerned when 10 yearly examination was compared with annual FOB testing it was estimated that each life year saved would cost 428,500 and when uncertainty was taken into account it became clear that to be 95% certain of cost-effectiveness it would be necessary to pay 490,000 per life year saved (Fig. 6). This is well above the threshold that most countries are willing to pay and again reflects the lack of good data on efficacy. Cost-effectiveness studies are dependent on efficacy data and are currently of limited value in the area of colorectal cancer screening for the reasons outlined earlier. What can be said at present is that FOB test

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Table 3 Assumptions Made in the Models of Fecal Occult Blood, Sigmoidoscopy, and Colonoscopy Screening to Prevent Colorectal Cancer Mortality

Variable Efficacy of FOB (28) Efficacy of FS (24) Efficacy of colonoscopy (24) Compliance Referral for colonoscopy with FOB Referral for colonoscopy with FS No screen colonoscopy rate Colorectal cancer care costs Colonoscopy cost FS cost FOB cost Invitation/administration costs

Uncertainty assumed

Value

Distribution given to this parameter in the model

RR ¼ 0.77 RR ¼ 0.67 RR ¼ 0.45

95% CI 0.57–0.89 95% CI 0.54–0.82 95% CI 0.30–0.66

Log normal Log normal Log normal

50% 5%

Data for 100 cases Data for 100 cases

Beta Beta

5%

Data for 100 cases

Beta

0.2%

No

NA

49024

No

NA

4350 480 42.80 43.00

No No No No

NA NA NA NA

Abbreviations: RR, relative risk of colon cancer compared with no screen; FOB, unhydrated fecal occult blood test; FS, flexible sigmoidoscopy; CI, confidence interval; NA, not applicable. Source: From Ref. 51.

screening is cost-effective, flexible sigmoidoscopy screening might be costeffective but we have to await further data, and colonoscopy is unlikely to be cost-effective for population screening. The uncertainty related to sigmoidoscopy and colonoscopy is extremely high and while this will be resolved for flexible sigmoidoscopy in the future, this seems unlikely for colonoscopy as there are no population-based randomized trials planned. NOVEL APPROACHES TO SCREENING Research into improving screening methods has focused largely on stool tests and these can be subdivided according to whether they involve DNA. Turning to the non-DNA-based stool testing first, a number of proteins have been studied including transferrin, albumin, and a-1 antitrypsin. Immunological detection of transferrin has shown high sensitivity and specificity when used along with immunological estimation of hemoglobin levels (53) but has never been developed. Albumin, which is known to be increased in the stool of patients with colorectal neoplasia, can be estimated

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Figure 4 Cost-effectiveness acceptability curve of annual fecal occult blood screening compared with no screening. Threshold of willingness to pay/life year saved that has a 50% chance of being cost-effective (dotted lines), and threshold of willingness to pay/life year saved that has a 95% chance of being cost-effective (dotted and dashed lines).

in stool but has a low sensitivity owing to its tendency to be degraded by colonic bacteria (54). a-1 antitrypsin, which inhibits proteolytic enzymes produced by both neoplastic and inflammatory lesions, is sensitive but not specific for neoplasia (55). There has been considerable interest in a calciumbinding protein known as calprotectin that is found in neutrophils, and a fecal calprotectin test has been developed that has been shown to be more sensitive in the detection of cancers and adenomas than FOB testing (56). Unfortunately, however, the specificity is highly variable from study to study, presumably related to the fact that it tends to be raised in inflammatory bowel disease. Another approach is stool cytology and this can be aided

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95

1.0 0.9 0.8

Probability cost-effective

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1.0

5,000.9 10,000.8 15,000.7 20,000.6 25,000.5 30,000.4 35,000.3 40,000.2 45,000.1 50,000.0

Willingness to pay ( )

Figure 5 Cost-effectiveness of sigmoidoscopy every five years compared with annual fecal occult blood (FOB) screening. Even at an infinite willingness to pay per life year saved there is less than 80% certainty that sigmoidoscopy is more cost-effective than annual FOB screening.

by the immunohistochemical detection of MCM2, a protein expressed strongly by neoplastic epithelium (57). The rapidly expanding body of information on genetic mutations in colorectal neoplasia has sparked considerable interest in developing tests that can detect these genetic abnormalities in DNA extracted from the stool. This has met with varying degrees of success. The basic principle involves extraction of DNA from the stool and amplification of abnormal DNA using a polymerase chain reaction (PCR). The technical difficulties in achieving this are considerable and include sample collection, DNA extraction, removal of PCR inhibitors, and the choice of primers for the PCR (58). DNA extraction is now quite feasible but the main problem is related to the heterogeneity of genetic mutations. Not only do colorectal cancers and adenomas display mutations in a wide and nonuniform range of genes, but,

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Figure 6 Cost-effectiveness of colonoscopy every 10 years compared with annual fecal occult blood screening. Threshold of willingness to pay/life year saved that has a 50% chance of being cost-effective (dotted lines), and threshold of willingness to pay/life year saved that has a 95% chance of being cost-effective (dotted and dashed lines).

in addition, the position of the mutation within the gene varies widely. Thus, in order to use this approach for screening it is essential to make a best guess as to the genes likely to be affected and the codons within these genes that are most frequently altered. The genes most commonly studied are K-ras, APC, and P53. In addition, markers of microsatellite instability (reflecting mutations in DNA mismatch repair genes) have been sought, and the most useful marker to date appears to be the mononucleotide BAT26 (58). In addition to looking for mutations DNA can also be utilized in a nonspecific way. Under normal circumstances cells shed from the colonic epithelium undergo apoptosis and nuclear endonucleases are activated giving rise to small fragments of DNA. Neoplasms on the other hand tend to shed long fragments of DNA

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so that an excess of long DNA in the stool can be used as a marker for neoplasia (59). Studies utilizing the detection in stool of single genetic mutations are insufficiently sensitive, and this has led to the development of panels of genetic abnormalities. Using this approach three groups have achieved high sensitivities for colorectal cancer and adenomas (59–61). In particular, Ahlquist’s group, using a combination of mutations in K-ras, APC and P53, BAT26 and long DNA achieved a sensitivity of 91% for cancer and 82% for adenoma with an initial specificity of 93% increasing to 100% if the K-ras marker was excluded from the panel. Molecular stool testing, although exciting, is still at a very early stage and is currently far too labor intensive to be considered seriously as a population screening tool. However, if the initial promise is sustained then automated analysis of inclusive panels of a wide range of abnormalities could be envisaged. CONCLUSIONS There is unequivocal, high-quality evidence that colorectal cancer screening reduces disease-specific mortality, and although this is strictly true only for guaiac-based FOB test screening, it is widely assumed that other, more sensitive modalities must be equally, if not more effective. This may be true as far as an individual is concerned, but given that the other methods have not been tested within the rigor of a randomized trial, it is impossible to be sure that the cost–benefit ratios associated with sigmoidoscopy, colonoscopy, or more sensitive fecal tests will be favorable. For flexible sigmoidoscopy, this is likely to change in the near future, but not for colonoscopy or for any other test, as the appropriate trials are not in place. However, the purpose of screening must be fully understood. The aim of population screening is to reduce the burden of disease on a community; this requires a test that is acceptable and affordable, and currently guaiacbased FOB testing is the only proven option. If, on the other hand, the aim of screening is to inform an individual, for whatever reason, regarding their disease status, then the sensitivity and specificity of the test are crucial. Here, colonoscopy, real or virtual, must be the test of choice. REFERENCES 1. Cancer Research Campaign. Cancer in the European Community. Factsheet 5.2 1992. 2. Slaney G, et al. Cancer of the large bowel. Clinical Cancer Monograph. Vol. 4. Macmillan Press, 1991. 3. Black RJ, Sharp L, Kendrick SW. Trends in Cancer Survival in Scotland 1968–1990. Edinburgh: ISD Publication, 1993.

