Single Sigmoidoscopy Could Prevent One Third of Colorectal Cancers

Zosia Chustecka

April 28, 2010

April 28, 2010 — New results from the United Kingdom show that a single examination with flexible sigmoidoscopy in healthy individuals between the ages of 55 and 64 years, and removal of any polyps that are found, reduced the incidence of colorectal cancer by one third and deaths from the disease by 43% over a median follow-up of 11 years.

"This is the first evidence from a randomized trial to show that removing polyps prevents colorectal cancer," said lead researcher Wendy Atkin, PhD, from Imperial College in London, United Kingdom. Previous evidence has come from case–controlled studies, she said at a press conference in London, held yesterday to announce the results published online April 28 in The Lancet.

The magnitude of these benefits "was quite a surprise to us," she reported.

The group is now proposing that a single flexible sigmoidoscopy at 55 years be introduced for population-wide screening in the United Kingdom, and Dr. Atkin estimated that this would save around 3,000 lives from colorectal cancer each year (from a current total of 16,000 deaths per year)

"It's not often that we use the word breakthrough," said Harpal Kumar, chief executive officer of Cancer Research UK, which partly funded the trial, "but it's extremely rare to see results that are so compelling and that have such a large potential impact on public health."

Dr. Atkin said the results so far suggest that flexible sigmoidoscopy will save 1 life for every 400 people who undergo this test, but as follow-up continues and the screened population ages, these results are expected to improve. "We have not yet seen the full benefit," she added, noting that the youngest of the screened participants is now 66 years old, and the greatest risk for colorectal cancer is seen in people in their 70s and 80s.

For comparison, mammography saves 1 life for every 500 women screened, Dr. Atkin added, but she emphasized that it does so by catching breast cancer at an earlier stage of the disease. In contrast, sigmoidoscopy and the removal of polyps prevents colorectal cancer and all the associated trauma of having a cancer diagnosis and undergoing surgery and treatment, she said.

Size of Benefit is Large

The size of benefit seen in this trial is "large for any cancer screening test, certainly compared with mammography for breast cancer or assay of prostate-specific antigen for prostate cancer," said David Ransohoff, MD, from the University of North Carolina at Chapel Hill, writing in an accompanying editorial.

The benefit seen is "both substantial and sustained," he added.

"This is a fine study" said Linda Rabeneck, MD, professor of medicine at the University of Toronto in Ontario, who was approached by Medscape Oncology for comment. "I am certainly impressed with these results. Prof. Atkin and her team are to be congratulated on this landmark trial."

"They have answered a question that has hovered over the field for a long time: Is 1-time flexible sigmoidoscopy associated with a reduction in colorectal cancer incidence and mortality?"

"Clearly it does. And they have estimated the magnitude of the benefit," she added.

"The results are indeed very positive and confirm previous case–control studies that showed that flexible sigmoidoscopy may be protective up to 16 years after screening," said Charles Kahi, MD, assistant professor of clinical medicine at the Indiana School of Medicine in Indianapolis, who was also approached for comment.

At the press briefing, Dr. Atkin said: "I hypothesize that this effect will last forever because most of the polyps that you are going to get are there already in your 50s."

Largest and Longest Trial So Far

"This is the largest and longest-running study so far," Dr. Atkin noted. The trial, conducted in 14 British centers, involved 170,432 healthy individuals who had indicated on a previous questionnaire that they would accept an invitation for screening. Of these, 57,237 were randomized to undergo sigmoidoscopy, and 40,674 (71%) did so.

"This is an extraordinarily large proportion," said coauthor Jane Wardle, PhD, from the Department of Public Health at University College in London. Despite pessimistic predictions that healthy people would be unwilling to undergo an unpleasant procedure, there was a good uptake, with slightly more men than women, and "people told us that they are happier and were reassured about their future health."

In an intention-to-treat analysis, colorectal cancer incidence in the intervention group was reduced by 23% and mortality by 31%.

In the per-protocol analysis, the incidence of colorectal cancer in people who underwent sigmoidoscopy was reduced by 33% and mortality by 43%.

The number needed to be screened to prevent 1 colorectal cancer diagnosis was 191, and the number to prevent 1 death was 489 by the end of the study period. But again, Dr. Atkin said that these numbers are likely to improve as follow-up continues and the trial participants grow older.

Add to UK National Screening Program?

Dr. Atkin and colleagues propose that a single screen with flexible sigmoidoscopy at age 55 be added to the UK National Screening Program for Colorectal Cancer. Currently, this program consists of routine screening with the fecal occult blood test (FOBT), which is offered every 2 years for older people (starting at age 65, although the exact age range differs in England, Scotland, and Wales).

