Guidelines Discourage NSAIDs for Colon Cancer Prevention

ROCKVILLE, Md., March 8 -- Although aspirin and other NSAIDs such as ibuprofen can prevent some colorectal cancer, the benefits are outweighed by the increased risk of gastrointestinal side effects, said the U.S. Preventive Services Task Force.

The task force recommendation against the routine use of NSAIDs for colorectal cancer chemoprevention emerged from two systematic risk-benefit analyses carried out by Catherine Dub, M.D., of the University of Calgary in Alberta, and colleagues.

The task force's NSAID-colorectal cancer guidelines and the Canadian review results appeared in the March 6 issue of the Annals of Internal Medicine. Dr. Dub and colleagues conducted a systematic review of randomized controlled trials, case-control studies, and cohort studies of aspirin chemoprophylaxis.

"Cyclo-oxygenase-2 inhibitors and NSAIDs reduce the incidence of colonic adenomas," the Canadian group concluded. "Nonsteroidal anti-inflammatory drugs also reduce the incidence of colorectal cancer. However, these agents are associated with important cardiovascular events and gastrointestinal harms. The balance of benefits to risk does not favor chemoprevention in average-risk individuals."

The task force recommendation against NSAID colorectal-cancer chemoprophylaxis applies to asymptomatic adults at average risk for the malignancy, including those with a family history of it, but not to people with familial adenomatous polyposis, hereditary nonpolyposis colon cancer syndromes (Lynch I or II), or a personal history of colorectal cancer or adenomas.

Dr. Dub and colleagues found that regular use of aspirin modestly reduced the relative risk of adenomas of the colon in all three study designs. In randomized controlled trials, the relative risk for adenomas among aspirin users was 0.82 (95% confidence interval 0.7 to 0.95). In case-control studies, the relative risk was 0.87 (95% CI, 0.77 to 0.98), and in cohort studies it was 0.72 (95% CI, 0.61 to 0.85).

"In cohort studies, regular use of aspirin was associated with relative risk reductions of 22% for incidence of colorectal cancer," they wrote. "Two randomized controlled trials of low-dose aspirin failed to show a protective effect. Data for colorectal cancer mortality were limited. Benefits from chemoprevention were more evident when aspirin was used at a high dose and for periods longer than 10 years."

But they also found that aspirin use was associated with a dose-related increase in incidence of gastrointestinal complications. In controlled trials, the relative risk for GI bleeding among aspirin users compared with non-aspirin users ranged from 1.6 to 2.5-fold, with similar risks seen in both case-control and cohort studies. Aspirin was also associated with a near doubling or risk for other GI symptoms, such as nausea and dyspepsia.

"Aspirin appears to be effective at reducing the incidence of colonic adenoma and colorectal cancer, especially if used in high doses for more than 10 years," the reviewer wrote. "However, the possible harms of such a practice require careful consideration. Further evaluation of the cost-effectiveness of chemoprevention compared with, and in combination with, a screening strategy is required."

In the second review, the same authors looked at NSAIDs other than aspirin and at cyclo-oxygenase-2 (Cox-2) inhibitors (such as Celebrex) for the prevention of colorectal cancer and adenoma, using the same general research criteria for the aspirin review.

Although in one cohort study there was no evidence of an effect of non-aspirin NSAIDs on mortality, there was good evidence in other trials to show a positive effect on the incidence of colorectal cancer.

When they looked at cohort studies, the relative risk for developing colorectal cancer among NSAID users was 0.61 (95% CI, 0.48 to 0.77), and in case-control studies the relative risk was 0.70 (95% CI, 0.63 to 0.78). Colorectal adenoma incidence was also reduced by NSAIDs other than aspirin, with relative risk in cohort studies of 0.64 (95% CI, 0.48 to 0.85) and in case-control studies of 0.54 (95%CI, 0.4 to 0.74).

Cox-2 inhibitors, in randomized controlled trials, also reduced the relative risk for colorectal adenoma incidence, to 0.72 (95% CI, 0.68 to 0.77).

"The ulcer complication rate associated with non-aspirin NSAIDs is 1.5% per year," the investigators wrote. "Compared with non-aspirin NSAIDs, Cox-2 inhibitors reduce this risk but, in multiyear use, have a higher ulcer complication rate than placebo."

They also found that Cox-2 inhibitors and NSAIDs other than naproxen (Aleve and generics) increased the risk for serious cardiovascular events, with a relative risk for the Cox-2 inhibitors (versus placebo) of 1.86 (95% CI, 1.33 to 2.59).

The investigators noted that both reviews were limited by heterogeneity in the dose, duration and frequency of use of the various drugs, requiring careful grouping for analysis.