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Aspirin Prevention of Colorectal Cancer: More or Less?

The concept of cancer chemoprevention is tantalizing. If we had a pill that could prevent cancer, we might escape the need for potentially disfiguring surgery or toxic chemotherapy. If the pill were familiar, cheap, and readily available, so much the better. In this issue, Chan and colleagues (1) provide additional evidence that we may actually have such an agent for colorectal cancer. Its identity? Aspirin. We first recognized that aspirin might decrease the risk for colorectal cancer more than 15 years ago (2). Since that time, a large number of retrospective and prospective studies have shown that regular aspirin users are less likely than nonusers to develop colorectal cancer or its precursor, adenomatous polyps (3, 4). The studies are remarkably consistentvirtually all demonstrate a protective effect of aspirin. In addition, we now have even stronger evidence: Randomized trials in which short-term use of a single daily aspirin reduced the risk for adenomas (5-7). This issue contains an analysis of the dose and duration of aspirin necessary to prevent colorectal adenomas (1). Chan and colleagues obtained detailed information on aspirin use from a large cohort of nurses who were followed prospectively. The findings are unambiguous. Women who used aspirin 2 or more times per week were 25% less likely to develop adenomas than were women who took aspirin less often. The duration of use was not important: Short- and long-term users had similar reductions in risk. The highest aspirin doses (>14 aspirin tablets each week) offered the best protection. The protective effect was similar whether the adenomas were large or small, tubular or villous, incident or prevalent, or proximal or distal. Age, family history, or indication for colonoscopic examination did not modify the findings. The doseresponse relationship was clear, and the effect at the highest level of aspirin was very strong. Women in the highest category of aspirin consumption were less than half as likely to develop adenomas than were nonusers. The paper shares the limitations of all observational studies. First, the investigators may have measured aspirin consumption inaccurately. They did not prescribe the dose of aspirin, and they did not monitor study patients' consumption. They did not question study participants about the size of the aspirin tablet until later years of the study. Second, patients took aspirin primarily for headaches and arthritis and took higher doses for arthritis. Could arthritis confound the purported relationship between larger aspirin intake and lower adenoma incidence by being the cause of both? It could if arthritis sufferers were less likely to develop adenomas. Similar confounding might result if persons whom physicians cautioned not to take aspirin were also more likely to develop adenomas. Finally, although all study participants underwent endoscopic examination of their colons, many examinations were sigmoidoscopies rather than complete colonoscopies. For that reason, the primary analysis was restricted to the relationship between aspirin use and distal colon lesions. Clearly, however, sigmoidoscopy would misclassify women who had only an adenoma of the proximal colon. The authors contend that they have studied a lower-risk cohort, because the proportion of patients with adenomas in this study is lower than that in published reports. The authors attribute the low rate to the low-risk status and younger age of the patients relative to patients in other studies, but failure to examine the entire colon in all patients may partially explain the lower prevalence of adenomas. The report by Chan and colleagues (1) lends additional support to the hypothesis that aspirin is an effective chemopreventive agent and suggests that higher doses may be more effective. Although the information on aspirin dose is novel, clinicians should exercise caution before recommending higher doses of aspirin for their patients on the basis of the results of this observational study. While not directly analogous, our recent experience with postmenopausal hormones is an example of observational studies and randomized trials reaching different conclusions. Because randomized trials of low-dose aspirin use demonstrate prevention, we should place greater trust in the trial results and use low doses of aspirin. Chan and colleagues conclude that optimal chemoprevention requires significantly higher doses than previously considered. Conclusions about what dose is optimal must balance considerations of both benefit and harm. Aspirin, even in low doses, has been associated with a dose-related increased risk for hemorrhagic stroke (8) and gastrointestinal bleeding (9). So while aspirin is cheap, the sometimes-serious complications that can result from aspirin are not. In cost-effectiveness studies, taking aspirin for colorectal cancer prevention has not been cost-effective, largely because of the costs associated with complications (10, 11). Given the dose-related toxicity of aspirin, the harms of higher doses of aspirin may outweigh the benefits in reduced risk for colon cancer, especially if the incidence of serious aspirin-related bleeding were much greater than the incidence of colon cancer. Who should take aspirin to prevent colorectal neoplasia? Until we have different or better information from randomized trials, aspirin use should be limited to persons at higher risk for adenomas (those with previous colon cancer or a worrisome personal or family history) and persons without a history of ulcer disease or hemorrhagic stroke. These individuals should consider a mixed strategy of surveillance and polyp prevention. Although high-risk persons probably derive substantial protection from colonoscopy at regular intervals, aspirin might decrease the size and number of polyps, making colonoscopy quicker, safer, and potentially less frequent. However, aspirin use will not eliminate the need for colonoscopy. In addition, persons who require aspirin for cardiovascular protection (12) can take comfort in the fact that they may also enjoy protection from colorectal adenomas. In the study by Chan and colleagues, doses at baby-aspirin levels provided some risk reduction. While their study (1) shows benefit from higher-than-cardioprotective aspirin doses, the additional risk for bleeding from higher doses may not be worth it.