Antioxidant supplements for preventing gastrointestinal cancers

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 Library2008, Issue 3

http://www.thecochranelibrary.com

Antioxidant supplements for preventing gastrointestinal cancers (Review)

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

13DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

68DATA 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Analysis 1.2. Comparison 1 Antioxidants versus placebo, Outcome 2 Occurrence of gastrointestinal cancers - generation of

the allocation sequence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Analysis 1.3. Comparison 1 Antioxidants versus placebo, Outcome 3 Occurrence of gastrointestinal cancers - allocation

concealment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Analysis 1.4. Comparison 1 Antioxidants versus placebo, Outcome 4 Occurrence of gastrointestinal cancers - follow-up. 76

Analysis 1.5. Comparison 1 Antioxidants versus placebo, Outcome 5 Occurrence of all gastrointestinal cancers - different

antioxidants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Analysis 1.6. Comparison 1 Antioxidants versus placebo, Outcome 6 Occurrence of different gastrointestinal cancers - all

antioxidants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

Analysis 1.7. Comparison 1 Antioxidants versus placebo, Outcome 7 Occurrence of oesophageal cancer. . . . . . 83

Analysis 1.8. Comparison 1 Antioxidants versus placebo, Outcome 8 Occurrence of gastric cancer. . . . . . . . 85

Analysis 1.9. Comparison 1 Antioxidants versus placebo, Outcome 9 Occurrence of colorectal cancer. . . . . . 87

Analysis 1.10. Comparison 1 Antioxidants versus placebo, Outcome 10 Occurrence of pancreatic cancer. . . . . 89

Analysis 1.11. Comparison 1 Antioxidants versus placebo, Outcome 11 Occurrence of hepatocellular carcinoma. . . 90

Analysis 1.12. Comparison 1 Antioxidants versus placebo, Outcome 12 Occurrence of biliary tract cancer. . . . . 92

Analysis 1.13. Comparison 1 Antioxidants versus placebo, Outcome 13 Mortality in trials with a low or high risk of bias. 93

Analysis 1.14. Comparison 1 Antioxidants versus placebo, Outcome 14 Mortality after excluding selenium trials. . . 94

Analysis 1.15. Comparison 1 Antioxidants versus placebo, Outcome 15 Mortality - different antioxidants. . . . . 95

Analysis 1.16. Comparison 1 Antioxidants versus placebo, Outcome 16 Adverse effects - beta-carotene. . . . . . 97

Analysis 1.17. Comparison 1 Antioxidants versus placebo, Outcome 17 Adverse effects - vitamin E. . . . . . . 99

Analysis 1.18. Comparison 1 Antioxidants versus placebo, Outcome 18 Adverse effects - selenium. . . . . . . . 99

100ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

106WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

107HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

107CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

107DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

107SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

108NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

108INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iAntioxidant supplements for preventing gastrointestinal cancers (Review)


[Intervention Review]

Antioxidant supplements for preventing gastrointestinalcancers

Goran Bjelakovic1 , Dimitrinka Nikolova2, Rosa G Simonetti3 , Christian Gluud2

1Copenhagen Trial Unit, Centre for Clinical Intervention Research„ Department 3344, Rigshospitalet, Copenhagen University Hos-

pital„ Copenhagen, Denmark. 2Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research„

Copenhagen, Denmark. 3Divisione 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. [email protected].

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.


A B S T R A C T

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 beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers.

Search methods

We identified trials through the trials registers of the four Cochrane Review Groups on gastrointestinal diseases, The Cochrane CentralRegister of Controlled Trials in The Cochrane Library (Issue 2, 2007), MEDLINE, EMBASE, LILACS, SCI-EXPANDED, and The ChineseBiomedical 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% confidence interval (CI) based

on random-effects and fixed-effect model meta-analysis. Meta-regression assessed the effect of covariates across the trials.

Main results

We identified 20 randomised trials (211,818 participants), assessing beta-carotene (12 trials), vitamin A (4 trials), vitamin C (8 trials),

vitamin E (10 trials), and selenium (9 trials). Trials quality was generally high. Heterogeneity was low to moderate. Antioxidant

supplements were without significant effects on gastrointestinal cancers (RR 0.94, 95% CI 0.83 to 1.06). However, there was significant

heterogeneity (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

1Antioxidant supplements for preventing gastrointestinal cancers (Review)


mailto:[email protected]

supplement (beta-carotene potentially increasing and selenium potentially decreasing cancer risk). The antioxidant supplements had no

significant effects on mortality in a random-effects model meta-analysis (RR 1.02, 95% CI 0.97 to 1.07, I2 = 53.5%), but significantly

increased mortality in a fixed-effect model meta-analysis (RR 1.04, 95% CI 1.02 to 1.07). Beta-carotene in combination with vitamin

A (RR 1.16, 95% CI 1.09 to 1.23) and vitamin E (RR 1.06, 95% CI 1.02 to 1.11) significantly increased mortality. Increased yellowing

of the skin and belching were non-serious adverse effects of beta-carotene. In five trials (four with high risk of bias), selenium seemed

to show significant beneficial effect on gastrointestinal cancer occurrence (RR 0.59, 95% CI 0.46 to 0.75, I2 = 0%).

Authors’ conclusions

We could not find convincing evidence that antioxidant supplements prevent gastrointestinal cancers. On the contrary, antioxidant

supplements seem to increase overall mortality. The potential cancer preventive effect of selenium should be tested in adequately

conducted randomised trials.

P L A I N L A N G U A G E S U M M A R Y

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 finding, however, is based on trials with flaws in their design and needs confirmation in properly

conducted randomised clinical trials.

B A C K G R O U N D

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 epi-

demiologic studies suggest a role of antioxidants in cancer pre-

vention (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 sufficient

amount of antioxidants, there are a number of people who reg-

ularly 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, un-

derstandable that antioxidant prevention of gastrointestinal can-

cers has drawn much attention (Garcea 2003; Sharma 2004; Grau

2006).

Oesophageal cancer is characterized by low likelihood of cure



(Enzinger 2003). Prevention is complicated by the fact that the

two major histologic types, ie, squamous-cell carcinoma and ade-

nocarcinoma, 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 Barrett’s

oesophagus, a precancerous condition for oesophageal adenocarci-

noma (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). Heli-cobacter pylori is the important aetiological agent of gastric cancer

(Sugiyama 2004). Eradication of Helicobacter pylori and chemo-

prevention 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 pre-

vention (Gwyn 2002). Observational studies postulate that diet

may be associated with colorectal cancer. A diet rich in antiox-

idants is claimed to be able to lower the risk of colorectal can-

cer (Boyle 1985; Bostick 1993; Kune 2006). Antioxidants were

the first agents evaluated in prevention of colorectal cancer (Grau

2006). However, antioxidant supplements have no significant ef-

fect 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, dia-

betes, and other medical conditions (Lowenfels 2006). Chronic

inflammation, 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 antiox-

idants might be effective in the prevention of pancreatic cancer

(Doucas 2006).

Hepatocellular carcinoma incidence has increased over the last

decades. Cirrhosis and aflatoxins are the main risk factors for its de-

velopment (Yates 2007). Viral or chemical damage to the liver re-

sults 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 mecha-

nisms 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 beneficial

is not clear.

The role of antioxidant supplements in preventing biliary tract

cancers is not sufficiently investigated. There are only a few exper-

imental studies dealing with this question (Takeda 2002).

Antioxidant supplements

Vitamin A is essential for growth. Since cancer involves distur-

bances in normal tissue growth and differentiation, it was one of

the first 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 polyun-

saturated fatty acids and block nitrosamine formation (Oshima

1982; Poppel 1997). Vitamin E supplementation can increase pro-

duction of humoral antibodies and may have antitumour prolif-

eration 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 impor-

tant enzymatic functions (Hughes 2000; Rayman 2000). There is

an inverse relationship between selenium intake and cancer mor-

tality (Schrauzer 1977). In the USA, cancer mortality rates are

significantly 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 un-

able to demonstrate convincing beneficial 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 supple-

ments, with the possible exception of selenium, may increase mor-

tality (Bjelakovic 2004a; Bjelakovic 2004b). This present review

is an update of the former review.

O B J E C T I V E S

To assess the beneficial and harmful effects of antioxidant supple-

ments in preventing gastrointestinal cancers (oesophageal, gastric,

small intestine, colorectal, pancreatic, liver, and biliary tract can-

cers).

M E T H O D S



Criteria for considering studies for this review

Types of studies

We included all randomised trials, irrespective of blinding, publi-

cation 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 sup-

plements (ie, beta-carotene, vitamin A, vitamin C, vitamin E, and

selenium) at any dose, duration, and route of administration ver-

sus 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 gastroin-

testinal 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, ad-

ministered separately or in combination, influenced 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.

Search methods for identification of studies

The trials search co-ordinators of The Cochrane Colorectal Can-

cer Group, The Cochrane Hepato-Biliary Group, The Cochrane

Inflammatory Bowel Disease Group, and The Cochrane Upper

Gastrointestinal and Pancreatic Diseases Group provided us with

searches of their respective trials registers on antioxidant supple-

ments and prevention of oesophageal, gastric, small intestinal, col-

orectal, pancreatic, liver, and biliary tract cancers. We also con-

ducted electronic searches in the Cochrane Central Register of Con-trolled 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 theChinese 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, manu-

facturers of antioxidant supplements, to ask for unpublished ran-

domised trials. Of these, Roche suggested some published trials,

which we knew of. No other information was received.

Data collection and analysis

Inclusion criteria application

We retrieved the identified 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: first 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 supplementa-

tion; duration of follow-up (ie, duration of intervention plus post-

intervention follow-up); co-interventions; and the occurrence of

gastrointestinal cancers (oesophageal, gastric, small intestinal, col-

orectal, 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 defined as the confidence

that the design and report restrict bias in the intervention compar-

ison based on the randomisation, blinding, and follow-up (Schulz

1995; Moher 1998; Kjaergard 2001). The following definitions



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, shuffling 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 quasi-

randomised.

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

specified 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 specifically

stated.

• Inadequate, if the number or reasons for dropouts and

withdrawals were not described.

Trials with adequate generation of the allocation sequence, ade-

quate allocation concealment, adequate blinding, and adequate

follow-up were considered low-bias risk trials (high methodolog-

ical quality) (Kjaergard 2001; Gluud 2006a). Trials with one or

more unclear or inadequate quality components were classified 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 classification of quality for sensitivity analyses and

not as exclusion criteria.

Statistical analyses

We performed the meta-analyses according to the recommenda-

tions of The Cochrane Handbook for Systematic Reviews of Interven-tions (Higgins 2006). For the statistical analyses, we used RevMan

Analyses (RevMan 2003), STATA 8.2 (STATA Corp, College Sta-

tion, Tex), Sigma Stat 3.0 (SPSS Inc, Chicago, Ill), and Stats-Di-

rect (StatsDirect Ltd, Altrincham, England).

We analysed the data with both random-effects (DerSimonian

1986) and fixed-effect (DeMets 1987) models meta-analyses. We

present the results of the random-effects model analysis if the two

models concur regarding statistical significance (P < 0.05). If not,

we present both analyses. Results are presented as the relative risk

(RR) with 95% confidence intervals (CI). We assessed heterogene-

ity with I2, which describes the percentage of total variation across

studies due to heterogeneity rather than chance (Higgins 2002). I2 can be calculated as I2 = 100% × (Q-df )/Q (Q = Cochran’s het-

erogeneity statistics, df = degrees of freedom). I2 ranged between

0% (ie, no observed heterogeneity) and 100% (maximal hetero-

geneity) (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 inter-

vention effects. The included covariates were type and dose of sup-

plement, 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 gastroin-

testinal cancers, and other patient groups with non-gastrointesti-

nal 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 ac-

counted 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 supple-

ments 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 in-

tervention 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 regres-

sion asymmetry test (Egger 1997) for detection of bias. A P < 0.10

was considered significant.



R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies; Characteristics of ongoing studies.

Search results

We identified a total of 1096 references through the four gastroin-

testinal disease Cochrane Groups (n = 90), the Cochrane CentralRegister of Controlled Trials in The Cochrane Library (n = 221),

MEDLINE (n = 224), EMBASE (n = 269), LILACS (n = 75), Sci-ence Citation Index Expanded (SCI-expanded) (n = 96), the ChineseBiomedical Database (n = 36), and reading references (n = 85).

We excluded 411 duplicates and 374 clearly irrelevant references

through reading abstracts. Accordingly, 311 references were re-

trived for further assessment. Of these, we excluded 58 references

because they did not fulfill our inclusion criteria. Reasons for ex-

clusion are listed in the table ’Characteristics of excluded studies’.

In total, 253 references describing 24 randomised trials fulfilled

our inclusion criteria. Among these references, 11 references de-

scribed 4 ongoing trials. These trials are listed under ’Characteris-

tics of ongoing studies’. The remaining 242 references, describing

20 trials, fulfilled 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 two-

by-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 pro-

ceeded 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 tri-

als. 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 five 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, min-

erals or other interventions (Table 2). The types, doses, dose reg-

imens, and duration of supplementation with antioxidants were

as follows: beta-carotene 6 mg to 30 mg (12 trials), vitamin A

1500 µg to 15000 µg (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 µg (9 trials), daily for

two to four years (Figure 1). In one trial antioxidant supplements

(vitamin A, riboflavin, and zinc) were given once weekly (Munoz

1985). One trial administered beta-carotene 30 mg daily for the

first year and 30 mg two times a week for the second (Zhu 2003).

One trial administered selenium 100 µg on alternate days for one

month of each year during two years (Li 2004).



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 adminis-

tered as a single antioxidant supplement (Table 2). Beta-carotene,

vitamin A, vitamin C, vitamin E, and selenium formed differ-

ent combinations of antioxidant supplements only or were ad-

ministered 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; beta-

carotene, 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 ex-

perimental arms and in the control arms. Four trials primarily con-

nected 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 (choles-

terol 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.



Only 14 of the trials (70%) could provide data on overall mortality.

Sponsorship

Pharmaceutical companies were the provider or sponsor of antiox-

idant 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


Twelve trials out of the 18 (66.7%) providing data on gastroin-

testinal cancers reported adequate generation of the allocation se-

quence, 13 trials (72.3%) reported adequate allocation conceal-

ment, 18 trials (100%) used placebo and hence had presumed

adequate blinding, and 16 trials (88.9%) reported adequate fol-

low-up. Twelve trials (66.7%) reported sample-size calculations.

Twelve trials (66.7%) based their analyses on the intention-to-

treat principle.

There were 12 trials (66.7%) of low-bias risk (high methodolog-

ical 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 fol-

low-up (NIT1 1993).

Effects of interventions


Antioxidant supplements had no significant influence on gastroin-

testinal cancer occurrence (RR 0.94, 95% CI 0.83 to 1.06, I2 =



54.0%). Approximately 2.2% of the participants in the antioxi-

dant 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 figure,

one may suspect bias. The asymmetry was statistically significant

(P = 0.009) by Egger’s test and (P = 0.096) by Begg’s test.

Figure 3. Funnel plot - occurrence of gastrointestinal cancers

Meta-regression analysis

Univariate meta-regression analyses revealed that the following co-

variates were significantly 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 supplemen-

tation; and primary or secondary prevention) were significantly

associated with estimated intervention effect on gastrointestinal

cancers.

In multivariate meta-regression analysis including all covariates,

dose of selenium was associated with a significantly 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

significantly associated with the estimated intervention effect on

the gastrointestinal cancers.

Methodological quality and antioxidant effect on gastrointesti-

nal cancer occurrence

The trials with low risk of bias (n = 12) did not show a signifi-

cant 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 significantly de-



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 statis-

tically significant by test of interaction (z = -3.53, P < 0.0005).

Generation of the allocation sequenceIn the trials with adequate generation of the allocation sequence,

antioxidant supplements did not significantly influence gastroin-

testinal 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 significant beneficial

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 significant by test of interac-

tion (z = -3.55, P < 0.0005).

Allocation concealmentIn the trials with adequate allocation concealment, antioxidant

supplements did not significantly influence gastrointestinal can-

cers (RR 1.05, 95% CI 0.98 to 1.13, I2 = 0%). In the trials with

unclear or inadequate allocation concealment, antioxidant sup-

plements showed a significant beneficial effect on gastrointestinal

cancers (RR 0.57, 95% CI 0.41 to 0.78, I2 = 19.6%). The differ-

ence between the estimates obtained by trials with adequate and

unclear or inadequate allocation concealment was statistically sig-

nificant by test of interaction (z = -3.64, P < 0.0003).

BlindingBlinding was assumed adequate in all the 18 trials due to the use

of placebo.

Follow-upIn the trials with adequate follow-up, antioxidant supplements

did not significantly influence 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 significant 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

significant 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 significantly in-

fluence gastrointestinal cancers. Different combinations of antiox-

idants, that is, beta-carotene and vitamin A; beta-carotene and vi-

tamin C; beta-carotene and vitamin E; vitamin A, riboflavin, and

zinc; beta-carotene, vitamin C, and vitamin E; vitamin C, vita-

min E, and selenium; beta-carotene, vitamin C, vitamin E, and

selenium, or combinations of 26 vitamins/minerals did not signif-

icantly influence 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 significantly decreased gastrointestinal cancers (RR

0.59, 95% CI 0.46 to 0.75, I2 = 0%). Selenium combined did

not significantly influence gastrointestinal cancers (RR 1.02, 95%

CI 0.87 to 1.19, I2 = 0%). Selenium given singly or combined

significantly 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 significant (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 significantly influence oe-

sophageal cancer (RR 1.06, 95% CI 0.89 to 1.28, I2 = 0%). Ap-

proximately 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, riboflavin, 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 significantly influence

oesophageal cancer.

Occurrence of gastric cancer

Antioxidant supplements did not significantly influence 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 significantly influence gastric cancer.

Occurrence of small intestine cancer

Only one trial had results about small intestine cancer (WHS

2005). Antioxidant supplements did not significantly influence

small intestine cancer (RR 4.00, 95% CI 0.45 to 35.79).

Occurrence of colorectal cancer

Antioxidant supplements did not significantly influence colorectal



cancer (RR 0.97, 95% CI 0.86 to 1.09, I2 = 19.7%). Approxi-

mately 1.07% of the participants in the antioxidant group com-

pared to 1.09% in the placebo group developed colorectal cancer

at the end of follow-up. Antioxidants administered singly, ie, beta-

carotene (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

significantly influence colorectal cancer.

Occurrence of pancreatic cancer

Antioxidant supplements did not significantly influence pancre-

atic cancer (RR 1.16, 95% CI 0.90 to 1.50, I2 = 31.4%). Ap-

proximately 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 significantly influence pancreatic cancer.

Occurrence of hepatocellular carcinoma

Antioxidant supplements did not significantly influence hepato-

cellular carcinoma (RR 0.80, 95% CI 0.56 to 1.14, I2 = 38.5%).

This effect was significantly beneficial in a fixed-effect model (RR

0.76, 95% CI 0.60 to 0.96). Approximately 0.20% of the partici-

pants in the antioxidant group compared to 0.24% in the placebo

group developed hepatocellular carcinoma at the end of follow-

up. 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 follow-

up up to 14.1 years did not significantly influence hepatocellular

carcinoma. Antioxidants in combinations as beta-carotene and vi-

tamin A (RR 1.35, 95% CI 0.51 to 3.54), beta-carotene and vita-

min 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 significantly influence hepatocellular carcinoma.

Selenium administered singly versus placebo for two to four years

significantly 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 significantly influence biliary

tract cancers (RR 0.61, 95% CI 0.21 to 1.78, I2 = 0%. Approxi-

mately 0.019% of the participants in the antioxidant group com-

pared to 0.034% in the placebo group developed biliary tract can-

cers at the end of follow-up. Antioxidants administered in combi-

nation as beta-carotene, vitamin C, vitamin E, and selenium had

no significant influence on biliary tract cancers (RR 0.20, 95% CI

0.01 to 4.20).

Overall mortality

Antioxidant supplements had no significant 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 significantly in-

creased mortality in the fixed-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 exclu-

sion, mortality was significantly higher in the antioxidant group

with both the random-effects (RR 1.06, 95% CI 1.01 to 1.10, I2 = 43.3%) and fixed-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 signif-

icant (P = 0.13) by Egger’s test and (P = 0.15) by Begg’s test.



Figure 4. Funnel plot - overall mortality

Meta-regression analysis

Univariate meta-regression analyses revealed that the following

covariates were significantly 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 significantly 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 significantly associated with the

estimated intervention effect on mortality.

Methodological quality and antioxidant effect on overall mor-

tality

The effect of antioxidant supplements on mortality in trials with

low risk of bias (high methodological quality) was not statistically

significant in a random-effects model meta-analysis (RR 1.03,

95% CI 0.98 to 1.08, I2 = 53.5%). Antioxidant supplements sig-

nificantly increased mortality in a fixed-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 significantly

influence mortality (RR 0.94, 95% CI 0.84 to 1.06). The differ-

ence between the estimate of antioxidant effect in low-bias and

high-bias risk trials was not significant 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 significantly influence mortality. Beta-

carotene used singly significantly increased mortality in a fixed-ef-

fect model meta-analysis (RR 1.06, 95% CI 1.02 to 1.10). Mortal-

ity 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 significantly 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

significantly influence mortality.



Non-serious adverse effects

Several adverse effects were recorded in the antioxidant group.

Persistent yellowing of the skin and belching were significantly

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 significantly influenced. Haemorrhagic stroke

was not significantly influenced by vitamin E (RR 1.01, 95%

CI 0.82 to 1.23, I2 = 0%). Gastrointestinal upset in participants

supplemented with selenium was not significantly 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 significantly different between the antioxidant and

the placebo group.

Quality of life and cost-effectiveness

We did not find any data on quality of life in the randomised trials

included in this review. We found cost-effectiveness analyses in

one trial (PHS 1996).

D I S C U S S I O N

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 large-

scale 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 findings

from 47 low-bias risk trials showing increased mortality in partic-

ipants undergoing primary or secondary prevention with similar

antioxidant supplements (Bjelakovic 2007). Selenium might po-

tentially 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 inves-

tigating 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, re-

sults of ongoing high-quality randomised trials with selenium are

needed (APPOSE 2001; SELECT 2003; HGPIN 2006).

Our review shows that beta-carotene possesses significantly harm-

ful effects on gastrointestinal cancers and seems to increase mor-

tality 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 iden-

tify trials assessing vitamin A alone in the prevention of gastroin-

testinal 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 sig-

nificantly higher in the vitamin A supplemented group. Recent

research in this field suggest that vitamin A might have pro-oxi-

dant abilities, which could lead to carcinogenesis (Murata 2000)

and may even increase mortality (Bjelakovic 2007). This finding

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

significant effect on gastrointestinal cancers, or on overall mor-

tality. Vitamin E did not significantly influence gastric, pancre-

atic, and colorectal cancer or overall mortality. According to re-

cent meta-analyses, vitamin E seems to increase overall mortality

(Miller 2005; Bjelakovic 2007). Therefore, preventive use of vita-

min E cannot be recommended.

