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Effects of antioxidant supplements on cancer prevention: meta-analysis of randomized controlled trials

      Abstract

      Background

      This meta-analysis aimed to investigate the effect of antioxidant supplements on the primary and secondary prevention of cancer as reported by randomized controlled trials.

      Methods

      We searched Medline (PubMed), Excerpta Medica database, and the Cochrane Review in October 2007.

      Results

      Among 3327 articles searched, 31 articles on 22 randomized controlled trials, which included 161 045 total subjects, 88 610 in antioxidant supplement groups and 72 435 in placebo or no-intervention groups, were included in the final analyses. In a fixed-effects meta-analysis of all 22 trials, antioxidant supplements were found to have no preventive effect on cancer [relative risk (RR) 0.99; 95% confidence interval (CI) 0.96–1.03). Similar findings were observed in 12 studies on primary prevention trials (RR 1.00; 95% CI 0.97–1.04) and in nine studies on secondary prevention trials (RR 0.97; 95% CI 0.83–1.13). Further, subgroup analyses revealed no preventive effect on cancer according to type of antioxidant, type of cancer, or the methodological quality of the studies. On the other hand, the use of antioxidant supplements significantly increased the risk of bladder cancer (RR 1.52; 95% CI 1.06–2.17) in a subgroup meta-analysis of four trials.

      Conclusions

      The meta-analysis of randomized controlled trials indicated that there is no clinical evidence to support an overall primary and secondary preventive effect of antioxidant supplements on cancer. The effects of antioxidant supplements on human health, particularly in relation to cancer, should not be overemphasized because the use of those might be harmful for some cancer.

      Keywords

      introduction

      Previous experimental studies using in vivo animal models and in vitro cancer cell lines have reported that antioxidants such as vitamins, beta-carotene, and selenium may reduce oxidative damage and prevent human diseases, including cancer [
      • Tomita Y.
      • Himeno K.
      • Nomoto K.
      • et al.
      Augmentation of tumor immunity against syngeneic tumors in mice by β-carotene.
      ,
      • Glatthaar B.E.
      • Hornig D.H.
      • Moser U.
      The role of ascorbic acid in carcinogenesis.
      ,
      • Sandhu J.K.
      • Haggani A.S.
      • Birnboim H.C.
      Effect of dietary E on spontaneous or nitric oxide donor-induced mutations in a mouse tumor model.
      ,
      • Wright G.L.
      • Wang S.
      • Fultz M.E.
      • et al.
      Effect of vitamin A deficiency on cardiovascular function in the rat.
      ]. Also, the previous 200 epidemiologic studies have indicated that persons with a low intake of fruits and vegetables that are rich in antioxidant substances are more susceptible to cancer [
      • Hercberg S.
      • Galan P.
      • Preziosi P.
      • et al.
      The potential role of antioxidant vitamins in preventing cardiovascular diseases and cancers.
      ].
      However, a systematic review of randomized controlled trials published in 2006 reported that the currently available evidence was insufficient to prove whether or not multivitamin supplements were beneficial toward the prevention of cancer and chronic disease [
      • Huang H.Y.
      • Caballero B.
      • Chang S.
      • et al.
      The efficacy and safety of multivitamin and mineral supplement use to prevent cancer and chronic disease in adults: a systematic review for a National Institutes of Health state-of-the-science conference.
      ]. A recently published meta-analysis of 47 low-bias trials involving 180 938 participants revealed that compared with the control group, the antioxidant supplement group exhibited a mortality rate that was significantly higher by at least 5% [
      • Bjelakovic G.
      • Nikolova D.
      • Guud L.L.
      • et al.
      Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.
      ]. A meta-analysis of randomized controlled trials also showed that antioxidant supplements do not exert any significant effects against the development of gastrointestinal cancers and that they increase all-cause mortality [
      • Bjelakovic G.
      • Nikolova D.
      • Simonetti R.G.
      • Gluud C.
      Antioxidant supplements for prevention of gastrointestinal cancer: a systematic review and meta-analysis.
      ]. Recently, in a meta-analysis of 12 randomized clinical trials, Bardia et al. [
      • Bardia A.
      • Tleyjeh I.M.
      • Cerhan J.R.
      • et al.
      Efficacy of antioxidant supplementation in reducing primary cancer incidence and mortality: systematic review and meta-analysis.
      ] reported that antioxidant supplementation did not significantly reduce total cancer incidence or mortality or any site-specific cancer incidence in participants who had neither history of cancer nor precancerous lesions (i.e. primary prevention only). Furthermore, according to the recent report from World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) published in 2007, the strongest evidence, corresponding to judgments of ‘convincing’ or ‘probable’, showed that high-dose beta-carotene supplements in tobacco smokers are a cause of lung cancer and that selenium probably protects against prostate cancer, while there was limited evidence indicating that vitamin A, vitamin E, and selenium protect against squamous cell carcinoma of the skin, prostate cancer, and either lung cancer or colorectal cancer, respectively [
      • World Cancer Research Fund/American Institute for Cancer Research
      Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective.
      ].
      This meta-analysis was conducted to investigate the quantitative preventive effects of the consumption of antioxidant supplements such as vitamins A, C, and E; beta-carotene; and selenium on cancer risks determined via randomized controlled trials by type of prevention (primary or secondary), type of antioxidant, and type of cancer.

      methods

       data sources and keywords

      We searched Medline (PubMed) (1968 to October 2007), Excerpta Medica database (1977 to October 2007), and the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (1953 to October 2007) by using select common keywords related to antioxidant supplements and cancer risk in randomized controlled trials. We also searched the bibliographies of relevant articles in order to identify additional studies. We selected the following keywords for the literature search: ‘retinol’, ‘beta-carotene’, ‘carotenoids’, ‘ascorbic acid’, ‘alpha-tocopherol’, ‘selenium’, ‘vitamin’, or ‘antioxidant’; ‘neoplasm’, ‘cancer’, or ‘carcinoma’; and ‘randomized controlled trials’, ‘randomized clinical trials’, or ‘randomized placebo-controlled trials’.

       selection criteria

      We included randomized controlled trials that reported the preventive effects of antioxidant supplements (beta-carotene; vitamins A, C, and E; and selenium) on cancer risk and compared the results of these trials with those in which placebo or no-intervention groups were used. The main outcome measure was cancer incidence. We excluded studies that were conducted to investigate the treatment effect, not the preventive effect, of antioxidant supplements.

       selection of relevant studies

      Two evaluators (S-KM and YK), who are two of the authors of this study, independently evaluated all the studies retrieved from the databases. Disagreements between evaluators concerning the selected studies were resolved by discussion or in consultation with a third author (WJ). In the case of insufficient or missing data, we contacted the authors of the articles and retrieved the relevant data. From the studies included in the final analysis, we extracted the following data: study name (along with the name of the first author and the year of publication), journal name, country and type of prevention, duration of supplement treatment and follow-up period (years), population (project name), study design (content of intervention), type of cancer (outcome measure), relative risk (RR) with 95% confidence intervals (CIs), and number of cancer/number of participants in each intervention group.

       main analysis

      We estimated the overall effect of antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) administered singly or in combination with other antioxidant supplements on prevention of cancer, compared with placebo administration or no intervention in all 22 trials.

       subgroup meta-analyses

      We evaluated the effects of antioxidant supplements according to the type of prevention, i.e. primary prevention or secondary prevention. Trials involving the healthy populations or patients with specific disease (nonmalignant or premalignant disease such as dysplasia or skin keratosis) were classified as those on primary prevention, and trials involving patients with cancer were classified as those on secondary prevention. Further, the effects of antioxidant supplements were evaluated according to the type of individual antioxidant administered singly and type of cancer.
      We also evaluated the methodological quality of the studies, because studies with low methodological quality tend to overestimate the effect of intervention [
      • Bjelakovic G.
      • Nikolova D.
      • Simonetti R.G.
      • Gluud C.
      Antioxidant supplements for prevention of gastrointestinal cancer: a systematic review and meta-analysis.
      ,
      • Kjaergard L.L.
      • Villumsen J.
      • Gluud C.
      Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses.
      ]. Studies with adequate quality components [generation of the allocation sequence (computer-generated random numbers or similar methods), allocation concealment (central independent unit, sealed envelopes, or similar), double-blinding (identical placebo tablets or similar), and follow-up (number of and reasons for dropouts and withdrawals described)] were classified as having high methodological quality [
      • Bjelakovic G.
      • Nikolova D.
      • Guud L.L.
      • et al.
      Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.
      ,
      • Bjelakovic G.
      • Nikolova D.
      • Simonetti R.G.
      • Gluud C.
      Antioxidant supplements for prevention of gastrointestinal cancer: a systematic review and meta-analysis.
      ,
      • Kjaergard L.L.
      • Villumsen J.
      • Gluud C.
      Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses.
      ]. Studies with one or more unclear or inadequate (not described like the adequate ones above) quality components were classified as having low methodological quality [
      • Bjelakovic G.
      • Nikolova D.
      • Guud L.L.
      • et al.
      Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.
      ,
      • Bjelakovic G.
      • Nikolova D.
      • Simonetti R.G.
      • Gluud C.
      Antioxidant supplements for prevention of gastrointestinal cancer: a systematic review and meta-analysis.
      ,
      • Kjaergard L.L.
      • Villumsen J.
      • Gluud C.
      Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses.
      ].

