The American Cancer Society guidelines for colorectal cancer screening: Have we gone too far (or not far enough)?

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these complexes, which leads to novel epitopes that can be recognized by the autoantibodies of celiac patients. This suggests that the released amount of small intestinal tTG that is confronted with dietary gliadin may in part determine the extent of the autoimmune response and perhaps the manifestation of the disease. T cells directed to these epitopes and tTG itself, rather than gliadin, may play an important role in the initiation and perpetuation of intestinal damage, a hypothesis that is currently under investigation by several groups. We want to comment on some of the points raised by Cronin and Shanahan. First, Picarelli et al. (Gastroenterology 1996;111:608–616) studied 10 patients with typical symptoms and positive IgA EMA who initially had inconspicuous small bowel histological findings. However, 3 of 6 patients who were then subjected to multiple rebiopsies had at least one sample with severe villous atrophy, suggesting that these individuals had classical celiac disease. On the other hand, only 4 of these patients demonstrated the typical HLA typing, which indicates that related intestinal diseases may also trigger an IgA immune response to tTG. Second, the approximately 10-fold higher incidence of celiac disease in IgA-deficient individuals who only have low-titer or absent EMA cannot be used as an argument against an important pathogenic role of tTG, because the T-cell mediated immune reaction to tTG and/or tTG-gliadin complexes could be more important than the humoral immune response. Furthermore, the IgG response to the autoantigen, which despite lower specificity is often high in these patients, was not determined. Third, similarly, the finding of Bu¨rgin-Wolff et al. (Arch Dis Child 1991;66:941–947) that only 90% of celiac children below 2 years of age demonstrated EMA does not argue against the importance of tTG. Again, it is only the humoral response in the form of IgA autoantibodies that is reflected by EMA. In addition, EMA immunofluorescence may simply not be sensitive enough to detect celiac disease in small children who may have borderline titers. We could indeed show that some EMA-negative patients with histologically proven celiac disease have low but still significantly elevated IgA anti-tTG titers in our ELISA assay (unpublished observations). DETLEF SCHUPPAN, M.D., Ph.D. WALBURGA DIETERICH, Ph.D. ERNST–OTTO RIECKEN, M.D.

THE AMERICAN CANCER SOCIETY GUIDELINES FOR COLORECTAL CANCER SCREENING: HAVE WE GONE TOO FAR (OR NOT FAR ENOUGH)? Byers T, Levin B, Rothenberger D, Dodd GD, Smith RA (for the American Cancer Society Detection and Treatment Advisory Group on Colorectal Cancer). American Cancer Society guidelines for screening and surveillance for early detection of colorectal polyps and cancer: update 1997. CA Cancer J Clin 1997;47:154–160. Life expectancy for those with colorectal cancer is strongly related to disease stage at diagnosis. Furthermore, most colorectal cancers arise in adenomatous polyps that can be detected and removed endoscopically. It seems likely, therefore, that detecting adenomas and early-stage cancers and removing them will improve overall survival from colorectal cancer. This is supported to some extent by prospective trials at tertiary centers such as the Minnesota Colon Cancer Control Study (N

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Engl J Med 1993;328:1365–1371) and the National Polyp Study (N Engl J Med 1993;329:1977–1981). The impact of screening large asymptomatic populations on colon cancer– related mortality is less clear, but the increasing volume of direct and indirect evidence of benefit has led even traditionally cautious agencies such as the U.S. Preventative Services Task Force to endorse colorectal cancer screening (Guide to Clinical Preventative Services. 2nd ed. Report of the US Preventative Services Task Force. Washington, DC: Department of Health and Human Services, 1995). Colorectal cancer screening will also be reimbursed under the new Medicare legislation beginning January 1998. Almost all major health-related agencies have endorsed screening for colorectal cancer, but the key questions of ‘‘who, how, and how often’’ remain a source of debate. In February 1997, clinical practice guidelines for colorectal cancer screening were published as a 48-page document in this journal (Gastroenterology 1997;112:594–642). These Agency for Health Care Policy Research (AHCPR) ‘‘guidelines’’ set forth a variety of options for colorectal cancer screening and provided a lengthy discussion of the rationale for each. The American Cancer Society (ACS) was among several organizations endorsing these guidelines. This organization has now published its own set of new guidelines for screening and surveillance for early detection of colorectal polyps and cancer. Options are presented with much less discussion. Some are based on strong clinical evidence, whereas for others the weight of evidence is less compelling. These guidelines provide recommendations in three major categories based on risk (average, moderate, and high). Moderate- and high-risk categories are further subdivided according to personal and family history of adenoma, carcinoma, or predisposing disease. Average risk is defined as all people 50 years or older who do not fall into moderate- or high-risk categories. This category encompasses 70%–80% of individuals in the U.S. population. Annual fecal occult blood testing (FOBT) plus flexible sigmoidoscopy every 5 years is recommended for this group. Colonoscopy every 10 years or double-contrast barium enema (DCBE) every 5–10 years are provided as alternative screening modalities. Moderate-risk individuals fall into five subgroups. First, it is recommended that those with single small (,1 cm) adenomatous polyps undergo colonoscopy at initial diagnosis and within 3 years after polyp removal. If the 3-year examination is negative, the patient returns to screening as an average-risk individual. Second, people with large ($1 cm) or multiple polyps should undergo colonoscopy at initial diagnosis and within 3 years of polyp removal. If the 3-year examination is negative, colonoscopy should be repeated every 5 years. Third, individuals with a personal history of curative-intent resection of colorectal cancer should undergo total colonic examination (TCE) within 1 year of resection and 3 years thereafter. Options include colonoscopy or DCBE. If normal, TCE is repeated every 5 years. Fourth, individuals with colorectal cancer or adenomatous polyps in a first-degree relative younger than age 60 or in 2 or more first-degree relatives of any age should undergo TCE

