CHICAGO — In the 13-year update from the Nordic-European Initiative on Colorectal Cancer (NordICC) trial, the risk for colorectal cancer (CRC) remained lower in people assigned to colonoscopy screening compared to no screening, and no significant differences were seen in mortality rates between the two groups, consistent with earlier results from the trial.

“The risk of colorectal cancer death is very low even without screening, and the hope of finding a screening benefit on colorectal cancer mortality with longer follow-up is so far not substantiated,” reported the study authors in their paper, simultaneously published in The Lancet, and presented at Digestive Disease Week (DDW) 2026.

In the trial’s previous 10-year follow-up, published in 2022, the risk of developing CRC was lower with colonoscopy, but only modestly so, with a 18% relative risk reduction (0.98% vs 1.20%; risk ratio [RR], 0.82).

Furthermore, the risk for CRC-related death between the two groups at 10 years was even smaller and nonsignificant, with a risk reduction of 10% (0.28% vs 0.31%; RR, 0.90). “Follow-up time of 10 years may [have been] too short to see the real benefits of colonoscopy screening,” said first author Michal F. Kaminski, MD, PhD, of the University of Oslo in Oslo, Norway, who presented the updated findings at the meeting.

13-Year Update

For the study, 84,583 asymptomatic men and women between the ages of 55 and 64 years from Norway, Poland, and Sweden were randomized 1:2 to be invited to receive a single colonoscopy screening or no screening between 2009 and 2014.

Importantly, of 28,220 participants who were invited to receive a colonoscopy, only 11,843 (42%) accepted the invitation and underwent the procedure.

Over the 13 years, the incidence of CRC increased to 1.46% in the screening group and to 1.80% in the no-screening group (RR, 0.81) in the intention-to-screen analysis. In the per-protocol analysis, which only compared those who received colonoscopy to the no-colonoscopy group, the RR was 0.55, with a relative risk reduction of 45%.

As seen in the 10-year follow-up in the intention-to-screen analysis, no significant differences were observed in terms of CRC mortality (0.41% in the screening group vs 0.47% in the no-screening group; RR, 0.88). In the per-protocol analysis, the RR for CRC mortality was 0.70. There were also no significant differences between the groups in terms of all-cause mortality (16.30% vs 16.34%; RR, 1.00).

Overall, “the study reveals that the risk of colorectal cancer death is significantly lower than was expected when the trial started, even without screening, and that screening does not provide additional reduction of an already low risk for colorectal cancer mortality with longer follow-up than 10 years,” said Kaminski.

Subgroup Analyses

With a higher number of events in the 13-year follow-up, the researchers were able to conduct some key subgroup analyses that were not possible at 10 years, including looking at the risk for CRC in men vs women.

In men, the risk for CRC was 1.69% with screening vs 2.19% with no screening in the intention-to-screen analysis (RR, 0.77), whereas the corresponding risks in women were 1.24% vs 1.43% (RR, 0.87; P for interaction < .005).

In addition, a significantly lower risk for CRC was observed with colonoscopy in the distal colon (0.87% vs 1.11% with no colonoscopy; RR, 0.79) vs no significant difference in the proximal colon (0.51% vs 0.56%; RR, 0.91; P for interaction < .005).

The study does provide some notable new insights in subgroups, said Aasma Shaukat, MD, MPH, Division of Gastroenterology, NYU Grossman School of Medicine, New York City, who wrote an editorial on the updated findings.

The lack of a reduction in CRC incidence in women “is quite concerning,” she told Medscape Medical News. “It implies women do not benefit from colonoscopy screening due to their low baseline risk of colorectal cancer.”

Likewise, she added, the lack of significant reduction in proximal CRC also implies that colonoscopy does not reduce this risk.

Earlier Results Spark Controversy

Reductions in CRC mortality with colonoscopy seen in observational studies conducted prior to the NordICC trial have generally been much greater, ranging from 65% to as much as 88%, as reported in American College of Gastroenterology clinical guidelines on CRC screening.

Therefore, the earlier NordICC results — the first large randomized controlled trial of its kind — sparked significant controversy, with many critics pointing to low colonoscopy uptake (42%), few events, and delays in cancer reporting.

For example, having accepted the invitation to receive the screening could suggest higher risk, Elena Stoffel, MD, MPH, a clinical professor of internal medicine at the University of Michigan Medical School, Ann Arbor, Michigan, told Medscape Medical News.

“You might think that people who receive an invitation for colonoscopy are more likely to get a colonoscopy if they are at higher risk or have a family history of colon cancer,” she said. Furthermore, “those individuals might need more colonoscopies in the future, but if they only received one colonoscopy and didn’t receive any follow-up, their risk was presumably higher than the average person’s risk.”

And in a 2023 review of the trial, Shaukat and colleagues noted that issues of varying endoscopist skill have also been raised, with as many as 30% of endoscopists in the NordICC study falling short of the quality indicator of having an adenoma detection rate of 25% that is commonly recognized in the US.

Lower-Than-Expected Mortality Rates

Kaminski noted that the rate of CRC mortality of 0.47% in the no-screening group was significantly lower than the rate of 0.82% that the authors had estimated at the time of the trial.

“We expected, based on the data available in the cancer registries, a death rate of about a little less than 1%,” he said. “However, the death rate in the trial is less than 0.5%.”

Shaukat also underscored the low mortality rates in her editorial. “The most striking aspect of these results is perhaps not the modest (or absence of) mortality effect of screening but the unexpectedly low colorectal cancer mortality in the no-screening group,” she said.

Both Kaminski and Shaukat attribute the trend to improvements in CRC care, ranging from earlier diagnosis and advances in surgery to more effective systemic therapy, including immunotherapy.

“Colonoscopy clearly prevents some cancers, but when prognosis for clinically detected colorectal cancer improves, the incremental mortality benefit that screening can deliver inevitably shrinks,” she explained.

Overall, “the study is still underpowered for colorectal cancer mortality. It will likely take 15 years or longer for that outcome,” said Shaukat. However, “even if prolonged follow-up eventually yields a statistically significant reduction in colorectal cancer mortality, the absolute effect is likely to remain small.”

The scenario that colonoscopy, after adjusting for all the various confounders, wouldn’t still provide a greater mortality benefit despite the declining CRC rates in the population, still has its skeptics, though.

“I am not excluding some contribution of [the role of declining colorectal cancer rates],” Douglas J. Robertson, MD, MPH, professor at the Dartmouth Geisel School of Medicine, Hanover, New Hampshire, told Medscape Medical News.

“But I would be surprised that it would entirely obviate the mortality benefit in the relatively short time since the completion of [previous] sigmoidoscopy studies, where only half the colon was examined,” he said, referring to a study showing a 26% reduction in CRC mortality with sigmoidoscopy over a 12-year follow-up.

The mortality debate aside, the study’s evidence supporting the prevention of the risk for CRC is nevertheless a profound benefit on its own, Robertson added. The trial demonstrates that colonoscopy is associated with “reductions in colorectal cancer incidence.”

The NordICC study was funded by the Norwegian Research Council, the Nordic Cancer Union, the Norwegian Cancer Society, and the Health Fund of South-East Norway. Kaminski reported having relationships with Fujifilm and Olympus. Shaukat and Stoffel had no disclosures to report. Robertson reported serving as an advisor for Freenome and a consultant to Amadix and Foley, Hoag LLP.