       statistical analyses

      We estimated the pooled RR with 95% CI on the basis of both the fixed- and random-effects models; the Mantel–Haenszel method was used in the fixed-effects model, and the DerSimonian and Laird method was used in the random-effects model. For the study with a 2 × 2 factorial design, we used the values of the control group and the ones which were calculated by summing up the ones of the remaining antioxidant groups. We estimated heterogeneity (between-studies variability) using the Higgins I2 statistic, which measures the percentage of total variation across studies due to heterogeneity rather than chance. I2 was calculated as follows:
      I2=100%×(Qdf)Q,


      where Q is Cochran's heterogeneity statistic and df is the degrees of freedom corresponding to it. Cochran's Q statistic was calculated as follows:
      Q=(θi-θ)2wi,


      where θi is the RR of each ith study, θ is the pooled RR of all the studies, and wi is the inverse variance of each ith study as a weight. Negative values of I2 are set at zero so that I2 lies between 0% (no observed heterogeneity) and 100% (maximal heterogeneity). An I2 value >50% was considered to indicate substantial heterogeneity. When substantial heterogeneity was not observed, the pooled estimate calculated based on the fixed-effects model was reported. When substantial heterogeneity was observed, the pooled estimate calculated based on the random-effects model was reported.
      We estimated publication bias by using Begg's funnel plot and Egger's test. Funnel plots are scatter plots of the log odds ratios (ORs) of individual studies on the x-axis against 1/standard error (SE) (or SEs or sample size; as a measure of precision) of each study on the y-axis. If a publication bias exists, the plot is asymmetrical. Egger's test is a test for linear regression of the normalized effect estimate (log OR/SE) against its precision (1/SE). If the P value is found to be <0.05 by Egger's test, the presence of a publication bias is considered. We used the Stata SE version 10.0 software package (StataCorp, College Station, TX) for statistical analysis.

