Study authors conclude consistent data warrant changes to CRC screening guidelines

A single colorectal cancer (CRC) screening using flexible sigmoidoscopy (FS) at age 55-64 years led to substantial long-term reductions in CRC incidence and mortality, according to follow-up data from the Italian Screening for COlon REctum (SCORE) trial.

The SCORE study is one of four large, randomized trials around the globe assessing the efficacy of an FS screening strategy for CRC—between the Italian study and three other analyses from the U.K.(The U.K. Flexible Sigmoidoscopy Screening trial), the U.S. (Prostate, Lung, Colorectal, and Ovarian [PLCO] Cancer Screening trial), and Norway (Norwegian Colorectal Cancer Prevention trial [NORCCAP]), FS screening demonstrated a substantial reduction in CRC incidence (range, 18% to 26%) and mortality (range, 22% to 31%) in the intention-to-treat (ITT) analysis over 10-12 years of follow-up, Carlo Senore, MD, MSc, of University Hospital Città della Salute e della Scienza in Turin, Italy, and fellow SCORE investigators explained in Annals of Internal Medicine.

More recently, longer follow-up data from the U.K., Norwegian, and U.S. trials demonstrated that this effect was maintained out to 15-17 years’ follow-up. Now, Senore and colleagues have added their own longer term SCORE findings, which conducted follow-up of 15 years for CRC incidence and 19 years for mortality.

Their results “confirm that a single FS screening confers a substantial and long-lasting protection from CRC risk when offered to average-risk persons aged 55 to 64 years,” they wrote. “Incidence of CRC was statistically significantly reduced in the intervention group by 19% (CI, 7%-29%) in the ITT analysis and 33% (CI, 19% to 44%) in the [per protocol] PP analysis after a median follow-up of 15 years, and CRC mortality was statistically significantly reduced by 22% (CI, 2%-39%) in the ITT analysis and 39% (CI, 16%-56%) in the PP analysis after a median follow-up of 19 years.”

Senore and colleagues concluded that this consistent evidence of long-lasting protection from a single FS screening “would suggest the need to revise existing guidelines, which still recommend repeated FS screening. The benefit-to-harm ratio of this strategy would be improved when adopting a once-in-a-lifetime approach because of the substantial reduction in the burden associated with screening as well as the reduction in health care costs.”

The initial SCORE trial, which was conducted at six centers in northern-central Italy (Turin, Biella, Genoa, Milan, Rimini, and Arezzo) from June 1995 through April 1999, recruited individuals ages 55-64 years and randomized them to receive either once-only FS screening or usual care. Participants assigned to the control group were not contacted further, while participants assigned to the intervention were sent a personal invitation to a prescheduled appointment for an FS examination.

“Diminutive polyps (≤5 mm) were removed during FS examination using the cold snare technique,” the study authors explained. “Participants detected to have at least 1 distal polyp greater than 5 mm or CRC and those with inadequate bowel preparation harboring at least 1 polyp were referred for colonoscopy. Colonoscopy was also indicated for participants detected to have more than 2 diminutive adenomas or 1 advanced (villous component >20% or high-grade dysplasia) adenoma.”

Colonoscopy surveillance was also indicated for participants “detected to have 1 adenoma 10 mm or greater, high-grade dysplasia, or villous component greater than 20% as well as for those with 3 or more adenomas of any type or 5 or more hyperplastic polyps located proximal to the rectum.” Participants with negative FS screening results or with other types of polyps were discharged and offered no further follow-up.

Only invasive adenocarcinomas were considered during the CRC incidence follow-up analysis; squamous and basal cell carcinomas, neuroendocrine tumors, and colorectal localizations of other primary types of cancer were excluded.

The study authors performed both an ITT and a PP analysis—the former compared all participants randomized to the intervention group against all participants in the usual care group; the latter compared all participants who underwent screening in the intervention group against all control participants. They also conducted subgroup analyses by sex and age at randomization (55-59 years and 60-64 years).

A total of 34,272 participants (17,136 in each group) were included in the analysis; 9,911 participants had one-time FS screening in the intervention group. Median follow-up was 15.4 years for incidence and 18.8 years for mortality.

Among the findings:

  • “Incidence of CRC was reduced by 19% (RR, 0.81 [95% CI, 0.71-0.93]) in the intention-to-treat (ITT) analysis, comparing the intervention with the control group, and by 33% (RR, 0.67 [CI, 0.56-0.81]) in the per protocol (PP) analysis, comparing participants screened in the intervention group with the control persons.
  • “Colorectal cancer mortality was reduced by 22% (RR, 0.78 [CI, 0.61 to 0.98]) in the ITT analysis and by 39% (RR, 0.61 [CI, 0.44-0.84]) in the PP analysis.
  • “Incidence of CRC was statistically significantly reduced among both men and women. Colorectal cancer mortality was statistically significantly reduced among men (ITT RR, 0.73 [CI, 0.54-0.97]) but not among women (ITT RR, 0.90 [CI, 0.59-1.37]).”

