SCREENING FOR COLON AND RECTAL CANCER

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1 Review Article SCREENING FOR COLON AND RECTAL CANCER Jack S. Mandel, PhD, MPH School of Public Health, University of Minnesota Introduction Approximately 138,200 new cases and 55,300 deaths occured in 1995 in the United States from cancer of the colon and rectum.[1] The age-adjusted incidence rate in the United States is approximately 50% higher in men than in women,[2] and a higher rate of colorectal cancer mortality occurs in blacks compared with whites (23.5 vs 19.2 per 100,000 population). Five-year survival rates are 59.3% for whites and 47.8% for blacks. Factors associated with the disease include a family history of colorectal cancer, exposure to asbestos, ulcerative colitis, and a diet high in fat, meat, and protein. Physical activity, nonsteroidal anti-inflammatory drugs, and a diet high in vegetables, fruits, and fibers may be protective.[3] Blood in Stool Heme is an iron compound of protoporphyrin that constitutes the pigment portion or protein-free part of the hemoglobin molecule. Fecal excretion of heme can be an indicator of gastrointestinal mucosal pathology. In the stomach, heme is rapidly released from the binding protein and precipitated. In the small intestine, heme is solubilized and 5% to 15% is absorbed.[4] Globin (a protein from hemoglobin) is rapidly digested in the stomach and small intestine. The majority of heme presenting to the upper gut is passed to the colon. Heme in the colonic lumen may be derived either from the small intestine as heme or from colonic bleeding or desquamation as hemoprotein. Hemoglobin, which enters the large intestine from bleeding in the upper gastrointestinal tract, either remains whole and is excreted as intact hemoglobin in the feces or undergoes proteolytic digestion of the globin to become heme.[5] Feces contain variable proportions of heme and heme-derived porphyrins.[6] The more proximal the bleeding, the more likely heme-derived porphyrins are to be the principal products. The more distal the bleeding, the more likely intact hemoglobin will be present in the feces.[5] Conditions that result in blood in stool include cancer, polyps, peptic ulcers, hemorrhoids, and diverticulitis. The bleeding from cancer or polyps tends to be intermittent, and the blood is not distributed equally throughout the stool.[7] These factors affect the sensitivity and specificity of all types of fecal occult blood tests (FOBTs).[5] Fecal blood levels are significantly higher in patients with advanced-stage cancers, with large tumors, with proximal lesion sites, and with stools collected before any bowel purgation.[8] Bleeding from polyps occurs less often than with cancer, especially when polyps are small.[9] Fecal Occult Blood Tests An FOBT for home use for colorectal cancer screening was developed in 1967.[10] Despite the absence of evidence of benefit, the FOBT was recommended for screening, yet agreement was not universal.[11] In 1993, results from the first randomized, controlled trial demonstrated the benefit of an FOBT.[12] The publication of a prospective study and three case-control studies added further evidence in support of FOBTs.[13-16] The principal FOBTs are immunochemical, hemoporphyrin, and guaiac assays. Immunochemical tests are predominantly qualitative tests that detect only hemoglobin, globin, and perhaps early degradation products of globin.[17] HemeSelect is a hemagglutination test with an intermediate threshold of sensitivity for hemoglobin. It has been compared to Hemoccult II and Hemoccult II Sensa.[18] The immunochemical tests generally are less predictive than the guaiac tests, but one study suggested that one-day immunochemical testing with HemeSelect might be an alternative to classic three-day guaiac testing and that a combination test in which HemeSelect is used to confirm positive Hemoccult Sensa results improves on Hemoccult II in screening patients for colorectal cancer.[19] The hemoporphyrin tests detect the broadest range of blood derivatives, namely de-ironed hemes (heme-derived porphyrins) as well as intact heme in any form (free or as hemoprotein). HemoQuant is a biochemical method for the assay of fecal heme and its degradation products in stool.[20] It probably is less sensitive and specific than Hemoccult.[21] The guaiac tests, which detect heme in any form provided that the iron has not been removed from the porphyrin ring, will react to any peroxidase. The performance of any given type of FOBT in a screening program is likely to be dependent on the nature of blood derivatives present in the feces in a given clinical situation.[5] Only the guaiac tests (namely Hemoccult) have been studied sufficiently to base a recommendation for screening. The sensitivity of Hemoccult and other FOBTs in detecting cancer varies widely. Most studies have shown sensitivity values of 65% or greater for colorectal cancer. [22] Studies using rehydrated Hemoccult slides have reported sensitivities between 83% and 92%.[23] Test sensitivity for adenomatous polyps is lower, ranging from 15% to 30% for all polyps, but is higher for larger polyps.[24] The wide range in sensitivity values reported is not surprising. Hemoccult is a test for blood in the stool rather than a direct test for cancer or polyps. Bleeding from cancer or polyps is intermittent and not evenly distributed throughout stool, but a test for blood in the stool should effectively identify most cancers and some polyps if applied repeatedly with multiple samples to overcome the intermittent bleeding and the unequal distribution of blood in stool. Influence of Diet on FOBTs Dietary recommendations for FOBTs vary from no restriction to exclusion of all types of meat or red meat plus uncooked fruit and vegetables.[25,26] Overall, the

