Supplementation With Vitamins C and E or Beta-Carotene May Not Prevent Cancer

Laurie Barclay, MD

December 30, 2008

December 30, 2008 — Supplementation with vitamin C, vitamin E, or beta-carotene does not help in the primary prevention of total cancer incidence or cancer mortality, according to the results of a double-blind, placebo-controlled study reported in the January 7, 2009, issue of the Journal of the National Cancer Institute.

"Observational studies suggested that a diet high in fruits and vegetables, both of which are rich with antioxidants, may prevent cancer development," write Jennifer Lin, PhD, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, and colleagues from the Women's Antioxidant Cardiovascular Study (WACS). "However, findings from randomized trials of the association between antioxidant use and cancer risk have been mostly negative."

WACS was a double-blind, placebo-controlled 2 × 2 × 2-factorial trial of vitamin C (500 mg of ascorbic acid daily), natural-source vitamin E (600 IU of alpha-tocopherol every other day), and beta-carotene (50 mg every other day). The total trial cohort included 8171 women; the study sample for this analysis consisted of 7627 women who were cancer-free before randomization.

Hospital reports and the National Death Index allowed confirmation of diagnoses and deaths from cancer at a specific site. Hazard ratios (relative risks [RRs]) of common cancers associated with individual or combined use of antioxidants were determined with Cox proportional hazards regression models, and subgroup analyses examined whether duration of use modified the association of supplement use with cancer risk. Statistical tests were 2 sided.

Average treatment duration was 9.4 years. During that time, incident invasive cancer developed in 624 women, and 176 women died from cancer. Use of any antioxidant was not associated with any statistically significant effects on total cancer incidence. Compared with placebo, RRs were 1.11 for vitamin C (95% confidence interval [CI], 0.95 - 1.30), 0.93 for vitamin E (95% CI, 0.79 - 1.09), and 1.00 for beta-carotene (95% CI, 0.85 - 1.17).

Deaths from cancer also did not vary significantly among groups. RRs vs placebo were 1.28 for vitamin C (95% CI, 0.95 - 1.73), 0.87 for vitamin E (95% CI, 0.65 - 1.17), and 0.84 for beta-carotene (95% CI, 0.62 - 1.13).

"Duration and combined use of the three antioxidants also had no effect on cancer incidence and cancer death," the study authors write. "Supplementation with vitamin C, vitamin E, or beta carotene offers no overall benefits in the primary prevention of total cancer incidence or cancer mortality."

Limitations of this study include lack of complete follow-up and compliance; lack of generalizability to the overall population; limited power to evaluate the combined effects of the 3 antioxidants on site-specific incident cancers; and possibly insufficient duration to evaluate effects on cancer incidence, given the long latency for cancer.

In an accompanying editorial, Demetrius Albanes, MD, from the National Cancer Institute, National Institutes of Health in Bethesda, Maryland, notes that taken as a whole, WACS offers limited or no evidence that vitamin supplementation as tested offers any measurable preventive effect on cancer in women. However, he points out 2 specific findings that show the potential of antioxidants for site-specific efficacy.

"The first is the possible effect of vitamin E supplementation in preventing colorectal cancer (RR = 0.63), similar to what was observed in the ATBC [Alpha Tocopherol Beta-Carotene Cancer Prevention] Study and in a pooled analysis of serum tocopherol levels in cohort studies," Dr. Albanes writes. "The second is the elevated lung cancer risk in the beta carotene arm, along with modest excess overall cancer risk in smokers and heavier drinkers.

"The suggested harmful effects from vitamin C for lung and pancreatic cancers, with the former effect achieving statistical significance, are also noteworthy and raise questions concerning the chemopreventive [potential] of ascorbic acid," Dr. Albanes concludes. "All these observations, based on the randomized design, represent value-added data that will contribute to a better understanding of cancer etiology and prevention and the appropriate role of these micronutrient supplements."

The National Heart, Lung, and Blood Institute and the National Cancer Institute sponsored this study. Wyeth Pharmaceuticals provided pills and packaging for another study to coauthor J. Michael Gaziano.

J Natl Cancer Inst. 2009;101:2-4, 14-23.

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