On the sensitivity of fecal occult blood test screening for colorectal cancer.

In this issue of the Journal, two publications (1,2) from the Minnesota Colon Cancer Control Study address the question of ‘‘how well’’ fecal occult blood test (FOBT) screening detects early colorectal cancer and how much of the ‘‘mechanism’’ of detection may be due to chance, as proposed by us 3 years ago (3). Our goals in a brief comment on a complicated subject are to identify the main issues and to discuss briefly how these new data relate to them. In our simple mathematical analysis (3) of the data published from the Minnesota study (4), we estimated that one third to one half of the mortality reduction observed in that study could be accounted for by chance colonoscopy done for work-up of a FOBT result that was ‘‘falsely positive’’ in a person who had a neoplasm that was not bleeding. The hypothesis is plausible because rehydrated FOBT slides are positive in 8%–16% of persons each time a FOBT is done (4), and chance detection of lesions can occur when a diagnostic test has a high false-positive rate (5,6). The Minnesota study investigators address these issues of sensitivity and specificity (i.e., false-positive rate) by providing new primary data from their study and a revised model (2), as well as a series of approaches about how to calculate test sensitivity (1) based on data from the original study. The modeling exercise reported by Ederer et al. (2) provides several advances. Although we have not examined the model itself, we believe that the role of chance should be revised downward on the basis of these new data and the revised model. In our analysis, we used the summary data published in the original report (4); however, because some parameters vary over time (particularly the positivity rate of FOBT), the use of primary data instead of summary estimates should provide a better picture of how FOBT works. Furthermore, the investigators have revised our model to add a concept of ‘‘dual detectability’’ to indicate that, for some neoplasms, the FOBT may be positive both because of bleeding and because of chance, and they suggest that these detections should not all be accounted to chance. Last, a lower rate is used for endoscopy efficacy in reducing mortality (60% versus 70%). With these revisions, the investigators calculate that the amount of mortality reduction due to chance in their study is about one sixth to one quarter, with the majority of that reduction being due to their use of primary data. On the basis of what is published here and without seeing the model itself, we believe that these new features are reasonable and that the role of chance should, quantitatively, be revised downward. Biologically, this analysis suggests that FOBT screening is more specific than in our analysis, since specificity is the main driving force of the ‘‘chance detection’’ phenomenon (3). We would ask whether some of this apparent increase in specificity might have been due to the use of nonrehydrated (and less falsely positive) slides in the initial phases of the trial, inasmuch as mortality reduction in a screening trial tends to be related to earlier screens(7). Church et al.(1) use several different arguments to suggest that FOBT sensitivity is very high. In the larger picture, the sensitivity of a screening test is critically important because it determines ‘‘how many’’ colorectal cancer deaths can be prev nted. In other words, if a test cannot detect the precursors of fatal colorectal cancer, then it cannot reduce colorectal cancer mortality. The several approaches used in the report by Church et al. (1) conclude that ‘‘sensitivity’’ of FOBT screening is on the order of the 80% or 90% originally reported in the Minnesota study(4). We are not persuaded by these approaches for several reasons. First, several of the calculations (including the followup-adjusted screen sensitivity estimate, the truncated productbinomial model, and the comparative incidence by test results) utilize results from the Minnesota study in which sensitivity rates were based on detection of colorectal cancer at any stage. By the inclusion of advanced colorectal cancer in the calculations, FOBT sensitivity is inflated when the test is given credit for detection of advanced lesions that are not primary targets of screening, because they are not readily treatable compared with early colorectal cancer or large adenomas. Furthermore, advanced lesions are more likely to have positive FOBT results than early lesions that are the targets of screening. Moreover, if the sensitivity of a program of FOBT screening is 80%–90%, as these several approaches suggest, then it is not clear why colorectal cancer mortality reduction is only 33.4% (4). We agree with the Minnesota investigators that imperfect