      results

       selection of studies

      As shown in Figure 1, 3327 articles were obtained after searching databases and relevant bibliographies. After excluding 533 duplicated articles and 2703 articles that did not satisfy the selection criteria, we reviewed the full texts of 91 articles. Among these, 31 articles [
      • Munoz N.
      • Wahrendorf J.
      • Bang L.J.
      • 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.
      ,
      • Greenberg E.R.
      • Baron J.A.
      • Stukel T.A.
      • et al.
      The Skin Cancer Prevention Study Group. A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin.
      ,
      • Yu S.Y.
      • Zhu Y.J.
      • Li W.G.
      • et al.
      A preliminary report on the intervention trials of primary liver cancer in high-risk populations with nutritional supplementation of selenium in China.
      ,
      • Li J.Y.
      • Taylor P.R.
      • Li B.
      • et al.
      Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia.
      ,
      • The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group
      The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers.
      ,
      • Clark L.C.
      • Combs Jr, G.F.
      • Turnbull B.W.
      • et al.
      Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group.
      ,
      • Jyothirmayi R.
      • Ramadas K.
      • Varghese C.
      • et al.
      Efficacy of vitamin A in the prevention of loco-regional recurrence and second primaries in head and neck cancer.
      ,
      • Omenn G.S.
      • Goodman G.E.
      • Thornquist M.D.
      • et al.
      Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.
      ,
      • Levine N.
      • Moon T.E.
      • Cartmel B.
      • et al.
      Trial of retinol and isotretinoin in skin cancer prevention: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group.
      ,
      • Moon T.E.
      • Levine N.
      • Cartmel B.
      • et al.
      Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group.
      ,
      • Clark L.C.
      • Dalkin B.
      • Krongrad A.
      • et al.
      Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial.
      ,
      • Heinonen O.P.
      • Albanes D.
      • Virtamo J.
      • et al.
      Prostate cancer and supplementation with (alpha)-tocopherol and (beta)-carotene: incidence and mortality in a controlled trial.
      ,
      • Lee I.M.
      • Cook N.R.
      • Manson J.E.
      • et al.
      Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study.
      ,
      • Rautalahti M.T.
      • Virtamo J.R.
      • Taylor P.R.
      • 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.
      ,
      • Albanes D.
      • Malila N.
      • Taylor P.R.
      • et al.
      Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: results from a controlled trial (Finland).
      ,
      • Frieling U.M.
      • Schaumberg D.A.
      • Kupper T.S.
      • et al.
      A randomized, 12-year primary-prevention trial of beta carotene supplementation for nonmelanoma skin cancer in the physician's health study.
      ,
      • Cook N.R.
      • Le I.M.
      • Manson J.E.
      • et al.
      Effects of beta-carotene supplementation on cancer incidence by baseline characteristics in the Physicians’ Health Study (United States).
      ,
      • van Zandwijk N.
      • Dalesio O.
      • Pastorino U.
      • et al.
      EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer.
      ,
      • Virtamo J.
      • Edwards B.K.
      • Virtanen M.
      • et al.
      Effects of supplemental alpha-tocopherol and beta-carotene on urinary tract cancer: incidence and mortality in a controlled trial (Finland).
      ,
      • Mayne S.T.
      • Cartmel B.
      • Baum M.
      • et al.
      Randomized trial of supplemental (beta)-carotene to prevent second head and neck cancer.
      ,
      MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      ,
      • Duffield-Lillico A.J.
      • Reid M.E.
      • Turnbull B.W.
      • et al.
      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.
      ,
      • Malila N.
      • Taylor P.R.
      • Virtanen M.J.
      • et al.
      Effects of alpha-tocopherol and beta-carotene supplementation on gastric cancer incidence in male smokers (ATBC Study, Finland).
      ,
      • Toma S.
      • Bonelli L.
      • Sartoris A.
      • et al.
      Beta-carotene supplementation in patients radically treated for stage I-II head and neck cancer: results of a randomized trial.
      ,
      • Virtamo J.
      Incidence of cancer and mortality following (alpha)-tocopherol and (beta)-carotene supplementation: a postintervention follow-up.
      ,
      • Bairati I.
      • Meyer F.
      • Gelinas M.
      • et al.
      A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients.
      ,
      • Lee I.M.
      • Cook N.R.
      • Gaziano J.M.
      • et al.
      Vitamin E in the primary prevention of cardiovascular disease and cancer. the Women's Health Study: a randomized controlled trial.
      ,
      • Lonn E.
      Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial.
      ,
      • Meyer F.
      • Galan P.
      • Douville P.
      • et al.
      Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial.
      ,
      • Wright M.E.
      • Virtamo J.
      • Hartman A.M.
      • et al.
      Effects of alpha-tocopherol and beta-carotene supplementation on upper aerodigestive tract cancers in a large, randomized controlled trial.
      ,
      • Dreno B.
      • Euvrard S.
      • Frances C.
      • et al.
      Effect of selenium intake on the prevention of cutaneous epithelial lesions in organ transplant recipients.
      ] on 22 randomized controlled trials (A trial by Yu [
      • Yu S.Y.
      • Zhu Y.J.
      • Li W.G.
      • et al.
      A preliminary report on the intervention trials of primary liver cancer in high-risk populations with nutritional supplementation of selenium in China.
      ], shown in Table 1, was classified into two individual randomized controlled trials because it was conducted for two different subpopulations) were included in the final analysis.
      Figure 1
      Figure 1Flow diagram of identification of relevant studies.
      Table 1Characteristics of the studies of antioxidant supplements and cancer risk included in the final analysis (n = 31)
      Study name (No. of reference)JournalCountry; type of preventionDuration of supplement treatment/follow-up period (years)Population (project name)Design; interventionsType of cancer; outcome measureRR (95% CI)No. of cancer/no. of participants in each group
      1Munoz, 1985 [
      • Munoz N.
      • Wahrendorf J.
      • Bang L.J.
      • 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.
      ]
      LancetChina; primary1.1/1.1610 subjectsParallel; 15 mg of retinol (vitamin A), 200 mg of riboflavin (vitamin B2), and 50 mg of zinc versus placebo per dayEsophageal cancer; incidenceNot statedPlacebo: 3/305; vitamin A (plus vitamin B2 and zinc): 4/305
      2Greenberg, 1990 [
      • Greenberg E.R.
      • Baron J.A.
      • Stukel T.A.
      • et al.
      The Skin Cancer Prevention Study Group. A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin.
      ]
      The New England Journal of MedicineUnited States; secondary5/51805 nonmelanoma skin cancer patientsParallel; 50 mg of beta-carotene or placebo per dayNew nonmelanoma skin cancer; incidence1.05 (0.91–1.22)Placebo: 340/892; beta-carotene: 362/913
      3Yu, 1991 [
      • Yu S.Y.
      • Zhu Y.J.
      • Li W.G.
      • 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 researchChina; primary2 and 4/2 and 42474 members of families with high risk of primary liver cancer and 226 hepatitis B virus surface antigen carriersParallel; 200 μg of selenium versus placebo per dayPrimary liver cancer; incidenceYu, 1991 (1): members of families with high risk of cancer: placebo: 1.26%; selenium: 0.69% (P < 0.05)Yu, 1991 (1): placebo: 13/1030; selenium: 10/1444
      Yu, 1991 (2): HBV Ag carriers: placebo: 4.4%; selenium; 0% (P < 0.05)Yu, 1991 (2): placebo: 5/113; selenium: 0/113
      4NIT, 1993 [
      • Li J.Y.
      • Taylor P.R.
      • Li B.
      • et al.
      Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia.
      ]
      China; primary6/63318 persons with cytologic evidence of esophageal dysplasia (the dysplasia trial, NITs in Linxian, China)Parallel; 15 mg of beta-carotene and a combination of 10 000 IU of vitamin A, 180 mg of vitamin C, 60 IU of vitamin E, 50 μg of selenium, etc. placebo per dayEsophagus, stomach, and other sties; incidence1.01 (0.841.22)Placebo: 221/1661; antioxidants (beta-carotene and the combination of vitamin A, vitamin C, vitamin E, selenium, etc.): 227/1657
      5ATBC, 1994 [
      • The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group
      The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers.
      ]
      The New England Journal of MedicineFinland; primary6.1/6.129 133 male smokers (ATBC)2 × 2; 50 mg of alpha-tocopherol (vitamin E), 20 mg of beta-carotene, and placebo per dayLung cancer; incidenceAlpha-tocopherol:-2% (-14% to 12%); beta-carotene: 18% (3%–36%)Placebo: 209/7287; antioxidants (vitamin E and/or beta-carotene): 686/21 846
      6NPCT, 1996 [
      • Clark L.C.
      • Combs Jr, G.F.
      • Turnbull B.W.
      • et al.
      Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group.
      ]
      United States; secondary4.5/6.41312 patients with a history of basal cell or squamous cell carcinomas of the skin (NPCT)Parallel; 200 μg of selenium placebo per daySkin cancers(basal cell and squamous cell carcinomas) and other cancers; incidenceNPCT, 1996(1): basal cell carcinoma:1.10 (0.951.28)squamous cell carcinoma:1.14 (0.931.39)NPCT, 1996 (1): placebo: 540/659selenium: 595/653
      NPCT, 1996 (2): other cancers: 0.63 (0.47–0.85)NPCT, 1996 (2): placebo: 119/659; selenium: 77/653
      7Jyothirmayi, 1996 [
      • Jyothirmayi R.
      • Ramadas K.
      • Varghese C.
      • et al.
      Efficacy of vitamin A in the prevention of loco-regional recurrence and second primaries in head and neck cancer.
      ]
      European journal of cancer. Part B, Oral oncologyIndia; secondary1/3106 head and neck cancer patients who had achieved complete regression of their diseaseParallel; 200 000 IU of retinyl palmitate (vitamin A) versus placebo per weekLocoregional recurrence and second primary cancers; incidenceNot presentedPlacebo: 7/50; vitamin A: 11/56
      8CARET, 1996 [
      • Omenn G.S.
      • Goodman G.E.
      • Thornquist M.D.
      • et al.
      Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.
      ]
      Journal of the National Cancer InstituteUnited States; primary4/418 314 men and women at high risk of developing lung ancer: 14 254 general smokers and 4060 asbestos-exposed male workers (the Beta-Carotene and Retinol Efficacy Trial: CARET)Parallel; A combination of 30 mg beta-carotene and 25 000 IU retinyl palmitate (vitamin A) versus placebo per dayLung cancer; incidence1.36 (1.07–1.73)Placebo: 159/8894; antioxidants (A combination of beta-carotene and vitamin A): 229/9420
      9Levine, 1997 [
