Our review shows that prior studies of chemical-based FOBT have reported a wide range of sensitivities for detecting colorectal cancer. In addition, the pooled sensitivity of FOBT in the studies that corrected for verification bias was significantly lower than in those with this bias (0.35 vs. 0.70, p
0.001). Studies without verification bias also had a higher specificity (0.95 vs. 0.88, p
0.03). We found no significant effect of verification bias on the AUC of the sROC function due to the large standard error for studies without verification bias. Furthermore, the AUC is a composite statistic reflecting both sensitivity (which is increased by verification bias) and specificity (which may be decreased by verification bias).67
Studies have used two different approaches to correct for verification bias: performing colonoscopy on all patients regardless of FOBT result or following screened patients longitudinally for a defined period of time. Both methods have some limitations. Many of the studies using screening or surveillance colonoscopy will exclude symptomatic patients and will be attempting to detect asymptomatic colorectal cancer. The sensitivity of FOBT for pre-clinical colorectal cancers may be lower than for symptomatic cases. Studies using longitudinal follow-up have other limitations as the optimal duration of follow-up has not been standardized. A two-year interval may fail to include some colorectal cancers with a long clinical latency. However, a longer observation interval may also include neoplasias that were not malignant at the time of the FOBT but then progressed to cancer during the follow-up period. An insufficient observation period may artificially increase the sensitivity of FOBT while a prolonged observation period will decrease the sensitivity. Finally, some patients with colorectal cancer at the time of screening may never present with clinical signs because they succumb to other diseases or have been lost to follow-up.
Another limitation of this meta-analysis relates to the heterogeneity of the FOBT studies. In order to have an adequate sample size, we had to include reports with a variety of study designs and different populations. Multiple regression was also used to correct for differences in study design (e.g., the year of publication, the primary method of cancer detection, number of FOBT specimens submitted) and still demonstrated a significant effect of verification bias on the sensitivity. Another source of heterogeneity may relate to the prevalence of benign gastrointestinal disorders such as internal hemorrhoids or gastritis which can result in recurrent GI bleeding. Thus, FOBT may have a higher sensitivity but lower specificity for colorectal cancer in populations with a higher consumption of alcohol or use of aspirin. Finally, the studies also had a wide variation in the number of cancer and control subjects. Most meta-analysis techniques give more weight to larger studies which generally have a lower variance.
Spectrum bias could also be a factor for the higher sensitivity in studies with verification bias as these studies probably had more advanced cases of colorectal cancer. We were not able to correct for this factor as almost all of the included studies did not report the FOBT sensitivity by either tumor stage or method of detection. Nevertheless, the sensitivity of FOBT was relatively high in a study with verification bias which primarily included subjects referred for screening.34
Regardless of the source of bias, we believe that the sensitivity of FOBT is low when used to screen for asymptomatic subjects for colorectal cancer.
Almost all of the studies analyzed the diagnostic characteristic of FOBT at a single point in time. As it is recommended that the test be performed annually for colorectal cancer screening, it is possible that serial determinations may improve its sensitivity. However, the improvement in sensitivity from serial testing cannot be readily determined from the studies included in our meta-analysis. Furthermore, it is possible that detecting a colorectal cancer after it takes 1-2 years for the FOBT to become positive may decrease its resectability.
Two systematic reviews of FOBT have reported that this test reduced colorectal CA mortality by only 14–16% as compared to no formal screening.68,69
Even after adjusting for patient compliance, the reduction in mortality was only 23%.69
Two possible explanations for the modest benefits of FOBT screening include a low sensitivity for colorectal cancer or failure of FOBT screening to detect most cancers when they are amenable to curative resection. We feel that the low sensitivity of FOBT is an important factor limiting its effectiveness. As described by Ransohoff and Lang’s aphorism,70
the sensitivity of a screening test determines the benefit of testing while the specificity determines the effort of screening. While this test has may have limited sensitivity for screening, the relatively high specificity should prompt further confirmatory testing.
A variety of methods have been developed to improve the detection of stool heme pseudoperoxidase activity. Generally, these tests increase the sensitivity but decrease the specificity for colorectal cancer. After excluding studies with verification bias, the pooled specificity of Hemoccult II® SENSA® was 91%. Assuming appropriate confirmation of a positive test, a health care program would have to anticipate that at least 9% of screened patients would require a colonoscopy during the initial screening. While this type of screening may result in more colonoscopies than guaiac-based FOBT lacking an enhancer, this approach would probably use less endoscopic resources than screening colonoscopy, at least in the short-run. Fecal immunochemical tests may have a similar sensitivity but higher specificity than Hemoccult II® SENSA®.64
As fecal immunochemical tests are significantly more expensive than guaiac-based FOBT,5
further comparative and cost-effective studies are needed.
In conclusion, prior studies have overestimated the sensitivity of chemical-based FOBT for screening as a result of verification bias and possibly spectrum bias. Many professional societies71,72
recommend a sensitive FOBT as a first-line option for colorectal screening while two gastroenterological societies73,74
consider this test as an alternative to the preferred option of screening colonoscopy. Thus, FOBT is an important screening modality for patients who refuse screening colonoscopy or in areas of inadequate endoscopic resources. We do not feel that most guaiac-based FOBT methods perform as “a highly sensitive test for colorectal cancer” as recommended by the American Cancer Society72
and the United States Preventive Task Force.71
Further studies are needed to determine whether non-endoscopic tests such as CT colonography, fecal immunochemical tests, or stool DNA tests can serve as adequate screening methods for colorectal cancer.