• G Bjelakovic, D Nikolova, R G Simonetti, and C Gluud.
• Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Dept. 7102, H:S Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK 2100 Copenhagen, Denmark. g.bjelakovic@ctu.rh.dk
• Cochrane Db Syst Rev. 2004 Jan 1(4):CD004183.

BackgroundOxidative stress may cause gastrointestinal cancers. The evidence on whether antioxidant supplements are effective in preventing gastrointestinal cancers is contradictory.ObjectivesTo assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers.Search StrategyWe identified trials through the trials registers of the four Cochrane Review Groups on gastrointestinal diseases, The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 1, 2003), MEDLINE, EMBASE, LILACS, and SCI-EXPANDED from inception to February 2003, and The Chinese Biomedical Database (March 2003). We scanned reference lists and contacted pharmaceutical companies.Selection CriteriaRandomised trials comparing antioxidant supplements to placebo/no intervention examining the incidence of gastrointestinal cancers.Data Collection And AnalysisTwo reviewers independently selected trials for inclusion and extracted data. The outcome measures were incidence of gastrointestinal cancers, overall mortality, and adverse events. Outcomes were reported as relative risks (RR) with 95% confidence interval (CI) based on fixed and random effects meta-analyses.Main ResultsWe identified 14 randomised trials (170,525 participants), assessing beta-carotene (9 trials), vitamin A (4 trials), vitamin C (4 trials), vitamin E (5 trials), and selenium (6 trials). Trial quality was generally high. Heterogeneity was low to moderate. Neither the fixed effect (RR 0.96, 95% CI 0.88 to 1.04) nor random effects meta-analyses (RR 0.90, 95% CI 0.77 to 1.05) showed significant effects of supplementation with antioxidants on the incidences of gastrointestinal cancers. Among the seven high-quality trials reporting on mortality (131,727 participants), the fixed effect (RR 1.06, 95% CI 1.02 to 1.10) unlike the random effects meta-analysis (RR 1.06, 95% CI 0.98 to 1.15) showed that antioxidant supplements significantly increased mortality. Two low-quality trials (32,302 participants) found no significant effect of antioxidant supplementation on mortality. The difference between the mortality estimates in high- and low-quality trials was significant by test of interaction (z = 2.10, P = 0.04). Beta-carotene and vitamin A (RR 1.29, 95% CI 1.14 to 1.45) and beta-carotene and vitamin E (RR 1.10, 95% CI 1.01 to 1.20) significantly increased mortality, while beta-carotene alone only tended to do so (RR 1.05, 95% CI 0.99 to 1.11). Increased yellowing of the skin and belching were non-serious adverse effects of beta-carotene. In four trials (three with unclear/inadequate methodology), selenium showed significant beneficial effect on gastrointestinal cancer incidences.Reviewers' ConclusionsWe could not find evidence that antioxidant supplements prevent gastrointestinal cancers. On the contrary, they seem to increase overall mortality. The potential cancer preventive effect of selenium should be studied in adequately conducted randomised trials.

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