CLINICAL GUIDELINE: PART II: Screening for Colorectal Cancer with the Fecal Occult Blood Test: A Background Paper

Colorectal cancer is the second leading cause of cancer-related death in the United States [1]; because of its favorable clinical biology, it is a reasonable target for screening. Data from three randomized clinical trials [2-4] have shown that mortality rates associated with colorectal cancer can be reduced by screening with fecal occult blood tests; other data have shown that such rates can be reduced by screening with sigmoidoscopy [5, 6]. Until recently, authoritative guidelines had generally [7-10] but not universally [11, 12] favored screening for colorectal cancer. However, the U.S. Preventive Services Task Force recently upgraded its recommendations on screening for colorectal cancer [13]. In the United States, the rate of screening for colorectal cancer is low compared with that for breast and cervical cancer [14, 15]. The implementation of any screening program for colorectal cancer poses substantial practical problems [16-18]. It seems likely, however, that screening for colorectal cancer, whether by fecal occult blood testing, sigmoidoscopy, or some other means, will soon become much more widespread. In this paper, we do not assess the decision of whether to screen for colorectal cancer; that topic has been discussed elsewhere ([13, 19, 20]; Eddy DM. Screening for colorectal cancer. In preparation). Instead, we focus on the interpretation and follow-up of results of screening with fecal occult blood tests. When such screening is done, clinicians confront several specific issues about technique. These issues may seem mundane, but they can greatly affect on the effort (including cost) and efficacy of screening. Among the issues addressed here are the procedures for screening with fecal occult blood tests, the definition of a positive test result, the timely evaluation of positive results, and the rescreening of persons with positive or negative results. Authoritative guidelines about screening for colorectal cancer have been remarkably silent on some of these important details. 1. Methods We identified relevant studies by searching the MEDLINE database for articles published between 1984 and 1996, using the terms fecal occult blood and colorectal cancer screening, and we reviewed articles from the bibliographies of materials identified through the MEDLINE search. We also searched for studies about the biology of colorectal cancer as it relates to screening with fecal occult blood tests, the validation of fecal occult blood tests, the clinical application of screening with fecal occult blood tests, and the cost-effectiveness of screening for colorectal cancer. This review is not a structured meta-analysis on trials of screening with fecal occult blood tests or of the validation of such tests because of the paucity of published data that meet typical criteria for assessing validation. However, we sought all published data that might relate to the optimal performance of fecal occult blood tests. The strength of estimates for each measure reflects the authors' overall assessment of the evidence and was graded subjectively because of the need to consider several types of studies. The special methodological challenges in assessing screening with occult blood tests are identified and emphasized in the body of this report. This discussion and comments in the guidelines published in this issue [21] provide details so that readers can judge the nature and quality of the evidence on their own. 2. Data Synthesis 2.1 Reducing Mortality Rates Associated with Colorectal Cancer by Screening with Fecal Occult Blood Tests Three clinical trials have credited screening done using fecal occult blood tests with reducing the mortality rate associated with colorectal cancer. A trial in the United States studied volunteers who were screened using an occult blood test with rehydrated slides. In the group of persons who were screened annually, mortality rates associated with colorectal cancer were reduced by about 33%; 39 deaths from colorectal cancer were prevented among 15 570 persons during the 13 years of screening. These data translate to a relative risk reduction for death from colorectal cancer of 33%, an absolute risk reduction of about 2.95 deaths per 1000 persons, and a number needed to screen to prevent one death over 13 years of about 300. Two European trials that reported mortality rates were population based and shorter in duration; these trials used biennial screening and no rehydration of slides. They reported a reduction in mortality rate of 15% to 18% [3, 4]. A third European trial is still being conducted [22]. Because compliance was about 50% in these trials, screening efficacy may be higher than reported effectiveness. In any case, it is now clear that screening with fecal occult blood tests can reduce the mortality rates associated with colorectal cancer. The major challenge now is to determine how well such screening works and how it can be