For personal use. Only reproduce with permission from Elsevier Ltd Articles Introduction Oxidative stress can cause cancer. 1,2 The human diet is a complex mixture of oxidants and antioxidants. The gastro- intestinal tract is thought to be the major site of antioxidant action. 3 The question of whether antioxidant supplements might protect against cancer has drawn much attention. 4,5 Oxidative injury might induce gene mutation and promote carcinogenesis. 6 In addition to the deleterious effects of reactive oxygen species on human cells, oxidative injury can lead to cell death (apoptosis). 7 Dysregulation of apoptosis has a role in gastrointestinal diseases, including cancer. 8 Oxidative stress can modulate the apoptotic programme 9,10 and could cause gastro-intestinal cancer. 11,12 Many observational epidemiological studies have shown that a high intake of fruit and vegetables (rich in antioxidants) is associated with a lower cancer incidence. 13,14 However, results of randomised trials looking at the possible pre- ventive effects of dietary supplementation with one or more selected antioxidants have been contradictory. 15–18 In this systematic review, including meta-analyses, we assess the beneficial and harmful effects of such anti- oxidant supplementation in the prevention of gastro- intestinal cancers. Methods We did this review by following the Cochrane Collabo- ration methodology 19 on the basis of our predefined, peer-reviewed, published Cochrane Hepato-Biliary Group protocol. 20 We included all trials that randomised participants to supplementation with antioxidants (-carotene, vitamins A, C, E, and selenium, as different combinations or separately) versus placebo, and reported the incidence of gastrointestinal cancers. 20 We included participants from the general population, mainly with non-gastrointestinal diseases, and at high risk of developing gastrointestinal cancers. 20 We identified trials from controlled-trial registers of the four Cochrane groups on gastrointestinal diseases (upper gastrointestinal and pancreatic diseases group; inflammatory bowel diseases group; colorectal cancer group; hepato-biliary group; February, 2003). We used the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 1, 2003; http://www.cochrane.org), MEDLINE (1966 to February, 2003), EMBASE (1985 to February, 2003), LILACS (1982 to February, 2003), Science Citation Index Expanded (1945 to February, 2003), and the Chinese Biomedical Database (from inception to Lancet 2004; 364: 1219–28 See Comment page 1193 The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, H:S Rigshospitalet, Copenhagen, Denmark (G Bjelakovic MD, D Nikolova MA, R G Simonetti MD, C Gluud MD); Department of Internal Medicine—Gastroenterology and Hepatology, Medical Faculty, University of Nis, Nis, Serbia and Montenegro (G Bjelakovic MD); and Divisione di Medicina, Ospedale V Cervello, Palermo, Italy (R G Simonetti MD) Correspondence to: Dr Goran Bjelakovic, Department of Internal Medicine— Gastroenterology and Hepatology, Medical Faculty, University of Nis, 18000 Nis, Serbia and Montenegro goranb@junis.ni.ac.yu www.thelancet.com Vol 364 October 2, 2004 1219 Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis Goran Bjelakovic, Dimitrinka Nikolova, Rosa G Simonetti, Christian Gluud Summary Background Oxidative stress can cause cancer. Our aim was to establish whether antioxidant supplements reduce the incidence of gastrointestinal cancer and mortality. Methods With the Cochrane Collaboration methodology, we reviewed all randomised trials comparing antioxidant sup- plements with placebo for prevention of gastrointestinal cancers. We searched electronic databases and reference lists (February, 2003). Outcome measures were incidence of gastrointestinal cancers, overall mortality, and adverse effects. Outcomes were analysed with fixed-effect and random-effects model meta-analyses and were reported as relative risk with 95% CIs. Findings We identified 14 randomised trials (n=170 525). Trial quality was generally high. Heterogeneity of results was low to moderate. Neither the fixed-effect (relative risk 0·96, 95% CI 0·88–1·04) nor random-effects meta- analyses (0·90, 0·77–1·05) showed significant effects of supplementation with -carotene, vitamins A, C, E, and selenium (alone or in combination) versus placebo on oesophageal, gastric, colorectal, pancreatic, and liver cancer incidences. In seven high-quality trials (n=131 727), the fixed-effect model showed that antioxidant significantly increased mortality (1·06, 1·02–1·10), unlike the random-effects meta-analysis (1·06, 0·98–1·15). Low-quality trials showed no significant effect of antioxidant supplementation on mortality. The difference between the mor- tality estimates in high-quality and low-quality trials was significant (Z=2·10, p=0·04 by test of interaction). -carotene and vitamin A (1·29, 1·14–1·45) and -carotene and vitamin E (1·10, 1·01–1·20) significantly increased mortality, whereas -carotene alone only tended to increase mortality (1·05, 0·99–1·11). In four trials (three with unclear or inadequate methodology), selenium showed significant beneficial effect on the incidence of gastrointestinal cancer. Interpretation We could not find evidence that antioxidant supplements can prevent gastrointestinal cancers; on the contrary, they seem to increase overall mortality. The potential preventive effect of selenium should be studied in adequate randomised trials.