      • Levine N.
      • Moon T.E.
      • Cartmel B.
      • et al.
      Trial of retinol and isotretinoin in skin cancer prevention: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group.
      ]
      Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive OncologyUnited States; secondary3/3525 participants with a history of at least four BCCs and/or cutaneous SCCsParallel; 25 000 U retinol (vitamin A) versus placebo per dayBCC or cutaneous SCC; incidencePresented using the proportion of occurrence; retinol group: 32.8%; placebo group: 32.8%Placebo: 41/174; vitamin A: 41/173
      10Skin Cancer Prevention Study, 1997 [
      • Moon T.E.
      • Levine N.
      • Cartmel B.
      • et al.
      Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group.
      ]
      Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive OncologyUnited States; primary and secondary5/52297 subjects with a history of at least 10 actinic keratosis and at most two prior skin cancers (the SKICAP-AK: Skin Cancer Prevention Studies-Actinic Keratosis)Parallel; 25 000 IU retinol versus placebo per dayBCC or SCC; incidenceSCC: 0.74 (0.56–0.99); BCC: 1.06 (0.86–1.32)Placebo: 400/1140; vitamin A: 378/1157
      11Clark, 1998 [
      • Clark L.C.
      • Dalkin B.
      • Krongrad A.
      • et al.
      Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial.
      ]
      British Journal of UrologyUnited States; secondary4.5/6.5974 men with a history of either a basal cell or a squamous cell carcinomaParallel; 200 μg of selenium versus placebo per dayProstate cancer; incidence0.37 (P = 0.002)Placebo: 35/495; selenium: 13/479
      12ATBC, 1998 [
      • Heinonen O.P.
      • Albanes D.
      • Virtamo J.
      • et al.
      Prostate cancer and supplementation with (alpha)-tocopherol and (beta)-carotene: incidence and mortality in a controlled trial.
      ]
      Journal of the National Cancer InstituteFinland; primary6.1/6.129 133 male smokers (ATBC)2 × 2; 50 mg of alpha-tocopherol (vitamin E), 20 mg of beta-carotene, and placebo per dayProstate cancer; incidenceAlpha-tocopherol: -32% (-47% to -12%); beta-carotene: 23% (-4% to 59%)Placebo: 67/7287; antioxidants (vitamin E and/or beta-carotene): 181/21 846
      13WHS, 1999 [
      • Lee I.M.
      • Cook N.R.
      • Manson J.E.
      • et al.
      Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study.
      ]
      Journal of the National Cancer InstituteUnited States; primary2.1/4.139 876 apparently healthy USA women aged at least 45 years (WHS)2 × 2; 600 IU of natural-source vitamin E, aspirin, and placebo on alternate daysAll cancers; incidence1.03 (0.89–1.18)Placebo: 369/19 937; vitamin E: 378/19 939
      14ATBC, 1999 [
      • Rautalahti M.T.
      • Virtamo J.R.
      • Taylor P.R.
      • 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.
      ]
      CancerFinland; primary6.1/6.129 133 male smokers (ATBC)2 × 2; 50 mg of alpha-tocopherol (vitamin E), 20 mg of beta-carotene, and placebo per daysPancreatic carcinoma; incidenceAlpha-tocopherol: 34% (-12% to 105%); beta-carotene: -25% (-51% to 14%)Placebo: 26/7287; antioxidants (vitamin E and/or beta-carotene): 63/21 846
      15ATBC, 2000 [
      • Albanes D.
      • Malila N.
      • Taylor P.R.
      • et al.
      Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: results from a controlled trial (Finland).
      ]
      Cancer causes & control: CCCFinland; primary6.1/6.129 133 male smokers (ATBC)2 × 2; 50 mg of alpha-tocopherol (vitamin E), 20 mg of beta-carotene, and placebo per dayColorectal cancer; incidenceAlpha-tocopherol: 0.78 (0.55–1.09); beta-carotene: 1.05 (0.75–1.47)Placebo: 37/7287; antioxidants (vitamin E and/or beta-carotene): 98/21 846
      16PHS, 2000 [
      • Frieling U.M.
      • Schaumberg D.A.
      • Kupper T.S.
      • et al.
      A randomized, 12-year primary-prevention trial of beta carotene supplementation for nonmelanoma skin cancer in the physician's health study.
      ]
      Archives of dermatologyUnited States; primary12/1222 071 male physicians (PHS)Parallel; 50 mg of beta-carotene versus placebo on alternate daysNonmelanoma skin cancer; incidence0.98 (0.92–1.05)Placebo: 1821/10 943; beta-carotene: 1786/10 941
      17PHS, 2000 [
      • Cook N.R.
      • Le I.M.
      • Manson J.E.
      • et al.
      Effects of beta-carotene supplementation on cancer incidence by baseline characteristics in the Physicians’ Health Study (United States).
      ]
      Cancer causes & control: CCCUnited States; primary12.9/12.922 071 male physicians (PHS)Parallel; 50 mg of beta-carotene versus placebo on alternate daysMalignant neoplasm excluding nonmelanoma skin cancer; incidence1.00 (0.9–1.0)Placebo: 1353/11 035; beta-carotene: 1314/11 036
      18EUROSCAN, 2000 [
      • van Zandwijk N.
      • Dalesio O.
      • Pastorino U.
      • et al.
      EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer.
      ]
      Journal of the National Cancer InstituteEuropean Union; secondary2/4.12592 patients with head and neck cancer (The EUROSCAN study)2 × 2; 300 000 IU for 1 year followed by 150 000 IU for a second year of retinyl palmitate (vitamin A), 600 mg of NAC, and placebo per dayRecurrence, distant metastasis, and second primary tumor; incidenceNo statistically significant difference observedControl (no drugs): 183/641; antioxidant (vitamin A and/or NAC): 401/1290
      19ATBC, 2000 [
      • Virtamo J.
      • Edwards B.K.
      • Virtanen M.
      • 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: CCCFinland; primary6.1/6.129 133 male smokers (ATBC)2 × 2; 50 mg of alpha-tocopherol (vitamin E), 20 mg of beta-carotene, and placebo per dayUrinary tract cancer; incidenceUrothelial cancer (bladder, renal pelvis, and ureter): alpha-tocopherol group: 1.1 (0.8–1.5); beta-carotene group: 1.0 (0.7–1.3)Placebo: 64/7287; antioxidants (vitamin E and/or beta-carotene): 207/21 846
      Renal cell cancer: alpha-tocopherol group: 1.1 (0.7–1.6); beta-carotene: 0.8 (0.6–1.3)
      20Mayne, 2001 [
      • Mayne S.T.
      • Cartmel B.
      • Baum M.
      • et al.
      Randomized trial of supplemental (beta)-carotene to prevent second head and neck cancer.
      ]
      Cancer researchUnited States; secondary4.3/4.3264 patients who had been curatively treated for a recent early-stage squamous cell carcinoma of the head and neckParallel; 50 mg of beta-carotene versus placebo per dayHead and neck cancer; incidence0.90 (0.56–1.45)Placebo: 34/129; beta-carotene: 33/135
      21HPSCG, 2002 [
      MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      ]
      LancetUK; primary5/520 536 adults with coronary disease, other occlusive arterial disease, or diabetesParallel; A combination of 600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene versus placebo per dayAll cancers; incidenceAny cancer except nonmelanoma skin: 0.98 (0.89–1.08)Placebo: 1045/10 267; antioxidants (vitamin E, vitamin C, and beta-carotene): 1017/10 269
      Nonmelanoma skin cancer: vitamin group (2.1%); placebo group (2.2%)
      22NPCT, 2002 [
      • Duffield-Lillico A.J.
      • Reid M.E.
      • Turnbull B.W.
      • et al.
      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: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive OncologyUnited States; secondary7/7 (about)1312 patients with a history of basal cell or squamous cell carcinomas of the skin (NPCT)Parallel; 200 μg of selenium versus placebo per dayAll cancers; incidence0.75 (0.58–0.97) (adjusted for age, gender, and smoking at randomization)Placebo: 137/621; selenium: 105/629
      23ATBC, 2002 [
      • Malila N.
      • Taylor P.R.
      • Virtanen M.J.
      • et al.
      Effects of alpha-tocopherol and beta-carotene supplementation on gastric cancer incidence in male smokers (ATBC Study, Finland).
      ]
      Cancer causes & control: CCCFinland; primary6.1/6.129 133 male smokers (ATBC)2 × 2; 50 mg of alpha-tocopherol (vitamin E), 20 mg of beta-carotene, and placebo per dayGastric cancer; incidenceAlpha-tocopherol: 1.21 (0.85–1.74); beta-carotene: 1.26 (0.88–1.80)Placebo: 24/7287; antioxidants (vitamin E and/or beta-carotene): 102/21 846
      24IHNCSG, 2003 [
      • Toma S.
      • Bonelli L.
      • Sartoris A.
      • et al.
      Beta-carotene supplementation in patients radically treated for stage I-II head and neck cancer: results of a randomized trial.
      ]
      Oncology reportsItaly; secondary3/5.1214 patients with a radically treated stage I–II squamous head and neck tumors (IHNCSG)Parallel; 75 mg of beta-carotene for 3-month cycles within 1-month intercycle intervals versus placebo per dayRelapse of the primary or second primary tumors; incidenceRelapse of the primary tumor: 1.14 (0.28–3.44); second primary tumor: 0.99 (0.28–3.44)Control: 14/110; beta-carotene: 15/104
      25ATBC, 2003 [
      • Virtamo J.
      Incidence of cancer and mortality following (alpha)-tocopherol and (beta)-carotene supplementation: a postintervention follow-up.
      ]
      JAMA: the journal of the American Medical AssociationFinland; primary6.1/6.129 133 male smokers (ATBC)2 × 2; 50 mg of alpha-tocopherol (vitamin E), 20 mg of beta-carotene, and placebo per dayAll cancers: incidenceNot stated for all cancers, but for individual cancersPlacebo: 551/7287; antioxidants (vitamin E and/or beta-carotene): 1719/21 846
      26Bairati, 2005 [
      • Bairati I.
      • Meyer F.
      • Gelinas M.
      • et al.
      A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients.
      ]
      Journal of the National Cancer InstituteCanada; secondary4.3/4.3540 patients with stage I or II head and neck cancer treated by radiation therapyParallel; 400 IU of alpha-tocopherol (vitamin E) and 30 mg of beta-carotene versus placebo per daySecond primary cancer; incidence2.88 (1.56–5.31)Placebo: 50/267; antioxidants (vitamin E and beta-carotene): 63/273
      27WHS, 2005 [
      • Lee I.M.
      • Cook N.R.
      • Gaziano J.M.
      • et al.
      Vitamin E in the primary prevention of cardiovascular disease and cancer. the Women's Health Study: a randomized controlled trial.
      ]
      JAMA: the journal of the American Medical AssociationUnited States; primary10.1/10.139 876 apparently healthy USA women aged at least 45 years (WHS)2 × 2; 600 IU of natural-source vitamin E, aspirin, and placebo on alternate daysTotal invasive cancer; incidence1.01 (0.94–1.08)Placebo: 1428/19 939; vitamin E: 1437/19 937
      28HOPE, 2005 [
      • Lonn E.
      Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial.
      ]
      JAMA: the journal of the American Medical AssociationCanada; primary7/79541 patients at least 55 years with vascular disease or diabetes (the initial HOPE trial)Parallel; 400 IU of natural-source vitamin E versus placebo per dayAll cancers; incidence0.94 (0.84–1.06)Placebo: 586/4780; vitamin E: 552/4761
      29SUVIMAX, 2005 [
      • Meyer F.
      • Galan P.
      • Douville P.
      • et al.
      Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial.
      ]