The bias risk of the trials had a significant impact on our results.

The low-bias risk trials either showed significant harmful effects

or no significant effects of antioxidant supplements on the pri-

mary outcome measures. On the contrary, trials with high-bias risk

found either no significant effects or significant beneficial effects.

These observations are in accordance with several studies linking

high-bias risk with significant overestimation of beneficial effects

(Schulz 1995; Moher 1998; Kjaergard 2001; Jüni 2001; Egger

2003; Gluud 2006a; Gluud 2006b) and underreporting of adverse

effects (D’Amico 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 significantly higher mortal-

ity 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 non-

significant tendency towards increased occurrence of gastrointesti-

nal 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 cardio-

vascular 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



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 sup-

plements (Haenen 2002). Antioxidant supplements in pills are

factory processed, biochemically unbalanced, and apparently un-

safe compared to their naturally occurring counterparts (Herbert

1997; Seifried 2003). Antioxidant supplements also possess pro-

oxidant 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 an-

tioxidant supplements administered at doses significantly 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 con-

ducted in middle- and high-income countries among populations

with already sufficient levels of antioxidant vitamins and trace ele-

ments. 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 unconfined 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 antioxi-

dant supplements are notified (Woo 2007). Consumers presume

antioxidant supplements to be safe and use them without physi-

cians’ supervision (Webb 2007). We find 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 clarification from the authors. However, this was not al-

ways possible. Diagnostic criteria and timing of screening differed

among the trials or were not always well defined. We have com-

pared the intervention effects of antioxidants of different types and

their influence on different gastrointestinal cancers with differ-

ent 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 influence the results. These populations

mostly came from countries without overt deficiencies of specific

supplements. Accordingly, we are unable to assess the influence of

antioxidant supplements on gastrointestinal cancer occurrence in

populations with specific needs. In general, the risk of individual

cancer was below 1%. This may make it difficult to detect any

effects - beneficial or harmful.

The reporting of the occurrence of gastrointestinal cancers and

overall mortality in the randomised trials was not always suffi-

cient and consistent. Regarding gastrointestinal cancers, all in-

cluded 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 influ-

ence the result of our meta-analysis. Outcome reporting bias is

defined 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 difficulties in collecting data on outcomes

in clinical trials focusing on safety and efficacy evaluations. The

worst result of outcome reporting bias and suppression of some

significant or non-significant findings could be the use of harmful

interventions. Most of the included trials lacked detailed infor-

mation on disease-specific 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 fixed-effect model meta-analysis assumes that the

true intervention effect is the same in every randomised trial, ie,

the effect is fixed 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 fixed- and random-effects mod-

els meta-analyses tend to give the same result. If heterogeneity in-

creases, the estimated intervention effect and the corresponding

95% confidence 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 incorporat-

ing 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 stud-

ies than the fixed-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’



(random errors)) increases. Therefore, we also analysed our meta-

analyses with the fixed-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 specific

dietary constituents of fruits and vegetables might have anticar-

cinogenic properties. The results of randomised clinical trials on

cancer prevention with high intake of fruits and vegetables are in-

consistent and vary by cancer type and affected organ (Neuhouser

2003; Nouraie 2005). Recently published results of a randomised

trial found non-significant effect of high fruit and vegetable diet

on colorectal adenoma recurrence (Lanza 2007). Results of epi-

demiologic studies differ significantly too, reporting beneficial or

null effects (Larsson 2006; Freedman 2007; Koushik 2007; Kubo

2007; Takachi 2007).

Our results are in accordance with the results of other recently pub-

lished meta-analyses and systematic reviews (Caraballoso 2003;

Vivekananthan 2003; Bjelakovic 2004a; Bjelakovic 2004b; Miller

2005; Bjelakovic 2006; Bjelakovic 2007), as well as recommen-

dations of the United States Preventive Services Task Force and

British Nutrition Foundation for the use of vitamin supplemen-

tation (McKevith 2003; Morris 2003; USPSTF 2003).

A U T H O R S ’ C O N C L U S I O N SImplications for practice

There is no convincing evidence that the studied antioxidant sup-

plements have beneficial effect on the occurrence of gastrointesti-

nal cancers or on overall mortality. Beta-carotene, vitamin A, vita-

min C, and/or vitamin E seem to increase overall mortality. There-

fore, we cannot recommend the use of these antioxidant supple-

ments as a preventive measure.

Implications for research

Selenium may potentially possess beneficial effects on gastroin-

testinal cancers. The potential anticarcinogenic effects of selenium

have to be elucidated. Randomised clinical trials with selenium

are ongoing and further trials may be needed.

The significant 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 benefits is sub-

jected to adequate assessment of benefits and harms before market

release. We suggest that antioxidant supplements should be regu-

lated as drugs.

Researches wishing to examine the influence of antioxidant sup-

plements on gastrointestinal cancers or other diseases should adopt

the CONSORT statement while performing and reporting ran-

domised clinical trials (CONSORT - Consolidated Standards of

Reporting Trials: www.consort-statement.org).

A C K N O W L E D G E M E N T S

We extend our gratitude to all participants in the randomised clin-

ical 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 For-

man, The Co-ordinating Editor of The Cochrane Upper Gastroin-

testinal and Pancreatic Diseases Group; John McDonald, The Co-

ordinating Editor of The Cochrane Inflammatory Bowel Disease

Group, and Peer Wille-Jørgensen, The Co-ordinating Editor of

The Cochrane Colorectal Cancer Group for their expert com-

ments 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 Maol-

ing 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 Her-

cberg, 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.



R E F E R E N C E S

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):

1427s–30s. [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 alpha-

tocopherol, beta-carotene cancer prevention study: effects

of base-line characteristics and study compliance. Journalof the National Cancer Institute 1996;88(21):1560–70.

[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):197–205. [MEDLINE: 10782653]

Blumberg J. The Alpha-Tocopherol, Beta-Carotene Cancer

Prevention Study in Finland. Nutrition Reviews 1994;52(7):

242–50. [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):1115–6. [MEDLINE: 10613346]

Hartman TJ, Dorgan JF, Woodson K, Virtamo J, Tangrea

JA, Heinonen OP, et al.Effects of long-term alpha-

tocopherol supplementation on serum hormones in older

men. Prostate 2001;46(1):33–8. [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 Thrombosisand Vascular Biology 2000;20(1):230–5. [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):542–6. [MEDLINE:

9920356]

Malila N, Taylor PR, Virtanen MJ, Korhonen P, Huttunen

JK, Albanes D, et al.Effects of alpha-tocopherol and beta-

carotene supplementation on gastric cancer incidence in

male smokers (ATBC Study, Finland). Cancer Causes &

Control 2002;13(7):617–23. [MEDLINE: 12296509]

Malila N, Virtamo J, Virtanen M, Albanes D, Tangrea

J, Huttunen J. The effect of alpha-tocopherol and beta-

carotene supplementation on colorectal adenomas in

middle-aged male smokers. Cancer Epidemiology, Biomarkers& Prevention 1999;8(6):489–93. [MEDLINE: 10385137]

Malila N, Virtamo J, Virtanen M, Pietinen P, Albanes

D, Teppo L. Dietary and serum alpha-tocopherol, beta-

carotene and retinol, and risk for colorectal cancer in male

smokers. European Journal of Clinical Nutrition 2002;56(7):

615–21. [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):960–5. [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):37–42. [MEDLINE:

10391561]

Stolzenberg-Solomon RZ, Blaser MJ, Limburg PJ, Perez-

Perez 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):937–41.

[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):68–73.

[MEDLINE: 9541437]

Teikari JM, Laatikainen L, Virtamo J, Haukka J, Rautalahti

M, Liesto K, et al.Six-year supplementation with alpha-

tocopherol and beta-carotene and age-related maculopathy.

Acta Ophthalmologica Scandinavica 1998;76(2):224–9.

[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 andCommunity Health 1998;52(7):468–72. [MEDLINE:

9799882]

The ATBC Cancer Prevention Study Group. The Alpha-

Tocopherol, Beta-Carotene Lung Cancer Prevention

Study: design, methods, participant characteristics, and

compliance. Annals of Epidemiology 1994;4(1):1–10.

[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 ofMedicine 1994;330(15):1029–35. [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):167–73. [MEDLINE: 11427217]

Tornwall ME, Virtamo J, Haukka JK, Aro A, Albanes D,

Huttunen JK. The effect of alpha-tocopherol and beta-

carotene supplementation on symptoms and progression of

intermittent claudication in a controlled trial. Atherosclerosis1999;147(1):193–7. [MEDLINE: 10525141]

Tornwall ME, Virtamo J, Korhonen PA, Virtanen MJ,

Albanes D, Huttunen JK. Postintervention effect of alpha



tocopherol and beta carotene on different strokes: a 6-

year follow-up of the Alpha Tocopherol, Beta Carotene

Cancer Prevention Study. Stroke 2004;35(8):1908–13.

[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 Journalof Gastroenterology 2000;35(9):950–6. [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):294–300. [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):933–9. [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. JAMA2003;290(4):476–85. [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 NationalCancer Institute 1999;91(20):1738–43. [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. CancerEpidemiology, Biomarkers & Prevention 2004;13(12):

2233–41. [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 efficacy trial. American Journal of Epidemiology2005;162(9):868–78. [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 asbestos-

exposed cohorts. American Journal of Industrial Medicine

1997;32(6):573–81. [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):39–50.

[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 Efficacy Trial (CARET). American Journal of

Industrial Medicine 1997;32(6):582–91. [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 Efficacy Trial (CARET). European Journal ofClinical Nutrition 2005;59(10):1173–80. [MEDLINE:

16015255]

Challem JJ. Re: Risk factors for lung cancer and for

intervention effects in CARET, the Beta-Carotene and

Retinol Efficacy Trial. Journal of the National Cancer

Institute 1997;89(4):325–6. [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 CareMedicine 1997;155(3):1066–71. [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

efficacy trial. American Journal of Epidemiology 2005;161

(3):160–70. [MEDLINE: 15671258]

Goodman GE, Omenn GS. Carotene and retinol

efficacy trial: lung cancer chemoprevention trial in heavy

cigarette smokers and asbestos-exposed workers. CARET

Coinvestigators and Staff. Advances in ExperimentalMedicine and Biology 1992;320:137–40. [MEDLINE:

1442278]

Goodman GE, Omenn GS, Thornquist MD, Lund B,

Metch B, Gylys-Colwell I. The Carotene and Retinol

Efficacy Trial (CARET) to prevent lung cancer in high-risk

populations: pilot study with cigarette smokers. CancerEpidemiology, Biomarkers & Prevention 1993;2(4):389–96.

[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 Efficacy Trial. CancerEpidemiology, Biomarkers & Prevention 2003;12(6):518–26.

[MEDLINE: 12814997]

Goodman GE, Thornquist M, Kestin M, Metch B,

Anderson G, Omenn GS. The association between

participant characteristics and serum concentrations of beta-

carotene, retinol, retinyl palmitate, and alpha-tocopherol

among participants in the Carotene and Retinol Efficacy

Trial (CARET) for prevention of lung cancer. CancerEpidemiology, Biomarkers & Prevention 1996;5(10):815–21.

[MEDLINE: 8896893]∗ Goodman GE, Thornquist MD, Balmes J, Cullen MR,

Meyskens FL Jr, Omenn GS, et al.The Beta-Carotene

and Retinol Efficacy 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):

1743–50. [MEDLINE: 15572756]

Goodman GE, Valanis B, Meyskens FL Jr, Williams JH Jr,

Metch BJ, Thornquist MD, et al.Strategies for recruitment



to a population-based lung cancer prevention trial: the

CARET experience with heavy smokers. Beta-Carotene and

Retinol Efficacy Trial. Cancer Epidemiology, Biomarkers &

Prevention 1998;7(5):405–12. [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 Efficacy Trial.

Cancer Epidemiology, Biomarkers & Prevention 2005;14(4):

988–92. [MEDLINE: 15824175]

Leo MA, Lieber CS. Re: Risk factors for lung cancer and

for intervention effects in CARET, the Beta-Carotene

and Retinol Efficacy Trial. Journal of the National CancerInstitute 1997;89(22):1722–3. [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 Efficacy Trial

(CARET). Cancer Epidemiology, Biomarkers & Prevention2003;12(4):350–8. [MEDLINE: 12692110]




arm of the Beta-Carotene and Retinol Efficacy Trial

(CARET). Cancer Epidemiology, Biomarkers & Prevention2003;12(4):350–8. [MEDLINE: 12692110]

Omenn GS. CARET, the Beta-Carotene and Retinol

Efficacy Trial to prevent lung cancer in high-risk

populations. Public Health Reviews 1991;19(1-4):205–8.

[MEDLINE: 1844268]

Omenn GS, Goodman G, Grizzle J, Thornquist M,

Rosenstock L, Barnhart S, et al.CARET, the Beta-Carotene

and Retinol Efficacy Trial to prevent lung cancer in asbestos-

exposed workers and in smokers. Anticancer Drugs 1991;2

(1):79–86. [MEDLINE: 1958856]

Omenn GS, Goodman G, Grizzle J, Thornquist M,

Rosenstock L, Barnhart S, et al.Recruitment for the

Beta-Carotene and Retinol Efficacy Trial (CARET) to

prevent lung cancer in smokers and asbestos-exposed

workers. Western Journal of Medicine 1992;156(5):540–4.

[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 Efficacy Trial

(CARET) in high-risk smokers and asbestos-exposed

workers. IARC Scientific Publications 1996;136:67–85.

[MEDLINE: 8791118]

Omenn GS, Goodman G, Thornquist M, Grizzle J,

Rosenstock L, Barnhart S, et al.The Beta-Carotene and

Retinol Efficacy Trial (CARET) for chemoprevention of

lung cancer in high risk populations: smokers and asbestos-

exposed workers. Cancer Research 1994;54(7 Suppl):

2038s–43s. [MEDLINE: 8137335]

Omenn GS, Goodman GE, Thornquist M, Brunzell JD.

Long-term vitamin A does not produce clinically significant

hypertriglyceridemia: results from CARET, the Beta-

Carotene and Retinol Efficacy Trial. Cancer Epidemiology,Biomarkers & Prevention 1994;3(8):711–3. [MEDLINE:

7881345]

Omenn GS, Goodman GE, Thornquist MD, Balmes J,

Cullen MR, Glass A. Risk factors for lung cancer and

for intervention effects in CARET, the Beta-Carotene

and Retinol Efficacy Trial. Journal of the National Cancer

Institute 1996;88(21):1550–9. [MEDLINE: 8901853]

Omenn GS, Goodman GE, Thornquist MD, Balmes J,

Cullen MR, Glass A, et al.Effects of a combination of beta

carotene and vitamin A on lung cancer and cardiovascular

disease. New England Journal of Medicine 1996;334(18):

1150–5. [MEDLINE: 8602180]

Omenn GS, Goodman GE, Thornquist MD, Rosenstock

L, Barnhart S, Gylys-Colwell I, et al.The Carotene and

Retinol Efficacy Trial (CARET) to prevent lung cancer in

high-risk populations: pilot study with asbestos-exposed

workers. Cancer Epidemiology, Biomarkers & Prevention1993;2(4):381–7. [MEDLINE: 8602180]

Redlich CA, Chung JS, Cullen MR, Blaner WS, Van-

Bennekum AM, Berglund L. Effect of long-term beta-

carotene and vitamin A on serum cholesterol and triglyceride

levels among participants in the Beta-Carotene and Retinol

Efficacy Trial (CARET). Atherosclerosis 1999;143(2):

427–34. [MEDLINE: 10217373]

Smigel K. Beta carotene fails to prevent cancer in two

major studies; CARET intervention stopped. Journal of the

National Cancer Institute 1996;88(3-4):145. [MEDLINE:

8632485]

Sondik EJ. CARET study: women included. Science 1991;

254(5030):360. [MEDLINE: 1925587]

Thornquist MD, Edelstein C, Goodman GE, Omenn GS.

Streamlining IRB review in multisite trials through single-

study IRB cooperative agreements: experience of the Beta-

Carotene and Retinol Efficacy Trial (CARET). Controlled

Clinical Trials 2002;23(1):80–6. [MEDLINE: 11852169]

Thornquist MD, Omenn GS, Goodman GE, Grizzle JE,

Rosenstock L, et al.Statistical design and monitoring of

the Beta-Carotene and Retinol Efficacy Trial (CARET).

Controlled Clinical Trials 1993;14(4):308–24. [MEDLINE:

8365195]

Thornquist MD, Patrick DL, Omenn GS. Participation

and adherence among older men and women recruited to

the Beta-Carotene and Retinol Efficacy Trial (CARET).

Gerontologist 1991;31(5):593–7. [MEDLINE: 1778482]

Thornquist MD, Urban N, Tseng A, Edelstein C, Lund

B, Omenn GS. Research cost analyses to aid in decision

making in the conduct of a large prevention trial, CARET.

Beta-Carotene and Retinol Efficacy Trial. Controlled

Clinical Trials 1993;14(4):325–39. [MEDLINE: 8365196]

Valanis B, Blank J, Glass A. Mailing strategies and

costs of recruiting heavy smokers in CARET, a large

chemoprevention trial. Controlled Clinical Trials 1998;19

(1):25–38. [MEDLINE: 9492967]

Correa 2000 {published data only}

Correa P, Fontham ET, Bravo JC, Bravo LE, Ruiz B, Zarama

G, et al.Chemoprevention of gastric dysplasia: randomized

trial of antioxidant supplements and anti-Helicobacter

pylori therapy. Journal of the National Cancer Institute 2000;



92(23):1881–8. [MEDLINE: 20560859]

Correa P, Fontham ETH, Bravo JC, Bravo LE, Ruiz B,

Zarama G, 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(7):559–60.∗ Gail MH, Brown LM, You WC. Re: chemoprevention

of gastric dysplasia: randomized trial of antioxidant

supplements and anti-Helicobacter pylori therapy. Journal


[MEDLINE: 11287457]

Mera R, Fontham ET, Bravo LE, Bravo JC, Piazuelo

MB, Camargo MC, et al.Long term follow up of patients

treated for Helicobacter pylori infection. Gut 2005;54(11):

1536–40. [MEDLINE: 15985559]

Ruiz B, Garay J, Correa P, Fontham ET, Bravo JC, Bravo

LE, et al.Morphometric evaluation of gastric antral atrophy:

improvement after cure of Helicobacter pylori infection.

American Journal of Gastroenterology 2001;96(12):3281–7.

[MEDLINE: 11774937]

HOPE TOO 2005 {published data only}

Bosch J, Lonn E, Pogue J, Arnold JM, Dagenais GR, Yusuf

S, HOPE/HOPE-TOO Study Investigators. Long-term

effects of ramipril on cardiovascular events and on diabetes:

results of the HOPE study extension. Circulation 2005;112

(9):1339–46. [MEDLINE: 16129815]

Gerstein HC. Reduction of cardiovascular events and

microvascular complications in diabetes with ACE

inhibitor treatment: HOPE and MICRO-HOPE. Diabetes/Metabolism Research and Reviews 2002;18(suppl 3):s82–s5.

[MEDLINE: 12324991]

Heart Outcomes Prevention Evaluation Study Investigators.

Effects of ramipril on cardiovascular and microvascular

outcomes in patients with diabetis mellitus: results of the

HOPE study and MIRCO-HOPE substudy. Lancet 2000;

355(9200):253–9. [MEDLINE: 10675071]


The HOPE (Heart Outcomes Prevention Evaluation)

Study: the design of a large, simple randomized trial of an

angiotensin-converting enzyme inhibitor (ramipril) and

vitamin E in patients at high risk of cardiovascular events.

Canadian Journal of Cardiology 1996;12(2):127–37.

Lamy A, Yusuf S, Pogue J, Gafni A, Heart Outcomes

Prevention Evaluation Investigators. Cost implications

of the use of ramipril in high-risk patients based on the

Heart Outcomes Prevention Evaluation (HOPE) study.

Circulation 2003;107(7):960–5. [MEDLINE: 12600907]∗ Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM,

et al.Effects of long-term vitamin E supplementation on

cardiovascular events and cancer: a randomized controlled

trial. JAMA 2005;293(11):1338–47. [MEDLINE:

15769967]

Lonn E, Mathew J, Pogue J, Johnstone D, Danisa K,

Bosch J, et al.Relationship of electrocardiographic left

ventricular hypertrophy to mortality and cardiovascular

morbidity in high-risk patients. European Journal of

Cardiovascular Prevention and Rehabilitation 2003;10(6):

420–8. [MEDLINE: 14671464]

Lonn E, Roccaforte R, Yi Q, Dagenais G, Sleight P, Bosch

J, et al.Effect of long-term therapy with ramipril in high-

risk women. Journal of the American College of Cardiology2002;40(4):693–702. [MEDLINE: 12204499]

Lonn E, Yusuf S, Hoogwerf B, Pogue J, Yi Q, Zinman B, et

al.Effects of vitamin E on cardiovascular and microvascular

outcomes in high-risk patients with diabetes: results of the

HOPE study and MICRO-HOPE substudy. Diabetes Care

2002;25(11):1919–27. [MEDLINE: 12401733]

Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal

insufficiency as a predictor of cardiovascular outcomes and

the impact of ramipril: the HOPE randomized trial. Annals

of Internal Medicine 2001;134(8):629–36. [MEDLINE:

11304102]

Mann JF, Gerstein HC, Yi QL, Franke J, Lonn EM,

Hoogwerf BJ, et al.Progression of renal insufficiency in type

2 diabetes with and without microalbuminuria: results of

the Heart Outcomes and Prevention Evaluation (HOPE)

randomized study. American Journal of Kidney Diseases2003;42(5):936–42. [MEDLINE: 14582037]

Mann JF, Gerstein HC, Yi QL, Lonn EM, Hoogwerf BJ,

Rashkow A, et al.Development of renal disease in people at

high cardiovascular risk: results of the HOPE randomized

study. Journal of the American Society of Nephrology 2003;14

(3):641–7. [MEDLINE: 12595499]

Mann JF, Lonn EM, Yi Q, Gerstein HC, Hoogwerf BJ,

Pogue J, et al.Effects of vitamin E on cardiovascular outcomes

in people with mild-to-moderate renal insufficiency: results

of the HOPE study. Kidney International 2004;65(4):

1375–80. [MEDLINE: 15086477]

Mann JF, Yi QL, Sleight P, Dagenais GR, Gerstein HC,

Lonn EM, et al.Serum potassium, cardiovascular risk, and

effects of an ACE inhibitor: results of the HOPE study.

