The Nordic-European Initiative on Colorectal Cancer (NordICC) is a large, multicentre, randomised study that investigated the effects of population-based colonoscopy screening on the risks of colorectal cancer and related death at 10 years. The study involved presumptively healthy men and women 55 to 64 years of age drawn from population registries between 2009 and 2014. The NordICC Study Group investigators reported at the United European Gastroenterology Week held from 8 to 11 October 2022 in Vienna, Austria that the risk of colorectal cancer at 10 years was lower among participants who were invited to undergo screening colonoscopy than among those who were assigned to no screening. However, screening colonoscopy was performed in only 42% of the participants who were invited to undergo screening. The study findings are simultaneously published on 9 October 2022 in The New England Journal of Medicine.
The authors wrote in the study background that colorectal cancer is an attractive target for population screening. Multiple screening options are available, but high-quality evidence to indicate the best strategies is limited. The most commonly used screening tests are foecal testing for occult blood and endoscopic screening with sigmoidoscopy or colonoscopy.
Colonoscopy is considered to be more effective than sigmoidoscopy, but colonoscopy has not been adopted in many parts of the world, partly because evidence from randomised studies regarding the benefits is lacking. A balance among benefits, harms, and cost-effectiveness of various colorectal cancer screening tests is important because colonoscopy is more invasive and burdensome for patients than foecal testing and sigmoidoscopy, and it requires more clinical resources.
In NordICC, the study participants were randomly assigned in a 1:2 ratio to either receive an invitation to undergo a single screening colonoscopy (the invited group) or to receive no invitation or screening (the usual-care group). The study primary endpoints were the risks of colorectal cancer and related death, and the secondary endpoint was death from any cause.
Follow-up data were available for 84,585 participants in Poland, Norway, and Sweden — 28,220 in the invited group, 11,843 of whom (42.0%) underwent screening, and 56,365 in the usual-care group. A total of 15 participants had major bleeding after polyp removal. No perforations or screening-related deaths occurred within 30 days after colonoscopy.
During a median follow-up of 10 years, 259 cases of colorectal cancer were diagnosed in the invited group as compared with 622 cases in the usual-care group. In intention-to-screen analyses, the risk of colorectal cancer at 10 years was 0.98% in the invited group and 1.20% in the usual-care group, a risk reduction of 18% (risk ratio 0.82; 95% confidence interval [CI] 0.70 to 0.93). The risk of death from colorectal cancer was 0.28% in the invited group and 0.31% in the usual-care group (risk ratio 0.90; 95% CI 0.64 to 1.16).
The number needed to invite to undergo screening to prevent one case of colorectal cancer was 455 (95% CI 270 to 1429). The risk of death from any cause was 11.03% in the invited group and 11.04% in the usual-care group (risk ratio 0.99; 95% CI 0.96 to 1.04).
The authors commented that in this large, population-based, randomised study, the risk of colorectal cancer at 10 years was 0.98% among study participants who were invited to undergo screening colonoscopy, as compared with 1.20% among those who were assigned to receive usual care. Screening colonoscopy was performed in only 42% of the participants who were invited to undergo screening. In adjusted analyses to estimate the effect of screening if all the participants who were randomly assigned to screening had actually undergone screening, the risk of colorectal cancer was decreased from 1.22% to 0.84%, and the risk of colorectal cancer–related death was decreased from 0.30% to 0.15%.
The study limitations include lower than expected participation in some countries and a lack of information about adherence to recommendations regarding surveillance for polyps. Although the study investigators adhered to the protocol by reporting the first results, longer follow-up may be needed to capture the full effect of colonoscopy screening. The authors stated that their results may serve to quantify the effectiveness of screening colonoscopy for the prevention of colorectal cancer and thus enable decision makers to properly prioritise resources for cancer screening and healthcare services.
In an accompanied editorial article, the editorialists wrote that colonoscopy has been the predominant form of screening for colorectal cancer in the United States. However, the best evidence to support its use has been limited to data from cohort studies. Unlike randomised, controlled studies, which have provided support for foecal occult blood testing and sigmoidoscopy, cohort studies probably overestimate the real-world effectiveness of colonoscopy because of the inability to adjust for important factors such as incomplete adherence to testing and the tendency of healthier persons to seek preventive care.
The editorialists emphasized that this evidence gap is now addressed by the landmark NordICC study; relatively small reduction in the risk of colorectal cancer and the non-significant reduction in the risk of death are both surprising and disappointing, raising the question of why previous studies would have shown greater effectiveness of sigmoidoscopy than colonoscopy.
Another large, randomised study is the ongoing SCREESCO (Screening of Swedish Colons) comparing colonoscopy with either a foecal immunochemical test performed every 2 years or usual care (no screening). However, a preliminary report of the SCREESCO study showed that only 35% of the participants who were invited to undergo colonoscopy underwent the procedure, and the endoscopists had a median adenoma detection rate of 20%.
The editorialists underlined that based on the modest effectiveness of screening colonoscopy in the NordICC study, it might be hard to justify the risk and expense of this form of screening when simpler, less invasive strategies are available. However, with increased levels of participation in screening and with high-quality examinations, greater reductions in the incidence of colorectal cancer and related death would be expected. Although the NordICC study results may, in the near term, temper enthusiasm for screening colonoscopy, additional analyses, including longer follow-up and results from other ongoing comparative-effectiveness studies, will help to fully understand the benefits of screening colonoscopy.
The NordICC study was funded by the Research Council of Norway and others.
Bretthauer M, Løberg M, Wieszczy P, et al., for the NordICC Study Group. Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death. NEJM; Published online 9 October 2022. DOI: 10.1056/NEJMoa2208375
Dominitz JA, Robertson DJ. Understanding the Results of a Randomized Trial of Screening Colonoscopy. NEJM; Published online 9 October 2022. DOI: 10.1056/NEJMe2211595