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Antioxidant supplements for preventing gastrointestinal cancers (Review)

Bjelakovic G, Nikolova D, Simonetti RG, Gluud C

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2008, Issue 3 http://www.thecochranelibrary.com

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Antioxidants versus placebo, Outcome 1 Occurrence of gastrointestinal cancers in trials with a low or high risk of bias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 Antioxidants versus placebo, Outcome 2 Occurrence of gastrointestinal cancers - generation of the allocation sequence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.3. Comparison 1 Antioxidants versus placebo, Outcome 3 Occurrence of gastrointestinal cancers - allocation concealment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.4. Comparison 1 Antioxidants versus placebo, Outcome 4 Occurrence of gastrointestinal cancers - follow-up. Analysis 1.5. Comparison 1 Antioxidants versus placebo, Outcome 5 Occurrence of all gastrointestinal cancers - different antioxidants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.6. Comparison 1 Antioxidants versus placebo, Outcome 6 Occurrence of different gastrointestinal cancers - all antioxidants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.7. Comparison 1 Antioxidants versus placebo, Outcome 7 Occurrence of oesophageal cancer. . . . . . Analysis 1.8. Comparison 1 Antioxidants versus placebo, Outcome 8 Occurrence of gastric cancer. . . . . . . . Analysis 1.9. Comparison 1 Antioxidants versus placebo, Outcome 9 Occurrence of colorectal cancer. . . . . . Analysis 1.10. Comparison 1 Antioxidants versus placebo, Outcome 10 Occurrence of pancreatic cancer. . . . . Analysis 1.11. Comparison 1 Antioxidants versus placebo, Outcome 11 Occurrence of hepatocellular carcinoma. . . Analysis 1.12. Comparison 1 Antioxidants versus placebo, Outcome 12 Occurrence of biliary tract cancer. . . . . Analysis 1.13. Comparison 1 Antioxidants versus placebo, Outcome 13 Mortality in trials with a low or high risk of bias. Analysis 1.14. Comparison 1 Antioxidants versus placebo, Outcome 14 Mortality after excluding selenium trials. . . Analysis 1.15. Comparison 1 Antioxidants versus placebo, Outcome 15 Mortality - different antioxidants. . . . . Analysis 1.16. Comparison 1 Antioxidants versus placebo, Outcome 16 Adverse effects - beta-carotene. . . . . . Analysis 1.17. Comparison 1 Antioxidants versus placebo, Outcome 17 Adverse effects - vitamin E. . . . . . . Analysis 1.18. Comparison 1 Antioxidants versus placebo, Outcome 18 Adverse effects - selenium. . . . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 2 2 3 3 6 7 8 9 12 13 15 15 16 36 68 72 73 75 76 77 79 82 84 86 88 89 91 92 93 94 96 97 98 98 105 105 106 106 106 106 106

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

[Intervention Review]

Antioxidant supplements for preventing gastrointestinal cancers


Goran Bjelakovic1 , Dimitrinka Nikolova2 , Rosa G Simonetti3 , Christian Gluud2
1 Copenhagen Trial Unit, Centre for Clinical Intervention Research Department 3344, Rigshospitalet, Copenhagen University Hospital Copenhagen, Denmark. 2 Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research Copenhagen, Denmark. 3 Divisione di Medicina, Ospedale V.Cervello, Palermo, Italy

Contact address: Goran Bjelakovic, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Rigshospitalet, Department 3344, Blegdamsvej 9, Copenhagen, DK-2100, Denmark. goranb@junis.ni.ac.yu. Editorial group: Cochrane Hepato-Biliary Group. Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 3, 2008. Review content assessed as up-to-date: 11 November 2007. Citation: Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for preventing gastrointestinal cancers. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD004183. DOI: 10.1002/14651858.CD004183.pub3. Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Oxidative stress may cause gastrointestinal cancers. The evidence on whether antioxidant supplements are effective in preventing gastrointestinal cancers is contradictory. Objectives To assess the benecial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers. Search methods We identied 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. Selection criteria Randomised trials comparing antioxidant supplements to placebo/no intervention examining occurrence of gastrointestinal cancers. Data collection and analysis 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% condence interval (CI) based on random-effects and xed-effect model meta-analysis. Meta-regression assessed the effect of covariates across the trials. Main results We identied 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 signicant effects on gastrointestinal cancers (RR 0.94, 95% CI 0.83 to 1.06). However, there was signicant heterogeneity (I2 = 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
Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1

supplement (beta-carotene potentially increasing and selenium potentially decreasing cancer risk). The antioxidant supplements had no signicant effects on mortality in a random-effects model meta-analysis (RR 1.02, 95% CI 0.97 to 1.07, I2 = 53.5%), but signicantly increased mortality in a xed-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) signicantly increased mortality. Increased yellowing of the skin and belching were non-serious adverse effects of beta-carotene. In ve trials (four with high risk of bias), selenium seemed to show signicant benecial effect on gastrointestinal cancer occurrence (RR 0.59, 95% CI 0.46 to 0.75, I2 = 0%). Authors conclusions We could not nd 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.

PLAIN LANGUAGE SUMMARY Antioxidant supplements cannot be recommended for gastrointestinal cancer prevention Our body cannot synthesize all compounds that are essential for health. Therefore such compounds must be taken through diet. Oxidative stress may cause cell damage that is implicated in chronic diseases like cancer. Gastrointestinal cancers are among the most common cancers worldwide. The poor prognosis of patients diagnosed with gastrointestinal cancers made primary prevention a potentially attractive approach. The evidence on whether antioxidant supplements are effective in decreasing gastrointestinal cancers is contradictory. In this review prevention with antioxidant supplements of oesophageal, gastric, small intestinal, colorectal, pancreatic, liver, and biliary tract cancers is assessed. The review includes 20 randomised clinical trials. In total, 211,818 participants were randomised to antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo. Trial quality was exceptionally good. Based on properly designed and conducted randomised clinical trials, convincing evidence that beta-carotene, vitamin A, vitamin C, and vitamin E or their combinations may prevent gastrointestinal cancers is not found. A total of 2057 of 95084 participants (2.2%) randomised to antioxidant supplements and 1548 of 78935 participants (2.0%) randomised to placebo developed gastrointestinal cancers. These antioxidant supplements even seem to increase mortality. A total of 17114 of 122,501 participants (14.0%) randomised to antioxidant supplements and 8799 of 78693 participants (11.2%) randomised to placebo died. Selenium alone may have preventive effects on gastrointestinal cancers. This nding, however, is based on trials with aws in their design and needs conrmation in properly conducted randomised clinical trials.

BACKGROUND
Our body cannot synthesize all compounds that are essential for health. Therefore they must be taken through diet. Oxidative stress may cause cell damage that is implicated in chronic diseases like cancer (Sies 1985; Ames 1995). Antioxidants are compounds that can protect against oxidative stress (Diplock 1994; Poppel 1997; Papas 1999; Tamimi 2002; Willcox 2004). Laboratory and epidemiologic studies suggest a role of antioxidants in cancer prevention (Schrauzer 1977; Peto 1981). The possibility to improve health and prevent diseases by ameliorating excessive oxidative stress has attracted the attention of researchers in the last decades (Willcox 2004). Even though a healthy diet provides a sufcient amount of antioxidants, there are a number of people who regularly take antioxidant supplements (Balluz 2000; Millen 2004; Radimer 2004; Lichtenstein 2005; Nichter 2006). Gastrointestinal cancers Gastrointestinal cancers are among the most common cancers and the leading cause of cancer death worldwide (Ferlay 2004). The poor prognosis of patients diagnosed with gastrointestinal cancers made chemoprevention an attractive approach. It is, therefore, understandable that antioxidant prevention of gastrointestinal cancers has drawn much attention (Garcea 2003; Sharma 2004; Grau 2006). Oesophageal cancer is characterized by low likelihood of cure
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

(Enzinger 2003). Prevention is complicated by the fact that the two major histologic types, ie, squamous-cell carcinoma and adenocarcinoma, differ substantially (Fitzgerald 2006; Holmes 2007). The role of oxidative stress in the aetiology of two histological types of oesophageal cancer is unclear (Tzonou 1996; Terry 2000; Mayne 2001). Antioxidants were discussed as protective agents in studies of oesophageal squamous-cell carcinoma as well as Barretts oesophagus, a precancerous condition for oesophageal adenocarcinoma (Cheng 1996; Terry 2000; Sihvo 2002; Mehta 2005; Stoner 2007). Gastric cancer is the fourth most common cancer and second leading cause of cancer death in the world (Ferlay 2004). Helicobacter pylori is the important aetiological agent of gastric cancer (Sugiyama 2004). Eradication of Helicobacter pylori and chemoprevention with antioxidants emerged as alternative strategies in reducing the incidence and mortality of gastric cancer (Leung 2006; SIT 2006; Plummer 2007). Small intestinal cancers are rare (Neugut 1998), and prevention with antioxidant supplements has, according to our knowledge, not been extensively tested. Colorectal cancer is the third most common cancer worldwide (Ferlay 2004). It develops in multiple steps (Potter 1999). Most colorectal cancers arise from adenomas, as a result of a series of molecular changes that transform normal colonic epithelial cells into colorectal cancer (Janne 2000; Lynch 2002). The transition from normal mucosa to carcinoma offer opportunities for prevention (Gwyn 2002). Observational studies postulate that diet may be associated with colorectal cancer. A diet rich in antioxidants is claimed to be able to lower the risk of colorectal cancer (Boyle 1985; Bostick 1993; Kune 2006). Antioxidants were the rst agents evaluated in prevention of colorectal cancer (Grau 2006). However, antioxidant supplements have no signicant effect on primary or secondary prevention of colorectal adenoma (Bjelakovic 2006). Pancreatic cancer has a poor prognosis. Possible aetiologic factors for pancreatic cancer include chronic pancreatitis, smoking, diabetes, and other medical conditions (Lowenfels 2006). Chronic inammation, resulting in chronic phagocytic activity, one of the major endogenous sources of free radicals, is associated with cancer of several organs (Collins 1987; Shimoda 1994; Holzinger 1999). Experimental and observational studies have shown that antioxidants might be effective in the prevention of pancreatic cancer (Doucas 2006). Hepatocellular carcinoma incidence has increased over the last decades. Cirrhosis and aatoxins are the main risk factors for its development (Yates 2007). Viral or chemical damage to the liver results in oxidative damage that may inhibit apoptosis and promote hepatocarcinogenesis (Patel 1998; Tabor 1999; MacDonald 2001; Sasaki 2006). The liver is well endowed with antioxidant mechanisms to combat oxidative stress, including micronutrients, such

as vitamin E and vitamin C, and some enzymes that metabolise reactive metabolites and reactive oxygen species (Kaplowitz 2000). Whether additional antioxidant supplements could be benecial is not clear. The role of antioxidant supplements in preventing biliary tract cancers is not sufciently investigated. There are only a few experimental studies dealing with this question (Takeda 2002). Antioxidant supplements Vitamin A is essential for growth. Since cancer involves disturbances in normal tissue growth and differentiation, it was one of the rst vitamins to be evaluated with respect to carcinogenesis. Later studies indicated that protective effects were only observed for dietary vitamin A from plant sources (beta-carotene) (Peto 1981; Ziegler 1989). Vitamin C has antioxidative properties with possible cancer preventive potential (Hanck 1988). Vitamin E acts as a free radical scavenger to prevent lipid peroxidation of polyunsaturated fatty acids and block nitrosamine formation (Oshima 1982; Poppel 1997). Vitamin E supplementation can increase production of humoral antibodies and may have antitumour proliferation capacities, possibly by modulating gene expression (Knekt 1994). Selenium, a trace element, is also important for antioxidant defences of the body as an integral component of metalloprotein enzymes. It is a component of selenoproteins, which have important enzymatic functions (Hughes 2000; Rayman 2000). There is an inverse relationship between selenium intake and cancer mortality (Schrauzer 1977). In the USA, cancer mortality rates are signicantly higher in low selenium regions (Clark 1991). The evidence on whether antioxidant supplements are effective in decreasing gastrointestinal cancers is contradictory (Nomura 1987; Dawsey 1994; Yu 1997). We conducted a systematic Cochrane review on the issue published in 2004 and were unable to demonstrate convincing benecial effects of antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) on gastrointestinal cancers (Bjelakovic 2004a; Bjelakovic 2004b). Our results even suggested that these supplements, with the possible exception of selenium, may increase mortality (Bjelakovic 2004a; Bjelakovic 2004b). This present review is an update of the former review.

OBJECTIVES
To assess the benecial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers (oesophageal, gastric, small intestine, colorectal, pancreatic, liver, and biliary tract cancers).

METHODS
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Criteria for considering studies for this review

Search methods for identication of studies


The trials search co-ordinators of The Cochrane Colorectal Cancer Group, The Cochrane Hepato-Biliary Group, The Cochrane Inammatory Bowel Disease Group, and The Cochrane Upper Gastrointestinal and Pancreatic Diseases Group provided us with searches of their respective trials registers on antioxidant supplements and prevention of oesophageal, gastric, small intestinal, colorectal, pancreatic, liver, and biliary tract cancers. We also conducted electronic searches in the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 2, 2007), MEDLINE (1966 to October 2007), EMBASE (Excerpta Medica Database) (1985 to October 2007), LILACS (1982 to October 2007), the Science Citation Index Expanded (SCI-EXPANDED) (1945 to October 2007) (Royle 2003). All search strategies are given in Table 1. In addition, we obtained a search result in the Chinese Biomedical Database (1978 to October 2007). We scanned reference lists from review articles retrieved from the searches above in order to identify additional trials. We contacted DSM, Roche, Bristol-Meyers Squibb, BASF AIS, Hoechst, Bayer, Aventis, Takeda, and Lederle Laboratories, manufacturers of antioxidant supplements, to ask for unpublished randomised trials. Of these, Roche suggested some published trials, which we knew of. No other information was received.

Types of studies We included all randomised trials, irrespective of blinding, publication status, publication year, or language. Types of participants Adult participants (age 18 years or over) who were: participants from the general population irrespective of age, sex, or ethnic origin; or participants at high risk of developing gastrointestinal cancers (with premalignant conditions, or living in areas with high incidence of gastrointestinal cancers); or participants coming from other patient groups, primarily with non-gastrointestinal diseases. Types of interventions We considered for inclusion trials that compared antioxidant supplements (ie, beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) at any dose, duration, and route of administration versus placebo or no intervention. The antioxidants could have been administered: singly; or in any combination among themselves; or in combination with other vitamins; or in combination with trace elements without antioxidant function. Concomitant interventions were allowed if used equally in both intervention arms of the trial. Studies concerning antioxidant supplements in prevention of other organ system disease (cardiovascular, respiratory, urinary tract, etc.) were considered if data on the occurrence of gastrointestinal cancers during the trial could be obtained. Types of outcome measures Our primary outcome measures were: (1) Number of patients developing gastrointestinal cancers. We determined whether supplementation with antioxidants, administered separately or in combination, inuenced the incidences of any of the gastrointestinal cancers (oesophageal, gastric, small intestinal, colorectal, pancreatic, liver, and biliary tract cancers) and all gastrointestinal cancers combined. (2) Overall mortality. Our secondary outcome measures were: (3) Any adverse effects as reported in the trials. Incidence and types of adverse effects connected with the active intervention. (4) Quality-of-life measures. (5) Health economics.

Data collection and analysis


Inclusion criteria application We retrieved the identied material for assessment. GB and DN independently applied the inclusion criteria to all potential studies. We performed this without blinding. No discrepancy occurred in the trial selection. Data extraction Participant characteristics, diagnosis, and interventions We recorded the following data from the individual randomised trials: rst author; country of origin; country income category (low, middle, high) (World Bank 2006); number of participants; characteristics of participants: age range (mean or median) and sex ratio; participation rate; dropout rate; trial design (parallel or factorial); type of antioxidant; dose; duration of supplementation; duration of follow-up (ie, duration of intervention plus postintervention follow-up); co-interventions; and the occurrence of gastrointestinal cancers (oesophageal, gastric, small intestinal, colorectal, pancreatic, liver, and biliary tract cancers). Trial characteristics We recorded the date, location, sponsor of the trial (known or unknown and type of sponsor) as well as publication status. Assessment of methodological quality We assessed the methodological quality dened as the condence that the design and report restrict bias in the intervention comparison based on the randomisation, blinding, and follow-up (Schulz 1995; Moher 1998; Kjaergard 2001). The following denitions
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

were used: Generation of the allocation sequence Adequate, if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing of a coin, shufing of cards, or throwing dice was considered as adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure. Unclear, if the trial was described as randomised, but the method used for the allocation sequence generation was not described. Inadequate, if a system involving dates, names, or admittance numbers were used for the allocation of patients. Allocation concealment Adequate, if the allocation of patients involved a central independent unit, on-site locked computer, identically appearing numbered drug bottles or containers prepared by an independent pharmacist or investigator, or sealed envelopes. Unclear, if the trial was described as randomised, but the method used to conceal the allocation was not described. Inadequate, if the allocation sequence was known to the investigators who assigned participants or if the study was quasirandomised. Blinding (or masking) Adequate, if the trial was described as double blind and the method of blinding involved identical placebo or active drugs. Unclear, if the trial was described as double blind, but the method of blinding was not described. Not performed, if the trial was not double blind. Follow-up Adequate, if the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specied that there were no dropouts or withdrawals. Unclear, if the report gave the impression that there had been no dropouts or withdrawals, but this was not specically stated. Inadequate, if the number or reasons for dropouts and withdrawals were not described. Trials with adequate generation of the allocation sequence, adequate allocation concealment, adequate blinding, and adequate follow-up were considered low-bias risk trials (high methodological quality) (Kjaergard 2001; Gluud 2006a). Trials with one or more unclear or inadequate quality components were classied as high-bias risk trials (low methodological quality) (Kjaergard 2001; Gluud 2006a). We also reported on whether the investigators had performed a sample-size calculation and used intention-to-treat analysis (Gluud 2001). We used the classication of quality for sensitivity analyses and not as exclusion criteria.

Statistical analyses We performed the meta-analyses according to the recommendations of The Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2006). For the statistical analyses, we used RevMan Analyses (RevMan 2003), STATA 8.2 (STATA Corp, College Station, Tex), Sigma Stat 3.0 (SPSS Inc, Chicago, Ill), and Stats-Direct (StatsDirect Ltd, Altrincham, England). We analysed the data with both random-effects (DerSimonian 1986) and xed-effect (DeMets 1987) models meta-analyses. We present the results of the random-effects model analysis if the two models concur regarding statistical signicance (P < 0.05). If not, we present both analyses. Results are presented as the relative risk (RR) with 95% condence intervals (CI). We assessed heterogeneity with I2 , which describes the percentage of total variation across studies due to heterogeneity rather than chance (Higgins 2002). I 2 can be calculated as I2 = 100% (Q-df )/Q (Q = Cochrans heterogeneity statistics, df = degrees of freedom). I2 ranged between 0% (ie, no observed heterogeneity) and 100% (maximal heterogeneity) (Higgins 2002). We used the STATA metareg command (Sharp 1998) for the random-effects meta-regression analyses to assess potential covariates predicting intertrial heterogeneity, ie, the covariates that are statistically associated with estimated intervention effects. The included covariates were type and dose of supplement, duration of supplementation, bias risk (low or high), and primary or secondary prevention. Trials with participants coming from the general population, areas with high incidence of gastrointestinal cancers, and other patient groups with non-gastrointestinal diseases were considered primary prevention trials. Trials in participants with premalignant conditions of the gastrointestinal tract were considered secondary prevention trials. We performed univariate and multivariate analyses including all covariates. All our analyses followed the intention-to-treat principle. We accounted all of the participants for each trial and performed the analyses irrespective of how the original trialists had analysed the data. Participants lost to follow-up were considered survivors. For trials with a factorial design, we based our results on at-margins analysis, comparing all groups that received antioxidant supplements with groups that did not receive antioxidant supplements (McAlister 2003). To determine the effect of a single antioxidant we performed inside the table analysis (McAlister 2003) in which we compared the single antioxidant arm with the placebo/no intervention arm. In the trials with parallel group design with more than two arms and additional therapy, we compared only the arms supplemented with antioxidants with the placebo arm (Higgins 2006). Comparison of intervention effects was conducted with test of interaction (Altman 2003). We performed adjusted rank correlation (Begg 1994) and regression asymmetry test (Egger 1997) for detection of bias. A P < 0.10 was considered signicant.

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

RESULTS

Description of studies
See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies. Search results We identied a total of 1096 references through the four gastrointestinal disease Cochrane Groups (n = 90), the Cochrane Central Register of Controlled Trials in The Cochrane Library (n = 221), MEDLINE (n = 224), EMBASE (n = 269), LILACS (n = 75), Science Citation Index Expanded (SCI-expanded) (n = 96), the Chinese Biomedical Database (n = 36), and reading references (n = 85). We excluded 411 duplicates and 374 clearly irrelevant references through reading abstracts. Accordingly, 311 references were retrived for further assessment. Of these, we excluded 58 references because they did not fulll our inclusion criteria. Reasons for exclusion are listed in the table Characteristics of excluded studies. In total, 253 references describing 24 randomised trials fullled our inclusion criteria. Among these references, 11 references described 4 ongoing trials. These trials are listed under Characteristics of ongoing studies. The remaining 242 references, describing 20 trials, fullled our inclusion criteria and provided data for the analyses. Details of the trials are shown in the table Characteristics of included studies. Trial design Nine trials used factorial designs (one trial half replicate of twoby-two-by-two-by-two, 4 trials two-by-two-by-two, and 4 trials two-by-two) and 11 trials used the two- or more-armed parallel group trial designs. One two-by-two-by-two factorial trial proceeded as a two-by-two factorial trial. Two of the two-by-two factorial trials proceeded as two-armed trials (Pocock 1991) (Table 2). Participants

A total of 211,818 participants were randomised in the 20 trials. The number of participants in each trial ranged from 216 to 39876. We were not able to extract relevant data on the sex of the participants from two trials. The percentage of men was 58% of the trials reporting sex. The age varied from 18 to 84 years with a mean age of 56.5 years. There were ve trials with 122,411 participants from the general population (PHS 1996; ATBC 2003: CARET 2004; SUVIMAX 2004; WHS 2005), four trials (Munoz 1985; Yu 1991; NIT1 1993; Li 2004) with 37701 healthy participants living in areas at higher risk of developing gastrointestinal cancers, and four trials (NPCT 1996: HPS 2002; HOPE TOO 2005: WACS 2007) with 39560 participants with non-gastrointestinal diseases; all were considered as primary prevention trials. There were seven trials (NIT2 1993; Yu 1997; Correa 2000; Li 2000; Zhu 2003; SIT 2006: Plummer 2007) with 12102 participants with premalignant conditions of the gastrointestinal tract; these were considered as secondary prevention trials. Experimental interventions The route of antioxidant administration was oral for all the trials. Antioxidants were administered either alone, or in combination with other antioxidants, or with or without other vitamins, minerals or other interventions (Table 2). The types, doses, dose regimens, and duration of supplementation with antioxidants were as follows: beta-carotene 6 mg to 30 mg (12 trials), vitamin A 1500 g to 15000 g (4 trials), vitamin C 120 to 2000 mg (8 trials), vitamin E 30 to 600 mg (10 trials), daily or on alternate days for 1.1 to 12 years; selenium 50 to 228 g (9 trials), daily for two to four years (Figure 1). In one trial antioxidant supplements (vitamin A, riboavin, and zinc) were given once weekly (Munoz 1985). One trial administered beta-carotene 30 mg daily for the rst year and 30 mg two times a week for the second (Zhu 2003). One trial administered selenium 100 g on alternate days for one month of each year during two years (Li 2004).

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Figure 1. Recommended dietary allowance, tolerable upper intake level, experimental doses, and regimen used in antioxidant supplements

Beta-carotene, vitamin C, vitamin E, or selenium were administered as a single antioxidant supplement (Table 2). Beta-carotene, vitamin A, vitamin C, vitamin E, and selenium formed different combinations of antioxidant supplements only or were administered together with non-antioxidant supplements (Table 3 and Table 2). The administered combinations consisting only of antioxidant supplements were: beta-carotene and vitamin A; beta-carotene and vitamin C; beta-carotene and vitamin E; betacarotene, vitamin C, and vitamin E; vitamin C, vitamin E, and selenium; beta-carotene, vitamin C, and vitamin E, and selenium (see Characteristics of included studies and Table 2). Six trials added non-antioxidant vitamins, ie, vitamin B12 and folic acid (Zhu 2003), vitamin B6 , vitamin B12 , and folic acid (WACS 2007), or non-antioxidant vitamins and minerals (Munoz 1985; NIT1 1993; NIT2 1993; SUVIMAX 2004) to the experimental arms (see Characteristics of included studies and Table 2). Control interventions All trials used placebo capsules or tablets as control intervention. Concomitant interventions The factorial designs of the trials permitted other interventions to

be administered to some of the participants in the antioxidant experimental arms and in the control arms. Four trials primarily connected with the occurrence of cancers and cardiovascular diseases tested additional therapies: aspirin 100 mg to 325 mg, given daily or on alternate days (PHS 1996; WHS 2005); simvastatin (cholesterol lowering therapy) 40 mg (HPS 2002); or ramipril 10 mg (angiotensin-converting enzyme inhibitor) (HOPE TOO 2005). Two trials assessed anti-Helicobacter pylori interventions (Correa 2000; SIT 2006), two trials aged garlic extract 200 mg (Li 2004; SIT 2006), and one trial vitamin B6 50 mg, vitamin B12 1 mg, and folic acid 2.5 mg (WACS 2007) (Table 2). Outcome measures All 20 trials examined gastrointestinal cancers. We were able to extract relevant data on the incidence of gastrointestinal cancers from 18 trials. We were not able to extract data on the incidence of gastrointestinal cancers for each arm separately from one trial (NIT1 1993), and the authors did not respond to our requests for further information. The data from WACS 2007 are not yet available.

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Only 14 of the trials (70%) could provide data on overall mortality. Sponsorship Pharmaceutical companies were the provider or sponsor of antioxidant supplements in 17 trials. This information was not available in three trials (Yu 1991; Yu 1997; Li 2000). Roche was the sponsor or provider in 8 out of 17 trials (47%).

Risk of bias in included studies


For an overview of the methodological quality of the included trials see Figure 2. Figure 2. Table 05.Bias risk of the trials

Gastrointestinal cancers Twelve trials out of the 18 (66.7%) providing data on gastrointestinal cancers reported adequate generation of the allocation sequence, 13 trials (72.3%) reported adequate allocation concealment, 18 trials (100%) used placebo and hence had presumed adequate blinding, and 16 trials (88.9%) reported adequate follow-up. Twelve trials (66.7%) reported sample-size calculations. Twelve trials (66.7%) based their analyses on the intention-totreat principle. There were 12 trials (66.7%) of low-bias risk (high methodological quality) with adequate generation of the allocation sequence, allocation concealment, blinding, as well as follow-up.

Overall mortality Among the 14 trials providing data on mortality, thirteen (92.9%) were of low-bias risk (high methodological quality) with adequate generation of the allocation sequence, allocation concealment, blinding, as well as follow-up. The 14th trial had inadequate follow-up (NIT1 1993).

Effects of interventions
Gastrointestinal cancers Antioxidant supplements had no signicant inuence on gastrointestinal cancer occurrence (RR 0.94, 95% CI 0.83 to 1.06, I2 =
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

54.0%). Approximately 2.2% of the participants in the antioxidant group compared with 2.0% in the placebo group developed gastrointestinal cancers at the end of follow-up. Funnel plot asymmetry We analysed the antioxidant effect on gastrointestinal cancers for funnel plot asymmetry (Figure 3). From inspection of the gure, one may suspect bias. The asymmetry was statistically signicant (P = 0.009) by Eggers test and (P = 0.096) by Beggs test. Figure 3. Funnel plot - occurrence of gastrointestinal cancers

Meta-regression analysis Univariate meta-regression analyses revealed that the following covariates were signicantly associated with estimated intervention effect on the occurrence of the gastrointestinal cancers: dose of beta-carotene (RR 1.01, 95% CI 1.002 to 1.02; P = 0.012) and dose of selenium (RR 0.997, 95% CI 0.995 to 0.998, P < 0.0001). None of the other covariates (dose of vitamin A; dose of vitamin C; dose of vitamin E; bias risk of the trials; duration of supplementation; and primary or secondary prevention) were signicantly associated with estimated intervention effect on gastrointestinal cancers. In multivariate meta-regression analysis including all covariates,

dose of selenium was associated with a signicantly lower estimated intervention effect on the gastrointestinal cancers (RR 0.996, 95% CI 0.994 to 0.999; P = 0.007). None of the other covariates was signicantly associated with the estimated intervention effect on the gastrointestinal cancers. Methodological quality and antioxidant effect on gastrointestinal cancer occurrence The trials with low risk of bias (n = 12) did not show a signicant effect of antioxidant supplements on gastrointestinal cancers (RR 1.04, 95% CI 0.96 to 1.13, I2 = 19.6%). In the trials with high risk of bias (n = 6) antioxidant supplements signicantly de9

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

creased gastrointestinal cancers (RR 0.59, 95% CI 0.43 to 0.80, I2 = 18.1%). The difference between the estimates obtained by trials with adequate and unclear or inadequate methodology was statistically signicant by test of interaction (z = -3.53, P < 0.0005). Generation of the allocation sequence In the trials with adequate generation of the allocation sequence, antioxidant supplements did not signicantly inuence gastrointestinal cancers (RR 1.05, 95% CI 0.98 to 1.13, I2 = 0%). In the trials with unclear or inadequate generation of the allocation sequence, antioxidant supplements showed a signicant benecial effect on gastrointestinal cancers (RR 0.59, 95% CI 0.43 to 0.80, I2 = 18.1%). The difference between the estimates obtained by trials with adequate and unclear or inadequate generation of the allocation sequence was statistically signicant by test of interaction (z = -3.55, P < 0.0005). Allocation concealment In the trials with adequate allocation concealment, antioxidant supplements did not signicantly inuence gastrointestinal cancers (RR 1.05, 95% CI 0.98 to 1.13, I2 = 0%). In the trials with unclear or inadequate allocation concealment, antioxidant supplements showed a signicant benecial effect on gastrointestinal cancers (RR 0.57, 95% CI 0.41 to 0.78, I2 = 19.6%). The difference between the estimates obtained by trials with adequate and unclear or inadequate allocation concealment was statistically signicant by test of interaction (z = -3.64, P < 0.0003). Blinding Blinding was assumed adequate in all the 18 trials due to the use of placebo. Follow-up In the trials with adequate follow-up, antioxidant supplements did not signicantly inuence gastrointestinal cancers (RR 0.98, 95% CI 0.87 to 1.10, I2 = 49.8%). In the trials with unclear follow-up, antioxidant supplements showed no signicant effect on gastrointestinal cancers (RR 0.72, 95% CI 0.51 to 1.02, I2 = 0%). The difference between the estimates obtained by trials with adequate and unclear or inadequate follow-up was not statistically signicant by test of interaction (z = -1.65, P = 0.0989). Type of antioxidant supplement Beta-carotene (RR 1.04, 95% CI 0.80 to 1.35) or vitamin E (RR 1.11, 95% CI 0.93 to 1.34) given singly did not signicantly inuence gastrointestinal cancers. Different combinations of antioxidants, that is, beta-carotene and vitamin A; beta-carotene and vitamin C; beta-carotene and vitamin E; vitamin A, riboavin, and zinc; beta-carotene, vitamin C, and vitamin E; vitamin C, vitamin E, and selenium; beta-carotene, vitamin C, vitamin E, and selenium, or combinations of 26 vitamins/minerals did not significantly inuence gastrointestinal cancers (RR 1.10, 95% CI 0.91 to 1.32; RR 2.90, 95% CI 0.12 to 70.52; RR 1.18, 95% CI 0.98 to 1.41; RR 1.33, 95% CI 0.30 to 5.91; RR 0.96, 95% CI 0.80 to 1.16; RR 1.01, 95% CI 0.60 to 1.68; RR 0.83, 95% CI 0.53 to 1.32; RR 1.05, 95% CI 0.88 to 1.25; respectively). Selenium given singly signicantly decreased gastrointestinal cancers (RR