2 results from studies of diet with the FOBTs indicate that some foods and reducing agents can interfere with the test and, therefore, restriction of red meat, fresh vegetables, and fresh fruit prior to and during the testing period should be recommended. The Colon Project, a controlled, nonrandomized study conducted between 1975 and 1984 by the Memorial Sloan-Kettering Cancer Center in collaboration with the Preventive Medicine Institute Strang Clinic in New York, was designed to evaluate FOBT as a supplement to 25-cm rigid sigmoidoscopy.[13] Between 1975 and Randomized Controlled Trials of FOBTs Randomized controlled trials (RCTs) provide the most persuasive evidence of the effectiveness of a screening test. The Hemoccult test is the only FOBT that has been evaluated in this way. A trial in Minnesota has been published, and three other trials currently are underway in Funen, Denmark; Göteborg, Sweden; and Nottingham, England. Minnesota Trial Initiated in 1975, the Minnesota trial enrolled 46,551 participants from 50 to 80 years of age and randomly assigned them to annual screening, biennial screening, or a control group.[12,27] Participants in the screening groups submitted six guaiac-impregnated paper slides (Hemoccult), prepared by two smears from each of three consecutive stools. Participants were instructed to abstain from red meat, poultry, fish, and certain vegetables and fruits, and to discontinue the use of vitamin C tablets and aspirin for at least 24 hours before and during the collection of the samples. Slide processing was modified early in the trial (May 1977) to incorporate rehydration with a drop of deionized water to restore the sensitivity that was reduced due to drying. Participants with one or more positive test slides in the set of six were invited for a diagnostic evaluation that included colonoscopy. A significant reduction (33%) in colorectal cancer mortality was seen in the annual-screen group compared with the control group. Survival was longest in the annualscreen group, poorest in the control group, and intermediate in the biennial-screened group. The screen-detected cases in both screening groups had the highest survival rate, whereas the survival for the nonscreen-detected cases was considerably lower and similar to survival for the control group. There was a 48% and 35% reduction in Dukes' D cancer in the annual and biennial screened groups, respectively, relative to the control group. This was noteworthy since these late stage cancers contributed substantially to mortality because of their poor prognosis. Göteborg Trial All 68,308 inhabitants of Göteborg, Sweden, born between 1918 and 1931 were enrolled and randomly allocated to a control or a screen group.[28] Three Hemoccult II tests were mailed to screen group participants, who prepared two samples from each of three consecutive stools while avoiding peroxidase-rich vegetables, food containing blood, and vitamin C and iron supplements for two days before and during the stool collection. The diagnostic examination for positive tests included rectosigmoidoscopy (60 cm) and double-contrast barium enema. Compliance rates were 63% and 60% with the first and second screen, respectively. As in the Minnesota trial, the positivity and sensitivity rates were higher for rehydrated than non-rehydrated tests. From the beginning of the first screening to the end of the rescreening, 117 colorectal cancers and 419 adenomas were detected in the screened group, while 44 cancers and 51 adenomas were detected in the control group. Significantly more Dukes' A cancers and significantly fewer Dukes' D cancers were diagnosed in the screen group. Nottingham Trial The Nottingham Colorectal Cancer Screening trial, which started in 1984, was designed to enroll 156,000 asymptomatic men and women, aged 50 to 74 years, and randomly allocate them to a control or screen group.[29] Compliers with the initial screen were rescreened every two years with FOBT (Hemoccult). The initial tests were carried out over three consecutive days without dietary restrictions and without rehydration. Since 1985, participants with a positive test repeated the test over a six-day period while excluding red meats and vegetables high in peroxidase from their diets. Early in the study, the diagnostic protocol included a 60-cm sigmoidoscopy and double-contrast barium enema. Later in the study, those with a second positive test underwent colonoscopy; if this was incomplete, a double-contrast barium enema was administered. Among the first 71,868 participants invited to participate, 53% complied.