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4. Ahmed S, Leslie A, Thaha M, Carey FA, Steele RJC. Lower gastrointestinal symptoms do not discriminate for colorectal neoplasia in a faecal occult blood scree-positive population. Br J Surg 2005; 92:478–481. 5. Wilson JM, Jungner F. Principles and practice of screening for disease. In: Public Health Papers No. 34. Geneva: WHO, 1968. 6. Rex DK, Rahmani EY, Haseman JA, Lemmel GT, Kaster S, Buckley JS. Relative sensitivity of colonoscopy and barium enema for detection of colorectal cancer in clinical practice. Gastroenterology 1997; 112:17–23. 7. Pickhardt PJ, Choi JR, Hwang I, et al. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. N Engl J Med 2003; 349:2191–2200. 8. McFarlane JK, Ryall RDH, Heald RJ. Mesorectal excision for rectal cancer. Lancet 1993; 341:457–460. 9. Whelan RL, Young-Fadouk TM. Should carcinoma of the colon be treated laparoscopically? Surg Endosc 2004; 18:857–862. 10. SIGN (Scottish Intercollegiate Guidelines Network) Guidelines on the Management of Colorectal Cancer. SIGN, Edinburgh March, 2003. 11. Leslie A, Carey FA, Pratt NR, Steele RJC. The colorectal adenoma-carcinoma sequence. Br J Surg 2002; 89:845–860. 12. Cancer Research UK. Factsheets on Cancer. Large Bowel—UK, 2003. 13. Young GP, Macrae FA, St. John DJB. Clinical methods for early detection: basis, use, and evaluation. In: Young GP, Rozen P, Levin B, eds. Prevention and Early Detection of Colorectal Cancer. WB Saunders, 1996; 241–270. 14. Pignone M, Campbell MK, Carr C, Phillips C. Meta-analysis of dietary restriction during fecal occult blood testing. Eff Clin Pract 2001; 4:150–156. 15. Robinson MH, Marks CG, Farrands PA, Bostock K, Hardcastle JD. Screening for colorectal cancer with an immunological faecal occult blood test: 2-year follow-up. Br J Surg 1996; 83:500–501. 16. Mandel JS, Bond JH, Church JR, et al. Reducing mortality from colorectal cancer by screening for faecal occult blood. N Engl J Med 1993; 328:1365–1371. 17. Hardcastle JD, Chamberlain JO, Robinson MHE, et al. Randomised controlled trial of faecal occult blood screening for colorectal cancer. Lancet 1996; 348: 1472–1477. 18. Kronborg O, Fenger C, Olsen J, Jorgensen OD, Sondergaard O. Randomized study of screening for colorectal cancer with faecal occult blood test. Lancet 1996; 348:1467–1471. 19. Faivre J, Dancourt V, Lejeune C, et al. Reduction in colorectal cancer mortality by fecal occult blood screening in a French controlled study. Gastroenterology 2004; 126:1674–1680. 20. Kewenter J, Brevinge H, Engaras B, Haglin E, Ahren C. Results of screening, rescreening, and follow-up in a prospect randomized study for detection of colorectal cancer by fecal occult blood testing. Results for 68,308 subjects. Scand J Gastroenterol 1994; 29:468–473. 21. Mandel JS, Church TR, Ederer F, Bond JH. Colorectal cancer mortality: effectiveness of biennial screening for fecal occult blood. J Natl Cancer Inst 1999; 91: 434–437.

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22. Mandel JS, Church TR, Bond JH, et al. The effect of fecal occult-blood screening on the incidence of colorectal cancer. N Engl J Med 2000; 343:1603–1607. 23. Scholefield JH, Moss S, Sufi F, Mangham CM, Hardcastle JD. Effect of faecal occult blood screening on mortality from colorectal cancer: results from a randomised controlled trial. Gut 2002; 50:840–844. 24. Robinson MHE, Thomas WM, Hardcastle JD, Chamberlain J, Mangham CM. Change towards earlier stage at presentation of colorectal cancer. Br J Surg 1993; 80:1610–1612. 25. Scholefield JH, Robinson MH, Mangham CM, Hardcastle JD. Screening for colorectal cancer reduces emergency admissions. Eur J Surg Oncol 1998; 24: 47–50. 26. Jorgensen OD, Krongborg O, Fenger C. A randomised study of screening for colorectal cancer using faecal occult blood testing: results after 13 years and seven biennial screening rounds. Gut 2002; 50:29–32. 27. Towler B, Irwig L, Glasziou P, Kewenter J, Weller D, Silagy C. A systematic review of the effects of screening for colorectal cancer using the faecal occult blood test, Hemoccult. Br Med J 1998; 317:559–565. 28. Steele RJC, Parker R, Patnick J, et al. A demonstration pilot for colorectal cancer screening in the United Kingdom: a new concept in the introduction of health care strategies. J Med Screen 2001; 8:197–202. 29. Steele RJC for the UK Colorectal Cancer Screening Pilot Group. Results of the first round of a demonstration pilot of screening for colorectal cancer in the United Kingdom. Br Med J 2004; 329:133–135. 30. Evaluation of the UK colorectal screening pilot. A report for the UK Department of Health. http://www.cancerscreening.nhs.uk/colorectal/finalreport.pdf Department of Health, June 2003. 31. Department of Health Press Release 2003/0047. http://www.info.doh.gov.uk/ doh/intpress.nsf/page/2003–0047. 32. Cancer in Scotland. Action for Change. Bowel cancer framework for Scotland. NHS Scotland. Scottish Executive 2004. 33. Atkin WS, Edwards R, Wardle J, et al. Design of a multicentre randomized trial to evaluate flexible sigmoidoscopy in colorectal cancer screening. J Med Screen 2001; 8:137–144. 34. UK Flexible Sigmoidoscopy Screening Trial Investigators. Single flexible sigmoidoscopy screening to prevent colorectal cancer: baseline findings of a UK multicentre randomized trial. Lancet 2002; 359:1291–1300. 35. Segnan N, Senore C, Andreoni B, et al. SCORE working group. Baseline findings of the Italian multicenter randomized controlled trial of ‘‘once-only sigmoidoscopy’’–SCORE. J Natl Canc Inst 2002; 94:1763–1772. 36. Schoen RE, Pinsky PF, Weissfeld JL, et al. Results of repeat sigmoidoscopy 3 years after a negative examination. JAMA 2003; 290:41–48. 37. Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997; 112:24–28. 38. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Working Group. N Engl J Med 1993; 329:1977–1981.

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39. Muller AD, Sonnenberg A. Protection by endoscopy against death from colorectal cancer. A case–control study among Veterans. Arch Intern Med 1995; 155:1741–1748. 40. Lieberman DA, Weiss DG, Bond JH, et al. Use of colonoscopy to screen asymptomatic adults for colorectal cancer. Veterans Affairs Cooperative Study Group 380. N Engl J Med 2000; 343:162–168. 41. Berry DP, Clarke P, Hardcastle JD, Vellacott KD. Randomized trial of the addition of flexible sigmoidscopy to faecal occult blood testing for colorectal neoplasia population screening. Br J Surg 1997; 84:1274–1276. 42. Brevinge H, Lindholm E, Buntzen S, Kewenter J. Screening for colorectal neoplasia with faecal occult blood testing compared with flexible sigmoidoscopy directly in a 55 years’ old population. Int J Colorectal Dis 1997; 12:291–295. 43. Gondal G, Grotmol T, Hofstad B, Bretthauer M, Eide TJ, Hoff G. The Norwegian Colorectal Cancer Prevention (NORCCAP) screening study: baseline findings and implementations for clinical work-up in age groups 50–64 years. Scand J Gastroenterol 2003; 38:635–642. 44. Rasmussen M, Fenger C, Kronborg O. Diagnostic yield in a biennial Haemoccult-II screening programme compared to a once-only screening with flexible sigmoidoscopy and Haemoccult-II. Scan J Gastroenterol 2003; 38: 114–118. 45. Robinson MHE, Hardcastle JD, Moss SM, et al. The risks of screening: data from the Nottingham randomised controlled trial of faecal occult blood screening for colorectal cancer. Gut 1999; 45:588–592. 46. Mella J, Biffin A, Radcliffe AG, Stamatakis JD, Steele RJC. Population-based audit of colorectal cancer management in two UK health regions. Br J Surg 1997; 84:1731–1736. 47. Black WC, Haggstrom DA, Welch HG. All-cause mortality in randomised trials of cancer screening. JNCI 2002; 94:167–173. 48. Lindholm E, Berglund B, Kewenter J, Halind E. Worry associated with screening for colorectal carcinomas. Scand J Gastroenterol 1997; 32:238–245. 49. Parker MA, Robinson MH, Scholefield JH, Hardcastle JD. Psychiatric morbidity and screening for colorectal cancer. J Med Screen 2002; 9:7–10. 50. Thomas WM, Hardcastle JD. Role of upper gastrointestinal investigations in a screening study for colorectal neoplasia. Gut 1990; 31:1294–1297. 51. Steele RJC, Gnauck R, Hrcka R, et al. ESGE/UEGF Colorectal Cancer– Public Awareness Campaign The Public/Professional Interface Workshop Oslo, Norway, June 20–22, 2003. Methods and Economic Considerations: Group 1 Report. Endoscopy 2004; 36:349–353. 52. Weinstein MC, Siegel JE, Gold MR, Kanlet MS, Russell LB. Recommendations of the Panel on cost-effectiveness in Health and Medicine. JAMA 1996; 276:1253–1258. 53. Miyoshi H, Ohshiba S, Asada S, Hirata I, Uchida K. Immunological determination of fecal haemoglobin and transferrin levels: a comparison with other fecal occult blood tests. Am J Gastroenterol 1992; 87:67–73. 54. Saitoh O, Matsumoto H, Sugimori K, et al. Intestinal protein loss and bleeding assessed by fecal hemoglobin, transferrin, albumin and alpha-1-antitrypsin levels in patients with colorectal diseases. Digestion 1995; 56:67–75.

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55. Moran A, Robinson M, Lawson N, Stanley J, Jones AF, Hardcastle JD. Fecal alpha 1-antitrypsin detection of colorectal neoplasia. An evaluation using HemoQuant. Dig Dis Sci 1995; 40:2522–2525. 56. Tibble J, Sigthorsson G, Foster R, Sherwood R, Fagerhol M, Bjarnason I. Faecal calprotectin and faecal occult blood tests in the diagnosis of colorectal carcinoma and adenoma. Gut 2001; 49:402–408. 57. Davies RJ, Freeman A, Morris LS, et al. Analysis of minichromosome maintenance proteins as a novel method for detection of colorectal cancer in stool. Lancet 2002; 359:1917–1919. 58. Mak T, Lalloo F, Evans DGR, Hill J. Molecular stool screening for colorectal cancer. Br J Surg 2004; 91:790–800. 59. Ahlquist DA, Skoletsky JE, Boynton KA, et al. Colorectal cancer screening by detection of altered DNA in stool: feasibility of a multitarget assay panel. Gastroenterology 2000; 119:1219–1227. 60. Rengucci C, Maiolo P, Saragoni L, Zoli W, Amadori D, Calistri D. Multiple detection of genetic alterations in tumors and stool. Clin Cancer Res 2001; 7:590–593. 61. Dong SM, Traverso G, Johnson C, et al. Detecting colorectal cancer in stool with the use of multiple genetic targets. J Natl Cancer Inst 2001; 93:858–865.

