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Abstract
Objectives
Colonoscopy screening is a widely recommended method for detecting colorectal cancer (CRC) in countries across the world. However, until recently, no randomized controlled trials demonstrated its effectiveness in average-risk individuals. Recently, Bretthauer et al published preliminary results of a multicenter randomized controlled trial, the Nordic-European Initiative on Colorectal Cancer (NordICC) trial, that investigated the effects of once-only colonoscopy screening on CRC incidence and mortality.2 In the intention-to-screen analysis, which compared participants not offered screening to those offered screening regardless of participation, they found that the invited group had an incidence and mortality reduction at 10 years of 18% and 10%, respectively. The investigators noted that although the incidence and mortality reductions were clinically important, they were lower than anticipated based on observational and modeling studies.
The publication of the NordICC trial results induced media attention and controversy regarding the effectiveness of colonoscopies. Experts advised people to interpret the results cautiously, noting aspects of the NordICC trial that could contribute to the underwhelming findings. A critical issue was the low screening uptake (42%). In the adjusted per-protocol analyses, which compared participants not offered screening to those offered screening who received colonoscopy, incidence and mortality reductions at 10 years increased to 31% and 50%, respectively. Another important consideration was the relatively short 10-year follow-up period. This study aimed to evaluate whether the NordICC trial results are lower than expected based on modeling and to what extent the results could be explained by screening uptake and follow-up period.
Methods
We used 3 Cancer Intervention and Surveillance Modeling Network CRC models to simulate NordICC trial outcomes: Colorectal Cancer Simulated Population Model for Incidence and Natural History (CRCSPIN), Microsimulation Screening Analysis Colorectal Cancer (MISCAN-Colon), and Simulation Model of Colorectal Cancer (SimCRC). Using these models, we simulated the NordICC trial population,2 with 42% of the invited group simulated to receive a 1-time colonoscopy and a usual-care group remaining unscreened (Supplementary Table 1). Our modeling assumptions included random selection into screening unrelated to CRC risk, full adherence to US guidelines for adenoma surveillance,4 and high sensitivity of colonoscopy (Supplementary Materials). We compared model predictions to reductions in CRC incidence and mortality observed in the trial. Additionally, we simulated 5 hypothetical scenarios: 42% adherence with 15- and 20-year follow-up and 100% adherence with 10-, 15-, and 20-year follow-up.
Results
With 42% uptake and 10-year follow-up, the models predicted CRC incidence and mortality reductions of 11%–28% and 24%–32% (ranges are across models), respectively. These estimates overlap the 95% confidence intervals (Cis) of the decreases observed in the NordICC intention-to-screen analyses, which were 18% (95% CI: 7–30) and 10% (95% CI: –16 to 36), respectively. The level of screening uptake had the largest impact on the findings: with 100% uptake, the model-predicted incidence and mortality reductions more than doubled to 26%–61% and 53%–70%, respectively. These estimates compared well with reductions of 31% (95% CI: 17–45) and 50% (95% CI: 23–73), respectively, in the per-protocol NordICC analyses. Although the relative differences in risk reduction are substantial, the absolute incidence and mortality reduction only increased from 0.14%–0.29% to 0.31%–0.64% and from 0.10%–0.12% to 0.22%–0.26%, respectively, with 42% vs 100% uptake.
Conclusions
In conclusion, our findings show that NordICC trial results are consistent with anticipated mortality reductions from screening colonoscopy, and that with further follow-up higher benefits may be realized, especially in the NordICC’s per-protocol analyses.