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Folic acid and cancer – 50,000 trial participants
Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals.
Overview
Vollset SE et al.. Lancet 2013 · PMID 23352552 · DOI 10.1016/S0140-6736(12)62001-7
No significant effect of folic acid on cancer over about 5 years.
Does the study support the specific claim? No · Methodological quality: high
Plain-language summary
Study explained simply
- What did the researchers want to find out?
Folic acid and cancer.
- How was the study done?
IPD meta-analysis.
- How many people, animals or samples were studied?
49,621.
- What was actually found?
No significant effect.
- How large was the observed effect?
RR 1.06 (0.99–1.13).
- What do the results mean in everyday life?
Folic acid does not cause cancer in the short term.
- What are the study's limitations?
5 years.
- What does it say about Elawady's specific claim?
Contradicts C-SUP-06.
- Do the results apply to Germany and Europe?
Applicable.
- What can explicitly not be concluded from this study?
Very long-term effects.
Scientific in-depth review
1. Full reference
- Authors
- Vollset SE et al.
- Journal
- Lancet
- Year
- 2013
- Identifier
- PMID 23352552 DOI 10.1016/S0140-6736(12)62001-7
- Verification
- verified – PubMed efetch 2026-10-25
- Retracted
- no
- Corrections
- none
- Extent checked
- full text
- Conflicts of interest and funding
British Heart Foundation, Medical Research Council, Cancer Research UK (core CTSU funding) and UK Food Standards Agency grant (N05072); CTSU accepts no industry fees or honoraria.
2. Research question
Effect of folic acid supplementation on cancer incidence
3. Study design and population
- Study design
- Meta-analysis – Prospectively planned (protocol agreed 2004 before results) individual-participant-data meta-analysis of placebo-controlled RCTs of folic acid (B-Vitamin Treatment Trialists' Collaboration)
- Population
Participants of 10 cardiovascular-prevention trials (n=46,969; people with or at high risk of CVD, incl. one renal trial) and 3 colorectal-adenoma trials (n=2652); two-thirds men, mean age 64
- Country
Multinational (UK, USA, Canada, Norway, France, Netherlands, Australia/India)
- Period
Trials completed by end of 2010; treatment 2.0-7.7 years (weighted mean 5.5 years)
- Sample size
13 trials, 49,621 participants (24,799 folic acid, 24,822 control); 3713 incident cancers; 2 further trials (5992 participants) did not record cancer incidence
- Inclusion and exclusion criteria
Randomised folic acid vs placebo, >=1 year scheduled treatment, >=500 participants, cancer incidence recorded
4. Methods and endpoints
- Exposure / intervention
Folic acid 0.5-5 mg/day (one trial 40 mg/day; median 2.0 mg), often combined with vitamin B12 and/or B6
- Comparator
Placebo (one trial 0.02 mg folic acid)
- Endpoints
First incident cancer (excluding non-melanoma skin) during scheduled treatment; 18 site-specific types
- Statistical methods
Log-rank observed-minus-expected IPD meta-analysis; 95% CI overall, 99% CI for sites/subgroups; Bonferroni-type correction across 18 sites; prespecified subgroups; sensitivity excluding the hypothesis-generating AFPPS trial
5. Actual results
- Results
Plasma folate quadrupled (57.3 vs 13.5 nmol/L); homocysteine fell by a quarter. Overall cancer 1904 (7.7%) vs 1809 (7.3%), RR 1.06 (95% CI 0.99-1.13), P=0.10; no heterogeneity between trials (P=0.23); vascular trials 1.04 (0.98-1.11), adenoma trials 1.33 (0.98-1.80). No trend with duration (P=0.46) or dose; 40 mg/day trial RR 0.94. Sites (99% CI): colorectal 1.07 (0.83-1.37), lung 1.08 (0.86-1.35), breast 0.89 (0.66-1.20), prostate 1.15 (0.94-1.41); none significant after correction. Excluding AFPPS: colorectal 1.08 (0.89-1.30), prostate 1.11 (0.95-1.30).