Clinical Nephrology 2005;63(8):181–7. [MEDLINE:

15786818]

McQueen MJ, Lonn E, Gerstein HC, Bosch J, Yusuf S.

The HOPE (Heart Outcomes Prevention Evaluation) Study

and its consequences. Scandinavian Journal of Clinical

and Laboratory Investigation 2005;Suppl 240:143–56.

[MEDLINE: 16112972]

Ostergren J, Sleight P, Dagenais G, Danisa K, Bosch J,

Qilong Y, et al.Impact of ramipril in patients with evidence

of clinical or subclinical peripheral arterial disease. EuropeanHeart Journal 2004;25(1):17–24. [MEDLINE: 14683738]

Sharpe N. The HOPE TIPS: The HOPE Study Translated

into Practices. Cardiovascular Drugs and Therapy 2005;19

(3):197–201. [MEDLINE: 16142597]

Teo KK, Mitchell LB, Pogue J, Bosch J, Dagenais G, Yusuf

S, et al.Effect of ramipril in reducing sudden deaths and

nonfatal cardiac arrests in high-risk individuals without

heart failure or left ventricular dysfunction. Circulation2004;110(11):1413–7. [MEDLINE: 15353497]

Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin

E supplementation and cardiovascular events in high-risk

patients. The Heart Outcomes Prevention Evaluation Study

Investigators. New England Journal of Medicine 2000;342



(3):154–60.

Yusuf S, Gerstein H, Hoogwerf B, Pogue J, Bosch J,

Wolffenbuttel BH, et al.Ramipril and the development

of diabetes. JAMA 2001;286(15):1882–5. [MEDLINE:

11597291]

Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais

G. Effect of an angiotensin-converting-enzyme inhibitor,

ramipril, on cardiovascular events in high-risk patients. The


New England Journal of Medicine 2000;342(3):145–53.

[MEDLINE: 10639539]

HPS 2002 {published data only}

Armitage J, Collins R. Need for large scale randomised

evidence about lowering LDL cholesterol in people with

diabetes mellitus: MRC/BHF Heart Protection Study and

other major trials. Heart 2000;84(4):357–60. [MEDLINE:

10995396]

Bates CJ. MRC/BHF Heart Protection Study. Lancet 2002;

360(9347):1781–2. [MEDLINE: 12480450]

Brown MJ. MRC/BHF Heart Protection Study. Lancet

2002;360(9347):1782. [MEDLINE: 12480451]

Collins R, Armitage J, Parish S, Sleight P, Peto R. MRC/

BHF Heart Protection Study. Lancet 2002;360(9347):

1783–4. [MEDLINE: 12480453]

Collins R, Peto R, Armitage J. The MRC/BHF Heart

Protection Study: preliminary results. International

Journal of Clinical Practice 2002;56(1):53–6. [MEDLINE:

11831837]

Durrington PN. MRC/BHF Heart Protection Study. Lancet2002;360(9347):1781. [MEDLINE: 12480449]

Farmer JA. MRC/BHF Heart Protection Study of

cholesterol lowering with simvastatin in 20,536 high-risk

individuals: a randomized, placebo-controlled trial. CurrentAtherosclerosis Reports 2003;5(2):93–4. [MEDLINE:

12573191]

Heart Protection Study Collaborative Group. MRC/BHF

Heart Protection Study of cholesterol-lowering therapy and

of antioxidant vitamin supplementation in a wide range of

patients at increased risk of coronary heart disease death:

early safety and efficacy experience. European Heart Journal

1999;20(10):725–41. [MEDLINE: 10329064]

Kris-Etherton PM. MRC/BHF Heart Protection Study of

antioxidant vitamin supplementation in 20,536 high-risk

individuals: a randomised placebo-controlled trial. Current

Atherosclerosis Reports 2002;4(6):411–2. [MEDLINE:

12361485]

Kulbertus H, Scheen AJ. Clinical study of the month.

The MRC/BHF Heart Protection Study [L’etude clinique

du mois. La MRC/BHF Heart Protection Study]. RevueMedicale de Liege 2002;57(9):613–6. [MEDLINE:

12440352]

Kumana CR, Cheung BM, Lauder IJ. MRC/BHF Heart

Protection Study. ACP Journal Club 2003;138(2):A15.

[MEDLINE: 12614142]∗ MRC/BHF Heart Protection Study Collaborative

Group. MRC/BHF Heart Protection Study of antioxidant

vitamin supplementation in 20,536 high-risk individuals:

a randomised placebo-controlled trial. Lancet 2002; Vol.

360, issue 9326:23–33. [MEDLINE: 12114037]

MRC/BHF Heart Protection Study Collaborative Group.

MRC/BHF Heart Protection Study of cholesterol-lowering

therapy and of antioxidant vitamin supplementation in

a wide range of patients at increased risk of coronary

heart disease death: early safety and efficacy experience.

European Heart Jornal 1999;20(10):725–41. [MEDLINE:

10329064]

MRC/BHF Heart Protection Study Collaborative Group.

MRC/BHF Heart Protection Study of cholesterol-lowering

with simvastatin in 20,536 high-risk individuals: a

randomized placebo controlled trial. Lancet 2002;360

(9326):7–22. [MEDLINE: 12114036]

Robins SJ, Despres JP. MRC/BHF Heart Protection Study.

Lancet 2002;360(9347):1780. [MEDLINE: 12480447]

Vaughan CJ, Buckley BM. MRC/BHF Heart Protection

Study. Lancet 2002;360(9347):1780–1. [MEDLINE:

12480446]

Violi F, Micheletta F, Iuliano L. MRC/BHF Heart

Protection Study. Lancet 2002;360(9347):1782–3.

[MEDLINE: 12480452]

Wald N, Law M. MRC/BHF Heart Protection Study.

Lancet 2002;360(9347):1781. [MEDLINE: 12480448]

Li 2000 {published data only}∗ Li W, Zhu Y, Yan X, Zhang Q, Li X, Ni Z, et al.The

prevention of primary liver cancer by selenium in high

risk populations. (Zhonghua Yu Fang Yi Xue Za Zhi)

Chinese Journal of Preventive Medicine 2000;34(6):336–8.

[MEDLINE: 11860943]

Li WG. Preliminary observations on effect of selenium

yeast on high risk populations with primary liver cancer.

(Zhonghua Yu Fang Yi Xue Za Zhi) Chinese Journal ofPreventive Medicine 1992;26(5):268–71. [MEDLINE:

1298601]

Li 2004 {published data only}

Li H, Li HQ, Wang Y, Xu HX, Fan WT, Wang ML, et

al.An intervention study to prevent gastric cancer by micro-

selenium and large dose of allitridum. Chinese MedicalJournal 2004;117(8):1155–60. [MEDLINE: 15361287]

Munoz 1985 {published data only}

Munoz N, Wahrendorf J, Bang LJ, Crespi M, Thurnham

DI, Day NE, et al.No effect of riboflavine, retinol, and

zinc on prevalence of precancerous lesions of oesophagus.

Randomised double-blind intervention study in high-

risk population of China. Lancet 1985;2(8447):111–4.

[MEDLINE: 85266610; : 00039020]

NIT1 1993 {published data only}

Blot WJ, Li JY. Some considerations in the design of a

Nutritional Intervention Trial in Linxian, People’s Republic

of China. National Cancer Institute Monographs 1984;69:

29–34. [MEDLINE: 3914622]∗ Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang

GQ, et al.Nutrition Intervention Trials in Linxian,

China: supplementation with specific vitamin/mineral

combinations, cancer incidence, and disease-specific

mortality in the general population. Journal of the National



Cancer Institute 1993;85(18):1483–92. [MEDLINE:

8360931]

Blot WJ, Li JY, Taylor PR, Guo W, Dawsey SM, Li B.

The Linxian trials: mortality rates by vitamin-mineral

intervention group. American Journal of Clinical Nutrition

1995;62(6 Suppl):1424s–6s. [MEDLINE: 7495242]

Li B, Taylor PR, Li JY, Dawsey SM, Wang W, Tangrea JA, et

al.Linxian Nutrition Intervention Trials. Design, methods,

participant characteristics, and compliance. Annals of

Epidemiology 1993;3(6):577–85. [MEDLINE: 7921303]

Li JY. Vitamins and minerals in cancer: The Nutrition

Intervention Trials in Linxian, China. Medecine BiologieEnvironnement 1998;26(2):187–209.

Mark SD, Qiao YL, Dawsey SM, Wu YP, Katki H,

Gunter EW, et al.Prospective study of serum selenium

levels and incident esophageal and gastric cancers. Journalof the National Cancer Institute 2000;92(21):1753–63.

[MEDLINE: 11058618]

Taylor PR, Li B, Dawsey SM, Li JY, Yang CS, Guo W,

et al.Prevention of esophageal cancer: the Nutrition

Intervention Trials in Linxian, China. Linxian Nutrition

Intervention Trials Study Group. Cancer Research 1994;54

(7 Suppl):2029s–31s. [MEDLINE: 8137333]

Wang GQ, Dawsey SM, Li JY, Taylor PR, Li B, Blot WJ,

et al.Effects of vitamin/mineral supplementation on the

prevalence of histological dysplasia and early cancer of

the esophagus and stomach: results from the General

Population Trial in Linxian, China. Cancer Epidemiology,Biomarkers & Prevention 1994;3(2):161–6. [MEDLINE:

8049638]

NIT2 1993 {published data only}

Li JY, Li B, Blot WJ, Taylor PR. Preliminary report on the

results of nutrition prevention trials of cancer and other

common diseases among residents in Linxian, China.

(Zhonghua Zhong Liu Za Zhi) Chinese Journal of Oncology

1993;15(3):165–81. [MEDLINE: 8261860]∗ Li JY, Taylor PR, Li B, Dawsey S, Wang GQ, Ershow

AG, et al.Nutrition Intervention Trials in Linxian,

China: multiple vitamin/mineral supplementation, cancer

incidence, and disease-specific mortality among adults with

esophageal dysplasia. Journal of the National Cancer Institute

1993;85(18):1492–8. [MEDLINE: 8360932]

Mark SD, Liu SF, Li JY, Gail MH, Shen Q, Dawsey SM, et

al.The effect of vitamin and mineral supplementation on

esophageal cytology: results from the Linxian Dysplasia

Trial. International Journal of Cancer 1994;57(2):162–6.

[MEDLINE: 8157352]

Taylor PR, Wang GQ, Dawsey SM, Guo W, Mark SD, Li

JY, et al.Effect of nutrition intervention on intermediate

endpoints in esophageal and gastric carcinogenesis.

American Journal of Clinical Nutrition 1995;62(6 Suppl):

1420s–3s. [MEDLINE: 7495241]

NPCT 1996 {published data only}∗ Clark LC, Combs GF Jr, Turnbull BW, Slate EH, Chalker

DK, Chow J, et al.Effects of selenium supplementation

for cancer prevention in patients with carcinoma of the

skin. A randomized controlled trial. Journal of American

Medical Association 1996;276(24):1957–63. [MEDLINE:

8971064]

Clark LC, Dalkin B, Krongrad A, Combs GF Jr, Turnbull

BW, Slate EH, et al.Decreased incidence of prostate cancer

with selenium supplementation: results of a double-blind

cancer prevention trial. British Journal of Urology 1998;81

(5):730–4. [MEDLINE: 9634050]

Combs GF, Clark LC, Turnbull BW. Reduction of cancer

risk with an oral supplement of selenium. Biomedical and

Environmental Sciences 1997;10(2-3):227–34. [MEDLINE:

9315315]

Combs GF Jr. Impact of selenium and cancer-prevention

findings on the nutrition-health paradigm. Nutrition and

Cancer 2001;40(1):6–11. [MEDLINE: 11799925]

Combs GF Jr, Clark LC, Turnbull BW. Reduction of cancer

mortality and incidence by selenium supplementation.

Medizinische Klinik 1997;92(Suppl 3):42–5. [MEDLINE:

9342915]

Duffield-Lillico AJ, Reid ME, Turnbull BW, Combs Jr

GF, Slate EH, Fischbach LA. 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

Epidemiology, Biomarkers & Prevention 2002;11(7):630–9.

Redman C, Xu MJ, Peng YM, Scott JA, Payne C, Clark

LC, et al.Involvement of polyamines in selenomethionine

induced apoptosis and mitotic alterations in human tumor

cells. Carcinogenesis 1997;18(6):1195–202. [MEDLINE:

9214603]

Reid ME, Duffield-Lillico AJ, Garland L, Turnbull BW,

Clark LC, Marshall JR. Selenium supplementation and lung

cancer incidence: an update of the Nutritional Prevention of

Cancer Trial. Cancer Epidemiology, Biomarkers & Prevention

2002;11(11):1285–91. [MEDLINE: 12433704]

PHS 1996 {published data only}

Albert CM, Gaziano JM, Willett WC, Manson JE. Nut

consumption and decreased risk of sudden cardiac death in

the Physicians’ Health Study. Archives of Internal Medicine

2002;162(12):1382–7. [MEDLINE: 12076237]

Andreotti F, Burzotta F, De-Stefano V, Maseri A, Iacoviello

L. The G20210A prothrombin mutation and the

Physicians’ Health Study. Circulation 2000;101(21):

E207–8. [MEDLINE: 10831536]

Berger K, Kase CS, Buring JE. Interobserver agreement in

the classification of stroke in the Physicians’ Health Study.

Stroke 1996;27(2):238–42. [MEDLINE: 8571416]

Buring JE, Hebert P, Romero J, Kittross A, Cook N,

Manson J, et al.Migraine and subsequent risk of stroke in

the Physicians’ Health Study. Archives of Neurology 1995;52

(2):129–34. [MEDLINE: 7848119]

Buring JE, Hennekens CH. Cost and efficiency in clinical

trials: the U.S. Physicians’ Health Study. Statistics in

Medicine 1990;9(1-2):29–33. [MEDLINE: 2345836]

Chan JM, Stampfer MJ, Ma J, Gann PH, Gaziano JM,

Giovannucci EL. Dairy products, calcium, and prostate

cancer risk in the Physicians’ Health Study. American Journal

of Clinical Nutrition 2001;74(4):549–54. [MEDLINE:



11566656]

Christen WG, Glynn RJ, Ajani UA, Schaumberg DA,

Manson JE, Buring JE, et al.Baseline self-reported cataract

and subsequent mortality in Physicians’ Health Study I.

Ophthalmic Epidemiology 2000;7(2):115–25. [MEDLINE:

10934462]

Christen WG, Glynn RJ, Seddon JM, Manson JE, Buring

JE, Hennekens CH. Confirmation of self-reported cataract

in the Physicians’ Health Study. Ophthalmic Epidemiology

1994;1(2):85–91. [MEDLINE: 8790615]

Cook NR, Le IM, Manson JE, Buring JE, Hennekens

CH. Effects of beta-carotene supplementation on cancer

incidence by baseline characteristics in the Physicians’

Health Study (United States). Cancer Causes & Control2000;11(7):617–26. [MEDLINE: 10977106]

Frieling UM, Schaumberg DA, Kupper TS, Muntwyler

J, Hennekens CH. A randomized, 12-year primary-

prevention trial of beta carotene supplementation for

nonmelanoma skin cancer in the Physician’s Health Study.

Archives of Dermatology 2000;136(2):179–84. [MEDLINE:

10677093]

Gaziano JM, Gaziano TA, Glynn RJ, Sesso HD, Ajani UA,

Stampfer MJ, et al.Light-to-moderate alcohol consumption

and mortality in the Physicians’ Health Study enrollment

cohort. Journal of the American College of Cardiology 2000;

35(1):96–105. [MEDLINE: 10636266]

Hennekens CH, Buring JE. Methodologic considerations

in the design and conduct of randomized trials: the U.S.

Physicians’ Health Study. Controlled Clinical Trials 1989;10

(4 Suppl):142S–50S. [MEDLINE: 2605963]∗ Hennekens CH, Buring JE, Manson JE, Stampfer M,

Rosner B, Cook NR, et al.Lack of effect of long-term

supplementation with beta carotene on the incidence of

malignant neoplasms and cardiovascular disease. NewEngland Journal of Medicine 1996;334(18):1145–9.

[MEDLINE: 8602179]

Hennekens CH, Eberlein K. A randomized trial of aspirin

and beta-carotene among U.S. physicians. PreventiveMedicine 1985;14(2):165–8. [MEDLINE: 3900975]

Jonas S. The Physician’s Health Study. A neurologist’s

concern. Archives of Neurology 1990;47(12):1352–3.

[MEDLINE: 2252454]

Lang JM, Buring JE, Rosner B, Cook N, Hennekens CH.

Estimating the effect of the run-in on the power of the

Physicians’ Health Study. Statistics in Medicine 1991;10

(10):1585–93. [MEDLINE: 1947514]

Lee IM, Manson JE, Ajani U, Paffenbarger RS Jr,

Hennekens CH, Buring JE. Physical activity and risk of

colon cancer: the Physicians’ Health Study (United States).

Cancer Causes & Control 1997;8(4):568–74. [MEDLINE:

9242472]

Liu S, Lee IM, Ajani U, Cole SR, Buring JE, Manson

JE. Intake of vegetables rich in carotenoids and risk of

coronary heart disease in men: the Physicians’ Health Study.

International Journal of Epidemiology 2001;30(1):130–5.

[MEDLINE: 11171873]

Lotufo PA, Chae CU, Ajani UA, Hennekens CH, Manson

JE. Male pattern baldness and coronary heart disease: the

Physicians’ Health Study. Archives of Internal Medicine2000;160(2):165–71. [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). InternationalJournal of Cancer 2000;87(1):141–4. [MEDLINE:

10861465]

Ma J, HennekensCH, Ridker PM, Stampfer MJ. A

prospective study of fibrinogen and risk of myocardial

infarction in the Physicians’ Health Study. Journal of

the American College of Cardiology 1999;33(5):1347–52.

[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):166–75.

[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):1641–6. [MEDLINE:

12376472]

Physicians’ Health Study Research Group. Peliminary

report: findings from the aspirin component of the ongoing

Physicians Health Study. New England Journal of Medicine

1988;318(4):262–4.

Satterfield 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):290–4. [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):686–702. [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):129–35. [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


[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):6708–12.

[MEDLINE: 11559540]

Vieth R. Dairy products, calcium, and prostate cancer risk

in the Physicians’ Health Study. American Journal of ClinicalNutrition 2002;76(2):490–1. [MEDLINE: 12145029]

Plummer 2007 {published data only}

de Sanjose S, Munoz N, Sobala G, Vivas J, Peraza S, Cano



E, et al.Antioxidants, Helicobacter pylori and stomach

cancer in Venezuela. European Journal of Cancer Prevention1996;5(1):57–62. [MEDLINE: 8664811]

Munoz N, Kato I, Peraza S, Lopez G, Carrillo E, Ramirez

H, et al.Prevalence of precancerous lesions of the stomach

in Venezuela. Cancer Epidemiology, Biomarkers & Prevention1996;5(1):41–6. [MEDLINE: 8770465]

Munoz N, Vivas J, Buiatti E, Kato I, Oliver W.

Chemoprevention trial on precancerous lesions of the

stomach in Venezuela: summary of study design and

baseline data. IARC Scientific Publications 1996;139:

125–33. [MEDLINE: 8923024]∗ Plummer M, Vivas J, Lopez G, Bravo JC, Peraza S, Carillo

E, et al.Chemoprevention of precancerous gastric lesions

with antioxidant vitamin supplementation: a randomized

trial in a high-risk population. Journal of the National CancerInstitute 2007;99(2):137–46. [MEDLINE: 17227997]

SIT 2006 {published data only}

Gail MH, Pfeiffer RM, Brown LM, Zhang L, Ma JL, Pan

KF, et al.Garlic, vitamin, and antibiotic treatment for

Helicobacter pylori: a randomized factorial controlled trial.

Helicobacter 2007;12(5):575–8. [MEDLINE: 17760729]

Gail MH, You WC. A factorial trial including garlic

supplements assesses effect in reducing precancerous gastric

lesions. Journal of Nutrition 2006;136(3 Suppl):813S–5S.

[MEDLINE: 16484571]

Gail MH, You WC, Chang YS, Zhang L, Blot WJ, Brown

LM, et al.Factorial trial of three interventions to reduce the

progression of precancerous gastric lesions in Shandong,

China: design issues and initial data. Controlled Clinical

Trials 1998;19(4):352–69. [MEDLINE: 9683311]∗ You WC, Brown LM, Zhang L, Li JY, Jin ML, Chang

YS, et al.Randomized double-blind factorial trial of three

treatments to reduce the prevalence of precancerous gastric

lesions. Journal of the National Cancer Institute 2006;98

(14):974–83. [MEDLINE: 16849680]

You WC, Chang YS, Heinrich J, Ma JL, Liu WD, Zhang

L, et al.An intervention trial to inhibit the progression

of precancerous gastric lesions: compliance, serum

micronutrients and S-allyl cysteine levels, and toxicity.

European Journal of Cancer Prevention 2001;10(3):257–63.

[MEDLINE: 11432713]

Zhang L, Gail MH, Wang YQ, Brown LM, Pan KF, Ma JL,

et al.A randomized factorial study of the effects of long-

term garlic and micronutrient supplementation and of 2-

wk antibiotic treatment for Helicobacter pylori infection

on serum cholesterol and lipoproteins. American Journalof Clinical Nutrition 2006;84(4):912–9. [MEDLINE:

17023720]

SUVIMAX 2004 {published data only}

Astorg P, Arnault N, Czernichow S, Noisette N, Galan P,

Hercberg S. Dietary intakes and food sources of n-6 and n-

3 PUFA in French adult men and women. Lipids 2004;39

(6):527–35. [MEDLINE: 15554151]

Barrere X, Valeix P, Preziosi P, Bensimon M, Pelletier B,

Galan P, et al.Determinants of thyroid volume in healthy

French adults participating in the SU.VI.MAX cohort.

Clinical Endocrinology 2000;52(3):273–8. [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):191–206. [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. Journalof Human Nutrition and Dietetics 2001;14(2):121–8.

[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(5-

6):249–55. [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):1560–6.

[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):803–11. [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 [Dépistage du cancer colorectal

par test Hémoccult : taux de participation et prise en

charge médicale des sujets à test positif au sein de l’étude

SU.VI.MAX]. Revue d’Epidémiologie et de Santé Publique2002;50(3):321–3. [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 BritishJournal of Nutrition 2000;84(6):891–6. [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). InternationalJournal of Obesity and Related Metabolic Disorders 2005;29

(7):826–32. [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:



relationships with educational level, smoking status and

physical inactivity. Diabetes & Metabolism 2004;30(2):

153–9. [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):

1138–43. [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-year-

old French adults. European Journal of Endocrinology 2003;

148(3):309–15. [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):1169–75. [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 Association2002;102(11):1658–62. [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):125–32. [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 biothèque dans l’étude SU.VI.MAX]. Revue

d’Epidemiologie et de Sante Publique 2003;51(1 Pt 2):

147–50. [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):321–8.

