ABSTRACT: There is level 1 evidence for CRC screening using fecal occult blood testing. Patients who test positive should undergo colonoscopy. Sigmoidoscopy and double-contrast barium enema is probably acceptable if colonoscopy is not available, although there is no level 1 evidence to support this belief. Investigation into the development of a combination test (two-tier test) is proceeding in the hope that more accuracy will result.
Three studies have shown that fecal occult blood testing reduces mortality from colorectal cancer, lending strong support for implementing CRC screening.
Colorectal cancer (CRC) is unique among the gastrointestinal cancers in that it is known that most arise from adenomatous/ villous polyps. All polyps do not necessarily progress to malignant transformation, and it is believed that it takes at least 6 years for this transformation to occur.[1,2] Under current accepted standards of screening and diagnosis, the earliest detectable sign of a cancer or a large polyp is occult bleeding. The blood loss tends to be intermittent and depends to some extent on the size and site of the neoplasm.
Most of the research in screening the average risk population for CRC has been devoted to investigating the use of fecal occult blood testing. There are now three prospective randomized studies providing level 1 evidence (i.e., evidence derived from multiple mature prospective randomized studies) that using fecal occult blood testing for screening results in reduction in mortality from CRC.[3-5] This reduction is due to detection of cancer at an earlier stage, resulting in a more favorable outcome and prevention of cancer by removal of polyps prior to transformation.
Each of the studies was carried out with different methodology. In 1993, Mandel showed in a large prospective randomized trial that a 33% reduction in mortality from CRC was achieved using annual Hemoccult II testing. The predicted reduction in mortality for those fully compliant was 44%. Interestingly, the group screened every 2 years had a reduction in mortality of 6%. The rate of positivity in this study using Hemoccult II and slide rehydration was 9.8%. This resulted in a high colonoscopy rate of 8%, which was not considered to be acceptable for widespread screening in asymptomatic people.
Kronborg et al. demonstrated an 18% mortality reduction using Hemoccult II without rehydration in a screening program conducted every 2 years. Their colonoscopy rate was 4.3%. The predicted reduction mortality for those fully compliant was 30%.
Hardcastle et al. have reported a mortality reduction of 15% using the non-rehydrated Hemoccult II test once every 2 years. Colonoscopy rate in this study was 4%. The predicted reduction in mortality for those fully compliant was 29%.
These studies strongly support the implementation of CRC screening.
The studies have important differences in periodicity and methodology, which have been summarized in Table 1. Any provincial screening program will be extremely costly, and the methodology adopted will be of paramount importance.
A stool occult blood test is the best current choice for screening.
The majority of stool occult blood tests are based on guaicum impregnated paper, which responds to an oxidizing agent by turning blue when an activator is added. The most common tests in use are Hemoccult, Hemoccult II, and Hemoccult SENSA. These three are in order from least to most sensitive. If the stool is fresh or rehydrated, there is a higher positivity than when it is dry. Agglutination tests, such as HemeSENSA, on the other hand, show the presence of the globulin moiety of human hemoglobin.
The difficulty with the guaicum-based tests is that they react positively to meat and other oxidizing substances in food, and therefore result in a high percentage of false positives, even with dietary restriction. For this reason, it is usual to put the patient on a 3-day meatless diet prior to testing. These restrictions are not necessary with the HemeSelect test. We currently are investigating the combination of the Hemoccult II test with the HemeSelect test in an effort to reduce the number of false positives and eliminate the need for a special diet prior to testing.
There are many ways to investigate the colon and rectum following positive testing. A rectal exam will detect fewer than 10% of colorectal neoplasms. Rigid sigmoidoscopy will detect up to 20% of colorectal neoplasms. Flexible sigmoidoscopy will detect up to 66% of colonic neoplasms if a complete exam is done. Double-contrast barium enema has a sensitivity of 50% to 80% for polyps <1 cm and 70% to 90% for polyps >1 cm, but this test has never been validated as a screening tool. Colonoscopy offers the greatest accuracy and combines the ability to visualize the entire colon with the potential to biopsy and possibly remove neoplastic changes. The combination of double-contrast barium enema and flexible sigmoidoscopy may prove to be an adequate substitute if colonoscopy is not available. Colonoscopy, however, remains the only validated investigative technique following a positive screening test.
About 25% of CRC may occur in individuals considered to be at higher than average risk. The majority of these cases occur in those with family history of CRC (15% to 20%) with the remainder being those with hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, and inflammatory bowel disease. The risk for close relatives of patients with CRC is outlined in Table 2. These individuals should be offered screening beginning at age 40. Patients with a likelihood of hereditary nonpolyposis colorectal cancer syndrome are those who meet the following criteria:
• At least three family members with CRC, two of whom are first-degree relatives
• At least two generations represented
• At least one individual younger than 50 years at diagnosis
Extracolonic cancers may also be associated with hereditary nonpolyposis colorectal cancer, particularly cancer of the endometrium, renal pelvis/ureter, stomach, small bowel, ovary, brain, and also sebaceous tumors. Such individuals should be referred for genetic testing, and it is recommended that they be offered examination of the colon every 1 to 2 years starting between 20 and 30 years of age and every year after age 40. Patients with long-standing and extensive inflammatory bowel disease affecting the colon should undergo surveillance colonoscopy. Screening does not apply to those with familial adenomatous polyposis because those individuals should undergo colectomy. There is no level 1 evidence for the effectiveness of screening the high-risk populations.
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4. Kronborg O, Fenger C, Olsen J, et al. Randomised study of screening for colorectal cancer with faecal-occult-blood. Lancet 1996;348(9040):1467-1471.
5. Hardcastle JD, Chamberlain JO, Robinson MH, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996;348(9040):1472-1477.
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8. Houlston RS, Murdoy V, Harocopos C, et al. Screening and genetic counseling for relatives of patients with colorectal cancer in a family cancer clinic. Br Med J 1990;301:366-368.
9. Vasen HFA, Watson P, Mecklin J, et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, lynch syndrome) proposed by the international collaborative group on HNPCC. Gastroenterology 1999; 116:1453-1456.
Dr Cleator is a professor of surgery at the University of British Columbia and consultant general surgeon at St Paul’s Hospital. Dr Barzuca is a post-graduate student, MSc program, Department of Surgery. Andrew Rae is the director of business development at Active Pass Pharmaceuticals, Vancouver. Dr McGregor is a clinical professor of surgery at the University of British Columbia and a consultant surgeon at the BC Cancer Agency, Vancouver Centre.
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