0.59, 95% CI 0.46 to 0.75, I2 = 0%). Selenium combined did not signicantly inuence gastrointestinal cancers (RR 1.02, 95% CI 0.87 to 1.19, I2 = 0%). Selenium given singly or combined signicantly decreased gastrointestinal cancers (RR 0.86, 95% CI 0.75 to 0.98, I2 = 60.8%). Five out of the nine trials assessing selenium had high-bias risk. The effect of selenium given singly or combined in 4 low-bias risk trials was not signicant (RR 0.89, 95% CI 0.68 to 1.18, I2 = 45.0%). For an overview of the effect of the different antioxidant supplements on different gastrointestinal cancers see (Table 3). Occurrence of oesophageal cancer Antioxidant supplements did not signicantly inuence oesophageal cancer (RR 1.06, 95% CI 0.89 to 1.28, I2 = 0%). Approximately 0.36% of the participants in the antioxidant group compared to 0.38% in the placebo group developed oesophageal cancer at the end of follow-up. Antioxidants administered singly, ie, beta-carotene (RR 0.75, 95% CI 0.25 to 2.30); vitamin E (RR 1.46, 95% CI 0.72 to 2.96); selenium (RR 0.40, 95% CI 0.08 to 2.07), or in certain combinations as beta-carotene and vitamin A (RR 1.43, 95% CI 0.90 to 2.29); beta-carotene and vitamin E (RR 1.23, 95% CI 0.59 to 2.56); vitamin A, riboavin, and zinc (RR 1.33, 95% CI 0.30 to 5.91); beta-carotene, vitamin C, and vitamin E (RR 1.19, 95% CI 0.71 to 2.01); beta-carotene, vitamin C, vitamin E and selenium (RR 1.01, 95% CI 0.14 to 7.16), or combination of 26 vitamins/minerals (RR 0.96, 95% CI 0.76 to 1.22) versus placebo for a period of 1.1 to 10.1 years, with a follow-up up to 14.1 years, did not signicantly inuence oesophageal cancer. Occurrence of gastric cancer Antioxidant supplements did not signicantly inuence gastric cancer (RR 1.14, 95% CI 0.97 to 1.33, I2 = 0%). Approximately 0.51% of the participants in the antioxidant group compared to 0.38% in the placebo group developed gastric cancer at the end of follow-up. Antioxidants administered singly, ie, beta-carotene (RR 1.12, 95% CI 0.79 to 1.59); vitamin E (RR 1.30, 95% CI 0.90 to 1.88); selenium (RR 0.76, 95% CI 0.44 to 1.31), or in certain combinations as beta-carotene and vitamin A (RR 0.89, 95% CI 0.46 to 1.73); beta-carotene and vitamin C (RR 2.90, 95% CI 0.12 to 70.52); beta-carotene and vitamin E (RR 1.40, 95% CI 0.98 to 2.01); beta-carotene, vitamin C, and vitamin E (RR 1.25, 95% CI 0.78 to 2.00); vitamin C, vitamin E, and selenium (RR 1.01, 95% CI 0.60 to 1.68); beta-carotene, vitamin C, vitamin E, and selenium (RR 1.01, 95% CI 0.14 to 7.16), or combination of 26 vitamins/minerals (RR 1.19, 95% CI 0.89 to 1.58) versus placebo for a period of 2.1 to 12 years and follow-up up to 14.1 years did not signicantly inuence gastric cancer. Occurrence of small intestine cancer Only one trial had results about small intestine cancer (WHS 2005). Antioxidant supplements did not signicantly inuence small intestine cancer (RR 4.00, 95% CI 0.45 to 35.79). Occurrence of colorectal cancer Antioxidant supplements did not signicantly inuence colorectal
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

cancer (RR 0.97, 95% CI 0.86 to 1.09, I2 = 19.7%). Approximately 1.07% of the participants in the antioxidant group compared to 1.09% in the placebo group developed colorectal cancer at the end of follow-up. Antioxidants administered singly, ie, betacarotene (RR 1,09 95%CI 0.79 to 1.51); vitamin E (RR 1.10, 95% CI 0.87 to 1.39); selenium (RR 0.48, 95% CI 0.22 to 1.05); or in combinations as beta-carotene and vitamin A (RR 0.97, 95% CI 0.76 to 1.25); beta-carotene and vitamin E (RR 1.20, 95% CI 0.89 to 1.63); beta-carotene, vitamin C, and vitamin E (RR 0.84, 95% CI 0.65 to 1.07); beta-carotene, vitamin C, vitamin E, and selenium (RR 0.88 95% CI 0.49 to 1.58) versus placebo for a period of 2.1 to 12 years and follow-up up to 14.1 years did not signicantly inuence colorectal cancer. Occurrence of pancreatic cancer Antioxidant supplements did not signicantly inuence pancreatic cancer (RR 1.16, 95% CI 0.90 to 1.50, I2 = 31.4%). Approximately 0.37% of the participants in the antioxidant group compared to 0.25% in the placebo group developed pancreatic cancer at the end of follow-up. Antioxidants administered singly, ie, beta-carotene (RR 1.02, 95% CI 0.54 to 1.90); vitamin E (RR 0.97, 95% CI 0.67 to 1.39); or in combinations as beta-carotene and vitamin A (RR 1.33, 95% CI 0.84 to 2.09); beta-carotene and vitamin E (RR 0.93, 95% CI 0.65 to 1.35); beta-carotene, vitamin C, and vitamin E (RR 1.00, 95% CI 0.57 to 1.76); beta-carotene, vitamin C, vitamin E, and selenium (RR 0.67, 95% CI 0.19 to 2.38) versus placebo for a period of 2.1 to 12 years and follow-up up to 14.1 years did not signicantly inuence pancreatic cancer. Occurrence of hepatocellular carcinoma Antioxidant supplements did not signicantly inuence hepatocellular carcinoma (RR 0.80, 95% CI 0.56 to 1.14, I2 = 38.5%). This effect was signicantly benecial in a xed-effect model (RR 0.76, 95% CI 0.60 to 0.96). Approximately 0.20% of the participants in the antioxidant group compared to 0.24% in the placebo group developed hepatocellular carcinoma at the end of followup. Beta-carotene administered singly (RR 1.92 95% CI 0.96 to 3.85), and vitamin E administered singly (RR 1.33, 95% CI 0.63 to 2.82) versus placebo for a period of 2 to 10.1 years and followup up to 14.1 years did not signicantly inuence hepatocellular

carcinoma. Antioxidants in combinations as beta-carotene and vitamin A (RR 1.35, 95% CI 0.51 to 3.54), beta-carotene and vitamin E (RR 1.25, 95% CI 0.59 to 2.67), beta-carotene, vitamin C, and vitamin E (RR 1.40, 95% CI 0.44 to 4.41), or beta-carotene, vitamin C, vitamin E, and selenium (RR 1.01, 95% CI 0.06 to 16.12) did not signicantly inuence hepatocellular carcinoma. Selenium administered singly versus placebo for two to four years signicantly decreased hepatocellular carcinoma (RR 0.56, 95% CI 0.42 to 0.76, I2 = 0%). All four trials assessing selenium singly had high-bias risk. Occurrence of biliary tract cancer Antioxidant supplements did not signicantly inuence biliary tract cancers (RR 0.61, 95% CI 0.21 to 1.78, I2 = 0%. Approximately 0.019% of the participants in the antioxidant group compared to 0.034% in the placebo group developed biliary tract cancers at the end of follow-up. Antioxidants administered in combination as beta-carotene, vitamin C, vitamin E, and selenium had no signicant inuence on biliary tract cancers (RR 0.20, 95% CI 0.01 to 4.20). Overall mortality Antioxidant supplements had no signicant effect on mortality in a random-effects model meta-analysis (RR 1.02, 95% CI 0.97 to 1.07, I2 = 54.9%). Antioxidant supplements signicantly increased mortality in the xed-effect model meta-analysis (RR 1.04, 95% CI 1.02 to 1.07). A total of 17114 of 122,501 participants (14.0%) that were randomised to antioxidant supplements and 8799 of 78693 participants (11.2%) randomised to placebo died. To explore the reason for the difference between the two models, we excluded the trials administering selenium. After their exclusion, mortality was signicantly higher in the antioxidant group with both the random-effects (RR 1.06, 95% CI 1.01 to 1.10, I 2 = 43.3%) and xed-effect model meta-analyses (RR 1.06, 95% CI 1.03 to 1.09). Funnel plot asymmetry We analysed the antioxidant effect on mortality for funnel plot asymmetry (Figure 4). The asymmetry was not statistically significant (P = 0.13) by Eggers test and (P = 0.15) by Beggs test.

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Figure 4. Funnel plot - overall mortality

Meta-regression analysis Univariate meta-regression analyses revealed that the following covariates were signicantly associated with estimated intervention effect on mortality: dose of beta-carotene (RR 1.007, 95% CI 1.002 to 1.012; P = 0.003), dose of vitamin A (RR 1.000006, 95% CI 1.000001 to 1.000011, P = 0.009), and dose of selenium (RR 0.998, 95% CI 0.997 to 0.999, P = 0.002). None of the other covariates, ie, dose of vitamin C; dose of vitamin E; bias risk of the trials; duration of supplementation; and primary or secondary prevention, were signicantly associated with estimated intervention effect on mortality. In multivariate meta-regression analysis including all covariates, dose of selenium was associated with the estimated intervention effect on mortality (RR 0.998, 95% CI 0.997 to 1.000, P = 0.043). None of the other covariates was signicantly associated with the estimated intervention effect on mortality. Methodological quality and antioxidant effect on overall mortality The effect of antioxidant supplements on mortality in trials with low risk of bias (high methodological quality) was not statistically signicant in a random-effects model meta-analysis (RR 1.03, 95% CI 0.98 to 1.08, I2 = 53.5%). Antioxidant supplements signicantly increased mortality in a xed-effect model meta-analysis (RR 1.05, 95% CI 1.02 to 1.07). In the one trial with high risk of

bias (NIT1 1993) antioxidant supplements did not signicantly inuence mortality (RR 0.94, 95% CI 0.84 to 1.06). The difference between the estimate of antioxidant effect in low-bias and high-bias risk trials was not signicant by test of interaction (z = 1.42, P = 0.156). Type of antioxidant supplement Antioxidants given singly, ie, beta-carotene (RR 1.05, 95% CI 0.99 to 1.11), vitamin C (RR 0.97, 95% CI 0.77 to 1.23); vitamin E (RR 1.02, 95% CI 0.98 to 1.06); and selenium (RR 0.84, 95% CI 0.67 to 1.07) did not signicantly inuence mortality. Betacarotene used singly signicantly increased mortality in a xed-effect model meta-analysis (RR 1.06, 95% CI 1.02 to 1.10). Mortality in participants supplemented with beta-carotene and vitamin A (RR 1.16, 95% CI 1.09 to 1.23), or beta-carotene and vitamin E (RR 1.06, 95% CI 1.02 to 1.11) was signicantly higher than in the placebo group. Antioxidants given in certain combinations, ie, beta-carotene and vitamin C (RR 2.79, 95% CI 0.57 to 13.68); beta-carotene, vitamin C, and vitamin E (RR 1.04, 95% CI 0.97 to 1.11); vitamin C, vitamin E, and selenium (RR 0.82, 95% CI 0.62 to 1.08); beta-carotene, vitamin C, vitamin E, and selenium (RR 0.78, 95% CI 0.58 to 1.05), or combination of 26 vitamins/ minerals (RR 0.94, 95% CI 0.85 to 1.05) versus placebo did not signicantly inuence mortality.

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Non-serious adverse effects Several adverse effects were recorded in the antioxidant group. Persistent yellowing of the skin and belching were signicantly increased in participants supplemented with beta-carotene (RR 29.14, 95% CI 21.60 to 39.32; RR 2.22, 95% CI 1.80 to 2.74; respectively). Transient yellowing of the skin (RR 1.85, 95% CI 0.74 to 4.67) and gastrointestinal upset (RR 1.03, 95% CI 1.00 to 1.06) were not signicantly inuenced. Haemorrhagic stroke was not signicantly inuenced by vitamin E (RR 1.01, 95% CI 0.82 to 1.23, I2 = 0%). Gastrointestinal upset in participants supplemented with selenium was not signicantly different when compared to placebo (RR 1.51, 95% CI 0.78 to 2.95). Increased yellowing of the urine and the feeling of being hot and dry in participants taking a combination of 13 vitamins and 13 minerals was also not signicantly different between the antioxidant and the placebo group. Quality of life and cost-effectiveness We did not nd any data on quality of life in the randomised trials included in this review. We found cost-effectiveness analyses in one trial (PHS 1996).

DISCUSSION
Compared to our previous review (Bjelakovic 2004a), the number of included trials in the present review is expanded with six new trials (42.9%) adding 41293 participants (24.2%). Moreover, we have obtained updated results of longer follow-up from three largescale randomised trials (ATBC 2003; CARET 2004; WHS 2005). Our results remain largely the same. Antioxidant supplements, ie, beta-carotene, vitamin A, vitamin C, and vitamin E given singly or in combinations, do not seem to prevent gastrointestinal cancers. Beta-carotene and vitamin A may increase the cancer risk. The studied antioxidants, other than selenium, also seem to increase overall mortality. Thus, the present results support our ndings from 47 low-bias risk trials showing increased mortality in participants undergoing primary or secondary prevention with similar antioxidant supplements (Bjelakovic 2007). Selenium might potentially reduce gastrointestinal cancers and mortality, but these observations run the risk of bias due to the low methodological quality of most of the assessed trials. Only one of the trials investigating selenium given as a single antioxidant had low-bias risk (NPCT 1996). Although several hypotheses have been explored, the mechanisms involved in the possible cancer preventive role of selenium are largely unknown (Rayman 2005; Papp 2007). Recently, a randomised trial has shown that selenium may carry health risks, eg, increasing the risk of diabetes mellitus (Stranges 2007). Before therapeutic or preventive actions are considered, results of ongoing high-quality randomised trials with selenium are needed (APPOSE 2001; SELECT 2003; HGPIN 2006).

Our review shows that beta-carotene possesses signicantly harmful effects on gastrointestinal cancers and seems to increase mortality when applied singly or in combination with vitamin A or vitamin E. A recent study suggests that beta-carotene may act as a co-carcinogen (Paolini 2003). In another review that we have performed, we have also demonstrated that beta-carotene seems to increase mortality (Bjelakovic 2007). We were unable to identify trials assessing vitamin A alone in the prevention of gastrointestinal cancers. The combination of beta-carotene and vitamin A was assessed in a high-quality, large-scale randomised trial having lung cancer prevention as the primary outcome (CARET 2004). Gastrointestinal cancer occurrence and overall mortality were signicantly higher in the vitamin A supplemented group. Recent research in this eld suggest that vitamin A might have pro-oxidant abilities, which could lead to carcinogenesis (Murata 2000) and may even increase mortality (Bjelakovic 2007). This nding was corroborated in the present systematic review. The trials in which vitamin C was applied alone or in different combinations with beta-carotene, vitamin A, vitamin E, and selenium found no signicant effect on gastrointestinal cancers, or on overall mortality. Vitamin E did not signicantly inuence gastric, pancreatic, and colorectal cancer or overall mortality. According to recent meta-analyses, vitamin E seems to increase overall mortality (Miller 2005; Bjelakovic 2007). Therefore, preventive use of vitamin E cannot be recommended. The bias risk of the trials had a signicant impact on our results. The low-bias risk trials either showed signicant harmful effects or no signicant effects of antioxidant supplements on the primary outcome measures. On the contrary, trials with high-bias risk found either no signicant effects or signicant benecial effects. These observations are in accordance with several studies linking high-bias risk with signicant overestimation of benecial effects (Schulz 1995; Moher 1998; Kjaergard 2001; Jni 2001; Egger 2003; Gluud 2006a; Gluud 2006b) and underreporting of adverse effects (DAmico 2003). Our meta-regression analysis failed to identify bias risk as associated with risk of cancer, but we observed that trials with high risk of bias found a decreased risk of cancer. We can only speculate what caused the signicantly higher mortality among the participants supplemented with antioxidants. Based on our present results as well as the results of previous randomised trials and meta-analysis it is likely that both cardiovascular diseases (ATBC 2003; Vivekananthan 2003) and cancers (ATBC 2003; CARET 2004) have led to increased mortality. We observed a nonsignicant tendency towards increased occurrence of gastrointestinal cancers in the supplemented group of low-bias risk trials (RR 1.04, 95% CI 0.96 to 1.13). Observational studies have shown possible detrimental effects of antioxidant supplements on cardiovascular mortality (Lee 2004), prostate cancer (Lawson 2007), and lung cancer (Slatore 2007). Cardiovascular diseases and cancers of the lung and gastrointestinal tract are the leading causes of death worldwide (Ferlay 2004; Lopez 2006; Mathers 2006). Reactive
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

oxygen species in moderate concentrations are essential mediators of reactions by which unwanted cells are deleted from the body. Schulz et al found that the inhibition of reactive oxygen species formation in cells decreases the life span of nematodes (Schulz 2007). Excessive suppression of free radicals may have unwanted consequences to our health (Salganik 2001). There are still many gaps in our knowledge of the mechanisms of bioavailability, biotransformation, and action of antioxidant supplements (Haenen 2002). Antioxidant supplements in pills are factory processed, biochemically unbalanced, and apparently unsafe compared to their naturally occurring counterparts (Herbert 1997; Seifried 2003). Antioxidant supplements also possess prooxidant effects (Podmore 1998; Paolini 1999; Murata 2000; Lee 2003; Duarte 2005). A balanced diet typically contains safe levels of antioxidant vitamins and trace elements (Camire 1999). Some of the trials included in our review investigated the effects of antioxidant supplements administered at doses signicantly higher than those found in a balanced diet. Some trials used dosages well above the recommended tolerable upper intake levels (Anonymous 2000a; Anonymous 2000b). The majority of the trials were conducted in middle- and high-income countries among populations with already sufcient levels of antioxidant vitamins and trace elements. This might be a cause for the lack of protective effects and for the increase in mortality of antioxidant supplements. For many years scientists have been concerned about possible harm caused by antioxidants (Herbert 1994; Schwartz 1996). However, large expectations and unconned belief in the cancer preventive potential of the antioxidants have overwhelmed these concerns. The available data on adverse effects of antioxidant supplements are still limited (Mulholland 2007) and often underreported (Woo 2007). Less than 1% of all adverse effects associated with antioxidant supplements are notied (Woo 2007). Consumers presume antioxidant supplements to be safe and use them without physicians supervision (Webb 2007). We nd that it is high time that antioxidant supplements are moved from the free over the counter market to the prescription regulatory market. Certain potential limitations of this review warrant consideration. We are dealing with a group of trials, which by the nature of their topic, that is, preventive efforts over a number of years, may have inherent mistakes. We found a number of inconsistencies among the different reports of the individual trials. We tried in all cases to obtain clarication from the authors. However, this was not always possible. Diagnostic criteria and timing of screening differed among the trials or were not always well dened. We have compared the intervention effects of antioxidants of different types and their inuence on different gastrointestinal cancers with different aetiology, biology, and epidemiology. Moreover, the examined populations varied. The effects of supplements were assessed in the general population, participants with premalignant conditions of gastrointestinal tract, and participants coming from other patient groups, primarily with non-gastrointestinal diseases. The variable

risk to develop cancer can inuence the results. These populations mostly came from countries without overt deciencies of specic supplements. Accordingly, we are unable to assess the inuence of antioxidant supplements on gastrointestinal cancer occurrence in populations with specic needs. In general, the risk of individual cancer was below 1%. This may make it difcult to detect any effects - benecial or harmful. The reporting of the occurrence of gastrointestinal cancers and overall mortality in the randomised trials was not always sufcient and consistent. Regarding gastrointestinal cancers, all included trials gave results. However, from one trial (NIT1 1993) we were unable to extract data for each arm separately. Data are awaited from another trial (WACS 2007). Of 20 trials included in our systematic review, only 14 (70%) reported overall mortality. We tried to obtain additional information from the authors but without success. Therefore, outcome reporting bias could inuence the result of our meta-analysis. Outcome reporting bias is dened as selective reporting of some results in trial publications and represent a threat to validity of meta-analysis (Chan 2004a; Chan 2004b; Chan 2005; Williamson 2005; Furukawa 2007). We are well aware of the difculties in collecting data on outcomes in clinical trials focusing on safety and efcacy evaluations. The worst result of outcome reporting bias and suppression of some signicant or non-signicant ndings could be the use of harmful interventions. Most of the included trials lacked detailed information on disease-specic causes of mortality as well as separate reporting of cancers according to sex. The choice of statistical model for performing meta-analysis is important. The xed-effect model meta-analysis assumes that the true intervention effect is the same in every randomised trial, ie, the effect is xed across trials. The random-effects model assumes that the effects being estimated based on the different randomised trials differ, but follow some general distribution. When there is no heterogeneity (I2 = 0%), then xed- and random-effects models meta-analyses tend to give the same result. If heterogeneity increases, the estimated intervention effect and the corresponding 95% condence interval will differ in the two models. The trials in the present review had clinical heterogeneity. This argues in favour of the random-effects model. The standard random-effects model used in RevMan Analysis is the DerSimonian and Laird method, which models the known differences between trials by incorporating a variance parameter tau to account for across-trial variation (DerSimonian 1986). Adoption of the random-effects model in meta-analysis permits inferences to a broader population of studies than the xed-effect model does namely because it includes the parameter tau in the model. The use of the random-effects model may come at a price. If there is between-trial heterogeneity, then the weight of the large trials (usually providing more realistic estimates of intervention effects) is reduced. At the same time, the weight of small trials (usually providing more unrealistic estimates of intervention effects due to bias (systematic errors) and chance
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

(random errors)) increases. Therefore, we also analysed our metaanalyses with the xed-effect model. We only examined certain antioxidant supplements that had been tested in randomised trials. Our results should not be translated to the potential effects of fruits and vegetables, which are rich not only in antioxidants but also in a number of other substances. In spite of intensive research, it is still not clear exactly which specic dietary constituents of fruits and vegetables might have anticarcinogenic properties. The results of randomised clinical trials on cancer prevention with high intake of fruits and vegetables are inconsistent and vary by cancer type and affected organ (Neuhouser 2003; Nouraie 2005). Recently published results of a randomised trial found non-signicant effect of high fruit and vegetable diet on colorectal adenoma recurrence (Lanza 2007). Results of epidemiologic studies differ signicantly too, reporting benecial or null effects (Larsson 2006; Freedman 2007; Koushik 2007; Kubo 2007; Takachi 2007). Our results are in accordance with the results of other recently published meta-analyses and systematic reviews (Caraballoso 2003; Vivekananthan 2003; Bjelakovic 2004a; Bjelakovic 2004b; Miller 2005; Bjelakovic 2006; Bjelakovic 2007), as well as recommendations of the United States Preventive Services Task Force and British Nutrition Foundation for the use of vitamin supplementation (McKevith 2003; Morris 2003; USPSTF 2003).

have to be elucidated. Randomised clinical trials with selenium are ongoing and further trials may be needed. The signicant association between unclear or inadequate methodological quality and overestimation of intervention effects has again focused on the need for more objective assessment of preventive and therapeutic interventions. National and international laws and regulations should require that anything sold to the public claiming health benets is subjected to adequate assessment of benets and harms before market release. We suggest that antioxidant supplements should be regulated as drugs. Researches wishing to examine the inuence of antioxidant supplements on gastrointestinal cancers or other diseases should adopt the CONSORT statement while performing and reporting randomised clinical trials (CONSORT - Consolidated Standards of Reporting Trials: www.consort-statement.org).

ACKNOWLEDGEMENTS
We extend our gratitude to all participants in the randomised clinical trials. We thank Ronald L. Koretz, Contact Editor of The CHBG for very helpful comments on the review. We thank Mike Clarke, The Director of The UK Cochrane Centre; David Forman, The Co-ordinating Editor of The Cochrane Upper Gastrointestinal and Pancreatic Diseases Group; John McDonald, The Coordinating Editor of The Cochrane Inammatory Bowel Disease Group, and Peer Wille-Jrgensen, The Co-ordinating Editor of The Cochrane Colorectal Cancer Group for their expert comments during preparation of the protocol. We thank Yan Gong and Bodil Als-Nielsen for useful advice and comments, Yan Gong and Wendong Chen for translation of Chinese articles, and Maoling Wei, The Chinese Cochrane Centre, for performing searches on the Chinese Database and providing us with some articles. We are grateful to Jarmo Virtamo, Nea Malila, Julie Buring, Nancy Cook, Pelayo Correa, John A Baron, Howard Sesso, Serge Hercberg, Mark Thornquist, Matt Barnett, Gary Goodman, I-Min Lee, Martyn Plummer and Mitchell H. Gail for the information on the trials they were involved in.

AUTHORS CONCLUSIONS Implications for practice


There is no convincing evidence that the studied antioxidant supplements have benecial effect on the occurrence of gastrointestinal cancers or on overall mortality. Beta-carotene, vitamin A, vitamin C, and/or vitamin E seem to increase overall mortality. Therefore, we cannot recommend the use of these antioxidant supplements as a preventive measure.

Implications for research


Selenium may potentially possess benecial effects on gastrointestinal cancers. The potential anticarcinogenic effects of selenium

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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REFERENCES

References to studies included in this review


ATBC 2003 {published data only} Albanes D, Heinonen OP, Huttunen JK, Taylor PR, Virtamo J, Edwards BK, et al.Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. American Journal of Clinical Nutrition 1995;62(6 Suppl): 1427s30s. [MEDLINE: 7495243] Albanes D, Heinonen OP, Taylor PR, Virtamo J, Edwards BK, Rautalahti M, et al.Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the alphatocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. Journal of the National Cancer Institute 1996;88(21):156070. [MEDLINE: 8901854] Albanes D, Malila N, Taylor PR, Huttunen JK, Virtamo J, Edwards BK, et al.Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: results from a controlled trial (Finland). Cancer Causes & Control 2000;11 (3):197205. [MEDLINE: 10782653] Blumberg J. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study in Finland. Nutrition Reviews 1994;52(7): 24250. [MEDLINE: 8090376] Freedman DM, Tangrea JA, Virtamo J, Albanes D. The effect of beta-carotene supplementation on serum vitamin D metabolite concentrations. Cancer Epidemiology, Biomarkers & Prevention 1999;8(12):11156. [MEDLINE: 10613346] Hartman TJ, Dorgan JF, Woodson K, Virtamo J, Tangrea JA, Heinonen OP, et al.Effects of long-term alphatocopherol supplementation on serum hormones in older men. Prostate 2001;46(1):338. [MEDLINE: 11170129] Leppala JM, Virtamo J, Fogelholm R, Huttunen JK, Albanes D, Taylor PR, et al.Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers. Arteriosclerosis Thrombosis and Vascular Biology 2000;20(1):2305. [MEDLINE: 10634823] Liede KE, Haukka JK, Saxen LM, Heinonen OP. Increased tendency towards gingival bleeding caused by joint effect of alpha-tocopherol supplementation and acetylsalicylic acid. Annals of Medicine 1998;30(6):5426. [MEDLINE: 9920356] Malila N, Taylor PR, Virtanen MJ, Korhonen P, Huttunen JK, Albanes D, et al.Effects of alpha-tocopherol and betacarotene supplementation on gastric cancer incidence in male smokers (ATBC Study, Finland). Cancer Causes & Control 2002;13(7):61723. [MEDLINE: 12296509] Malila N, Virtamo J, Virtanen M, Albanes D, Tangrea J, Huttunen J. The effect of alpha-tocopherol and betacarotene supplementation on colorectal adenomas in middle-aged male smokers. Cancer Epidemiology, Biomarkers & Prevention 1999;8(6):48993. [MEDLINE: 10385137] Malila N, Virtamo J, Virtanen M, Pietinen P, Albanes D, Teppo L. Dietary and serum alpha-tocopherol, betacarotene and retinol, and risk for colorectal cancer in male

smokers. European Journal of Clinical Nutrition 2002;56(7): 61521. [MEDLINE: 12080400] Michaud DS, Pietinen P, Taylor PR, Virtanen M, Virtamo J, Albanes D. Intakes of fruits and vegetables, carotenoids and vitamins A, E, C in relation to the risk of bladder cancer in the ATBC cohort study. British Journal of Cancer 2002; 87(9):9605. [MEDLINE: 12434284] Rautalahti MT, Virtamo JR, Taylor PR, Heinonen OP, Albanes D, Haukka JK, et al.The effects of supplementation with alpha-tocopherol and beta-carotene on the incidence and mortality of carcinoma of the pancreas in a randomized, controlled trial. Cancer 1999;86(1):3742. [MEDLINE: 10391561] Stolzenberg-Solomon RZ, Blaser MJ, Limburg PJ, PerezPerez G, Taylor PR, Virtamo J, et al.Helicobacter pylori seropositivity as a risk factor for pancreatic cancer. Journal of the National Cancer Institute 2001;93(12):93741. [MEDLINE: 11416115] Teikari JM, Laatikainen L, Rapola JM, Virtamo J, Haukka J, Liesto K, et al.Retinal vascular changes following supplementation with alpha-tocopherol or beta-carotene. Acta Ophthalmologica Scandinavica 1998;76(1):6873. [MEDLINE: 9541437] Teikari JM, Laatikainen L, Virtamo J, Haukka J, Rautalahti M, Liesto K, et al.Six-year supplementation with alphatocopherol and beta-carotene and age-related maculopathy. Acta Ophthalmologica Scandinavica 1998;76(2):2249. [MEDLINE: 9591958] Teikari JM, Rautalahti M, Haukka J, Jarvinen P, Hartman AM, Virtamo J, et al.Incidence of cataract operations in Finnish male smokers unaffected by alpha tocopherol or beta carotene supplements. Journal of Epidemiology and Community Health 1998;52(7):46872. [MEDLINE: 9799882] The ATBC Cancer Prevention Study Group. The AlphaTocopherol, Beta-Carotene Lung Cancer Prevention Study: design, methods, participant characteristics, and compliance. Annals of Epidemiology 1994;4(1):110. [MEDLINE: 8205268] The ATBC Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. New England Journal of Medicine 1994;330(15):102935. [MEDLINE: 8127329] Tornwall ME, Virtamo J, Haukka JK, Albanes D, Huttunen JK. Alpha-tocopherol (vitamin E) and beta-carotene supplementation does not affect the risk for large abdominal aortic aneurysm in a controlled trial. Atherosclerosis 2001; 157(1):16773. [MEDLINE: 11427217] Tornwall ME, Virtamo J, Haukka JK, Aro A, Albanes D, Huttunen JK. The effect of alpha-tocopherol and betacarotene supplementation on symptoms and progression of intermittent claudication in a controlled trial. Atherosclerosis 1999;147(1):1937. [MEDLINE: 10525141] Tornwall ME, Virtamo J, Korhonen PA, Virtanen MJ, Albanes D, Huttunen JK. Postintervention effect of alpha
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

tocopherol and beta carotene on different strokes: a 6year follow-up of the Alpha Tocopherol, Beta Carotene Cancer Prevention Study. Stroke 2004;35(8):190813. [MEDLINE: 15205487] Varis K, Sipponen P, Laxen F, Samloff IM, Huttunen JK, Taylor PR, et al.Implications of serum pepsinogen I in early endoscopic diagnosis of gastric cancer and dysplasia. Helsinki Gastritis Study Group. Scandinavian Journal of Gastroenterology 2000;35(9):9506. [MEDLINE: 11063155] Varis K, Taylor PR, Sipponen P, Samloff IM, Heinonen OP, Albanes D, et al.Gastric cancer and premalignant lesions in atrophic gastritis: a controlled trial on the effect of supplementation with alpha-tocopherol and beta-carotene. The Helsinki Gastritis Study Group. Scandinavian Journal of Gastroenterology 1998;33(3):294300. [MEDLINE: 9548624] Virtamo J, Edwards BK, Virtanen M, Taylor PR, Malila N, Albanes D, et al.Effects of supplemental alpha-tocopherol and beta-carotene on urinary tract cancer: incidence and mortality in a controlled trial (Finland). Cancer Causes & Control 2000;11(10):9339. [MEDLINE: 11142528] Virtamo J, Pietinen P, Huttunen JK, Korhonen P, Malila N, Virtanen MJ, et al.Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA 2003;290(4):47685. [MEDLINE: 12876090] Woodson K, Tangrea JA, Barrett MJ, Virtamo J, Taylor PR, Albanes D. Serum alpha-tocopherol and subsequent risk of lung cancer among male smokers. Journal of the National Cancer Institute 1999;91(20):173843. [MEDLINE: 10528024] CARET 2004 {published data only} Alfano CM, Klesges RC, Murray DM, Bowen DJ, McTiernan A, Vander Weg MW, et al.Physical activity in relation to all-site and lung cancer incidence and mortality in current and former smokers. Cancer Epidemiology, Biomarkers & Prevention 2004;13(12): 223341. [MEDLINE: 15598785] Aliyu OA, Cullen MR, Barnett MJ, Balmes JR, Cartmel B, Redlich CA, et al.Evidence for excess colorectal cancer incidence among asbestos-exposed men in the beta-carotene and retinol efcacy trial. American Journal of Epidemiology 2005;162(9):86878. [MEDLINE: 16177148] Barnhart S, Keogh J, Cullen MR, Brodkin C, Liu D, Goodman G, et al.The CARET asbestos-exposed cohort: baseline characteristics and comparison to other asbestosexposed cohorts. American Journal of Industrial Medicine 1997;32(6):57381. [MEDLINE: 9358912] Bowen DJ, Thornquist M, Anderson K, Barnett M, Powell C, Goodman G, et al.Stopping the active intervention: CARET. Controlled Clinical Trials 2003;24(1):3950. [MEDLINE: 12559641] Brodkin CA, McCullough J, Stover B, Balmes J, Hammar S, Omenn GS, et al.Lobe of origin and histologic type of lung cancer associated with asbestos exposure in the Carotene and Retinol Efcacy Trial (CARET). American Journal of