[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):315–21. [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 influenced by

sex, age, diet, smoking status, alcohol consumption and

corpulence in a general French adult population. European

Journal of Clinical Nutrition 2005;59(10):1181–90.

[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):383–8. [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):535–42. [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):505–16. [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 andPhotobiology 2005;81(4):934–40. [MEDLINE: 15850423]

Hercberg S. Antioxidant micronutrients and chronic

degenerative pathology: the role of complementary

nutritional doses. Bulletin et Memoires de l’AcademieRoyale de Medecine de Belgique 1997;152(10-11):379–85.

[MEDLINE: 9627441]

Hercberg S, Bertrais S, Czernichow S, Noisette N, Galan

P, Jaouen A, et al.Alterations of the lipid profile after

7.5 years of low-dose antioxidant supplementation in

the SU.VI.MAX Study. Lipids 2005;40(4):335–42.

[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):2335–42. [MEDLINE: 15557412]

Hercberg S, Galan P, Preziosi P, Malvy M, Briancon S, Ait

HM, et al.The SU.VI.MAX trial on antioxidants. IARCScientific Publications 2002;156:451–5. [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


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 field of nutritional prevention:

results of a pilot study of the SU.VI.MAX project. Revued’Epidemiologie et de Sante Publique 1995;43(2):139–46.

[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.


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



vitamins and minerals in cardiovascular diseases and cancers.

SUpplementation on VItamines et Mineraux AntioXydants.

Food and Chemical Toxicology 1999;37(9-10):925–30.

[MEDLINE: 10541446]

Lairon D, Bertrais S, Vincent S, Arnault N, Galan P,

Boutron MC, et al.Dietary fibre intake and clinical indices

in the French Supplementation en Vitamines et Mineraux

AntioXydants (SU.VI.MAX) adult cohort. The Proceedingsof the Nutrition Society 2003;62(1):11–5. [MEDLINE:

12740051]

Leclere J. Multinodular goiters. La Revue du Praticien 2005;

55(2):167–73. [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):

315–20. [MEDLINE: 15918929]

Malkin JE, Morand P, Malvy D, Ly TD, Chanzy B, de

Labareyre C, et al.Seroprevalence of HSV-1 and HSV-

2 infection in the general French population. SexuallyTransmitted Infections 2002;78(3):201–3. [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):479–85.

[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):47–55. [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):659–65. [MEDLINE: 12080407]

Mennen LI, Sapinho D, de Bree A, Arnault N, Bertrais

S, Galan P, et al.Consumption of foods rich in flavonoids

is related to a decreased cardiovascular risk in apparently

healthy French women. The Journal of Nutrition 2004;134

(4):923–6. [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):182–6.

[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):477–82. [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):

1120–3. [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, Clinicaland Experimental Research 2005;29(1):84–8. [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 Nutrition2004;43(2):69–76. [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 thyroïdien et fréquences

des dysthyroïdies chez les adultes inclus dans l’étude

SU.VI.MAX en 1994–1995]. Annales d’Endocrinologie

2004;65(6):477–86. [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 thyroïdiens à l’échographie

et statut en iode des adultes volontaires de l’étude

SU.VI.MAX]. Annales d’Endocrinologie 2001;62(6):

499–506. [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):

173–83. [MEDLINE: 9810825]

Vercherin P, Gutknecht C, Guillemin F, Ecochard R,

Mennen LI, Mercier M. Missing data mechanisms of the

questionnaire SF-36’s items in the SU.VI.MAX study

[Non–réponses aux questionnaires de qualité de vie SF–36

dans un échantillon de l’étude SU.VI.MAX]. Revue

d’Epidémiologie et de Santé Publique 2003;51(5):513–25.

[MEDLINE: 14657798]

Vuillemin A, Boini S, Bertrais S, Tessier S, Oppert JM,

Hercberg S, et al.Leisure time physical activity and health-

related quality of life. Preventive Medicine 2005;41(2):

562–9. [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):1119–24. [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):1485–91.

[MEDLINE: 15217803]

WACS 2007 {published data only}

Bassuk SS, Albert CM, Cook NR, Zaharris E, MacFadyen

JG, Danielson E, et al.The Women’s Antioxidant



Cardiovascular Study: design and baseline characteristics of

participants. Journal of Women’s Health 2004;13(1):99–117.

[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 Women’s Antioxidant Cardiovascular Study. Archivesof Internal Medicine 2007;167(15):1610–8. [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):261–9.

[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 Women’s Antioxidant

Cardiovascular Study (WACS). Circulation 2004;109(13):

1623–9. [MEDLINE: 15023883]

WHS 2005 {published data only}

Buring JE, Hennekens CH. The Women’s Health Study:

rationale and background. The Journal of Myocardial

Ischemia 1992;4(3):30–40.

Buring JE, Hennekens CH. The Women’s Health Study:

summary of study design. The Journal of MyocardialIschemia 1992;4(3):27–9.

Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker

PM, Manson JE, et al.Low-dose aspirin in the primary

prevention of cancer: the Women’s Health Study: a

randomized controlled trial. JAMA 2005;294(1):47–55.

[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 Women’s Health Cohort Study.


[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 Women’s Health

Study: a randomized controlled trial. JAMA 2005;294(1):

56–65. [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 modified

by baseline plasma level. British Journal of Cancer 2002;86

(5):698–701. [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 Women’s

Health Study. Journal of the National Cancer Institute 1999;

91:2102–6. [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 Women’s Health Study.

American Journal of Clinical Nutrition 2000;72(4):922–8.

[MEDLINE: 11010932]

Rexrode KM, Lee IM, Cook NR, Hennekens CH, Buring

JE. Baseline characteristics of participants in the Women’s

Health Study. Journal of Women’s Health and Gender Based


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):1293–304.

[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):289–94.

[MEDLINE: 1726411]


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;56:117–24.

[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):15–9. [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 2:73–8.

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 atroficeskim gastritom].

Voprosii Onkologii 2004;50(1):81–5. [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 Women’s Health

Study. Cancer Research 1993;53(18):4230–7. [MEDLINE:

8364919]

Bukin 1996 {published data only}

Bukin YV, Poddubniy BK, Kuvshinov YP, Draudin-

Krylenko 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):

184–91. [MEDLINE: 1996267562]



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):1434–9. [MEDLINE:

7049351]

Chuang 2002 {published data only}

Chuang CH, Sheu BS, Huang AH, Yang HB, Wu JJ.

Vitamin C and E supplements to lansoprazole-amoxicillin-

metronidazole triple therapy may reduce the eradication rate

of metronidazole-susceptible Helicobacter pylori infection.

Helicobacter 2002;7(5):310–6. [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 tract-

II. Nutrients. Oral Oncology 1999;35(1):22–6.

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 tract-

I. Foods. Oral Oncology 1999;35(1):17–21. [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):23–9.

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):608–12.

[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 fiber

and vitamins C and E on rectal polyps in patients with

familial adenomatous polyposis. Journal of the National

Cancer Institute 1989; Vol. 81, issue 17:1290–7.

ECP-IM 1994 {published data only}∗ Reed PI. The ECP-IM intervention study. European

Journal of Cancer Prevention 1994;3(Suppl 2):99–104.

[MEDLINE: 7735056]

Reed PI, Johnston BJ. Primary prevention of gastric cancer

- The ECP-IM intervention study. Acta Endoscopica 1995;

25(1):45–54.

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):977–86. [MEDLINE: 10861309]

Frank 1995 {published data only}

Frank E. The Women Physicians’ Health Study:

background, objectives, and methods. Journal of the

American Medical Women’s Association 1995;50(2):64–6.

[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 EnglandJournal of Medicine 1990;323(12):789–95. [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):707–10. [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 andPrevention 2001;10(1):17–23. [MEDLINE: 11205484]

Jansen 1999 {published data only}

Jansen MC, Bueno de Mesquita HB, Buzina R, Fidanza

F, Menotti A, Blackburn H, et al.Dietary fiber and plant

foods in relation to colorectal cancer mortality: the Seven

Countries Study. International Journal of Cancer 1999;81

(2):174–9. [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. CancerEpidemiology, Biomarkers & Prevention 1995;4(8):885–93.

[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):499–503.

[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 ofMedical Research 1993;98:124–8.

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):860–3.

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):108–14.

[MEDLINE: 3554082]



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 &


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, high-

fiber, 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):387–401.

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):2115–9. [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):863–73.

[MEDLINE: 16143126]

Macrae 1999 {published data only}

Macrae F. Wheat bran fiber and development of

adenomatous polyps: evidence from randomized, controlled

clinical trials. American Journal of Medicine 1999;106(1 A):

38S–42S.

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 CongressSeries 2003;1255:291–4.

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 ofSciences 2004;1019:195–9. [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. CancerEpidemiology, Biomarkers & Prevention 2001;10(10):

1055–62. [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):27–31. [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):

1561–7. [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):1295–301. [MEDLINE:

11012474]

Nomura 1987a {published data only}

Nomura A, Heilbrun LK, Morris JS, Stemmermann GN.

Serum selenium and the risk of cancer, by specific sites:

case-control analysis of prospective data. Journal of theNational Cancer Institute 1987;79(1):103–8. [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


Podmore 1998a {published data only}

Podmore ID, Griffiths HR, Herbert KE, Mistry N, Mistry

P, et al.Vitamin C exhibits pro-oxidant properties. Nature1998;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 NationalCancer Institute 2007;99(16):1240–7. [MEDLINE:

17686823]

Rocchi 1997 {published data only}

Rocchi E, Seium Y, Camellini L, Casalgrandi G, Borghi A,

D’Alimonte P, et al.Hepatic tocopherol content in primary

hepatocellular carcinoma and liver metastases. Hepatology

1997;26(1):67–72. [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):125–9.

[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):797–803. [MEDLINE: 12468560]

Kim MK, Sasazuki S, Sasaki S, Okubo S, Hayashi M,

Tsugane S. Effect of five-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):208–16. [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



of Cancer Research 2000;91(5):464–70. [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):

378–82. [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 modification. Japanese Journal of

Cancer Research 1997;88(4):344–9. [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 CancerResearch 1996;87(7):676–9. [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.


375–83. [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):546–50. [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 (n-

acetylcysteine, selenium, vitamin C) therapy in severe acute

pancreatitis. Gut 2007;56(10):1439–44. [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):432–41. [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):750–4.

[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):

S226–S237. [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 ofthe Colon and Rectum 1999;42(2):212–7. [MEDLINE:

10211498]

Yang 2000 {published data only}

Yang CS. Vitamin nutrition and gastroesophageal cancer.

Journal of Nutrition 2000;130(2):338S–9S. [MEDLINE:

10721901]


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):

1301–5. [MEDLINE: 7882326]


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):

367–74. [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):955–60. [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):182–4.

[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 &


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


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):627–33.

[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



Results in Cancer Research 2003;163:212–25. [MEDLINE:

12903856]

Klein EA. Selenium and vitamin E Cancer Prevention Trial.

Annals of the New York Academy of Sciences 2004;1031:

234–41. [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):21–7. [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):

1311–5. [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):59–65. [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):145–51.

[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). Journalof the National Cancer Institute 2005;97(2):94–102.

[MEDLINE: 15657339]

Additional references

Altman 2003

Altman DG, Bland JM. Interaction revisited: the difference

between two estimates. BMJ 2003;326(7382):219.

[MEDLINE: 12543843]

Ames 1995

Ames BN, Gold LS, Willett WC. The causes and prevention

of cancer. Proceedings of the National Academy of Sciences of

the United States of America Sci USA 1995;92(12):5258–65.

Anonymous 2000a

Panel on Micronutrients, Subcommittees on Upper

Reference Levels of Nutrients and of Interpretation and Use

of Dietary Reference Intakes, and the Standing Committee

on the Scientific Evaluation of Dietary Reference Intakes.

Institute of Medicine, Food and Nutrition Board. Dietary

reference intakes for Vitamin A, Vitamin K, Arsenic,

Boron, Chromium, Copper, Iodine, Iron, Manganese,

Molybdenum, Nickel, Silicon, Vanadium, and Zinc.

National Academy Press, Washington DC 2000:1–800.

Anonymous 2000b

Panel on Dietary Antioxidants and Related Compounds,

Subcommittees on Upper Reference Levels of Nutrients

and Interpretation and Uses of DRIs, Standing Committee

on the Scientific Evaluation of Dietary Reference Intakes,

Food and Nutrition Board. Institute of Medicine. Dietary

reference intakes for Vitamin C, Vitamin E, Selenium, and

Carotenoids. National Academy Press, Washington, DC

2000:1–529.

Balluz 2000

Balluz LS, Kieszak SM, Philen RM, Mulinare J. Vitamin

and mineral supplement use in the United States. Results

from the third National Health and Nutrition Examination

Survey. Archives of Family Medicine 2000;9:258–62.

Begg 1994

Begg CB, Mazumdar M. Operating characteristics of a rank

correlation test for publication bias. Biometrics 1994;50(4):

1088–101. [MEDLINE: 7786990]

Bjelakovic 2006

Bjelakovic G, Nagorni A, Nikolova D, Simonetti RG,

Bjelakovic M, Gluud C. Meta-analysis: antioxidant

supplements for primary and secondary prevention

of colorectal adenoma. Alimentary Pharmacology &

Therapeutics 2006;24(2):281–91. [MEDLINE: 16842454]

Bjelakovic 2007

Bjelakovic G, Nikolova D, Gluud LL, Simoneti RG,

Gluud C. Mortality in randomized trials on antioxidant

supplements for primary and secondary prevention.

Systematic review and meta-analysis. JAMA 2007;297(8):

842–57. [MEDLINE: 17327526]

Boyle 1985

Boyle P, Zaridze DG, Smans M. Descriptive epidemiology

of colorectal cancer. International Journal of Cancer 1985;

36(1):9–18. [MEDLINE: 2991145]

Camire 1999

Camire ME, Kantor MA. Dietary supplements: nutritional

and legal considerations. Food Technology 1999;53(7):

87–95.

Caraballoso 2003

Caraballoso M, Sacristan M, Serra C, Bonfill X. Drugs

for preventing lung cancer in healthy people. Cochrane

Database of Systematic Reviews 2003, Issue 2. Art. No.:

CD002141. DOI: 10.1002/14651858.CD002141.

Chan 2004a

Chan AW, Hróbjartsson A, Haahr MT, Gøtzsche PC,

Altman DG. Empirical evidence for selective reporting of

outcomes in randomized trials: comparison of protocols

to published articles. JAMA 2004;291(20):2457–65.

[MEDLINE: 15161896]

Chan 2004b

Chan AW, Krleza-Jeric’ K, Schmid I, Altman DG. Outcome

reporting bias in randomized trials funded by the Canadian

Institutes of Health Research. Canadian Medical AssociationJournal 2004;171(7):735–40. [MEDLINE: 15451835]

Chan 2005

Chan AW, Altman DG. Identifying outcome reporting bias

in randomised trials on PubMed: review of publications

and survey of authors. BMJ (Clinical Research Ed) 2005;330

(7494):753. [MEDLINE: 15681569]

Cheng 1996

Cheng K, Day N. Nutrition and esophageal cancer.

Cancer Causes and Control 1996;7(1):33–40. [MEDLINE:

8850433]



Clark 1991

Clark LC, Cantor KP, Allaway WH. Selenium in forage

crops and cancer mortality in U.S. counties. Archives of

Environmental Health 1991;46(1):37–42. [MEDLINE:

1992931]

Collins 1987

Collins RH, Feldman M, Fordtran JS. Colon cancer,

dysplasia and surveillance in patients with ulcerative colitis.

A critical review. New England Journal of Medicine 1987;

316:1654–8. [MEDLINE: 3295551]

D’Amico 2003

D’Amico G, Pietrosi G, Tarantino I, Pagliaro L. Emergency

sclerotherapy versus vasoactive drugs for variceal bleeding in

cirrhosis: a Cochrane meta-analysis. Gastroenterology 2003;

124(5):1277–91. [MEDLINE: 12730868]

Dawsey 1994

Dawsey SM, Wang GQ, Taylor PR, Li JY, Blot WJ, Li B,

et al.Effects of vitamin/mineral supplementation on the

prevalence of histological dysplasia and early cancer of the

esophagus and stomach: results from the Dysplasia Trial

in Linxian, China. Cancer Epidemiology, Biomarkers &Prevention 1994;3(2):167–72. [MEDLINE: 8049639]

DeMets 1987

DeMets DL. Methods for combining randomized clinical

trials: strengths and limitations. Statistics in Medicine 1987;

6(3):341–50. [MEDLINE: 3616287]

DerSimonian 1986

DerSimonian R, Laird N. Meta-analysis in clinical trials.


3802833]

Diplock 1994

Diplock AT. Antioxidants and disease prevention. Molecular

Aspects of Medicine 1994;15:293–376. [MEDLINE:

95147668]

Doucas 2006

Doucas H, Garcea G, Neal CP, Manson MM, Berry DP.

Chemoprevention of pancreatic cancer: a review of the

molecular pathways involved, and evidence for the potential

for chemoprevention. Pancreatology 2006;6(5):429–39.

[MEDLINE: 16847380]

Duarte 2005

Duarte TL, Lunec J. Review: When is an antioxidant not

an antioxidant? A review of novel actions and reactions

of vitamin C. Free Radical Research 2005;39(7):671–86.

[MEDLINE: 16036346]

Egger 1997

Egger M, Davey SG, Schneider M, Minder C. Bias in meta-

analysis detected by a simple, graphical test. BMJ (Clinical

Research Ed) 1997;315(7109):629–34. [MEDLINE:

1997456606]

Egger 2003

Egger M, Juni P, Bartlett C, Holenstein F, Sterne J. How

important are comprehensive literature searches and the

assessment of trial quality in systematic reviews? Empirical

study. Health Technolology Assessment 2003;7(1):1–76.

[MEDLINE: 12583822]

Enzinger 2003

Enzinger PC, Mayer RJ. Esophageal cancer. New EnglandJournal of Medicine 2003;349(23):2241–52. [MEDLINE:

14657432]

Ferlay 2004

Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002:

Cancer Incidence, Mortality and Prevalence Worldwide.

IARC CancerBase No 5, version 2.0. IARC Press, Lyon,

France, 2004.

Fitzgerald 2006

Fitzgerald RC. Molecular basis of Barrett’s oesophagus and

oesophageal adenocarcinoma. Gut 2006;55(12):1810–20.

[MEDLINE: 17124160]

Freedman 2007

Freedman ND, Park Y, Subar AF, Hollenbeck AR,

Leitzmann MF, Schatzkin A, et al.Fruit and vegetable intake

and esophageal cancer in a large prospective cohort study.

International Journal of Cancer 2007;121(12):2753–60.

[MEDLINE: 17691111]

Furukawa 2007

Furukawa TA, Watanabe N, Omori IM, Montori VM,

Guyatt GH. Association between unreported outcomes and

effect size estimates in Cochrane meta-analyses. JAMA

2007;297(5):468–70. [MEDLINE: 17284696]

Garcea 2003

Garcea G, Dennison AR, Steward WP, Berry DP.

Chemoprevention of gastrointestinal malignancies. ANZJournal of Surgery 2003;73:680–6. [MEDLINE: 12956781]

Gluud 2001

Gluud C. Alcoholic hepatitis: no glucocorticosteroids?

. In: Leuschner U, James OFW, Dancygier H editor(s).

Steatohepatitis (NASH and ASH) - Falk Symposium 121.

Lancaster: Kluwer Academic Publisher, 2001:322–42.

Gluud 2006a

Gluud LL. Bias in clinical intervention research.


[MEDLINE: 16443796]

Gluud 2006b

Gluud C. The culture of designing hepato-biliary

randomised trials. Journal of Hepatology 2006;44(3):

607–15. [MEDLINE: 16434120]

Grau 2006

Grau MV, Rees JR, Baron JA. Chemoprevention

in gastrointestinal cancers: current status. Basic &

Clinical Pharmacology & Toxicology 2006;98(3):281–7.

[MEDLINE: 16611203]

Gwyn 2002

Gwyn K, Sinicrope FA. Chemoprevention of colorectal

cancer. American Journal of Gastroenterology 2002;97(1):

13–21. [MEDLINE: 11808936]

Haenen 2002

Haenen GR, Bast A. The use of vitamin supplements in self-

medication. Therapie 2002;57(2):119–22. [MEDLINE:

12185958]



Hanck 1988

Hanck AB. Vitamin C and cancer. Progress in Clinicaland Biological Research 1988;259:307–20. [MEDLINE:

88203700]

Herbert 1994

Herbert V. The antioxidant supplement myth. American

Journal of Clinical Nutrition 1994;60(2):157–8.

[MEDLINE: 8030591]

Herbert 1997

Herbert V. The value of antioxidant supplements vs their

natural counterparts. Journal of the American DieteticAssociation 1997;97(4):375–6. [MEDLINE: 9120187]

Higgins 2002

Higgins JP, Thompson SG. Quantifying heterogeneity in a

meta-analysis. Statistics in Medicine 2002;21(11):1539–58.

[MEDLINE: 12111919]

Higgins 2006

Higgins JPT, Green S, editors. Cochrane Handbook

for Systematic Reviews of Interventions 4.2.6 [updated

September 2006]. In: The Cochrane Library, Issue 4, 2006.

Chichester, UK. John Wiley & sons, Ltd, 2006.

Holmes 2007

Holmes RS, Vaughan TL, Holmes RS, Vaughan TL.

Epidemiology and pathogenesis of esophageal cancer.

Seminars in Radiation Oncology 2007;17(1):2–9.

[MEDLINE: 17185192]

Holzinger 1999

Holzinger F, Z’graggen K, Büchler MW. Mechanisms of

biliary carcinogenesis: a pathogenetic multi-stage cascade

towards cholangiocarcinoma. Annals of Oncology 1999;10

(Suppl 4):S122–S6. [MEDLINE: 10436802]

Hughes 2000

Hughes D. Dietary antioxidants and human immune

function. Nutrition Bulletin 2000;25:35–41.

Janne 2000

Janne PA, Mayer RJ. Chemoprevention of colorectal cancer.

New England Journal of Medicine 2000;342:1960–8.

[MEDLINE: 10874065]

Jüni 2001

Jüni P, Altman DG, Egger M. Systematic reviews in health

care: assessing the quality of controlled clinical trials. BMJ(Clinical Research Ed) 2001;323(7303):42–6. [MEDLINE:

11440947]

Kaplowitz 2000

Kaplowitz N. Cell death at the millennium. Implications

for liver diseases. Clinics in Liver Disease 2000;4(1):1–23.