These findings, along with the long-term data from the U.K., U.S., and Norway trials, conclude “a remarkable three-decades long era in colorectal cancer screening and [provide] an opportunity to summarize and look ahead,” Michael Bretthauer, MD, PhD, of the Clinical Effectiveness Research Group at the University of Oslo and University of Tromsø in Oslo, Norway, NORCCAP trial investigator, member of the guideline committee for the European Society of Gastrointestinal Endoscopy, and associate editor of Annals of Internal Medicine, and colleagues wrote in an accompanying editorial.

They pointed out that, despite design differences between the four trials, they all showed comparable benefits for one-time FS screening for CRC: 18% to 26% reduction in CRC incidence and 21% to 30% reduction in mortality, which “translates to absolute risk reductions with screening of about 6 to 8 per 1000 screened for colorectal cancer incidence and about 3 to 5 per 1,000 persons screened for colorectal cancer mortality over 15 to 20 years.”

That being said, the four trials also had one important point in common, Bretthauer and colleagues pointed out: While the reduction in CRC incidence and mortality in the screening group was clinically significant across all trials, the magnitude of these effects was moderate. The editorialists offered three possible explanations.

“First, effect estimates derive from intention-to-screen analyses, and screening adherence was only 57% to 84% across the trials,” they wrote. “However, even in adjusted per protocol analyses comparing those adherent with screening to the control group, relative risk reductions for colorectal cancer incidence and mortality rarely exceeded 60%. Second, sigmoidoscopy does not examine the entire colon… Even though patients with pathologic findings at sigmoidoscopy were referred to full colonoscopy, screening had little effect on proximal colorectal cancer incidence. Finally, a single screening (or even two as applied in the U.S. trial) can obviously not prevent all subsequent cancer.”

The editorialists also noted that the potential difference in one-time FS screening benefits between men and women requires further investigation.

Senore and colleagues speculated that the different distribution of CRC by colonic site, “with a shift to a higher proportion of proximal lesions at earlier age among women as compared with men,” may explain the reduced effect of FS screening on CRC mortality among women.

“The protective effect of FS screening for distal CRC was similar among men and women, suggesting a similar benefit, whereas the effect on overall CRC incidence tended to weaken more rapidly among women than men, which would suggest a higher incidence of proximal interval CRC among women with a negative FS screening result,” they wrote. “A higher proportion of proximal CRC, which may show a more aggressive course than distal cancer, may have been missed among women.”

When taken together, Bretthauer and colleagues argued, the results from the four FS trials suggest that it might be time to reassess screening guidelines, most of which currently recommend repeating sigmoidoscopy screening every five years and colonoscopy every 10 years.

“The new Italian report and the reports from the sister trials establish a benefit of screening far beyond the currently recommended screening intervals,” they wrote. “Guideline makers may consider prolonging recommended screening intervals for sigmoidoscopy and colonoscopy. Longer intervals result in lower costs as well as reduced harms and burdens through less exposure to screening and surveillance endoscopy and may not substantially compromise the benefit of screening. This may be especially relevant to persons at the lower end of the screening age where cancer risk is smaller and absolute benefits more marginal.”

  1. Long-term follow-up data from the Italian Screening for COlon REctum (SCORE) trial suggest that one-time colorectal cancer (CRC) screening using flexible sigmoidoscopy (FS) from age 55-64 years had a strong protective effect against CRC incidence and mortality.

  2. The authors argued that, based on the SCORE findings and long-term data from similar trials conducted in the U.K., the U.S., and Norway, consistent evidence of long-lasting protection from a single FS screening suggests that current CRC screening guidelines should be revised.

John McKenna, Associate Editor, BreakingMED™

Senore reported grants from the Italian Association for Cancer Research, Italian National Research Council, as well as financial support from the Instituto Oncologico Romagnolo (IOR), Fondo “E Tempia,” University of Milano, and Local Health Unit ASL-Torino during the conduct of the study; Senore is also the president of the Italian Group for CRC Screening.

Bretthauer is a member of the guideline committee for the European Society of Gastrointestinal Endoscopy and an associate editor of Annals of Internal Medicine. Editorial co-author Cross reported grants from NIHR-HTA, the Cancer Research UK Programme, and Cancer Research UK Project.

Cat ID: 23

Topic ID: 78,23,730,16,23,192,925