CRD summary

The review concluded that folic acid supplementation did not substantially increase or decrease incidence of site-specific cancer during the first five years of treatment. These conclusions represent a fair reflection of the available data and appear likely to be reliable.

Authors' objectives

To evaluate the effects of folic acid supplementation (at doses higher than fortification doses) on site-specific cancer rates.

Searching

Studies were identified by searching PubMed, checking reference lists of identified studies and contacting trial investigators. Unpublished studies completed before 2011 were sought using (unspecified) electronic searches and by discussion with experts in the field.

Study selection

Randomised placebo-controlled trials of folic acid with a scheduled treatment duration of at least one year that included at least 500 participants were eligible for inclusion. Cancer incidence data had to have been recorded.

The included studies were either of patients with previous vascular disease (or increased risk of cardiovascular disease) or with colorectal adenoma. Mean ages ranged from 52 to 69 years and around two-thirds of the participants were male. Studies were conducted in North America and Europe. Daily doses of folic acid ranged from 0.5 to 40mg (all but two of the trials used a dose of ≤2.5mg). Mean treatment durations ranged from 1.8 to 7.4 years.

The authors did not state how many reviewers selected studies for inclusion.

Assessment of study quality

Analyses of the individual participant data were checked for consistency with any published reports and with trialists. Investigators were asked to confirm summary data for every treatment group on the number of randomised participants, plasma concentrations of folate before and after start of treatment and on the number of participants who developed each of the predefined outcomes.

Data extraction

Individual patient data for all participants were sought from trial investigators. Log-rank analyses were used to calculate rate ratios (RR) with 99% confidence intervals (CI) for cancer incidence.

Methods of synthesis

Rate ratios were pooled using a two-stage meta-analysis. Estimates were reported with 95% confidence intervals. It appeared that a fixed-effect model was used. Heterogeneity was assessed using the Χ² test. Subgroup analyses examined the effect of year of follow-up (first three years or later), age, sex, plasma folate concentration, plasma homocysteine concentration and whether or not there was a nationwide folic acid fortification programme.

Results of the review

Thirteen trials (49,621 participants) were included. The authors stated that all trials were evenly randomised. Individual patient data were not available for two trials (5,992 participants).

Folic acid treatment had no significant effect on overall cancer incidence (RR 1.06, 95% CI 0.99 to 1.13). There was no evidence of statistically significant heterogeneity. There was no evidence of a change in the effect of folic acid with increasing treatment duration.

There was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast or any other specific site.

Authors' conclusions

Folic acid supplementation did not substantially increase or decrease incidence of site-specific cancer during the first five years of treatment.

CRD commentary

The review question and eligibility criteria were clear and reproducible. This meta-analysis of individual patient data was produced by a large trialist collaborative group so it was unlikely that any relevant studies were missed. Data were unavailable for two trials and these were excluded; the authors noted that these trials were small and their exclusion would not affect the conclusions.

Only basic details of data checking methods were reported; all studies had large sample sizes, reported even randomisation and were placebo-controlled so it was likely that the studies were not subject to important biases. Appropriate methods were used to pool data and assess heterogeneity and individual study details were provided.

The authors' conclusions represent a fair reflection of the available data and appear likely to be reliable.

Implications of the review for practice and research

Practice: The authors stated that fortification of flour and other cereal products involved doses of folic acid that were, on average, an order of magnitude smaller than the doses used in the studied trials.

Research: The authors noted that further (post-treatment) follow-up in the studies might be feasible to evaluate effects on cancer incidence in the longer-term.

Funding

British Heart Foundation; Medical Research Council; Cancer Research UK; Food Standards Agency

Bibliographic details

Vollset SE, Clarke R, Lewington S, Ebbing M, Halsey J, Lonn E, Armitage J, Manson JA, Hankey GJ, Spence JD, Galan P, Bonaa KH, Jamison R, Gaziano JM, Guarino P, Baron JA, Logan RF, Giovannucci EL, den Heijer M, Ueland PM, Bennett D, Collins R, Peto R; B-Vitamin Treatment Trialists' Collaboration. Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50 000 individuals. Lancet 2013; 381(9871): 1029-1036. [PMC free article: PMC3836669] [PubMed: 23352552]

Original Paper URL

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)62001-7/abstract

Indexing Status

Subject indexing assigned by NLM

MeSH

Carcinogens /administration & dosage; Dietary Supplements /adverse effects; Female; Folic Acid /administration & dosage /adverse effects; Humans; Incidence; Male; Middle Aged; Neoplasms /chemically induced /epidemiology; Randomized Controlled Trials as Topic

AccessionNumber

12013004930

Database entry date

14/02/2013

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.