Outcomes Associated With Colorectal Cancer After Population-Based Colonoscopy Screening: Results From a European Pragmatic Randomized Trial

Abstract

Bretthauer M, Løberg M, Wieszczy P, et al. Effect of colonoscopy screening on risks of colorectal cancer and related death. N Engl J Med 2022;387:1547–1556. Colorectal cancer (CRC) is an ideal target for both opportunistic and population-based screening. Currently recommended screening strategies rely primarily on stool-based modalities such as fecal immunochemical testing (FIT) and endoscopic modalities such as sigmoidoscopy and colonoscopy. Bretthauer et al performed the first randomized trial to assess the effects of population-based screening colonoscopy on CRC and CRC-associated death. Screening-naïve healthy participants aged 55 to 64 years from 4 European countries were identified from population registries and, in a 1:2 ratio, randomly invited to undergo screening colonoscopy or not invited for screening. Screening colonoscopies were performed from 2009 to 2014. Importantly, no participants received any competing CRC screening modalities outside of the trial during either the screening or follow-up periods. Follow-up data were available for 84,585 patients. Among the invited group, 42.0% of participants accepted their invitation and underwent colonoscopy. The mean adenoma detection rate (ADR) was 30.7%. In intention-to-treat analyses, the 10-year risk ratio (RR) of CRC was 0.82 (95% confidence interval [CI] 0.70–0.93) in the screening arm, although the risk of CRC-related death was not significantly different (RR 0.90, 95% CI 0.64–1.16). In per-protocol analyses, RRs of CRC and CRC-related death with screening were 0.69 (95% CI 0.55–0.83) and 0.50 (95% CI 0.27–0.77), respectively. These results have triggered a broad range of reactions. Given the acceptance rate of 42%, one widely repeated stance is that colonoscopy can be effective only if performed, and that the per-protocol analyses may be a better representation of colonoscopy’s benefits (Dominitz and Robertson, N Engl J Med 2022;387:1609–1611). While perhaps true at the patient level, the aims of this study were to assess the efficacy of colonoscopy as a population-based screening tool. Therefore, barriers to dissemination, acceptability, and uptake are all relevant. Put another way, one might ask whether offering screening colonoscopy as a primary population-based screening modality increases or decreases health equity. Furthermore, existing cohort studies, which likely overestimate colonoscopy’s effectiveness given healthy user bias and inability to adjust for poor uptake, have demonstrated similar results (Nishihara et al, N Engl J Med 2013;369:1095–1105). The issue of justifying the costs (and risks) of colonoscopy as a primary screening modality is therefore also paramount, especially in single-payer resource-limited health care systems, given the established benefits of FIT in reducing CRC incidence and mortality (Chiu et al, Cancer 2015;121:3221–3229). Another debatable point is that the mean ADR was potentially suboptimal at 30.7%. However, given (1) the study period (2009–2014), (2) the screening-naïve non-FIT population, and (3) the upper age limit of 64 years (with established increases in ADR with increasing age [Shaukat et al, Am J Gastroenterol 2021;116:1946–1949]), these results are likely generalizable. Furthermore, inter-endoscopist variations in ADR are well established, with outliers prevalent in most practice settings (Mazurek et al, Clin Gastroenterol Hepatol 2022;20:1931–1946; Bishay et al, Gastrointest Endosc 2020;92:1030–1040.e9). Although the benefits of screening colonoscopy are clear at the patient level, providers and policy makers should carefully consider its role in population-based average-risk screening. Similar studies with long(er) follow-up periods, studies comparing colonoscopy and FIT for population screening, and studies carried out in different populations are all needed. Regardless of the modalities employed, ongoing efforts should be made to provide widespread patient education on CRC screening to improve uptake and optimize health equity.