Chemoprevention of Colorectal Cancer: Dietary and Pharmacologic Approaches

Colorectal cancer is one of the most commonly occurring cancers in the United States. In an effort to prevent the occurrence of colorectal cancer, agents identified as reducing risk of the disease are being targeted as potential chemoprevention tools. However, complex associations exist among diet, lifestyle factors, and genetic susceptibility and the eventual development of colon cancer, sometimes making the transition from associations identified in epidemiologic studies to the clinical use of chemoprevention agents difficult. Environmental factors that may serve as chemoprevention agents are addressed in the article by Garay and Engstrom. Does our current knowledge allow us to embrace these agents as tools for chemoprevention?

Studies Differ

Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS) were identified by epidemiologists as reducing the colon cancer risk over 10 years ago.[1] Since then, numerous studies have reconfirmed the original observation that people who took high levels of aspirin or NSAIDS were at a lower risk of colon cancer.[2] However, there are still unknowns in the transition from current epidemiologic research to chemoprevention. The dose at which a protective effect is achieved generally has not been evaluated in epidemiologic studies. It has been suggested that the protective effect exists only while the person is still taking aspirin and/or NSAIDS. However, low doses of these agents are likely candidates for chemoprevention.

Dietary antioxidants, including vitamin E, vitamin C, and beta-carotene, are not consistently associated with colon cancer.[3] While some studies have shown these antioxidants to be protective, others do not show an association.[4-6] Evaluation of various forms of vitamin E suggests that some forms possibly may contribute to the risk of colon cancer.[7] Among smokers, beta-carotene has been shown to increase risk of colon cancer.[8] The evidence for using these factors as chemoprevention agents for colon cancer is questionable at this time.

Epidemiologic data on folate are mixed in terms of their association with colorectal cancer.[2] Folate has been associated with a decreased risk of colorectal cancer in some, but not all, studies.[9-11] The protective effect may be attributed, in part, to dietary fiber.[10] The protective effect from folate may depend on other factors, such as level of alcohol or methionine or red meat intake.[9]. Studies that now incorporate genotype data into the analyses find that these effects may actually vary by genotype.[reference 12; and M. L. Slattery et al, unpublished data, 1998] Thus, the utility of folate as a tool for chemoprevention is unclear.

As with folate, the data that support calcium as a protective agent for colorectal cancer are unclear. While several studies have shown significant protection from colon cancer among those who consume the highest amounts of calcium, other studies have found no association.[2] Underlying differences in the populations studied and levels of calcium consumed among populations have not been thoroughly evaluated. While biological mechanisms by which calcium may reduce the risk of colon cancer do exist, our understanding of the association between calcium and colorectal cancer raises questions about its suitability as a chemoprevention agent at this time.

Other dietary factors, such as consumption of fat, fiber, and certain foods, merit mention. Most recent studies have failed to identify an increase in colorectal cancer with high consumption of dietary fat.[13,14] This may be attributed to changes in the underlying characteristics of the population over time or to better control for the effects of energy intake and expenditure that may have confounded previous studies. Dietary fiber is one of the dietary factors that have consistently shown an inverse association with colon cancer.[2] Of all the dietary factors studied, consumption of plant foods, especially vegetables, appears to be consistently associated with a decreased risk of colorectal cancer. However, vegetables contain many unmeasured constituents that may be protective.[15] A better understanding of these constituents may lead eventually to agents that will lend themselves to chemoprevention.

Population Characteristics Must Be Considered

Inconsistencies in the epidemiologic data require a better understanding before many of the diet and lifestyle factors studied can be used as chemoprevention agents. Although studies report on the same nutrient or exposure, often what is measured, how it is measured, when it is measured in terms of referent period, and how it is analyzed can contribute to differences in associations observed between studies. The underlying characteristics of the population being studied and factors that may modify associations with cancer may also contribute to observed differences between studies. For instance, high levels of physical activity may modify dietary associations with colon cancer[16]; the association between folate and colon cancer may be influenced by intake of alcohol[9]; and smoking may modify the effects of dietary antioxidants.[8]

 Genetic susceptibility adds to the complexity. While studies often examine one or two genes that may influence susceptibility, the cadre of other genes involved in the same mechanisms is not examined, thus further complicating the interpretation of results. Furthermore, adaptive changes that individuals make to environmental exposure and to genetic make-up generally are not and often cannot be measured. Thus, identifying the population, or subsets of the population, who may benefit from a given chemoprevention tool is as important and as challenging as identifying the chemoprevention tool to be applied.

In practicing the art of chemoprevention, one must account for many complex variations among people, including patterns of diet and lifestyle. Chemoprevention strategies will most probably vary by individual. Perhaps one of the more consistent associations with colon cancer is a protective association with physical activity. Some studies indicate that intense activities are most protective. Sound advice in terms of prevention is to incorporate physical activity into one’s lifestyle. Epidemiologic data suggest that it is prudent to run, jog, or walk at a vigorous pace to the nearest vegetable market.

References:

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4. Bostick RM, Potter JD, McKenzie DR, et al: Reduced risk of colon cancer with high intake of vitamin E: The Iowa Women’s Health Study. Cancer Res 53:4230-4237, 1993.

5. Flagg EW, Coates RJ, Greenberg RS: Epidemiologic studies of antioxidants and cancer in humans. J Am Coll Nutr 14:419-427, 1995.

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8. Slattery ML, Friedman GF, Potter JD, et al: Tobacco use and colon cancer. Int J Cancer 70:259-264, 1997.

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10. Freudenheim JL, Graham S, Marshall JR, et al: Folate intake and carcinogenesis of the colon and rectum. Int J Epidemiol 20:368-374, 1991.

11. Slattery ML, Schaffer D, Edwards SL, et al: Are dietary factors involved in DNA methylation associated with colon cancer? Nutr Cancer 28:52-62, 1997.

12. Chen J, Giovannucci E, Kelsey K, et al: A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res 56:4862-4864, 1996.

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14. Willett WC, Stampfer MJ, Colditz GA, et al: Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med 323:1664-1672, 1990.

15. Steinmetz KA, Potter JD: Vegetables, fruits, and cancer: II. Mechanisms. Cancer Causes Control 2:427-442, 1991.

16. Slattery ML, Potter JD, Caan BJ, et al: Energy balance and colon cancer: Beyond physical activity. Cancer Res 57:75-80, 1997.