Industrial Medicine 1997;32(6):58291. [MEDLINE: 9358913] Cartmel B, Dziura J, Cullen MR, Vegso S, Omenn GS, Goodman GE, et al.Changes in cholesterol and triglyceride concentrations in the Vanguard population of the Carotene and Retinol Efcacy Trial (CARET). European Journal of Clinical Nutrition 2005;59(10):117380. [MEDLINE: 16015255] Challem JJ. Re: Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efcacy Trial. Journal of the National Cancer Institute 1997;89(4):3256. [MEDLINE: 9048840] Chuwers P, Barnhart S, Blanc P, Brodkin CA, Cullen M, Kelly T, et al.The protective effect of beta-carotene and retinol on ventilatory function in an asbestos-exposed cohort. American Journal of Respiratory and Critical Care Medicine 1997;155(3):106671. [MEDLINE: 9116988] Cullen MR, Barnett MJ, Balmes JR, Cartmel B, Redlich CA, Brodkin CA, et al.Predictors of lung cancer among asbestos-exposed men in the beta-carotene and retinol efcacy trial. American Journal of Epidemiology 2005;161 (3):16070. [MEDLINE: 15671258] Goodman GE, Omenn GS. Carotene and retinol efcacy trial: lung cancer chemoprevention trial in heavy cigarette smokers and asbestos-exposed workers. CARET Coinvestigators and Staff. Advances in Experimental Medicine and Biology 1992;320:13740. [MEDLINE: 1442278] Goodman GE, Omenn GS, Thornquist MD, Lund B, Metch B, Gylys-Colwell I. The Carotene and Retinol Efcacy Trial (CARET) to prevent lung cancer in high-risk populations: pilot study with cigarette smokers. Cancer Epidemiology, Biomarkers & Prevention 1993;2(4):38996. [MEDLINE: 8348063] Goodman GE, Schaffer S, Omenn GS, Chen C, King I. The association between lung and prostate cancer risk, and serum micronutrients: results and lessons learned from Beta-Carotene and Retinol Efcacy Trial. Cancer Epidemiology, Biomarkers & Prevention 2003;12(6):51826. [MEDLINE: 12814997] Goodman GE, Thornquist M, Kestin M, Metch B, Anderson G, Omenn GS. The association between participant characteristics and serum concentrations of betacarotene, retinol, retinyl palmitate, and alpha-tocopherol among participants in the Carotene and Retinol Efcacy Trial (CARET) for prevention of lung cancer. Cancer Epidemiology, Biomarkers & Prevention 1996;5(10):81521. [MEDLINE: 8896893] Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens FL Jr, Omenn GS, et al.The Beta-Carotene and Retinol Efcacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. Journal of the National Cancer Institute 2004;96(23): 174350. [MEDLINE: 15572756] Goodman GE, Valanis B, Meyskens FL Jr, Williams JH Jr, Metch BJ, Thornquist MD, et al.Strategies for recruitment
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

to a population-based lung cancer prevention trial: the CARET experience with heavy smokers. Beta-Carotene and Retinol Efcacy Trial. Cancer Epidemiology, Biomarkers & Prevention 1998;7(5):40512. [MEDLINE: 9610790] King IB, Kristal AR, Schaffer S, Thornquist M, Goodman GE. Serum trans-fatty acids are associated with risk of prostate cancer in Beta-Carotene and Retinol Efcacy Trial. Cancer Epidemiology, Biomarkers & Prevention 2005;14(4): 98892. [MEDLINE: 15824175] Leo MA, Lieber CS. Re: Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efcacy Trial. Journal of the National Cancer Institute 1997;89(22):17223. [MEDLINE: 9390543] Neuhouser ML, Patterson RE, Thornquist MD, Omenn GS, King IB, Goodman GE. Fruits and vegetables are associated with lower lung cancer risk only in the placebo arm of the Beta-Carotene and Retinol Efcacy Trial (CARET). Cancer Epidemiology, Biomarkers & Prevention 2003;12(4):3508. [MEDLINE: 12692110] Neuhouser ML, Patterson RE, Thornquist MD, Omenn GS, King IB, Goodman GE. Fruits and vegetables are associated with lower lung cancer risk only in the placebo arm of the Beta-Carotene and Retinol Efcacy Trial (CARET). Cancer Epidemiology, Biomarkers & Prevention 2003;12(4):3508. [MEDLINE: 12692110] Omenn GS. CARET, the Beta-Carotene and Retinol Efcacy Trial to prevent lung cancer in high-risk populations. Public Health Reviews 1991;19(1-4):2058. [MEDLINE: 1844268] Omenn GS, Goodman G, Grizzle J, Thornquist M, Rosenstock L, Barnhart S, et al.CARET, the Beta-Carotene and Retinol Efcacy Trial to prevent lung cancer in asbestosexposed workers and in smokers. Anticancer Drugs 1991;2 (1):7986. [MEDLINE: 1958856] Omenn GS, Goodman G, Grizzle J, Thornquist M, Rosenstock L, Barnhart S, et al.Recruitment for the Beta-Carotene and Retinol Efcacy Trial (CARET) to prevent lung cancer in smokers and asbestos-exposed workers. Western Journal of Medicine 1992;156(5):5404. [MEDLINE: 1595284] Omenn GS, Goodman G, Thornquist M, Barnhart S, Balmes J, Cherniack M, et al.Chemoprevention of lung cancer: the Beta-Carotene and Retinol Efcacy Trial (CARET) in high-risk smokers and asbestos-exposed workers. IARC Scientic Publications 1996;136:6785. [MEDLINE: 8791118] Omenn GS, Goodman G, Thornquist M, Grizzle J, Rosenstock L, Barnhart S, et al.The Beta-Carotene and Retinol Efcacy Trial (CARET) for chemoprevention of lung cancer in high risk populations: smokers and asbestosexposed workers. Cancer Research 1994;54(7 Suppl): 2038s43s. [MEDLINE: 8137335] Omenn GS, Goodman GE, Thornquist M, Brunzell JD. Long-term vitamin A does not produce clinically signicant hypertriglyceridemia: results from CARET, the BetaCarotene and Retinol Efcacy Trial. Cancer Epidemiology, Biomarkers & Prevention 1994;3(8):7113. [MEDLINE:

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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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JE. Male pattern baldness and coronary heart disease: the Physicians Health Study. Archives of Internal Medicine 2000;160(2):16571. [MEDLINE: 10647754] Lotufo PA, Lee IM, Ajani UA, Hennekens CH, Manson JE. Cigarette smoking and risk of prostate cancer in the Physicians Health Study (United States). International Journal of Cancer 2000;87(1):1414. [MEDLINE: 10861465] Ma J, HennekensCH, Ridker PM, Stampfer MJ. A prospective study of brinogen and risk of myocardial infarction in the Physicians Health Study. Journal of the American College of Cardiology 1999;33(5):134752. [MEDLINE: 10193737] Morris MC, Manson JE, Rosner B, Buring JE, Willett WC, Hennekens CH. Fish consumption and cardiovascular disease in the physicians health study: a prospective study. American Journal of Epidemiology 1995;142(2):16675. [MEDLINE: 7598116] Perera FP, Mooney L A, Stampfer M, Phillips DH, Bell DA, Rundle A, et al.Associations between carcinogen-DNA damage, glutathione S-transferase genotypes, and risk of lung cancer in the prospective Physicians Health Cohort Study. Carcinogenesis 2002;23(10):16416. [MEDLINE: 12376472] Physicians Health Study Research Group. Peliminary report: ndings from the aspirin component of the ongoing Physicians Health Study. New England Journal of Medicine 1988;318(4):2624. Sattereld S, Greco PJ, Goldhaber SZ, Stampfer MJ, Swartz SL, Stein EA, et al.Biochemical markers of compliance in the Physicians Health Study. American Journal of Preventive Medicine 1990;6(5):2904. [MEDLINE: 2268456] Sesso HD, Gaziano JM, VanDenburgh M, Hennekens CH, Glynn RJ, Buring JE. Comparison of baseline characteristics and mortality experience of participants and nonparticipants in a randomized clinical trial: the Physicians Health Study. Controlled Clinical Trials 2002;23 (6):686702. [MEDLINE: 12505246] Steering Committee of the Physicians Health Study Research Group. Final report on the aspirin component of the ongoing Physicians Health Study. New England Journal of Medicine 1989;321(3):12935. [MEDLINE: 2664509] Sturmer T, Glynn RJ, Lee IM, Christen WG, Hennekens CH. Lifetime cigarette smoking and colorectal cancer incidence in the Physicians Health Study I. Journal of the National Cancer Institute 2000;92(14):117881. [MEDLINE: 10904092] Tang D, Phillips DH, Stampfer M, Mooney LA, Hsu Y, Cho S, et al.Association between carcinogen-DNA adducts in white blood cells and lung cancer risk in the Physicians Health Study. Cancer Research 2001;61(18):670812. [MEDLINE: 11559540] Vieth R. Dairy products, calcium, and prostate cancer risk in the Physicians Health Study. American Journal of Clinical Nutrition 2002;76(2):4901. [MEDLINE: 12145029] Plummer 2007 {published data only} de Sanjose S, Munoz N, Sobala G, Vivas J, Peraza S, Cano
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Clinical Endocrinology 2000;52(3):2738. [MEDLINE: 10718824] Bellisle F, Altenburg de Assis MA, Fieux B, Preziosi P, Galan P, Guy-Grand B, et al.Use of light foods and drinks in French adults: biological, anthropometric and nutritional correlates. Journal of Human Nutrition and Dietetics 2001; 14(3):191206. [MEDLINE: 11424511] Bertrais S, Galan P, Renault N, Zarebska M, Preziosi P, Hercberg S. Consumption of soup and nutritional intake in French adults: consequences for nutritional status. Journal of Human Nutrition and Dietetics 2001;14(2):1218. [MEDLINE: 11330261] Bertrais S, Polo Luque ML, Preziosi P, Fieux B, Torra De Flot M, Galan P, et al.Contribution of ready-to-eat cereals to nutrition intakes in French adults and relations with corpulence. Annals of Nutrition & Metabolism 2000;44(56):24955. [MEDLINE: 11146332] Bertrais S, Preziosi P, Mennen L, Galan P, Hercberg S, Oppert JM. Sociodemographic and geographic correlates of meeting current recommendations for physical activity in middle-aged French adults: the Supplementation en Vitamines et Mineraux Antioxydants (SUVIMAX) Study. American Journal of Public Health 2004;94(9):15606. [MEDLINE: 15333315] Boini S, Briancon S, Guillemin F, Galan P, Hercberg S. Impact of cancer occurrence on health-related quality of life: a longitudinal pre-post assessment. Health and Quality of Life Outcomes 2004;2(1):4. [MEDLINE: 14715085] Bruckert E, Czernichow S, Bertrais S, Paillard F, Tichet J, Galan P, et al.Blood lipid and lipoprotein levels: relationships with educational level and region of residence in the French SU.VI.MAX study. Preventive Medicine 2005; 40(6):80311. [MEDLINE: 15850882] Cailhol J, Czernichow S, Mennen L, Boutron-Ruault MC, Zarebska M, Franchisseur C, et al.Participation and medical follow-up in screening of colorectal cancer in France within the SU.VI.MAX study [Dpistage du cancer colorectal par test Hmoccult : taux de participation et prise en charge mdicale des sujets test positif au sein de ltude SU.VI.MAX]. Revue dEpidmiologie et de Sant Publique 2002;50(3):3213. [MEDLINE: 12122348] Chango A, Potier De Courcy G, Boisson F, Guilland JC, Barbe F. 5,10-methylenetetrahydrofolate reductase common mutations, folate status and plasma homocysteine in healthy French adults of the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) cohort. The British Journal of Nutrition 2000;84(6):8916. [MEDLINE: 11177206] Czernichow S, Bertrais S, Oppert JM, Galan P, Blacher J, Ducimetiere P, et al.Body composition and fat repartition in relation to structure and function of large arteries in middle-aged adults (the SU.VI.MAX study). International Journal of Obesity and Related Metabolic Disorders 2005;29 (7):82632. [MEDLINE: 15917850] Czernichow S, Bertrais S, Preziosi P, Galan P, Hercberg S, Oppert JM, et al.Indicators of abdominal adiposity in middle-aged participants of the SU.VI.MAX study:
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

relationships with educational level, smoking status and physical inactivity. Diabetes & Metabolism 2004;30(2): 1539. [MEDLINE: 15223987] Czernichow S, Mennen L, Bertrais S, Preziosi P, Hercberg S, Oppert JM. Relationships between changes in weight and changes in cardiovascular risk factors in middle-aged French subjects: effect of dieting. International Journal of Obesity and Related Metabolic Disorders 2002;26(8): 113843. [MEDLINE: 12119581] Derumeaux H, Valeix P, Castetbon K, Bensimon M, Boutron-Ruault MC, Arnaud J, et al.Association of selenium with thyroid volume and echostructure in 35- to 60-yearold French adults. European Journal of Endocrinology 2003; 148(3):30915. [MEDLINE: 12611611] Duport N, Preziosi P, Boutron-Ruault MC, Bertrais S, Galan P, Favier A, et al.Consequences of iron depletion on health in menstruating women. European Journal of Clinical Nutrition 2003;57(9):116975. [MEDLINE: 12947438] Galan P, Arnaud MJ, Czernichow S, Delabroise AM, Preziosi P, Bertrais S, et al.Contribution of mineral waters to dietary calcium and magnesium intake in a French adult population. Journal of the American Dietetic Association 2002;102(11):165862. [MEDLINE: 12449291] Galan P, Briancon S, Favier A, Bertrais S, Preziosi P, Faure H, et al.Antioxidant status and risk of cancer in the SU.VI.MAX study: is the effect of supplementation dependent on baseline levels?. British Journal of Nutrition 2005;94(1):12532. [MEDLINE: 12484233] Galan P, Favier A, Preziosi P, Bertrais S, Arnault N, Hercberg S. The bank of biological material in the SU.VI.MAX study [La biothque dans ltude SU.VI.MAX]. Revue dEpidemiologie et de Sante Publique 2003;51(1 Pt 2): 14750. [MEDLINE: 12684572] Galan P, Preziosi P, Durlach V, Valeix P, Ribas L, Bouzid D, et al.Dietary magnesium intake in a French adult population. Magnesium Research 1997;10(4):3218. [MEDLINE: 9513928] Galan P, Renault N, Aissa M, Adad HA, Rahim B, Potier de Courcy G, et al.Relationship between soup consumption, folate, beta-carotene, and vitamin C status in a French adult population. International Journal for Vitamin and Nutrition Research 2003;73(5):31521. [MEDLINE: 14639794] Galan P, Viteri FE, Bertrais S, Czernichow S, Faure H, Arnaud J, et al.Serum concentrations of beta-carotene, vitamins C and E, zinc and selenium are inuenced by sex, age, diet, smoking status, alcohol consumption and corpulence in a general French adult population. European Journal of Clinical Nutrition 2005;59(10):118190. [MEDLINE: 16034362] Galan P, Yoon HC, Preziosi P, Viteri F, Valeix P, Fieux B, et al.Determining factors in the iron status of adult women in the SU.VI.MAX study. SUpplementation en VItamines et Mineraux AntioXydants. European Journal of Clinical Nutrition 1998;52(6):3838. [MEDLINE: 9683388] Gauthier-Chelle K, Mennen L, Arnault N, Rigalleau V, Hercberg S, Gin H. Comparison of the diet of self-declared diabetics with non-diabetic patients in the SU.VI.MAX

study: did the diabetics modify their nutritional behavior?. Diabetes & Metabolism 2004;30(6):53542. [MEDLINE: 15671923] Guinot C, Latreille J, Malvy D, Preziosi P, Galan P, Hercberg S, et al.Use of multiple correspondence analysis and cluster analysis to study dietary behaviour: food consumption questionnaire in the SU.VI.MAX. cohort. European Journal of Epidemiology 2001;17(6):50516. [MEDLINE: 11949721] Guinot C, Malvy DJ, Latreille J, Ezzedine K, Galan P, Tenenhaus M, et al.Sun-reactive skin type in 4912 French adults participating in the SU.VI.MAX. Photochemistry and Photobiology 2005;81(4):93440. [MEDLINE: 15850423] Hercberg S. Antioxidant micronutrients and chronic degenerative pathology: the role of complementary nutritional doses. Bulletin et Memoires de lAcademie Royale de Medecine de Belgique 1997;152(10-11):37985. [MEDLINE: 9627441] Hercberg S, Bertrais S, Czernichow S, Noisette N, Galan P, Jaouen A, et al.Alterations of the lipid prole after 7.5 years of low-dose antioxidant supplementation in the SU.VI.MAX Study. Lipids 2005;40(4):33542. [MEDLINE: 16032784] Hercberg S, Galan P, Preziosi P, Bertrais S, Mennen L, Malvy D, et al.The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Archives of Internal Medicine 2004; 164(21):233542. [MEDLINE: 15557412] Hercberg S, Galan P, Preziosi P, Malvy M, Briancon S, Ait HM, et al.The SU.VI.MAX trial on antioxidants. IARC Scientic Publications 2002;156:4515. [MEDLINE: 12484233] Hercberg S, Galan P, Preziosi P, Roussel AM, Arnaud J, Richard MJ, et al.Background and rationale behind the SU.VI.MAX Study, a prevention trial using nutritional doses of a combination of antioxidant vitamins and minerals to reduce cardiovascular diseases and cancers. SUpplementation en VItamines et Mineraux AntioXydants Study. International Journal for Vitamin and Nutrition Research 1998;68(1):320. [MEDLINE: 9503043] Hercberg S, Hebel P, Preziosi P, Briancon S, Favier A, Galan P, et al.Motivations of volunteers for participation in an interventional study in the eld of nutritional prevention: results of a pilot study of the SU.VI.MAX project. Revue dEpidemiologie et de Sante Publique 1995;43(2):13946. [MEDLINE: 7732200] Hercberg S, Preziosi P, Briancon S, Galan P, Triol I, Malvy D, et al.A primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers in a general population: the SU.VI.MAX study-design, methods, and participant characteristics. SUpplementation en VItamines et Mineraux AntioXydants. Controlled Clinical Trials 1998;19(4):33651. [MEDLINE: 9683310] Hercberg S, Preziosi P, Galan P, Faure H, Arnaud J, Duport N, et al.The SU.VI.MAX Study: a primary prevention trial using nutritional doses of antioxidant
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

vitamins and minerals in cardiovascular diseases and cancers. SUpplementation on VItamines et Mineraux AntioXydants. Food and Chemical Toxicology 1999;37(9-10):92530. [MEDLINE: 10541446] Lairon D, Bertrais S, Vincent S, Arnault N, Galan P, Boutron MC, et al.Dietary bre intake and clinical indices in the French Supplementation en Vitamines et Mineraux AntioXydants (SU.VI.MAX) adult cohort. The Proceedings of the Nutrition Society 2003;62(1):115. [MEDLINE: 12740051] Leclere J. Multinodular goiters. La Revue du Praticien 2005; 55(2):16773. [MEDLINE: 15825997] Lukasiewicz E, Mennen LI, Bertrais S, Arnault N, Preziosi P, Galan P, et al.Alcohol intake in relation to body mass index and waist-to-hip ratio: the importance of type of alcoholic beverage. Public Health Nutrition 2005;8(3): 31520. [MEDLINE: 15918929] Malkin JE, Morand P, Malvy D, Ly TD, Chanzy B, de Labareyre C, et al.Seroprevalence of HSV-1 and HSV2 infection in the general French population. Sexually Transmitted Infections 2002;78(3):2013. [MEDLINE: 12238654] Malvy DJ, Favier A, Faure H, Preziosi P, Galan P, Arnaud J, et al.Effect of two years supplementation with natural antioxidants on vitamin and trace element status biomarkers: preliminary data of the SU.VI.MAX study. Cancer Detection and Prevention 2001;25(5):47985. [MEDLINE: 11718454] Malvy J, Guinot C, Preziosi P, Vaillant L, Tenenhaus M, Galan P, et al.Epidemiologic determinants of skin photoaging: baseline data of the SU.VI.MAX. cohort. Journal of the American Academy of Dermatology 2000;42(1 pt 1):4755. [MEDLINE: 10607319] Mennen LI, Bertrais S, Galan P, Arnault N, Potier de Couray G, Hercberg S. The use of computerised 24 h dietary recalls in the French SU.VI.MAX Study: number of recalls required. European Journal of Clinical Nutrition 2002;56(7):65965. [MEDLINE: 12080407] Mennen LI, Sapinho D, de Bree A, Arnault N, Bertrais S, Galan P, et al.Consumption of foods rich in avonoids is related to a decreased cardiovascular risk in apparently healthy French women. The Journal of Nutrition 2004;134 (4):9236. [MEDLINE: 15051848] Meyer F, Galan P, Douville P, Bairati I, Kegle P, Bertrais S, et al.Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial. International Journal of Cancer 2005;116(2):1826. [MEDLINE: 15800922] Mohammed-Cherif S, Briancon S, Potier de Courcy G, Preziosi P, Fieux B, Zarebska M, et al.Factors determining the use of hormone replacement therapy in recent naturally postmenopausal women participating in the French SU.VI.MAX cohort. European Journal of Epidemiology 2000;16(5):47782. [MEDLINE: 10997836] Preziosi P, Czernichow S, Gehanno P, Hercberg S. Workplace air-conditioning and health services attendance among French middle-aged women: a prospective cohort

study. International Journal of Epidemiology 2004;33(5): 11203. [MEDLINE: 15319412] Rouillier P, Boutron-Ruault MC, Bertrais S, Arnault N, Daudin JJ, Bacro JN, et al.Alcohol and atherosclerotic vascular disease risk factors in French men: relationships are linear, J-shaped, and U-shaped. Alcoholism, Clinical and Experimental Research 2005;29(1):848. [MEDLINE: 15654296] Rouillier P, Boutron-Ruault MC, Bertrais S, Arnault N, Daudin JJ, Bacro JN, et al.Drinking patterns in French adult men - a cluster analysis of alcoholic beverages and relationship with lifestyle. European Journal of Nutrition 2004;43(2):6976. [MEDLINE: 15083313] Valeix P, Dos Santos C, Castetbon K, Bertrais S, Cousty C, Hercberg S. Thyroid hormone levels and thyroid dysfunction of French adults participating in the SU.VI.MAX study [Statut thyrodien et frquences des dysthyrodies chez les adultes inclus dans ltude SU.VI.MAX en 19941995]. Annales dEndocrinologie 2004;65(6):47786. [MEDLINE: 15731735] Valeix P, Zarebska M, Bensimon M, Cousty C, Bertrais S, Galan P, et al.Ultrasonic assessment of thyroid nodules, and iodine status of French adults participating in the SU.VI.MAX study [Nodules thyrodiens lchographie et statut en iode des adultes volontaires de ltude SU.VI.MAX]. Annales dEndocrinologie 2001;62(6): 499506. [MEDLINE: 11845024] Vazquez Martinez C, Galan P, Preziosi P, Ribas L, Serra LL, Hercberg S. The SUVIMAX (France) study: the role of antioxidants in the prevention of cancer and cardiovascular disorders. Revista Espanola de Salud Publica 1998;72(3): 17383. [MEDLINE: 9810825] Vercherin P, Gutknecht C, Guillemin F, Ecochard R, Mennen LI, Mercier M. Missing data mechanisms of the questionnaire SF-36s items in the SU.VI.MAX study [Nonrponses aux questionnaires de qualit de vie SF36 dans un chantillon de ltude SU.VI.MAX]. Revue dEpidmiologie et de Sant Publique 2003;51(5):51325. [MEDLINE: 14657798] Vuillemin A, Boini S, Bertrais S, Tessier S, Oppert JM, Hercberg S, et al.Leisure time physical activity and healthrelated quality of life. Preventive Medicine 2005;41(2): 5629. [MEDLINE: 15917053] Vuillemin A, Oppert JM, Guillemin F, Essermeant L, Fontvieille AM, Galan P, et al.Self-administered questionnaire compared with interview to assess past-year physical activity. Medicine and Science in Sports and Exercise 2000;32(6):111924. [MEDLINE: 10862539] Zureik M, Galan P, Bertrais S, Mennen L, Czernichow S, Blacher J, et al.Effects of long-term daily low-dose supplementation with antioxidant vitamins and minerals on structure and function of large arteries. Arteriosclerosis, Thrombosis, and Vascular Biology 2004;24(8):148591. [MEDLINE: 15217803] WACS 2007 {published data only} Bassuk SS, Albert CM, Cook NR, Zaharris E, MacFadyen JG, Danielson E, et al.The Womens Antioxidant
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Cardiovascular Study: design and baseline characteristics of participants. Journal of Womens Health 2004;13(1):99117. [MEDLINE: 15006283] Cook NR, Albert CM, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, et al.A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Womens Antioxidant Cardiovascular Study. Archives of Internal Medicine 2007;167(15):16108. [MEDLINE: 17698683] Manson JE, Gaziano JM, Spelsberg A, Ridker PM, Cook NR, Buring JE, et al.A secondary prevention trial of antioxidant vitamins and cardiovascular disease in women. Rationale, design, and methods. The WACS Research Group. Annals of Epidemiology 1995;5(4):2619. [MEDLINE: 8520707] Mason PJ, Manson JE, Sesso HD, Albert CM, Chown MJ, Cook NR, et al.Blood pressure and risk of secondary cardiovascular events in women: the Womens Antioxidant Cardiovascular Study (WACS). Circulation 2004;109(13): 16239. [MEDLINE: 15023883] WHS 2005 {published data only} Buring JE, Hennekens CH. The Womens Health Study: rationale and background. The Journal of Myocardial Ischemia 1992;4(3):3040. Buring JE, Hennekens CH. The Womens Health Study: summary of study design. The Journal of Myocardial Ischemia 1992;4(3):279. Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker PM, Manson JE, et al.Low-dose aspirin in the primary prevention of cancer: the Womens Health Study: a randomized controlled trial. JAMA 2005;294(1):4755. [MEDLINE: 15998890] Karlson EW, Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. Comparison of self-reported diagnosis of connective tissue disease with medical records in female health professionals: the Womens Health Cohort Study. American Journal of Epidemiology 1999;150(6):65260. [MEDLINE: 10490005] Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, et al.Vitamin E in the primary prevention of cardiovascular disease and cancer: the Womens Health Study: a randomized controlled trial. JAMA 2005;294(1): 5665. [MEDLINE: 15998891] Lee IM, Cook NR, Manson JE, Buring JE. Randomized beta-carotene supplementation and incidence of cancer and cardiovascular disease in women: is the association modied by baseline plasma level. British Journal of Cancer 2002;86 (5):698701. [MEDLINE: 11875728] Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. Randomised beta-carotene supplementation and incidence of cancer and cardiovascular disease in women: the Womens Health Study. Journal of the National Cancer Institute 1999; 91:21026. [MEDLINE: 11875728] Liu S, Manson JE, Lee IM, Cole SR, Hennekens CH, Willett WC, et al.Fruit and vegetable intake and risk of cardiovascular disease: the Womens Health Study.

American Journal of Clinical Nutrition 2000;72(4):9228. [MEDLINE: 11010932] Rexrode KM, Lee IM, Cook NR, Hennekens CH, Buring JE. Baseline characteristics of participants in the Womens Health Study. Journal of Womens Health and Gender Based Medicine 2000;9(1):1927. [MEDLINE: 10718501] Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et al.A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. New England Journal of Medicine 2005;352(13):1293304. [MEDLINE: 15753114] Yu 1991 {published data only} Yu SY, Zhu YJ, Li WG, Huang QS, Huang CZ, Zhang QN, et al.A preliminary report on the intervention trials of primary liver cancer in high-risk populations with nutritional supplementation of selenium in China. Biological Trace Element Research 1991;29(3):28994. [MEDLINE: 1726411] Yu 1997 {published data only} Yu SY, Zhu YJ, Li WG. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biological Trace Element Research 1997;56:11724. [MEDLINE: 97297046] Zhu 2003 {published data only} Zhu S, Mason J, Shi Y, Hu Y, Li R, Wahg M, et al.The effect of folic acid on the development of stomach and other gastrointestinal cancers. Chinese Medical Journal 2003;116 (1):159. [MEDLINE: 12667380] Zhu S, Mason J, Shi Y, Hu Y, Li R, Wang M, et al.The interventional effect of folic acid on the development of gastric and other gastrointestinal cancers -Clinical trial and follow-up for seven years. Chinese Journal of Gastroenterology 2002; Vol. 7, issue 2:738.

References to studies excluded from this review


Bespalov 2004 {published data only} Berspalov VG, Shcherbakov AM, Kalinovskii VP, Novik VI, Chepik OF, Aleksandrov VA, et al.Study of the antioxidant drug Karinat in patients with chronic atrophic gastritis [Izucenie antioksidatnogo preparata Karinat kak sredstva dla lecenih boljnih s hroniceskim atroceskim gastritom]. Voprosii Onkologii 2004;50(1):815. [MEDLINE: 15088527] Bostick 1993 {published data only} Bostick RM, Potter JD, McKenzie DR, Sellers TA, Kushi LH, Steinmetz KA, et al.Reduced risk of colon cancer with high intake of vitamin E: the Iowa Womens Health Study. Cancer Research 1993;53(18):42307. [MEDLINE: 8364919] Bukin 1996 {published data only} Bukin YV, Poddubniy BK, Kuvshinov YP, DraudinKrylenko VA, Shabanov MA. The effects of certain vitamins and natural anti-oxidants on ornithine decarboxylase activity and on atrophic and premalignant changes in the human gastric mucosa. Digestive Endoscopy 1996;8(3): 18491. [MEDLINE: 1996267562]
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Bussey 1982 {published data only} Bussey HJ, DeCosse JJ, Deschner EE, Eyers AA, Lesser ML, Morson BC, et al.A randomized trial of ascorbic acid in polyposis coli. Cancer 1982;50(7):14349. [MEDLINE: 7049351] Chuang 2002 {published data only} Chuang CH, Sheu BS, Huang AH, Yang HB, Wu JJ. Vitamin C and E supplements to lansoprazole-amoxicillinmetronidazole triple therapy may reduce the eradication rate of metronidazole-susceptible Helicobacter pylori infection. Helicobacter 2002;7(5):3106. [MEDLINE: 12390211] De Stefani 1999 {published data only} De Stefani E, Ronco A, Mendilaharsu M, Deneo-Pellegrini H. Diet and risk of cancer of the upper aerodigestive tractII. Nutrients. Oral Oncology 1999;35(1):226. De Stefani 1999a {published data only} De Stefani E, Deneo-Pellegrini H, Mendilaharsu M, Ronco A. Diet and risk of cancer of the upper aerodigestive tractI. Foods. Oral Oncology 1999;35(1):1721. [MEDLINE: 10211305] De Stefani 2000 {published data only} De Stefani E, Brennan P, Boffetta P, Ronco AL, Mendilaharsu M, Deneo-Pellegrini H. Vegetables, fruits, related dietary antioxidants, and risk of squamous cell carcinoma of the esophagus: a case-control study in Uruguay. Nutrition and Cancer 2000;38(1):239. DeCosse 1975 {published data only} DeCosse JJ, Adams MB, Kuzma JF, LoGerfo P, Condon RE. Effect of ascorbic acid on rectal polyps of patients with familial polyposis. Surgery 1975;78(5):60812. [MEDLINE: 1188603] De Cosse JJ, Adams MB, Kuzma JF, Lo Gerfo P, Condon RE. Effect of ascorbic acid on rectal polyps of patients with familial polyposis. Wisconsin Medical Journal 1976;75(1): S8. [MEDLINE: 1246900] DeCosse 1989 {published data only} DeCosse JJ, Miller HH, Lesser ML. Effect of wheat ber and vitamins C and E on rectal polyps in patients with familial adenomatous polyposis. Journal of the National Cancer Institute 1989; Vol. 81, issue 17:12907. ECP-IM 1994 {published data only} Reed PI. The ECP-IM intervention study. European Journal of Cancer Prevention 1994;3(Suppl 2):99104. [MEDLINE: 7735056] Reed PI, Johnston BJ. Primary prevention of gastric cancer - The ECP-IM intervention study. Acta Endoscopica 1995; 25(1):4554. EUROSCAN 2000 {published data only} van Zandwijk N, Dalesio O, Pastorino U, de-Vries N, van Tinteren H. EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the European Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. Journal of the National Cancer Institute 2000;92(12):97786. [MEDLINE: 10861309]

