A novel hypothesis on the sensitivity of the fecal occult blood test: Results of a joint analysis of 3 randomized controlled trials

Abstract

Background: Estimates of the fecal occult blood test (FOBT) (Hemoccult II) sensitivity differed widely between screening trials and led to divergent conclusions on the effects of FOBT screening. We used microsimulation modeling to estimate a preclinical colorectal cancer (CRC) duration and sensitivity for unrehydrated FOBT from the data of 3 randomized controlled trials of Minnesota, Nottingham, and Funen. In addition to 2 usual hypotheses on the sensitivity of FOBT, we tested a novel hypothesis where sensitivity is linked to the stage of clinical diagnosis in the situation without screening.

Methods: We used the MISCAN-Colon microsimulation model to estimate sensitivity and duration, accounting for differences between the trials in demography, background incidence, and trial design. We tested 3 hypotheses for FOBT sensitivity: sensitivity is the same for all preclinical CRC stages, sensitivity increases with each stage, and sensitivity is higher for the stage in which the cancer would have been diagnosed in the absence of screening than for earlier stages. Goodness-of-fit was evaluated by comparing expected and observed rates of screen-detected and interval CRC.

Results: The hypothesis with a higher sensitivity in the stage of clinical diagnosis gave the best fit. Under this hypothesis, sensitivity of FOBT was 51% in the stage of clinical diagnosis and 19% in earlier stages. The average duration of preclinical CRC was estimated at 6.7 years.

Conclusions: Our analysis corroborated a long duration of preclinical CRC, with FOBT most sensitive in the stage of clinical diagnosis.

Figure 1

Adenoma and cancer stages in the MISCAN-Colon model. Cancer stages correspond to the Dukes staging system for colorectal cancer. Adenomas are categorized by size. The size-specific prevalence of adenomas as well as the proportion of adenomas that ever develop into cancer is dependent on age. It is assumed that the proportion of progressive adenomas increases from 16% at age 65 to 37% at age 75, and 96% at age 100. It is assumed that 50% of non-progressive adenomas will remain 6-9 mm stage until death and that 50% will progress to the ≥10 mm stage. For progressive adenomas, it is assumed that 30% will develop through the sequence ≤5 mm adenoma → 6-9 mm adenoma → preclinical cancer stage I and that 70% will develop through the sequence ≤5 mm adenoma →6-9 mm adenoma → ≥10 mm adenoma → preclinical cancer stage I. The mean duration time for progressive adenoma to clinical cancer is assumed to be 20 years (with an exponential distribution). The model is calibrated to reproduce observed CRC incidence and stage distribution in the control groups for each of the three trials (see Methods and Materials).