Diagnostic Yield of One-Time Colonoscopy vs One-Time Flexible Sigmoidoscopy vs Multiple Rounds of Mailed Fecal Immunohistochemical Tests in Colorectal Cancer Screening

Background & Aims: We compared the diagnostic yields of colonoscopy, flexible sigmoidoscopy, and fecal immunochemical tests (FITs) in colorectal cancer (CRC) screening. Methods: A total of 30,007 asymptomatic persons, 50–74 years old, were invited for CRC screening in the Netherlands. Participants were assigned to groups that received 4 rounds of FIT (mailed to 15,046 participants), once-only flexible sigmoidoscopy (n = 8407), or once-only colonoscopy (n = 6600). Patients with positive results from the FIT (≥10 μg Hb/g feces) were referred for colonoscopy. Patients who underwent flexible sigmoidoscopy were referred for colonoscopy if they had a polyp of ≥10 mm; adenoma with ≥25% villous histology or high-grade dysplasia; sessile serrated adenoma; ≥3 adenomas; ≥20 hyperplastic polyps; or invasive CRC. The primary outcome was number of advanced neoplasia detected (diagnostic yield) by each test. Secondary outcomes were number of colonoscopies needed to detect advanced neoplasia and number of interval CRCs found during each primary screening test. Patients with interval CRCs were found through linkage with Netherlands Cancer Registry. Advanced neoplasia were defined as CRC, adenomas ≥ 10 mm, adenomas with high-grade dysplasia, or adenomas with a villous component of at least 25%. Results: The cumulative participation rate was significantly higher for FIT screening (73%) than for flexible sigmoidoscopy (31%; P < .001) or colonoscopy (24%; P < .001). The percentage of colonoscopies among invitees was higher for colonoscopy (24%) compared to FIT (13%; P < .001) or flexible sigmoidoscopy (3%; P < .001). In the intention to screen analysis, the cumulative diagnostic yield of advanced neoplasia was higher with FIT screening (4.5%; 95% CI 4.2–4.9) than with colonoscopy (2.2%; 95% CI, 1.8–2.6) or flexible sigmoidoscopy (2.3%; 95% CI, 2.0–2.7). In the as-screened analysis, the cumulative yield of advanced neoplasia was higher for endoscopic screening with colonoscopy (9.1%; 95% CI, 7.7–10.7) or flexible sigmoidoscopy (7.4%; 95% CI, 6.5–8.5) than with the FIT (6.1%; 95% CI, 5.7–6.6). All 3 screening strategies detected a similar proportion of patients with CRC. Follow-up times differed for each test (median 8.3 years for FIT and flexible sigmoidoscopy and 5.8 years for colonoscopy). Proportions of patients that developed interval CRC were 0.13% for persons with a negative result from FIT, 0.09% for persons with a negative result from flexible sigmoidoscopy, and 0.01% for persons with a negative result from colonoscopy. Conclusions: Mailed multiple-round FITs detect significantly more advanced neoplasia, on a population level, compared with once-only flexible sigmoidoscopy or colonoscopy screening. Significantly fewer colonoscopies are required by individuals screened by multiple FITs. Trialregister.nl numbers: first round, NTR1096; second round and additional invitees, NTR1512; fourth round, NTR5874; COCOS trial NTR1829.