Cancer incidence and mortality after treatment with folic acid and vitamin B12.
BACKGROUND
Recently, concern has been raised about the safety of folic acid, particularly in relation to cancer risk.


OBJECTIVE
To evaluate effects of treatment with B vitamins on cancer outcomes and all-cause mortality in 2 randomized controlled trials.


METHODS
Combined analysis and extended follow-up of participants from 2 randomized, double-blind, placebo-controlled clinical trials (Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial). A total of 6837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005, and were followed up through December 31, 2007.


METHODS
Oral treatment with folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) and vitamin B(6) (40 mg/d) (n = 1708); folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) (n = 1703); vitamin B(6) alone (40 mg/d) (n = 1705); or placebo (n = 1721).


METHODS
Cancer incidence, cancer mortality, and all-cause mortality.


RESULTS
During study treatment, median serum folate concentration increased more than 6-fold among participants given folic acid. After a median 39 months of treatment and an additional 38 months of posttrial observational follow-up, 341 participants (10.0%) who received folic acid plus vitamin B(12) vs 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03-1.41; P = .02). A total of 136 (4.0%) who received folic acid plus vitamin B(12) vs 100 (2.9%) who did not receive such treatment died from cancer (HR, 1.38; 95% CI, 1.07-1.79; P = .01). A total of 548 patients (16.1%) who received folic acid plus vitamin B(12) vs 473 (13.8%) who did not receive such treatment died from any cause (HR, 1.18; 95% CI, 1.04-1.33; P = .01). Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B(12). Vitamin B(6) treatment was not associated with any significant effects.


CONCLUSIONS
Treatment with folic acid plus vitamin B(12) was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods.


BACKGROUND
clinicaltrials.gov Identifier: NCT00671346.
Ebbing
Marta
M
Department of Heart Disease, Haukeland University Hospital, Jonas Liesvei 65, Bergen, Norway 5021. marta.ebbing@helse-bergen.no
Bønaa
Kaare Harald
KH
Nygård
Ottar
O
Arnesen
Egil
E
Ueland
Per Magne
PM
Nordrehaug
Jan Erik
JE
Rasmussen
Knut
K
Njølstad
Inger
I
Refsum
Helga
H
Nilsen
Dennis W
DW
Tverdal
Aage
A
Meyer
Klaus
K
Vollset
Stein Emil
SE
D000368:Aged; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009026:Mortality; D017202:Myocardial Ischemia / Q000517:prevention & control; D009369:Neoplasms / Q000453:epidemiology* / Q000401:mortality; D009664:Norway; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D014805:Vitamin B 12 / Q000097:blood / Q000627:therapeutic use*; D025101:Vitamin B 6 / Q000627:therapeutic use; D014803:Vitamin B Complex / Q000627:therapeutic use*
D014803:Vitamin B Complex; D025101:Vitamin B 6; D005492:Folic Acid; D014805:Vitamin B 12