Frank 1995 {published data only} Frank E. The Women Physicians Health Study: background, objectives, and methods. Journal of the American Medical Womens Association 1995;50(2):646. [MEDLINE: 7722210] Greenberg 1990 {published data only} Greenberg ER, Baron JA, Stukel TA, Stevens MM, Mandel JS, Spencer SK, et al.A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin. The Skin Cancer Prevention Study Group. New England Journal of Medicine 1990;323(12):78995. [MEDLINE: 2202901] Ishikawa 1995 {published data only} Ishikawa H, Akedo I, Suzuki T, Otani T, Sobue T. Interventional trial for colorectal cancer prevention in Osaka: an introduction to the protocol. Japanese Journal of Cancer Research 1995;86(8):70710. [MEDLINE: 7559090] Jacobs 2001 {published data only} Jacobs EJ, Connell CJ, Patel AV, Chao A, Rodriguez C, Seymour J, et al.Vitamin C and vitamin E supplement use and colorectal cancer mortality in a large American Cancer Society cohort. Cancer Epidemiology Biomarkers and Prevention 2001;10(1):1723. [MEDLINE: 11205484] Jansen 1999 {published data only} Jansen MC, Bueno de Mesquita HB, Buzina R, Fidanza F, Menotti A, Blackburn H, et al.Dietary ber and plant foods in relation to colorectal cancer mortality: the Seven Countries Study. International Journal of Cancer 1999;81 (2):1749. [MEDLINE: 10188715] Ji 1995 {published data only} Ji BT, Chow WH, Gridley G, Mclaughlin JK, Dai Q, Wacholder S, et al.Dietary factors and the risk of pancreatic cancer: a case-control study in Shanghai China. Cancer Epidemiology, Biomarkers & Prevention 1995;4(8):88593. [MEDLINE: 8634662] Kirk 2006 {published data only} Kirk GR, White JS, McKie L, Stevenson M, Young I, Clements WD, et al.Combined antioxidant therapy reduces pain and improves quality of life in chronic pancreatitis. Journal of Gastrointestinal Surgery 2006;10(4):499503. [MEDLINE: 16627214] Krishnaswamy 1993 {published data only} Krishnaswamy K, Prasad MPR, Krishna TP, Pasricha S. A case-control study of selenium in cancer. Indian Journal of Medical Research 1993;98:1248. La Vecchia 2002 {published data only} La Vecchia C. Tomatoes, lycopene intake, and digestive tract and female hormone-related neoplasms. Experimental Biology and Medicine 2002;227(10):8603. Lacroix 1987 {published data only} Lacroix A, Bhat PV, Karabatsos A, Couture P, Latreille J, Beaulieu R, et al.Plasma levels of retinol in cancer patients supplemented with retinol. Oncology 1987;44(2):10814. [MEDLINE: 3554082]
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Lanza 1996 {published data only} Lanza E, Schatzkin A, Ballard-Barbash R, Corle D, Clifford C, Paskett E, et al.The polyp prevention trial II: dietary intervention program and participant baseline dietary characteristics. Cancer Epidemiology, Biomarkers & Prevention 1996;5(5):38592. [MEDLINE: 9162305] Lanza 2001 {published data only} Lanza E, Schatzkin A, Daston C, Corle D, Freedman L, Ballard-Barbash R, et al.Implementation of a 4-Y, highber, high-fruit-and-vegetable, low-fat dietary intervention: results of dietary changes in the Polyp Prevention Trial. American Journal of Clinical Nutrition 2001;74(3):387401. Levi 2000 {published data only} Levi F, Pasche C, Lucchini F, La Vecchia C. Selected micronutrients and colorectal cancer: case-control study from the Canton of Vaud, Switzerland. European Journal of Cancer 2000;36(16):21159. [MEDLINE: 11044650] Limburg 2005 {published data only} Limburg PJ, Wei W, Ahnen DJ, Qiao Y, Hawk ET, Wang G, et al.Randomized, placebo-controlled, esophageal squamous cell cancer chemoprevention trial of selenomethionine and celecoxib. Gastroenterology 2005;129(3):86373. [MEDLINE: 16143126] Macrae 1999 {published data only} Macrae F. Wheat bran ber and development of adenomatous polyps: evidence from randomized, controlled clinical trials. American Journal of Medicine 1999;106(1 A): 38S42S. Marotta 2003 {published data only} Marotta F, Barretto R, Tajiri H, Bertuccelli J, Safran P, Bobadilla J, et al.Atrophic/metaplastic changes of gastric mucosa: a preliminary interventional trial comparing different antioxidant supplements. International Congress Series 2003;1255:2914. Marotta 2004 {published data only} Marotta F, Barreto R, Tajiri H, Bertuccelli J, Safran P, Yoshida C, et al.The aging/precancerous gastric mucosa: a pilot nutraceutical trial. Annals of the New York Academy of Sciences 2004;1019:1959. [MEDLINE: 15247013] Mayne 2001 {published data only} Mayne ST, Risch HA, Dubrow R, Chow WH, Gammon MD, Vaughan Tl, et al.Nutrient intake and risk of subtypes of esophageal and gastric cancer. Cancer Epidemiology, Biomarkers & Prevention 2001;10(10): 105562. [MEDLINE: 11588131] Moriwaki 2002 {published data only} Moriwaki H. Prevention of liver cancer: current strategies and future perspectives. International Journal of Clinical Oncology 2002;7(1):2731. [MEDLINE: 11942046] Muto 1996 {published data only} Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT, et al.Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. New England Journal of Medicine 1996;334(24): 15617. [MEDLINE: 8628336]

Newsome 2000 {published data only} Newsome PN, Beldon I, Moussa Y, Delahooke TE, Poulopoulos G, Hayes PC, et al.Low serum retinol levels are associated with hepatocellular carcinoma in patients with chronic liver disease. Alimentary Pharmacology & Therapeutics 2000;14(10):1295301. [MEDLINE: 11012474] Nomura 1987a {published data only} Nomura A, Heilbrun LK, Morris JS, Stemmermann GN. Serum selenium and the risk of cancer, by specic sites: case-control analysis of prospective data. Journal of the National Cancer Institute 1987;79(1):1038. [MEDLINE: 3474437] Pan 1993 {published data only} Pan WH, Wang CY, Huang SM, Yeh SY, Lin WG, Lin DI, et al.Vitamin A, Vitamin E or beta-carotene status and hepatitis B-related hepatocellular carcinoma. Annals of Epidemiology 1993;3(3):21724. [MEDLINE: 8275192] Podmore 1998a {published data only} Podmore ID, Grifths HR, Herbert KE, Mistry N, Mistry P, et al.Vitamin C exhibits pro-oxidant properties. Nature 1998;392(6676):559. [MEDLINE: 9560150] Qu 2007 {published data only} Qu CX, Kamangar F, Fan JH, Yu B, Sun XD, Taylor PR, et al.Chemoprevention of primary liver cancer: a randomized, double-blind trial in Linxian, China. Journal of the National Cancer Institute 2007;99(16):12407. [MEDLINE: 17686823] Rocchi 1997 {published data only} Rocchi E, Seium Y, Camellini L, Casalgrandi G, Borghi A, DAlimonte P, et al.Hepatic tocopherol content in primary hepatocellular carcinoma and liver metastases. Hepatology 1997;26(1):6772. [MEDLINE: 9214453] Russo 1997 {published data only} Russo MW, Murray SC, Wurzelmann JI, Woosley JT, Sandler RS. Plasma selenium levels and the risk of colorectal adenomas. Nutrition and Cancer 1997;28(2):1259. [MEDLINE: 9290116] Sasazuki 2003 {published data only} Kim MK, Sasaki S, Sasazuki S, Okubo S, Hayashi M, Tsugane S. Lack of long-term effect of vitamin C supplementation on blood pressure. Hypertension 2002;40 (6):797803. [MEDLINE: 12468560] Kim MK, Sasazuki S, Sasaki S, Okubo S, Hayashi M, Tsugane S. Effect of ve-year supplementation of vitamin C on serum vitamin C concentration and consumption of vegetables and fruits in middle-aged Japanese: a randomized controlled trial. Journal of the American College of Nutrition 2003;22(3):20816. [MEDLINE: 12805247] Sasaki S, Tsubono Y, Okubo S, Hayashi M, Kakizoe T, Tsugane S. Effects of three-month oral supplementation of beta-carotene and vitamin C on serum concentrations of carotenoids and vitamins in middle-aged subjects: a pilot study for a randomized controlled trial to prevent gastric cancer in high-risk Japanese population. Japanese Journal
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

of Cancer Research 2000;91(5):46470. [MEDLINE: 10835489] Sasazuki S, Sasaki S, Tsubono Y, Okubo S, Hayashi M, Kakizoe T, et al.The effect of 5-year vitamin C supplementation on serum pepsinogen level and Helicobacter pylori infection. Cancer Science 2003;94(4): 37882. [MEDLINE: 12824908] Tsubono Y, Okubo S, Hayashi M, Kakizoe T, Tsugane S. A randomized controlled trial for chemoprevention of gastric cancer in high-risk Japanese population; study design, feasibility and protocol modication. Japanese Journal of Cancer Research 1997;88(4):3449. [MEDLINE: 9197524] Tsugane S, Tsubono Y, Okubo S, Hayashi M, Kakizoe T. A pilot study for a randomized controlled trial to prevent gastric cancer in high-risk Japanese population: study design and feasibility evaluation. Japanese Journal of Cancer Research 1996;87(7):6769. [MEDLINE: 8698614] Schatzkin 1996 {published data only} Schatzkin A, Lanza E, Freedman LS, Tangrea J, Cooper MR, Marshall JR, et al.The polyp prevention trial I: rationale, design, recruitment, and baseline participant characteristics. Cancer Epidemiology, Biomarkers & Prevention 1996;5(5): 37583. [MEDLINE: 9162304] Simone 2002 {published data only} Simone F, Pappalardo G, Maiani G, Guadalaxara A, Bugianesi R, Conte AM, et al.Accumulation and interactions of beta-carotene and alpha-tocopherol in patients with adenomatous polyps. European Journal of Clinical Nutrition 2002;56(6):54650. [MEDLINE: 12032655] Siriwardena 2007 {published data only} Siriwardena AK, Mason JM, Balachandra S, Bagul A, Galloway S, Formela L, et al.Randomised, double blind, placebo controlled trial of intravenous antioxidant (nacetylcysteine, selenium, vitamin C) therapy in severe acute pancreatitis. Gut 2007;56(10):143944. [MEDLINE: 17356040] Takshashi 2003 {published data only} Takashashi Y, Sasaki S, Takahashi M, Okubo S, Hayashi M, Tsugane S. A population-based dietary intervention trial in a high-risk area for stomach cancer and stroke: changes in intakes and related biomarkers. Preventive Medicine 2003; 37(5):43241. [MEDLINE: 14572428] Terry 2000 {published data only} Terry P, Lagergren J, Ye WM, Nyren O, Wolk A. Antioxidants and cancers of the esophagus and gastric cardia. International Journal of Cancer 2000;87(5):7504. [MEDLINE: 10925371] Weisburger 1991 {published data only} Weisburger JH. Nutritional approach to cancer prevention with emphasis on vitamins, antioxidants, and carotenoids. American Journal of Clinical Nutrition 1991;53(1): S226S237. [MEDLINE: 1985392] Whelan 1999 {published data only} Whelan RL, Horvath KD, Gleason NR, Forde KA, Treat MD, Teitelbaum SL, et al.Vitamin and calcium supplement

use is associated with decreased adenoma recurrence in patients with a previous history of neoplasia. Diseases of the Colon and Rectum 1999;42(2):2127. [MEDLINE: 10211498] Yang 2000 {published data only} Yang CS. Vitamin nutrition and gastroesophageal cancer. Journal of Nutrition 2000;130(2):338S9S. [MEDLINE: 10721901] Yu 1995 {published data only} Yu MW, Hsieh HH, Pan WH, Yang CS, Chen CJ. Vegetable consumption, serum retinol level, and risk of hepatocellular carcinoma. Cancer Research 1995;55(6): 13015. [MEDLINE: 7882326] Yu 1999 {published data only} Yu M W, Horng IS, Hsu KH, Chiang YC, Liaw Y F, Chen CJ. Plasma selenium levels and risk of hepatocellular carcinoma among men with chronic hepatitis virus infection. American Journal of Epidemiology 1999;150(4): 36774. [MEDLINE: 99381616] Zheng 1995 {published data only} Zheng W, Sellers TA, Doyle TJ, Kushi LH, Potter JD, Folsom AR. Retinol, antioxidant vitamins, and cancers of the upper digestive tract in a prospective cohort study of postmenopausal women. American Journal of Epidemiology 1995;142(9):95560. [MEDLINE: 7572976]

References to ongoing studies


APPOSE 2001 {published data only} Costello AJ. A randomized, controlled chemoprevention trial of selenium in familial prostate cancer: rationale, recruitment, and design issues. Urology 2001;57(4):1824. [MEDLINE: 11295622] HGPIN 2006 {published data only} Marshall JR, Sakr W, Wood D, Berry D, Tangen C, Parker F, et al.Design and progress of a trial of selenium to prevent prostate cancer among men with high-grade prostatic intraepithelial neoplasia. Cancer Epidemiology, Biomarkers & Prevention 2006;15(8):147984. [MEDLINE: 16896036] PHS II 2000 {published data only} Christen WG, Gaziano JM, Hennekens CH. Design of Physicians Health Study II a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials. Annals of Epidemiology 2000;10(2):12534. [MEDLINE: 10691066] SELECT 2003 {published data only} Hoque A, Albanes D, Lippman SM, Spitz MR, Taylor PR, Klein EA, et al.Molecular epidemiologic studies within the Selenium and vitamin E Cancer Prevention Trial (SELECT). Cancer Causes & Control 2001;12(7):62733. [MEDLINE: 11552710] Klein EA. Clinical models for testing chemopreventative agents in prostate cancer and overview of SELECT: the Selenium and vitamin E Cancer Prevention Trial. Recent
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Results in Cancer Research 2003;163:21225. [MEDLINE: 12903856] Klein EA. Selenium and vitamin E Cancer Prevention Trial. Annals of the New York Academy of Sciences 2004;1031: 23441. [MEDLINE: 15753149] Klein EA, Lippman SM, Thompson IM, Goodman PJ, Albanes D, Taylor PR, et al.The Selenium and vitamin E Cancer Prevention Trial. World Journal of Urology 2003;21 (1):217. [MEDLINE: 12756490] Klein EA, Thompson IM, Lippman SM, Goodman PJ, Albanes D, Taylor PR, et al.SELECT: the next prostate cancer prevention trial. Selenum and vitamin E Cancer Prevention Trial. The Journal of Urology 2001;166(4): 13115. [MEDLINE: 11547064] Klein EA, Thompson IM, Lippman SM, Goodman PJ, Albanes D, Taylor PR, et al.SELECT: the Selenium and vitamin E Cancer Prevention Trial. Urologic Oncology 2003; 21(1):5965. [MEDLINE: 12684129] Klein EA, Thompson IM, Lippman SM, Goodman PJ, Albanes D, Taylor PR, et al.SELECT: the Selenium and vitamin E Cancer Prevention Trial: rationale and design. Prostate Cancer and Prostatic Diseases 2000;3(3):14551. [MEDLINE: 12497090] Lippman SM, Goodman PJ, Klein EA, Parnes HL, Thompson IM Jr, Kristal AR, et al.Designing the Selenium and vitamin E Cancer Prevention Trial (SELECT). Journal of the National Cancer Institute 2005;97(2):94102. [MEDLINE: 15657339]

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References to other published versions of this review


Bjelakovic 2004a Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for preventing gastrointestinal cancers. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD004183. DOI: 10.1002/ 14651858.CD004183.pub2. Bjelakovic 2004b Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for prevention of gastrointestinal
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

cancers: a systematic review and meta-analysis. Lancet 2004;364(9441):121928. [MEDLINE: 15464182] Indicates the major publication for the study

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

36

CHARACTERISTICS OF STUDIES Characteristics of included studies [ordered by study ID]


ATBC 2003 Methods Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) Randomised, double-blind, placebo-controlled trial with two-by-two factorial design Generation of the allocation sequence: adequate, centrally by computer. Randomisation performed in blocks of eight within each of the study areas Allocation concealment: adequate, coded capsule packs maintained centrally Blinding: adequate, identical placebo capsules. Follow-up: adequate, no losses to follow-up. Intention-to-treat analysis: yes. Sample size calculations: yes. Country: Finland. Number of participants randomised: 29,133 males Inclusion criteria: male smokers (ve or more cigarettes daily), aged 50 to 69 years, averaged 57.2 years of age at study entry, who lived in south-western Finland Exclusion criteria: men with a prior cancer or with other serious illness, or who used vitamin E, vitamin A, or beta-carotene supplements in excess of predened doses (> 20 mg, > 20000 IU, or > 6 mg, respectively) , or anticoagulants Participants were randomly assigned in four groups to receive: group 1: alpha-tocopherol 50 mg (n = 7286); group 2: beta-carotene 20 mg (n = 7282); group 3: alpha-tocopherol and beta-carotene, (n = 7278); group 4: placebo (n = 7287); daily for ve to eight years (median 6.1 years) All participants took a single capsule daily. The four trial intervention groups were well balanced for all baseline characteristics evaluated. The two-by-two factorial design allowed assessment of the two intervention agents independently, with one-half of participants receiving alpha-tocopherol (n = 14,564) and the other half not (n = 14,569); similarly, half of the participants received beta-carotene (n = 14,560) and half did not (n = 14,573). The study was conducted between 1985 and 1993. The active intervention continued through April 30, 1993 and postintervention follow-up until April 30, 2001. Mean follow-up time was 14.1 years The primary outcome measure was: incidence of lung cancer. Secondary outcome measures were: occurrence of other major cancers, overall and cause specic mortality, and occurrence of other diseases Compliance with treatment was assessed by counts of the remaining capsules at each visit, by measurement of serum alpha-tocopherol and beta-carotene levels after three years of supplementation, and by measurements in random serum samples throughout the study. Compliance with treatment was excellent with four out of ve active participants taking more than 95% of the scheduled capsules. Dropout rate and compliance were similar between all four groups. All capsules were supplied by Hoffmann-La Roche, Basel, Switzerland. Additional information received through personal communication with the authors

Participants

Interventions

Outcomes

Notes

Risk of bias Item Authors judgement Description

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

37

ATBC 2003

(Continued)

Allocation concealment?

Yes

A - Adequate

CARET 2004 Methods The Beta-Carotene and Retinol Efcacy Trial (CARET). Randomised, double-blind, placebo-controlled trial with two-by-two factorial design in a pilot phase and then one-by-one Generation of the allocation sequence: adequate, permuted block design with random block size chosen uniformly among 8, 10, 12, 14, and 16 Allocation concealment: adequate, locked central database with the link between study identier and intervention assignment; all data analyses were performed centrally; the analyses that involved intervention assignment were performed only by the Co-ordinating Centers statisticians using coded intervention assignment unknown to the statisticians; analyses involving the coded intervention assignments were seen only by CARETs Data and Safety Monitoring Board, Co-ordinating Center statisticians, and a single CARET investigator who saw no participants Blinding: adequate, identical placebo capsules provided by a sponsor Follow-up: adequate. The losses to follow-up were less than 2% at the end of treatment Intention-to-treat analysis: yes. Sample size calculations: yes. Country: United States of America. Number of participants randomised: 18314; 12025 males and 6289 females Inclusion criteria: smokers, former smokers, and workers exposed to asbestos at high risk of developing lung cancer. A total of 4060 male workers, mean age 57 years, exposed to asbestos and 14254 heavy smokers (44% of whom were women), mean age 58 years, were randomised. The participants agreed to limit their supplemental intake of vitamin A to less than 5500 IU per day and to take no supplemental beta-carotene CARET builds on the experience of two pilot studies performed in Seattle (1985-1988). The rst pilot study initiated a phase III trial of the safety and efcacy of the study vitamins in 816 asbestos-exposed participants randomised to a daily combination of 15 mg 13-carotene and 25,000 IU retinol or a placebo medication. Participants were eligible up to age 74 and were not required to have a history of cigarette smoking; otherwise, the eligibility criteria were the same as for the asbestos-exposed population in CARET The second pilot study was a phase II trial of the comparative safety of the study vitamins in heavy smokers. The eligibility criteria were identical to those for heavy smokers in CARET. Overall 539 men and 490 women were randomised to one of four intervention groups: group 1: a daily combination of 30 mg 13-carotene and 25,000 IU retinol; group 2: 30 mg 13-carotene only; group 3: 25,000 IU retinol only; group 4: placebo medication. All 1845 participants in the two pilot studies continue to be followed for outcomes in CARET, together with approximately 16,000 additional participants Participants of CARET trial were randomly assigned to receive: group 1: combination of 30 mg beta-carotene and 25,000 IU vitamin A (n = 9420); group 2: placebo, (n = 8894). Both formulations were given as capsules. Beta-carotene beadlets were combined with retinyl palmitate in a single capsule and dispensed in bottles, which were weighed and their content checked. The design projected active intervention until late 1997.
38

Participants

Interventions

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

CARET 2004

(Continued)

The CARET active intervention was stopped 21 months earlier because of clear evidence of no benet and substantial evidence of possible harm The average duration of follow-up was 10.0 years. Outcomes The primary outcome measure was: the occurrence of lung cancer Other outcomes reported are: mortality rates and occurrence of other cancers Compliance was assessed by weighing the returned bottles to estimate the number of capsules remaining (in 85% of the assessments), or by relying on the participants own estimates (in 15% of the assessments) Compliance with treatment was excellent. Among the active participants, the mean rate of capsule consumption was 93% through ve years of follow-up, with no signicant differences between the treatment groups. Participants who stopped receiving trial vitamins for any reason other than death were dened as inactive participants and were still followed for outcomes and counted in the analysis. As of December 15, 1995 ascertainment of vital status for more than 98% was complete Active agents and placebos were purchased from Hoffmann-La Roche and formulated by Tischon Corporation Data were extracted from the primary publication, but additional information was received through personal communication with the authors

Notes

Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate

Correa 2000 Methods Randomised, controlled, partially double-blind, chemoprevention trial with two-by-two-by-two factorial design Generation of the allocation sequence: adequate, computer-generated lists. Participants were randomly assigned in a single step, using a permuted block design, to one of eight different treatment regimens Allocation concealment: adequate, coded capsules. Blinding: adequate, using identical placebo capsules. Follow-up: adequate, the average rate of loss was 4.3% per year over the six-year trial. Two hundred twentyone participants withdrew from the study before their 72-month evaluation: 102 quitted treatment, 59 were lost to follow-up, 34 dropped out of the study because of pregnancy and other medical conditions, 18 died of causes unrelated to gastric cancer, and eight developed cancer other than gastric cancer. In one participant, the 72-month biopsy specimen was inadequate for histologic evaluation and determination of outcome. A total of 684 participants came to the 36-month biopsy; of those, 92% (631) came for the 72-month biopsy, there was a dropout rate of 2.6% per year for the last three years of the trial. Overall 24 participants from the placebo group, 25 from anti-Helicobacter pylori (anti-HP), 34 from the betacarotene (BC), 23 from the ascorbic acid (AA), 20 from the anti-HP + BC, 23 from anti-HP + AA, 17 from BC + AA, and 37 from anti-HP + BC + AA were lost to follow-up Intention-to-treat analysis: no. Sample size calculations: no. Country: Colombia. Number of participants randomised: 976; 46% males, aged 29 to 69 years, mean age 51.1 years
39

Participants

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Correa 2000

(Continued)

Inclusion criteria: preliminary histologic diagnosis of multifocal atrophic gastritis with or without intestinal metaplasia and dysplasia, good health Exclusion criteria: normal histology, non-atrophic gastritis, gastric cancer Before randomisation, participants were classied into one of three strata: atrophy (without metaplasia), intestinal metaplasia, or dysplasia according to baseline histologic diagnosis Interventions Participants were randomly assigned to a dietary supplement of beta-carotene (30 mg once per day) and/ or ascorbic acid (1 g twice a day) or their corresponding placebos, for a six-year period. The prevalence of Helicobacter pylori infection among all gastric biopsy specimens was 97%. Anti-Helicobacter pylori treatment consisting of amoxicillin (500 mg three times per day), metronidazole (375 mg three times per day), and bismuth subsalicylate (262 mg three times per day) was given for 14 days to half of the study participants assigned randomly. This treatment was not blinded or placebo controlled because an appropriate placebo was not available for bismuth subsalicylate Participants were divided in eight treatment groups to receive: group 1: placebo (n = 117); group 2: anti-Helicobacter pylori treatment, which consisted of amoxicillin, metronidazole, and bismuth subsalicylate (n = 120); group 3: beta-carotene (n = 117); group 4: ascorbic acid (n = 130); group 5: Helicobacter pylori treatment consisting of amoxicillin, metronidazole, and bismuth subsalicylate, and additionally beta-carotene (n = 126); group 6: Helicobacter pylori treatment consisting of amoxicillin, metronidazole, and bismuth subsalicylate, and additionally ascorbic acid (n = 111); group 7: beta-carotene and ascorbic acid (n = 121); group 8: Helicobacter pylori treatment, consisting of amoxicillin, metronidazole, and bismuth subsalicylate, and additionally beta-carotene and ascorbic acid (n = 134) Gastric biopsy specimens taken at baseline were compared with those taken at 72 months The primary outcome measures were: progression, no change or regression of gastric precancerous lesions (preliminary histologic diagnosis of multifocal atrophic gastritis with or without intestinal metaplasia and dysplasia). For our purposes we extracted data about the occurrence of gastric cancer We have also extracted data on overall mortality for all antioxidants as well as for beta-carotene and vitamin C Compliance with treatment was constantly encouraged and monitored by a social worker who interviewed the participants and recorded pill counts every three months. In addition, blood levels of beta-carotene and ascorbic acid were measured every three months in a 20% random sample of the participants. Compliance with treatment among participants who completed the study was high for all intervention modalities (mean compliance for ascorbic acid, 91.8%; for beta-carotene, 92.3%; and for anti-Helicobacter pylori treatment, 99.1%). Active medication and placebos were provided like identical coded tablets by Hoffmann-La Roche Inc. (Nutley, NJ). Additional information received through personal communication with the authors. Data were extracted from the article: Correa, et al. Re: Chemoprevention of gastric dysplasia: Randomized trial of antioxidant supplements and anti-Helicobacter pylori therapy. Journal of the National Cancer Institute 2001; 93: 559

Outcomes

Notes

Risk of bias Item Authors judgement Description

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Correa 2000

(Continued)

Allocation concealment?

Yes

A - Adequate

HOPE TOO 2005 Methods The Heart Outcomes Prevention Evaluation Study (HOPE). Randomised, double-blind, placebo-controlled trial with two-by-two factorial design Generation of the allocation sequence: adequate, by computer Allocation concealment: adequate, randomisation is done by a telephone call to a central ofce. After receipt of appropriate baseline data over the telephone, the patient is randomised Blinding: adequate, identical placebo capsules. Follow-up: adequate. At the end of the initial HOPE trial, vital status was ascertained for 9535 (99.9%) of 9541 randomised patients. At the end of the HOPE-TOO trial, vital status was ascertained for 4724 (99.8%) of 4732 patients who participated in the extension trial Intention-to-treat analysis: yes. Sample size calculations: yes. Country: International, North America, South America, Europe (19 countries) Number of participants randomised: 9541; 6996 males and 2545 females, 55 years old or older, mean age 66 years Inclusion criteria: 55 years or older, had a history of CV disease (coronary artery disease, stroke or peripheral arterial disease) or diabetes in the presence of at least one additional CV risk factor (total cholesterol > 5. 2 mmol/l, HDL cholesterol =0.9 mmol/l, hypertension, dened as use of medications to treat high blood pressure, or blood pressure at time of recruitment > 160 mmHg systolic or > 90 mmHg diastolic, known microalbuminuria, or current smoking) Exclusion criteria: Dipstick-positive proteinuria, diabetic nephropathy, serum creatinine > 200 mmol/ l, history of congestive heart failure, or known left ventricular ejection fraction (< 40%), hyperkalemia, uncontrolled hypertension, myocardial infarction, unstable angina or stroke within 1 month before trial enrollment, and use of or intolerance to vitamin E or angionetsin-converting-enzyme (ACE) inhibitors Patients were randomly assigned to receive: group 1: 400 IU of vitamin E (RRR-a-tocopheryl acetate) daily from natural sources (n = 4761); group 2: matching placebo (n = 4780); group 3: an angiotensin-converting-enzyme inhibitor (ramipril 10 mg) (n = 4645); group 4: matching placebo (n = 4652), once a day for a four to six years, mean 4.5 years. The Heart Outcomes Prevention Evaluation [HOPE] trial was conducted between December 21, 1993, and April 15, 1999. The Heart Outcomes Prevention was extended (HOPE-The Ongoing Outcomes [HOPE-TOO]) between April 16, 1999, and May 26, 2003. Of the initial 267 HOPE centres that had enrolled 9541 patients, 174 centres participated in the HOPE-TOO trial. Of 7030 patients enrolled at these centres, 916 were deceased at the beginning of the extension of the trial, 1382 refused participation, 3994 continued to take the study intervention, and 738 agreed to passive follow-up. The mean followup period was 7 years The primary outcome measures were: cancer occurrence, cancer deaths, major cardiovascular events (myocardial infarction, stroke, and cardiovascular death) The secondary outcome measures were: unstable angina, congestive heart failure, revascularization or amputation, death from any cause, complications of diabetes, and cancer

Participants

Interventions

Outcomes

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

41

HOPE TOO 2005

(Continued)

Notes

Compliance with treatment was checked by measuring the plasma vitamin E levels in randomly selected patients. The rate of compliance with the assigned regimen was high throughout the study. The percentages of patients who were taking vitamin E in the vitamin E and placebo groups, respectively, were 94.2% and 1.0% at 1 year, 93.3% and 1.7% at 2 years, 91.3% and 2.0% at 3 years, 90.2% and 2.7% at 4 years, and 89.2% and 3.4% at the nal visit. There was no signicant interaction between the study treatments (ramipril and vitamin E) for the primary, secondary, and other study outcomes. At the end of the initial HOPE trial, vital status was ascertained for 9535 (99.9%) of 9541 randomised patients. Funded by the Medical Research Council of Canada, Natural Source Vitamin E Association, Negma, Hoechst-Marion Roussel, AstraZeneca, King Pharmaceuticals, and the Heart and Stroke Foundation of Ontario

Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate

HPS 2002 Methods Heart Protection Study. Randomised, double-blind, placebo-controlled trial with two-by-two factorial design Generation of the allocation sequence: adequate, computer generated random numbers Allocation concealment: adequate, central telephone randomisation system Blinding: adequate, identical placebo capsules. Follow-up: adequate. 99.7% of the participants were with complete follow-up for average of 5 years in vitamins allocated group and 99.6% in placebo group. Overall, 25 participants allocated to vitamins group and 35 participants to placebo group were lost to follow-up Intention-to-treat analysis: yes. Sample size calculations: yes. Country: United Kingdom. Number of participants randomised: 20536; 15454 males and 5082 females at an age 40 to 80 years Inclusion criteria: adults with coronary disease, other occlusive arterial disease, or diabetes, and non-fasting blood total cholesterol concentrations of at least 3.5 mmol/L Exclusion criteria: other life-threatening conditions, such as chronic liver disease, severe renal disease, severe heart failure, severe chronic airways disease, or diagnosed cancer (other than non-melanoma skin cancer). In addition, anyone already taking high-dose vitamin E supplements or in whom such supplements were considered indicated, was not to be randomised Participants were randomly assigned to receive: group 1: 600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily (n = 10,269); or group 2: matching placebo capsules (n = 10,267), daily during the scheduled 5-year treatment period The primary outcome measures were: major coronary events (for overall analyses) and fatal or nonfatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity

Participants

Interventions

Outcomes

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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HPS 2002

(Continued)

Notes

Compliance with treatment was assessed at each follow-up by reviewing the calendar packed tablets remaining and for those who had stopped, the reasons for doing so were sought. An average of 83% of the participants in each treatment group remained compliant during the scheduled ve-year treatment period. To assess the effects of the treatment allocation on blood concentrations of the vitamins being studied, assays were performed in non-fasting samples collected from about 5% of the participants at the initial screening visit and at an average of about three years of follow-up (the approximate mid-point of the study) Vitamins were provided by Roche. Data were extracted from the primary publication, but additional information was received through personal communication with the authors

Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate

Li 2000 Methods Randomised, placebo-controlled trial with parallel group design Generation of the allocation sequence: unclear, not described Allocation concealment: unclear, not described. Blinding: adequate, matching placebo. Follow-up: adequate, no losses to follow-up. Intention-to-treat analysis: yes. Sample size calculations: no. Country: China. Number of participants randomised: 2065 males, aged 20 to 65 years. Inclusion criteria: males living in Qidong, Jiangsu province (a high risk area for liver cancer), HBsAg positive, AFP negative with normal liver function Exclusion criteria: none stated. Participants were randomly assigned to receive: group 1: sodium selenite 0.5 mg (228 g of selenium) (n = 1112); group 2: placebo (n = 953); per day for three years. The primary outcome measure was the occurrence of liver cancer Compliance with treatment: good, between 81.5% in the rst year and 79.8% in the third year Data were extracted from the primary publication.