      International journal of cancer. Journal international du cancerCanada; primary8/95141 men; 107 men among 5141 were withdrawn early (supplementation en vitamins et mineraux antioxydants: The SUVIMAX trial)Parallel; A combination of 120 mg vitamin C, 30 mg alpha-tocopherol, 6 mg beta-carotene, 100 μg selenium, and 20 mg zinc versus placebo per dayProstate cancer; incidence0.88 (0.60–1.29)Placebo: 54/2512; antioxidants (vitamin C, vitamin E, beta-carotene, and selenium): 49/2522
      30ATBC, 2007 [
      • Wright M.E.
      • Virtamo J.
      • Hartman A.M.
      • et al.
      Effects of alpha-tocopherol and beta-carotene supplementation on upper aerodigestive tract cancers in a large, randomized controlled trial.
      ]
      CancerFinland; primary6.1/6.129 133 male smokers (ATBC)2 × 2; 50 mg of alpha-tocopherol (vitamin E), 20 mg of beta-carotene, and placebo per dayUpper aerodigestive tract cancer; incidenceAlpha-tocopherol: 1.21 (0.85–1.74); beta-carotene: 1.26 (0.88–1.80)Placebo: 42/7287; antioxidants (vitamin E and/or beta-carotene): 103/21 846
      31Dreno, 2007 [
      • Dreno B.
      • Euvrard S.
      • Frances C.
      • et al.
      Effect of selenium intake on the prevention of cutaneous epithelial lesions in organ transplant recipients.
      ]
      European journal of dermatology: EJDFrance; primary3/5184 recent organ transplant recipientsParallel; 200 μg of selenium versus placebo per daySkin cancer; incidence3.08 (P = 0.15)Placebo: 2/93; selenium: 6/91
      RR, relative risk; CI, confidence interval; HBV Ag, hepatitis B virus antigen; NIT, nutrition intervention trial; ATBC, Alpha-Tocopherol Beta-carotene Cancer Prevention Study; BCCs, basal cell carcinomas; SCCs, squamous cell carcinomas; WHS, Women's Health Study; PHS, Physicians’ Health Study; NAC, N-acetylcysteine; HPSCG, Heart Protection Study Collaborative Group; IHNCSG, Italian Head and Neck Chemoprevention Study Group; HOPE, Heart Outcomes Prevention Evaluation; CARET, beta-carotene and retinol efficacy trail; EUROSCAN; European study on chemoprevention with vitamin A and N-acetylcysteine; SUVIMAX, supplementation en vitamins et mineraux antioxydants.
      We excluded 60 articles [
      • Bjelakovic G.
      • Nikolova D.
      • Simonetti R.G.
      • Gluud C.
      Antioxidant supplements for prevention of gastrointestinal cancer: a systematic review and meta-analysis.
      ,
      • Blot W.J.
      • Li J.Y.
      • Taylor P.R.
      • et al.
      Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population.
      ,
      • Moon T.E.
      • Levine N.
      • Cartmel B.
      • Bangert J.L.
      Retinoids in prevention of skin cancer.
      ,
      • Kirsh V.A.
      • Hayes R.B.
      • Mayne S.T.
      • et al.
      Supplemental and dietary vitamin E, (beta)-carotene, and vitamin C intakes and prostate cancer risk.
      ,
      • Goodman G.E.
      • Omenn G.S.
      • Thornquist M.D.
      • et al.
      The Carotene and Retinol Efficacy Trial (CARET) to prevent lung cancer in high-risk populations: pilot study with cigarette smokers.
      ,
      • Omenn G.S.
      • Goodman G.
      • Thornquist M.
      • et al.
      The (beta)-carotene and retinol efficacy trial (CARET) for chemoprevention of lung cancer in high risk populations: smokers and asbestos-exposed workers.
      ,
      • Christen W.G.
      • Gaziano J.M.
      • Hennekens C.H.
      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.
      ,
      • Costello A.J.
      A randomized, controlled chemoprevention trial of selenium in familial prostate cancer: rationale, recruitment, and design issues.
      ,
      • Dawsey S.M.
      • Wang G.Q.
      • Taylor P.R.
      • 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.
      ,
      • Mark S.D.
      • Liu S.F.
      • Li J.Y.
      • et al.
      The effect of vitamin and mineral supplementation on esophageal cytology: results from the Linxian Dysplasia Trial.
      ,
      • Albanes D.
      • Heinonen O.P.
      • Huttunen J.K.
      • et al.
      Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study.
      ,
      • Blot W.J.
      • Li J.Y.
      • Taylor P.R.
      • et al.
      The Linxian trials: mortality rates by vitamin-mineral intervention group.
      ,
      • Albanes D.
      • Heinonen O.P.
      • Taylor P.R.
      • 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.
      ,
      • Hennekens C.H.
      • Buring J.E.
      • Manson J.E.
      • et al.
      Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease.
      ,
      • Combs Jr, G.F.
      • Clark L.C.
      • Turnbull B.W.
      Reduction of cancer risk with an oral supplement of selenium.
      ,
      • Yu S.Y.
      • Zhu Y.J.
      • Li W.G.
      Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong.
      ,
      • Cook N.R.
      • Stampfer M.J.
      • Ma J.
      • et al.
      Beta-carotene supplementation for patients with low baseline levels and decreased risks of total and prostate carcinoma.
      ,
      • Reid M.E.
      • Duffield-Lillico A.J.
      • Garland L.
      • et al.
      Selenium supplementation and lung cancer incidence: an update of the nutritional prevention of cancer trial.
      ,
      • Duffield-Lillico A.J.
      • Dalkin B.L.
      • Reid M.E.
      • et al.
      Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial.
      ,
      • Duffield-Lillico A.J.
      • Slate E.H.
      • Reid M.E.
      • et al.
      Selenium supplementation and secondary prevention of nonmelanoma skin cancer in a randomized trial.
      ,
      • Hercberg S.
      • Czernichow S.
      • Galan P.
      Antioxidant vitamins and minerals in prevention of cancers: lessons from the SU.VI.MAX study.
      ,
      • Kamangar F.
      • Qiao Y.L.
      • Yu B.
      • et al.
      Lung cancer chemoprevention: a randomized, double-blind trial in Linxian, China.
      ,
      • Omenn G.S.
      • Goodman G.E.
      • Thornquist M.D.
      • et al.
      Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.
      ,
      • de Vet H.C.
      • Knipschild P.G.
      • Willebrand D.
      • et al.
      The effect of beta-carotene on the regression and progression of cervical dysplasia: a clinical experiment.
      ,
      • Correa P.
      • Fontham E.T.
      • Bravo J.C.
      • et al.
      Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-Helicobacter pylori therapy.
      ,
      • Benner S.E.
      • Lippman S.M.
      • Hong W.K.
      Retinoid chemoprevention of second primary tumors.
      ,
      • Benner S.E.
      • Pajak T.F.
      • Lippman S.M.
      • et al.
      Prevention of second primary tumors with isotretinoin in patients with squamous cell carcinoma of the head and neck: long-term follow-up.
      ,
      • Bolla M.
      • Lefur R.
      • Ton Van J.
      • et al.
      Prevention of second primary tumours with etretinate in squamous cell carcinoma of the oral cavity and oropharynx. Results of a multicentric double-blind randomised study.
      ,
      • Costa A.
      • De Palo G.
      • Decensi A.
      • et al.
      Retinoids in cancer chemoprevention. Clinical trials with the synthetic analogue fenretinide.
      ,
      • Ansari M.S.
      • Gupta N.P.
      A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer.
      ,
      • Perry C.F.
      • Stevens M.
      • Rabie I.
      • et al.
      Chemoprevention of head and neck cancer with retinoids: a negative result.
      ,
      • Khuri F.R.
      • Lee J.J.
      • Lippman S.M.
      • et al.
      Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients.
      ,
      • Blot W.J.
      • Li J.Y.
      • Taylor P.R.
      • Li B.
      Lung cancer and vitamin supplementation.
      ,
      • Blumberg J.
      • Block G.
      The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study in Finland.
      ,
      • Buiatti E.
      Prevention trials on oesophageal and stomach cancer.
      ,
      • Taylor P.R.
      • Li B.
      • Dawsey S.M.
      • et al.
      Prevention of esophageal cancer: the nutrition intervention trials in Linxian, China. Linxian Nutrition Intervention Trials Study Group.
      ,
      • Wang G.Q.
      • Dawsey S.M.
      • Li J.Y.
      • 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.
      ,
      • Brawer M.K.
      • Ellis W.J.
      Chemoprevention for prostate cancer.
      ,
      • Bolla M.
      • Laplanche A.
      • Lefur R.
      • et al.
      Prevention of second primary tumours with a second generation retinoid in squamous cell carcinoma of oral cavity and oropharynx: long term follow-up.
      ,
      • Brawley O.W.
      • Thompson I.M.
      The chemoprevention of prostate cancer and the Prostate Cancer Prevention Trial.
      ,
      • Blot W.J.
      Vitamin/mineral supplementation and cancer risk: international chemoprevention trials.
      ,
      • Biasco G.
      • Paganelli G.M.
      European trials on dietary supplementation for cancer prevention.
      ,
      • Del Mar C.
      Does daily use of sunscreen or beta-carotene supplements prevent skin cancer in healthy adults?.
      ,
      • Bollschweiler E.
      • Wolfgarten E.
      • Nowroth T.
      • et al.
      Vitamin intake and risk of subtypes of esophageal cancer in Germany.
      ,
      • Holick C.N.
      • Michaud D.S.
      • Stolzenberg-Solomon R.
      • et al.
      Dietary carotenoids, serum (beta)-carotene, and retinol and risk of lung cancer in the alpha-tocopherol, beta-carotene cohort study.
      ,
      • Malila N.
      • Virtamo J.
      • Virtanen M.
      • et al.
      Dietary and serum alpha-tocopherol, beta-carotene and retinol, and risk for colorectal cancer in male smokers.
      ,
      • Michaud D.S.
      • Pietinen P.
      • Taylor P.R.
      • et al.
      Intakes of fruits and vegetables, carotenoids and vitamins A, E, C in relation to the risk of bladder cancer in the ATBC cohort study.
      ,
      • Akbaraly N.T.
      • Arnaud J.
      • Hininger-Favier I.
      • et al.
      Selenium and mortality in the elderly: results from the EVA study.
      ,
      • Cullen M.R.
      • Barnett M.J.
      • Balmes J.R.
      • et al.
      Predictors of lung cancer among asbestos-exposed men in the {beta}-carotene and retinol efficacy trial.
      ,
      • Buring J.E.
      Aspirin prevents stroke but not MI in women; vitamin E has no effect on CV disease or cancer.
      ,
      • Zhang S.M.
      • Moore S.C.
      • Lin J.
      • et al.
      Folate, vitamin B6, multivitamin supplements, and colorectal cancer risk in women.
      ,
      • Bairati I.
      • Brochet F.
      • Roy J.
      • et al.
      ,
      • Combs Jr, G.F.
      • Clark L.C.
      • Turnbull B.W.
      Reduction of cancer mortality and incidence by selenium supplementation.
      ,
      • de Klerk N.H.
      • Musk A.W.
      • Ambrosini G.L.
      • et al.
      Vitamin A and cancer prevention II: comparison of the effects of retinol and beta-carotene.
      ,
      • Hartman T.J.
      • Albanes D.
      • Pietinen P.
      • et al.
      The association between baseline vitamin E, selenium, and prostate cancer in the alpha-tocopherol, beta-carotene cancer prevention study.
      ,
      • Takagi H.
      • Kakizaki S.
