Folic Acid Supplementation Not Linked to Cancer

Joe Barber Jr, PhD

January 24, 2013

Folic acid supplementation does not appear to increase or decrease the risk for site-specific or overall cancer in the first 5 years of treatment, according to the findings of a meta-analysis.

Stein Emil Vollset, MD, from the University of Bergen in Norway, and colleagues published their findings online January 25 in the Lancet.

The authors note that some trials revealed an increased incidence of cancer after folic acid supplementation. "One of these trials, the Aspirin and Folic Acid Polyp Prevention Study (AFPPS), reported in 2007 unexpected increases in the incidence of advanced colorectal adenomas and of prostate cancer during 7 years of treatment with folic acid," the authors write. "Also in 2007, it was suggested that transient increases in colorectal cancer incidence in Canada and the USA during 1996-98 might have been due to the 1996-98 introduction of folic acid fortification programmes in North America."

In this meta-analysis, the authors reviewed 13 trials comparing the effects of folic acid and placebo supplementation on cancer incidence according to the following 3 criteria: at least a single randomized comparison of folic acid vs placebo for at least 1 year of treatment, at least 500 participants, and recorded incidence of cancer. Among the trials, including a total of 49,621 patients, folic acid supplementation had no effect on the incidence of overall cancer (rate ratio [RR], 1.06; 95% confidence interval [CI], 0.99 - 1.13; P = .10).

The weighted mean duration of treatment was 5.2 years, and the daily doses of folic acid ranged from 0.5 to 5 mg, excluding a single trial that used a dose of 40 mg. The lack of an effect of folic acid supplementation on cancer incidence persisted for either less than 3 years (RR, 1.05; 95% CI, 0.96 - 1.14) or 3 years or more (RR, 1.06; 95% CI, 0.96 - 1.17) of treatment.

In addition, in multiple comparison analysis, no significant difference was observed in the incidence of any type of cancer for less than 3 years or 3 years or more of treatment. Age, sex, plasma folate concentration, and whether or not there was a national folic acid fortification program were also taken into account.

"The present meta-analysis rules out moderate increases in overall cancer incidence from folic acid supplementation during the trials," the authors conclude. "Large increases during the trials in any of the common types of cancer are similarly unlikely."

In a linked commentary, Joshua W. Miller, PhD, from Rutgers University in New Brunswick, New Jersey, and Cornelia M. Ulrich, PhD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, and the German Cancer Research Center in Heidelberg, Germany, mention that further research is needed to clarify the effects of folic acid supplementation on cancer. "Additional epidemiological and statistical analyses are warranted to address population-based hypotheses that are consistent with our current understanding of the biochemistry and biology of folate and cancer," they write. "In particular, analyses stratified by the presence of early lesions, by nutritional supplement use, and with longer follow-up will add important information."

Support for this project was provided by a grant from the UK Food Standards Agency. The authors and commentators have disclosed no relevant financial relationships.

Lancet. Published online January 25, 2013.