'Vanished' in US, Sigmoidoscopy Saves Lives in Norway

Nick Mulcahy

August 12, 2014

Screening with flexible sigmoidoscopy significantly reduces colorectal cancer (CRC) incidence and mortality, compared with no screening, a large randomized trial has found. The study results were published in the August 13 issue of JAMA.

The findings from the Norwegian Colorectal Cancer Prevention Trial are not surprising. Three previous randomized clinical trials have reported similar results with sigmoidoscopy.

The sum total of evidence is, however, "ironic" for clinicians in the United States, according to an accompanying editorial.

"Screening by sigmoidoscopy has all but vanished" in the United States, writes editorialist Allan Brett, MD, professor of clinical internal medicine at the University of South Carolina in Columbia.

That extinction took place despite the fact that colonoscopy, which is the pre-eminent form of screening in the United States, has never been shown to reduce cancer-specific mortality in a randomized trial.

The merits of both colonoscopy and sigmoidoscopy have been much discussed, adds Dr. Brett. Proponents of colonoscopy, with support from observational studies, argue that "examining the entire colon must be preferable to examining half of it," he says.

But clinical data aside, the pivotal event in the uptake of colonoscopy was bureaucratic, he explains, when Medicare began paying for it in 2001 and "many private insurers followed."

"Gastroenterologists began to recommend colonoscopy as the test of choice and had economic incentives to do so," writes Dr. Brett.

But another irony is in the offing in this clinical scenario, says Dr. Brett. Both scope technologies might eventually be somewhat trumped by stool DNA testing as an initial screening tool.

The stool DNA test known as Cologuard (Exact Sciences Corp.), approved just yesterday by the US Food and Drug Administration (FDA), "has the potential to reduce CRC mortality substantially while sharply reducing the number of routine colonoscopies," writes Dr. Brett.

He explains that the multitarget stool test identifies "several DNA abnormalities" associated with CRC or precancerous adenomas. In a large randomized clinical trial, with colonoscopy as the reference standard, the sensitivity of the stool DNA test was 92% for detecting cancer and 42% for detecting advanced precancerous lesions. The specificity was 90% (N Engl J Med. 2014;370:1287-1297).

The stool DNA test was also "much more sensitive" than a separate fecal immunochemical test for hemoglobin performed for each participant in that trial.

But another expert disagrees with Dr. Brett's suggestion that stool DNA testing will eclipse colonoscopy as the initial screening test of choice in the clinic.

Stool DNA testing is an "expensive test," and that "will limit use," said David A. Johnson, MD, chief of gastroenterology at the Eastern Virginia School of Medicine in Norfolk, in an email to Medscape Medical News.

He explained that Medicare currently reimburses a practice $64 for a sigmoidoscopy done in a facility and $215 for a colonoscopy, which is the "gold standard" of screening.

However, Dr. Johnson does agree with Dr. Brett's observation that sigmoidoscopy has "vanished." The tool is used by the Veteran's Administration system but not much anywhere else, he said.

A 2010 report from the Centers for Disease Control and Prevention indicated that about 64% of people eligible for CRC screening in the United States met screening recommendations. However, only 1.3% had undergone a flexible sigmoidoscopy, whereas around 60% of the population had undergone a colonoscopy.

The debate about the merits of the stool DNA test has undoubtedly just begun, based on readers' comments on the Medscape Medical News story about the FDA approval.

Results from Norway

In the meantime, clinicians can ponder the results of the trial from Norway.

Of the 4 major trials to date, the Norway trial is "ideal," say Øyvind Holme, MD, from the Sorlandet Hospital Kristiansand, and colleagues.

That's because the population-based trial addresses the limitations of the other 3 trials, which were conducted in Italy, the United Kingdom, and the United States. That trio of trials depended on volunteers, afforded participants opportunities to be screened outside the trials, and only included people 55 years and older. None of those limitations were at play in the latest trial.

In the Norwegian trial, more than 20,000 adults were screened and more than 70,000, the control group, were not screened.

The screening consisted of either once-only sigmoidoscopy or sigmoidoscopy plus fecal occult blood testing (FOBT). Participants with positive screening results (cancer, adenoma, a polyp 10 mm or larger, or positive FOBT) were offered colonoscopy. The average follow-up was 10.9 years.

The results showed that once-only sigmoidoscopy in adults 50 to 64 years of age significantly reduced both the incidence of CRC and disease-specific mortality.

The incidence of CRC was lower in the screening than in the control group (112.6 vs 141.0 cases per 100,000 person-years; hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.70 - 0.92). In fact, with screening, there was a relative risk reduction of 20% in CRC incidence, the researchers report.

CRC incidence was also lower in people 50 to 54 years of age who underwent screening, and in those 55 to 64 years of age. This finding is notable because in the United States, it is recommended that screening start at age 50.

In addition, disease-specific mortality was lower in the screening group than in the control group (31.4 vs 43.1 deaths per 100,000 person-years; HR, 0.73; 95% CI, 0.56 - 0.94). The relative risk reduction was 27%.

The success of screening was likely muted because only 63% of people invited for screening actually participated, observes Dr. Brett.

The addition of FOBT to sigmoidoscopy did not lead to additional cancer detection or detection of more advanced adenomas, Dr. Holme and colleagues report. "This is in keeping with previous results," they note.

The combined screening approach was actually a drag on the study. It "led to lower adherence in our trial and could thus have a negative impact on a screening program," the researchers write.

The Norwegian Colorectal Cancer Prevention Trial was funded by research grants from the Norwegian government and the Norwegian Cancer Society. Dr. Brett has disclosed no relevant financial relationships. Study coauthor Michael Bretthauer, MD, PhD, from the Sorlandet Hospital Kristiansand, reports financial relationships with Exact Sciences, Olympus, Fujinon, Falk Phgroup, and CCS Healthcare.

JAMA. 2014;312: 601-602, 606-615. Editorial, Abstract

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