10/10/22, 3:37 AM In gold-standard trial, colonoscopy fails to cut rate of cancer deaths - STAT

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In gold-standard trial, colonoscopy fails to reduce rate of

cancer deaths

By Angus Chen Oct. 9, 2022

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10/10/22, 3:37 AM In gold-standard trial, colonoscopy fails to cut rate of cancer deaths - STAT

Pedro Jose Greer, gastroenterologist, right, preparing to do a colonoscopy at Mercy Hospital in Miami.
Lynne Sladky/AP

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.”

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10/10/22, 3:37 AM In gold-standard trial, colonoscopy fails to cut rate of cancer deaths - STAT

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,
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10/10/22, 3:37 AM In gold-standard trial, colonoscopy fails to cut rate of cancer deaths - STAT

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.
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10/10/22, 3:37 AM In gold-standard trial, colonoscopy fails to cut rate of cancer deaths - STAT

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
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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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About the Author

Angus Chen

Cancer Reporter

Angus is a cancer reporter at STAT.

angus.chen@statnews.com
@angrchen
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