4 Pathology Christian Wittekind Institut fu¨r Pathologie des Universita¨tsklinikums Leipzig, Leipzig, Germany

INTRODUCTION Colorectal cancer pathology covers a wide spectrum of aspects beginning with etiology and ranging to metastasis and causes of death of colorectal cancer patients. In this chapter, only those areas of pathology that are relevant for treatment decisions, analysis of treatment results, and quality management are covered. Aspects of diagnosis and differential diagnosis, epidemiology, genetics, causal and formal pathogenesis, which are dealt with in other chapters of this book, are not included in this chapter. Because about 95% of all malignant tumors of the colon and rectum are carcinomas, predominantly the pathology of carcinomas is discussed. At the end a short overview of the other, very uncommon, malignant tumors (endocrine, mesenchymal, and lymphoid) is presented. DEFINITION Colorectal cancer comprises all malignant tumors of the colorectum, the most frequent of which is colorectal adenocarcinoma. In contrast to the stomach or small intestine, a neoplasm of the colon and rectum has metastatic potential only after invasion of at least the submucosa. For the colorectum in the biological and clinical sense, carcinoma is present only after the lamina submucosa has been invaded. This definition has been adopted by the World Health Organization (WHO) classification (1). Between intraepithelial neoplasia (formerly: dysplasia) and an invasive carcinoma as defined earlier, we find an intermediate step of malignant 103

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Table 1 Differences in Classification Between Carcinoma In Situ and Invasive Carcinomas of the Colorectum T category Tis

T1

Tumor entities

ICD-O M code

Severe dysplasia High-grade dysplasia Intraepithelial neoplasia Intramucosal carcinoma Invasive carcinoma (¼invasion of submucosa)

8140/2

8140/3

Abbreviation: ICD-O, International Classification of Disease-Oncology. Source: From Refs. 1, 6.

progression, namely, a neoplastic lesion that shows invasive growth into the lamina propria mucosae or between the fibers of the muscularis mucosae, but does not invade the submucosa. Unfortunately, outside the United Kingdom and the Germanspeaking countries, the term ‘‘carcinoma’’ is not used uniformly. Thus, in any cancer statistics and in any report of treatment results, one has to make sure whether the data relate to invasive carcinoma only or include highgrade intraepithelial neoplasia (formerly: high-grade dysplasia). Differences in definitions and nomenclature are summarized in Table 1. Another classification of flat and depressed types of early colorectal cancer has recently been published in Japan (2). However, not all of the Japanese definitions fulfill the Western criteria of invasive colorectal carcinoma. SITE DISTRIBUTION The pathologies of carcinoma of the colon and rectum are essentially the same, although there are differences in epidemiology and etiology, which has led some to speculate about the existence of two completely different tumor entities. In the literature, the definitions of colon and rectum vary. This renders comparisons difficult and explains some differences among data. According to the updated International Documentation System for Colorectal Cancer (IDS for CRC) (3,4) carcinomas with a lower border of the tumor 16 cm or less from the anal verge (measured by a rigid rectosigmoidoscope) are classified as rectal carcinomas. The rectum is further subdivided in thirds: upper third 12 to 16 cm; middle third 6 to < 12 cm; and lower third: 5 ng/mL) Comorbid disease (present, Higher ASA grade) Surgeon

Patient-related

For subgroups: multimodal therapy (not performed)

Peritumoral lymphoid cells/lymphoid aggregates (nonconspicuous/absent) Gender (male)

Tumor perforation/obstruction (present) Lymphatic and perineural invasion (present)

Anatomical site of primary (rectum)

Probable prognostic factors

Abbreviations: ECOG, European Cooperative Oncology Group; CEA, carcinoembryonic antigen; ASA, American Society of Anaesthesia; R1, microscopic residual tumor; R2, macroscopic residual tumor; pTNM, pathological tumor node metastasis. Source: From Refs. 7 and 9.

Treatment-related

Anatomical extent: pTNM and stage grouping (higher category) Histological grade Venous invasion (present, predominantly extramural) Histological pattern of tumor margin (infiltrative)

Proven prognostic factors

Patients with complete resection of tumor (no residual tumor, R0)

Tumor-related

B.

A. Patients with residual tumor (R1, R2) Proven prognostic factors Distant metastasis (present) Localization of residual tumor (distal) For patients with multiple distant metastases: performance status (increasing ECOG grade, decreasing Karnofsky score)

Table 4 Prognostic Factors in Colorectal Carcinoma (Unfavorable Level of Covariates Is Shown in Parentheses)

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procedure, and prognostic factors. This enables a reliable diagnosis, treatment decisions, estimation of prognosis, and analysis of treatment results and of the quality of diagnosis and treatment. Specific recommendations for the content of surgical pathology reports have been published in various countries since the 1980s. The minimal data to be included in a present-day surgical pathology report are listed in Table 5. It is based on recent publications (4,32–34). QUALITY MANAGEMENT WITHIN PATHOLOGY DEPARTMENTS Quality management is a requirement for diagnostic activities in pathology departments as well as for the treatment of cancer and for clinical studies. The methods of quality management within pathology departments have recently been described and summarized by Rosai (35). There are indicators of the quality of histopathological assessment and workup (Table 6). In all pathology departments, the respective data should currently be collected and analyzed. Any deviation from the usual values (ranges) and changes in frequencies should lead to careful analysis and response. Special attention should be paid to careful examination of the circumferential resection margins and lymph nodes because of the crucial prognostic significance of the respective findings (23,34). PATHOLOGY FINDINGS IN RESECTION SPECIMENS INDICATIVE OF ONCOLOGICAL QUALITY OF SURGERY The most important goal of surgical treatment is to achieve complete tumor resection (R0 resection). Thus the rate of R0 resections related to all patients is an important intermediate indicator of quality. The pathological findings below on resection specimens give further information on the oncological quality of surgery: 1. Evidence of local spillage of tumor cells: iatrogenic tumor perforation or tumor resection not en bloc with transsection of tumor tissue. 2. Length of resected bowel: limited (segmental) resection or radical resection with ligature of the trunk of the supplying vessels. 3. In cases of colon carcinomas with multidirectional lymphatic drainage: dissection of one or two lymph drainage areas. 4. Number of removed lymph nodes (provided that there is an adequate node examination technique). 5. In rectal carcinoma of the upper third: distal margin of clearance in muscular walls as well as in mesorectum (no coning) not less than 5 cm in situ corresponding to 3 cm measured on the fresh resection specimen without tension.

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Table 5 Minimal Data to Be Included in Surgical Pathology Reports on Colorectal Carcinoma Specimens Incision biopsies Gross description Histology

Number of pieces Extension (intraepithelial/intramucosal/invasion of submucosa) Histological type Histological grade

Polypectomies Gross description

Number of pieces Macroscopic type (flat/sessile/semi-pedunculated/ pedunculated) Greatest dimension (without stalk) Histology: tumor Histological type Histological grade Extension (intra-epithelial/intramucosal/invasion of submucosa) In semi-pedunculated and pedunculated polyps: extension of invasion of submucosa (none/ head/stalk) Lymphatic invasion (L classification) Venous invasion involvement Histology: margins Minimal distance of tumor from margin (mucosal margins, deep margin) Local excision (submucosal, full thickness) Gross description Number of pieces Tumor configuration (exophytic-fungating/ endophytic-ulcerative/diffusely infiltrating) Greatest dimension of tumor Margins: minimal distance of tumor from mucosal and deep margins Histology: tumor Histological type Histological grade Extension (pT classification) Lymphatic invasion (L classification) Venous invasion (intramural, extramural) Perineural invasion (Pn classification) Histology: margins Involvement. Minimal distance of tumor from mucosal and deep margins Histology Additional pathological findings (e.g., adenoma. intra-epithelial neoplasia) Resection specimens Gross description: Parts of colorectum removed resection specimen (Continued)

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Table 5 Minimal Data to Be Included in Surgical Pathology Reports on Colorectal Carcinoma Specimens (Continued )

Gross description: tumor localization

Gross description: margins

Histology: tumor

Histology: margins

Histology: additional lesions

Adjacent organs removed Number of pieces received (resection en bloc/not en bloc) Number of malignant tumors In rectal carcinomas: Site in relation to peritoneal reflection (above/ at/below) Site of distal border of tumor (upper/middle/ lower third) In case of abdominoperineal excision: distance between distal border of tumor and anal verge/ method of measurement Greatest dimension Tumor perforation (spontaneous/iatrogenic) Minimal distance from proximal and distal margin/ method of measurement Minimal distance from circumferential (radial, lateral) margin/method of measurement Anatomical extent: pTNM classification Number of regional lymph nodes examined Number of regional lymph nodes involved Apical lymph node status Histological type Histological grade Lymphatic invasion (L classification) Venous invasion (intramural, extramural) Perineural invasion (Pn classification) Histological pattern of infiltrating margins (pushing-expanding/diffusely infiltrating) Involvement, minimal distance for Proximal margin Distal margin Doughnut Circumferential (radial, lateral) Resected adjacent organs Adenoma/intraepithelial neoplasia/familial adenomatous polyposis/ulcerative colitis/ other chronic inflammatory bowel diseases/other

Abbreviations: L, lymphatic invasion; pT, pathological T; Pn, perineural invasion; pTNM, pathological tumor node metastasis. Source: From Refs. 4, 32–34.