Participants

Interventions

Outcomes Notes

Risk of bias

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Li 2000

(Continued)

Item Allocation concealment? Li 2004 Methods

Authors judgement Unclear

Description B - Unclear

Randomised double-blind, placebo-controlled trial with parallel group design Generation of the allocation sequence: unclear, not reported Allocation concealment: unclear, not reported. The whole process was conducted by the double-blind method Blinding: adequate, identical looking placebo capsules and placebo tablets Follow-up: inadequate. Intention-to-treat analysis: no. Sample size calculations: yes. Country: China. Number of participants randomised: 5033, aged 34 to 74 years, 3250 men and 1783 women Inclusion criteria: 34 to 74 years old, stomach disorder, or tumours in other family members, or smoking and/or alcohol consumption Exclusion criteria: none stated. Participants were randomly assigned to receive: group 1: selenium (sodium selenite) 100 g and synthetic allitridum 200 mg (n = 2526); group 2: placebo (n = 2507); Each participant took orally two soft intestinal dissolving capsules that contained synthetic allitridum every day and one table of sodium selenite which contained selenium every other day for one month of each year during two years and at the same time each participant in the control group was given two placebo capsules which contained corn oil and one starch table of identical appearance to that in intervention group. Participants were treated from 1989 to 1991, and followed during next ve years (1192 to 1997), overall 7 years Allitridum is an extract of garlic. The primary outcome measure was the occurrence of gastric cancer Compliance with treatment was checked by interviews face to face and by measuring thiamine concentration in the urine Compliance with treatment was excellent. Mean compliance estimated for the taking of the medication was 93% Synthetic allitridum was made from in Dongfeng Pharmaceutical Factory, Lianyuguang, China, and the soft intestinal dissolving capsule of allitridum turned out in the Weihai Branch Factory of Shangdong Xinhua Pharmaceutical Factory, Zibo, China. The tables of sodium seletine came from the Ofce of Shangdong Endemic Diseases, and were manufactured by Hezhe Pharmaceutical Factory, Hezhe, China Authors reported that the major side effects of the drugs were garlic-odour and heartburn, but did not provide numbers

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Outcomes Notes

Risk of bias Item Authors judgement Description


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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Li 2004

(Continued)

Allocation concealment? Munoz 1985 Methods

Unclear

B - Unclear

Randomised, double-blind, placebo-controlled trial with parallel group design Generation of the allocation sequence: unclear, not described Allocation concealment: adequate, the capsules were packed individually on two and three blister charts, respectively. On the reverse side of the blisters was self-adhesive label with the individuals study number. The participants, barefoot doctors, and eld supervisors were unaware of the treatment assignment. The code for the treatment assignment was not opened until the histological evaluation was completed Blinding: adequate, identical-looking gelatin capsules. Follow-up: adequate, 567 persons (93%) attended the nal endoscopic examination Intention-to-treat analysis: no. Sample size calculations: no. Country: China, Huixian, Henan Province. Number of participants randomised: 610, 50% males, aged 35 to 64 years. Inclusion criteria: inhabitants of Huixian, Henan province of China with high risk of oesophageal cancer Exclusion criteria: none stated. In September, 1983 a random population sample was drawn from two production brigades (Meng Zhuang and Dong Xia Feng) in Huixian, Henan province Participants were randomly assigned to receive: group 1: 15 mg (50,000 IU) retinol, 200 mg riboavine, and 50 mg zinc (as zinc gluconate), (n = 305); group 2: matching placebo (n = 305). once a week for 13.5 months. The nal examination was in October/November 1984, 13.5 months after the beginning of the trial and included endoscopy. Two biopsy specimens were taken at random from the middle and lower third of the oesophagus, and additional ones from any macroscopic lesion. Of 567 persons (93%) who attended the nal endoscopic examination, histological slides were evaluated from 552 persons (90.5%). In the other 15 the available material was inadequate The primary outcome measures were the prevalence of precancerous lesions of the oesophagus, as well as occurrence of oesophageal cancer In the early stages of the trial compliance was assessed by vitamin measurements in blood two months after the start of the trial from a sample of 100 participants stratied by age, sex, production brigade, and treatment. Follow-up forms and remaining capsules were inspected every two months by elds supervisors. Compliance was excellent. The nal examination on 567 (93%) participants included oesophagoscopy and at least two biopsies All vitamin and placebo preparations were provided by Hoffmann-La Roche, Basel, Switzerland Data were extracted from the primary publication. During the trial one patient died, but authors did not report from which arm and we were unable to obtain this information

Participants

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Outcomes

Notes

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Munoz 1985

(Continued)

Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate

NIT1 1993 Methods Nutrition Intervention Trial (NIT); The General Population Trial, in Linxian, China Randomised, placebo-controlled trial with one-half replicate of a two-by-two-by-two-by-two factorial design Generation of the allocation sequence: adequate, random numbers generated by independent data management centre in USA. The randomisation sequence was known only at data management centre until the intervention ended Allocation concealment: adequate, sequentially numbered coded bottles. Pill containers were labelled in the USA at the pill distribution centre Blinding: adequate, identical placebo pills. Follow-up: inadequate, losses to follow-up not reported. Intention-to-treat analysis: yes. Sample size calculations: yes. Country: China, Henan Province of north central China, Linxian County. Number of participants randomised: 29584; 45% males, aged 40 to 69 years Inclusion criteria: residents willing to take part in a multi-year, daily pill-taking regimen Exclusion criteria: debilitating disease or prior oesophageal or stomach cancer Participants were randomly assigned to receive one of eight vitamin/mineral supplement combinations in the form of individual oral tablets. The eight intervention groups (each with 3677 to 3709 participants) were derived from a one-half replicate of a two-by-two-by-two-by-two factorial design which allowed to asses four factors (ie, nutrient combinations) in a single experiment. The four factors designated by the letters A, B, C, D were: A - retinol (as palmitate) 5000 IU, zinc (as zinc oxide) 22.5 mg; B - riboavin (vitamin B2) 3.2 mg and niacin (vitamin B3) 40 mg; C - ascorbic acid 120 mg and molybdenum (as molybdenum yeast complex) 30 g; D - beta carotene 15 mg, selenium (as selenium yeast) 50 g, and alpha-tocopherol 30 mg. Doses of each nutrient varied from one to two times US Recommended Daily Allowances (RDAs). The eight intervention groups were dened by the following combinations of supplements; AB, AC, AD, BC, BD, CD, ABCD, or placebo and packed in coded bottles containing a one-month supply. Bottles were distributed monthly beginning in March 1986 and continuing through May 1991, average 5.25 years The primary outcome measures were: cancer occurence, cancer mortality, and overall mortality Compliance with study treatment was assessed by monthly pill counts and biochemical measures Compliance was excellent throughout the study. The overall pill disappearance rate was 93% for all participants, with no difference by treatment group (range 92% to 93%) and little change during the trial. All vitamin/mineral supplements and placebos were provided by Hoffmann-La Roche, Basel, Switzerland and Lederle Laboratories, Inc Data were extracted from the primary publication.
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

NIT1 1993

(Continued)

Additional information was received through personal communication with the authors. However, we did not receive information on gastrointestinal cancer occurrence per group Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate

NIT2 1993 Methods The Dysplasia Trial. Randomised, placebo-controlled trial with parallel group design Generation of the allocation sequence: adequate, random numbers generated by independent data management centre in USA Allocation concealment: adequate, sequentially numbered coded bottles. Pill containers were labelled in the USA at the pill distribution centre Blinding: adequate, identical placebo pills. Follow-up: adequate, the morbidity and mortality follow-up rates were 99% Intention-to-treat analysis: yes. Sample size calculation: yes. Country: China, Henan Province of north central China, Linxian County. Number of participants randomised: 3318; 1461 males and 1857 females at age 40 to 69 years, mean age 54 years Inclusion criteria: place of living in one of the three northern Linxian communes (Yaocun, Rencun, or Donggang), provided consent, diagnosis of oesophageal dysplasia on a balloon cytology examination Exclusion criteria: taking vitamins of any type regularly, or antitumour B (a traditional Chinese drug consisting of a mixture of six medical herbs), history of malignancy or other debilitating disease Participants were randomly assigned to receive: group 1: 13 vitamins and 13 minerals (vitamin A (acetate) 10000 IU; vitamin E (dl-alpha tocopherol acetate) 60 IU, vitamin C (ascorbic acid) 180 mg, vitamin B1 5 mg, vitamin B2 5.2 mg, vitamin B6 6 mg, vitamin B12 18 g, vitamin D 800 IU; beta-carotene 15 mg, folic acid 800 g, niacinamide 40 mg, biotin 90 g, pantothenic acid 20 mg, calcium 324 mg, phosphorus 250 mg, iodine 300 g, iron 54 mg, magnesium 200 mg, copper 6 mg, manganese 15 mg, potassium 15.4 mg, chloride 14 mg, chromium 30 g, molybdenum 30 g, selenium (sodium selenate) 50 g, and zinc 45 mg (n = 1657); group 2: placebo (n = 1661); for a period of 6 years. The doses were typically two to three times the US Recommended Daily Allowances (RDAs), but ranged from 0.26 to seven times the RDA depending on the vitamin or mineral. Each participant was given three pills daily, including one capsule beta-carotene or placebos and two tablets of vitamin/mineral supplement, or placebos The primary outcome measures were: cancer occurrence, cancer mortality, and overall mortality

Participants

Interventions

Outcomes

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NIT2 1993

(Continued)

Notes

Compliance with treatment was assessed by counting unused pills for all trial participants and by assessing nutrient levels in blood collected from samples of individuals randomly selected without replacement every three months throughout the trial. Compliance with treatment was excellent. The overall pill disappearance rate was 94% in both groups with slight decline (from 96% in year 1 to 92% in year 6 in both groups) over the duration of the trial Data were extracted from the primary publication. Active medications and placebos were provided: beta-carotene as Solatane by Hoffmann-La Roche, Inc., Nutley, N.Y., and vitamin/mineral supplement as Centrum Lederle Laboratories, Inc., Pearl River, N.Y Additional information was received through personal communication with the authors

Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate

NPCT 1996 Methods Nutritional Prevention of Cancer Trial (NPCT). Randomised, double-blind, placebo-controlled trial with parallel group design Generation of the allocation sequence: adequate, computer generated random numbers Allocation concealment: adequate, treatment group assignment was made centrally. The co-ordinating centre held all treatment information in blinded form. Medications were distributed using sealed pill bottles Blinding: adequate, identical placebo tablets. Follow-up: adequate. At the end of the blinded period of treatment no participants were lost to vital follow-up, and only 7 participants (3 in the selenium group and 4 in the placebo group) declined to provide additional information about the illness Intention-to-treat analysis: yes. Sample size calculations: yes. Country: United States of America. Number of participants randomised: 1312; 75% males, aged 18 to 80 years, mean age 63 years Inclusion criteria: history of two or more basal cell skin cancers (BCC) or one squamous cell skin cancer (SCC), with one of this occurring within the year prior the randomisation, life expectancy of at least ve years and no internal malignancies treated within the previous ve years Exclusion criteria: history of signicant liver or kidney disorders. Recruitment began on September 15, 1983 and continued each year through 1991 Patients were randomly assigned to receive: group 1: 200 g of selenium supplied in a 0.5 g high-selenium bakers yeast tablet (n = 653); group 2: placebo (n = 659); The end of a blinded period of treatment was on February 1, 1996. Mean length of treatment was 4.5 years and follow-up 7.4 years The primary outcome measures were: incidences of basal cell and squamous cell carcinoma of the skin. In 1990 secondary outcome measures were identied, which included: total mortality and cancer mortality, as well as the incidence of the lung, colorectal, and prostate cancers
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

NPCT 1996

(Continued)

Notes

Compliance with treatment: excellent, 79.3% of the participants (80.3% in the placebo group and 78. 4% in the selenium group) missed taking a pill less than twice a month Trial medications were provided by Nutrition 21 (La Jolla, CA), through 1995 and by Cypress Systems (Fresno, CA) thereafter Data about the gastrointestinal cancer occurrence were extracted from the article: Dufeld-Lillico AJ, Reid ME, Turnbull BW, Combs GF Jr, Slate EH, Fischbach LA, Marshall JR, Clark LC. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol Biomarkers Prev 2002;11(7):6309

Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate

PHS 1996 Methods Physicians Health Study (PHS). Randomised, double-blind, placebo-controlled trial with two-by-two factorial design Generation of the allocation sequence: adequate, by computer in blocks Allocation concealment: adequate, the shipping department sent out calendar packs (which were identical whether active or placebo) to individual participants depending on this code. All of the calendar packs were in coded boxes, supplied by the drug manufacturer, so that the shippers did not know which drug they were shipping Blinding: adequate, identical placebo capsules. Follow-up: adequate. By December 31, 1995, the scheduled end of the trial, less than 1% of the participants were lost to follow up Intention-to-treat analysis: yes. Sample size calculations: yes. Country: United States of America. Number of participants randomised: 22071 US male physicians at age 40 to 84 years, mean age 53 years Inclusion criteria: US male physicians willing to take part in this trial Exclusion criteria: chronic liver disease or evidence of abnormal liver function, severe renal disease or evidence of impaired renal function, inammatory muscle disease or evidence of muscle problems (creatine kinase > 750 IU/L); concurrent treatment with cyclosporin, brates, or high-dose niacin; child-bearing potential; severe heart failure; some life-threatening condition other than vascular disease or diabetes (eg, severe chronic airways disease or any cancer other than non-melanoma skin cancer); or conditions that might limit long-term compliance (eg, severely disabling stroke, dementia, or psychiatric disorder) Physicians were randomly assigned to one of the four groups to receive: group 1: active aspirin 325 mg on alternate days plus beta-carotene placebo; group 2: active beta-carotene 50 mg on alternate days plus aspirin placebo; group 3: both active agents; or group 4: both placebos. The randomised aspirin component of the trial was terminated early, on 25 January 1988. The beta49

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carotene component continued uninterrupted until its scheduled end in December 1995 A total of 11036 physicians were assigned at random to receive beta-carotene and 11035 to receive betacarotene placebo Time from randomisation to the end of the trial averaged 12 years, and time of follow-up 12.9 years Outcomes The primary outcome measures were: overall and within subgroups, occurrence of malignant neoplasms (except non melanoma skin cancer), incidence of cardiovascular disease, and overall mortality Compliance with treatment was checked by random serum assessments obtained at unannounced visits to trial participants. Compliance with treatment excellent, the average per cent of pills taken was 97% in both the active and placebo groups. There was 85% compliance with beta-carotene treatment after ve years and 78% after 12 years. The use of vitamin A supplements was reported by only 6% of the placebo group even by the end of trial. Active trial packs and matching placebos were provided by: aspirin (Bufferin) by Bristol Meyers; beta-carotene (Lurotin), BASF corporation. Additional information received through personal communication with the authors. Data were extracted from the article: Cook et al. Effects of beta-carotene supplementation on cancer incidence by baseline characteristics in the Physicians Health Study (United States). Cancer Causes and Control 2000; 11: 617-26, with extended follow-up of 12.9 years

Notes

Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate

Plummer 2007 Methods Randomized, double-blind, placebo-controlled, primary-prevention trial with parallel group design Generation of the allocation sequence: adequate, the random allocation sequence to determine treatment group was generated by Hoffmann-La Roche, using random permuted blocks of size eight Allocation concealment: adequate, all histologic diagnoses and assays on biologic samples were conducted blind to the treatment allocation. During the trial, the central study database at IARC did not contain data on treatment allocation. The data were added to the database after the trial had been completed Blinding: adequate, the placebo was prepared in the form of capsules identical to those containing the vitamins Follow-up: adequate, overall 302 participants from active and 278 participants from placebo group dropped-out during the trial. The number of participants who dropped out was slightly higher in the vitamin group than in the placebo group, but the difference was not statistically signicant (P = 0.14, for difference of two proportions) Intention-to-treat analysis: no. Sample size calculations: yes. Country: Venezuela Number of participants randomised: 1980, aged 35 to 69 years, 52.7% females Inclusion criteria: population at high risk for stomach cancer in general good health, and permanent residents of Tachira State Exclusion criteria: serious illness, including any type of cancer, those whose mental status made long-term adherence to the treatment regimen unlikely and pregnant women
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Interventions

Participants were randomly assigned to receive: group 1: vitamin C (750 mg), vitamin E (600 mg), and beta-carotene (18 mg) (n = 990); group 2: placebo (n = 990); daily for 3 years. The treatment was taken in the form of three capsules per day, one with each of the three main meals. Each capsule contained 250 mg vitamin C, 200 mg vitamin E, and 6 mg of beta-carotene, for a daily dose of 750 mg of vitamin C (12.5 times the recommended daily allowance), 600 mg vitamin E (20 times the recommended daily allowance), and 18 mg beta-carotene (considered the maximum dose if carotenoderma is to be avoided) The primary outcome of the trial was the progression and regression of precancerous lesions of the stomach, as determined by histologic ndings Compliance for the intervention group was conrmed by the pill counts and measuring the biochemical markers of supplementation. Excellent compliance was indicated by pill counts when participants returned for their vitamin pills: 91% of all containers were returned with less than 10% of pills. There were clear increases in beta-carotene and vitamin E levels in the treated group beyond the levels observed at baseline. In the placebo group, by contrast, no changes were observed. Participants who did not return for their supply of capsules were contacted rst by telephone, then visited at home by social workers who enquired about the reasons for nonattendance, encouraged continuing participation, and provided the next months supply of capsules Both vitamin capsules and placebo were supplied by Hoffman-La Roche

Outcomes

Notes

Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate

SIT 2006 Methods Shandong Intervention Trial Randomised, double-blind, placebo controlled, primary prevention trial with stratied, factorial design 2x2x2 versus 2x2 Generation of the allocation sequence: adequate, randomized treatment assignments were generated at Westat in the United States Allocation concealment: adequate, pill bottles bearing codes corresponding to assignments were then distributed to the study participants Blinding: adequate, using identical placebo capsules. Follow-up: adequate, overall 15 participants from placebo and 19 participants from active intervention group were lost to follow-up Intention-to-treat analysis: yes. Sample size calculations: yes. Country: China (Linqu County, Shandong Province). Number of participants randomised: 3411, 1753 men and 1658 women aged 35 to 64 years Inclusion criteria: participants aged 35 to 64 years willing to participate in 42-month study, baseline gastroscopy with biopsies, known Helicobacter pylori status
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Exclusion criteria: illness, bleeding disorders, cancers (except nonmelanoma skin cancer), heart failure, emphysema, renal or liver diseases, other life-threatening illnesses, allergy to penicillin or related antibiotics Interventions Participants were rst divided on the basis of whether they showed serologic evidence of Helicobacter pylori infection at baseline (2285) or not (1126). Participants with serologic evidence of Helicobacter pylori at baseline were eligible to receive amoxicillin (1 g twice a day) and omeprazole (20 mg twice a day) in three capsules (two 500 mg amoxicillin and one 20 mg omeprazole) to be taken twice daily (before breakfast and dinner) for 2 weeks. Look-alike placebo capsules containing lactose and starch for amoxicillin and sucrose and starch for omeprazole were given to serologically positive controls and to all seronegative participants. Approximately 3 months after initial treatment for Helicobacter pylori, supplementation with 100 IU alpha-tocopherol, 250 mg vitamin C, and 37.5 g selenium twice a day began its 39-month course. Participants received this mixture in one capsule, to be taken twice daily before or after breakfast and dinner. From December 1995 to May 1996, this mixture also contained beta-carotene (7.5 mg twice a day). Look-alike placebo capsules contained cellulose, lactose, and magnesium stearate In the garlic group, participants took two capsules twice a day before or after breakfast and dinner. Each capsule contains 200 mg Kyolic aged garlic extract and 1 mg steam-distilled garlic oil. To prepare the extract, the manufacturer sliced garlic cloves and soaks them in aqueous ethanol (about 20%) for over 18 months at room temperature. The extract is then ltered, concentrated, and dried. The look-alike placebo capsules contained cellulose, granulated sugar, caramel, and magnesium stearate. Bottles holding placebo capsules contained minute quantities of garlic oil so they would smell like garlic HP-seropositive at baseline (2258) entered 2x2x2 factorial of antibiotics, vitamins, and garlic. HP-seronegative at baseline (1126) entered 2x2 factorial trial of vitamins, and garlic Participants were randomised in 12 groups: group 1: amoxicillin and omeprazole, garlic, vitamin and selenium (n = 286); group 2: amoxicillin and omeprazole, garlic, vitamin and selenium placebo (n = 285); group 3: amoxicillin and omeprazole, garlic placebo, vitamin and selenium (n = 286); group 4: amoxicillin and omeprazole, garlic placebo, vitamin and selenium placebo (n = 285); group 5: amoxicillin and omeprazole placebo, garlic, vitamin and selenium (n = 285); group 6: amoxicillin and omeprazole placebo, garlic, vitamin and selenium placebo (n = 286); group 7: amoxicillin and omeprazole placebo, garlic placebo, vitamin and selenium (n = 286); group 8: amoxicillin and omeprazole placebo, garlic placebo, vitamin and selenium placebo (n = 286); group 9: amoxicillin and omeprazole placebo, garlic; vitamin and selenium (n = 282); group 10: amoxicillin and omeprazole placebo, garlic, vitamin and selenium placebo (n = 281); group 11: amoxicillin and omeprazole placebo, garlic placebo, vitamin and selenium (n = 281); group 12: amoxicillin and omeprazole placebo, garlic placebo, vitamin and selenium placebo (n = 282); daily for 7.3 years. The primary outcome measures were: prevalence of dysplasia or gastric cancer, prevalence of severe chronic atrophic gastritis, intestinal metaplasia, dysplasia or gastric cancer, and average severity score. Secondary outcome measures were: rates of transition from baseline to nal histopathologic states and the effects of treatments on these rates of transition; evidence of the effectiveness of amoxicillin and omeprazole in eradicating Helicobacter pylori, based on 13C-urea breath tests 3 months following treatment, on annual serology, and on a nal pathologic examination of biopsies to look for Helicobacter pylori; and blood pressure at the time of the nal examination Compliance with treatment was checked by measuring the plasma vitamin levels in randomly selected participants every 3 months and counting of the pills. Compliance with treatment was good. The average monthly proportion of participants taking all pills was 92.3%. Serum samples obtained from randomly selected participants demonstrate higher levels of vitamins C and E in participants assigned to vitamins
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Notes

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2 and higher levels of S-allylcysteine in those assigned to garlic preparation. (Wakunaga of America, Co., Ltd, Mission Viejo, CA) provided the garlic preparation, Astra (East Asia Region) provided amoxicillin and omeprazole; and Sino-American Shanghai-Squibb Pharmaceuticals, Ltd. provided vitamin and mineral supplement Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate

SUVIMAX 2004 Methods The SUpplementation en VItamines et Mine raux AntioXydants (SU.VI.MAX) Study Randomised, double-blind, placebo-controlled, primary-prevention trial with parallel group design Generation of the allocation sequence: adequate, random treatment allocation was performed by blocksequence generation stratied by sex and age group by computer Allocation concealment: adequate, capsule boxes were labelled with the participants number, using partitioned organisation to ensure total security of the blind study Blinding: adequate, identical placebo capsules. Follow-up: adequate. Losses to follow-up; 5.4 % in the intervention group and 6.2% in the placebo group. Overall, 739 participants in the active and 828 participants in the placebo group were lost to follow-up Intention-to-treat analysis: yes. Sample size calculations: yes. Country: France. Number of participants randomised: 13017 French adults, 5141 men and 7876 women, aged from 35 to 60 years, mean age 48.95 years Inclusion criteria: lack of disease likely to hinder active participation or threatened 5-year survival; acceptance of possibility to be given placebo and acceptance of the constraints of participation; lack of previous regular supplementation with any of the vitamins and minerals in the supplement provided and absence of extreme beliefs or behaviour regarding diet Exclusion criteria: none stated. Participants were randomly assigned to receive: group 1: beta-carotene 6 mg; vitamin C 120 mg; vitamin E 30 mg; selenium 100 g; zinc 20 mg (n = 6481); group 2: placebo (n = 6536). All participants took a single daily capsule. Median follow-up time was 7.5 years The primary outcome measures were: major fatal and nonfatal ischaemic cardiovascular events and cancer of any kind, except for the basal cell carcinoma of the skin. The secondary outcome measure was: all cause mortality Compliance for the intervention group was conrmed by measuring the biochemical markers of supplementation after 2 years and after 7 years for beta-carotene, vitamin C and selenium. At the end of followup, 74% of participants reported having taken at least two thirds of the capsules. There were no differences between the groups mean percentage of capsules taken, ie, 79% in each group). Sponsors of the trial: Fruit dOr Recherche, Candia, Lipton, Kelloggs, Centre dInformation sur Canderel, Orangina, Este e Lauder, Cereal, Grands Moulins de Paris, CERIN, LOre al, Peugeot, Jet Service, RP Scherer, Sodexho,
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France Telecom, Santogen, Becton Dickinson, Fould Springer, Boehringer Diagnostic, Seppic Givaudan Lavirotte, Le Grand Canal Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate

WACS 2007 Methods The Womens Antioxidant Cardiovascular Study Randomised, double-blind, placebo-controlled secondary prevention trial with two-by-two-by-two factorial design Generation of the allocation sequence: adequate, centrally by computer Allocation concealment: adequate, the randomisation allocation is coded. Shipping department sends out calendar packs (which are identical whether active or placebo) to individual participants depending on this code. All of the calendar packs are in coded boxes, supplied by the drug manufacturer, so that the shippers do not know which drug they are shipping Blinding: adequate, identical placebo capsules and tablets. Follow-up: adequate. Losses to follow-up almost equal in the intervention arms (62 to 78 participants) Intention-to-treat analysis: yes. Sample size calculations: yes. Country: United States of America. Number of participants randomised: 8171, women at high risk with either a history of vascular disease or at least 3 cardiovascular risk factors Inclusion criteria: women 40 years or older, postmenopausal, or had no intention of becoming pregnant, had a self-reported history of cardiovascular disease (CVD), or had at least 3 cardiac risk factors. The cardiac risk factors determining eligibility were self-reported diagnosis of hypertension, high cholesterol level, or diabetes mellitus; parental history of premature myocardial infarction (MI) (before age 60 years) ; obesity (body mass index [BMI] >30 [calculated as weight in kilograms divided by height in meters squared]), current cigarette smoking; and inconsistent report of prior CVD Exclusion criteria: self-reported history of cancer (excluding nonmelanoma skin cancer) within the past 10 years, any serious non-CVD illness, or were currently using warfarin sodium or other anticoagulants Women were randomly assigned according to a 2 x 2 x 2 factorial design to take ascorbic acid (500 mg/d) , vitamin E (600 IU every other day), and beta carotene (50 mg every other day) yielding eight treatment groups A fourth arm was subsequently added to test a combination of folic acid 2.5 mg, vitamin B6 (50 mg, and vitamin B12 1 mg. Surviving members of the original cohort of 8171 women were invited to participate in this arm (referred to hereafter as the folic acid arm). Of 8026 survivors, a total of 5442 were additionally randomised to a folic acid/vitamin B6/vitamin B12 combination or its placebo on April 16, 1998, thus creating a total of 24 distinct treatment groups (16 groups in the folic acid arm, plus 8 groups not in that arm) group 1: beta-carotene, vitamin C, and vitamin E (n = 1020); group 2: beta-carotene placebo, vitamin C, and vitamin E (n = 1021); group 3: beta-carotene, vitamin C, vitamin E placebo (n = 1023);
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group 4: beta-carotene placebo, vitamin C, vitamin E placebo (n = 1023); group 5: beta-carotene, vitamin C placebo, vitamin E (n = 1021); group 6: beta-carotene placebo, vitamin C placebo, vitamin E (n = 1021); group 7: beta-carotene, vitamin C placebo, vitamin E placebo (n = 1020); group 8: beta-carotene placebo, vitamin C placebo, vitamin E placebo (n = 1022); for a mean duration of 9.4 years. Outcomes The primary outcome was a combined outcome measure of cardiovascular disease morbidity and mortality, including incident myocardial infarction, stroke, coronary revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty), and cardiovascular mortality. The individual components of myocardial infarction, stroke, coronary revascularization, and cardiovascular disease death were prespecied secondary outcome measures. Information on transient ischaemic attack and total mortality was also collected and reviewed Compliance was assessed through self-report and dened as taking at least two-thirds of study pills. Reported compliance was, on average, 76% at 4 years and 68% at 8 years of follow-up for each antioxidant, with no signicant difference between active and placebo groups at these times except for ascorbic acid at 8 years (70% versus 67% in the active vs placebo group; P = .01). Mean compliance over follow-up was approximately 73% for all active and placebo agents. In 1999, blood samples were obtained from 30 local participants to evaluate biomarkers for compliance. Blood levels were elevated in each active vs placebo group Vitamin C (ascorbic acid), was provided by BASF Corporation (Mount Olive, New Jersey), vitamin E (600 IU of natural vitamin E (d-alpha tocopherol acetate) by Cognis Corporation (La Grange, Illinois), and beta carotene (50 mg of Lurotin, provided by BASF Corporation)

Notes

Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate

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WHS 2005 Methods Womens Health Study (WHS). Randomised, double-blind, placebo-controlled trial with two-by-two-by-two factorial design in the beginning and than two-by-two Generation of the allocation sequence: adequate, centrally by computer in batches of blocks of size 16 Allocation concealment: adequate, the randomisation allocation is coded. Shipping department sends out calendar packs (which are identical whether active or placebo) to individual participants depending on this code. All of the calendar packs are in coded boxes, supplied by the drug manufacturer, so that the shippers do not know which drug they are shipping Blinding: adequate, identical placebo capsules. Follow-up: adequate. Losses to follow-up; 0.01% in beta-carotene group and 0.005% in placebo group. Overall, 132 participants in the active group and 102 participants in the placebo group had unknown vital status Intention-to-treat analysis: yes. Sample size calculations: yes. Country: United States of America. Number of participants randomised: 39876 females aged 45 years or older, mean age 54.6 years Inclusion criteria: female health professionals willing to take part in the trial. Age 45 years or older; no previous history of coronary heart disease, cerebrovascular disease, cancer (except nonmelanoma skin cancer), or other major chronic illnesses; no history of adverse effects from aspirin; no use of aspirin or nonsteroidal anti-inammatory drugs (NSAIDs) more than once a week, or willingness to forgo their use; no use of anticoagulants or corticosteroids; and no use of individual supplements of vitamin A, E, or beta carotene for more than once a week Exclusion criteria: history of cancer (except non-melanoma skin cancer), coronary heart disease, or cerebrovascular disease Participants were randomly assigned to one of the eight treatment groups. The active agents were 100 mg of aspirin, given on alternate days; 600 IU of vitamin E, given on alternate days; and 50 mg of betacarotene, given on alternate days group 1: aspirin 100 mg, beta-carotene 50 mg, vitamin E 600 IU; group 2: aspirin 100 mg, beta-carotene 50 mg, vitamin E placebo; group 3: aspirin 100 mg, beta-carotene 50 mg placebo, vitamin E 600 IU; group 4: aspirin 100 mg, beta-carotene placebo, vitamin E placebo; group 5: aspirin placebo, beta-carotene 50 mg, vitamin E 600 IU; group 6: aspirin placebo, beta-carotene 50 mg, vitamin E placebo; group 7: aspirin placebo, beta-carotene placebo, vitamin E 600 IU; group 8: aspirin placebo, beta-carotene placebo, vitamin E placebo; A total of 19939 women were assigned at random to receive beta-carotene and 19937 to receive placebo in the beginning of April 1993. A total of 19937 women were assigned at random to receive vitamin E and 19939 to receive placebo. The beta-carotene component of the trial was terminated early, on January 18, 1996. The aspirin and vitamin E components of the trial continued uninterrupted. The time from randomisation to the end of beta-carotene component of the trial averaged 2.1 years. Authors published results of the beta-carotene component of the trial on February 6, 1998, after a median total follow-up of 4.1 years (2.1 years treatment plus 2.0 years follow-up). From that time trials proceeded as two-arm (vitamin E and placebo). Follow-up and validation of reported end points were completed in February 2005. The average duration of follow-up from randomisation to the end of the trial was 10.1 years (range, 8.2 to 10.9 years)

Participants

Interventions

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WHS 2005

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Outcomes

The primary outcome measures were: incidence of invasive cancer (except non-melanoma skin cancer), myocardial infarction, and stroke. The secondary outcome measures were: non-fatal myocardial infarction, non-fatal stroke, death from cardiovascular causes, and death from any cause Compliance with treatment was checked by random serum assessments. Compliance with treatment was excellent. At the time of termination of the beta-carotene component, 87% of the active group have taken at least two thirds of the study capsules, while 9.9% of the women in the placebo group have taken betacarotene or vitamin A supplements outside the trial The active agents were provided as follows: aspirin by Bayer AG, Leverkusen, Germany; vitamin E by Natural Source Vitamin E Association, Washington DC; and beta-carotene by Lurotin, BASF Corporation, Wiandotte, MI Data were extracted from the primary publication, but additional information was received through personal communication with the authors

Notes

Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate

Yu 1991 Methods Randomised clinical placebo-controlled trial with parallel group design Generation of the allocation sequence: unclear, not reported Allocation concealment: unclear, not reported. Blinding: adequate, identical placebo tablets. Follow-up: inadequate. Intention-to-treat analysis: no. Sample size calculations: no. Country: China. Number of participants randomised: 2474, aged 18 to 75 years. Inclusion criteria: members of families with high incidences of liver cancer. Exclusion criteria: none stated. Participants were randomly assigned to receive: group 1: 200 g of selenium in the form of selenized yeast tablet (n = 1444); group 2: identical placebo of yeast tablet (n = 1030); daily for two years. The primary outcome measure was the occurrence of liver cancer Compliance with treatment is not reported. Data were extracted from the primary publication.
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Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Risk of bias Item Allocation concealment? Yu 1997 Methods Randomised clinical placebo-controlled trial with parallel group design Generation of the allocation sequence: unclear, not reported Allocation concealment: unclear, not reported. Blinding: adequate, identical placebo tablets. Follow-up: adequate, no losses to follow-up. Intention-to-treat analysis: yes. Sample size calculations: no. Country: China. Number of participants randomised: 226, aged 21 to 63 years. Inclusion criteria: HBsAg carriers with normal liver function Exclusion criteria: none stated. Participants were randomly assigned to receive: group 1: 200 g of selenium in the form of selenized yeast tablet (n = 113); group 2: identical placebo of yeast tablet (n = 113); daily for four years. Patients were followed-up eight years from 1987 to 1994. The primary outcome measure was the occurrence of liver cancer Compliance with treatment is not reported. Data were extracted from the primary publication. Authors judgement Unclear Description B - Unclear

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Outcomes Notes

Risk of bias Item Allocation concealment? Authors judgement Unclear Description B - Unclear

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Zhu 2003 Methods Randomised double-blind, placebo-controlled trial with parallel group design Generation of the allocation sequence: unclear, not reported Allocation concealment: unclear, not reported. Blinding: adequate. Patients were allocated to four arms (see Interventions). The three arms (group 2 to 4), used in this review, seem to have been adequately placebo controlled Follow-up: adequate, 3.7 % of patients were lost to follow up, and the losses were similar between the treatment groups Intention-to-treat analysis: yes. Sample size calculations: no. Country: China. Number of participants randomised: 216; 137 males, 79 females, aged 28 to 77 years, mean age 55.6 years Inclusion criteria: patients with atrophic gastritis. Exclusion criteria: history of malignant tumour, gastrointestinal operation, chronic heart, lung, liver, and renal disease, taking vitamin pills in the last three months Patients were assigned to four treatment groups to receive: group 1: folate 20 mg per day plus vitamin B12, 1 mg intramuscularly, per month for one year, then folate 20 mg twice a week plus vitamin B12 1 mg per three months for the next year (n = 44); group 2: natural beta-carotene, 30 mg per day in the rst year, then 30 mg twice a week for the next year (n = 61); group 3: synthetic beta-carotene administered as natural beta-carotene (n = 57); group 4: placebo (n = 54). All patients were followed-up from 1994 to 2001, in total seven years The primary outcome measures were the occurrence of gastrointestinal tumors and mortality Compliance with treatment was checked by counting the remaining pills at each visit, as well as by measurement of relevant vitamin concentrations in serum randomly at 15 days, 3, 6, 12, and 24 months Compliance, as assessed by quarterly pill counting and random blood sampling, was excellent throughout the trial. More than 90% of all patients took pills according to the protocol. After the supplementation, the serum levels of folic acid or relative carotenoids increased several times in the three active treated groups, but not in placebo Folate and vitamin B12 were provided by Shanghai Huanghe Pharmacy and Shanghai First Pharmacy, China; natural beta-carotene by Betatene Co. Australia and Henkel Co.; synthetic beta-carotene by Shanghai Sixth Pharmacy and Henkel Co Data were extracted from the primary publication.