      • Sohara N.
      • et al.
      Pilot clinical trial of the use of alpha-tocopherol for the prevention of hepatocellular carcinoma in patients with liver cirrhosis.
      ,
      • Goodman G.E.
      • Thornquist M.D.
      • Balmes J.
      • 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.
      ,
      • Galan P.
      • Briancon S.
      • Favier A.
      • et al.
      Antioxidant status and risk of cancer in the SU.VI.MAX study: is the effect of supplementation dependent on baseline levels?.
      ,
      • Stranges S.
      • Marshall J.R.
      • Trevisan M.
      • et al.
      Effects of selenium supplementation on cardiovascular disease incidence and mortality: secondary analyses in a randomized clinical trial.
      ] because they lacked sufficient data [
      • Blot W.J.
      • Li J.Y.
      • Taylor P.R.
      • et al.
      Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population.
      ,
      • Moon T.E.
      • Levine N.
      • Cartmel B.
      • Bangert J.L.
      Retinoids in prevention of skin cancer.
      ,
      • Kirsh V.A.
      • Hayes R.B.
      • Mayne S.T.
      • et al.
      Supplemental and dietary vitamin E, (beta)-carotene, and vitamin C intakes and prostate cancer risk.
      ], described only the study protocol or rationale [
      • Goodman G.E.
      • Omenn G.S.
      • Thornquist M.D.
      • et al.
      The Carotene and Retinol Efficacy Trial (CARET) to prevent lung cancer in high-risk populations: pilot study with cigarette smokers.
      ,
      • Omenn G.S.
      • Goodman G.
      • Thornquist M.
      • et al.
      The (beta)-carotene and retinol efficacy trial (CARET) for chemoprevention of lung cancer in high risk populations: smokers and asbestos-exposed workers.
      ,
      • Christen W.G.
      • Gaziano J.M.
      • Hennekens C.H.
      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.
      ,
      • Costello A.J.
      A randomized, controlled chemoprevention trial of selenium in familial prostate cancer: rationale, recruitment, and design issues.
      ], had identical populations and study results [
      • Dawsey S.M.
      • Wang G.Q.
      • Taylor P.R.
      • 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.
      ,
      • Mark S.D.
      • Liu S.F.
      • Li J.Y.
      • et al.
      The effect of vitamin and mineral supplementation on esophageal cytology: results from the Linxian Dysplasia Trial.
      ,
      • Albanes D.
      • Heinonen O.P.
      • Huttunen J.K.
      • et al.
      Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study.
      ,
      • Blot W.J.
      • Li J.Y.
      • Taylor P.R.
      • et al.
      The Linxian trials: mortality rates by vitamin-mineral intervention group.
      ,
      • Albanes D.
      • Heinonen O.P.
      • Taylor P.R.
      • 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.
      ,
      • Hennekens C.H.
      • Buring J.E.
      • Manson J.E.
      • et al.
      Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease.
      ,
      • Combs Jr, G.F.
      • Clark L.C.
      • Turnbull B.W.
      Reduction of cancer risk with an oral supplement of selenium.
      ,
      • Yu S.Y.
      • Zhu Y.J.
      • Li W.G.
      Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong.
      ,
      • Cook N.R.
      • Stampfer M.J.
      • Ma J.
      • et al.
      Beta-carotene supplementation for patients with low baseline levels and decreased risks of total and prostate carcinoma.
      ,
      • Reid M.E.
      • Duffield-Lillico A.J.
      • Garland L.
      • et al.
      Selenium supplementation and lung cancer incidence: an update of the nutritional prevention of cancer trial.
      ,
      • Duffield-Lillico A.J.
      • Dalkin B.L.
      • Reid M.E.
      • et al.
      Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial.
      ,
      • Duffield-Lillico A.J.
      • Slate E.H.
      • Reid M.E.
      • et al.
      Selenium supplementation and secondary prevention of nonmelanoma skin cancer in a randomized trial.
      ,
      • Hercberg S.
      • Czernichow S.
      • Galan P.
      Antioxidant vitamins and minerals in prevention of cancers: lessons from the SU.VI.MAX study.
      ,
      • Kamangar F.
      • Qiao Y.L.
      • Yu B.
      • et al.
      Lung cancer chemoprevention: a randomized, double-blind trial in Linxian, China.
      ,
      • Omenn G.S.
      • Goodman G.E.
      • Thornquist M.D.
      • et al.
      Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.
      ], included precancerous lesions as outcome measure [
      • de Vet H.C.
      • Knipschild P.G.
      • Willebrand D.
      • et al.
      The effect of beta-carotene on the regression and progression of cervical dysplasia: a clinical experiment.
      ,
      • Correa P.
      • Fontham E.T.
      • Bravo J.C.
      • et al.
      Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-Helicobacter pylori therapy.
      ], contained supplements not relevant to the study subject [
      • Costello A.J.
      A randomized, controlled chemoprevention trial of selenium in familial prostate cancer: rationale, recruitment, and design issues.
      ,
      • Benner S.E.
      • Lippman S.M.
      • Hong W.K.
      Retinoid chemoprevention of second primary tumors.
      ,
      • Benner S.E.
      • Pajak T.F.
      • Lippman S.M.
      • et al.
      Prevention of second primary tumors with isotretinoin in patients with squamous cell carcinoma of the head and neck: long-term follow-up.
      ,
      • Bolla M.
      • Lefur R.
      • Ton Van J.
      • et al.
      Prevention of second primary tumours with etretinate in squamous cell carcinoma of the oral cavity and oropharynx. Results of a multicentric double-blind randomised study.
      ,
      • Costa A.
      • De Palo G.
      • Decensi A.
      • et al.
      Retinoids in cancer chemoprevention. Clinical trials with the synthetic analogue fenretinide.
      ,
      • Ansari M.S.
      • Gupta N.P.
      A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer.
      ,
      • Perry C.F.
      • Stevens M.
      • Rabie I.
      • et al.
      Chemoprevention of head and neck cancer with retinoids: a negative result.
      ,
      • Khuri F.R.
      • Lee J.J.
      • Lippman S.M.
      • et al.
      Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients.
      ], or did not include randomized clinical trials [
      • Bjelakovic G.
      • Nikolova D.
      • Simonetti R.G.
      • Gluud C.
      Antioxidant supplements for prevention of gastrointestinal cancer: a systematic review and meta-analysis.
      ,
      • Blot W.J.
      • Li J.Y.
      • Taylor P.R.
      • Li B.
      Lung cancer and vitamin supplementation.
      ,
      • Blumberg J.
      • Block G.
      The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study in Finland.
      ,
      • Buiatti E.
      Prevention trials on oesophageal and stomach cancer.
      ,
      • Taylor P.R.
      • Li B.
      • Dawsey S.M.
      • et al.
      Prevention of esophageal cancer: the nutrition intervention trials in Linxian, China. Linxian Nutrition Intervention Trials Study Group.
      ,
      • Wang G.Q.
      • Dawsey S.M.
      • Li J.Y.
      • 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.
      ,
      • Brawer M.K.
      • Ellis W.J.
      Chemoprevention for prostate cancer.
      ,
      • Bolla M.
      • Laplanche A.
      • Lefur R.
      • et al.
      Prevention of second primary tumours with a second generation retinoid in squamous cell carcinoma of oral cavity and oropharynx: long term follow-up.
      ,
      • Brawley O.W.
      • Thompson I.M.
      The chemoprevention of prostate cancer and the Prostate Cancer Prevention Trial.
      ,
      • Blot W.J.
      Vitamin/mineral supplementation and cancer risk: international chemoprevention trials.
      ,
      • Biasco G.
      • Paganelli G.M.
      European trials on dietary supplementation for cancer prevention.
      ,
      • Del Mar C.
      Does daily use of sunscreen or beta-carotene supplements prevent skin cancer in healthy adults?.
      ,
      • Bollschweiler E.
      • Wolfgarten E.
      • Nowroth T.
      • et al.
      Vitamin intake and risk of subtypes of esophageal cancer in Germany.
      ,
      • Holick C.N.
      • Michaud D.S.
      • Stolzenberg-Solomon R.
      • et al.
      Dietary carotenoids, serum (beta)-carotene, and retinol and risk of lung cancer in the alpha-tocopherol, beta-carotene cohort study.
      ,
      • Malila N.
      • Virtamo J.
      • Virtanen M.
      • et al.
      Dietary and serum alpha-tocopherol, beta-carotene and retinol, and risk for colorectal cancer in male smokers.
      ,
      • Michaud D.S.
      • Pietinen P.
      • Taylor P.R.
      • et al.
      Intakes of fruits and vegetables, carotenoids and vitamins A, E, C in relation to the risk of bladder cancer in the ATBC cohort study.
      ,
      • Akbaraly N.T.
      • Arnaud J.
      • Hininger-Favier I.
      • et al.
      Selenium and mortality in the elderly: results from the EVA study.
      ,
      • Cullen M.R.
      • Barnett M.J.
      • Balmes J.R.
      • et al.
      Predictors of lung cancer among asbestos-exposed men in the {beta}-carotene and retinol efficacy trial.
      ,
      • Buring J.E.
      Aspirin prevents stroke but not MI in women; vitamin E has no effect on CV disease or cancer.
      ,
      • Zhang S.M.
      • Moore S.C.
      • Lin J.
      • et al.
      Folate, vitamin B6, multivitamin supplements, and colorectal cancer risk in women.
      ]. Further, the complete papers were not available for some articles [
      • Bairati I.
      • Brochet F.
      • Roy J.
      • et al.
      ,
      • Combs Jr, G.F.
      • Clark L.C.
      • Turnbull B.W.
      Reduction of cancer mortality and incidence by selenium supplementation.
      ], and some did not fulfill the inclusion criteria [
      • de Klerk N.H.
      • Musk A.W.
      • Ambrosini G.L.
      • et al.
      Vitamin A and cancer prevention II: comparison of the effects of retinol and beta-carotene.
      ,
      • Hartman T.J.
      • Albanes D.
      • Pietinen P.
      • et al.
      The association between baseline vitamin E, selenium, and prostate cancer in the alpha-tocopherol, beta-carotene cancer prevention study.
      ,
      • Takagi H.
      • Kakizaki S.
      • Sohara N.
      • et al.
      Pilot clinical trial of the use of alpha-tocopherol for the prevention of hepatocellular carcinoma in patients with liver cirrhosis.
      ,
      • Goodman G.E.
      • Thornquist M.D.
      • Balmes J.
      • 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.
      ,
      • Galan P.
      • Briancon S.
      • Favier A.
      • et al.
      Antioxidant status and risk of cancer in the SU.VI.MAX study: is the effect of supplementation dependent on baseline levels?.
      ,
      • Stranges S.
      • Marshall J.R.
      • Trevisan M.
      • et al.
      Effects of selenium supplementation on cardiovascular disease incidence and mortality: secondary analyses in a randomized clinical trial.
      ].