[30] The positivity rate was 2.0%. Compliance was 77% and 84% for the first and second two-year rescreens, respectively, for those with negative tests. Positivity rates for these rescreens were 1.3% and 0.6%. The proportion of Dukes' A cancers was lower in the control group (14%) than in the screen-detected group (47%) or in the entire screened group (28%). The proportion of Dukes' D cancers was higher in the control group (21%) than in the screen-detected group (6%) but similar in the entire screened group. The sensitivity of the test for cancer was 67.6% and was higher when tests were completed over six rather than three days (74% vs 65%).[31] Funen Trial In Funen, Denmark, 30,970 residents aged 45 to 75 were randomly assigned to biennial screening with Hemoccult and 30,968 were randomly assigned to serve as controls.[32] Six Hemoccult II slides were obtained from three consecutive stools while participants maintained a restricted diet. Three screens were conducted at twoyear intervals. Only those who completed the previous screening were invited for the following screening. Persons with positive FOBT slides underwent colonoscopy. Fewer colorectal cancer deaths occurred among participants in the screen group participants than in the control group.[33] The proportions of colorectal cancer deaths among screenees, nonresponders, and participants in the control group were 0.17%, 0.34%, and 0.30%, respectively. Dukes' A and B tumors accounted for 55% and 45% of the screened and control group cancers, respectively, while Dukes' D comprised approximately 25% of the classified cancers in both groups. Interval cancers were larger than screen-detected cancers, and cancers of 2 cm or less occurred more often among the screendetected population. Comparison of Trials The Minnesota trial is the only study to date that has demonstrated a statistically significant mortality reduction. A larger reduction may be observed with additional follow-up based on the stage distribution, which showed a 35% reduction in Dukes' D cancers in the biennial group compared with the control group and a more favorable survival rate. While final mortality results are not yet available from the three trials still in progress, interim results from the Funen study show a reduced colorectal cancer mortality rate. Current Nonrandomized, Controlled Studies of FOBTs Two prospective, controlled, nonrandomized studies of FOBT are underway in the Burgundy area of France[34] and in New York.[13,35] The Hemoccult study in France was initiated in 1988 and involves 91,000 participants aged 45 to 74 years.[34,36] Results are not yet available.

3 1979, 21,756 patients over the age of 40 were enrolled and divided into two groups - those who responded regularly to reminders for annual checkups (regulars) and those who came for single visits, often because of specific health concerns (first-timers). The regulars and first-timers were separately allocated to study or control groups based on enrollment dates. Those assigned to a study group were sent three Hemoccult slides and were asked to adhere to a meat-free, high-bulk diet for one day prior to, and for three days during, slide preparation. Slides were tested without rehydration. Participants with a positive FOBT were referred for double-contrast barium enema and colonoscopy. All participants had a 25-cm rigid proctosigmoidoscopy. The prevalence rates of colorectal cancer were higher in the study group than in the control group, whereas incidence rates were approximately equal. At the prevalence screen, a greater proportion of Dukes' A cancers and a smaller proportion of Dukes' D cancers were seen in the study group compared with the control group for both regulars and first-timers. The stage distribution correlated more closely for incident cancers, which was probably due to the low compliance that resulted in few screen-detected cancers. A significant difference in survival was noted between the study and control groups for the first-timers (70% vs 48%) but not the study and control groups for the regulars. A 43% reduction (P=.053) in colorectal cancer mortality occurred between the study and control groups for first-timers. This reduction occurred among all age groups but was somewhat greater among those over age 65 years than those under 65 years of age. The reduction in colorectal cancer, the shift to earlier-stage cancers, and the improved survival rate for first-timers provide evidence of a screening benefit. Case-Control Studies of FOBTs Case-control studies of cancer screening must be interpreted cautiously because of selection bias.[37] Nevertheless, they warrant consideration to evaluate whether the results support findings from randomized, controlled trials. A Kaiser Permanente Medical Care Program study indicated that colorectal cancer mortality might be reduced by 31% with FOBT screening.[14] In a German population-based case-control study for men where screening participation rates were very low, a 27% nonsignificant benefit was seen, but for women (whose participation rates were considerably higher), a significant 60% benefit from screening was observed.