- Absolute risks
Cancer incidence 7.7% (folic acid) vs 7.3% (placebo) over a weighted mean of 5.5 years (difference 0.4 percentage points, not statistically significant)
- Authors' conclusion
Folic acid supplementation does not substantially increase or decrease overall or site-specific cancer incidence during the first ~5 years; moderate increases in overall cancer are ruled out; long-term post-trial effects are not addressed.
6. Strengths
- Prospectively agreed protocol before results
- Individual participant data from all eligible large trials
- Uniform cancer classification; multiplicity correction; sensitivity excluding hypothesis-generating trial
- Independent academic funding
7. Weaknesses
- Only in-trial follow-up (~5 years); late effects not addressed
- Search limited to PubMed and reference lists
- Upper CI (1.13) does not exclude a small overall increase; adenoma-trial subgroup RR 1.33 (0.98-1.80)
- Mostly older high-CV-risk participants; many trials combined folic acid with B12/B6, so effects of folic acid alone cannot be fully separated
- Risk of bias of individual trials not formally scored
8. Risk of bias
- Orienting tool
- AMSTAR 2
- Type of assessment
- structured assessment based on the full text by a single reviewer (no formal double review)
- Full formal assessment
- no
- Overall risk of bias
- low
- Rationale
Single-reviewer structured AMSTAR 2 appraisal from full text; not formal (needs two independent reviewers). IPD design with prospective protocol mitigates most concerns.
| Domain | Judgement | Rationale |
|---|---|---|
| Item 1 PICO components | low | Clearly defined. |
| Item 2 Protocol a priori (critical) | low | Collaborative protocol agreed in 2004 before results and published. |
| Item 3 Explanation of included designs | low | Large placebo-controlled RCTs. |
| Item 4 Comprehensive search (critical) | some concerns | PubMed plus reference lists and expert contact; trialist network likely complete for large trials. |
| Item 5 Duplicate selection | some concerns | Not described. |
| Item 6 Duplicate extraction | low | IPD checked against publications and confirmed with trialists. |
| Item 7 Excluded studies justified (critical) | low | Two trials without cancer data named and justified. |
| Item 8 Description of included studies | low | Table of trial characteristics. |
| Item 9 RoB assessment (critical) | some concerns | All trials randomised and placebo-controlled, but no formal RoB tool. |
| Item 10 Funding of included studies | some concerns | Referred to individual publications. |
| Item 11 Appropriate meta-analytic methods (critical) | low | IPD log-rank stratified by trial. |
| Item 12 Impact of RoB on results | some concerns | Not assessed by RoB, but sensitivity excluding AFPPS. |
| Item 13 RoB considered in interpretation (critical) | low | Limitations on duration and power discussed. |
| Item 14 Heterogeneity | low | No significant heterogeneity. |
| Item 15 Publication bias (critical) | low | All large trials included via IPD, minimising publication bias. |
| Item 16 Conflicts of interest | low | Declared; no industry funding. |
Full-text review (25 October 2026): Added prospective protocol, trial list/doses (many with B12/B6), absolute cancer proportions (7.7% vs 7.3%), adenoma vs vascular subgroup, site-specific 99% CIs, AFPPS sensitivity analysis, independent funding; AMSTAR 2 item-level appraisal (overall unchanged: low).
9. Assessment of the statistical interpretation
Precise null-to-small estimate for overall cancer (RR 1.06, 0.99-1.13) that rules out moderate increases over ~5 years but not a small one; site-specific findings null after multiplicity correction.
10. Relevance to the specific claim
11. Independent contrary findings
12. Transferability to Germany and Europe
High.
13. Overall methodological judgement
Best evidence on folic acid and cancer.
| Multidimensional assessment | |
|---|---|
| Authenticity of the source | verified |
| Methodological quality | high |
| Risk of bias | low |
| Precision of results | high |
| Directness | direct |
| Reproducibility | replicated |
| Consistency with the overall evidence | consistent |
| Regional transferability | high |
| Adequacy of the interpretation (by the archive) | not applicable |
14. Open questions
Long-term post-trial cancer incidence; effects in younger populations and at fortification doses.
15. Linked fact checks
- Multivitamins, iron, folic acid, B6, magnesium, zinc and copper supplements increase mortality, and folic acid (with B12) increases cancer. – Studies contradicting or limiting the claim