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Table 6 Quality Indicators for Pathological Diagnosis Range Parameter Tumor type Mucinous adenocarcinoma/ frequency Tumor grade High-grade/frequency R classification Frequency of R1 related to resections considered as complete by the surgeon Regional lymph nodes Frequency of node-positive cases related to radical resections for cure (R0 resections) Number of examined nodes in radical standard resections for cure (R0)b,c/mean Frequency of cases with fewer than 12 lymph nodesc

Colon

Rectum

15%

10%

Indicative of Adherence to WHO classification

20–25% 0–5%

5–10 (-20)%

Carefulness of histological examination of resection linesa

40–50%

20–30%

Carefulness of histological examination of lymph node drainage areaa

< 5%

a

Also influenced by the surgeon. Radical standard resection is defined as bowel resection with formal dissection of the lymph node drainage area. c Except cases with neoadjuvant therapy. Abbreviation: WHO, World Health Organization. Source: From Refs. 38 and 39. b

6. In rectal carcinoma of the middle and lower third:
Careful gross inspection of the surface of the specimen: appearance of the correctly mobilized mesorectum with intact smooth surface.
Distal margin of clearance in muscular wall not less than 1 cm measured on the fresh resection specimen without tension. QUALITY ASSURANCE OF CLINICAL TRIALS ON ADJUVANT AND NEOADJUVANT THERAPY: THE SURGICAL PATHOLOGIST’S POINT OF VIEW In adjuvant treatment, the quality of pathological examination of resection specimens influences the selection of patients and thus the results. Therefore, data indicating the quality of pathology (Table 6) should always be included

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in reports on respective clinical trials. The frequency of all tumor resections, of resections without and with microscopic residual tumor (R0, R1), and the pN classification for all patients seen at the institution(s) during the study period should be stated. This information indicates the general surgical attitude as well as the quality of pathological examination. Tumor classifications performed according to international recommendations are important indicators of the quality of oncological studies. Any comparison of results will be made impossible by authors who do not classify their tumors according to the generally accepted international systems. MALIGNANT TUMORS OTHER THAN CARCINOMAS Traditionally, neuroendocrine tumors have been separated from epithelial tumors and classified in a special way. They are classified as:
Well-differentiated neuroendocrine tumor (formerly: carcinoid), ICD-O code 8240/1
Well-differentiated neuroendocrine carcinoma (formerly: malignant carcinoid), ICD-O code 8240/3
Poorly differentiated neuroendocrine carcinoma (small cell carcinoma), ICD-O code 8041/3 Most endocrine tumors of the appendix are localized at the distal tip, and cause local symptoms leading to appendectomy. Most tumors produce serotonin and show benign behavior. The uncommon malignant carcinoids require radical right hemicolectomy. In the colon neuroendocrine tumors are very rare, mostly of the poorly differentiated type, and affected patients have a poor prognosis. The rectum is the preferred site of endocrine tumors. They are mostly small (65 30–35

1 2 5 1–3 depending on findings

12

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Table 4 Modified Spigelman’s Score and Classification Factor No. of polyps Polyp size, mm Histology Dysplasia

1 point

2 points

3 points

1–4 1–4 Tubulous Low grade

5–20 5–10 Tubulovillous –

>20 >10 Villous High grade

Note: Classification—no polyps: stage 0; 1–4 points: stage I; 5–6 points: stage II; 7–8 points; stage III; 9–12 points: stage IV.

of malignancy, but because there is a relatively long time span between the onset of adenomas and the appearance of cancer, school and work schedules are taken into account in these teenage patients. Surgical options include subtotal colectomy with ileorectal anastomosis, total proctocolectomy with Brooke ileostomy (or continent ileostomy), and proctocolectomy with mucosal proctectomy and ileoanal pull-through (with pouch formation). Because CRC can occur in the rectal segment, the two latter procedures are favored. In patients with subtotal colectomy routine endoscopic surveillance of the remaining rectum every six months is mandatory. Even patients with proctocolectomies and ileoanal pouch should be followed because rare cases of adenomas in the pouch have been reported. Adenomas in the duodenum occur in the majority of FAP patients, with a lifetime risk of periampullary carcinoma of about 5%. There is limited knowledge about the causation, prevention, and management of duodenal polyposis in FAP. However, a recent detailed analysis of the natural history of duodenal polyposis in FAP patients shows a strong association between stage IV (according to the Spigelman classification, Table 4), duodenal adenomas, and duodenal cancer. Patients with Spigelman stage IV disease should be offered prophylactic surgery. Screening with upper GI endoscopy is recommended every one to three years, according to the Spigelman stage (Table 5) (5). As a Table 5 Proposed Program for Surveillance and Treatment of Duodenal Adenomatosis Spigelman Spigelman Spigelman Spigelman Spigelman

a

stage stage stage stage stage

0 I II III IV

Endoscopya at intervals 5 years Endoscopyb at intervals 5 years Endoscopy at intervals 3 years Endoscopy at intervals 1–2 years Endoscopic ultrasonography Consider pancreas-sparing or pylorussparing duodenectomy

Including random biopsies from mucosal folds in patients without polyps. Including multiple biopsies from polyps.

b

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result of the increased risk of extracolonic tumors, including thyroid cancer and hepatoblastoma in young children, optimal management of FAP includes follow-up on thyroid function, liver function tests, and ultrasound of the liver in young children. Chemoprevention Patients with FAP who were treated with 400 mg of celecoxib, a selective inhibitor of cyclooxygenase-2, twice a day for six months had a 28.0% reduction in the mean number size of colorectal polyps when compared with patients in the placebo group. However, polyps may return while the patient is taking nonsteroidal anti-inflammatory drugs and certainly do at discontinuation of the drug. Moreover, selective COX-2 inhibitors and nonsteroidal anti-inflammatory drugs do not influence the progression of polyps toward malignancy. Currently, none of these chemoprevention strategies should replace screening or prophylactic colectomy. Potentially they can impact on the endoscopic management of the remaining rectum after subtotal coloctomy by reducing polyp burden. Genetic Testing for FAP As for all hereditary syndromes, genetic testing starts by a mutation analysis in an affected proband. If the mutation is found, at-risk family members can now be tested for this mutation. In classic FAP, the indications to start mutation screening in a family is classic polyposis (Table 9). At-risk family members will be tested for the specific mutation at age 10 to 12 years, the age at which colon cancer screening should start. For AFAP (6) it is recommended that mutation analysis be initiated in any patient with 20 or more adenomas at one colonoscopy or over time. MYH mutation analysis should be initiated in kindreds with a recessive inheritance pattern of CRC or moderate polyposis. Hereditary Nonpolyposis Colorectal Cancer HNPCC patients have a germline mutation in one copy of an MMR (mismatch repair) gene in every cell (most of the HNPCC kindreds are due to germline mutations in hMSH2 or hMLH1) (7). During the lifetime of this person, inactivation of the second allele will occur at random in certain cells. This event leads to absence of the gene product in these cells, causing MMR deficiency. MMR deficiency has been described in many malignancies, for example,endometrium,ovary,stomach,ureters,andothers. However,HNPCC patients seem to develop predominantly CRC. The lifetime risk for an HNPCC carrier to develop a colorectal carcinoma is 78%, and for endometrial carcinoma it is 48% (8). This is difficult to explain. Genes important in colon epithelial homeostasis might be particularly sensitive to MMR deficiency. For

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example, the gene coding for the TGF-b type II receptor, which contains many microsatellite repeats, is frequently mutated in HNPCC CRCs. Clinical Manifestations HNPCC is characterized by early-onset colon cancer (median age 42) and extracolonic cancers (Table 2) (e.g., endometrial, ovarian, gastric, urinary tract, renal cell, biliary and gallbladder, central nervous system, and small bowel) in multiple individuals in a family (9). There is a predominance of right-sided tumors with frequent synchronous and metachronous tumors. Furthermore, cancers that arise in HNPCC appear to have an advanced rate of malignant transformation. The adenomas found in patients with HNPCC are more often histologically advanced and have areas of high-grade dysplasia. The true incidence of HNPCC is not well known, but it is thought to account for 5% of all CRCs. The disorder is inherited according to an autosomal dominant mode and is highly penetrant, so that about 80% of gene carriers will develop the disease. Clinically the disorder is often divided into two syndromes, called Lynch I and Lynch II, based on the presence or absence of extraintestinal malignancies (Table 2) (10). In Lynch I syndrome, neoplastic manifestations are confined to the large bowel, whereas in Lynch II syndrome affected individuals develop colorectal carcinoma as well as extracolonic tumors in the endometrium, stomach, small intestine, brain, hepatobiliary tract, urinary tract, and ovary. These extraintestinal manifestions should not be omitted when taking a family history of a CRC patient and might lead to the suspicion of HNPCC in certain atypical families. Criteria The most widely used criteria for the clinical diagnosis of HNPCC are the Amsterdam criteria (Table 6). These were developed to be able to focus genetic analysis in high-risk families and to allow uniform international studies (11). In clinical practice, however, the criteria are sometimes too strict and might lead to the exclusion of some true HNPCC families. For example, it is now widely recognized that endometrial cancer can be substituted for CRC in one of the family members. It is important for the clinician to bear in mind the possible variations in the presentation of an HNPCC kindred, due to predominant extraintestinal malignancies, for example, small family size, or later age of onset (12). Consequently, the Bethesda criteria (13) were developed to create a set of clinical criteria that would be more sensitive than the Amsterdam criteria and could be used to identify patients who should be considered for genetic testing for HNPCC. The Bethesda criteria turned out to be too unspecific, and were followed by the more stringent Amsterdam II (14) criteria. Most recently, in 2004, a revised version of the Bethesda criteria was published (15) that has been developed in another attempt to use clinical and pathological features to more accurately identify