[15] A small study of the Greater Marshfield Community Health Plan[38] reported that FOBT screening was not associated with a lower colorectal cancer mortality. However, only 21% of the cases and 16% of the controls received multiple-slide evaluation of stool. Most screening was done on a single sample obtained during a digital rectal examination. A fourth case-control study consisted of members of an HMO who died of colorectal adenocarcinoma.[16] A significantly reduced odds ratio (0.65) was found for those screened before age 75 but not for those screened after age 75. Conclusions From FOBT Studies Of the many FOBTs, only Hemoccult has been adequately studied. While most cancers and some polyps bleed, the bleeding is intermittent and the blood is not uniformly distributed throughout the stool. The test is sensitive for cancer but not for polyps, although it is better for larger than smaller polyps. The test is inexpensive and is generally acceptable to the general population. Compliance in the randomized trials ranged from 53% to 75%. Evidence from two randomized, controlled clinical trials, one prospective, nonrandomized study, and three case-control studies that screening for FOB with Hemoccult can reduce colorectal cancer mortality within a range of 31% to 60%. Thus, the weight of evidence supports the recommendations for screening with FOBT by both the American Cancer Society and the United States Preventive Task Force. Flexible Sigmoidoscopy Screening with 60-cm flexible sigmoidoscopy has received considerable attention recently.[39] The underlying assumption is that since most cancers arise from polyps, removal of polyps with continued surveillance to identify and remove new or recurrent polyps will prevent cancer. The indirect evidence that the majority of colorectal cancers evolve from benign adenomas is widely accepted,[40,41] but the de novo origin of cancer is an alternative pathway in some cases of colorectal cancer.[42] The time required to develop colorectal cancer was recently studied in the National Polyp Study (NPS).[43] Age frequency distributions indicated a 10-year interval from clean colon to invasive cancer with a five-year interval from clean colon to adenomas. The interval was shorter for patients with a single adenoma, while a longer interval occurred from clean colon to multiple adenomas, adenomas with infiltrating cancer. or significant dysplasia, all of which fell in the same general time frame. Support for the adenoma-carcinoma sequence is also found in inherited colorectal cancer syndromes.[44] NPS has evaluated follow-up surveillance strategies in 1,418 patients who have undergone polypectomy.[43,45,46] Patients were randomly assigned to more frequent follow-up (one and three years after initial polypectomy) or less frequent follow-up (three years) with colonoscopy and barium enema. Reference groups from the Mayo Clinic, St. Mark's Hospital (London), and the National Cancer Institute's Surveillance, Epidemiology, and End Results program were used to determine expected colorectal cancer incidence rates. The reduced incidence of colorectal cancer in the study cohort provided evidence of the progression of adenoma to adenocarcinoma and of the effectiveness of the current practice of identifying and removing adenomatous polyps. The goal of the Funen Adenoma Follow-Up Study[47] was to reduce the incidence of colorectal carcinoma in adenoma patients and thereby reduce mortality. Between 1978 and 1992, 1,042 adenomatous polyp patients were allocated to different follow-up intervals ranging from six to 48 months. The size of the largest adenoma and the structure of the most villous adenoma were found to be independent predictors of severe dysplasia. At St. Mark's Hospital,[49] more than 2,000 symptomatic patients who underwent excision of one or more rectosigmoid adenomas were followed for up to 30 years to determine their incidence of colorectal cancer. The incidence of rectal cancer overall was similar to that in the general population. However, those with a rectosigmoid adenoma that was tubulovillous, villous, or more than 1 cm had almost four times the risk of developing colon cancer. Those with multiple rectosigmoid adenomas had almost seven times the risk of developing colon cancer. Those with only small tubular adenomas (43% of the case group) had no increased risk of colorectal cancer. Given that there is an arguable basis for the adenoma-carcinoma sequence and that removal of adenomas might prevent colorectal cancers, the question then becomes how best to accomplish this. FOBT is not a sensitive enough test for adenomas because most do not bleed. Flexible sigmoidoscopy (60 cm) has the advantage of direct visualization of adenomas but the disadvantage of examining only the distal portion of the colon. It is recommended based on observational (mainly case-control) studies,[49] despite the biases associated with these types of studies. Atkin et al[50] suggest that a one-time flexible sigmoidoscopy at approximately 55 years of age could reduce colorectal cancer mortality by about 45%, and they propose a randomized trial to evaluate their hypothesis. Such a trial is necessary to provide definitive evidence of the effectiveness of flexible sigmoidoscopy screening.