[MEDLINE: 11232179]

Kjaergard 2001

Kjaergard LL, Villumsen J, Gluud C. Reported

methodologic quality and discrepancies between large and

small randomized trials in meta-analyses. Annals of InternalMedicine 2001;135(11):982–9. [MEDLINE: 11730399]

Knekt 1994

Knekt P. Vitamin E and cancer prevention. In: Balz Frei

editor(s). Natural Antioxidants in Human Health and

Disease. San Diego: Academic Press, Inc., 1994:199–239.

Koushik 2007

Koushik A, Hunter DJ, Spiegelman D, Beeson WL, van den

Brandt PA, Buring JE, et al.Fruits, vegetables, and colon

cancer risk in a pooled analysis of 14 cohort studies. Journalof the National Cancer Institute 2007;99(19):1471–83.

[MEDLINE: 17895473]

Kubo 2007

Kubo A, Corley DA. Meta-analysis of antioxidant intake and

the risk of esophageal and gastric cardia adenocarcinoma.

American Journal of Gastroenterology 2007;102(10):

2323–30. [MEDLINE: 17581269]

Kune 2006

Kune G, Watson L. Colorectal cancer protective effects and

the dietary micronutrients folate, methionine, vitamins B6,

B12, C, E, selenium, and lycopene. Nutrition and Cancer2006;56(1):11–21. [MEDLINE: 17176213]

Lanza 2007

Lanza E, Yu B, Murphy G, Albert PS, Caan B, Marshall JR,

et al.The polyp prevention trial continued follow-up study:

no effect of a low-fat, high-fiber, high-fruit, and -vegetable

diet on adenoma recurrence eight years after randomization.


1745–52. [MEDLINE: 17855692]

Larsson 2006

Larsson SC, Håkansson N, Näslund I, Bergkvist L, Wolk A.

Fruit and vegetable consumption in relation to pancreatic

cancer risk: a prospective study. Cancer Epidemiology,

Biomarkers & Prevention 2006;15(10):1998–2001.

[MEDLINE: 17855692]

Lawson 2007

Lawson KA, Wright ME, Subar A, Mouw T, Hollenbeck

A, Schatzkin A, et al.Multivitamin use and risk of prostate

cancer in the National Institutes of Health - AARP diet and

health study. Journal of the National Cancer Institute 2007;

99(10):754–64. [MEDLINE: 17505071]

Lee 2003

Lee BM, Park KK. Beneficial and adverse effects of

chemopreventive agents. Mutation Research 2003;523-4:

265–78. [MEDLINE: 12628524]

Lee 2004

Lee DH, Folsom AR, Harnack L, Halliwell B, Jacobs DR

Jr. Does supplemental vitamin C increase cardiovascular

disease risk in women with diabetes?. American Journal of

Clinical Nutrition 2004;80(5):1194–200. [MEDLINE:

15531665]

Leung 2006

Leung WK, Sung JJ, Leung WK, Sung JJ. Chemoprevention

of gastric cancer. European Journal of Gastroenterology andHepatology 2006;18(8):867–71. [MEDLINE: 16825903]

Lichtenstein 2005

Lichtenstein AH, Russell RM. Essential nutrients: food or

supplements? Where should the emphasis be. JAMA 2005;

294(3):351–8. [MEDLINE: 16030280]

Lopez 2006

Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray

CJ. Global and regional burden of disease and risk factors,



2001: systematic analysis of population health data. Lancet

2006;367(9524):1747–57. [MEDLINE: 16731270]

Lowenfels 2006

Lowenfels AB, Maisonneuve P. Epidemiology and risk

factors for pancreatic cancer. Best Practice & Research Clinical

Gastroenterology 2006;20(2):197–209. [MEDLINE:

16549324]

Lynch 2002

Lunch JP, Hoops TC. The genetic pathogenesis of colorectal

cancer. Hematology/oncology Clinics of North America 2002;

16(4):775–810. [MEDLINE: 12418049]

MacDonald 2001

MacDonald GA. Pathogenesis of hepatocellular carcinoma.

Clinics in Liver Disease 2001;5(1):69–85. [MEDLINE:

11218920]

Mathers 2006

Mathers CD, Loncar D. Projections of global mortality and

burden of disease from 2002 to 2030. PLoS Medicine 2006;

3(11):e442. [MEDLINE: 17132052]

McAlister 2003

McAlister FA, Straus SE, Sackett DL, Altman DG. Analysis

and reporting of factorial trials. A systematic review. JAMA

2004;289(19):2545–53. [MEDLINE: 12759326]

McKevith 2003

McKevith B, Kelly C, Stanner S, Hughes J, Buttriss J. The

Food Standards Agency’s antioxidants in food programme-a

summary. Journal of Human Nutrition and Dietetics 2003;

16(4):257–63. [MEDLINE: 12859707]

Mehta 2005

Mehta S, Johnson IT, Rhodes M. Systematic review:

the chemoprevention of oesophageal adenocarcinoma.

Alimentary Pharmacology & Therapeutics 2005;22(9):

759–68. [MEDLINE: 16225483]

Millen 2004

Millen AE, Dodd KW, Subar AF. Use of vitamin, mineral,

nonvitamin, and nonmineral supplements in the United

States: The 1987, 1992, and 2000 National Health

Interview Survey results. Journal of the American Dietetic

Association 2004;104(6):942–50. [MEDLINE: 15175592]

Miller 2005

Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA,

Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E

supplementation may increase all-cause mortality. Annalsof Internal Medicine 2005;142(1):37–46. [MEDLINE:

15537682]

Moher 1998

Moher D, Pham B, Jones A, Cook DJ, Jadad A, Moher

M, et al.Does quality of reports of randomised trials affect

estimates of intervention efficacy reported in meta-analysis.

Lancet 1998;352(9128):609–13. [MEDLINE: 9746022]

Morris 2003

Morris CD, Carson S. Routine vitamin supplementation to

prevent cardiovascular disease: a summary of the evidence

for the U.S. Preventive Services Task Force. Annals ofInternal Medicine 2003;139(1):56–70. [MEDLINE:

12834320]

Mulholland 2007

Mulholland CA, Benford DJ. What is known about the

safety of multivitamin-multimineral supplements for

the generally healthy population? Theoretical basis for

harm. American Journal of Clinical Nutrition 2007;85(1):

318S–322S. [MEDLINE: 17209218]

Murata 2000

Murata M, Kawanishi S. Oxidative DNA damage by

vitamin A and its derivative via superoxide generation.

The Journal of Biological Chemistry 2000;275(3):2003–8.

[MEDLINE: 10636903]

Neugut 1998

Neugut AI, Jacobson JS, Suh S, Mukherjee R, Arber N.

The epidemiology of cancer of the small bowel. Cancer

Epidemiology, Biomarkers & Prevention 1998;7(3):243–51.

[MEDLINE: 9521441]

Neuhouser 2003




arm of the beta-carotene and retinol efficacy trial (CARET).


350–8. [MEDLINE: 12692110]

Nichter 2006

Nichter M, Thompson JJ. For my wellness, not just my

illness: North Americans’ use of dietary supplements.

Culture, Medicine and Psychiatry 2006;30(2):175–222.

[MEDLINE: 16841188]

Nomura 1987

Nomura A, Heilbrun LK, Morris JS, Stemmermann GN.

Serum selenium and the risk of cancer, by specific sites:

case-control analysis of prospective data. Journal of theNational Cancer Institute 1987;79(1):103–8. [MEDLINE:

3474437]

Nouraie 2005

Nouraie M, Pietinen P, Kamangar F, Dawsey SM, Abnet

CC, Albanes D, et al.Fruits, vegetables, and antioxidants

and risk of gastric cancer among male smokers. CancerEpidemiology, Biomarkers & Prevention 2005;14(9):

2087–92. [MEDLINE: 16172214]

Oshima 1982

Oshima H, Berezial J. Monitoring N-nitrosamino acids

excreted in the urine and feces of rats as an index of

endogenous nitrozation. Carcinogenesis 1982;3(1):115–20.

[MEDLINE: 6175434]

Paolini 1999

Paolini M, Pozzetti L, Pedulli GF, Marchesi E, Cantelli-

Forti G. The nature of prooxidant activity of vitamin C. Life

Sciences 1999;64(23):PL 273-8. [MEDLINE: 10372660]

Paolini 2003

Paolini M, Abdel-Rahman SZ, Sapone A, Pedulli GF,

Perocco P, Cantelli-Forti G, et al.Beta-carotene: a cancer

chemopreventive agent or a co-carcinogen?. Mutation




Papas 1999

Papas A. Antioxidant Status, Diet, Nutrition and Health.

London, New York, Washington DC: Boca Raton FL:

CRC: Press, 1999.

Papp 2007

Papp LV, Lu J, Holmgren A, Khanna KK. From selenium to

selenoproteins: synthesis, identity, and their role in human

health. Antioxidants & Redox Signaling 2007;9(7):775–806.

[MEDLINE: 17508906]

Patel 1998

Patel T, Roberts LR, Jones BA, Gores GJ. Dysregulation of

apoptosis as a mechanism of liver disease: An overview.

Seminars in Liver Disease 1998;18(2):105–14. [MEDLINE:

9606808]

Peto 1981

Peto R, Doll R, Buckley JD, Sporn MB. A dietary carotene

materially reduces human cancer rates?. Nature 1981;290

(5803):201–8. [MEDLINE: 7010181]

Pocock 1991

Pocock SJ. Clinical Trials. A Practical Approach. John Wiley

and Sons, 1991.

Podmore 1998

Podmore ID, Griffiths HR, Herbert KE, Mistry N, Mistry

P, Lunec J. Vitamin C exhibits pro-oxidant properties.

Nature 1998;392(6676):559. [MEDLINE: 9560150]

Poppel 1997

Poppel G, Berg H. Vitamins and cancer. Cancer Letters

1997;114(1-2):195–202. [MEDLINE: 9103291]

Potter 1999

Potter JD. Colorectal cancer: molecules and populations.

Journal of the National Cancer Institute 1999;91(11):

916–32. [MEDLINE: 10359544]

Radimer 2004

Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C,

Picciano MF. Dietary supplement use by US adults: data

from the National Health and Nutrition Examination

Survey, 1999-2000. American Journal of Epidemiology 2004;

160(4):339–49. [MEDLINE: 15286019]

Rayman 2000

Rayman M. The importance of selenium to human health.

Lancet 2000;356(9225):233–41. [MEDLINE: 10963212]

Rayman 2005

Rayman MP. Selenium in cancer prevention: a review of

the evidence and mechanism of action. The Proceedingsof the Nutrition Society 2005;64(4):527–42. [MEDLINE:

16313696]

RevMan 2003

Copenhagen: The Nordic Cochrane Centre, The Cochrane

Collaboration. Review Manager (RevMan). 4.2 for

Windows. Copenhagen: The Nordic Cochrane Centre,

The Cochrane Collaboration, 2003.

Royle 2003

Royle P, Milne R. Literature searching for randomized

controlled trials used in Cochrane reviews: rapid versus

exhaustive searches. International Journal of Technology

Assessment in Health Care 2003;19:591–603.

Salganik 2001

Salganik RI. The benefits and hazards of antioxidants:

controlling apoptosis and other protective mechanisms in

cancer patients and the human population. Journal of theAmerican College of Nutrition 2001;20(5 Suppl):464S–72S.

[MEDLINE: 11603657]

Sasaki 2006

Sasaki Y. Does oxidative stress participate in the development

of hepatocellular carcinoma?. Journal of Gastroenterology2006;41(12):1135–48. [MEDLINE: 17287893]

SCF 2003

European Commission Scientific Committee on Food.

Opinion of the Scientific Committee on Food on the

Tolerable Upper Intake Level of Vitamin E. 2003.

Schrauzer 1977

Schrauzer GN, White DA, Schneider CJ. Cancer mortality

correlation studies. III. Statistical association with dietary

selenium intakes. Bioinorganic Chemistry 1977;7(1):35–56.

[MEDLINE: 856292]

Schulz 1995

Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical

evidence of bias. Dimensions of methodological quality

associated with estimates of treatment effects in controlled

trials. Journal of the American Medical Association 1995;273

(5):408–12. [: 7823387]

Schulz 2007

Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow

M. Glucose restriction extends Caenorhabditis elegans life

span by inducing mitochondrial respiration and increasing

oxidative stress respiration and increasing oxidative

stress. Cell Metabolism 2007;6(4):280–93. [MEDLINE:

17908557]

Schwartz 1996

Schwartz JL. The dual roles of nutrients as antioxidants and

prooxidants: their effects on tumor cell growth. Journalof Nutrition 1996;126(4 Suppl):1221S–7S. [MEDLINE:

8642460]

Seifried 2003

Seifried HE, McDonald SS, Anderson DE, Greenwald P,

Milner JA. The antioxidant conundrum in cancer. Cancer


Sharma 2004

Sharma N, Trope B, Lipman TO. Vitamin supplementation:

what the gastroenterologist needs to know. Journal

of Clinical Gastroenterology 2004;38(10):844–54.

[MEDLINE: 15492599]

Sharp 1998

Sharp SJ. Metaanalysis regression. Stata Technical Bulletin

1998;42:16–22.

Shimoda 1994

Shimoda R, Nagashima M, Sakamoto M, Yamaguchi N,

Hirohashi S, Yokota J, et al.Increased formation of oxidative

DNA damage, 8-hydroxydeoxyguanosine, in human livers

with chronic hepatitis. Cancer Research 1994;54(12):

3171–2. [MEDLINE: 8205535]



Sies 1985

Sies H. Introductory remarks. In: Sies H editor(s).

Oxidative Stress. Orlando: Academic Press, 1985:1–7.

Sihvo 2002

Sihvo EI, Salminen JT, Rantanen TK, Ramo OJ, Ahotupa

M, Farkkila M, et al.Oxidative stress has a role in malignant

transformation in Barrett’s oesophagus. International

Journal of Cancer 2002;102(6):551–5. [MEDLINE:

12447994]

Slatore 2007

Slatore CG, Littman AJ, Au DH, Satia JA, White E. Long-

term use of supplemental multivitamins, vitamin C, vitamin

E, and folate does not reduce the risk of lung cancer.

American Journal of Respiratory and Critical Care Medicine

2007;177(5):524–30.

Stoner 2007

Stoner GD, Wang LS, Chen T. Chemoprevention of

esophageal squamous cell carcinoma. Toxicology andApplied Pharmacology 2007;224(3):337–49. [MEDLINE:

17475300]

Stranges 2007

Stranges S, Marshall JR, Natarajan R, Donahue RP,

Trevisan M, Combs GF, et al.Effects of long-term selenium

supplementation on the incidence of type 2 diabetes: a

randomized trial. Annals of Internal Medicine 2007;147(4):

217–23. [MEDLINE: 17620655]

Sugiyama 2004

Sugiyama T. Development of gastric cancer associated with

Helicobacter pylori infection. Cancer Chemotherapy and

Pharmacology 2004;54(Suppl 1):S12–S20. [MEDLINE:

15309509]

Tabor 1999

Tabor E, Di Bisceglie AM. Hepatitis B. Hepatocellular

carcinoma. Clinics in Liver Disease 1999;3(2):327–48.

Takachi 2007

Takachi R, Inoue M, Ishihara J, Kurahashi N, Iwasaki

M, Sasazuki S, et al.Fruit and vegetable intake and risk

of total cancer and cardiovascular disease: Japan Public

Health Center-Based Prospective Study. American Journalof Epidemiology 2007;167(1):59–70.

Takeda 2002

Takada M, Ku Y, Habara K, Ajiki T, Suzuki Y, Kuroda Y.

Inhibitory effect of epigallocatechin-3-gallate on growth

and invasion in human biliary tract carcinoma cells.

World Journal of Surgery 2002;26(6):683–6. [MEDLINE:

12053219]

Tamimi 2002

Tamimi RM, Lagiou P, Adami HO, Trichopoulos D.

Prospect for chemoprevention of cancer. Journal of InternalMedicine 2002;251:286–300. [MEDLINE: 11952879]

Tzonou 1996

Tzonou A, Lipworth L, Garidou A, Signorello LB, Lagiou

P, Hsieh C, et al.Diet and risk of esophageal cancer by

histologic type in a low-risk population. International

Journal of Cancer 1996;68(3):300–4. [MEDLINE:

8903470]

USPSTF 2003

U.S. Preventive Services Task Force. Routine vitamin

supplementation to prevent cancer and cardiovascular

disease: recommendations and rationale. Annals of Internal


Vivekananthan 2003

Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol

EJ. Use of antioxidant vitamins for the prevention of

cardiovascular disease: meta-analysis of randomised trials.

Lancet 2003;361(9374):2017–23. [MEDLINE: 12814711]

Webb 2007

Webb GP. Nutritional supplements and conventional

medicine; what should the physician know?. The Proceedingsof the Nutrition Society 2007;66(4):471–8. [MEDLINE:

17961267]

Willcox 2004

Willcox JK, Ash SL, Catignani GL. Antioxidants and

prevention of chronic disease. Critical Reviews in Food

Science and Nutrition 2004;44(4):275–95. [MEDLINE:

15462130]

Williamson 2005

Williamson PR, Gamble C, Altman DG, Hutton JL.

Outcome selection bias in meta-analysis. Statistical Methods

in Medical Research 2005;14(5):515–24. [MEDLINE:

16248351]

Woo 2007

Woo JJ. Adverse event monitoring and multivitamin-

multimineral dietary supplements. American Journal of

Clinical Nutrition 2007;85(1):323S–4S. [MEDLINE:

17209219]

World Bank 2006

World Bank List of Economies (July 2006). http:

//siteresources.worldbank.org/DATASTATISTICS/

Resources/CLASS.XLS (accessed 31 October 2007).

Yates 2007

Yates MS, Kensler TW. Keap1 eye on the target:

chemoprevention of liver cancer. Acta Pharmacologica Sinica

2007;28(9):1331–42. [MEDLINE: 17723167]

Ziegler 1989

Ziegler RG. A review of epidemiologic evidence that

carotenoids reduce the risk of cancer. Journal of Nutrition

1989;119(1):116–22. [MEDLINE: 2643694]

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



cancers: a systematic review and meta-analysis. Lancet

2004;364(9441):1219–28. [MEDLINE: 15464182]∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

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.

Participants Country: Finland. Number of participants randomised: 29,133 males

Inclusion criteria: male smokers (five 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 predefined doses (> 20 mg, > 20000 IU, or > 6 mg, respectively)

, or anticoagulants

Interventions 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 five 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

Outcomes The primary outcome measure was: incidence of lung cancer.

Secondary outcome measures were: occurrence of other major cancers, overall and cause specific mortality,

and occurrence of other diseases

Notes Compliance with treatment was assessed by counts of the remaining capsules at each visit, by measure-

ment 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 five 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

Risk of bias

Item Authors’ judgement Description



ATBC 2003 (Continued)

Allocation concealment? Yes A - Adequate

CARET 2004

Methods The Beta-Carotene and Retinol Efficacy 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 identifier and

intervention assignment; all data analyses were performed centrally; the analyses that involved intervention

assignment were performed only by the Co-ordinating Center’s statisticians using coded intervention

assignment unknown to the statisticians; analyses involving the coded intervention assignments were seen

only by CARET’s 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



Participants 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

Interventions CARET builds on the experience of two pilot studies performed in Seattle (1985-1988). The first pilot

study initiated a phase III trial of the safety and efficacy 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.



CARET 2004 (Continued)

The CARET active intervention was stopped 21 months earlier because of clear evidence of no benefit

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

Notes 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 con-

sumption was 93% through five years of follow-up, with no significant differences between the treatment

groups. Participants who stopped receiving trial vitamins for any reason other than death were defined 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 Cor-

poration

Data were extracted from the primary publication, but additional information was received through

personal communication with the authors

Risk of bias



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 twenty-

one 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 beta-

carotene (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.

Participants Country: Colombia.

Number of participants randomised: 976; 46% males, aged 29 to 69 years, mean age 51.1 years



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 classified 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 subsalicy-

late, and additionally beta-carotene and ascorbic acid (n = 134)

Gastric biopsy specimens taken at baseline were compared with those taken at 72 months

Outcomes 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

Notes 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

Risk of bias




Correa 2000 (Continued)


HOPE TOO 2005

Methods The Heart Outcomes Prevention Evaluation Study (HOPE).


Generation of the allocation sequence: adequate, by computer

Allocation concealment: adequate, randomisation is done by a telephone call to a central office. After

receipt of appropriate baseline data over the telephone, the patient is randomised


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



Participants 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, defined 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

Interventions 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 follow-

up period was 7 years

Outcomes The primary outcome measures were: cancer occurrence, cancer deaths, major cardiovascular events (my-

ocardial 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



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 final visit. There was no significant 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



HPS 2002

Methods Heart Protection Study.


Generation of the allocation sequence: adequate, computer generated random numbers

Allocation concealment: adequate, central telephone randomisation system


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



Participants 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

Interventions 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

Outcomes The primary outcome measures were: major coronary events (for overall analyses) and fatal or non-

fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major

morbidity



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 five-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.



Risk of bias



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.




Participants 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.


group 1: sodium selenite 0.5 mg (228 µg of selenium) (n = 1112);


per day for three years.

Outcomes The primary outcome measure was the occurrence of liver cancer

Notes Compliance with treatment: good, between 81.5% in the first year and 79.8% in the third year

Data were extracted from the primary publication.

Risk of bias



Li 2000 (Continued)


Allocation concealment? Unclear B - Unclear

Li 2004

Methods 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.




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



group 1: selenium (sodium selenite) 100 µg and synthetic allitridum 200 mg (n = 2526);


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 five years (1192 to 1997),

overall 7 years

Allitridum is an extract of garlic.

Outcomes The primary outcome measure was the occurrence of gastric cancer

Notes Compliance with treatment was checked by interviews face to face and by measuring thiamine concen-

tration 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 Office 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

Risk of bias




Li 2004 (Continued)


Munoz 1985

Methods 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 individual’s study number.

The participants, barefoot doctors, and field 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 final endoscopic examination



Participants Country: China, Huixian, Henan Province.


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


group 1: 15 mg (50,000 IU) retinol, 200 mg riboflavine, and 50 mg zinc (as zinc gluconate), (n = 305);

group 2: matching placebo (n = 305).

once a week for 13.5 months.

The final 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

final endoscopic examination, histological slides were evaluated from 552 persons (90.5%). In the other

15 the available material was inadequate

Outcomes The primary outcome measures were the prevalence of precancerous lesions of the oesophagus, as well as

occurrence of oesophageal cancer

Notes 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 stratified by age, sex, production brigade, and

treatment. Follow-up forms and remaining capsules were inspected every two months by fields supervisors.

