Elsevier

The Lancet

Volume 364, Issue 9441, 2–8 October 2004, Pages 1219-1228
The Lancet

Articles
Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis

https://doi.org/10.1016/S0140-6736(04)17138-9Get rights and content

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 supplements 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 β-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 mortality estimates in high-quality and low-quality trials was significant (Z=2·10, p=0·04 by test of interaction). β-carotene and vitamin A (1·29, 1·14–1·45) and β-carotene and vitamin E (1·10, 1·01–1·20) significantly increased mortality, whereas β-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.

Introduction

Oxidative stress can cause cancer.1, 2 The human diet is a complex mixture of oxidants and antioxidants. The gastrointestinal 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 programme9, 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 preventive effects of dietary supplementation with one or more selected antioxidants have been contradictory.15, 16, 17, 18 In this systematic review, including meta-analyses, we assess the beneficial and harmful effects of such antioxidant supplementation in the prevention of gastro-intestinal cancers.

Section snippets

Methods

We did this review by following the Cochrane Collaboration methodology19 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 (β-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

Role of the funding source

The funding sources had no role in the collection, analyses, interpretation of data, writing of the report, or decision to publish. The authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

We identified 681 references through database searches. After exclusion of duplicate and irrelevant references, we retrieved 116. Additionally, we identified 81 through scanning reference lists. Of these 197 references, we excluded 36 non-randomised trials, 11 describing six continuing trials, and 13 describing five trials that did not contain relevant data. The remaining 137 references, describing 14 trials,15, 16, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 fulfilled our inclusion criteria

Discussion

Our systematic review contains several major findings. β-carotene, vitamin A, vitamin C, and vitamin E supplements given alone or in combinations do not seem to have much effect in the prevention of gastrointestinal cancers. Further, these antioxidant supplements seem to increase overall mortality. Selenium might be an exception, potentially leading to reduction of gastrointestinal cancers, but this result might be biased because of low methodological quality in three of four trials. Compared

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