In gold-standard trial, invitation to colonoscopy reduced cancer incidence but not death

For decades, gastroenterologists put colonoscopies on a pedestal. If everyone would get the screening just once a decade, clinicians believed it could practically make colorectal cancer “extinct,” said Michael Bretthauer, a gastroenterologist and researcher in Norway. But new results from a clinical trial that he led throw confidence in colonoscopy’s dominance into doubt.

The trial’s primary analysis found that colonoscopy only cut colon cancer risk by roughly a fifth, far below past estimates of the test’s efficacy, and didn’t provide any significant reduction in colon cancer mortality. Gastroenterologists, including Bretthauer, reacted to the trial’s results with a mixture of shock, disappointment, and even some mild disbelief.

“This is a landmark study. It’s the first randomized trial showing outcomes of exposing people to colonoscopy screening versus no colonoscopy. And I think we were all expecting colonoscopy to do better,” said Samir Gupta, a gastroenterologist at the University of California, San Diego and the VA who didn’t work on the trial. And, he said, it raises an uncomfortable question for doctors. “Maybe colonoscopy isn’t as good as we always thought it is.”

He stressed that the study does not invalidate colonoscopies as a useful screening tool. Colonoscopies are still a good test, Gupta said, but it may be time to reevaluate their standing as the gold standard of colon cancer screens. “This study provides clear data,” he said, “that it’s not as simple as saying, ‘Colonoscopy is the most sensitive test, and therefore it is the best.’ It still prevented cancers.”

Colonoscopies search for pre-cancerous polyps, known as adenomas, by inserting a camera up the rectum. If the endoscopist discovers a suspicious polyp, then it’s promptly removed, thus nipping the cancer before it spreads. Past research always showed that colonoscopy could put a huge dent, on the order of 70%, in the incidence and mortality from colon cancer.

But none of those studies were large randomized trials, the ultimate experiment in clinical research. So Bretthauer, of the University of Oslo and Oslo University Hospital, and several colleagues started one a decade ago, recruiting more than 80,000 people aged 55 to 64 in Poland, Norway, and Sweden to test if colonoscopy was truly as good as they all believed. Roughly 28,000 of the participants were randomly selected to receive an invitation to get a colonoscopy, and the rest went about their usual care, which did not include regular colonoscopy screening.

The researchers then kept track of colonoscopies, colon cancer diagnoses, colon cancer deaths, and deaths from any cause. After 10 years, the researchers found that the participants who were invited to colonoscopy had an 18% reduction in colon cancer risk but were no less likely to die from colon cancer than those who were never invited to screening. Of the participants who were invited to colonoscopy, only 42% actually did one. The team published their findings in the New England Journal of Medicine on Sunday.

The results are incongruent with some past investigations in other colon cancer screens. “We know from other screening tests that we can reduce cancer mortality by more than this,” said Jason Dominitz, the executive director of the national gastroenterology and hepatology program at the VA who wrote an accompanying editorial in NEJM and didn’t work on the trial. Sigmoidoscopy, which only examines a smaller portion of the colon, has been shown to reduce colon cancer mortality in randomized studies, Dominitz pointed out. “Colonoscopy is sigmoidoscopy and more, so you’d think it can’t be less effective than sigmoidoscopy,” he said.

But nuances abound in interpreting the data, Dominitz said. For one, a minority of participants who were invited to colonoscopy actually showed up for one. That may have diluted the observed benefits of colonoscopy in the study. Cancer treatment has also progressed over the last couple of decades, too, and the study only had 10 years of follow-up thus far, both of which would make it harder to see a mortality benefit from the screen. “They’re doing a 15-year follow, and I would expect to see a significant reduction in cancer mortality in the long term,” Dominitz said. “Time will tell.”

Even if cancer therapy has progressed to the point where a 15-year follow-up fails to eke out a mortality reduction, UCSD’s Gupta pointed out that preventing cancer nonetheless can have a great benefit. The study still showed that colonoscopies reduced cancer incidence, which also means a reduction in surgeries, chemotherapies, immunotherapies, and other bad times. “The process of being treated is awful,” Gupta said. “If you ask patients if you’d rather be treated or prevented, a lot would say prevented.”

A secondary analysis also offers another silver lining, Gupta said. When the investigators compared just the 42% of participants in the invited group who actually showed up for a colonoscopy to the control group, they saw about a 30% reduction in colon cancer risk and a 50% reduction in colon cancer death. “That adds to a bunch of observational study data that suggests exposing people to colonoscopy can reduce risk of developing and dying of colon cancer,” Gupta said.

But the secondary analysis isn’t as robust as the primary or intention-to-treat analysis. “The intention-to-treat analysis is the premium methodology, the analysis you put all your trust in,” Oslo’s Bretthauer said. That’s led him to consider that he and everyone else in the colon cancer field may have been wrong about how useful colonoscopy truly is.

“It’s not the magic bullet we thought it was,” he said. “I think we may have oversold colonoscopy. If you look at what the gastroenterology societies say, and I’m one myself so these are my people, we talked about 70, 80, or even 90% reduction in colon cancer if everyone went for colonoscopy. That’s not what these data show.”

Rather, he said, colonoscopy screening’s true benefit may lie somewhere in between the primary and secondary analyses in his study. “You may reduce your risk of getting colorectal cancer by 20 to 30% if you get a colonoscopy,” Bretthauer said. That brings it more in line with the other main colorectal cancer tests, which analyze feces for signs of cancer, either abnormal DNA or blood, and can be taken at home.

That raises an important point for policymakers, Bretthauer added. Colonoscopy is more expensive, more time-intensive, and more unpleasant in preparation for patients. Many European countries balked at putting public health dollars towards a large, expensive program, he said, when the fecal testing was cheaper, easier, and had greater uptake in certain studies. “Now, the European approach makes much more sense. It’s not only cheaper, but maybe equally effective,” Bretthauer said.

That, too, is being put to the test. Gupta, Dominitz, and others are working on large randomized trials that pit colonoscopy against fecal screens.

This study may not change the calculus very much for any individual patient, though, Gupta said. In the end, which colon cancer screening you decide to go with is a matter of personal preference. “The first message is that screening saves lives and prevents cancer. If we could have a chance to start everyone at age 45, I’d like that. Second is you have many options,” he said. “Someone who says, ‘I’m way too busy, can’t take 2 days off of work for a colonoscopy.’ OK, we have stool-based options.”

But for someone who just wants to be screened once every 10 years rather than every 1 or 2 and wants the most sensitive test, Gupta said, then colonoscopy is still king.

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