Analyses from the 1994 Alpha-Tocopherol, Beta Carotene intervention trial raise "serious questions" about vitamin E's role in modifying cancer risk, FDA's Center for Food Safety & Applied Nutrition concludes May 4 in rejecting an antioxidant vitamins/cancer health claim.

The ATBC study investigators' "observation of a higher cancer incidence at two sites other than the lung...suggests that there may be potential safety concerns" with vitamin E supplementation, the agency says in a letter to Pearson plaintiffs' counsel Emord & Associates (Washington, D.C.).

In particular, the agency points to ATBC study findings of a higher incidence of bladder cancers (9.6 versus 8.7 cases per 10,000 person-years) in participants who received vitamin E supplements compared to subjects in a placebo group.

Similarly, the investigators found a greater occurrence of stomach cancers (8.3 versus 6.6 cases per 10,000 person-years) in vitamin E-supplemented participants, FDA notes.

The agency acknowledges the ATBC results, which were initially published in the April 14, 1994 New England Journal of Medicine, "must be interpreted with caution" because enrollment protocols originally were intended to evaluate only lung cancer.

Although the study was designed primarily to investigate the effects of beta carotene and vitamin E dietary supplements on lung cancer risk among male Finnish smokers, data on bladder, stomach, prostate and colorectal cancers also were reported.

FDA notes its analysis of the trial results produced a mixed message; while prostate and colorectal cancers appeared to benefit from vitamin E supplementation, the nutrient had no effect on lung cancer and negative effects on bladder and stomach cancers.

As a result, FDA continues, "no disclaimer could render a claim for a relationship of vitamin E and reduced risk of cancer non-misleading."

Overall, the agency concludes: "The scientific evidence against a claim relating vitamin C or vitamin E, alone or in combination (i.e., antioxidant vitamins) and reduced risk of certain kinds of cancer or of individual cancers...outweighs the scientific evidence for a claim about such a relationship."

Further, "the scientific evidence was not sufficient to attribute a decreased risk of some cancers specifically to vitamin C or vitamin E," FDA adds.

The agency's rejection of the proposed claim, "Consumption of antioxidant vitamins may reduce the risk of certain kinds of cancers," represents the last of four health claims to be evaluated by FDA as part of the Pearson v. Shalala litigation.

The agency allowed a qualified health claim for omega-3 fatty acids/coronary heart disease but denied a fiber/colon cancer claim. Although FDA rejected a proposed health claim for folic acid/neural tube defects, a federal judge in February granted the Pearson plaintiffs' request for a preliminary injunction and ordered the agency to draft disclaimers to accompany such a claim (¹ Also see "Pearson" - Pink Sheet, 14 May, 2001.).

FDA focused its current review on studies addressing whether a link exists between vitamins C and E, alone or in combination, and 12 types of cancer: bladder, breast, cervical, colorectal, lung, oral, pharyngeal, esophageal, pancreatic, prostate, skin and stomach.

The agency's conclusions are consistent with the Institute of Medicine's April 2000 Dietary Reference Intakes report, which found the relationship between vitamins C or E, selenium and carotenoids and the prevention of chronic diseases has not conclusively been proven (² Also see "Vitamins C, E, Selenium Upper Limits Set For First Time By FNB" - Pink Sheet, 17 April, 2000.).

FDA says it did not include beta carotene in its review of the health claim based on the IoM report's finding that although the carotenoids display antioxidant activity in vitro, "there is inadequate evidence that they have antioxidant activity in vivo when consumed in food by humans and, therefore, do not meet the definition of a dietary antioxidant."

The IoM report also cited potential adverse effects associated with high intakes of vitamins C and E, including diarrhea and other gastrointestinal disturbances for vitamin C, and prolonged bleeding time for individuals concurrently using vitamin E and non-steroidal anti-inflammatory drugs.

Additional trials FDA cites as key are the Dysplasia Trial and the General Population Trial, both conducted in Linxian, China in 1993-1994. Researchers demonstrated an increased prevalence of gastric cancer among subjects receiving supplements containing 120 mg vitamin C and molybdenum.

Although it is not clear the increased prevalence of gastric cancer resulted from vitamin C consumption, "it cannot be ruled out that vitamin C contributed to this adverse finding," FDA says.

The agency further notes the studies were unable to link use of a multivitamin containing vitamins C and E with a reduced esophageal cancer risk. These findings are particularly important, FDA says, because the Chinese population is at high risk for cancer due to vitamin-deficient diets, and absence of effect in such a population "is strong evidence that there is no relationship between vitamin C and esophageal cancer risk."

Findings from a separate prospective study conducted by Zhang, et al., in 1999 indicate vitamins C and E obtained from a fruit- and vegetable-rich diet, rather than from supplements, were associated with breast cancer risk reduction. Such results suggest dietary components of the types of foods high in vitamins C and E, but not the vitamins themselves, may affect cancer risk, the agency notes.

Similarly, in trials investigating vitamin E's effects on cervical cancer, FDA maintains "none of the available studies was able to accurately estimate vitamin E intakes, or to isolate the effects of vitamin E from other components in the diet, where the data suggested that vitamin E was responsible for a protective effect."

The 1994 polyp prevention trial by Greenberg et al., Dartmouth-Hitchcock Medical Center, which FDA considers one of the most persuasive in terms of size, duration of intervention and completeness of follow-up, "provides clear and compelling evidence that there is no relationship between vitamin C and reduced risk of colorectal cancer," according to the agency.

Results from the many trials analyzed "underscore the critical need for more clinical research to ensure that any suggestion of benefit or increased risk" from vitamin C and E supplementation is "real, and that safe conditions of use...can be ascertained," FDA asserts.

Emord & Associates said the plaintiffs' scientific advisors are reviewing FDA's 77-page decision; the firm said it may consider bringing new legal action against the agency.

Antioxidants/Cancer Health Claim Contradicted By ATBC Study - FDA

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