Aspirin was not associated with a decreased risk for colorectal cancer
ACP J Club. 1998 Nov-Dec; 129:74. doi:10.7326/ACPJC-1998-129-3-074
Stürmer T, Glynn RJ, Lee I-M, et al. Aspirin use and colorectal cancer: post-trial follow-up data from the Physicians' Health Study. Ann Intern Med. 1998 May 1;128:713-20.
In U.S. male physicians, is the use of aspirin associated with a decreased long-term risk for colorectal cancer? What factors are associated with aspirin use?
Cohort analysis using data from a randomized controlled trial (Physicians' Health Study) at 12 years of follow-up.
Community-based study of physicians in the United States.
22 071 healthy male physicians who were 40 to 84 years of age in 1982. At baseline, mean age was 53 years; 11% of the cohort smoked, 49% consumed alcohol weekly, and 72% reported vigorous exercise at least once per week. Follow-up for mortality was 100%. 115 men (0.6%) with missing data on aspirin use were excluded.
Assessment of risk factors
11 037 physicians were allocated to aspirin, 325 mg every other day for 5 years, and 11 034 physicians were allocated to placebo. After 5 years, participants could take aspirin at their own discretion, and this use was reported on a questionnaire at 6 to 7 years as regular use (≥ 3 times/wk) or no regular use (< 3 times/wk). Other risk factors were ascertained and used for adjustment and to determine factors associated with aspirin use.
Main outcome measures
Participants completed yearly questionnaires and reported incidences of colorectal cancer. Medical records and pathology reports were requested and reviewed by study personnel who were blinded to aspirin use. Data on gastrointestinal symptoms and diseases were also collected.
341 cases of colorectal cancer were reported overall (159 cases after 1988). Aspirin use in the study (1982 to 1988) was not associated with a decreased risk for colorectal cancer at 12 years (relative risk [RR] 1.03, 95% CI 0.83 to 1.28), and no decreased risk was seen in men who regularly used aspirin after 1988 (RR 1.07, CI 0.75 to 1.53). Frequent use of aspirin was associated with random allocation to aspirin in the trial, age in 10-year increments, vigorous exercise at least once per week, body mass index (in 5-unit increments), daily or weekly alcohol consumption, hypertension, coronary artery disease, and headache. Irregular use of aspirin was associated with ischemic or hemorrhagic stroke, use of warfarin, gastrointestinal symptoms (gastritis, nausea, and constipation), and gastrointestinal diagnoses and procedures (peptic ulcer, gastrointestinal bleeding, and cholecystectomy).
For men in the Physicians' Health Study, random allocation to aspirin for 5 years or regular use thereafter was not associated with a decreased risk for colorectal cancer for up to 12 years.
Sources of funding: In part, National Institutes of Health; German Academic Exchange Service; Swiss National Science Foundation.
For correspondence: Dr. C.H. Hennekens, Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA 02215, USA. FAX 617-732-6439.
Can aspirin and other nonsteroidal anti-inflammatory drugs prevent colorectal cancer by retarding the progression from normal mucosa to adenomatous polyps to cancer? Several observational studies suggest that they can. But we do not ordinarily recommend these drugs to patients at risk for colorectal cancer. Are we being wise or too conservative?
The study by Stürmer and colleagues suggests that we do not yet know enough to begin recommending aspirin to prevent colorectal cancer. In a large randomized controlled trial (5 y in the trial and 7 additional y of follow-up, when participants were free to choose whether to take aspirin), the investigators found no difference in the incidence of colorectal cancer in men taking aspirin and men taking placebo. It is difficult to discount the findings: Aspirin was randomly allocated for 5 years, and its use was carefully estimated for the other 7; other risk factors for colorectal cancer were taken into account; CIs were relatively narrow; and 12 years is enough time, given the natural history of the disease, to begin to see effects.
If the many observational studies that show an inverse relation between aspirin and colorectal cancer have been misleading, it would not be the first time that this has happened. For example, many cohort studies have shown that antioxidant vitamins protect against cardiovascular disease, but randomized controlled trials generally have not (1).
The weight of the evidence has now shifted toward the conclusion that aspirin has no clinically important effect on the development of colorectal cancer. But the hypothesis, although wounded, is not dead. Perhaps a larger dose of aspirin, longer follow-up, or a trial in women would show a treatment effect. In any case, it is not yet time to recommend aspirin as part of a strategy for primary prevention of colorectal cancer.
Robert H. Fletcher, MD, MSc
Harvard Medical School and Pilgrim Health CareBoston, Massachusetts, USA