4 Studies of Screening With Sigmoidoscopy Gilbertsen[51] reported on 113,800 proctosigmoidoscopies of 21,140 adults attending a cancer detection center. Follow-up of patients with adenomas diagnosed and removed failed to find a single death from rectal cancer. This widely cited finding has been used to support screening sigmoidoscopy; however, the study was flawed and misinterpreted.[52] The Multiphasic Checkup Evaluation Study, a randomized trial to test the effectiveness of periodic multiphasic health checkups, was initiated in 1964 as part of the Kaiser Permanente Medical Care Program.[53] More than 5,000 individuals aged 35 to 54 years were urged to attend an annual comprehensive screening examination which included a 25-cm screening rigid sigmoidoscopy examination for men and women 40 years of age and older. A similar control group was not urged to take any of the tests but were free to do so. By the seventh year of follow-up (1971), two colorectal cancer deaths occurred in the study group and 10 in the control group.[54] By 1980, colorectal cancer deaths increased to 12 and 29 in the study and control groups, respectively.[55] This mortality difference was accompanied by a stage shift toward earlier cancers in the study group. Two recent case-control studies concluded that a single screening sigmoidoscopy could reduce mortality from cancers of the rectum and distal colon by between 59% and 79%.[38,56] The Kaiser Permanente Medical Care Program study suggests that screening with rigid sigmoidoscopy could reduce mortality from cancers by 59%. Extrapolation of the finding to 60 cm of the colon suggests that overall colorectal cancer mortality might be reduced by up to 30%, assuming that 50% of the colorectal cancers and adenomatous polyps arise within 60 cm and that screening with 60-cm flexible sigmoidoscopy will reduce deaths from distal cancers by 59%. A casecontrol study[38] of 66 colorectal cancer deaths of patients in Greater Marshfield Community Health Plan also showed that the mortality risk of cancers of the rectum and distal colon was reduced among individuals who had a single screening sigmoidoscopy. Thus, flexible sigmoidoscopy screening has appeal, and the observational studies suggest that sigmoidoscopy screening may reduce colorectal cancer mortality, but these studies are not adequate proof of effectiveness, and the two casecontrol studies could have overstated the benefit due to selection bias. Nevertheless, the United States Preventive Task Force now recommends periodic flexible sigmoidoscopy for adults over 50 years of age. Screening With Colonoscopy Colonoscopy has been suggested as a one-time screen during the sixth decade of life.[57] Visualizing the entire colon could lead to the identification of 95% of patients with larger adenomatous polyps or cancers. Follow-up examinations would depend on the findings from the baseline colonoscopy. Lieberman[57] has proposed no follow-up if no polyps or hyperplastic polyps are found, a 10-year follow-up for tubular adenomas, a one-year then five-year follow-up for adenomas greater than 1 cm or villous adenomas, and a one-year then three- to five-year follow-up for carcinomas. His theoretical cost-effectiveness analysis showed that colonoscopy screening was more cost effective than flexible sigmoidoscopy of FOBT screening. This idea warrants further exploration. Two additional issues to consider are compliance and risk. There are no data on colonoscopy compliance of an asymptomatic average-risk population. Additional studies are needed to provide data on effectiveness and compliance before considering colonoscopy as a screening procedure. Conclusions At present, the only test proven to be effective in reducing colorectal cancer mortality is Hemoccult applied annually to a population over the age of 50 years. Other FOBTs show promise, but there is insufficient evidence to recommend their general use. Problems with the Hemoccult include low sensitivity for adenomas, a large number of false positives and therefore relatively high cost. If the ongoing randomized trials demonstrate a significant benefit from biennial screening, as has been demonstrated for annual screening, then the screening cost will be substantially reduced by screening half as often. Observational studies show a benefit from flexible sigmoidoscopy screening. If these studies are correct, then colorectal cancer mortality could be reduced by approximately 30% to 40%. References 1. Wingo PA, Tong T, Bolden S. Cancer statistics, CA Cancer J Clin. 1995;45: Miller BA, Ries LAG, Hankey BF, et al. 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Multiphasic health checkup evaluation: a 16-year follow-up. J Chron Dis. 1986;39: Selby JV, Friedman GD, Quesenberry CP Jr, et al. A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med. 1992;326: Lieberman D. Screening colonoscopy. Has the time come? In: Swak MV, ed. Gastrointestinal Endoscopy Clinics of America. Vol 3. Philadelphia, Pa: WB Saunders Co; 1993: This article was adapted from the book Cancer Screening, St. Louis, Mo, Mosby-Year Book, Inc, 1996