ASPIRIN REDUCES COLON CANCER INCIDENCE AND MORTALITY

October 26, 2010 — The use of low-dose aspirin reduced the long-term incidence of and mortality related to colorectal cancer, according to British researchers.

Notably, the benefit was greatest for cancers of the proximal colon, which are not prevented effectively by screening with sigmoidoscopy or colonoscopy, say the researchers, led by Peter Rothwell, MD, PhD, from the University of Oxford, United Kingdom.

Their study, which is the first to assess the long-term effectiveness of lower doses (75 to 300 mg daily) of aspirin on colorectal cancer, was published online October 21 in the Lancet.

The same investigators have previously shown that high-dose aspirin (≥500 mg daily) reduces the long-term incidence of colorectal cancer, but with the spectre of adverse effects, especially increased bleeding.

They also previously reported a beneficial effect of low-dose aspirin after 10 years of use.

Now, the team reports 20-year data from 14,033 Swedish and British patients who participated in randomized trials that were originally designed to evaluate low-dose aspirin for the prevention of vascular disease.

They found that in 4 trials of aspirin vs placebo (with a mean duration of 6 years of scheduled treatment), aspirin reduced the long-term risk for colon cancer by 24% and mortality from colon cancer by 35%.

In other words, being on aspirin instead of placebo for an average of 6 years reduced the 20-year risk for the incidence of colon cancer (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.60 - 0.96; P = .02) and the related mortality (HR, 0.65; 95% CI, 0.48 - 0.88; P = .005). No overall risk reduction was seen for rectal cancer during this period.

A total of 391 patients (2.8%) had colorectal cancer during follow-up.

Limited data were available on the specific site of the cancer in the colon. However, in that subset of patients, the investigators found that aspirin reduced the risk for the incidence of cancer of the proximal colon (HR, 0.45; 95% CI, 0.28 - 0.74; P = .001) and the related mortality (HR, 0.34; 0.18 - 0.66; P = .001), but did not reduce the risk for cancer of the distal colon.

The investigators indicate that the benefit for the range of doses of aspirin was the same, with 75 mg daily being as effective as 300 mg. However, doses of 30 mg per day seemed to be less effective, they say.

"This interesting study could incite clinicians to turn to primary prevention of colorectal cancer by aspirin, at least in high-risk populations," say Robert Benamouzig, MD, and Bernard Uzzan, MD, from the Avicenne Hospital in Bobigny, France, in an editorial accompanying the study.

"Specific guidelines for aspirin chemoprevention would be the next logical step," they add.

The study authors make an effort to place their findings in the context of recent research. The trials that they studied "all predated endoscopic screening for adenomas, which also reduces colorectal cancer incidence and mortality, and might therefore reduce the absolute benefit of aspirin," they say. However, the study authors also note that, with aspirin, the prevention of proximal colonic cancers, which would not be identified by sigmoidoscopy, is "clearly important." The use of screening and aspirin might be "synergistic," they speculate.

For Men Only, and Smokers

In their comment, the editorialists review a number of the original aspects of the study. It provides "extremely long follow-up" and new data for an issue in which data are "scarce."

The findings are in contrast to at least 1 other major randomized trial, the US Physicians' Health Study, which randomized 22,071 men to aspirin 325 mg or placebo every other day for 5 years, but found that the risk for colorectal cancer was similar in both groups (J Natl Cancer Inst. 1993;85:1220-1224).

The authors and the editorialists emphasize that, in the new study, the preventive effect of aspirin predominated in proximal cancers. However, the editorialists temper that observation by pointing out that this was a subgroup analysis and relied on relatively small numbers. They also note that, to date, only 1 randomized preventive study, which was restricted to evaluating serrated polyps, showed that the effect of aspirin was mainly on proximal lesions (40% to 50% reduction), with no effect on distal lesions (Cancer Epidemiol Biomarkers Prev. 2009;18:2310-2017).

Nevertheless, this finding about the proximal lesions has the potential to be very important, say the editorialists. "If confirmed, this original finding might present a strong argument for the addition of aspirin chemoprevention to screening sigmoidoscopy," they write.

This study has a variety of important limitations, say the editorialists.

The investigators reported disease-specific mortality and not overall mortality. Thus, they did not assess mortality related to the adverse effects of aspirin, write the editorialists.

An earlier systematic review of the literature found that aspirin reduced colorectal cancer incidence, especially when used for more than 10 years, but with a dose-related increase in gastrointestinal complications (Ann Intern Med. 2007;146:365-375).

Also, the patients in the trials were mostly men with cardiovascular risk (2 of the trials were men only). "Thus, no conclusions can be made about women and patients with no cardiovascular risk," say the editorialists.

In addition, the proportion of current smokers in the trials ranged from 27% to 53%. "The mechanisms of colon carcinogenesis might differ between cardiovascular and other patients because of increased tobacco consumption," the editorialists point out.

A Few More Study Details

The study authors followed-up on 4 randomized trials of aspirin vs placebo in primary (Thrombosis Prevention Trial, British Doctors Aspirin Trial) and secondary (Swedish Aspirin Low Dose Trial, UK-TIA Aspirin Trial) prevention of vascular events. They also followed-up on 1 trial of different doses of aspirin (Dutch TIA Aspirin Trial) that had no placebo control. The goal was to establish the effect of aspirin on risk for colorectal cancer over 20 years with an analysis of pooled individual patient data.

These analyses were stratified by dose categories (as low as 30 mg daily and as high as 1200 mg daily), duration of treatment during the initial trial period (which varied from 1 to 7 years), and, where the data were available, by site of cancer in predefined categories.

Dr. Rothwell and a coauthor report receiving honoraria for talks, advisory boards, and clinical trial committees from several pharmaceutical companies with an interest in antiplatelet agents, including AstraZeneca, Bayer, Boehringer Ingelheim, Sanofi-BMS, and Servier.

Lancet. Published online October 21, 2010. Abstract