improved. These randomized clinical trials provide important data not only about reduction in mortality rates but also about the ways in which clinicians and patients can interpret the results of fecal occult blood tests. Table 1 clearly shows that no consensus exists (at least as reflected in the design of the clinical trials) about such important technical issues as diet restriction, rehydration of test slides, frequency of screening, and the strategy for evaluating persons who have positive results (that is, retesting patients with positive results before doing a work-up or immediately doing a work-up for all patients with positive results). Because the trials also differ with regard to such features as targets of study (volunteers or population based), compliance, and duration of follow-up, it may be difficult to sort out which features have the greatest effect on mortality rates. Table 2 summarizes some of the expected results on screening with fecal occult blood tests based on data from randomized clinical trials. Table 1. Overview of Randomized Clinical Trials of Screening with Fecal Occult Blood Tests* Table 2. Expected Results of Screening for Colorectal Cancer with Fecal Occult Blood Testing Although it is now agreed that mortality rates associated with colorectal cancer can be reduced by screening with fecal occult blood tests, the degree of reduction in these rates and the approaches needed to decrease them further remain uncertain. The degree of reduction in mortality rates ultimately depends on the sensitivity of fecal occult blood tests; thus, because false-negative results do occur, mortality rates associated with colorectal cancer will not be optimally reduced by screening with occult blood tests. In addition, patients and physicians must not interpret a negative test result to mean that the patient is protected from colorectal cancer. A corollary is that worrisome signs and symptoms that occur after a negative screening result must still be assessed vigorously. Clinicians can also anticipate the development of new strategies to improve screening efficacy by improving test sensitivity or specificity. 2.2 Types of Fecal Occult Blood Tests and Procedures for Performing Them All screening with fecal occult blood tests is based on the concept that important target colonic neoplasms, such as early-stage cancer (Dukes stage A or B) and large adenomatous polyps, will bleed and may be detected by an occult blood test. When implementing screening with fecal occult blood tests, clinicians must choose from among various types of tests and techniques for applying these tests. The types of occult blood tests that are currently available and the procedures used to perform the tests are discussed below. 2.2.1 Types of Tests The fecal occult blood tests currently available in the United States include such guaiac-based tests as Hemoccult II and HemoccultSENSA (SmithKline Diagnostics, San Jose, California), such immunochemical tests as HemeSelect (SmithKline Diagnostics), and the HemoQuant test (Mayo Medical Laboratories, Rochester, Minnesota) [28, 29]. When gastrointestinal blood is lost, the stool will contain a combination of intact or nearly intact hemoglobin, intact heme, and heme-derived porphyrins in amounts that depend on the site and amount of bleeding and the transit time through the gut. These blood products are detected in different ways by the various tests. Several reviews [28-32] discuss the mechanics of fecal occult blood testing and nonneoplastic causes for positive results. Several mechanisms are used to detect occult blood. Guaiac-based tests detect occult blood on the basis of the pseudoperoxidase activity of heme or hemoglobin; such activity converts colorless guaiac to a blue color in the presence of the hydrogen peroxide in the developing reagent. The HemoQuant test detects some heme and heme-derived porphyrin. Immunochemical tests detect intact or nearly intact human hemoglobin by various immunochemical techniques; at least theoretically, this technique is more specific for detecting loss of blood from the lower intestine because blood from lower sites is less degraded during transit. Because Hemoccult II and HemoccultSENSA are simple tests that can be done in a physician's office, they are considered waived laboratory tests according to the Clinical Laboratory Improvement Amendments of 1988. The HemeSelect test, which is similar to an enzyme-linked immunosorbent assay, is more complex and thus must be done in a laboratory. Although this test could be done in many laboratories, few currently perform it. The manufacturer has developed and is planning to market a simpler immunoassay, FlexSure OBT (SmithKline Diagnostics), which can be done in a physician's office (Baker J. Personal communication). Ease of use could help reduce what may be a substantial barrier to the implementation of immunochemical tests. A product that is identical to HemeSelect is used in mass screening in Japan; this test is processed using automated instrumentation [33]. 2.