Prospects for preventing colorectal cancer death.

Cancers of the colon and rectum account for about 150000 new cases and 60000 deaths each year, placing these tumors in the top three—with lung cancer and breast cancer—in overall importance in the United States (7). Although incidence and mortality rates for large-bowel cancer are somewhat higher in men, the burden of colorectal cancer weighs heavily on women as well, a fact that may have been lost amid the furor over other issues related to women's health. Indeed, for a woman currently aged 65 years, the risk of death from colorectal cancer over the next 20 years is about equal to the risk of death from breast cancer (2). After years of little apparent progress against colorectal cancer, prospects are now better for averting the mortality and morbidity associated with this malignancy. Although the incidence of colorectal cancer had been increasing moderately in recent decades, rates now appear to be declining (2). Mortality rates from these cancers have been dropping in many industrialized countries (5), decreasing in the United States by almost 1% per year since 1973 (2). Lifestyle changes and earlier diagnosis due to screening are plausible explanations for much of the decline (4,5), and these approaches offer great promise for further mortality reductions in the near future. This year, the long-awaited results of the Minnesota trial of fecal occult blood testing showed that annual screening reduced colorectal cancer mortality by one third (6). Casecontrol studies have indicated that screening with sigmoidoscopy may decrease mortality even more, perhaps by as much as one half (7,8). Since a high proportion of patients tested for fecal occult blood have positive tests and are referred for colonoscopy (6), it may be more efficient to bypass occult blood testing entirely and move directly to endoscopy as a screening tool. At present, flexible sigmoidoscopy appears to us to be the most practical means of reducing colorectal cancer mortality, but the cost may be prohibitive unless the procedure is performed by nonphysicians (e.g., nurses and technicians) and not more often than once every 3 years (9). Prospects for primary prevention of colorectal cancer are also promising. Data from epidemiologic studies consistently show that a dietary pattern of high intake of fat and low intake of fruits, vegetables, and fiber is associated with increased risk of colorectal tumors (10-12). At least one current clinical trial is testing a diet of reduced fat and increased fruits and vegetables for preventing large-bowel adenoma, a precursor of invasive cancer (4). Other studies are testing more limited nutritional interventions, including addition of antioxidant vitamins, calcium, and fiber supplements to the diet (4,5). The findings of these trials should help to determine the value of dietary modification and nutritional supplementation. For now, adoption of the dietary pattern associated with lower risk may be effective and seems to pose few risks. Another approach to primary prevention of cancer is use of pharmacologic agents. The most promising of these are the nonsteroidal anti-inflammatory drugs (NSAIDs), including piroxicam, indomethacin, and aspirin. Experiments with animals have shown that each of these drugs can prevent development of colorectal tumors after tumor initiation with carcinogens. The presumed mechanism of action is inhibition of cyclo-oxygenase activity, resulting in decreased synthesis of prostaglandins, some of which may function as signals for tumor cell proliferation (75). Although there had been laboratory evidence indicating an antitumor effect of NSAIDs since the mid 1970s (14), interest in these agents as possible preventives in human cancer crystallized with the publication, in 1991, of a casecontrol study (75) indicating a 50% reduction in colorectal cancer incidence among persons who regularly used aspirin. A previous case-control study (16) had found a similar result, but a cohort study (17) had shown no effect; neither study had focused primarily on the hypothesis that NSAIDs may have an antitumor effect. Publications from two large cohort studies have now specifically addressed this topic. Among a group of over 600000 adults enrolled in an American Cancer Society study, mortality in regular users of aspirin was about 40% lower for cancers of the colon (18) and rectum (79). In a study (20) of over 11000 men and women in Sweden who had rheumatoid arthritis and therefore were likely to have a higher frequency of NSAID use, colon cancer incidence was 37% lower than predicted from cancer registry data, and rectal cancer incidence was 28% lower. However, concerns about possible confounding and biased detection of cancer have complicated interpretation of all of these epidemiologic studies (27). Data on the effects of NSAIDs are now emerging from several sources. In this issue of the Journal, Gann et al. (22) report results from the Physicians' Health Study, a randomized controlled trial designed to test whether lowdose aspirin (325 mg every other day) would reduce cardiovascular disease mortality. In their analyses, the authors found no clear evidence of a reduction in invasive cancers or adenomas among the participants assigned to receive aspirin. Because aspirin use in this study was determined through random assignment, there is no realistic possibility that confounding factors could have influenced these results. As the authors point out, however, the