FOBT has been shown in clinical trials to reduce mortality from colorectal cancer by 23% in individuals who take the test, but it does so by finding cancer at an earlier stage of the disease and does not prevent colorectal cancer, Dr. Atkin explained. For comparison, the results for flexible sigmoidoscopy show that the reduction in mortality is nearly double (43%) and that this procedure prevents about one third of cases. But she acknowledged that FOBT detects cancer in the entire colon, whereas sigmoidoscopy screens only the distal colon.

Many other countries use FOBT for population-based organized colorectal cancer screening, and for these jurisdictions, the new results with flexible sigmoidoscopy will give impetus to consider how this test can/should be integrated into their programs, Dr. Rabeneck said.

"Colonoscopy is Preferred" in the United States

In the United States, however, "colonoscopy is preferred" has been a strong message, Dr. Ransohoff notes in the accompanying editorial.

Indeed, the latest guidelines from the American College of Gastroenterologists (ACG), issued last year, state that colonoscopy every 10 years, starting at age 50, is the preferred strategy for colorectal cancer screening. At the time, first author Douglas Rex, MD, FAGG, director of endoscopy at Indiana University and past president of the ACG, said that although there is a range of tests that can be used for colorectal cancer screening, colonoscopy, when carried out by well-trained examiners, is the "best test."

Now, however, in an interview with Medscape Oncology, Dr. Rex said that "colonoscopy is currently being very carefully scrutinized."

The appeal of colonoscopy is that it screens the entire colon, he explained, whereas flexible sigmoidoscopy screens only the distal colon, which accounts for about 50% to 60% — or some would argue more like 65% to 70% — of the areas in which there could be cancer and/or polyps.

Dr. Rex said the new results from the United Kingdom show that a 1-time screen with flexible sigmoidoscopy has "a very significant benefit" and that this evidence comes from a prospective randomized trial, which is a "better level of evidence" than that collected so far for colonoscopy from case–controlled studies.

Some of these case–controlled studies have suggested that colonoscopy can reduce colorectal cancer by 60% to 80%, Dr. Rex added. However, in the editorial, Dr. Ransohoff writes that this design can inflate the estimate of benefit, and he has previously suggested that colonoscopy might have been "oversold" (Gastroenterology 2005;129:1815).

The United States has embraced colonoscopy, and there has been an acceptance among physicians and patients that it is the better strategy because it screens the entire colon, rather than just a part of it, Dr. Rex explained.

But Dr. Rex told Medscape Oncology that "we are concerned whether we have gone in the right direction."

There have been a number of recent studies suggesting that most of the benefit from colonoscopy is seen in terms of cancer in the left colon — which is similar to but not entirely the same as the distal colon, he explained. At the same time, there is a suggestion that cancer in the proximal colon (which is detected on colonoscopy but not on sigmoidoscopy) might be biologically different, and it is not clear if it can be prevented, he added.

In addition, there is concern about quality with colonoscopy; it is a "very operator-dependent procedure," he said.

If it turns out that disease in the proximal colon is biologically different and does not lend itself equally well to early detection, then "the relative merits of sigmoidoscopy and colonoscopy in the early detection and prevention of colorectal cancer would need to be re-evaluated," Dr. Rabeneck and coauthor Nancy Baxter, MD, PhD, from St Michael's Hospital in Toronto, wrote in a recent editorial in the Journal of the National Cancer Institute (2010;102:70-71), as previously reported by Medscape Oncology.

Speaking now with Medscape Oncology, Dr. Rabeneck said: "We know that flexible sigmoidoscopy is safer than colonoscopy, requires no sedation, and can readily be performed by appropriately trained nonphysicians."

It is also a much simpler procedure, Dr. Atkin said. Flexible sigmoidoscopy takes about 5 minutes and requires no medication, apart from an enema taken in the morning before the procedure, she explained. In contrast, colonoscopy takes about 20 minutes and is performed under sedation, so the individual is not allowed to drive afterward. In addition, it involves a liquid bowel preparation, taken the day before, to clear the entire colon, and dietary restrictions (such as not eating fiber) for a couple of days beforehand, she added.

But is it a better test for colorectal cancer screening because it screens the entire colon, whereas sigmoidoscopy screens only a part of it?

The answer appears to be unclear. The new results suggesting that the benefits of colonoscopy are confined to the left colon have raised a lot of issues, Dr. Rabeneck and Dr. Baxter write in their recent editorial.

Is there an incremental benefit of colonoscopy over flexible sigmoidoscopy for colorectal cancer screening? If there is, is it large enough to justify the additional risks and cost of colonoscopy for screening in the population, they ask.

Dr. Atkin and coauthors, and Dr. Rabeneck, Dr. Baxter, and Dr. Rex have disclosed no relevant financial relationships. Editorialist Dr. Ransohoff reports serving as an unpaid academic adviser to and investigator for Correlogic Systems, and serving as an unpaid adviser to Epigenomics and EXACT.

Lancet. Published online April 28, 2010.


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