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Colonoscopy may not be gold standard of colon cancer screening – large randomised trial

Results from a clinical trial in Norway have cast doubts on the commonly held belief that if everyone would get a colonoscopy screening just once a decade, it could practically make colorectal cancer extinct, writes Medical Brief.

Michael Bretthauer, a gastroenterologist and researcher who led the trial, said primary analysis found that colonoscopy cut colon cancer risk only 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, and first randomised trial showing outcomes of exposing people to colonoscopy screening versus no colonoscopy,” 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 raised an uncomfortable question for doctors. “Maybe colonoscopy isn’t as good as we always thought it is.”

Colonoscopies are still a good test, he said, but it might be time to re-evaluate their standing as the gold standard of colon cancer screens. “This study provides clear data 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, it’s promptly removed, thus nipping the cancer before it spreads. Past research always showed colonoscopy could put a huge dent, on the order of 70%, in the incidence and mortality from colon cancer.

But none of those studies was large randomised trials, the ultimate experiment in clinical research, reports Stat News.

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 colonoscopies were truly as good as they all believed.

Some 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 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 invited to colonoscopy, only 42% actually did one. The team published their findings in the New England Journal of Medicine (NEJM).

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 programme 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 randomised studies, Dominitz pointed out. “Colonoscopy is sigmoidoscopy and more, so you’d think it can’t be less effective than sigmoidoscopy.”

But nuances abound in interpreting the data, he added. 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 past 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.

For more than two decades, he added, colonoscopy has been recommended as one of several available options for colorectal cancer screening. However, the best evidence to support its use has been limited to data from cohort studies, which have estimated that this type of screening has been associated with a 40 to 69% decrease in the incidence of colorectal cancer and a 29 to 88% decrease in the risk of death from this disease.

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 said 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 suggesting exposing people to colonoscopy can reduce risk of developing and dying of colon cancer.”

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 in which you put all your trust,” 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 added. “I think we may have oversold colonoscopy. If you look at what the gastroenterology societies say, and I’m one myself, 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.” That brings it more in line with the other main colorectal cancer tests, which analyse faeces 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 programme, he said, when the faecal 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.”

That, too, is being put to the test. Gupta, Dominitz, and others are working on large randomised trials that pit colonoscopy against faecal 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. Someone who says: ‘I’m way too busy, can’t take two 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 one or two and wants the most sensitive test, Gupta said, then colonoscopy is still king.

In his accompanying editorial in NEJM, Dominitiz wrote that this relatively small reduction in the risk of colorectal cancer and the non-significant reduction in the risk of death was both surprising and disappointing; these findings raise the question of why previous studies would have shown greater effectiveness of sigmoidoscopy than colonoscopy. In fact, a pooled analysis of four large, randomised sigmoidoscopy trials showed significant reductions in both the incidence of colorectal cancer and the risk of related deaths (22% and 26%, respectively).

He believes there are several potential explanations for these discouraging results. For example, screening can be effective only if it is performed; only 42% of the participants in the NordICC trial who were invited to undergo screening underwent colonoscopy, as compared with 58 to 87% in the sigmoidoscopy trials.

In the adjusted per-protocol analysis of the NordICC trial, colonoscopy was estimated to reduce the incidence of colorectal cancer by 31% and the risk of colorectal cancer–related death by 50%, findings that approximated those of cohort studies. Although consent after randomisation, as used in this trial, offers some advantages over consent before randomisation with respect to estimating adherence to population-based screening efforts, participation in countries where screening colonoscopy is not well established may be very different than that in countries (e.g. the United States) where its use is broadly recommended.

Therefore, the actual effectiveness of colonoscopy in populations that are more accepting of colonoscopy could more closely resemble the effectiveness shown in the per-protocol analysis in this trial.

Another explanation for these results is that the benefits of screening colonoscopy take time to be realised, because the incidence of colorectal cancer is initially increased when presymptomatic cancers are identified. With the use of polypectomy, the future risks of colorectal cancer and related death can be reduced if polyp resection is adequate.

The NordICC investigators plan to repeat their analysis at 15 years.

Another consideration with respect to the results of the trial is that colonoscopy is highly operator dependent. The proportion of screening colonoscopies in which one or more adenomas is detected is called the adenoma detection rate. Endoscopists with a higher adenoma detection rate offer their patients greater protection from the risks of colorectal cancer and related death than endoscopists who find fewer precancerous polyps.

One study showed that every one percentage-point increase in the adenoma detection rate is associated with a 3% reduction in the future incidence of colorectal cancer and a 5% reduction in colorectal cancer–related death. Bretthauer et al. previously reported that in the NordICC trial, 29% of the endoscopists had an adenoma detection rate below the recommended minimum threshold of 25%.