Compliance was excellent. The final 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


During the trial one patient died, but authors did not report from which arm and we were unable to

obtain this information



Munoz 1985 (Continued)

Risk of bias



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 man-

agement 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.



Participants Country: China, Henan Province of north central China, Linxian County. Number of participants ran-

domised: 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

Interventions 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 - riboflavin

(vitamin B2) 3.2 mg and niacin (vitamin B3) 40 mg; C - ascorbic acid 120 mg and molybdenum

(as molybdenum yeast complex) 30 µg; D - beta carotene 15 mg, selenium (as selenium yeast) 50 µg,

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 defined 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

Outcomes The primary outcome measures were: cancer occurence, cancer mortality, and overall mortality

Notes 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




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



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 man-

agement 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%


Sample size calculation: yes.

Participants Country: China, Henan Province of north central China, Linxian County. Number of participants ran-

domised: 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


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 µg, vitamin D 800 IU; beta-carotene 15 mg, folic acid 800 µg,

niacinamide 40 mg, biotin 90 µg, pantothenic acid 20 mg, calcium 324 mg, phosphorus 250 mg, iodine

300 µg, iron 54 mg, magnesium 200 mg, copper 6 mg, manganese 15 mg, potassium 15.4 mg, chloride

14 mg, chromium 30 µg, molybdenum 30 µg, selenium (sodium selenate) 50 µg, and zinc 45 mg (n =

1657);


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

Outcomes The primary outcome measures were: cancer occurrence, cancer mortality, and overall mortality



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


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



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



Participants 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 five

years and no internal malignancies treated within the previous five years

Exclusion criteria: history of significant liver or kidney disorders. Recruitment began on September 15,

1983 and continued each year through 1991

Interventions Patients were randomly assigned to receive:

group 1: 200 µg of selenium supplied in a 0.5 g high-selenium bakers yeast tablet (n = 653);


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

Outcomes The primary outcome measures were: incidences of basal cell and squamous cell carcinoma of the skin. In

1990 secondary outcome measures were identified, which included: total mortality and cancer mortality,

as well as the incidence of the lung, colorectal, and prostate cancers



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: Duffield-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):630-

9

Risk of bias



PHS 1996

Methods Physicians Health Study (PHS).


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


Follow-up: adequate. By December 31, 1995, the scheduled end of the trial, less than 1% of the participants

were lost to follow up



Participants 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, inflammatory muscle disease or evidence of muscle problems (creatine

kinase > 750 IU/L); concurrent treatment with cyclosporin, fibrates, 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)

Interventions 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 beta-



PHS 1996 (Continued)

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 beta-

carotene 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

Notes 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 five 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

Risk of bias



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 significant (P = 0.14, for

difference of two proportions)



Participants 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



Plummer 2007 (Continued)


group 1: vitamin C (750 mg), vitamin E (600 mg), and beta-carotene (18 mg) (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)

Outcomes The primary outcome of the trial was the progression and regression of precancerous lesions of the stomach,

as determined by histologic findings

Notes Compliance for the intervention group was confirmed 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 first by telephone, then visited at home by social workers who enquired

about the reasons for nonattendance, encouraged continuing participation, and provided the next month’s

supply of capsules

Both vitamin capsules and placebo were supplied by Hoffman-La Roche

Risk of bias



SIT 2006

Methods Shandong Intervention Trial

Randomised, double-blind, placebo controlled, primary prevention trial with stratified, 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



Participants 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



SIT 2006 (Continued)

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 first 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 µg 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 filtered, 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-seroneg-

ative 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.

Outcomes 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 final 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 final pathologic examination of biopsies to look for Helicobacter pylori; and blood

pressure at the time of the final examination

Notes 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



SIT 2006 (Continued)

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



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 block-

sequence generation stratified by sex and age group by computer

Allocation concealment: adequate, capsule boxes were labelled with the participant’s number, using par-

titioned organisation to ensure total security of the blind study


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



Participants 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; accep-

tance 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


Interventions Participants were randomly assigned to receive: group 1: beta-carotene 6 mg; vitamin C 120 mg; vitamin

E 30 mg; selenium 100 µg; 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

Outcomes 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

Notes Compliance for the intervention group was confirmed by measuring the biochemical markers of supple-

mentation after 2 years and after 7 years for beta-carotene, vitamin C and selenium. At the end of follow-

up, 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 d’Or Recherche, Candia, Lipton, Kellogg’s, Centre d’Information sur Canderel, Orangina, Este e

Lauder, Cereal, Grands Moulins de Paris, CERIN, L’Ore al, Peugeot, Jet Service, RP Scherer, Sodexho,



SUVIMAX 2004 (Continued)

France Telecom, Santogen, Becton Dickinson, Fould Springer, Boehringer Diagnostic, Seppic Givaudan

Lavirotte, Le Grand Canal

Risk of bias



WACS 2007

Methods The Women’s Antioxidant Cardiovascular Study

Randomised, double-blind, placebo-controlled secondary prevention trial with two-by-two-by-two fac-

torial 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)




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

Interventions 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);



WACS 2007 (Continued)

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 prespecified secondary outcome measures. Information on transient ischaemic attack

and total mortality was also collected and reviewed

Notes Compliance was assessed through self-report and defined 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 significant 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)

Risk of bias





WHS 2005

Methods Women’s Health Study (WHS).

Randomised, double-blind, placebo-controlled trial with two-by-two-by-two factorial design in the be-

ginning 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


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



Participants 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-inflammatory 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 cere-

brovascular disease

Interventions 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 beta-

carotene, 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)



WHS 2005 (Continued)

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

Notes 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 beta-

carotene 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 Corpora-

tion, Wiandotte, MI



Risk of bias



Yu 1991

Methods Randomised clinical placebo-controlled trial with parallel group design


Allocation concealment: unclear, not reported.


Follow-up: inadequate.





2474, aged 18 to 75 years.

Inclusion criteria:

members of families with high incidences of liver cancer.

Exclusion criteria:

none stated.


group 1: 200 µg of selenium in the form of selenized yeast tablet (n = 1444);

group 2: identical placebo of yeast tablet (n = 1030);

daily for two years.


Notes Compliance with treatment is not reported.




Yu 1991 (Continued)

Risk of bias



Yu 1997

Methods Randomised clinical placebo-controlled trial with parallel group design








Number of participants randomised: 226, aged 21 to 63 years.

Inclusion criteria: HBsAg carriers with normal liver function



group 1: 200 µg 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.


Notes Compliance with treatment is not reported.


Risk of bias





Zhu 2003

Methods Randomised double-blind, placebo-controlled trial with parallel group design



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




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

Interventions 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 first 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

Outcomes The primary outcome measures were the occurrence of gastrointestinal tumors and mortality

Notes 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 Shang-

hai Sixth Pharmacy and Henkel Co


Risk of bias



ATBC: Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study

CARET: The Beta-Carotene and Retinol Efficacy Trial

HOPE: Heart Outcomes Prevention Evaluation Study



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: Women’s 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 Reason for exclusion

Bespalov 2004 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

Bostick 1993 A prospective cohort study.

Bukin 1996 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

Bussey 1982 We have been unable to obtain data on gastrointestinal cancers from this trial

Chuang 2002 Randomised clinical trial to test test whether vitamin C and E supplements to triple therapy can improve the

Helicobacter pylori eradication rate and gastric inflammation. Trial is of short follow-up period without data

on incidence of gastrointestinal cancers

De Stefani 1999 A case-control study in Uruguay with patients already afflicted 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

De Stefani 1999a A case-control study in Uruguay with patients already afflicted 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

De Stefani 2000 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



(Continued)

DeCosse 1975 Ascorbic acid, 3 g daily, was given to five patients who had active rectal adenomatous polyp formation long

after ileorectal anastomosis for familial polyposis. This is not randomised clinical trial

DeCosse 1989 We have been unable to obtain data on gastrointestinal cancers from this trial

ECP-IM 1994 We have been unable to obtain data on gastrointestinal cancers from this trial

EUROSCAN 2000 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

Frank 1995 An observational study of the demographic and psychosocial characteristics as well as the health behaviours,

health status, and counselling practices of women physicians

Greenberg 1990 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

Ishikawa 1995 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

Jacobs 2001 A large prospective cohort study that examined the association between colorectal cancer mortality and use

of individual vitamin C and E supplements in the American’s Cancer Society’s Cancer Prevention Study II

cohort. Intake of vitamin C and vitamin E was calculated based on self-administrated questionnaire

Jansen 1999 Ecological analysis of data from The Seven Countries Study to investigate whether intake of fiber and plant

foods contributes to cross cultural diferences in 25-year colorectal-cancer mortality in man

Ji 1995 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

Kirk 2006 Randomised, double-blind, placebo-controlled crossover trial, evaluating the efficacy of a combined antiox-

idant preparation in the management of chronic pancreatitis. Patients with confirmed 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 fulfil our inclusion criteria

Krishnaswamy 1993 A case-control study. Serum selenium levels were measured in patients with oral or oesophageal cancer and

compared with matched controls

La Vecchia 2002 A case-control study in Italy concerning intake of lycopene in patients with histologically confirmed 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



(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

Lanza 1996 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 low-

fat, high-fiber, high-vegetable and -fruit dietary pattern on the recurrence of colorectal adenomatous polyps

Lanza 2001 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-fiber, high-fruit and -vegetable, low-fat dietary

intervention) on the recurrence of adenomatous polyps in large the bowel

Levi 2000 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

Limburg 2005 Randomised clinical trial of selenomethionine 200 microg daily and/or celecoxib 200 mg twice daily (2 x 2

factorial design) among residents of Linxian, People’s Republic of China. Subjects had histologically confirmed

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 defined as the primary end point. Results were compared by agent group (selenomethionine

versus placebo; celecoxib versus placebo). Two hundred sixty-seven subjects fulfilled all eligibility criteria, and

238 (89%) completed the trial. Authors did not report incidence of oesophageal cancer

Macrae 1999 A review, discussing the results of several randomised clinical trials concerning the wheat bran fiber and

development of adenomatous polyps

Marotta 2003 The aim of this study was to test the effect of antioxidants on enzymatic abnormalities and free radicals-

modified 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 8-

hydroxydeoxyguanosine. Patients were randomly allocated into three groups supplemented for 6 months

with: vitamin E, 300 mg/day; Multivitamin, 2 tablets/day and a certified 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

Marotta 2004 Randomised trial to test the effect of antioxidant supplementation on enzymatic abnormalities and free radical-

modified DNA adducts associated with premalignant changes in the gastric mucosa of elderly patients with HP-

negative 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 certified 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



(Continued)

Mayne 2001 A case-control study, which examined nutrient intake as a risk factor for oesophageal and gastric cancers

Moriwaki 2002 A review concerning current perspectives in prevention of liver cancer

Muto 1996 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

confirmed recurrence or new hepatoma. The reason for excluding this trial was existence of liver cancer at the

time of randomisation

Newsome 2000 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

Nomura 1987a A case-control study comparing plasma selenium levels and risk of cancer by specific sites

Pan 1993 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

Podmore 1998a 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 modified DNA

bases were assessed. It is not a randomised trial

Qu 2007 Substudy of the Nutrition Prevention Trial already included in the analyses

Rocchi 1997 An observational study, which compared plasma liposoluble vitamins with tocopherol content in healthy and

neoplastic liver tissue in humans

Russo 1997 A cross-sectional observational study among patients with colorectal adenomas, comparing the incidence of

adenomas with plasma selenium levels

Sasazuki 2003 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 modification of protocol primary

end point was not incidence of gastric cancer as it was first planned

Schatzkin 1996 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-fiber

high-vegetable and -fruit dietary pattern on the recurrence of colorectal adenomatous polyps, precursors of

most colorectal malignancies



(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

Siriwardena 2007 Randomised clinical trial of intravenous antioxidant (n-acetylcysteine, selenium, vitamin C) therapy in patients

with predicted severe acute pancreatitis. This trial did not fulfill our inclusion criteria

Takshashi 2003 The Hiraka Dietary Intervention Study is a community-based randomized cross-over trial designed to develop

an effective dietary modification 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 first 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

Terry 2000 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

Weisburger 1991 A review of the causes of the main human cancers, analysing the mechanisms of the protective effects of fruits

and vegetables

Whelan 1999 The purpose of this case-control study was to further investigate whether regular vitamin or calcium supplement

intake influenced the incidence of recurrent adenomatous polyps in patients with previous neoplasia who were

undergoing follow-up colonoscopy

Yang 2000 A review discussing the problem of vitamin nutrition and gastroesophageal cancer

Yu 1995 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

Yu 1999 An observational study, which examined the association between plasma selenium levels and risk of hepato-

cellular carcinoma among chronic carriers of hepatitis B and/or C virus in a cohort of 7342 men in Taiwan

Zheng 1995 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 Women’s Health Study

PPT: Polyp Prevention Trial

t.i.d: ter in die (three times a day).



Characteristics of ongoing studies [ordered by study ID]

APPOSE 2001

Trial name or title The Australian Prostate Cancer Prevention Trial Using Selenium (APPOSE) trial

Methods

Participants Country: Australia. Inclusion criteria: men at risk of prostate cancer. The cohort size will be 2000 participants

in each arm

Interventions Parallel group design. Participants were randomly assigned to receive either 200 microg selenium or matching

placebo daily

Outcomes The primary outcome measure is incidence of prostate cancer.

Starting date 2001

Contact information Anthony J. Costello, MD, Level 1, 77 Victoria Parade, Fitzroy, Melbourne 3065, Australia; email: co-

[email protected]

Notes

HGPIN 2006

Trial name or title High-grade prostatic intraepithelial neoplasia (HGPIN) trial

Methods

Participants Country: United States of America

Inclusion criteria: men high-grade prostatic intraepithelial neoplasia (HGPIN) must be identified by biopsy;

the tissue must then be confirmed by centralized pathology review to show HGPIN and no cancer

Exclusion criteria: taking finasteride or any other drug known to affect PSA, or selenium supplements in

excess of 50 µg/d

Interventions The patient is randomly assigned to 200 µg/d of selenium as L-selenomethionine, or to placebo, with treatment

scheduled for 3 years

Outcomes The primary outcome measure is incidence of prostate cancer.

Starting date 1999

Contact information James R. Marshall, Roswell Park Cancer Institute, Buffalo, NY 14263. Phone: 716-845-8444; Fax: 716-845-

8487. E-mail: [email protected]

Notes



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



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

Interventions Physicians’ Health Study II utilized a two-by-two-by-two-by-two factorial design to test alternate day beta-

carotene, alternate day vitamin E, daily vitamin C, and a daily multivitamin. During the first 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

Outcomes The primary outcome measures are the incidence of total and prostate cancer, cardiovascular and eye diseases

Starting date 1999

Contact information Charles H. Hennekens MD

1415 W. Camino Real, Boca Raton, FL 33486, United States of America

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



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 specific 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.

Interventions Participants were randomly assigned to receive either 200 µg 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 2: vitamin E (n = 8100);

group 3: selenium (n = 8100);



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 specific 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.

Starting date 2001

Contact information Eric A. Klein, Section of Urologic Oncology, Department of Urology, Cleveland Clinic Foundation, Cleveland,

OH, USA Tel.: +1-216-444-5591; Fax: +1-216-445-

3532, e-mail address: [email protected].

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-specific antigen



D A T A A N D A N A L Y S E S

Comparison 1. Antioxidants versus placebo

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Occurrence of gastrointestinal

cancers in trials with a low or

high risk of bias

18 174019 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.83, 1.06]

1.1 Trials with low risk of bias 12 163439 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.96, 1.13]

1.2 Trials with high risk of

bias



cancers - generation of the

allocation sequence

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

2.1 Adequate 12 162948 Risk Ratio (M-H, Random, 95% CI) 1.05 [0.98, 1.13]

2.2 Unclear/Inadequate 6 10580 Risk Ratio (M-H, Random, 95% CI) 0.59 [0.43, 0.80]


cancers - allocation

concealment





cancers - follow-up




5 Occurrence of all gastrointestinal

cancers - different antioxidants


5.1 Beta-carotene 4 37046 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.80, 1.35]

5.2 Vitamin C 1 247 Risk Ratio (M-H, Random, 95% CI) Not estimable

5.3 Vitamin E 1 14573 Risk Ratio (M-H, Random, 95% CI) 1.11 [0.93, 1.34]

5.4 Selenium 5 11110 Risk Ratio (M-H, Random, 95% CI) 0.59 [0.46, 0.75]

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, riboflavin, 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)




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





7.4 Vitamin A and

beta-carotene



E


7.6 Vitamin A, riboflavin, and

zinc



and vitamin E



vitamin E, and selenium


7.9 Combination of

antioxidants


8 Occurrence of gastric cancer 11 Risk Ratio (M-H, Random, 95% CI) Subtotals only


8.2 Vitamin C 1 247 Risk Ratio (M-H, Random, 95% CI) Not estimable



8.5 Vitamin A and

beta-carotene



C



E



and vitamin E



and selenium







8.11 Combination of

antioxidants


9 Occurrence of colorectal cancer 8 Risk Ratio (M-H, Random, 95% CI) Subtotals only




9.4 Vitamin A and

beta-carotene



E



and vitamin E



vitamin E, and selenium


10 Occurrence of pancreatic

cancer




10.3 Vitamin A and

beta-carotene


10.4 Beta-carotene and

vitamin E



C, and vitamin E





11 Occurrence of hepatocellular

carcinoma





11.4 Vitamin A and

beta-carotene



vitamin E



C, and vitamin E





12 Occurrence of biliary tract

cancer





13 Mortality in trials with a low or

high risk of bias


13.1 Trials with low risk of

bias



bias


14 Mortality after excluding

selenium trials




14.1 Trials with low risk of

bias



bias

0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

15 Mortality - different

antioxidants



15.2 Vitamin C 2 2523 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.77, 1.23]



15.5 Vitamin A and

beta-carotene



vitamin C



vitamin E



C, and vitamin E



and selenium





15.11 Combination of

antioxidants


16 Adverse effects - beta-carotene 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only

16.1 Transient yellowing of

the skin


16.2 Persistent yellowing of

the skin


16.3 Belching 1 22071 Risk Ratio (M-H, Random, 95% CI) 2.22 [1.80, 2.74]

16.4 Gastrointestinal upset 1 8171 Risk Ratio (M-H, Random, 95% CI) 1.03 [1.00, 1.06]

17 Adverse effects - vitamin E 3 Risk Ratio (M-H, Random, 95% CI) Subtotals only

17.1 Haemorrhagic stroke 3 74985 Risk Ratio (M-H, Random, 95% CI) 1.01 [0.82, 1.23]

18 Adverse effects - selenium 1 Risk Ratio (M-H, Random, 95% CI) Subtotals only

18.1 Gastrointestinal upset 1 1312 Risk Ratio (M-H, Random, 95% CI) 1.51 [0.78, 2.95]



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 Control Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Trials with low risk of bias

ATBC 2003 722/21846 209/7287 11.8 % 1.15 [ 0.99, 1.34 ]

CARET 2004 243/9420 209/8894 10.9 % 1.10 [ 0.91, 1.32 ]

Correa 2000 2/739 3/237 0.5 % 0.21 [ 0.04, 1.27 ]

HOPE TOO 2005 69/4761 57/4780 6.6 % 1.22 [ 0.86, 1.72 ]

HPS 2002 215/10269 225/10267 10.9 % 0.96 [ 0.79, 1.15 ]

NIT2 1993 219/1657 209/1661 11.1 % 1.05 [ 0.88, 1.25 ]

NPCT 1996 11/653 24/659 2.5 % 0.46 [ 0.23, 0.94 ]

PHS 1996 219/11036 217/11035 10.8 % 1.01 [ 0.84, 1.22 ]

Plummer 2007 3/990 1/990 0.3 % 3.00 [ 0.31, 28.79 ]

SIT 2006 29/1677 29/1688 4.1 % 1.01 [ 0.60, 1.68 ]

SUVIMAX 2004 33/6481 40/6536 4.7 % 0.83 [ 0.53, 1.32 ]

WHS 2005 194/19937 180/19939 10.4 % 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 34/1112 57/953 5.4 % 0.51 [ 0.34, 0.77 ]

Li 2004 44/2526 57/2507 5.8 % 0.77 [ 0.52, 1.13 ]

Munoz 1985 4/305 3/305 0.6 % 1.33 [ 0.30, 5.91 ]

Yu 1991 10/1444 13/1030 1.9 % 0.55 [ 0.24, 1.25 ]

Yu 1997 4/113 11/113 1.1 % 0.36 [ 0.12, 1.11 ]

Zhu 2003 2/118 5/54 0.6 % 0.18 [ 0.04, 0.91 ]

Subtotal (95% CI) 5618 4962 15.4 % 0.59 [ 0.43, 0.80 ]



0.1 0.2 0.5 1 2 5 10

Favours antioxidants Favours control

(Continued . . . )



(. . . Continued)Study or subgroup Antioxidants Control Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


Total (95% CI) 95084 78935 100.0 % 0.94 [ 0.83, 1.06 ]




0.1 0.2 0.5 1 2 5 10



- generation of the allocation sequence.



Outcome: 2 Occurrence of gastrointestinal cancers - generation of the allocation sequence


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Adequate

ATBC 2003 722/21846 209/7287 14.4 % 1.15 [ 0.99, 1.34 ]

CARET 2004 243/9420 209/8894 13.1 % 1.10 [ 0.91, 1.32 ]

Correa 2000 2/368 0/117 0.2 % 1.60 [ 0.08, 33.07 ]

HOPE TOO 2005 69/4761 57/4780 7.6 % 1.22 [ 0.86, 1.72 ]

HPS 2002 215/10269 225/10267 13.0 % 0.96 [ 0.79, 1.15 ]

NIT2 1993 219/1657 209/1661 13.4 % 1.05 [ 0.88, 1.25 ]

NPCT 1996 11/653 24/659 2.7 % 0.46 [ 0.23, 0.94 ]

PHS 1996 219/11036 217/11035 13.0 % 1.01 [ 0.84, 1.22 ]

Plummer 2007 3/990 1/990 0.3 % 3.00 [ 0.31, 28.79 ]

SIT 2006 29/1677 29/1688 4.6 % 1.01 [ 0.60, 1.68 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

SUVIMAX 2004 33/6481 40/6536 5.3 % 0.83 [ 0.53, 1.32 ]

WHS 2005 194/19937 180/19939 12.4 % 1.08 [ 0.88, 1.32 ]

Subtotal (95% CI) 89095 73853 100.0 % 1.05 [ 0.98, 1.13 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 10.68, df = 11 (P = 0.47); I2 =0.0%


2 Unclear/Inadequate

Li 2000 34/1112 57/953 35.2 % 0.51 [ 0.34, 0.77 ]

Li 2004 44/2526 57/2507 38.3 % 0.77 [ 0.52, 1.13 ]

Munoz 1985 4/305 3/305 4.0 % 1.33 [ 0.30, 5.91 ]

Yu 1991 10/1444 13/1030 12.1 % 0.55 [ 0.24, 1.25 ]

Yu 1997 4/113 11/113 6.9 % 0.36 [ 0.12, 1.11 ]

Zhu 2003 2/118 5/54 3.4 % 0.18 [ 0.04, 0.91 ]

Subtotal (95% CI) 5618 4962 100.0 % 0.59 [ 0.43, 0.80 ]




0.1 0.2 0.5 1 2 5 10





- allocation concealment.