Participants

Interventions

Outcomes Notes

Risk of bias Item Allocation concealment? Authors judgement Unclear Description B - Unclear

ATBC: Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study CARET: The Beta-Carotene and Retinol Efcacy Trial HOPE: Heart Outcomes Prevention Evaluation Study
Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 59

HOPE TOO: Heart Outcomes Prevention Evaluation Study The Ongoing Outcomes HPS: Heart Protection Study. NIT: Nutrition Intervetion Trial NPCT: Nutritional Prevention of Cancer Trial PHS: Physicians Health Study SIT: Shandong Intervention Trial SUVIMAX: The SUpplementation en VItamines et Mine raux AntioXydants WACS: Women Antioxidant Cardiovascular Study WHS: Womens Health Study BCC: basal cell skin cancers SCC: squamous cell skin cancer RDA: recommended daily allowance HBsAg: hepatitis B surface antigen AFP: alpha fetoprotein US: United States

Characteristics of excluded studies [ordered by study ID]

Study Bespalov 2004

Reason for exclusion Randomised clinical trial of the drug karinat was carried out in patients with chronic multifocal atrophic gastritis. Karinat contains beta-carotene 2.5 mg, alpha-tocopherol 5 mg, ascorbic acid 30 mg and garlic powder 150 mg per tablet. Out of 66 patients, 34 received karinat and 32 placebo. This is phase II clinical trial. There were no participants with gastrointestinal cancers at the end of the trial A prospective cohort study. Randomised clinical trial which studied the effects of beta-carotene, vitamin E, and pharmaceutical complex of natural antioxidants on abnormally high ornithine decarboxylase activity in antral gastric mucosa of patients with atrophic gastritis accompanied by intestinal metaplasia We have been unable to obtain data on gastrointestinal cancers from this trial Randomised clinical trial to test test whether vitamin C and E supplements to triple therapy can improve the Helicobacter pylori eradication rate and gastric inammation. Trial is of short follow-up period without data on incidence of gastrointestinal cancers A case-control study in Uruguay with patients already aficted with cancer of the oral cavity, pharynx, larynx, and oesophagus. Patients were interviewed about their dietary habits. Based on food frequency questionnaire, intake of certain nutrients was calculated A case-control study in Uruguay with patients already aficted with cancer of the oral cavity, pharynx, larynx, and oesophagus. Patients were interviewed about their dietary habits and based on food frequency questionnaire intake of certain food groups was calculated A case-control study in Uruguay. Intake of antioxidants and other dietary habits were obtained indirectly by face-to-face interviews with patients already having oesophageal cancer and control group of patients by the food frequency questionnaire
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Bostick 1993 Bukin 1996

Bussey 1982 Chuang 2002

De Stefani 1999

De Stefani 1999a

De Stefani 2000

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

(Continued)

DeCosse 1975

Ascorbic acid, 3 g daily, was given to ve patients who had active rectal adenomatous polyp formation long after ileorectal anastomosis for familial polyposis. This is not randomised clinical trial We have been unable to obtain data on gastrointestinal cancers from this trial We have been unable to obtain data on gastrointestinal cancers from this trial Randomised clinical trial in patients with head and neck cancer or with lung cancer, most of whom had a history of smoking. Patients were supplemented with vitamin A and N-acetylcysteine An observational study of the demographic and psychosocial characteristics as well as the health behaviours, health status, and counselling practices of women physicians Randomised clinical trial of beta-carotene in prevention of basal-cell and squamous-cell cancers of the skin. The trial did not provide data about the incidence of gastrointestinal cancers in supplemented and placebo group Randomised trial for prevention of colorectal cancer where patients with multiple colorectal tumours were enrolled in two regimens. One was dietary guidance alone, and the other was dietary guidance plus eating wheat bran biscuits A large prospective cohort study that examined the association between colorectal cancer mortality and use of individual vitamin C and E supplements in the Americans Cancer Societys Cancer Prevention Study II cohort. Intake of vitamin C and vitamin E was calculated based on self-administrated questionnaire Ecological analysis of data from The Seven Countries Study to investigate whether intake of ber and plant foods contributes to cross cultural diferences in 25-year colorectal-cancer mortality in man A population-based case control study, which examined the effects of diet on pancreatic cancer among the residents of Shanghai, newly diagnosed with this type of cancer. Information of usual adult dietary intake was obtained by interviewers, using a food frequency questionnaire. Intake of certain group foods was compared with incidence of pancreatic cancer Randomised, double-blind, placebo-controlled crossover trial, evaluating the efcacy of a combined antioxidant preparation in the management of chronic pancreatitis. Patients with conrmed chronic pancreatitis (N = 36) were randomised to receive treatment with either antioxidants, which contains the antioxidants selenium, beta-carotene, L-methionine, and vitamins C and E, or placebo for 10 weeks. Each group of patients then switched to receive the alternative treatment for a further 10 weeks. Markers of antioxidant status were measured by blood sampling, whereas quality of life and pain were assessed using the SF-36 questionnaire. Nineteen patients completed the full 20 weeks of treatment. This trial did not full our inclusion criteria A case-control study. Serum selenium levels were measured in patients with oral or oesophageal cancer and compared with matched controls A case-control study in Italy concerning intake of lycopene in patients with histologically conrmed cancer of several organs (between them oesophageal and colorectal). Intake of antioxidants was calculated retrospectively based on the interview with patients using a food frequency questionnaire

DeCosse 1989 ECP-IM 1994 EUROSCAN 2000

Frank 1995

Greenberg 1990

Ishikawa 1995

Jacobs 2001

Jansen 1999

Ji 1995

Kirk 2006

Krishnaswamy 1993

La Vecchia 2002

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(Continued)

Lacroix 1987

An observational study conducted to determine whether it is possible to increase plasma levels of retinol in cancer patients. Plasma levels of retinol were measured in 46 patients treated with chemotherapy for various malignancies and in 43 control individuals, before and after supplementation An article describing the rationale, design, recruitment, and baseline participant characteristics of the Polyp Prevention Trial (Schatzkin 1996), a multicenter randomised controlled trial examining the effect of a lowfat, high-ber, high-vegetable and -fruit dietary pattern on the recurrence of colorectal adenomatous polyps A multicenter randomised clinical trial, as a part of Polyp Prevention Trial (Schatzkin 1996), which examined results of dietary changes (implementation of four year high-ber, high-fruit and -vegetable, low-fat dietary intervention) on the recurrence of adenomatous polyps in large the bowel The association between dietary intake of various micronutrients and colorectal cancer risk was analysed using data from a case-control study conducted between 1992 and 1997 in the Swiss Canton of Vaud. Dietary habits were investigated using a validated food frequency questionnaire Randomised clinical trial of selenomethionine 200 microg daily and/or celecoxib 200 mg twice daily (2 x 2 factorial design) among residents of Linxian, Peoples Republic of China. Subjects had histologically conrmed mild or moderate esophageal squamous dysplasia at baseline. Esophagogastroduodenoscopy was performed before and after a 10-month intervention. Per-subject change (regression, stable, or progression) in the worst dysplasia grade was dened as the primary end point. Results were compared by agent group (selenomethionine versus placebo; celecoxib versus placebo). Two hundred sixty-seven subjects fullled all eligibility criteria, and 238 (89%) completed the trial. Authors did not report incidence of oesophageal cancer A review, discussing the results of several randomised clinical trials concerning the wheat bran ber and development of adenomatous polyps The aim of this study was to test the effect of antioxidants on enzymatic abnormalities and free radicalsmodied DNA adducts associated with pre-malignant changes in HP-negative chronic atrophic gastritis patients. 60 patients with and intestinal metaplasia underwent a GI endoscopy with biopsy samples for histology and for: alpha-tocopherol, malonyldialdehyde, xanthine oxidase, ornithine decarboxylase and 8hydroxydeoxyguanosine. Patients were randomly allocated into three groups supplemented for 6 months with: vitamin E, 300 mg/day; Multivitamin, 2 tablets/day and a certied fermented papaya preparation 6 g (Immune-Age FPP, Osato Research Institute, Gifu, Japan). Ten dyspeptic patients without histological abnormalities served as control. Histological and biochemical parameters were blindly repeated at 3 and 6 months. There are no results about the incidence of gastric cancer. This is phase II clinical trial Randomised trial to test the effect of antioxidant supplementation on enzymatic abnormalities and free radicalmodied DNA adducts associated with premalignant changes in the gastric mucosa of elderly patients with HPnegative atrophic gastritis (CAG). Sixty patients with atrophic gastritis and intestinal metaplasia underwent a nutritional interview and a gastroscopy with multiple biopsy samples in the antrum that were processed for histology and for assaying: alpha-tocopherol, MDA, xanthine oxidase (XO), ornithine decarboxylase (ODC), and 8-OHdG. Patients were randomly allocated into three matched groups and supplemented for 6 months with (1) vitamin E, 300 mg/day; (2) multivitamin, two tablets t.i.d.; and (3) Immun-Age 6 g/day nocte (ORI, Gifu, Japan), a certied fermented papaya preparation with basic science-validated antioxidant/ immunomodulant properties. Ten dyspeptic patients served as controls. Histology and biochemistry were blindly repeated at 3 and 6 months

Lanza 1996

Lanza 2001

Levi 2000

Limburg 2005

Macrae 1999

Marotta 2003

Marotta 2004

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(Continued)

Mayne 2001 Moriwaki 2002 Muto 1996

A case-control study, which examined nutrient intake as a risk factor for oesophageal and gastric cancers A review concerning current perspectives in prevention of liver cancer Randomised clinical trial in which 89 patients were studied after surgical resection of primary hepatoma or the percutaneous injection of ethanol. They were randomly assigned to receive either polyprenoic acid (600 mg daily) or placebo for 12 months. The primary outcome measure of the study was appearance of a histologically conrmed recurrence or new hepatoma. The reason for excluding this trial was existence of liver cancer at the time of randomisation An observational study investigated serum retinol levels in patients with liver disease and hepatocellular carcinoma, assessing its importance as a risk factor for the development of hepatocellular carcinoma A case-control study comparing plasma selenium levels and risk of cancer by specic sites A case-control study carried out on patients with newly diagnosed hepatocellular carcinoma and controls without hepatocellular carcinoma. Plasma levels of vitamin A, vitamin E, or beta-carotene were compared among the two groups as well as education level, consumption of alcohol, and smoking status Study involving healthy volunteers whose diets were supplemented with 500 milligrams per day of vitamin C for six weeks. The levels of oxidative damage to peripheral blood lymphocytes in terms of modied DNA bases were assessed. It is not a randomised trial Substudy of the Nutrition Prevention Trial already included in the analyses An observational study, which compared plasma liposoluble vitamins with tocopherol content in healthy and neoplastic liver tissue in humans A cross-sectional observational study among patients with colorectal adenomas, comparing the incidence of adenomas with plasma selenium levels Randomised clinical trial to examine the effect of vitamin C supplementation on serum pepsinogen level, Helicobacter pylori infection, and cytotoxin-associated gene A status. Subjects aged 40 to 69 years living in one village in Akita prefecture, a high-risk area for gastric cancer in Japan, were recruited through annual health check-up programs. Among 635 participants diagnosed as having chronic gastritis on the basis of serum PG levels, after excluding ineligible cases, 439 subjects were assigned to one of four groups using a 2 x 2 factorial design (0 or 15 mg/day beta-carotene and 50 or 500 mg/day vitamin C). However, based on the results from two beta-carotene trials in the United States, beta-carotene was discontinued (vitamin C supplementation was continued). Finally, 120 subjects in the low-dose group (vitamin C 50 mg), and 124 subjects in the high-dose group (vitamin C 500 mg) completed the 5-year supplementation. Due to modication of protocol primary end point was not incidence of gastric cancer as it was rst planned A study describing the dietary intervention programme and participant baseline dietary characteristics of the Polyp Prevention Trial (PPT), a multicenter randomised trial examining the effect of a low-fat, high-ber high-vegetable and -fruit dietary pattern on the recurrence of colorectal adenomatous polyps, precursors of most colorectal malignancies

Newsome 2000

Nomura 1987a Pan 1993

Podmore 1998a

Qu 2007 Rocchi 1997

Russo 1997

Sasazuki 2003

Schatzkin 1996

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(Continued)

Simone 2002

An observational study with aim to determine whether short-term supplementation of beta-carotene or vitamin E would result in their respective accumulation in normal colonic mucosa and in adenomatous polyps and to determine whether the intake of beta-carotene would interfere with the concentration of vitamin E in these target tissues Randomised clinical trial of intravenous antioxidant (n-acetylcysteine, selenium, vitamin C) therapy in patients with predicted severe acute pancreatitis. This trial did not fulll our inclusion criteria The Hiraka Dietary Intervention Study is a community-based randomized cross-over trial designed to develop an effective dietary modication tool and system in an area with high mortality of stomach cancer and stroke. The participants were 550 healthy volunteers and were randomized into two groups with tailored dietary education to decrease sodium intake and to increase vitamin C and carotene intakes either in the rst year (intervention group) or in the second year (control group). Dietary changes were assessed using a validated self-administered diet history questionnaire, fasting blood samples, and 48-hour urine samples, which were obtained before and after the one year period A nation-wide, population-based, case-control study in Sweden. Intake of antioxidants in newly diagnosed patients with oesophageal cancer was calculated indirectly by interviews with patients about their dietary habits, by food frequency questionnaires, during the 20 years period prior to interview A review of the causes of the main human cancers, analysing the mechanisms of the protective effects of fruits and vegetables The purpose of this case-control study was to further investigate whether regular vitamin or calcium supplement intake inuenced the incidence of recurrent adenomatous polyps in patients with previous neoplasia who were undergoing follow-up colonoscopy A review discussing the problem of vitamin nutrition and gastroesophageal cancer An observational cohort study of 8436 men in Taiwan recruited between 1984 and 1986. Serum retinol levels were compared between patients with hepatocellular carcinoma and matched controls An observational study, which examined the association between plasma selenium levels and risk of hepatocellular carcinoma among chronic carriers of hepatitis B and/or C virus in a cohort of 7342 men in Taiwan An observational prospective cohort study evaluating the association of retinol and antioxidant vitamins intake and the risk of cancers of upper digestive tract in Iowa Womens Health Study

Siriwardena 2007

Takshashi 2003

Terry 2000

Weisburger 1991

Whelan 1999

Yang 2000 Yu 1995

Yu 1999

Zheng 1995

PPT: Polyp Prevention Trial t.i.d: ter in die (three times a day).

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Characteristics of ongoing studies [ordered by study ID]


APPOSE 2001 Trial name or title Methods Participants Country: Australia. Inclusion criteria: men at risk of prostate cancer. The cohort size will be 2000 participants in each arm Parallel group design. Participants were randomly assigned to receive either 200 microg selenium or matching placebo daily The primary outcome measure is incidence of prostate cancer. 2001 Anthony J. Costello, MD, Level 1, 77 Victoria Parade, Fitzroy, Melbourne 3065, Australia; email: cosurol@mpx.com.au The Australian Prostate Cancer Prevention Trial Using Selenium (APPOSE) trial

Interventions

Outcomes Starting date Contact information

Notes HGPIN 2006 Trial name or title Methods Participants Country: United States of America Inclusion criteria: men high-grade prostatic intraepithelial neoplasia (HGPIN) must be identied by biopsy; the tissue must then be conrmed by centralized pathology review to show HGPIN and no cancer Exclusion criteria: taking nasteride or any other drug known to affect PSA, or selenium supplements in excess of 50 g/d The patient is randomly assigned to 200 g/d of selenium as L-selenomethionine, or to placebo, with treatment scheduled for 3 years The primary outcome measure is incidence of prostate cancer. 1999 James R. Marshall, Roswell Park Cancer Institute, Buffalo, NY 14263. Phone: 716-845-8444; Fax: 716-8458487. E-mail: james.marshall@roswellpark.org High-grade prostatic intraepithelial neoplasia (HGPIN) trial

Interventions

Outcomes Starting date Contact information

Notes

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PHS II 2000 Trial name or title Physicians Health Study II (PHS II). Randomised double-blind, placebo-controlled trial with two-by-two-by-two-by-two factorial design

Methods Participants Country: United States of America. Number of participants randomised: 15,000 US male physicians, aged 55 years and older. Inclusion criteria: willing and eligible physicians to take part in this trial, including all willing and eligible participants from Physician Health Study I Physicians Health Study II utilized a two-by-two-by-two-by-two factorial design to test alternate day betacarotene, alternate day vitamin E, daily vitamin C, and a daily multivitamin. During the rst half of 2003 the beta-carotene component of the ongoing Physicians Healthy Study II has been terminated. It continues to examine a multivitamin, vitamin C, and vitamin E The primary outcome measures are the incidence of total and prostate cancer, cardiovascular and eye diseases 1999 Charles H. Hennekens MD 1415 W. Camino Real, Boca Raton, FL 33486, United States of America

Interventions

Outcomes Starting date Contact information

Notes SELECT 2003 Trial name or title The selenium and vitamin E cancer prevention trial, SELECT). Randomised double-blind, placebo-controlled trial with two-by-two factorial design

Methods Participants Country: United States of America. Number of participants randomised: 32,400 males, aged 50 years or older. Inclusion criteria: age > 55 years for Caucasians and > 50 years for African-Americans, digital rectal examination not suspicious for prostate cancer, total serum prostate specic antigen < 4.0 ng/ml, no prior history of prostate cancer or high-grade prostatic intraepithelial neoplasia, no anticoagulation therapy, except low-dose aspirin, normal blood pressure (systolic blood pressure < 150 mm Hg and diastolic blood pressure < 90 mm Hg), willing to restrict supplementation of selenium and vitamin E during participation. Participants were randomly assigned to receive either 200 g of 1-selenomethionine, 400 mg of racaemic alpha-tocopherol, and an optional multivitamin containing no selenium or vitamin E. The racaemic mix of alpha-tocopherol will include both the d- and l-isomers. Participants will be divided in four group according to two-by-two factorial design: group 1: placebo (n = 8100); group 2: vitamin E (n = 8100); group 3: selenium (n = 8100);
66

Interventions

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SELECT 2003

(Continued)

group 4: vitamin E and selenium (n = 8100). Outcomes The primary outcome measure is the clinical incidence of prostate cancer as determined by a clinical diagnostic work-up, including yearly digital rectal examination and serum prostate specic antigen level. Secondary outcome measures will include prostate cancer-free survival, all cause mortality, and the incidence and mortality of other cancers and diseases potentially impacted by the chronic use of selenium and vitamin E. Other trial objectives will include periodic quality of life assessments, assessment of serum micronutrient levels and prostate cancer risk, and studies of the evaluation of biological and genetic markers with the risk of prostate cancer. 2001 Eric A. Klein, Section of Urologic Oncology, Department of Urology, Cleveland Clinic Foundation, Cleveland, OH, USA Tel.: +1-216-444-5591; Fax: +1-216-4453532, e-mail address: kleine@ccf.org.

Starting date Contact information

Notes

APOSE: The Australian Prostate Cancer Prevention Trial HGPIN: High-Grade Prostatic Intraepithelial Neoplasia PHS II: Physicians Health Study II SELECT: The selenium and vitamin E cancer prevention trial PSA: prostate-specic antigen

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DATA AND ANALYSES

Comparison 1. Antioxidants versus placebo


No. of studies 18 No. of participants 174019

Outcome or subgroup title 1 Occurrence of gastrointestinal cancers in trials with a low or high risk of bias 1.1 Trials with low risk of bias 1.2 Trials with high risk of bias 2 Occurrence of gastrointestinal cancers - generation of the allocation sequence 2.1 Adequate 2.2 Unclear/Inadequate 3 Occurrence of gastrointestinal cancers - allocation concealment 3.1 Adequate 3.2 Unclear/Inadequate 4 Occurrence of gastrointestinal cancers - follow-up 4.1 Adequate 4.2 Unclear/Inadequate 5 Occurrence of all gastrointestinal cancers - different antioxidants 5.1 Beta-carotene 5.2 Vitamin C 5.3 Vitamin E 5.4 Selenium 5.5 Vitamin A and beta-carotene 5.6 Beta-carotene and vitamin C 5.7 Beta carotene and vitamin E 5.8 Vitamin A, riboavin, and zinc 5.9 Beta-carotene, vitamin C, and vitamin E 5.10 Vitamin C, vitamin E, and selenium 5.11 Beta-carotene, vitamin C, vitamin E, and selenium 5.12 Combination of antioxidants (13 vitamins and 13 minerals)

Statistical method Risk Ratio (M-H, Random, 95% CI)

Effect size 0.94 [0.83, 1.06]

12 6 18

163439 10580

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

1.04 [0.96, 1.13] 0.59 [0.43, 0.80] Subtotals only

12 6 18

162948 10580

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

1.05 [0.98, 1.13] 0.59 [0.43, 0.80] Subtotals only

13 5 18 16 2 16 4 1 1 5 1 1 1 1 2 1 1 1

163558 9970

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

1.05 [0.98, 1.13] 0.57 [0.41, 0.78] Subtotals only 0.98 [0.87, 1.10] 0.72 [0.51, 1.02] Subtotals only 1.04 [0.80, 1.35] Not estimable 1.11 [0.93, 1.34] 0.59 [0.46, 0.75] 1.10 [0.91, 1.32] 2.90 [0.12, 70.52] 1.18 [0.98, 1.41] 1.33 [0.30, 5.91] 0.96 [0.80, 1.16] 1.01 [0.60, 1.68] 0.83 [0.53, 1.32] 1.05 [0.88, 1.25]

166021 7507

37046 247 14573 11110 18314 238 14565 610 22516 3365 13017 3318

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6 Occurrence of different gastrointestinal cancers - all antioxidants 6.1 Occurrence of oesophageal cancer 6.2 Occurrence of gastric cancer 6.3 Occurrence of small intestine cancer 6.4 Occurrence of colorectal cancer 6.5 Occurrence of pancreatic cancer 6.6 Occurrence of hepatocellular carcinoma 6.7 Occurrence of biliary tract cancer 7 Occurrence of oesophageal cancer 7.1 Beta-carotene 7.2 Vitamin E 7.3 Selenium 7.4 Vitamin A and beta-carotene 7.5 Beta-carotene and vitamin E 7.6 Vitamin A, riboavin, and zinc 7.7 Beta-carotene, vitamin C, and vitamin E 7.8 Beta-carotene, vitamin C, vitamin E, and selenium 7.9 Combination of antioxidants 8 Occurrence of gastric cancer 8.1 Beta-carotene 8.2 Vitamin C 8.3 Vitamin E 8.4 Selenium 8.5 Vitamin A and beta-carotene 8.6 Beta-carotene and vitamin C 8.7 Beta-carotene and vitamin E 8.8 Beta-carotene, vitamin C, and vitamin E 8.9 Vitamin C, vitamin E, and selenium 8.10 Beta-carotene, vitamin C, vitamin E, and selenium

18

Risk Ratio (M-H, Random, 95% CI)

Subtotals only

9 12 1 9 6 9 2 8 2 1 1 1 1 1 1 1 1 11 4 1 1 1 1 1 1 2 1 1

126288 157300 39876 153972 142947 130674 52893

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

1.06 [0.89, 1.28] 1.14 [0.97, 1.33] 4.00 [0.45, 35.79] 0.97 [0.86, 1.09] 1.16 [0.90, 1.50] 0.80 [0.56, 1.14] 0.61 [0.21, 1.78] Subtotals only 0.75 [0.25, 2.30] 1.46 [0.72, 2.96] 0.40 [0.08, 2.07] 1.43 [0.90, 2.29] 1.23 [0.59, 2.56] 1.33 [0.30, 5.91] 1.19 [0.71, 2.01] 1.01 [0.14, 7.16] 0.96 [0.76, 1.22] Subtotals only 1.12 [0.79, 1.59] Not estimable 1.30 [0.90, 1.88] 0.76 [0.44, 1.31] 0.89 [0.46, 1.73] 2.90 [0.12, 70.52] 1.40 [0.98, 2.01] 1.25 [0.78, 2.00] 1.01 [0.60, 1.68] 1.01 [0.14, 7.16]

14741 14573 1312 18314 14565 610 20536 13017 3318

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

37046 247 14573 5033 18314 238 14565 22516 3365 13017

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8.11 Combination of antioxidants 9 Occurrence of colorectal cancer 9.1 Beta-carotene 9.2 Vitamin E 9.3 Selenium 9.4 Vitamin A and beta-carotene 9.5 Beta-carotene and vitamin E 9.6 Beta-carotene, vitamin C, and vitamin E 9.7 Beta-carotene, vitamin C, vitamin E, and selenium 10 Occurrence of pancreatic cancer 10.1 Beta-carotene 10.2 Vitamin E 10.3 Vitamin A and beta-carotene 10.4 Beta-carotene and vitamin E 10.5 Beta-carotene, vitamin C, and vitamin E 10.6 Beta-carotene, vitamin C, vitamin E, and selenium 11 Occurrence of hepatocellular carcinoma 11.1 Beta-carotene 11.2 Vitamin E 11.3 Selenium 11.4 Vitamin A and beta-carotene 11.5 Beta-carotene and vitamin E 11.6 Beta-carotene, vitamin C, and vitamin E 11.7 Beta-carotene, vitamin C, vitamin E, and selenium 12 Occurrence of biliary tract cancer 12.1 Beta-carotene, vitamin C, vitamin E, and selenium 13 Mortality in trials with a low or high risk of bias 13.1 Trials with low risk of bias 13.2 Trials with high risk of bias 14 Mortality after excluding selenium trials

1 8 3 2 1 1 1 1 1 5 2 1 1 1 1 1 8 1 1 4 1 1 1 1 1 1 14 13 1 9

3318

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

1.19 [0.89, 1.58] Subtotals only 1.09 [0.79, 1.51] 1.10 [0.87, 1.39] 0.48 [0.22, 1.05] 0.97 [0.76, 1.25] 1.20 [0.89, 1.63] 0.84 [0.65, 1.07] 0.88 [0.49, 1.58] Subtotals only 1.02 [0.54, 1.90] 0.97 [0.67, 1.39] 1.33 [0.84, 2.09] 0.93 [0.65, 1.35] 1.00 [0.57, 1.76] 0.67 [0.19, 2.38] Subtotals only 1.92 [0.96, 3.85] 1.33 [0.63, 2.82] 0.56 [0.42, 0.76] 1.35 [0.51, 3.54] 1.25 [0.59, 2.67] 1.40 [0.44, 4.41] 1.01 [0.06, 16.12] Subtotals only 0.20 [0.01, 4.20] 1.02 [0.97, 1.07] 1.03 [0.98, 1.08] 0.94 [0.84, 1.06] 1.06 [1.01, 1.10]

36812 24114 1312 18314 14565 20536 13017

36640 14573 18314 14565 20536 13017

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

14569 14573 9798 18314 14565 20536 13017

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

13017 201194 171610 29584 150598

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

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14.1 Trials with low risk of bias 14.2 Trials with high risk of bias 15 Mortality - different antioxidants 15.1 Beta-carotene 15.2 Vitamin C 15.3 Vitamin E 15.4 Selenium 15.5 Vitamin A and beta-carotene 15.6 Beta-carotene and vitamin C 15.7 Beta-carotene and vitamin E 15.8 Beta-carotene, vitamin C, and vitamin E 15.9 Vitamin C, vitamin E, and selenium 15.10 Beta-carotene, vitamin C, vitamin E, and selenium 15.11 Combination of antioxidants 16 Adverse effects - beta-carotene 16.1 Transient yellowing of the skin 16.2 Persistent yellowing of the skin 16.3 Belching 16.4 Gastrointestinal upset 17 Adverse effects - vitamin E 17.1 Haemorrhagic stroke 18 Adverse effects - selenium 18.1 Gastrointestinal upset

9 0 13 4 2 3 1 1 1 1 3 1 1 2 5 4 1 1 1 3 3 1 1

150598 0

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

1.06 [1.01, 1.10] Not estimable Subtotals only 1.05 [0.99, 1.11] 0.97 [0.77, 1.23] 1.02 [0.98, 1.06] 0.84 [0.67, 1.07] 1.16 [1.09, 1.23] 2.79 [0.57, 13.68] 1.06 [1.02, 1.11] 1.04 [0.97, 1.11] 0.82 [0.62, 1.08] 0.78 [0.58, 1.05] 0.94 [0.85, 1.05] Subtotals only 1.85 [0.74, 4.67] 29.14 [21.60, 39.32] 2.22 [1.80, 2.74] 1.03 [1.00, 1.06] Subtotals only 1.01 [0.82, 1.23] Subtotals only 1.51 [0.78, 2.95]

39162 2523 26157 1312 18314 492 14565 30687 3365 13017 32902

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

91252 29133 22071 8171 74985 1312

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Analysis 1.1. Comparison 1 Antioxidants versus placebo, Outcome 1 Occurrence of gastrointestinal cancers in trials with a low or high risk of bias.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 1 Occurrence of gastrointestinal cancers in trials with a low or high risk of bias

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Trials with low risk of bias ATBC 2003 CARET 2004 Correa 2000 HOPE TOO 2005 HPS 2002 NIT2 1993 NPCT 1996 PHS 1996 Plummer 2007 SIT 2006 SUVIMAX 2004 WHS 2005 722/21846 243/9420 2/739 69/4761 215/10269 219/1657 11/653 219/11036 3/990 29/1677 33/6481 194/19937 209/7287 209/8894 3/237 57/4780 225/10267 209/1661 24/659 217/11035 1/990 29/1688 40/6536 180/19939 11.8 % 10.9 % 0.5 % 6.6 % 10.9 % 11.1 % 2.5 % 10.8 % 0.3 % 4.1 % 4.7 % 10.4 % 1.15 [ 0.99, 1.34 ] 1.10 [ 0.91, 1.32 ] 0.21 [ 0.04, 1.27 ] 1.22 [ 0.86, 1.72 ] 0.96 [ 0.79, 1.15 ] 1.05 [ 0.88, 1.25 ] 0.46 [ 0.23, 0.94 ] 1.01 [ 0.84, 1.22 ] 3.00 [ 0.31, 28.79 ] 1.01 [ 0.60, 1.68 ] 0.83 [ 0.53, 1.32 ] 1.08 [ 0.88, 1.32 ]

Subtotal (95% CI)

89466

73973

84.6 %

1.04 [ 0.96, 1.13 ]

Total events: 1959 (Antioxidants), 1403 (Control) Heterogeneity: Tau2 = 0.00; Chi2 = 13.68, df = 11 (P = 0.25); I2 =20% Test for overall effect: Z = 1.01 (P = 0.31) 2 Trials with high risk of bias Li 2000 Li 2004 Munoz 1985 Yu 1991 Yu 1997 Zhu 2003 34/1112 44/2526 4/305 10/1444 4/113 2/118 57/953 57/2507 3/305 13/1030 11/113 5/54 5.4 % 5.8 % 0.6 % 1.9 % 1.1 % 0.6 % 0.51 [ 0.34, 0.77 ] 0.77 [ 0.52, 1.13 ] 1.33 [ 0.30, 5.91 ] 0.55 [ 0.24, 1.25 ] 0.36 [ 0.12, 1.11 ] 0.18 [ 0.04, 0.91 ]

Subtotal (95% CI)

5618

4962

15.4 %

0.59 [ 0.43, 0.80 ]

Total events: 98 (Antioxidants), 146 (Control) Heterogeneity: Tau2 = 0.03; Chi2 = 6.10, df = 5 (P = 0.30); I2 =18%

0.1 0.2

0.5

10

Favours antioxidants

Favours control

(Continued . . . )

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72

(. . .
Study or subgroup Antioxidants n/N Test for overall effect: Z = 3.34 (P = 0.00085) Control n/N Risk Ratio MH,Random,95% CI Weight

Continued) Risk Ratio MH,Random,95% CI

Total (95% CI)

95084

78935

100.0 %

0.94 [ 0.83, 1.06 ]

Total events: 2057 (Antioxidants), 1549 (Control) Heterogeneity: Tau2 = 0.03; Chi2 = 36.98, df = 17 (P = 0.003); I2 =54% Test for overall effect: Z = 1.03 (P = 0.30)

0.1 0.2

0.5

10

Favours antioxidants

Favours control

Analysis 1.2. Comparison 1 Antioxidants versus placebo, Outcome 2 Occurrence of gastrointestinal cancers - generation of the allocation sequence.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 2 Occurrence of gastrointestinal cancers - generation of the allocation sequence

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Adequate ATBC 2003 CARET 2004 Correa 2000 HOPE TOO 2005 HPS 2002 NIT2 1993 NPCT 1996 PHS 1996 Plummer 2007 SIT 2006 SUVIMAX 2004 WHS 2005 722/21846 243/9420 2/368 69/4761 215/10269 219/1657 11/653 219/11036 3/990 29/1677 33/6481 194/19937 209/7287 209/8894 0/117 57/4780 225/10267 209/1661 24/659 217/11035 1/990 29/1688 40/6536 180/19939
0.1 0.2 0.5 1 2 5 10

