Colonoscopy Trial Highlights Strengths, Weaknesses in Benefits

Updated findings from a European randomized trial continued to show that colonoscopy screening significantly reduced colorectal cancer (CRC) incidence, but its impact on CRC mortality was less clear.

At 13 years of follow-up, the incidence of CRC was 1.46% among participants who underwent colonoscopy screening versus 1.80% in the no-screening group, with a risk ratio (RR) of 0.81 (95% CI 0.71-0.90) in intention-to-screen analyses and 0.55 (95% CI 0.33-0.81) in per-protocol analyses, reported Michael Bretthauer, MD, PhD, of the University of Oslo in Norway, and colleagues.

However, there was no statistically significant difference in CRC mortality in the screening and no-screening groups (0.41% vs 0.47%, respectively), with risk ratios of 0.88 (95% CI 0.68-1.08) and 0.70 (95% CI 0.26-1.25) in the two types of analyses.

Results from the study were presented at the annual Digestive Disease Week meeting, and published simultaneously in The Lancet.

The results were similar to those observed at 10-year follow-up, which showed the risk of CRC was 0.98% in the screening group and 1.20% in the no-screening group (RR 0.82, 95% CI 0.70-0.93) in intention-to-screen analyses, while CRC mortality was 0.28% and 0.31%, respectively (RR 0.90, 95% CI 0.64-1.16).

In an interview with MedPage Today, Bretthauer noted that a major criticism of the study at the 10-year mark was that it was too short of a follow-up to accurately gauge the impact of colonoscopy on CRC mortality.

“Lesson learned number one with this paper is that it doesn’t get better with longer follow-up time,” Bretthauer said.

Moreover, he noted that CRC mortality in the no-screening group (0.47%) was substantially lower than expected at the time of designing the trial (0.82%).

“We know from cancer statistics that survival rates for patients with colorectal cancer have become a lot higher than they were 10, or even 5, years ago,” Bretthauer noted. “So, a lot more people who get the disease survive because we have much better oncological treatments — better surgical treatment, better radiation treatment, and immunotherapy in the last 4 or 5 years. That’s all good news for patients.”

While the CRC mortality rate “is not zero in the no-screening group, it’s approaching zero, and it’s hard to be better than that,” he said.

In a commentary accompanying the study, Aasma Shaukat, MD, MPH, of the NYU Grossman School of Medicine in New York City, noted that the trial’s longer-term results “compel a recalibration of what colonoscopy can — and cannot — achieve at the population level.”

“This evolving therapeutic landscape fundamentally changes the arithmetic of screening benefit,” she wrote. “Colonoscopy clearly prevents some cancers, but when prognosis for clinically detected colorectal cancer improves, the incremental mortality benefit that screening can deliver inevitably shrinks.”

“Even if prolonged follow-up eventually yields a statistically significant reduction in colorectal cancer mortality, the absolute effect is likely to remain small,” Shaukat added. “From a clinical perspective, the question becomes not just one of whether colonoscopy saves lives, but one of how many procedures, with what opportunity costs, are required to avert one death in contemporary practice.”

“For now, the message is clear: colonoscopy prevents some cancers, but in an era of improving colorectal cancer care, the scale and nature of its benefits are more modest — and more nuanced — than many had long assumed,” she concluded.

The NordICC trial included 84,583 individuals from Norway, Poland, and Sweden, of whom 28,217 were randomly allocated to the screening group and 56,366 to the no-screening group. Overall, 42% of participants allocated to screening attended.

Bretthauer said that another major takeaway from the updated analysis is that, with more events, “what we see is that colonoscopy is more effective in men as compared to women, which I think is important for policymaking … and that colonoscopy is better in the lower parts of the colon as compared to the upper parts of the colon, which also is important.”

Specifically, the risk for distal CRC was significantly reduced in the screening group versus the no-screening group (0.87% vs 1.11%, RR 0.79, 95% CI 0.65-0.89), while the risk for proximal CRC was 0.51% versus 0.56%, respectively (RR 0.91, 95% CI 0.71-1.09).

Among men, the CRC risk was 1.69% in the screening group and 2.19% in the no-screening group (RR 0.77, 95% CI 0.64-0.88), while in women, the risk was 1.24% and 1.43%, respectively (RR 0.87, 95% CI 0.70-1.02).

Shaukat noted that NordICC has limitations, including the fact that colonoscopy uptake was just 42%. However, its strengths — including randomization, screening-naive populations, minimal contamination, and complete long-term registry follow-up — “make it uniquely informative,” she wrote.

As for how the results of the trial should inform clinical practice, Bretthauer said that when he explains the risks and benefits of colonoscopy, “most people understand the numbers pretty quickly.”

“People will decide very differently, with the same information and the same numbers,” he added. “At least they’re informed in the way they understand, and then it’s up to [them] to decide.”

Shaukat pointed out that, for policymakers, it should be understood that colonoscopy is an effective cancer-prevention intervention, particularly when it is actually performed.

At the same time, she suggested that “modest or uncertain mortality benefits, combined with low background colorectal cancer mortality, demand explicit consideration of value; in many settings, investments in tobacco control, obesity prevention, or optimizing treatment pathways could yield larger gains in population health per unit of expenditure.”