The overwhelmingly positive data from these experimental and epidemiological studies led to a series of clinical trials using purified beta-carotene supplements (Alpha Tocopherol Beta Carotene Cancer Prevention Study Group, 1994, Blot et al., 1995; Hennekens et al., 1996; Omenn et al., 1996) in an effort to delay cancer incidence (Table 11.3); however, these clinical trials have been very disappointing. While some studies showed no difference, others had adverse effects.
Beta Carotene Phase III Trials
Trial Dosage (per day) Results
PHS 25 mg BC none
ATBC 30 mg BC harm
CARET 30 mg BC + 25 mg retinoid discontinued (potential harm)
Linxian 15 mg BC + Se + vitamin E benefit
Note: PHS = Physician's Health Study (Hennekens, C.H., et al., NEJM, 1996; 334:1145.With permission.); ATBC = Alpha-Tocopherol Beta-Carotene Study (Alpha-Tocopherol Beta-Carotene Cancer Prevention Study Group, NEJM, 1994; 330:1029. With permission.); CARET = Carotene and Retinoid Study (Omenn, G.S., et al., J. Natl. Cancer Inst., 1996; 88:1550. With permission.); Linxian = Linxian Study (Blot, W.J., et al., Am. J. Clin. Nutr, 1995; 62:14245. With permission.); BC = beta-carotene, Se = selenium
Unfortunately, most clinical trials of beta-carotene were conducted by feeding high dosages of purified beta-carotene to well-fed individuals with easy access to beta-carotene-rich foods. For example, in the Physician's Health Study middle-aged and elderly male medical doctors ate a supplement containing approximately ten times the median dietary intake of beta-carotene, provided in a highly bioavailable form. No significant differences, positive or negative, between the treatment and control group occurred (Hennekens et al., 1996). Other clinical trials fed even larger amounts of beta-carotene, or beta-carotene plus retinol to Finnish smokers, or U.S. smokers and asbestos workers (Alpha Tocopherol Beta Carotene Cancer Prevention Study Group, 1994; Omenn et al., 1996). These trials indicated that high doses of beta-carotene were harmful. Smokers and asbestos workers who ate the beta-carotene supplements had higher rates of cancer than the control group. However, a clinical trial of a mixed antioxidant supplement containing lower dosages of beta-carotene (plus selenium and vitamin E) given to marginally malnourished adults in Linxian China showed positive results (Blot et al., 1995). In this poorly fed group of adults, moderate antioxidant supplementation decreased cancer risk and death.
The dosage of beta-carotene selected, the other nutrients provided, and the populations studied may all have made a difference between success and failure in these trials. In fact, clinical trials for many nutrients are problematic, because they may give significant results for one population and not another. Nutrient interventions generally only give good results if the amount of the nutrient that is beneficial is higher than typical dietary intakes. Studies that deplete people of nutrients can be difficult and expensive, but they identify physiologically important functions with more certainty.
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