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Table 6 Clinical Criteria for Hereditary Nonpolyposis Colorectal Cancer Amsterdam criteria I (all criteria must be met) One member diagnosed with colorectal cancer before age 50 years Two affected generations Three affected relatives, one of them a first-degree relative of the other two FAP should be excluded Tumors should be verified by pathologic examination Amsterdam criteria II (all criteria must be met) There should be at least three relatives with an HNPCC-associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter, or renal pelvis) One should be a first-degree relative of the other two At least two successive generations should be affected At least one should be diagnosed before age 50 years FAP should be excluded in the colorectal cancer cases Tumors should be verified by pathologic examination Revised Bethesda guidelines for testing colorectal tumors for microsatellite instability (meeting features listed under any of the criteria is sufficient) Colorectal cancer diagnosed in a patient who is less than 50 years of age Presence of synchronous, metachronous colorectal cancers or associated extracolonic cancers (Note: endometrial, ovarian, gastric, hepatobiliary, pancreas or small bowel cancer or transitional cell carcinoma of the renal pelvis or ureter, brain tumors usually glioblastoma, sebaceous gland adeomas and keratoacanthomas) regardless of age Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed under age 50. Colorectal cancer diagnosed in two or more first- or second-degree relatives with an HNPCC-related tumor, regardless of age Colorectal cancers with MSI-H histology (presence of tumor infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet-ring differentiation or medullary growth pattern) diagnosed in a patient who is less than 60 years of age Abbreviations: FAP, familial adenomatous polyposis; HNPCC, hereditary nonpolyposis colorectal cancer; MSI-H, microsatellite instability high.

individuals who should have microsatellite instability (MSI) or immunohistochemistry as a pretest to determine who should go on to mutation analysis of the MMR genes. If any of these criteria are met one should then perfom the tumor tests (MSI and immunohistochemistry); if either is positive, then perform genetic testing. The issue of diagnostic criteria for HNPCC is complex mainly because there are two endpoints. On the one hand, the criteria should be broad enough to allow a clinician to suspect HNPCC in a kindred, thus encouraging the necessary endoscopic screening in this family. On the other hand, mutation analysis for this disorder is laborious and time-consuming. This restricts the amount of testing that can be performed

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and implies the need for stricter selection criteria. At the moment, even in kindreds fulfilling the Amsterdam criteria, the rate of mutation detection is only about 50%. Nonetheless, a clinician or clinical geneticist will be faced with quite a few kindreds where molecular analysis is inconclusive or was not performed due to unfulfilled selection criteria. These families are still at risk of carrying HNPCC mutations and developing CRC and should be managed as such. An algorithm that incorporates recommendations based on more recent studies as well as the American Gastroenterological Association guidelines is shown in Figure 1. In general, it is recommended that if a patient is being considered for genetic testing, which includes either MSI testing of the tumor from an affected individual or germline mutation testing, the clinician should consult with a specialist who routinely manages HNPCC family members to determine an optimal diagnostic strategy that incorporates the clinical features and psychosocial issues of the family. Microsatellite Instability The key molecular feature of HNPCC tumors, MSI, can also be integrated in the selection of possible HNPCC mutation carriers (16,17). MSI is recognized by the frequent occurrence of insertion and deletion mutations in

Figure 1 Genetic testing for hereditary nonpolyposis colorectal cancer. Abbreviations: MSI, microsatellite instability; HNPCC, hereditary nonpolyposis colorectal cancer; IHC, immunohistochemistry.

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microsatellite repeats, which are variable numbers of repeating sequences of mononucleotides, dinucleotides, and trinucleotides found throughout the human genome (18). Clinically, MSI is identified by a test that is done on DNA extracted from fresh or paraffin-embedded, formalin-fixed tumor tissue obtained from the tumors of individuals suspected of having HNPCC. MSI is present less often in adenomas than in cancers, but large adenomas with dysplasia in HNPCC are often MSI. It is important to bear in mind, however, that MSI is not restricted to HNPCC cancers. Somatic inactivation of MLH1 by aberrant methylation of the MLH1 promoter occurs in approximately 15% of sporadic colon cancers. The older the patient with an MSI tumor at diagnosis, the less likely this is due to a germline MMR defect. Conversely only 90% of HNPCC tumors show MSI. This could be due to limitations in detection of MSI or due to low levels of instability such as in hMSH6 mutants. Immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 has been proposed as a tumor-based assay to identify families that should be considered for germline mutation testing. Loss of expression of these proteins is correlated with the presence of MSI and may suggest which specific mismatch repair gene is altered in a particular patient. As immunohistochemistry has a less than 100% sensitivity for detecting MSI, and because this rate can vary according to more or less experienced hands, immunohistochemistry is usually performed in parallel and not as a substitute for MSI (19). Clinical Management Endoscopic screening is still the cornerstone in the management of HNPCC patients. When genetic testing is positive, surveillance is mandatory, but even in families with negative test results and strong clinical suspicion for HNPCC, regular follow-up is necessary. This approach has been proved to be useful. Indeed, CRC rates in HNPCC kindreds can be reduced by screening. Jarvinen et al. (20) showed a decrease of CRC incidence by 62% in asymptomatic screened family members at 50% risk for HNPCC. To be effective, screening must be continued for a lifetime, and should be tailored to the natural history of the malignancies occuring in HNPCC (21). The current screening guidelines, as issued by the international collaborative group on HNPCC, are described in Table 7. These recommendations have been based on several studies. For example, the interval between colonoscopies was prompted by the observation of more rapid adenoma-to-carcinoma progression in HNPCC. International collaborative trials addressing these questions are still ongoing and might further improve the recommendations. In view of the high penetrance of the disease and of the high incidence of metachronous tumors, more aggressive measures such as prophylactic total colectomy in mutation carriers have been proposed. Prophylactic hysterectomy and oophorectomy have been proposed due to lack of validated

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Table 7 Recommendations for Hereditary Nonpolyposis Colorectal Cancer Screening Site

Procedure

Colon Endometrium and ovaries

Stomacha Urinary tracta a

Colonoscopy Gyn. examination Transvaginal ultrasound CA 125 Gastroscopy Sonography Urine analysis

Lower age limit (years)

Interval (years)

20–25 30–35

1–2 1–2

30–35 30–35

1–2 1–2

Only if present in family.

screening procedures in the prevention of endometrial and ovarian cancer. Such measures, however, are still a controversial issue, and have to be debated in the individual setting. Genetic Testing A suggested approach (Fig. 1) for genetic testing in HNPCC is to go directly to mutation analysis of the MMR genes if the Amsterdam I or II criteria are met. If the revised Bethesda criteria are met, then proceed to MSI and immunohistochemistry, and if either one is positive, proceed to mutation analysis. Alternatively, if no tumor tissue is available in individuals meeting the Bethesda criteria, genetic testing should be performed. Genetic testing is usually recommended for family members at risk around age 20 to 25, as clinical screening would start around that age. Identifying which MMR gene is responsible can impact on the management, for example, the relative risk of gastric cancer, ovarian cancer, and cancer of the urinary tract has been shown to be higher in patients with mutations in MSH2 compared with MLH1. Similarly, women with MSH6 mutations seem to be more likely to develop endometrial cancer (22). Germline mutations in MSH6 are also associated with an atypical form of HNPCC that often does not meet Amsterdam criteria because of a later age at onset and tumors that display low-level MSI. In HNPCC, in general, there is improved survival for individuals with colon cancer even when corrected for stage. Germline mutations in MSH2 and MLH1 have been found in 45% to 70% of families that meet strict clinical criteria for HNPCC, and thus these two genes account for most HNPCC cases. HMSH6 and PMS2 mutations account for a small number of families. There is large spectrum of mutations in all these genes,

Mismatch repair genes

HNPCC

Peutz–Jeghers

Adenomatous

Adenomatous except stomach, fundic cystic glands

Polyp histology

Cowden’s

PTEN

Juvenile,

Juvenile Juvenile SMAD4, BMPR1A polyposis

Peutz– STK11 Jeghers syndrome

APC

FAP

Syndrome

Relevant gene

Benign extracolonic features

Malignant extracolonic features. cumm. life-time risk

(Continued )

