Landmark US Trial Shows Screening Cuts Colorectal Cancer

Caroline Helwick

May 22, 2012

May 22, 2012 — Colorectal cancer (CRC) screening with flexible sigmoidoscopy (FSG) prevents cancer from developing in the left and right colon, and prevents CRC-related deaths, according to a study conducted in the United States, known as the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO).

The results of the trial, which was sponsored by the National Cancer Institute, were presented at a plenary session here at Digestive Disease Week 2012 and were published online May 21 in the New England Journal of Medicine.

PLCO evaluated the impact of FSG with subsequent colonoscopy. It provides the strongest evidence so far that screening not only prevents CRCs, but also reduces related deaths, the researchers report.

It's the ultimate public health success story.

"The findings provide the strongest evidence yet for the benefit of endoscopic screening in both the proximal and distal colon, and it confirms colorectal cancer screening as a public health imperative," said Robert E. Schoen, MD, MPH, professor of medicine and epidemiology at the University of Pittsburgh, Pennsylvania. "We are identifying the precursors of cancer — colorectal polyps — and removing them. By doing so, we are preventing cancer from developing. It's the ultimate public health success story."

Previous studies conducted in the United Kingdom and Italy have demonstrated a reduction in distal CRC incidence and mortality with FSG screening, but no significant effect in the proximal colon. However, only 5% to 8% of subjects underwent subsequent colonoscopy. In the United States, the multicenter randomized PLCO compared FSG with usual care. Most subjects with abnormal FSG results underwent colonoscopy for diagnostic follow-up.

From 1993 to 2001, people 55 to 74 years of age were randomized to FSG screening with a repeat exam at 3 or 5 years (n = 77,445) or to usual care (n = 77,455). CRCs and deaths were identified, and cause of death was evaluated in a formal adjudication process.

Participants were followed for a mean of 11.2 years. More than 86% underwent at least 1 screen, and more than half underwent 2 screens.

In the screened group, 28.5% of subjects had at least 1 exam positive for a polyp or mass; of these, 80.5% (n = 17,772) underwent diagnostic intervention within 1 year (all but 4% with colonoscopy). This yielded 16,990 people who underwent colonoscopy during the study; the rate of colonoscopy performed as a direct result of FSG screening was 21.9%.

The incidence of colorectal cancer was 11.9 per 10,000 person-years in the screening group and 15.2 per 10,000 person-years in the usual-care group — a 21% reduction in cancer incidence (relative risk [RR], 0.79; 95% confidence interval [CI], 0.72 to 0.85; P < .0001), Dr. Schoen reported.

The rate of CRC-related death was 3.9 per 10,000 person-years in the usual-care group and 2.9 per 10,000 person-years in the screening (341 vs 252 deaths) — a 26% reduction in mortality (RR, 0.74; 95% CI, 0.63 to 0.87; P < 0.001).

Mortality Reduction Only in Distal Cancer Group

Screening with FSG resulted in a statistically significant and clinically important decrease in overall CRC incidence and mortality; however, this benefit was site-specific.

In people with distal CRC, mortality was reduced by 50% (P < .001); in people with proximal CRC, there was no difference in mortality (P = .81), Dr. Schoen reported.

"Why was there no difference in proximal cancer mortality? I can't directly answer this question," Dr. Schoen said.

He suggested that the differences might pertain to the stage of cancer at diagnosis. Nearly 80% of stage IV cancer patients died of CRC in the 2 groups. In the distal colon, there was a reduction of more than 60% in stage IV cancer incidence and mortality, but in the proximal colon, there were no significant differences in stage IV incidence or mortality, he said.

"Proximal colon cancer incidence was reduced by detecting and removing adenomas destined to advance to cancer, but in the [screening] group, compared to usual care, we did not succeed in identifying or removing a proportionally greater number of adenomas destined to proceed to fatal cancer," he said. "There is room for improvement in protecting against proximal cancer."

Dr. Schoen explained that the different findings for distal and proximal lesions probably reflects a "biological issue." "We have come to learn there are differences in polyps in the proximal colon, in their propensity to proceed to fatal cancers," he said, adding that once they are detected, perhaps "the cat is out of the bag."

One Issue Settled, Another Remains

This issue is settled.

David Lieberman, MD, professor of medicine and chief of gastroenterology at Oregon Health & Science University, Portland, commented on the study for Medscape Medical News. "If you combine the PLCO trial with the British and Italian studies, there is a huge effect showing a reduction in incidence and mortality if you visualize the distal colon and remove polyps. So this issue is settled." "

The issue with the proximal colon is interesting; "there is a decrease in incidence but not mortality," Dr. Lieberman noted.

"Dr. Schoen's interpretation of this discrepancy is that we are reducing the incidence of proximal cancers by removing precancerous adenomas, but perhaps not the most important ones," Dr. Lieberman said.

He noted that the PLCO lacked the advantage of contemporary technology (such as high-definition scopes that enhance visualization), having been initiated in the early 1990s. In addition, there was no awareness at the time of sessile serrated polyps, which are the likely culprits in the proximal colon.

"With better recognition of these lesions, we can do much better now," he said, "although it is still an open question whether we can successfully prevent cancer mortality in the proximal colon."

PLCO adds to existing data from other countries supporting the notion that "endoscopic screening works," he concluded. "It works best in the distal colon...but now we need to do these studies in the entire colon."

The issue of FSG being successful in only part of the colon is raised in an accompanying editorial by John Inadomi, MD, from the division of gastroenterology at the University of Washington in Seattle.

"The real question for American clinicians is whether we are prepared to refocus attention on a screening strategy that has been likened to performing mammography on one breast," he writes.

FSG is not used widely in the United States; colonoscopy is the preferred screening approach.

However, the quality of evidence supporting colonoscopy is inferior to that for FSG, Dr. Inadomi notes. There is no randomized trial proving that colonoscopy reduces CRC mortality, he points out.

In contrast, there are now 3 large trials to show that FSG does.

"It should be acknowledged that flexible sigmoidoscopy reduces colorectal cancer incidence and mortality for the portion of colon that it is designed to examine," Dr. Inadomi explains.

He highlights data showing that not all people agree to undergo a screening colonoscopy, and says that alternatives should be available to maximize adherence to CRC screening.

Dr. Schoen reports owning stock in Onconome. Dr. Lieberman has disclosed no relevant financial relationships. Dr. Inadomi reports consulting for Roche and Takeda.

N Engl J Med. Published online May 21, 2012. Abstract, Editorial

Digestive Disease Week (DDW) 2012: Abstract 588. Presented May 21, 2012.

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