Chemoprevention of Colorectal Cancer: Dietary and Pharmacologic Approaches
Chemoprevention of Colorectal Cancer: Dietary and Pharmacologic Approaches
Remarkable progress has been made in recent years in our understanding of colorectal cancer etiology. The various hypotheses of causality continue to be tested in human observational and intervention studies, as well as experimental models. Drs. Garay and Engstrom provide a comprehensive review of the dietary and chemopreventive factors for colorectal cancer. While their conclusions are noteworthy, those related to dietary factors are debatable.
Results of epidemiologic studies indicate that use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) reduces colorectal cancer risk by approximately 50%. Perhaps the strongest evidence to date for the preventive activity of aspirin comes from the Nurses Health Study, which showed a 44%, statistically significant reduction in colorectal cancer in women after 20 years of consistent use. Given this long induction period, the negative results of such trials as the Physicians Health Study, noted by Garay and Engstrom, may be due to a shorter duration of follow-up. However, as also noted by the authors, given the toxicities of NSAIDs, these agents do not seem to be a feasible strategy for primary prevention of colorectal cancer in average-risk persons.
As mentioned by Garay and Engstrom, ongoing trials, such as that being conducted by the Cancer and Leukemia Group B (CALGB), may provide further insights. The goal of the CALGB trial is to study aspirins effects on the development of new adenomas among individuals with a history of colorectal cancer. However, the results may not be generalizable to average- or lower-risk individuals.
Dietary Fat and Fiber
Although results of epidemiologic studies show strong correlations between per capita intakes of total fat and rates of colon cancer, it is not possible to account for potential confounding factors in these studies. Earlier prospective studies of colon cancer have shown inconsistent findings for the association of fat intake and colon cancer. One of these studies (cited by Garay and Engstrom) showed a decreased risk of colorectal cancer among Hawaiian-Japanese men with higher intakes of total fat. However, careful attention must be placed to the source of the dietary data in this study, which used a single 24-hour recall method.
The vast majority of earlier case-control studies also support a positive association between total fat consumption and colorectal cancer risk. However, many of these studies failed to disentangle the effects of total fat from those of total energy intake, which is strongly correlated to total fat. Of those studies that statistically adjusted for total energy intake, most did not find a positive association between total fat and colon or colorectal cancer. Of particular importance is the combined analysis of 13 case-control studies, which found no evidence of an increased risk of colorectal cancer with higher dietary fat after adjustment was made for total energy.
In addition, studies that have investigated various sources of fat suggest a stronger, more consistent association between consumption of red meat and risk of colorectal cancer. For example, data from two large cohort studies, the Nurses Health Study and the Health Professionals Follow-up Study, showed a direct association between consumption of red meat and risk of colon cancer, but no association was observed with other sources of fat.
Overall, the epidemiologic evidence for the protective role of fiber against risk of colorectal cancer is inconsistent. This may be due to the heterogeneous nature of fiber and the differences in its measurement. Although the results of two meta-analyses, cited by the authors, show a lower risk of colon cancer with increased fiber intake, these are based solely on data from case-control studies. Conversely, this association is not generally supported by prospective studies. However, a vast majority of published studies have shown an inverse association between intake of vegetables and colon cancer. It is possible that the more consistent findings for intake of vegetables as compared with fiber are the result of the ability to measure vegetable sources of fiber better than nonvegetable sources.
Garay and Engstrom mention that results of the Polyp Prevention Trial should provide more conclusive information about these relationships. However, it must be emphasized that the intervention in this trial consists of an alteration in dietary patterns; therefore, any observed effect on polyp recurrence cannot be attributed to the independent effects of fiber or fat.
Vitamins and Minerals
Based on their thorough review of the literature on antioxidant vitamins, Garay and Engstrom arrive at the sound conclusion that there is insufficient evidence for their preventive effect against colorectal cancer. Regarding the role of folate, a protective effect against colon cancer is supported by few published studies. However, as pointed out by
Giovannucci et al, this association must be considered together with the effects of methionine and alcohol consumption, since the increased risk of colon cancer is marked among individuals with lower intakes of folate and methionine in the presence of high alcohol consumption. Since the proposed mechanism relates to dietary factors that influence methyl group availability, the assessment of folate, methionine, and alcohol in colon carcinogenesis underscores the importance of considering complex dietary interactions. Results from ongoing chemoprevention trials should elucidate this area of study.
Despite the considerable number of studies in a variety of settings, results of published epidemiologic studies suggest that higher calcium intake is not associated with a substantially lower risk of colorectal cancer. The possibility that calcium intake has a weak or modest effect on the occurrence of colorectal cancer cannot be excluded, however. As noted by the authors, further insights may come from ongoing randomized trials, such as the recently completed Dartmouth trial of calcium supplementation and recurrence of colon adenoma.
Based on the data presented to date, while a positive association exists between red meat consumption and colorectal cancer, there appears to be no clear evidence for an association between dietary fat and this cancer. With respect to dietary fiber, although the particular components of fiber that contribute to a decreased risk for colorectal cancer have not been clearly identified, the current evidence suggests that a diet high in fruits and vegetables is protective. Finally, in the area of primary prevention of this malignancy, greater focus should be placed on increasing physical activity, given the overwhelming evidence for its risk-reducing potential.
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