Desmoid tumors: 8% males, Duodenal cancer: 3–5%, Stomach: 23–100%, 100% pancreatic: 2%, 15% females; fundic (39 years) duodenum: papillary thyroid: 2%, glands: 50%; epidermal AFAP: 50–90%, gastric: 0.5%, CNS: 1%, cysts, osteoma: 17%; 80% jejunum: 50%, hepatoblastoma: 1.6% CHRPE, dental (50 years) ileum: 20%, abnormality, colon: 100% nonfunctioning adrenal adenoma: 13% Uterine: 40%, ovarian: 80% Keratoacanthomas, Colon: 2–3-fold 12%, gastric: 13%, sporadic rate (44 years) sebaceous adenomas, urinary: 10%, biliary: epitheliomas 10–20%, renal, CNS, small bowel: rare 39% Pancreatic: 36%, gastric: Orocutaneous melanin Stomach: 24%, (46 years) 29%, small bowel: 19%, pigment spots small bowel: breast: 54%, ovarian: 90%, rectum: 21%, lung 15%, sex 24%, colon: 27% cord: 10–20% Stomach and small 9–68% Stomach and duodenum Macrocephaly, bowel: may (34 years) combined: 20% hypertelorism:20%, occur, colon: congenital anomalies usually Esophagus: 66%, About 10% Facial tricholemmomas, Follicular or papillary

CRC risk Polyp distribution (mean age of diagnosis) and frequency

Table 8 Features of Inherited Colorectal Cancers Syndromes

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lipomas, inflammatory

Polyp histology stomach: 75%, duodenum: 37%, colon: 66%

CRC risk Polyp distribution (mean age of diagnosis) and frequency oral papillomas, multinodular goiter, fibrocystic breast disease, cerebellar gangliocytomatosis, hemangiomas

Benign extracolonic features

thyroid: 3–10%, breast: 25–50%, uterine 5–10%

Malignant extracolonic features. cumm. life-time risk

Abbreviations: CRC, colorectal cancer; FAP, familial adenomatous polyposis; APC, adenomatous polyposis coli; AFAP, attenuated FAP; HNPCC, hereditary nonpolypois colorectal cancer; CNS, central nervous system; CHRPE, congenital hypertrophy of the retinal pigment epithelium; PTEN, phosphatase and tensin homolog.

Relevant gene

Features of Inherited Colorectal Cancers Syndromes (Continued )

syndrome

Syndrome

Table 8

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and very often the results obtained from mutation analysis may be inconclusive because the identified base pair change is a variant of unknown significance. Genetic testing in HNPCC is still complicated by factors such as patient selection, difficulty in detecting the heterogeneous mutations, and because not all the responsible genes nor their disease penetrance are known. A positive test result can bring about a lot of anxiety and psychological; on the other hand, it does allow a person to make informed decisions about the future. Genetic testing should always be performed in specialized genetic centers where correct pre- and post-test counseling and psychosocial follow-up can be offered. High-risk kindreds who cannot be offered molecular diagnosis will benefit from risk assessment and information on screening procedures by the genetic counselor.

PEUTZ–JEGHERS SYNDROME Peutz–Jeghers Syndrome (PJS) is a rare autosomal dominant disorder that is generally recognized by the association of melanocytic macules of the lips and buccal mucosa, and digits and GI hamartomatous polyps (23). There is still some debate on the matter, but a clinical diagnosis of PJS can probably be made if two Peutz–Jeghers polyps are found in the GI tract or if one Peutz–Jeghers polyp in the GI tract is found in association with classic Peutz– Jeghers pigmentation, or a family history of the syndrome. In addition to an increased risk of colon cancer, PJS is associated with an increased risk of various neoplasms, including sex cord tumors, pancreatic cancer, lung cancer, breast cancer, uterine cancer, melanoma, and gastric cancer (Table 8) (24,25). In light of this increased cancer risk in multiple tissue types, an extensive surveillance regimen has been recommended including upper and lower endoscopy, breast examination, and some form of surveillance for pancreatic and gynecologic malignancies. Guidelines, however, differ considerably over when to initiate screening, intervals between screening, and which techniques to use. The optimal surveillance strategy is unclear and to date the efficacy of intensive surveillance for cancer associated with PJS has not been established. Recommendations from the St. Mark’s Polyposis Registry consist of annual assessment including a full blood count, pelvic ultrasound in females, testicular ultrasound in males, and pancreatic ultrasound in all individuals. Every two years, patients should have an upper and lower endoscopy and some form of examination of the small bowel, preferably an enteroclysis. Patients should be screened for breast cancer according to the clinical recommendations for other high-risk individuals. Patients should be encouraged to perform monthly breast self-examination; clinical exams should be performed annually, beginning in the late teen years or as concerns arise. Mammography should begin at the age of 25 years. Pap smears should be done at least every three years (26).

Colon cancer risk (average age at diagnosis)

Colonoscopy every 3 years, starting late teens or at symptoms if earlier Colonoscopy every 3 years, starting early teens or at symptoms if earlier None established

Annual sigmoidoscopy beginning 12 years: colonoscopy late teens if AFAP Annual colonoscopy starting age 25

Colon cancer screening recommendations

Abbreviations: FAP, familial adenomatous polyposis; APC, adenomatous polyposis coli; AFAP, attenuated FAP; HNPCC, hereditary nonpolyposis colorectal cancer; MYH, MutY associated polyposis; PTEN, phosphatase and tensin homolog.

9%

Typical colonic polyps

PTEN (80–90%)

Cowden 25 years

5 or more juvenile polyps 9–68% (34 years)

Early teens or at SMAD4, BMPR1A (50%) symptoms if earlier

Any Peutz–Jeghers polyp 39% (46 years) or pigmentation

20 or more adenomatous FAP 100% (39 years), polyps AFAP 80% (50 years) Amsterdam II or revised 80% (44 years) Bethesda

Clinical signs that should initiate genetic testing

Juvenile polyposis

Late teens or at symptoms if earlier

20–25 years

MLH1, MSH2 (50–70%), MSH6, PMS2 STK11/LKB1 (50–60%)

HNPCC

Peutz–Jeghers

10–12 years

APC (80–90%) MYH

Age to consider predictive genetic testing if mut. known

FAP

Disorder

Causative gene and frequency mut. found

Table 9 Gene Frequency, Genetic Testing, and Management Guidelines

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About 50% of patients with clinical Peutz–Jeghers disease are found to have a mutation in the STK11 gene (Table 9) (27). Additional genes probably exist, but have not yet been identified. Genetic testing for PJS can be initiated when a typical Peutz–Jeghers polyp is found (bands of arborizing smooth muscle in the lamina propria) or characteristic melanin pigmentation is present. In general, referring such patients to physicians with extensive experience with these disorders is recommended.

JUVENILE POLYPOSIS Juvenile polyposis (JPS) is an autosomal dominant syndrome that is associated with an increased risk of CRC. Classic juvenile polyps consist of stromal elements with a normal epithelial layer (dilated, mucus-filled cysts and abundant lamina propria that is lacking in smooth muscle) and are distinct from both adenomatous polyps and those of the Peutz–Jeghers type. Although solitary juvenile polyps are common in children, juvenile polyposis is marked by the presence of many polyps either in the colon or throughout the GI tract (28). Patients with juvenile polyposis typically present with benign complications, including GI bleeding, obstruction, and intussusception, in the first three decades of life. Malignant degeneration and complications start after the fourth decade. JPS is associated with a 10% to 38% lifetime risk of colon cancer, and the cancers appear to arise from adenomatous components present in some juvenile polyps (Table 8) (29). Colonoscopy every one to two years starting age 15 to 18 is advised, with removal of the larger polyps to be examined for adenomatous components. In addition, the lifetime risk of gastric and duodenal cancer appears to be approximately 15% to 21%. Thus the upper GI tract should be surveyed every one to two years and the larger polyps removed (30). In light of the recently found association between juvenile polyposis and hereditary hemorrhagic telangiectasia in patients with SMAD4 mutations, JPS patients with these mutations should be actively screened for the vascular lesions, especially occult arteriovenous malformations in visceral organs that may otherwise present acutely with serious consequences (31). Although juvenile polyps are also a feature of other genetic syndromes, juvenile polyposis is a distinct disorder that is caused by mutations in either SMAD4 or BMPR1A (32). SMAD4 and BMPR1A (33) genes account for about 50% of juvenile polyposis cases (Table 9). Mutations in other genes involved in TGF-b signaling are likely to be involved in the remaining families (34). Genetic testing is recommended in the first decade in families that have the disorder, since children often become symptomatic (rectal bleeding, abdominal pain, diarrhea) early on.