Outcome: 3 Occurrence of gastrointestinal cancers - allocation concealment


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Adequate

ATBC 2003 722/21846 209/7287 14.3 % 1.15 [ 0.99, 1.34 ]

CARET 2004 243/9420 209/8894 13.0 % 1.10 [ 0.91, 1.32 ]

Correa 2000 2/368 0/117 0.2 % 1.60 [ 0.08, 33.07 ]

HOPE TOO 2005 69/4761 57/4780 7.6 % 1.22 [ 0.86, 1.72 ]

HPS 2002 215/10269 225/10267 13.0 % 0.96 [ 0.79, 1.15 ]

Munoz 1985 4/305 3/305 0.7 % 1.33 [ 0.30, 5.91 ]

NIT2 1993 219/1657 209/1661 13.3 % 1.05 [ 0.88, 1.25 ]

NPCT 1996 11/653 24/659 2.7 % 0.46 [ 0.23, 0.94 ]

PHS 1996 219/11036 217/11035 12.9 % 1.01 [ 0.84, 1.22 ]

Plummer 2007 3/990 1/990 0.3 % 3.00 [ 0.31, 28.79 ]

SIT 2006 29/1677 29/1688 4.5 % 1.01 [ 0.60, 1.68 ]

SUVIMAX 2004 33/6481 40/6536 5.3 % 0.83 [ 0.53, 1.32 ]

WHS 2005 194/19937 180/19939 12.3 % 1.08 [ 0.88, 1.32 ]

Subtotal (95% CI) 89400 74158 100.0 % 1.05 [ 0.98, 1.13 ]





Li 2000 34/1112 57/953 36.7 % 0.51 [ 0.34, 0.77 ]

Li 2004 44/2526 57/2507 39.9 % 0.77 [ 0.52, 1.13 ]

Yu 1991 10/1444 13/1030 12.6 % 0.55 [ 0.24, 1.25 ]

Yu 1997 4/113 11/113 7.2 % 0.36 [ 0.12, 1.11 ]

Zhu 2003 2/118 5/54 3.6 % 0.18 [ 0.04, 0.91 ]

Subtotal (95% CI) 5313 4657 100.0 % 0.57 [ 0.41, 0.78 ]




0.1 0.2 0.5 1 2 5 10





- follow-up.



Outcome: 4 Occurrence of gastrointestinal cancers - follow-up


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Adequate

ATBC 2003 722/21846 209/7287 13.2 % 1.15 [ 0.99, 1.34 ]

CARET 2004 243/9420 209/8894 12.1 % 1.10 [ 0.91, 1.32 ]

Correa 2000 2/368 0/117 0.2 % 1.60 [ 0.08, 33.07 ]

HOPE TOO 2005 69/4761 57/4780 7.0 % 1.22 [ 0.86, 1.72 ]

HPS 2002 215/10269 225/10267 12.0 % 0.96 [ 0.79, 1.15 ]

Li 2000 34/1112 57/953 5.6 % 0.51 [ 0.34, 0.77 ]

Munoz 1985 4/305 3/305 0.6 % 1.33 [ 0.30, 5.91 ]

NIT2 1993 219/1657 209/1661 12.3 % 1.05 [ 0.88, 1.25 ]

NPCT 1996 11/653 24/659 2.5 % 0.46 [ 0.23, 0.94 ]

PHS 1996 219/11036 217/11035 12.0 % 1.01 [ 0.84, 1.22 ]

Plummer 2007 3/990 1/990 0.3 % 3.00 [ 0.31, 28.79 ]

SIT 2006 29/1677 29/1688 4.2 % 1.01 [ 0.60, 1.68 ]

SUVIMAX 2004 33/6481 40/6536 4.9 % 0.83 [ 0.53, 1.32 ]

WHS 2005 194/19937 180/19939 11.4 % 1.08 [ 0.88, 1.32 ]

Yu 1997 4/113 11/113 1.1 % 0.36 [ 0.12, 1.11 ]

Zhu 2003 2/118 5/54 0.5 % 0.18 [ 0.04, 0.91 ]

Subtotal (95% CI) 90743 75278 100.0 % 0.98 [ 0.87, 1.10 ]





Li 2004 44/2526 57/2507 76.0 % 0.77 [ 0.52, 1.13 ]

Yu 1991 10/1444 13/1030 24.0 % 0.55 [ 0.24, 1.25 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Subtotal (95% CI) 3970 3537 100.0 % 0.72 [ 0.51, 1.02 ]




0.1 0.2 0.5 1 2 5 10


Analysis 1.5. Comparison 1 Antioxidants versus placebo, Outcome 5 Occurrence of all gastrointestinal

cancers - different antioxidants.



Outcome: 5 Occurrence of all gastrointestinal cancers - different antioxidants

Study or subgroup Antioxidants Control Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Beta-carotene

ATBC 2003 243/7282 209/7287 1.16 [ 0.97, 1.40 ]

Correa 2000 1/117 0/117 3.00 [ 0.12, 72.90 ]

PHS 1996 219/11036 217/11035 1.01 [ 0.84, 1.22 ]

Zhu 2003 2/118 5/54 0.18 [ 0.04, 0.91 ]

Subtotal (95% CI) 18553 18493 1.04 [ 0.80, 1.35 ]




2 Vitamin C

Correa 2000 0/130 0/117 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 130 117 0.0 [ 0.0, 0.0 ]


Heterogeneity: not applicable

0.01 0.1 1 10 100


(Continued . . . )



(. . . Continued)Study or subgroup Antioxidants Control Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Test for overall effect: Z = 0.0 (P < 0.00001)

3 Vitamin E

ATBC 2003 233/7286 209/7287 1.11 [ 0.93, 1.34 ]

Subtotal (95% CI) 7286 7287 1.11 [ 0.93, 1.34 ]




4 Selenium

Li 2000 34/1112 57/953 0.51 [ 0.34, 0.77 ]

Li 2004 44/2526 57/2507 0.77 [ 0.52, 1.13 ]

NPCT 1996 11/653 24/659 0.46 [ 0.23, 0.94 ]

Yu 1991 10/1444 13/1030 0.55 [ 0.24, 1.25 ]

Yu 1997 4/113 11/113 0.36 [ 0.12, 1.11 ]

Subtotal (95% CI) 5848 5262 0.59 [ 0.46, 0.75 ]




5 Vitamin A and beta-carotene

CARET 2004 243/9420 209/8894 1.10 [ 0.91, 1.32 ]

Subtotal (95% CI) 9420 8894 1.10 [ 0.91, 1.32 ]




6 Beta-carotene and vitamin C

Correa 2000 1/121 0/117 2.90 [ 0.12, 70.52 ]

Subtotal (95% CI) 121 117 2.90 [ 0.12, 70.52 ]




7 Beta carotene and vitamin E

ATBC 2003 246/7278 209/7287 1.18 [ 0.98, 1.41 ]

Subtotal (95% CI) 7278 7287 1.18 [ 0.98, 1.41 ]




8 Vitamin A, riboflavin, and zinc

Munoz 1985 4/305 3/305 1.33 [ 0.30, 5.91 ]

Subtotal (95% CI) 305 305 1.33 [ 0.30, 5.91 ]



0.01 0.1 1 10 100


(Continued . . . )



(. . . Continued)Study or subgroup Antioxidants Control Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


9 Beta-carotene, vitamin C, and vitamin E

HPS 2002 215/10269 225/10267 0.96 [ 0.79, 1.15 ]

Plummer 2007 3/990 1/990 3.00 [ 0.31, 28.79 ]

Subtotal (95% CI) 11259 11257 0.96 [ 0.80, 1.16 ]




10 Vitamin C, vitamin E, and selenium

SIT 2006 29/1677 29/1688 1.01 [ 0.60, 1.68 ]

Subtotal (95% CI) 1677 1688 1.01 [ 0.60, 1.68 ]




11 Beta-carotene, vitamin C, vitamin E, and selenium

SUVIMAX 2004 33/6481 40/6536 0.83 [ 0.53, 1.32 ]

Subtotal (95% CI) 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) 1657 1661 1.05 [ 0.88, 1.25 ]




0.01 0.1 1 10 100




Analysis 1.6. Comparison 1 Antioxidants versus placebo, Outcome 6 Occurrence of different

gastrointestinal cancers - all antioxidants.



Outcome: 6 Occurrence of different gastrointestinal cancers - all antioxidants


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Occurrence of oesophageal cancer

ATBC 2003 47/21846 13/7287 11.8 % 1.21 [ 0.65, 2.23 ]

CARET 2004 44/9420 29/8894 18.6 % 1.43 [ 0.90, 2.29 ]

HPS 2002 31/10269 26/10267 15.6 % 1.19 [ 0.71, 2.01 ]

Munoz 1985 4/305 3/305 2.2 % 1.33 [ 0.30, 5.91 ]

NIT2 1993 123/1657 128/1661 45.9 % 0.96 [ 0.76, 1.22 ]

NPCT 1996 2/653 5/659 1.9 % 0.40 [ 0.08, 2.07 ]

SUVIMAX 2004 2/6481 2/6536 1.3 % 1.01 [ 0.14, 7.16 ]

WHS 2005 4/19937 3/19939 2.2 % 1.33 [ 0.30, 5.96 ]

Zhu 2003 0/118 1/54 0.5 % 0.15 [ 0.01, 3.72 ]

Subtotal (95% CI) 70686 55602 100.0 % 1.06 [ 0.89, 1.28 ]




2 Occurrence of gastric cancer

ATBC 2003 199/21846 50/7287 22.5 % 1.33 [ 0.97, 1.81 ]

CARET 2004 17/9420 18/8894 6.8 % 0.89 [ 0.46, 1.73 ]

Correa 2000 2/368 0/117 0.4 % 1.60 [ 0.08, 33.07 ]

HPS 2002 36/10269 30/10267 11.6 % 1.20 [ 0.74, 1.95 ]

Li 2004 23/2526 30/2507 9.7 % 0.76 [ 0.44, 1.31 ]

NIT2 1993 96/1657 81/1661 24.5 % 1.19 [ 0.89, 1.58 ]

PHS 1996 20/11036 21/11035 7.8 % 0.95 [ 0.52, 1.76 ]

Plummer 2007 3/990 1/990 0.6 % 3.00 [ 0.31, 28.79 ]

SIT 2006 29/1677 29/1688 10.7 % 1.01 [ 0.60, 1.68 ]

SUVIMAX 2004 2/6481 2/6536 0.9 % 1.01 [ 0.14, 7.16 ]

WHS 2005 14/19937 6/19939 3.5 % 2.33 [ 0.90, 6.07 ]

0.001 0.01 0.1 1 10 100 1000


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Zhu 2003 2/118 3/54 1.1 % 0.31 [ 0.05, 1.77 ]

Subtotal (95% CI) 86325 70975 100.0 % 1.14 [ 0.97, 1.33 ]




3 Occurrence of small intestine cancer

WHS 2005 4/19937 1/19939 100.0 % 4.00 [ 0.45, 35.79 ]

Subtotal (95% CI) 19937 19939 100.0 % 4.00 [ 0.45, 35.79 ]




4 Occurrence of colorectal cancer

ATBC 2003 265/21846 75/7287 15.3 % 1.18 [ 0.91, 1.52 ]

CARET 2004 127/9420 123/8894 15.9 % 0.97 [ 0.76, 1.25 ]

HOPE TOO 2005 69/4761 57/4780 10.4 % 1.22 [ 0.86, 1.72 ]

HPS 2002 117/10269 140/10267 16.0 % 0.84 [ 0.65, 1.07 ]

NPCT 1996 9/653 19/659 2.7 % 0.48 [ 0.22, 1.05 ]

PHS 1996 170/11036 176/11035 18.6 % 0.97 [ 0.78, 1.19 ]

SUVIMAX 2004 21/6481 24/6536 4.6 % 0.88 [ 0.49, 1.58 ]

WHS 2005 129/19937 140/19939 16.4 % 0.92 [ 0.73, 1.17 ]

Zhu 2003 0/118 1/54 0.2 % 0.15 [ 0.01, 3.72 ]

Subtotal (95% CI) 84521 69451 100.0 % 0.97 [ 0.86, 1.09 ]




5 Occurrence of pancreatic cancer

ATBC 2003 157/21846 59/7287 36.1 % 0.89 [ 0.66, 1.20 ]

CARET 2004 45/9420 32/8894 19.9 % 1.33 [ 0.84, 2.09 ]

HPS 2002 24/10269 24/10267 13.8 % 1.00 [ 0.57, 1.76 ]

PHS 1996 29/11036 20/11035 13.6 % 1.45 [ 0.82, 2.56 ]

SUVIMAX 2004 4/6481 6/6536 3.1 % 0.67 [ 0.19, 2.38 ]

WHS 2005 33/19937 18/19939 13.4 % 1.83 [ 1.03, 3.26 ]

Subtotal (95% CI) 78989 63958 100.0 % 1.16 [ 0.90, 1.50 ]




6 Occurrence of hepatocellular carcinoma

0.001 0.01 0.1 1 10 100 1000


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

ATBC 2003 54/21846 12/7287 16.1 % 1.50 [ 0.80, 2.80 ]

CARET 2004 10/9420 7/8894 7.3 % 1.35 [ 0.51, 3.54 ]

HPS 2002 7/10269 5/10267 5.2 % 1.40 [ 0.44, 4.41 ]

Li 2000 34/1112 57/953 31.6 % 0.51 [ 0.34, 0.77 ]

Li 2004 21/2526 27/2507 19.0 % 0.77 [ 0.44, 1.36 ]

SUVIMAX 2004 1/6481 1/6536 0.9 % 1.01 [ 0.06, 16.12 ]

WHS 2005 5/19937 5/19939 4.5 % 1.00 [ 0.29, 3.45 ]

Yu 1991 10/1444 13/1030 9.8 % 0.55 [ 0.24, 1.25 ]

Yu 1997 4/113 11/113 5.5 % 0.36 [ 0.12, 1.11 ]

Subtotal (95% CI) 73148 57526 100.0 % 0.80 [ 0.56, 1.14 ]




7 Occurrence of biliary tract cancer

SUVIMAX 2004 0/6481 2/6536 12.9 % 0.20 [ 0.01, 4.20 ]

WHS 2005 5/19937 7/19939 87.1 % 0.71 [ 0.23, 2.25 ]

Subtotal (95% CI) 26418 26475 100.0 % 0.61 [ 0.21, 1.78 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 1.7. Comparison 1 Antioxidants versus placebo, Outcome 7 Occurrence of oesophageal cancer.



Outcome: 7 Occurrence of oesophageal cancer


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Beta-carotene

ATBC 2003 12/7282 13/7287 94.3 % 0.92 [ 0.42, 2.02 ]

Zhu 2003 0/118 1/54 5.7 % 0.15 [ 0.01, 3.72 ]

Subtotal (95% CI) 7400 7341 100.0 % 0.75 [ 0.25, 2.30 ]




2 Vitamin E

ATBC 2003 19/7286 13/7287 100.0 % 1.46 [ 0.72, 2.96 ]

Subtotal (95% CI) 7286 7287 100.0 % 1.46 [ 0.72, 2.96 ]




3 Selenium

NPCT 1996 2/653 5/659 100.0 % 0.40 [ 0.08, 2.07 ]

Subtotal (95% CI) 653 659 100.0 % 0.40 [ 0.08, 2.07 ]





CARET 2004 44/9420 29/8894 100.0 % 1.43 [ 0.90, 2.29 ]

Subtotal (95% CI) 9420 8894 100.0 % 1.43 [ 0.90, 2.29 ]




5 Beta-carotene and vitamin E

ATBC 2003 16/7278 13/7287 100.0 % 1.23 [ 0.59, 2.56 ]

Subtotal (95% CI) 7278 7287 100.0 % 1.23 [ 0.59, 2.56 ]




6 Vitamin A, riboflavin, and zinc

Munoz 1985 4/305 3/305 100.0 % 1.33 [ 0.30, 5.91 ]

0.01 0.1 1 10 100


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Subtotal (95% CI) 305 305 100.0 % 1.33 [ 0.30, 5.91 ]





HPS 2002 31/10269 26/10267 100.0 % 1.19 [ 0.71, 2.01 ]

Subtotal (95% CI) 10269 10267 100.0 % 1.19 [ 0.71, 2.01 ]





SUVIMAX 2004 2/6481 2/6536 100.0 % 1.01 [ 0.14, 7.16 ]

Subtotal (95% CI) 6481 6536 100.0 % 1.01 [ 0.14, 7.16 ]




9 Combination of antioxidants

NIT2 1993 123/1657 128/1661 100.0 % 0.96 [ 0.76, 1.22 ]

Subtotal (95% CI) 1657 1661 100.0 % 0.96 [ 0.76, 1.22 ]




0.01 0.1 1 10 100




Analysis 1.8. Comparison 1 Antioxidants versus placebo, Outcome 8 Occurrence of gastric cancer.



Outcome: 8 Occurrence of gastric cancer


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Beta-carotene

ATBC 2003 64/7282 50/7287 1.28 [ 0.89, 1.85 ]

Correa 2000 1/117 0/117 3.00 [ 0.12, 72.90 ]

PHS 1996 20/11036 21/11035 0.95 [ 0.52, 1.76 ]

Zhu 2003 2/118 3/54 0.31 [ 0.05, 1.77 ]

Subtotal (95% CI) 18553 18493 1.12 [ 0.79, 1.59 ]




2 Vitamin C

Correa 2000 0/130 0/117 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 130 117 0.0 [ 0.0, 0.0 ]




3 Vitamin E

ATBC 2003 65/7286 50/7287 1.30 [ 0.90, 1.88 ]

Subtotal (95% CI) 7286 7287 1.30 [ 0.90, 1.88 ]




4 Selenium

Li 2004 23/2526 30/2507 0.76 [ 0.44, 1.31 ]

Subtotal (95% CI) 2526 2507 0.76 [ 0.44, 1.31 ]





CARET 2004 17/9420 18/8894 0.89 [ 0.46, 1.73 ]

Subtotal (95% CI) 9420 8894 0.89 [ 0.46, 1.73 ]



0.01 0.1 1 10 100


(Continued . . . )



(. . . Continued)


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI



Correa 2000 1/121 0/117 2.90 [ 0.12, 70.52 ]

Subtotal (95% CI) 121 117 2.90 [ 0.12, 70.52 ]





ATBC 2003 70/7278 50/7287 1.40 [ 0.98, 2.01 ]

Subtotal (95% CI) 7278 7287 1.40 [ 0.98, 2.01 ]





HPS 2002 36/10269 30/10267 1.20 [ 0.74, 1.95 ]

Plummer 2007 3/990 1/990 3.00 [ 0.31, 28.79 ]

Subtotal (95% CI) 11259 11257 1.25 [ 0.78, 2.00 ]





SIT 2006 29/1677 29/1688 1.01 [ 0.60, 1.68 ]

Subtotal (95% CI) 1677 1688 1.01 [ 0.60, 1.68 ]





SUVIMAX 2004 2/6481 2/6536 1.01 [ 0.14, 7.16 ]

Subtotal (95% CI) 6481 6536 1.01 [ 0.14, 7.16 ]





NIT2 1993 96/1657 81/1661 1.19 [ 0.89, 1.58 ]

Subtotal (95% CI) 1657 1661 1.19 [ 0.89, 1.58 ]




0.01 0.1 1 10 100




Analysis 1.9. Comparison 1 Antioxidants versus placebo, Outcome 9 Occurrence of colorectal cancer.



Outcome: 9 Occurrence of colorectal cancer


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Beta-carotene

ATBC 2003 99/7282 75/7287 39.8 % 1.32 [ 0.98, 1.78 ]

PHS 1996 170/11036 176/11035 59.7 % 0.97 [ 0.78, 1.19 ]

Zhu 2003 0/118 1/54 0.5 % 0.15 [ 0.01, 3.72 ]

Subtotal (95% CI) 18436 18376 100.0 % 1.09 [ 0.79, 1.51 ]




2 Vitamin E

ATBC 2003 76/7286 75/7287 53.3 % 1.01 [ 0.74, 1.39 ]

HOPE TOO 2005 69/4761 57/4780 46.7 % 1.22 [ 0.86, 1.72 ]

Subtotal (95% CI) 12047 12067 100.0 % 1.10 [ 0.87, 1.39 ]




3 Selenium

NPCT 1996 9/653 19/659 100.0 % 0.48 [ 0.22, 1.05 ]

Subtotal (95% CI) 653 659 100.0 % 0.48 [ 0.22, 1.05 ]





CARET 2004 127/9420 123/8894 100.0 % 0.97 [ 0.76, 1.25 ]

Subtotal (95% CI) 9420 8894 100.0 % 0.97 [ 0.76, 1.25 ]





ATBC 2003 90/7278 75/7287 100.0 % 1.20 [ 0.89, 1.63 ]

Subtotal (95% CI) 7278 7287 100.0 % 1.20 [ 0.89, 1.63 ]

0.01 0.1 1 10 100


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI





HPS 2002 117/10269 140/10267 100.0 % 0.84 [ 0.65, 1.07 ]

Subtotal (95% CI) 10269 10267 100.0 % 0.84 [ 0.65, 1.07 ]





SUVIMAX 2004 21/6481 24/6536 100.0 % 0.88 [ 0.49, 1.58 ]

Subtotal (95% CI) 6481 6536 100.0 % 0.88 [ 0.49, 1.58 ]




0.01 0.1 1 10 100




Analysis 1.10. Comparison 1 Antioxidants versus placebo, Outcome 10 Occurrence of pancreatic cancer.