14.4 % 13.1 % 0.2 % 7.6 % 13.0 % 13.4 % 2.7 % 13.0 % 0.3 % 4.6 % 5.3 % 12.4 %

1.15 [ 0.99, 1.34 ] 1.10 [ 0.91, 1.32 ] 1.60 [ 0.08, 33.07 ] 1.22 [ 0.86, 1.72 ] 0.96 [ 0.79, 1.15 ] 1.05 [ 0.88, 1.25 ] 0.46 [ 0.23, 0.94 ] 1.01 [ 0.84, 1.22 ] 3.00 [ 0.31, 28.79 ] 1.01 [ 0.60, 1.68 ] 0.83 [ 0.53, 1.32 ] 1.08 [ 0.88, 1.32 ]

Favours antioxidants

Favours control

(Continued . . . )

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73

(. . .
Study or subgroup Antioxidants n/N Control n/N Risk Ratio MH,Random,95% CI Weight

Continued) Risk Ratio MH,Random,95% CI

Subtotal (95% CI)

89095

73853

100.0 %

1.05 [ 0.98, 1.13 ]

Total events: 1959 (Antioxidants), 1400 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 10.68, df = 11 (P = 0.47); I2 =0.0% Test for overall effect: Z = 1.47 (P = 0.14) 2 Unclear/Inadequate Li 2000 Li 2004 Munoz 1985 Yu 1991 Yu 1997 Zhu 2003 34/1112 44/2526 4/305 10/1444 4/113 2/118 57/953 57/2507 3/305 13/1030 11/113 5/54 35.2 % 38.3 % 4.0 % 12.1 % 6.9 % 3.4 % 0.51 [ 0.34, 0.77 ] 0.77 [ 0.52, 1.13 ] 1.33 [ 0.30, 5.91 ] 0.55 [ 0.24, 1.25 ] 0.36 [ 0.12, 1.11 ] 0.18 [ 0.04, 0.91 ]

Subtotal (95% CI)

5618

4962

100.0 %

0.59 [ 0.43, 0.80 ]

Total events: 98 (Antioxidants), 146 (Control) Heterogeneity: Tau2 = 0.03; Chi2 = 6.10, df = 5 (P = 0.30); I2 =18% Test for overall effect: Z = 3.34 (P = 0.00085)

0.1 0.2

0.5

10

Favours antioxidants

Favours control

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Analysis 1.3. Comparison 1 Antioxidants versus placebo, Outcome 3 Occurrence of gastrointestinal cancers - allocation concealment.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 3 Occurrence of gastrointestinal cancers - allocation concealment

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Adequate ATBC 2003 CARET 2004 Correa 2000 HOPE TOO 2005 HPS 2002 Munoz 1985 NIT2 1993 NPCT 1996 PHS 1996 Plummer 2007 SIT 2006 SUVIMAX 2004 WHS 2005 722/21846 243/9420 2/368 69/4761 215/10269 4/305 219/1657 11/653 219/11036 3/990 29/1677 33/6481 194/19937 209/7287 209/8894 0/117 57/4780 225/10267 3/305 209/1661 24/659 217/11035 1/990 29/1688 40/6536 180/19939 14.3 % 13.0 % 0.2 % 7.6 % 13.0 % 0.7 % 13.3 % 2.7 % 12.9 % 0.3 % 4.5 % 5.3 % 12.3 % 1.15 [ 0.99, 1.34 ] 1.10 [ 0.91, 1.32 ] 1.60 [ 0.08, 33.07 ] 1.22 [ 0.86, 1.72 ] 0.96 [ 0.79, 1.15 ] 1.33 [ 0.30, 5.91 ] 1.05 [ 0.88, 1.25 ] 0.46 [ 0.23, 0.94 ] 1.01 [ 0.84, 1.22 ] 3.00 [ 0.31, 28.79 ] 1.01 [ 0.60, 1.68 ] 0.83 [ 0.53, 1.32 ] 1.08 [ 0.88, 1.32 ]

Subtotal (95% CI)

89400

74158

100.0 %

1.05 [ 0.98, 1.13 ]

Total events: 1963 (Antioxidants), 1403 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 10.78, df = 12 (P = 0.55); I2 =0.0% Test for overall effect: Z = 1.48 (P = 0.14) 2 Unclear/Inadequate Li 2000 Li 2004 Yu 1991 Yu 1997 Zhu 2003 34/1112 44/2526 10/1444 4/113 2/118 57/953 57/2507 13/1030 11/113 5/54 36.7 % 39.9 % 12.6 % 7.2 % 3.6 % 0.51 [ 0.34, 0.77 ] 0.77 [ 0.52, 1.13 ] 0.55 [ 0.24, 1.25 ] 0.36 [ 0.12, 1.11 ] 0.18 [ 0.04, 0.91 ]

Subtotal (95% CI)

5313

4657

100.0 %

0.57 [ 0.41, 0.78 ]

Total events: 94 (Antioxidants), 143 (Control) Heterogeneity: Tau2 = 0.03; Chi2 = 4.98, df = 4 (P = 0.29); I2 =20% Test for overall effect: Z = 3.51 (P = 0.00045)

0.1 0.2

0.5

10

Favours antioxidants

Favours control

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Analysis 1.4. Comparison 1 Antioxidants versus placebo, Outcome 4 Occurrence of gastrointestinal cancers - follow-up.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 4 Occurrence of gastrointestinal cancers - follow-up

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Adequate ATBC 2003 CARET 2004 Correa 2000 HOPE TOO 2005 HPS 2002 Li 2000 Munoz 1985 NIT2 1993 NPCT 1996 PHS 1996 Plummer 2007 SIT 2006 SUVIMAX 2004 WHS 2005 Yu 1997 Zhu 2003 722/21846 243/9420 2/368 69/4761 215/10269 34/1112 4/305 219/1657 11/653 219/11036 3/990 29/1677 33/6481 194/19937 4/113 2/118 209/7287 209/8894 0/117 57/4780 225/10267 57/953 3/305 209/1661 24/659 217/11035 1/990 29/1688 40/6536 180/19939 11/113 5/54 13.2 % 12.1 % 0.2 % 7.0 % 12.0 % 5.6 % 0.6 % 12.3 % 2.5 % 12.0 % 0.3 % 4.2 % 4.9 % 11.4 % 1.1 % 0.5 % 1.15 [ 0.99, 1.34 ] 1.10 [ 0.91, 1.32 ] 1.60 [ 0.08, 33.07 ] 1.22 [ 0.86, 1.72 ] 0.96 [ 0.79, 1.15 ] 0.51 [ 0.34, 0.77 ] 1.33 [ 0.30, 5.91 ] 1.05 [ 0.88, 1.25 ] 0.46 [ 0.23, 0.94 ] 1.01 [ 0.84, 1.22 ] 3.00 [ 0.31, 28.79 ] 1.01 [ 0.60, 1.68 ] 0.83 [ 0.53, 1.32 ] 1.08 [ 0.88, 1.32 ] 0.36 [ 0.12, 1.11 ] 0.18 [ 0.04, 0.91 ]

Subtotal (95% CI)

90743

75278

100.0 %

0.98 [ 0.87, 1.10 ]

Total events: 2003 (Antioxidants), 1476 (Control) Heterogeneity: Tau2 = 0.02; Chi2 = 29.88, df = 15 (P = 0.01); I2 =50% Test for overall effect: Z = 0.39 (P = 0.69) 2 Unclear/Inadequate Li 2004 Yu 1991 44/2526 10/1444 57/2507 13/1030 76.0 % 24.0 % 0.77 [ 0.52, 1.13 ] 0.55 [ 0.24, 1.25 ]

Subtotal (95% CI)

3970

3537

100.0 %

0.72 [ 0.51, 1.02 ]

Total events: 54 (Antioxidants), 70 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.52, df = 1 (P = 0.47); I2 =0.0% Test for overall effect: Z = 1.83 (P = 0.068)

0.1 0.2

0.5

10

Favours antioxidants

Favours control

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Analysis 1.5. Comparison 1 Antioxidants versus placebo, Outcome 5 Occurrence of all gastrointestinal cancers - different antioxidants.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 5 Occurrence of all gastrointestinal cancers - different antioxidants

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Risk Ratio MH,Random,95% CI

1 Beta-carotene ATBC 2003 Correa 2000 PHS 1996 Zhu 2003 243/7282 1/117 219/11036 2/118 209/7287 0/117 217/11035 5/54 1.16 [ 0.97, 1.40 ] 3.00 [ 0.12, 72.90 ] 1.01 [ 0.84, 1.22 ] 0.18 [ 0.04, 0.91 ]

Subtotal (95% CI)

18553

18493

1.04 [ 0.80, 1.35 ]

Total events: 465 (Antioxidants), 431 (Control) Heterogeneity: Tau2 = 0.03; Chi2 = 6.22, df = 3 (P = 0.10); I2 =52% Test for overall effect: Z = 0.32 (P = 0.75) 2 Vitamin C Correa 2000 0/130 0/117 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI)


Total events: 0 (Antioxidants), 0 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P < 0.00001) 3 Vitamin E ATBC 2003

130

117

0.0 [ 0.0, 0.0 ]

233/7286

209/7287

1.11 [ 0.93, 1.34 ]

Subtotal (95% CI)


Heterogeneity: not applicable Test for overall effect: Z = 1.16 (P = 0.25) 4 Selenium Li 2000 Li 2004 NPCT 1996 Yu 1991 Yu 1997

7286

7287

1.11 [ 0.93, 1.34 ]

Total events: 233 (Antioxidants), 209 (Control)

34/1112 44/2526 11/653 10/1444 4/113

57/953 57/2507 24/659 13/1030 11/113

0.51 [ 0.34, 0.77 ] 0.77 [ 0.52, 1.13 ] 0.46 [ 0.23, 0.94 ] 0.55 [ 0.24, 1.25 ] 0.36 [ 0.12, 1.11 ]

Subtotal (95% CI)

5848

5262

0.59 [ 0.46, 0.75 ]

Total events: 103 (Antioxidants), 162 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 3.40, df = 4 (P = 0.49); I2 =0.0%

0.01

0.1

10

100

Favours antioxidants

Favours control

(Continued . . . )

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(. . .
Study or subgroup Antioxidants n/N Test for overall effect: Z = 4.27 (P = 0.000020) 5 Vitamin A and beta-carotene CARET 2004 243/9420 209/8894 Control n/N Risk Ratio MH,Random,95% CI

Continued) Risk Ratio MH,Random,95% CI

1.10 [ 0.91, 1.32 ]

Subtotal (95% CI)


Heterogeneity: not applicable Test for overall effect: Z = 1.00 (P = 0.32) 6 Beta-carotene and vitamin C Correa 2000

9420

8894

1.10 [ 0.91, 1.32 ]

Total events: 243 (Antioxidants), 209 (Control)

1/121

0/117

2.90 [ 0.12, 70.52 ]

Subtotal (95% CI)


Total events: 1 (Antioxidants), 0 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.65 (P = 0.51) 7 Beta carotene and vitamin E ATBC 2003

121

117

2.90 [ 0.12, 70.52 ]

246/7278

209/7287

1.18 [ 0.98, 1.41 ]

Subtotal (95% CI)


Heterogeneity: not applicable Test for overall effect: Z = 1.77 (P = 0.076) 8 Vitamin A, riboavin, and zinc Munoz 1985

7278

7287

1.18 [ 0.98, 1.41 ]

Total events: 246 (Antioxidants), 209 (Control)

4/305

3/305

1.33 [ 0.30, 5.91 ]

Subtotal (95% CI)


Total events: 4 (Antioxidants), 3 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.38 (P = 0.70) 9 Beta-carotene, vitamin C, and vitamin E HPS 2002 Plummer 2007

305

305

1.33 [ 0.30, 5.91 ]

215/10269 3/990

225/10267 1/990

0.96 [ 0.79, 1.15 ] 3.00 [ 0.31, 28.79 ]

Subtotal (95% CI)

11259

11257

0.96 [ 0.80, 1.16 ]

Total events: 218 (Antioxidants), 226 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.98, df = 1 (P = 0.32); I2 =0.0% Test for overall effect: Z = 0.40 (P = 0.69) 10 Vitamin C, vitamin E, and selenium SIT 2006 29/1677 29/1688 1.01 [ 0.60, 1.68 ]

Subtotal (95% CI)


Total events: 29 (Antioxidants), 29 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.03 (P = 0.98)

1677

1688

1.01 [ 0.60, 1.68 ]

11 Beta-carotene, vitamin C, vitamin E, and selenium SUVIMAX 2004 33/6481 40/6536


0.01 0.1 1 10 100

0.83 [ 0.53, 1.32 ]

Favours antioxidants

Favours control

(Continued . . . )
Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 78

(. . .
Study or subgroup Antioxidants n/N Control n/N Risk Ratio MH,Random,95% CI

Continued) Risk Ratio MH,Random,95% CI

Subtotal (95% CI)


Total events: 33 (Antioxidants), 40 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.78 (P = 0.43)

6481

6536

0.83 [ 0.53, 1.32 ]

12 Combination of antioxidants (13 vitamins and 13 minerals) NIT2 1993 219/1657 209/1661 1.05 [ 0.88, 1.25 ]

Subtotal (95% CI)


Heterogeneity: not applicable Test for overall effect: Z = 0.54 (P = 0.59)

1657

1661

1.05 [ 0.88, 1.25 ]

Total events: 219 (Antioxidants), 209 (Control)

0.01

0.1

10

100

Favours antioxidants

Favours control

Analysis 1.6. Comparison 1 Antioxidants versus placebo, Outcome 6 Occurrence of different gastrointestinal cancers - all antioxidants.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 6 Occurrence of different gastrointestinal cancers - all antioxidants

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Occurrence of oesophageal cancer ATBC 2003 CARET 2004 HPS 2002 Munoz 1985 NIT2 1993 NPCT 1996 SUVIMAX 2004 47/21846 44/9420 31/10269 4/305 123/1657 2/653 2/6481 13/7287 29/8894 26/10267 3/305 128/1661 5/659 2/6536
0.001 0.01 0.1 Favours antioxidants 1 10 100 1000 Favours control

11.8 % 18.6 % 15.6 % 2.2 % 45.9 % 1.9 % 1.3 %

1.21 [ 0.65, 2.23 ] 1.43 [ 0.90, 2.29 ] 1.19 [ 0.71, 2.01 ] 1.33 [ 0.30, 5.91 ] 0.96 [ 0.76, 1.22 ] 0.40 [ 0.08, 2.07 ] 1.01 [ 0.14, 7.16 ]

(Continued . . . )

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(. . .
Study or subgroup Antioxidants n/N WHS 2005 Zhu 2003 4/19937 0/118 Control n/N 3/19939 1/54 Risk Ratio MH,Random,95% CI Weight

Continued) Risk Ratio MH,Random,95% CI

2.2 % 0.5 %

1.33 [ 0.30, 5.96 ] 0.15 [ 0.01, 3.72 ]

Subtotal (95% CI)

70686

55602

100.0 %

1.06 [ 0.89, 1.28 ]

Total events: 257 (Antioxidants), 210 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 5.51, df = 8 (P = 0.70); I2 =0.0% Test for overall effect: Z = 0.66 (P = 0.51) 2 Occurrence of gastric cancer ATBC 2003 CARET 2004 Correa 2000 HPS 2002 Li 2004 NIT2 1993 PHS 1996 Plummer 2007 SIT 2006 SUVIMAX 2004 WHS 2005 Zhu 2003 199/21846 17/9420 2/368 36/10269 23/2526 96/1657 20/11036 3/990 29/1677 2/6481 14/19937 2/118 50/7287 18/8894 0/117 30/10267 30/2507 81/1661 21/11035 1/990 29/1688 2/6536 6/19939 3/54 22.5 % 6.8 % 0.4 % 11.6 % 9.7 % 24.5 % 7.8 % 0.6 % 10.7 % 0.9 % 3.5 % 1.1 % 1.33 [ 0.97, 1.81 ] 0.89 [ 0.46, 1.73 ] 1.60 [ 0.08, 33.07 ] 1.20 [ 0.74, 1.95 ] 0.76 [ 0.44, 1.31 ] 1.19 [ 0.89, 1.58 ] 0.95 [ 0.52, 1.76 ] 3.00 [ 0.31, 28.79 ] 1.01 [ 0.60, 1.68 ] 1.01 [ 0.14, 7.16 ] 2.33 [ 0.90, 6.07 ] 0.31 [ 0.05, 1.77 ]

Subtotal (95% CI)

86325

70975

100.0 %

1.14 [ 0.97, 1.33 ]

Total events: 443 (Antioxidants), 271 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 9.38, df = 11 (P = 0.59); I2 =0.0% Test for overall effect: Z = 1.63 (P = 0.10) 3 Occurrence of small intestine cancer WHS 2005 4/19937 1/19939 100.0 % 4.00 [ 0.45, 35.79 ]

Subtotal (95% CI)


Heterogeneity: not applicable

19937

19939

100.0 %

4.00 [ 0.45, 35.79 ]

Total events: 4 (Antioxidants), 1 (Control) Test for overall effect: Z = 1.24 (P = 0.21) 4 Occurrence of colorectal cancer ATBC 2003 CARET 2004 HOPE TOO 2005 HPS 2002 NPCT 1996 265/21846 127/9420 69/4761 117/10269 9/653 75/7287 123/8894 57/4780 140/10267 19/659
0.001 0.01 0.1 Favours antioxidants 1 10 100 1000 Favours control

15.3 % 15.9 % 10.4 % 16.0 % 2.7 %

1.18 [ 0.91, 1.52 ] 0.97 [ 0.76, 1.25 ] 1.22 [ 0.86, 1.72 ] 0.84 [ 0.65, 1.07 ] 0.48 [ 0.22, 1.05 ]

(Continued . . . )

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(. . .
Study or subgroup Antioxidants n/N PHS 1996 SUVIMAX 2004 WHS 2005 Zhu 2003 170/11036 21/6481 129/19937 0/118 Control n/N 176/11035 24/6536 140/19939 1/54 Risk Ratio MH,Random,95% CI Weight

Continued) Risk Ratio MH,Random,95% CI

18.6 % 4.6 % 16.4 % 0.2 %

0.97 [ 0.78, 1.19 ] 0.88 [ 0.49, 1.58 ] 0.92 [ 0.73, 1.17 ] 0.15 [ 0.01, 3.72 ]

Subtotal (95% CI)

84521

69451

100.0 %

0.97 [ 0.86, 1.09 ]

Total events: 907 (Antioxidants), 755 (Control) Heterogeneity: Tau2 = 0.01; Chi2 = 9.97, df = 8 (P = 0.27); I2 =20% Test for overall effect: Z = 0.57 (P = 0.57) 5 Occurrence of pancreatic cancer ATBC 2003 CARET 2004 HPS 2002 PHS 1996 SUVIMAX 2004 WHS 2005 157/21846 45/9420 24/10269 29/11036 4/6481 33/19937 59/7287 32/8894 24/10267 20/11035 6/6536 18/19939 36.1 % 19.9 % 13.8 % 13.6 % 3.1 % 13.4 % 0.89 [ 0.66, 1.20 ] 1.33 [ 0.84, 2.09 ] 1.00 [ 0.57, 1.76 ] 1.45 [ 0.82, 2.56 ] 0.67 [ 0.19, 2.38 ] 1.83 [ 1.03, 3.26 ]

Subtotal (95% CI)

78989

63958

100.0 %

1.16 [ 0.90, 1.50 ]

Total events: 292 (Antioxidants), 159 (Control) Heterogeneity: Tau2 = 0.03; Chi2 = 7.29, df = 5 (P = 0.20); I2 =31% Test for overall effect: Z = 1.13 (P = 0.26) 6 Occurrence of hepatocellular carcinoma ATBC 2003 CARET 2004 HPS 2002 Li 2000 Li 2004 SUVIMAX 2004 WHS 2005 Yu 1991 Yu 1997 54/21846 10/9420 7/10269 34/1112 21/2526 1/6481 5/19937 10/1444 4/113 12/7287 7/8894 5/10267 57/953 27/2507 1/6536 5/19939 13/1030 11/113 16.1 % 7.3 % 5.2 % 31.6 % 19.0 % 0.9 % 4.5 % 9.8 % 5.5 % 1.50 [ 0.80, 2.80 ] 1.35 [ 0.51, 3.54 ] 1.40 [ 0.44, 4.41 ] 0.51 [ 0.34, 0.77 ] 0.77 [ 0.44, 1.36 ] 1.01 [ 0.06, 16.12 ] 1.00 [ 0.29, 3.45 ] 0.55 [ 0.24, 1.25 ] 0.36 [ 0.12, 1.11 ]

Subtotal (95% CI)

73148

57526

100.0 %

0.80 [ 0.56, 1.14 ]

Total events: 146 (Antioxidants), 138 (Control) Heterogeneity: Tau2 = 0.10; Chi2 = 13.01, df = 8 (P = 0.11); I2 =38% Test for overall effect: Z = 1.25 (P = 0.21) 7 Occurrence of biliary tract cancer SUVIMAX 2004 0/6481 2/6536
0.001 0.01 0.1 Favours antioxidants 1 10 100 1000 Favours control

12.9 %

0.20 [ 0.01, 4.20 ]

(Continued . . . )

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(. . .
Study or subgroup Antioxidants n/N WHS 2005 5/19937 Control n/N 7/19939 Risk Ratio MH,Random,95% CI Weight

Continued) Risk Ratio MH,Random,95% CI

87.1 %

0.71 [ 0.23, 2.25 ]

Subtotal (95% CI)

26418

26475

100.0 %

0.61 [ 0.21, 1.78 ]

Total events: 5 (Antioxidants), 9 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.59, df = 1 (P = 0.44); I2 =0.0% Test for overall effect: Z = 0.90 (P = 0.37)

0.001 0.01 0.1 Favours antioxidants

10 100 1000 Favours control

Analysis 1.7. Comparison 1 Antioxidants versus placebo, Outcome 7 Occurrence of oesophageal cancer.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 7 Occurrence of oesophageal cancer

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Beta-carotene ATBC 2003 Zhu 2003 12/7282 0/118 13/7287 1/54 94.3 % 5.7 % 0.92 [ 0.42, 2.02 ] 0.15 [ 0.01, 3.72 ]

Subtotal (95% CI)

7400

7341

100.0 %

0.75 [ 0.25, 2.30 ]

Total events: 12 (Antioxidants), 14 (Control) Heterogeneity: Tau2 = 0.21; Chi2 = 1.15, df = 1 (P = 0.28); I2 =13% Test for overall effect: Z = 0.50 (P = 0.62) 2 Vitamin E ATBC 2003 19/7286 13/7287 100.0 % 1.46 [ 0.72, 2.96 ]

Subtotal (95% CI)


Heterogeneity: not applicable

7286

7287

100.0 %

1.46 [ 0.72, 2.96 ]

Total events: 19 (Antioxidants), 13 (Control) Test for overall effect: Z = 1.06 (P = 0.29) 3 Selenium NPCT 1996 2/653 5/659 100.0 % 0.40 [ 0.08, 2.07 ]

Subtotal (95% CI)

653

659
0.01 0.1 1 10 100

100.0 %

0.40 [ 0.08, 2.07 ]

Favours antioxidants

Favours control

(Continued . . . )

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(. . .
Study or subgroup Antioxidants n/N Total events: 2 (Antioxidants), 5 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.09 (P = 0.28) 4 Vitamin A and beta-carotene CARET 2004 44/9420 29/8894 100.0 % Control n/N Risk Ratio MH,Random,95% CI Weight

Continued) Risk Ratio MH,Random,95% CI

1.43 [ 0.90, 2.29 ]

Subtotal (95% CI)


Heterogeneity: not applicable

9420

8894

100.0 %

1.43 [ 0.90, 2.29 ]

Total events: 44 (Antioxidants), 29 (Control) Test for overall effect: Z = 1.51 (P = 0.13) 5 Beta-carotene and vitamin E ATBC 2003 16/7278 13/7287 100.0 % 1.23 [ 0.59, 2.56 ]

Subtotal (95% CI)


Heterogeneity: not applicable

7278

7287

100.0 %

1.23 [ 0.59, 2.56 ]

Total events: 16 (Antioxidants), 13 (Control) Test for overall effect: Z = 0.56 (P = 0.58) 6 Vitamin A, riboavin, and zinc Munoz 1985 4/305 3/305 100.0 % 1.33 [ 0.30, 5.91 ]

Subtotal (95% CI)


Total events: 4 (Antioxidants), 3 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.38 (P = 0.70) 7 Beta-carotene, vitamin C, and vitamin E HPS 2002

305

305

100.0 %

1.33 [ 0.30, 5.91 ]

31/10269

26/10267

100.0 %

1.19 [ 0.71, 2.01 ]

Subtotal (95% CI)


Heterogeneity: not applicable

10269

10267

100.0 %

1.19 [ 0.71, 2.01 ]

Total events: 31 (Antioxidants), 26 (Control) Test for overall effect: Z = 0.66 (P = 0.51) 8 Beta-carotene, vitamin C, vitamin E, and selenium SUVIMAX 2004 2/6481 2/6536 100.0 % 1.01 [ 0.14, 7.16 ]

Subtotal (95% CI)


Heterogeneity: not applicable

6481

6536

100.0 %

1.01 [ 0.14, 7.16 ]

Total events: 2 (Antioxidants), 2 (Control) Test for overall effect: Z = 0.01 (P = 0.99) 9 Combination of antioxidants NIT2 1993 123/1657 128/1661 100.0 % 0.96 [ 0.76, 1.22 ]

Subtotal (95% CI)


Heterogeneity: not applicable

1657

1661

100.0 %

0.96 [ 0.76, 1.22 ]

Total events: 123 (Antioxidants), 128 (Control) Test for overall effect: Z = 0.31 (P = 0.76)

0.01

0.1

10

100

Favours antioxidants

Favours control

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Analysis 1.8. Comparison 1 Antioxidants versus placebo, Outcome 8 Occurrence of gastric cancer.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 8 Occurrence of gastric cancer

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Risk Ratio MH,Random,95% CI

1 Beta-carotene ATBC 2003 Correa 2000 PHS 1996 Zhu 2003 64/7282 1/117 20/11036 2/118 50/7287 0/117 21/11035 3/54 1.28 [ 0.89, 1.85 ] 3.00 [ 0.12, 72.90 ] 0.95 [ 0.52, 1.76 ] 0.31 [ 0.05, 1.77 ]

Subtotal (95% CI)

18553

18493

1.12 [ 0.79, 1.59 ]

Total events: 87 (Antioxidants), 74 (Control) Heterogeneity: Tau2 = 0.01; Chi2 = 3.22, df = 3 (P = 0.36); I2 =7% Test for overall effect: Z = 0.65 (P = 0.51) 2 Vitamin C Correa 2000 0/130 0/117 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI)


Total events: 0 (Antioxidants), 0 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P < 0.00001) 3 Vitamin E ATBC 2003

130

117

0.0 [ 0.0, 0.0 ]

65/7286

50/7287

1.30 [ 0.90, 1.88 ]

Subtotal (95% CI)


Total events: 65 (Antioxidants), 50 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.40 (P = 0.16) 4 Selenium Li 2004

7286

7287

1.30 [ 0.90, 1.88 ]

23/2526

30/2507

0.76 [ 0.44, 1.31 ]

Subtotal (95% CI)


Total events: 23 (Antioxidants), 30 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.99 (P = 0.32) 5 Vitamin A and beta-carotene CARET 2004

2526

2507

0.76 [ 0.44, 1.31 ]

17/9420

18/8894

0.89 [ 0.46, 1.73 ]

Subtotal (95% CI)


Total events: 17 (Antioxidants), 18 (Control) Heterogeneity: not applicable

9420

8894

0.89 [ 0.46, 1.73 ]

0.01

0.1

10

100

Favours antioxidants

Favours control

(Continued . . . )

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(. . .
Study or subgroup Antioxidants n/N Test for overall effect: Z = 0.34 (P = 0.73) 6 Beta-carotene and vitamin C Correa 2000 1/121 0/117 Control n/N Risk Ratio MH,Random,95% CI

Continued) Risk Ratio MH,Random,95% CI

2.90 [ 0.12, 70.52 ]

Subtotal (95% CI)


Total events: 1 (Antioxidants), 0 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.65 (P = 0.51) 7 Beta-carotene and vitamin E ATBC 2003

121

117

2.90 [ 0.12, 70.52 ]

70/7278

50/7287

1.40 [ 0.98, 2.01 ]

Subtotal (95% CI)


Total events: 70 (Antioxidants), 50 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.83 (P = 0.067) 8 Beta-carotene, vitamin C, and vitamin E HPS 2002 Plummer 2007

7278

7287

1.40 [ 0.98, 2.01 ]

36/10269 3/990

30/10267 1/990

1.20 [ 0.74, 1.95 ] 3.00 [ 0.31, 28.79 ]

Subtotal (95% CI)

11259

11257

1.25 [ 0.78, 2.00 ]

Total events: 39 (Antioxidants), 31 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.60, df = 1 (P = 0.44); I2 =0.0% Test for overall effect: Z = 0.92 (P = 0.36) 9 Vitamin C, vitamin E, and selenium SIT 2006 29/1677 29/1688 1.01 [ 0.60, 1.68 ]

Subtotal (95% CI)


Total events: 29 (Antioxidants), 29 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.03 (P = 0.98)

1677

1688

1.01 [ 0.60, 1.68 ]

10 Beta-carotene, vitamin C, vitamin E, and selenium SUVIMAX 2004 2/6481 2/6536 1.01 [ 0.14, 7.16 ]

Subtotal (95% CI)


Total events: 2 (Antioxidants), 2 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.01 (P = 0.99) 11 Combination of antioxidants NIT2 1993

6481

6536

1.01 [ 0.14, 7.16 ]

96/1657

81/1661

1.19 [ 0.89, 1.58 ]

Subtotal (95% CI)


Total events: 96 (Antioxidants), 81 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.17 (P = 0.24)

1657

1661

1.19 [ 0.89, 1.58 ]

0.01

0.1

10

100

Favours antioxidants

Favours control

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Analysis 1.9. Comparison 1 Antioxidants versus placebo, Outcome 9 Occurrence of colorectal cancer.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 9 Occurrence of colorectal cancer

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Beta-carotene ATBC 2003 PHS 1996 Zhu 2003 99/7282 170/11036 0/118 75/7287 176/11035 1/54 39.8 % 59.7 % 0.5 % 1.32 [ 0.98, 1.78 ] 0.97 [ 0.78, 1.19 ] 0.15 [ 0.01, 3.72 ]

Subtotal (95% CI)

18436

18376

100.0 %

1.09 [ 0.79, 1.51 ]

Total events: 269 (Antioxidants), 252 (Control) Heterogeneity: Tau2 = 0.04; Chi2 = 4.26, df = 2 (P = 0.12); I2 =53% Test for overall effect: Z = 0.51 (P = 0.61) 2 Vitamin E ATBC 2003 HOPE TOO 2005 76/7286 69/4761 75/7287 57/4780 53.3 % 46.7 % 1.01 [ 0.74, 1.39 ] 1.22 [ 0.86, 1.72 ]

Subtotal (95% CI)

12047

12067

100.0 %

1.10 [ 0.87, 1.39 ]

Total events: 145 (Antioxidants), 132 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.57, df = 1 (P = 0.45); I2 =0.0% Test for overall effect: Z = 0.80 (P = 0.42) 3 Selenium NPCT 1996 9/653 19/659 100.0 % 0.48 [ 0.22, 1.05 ]

Subtotal (95% CI)


Heterogeneity: not applicable

653

659

100.0 %

0.48 [ 0.22, 1.05 ]

Total events: 9 (Antioxidants), 19 (Control) Test for overall effect: Z = 1.84 (P = 0.066) 4 Vitamin A and beta-carotene CARET 2004 127/9420 123/8894 100.0 % 0.97 [ 0.76, 1.25 ]

Subtotal (95% CI)


Heterogeneity: not applicable

9420

8894

100.0 %

0.97 [ 0.76, 1.25 ]

Total events: 127 (Antioxidants), 123 (Control) Test for overall effect: Z = 0.20 (P = 0.84) 5 Beta-carotene and vitamin E ATBC 2003 90/7278 75/7287 100.0 % 1.20 [ 0.89, 1.63 ]

Subtotal (95% CI)


Heterogeneity: not applicable

7278

7287

100.0 %

1.20 [ 0.89, 1.63 ]

Total events: 90 (Antioxidants), 75 (Control)

0.01

0.1

10

100

Favours antioxidants

Favours control

(Continued . . . )

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(. . .
Study or subgroup Antioxidants n/N Test for overall effect: Z = 1.18 (P = 0.24) 6 Beta-carotene, vitamin C, and vitamin E HPS 2002 117/10269 140/10267 100.0 % Control n/N Risk Ratio MH,Random,95% CI Weight

Continued) Risk Ratio MH,Random,95% CI

0.84 [ 0.65, 1.07 ]

Subtotal (95% CI)


Heterogeneity: not applicable

10269

10267

100.0 %

0.84 [ 0.65, 1.07 ]

Total events: 117 (Antioxidants), 140 (Control) Test for overall effect: Z = 1.44 (P = 0.15) 7 Beta-carotene, vitamin C, vitamin E, and selenium SUVIMAX 2004 21/6481 24/6536 100.0 % 0.88 [ 0.49, 1.58 ]

Subtotal (95% CI)


Heterogeneity: not applicable

6481

6536

100.0 %

0.88 [ 0.49, 1.58 ]

Total events: 21 (Antioxidants), 24 (Control) Test for overall effect: Z = 0.42 (P = 0.67)

0.01

0.1

10

100

Favours antioxidants

Favours control

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Analysis 1.10. Comparison 1 Antioxidants versus placebo, Outcome 10 Occurrence of pancreatic cancer.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 10 Occurrence of pancreatic cancer

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Beta-carotene ATBC 2003 PHS 1996 45/7282 29/11036 59/7287 20/11035 68.4 % 31.6 % 0.76 [ 0.52, 1.12 ] 1.45 [ 0.82, 2.56 ]