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Table 10 International Cowden Consortium Operational Criteria for the Diagnosis of Cowden Syndrome Ver 2000 Pathognomonic criteria

Major criteria

Minor criteria

Mucocutaneous lesions Breast cancer

Other thyroid lesions (e.g., goiter) Trichilemmomas, facial Thyroid cancer, especially Mental retardation follicular thyroid cancer (IQ75) Acral keratoses, Macrocephaly (occipital frontal Hamartomatous papillomatous lesions circumference 97th percentile) intestinal polyps Fibrocystic disease of the breast Lipomas, fibromas Mucosal lesions Lhermitte–Duclos disease, defined as presence of a cerebellar dysplastic gangliocytoma Endometrial carcinoma Genitourinary tumors (e.g., uterine fibroids, renal cell carcinoma) or genitourinary malformation An operational diagnosis of Cowden syndrome is made if an individual meets any one of the following criteria: Pathognomic mucocutaneous lesions alone if there are: Six or more facial papules of which three or more must be trichilemmoma, or Cutaneous facial papules and oral mucosal papillomatosis, or Oral mucosal papillomatosis and acral keratoses, or Six or more palmo plantar keratoses Two major criteria but one must be either macrocephaly or Lhermitte–Duclos disease One major and three minor criteria (Continued )

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Table 10 International Cowden Consortium Operational Criteria for the Diagnosis of Cowden Syndrome Ver 2000 (Continued ) Pathognomonic criteria

Major criteria

Minor criteria

Four minor criteria In a family in which one individual meets the diagnostic criteria for Cowden syndrome, other relatives are considered to have a diagnosis of Cowden syndrome if they meet any of the following criteria: A pathognomonic mucocutaneous lesion Any one major criterion with or without minor criteria Two minor criteria

COWDEN SYNDROME OR PTEN HAMARTOMA SYNDROME Germline mutation of PTEN leads to the development of the related hereditary cancer predisposition syndromes, Cowden’s disease and Bannayan–Zonana syndrome, wherein breast and thyroid cancer incidence is elevated (35). Hamartomas involve the skin, intestine, breast, and thyroid gland (Table 8). Eighty percent of patients present with dermatologic manifestations. The diagnostic criteria for Cowden’s disease are summarized in Table 10 (36). Only 35% of patients who meet the diagnostic criteria for Cowden’s disease have GI polyposis. Patients meeting the clinical criteria of the disease are found to have identifiable PTEN mutations in as many as 80% to 90% of cases (Table 9). The majority of patients with Cowden’s disease will have some form of benign thyroid or breast disease (37). In addition, the projected lifetime risk of thyroid malignancy is 10% and of breast malignancy is approximately 30% to 50% (Table 9). Clinical breast examinations are recommended annually for women beginning at age 25, and annual mammography starting at age 30 to 35. Breast cancer can also occur in men. A baseline thyroid ultrasound is also recommended at age 18, followed by an annual thyroid ultrasound thereafter. Women with Cowden syndrome should also undergo endometrial screening involving annual blind biopsies starting at age 35 to 40, and annual endometrial ultrasound after menopause, with biopsy of suspicious lesions. Annual urine analysis for the detection of renal cell carcinoma is also recommended along with annual urine cytology and renal ultrasound if there is a family history of renal cancer. Typical hamartamatous polyps can occur in the small and large bowel, with a low lifetime risk of CRC. There are no specific guidelines for endoscopic screening, but regular upper and lower GI endoscopy with biopsy of the polyps seems prudent.

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FAMILIAL GASTRIC CANCER Hereditary diffuse gastric cancer arises from mutations of the E-cadherin gene that are inherited in an autosomal dominant fashion with a high penetrance over 70% (38). Only ‘‘diffuse type’’ histology arises, and this syndrome does not account for familial clustering of intestinal-type gastric cancer. Management of these families is very complex, but because of the very high penetrance of the disease, prophylactic surgery should be discussed. In general, referring such patients to physicians with extensive experience with these disorders is recommended. FAMILIAL PANCREATIC CANCER On the basis of detailed family history it is estimated that 15% to 38% of pancreatic ductal adenocarcinomas arise owing to inherited susceptibility. The genetic etiology relates to several syndromes in which pancreatic cancer is sometimes observed and also to additional families in which no specific syndrome can be identified. These syndromes include familial atypical multiple mole-melanoma (FAMM), breast–ovarian cancer syndrome, von Hippel-Lindau syndrome, HNPCC, PJS, ataxia-telangiectasia, and pure pancreatic cancer kindreds. In about 15% an inherited germline mutation can be identified. The genes that are known to give rise to familial pancreatic cancer include the BRCA2, p16, STK11, MLH1, FancC, and FancG genes and the cationic trypsinogen gene (39). Currently, the gene identified most commonly as mutated in familial pancreatic cancer families is the BRCA2 gene (40); 17% to 19% of patients with pancreatic cancer and two or more affected relatives carry a germline mutation in the BRCA2 gene. Germline BRCA2 mutations also have been identified in 5% to 10% of patients who present with pancreatic cancer without a family history of the disease. Presently, the optimal approach to screening this high-risk population for early pancreatic cancer is unknown and still under study. Minimally invasive tests and procedures such as Endoscopis Ultrasonography (EUS), magnetic resonance imaging/magnetic resonance cholangiopancreatography, computed tomography (CT), positron emission tomography, biochemistry, and CA19–9 are good candidates (41). In general, referring such patients to physicians with extensive experience with these disorders is recommended. HEREDITARY MIXED POLYPOSIS This apparently rare hereditary polyposis syndrome is characterized by the presence of a mixture of adenomatous polyps, hyperplastic polyps, juvenile polyps, and polyps with mixed histology in one individual. CRC has been reported in these kindreds at varying ages (42). The causative gene for this syndrome has not been identified, and there are no available tests to identify

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asymptomatic carriers of hereditary mixed polyposis syndrome (HMPS) (43). Any individual suspected of having HMPS should be referred to a center with physicians who are specialized in polyposis syndromes and colon cancer family syndromes to obtain current management recommendations.

FAMILIAL COLORECTAL CANCER In addition to the well-recognized syndromes described earlier (FAP, HNPCC), clusters of CRCs occur in families much more often than would be expected by chance. Postulated reasons for this increased risk include ‘‘mild’’ and undetected mutations of APC and mismatch repair genes, as well as yet unknown polymorphisms in genes involved in nutrient or carcinogen metabolism (44). Candidate alleles that have been shown to be associated with modest increased frequencies of colon cancer include the APC, I1207K, and E1317Q polymorphisms and loss of imprinting of the IGF2 gene. However, none of these alleles have been characterized well enough to support its routine use in a clinical setting at this time. This familial clustering in about 10% to 20% of CRCs has implications for screening because the immediate family members of a patient with apparent sporadic CRC have a twofold to threefold increased risk of the disease (45). The magnitude of the risk depends on the age at diagnosis of the index case, the degree of kinship of the index case to the at-risk case, and the number of affected relatives. Thus, in addition to screening the easily identifiable high-risk groups such as FAP and HNPCC, care should be taken to recognize intermediate-risk patients and to provide them with appropriate screening recommendations (Fig. 2) (46). Because the molecular basis and the natural history of these intermediate-risk patients is largely unknown, screening recommendations are as yet more empirical. Future research into the molecular basis of these syndromes should allow more definite risk evaluation. Screening strategies have been developed to address the familial risk of commonly observed colon cancer. Screening recommendations are empiric and combine the known effectiveness of available screening tools with the observed risks associated with family history. If a person has a first-degree relative with colon cancer, average-risk colon cancer screening is recommended, but starting at age 40 years. The decreased age is given because the risk at age 40 years for those with an affected first-degree relative is similar to the risk at age 50 years for the general population. An individual with two first-degree relatives affected with colon cancer or one first-degree relative diagnosed under the age of 60 years should have colonoscopy beginning at age 40 years, or 10 years younger than the earliest case in the family. Colonoscopy should be repeated every five years if negative. An even stronger family history of colon cancer should suggest the consideration of one of the inherited syndromes of colon cancer.

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Figure 2 Screening according to family history. Abbreviations: FAP, familial adenomatous polyposis; HNPCC, hereditary nonpolyposis colorectal cancer; CRC, colorectal cancer. Source: Ref. 46.

ASPECTS OF GENETIC TESTING FOR GI CANCER SUSCEPTIBILITY Genetic counseling should be a component of any genetic testing to ensure that optimal family histories are obtained and that appropriate risk assessment and test selection are performed (47). Because of the complexity of this rapidly evolving and vast field, a multidisciplinary approach is necessary, bringing together gastroenterologists, other organ specialists, geneticists, oncologists, and psychologists. Issues that become relevant during genetic testing are patient’s perception of risk, psychological stability and concerns, coping with anger, anxiety, responsibility, guilt, stress, self-image issues, survivor guilt, and optimal screening and prevention strategies (48). These questions need to be addressed by an experienced and multidisciplinary team. Genetic testing is indicated for each of the inherited syndromes when certain features of the syndrome are present (Table 9) (49). DNA is extracted from white blood cells and the relevant genes are analyzed to detect disease-causing mutations (50). The success of finding a mutation in a person in a family clinically identified as having one of the syndromes is also given in Table 9. Finding the mutation confirms the clinical diagnosis. Failure to find a mutation in a person suspected to have an inherited condition, however, does not rule out the syndrome. There are a number of technical reasons why mutations cannot always be found. In this case, further testing in relatives of the index person tested is not useful because

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mutations would not be found in them either. If a mutation cannot be found in that first person, the genetic test is said to be ‘‘uninformative.’’ Cancer screening must be continued on all family members. But if a relevant mutation is found in the first person, or index case, then other family members can undergo ‘‘mutation specific’’ genetic testing. Only the exact mutation found in the first family member is tested for in other family members. Special screening can then be directed to those who have the disease-causing mutation, while those who do not have the mutation need no more than average-risk screening. In reality, genetic testing in a cancer syndrome very often leads to inconclusive results either because the mutation is not found, because a mutation of unknown significance is found, or because the syndrome was misclassified and the correct genes were not searched. Despite best efforts of everyone involved this scenario remains frequent. Current basic science knowledge on the pathogenesis of many of these syndromes is sorely lacking. Often mutations are found in an affected individual, but due to lack of knowledge on the exact function of the encoded protein, or lack of assays to test the effect of the mutation, the mutation will be classified as of unknown significance. No genetic testing or clinical guidelines can be based on a mutation of unknown significance. Another problem is posed by small families, lack of information on relatives or untraceable relatives, which can lead to misclassification of a syndrome. An optimal approach would include a registry-based, multidisciplinary approach, ensuring correct data gathering, verification, and updating over time. Without this many familial syndromes will go unrecognized and not be managed or tested correctly. A slightly provocative statement is that genetic testing should be considered the ‘‘icing on the cake’’ for many families. In these families in which a mutation is identified, genetic testing confirms the clinical suspicion, reinforces the surveillance recommendations, and allows predictive mutation-specific testing in at-risk individuals. However, the most important task is already performed by the clinicians recognizing the syndrome, and the most important remaining task is the implementation of tailored surveillance exams in these patients. The continuous need for motivating the patients and providing correct follow-up of the lifelong surveillance exams is a formidable task for the clinicians. For the majority of families, genetic testing will not be informative. For these families, there is still often the misconception that if no mutation is found, no hereditary cancer predisposition exists. Nothing is less true, and letting the guard down in the management of these families can lead to tragic situations. However, without molecular confirmation of the diagnosis, and with only often empiric and loosely defined risk assessments available, daily management of these families can be very difficult. Resources directed toward continuing education of physicians and providing administrative and other support are well directed. For these families the improvement in outcome and the potential lives saved will depend solely on the dedication of patients and physicians working together.