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at age 40 or 10 years before the youngest case in the family (whichever is earlier) and every 5 years thereafter. Fifth, those with colorectal cancer in other relatives should undergo screening as per average-risk individuals, but one may consider screening before age 50. High-risk individuals are defined as those with a family history of familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), or a personal history of inflammatory bowel disease. Those with a family history of FAP should undergo early endoscopic surveillance at puberty and be considered for genetic counseling and testing. If polyposis is discovered or genetic testing is positive for mutations of the APC gene, colectomy should be considered. Otherwise, endoscopy should be performed every 1–2 years. Those with a family history of HNPCC should undergo colonoscopy and genetic counseling and testing beginning at age 21. If genetic testing is positive or not done, colonoscopy should be performed every 2 years until age 40, then yearly. Patients with inflammatory bowel disease (pancolitis) should undergo colonoscopy with biopsies for dysplasia beginning 8 years after colitis is determined to have begun, and every 1–2 years thereafter. Surveillance should begin in those with left-sided colitis (distal to the splenic flexure) 12–15 years after the start of disease. Comment. The ACS issues guidelines for practitioners and the general public, and these guidelines often dictate clinical practice. The newly revised ACS guidelines represent a major departure from previous guidelines published in 1992, and were prompted by growing evidence about the efficacy of colorectal cancer screening and knowledge concerning the genetics of colorectal cancer. It was determined that specific advice would be offered ‘‘when scientific data could support specific methods, and a range of acceptable options would be offered when scientific data were insufficient to contrast alternative effective methods.’’ Furthermore, the guidelines would be ‘‘clear enough for widespread clinical use’’ but flexible enough to allow for ‘‘tailoring of approaches to meet clinical needs.’’ The ACS has taken an important step in recognizing the need to expand screening recommendations based on relative risk and on being as up-to-date as possible in considering available data. Guidelines for practicing physicians should be straightforward and based on a preponderance of scientific data. The weight of evidence should dictate specific recommendations. A ‘‘range of options’’ is acceptable when supportive evidence is compelling for each option. Do the ACS guidelines meet these expectations? Colorectal cancer in the general or ‘‘average-risk’’ population is uncommon below age 50, and it seems reasonable to begin screening at this age in most individuals. Three long-term, prospective controlled clinical trials involving more than 260,000 individuals have shown a beneficial impact of FOBT on colorectal cancer survival in the United States and Europe (N Engl J Med 1993;328:1365–1371, Lancet 1996;348:1472–1477, Lancet 1996;348:1467–1471). The Minnesota Colon Cancer Control Study showed a 33% reduction in colorectal cancer–related mortality in those screened with yearly FOBT. The majority of this effect was due to FOBT and not chance detection by colonoscopy ( J Natl Cancer Inst 1997;89:1423–1428). The recommendation for yearly FOBT thus stands on a firm scientific base. Data on the efficacy of sigmoidoscopy are compelling, but less direct. The effectiveness of sigmoidoscopy in reducing colorectal