       characteristics of selected studies

      The final analysis included 161 045 total subjects, 88 610 in antioxidant supplement groups and 72 435 in placebo or no-intervention groups, from 22 randomized controlled trials reported in 31 articles. In the studies in which the age and sex were reported, the mean (median) age was 58.4 years (age range 15–91 years), and 74.7% of the subjects were male.
      Table 1 shows the general characteristics of the 31 articles included in the analysis. The selected articles were published from 1985 through 2007, spanning 22 years. Besides the countries belonging to the European Union (n = 1), the countries in which the studies were conducted were as follows: United States (n = 13), Finland (n = 7), China (n = 4), Canada (n = 3), UK (n = 1), France (n = 1), Italy (n = 1), and India (n = 1). The mean (median) treatment and follow-up periods were 5.3 and 5.8 years, respectively. The following four trials were reported in 14 articles: the Alpha-Tocopherol Beta-Carotene Prevention Study (n = 8), the Nutritional Prevention of Cancer Trial (n = 2), the Women's Health Study (n = 2), and the Physicians’ Health Study (n = 2). Of the 22 trials, 12 were primary prevention trials, nine were secondary prevention trials, and the remaining one [
      • Moon T.E.
      • Levine N.
      • Cartmel B.
      • et al.
      Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group.
      ] was a mixed one (this study was excluded in the subgroup analysis by type of prevention due to a lack of data by type of prevention). The studies included healthy subjects (among the general population, physicians, and nurses); patients with skin, head and neck cancers; adults with underlying coronary disease, occlusive disease, and diabetes; hepatitis B virus surface antigen carriers; persons at high risk for primary liver cancer; smokers; male asbestos-industry workers; and organ transplant recipients.
      Among the 22 trials, 20 had a placebo group as the control and two had a no-intervention group as the control [
      • van Zandwijk N.
      • Dalesio O.
      • Pastorino U.
      • et al.
      EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer.
      ,
      • Toma S.
      • Bonelli L.
      • Sartoris A.
      • et al.
      Beta-carotene supplementation in patients radically treated for stage I-II head and neck cancer: results of a randomized trial.
      ]. Further, 19 trials used the parallel design, and three used the 2 × 2 design. In all studies, the antioxidant supplements were administered orally, and the dosage regimens used were as follows: vitamin A (15 mg or 10 000, 15 000, 25 000, 200 000, or 300 000 IU; daily or weekly), vitamin C (120, 180, or 250 mg; daily), vitamin E (30, 50, or 600 mg or 60, 400, or 600 IU; daily or on alternate days), beta-carotene (6, 20, 30, 50, or 75 mg; daily or on alternate days), and selenium (50, 100, or 200 μg; daily).
      The main outcome measure was the incidence of cancer, and the types of cancer were as follows: esophageal cancer, nonmelanoma skin cancer, primary liver cancer, stomach cancer, lung cancer, locoregionally recurrent and second primary cancer in head and neck cancer patients, prostate cancer, pancreatic cancer, colorectal cancer, urinary tract cancer, head and neck cancer, and upper aerodigestive tract cancer.