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6 The Surgical Principles of Managing Colorectal Cancer Ian R. Daniels and Richard J. Heald Pelican Cancer Foundation, North Hampshire Hospital, Basingstoke, U.K.

INTRODUCTION Of infinite importance is the dissemination of cancer cells through the lymphatic channels, so that a knowledge of the lymphatic system is essential to the performance of any radical operation for cancer. —W.E. Miles, 1939 The key to the successful management of colorectal cancer is the understanding of the embryological origin of the colon and rectum. Surgery, performed along embryological planes, is the key to achieving a cure in colorectal cancer. With the development of accurate preoperative staging, recognition that the disease has spread into an area of tissue of differing origin influences the use of preoperative therapy or the performance of a more radical resection. Following resection, the pathologist influences further management by assessing the completeness of resection and identifying other factors that impact on the patient’s prognosis. In this chapter, we will address the surgical management of colorectal cancer, the lessons that have been learned during the advancement of treatment for rectal cancer, the surgical principles, and how they may be applied to colonic cancer. While it has been uniquely demonstrated, in the case of rectal cancer, that inadequate surgery leads to local failure and, therefore, distressing symptoms for the patient, the improvements we have now seen 151

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may be transferred to the treatment of colonic cancer. Indeed, in Sweden, a nation that has led the improvements in developing the use of radiotherapy for rectal cancer, for the first time in any nation, survival of patients with rectal cancer is better than with colon cancer. THE ‘‘EMBRYOLOGICAL APPROACH’’ TO RECTAL CANCER An understanding of the embryological development of the rectum underlies the principle to the successful management of rectal cancer. The artery of the rectum, the inferior mesenteric artery, is the integral vessel of the hindgut, the distal portion of the embryological gastrointestinal tract. Its relationship to the cloaca and the corresponding anatomy allow the surgeon to understand the basics of rectal cancer surgery. The mesorectal fascia and the contained mesorectum (the fatty pad surrounding the rectal muscle wall) represent the mesentery of the hindgut. This contains the vessels and lymphatics of the primitive hindgut. Containment of the tumor within this mesorectal package and the complete removal of the intact package during surgery are the key elements in the prevention of local recurrence (LR) and achieving a cure. Tumor spread beyond the mesorectal envelope or incomplete surgical excision leads to the development of LR in the patient. THE MULTIDISCIPLINARY APPROACH While the patient usually presents to the surgeon, the diagnosis and management of colorectal cancer is multidisciplinary. After recognition of symptoms, or clinical suspicion, the patient will be referred for radiological and/or endoscopic assessment. Prior to surgery, assessment of local disease spread and metastatic disease is performed. In rectal cancer, regimes of preoperative therapy have been advocated to downstage/downsize the tumor prior to surgery. In the colon, tumor invasion into other structures provides the surgeon with advance warning of the potential problems at operation. THE PRINCIPLES OF RECTAL CANCER EXCISION: TOTAL MESORECTAL EXCISION All carcinomas of the lower sigmoid and upper rectum are tabooed by all practical surgeons . . . on account of their inaccessibility. All are abandoned without hope to linger on for a few months until death relieves them of their loathsome condition. —H. Maunsell, 1892 In the century following Maunsell’s (1) observation, the management of rectal cancer was revolutionized. As surgeons, we have taken up the challenge, aiming to provide more sphincter-preserving surgery, better function, lower LR rates, minimal urogenital morbidity, and improved overall survival.

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However, at the beginning of the 20th century rectal cancer was treated, if at all, by attempted surgical resection. The standard operation for rectal cancer, in most parts of the western world, throughout the whole of the last century was the abdominoperineal excision, as advocated by the English surgeon Ernest Miles in 1908 (2). As recently as 1993, Murray and Veidenheimer (3) described it as the ‘‘gold standard’’ by which all other operations must be judged, not only for carcinomas of the distal third of the rectum but also for bulky tumors of the middle third. It is notable that the technique described by Miles had become standard practice soon after Miles’ original paper but its acceptance was not challenged. This must be contrasted with the work of Henri Hartmann (4,5), which was largely disregarded, leading to the additional morbidity involved in the extirpation of many anal canals. Miles’ theory behind the development of the abdominoperineal excision was based upon observations on the spread of rectal cancer. Miles recognized the upward spread of the lymphatics to the root of the inferior mesenteric artery and dismissed earlier work suggesting submucosal spread of carcinoma within the rectum concluding that: . . . Observations lead us to believe that detached cancer cells pass through the bowel wall somewhat rapidly by means of the intramural lymphatic system and, gaining the external lymphatics, give rise to extramural metastases scattered over a fairly wide area, long before the muscular coat has been penetrated by direct extension of the growth. While this may occur from time to time, we now realize that a relatively orderly progression from local to lymphovascular, and finally distant spread, is a much more common pattern. Miles felt that the extramural pathways existed in three divisions: 1. The ‘‘zone of downward spread’’—evidence for these channels came from Miles’ experience of locally recurrent disease within the ischioanal fossae from perineal resections. 2. The ‘‘zone of lateral spread’’—evidence for these came from the reported findings of plaques of tumor found within the levator ani. Miles also observed peritoneal deposits on the pelvic sidewalls and again implicated these channels. 3. The ‘‘zone of upward spread’’—the lymphatics of this zone were the retrorectal glands, those of the pelvic mesocolon, the glands situated at the bifurcation of the left common iliac artery, and the median lumbar (aortic) glands. Miles (6) recognized these as, ‘‘the most constant and, therefore, the most important of all the routes of spread.’’

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In 1939, while Miles (6) was publishing his book ‘‘Rectal Surgery. A Practical Guide to the Modern Treatment of Surgical Disease,’’ Dixon (7), in America, described the sphincter-preserving anterior resection (AR). Although previously alluded to by Moynihan (8) in the United Kingdom, it was Dixon who described the first large series. Dixon performed the operation in three stages: initially, by defunctioning the rectum with a colostomy, then an AR with the colostomy remaining, and lastly, closure of the colostomy. Dixon agreed with Miles that the ‘‘zone of upward spread’’ was the most important factor associated with the development of metastases. Dixon (7) believed that AR led to reduced perioperative morbidity and improved functional outcome and quality of life for the patients by restoring bowel continuity. The reports of AR raised questions about whether local control would be achieved. Such leading surgeons as Gabriel, of St. Mark’s, intoned against ‘‘the evils of such irresponsible challenges to established practice.’’ Those who were determined to persevere produced a further ‘‘standard’’ that had little scientific basis, namely, ‘‘the 5-cm rule’’ (9–11). However, later studies by Scott et al. (12) showed that microscopic tumor spread distal to the main tumor is rare, and occurs in cases with lymph node involvement and an almost invariably unfavorable prognosis. The discussions that limited the use of the AR in the 1940s resurfaced again in the 1970s and 1980s following the introduction of circular stapling devices. The early reports were followed by suggestions that the new technology would lead to increases in anastomotic failure and LR (13). Performing surgery within the confines of the pelvis is one of the most challenging aspects of colorectal surgery. The importance of accuracy in rectal cancer surgery is paramount in aiming to provide a cure for the patient. Conventional surgical techniques, using blunt dissection of the rectum and mesorectum (the embryological hindgut package), pose a high risk of damage to the hypogastric nerves and breaching of the mesorectum. A significant morbidity in bladder and sexual dysfunction is attributed to the damage of both the superior and inferior hypogastric nerve plexuses. This can vary between 20% and 60% of patients in different centers (14). When the mesorectum is excised intact, enveloped by the visceral pelvic fascia, all components of the pelvic autonomic nervous system can be preserved. This means that there is sparing of the superior hypogastric nerves, anterior roots of S2, S3, S4, and the nervi erigentes along the pelvic sidewalls. Similarly, breaching of the mesorectum influences LR of the tumor and therefore increases morbidity and mortality for the patient—symptoms include pelvic pain, ureteric obstruction, fistulation, and poor bowel function. LR rates, after potentially curative surgery, have varied between 5% and 40% in different reports. Five-year survival in patients with LR is 1 mm between the CRM and the tumor. The results showed that in 1994, 78% of patients had a TME and, by 1997, this figure had risen to 92%. The LR rate at 30 months was 6% in the TME group, compared with 12% in the conventional surgery group. The four-year survival was also greater in the TME group, 73% versus 60% in the conventional surgery group. The risk factors for LR identified as significant were male gender tumor at