Folic acid supplementation had no statistically significant effect on the incidence of cancer over the course of 5 years, a meta-analysis found, but questions remain.
Among almost 50,000 individuals enrolled in 13 clinical trials, 7.7% of those receiving folic acid developed malignancies, as did 7.3% of those receiving placebo, according to Robert Clarke, MD, of the University of Oxford in the U.K., and colleagues.
This represented a nonsignificant 6% increase in various types of cancer in participants taking folic acid supplements (RR 1.06, 95% CI 0.99 to 1.13, P=0.10), the researchers reported online in the Lancet.
However, an accompanying comment urged caution in drawing conclusions from the meta-analysis.
“Although the results presented in the meta-analysis are an important addition to the debate, the complexity of the biological relation between folate and cancer requires cautious interpretation,” argued Joshua W. Miller, PhD, of Rutgers University in New Brunswick, N.J., and Cornelia M. Ulrich, PhD, of the German Cancer Research Center in Heidelberg.
Since the late 1990s, flour has been fortified with folate in the U.S. and Canada to help prevent neural tube defects, but countries in Western Europe have declined to do so out of fears of increased risks for certain types of cancer.
Epidemiologic studies had suggested that a high intake of folate was associated with lower rates of colorectal cancer and cardiovascular disease, but in the years immediately following the mandated folic acid fortification, a transient rise was reported for colorectal cancer in North America.
Adding to the concern was the finding in the Aspirin and Folic Acid Polyp Prevention Study (AFPPS) of an increase in prostate cancer and in advanced colorectal adenomas.
To explore the impact of folate supplementation on incident cancer, Clarke and colleagues conducted a literature search and meta-analysis in which they examined patient-level data for 49,621 adults who had previously had colorectal adenomas or were at risk for cardiovascular disease.
Mean age was 64, and two-thirds were men.
The doses of folic acid used in the studies varied from 0.5 mg to 5 mg per day, with the exception of one study that used a daily dose of 40 mg.
Study duration ranged from 1.8 years to 7.4 years, with an average of 5.2 years.
No increases were seen for individual types of common cancer:
Colorectal, RR 1.07 (95% CI 0.83 to 1.37)
Lung, RR 1.08 (95% CI 0.86 to 1.35)
Breast, RR 0.89 (95% CI 0.66 to 1.20)
Prostate, RR 1.15 (95% CI 0.94 to 1.41)
“Importantly,” the researchers stated, they saw no increased risk for cancer with longer treatment, although they noted that only four of the studies were of 5 years’ duration or more.
They also found no differences in cancer incidence according to age, sex, pretreatment levels of folate, or dose of folic acid.
Even in the trial with the 40-mg dose, there was no increase in incidence of cancer (RR 0.94, 95% CI 0.61 to 1.47).
The authors noted that a previous meta-analysis which relied on summary data from a smaller group of trials had identified a “marginally significant excess” in cases of prostate cancer.
However, the current analysis used individual-patient data from all of the trials, and the association of folic acid with prostate cancer supplementation seen in the AFPPS study “was most likely produced or exaggerated by the play of chance,” they stated.
They acknowledged that their analysis did not attempt to assess the longer-term effects of folic acid, suggesting that decades-long follow-up might be “feasible” in groups with linkages between cancer and death registries.
“The present meta-analysis rules out moderate increases in overall cancer incidence from folic acid supplementation,” they concluded.
In their comment, Miller and Ulrich explained that all cells, including cancer cells, require folate for the process of mitosis, and inhibiting the metabolism of folate – as occurs with anti-cancer drugs such as methotrexate – can interfere with the progression of some malignancies.
But increasing the availability of folate can increase the proliferation of cancer cells, they explained.
“Thus, folate has a putative two-faced relationship with cancer: it can protect against initiation, but promote proliferation,” they stated.
They also sounded a note of caution with regard to the statistical findings.
“Although the overall RR for cancer did not reach the conventional (and somewhat arbitrary) definition of statistical significance (ie, P<0.05), the lower bound of the [confidence interval] was very close to 1, and the overall cancer incidence increased by 6%. For prostate cancer the risk estimate was 1.15 (99% CI 0.94 to 1.41) – again, a finding close to significance,” they wrote.
“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 stated.