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cancer–related mortality is supported by at least three case-control studies showing an almost two-thirds reduction in mortality from cancers within reach of the sigmoidoscope compared with matched controls (N Engl J Med 1982;326:653–657, J Natl Cancer Inst 1993;85:1311–1318, Arch Intern Med 1995;155:1741–1748). There have been no completed prospective controlled trials, however, that address the effectiveness of screening flexible sigmoidoscopy. It is hoped that the ongoing Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) sponsored by the National Cancer Institute will provide these data. Nonetheless, the recommendation for screening flexible sigmoidoscopy seems to be based on strong indirect evidence. Recommendations for a 5-year interval between sigmoidoscopies is inferred from the protective effect of sigmoidoscopy in case-control studies and from polyp occurrence rates after serial colonoscopy in average-risk asymptomatic individuals (Gastroenterology 1996;111:1178–1181). Although there is insufficient evidence to directly determine whether combined sigmoidoscopy and FOBT produce greater benefits than does either test alone (Guide to Clinical Preventative Services. 2nd ed. Report of the US Preventative Services Task Force. Washington DC: Department of Health and Human Services, 1995), the incremental benefit of combined testing is strongly suggested by circumstantial evidence (Gastroenterology 1997;112:594–642). The use of FOBT and flexible sigmoidoscopy as outlined in the ACS guidelines would seem to be supported by strong direct or indirect scientific evidence, but recommendations for colonoscopy every 10 years or DCBE every 5–10 years do not equally meet the burden of proof. There have been no randomized trials of TCE as a method of primary screening. The concept of one-time or periodic TCE is appealing because the total colon is examined and examinations are infrequent, yielding a potential cumulative cost benefit (Gastroenterology 1996;111:1385–1389). Nonetheless, without further direct evidence, this should remain a ‘‘future direction.’’ While TCE as a means of primary screening is discussed at length by the AHCPR task force (including the circumstantial weight of the evidence), the ACS guidelines suggest an equal weight of evidence, which is misleading. This is emphasized by the recent heated debate surrounding whether Medicare should cover barium enema to screen average-risk or high-risk individuals. Currently Medicare will cover colonoscopy every 2 years for high-risk individuals only. Barium enema is covered as an alternate test for these individuals if ordered in writing, and the physician attests to equal or greater screening potential. A personal or family history of colorectal adenomas or carcinoma carries an increased relative risk for development of colorectal cancer (N Engl J Med 1994;331:1669–1674, Ann Intern Med 1993;118:785– 790, N Engl J Med 1996;334:82–87). The ACS guidelines suggest that for those with a personal history of adenomas, only individuals with large ($1 cm) or multiple adenomas require increased surveillance if an initial 3-year follow-up TCE is negative. This is a recommendation that will, no doubt, stir some controversy. A growing body of indirect evidence suggests that few important lesions will be detected at follow-up of those whose only index lesion was a small singular tubular adenoma (N Engl J Med 1992;326:658–662). The weight of the evidence remains circumstantial, however, and this recommendation will be viewed by many as premature. Furthermore, whether colonoscopy and DCBE should be interchangeable for follow-up of those with a documented history of colonic adenomas or carcinomas may be questioned, because colonoscopy is more sensitive for detection of colonic lesions (Gastroenterology 1997;112:217– 223), and surveillance intervals after polypectomy have been exten-

