The NordICC Trial: Analyzing the Effectiveness of a Colonoscopy Screening Program at Reducing Colorectal Cancer Incidence and Mortality

Chiara Maruggi, MD

While colorectal cancer remains the third leading cause of death in the United States, mortality rates have been declining in the past several years.¹

This decline has largely been attributed to the effectiveness of preventive and early-detection screening strategies advocated for by the US Preventive Services Task Force (USPTF) and other medical societies and including colonoscopy, flexible sigmoidoscopy, fecal occult blood testing (FOBT), fecal immunochemical testing (FIT), and computed colonography.²

While the most robust evidence exists for screening using FOBT and flexible sigmoidoscopy testing, colonoscopy has become the leading endoscopic screening in the United States partially due to its inferred benefit in reducing colorectal cancer mortality by increasing detection and removal of polyps throughout the colon.³

Other countries, however, have not adopted this screening modality partially due to the lack of strong evidence to support this practice.⁴

In the Nordic-European Initiative on Colorectal Cancer (NordICC) study, Bretthauer et al. aimed to study the effects of population-based colonoscopy screening on the risks of colorectal cancer and related death at 10 years through a large, multicenter randomized trial in geographic areas where colorectal cancer screening programs were not available at the time of study enrollment.

Investigators enrolled 84,585 participants aged 55 – 64 years old from Poland, Norway, and Sweden in this pragmatic study and randomly assigned them in a 1:2 ratio to either receive an invitation for first-time colonoscopy screening or no invitation, respectively.

The primary end points for the trial were the risk of colorectal cancer and death from the disease (median follow-up, 10 years) and the secondary end point was death from any cause.

Of the cohort randomized to invitation for first-time colonoscopy screening, participation ranged widely across different countries (from 33% in Poland to 60.7% in Norway) as well as across different genders and age groups, with screening being more likely to be completed by older individuals and males. Further, while the bowel preparation was noted to be adequate in >90% of colonoscopies in all regions, the adenoma detection rates (ADR) ranged from 14.4% (Sweden) to 35.2% (Poland).

These rates are in comparison to the 25% ADR benchmark recommended by the American College of Gastroenterology (ACG) and American Society of Gastrointestinal Endoscopy (ASGE) for a high-quality endoscopist.⁵

Using an intention-to-treat analysis and Kaplan-Meier estimator, cumulative 10-year risks of colorectal cancer and colorectal cancer-related death in the 2 cohorts were calculated.The risk of colorectal cancer at 10 years was 0.98% in the invited group (95% confidence interval [CI], 0.86 - 1.90) vs. 1.20% in the usual-care group (95% CI, 1.10 - 1.29) with a calculated risk ratio of 0.82 (95% CI, 0.70 - 0.93).

Surprisingly, neither colorectal cancer-related death at 10 years (screening group, 0.28% vs usual care group, 0.31%) nor all-cause mortality (11.03% vs 11.04%) were found to be statistically different between the 2 groups.

But regarding the per-protocol adjusted analyses for the 42% of participants that did undergo colonoscopy screening, there was a significant 31% reduction in the risk of colorectal cancer and 50% reduction in colorectal cancer-related death in the screening group as compared to the usual-care group. These findings would appear to support the notion that completed colonoscopies do in fact significantly reduce the risk of colorectal cancer and mortality from this disease as previously shown, in even greater degrees, in previous studies.⁵

While the well-designed, population-based NordICC study does pose some questions of the success of a colonoscopy screening program in reducing incidence and mortality of colorectal cancer, there are several limitations. In addition to the low ADR noted earlier, these limitations include the unclear baseline characterists of this seemingly homogenous population, as well as the low participation rate in the colonoscopy screening—which stands in contrast to the >80% screening participation rate seen in a previous randomized controlled trial showing a mortality benefit of colorectal cancer screening via FOBT.⁶ 

Finally, focusing on the length of follow-up time, perhaps the largest limitation in the study is the relatively small length of follow-up—defined by initial enrollment and randomization rather than screening completion—placing this trial at risk of being under-powered to detect a difference in the primary end points, particularly in mortality from colorectal cancer.

Despite these limitations, an overall important takeaway of this project is the importance for clinicians to ensure patient colonoscopy screening, and to continue to work in furthering community awareness of colorectal cancer screening and removing barriers to its access. Further randomized control trials will be needed to guide colorectal cancer screening recommendations.

References

• Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022 Jan;72(1):7-33. doi: 10.3322/caac.21708. Epub 2022 Jan 12. PMID: 35020204.
• Ladabaum U, Dominitz JA, Kahi C, Schoen RE. Strategies for Colorectal Cancer Screening. Gastroenterology. 2020 Jan;158(2):418-432. doi: 10.1053/j.gastro.2019.06.043. Epub 2019 Aug 5. PMID: 31394083.

Helsingen LM, Kalager M. Colorectal cancer screening — approach, evidence, and Future Directions. NEJM Evidence. 2022 Jan;1(1). doi: https://doi.org/10.1056/EVIDra2100035. Epub 2022 Jan 10.

• Bretthauer M, Løberg M, Wieszczy P, Kalager M, Emilsson L, Garborg K, Rupinski M, Dekker E, Spaander M, Bugajski M, Holme Ø, Zauber AG, Pilonis ND, Mroz A, Kuipers EJ, Shi J, Hernán MA, Adami HO, Regula J, Hoff G, Kaminski MF; NordICC Study Group. Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death. N Engl J Med. 2022 Oct 27;387(17):1547-1556. doi: 10.1056/NEJMoa2208375. Epub 2022 Oct 9. PMID: 36214590.
• Anderson JC, Butterly LF. Colonoscopy: quality indicators. Clin Transl Gastroenterol. 2015 Feb 26;6(2):e77. doi: 10.1038/ctg.2015.5. PMID: 25716302; PMCID: PMC4418496.
• Shaukat A, Mongin SJ, Geisser MS, Lederle FA, Bond JH, Mandel JS, Church TR. Long-term mortality after screening for colorectal cancer. N Engl J Med. 2013 Sep 19;369(12):1106-14. doi: 10.1056/NEJMoa1300720. PMID: 24047060.