First Randomized Controlled Trial Comparing Colonoscopy With No Screening Finds Less Benefit Than Expected for Colonoscopy

First Randomized Controlled Trial Comparing Colonoscopy With No Screening Finds Less Benefit Than Expected for Colonoscopy

Douglas K. Rex, MD, MASGE, reviewing Bretthauer M, et al. N Engl J Med 2022 Oct 9.

In the first report of incidence and mortality results from a randomized controlled trial (RCT) comparing colonoscopy with no screening, 84,585 previously unscreened persons aged 55 to 64 years old were randomized to an invitation for colonoscopy versus usual care (no invitation) in a 1:2 ratio between 2009 and 2014. The study results are from Norway, Poland, and Sweden and have a median follow-up of 10 years.

In the group invited to undergo colonoscopy, 42% underwent screening. There were no perforations or screening-related deaths after colonoscopy.

On an intent-to-screen basis, the reduction in colorectal cancer (CRC) incidence was 18% in the invited group compared with the usual-care group. In the invited group, the risk of death from CRC was reduced by only 10%, and the difference did not reach significance.

In the per-protocol analysis, the reduction in CRC incidence was 31% and the reduction in CRC death was 50%. For uncertain reasons, the incidence reduction was 45% in Norway and 15% in Poland.

The fraction of cancers in the screen-detected group that were early stage was similar to that of the usual-care group.

The overall adenoma detection rate (ADR) was 30.7%, with no report of adenomas per colonoscopy. There was no analysis of reductions in proximal versus distal cancer incidence.

Douglas K. Rex, MD, FASGE

COMMENT

This study shows a reduction in CRC incidence with colonoscopy compared with usual care, but the reduction in rate is low in the intent-to-screen analysis and numerically lower than in some sigmoidoscopy trials. In the U.S., where colonoscopy is widely accepted, the per-protocol analysis is of greatest importance. In the U.S., we should move the discussions with media and patients away from the intent-to-screen analysis to the per-protocol analysis. There are some issues with the study:

  • The minimal shift in cancer stage in the invited group suggests the patients could reflect some bias toward high-risk or symptomatic patients undergoing colonoscopy.
  • The overall ADR was 31%. An accompanying editorial noted that the investigators previously reported that 29% of endoscopists were below the current U.S.-recommended minimum ADR threshold of 25%. Recent registry data indicate ADRs in the U.S. now average 40%.
  • There are no data on adenomas per colonoscopy, which would provide additional information on how well colons were cleared.
  • The extent to which patients with adenomas underwent appropriate surveillance is not known. 
  • The higher incidence reduction in the per-protocol analysis in Norway (45%) versus Poland (15%) is unexplained.
  • In the intent-to-screen arm, the incidence reduction was higher than the mortality reduction, which is unexpected.

Given the issues noted here and the short follow-up for an RCT of this type, the study’s estimate of the reduction in cancer incidence associated with screening colonoscopy is almost certainly low. The study supports that sending out invitations for colonoscopy is inadequate and that colonoscopy must be done well. Hopefully, the limitations will be widely understood and not set colorectal cancer screening back. For now, this study should not affect our approach or commitment to colorectal cancer screening.

Note to readers: At the time we reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.

CITATION(S)

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 Oct 9. (Epub ahead of print) (https://doi.org/10.1056/nejmoa2208375)

Dominitz JA, Robertson DJ. Understanding the results of a randomized trial of screening colonoscopy. N Engl J Med 2022 Oct 9. (Epub ahead of print) (https://doi.org/10.1056/nejme2211595)

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