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sively studied only for those undergoing repeat colonoscopy (N Engl J Med 1993;328:901–906). The relative risk of developing colorectal cancer is increased approximately twofold in those with affected first-degree relatives with colorectal carcinoma or adenoma compared with controls without affected family members (N Engl J Med 1994;331:1669– 1674, N Engl J Med 1996;334:82–87). The risk is greater when 2 or more first-degree relatives are affected, or when neoplasms occur at an early age. The relative risk for colorectal carcinoma in siblings of patients in whom adenomas were diagnosed before 60 years of age was recently reported to be 2.59 compared with siblings of patients who were 60 or older at the time of diagnosis. Does this merit periodic TCE in those with only 1 first-degree relative with an adenoma diagnosed before age 60? Given the high prevalence of adenomas in our society, the number of necessary examinations may be prohibitive. Again, more information is needed. Recommendations for screening high-risk individuals are less controversial. Both FAP and HNPCC are autosomal dominant diseases. Phenotypic expression of polyposis carries an extremely high risk of colorectal cancer development, meriting frequent endoscopic screening. Genetic testing for the product of mutated APC in FAP kindreds or for replication errors in those with HNPCC may help distinguish individuals at high risk from unaffected family members. Genetic testing must be combined with adequate genetic counseling (N Engl J Med 1997;336:823–827). If polyposis is demonstrated in those with FAP, colectomy should be strongly recommended (not just considered), because development of carcinoma is inevitable if the colon is not removed. The ACS guidelines recommend periodic colonoscopy and biopsies in patients with long-standing inflammatory bowel disease. Patients with inflammatory bowel disease have an increased risk for developing colorectal carcinoma in dysplastic mucosa. The cumulative cancer risk in patients with pancolitis is 0.5%–1% per year after 7–10 years of disease. Ulcerative colitis and Crohn’s disease are not considered separately, although the evidence for the efficacy of surveillance is strongest for those with ulcerative colitis. Patients with pancolitis are distinguished from those with left-sided colitis, although the difference in cancer risk is not universally agreed on (Gastroenterology 1991;100:1241–1248). While acknowledging the lack of comprehensive controlled data detailing the optimal means and interval for surveillance in those with inflammatory bowel disease, the high risk of colorectal cancer in such patients merits surveillance as outlined in the ACS guidelines. Strong and growing evidence supports screening for colorectal cancer. This has led several major health organizations to advocate and vigorously promote its use. If screening is to be successful, however, compliance by both patients and primary care physicians is paramount (Gastroenterology 1995;109:1781–1790, J Natl Cancer Inst 1997;89: 1406–1422). The compliance of practicing physicians with colorectal cancer screening will be dictated to some extent by how well they understand and how much they agree with the guidelines at hand. The ACS Detection and Treatment Advisory Group on Colorectal Cancer is to be commended for condensing a vast and controversial body of literature into succinct and specific guidelines that take into account the degree of risk in various subgroups. The questions of who, how, and how often are specifically addressed. In reducing what took the AHCPR 48 pages to summarize to a single table and 6 pages of discussion, many of the fine points have been sacrificed. Nonetheless, these ACS guidelines provide a useful framework for the practical application of colorectal cancer screening. ROBERT S. BRESALIER, M.D.

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Reply. We thank Dr. Bresalier for his thoughtful review and commentary on the 1997 ACS guidelines for early detection of colorectal polyps and cancer. As he points out, the guidelines were intended to be ‘‘clear, concise, and specific.’’ These guidelines updated the previous ones, considering newer information both from trials and observational studies, to provide clear guidance to physicians on screening and surveillance both for average-risk patients and those at higher risk. As noted by Dr. Bresalier, more extensive descriptions and discussions of the scientific basis for the recommendations are contained in more lengthy papers, such as the AHCPR report. Dr. Bresalier rightfully identifies several recommendations of the ACS Committee for which the scientific data needed to support definitive and unequivocal recommendations are not yet available. These include long-term surveillance for those with a single small adenoma, the use of the DCBE for screening and surveillance, and the option of colonoscopy for primary screening. Our approach was to formulate recommendations considering the totality of evidence, even when randomized trials have not been performed. The option of colonoscopy for primary screening is a good example of a recommendation made as a logical extension of existing information. As the Committee accepted the premise that sigmoidoscopic screening reduces mortality for colorectal cancer distal to the splenic flexure, it therefore regarded as reasonable the conclusion that this same screening modality extended by a colonoscope would also reduce mortality from colon cancer proximal to the splenic flexure. Future studies will need to answer the important questions of costs, operational efficiencies, and the cost/benefit ratio of colonoscopic screening. The various ‘‘gray areas,’’ in which the scientific data are sparse, including those pointed out by Dr. Bresalier, need to be clarified by future research. We believe, however, that in the meantime these uncertainties should not deter us from acting on the substantial evidence now in hand that the early detection of colorectal polyps and cancer is an effective way to reduce mortality and morbidity from colorectal cancer. The growing consensus that screening for colorectal polyps and cancer is a sound idea and the recent inclusion of colorectal cancer screening as a Medicare benefit have now created an important opportunity to reduce the current burden of suffering and premature death caused by colorectal cancer in the United States. DAVID ROTHENBERGER, M.D.

PANETH CELLS: ON THE FRONT LINE OR IN THE BACKFIELD? Garabedian EM, Roberts LJJ, McNevin MS, Gordon JI (Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO). Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice. J Biol Chem 1997;272:23729–23740. Paneth cells are located at the base of the crypts of Lieberku¨hn adjacent to or surrounding the multipotent stem cells. They represent a relatively stable cell population in the intestine and exhibit a secretory phenotype similar to that of zymogenic cells in the parotid, pancreatic, and gastric glands. Paneth cells contain messenger RNA (mRNA) for tumor necrosis factor (Am J Pathol 1993;142:1858–1865), epidermal growth factor (Histochemistry 1986;85:389–394), and guanylin (Proc Natl Acad Sci USA 1992;89:9089–9093). Secre-