Subtotal (95% CI)

18318

18322

100.0 %

1.02 [ 0.54, 1.90 ]

Total events: 74 (Antioxidants), 79 (Control) Heterogeneity: Tau2 = 0.14; Chi2 = 3.34, df = 1 (P = 0.07); I2 =70% Test for overall effect: Z = 0.05 (P = 0.96) 2 Vitamin E ATBC 2003 57/7286 59/7287 100.0 % 0.97 [ 0.67, 1.39 ]

Subtotal (95% CI)


Heterogeneity: not applicable

7286

7287

100.0 %

0.97 [ 0.67, 1.39 ]

Total events: 57 (Antioxidants), 59 (Control) Test for overall effect: Z = 0.19 (P = 0.85) 3 Vitamin A and beta-carotene CARET 2004 45/9420 32/8894 100.0 % 1.33 [ 0.84, 2.09 ]

Subtotal (95% CI)


Heterogeneity: not applicable

9420

8894

100.0 %

1.33 [ 0.84, 2.09 ]

Total events: 45 (Antioxidants), 32 (Control) Test for overall effect: Z = 1.23 (P = 0.22) 4 Beta-carotene and vitamin E ATBC 2003 55/7278 59/7287 100.0 % 0.93 [ 0.65, 1.35 ]

Subtotal (95% CI)


Heterogeneity: not applicable

7278

7287

100.0 %

0.93 [ 0.65, 1.35 ]

Total events: 55 (Antioxidants), 59 (Control) Test for overall effect: Z = 0.37 (P = 0.71) 5 Beta-carotene, vitamin C, and vitamin E HPS 2002 24/10269 24/10267 100.0 % 1.00 [ 0.57, 1.76 ]

Subtotal (95% CI)


Heterogeneity: not applicable

10269

10267

100.0 %

1.00 [ 0.57, 1.76 ]

Total events: 24 (Antioxidants), 24 (Control) Test for overall effect: Z = 0.00 (P = 1.0) 6 Beta-carotene, vitamin C, vitamin E, and selenium SUVIMAX 2004 4/6481 6/6536
0.2 0.5 1 2 5

100.0 %

0.67 [ 0.19, 2.38 ]

Favours antioxidants

Favours control

(Continued . . . )

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(. . .
Study or subgroup Antioxidants n/N Control n/N Risk Ratio MH,Random,95% CI Weight

Continued) Risk Ratio MH,Random,95% CI

Subtotal (95% CI)


Heterogeneity: not applicable

6481

6536

100.0 %

0.67 [ 0.19, 2.38 ]

Total events: 4 (Antioxidants), 6 (Control) Test for overall effect: Z = 0.62 (P = 0.54)

0.2

0.5

Favours antioxidants

Favours control

Analysis 1.11. Comparison 1 Antioxidants versus placebo, Outcome 11 Occurrence of hepatocellular carcinoma.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 11 Occurrence of hepatocellular carcinoma

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Beta-carotene ATBC 2003 23/7282 12/7287 100.0 % 1.92 [ 0.96, 3.85 ]

Subtotal (95% CI)


Heterogeneity: not applicable

7282

7287

100.0 %

1.92 [ 0.96, 3.85 ]

Total events: 23 (Antioxidants), 12 (Control) Test for overall effect: Z = 1.83 (P = 0.067) 2 Vitamin E ATBC 2003 16/7286 12/7287 100.0 % 1.33 [ 0.63, 2.82 ]

Subtotal (95% CI)


Heterogeneity: not applicable

7286

7287

100.0 %

1.33 [ 0.63, 2.82 ]

Total events: 16 (Antioxidants), 12 (Control) Test for overall effect: Z = 0.75 (P = 0.45) 3 Selenium Li 2000 Li 2004 Yu 1991 34/1112 21/2526 10/1444 57/953 27/2507 13/1030
0.01 0.1 1 10 100

34.9 % 29.3 % 21.2 %

0.51 [ 0.34, 0.77 ] 0.77 [ 0.44, 1.36 ] 0.55 [ 0.24, 1.25 ]

Favours antioxidants

Favours control

(Continued . . . )

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(. . .
Study or subgroup Antioxidants n/N Yu 1997 4/113 Control n/N 11/113 Risk Ratio MH,Random,95% CI Weight

Continued) Risk Ratio MH,Random,95% CI

14.6 %

0.36 [ 0.12, 1.11 ]

Subtotal (95% CI)

5195

4603

100.0 %

0.56 [ 0.42, 0.76 ]

Total events: 69 (Antioxidants), 108 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 1.99, df = 3 (P = 0.57); I2 =0.0% Test for overall effect: Z = 3.75 (P = 0.00018) 4 Vitamin A and beta-carotene CARET 2004 10/9420 7/8894 100.0 % 1.35 [ 0.51, 3.54 ]

Subtotal (95% CI)


Heterogeneity: not applicable

9420

8894

100.0 %

1.35 [ 0.51, 3.54 ]

Total events: 10 (Antioxidants), 7 (Control) Test for overall effect: Z = 0.61 (P = 0.54) 5 Beta-carotene and vitamin E ATBC 2003 15/7278 12/7287 100.0 % 1.25 [ 0.59, 2.67 ]

Subtotal (95% CI)


Heterogeneity: not applicable

7278

7287

100.0 %

1.25 [ 0.59, 2.67 ]

Total events: 15 (Antioxidants), 12 (Control) Test for overall effect: Z = 0.58 (P = 0.56) 6 Beta-carotene, vitamin C, and vitamin E HPS 2002 7/10269 5/10267 100.0 % 1.40 [ 0.44, 4.41 ]

Subtotal (95% CI)


Heterogeneity: not applicable

10269

10267

100.0 %

1.40 [ 0.44, 4.41 ]

Total events: 7 (Antioxidants), 5 (Control) Test for overall effect: Z = 0.57 (P = 0.57) 7 Beta-carotene, vitamin C, vitamin E, and selenium SUVIMAX 2004 1/6481 1/6536 100.0 % 1.01 [ 0.06, 16.12 ]

Subtotal (95% CI)


Heterogeneity: not applicable Test for overall effect: Z = 0.01 (P = 1.0)

6481

6536

100.0 %

1.01 [ 0.06, 16.12 ]

Total events: 1 (Antioxidants), 1 (Control)

0.01

0.1

10

100

Favours antioxidants

Favours control

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Analysis 1.12. Comparison 1 Antioxidants versus placebo, Outcome 12 Occurrence of biliary tract cancer.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 12 Occurrence of biliary tract cancer

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Beta-carotene, vitamin C, vitamin E, and selenium SUVIMAX 2004 0/6481 2/6536 100.0 % 0.20 [ 0.01, 4.20 ]

Subtotal (95% CI)


Heterogeneity: not applicable

6481

6536

100.0 %

0.20 [ 0.01, 4.20 ]

Total events: 0 (Antioxidants), 2 (Control) Test for overall effect: Z = 1.03 (P = 0.30)

0.001 0.01 0.1 Favours treatment

10 100 1000 Favours control

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Analysis 1.13. Comparison 1 Antioxidants versus placebo, Outcome 13 Mortality in trials with a low or high risk of bias.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 13 Mortality in trials with a low or high risk of bias

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Trials with low risk of bias ATBC 2003 CARET 2004 Correa 2000 HOPE TOO 2005 HPS 2002 NIT2 1993 NPCT 1996 PHS 1996 Plummer 2007 SIT 2006 SUVIMAX 2004 WACS 2007 WHS 2005 8226/21846 1855/9420 16/739 799/4761 1446/10269 157/1657 108/653 979/11036 16/990 82/1677 76/6481 871/7149 636/19937 2605/7287 1509/8894 2/237 801/4780 1389/10267 167/1661 129/659 968/11035 11/990 101/1688 98/6536 124/1022 615/19939 16.5 % 13.8 % 0.1 % 10.9 % 13.1 % 3.9 % 3.3 % 11.3 % 0.4 % 2.3 % 2.1 % 5.0 % 9.1 % 1.05 [ 1.02, 1.09 ] 1.16 [ 1.09, 1.23 ] 2.57 [ 0.59, 11.08 ] 1.00 [ 0.92, 1.10 ] 1.04 [ 0.97, 1.11 ] 0.94 [ 0.77, 1.16 ] 0.84 [ 0.67, 1.07 ] 1.01 [ 0.93, 1.10 ] 1.45 [ 0.68, 3.12 ] 0.82 [ 0.62, 1.08 ] 0.78 [ 0.58, 1.05 ] 1.00 [ 0.84, 1.20 ] 1.03 [ 0.93, 1.15 ]

Subtotal (95% CI)

96615

74995

91.9 %

1.03 [ 0.98, 1.08 ]

Total events: 15267 (Antioxidants), 8519 (Control) Heterogeneity: Tau2 = 0.00; Chi2 = 25.80, df = 12 (P = 0.01); I2 =53% Test for overall effect: Z = 1.11 (P = 0.27) 2 Trials with high risk of bias NIT1 1993 1847/25886 280/3698 8.1 % 0.94 [ 0.84, 1.06 ]

Subtotal (95% CI)


Heterogeneity: not applicable

25886

3698

8.1 %

0.94 [ 0.84, 1.06 ]

Total events: 1847 (Antioxidants), 280 (Control) Test for overall effect: Z = 0.96 (P = 0.34)

Total (95% CI)

122501

78693

100.0 %

1.02 [ 0.97, 1.07 ]

Total events: 17114 (Antioxidants), 8799 (Control) Heterogeneity: Tau2 = 0.00; Chi2 = 28.82, df = 13 (P = 0.01); I2 =55% Test for overall effect: Z = 0.79 (P = 0.43)

0.5

0.7

1.5

Favours antioxidants

Favours control

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Analysis 1.14. Comparison 1 Antioxidants versus placebo, Outcome 14 Mortality after excluding selenium trials.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 14 Mortality after excluding selenium trials

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Trials with low risk of bias ATBC 2003 CARET 2004 Correa 2000 HOPE TOO 2005 HPS 2002 PHS 1996 Plummer 2007 WACS 2007 WHS 2005 8226/21846 1855/9420 16/739 799/4761 1446/10269 979/11036 16/990 871/7149 636/19937 2605/7287 1509/8894 2/237 801/4780 1389/10267 968/11035 11/990 124/1022 615/19939 25.4 % 18.2 % 0.1 % 12.4 % 16.5 % 13.2 % 0.3 % 4.5 % 9.5 % 1.05 [ 1.02, 1.09 ] 1.16 [ 1.09, 1.23 ] 2.57 [ 0.59, 11.08 ] 1.00 [ 0.92, 1.10 ] 1.04 [ 0.97, 1.11 ] 1.01 [ 0.93, 1.10 ] 1.45 [ 0.68, 3.12 ] 1.00 [ 0.84, 1.20 ] 1.03 [ 0.93, 1.15 ]

Subtotal (95% CI)

86147

64451

100.0 %

1.06 [ 1.01, 1.10 ]

Total events: 14844 (Antioxidants), 8024 (Control) Heterogeneity: Tau2 = 0.00; Chi2 = 14.12, df = 8 (P = 0.08); I2 =43% Test for overall effect: Z = 2.61 (P = 0.0091) 2 Trials with high risk of bias

Subtotal (95% CI)


Total events: 0 (Antioxidants), 0 (Control) Heterogeneity: not applicable Test for overall effect: not applicable

0.0 %

0.0 [ 0.0, 0.0 ]

Total (95% CI)

86147

64451

100.0 %

1.06 [ 1.01, 1.10 ]

Total events: 14844 (Antioxidants), 8024 (Control) Heterogeneity: Tau2 = 0.00; Chi2 = 14.12, df = 8 (P = 0.08); I2 =43% Test for overall effect: Z = 2.61 (P = 0.0091)

0.5

0.7

1.5

Favours antioxidants

Favours control

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Analysis 1.15. Comparison 1 Antioxidants versus placebo, Outcome 15 Mortality - different antioxidants.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 15 Mortality - different antioxidants

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Beta-carotene ATBC 2003 Correa 2000 PHS 1996 WACS 2007 2793/7282 7/243 979/11036 124/1020 2605/7287 2/237 968/11035 124/1022 56.5 % 0.2 % 35.1 % 8.1 % 1.07 [ 1.03, 1.12 ] 3.41 [ 0.72, 16.26 ] 1.01 [ 0.93, 1.10 ] 1.00 [ 0.79, 1.27 ]

Subtotal (95% CI)

19581

19581

100.0 %

1.05 [ 0.99, 1.11 ]

Total events: 3903 (Antioxidants), 3699 (Control) Heterogeneity: Tau2 = 0.00; Chi2 = 3.91, df = 3 (P = 0.27); I2 =23% Test for overall effect: Z = 1.67 (P = 0.095) 2 Vitamin C Correa 2000 WACS 2007 3/241 120/1023 2/237 124/1022 1.9 % 98.1 % 1.48 [ 0.25, 8.75 ] 0.97 [ 0.76, 1.22 ]

Subtotal (95% CI)

1264

1259

100.0 %

0.97 [ 0.77, 1.23 ]

Total events: 123 (Antioxidants), 126 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.21, df = 1 (P = 0.64); I2 =0.0% Test for overall effect: Z = 0.22 (P = 0.82) 3 Vitamin E ATBC 2003 HOPE TOO 2005 WACS 2007 2671/7286 799/4761 120/1021 2605/7287 801/4780 124/1022 57.6 % 34.1 % 8.2 % 1.03 [ 0.98, 1.07 ] 1.00 [ 0.92, 1.10 ] 0.97 [ 0.77, 1.23 ]

Subtotal (95% CI)

13068

13089

100.0 %

1.02 [ 0.98, 1.06 ]

Total events: 3590 (Antioxidants), 3530 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.41, df = 2 (P = 0.81); I2 =0.0% Test for overall effect: Z = 0.99 (P = 0.32) 4 Selenium NPCT 1996 108/653 129/659 100.0 % 0.84 [ 0.67, 1.07 ]

Subtotal (95% CI)


Heterogeneity: not applicable

653

659

100.0 %

0.84 [ 0.67, 1.07 ]

Total events: 108 (Antioxidants), 129 (Control) Test for overall effect: Z = 1.43 (P = 0.15) 5 Vitamin A and beta-carotene

0.01

0.1

10

100

Favours antioxidants

Favours control

(Continued . . . )

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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(. . .
Study or subgroup Antioxidants n/N CARET 2004 1855/9420 Control n/N 1509/8894 Risk Ratio MH,Random,95% CI Weight

Continued) Risk Ratio MH,Random,95% CI

100.0 %

1.16 [ 1.09, 1.23 ]

Subtotal (95% CI)


Heterogeneity: not applicable

9420

8894

100.0 %

1.16 [ 1.09, 1.23 ]

Total events: 1855 (Antioxidants), 1509 (Control) Test for overall effect: Z = 4.75 (P < 0.00001) 6 Beta-carotene and vitamin C Correa 2000 6/255 2/237 100.0 % 2.79 [ 0.57, 13.68 ]

Subtotal (95% CI)


Total events: 6 (Antioxidants), 2 (Control) Heterogeneity: not applicable

255

237

100.0 %

2.79 [ 0.57, 13.68 ]

Test for overall effect: Z = 1.26 (P = 0.21) 7 Beta-carotene and vitamin E ATBC 2003 2762/7278 2605/7287 100.0 % 1.06 [ 1.02, 1.11 ]

Subtotal (95% CI)


Heterogeneity: not applicable

7278

7287

100.0 %

1.06 [ 1.02, 1.11 ]

Total events: 2762 (Antioxidants), 2605 (Control) Test for overall effect: Z = 2.75 (P = 0.0059) 8 Beta-carotene, vitamin C, and vitamin E HPS 2002 Plummer 2007 WACS 2007 1446/10269 16/990 871/7149 1389/10267 11/990 124/1022 75.3 % 1.5 % 23.2 % 1.04 [ 0.97, 1.11 ] 1.45 [ 0.68, 3.12 ] 1.00 [ 0.84, 1.20 ]

Subtotal (95% CI)

18408

12279

100.0 %

1.04 [ 0.97, 1.11 ]

Total events: 2333 (Antioxidants), 1524 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.89, df = 2 (P = 0.64); I2 =0.0% Test for overall effect: Z = 1.16 (P = 0.24) 9 Vitamin C, vitamin E, and selenium SIT 2006 82/1677 101/1688 100.0 % 0.82 [ 0.62, 1.08 ]

Subtotal (95% CI)


Heterogeneity: not applicable

1677

1688

100.0 %

0.82 [ 0.62, 1.08 ]

Total events: 82 (Antioxidants), 101 (Control) Test for overall effect: Z = 1.40 (P = 0.16) 10 Beta-carotene, vitamin C, vitamin E, and selenium SUVIMAX 2004 76/6481 98/6536 100.0 % 0.78 [ 0.58, 1.05 ]

Subtotal (95% CI)


Heterogeneity: not applicable

6481

6536

100.0 %

0.78 [ 0.58, 1.05 ]

Total events: 76 (Antioxidants), 98 (Control) Test for overall effect: Z = 1.62 (P = 0.11) 11 Combination of antioxidants NIT1 1993 1847/25886 280/3698
0.01 0.1 1 10 100

69.7 %

0.94 [ 0.84, 1.06 ]

Favours antioxidants

Favours control

(Continued . . . )

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(. . .
Study or subgroup Antioxidants n/N NIT2 1993 157/1657 Control n/N 167/1661 Risk Ratio MH,Random,95% CI Weight

Continued) Risk Ratio MH,Random,95% CI

30.3 %

0.94 [ 0.77, 1.16 ]

Subtotal (95% CI)

27543

5359

100.0 %

0.94 [ 0.85, 1.05 ]

Total events: 2004 (Antioxidants), 447 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.00, df = 1 (P = 1.00); I2 =0.0% Test for overall effect: Z = 1.11 (P = 0.26)

0.01

0.1

10

100

Favours antioxidants

Favours control

Analysis 1.16. Comparison 1 Antioxidants versus placebo, Outcome 16 Adverse effects - beta-carotene.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 16 Adverse effects - beta-carotene

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Transient yellowing of the skin ATBC 2003 PHS 1996 WHS 2005 Zhu 2003 4950/14560 1745/11036 2131/19939 2/118 1020/14573 1535/11035 1944/19937 0/54 31.1 % 31.1 % 31.1 % 6.8 % 4.86 [ 4.56, 5.18 ] 1.14 [ 1.07, 1.21 ] 1.10 [ 1.03, 1.16 ] 2.31 [ 0.11, 47.33 ]

Subtotal (95% CI)

45653

45599

100.0 %

1.85 [ 0.74, 4.67 ]

Total events: 8828 (Antioxidants), 4499 (Control) Heterogeneity: Tau2 = 0.72; Chi2 = 1455.74, df = 3 (P<0.00001); I2 =100% Test for overall effect: Z = 1.31 (P = 0.19) 2 Persistent yellowing of the skin ATBC 2003 1281/14560 44/14573 100.0 % 29.14 [ 21.60, 39.32 ]

Subtotal (95% CI)


Heterogeneity: not applicable

14560

14573

100.0 %

29.14 [ 21.60, 39.32 ]

Total events: 1281 (Antioxidants), 44 (Control) Test for overall effect: Z = 22.06 (P < 0.00001) 3 Belching

0.01

0.1

10

100

Favours antioxidants

Favours control

(Continued . . . )

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(. . .
Study or subgroup Antioxidants n/N PHS 1996 275/11036 Control n/N 124/11035 Risk Ratio MH,Random,95% CI Weight

Continued) Risk Ratio MH,Random,95% CI

100.0 %

2.22 [ 1.80, 2.74 ]

Subtotal (95% CI)


Heterogeneity: not applicable

11036

11035

100.0 %

2.22 [ 1.80, 2.74 ]

Total events: 275 (Antioxidants), 124 (Control) Test for overall effect: Z = 7.42 (P < 0.00001) 4 Gastrointestinal upset WACS 2007 2785/4084 2717/4087 100.0 % 1.03 [ 1.00, 1.06 ]

Subtotal (95% CI)


Heterogeneity: not applicable

4084

4087

100.0 %

1.03 [ 1.00, 1.06 ]

Total events: 2785 (Antioxidants), 2717 (Control) Test for overall effect: Z = 1.65 (P = 0.099)

0.01

0.1

10

100

Favours antioxidants

Favours control

Analysis 1.17. Comparison 1 Antioxidants versus placebo, Outcome 17 Adverse effects - vitamin E.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 17 Adverse effects - vitamin E

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Haemorrhagic stroke ATBC 2003 HPS 2002 WHS 2005 92/7286 51/10269 44/19937 85/7287 53/10267 48/19939 47.7 % 27.8 % 24.5 % 1.08 [ 0.81, 1.45 ] 0.96 [ 0.66, 1.41 ] 0.92 [ 0.61, 1.38 ]

Subtotal (95% CI)

37492

37493

100.0 %

1.01 [ 0.82, 1.23 ]

Total events: 187 (Antioxidants), 186 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.49, df = 2 (P = 0.78); I2 =0.0% Test for overall effect: Z = 0.06 (P = 0.96)

0.5

0.7

1.5

Favours antioxidants

Favours control

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Analysis 1.18. Comparison 1 Antioxidants versus placebo, Outcome 18 Adverse effects - selenium.
Review: Antioxidant supplements for preventing gastrointestinal cancers

Comparison: 1 Antioxidants versus placebo Outcome: 18 Adverse effects - selenium

Study or subgroup

Antioxidants n/N

Control n/N

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

1 Gastrointestinal upset NPCT 1996 21/653 14/659 100.0 % 1.51 [ 0.78, 2.95 ]

Subtotal (95% CI)


Heterogeneity: not applicable Test for overall effect: Z = 1.22 (P = 0.22)

653

659

100.0 %

1.51 [ 0.78, 2.95 ]

Total events: 21 (Antioxidants), 14 (Control)

0.2

0.5

Favours antioxidants

Favours control

ADDITIONAL TABLES
Table 1. Table Database Search performed Search strategy Digestive system neoplasms / explode all trees (MeSH), antioxidants / explode all trees (MeSH), (#1 and #2). oesophageal cancer or gastric cancer or stomach cancer or bowel cancer or colorectal cancer or colon cancer or rectal cancer or pancreatic cancer or hepatocellular carcinoma or liver cancer or biliary tract cancer AND antioxidant* or vitamin* and supplement* and random* #1 explode Digestive-System-Neoplasms/ all subheadings #2 retinol or beta carotene or ascorbic acid or alpha tocopherol or selenium or vitamin* or antioxidant* #3 TG = ANIMAL #4 random* #5 ((#1 and #2) not #3) and random* #1 explode digestive-system-tumor/ all subheadings #2 retinol or beta carotene or ascorbic acid or alpha tocopherol or selenium or vitamin* or antioxidant* #3 random* #4 #1 and #2 and #3
98

The Cochrane Central Register of Con- October 2007 trolled Trials on the Cochrane Library The Controlled Trials Registers of the four October 2007 Cochrane gastrointestinal groups

MEDLINE

October 2007

EMBASE

October 2007

Antioxidant supplements for preventing gastrointestinal cancers (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Table 1. Table

(Continued)

LILACS The Web of Science (http://portal.isiknowledge.com/portal. cgi?DestApp=WOS&Func=Frame)

October 2007 Accessed 01 October 2007

#1 antioxidantes and cancer #1 - > [TS=(retinol or beta-carotene or ascorbic acid or alpha tocopherol or selenium or vitamin* or antioxidant*) DocType=All document types; Language=All languages; Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1945-2003] #2 - ((o)esophageal or gastric or small intestin* or colorectal or pancreatic or liver or biliary tract) and cancer* #3 - > TS=(random*) DocType=All document types; Language=All languages; Database(s)=SCI-EXPANDED; Timespan = 1945-2003 #4 - 62 #1 and #2 and #3 (retinol or beta-carotene or ascorbic acid or alpha tocopherol or selenium or vitamin* or antioxidant*) and #1 ((o)esophageal or gastric or small intestin* or colorectal or pancreatic or liver or biliary tract) and cancer*

The Chinese Biomedical Database

October 2007

Table 2. Table

Trial

Design of the trials

Number of arms

AntioxControl group idant vitamin supplements plus any additional non-antioxidant interventions in the experimental arm/arms Vitamin A, vitamin Placebo. B2, and zinc. Selenium. Placebo.

Analysis reported

Munoz 1985

Parallel.

Yu 1991 NIT1 1993

Parallel.

Half replicate 8 of a 2x2x2x2 factorial trial.

A) Vitamin A, vita- Placebo. min B2, vitamin B3, and zinc. B) Vitamin A, vitamin C, zinc, and molybdenum. C) Vitamin A, betacarotene, vitamin E, selenium, and zinc. D) Vitamin C, vitamin B2, vitamin B3, and molybdenum.

Four-way.

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Table 2. Table

(Continued)

E) Beta-carotene, vitamin E, selenium, vitamin B2, and vitamin B3. F) Beta-carotene, vitamin C, vitamin E, selenium, and molybdenum. G) Vitamin A, betacarotene, vitamin C, vitamin E, selenium, zinc, vitamin B2, vitamin B3, and molybdenum NIT2 1993 Parallel. 2 13 vitamins (vita- Placebo. min A, beta-carotene, vitamin E, vitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin D, folic acid, niacinamide, biotin, pantothenic acid) and 13 minerals (calcium, phosphorus, iodine, iron, magnesium, copper, manganese, potassium, chloride, chromium, molybdenum, selenium, and zinc) Selenium. Placebo. Two-way.

NPCT 1996 PHS 1996

Parallel.

2x2 factorial trial Initially 4, then A) Aspirin. Placebo. changed into two- changed into 2. B) Beta-carotene. armed trial. C) Beta-carotene and aspirin. Parallel. 2 Selenium. Placebo.

Yu 1997 Correa 2000

2x2x2 factorial trial. 8

A random half of Placebo. the patients were treated with anti-

Eight-way.

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Table 2. Table

(Continued)

Helicobacter pylori treatment medication (which consisted of amoxicillin, metronidazole, and bismuth subsalicylate) before the start of the 2x2 factorial design of beta-carotene and/ or vitamin C versus placebo. A) Beta-carotene. B) Vitamin C. C) Betacarotene plus antiHelicobacter pylori treatment. D) Vitamin C plus anti-Helicobacter pylori treatment. E) Beta-carotene and vitamin C. F) Betacarotene and vitamin C plus antiHelicobacter pylori treatment. G) anti-Helicobacter pylori treatment. Li 2000 HPS 2002 Parallel. 2x2 factorial trial. 2 4 Selenium. Placebo. Two-way.

A) Vitamin E, vi- Placebo. tamin C, and betacarotene. B) Simvastatin. C) Vitamin E, vitamin C, betacarotene, and simvastatin. A) Vitamin E. Placebo. B) Beta-carotene. C) Beta carotene and vitamin E.

ATBC 2003

2x2 factorial trial.

Four-way

Zhu 2003

Parallel.

3 (A fourth group A) Beta-carotene Placebo. assessing folate and (natural). vitamin B12 was B) Beta-carotene
101

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Table 2. Table

(Continued)

disregarded.) CARET 2004

(synthetic).

2x2 factorial trial Initially 4, then Vitamin A and beta- Placebo. changed into two- changed into 2. carotene. armed trial. Parallel. 2 Selenium, synthetic Placebo. allitridum (garlic extract). Beta-carotene, vita- Placebo. min C, vitamin E, selenium, and zinc [as gluconate]) A) Vitamin E. Placebo. B) Ramipril (angiotensin-converting enzyme inhibitor). C) Vitamin E plus ramipril. Two-way.

Li 2004

SUVIMAX 2004

Parallel.

HOPE TOO 2005

2x2

WHS 2005

2x2x2 factorial trial. Initially 8, changed A) Beta-carotene Placebo. into 4. (abandoned after 22.8 months). B) Vitamin E. C) Beta-carotene and vitamin E. D) Beta-carotene and aspirin. E) Vitamin E and aspirin. F) Beta-carotene, vitamin E, and aspirin. G) Aspirin. 2x2x2; 2x2 8 plus 4 A) Amoxicillin and Placebo. omeprazole, garlic, vitamin capsule* and selenium. B) Amoxicillin and omeprazole, garlic, vitamin placebo C) Amoxicillin and omeprazole, vitamin capsule* and selenium.

Two-way.

SIT 2006

Two-way

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Table 2. Table

(Continued)

D) Amoxicillin and omeprazole and vitamin placebo E) Garlic, vitamin capsule*, and selenium. F) Garlic and vitamin placebo. G) Vitamin capsule* and selenium. H) Garlic and selenium placebo. I) Garlic. J) Vitamin placebo. K) Selenium. *The vitamin capsule contained vitamin C (250 mg), vitamin E (100 IU), and selenium from yeast (37.5 g) Plummer 2007 Parallel 2 Beta-carotene, vita- Placebo. min C, and vitamin E. A) Beta-carotene, Placebo. vitamin C, and vitamin E. B) Beta-carotene placebo, vitamin C, and vitamin E. C) Beta-carotene, vitamin C, and vitamin E placebo. D) Beta-carotene placebo, vitamin C, and vitamin E placebo. E) Beta-carotene, vitamin C placebo, and vitamin E. F) Beta-carotene placebo, vitamin C placebo, and vitamin E. G) Eight-way

WACS 2007

2x2x2

8 Another arm testing a combination of folic acid (2.5 mg), vitamin B6 (50 mg), and vitamin B12 (1 mg) was disregarded

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Table 2. Table

(Continued)

Beta-carotene, vitamin C placebo, and vitamin E placebo.

Table 3. Table

ExperimenOesophageal cancer Gastric cancer tal antioxidant supplements Beta-carotene (PHS 0.75, 0.25 to 2.30 1996; Correa 2000; ATBC 2003; Zhu 2003) Vitamin E (ATBC 1.46, 0.72 to 2.96 2003; HOPE TOO 2005) Selenium (Yu 1991; 0.40, 0.08 to 2.07 NPCT 1996; Yu 1997; Li 2000; Li 2004) Beta-carotene and 1.43, 0.90 to 2.29 vitamin A (CARET 2004) Beta-carotene ND and vitamin C (Correa 2000) Beta-carotene and 1.23, 0.59 to 2.56 vitamin E (ATBC 2003) Beta-carotene, vita- 1.19, 0.71 to 2.01 min C, and vitamin E (HPS 2002; Plummer 2007) Vitamin A, 1.33, 0.30 to 5.91 riboavin, and zinc (Munoz 1985) 1.12, 0.79 to 1.59

Colorectal cancer

Pancreatic cancer

Hepatocellular carcinoma

1.09, 0.79 to 1.51

1.02, 0.54 to 1.90

1.92, 0.96 to 3.85

1.30, 0.90 to 1.88

1.10, 0.87 to 1.39

0.97, 0.67 to 1.39

1.33, 0.63 to 2.82

0.76, 0.44 to 1.31

0.48, 0.22 to 1.05

ND

0.56, 0.42 to 0.76

0.89, 0.46 to 1.73

0.97, 0.76 to 1.25

1.33, 0.84 to 2.09

1.35, 0.51 to 3.54

2.90, 0.12 to 70.52

ND

ND

ND

1.40, 0.98 to 2.01

1.20, 0.89 to 1.63

0.93, 0.65 to 1.35

1.25, 0.59 to 2.67

1.25, 0.78 to 2.00

0.84, 0.65 to 1.07

1.00, 0.57 to 1.76

1.40, 0.44 to 4.41

ND

ND

ND

ND

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Table 3. Table

(Continued)

Vitamin C, vita- ND min E, and selenium (SIT 2006) Beta-carotene, vita- 1.01, 0.14 to 7.16 min C, vitamin E, and selenium (SUVIMAX 2004) 26 vitamins/miner- 0.96, 0.76 to 1.22 als (NIT2 1993)

1.01, 0.60 to 1.68

ND

ND

ND

1.01, 0.14 to 7.16

0.88, 0.49 to 1.58

0.67, 0.19 to 2.38

1.01, 0.06 to 16.12

1.19, 0.89 to 1.58

ND

ND

ND

GI = gastrointestinal; ND = No data Relative risk, 95% condence interval (random).

WHATS NEW
Last assessed as up-to-date: 11 November 2007.

Date 17 April 2008 30 September 2007 30 September 2007

Event Amended New search has been performed

Description Converted to new review format. Six new trials were added.

New citation required but conclusions have not Conclusions did not change. changed

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HISTORY
Protocol rst published: Issue 2, 2003 Review rst published: Issue 4, 2004

CONTRIBUTIONS OF AUTHORS
Goran Bjelakovic conceived the idea for and drafted the protocol and the review. Dimitrinka Nikolova developed the search strategy and revised the protocol and the review. Rosa Simonetti revised the protocol and the review. Christian Gluud provided input during the protocol stage as Contact Editor and joined the team of authors during the preparation of the review providing strategy for data analyses, data interpretation, and revisions of the review. All co-reviewers contributed to the data extraction, data verication, and update of the review.

DECLARATIONS OF INTEREST
None known.

SOURCES OF SUPPORT Internal sources


The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Denmark.

External sources
Knowledge and Research Centre for Alternative Medicine (ViFAB), Denmark.

NOTES
The Protocol for this Review was published with a title Antioxidats for preventing gastrointestinal cancers.

INDEX TERMS Medical Subject Headings (MeSH)


Dietary

Supplements [adverse effects]; Antioxidants [ administration & dosage; adverse effects]; Gastrointestinal Neoplasms [mortality; prevention & control]; Liver Neoplasms [mortality; prevention & control]; Pancreatic Neoplasms [mortality; prevention & control]; Randomized Controlled Trials as Topic

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MeSH check words


Humans

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