Finally, some data from the trial suggest that high-risk persons in Poland tended to choose to undergo colonoscopy; rates of detection of colorectal cancer were high, and the incidence of colorectal cancer was lower among participants in the invited group who did not undergo screening than among those in the usual-care group. Therefore, it is plausible that some persons agreed to participate in the trial and undergo screening because of an underlying concern about symptoms.

If true, this would lead to an underestimation of the per-protocol effectiveness of colonoscopy and would also help to explain why the expected shift toward detection of earlier-stage colorectal cancer with screening colonoscopy was not observed.

The results of this trial are unique and important. Another large, randomised trial is the ongoing SCREESCO (Screening of Swedish Colons) trial comparing colonoscopy with either a faecal immunochemical test (FIT) performed every two years or usual care (no screening).

However, a preliminary report of the SCREESCO trial showed that only 35% of the participants who were invited to undergo colonoscopy underwent the procedure, and the endoscopists had a median adenoma detection rate of 20%. Two other large trials comparing colonoscopy with either FIT every two years or annual FIT may eventually shed additional light on the relative effectiveness of colonoscopy, although these trials do not include a comparison of colonoscopy screening with no screening.

Given the modest effectiveness of screening colonoscopy in the NordICC trial, what should we conclude about the role of this test? If the trial truly represents the real-world performance of population-based screening colonoscopy, it might be hard to justify the risk and expense of this form of screening when simpler, less-invasive strategies (e.g. sigmoidoscopy and FIT) are available.

However, with increased levels of participation in screening and with high-quality examinations, greater reductions in the incidence of colorectal cancer and related death would be expected. Although the results reported by Bretthauer et al. may, in the near term, temper enthusiasm for screening colonoscopy, additional analyses, including longer follow-up and results from other ongoing comparative-effectiveness trials, will help us to fully understand the benefits of this test.

Study details

Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death

Michael Bretthauer, Magnus Løberg, Paulina Wieszczy, Mette Kalager, Louise Emilsson, Kjetil Garborg, Maciej Rupinski, Evelien Dekker, Manon Spaander, Marek Bugajski, Øyvind Holme, Ann G. Zauber, et al.,for the NordICC Study Group*

Abstract

Background
Although colonoscopy is widely used as a screening test to detect colorectal cancer, its effect on the risks of colorectal cancer and related death is unclear.

Methods
We performed a pragmatic, randomised trial involving presumptively healthy men and women 55 to 64 years of age drawn from population registries in Poland, Norway, Sweden, and the Netherlands between 2009 and 2014. The participants were randomly assigned in a 1:2 ratio to either receive an invitation to undergo a single screening colonoscopy (the invited group) or to receive no invitation or screening (the usual-care group). The primary end points were the risks of colorectal cancer and related death, and the secondary end point was death from any cause.

Results
Follow-up data were available for 84,585 participants in Poland, Norway, and Sweden — 28,220 in the invited group, 11,843 of whom (42.0%) underwent screening, and 56,365 in the usual-care group. A total of 15 participants had major bleeding after polyp removal. No perforations or screening-related deaths occurred within 30 days after colonoscopy. During a median follow-up of 10 years, 259 cases of colorectal cancer were diagnosed in the invited group as compared with 622 cases in the usual-care group. In intention-to-screen analyses, the risk of colorectal cancer at 10 years was 0.98% in the invited group and 1.20% in the usual-care group, a risk reduction of 18% (risk ratio, 0.82; 95% confidence interval [CI], 0.70 to 0.93). The risk of death from colorectal cancer was 0.28% in the invited group and 0.31% in the usual-care group (risk ratio, 0.90; 95% CI, 0.64 to 1.16). The number needed to invite to undergo screening to prevent one case of colorectal cancer was 455 (95% CI, 270 to 1429). The risk of death from any cause was 11.03% in the invited group and 11.04% in the usual-care group (risk ratio, 0.99; 95% CI, 0.96 to 1.04).

Conclusions
In this randomised trial, the risk of colorectal cancer at 10 years was lower among participants who were invited to undergo screening colonoscopy than among those who were assigned to no screening.

 

NEJM article – Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death

 

STAT News article – In gold-standard trial, invitation to colonoscopy reduced cancer incidence but not death (Open access)

 

NEJM article – Understanding the Results of a Randomized Trial of Screening Colonoscopy (Open access)

 

See more from MedicalBrief archives:

 

A FIT alternative to colonoscopy comes home in the US

 

Annual non-invasive test effective for colon cancer screening

 

Increased colon cancer risk extends to second- and third-degree relatives

 

ACS recommends earlier colorectal cancer screening

 

 

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