NUTRITIONAL SUPPLEMENTS DO NOT PREVENT CANCER

Common Nutritional Supplements Do Not Prevent Cancer in Women

November 4, 2008 — Folic acid, vitamin B₆, and vitamin B₁₂ — all of which are thought to play a role in cancer prevention and are common ingredients in multivitamin supplements — have no significant effect on cancer risk in women.

This conclusion comes from the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a randomized trial of 5442 female health professionals in the United States who had an average age of 62.8 years at baseline and who were observed for an average of 7.3 years.

"Our trial says that this [using the 3 nutritional supplements daily] does not appear to be an effective approach to preventing cancer in women. We know that there are other things that women can do that help prevent cancer, such as stopping smoking and exercising," said lead author Shumin M. Zhang, MD, ScD, associate professor of medicine at Harvard Medical School in Boston, Massachusetts, in an interview with Medscape Oncology.

"There is very good biology behind the hypothesis that they [the 3 nutritional supplements] could play a role in cancer prevention," she added. Approximately one third of adults in the United States take multivitamin supplements containing folic acid, vitamin B₆, and vitamin B₁₂, according the authors of the study, which appears in the in the November 5 issue of the Journal of the American Medical Association.

Despite its main conclusion, the study reveals that 1 treatment subgroup received some benefit: women aged 65 years or older at study entrance had a significantly reduced risk for overall cancer and breast cancer. "This effect in older women may be due to chance," said Dr. Zhang, who said the finding needs to be further substantiated.

The study also serves as further evidence that folic acid (the synthetic form of folate) does not appear to increase cancer occurrences when taken as a daily supplement.

Study Results and a Note of Doubt

WAFACS is a study that is the outgrowth of a parent trial, the Women's Antioxidant Cardiovascular Study. As a result, the women in WAFACS are all older than 42 years and have preexisting cardiovascular disease (CVD) or 3 or more coronary risk factors.

In the randomized WAFACS, participants took either a daily combination of 2.5 mg of folic acid, 50 mg of vitamin B₆, 1 mg of vitamin B₁₂, or a matching placebo starting in 1998. The doses are higher than the adult recommended daily allowances for folate (400 μg/day), vitamin B₆ (1.5 mg/day), and vitamin B₁₂ (2.4 μg/day) in women. The mean age for the women participants was 62.8 years, and the mean body mass index was 30.6 kg/m².

Cancer developed in a total of 379 women (n = 187, treatment group; n = 192, placebo group) during the study, which ended in 2005. Treatment with supplements had no significant effect on the risk for total cancer (101.1/10,000 person-years for the active treatment group vs 104.3/10,000 person-years for the placebo group; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.79 - 1.18; P = .75) or individual cancer endpoints, including breast, colorectal, lung, and uterine cancer. There was also no difference in cancer death or death from any cause.

The lack of effect, beneficial or harmful, of the supplements on cancer risk in these women may be related to the length of the study and latency period of cancer, admitted the study authors.

"Because cancer has a long latency period, we cannot exclude the possibility that there might be beneficial or harmful effects of combined B vitamins on cancer that were not detectable within 7.3 years of treatment," write the authors.

The current study also notes that there were no differences according to current use of multivitamin supplements at the start of the study; intakes of total folate, vitamin B₆, and vitamin B₁₂; or a history of cancer or other risk factors at baseline. Lack of effect for total cancer did not vary with time.

However, among the women in the trial in whom breast cancer developed and who received the supplements, the study shows a "borderline" significant reduction for estrogen receptor–positive and progesterone receptor–negative tumors.

What Other Large Trials Have Shown

Two other large, randomized trials assessing folic acid, vitamin B₆, and vitamin B₁₂ in relationship to CVD risk have reported similar cancer outcomes but during fewer years, according to the study authors.

In the Heart Outcomes Protection Evaluation-2 trial, an average of 5 years of treatment with the same daily combination of 2.5 mg of folic acid, 50 mg of vitamin B₆, and 1 mg of vitamin B₁₂ had no significant effect on the risk for total cancer; cancers of the breast, colon, lung, or prostate; or cancer death. Also, 71.1% of participants were from countries with folic acid fortification, which has been proven to reduce the risk for neural tube defects.

The Norwegian Vitamin Trial in Norway, a country that has no mandatory folic acid fortification in foods, also reported no effect on cancer outcomes in a placebo-controlled trial, with an average of 3.3 years of treatment and follow-up. Compared with the placebo group, there was no difference in cancer risk in those patients receiving the combined folic acid (0.8 mg), vitamin B₆ (40 mg), and vitamin B₁₂ (0.4 mg) treatment or combined folic acid (0.8 mg) and vitamin B₁₂ (0.4 mg) treatment at an average of 3.3 years of treatment and follow-up. However, in this trial, there was a suggestion of beneficial effect on cancer risk in those patients treated with vitamin B₆ alone vs those assigned to placebo.

These 3 trials, including WAFACS, are an endorsement of the safety of folic acid daily supplementation with regard to cancer risk, suggest the study authors. The combined data from these randomized trials of combined B vitamins provide "reassurance that folic acid supplementation up to a dose of 2.5 mg/d when combined with vitamin B₆ and vitamin B₁₂ does not appear to increase cancer occurrences and deaths among individuals at high risk for CVD during the folic acid fortification era" write the study authors. Folate has been a concern because of its potential to promote tumor development when administered late in carcinogenesis, note the study authors.

A Note on Participant Adherence

Participant adherence to the pill-taking regimen seemed strong in the new study. Adherence is defined as taking at least two thirds of the study pills during the course of participation; adherence was 83% for both treatment and placebo groups. Also, in a random sample of 300 women, there were no differences in median plasma folate levels between the 2 groups at the start of the study, but it was significantly higher at the end of the trial, which is a sign of participant adherence.