October 27, 2011 (Boston, Massachusetts) — Randomized trials have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce precancerous polyps, but a new study suggests that long-term use can reduce colorectal-cancer-specific mortality.

Postmenopausal women who participated in the Women's Health Initiative (WHI) and who used NSAIDs for an extended period of time had a lower risk for death from colorectal cancer than those who did not use NSAIDs at enrollment. The results of this analysis were presented during a poster session here at the Tenth Annual American Association for Cancer Research International Conference on Frontiers in Cancer Prevention Research.

"Our results suggest that NSAID use is associated with lower colorectal cancer mortality among postmenopausal women who use them consistently and for longer periods of time," said study author Anna E. Coghill, MPH, a doctoral student in epidemiology at the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle.

In their study, Ms. Coghill and colleagues evaluated the effect of NSAID use on colorectal cancer mortality in 160,143 women who participated in the WHI who did not report a history of colorectal cancer at enrollment. Overall, there were 2119 confirmed cases of colorectal cancer and 492 deaths among women with colorectal cancer listed as the cause of death.

The researchers looked at death due to colorectal cancer in the whole WHI population. Both aspirin and nonaspirin NSAID use were considered in the analysis.

"Women who reported ever using NSAIDs for any amount of time really didn't have much benefit, but women who used them for longer periods of time at baseline had a lower rate of death due to colorectal cancer at follow-up," Ms. Coghill said in an interview.

The use of NSAIDs (including aspirin, ibuprofen, and prescription agents) at baseline was not associated with a reduced rate of colorectal cancer mortality (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.76 to 1.14). However, women who reported using these agents at both baseline and 3 years into the initiative experienced an approximate 30% decrease in colorectal cancer mortality (HR, 0.72; 95% CI, 0.54 to 0.95), compared with women who did not report their use at both timepoints.

Higher Doses, Longer Time Period

The authors note that there were significant reductions in colorectal cancer mortality among women who were using NSAIDs for at least 10 years when they enrolled in the WHI, compared with those who were not using them at all.

Higher doses of NSAIDs (greater than 325 mg at baseline) had an association with a lower rate of death, explained Ms. Coghill. "It looks like it is a duration-dependent relationship, which is consistent with the randomized trial data," she said. "In the randomized trials, there was really only a benefit after using them for 5 years."

"In the observational data, we had more than 10 years of data," she continued. "We found that women who had used them for at least 10 years had about a 35% reduced rate of mortality, compared with women who hadn't used them at all at baseline. Women who used NSAIDs for more than 5 years had a lower mortality than those who hadn't used them; it wasn't statistically significant, but the 10-year estimate was."

In addition, the results from a sensitivity analysis demonstrated that the prolonged use of NSAIDs before diagnosis, which encompassed use at both baseline and year 3, was significantly associated with reduced colorectal cancer mortality (HR, 0.70; 95% CI, 0.52 to 0.93).

Adverse events weren't captured in this analysis, but Ms. Coghill noted that "they are going to primarily be cardiovascular; that has already been well documented. It is certainly something to consider when using NSAIDs; you have to consider the risk and benefits."

Evidence Continues to Grow

A growing body of evidence suggests that NSAIDs might exert a chemopreventive effect; this has been particularly true for colorectal cancers. "The use of aspirin in relation to a vascular event is virtually proven," said Alison M. Gallagher, RPHNutr, DPhil, coauthor of a review paper on the use of aspirin as a chemopreventive agent (Lancet. 2009;373:1301-1309).

Dr. Gallagher, senior lecturer in biomedical sciences at the University of Ulster in Northern Ireland, United Kingdom, told Medscape Medical News at the time of her paper's publication that the "evidence for aspirin in colorectal cancer is very persuasive and there is some evidence for similar beneficial effects on other cancers, although the evidence overall for other cancer sites is less consistent."

As previously reported by Medscape Medical News, one study found that low-dose aspirin (75 mg/day) might protect against colorectal cancer. A reduced risk was apparent at 1 year in low-dose aspirin users (odds ratio, 0.78), compared with control subjects, and the effect was greater with increased duration of use.

However, no effect was seen in all-cause or colorectal-cancer-specific survival.

An observational follow-up of the Aspirin/Folate Polyp Prevention Study showed that the risk for all colorectal adenomas was substantially reduced in patients who continued to use aspirin after 3 years. In addition, the chemopreventive effect of aspirin strengthened when used for at least 4 days per week.

A meta-analysis of 4 clinical trials with aspirin doses ranging from 81 to 325 mg/day and a median follow-up of 33 months also suggested a protective effect; advanced lesions were found in 137 individuals (12%) in the placebo group and 134 (9%) in the aspirin group.

Tenth Annual American Association for Cancer Research (AACR) International Conference on Frontiers in Cancer Prevention Research: Abstract A69. Presented October 24, 2011.


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