Outcome: 10 Occurrence of pancreatic cancer


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Beta-carotene

ATBC 2003 45/7282 59/7287 68.4 % 0.76 [ 0.52, 1.12 ]

PHS 1996 29/11036 20/11035 31.6 % 1.45 [ 0.82, 2.56 ]

Subtotal (95% CI) 18318 18322 100.0 % 1.02 [ 0.54, 1.90 ]




2 Vitamin E

ATBC 2003 57/7286 59/7287 100.0 % 0.97 [ 0.67, 1.39 ]

Subtotal (95% CI) 7286 7287 100.0 % 0.97 [ 0.67, 1.39 ]





CARET 2004 45/9420 32/8894 100.0 % 1.33 [ 0.84, 2.09 ]

Subtotal (95% CI) 9420 8894 100.0 % 1.33 [ 0.84, 2.09 ]





ATBC 2003 55/7278 59/7287 100.0 % 0.93 [ 0.65, 1.35 ]

Subtotal (95% CI) 7278 7287 100.0 % 0.93 [ 0.65, 1.35 ]





HPS 2002 24/10269 24/10267 100.0 % 1.00 [ 0.57, 1.76 ]

Subtotal (95% CI) 10269 10267 100.0 % 1.00 [ 0.57, 1.76 ]





SUVIMAX 2004 4/6481 6/6536 100.0 % 0.67 [ 0.19, 2.38 ]

0.2 0.5 1 2 5


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Subtotal (95% CI) 6481 6536 100.0 % 0.67 [ 0.19, 2.38 ]




0.2 0.5 1 2 5


Analysis 1.11. Comparison 1 Antioxidants versus placebo, Outcome 11 Occurrence of hepatocellular

carcinoma.



Outcome: 11 Occurrence of hepatocellular carcinoma


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Beta-carotene

ATBC 2003 23/7282 12/7287 100.0 % 1.92 [ 0.96, 3.85 ]

Subtotal (95% CI) 7282 7287 100.0 % 1.92 [ 0.96, 3.85 ]




2 Vitamin E

ATBC 2003 16/7286 12/7287 100.0 % 1.33 [ 0.63, 2.82 ]

Subtotal (95% CI) 7286 7287 100.0 % 1.33 [ 0.63, 2.82 ]




3 Selenium

Li 2000 34/1112 57/953 34.9 % 0.51 [ 0.34, 0.77 ]

Li 2004 21/2526 27/2507 29.3 % 0.77 [ 0.44, 1.36 ]

0.01 0.1 1 10 100


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Yu 1991 10/1444 13/1030 21.2 % 0.55 [ 0.24, 1.25 ]

Yu 1997 4/113 11/113 14.6 % 0.36 [ 0.12, 1.11 ]

Subtotal (95% CI) 5195 4603 100.0 % 0.56 [ 0.42, 0.76 ]





CARET 2004 10/9420 7/8894 100.0 % 1.35 [ 0.51, 3.54 ]

Subtotal (95% CI) 9420 8894 100.0 % 1.35 [ 0.51, 3.54 ]





ATBC 2003 15/7278 12/7287 100.0 % 1.25 [ 0.59, 2.67 ]

Subtotal (95% CI) 7278 7287 100.0 % 1.25 [ 0.59, 2.67 ]





HPS 2002 7/10269 5/10267 100.0 % 1.40 [ 0.44, 4.41 ]

Subtotal (95% CI) 10269 10267 100.0 % 1.40 [ 0.44, 4.41 ]





SUVIMAX 2004 1/6481 1/6536 100.0 % 1.01 [ 0.06, 16.12 ]

Subtotal (95% CI) 6481 6536 100.0 % 1.01 [ 0.06, 16.12 ]




0.01 0.1 1 10 100




Analysis 1.12. Comparison 1 Antioxidants versus placebo, Outcome 12 Occurrence of biliary tract cancer.



Outcome: 12 Occurrence of biliary tract cancer


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


SUVIMAX 2004 0/6481 2/6536 100.0 % 0.20 [ 0.01, 4.20 ]

Subtotal (95% CI) 6481 6536 100.0 % 0.20 [ 0.01, 4.20 ]




0.001 0.01 0.1 1 10 100 1000

Favours treatment Favours control



Analysis 1.13. Comparison 1 Antioxidants versus placebo, Outcome 13 Mortality in trials with a low or high

risk of bias.



Outcome: 13 Mortality in trials with a low or high risk of bias


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


ATBC 2003 8226/21846 2605/7287 16.5 % 1.05 [ 1.02, 1.09 ]

CARET 2004 1855/9420 1509/8894 13.8 % 1.16 [ 1.09, 1.23 ]

Correa 2000 16/739 2/237 0.1 % 2.57 [ 0.59, 11.08 ]

HOPE TOO 2005 799/4761 801/4780 10.9 % 1.00 [ 0.92, 1.10 ]

HPS 2002 1446/10269 1389/10267 13.1 % 1.04 [ 0.97, 1.11 ]

NIT2 1993 157/1657 167/1661 3.9 % 0.94 [ 0.77, 1.16 ]

NPCT 1996 108/653 129/659 3.3 % 0.84 [ 0.67, 1.07 ]

PHS 1996 979/11036 968/11035 11.3 % 1.01 [ 0.93, 1.10 ]

Plummer 2007 16/990 11/990 0.4 % 1.45 [ 0.68, 3.12 ]

SIT 2006 82/1677 101/1688 2.3 % 0.82 [ 0.62, 1.08 ]

SUVIMAX 2004 76/6481 98/6536 2.1 % 0.78 [ 0.58, 1.05 ]

WACS 2007 871/7149 124/1022 5.0 % 1.00 [ 0.84, 1.20 ]

WHS 2005 636/19937 615/19939 9.1 % 1.03 [ 0.93, 1.15 ]

Subtotal (95% CI) 96615 74995 91.9 % 1.03 [ 0.98, 1.08 ]





NIT1 1993 1847/25886 280/3698 8.1 % 0.94 [ 0.84, 1.06 ]

Subtotal (95% CI) 25886 3698 8.1 % 0.94 [ 0.84, 1.06 ]




Total (95% CI) 122501 78693 100.0 % 1.02 [ 0.97, 1.07 ]




0.5 0.7 1 1.5 2




Analysis 1.14. Comparison 1 Antioxidants versus placebo, Outcome 14 Mortality after excluding selenium

trials.



Outcome: 14 Mortality after excluding selenium trials


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


ATBC 2003 8226/21846 2605/7287 25.4 % 1.05 [ 1.02, 1.09 ]

CARET 2004 1855/9420 1509/8894 18.2 % 1.16 [ 1.09, 1.23 ]

Correa 2000 16/739 2/237 0.1 % 2.57 [ 0.59, 11.08 ]

HOPE TOO 2005 799/4761 801/4780 12.4 % 1.00 [ 0.92, 1.10 ]

HPS 2002 1446/10269 1389/10267 16.5 % 1.04 [ 0.97, 1.11 ]

PHS 1996 979/11036 968/11035 13.2 % 1.01 [ 0.93, 1.10 ]

Plummer 2007 16/990 11/990 0.3 % 1.45 [ 0.68, 3.12 ]

WACS 2007 871/7149 124/1022 4.5 % 1.00 [ 0.84, 1.20 ]

WHS 2005 636/19937 615/19939 9.5 % 1.03 [ 0.93, 1.15 ]

Subtotal (95% CI) 86147 64451 100.0 % 1.06 [ 1.01, 1.10 ]





Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]



Test for overall effect: not applicable

Total (95% CI) 86147 64451 100.0 % 1.06 [ 1.01, 1.10 ]




0.5 0.7 1 1.5 2




Analysis 1.15. Comparison 1 Antioxidants versus placebo, Outcome 15 Mortality - different antioxidants.



Outcome: 15 Mortality - different antioxidants


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Beta-carotene

ATBC 2003 2793/7282 2605/7287 56.5 % 1.07 [ 1.03, 1.12 ]

Correa 2000 7/243 2/237 0.2 % 3.41 [ 0.72, 16.26 ]

PHS 1996 979/11036 968/11035 35.1 % 1.01 [ 0.93, 1.10 ]

WACS 2007 124/1020 124/1022 8.1 % 1.00 [ 0.79, 1.27 ]

Subtotal (95% CI) 19581 19581 100.0 % 1.05 [ 0.99, 1.11 ]




2 Vitamin C

Correa 2000 3/241 2/237 1.9 % 1.48 [ 0.25, 8.75 ]

WACS 2007 120/1023 124/1022 98.1 % 0.97 [ 0.76, 1.22 ]

Subtotal (95% CI) 1264 1259 100.0 % 0.97 [ 0.77, 1.23 ]




3 Vitamin E

ATBC 2003 2671/7286 2605/7287 57.6 % 1.03 [ 0.98, 1.07 ]

HOPE TOO 2005 799/4761 801/4780 34.1 % 1.00 [ 0.92, 1.10 ]

WACS 2007 120/1021 124/1022 8.2 % 0.97 [ 0.77, 1.23 ]

Subtotal (95% CI) 13068 13089 100.0 % 1.02 [ 0.98, 1.06 ]




4 Selenium

NPCT 1996 108/653 129/659 100.0 % 0.84 [ 0.67, 1.07 ]

Subtotal (95% CI) 653 659 100.0 % 0.84 [ 0.67, 1.07 ]





0.01 0.1 1 10 100


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

CARET 2004 1855/9420 1509/8894 100.0 % 1.16 [ 1.09, 1.23 ]

Subtotal (95% CI) 9420 8894 100.0 % 1.16 [ 1.09, 1.23 ]





Correa 2000 6/255 2/237 100.0 % 2.79 [ 0.57, 13.68 ]

Subtotal (95% CI) 255 237 100.0 % 2.79 [ 0.57, 13.68 ]





ATBC 2003 2762/7278 2605/7287 100.0 % 1.06 [ 1.02, 1.11 ]

Subtotal (95% CI) 7278 7287 100.0 % 1.06 [ 1.02, 1.11 ]





HPS 2002 1446/10269 1389/10267 75.3 % 1.04 [ 0.97, 1.11 ]

Plummer 2007 16/990 11/990 1.5 % 1.45 [ 0.68, 3.12 ]

WACS 2007 871/7149 124/1022 23.2 % 1.00 [ 0.84, 1.20 ]

Subtotal (95% CI) 18408 12279 100.0 % 1.04 [ 0.97, 1.11 ]





SIT 2006 82/1677 101/1688 100.0 % 0.82 [ 0.62, 1.08 ]

Subtotal (95% CI) 1677 1688 100.0 % 0.82 [ 0.62, 1.08 ]





SUVIMAX 2004 76/6481 98/6536 100.0 % 0.78 [ 0.58, 1.05 ]

Subtotal (95% CI) 6481 6536 100.0 % 0.78 [ 0.58, 1.05 ]





NIT1 1993 1847/25886 280/3698 69.7 % 0.94 [ 0.84, 1.06 ]

0.01 0.1 1 10 100


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

NIT2 1993 157/1657 167/1661 30.3 % 0.94 [ 0.77, 1.16 ]

Subtotal (95% CI) 27543 5359 100.0 % 0.94 [ 0.85, 1.05 ]




0.01 0.1 1 10 100


Analysis 1.16. Comparison 1 Antioxidants versus placebo, Outcome 16 Adverse effects - beta-carotene.



Outcome: 16 Adverse effects - beta-carotene


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Transient yellowing of the skin

ATBC 2003 4950/14560 1020/14573 31.1 % 4.86 [ 4.56, 5.18 ]

PHS 1996 1745/11036 1535/11035 31.1 % 1.14 [ 1.07, 1.21 ]

WHS 2005 2131/19939 1944/19937 31.1 % 1.10 [ 1.03, 1.16 ]

Zhu 2003 2/118 0/54 6.8 % 2.31 [ 0.11, 47.33 ]

Subtotal (95% CI) 45653 45599 100.0 % 1.85 [ 0.74, 4.67 ]


Heterogeneity: Tau2 = 0.72; Chi2 = 1455.74, df = 3 (P<0.00001); I2 =100%


2 Persistent yellowing of the skin

ATBC 2003 1281/14560 44/14573 100.0 % 29.14 [ 21.60, 39.32 ]

Subtotal (95% CI) 14560 14573 100.0 % 29.14 [ 21.60, 39.32 ]



0.01 0.1 1 10 100


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


3 Belching

PHS 1996 275/11036 124/11035 100.0 % 2.22 [ 1.80, 2.74 ]

Subtotal (95% CI) 11036 11035 100.0 % 2.22 [ 1.80, 2.74 ]




4 Gastrointestinal upset

WACS 2007 2785/4084 2717/4087 100.0 % 1.03 [ 1.00, 1.06 ]

Subtotal (95% CI) 4084 4087 100.0 % 1.03 [ 1.00, 1.06 ]




0.01 0.1 1 10 100




Analysis 1.17. Comparison 1 Antioxidants versus placebo, Outcome 17 Adverse effects - vitamin E.



Outcome: 17 Adverse effects - vitamin E


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Haemorrhagic stroke

ATBC 2003 92/7286 85/7287 47.7 % 1.08 [ 0.81, 1.45 ]

HPS 2002 51/10269 53/10267 27.8 % 0.96 [ 0.66, 1.41 ]

WHS 2005 44/19937 48/19939 24.5 % 0.92 [ 0.61, 1.38 ]

Subtotal (95% CI) 37492 37493 100.0 % 1.01 [ 0.82, 1.23 ]




0.5 0.7 1 1.5 2


Analysis 1.18. Comparison 1 Antioxidants versus placebo, Outcome 18 Adverse effects - selenium.



Outcome: 18 Adverse effects - selenium


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Gastrointestinal upset

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

Subtotal (95% CI) 653 659 100.0 % 1.51 [ 0.78, 2.95 ]




0.2 0.5 1 2 5




A D D I T I O N A L T A B L E S

Table 1. Table

Database Search performed Search strategy

The Cochrane Central Register of Con-

trolled Trials on the Cochrane Library

October 2007 Digestive system neoplasms / explode all trees (MeSH),

antioxidants / explode all trees (MeSH), (#1 and #2).

The Controlled Trials Registers of the four

Cochrane gastrointestinal groups

October 2007 ’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*’

MEDLINE October 2007 #1 explode “Digestive-System-Neoplasms”/ all subhead-

ings

#2 retinol or beta carotene or ascorbic acid or alpha toco-

pherol or selenium or vitamin* or antioxidant*

#3 TG = ANIMAL

#4 random*

#5 ((#1 and #2) not #3) and random*

EMBASE October 2007 #1 explode “digestive-system-tumor”/ all subheadings

#2 retinol or beta carotene or ascorbic acid or alpha toco-

pherol or selenium or vitamin* or antioxidant*

#3 random*

#4 #1 and #2 and #3

LILACS October 2007 #1 antioxidantes and cancer

The Web of Science

(http://portal.isiknowledge.com/portal.

cgi?DestApp=WOS&Func=Frame)

Accessed 01 October 2007 #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; Times-

pan=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

The Chinese Biomedical Database October 2007 (retinol or beta-carotene or ascorbic acid or alpha toco-

pherol 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*



Table 2. Table

Trial Design of the trials Number of arms Antiox-

idant vitamin sup-

plements plus any

additional non-an-

tioxidant interven-

tions in the experi-

mental arm/arms

Control group Analysis reported

Munoz 1985 Parallel. 2 Vitamin A, vitamin

B2, and zinc.

Placebo.

Yu 1991 Parallel. 2 Selenium. Placebo.

NIT1 1993 Half replicate

of a 2x2x2x2 facto-

rial trial.

8 A) Vitamin A, vita-

min B2, vitamin B3,

and zinc.

B) Vitamin A, vi-

tamin C, zinc, and

molybdenum.

C) Vitamin A, beta-

carotene, vitamin E,

selenium, and zinc.

D) Vitamin C, vita-

min B2, vitamin B3,

and molybdenum.

E) Beta-carotene, vi-

tamin E, selenium,

vitamin B2, and vi-

tamin B3.

F) Beta-carotene, vi-

tamin C, vitamin

E, selenium, and

molybdenum.

G) Vitamin A, beta-

carotene, vitamin C,

vitamin E, sele-

nium, zinc, vitamin

B2, vitamin B3, and

molybdenum

Placebo. Four-way.

NIT2 1993 Parallel. 2 13 vitamins (vita-

min

A, beta-carotene, vi-

tamin E, vitamin

C, vitamin B1, vi-

tamin B2, vitamin

B6, vitamin B12, vi-

Placebo.



Table 2. Table (Continued)

tamin D, folic acid,

niacinamide, biotin,

pan-

tothenic acid) and

13 minerals (cal-

cium, phosphorus,

iodine, iron, magne-

sium, copper, man-

ganese,

potassium, chloride,

chromium,

molybdenum, sele-

nium, and zinc)

NPCT 1996 Parallel. 2 Selenium. Placebo.

PHS 1996 2x2 factorial trial

changed into two-

armed trial.

Initially 4, then

changed into 2.

A) Aspirin.

B) Beta-carotene.

C) Beta-carotene

and aspirin.

Placebo. Two-way.

Yu 1997 Parallel. 2 Selenium. Placebo.

Correa 2000 2x2x2 factorial trial. 8 A random half of

the patients were

treated with anti-

Helicobac-

ter pylori treatment

medication (which

consisted of amoxi-

cillin, metronida-

zole, 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) Beta-

carotene plus anti-

Helicobacter pylori

treatment.

D) Vitamin C plus

anti-Helicobacter

pylori treatment.

E) Beta-carotene

Placebo. Eight-way.




and vitamin C.

F) Beta-

carotene and vita-

min C plus anti-

Helicobacter pylori

treatment.

G) anti-Helicobac-

ter pylori treatment.

Li 2000 Parallel. 2 Selenium. Placebo.

HPS 2002 2x2 factorial trial. 4 A) Vitamin E, vi-

tamin C, and beta-

carotene.

B) Simvastatin.

C) Vitamin

E, vitamin C, beta-

carotene, and sim-

vastatin.

Placebo. Two-way.

ATBC 2003 2x2 factorial trial. 4 A) Vitamin E.

B) Beta-carotene.

C) Beta carotene

and vitamin E.

Placebo. Four-way

Zhu 2003 Parallel. 3 (A fourth group

assessing folate and

vitamin B12 was

disregarded.)

A) Beta-carotene

(natural).

B) Beta-carotene

(synthetic).

Placebo.

CARET 2004 2x2 factorial trial

changed into two-

armed trial.

Initially 4, then

changed into 2.

Vitamin A and beta-

carotene.

Placebo.

Li 2004 Parallel. 2 Selenium, synthetic

allitridum (garlic ex-

tract).

Placebo.

SUVIMAX 2004 Parallel. 2 Beta-carotene, vita-

min C, vitamin E,

selenium, and zinc

[as gluconate])

Placebo.

HOPE TOO 2005 2x2 4 A) Vitamin E.

B) Ramipril (an-

giotensin-con-

verting enzyme in-

hibitor).

C) Vitamin E plus

Placebo. Two-way.




ramipril.

WHS 2005 2x2x2 factorial trial. Initially 8, changed

into 4.

A) Beta-carotene

(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, vi-

tamin E, and as-

pirin.

G) Aspirin.

Placebo. Two-way.

SIT 2006 2x2x2; 2x2 8 plus 4 A) Amoxicillin and

omeprazole, gar-

lic, vitamin capsule*

and selenium.

B) Amoxicillin and

omeprazole, garlic,

vitamin placebo

C) Amoxicillin and

omeprazole, vita-

min capsule* and se-

lenium.

D) Amoxicillin and

omeprazole and vi-

tamin placebo

E) Garlic, vitamin

capsule*, and sele-

nium.

F) Garlic and vita-

min placebo.

G) Vitamin cap-

sule* and selenium.

H) Garlic and sele-

nium placebo.

I) Garlic.

J) Vitamin placebo.

K) Selenium.

*The vitamin cap-

sule contained vita-

min C (250 mg), vi-

tamin E (100 IU),

Placebo. Two-way




and selenium from

yeast (37.5 µg)

Plummer 2007 Parallel 2 Beta-carotene, vita-

min C, and vitamin

E.

Placebo.

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

A) Beta-carotene,

vitamin C, and vita-

min E.

B) Beta-carotene

placebo, vitamin C,

and vitamin E.

C) Beta-carotene,

vitamin C, and vita-

min 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 vita-

min E.

G)

Beta-carotene, vita-

min C placebo, and

vitamin E placebo.

Placebo. Eight-way

Table 3. Table

Experimen-

tal antioxidant sup-

plements

Oesophageal cancer Gastric cancer Colorectal cancer Pancreatic cancer Hepatocellular carci-

noma

Beta-carotene (PHS

1996; Correa 2000;

ATBC 2003; Zhu

2003)

0.75, 0.25 to 2.30 1.12, 0.79 to 1.59 1.09, 0.79 to 1.51 1.02, 0.54 to 1.90 1.92, 0.96 to 3.85

Vitamin E (ATBC

2003; HOPE TOO

2005)

1.46, 0.72 to 2.96 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




Selenium (Yu 1991;

NPCT 1996; Yu

1997; Li 2000; Li

2004)

0.40, 0.08 to 2.07 0.76, 0.44 to 1.31 0.48, 0.22 to 1.05 ND 0.56, 0.42 to 0.76

Beta-carotene and

vitamin A (CARET

2004)

1.43, 0.90 to 2.29 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

Beta-carotene

and vitamin C (Cor-

rea 2000)

ND 2.90, 0.12 to 70.52 ND ND ND

Beta-carotene and

vitamin E (ATBC

2003)

1.23, 0.59 to 2.56 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


min C, and vita-

min E (HPS 2002;

Plummer 2007)

1.19, 0.71 to 2.01 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

Vitamin A,

riboflavin, and zinc

(Munoz 1985)

1.33, 0.30 to 5.91 ND ND ND ND

Vitamin C, vita-

min E, and selenium

(SIT 2006)

ND 1.01, 0.60 to 1.68 ND ND ND


min C, vitamin E,

and selenium (SU-

VIMAX 2004)

1.01, 0.14 to 7.16 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

26 vitamins/miner-

als (NIT2 1993)

0.96, 0.76 to 1.22 1.19, 0.89 to 1.58 ND ND ND

GI = gastrointesti-

nal; ND = No data

Relative risk, 95%

confidence interval

(random).



W H A T ’ S N E W

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

Date Event Description

17 April 2008 Amended Converted to new review format.

30 September 2007 New search has been performed Six new trials were added.

30 September 2007 New citation required but conclusions have not

changed

Conclusions did not change.

H I S T O R Y

Protocol first published: Issue 2, 2003

Review first published: Issue 4, 2004

C O N T R I B U T I O N S O F A U T H O R S

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 verification, and

update of the review.

D E C L A R A T I O N S O F I N T E R E S T

None known.

S O U R C E S O F S U P P O R T

Internal sources

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



External sources

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

N O T E S

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

I N D E X T E R M S

Medical Subject Headings (MeSH)

∗Dietary Supplements [adverse effects]; Antioxidants [∗administration & dosage; adverse effects]; Gastrointestinal Neoplasms [mor-

tality; ∗prevention & control]; Liver Neoplasms [mortality; ∗prevention & control]; Pancreatic Neoplasms [mortality; ∗prevention &

control]; Randomized Controlled Trials as Topic

MeSH check words

Humans



Documents

Antioxidant supplements for preventing gastrointestinal cancers