Antioxidant supplements for preventing gastrointestinal cancers.
BACKGROUND
Oxidative stress may cause gastrointestinal cancers. The evidence on whether antioxidant supplements are effective in preventing gastrointestinal cancers is contradictory.


OBJECTIVE
To assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers.


METHODS
We identified trials through the trials registers of the four Cochrane Review Groups on gastrointestinal diseases, The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2007), MEDLINE, EMBASE, LILACS, SCI-EXPANDED, and The Chinese Biomedical Database from inception to October 2007. We scanned reference lists and contacted pharmaceutical companies.


METHODS
Randomised trials comparing antioxidant supplements to placebo/no intervention examining occurrence of gastrointestinal cancers.


METHODS
Two authors (GB and DN) independently selected trials for inclusion and extracted data. Outcome measures were gastrointestinal cancers, overall mortality, and adverse effects. Outcomes were reported as relative risks (RR) with 95% confidence interval (CI) based on random-effects and fixed-effect model meta-analysis. Meta-regression assessed the effect of covariates across the trials.


RESULTS
We identified 20 randomised trials (211,818 participants), assessing beta-carotene (12 trials), vitamin A (4 trials), vitamin C (8 trials), vitamin E (10 trials), and selenium (9 trials). Trials quality was generally high. Heterogeneity was low to moderate. Antioxidant supplements were without significant effects on gastrointestinal cancers (RR 0.94, 95% CI 0.83 to 1.06). However, there was significant heterogeneity (I(2) = 54.0%, P = 0.003). The heterogeneity may have been explained by bias risk (low-bias risk trials RR 1.04, 95% CI 0.96 to 1.13 compared to high-bias risk trials RR 0.59, 95% CI 0.43 to 0.80; test of interaction P < 0.0005), and type of antioxidant supplement (beta-carotene potentially increasing and selenium potentially decreasing cancer risk). The antioxidant supplements had no significant effects on mortality in a random-effects model meta-analysis (RR 1.02, 95% CI 0.97 to 1.07, I(2) = 53.5%), but significantly increased mortality in a fixed-effect model meta-analysis (RR 1.04, 95% CI 1.02 to 1.07). Beta-carotene in combination with vitamin A (RR 1.16, 95% CI 1.09 to 1.23) and vitamin E (RR 1.06, 95% CI 1.02 to 1.11) significantly increased mortality. Increased yellowing of the skin and belching were non-serious adverse effects of beta-carotene. In five trials (four with high risk of bias), selenium seemed to show significant beneficial effect on gastrointestinal cancer occurrence (RR 0.59, 95% CI 0.46 to 0.75, I(2) = 0%).


CONCLUSIONS
We could not find convincing evidence that antioxidant supplements prevent gastrointestinal cancers. On the contrary, antioxidant supplements seem to increase overall mortality. The potential cancer preventive effect of selenium should be tested in adequately conducted randomised trials.
Bjelakovic
Goran
G
Copenhagen Trial Unit, Centre for Clinical Intervention Research,, Department 3344, Rigshospitalet, Copenhagen University Hospital,, Blegdamsvej 9, Copenhagen, Denmark, DK-2100. goranb@junis.ni.ac.yu
Nikolova
Dimitrinka
D
Simonetti
Rosa G
RG
Gluud
Christian
C
D000975:Antioxidants / Q000008:administration & dosage* / Q000009:adverse effects; D019587:Dietary Supplements / Q000009:adverse effects; D005770:Gastrointestinal Neoplasms / Q000401:mortality / Q000517:prevention & control*; D006801:Humans; D008113:Liver Neoplasms / Q000401:mortality / Q000517:prevention & control*; D010190:Pancreatic Neoplasms / Q000401:mortality / Q000517:prevention & control*; D016032:Randomized Controlled Trials as Topic
D000975:Antioxidants