Colorectal cancer (CRC) incidence and mortality of China account for nearly 30% of the global attributable fraction. We aimed to estimate the yield and effectiveness of two-sample fecal immunochemical test (FIT)-based screening program in China. Eligible individuals were invited for two-sample FIT between 2007 and 2021, with positive ones (cutoff: 40 μg/g before 2013, and 20 μg/g thereafter) referred for colonoscopy. Participation rates, detection rates, and positive predictive values (PPVs) were calculated. Participants were classified into: FIT+ / colonoscopy compliers, FIT+ / colonoscopy non-compliers, and FIT- as controls. We compared CRC incidence and mortality, and calculated the age reaching comparable risk. Among 246,349 invitees, 150,524 (61.10%) participated in two-sample FIT, with 16,994 (11.29%) identified as FIT+; 12,816 (75.41%) underwent colonoscopy, yielding a detection rate and PPV of 0.57% and 6.70% for advanced neoplasia. Median follow-up was 10.58 years. Compared with FIT- participants, CRC incidence and mortality were relatively similar among FIT+ / colonoscopy compliers with hazard ratio (HR) and 95% confidence interval (CI) of 0.94 (0.75-1.19) and 1.62 (1.09-2.41), but higher among non-compliers with HR and 95% CI of 3.52 (2.85-4.34) and 4.41 (2.96-6.55). Taking CRC incidence and mortality risk of FIT- participants at age 50.0 as the benchmark, FIT+ / colonoscopy compliers reached same risk at 50.6 and 46.1 years, while non-compliers at age 38.0 and 37.9 years, respectively. Two-sample FIT could effectively identify high-risk populations, and colonoscopy compliance is associated with a lower risk of CRC incidence and mortality. This strategy might facilitate CRC screening practice in countries with large populations.
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