       effect of antioxidant supplements on prevention of cancer in all 22 trials

      Overall, in a fixed-effects model meta-analysis of all 22 trials, administration of antioxidant supplements had no significant influence on the incidence of cancer compared with placebo administration or no intervention (RR 0.99; 95% CI 0.96–1.03) (Figure 2). Heterogeneity was not found across the selected studies (I2 = 46.6%). There was no evidence of publication bias in the selected studies (Egger's test, P for bias = 0.98; Begg's funnel plot was symmetrical).
      Figure 2
      Figure 2Effect of antioxidant supplements versus placebo or no intervention on cancer incidence in randomized controlled trials (n = 22). A trial of Yu [
      • Yu S.Y.
      • Zhu Y.J.
      • Li W.G.
      • et al.
      A preliminary report on the intervention trials of primary liver cancer in high-risk populations with nutritional supplementation of selenium in China.
      ] was classified into two individual randomized controlled trials because it was conducted for the two different subpopulations. afixed-effects model; RR, relative risk; CI, confidence interval.

       subgroup analyses by type of prevention

      In the 12 studies on primary prevention trials, administration of antioxidant supplements had no significant effect on cancer prevention (RR 1.00; 95% CI 0.97–1.04; fixed-effects model) (Figure 3). Even in the nine studies on secondary prevention trials, no significant effect was observed (RR 0.97; 95% CI 0.83–1.13; random-effects model) (Figure 3).
      Figure 3
      Figure 3Effects of antioxidant supplements versus placebo or no intervention on cancer incidence by type of prevention. afixed-effects model; brandom-effects model; RR, relative risk; CI, confidence interval.

       subgroup analyses by type of antioxidant administered singly

      None of the antioxidant supplements had any significant influence on cancer prevention: beta-carotene (RR 1.01; 95% CI 0.96–1.07; n = 5; fixed-effects model), vitamin A (RR 0.98; 95% CI 0.90–1.08; n = 4; fixed-effects model), vitamin E (RR 1.02; 95% CI 0.90–1.16; n = 4; random-effects model), and selenium (RR 0.62; 95% CI 0.36–1.08; n = 5; random-effects model) (Figure 4).
      Figure 4
      Figure 4Effects of antioxidant supplements versus placebo or no intervention on cancer incidence by type of antioxidant. afixed-effects model; brandom-effects model; RR, relative risk; CI, confidence interval.

       subgroup analyses by type of cancer

      Table 2 shows the results of the subgroup analyses by type of cancer. Antioxidant supplements had no preventive effect on the following 11 of the 13 types of cancers included in this analysis: skin cancer, colorectal cancer, head and neck cancer, lung cancer, prostate cancer, esophageal cancer, breast cancer, stomach cancer, lymphoma and leukemia, renal cancer, and brain tumor. However, the use of antioxidant supplements significantly increased the risk of bladder cancer (RR 1.52; 95% CI 1.06–2.17; n = 4; fixed-effects model).
      Table 2Effects of antioxidant supplements versus placebo or no intervention on cancer incidence by type of cancer
      Cancer typeNo. of studiesSummary RR (95% CI)Heterogeneity, I2 (%)Model used
      Skin cancer90.98 (0.91–1.05)0.0Fixed effects
      Colorectal cancer70.97 (0.84–1.12)21.7Fixed effects
      Head and neck cancer70.87 (0.68–1.13)0.0Fixed effects
      Lung cancer71.00 (0.83–1.20)62.9Random effects
      Prostate cancer70.84 (0.69–1.02)57.8Random effects
      Esophageal cancer51.01 (0.81–1.26)0.0Fixed effects
      Bladder cancer
      Statistically significant.
      41.52 (1.06–2.17)0.0Fixed effects
      Breast cancer41.00 (0.90–1.11)0.0Fixed effects
      Stomach cancer30.99 (0.79–1.24)43.5Fixed effects
      Lymphoma and leukemia30.98 (0.81–1.20)0.0Fixed effects
      Renal cancer20.95 (0.62–1.46)0.0Fixed effects
      Brain tumor10.76 (0.45–1.27)
      Thyroid cancer19.50 (2.21–40.77)
      RR, relative risk; CI, confidence interval.
      a Statistically significant.

       subgroup analyses by methodological quality

      After referring to previously published reports [
      • Bjelakovic G.
      • Nikolova D.
      • Guud L.L.
      • et al.
      Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.
      ,
      • Bjelakovic G.
      • Nikolova D.
      • Simonetti R.G.
      • Gluud C.
      Antioxidant supplements for prevention of gastrointestinal cancer: a systematic review and meta-analysis.
      ], 12 studies [
      • Greenberg E.R.
      • Baron J.A.
      • Stukel T.A.
      • et al.
      The Skin Cancer Prevention Study Group. A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin.
      ,
      • Li J.Y.
      • Taylor P.R.
      • Li B.
      • et al.
      Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia.
      ,
      • Omenn G.S.
      • Goodman G.E.
      • Thornquist M.D.
      • et al.
      Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.
      ,
      • Moon T.E.
      • Levine N.
      • Cartmel B.
      • et al.
      Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group.
      ,
      • Frieling U.M.
      • Schaumberg D.A.
      • Kupper T.S.
      • et al.
      A randomized, 12-year primary-prevention trial of beta carotene supplementation for nonmelanoma skin cancer in the physician's health study.
      ,
      MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      ,
      • Duffield-Lillico A.J.
      • Reid M.E.
      • Turnbull B.W.
      • et al.
      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.
      ,
      • Virtamo J.
      Incidence of cancer and mortality following (alpha)-tocopherol and (beta)-carotene supplementation: a postintervention follow-up.
      ,
      • Bairati I.
      • Meyer F.
      • Gelinas M.
      • et al.
      A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients.
      ,
      • Lee I.M.
      • Cook N.R.
      • Gaziano J.M.
      • et al.
      Vitamin E in the primary prevention of cardiovascular disease and cancer. the Women's Health Study: a randomized controlled trial.
      ,
      • Lonn E.
      Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial.
      ,
      • Meyer F.
      • Galan P.
      • Douville P.
      • et al.
      Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial.
      ] of the 22 were classified as having a high methodological quality. The remaining 10 studies had one or more inadequate components. No significant preventive effects of the antioxidant supplements were found in studies of either high (RR 1.00; 95% CI 0.96–1.03; fixed-effects model) or low (RR 0.92; 95% CI 0.70–1.20; random-effects model) methodological quality.
      Meanwhile, when we assessed the methodological quality of the studies on the basis of what is stated in those articles without getting additional information on the study method by direct contact with those authors, only three studies [
      • Greenberg E.R.
      • Baron J.A.
      • Stukel T.A.
      • et al.
      The Skin Cancer Prevention Study Group. A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin.
      ,
      • Bairati I.
      • Meyer F.
      • Gelinas M.
      • et al.
      A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients.
      ,
      • Lonn E.
      Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial.
      ] were classified as having a high methodological quality. Likewise, no significant effects were found in studies of either high (OR 0.99; 95% CI 0.92–1.07; n = 3; fixed-effects model) or low (OR 0.99; 95% CI 0.93–1.06; n = 19; random-effects model) methodological quality.

      acknowledgements

      Contributorship statement and guarantor: S-KM was responsible for the initial plan, study design, and statistical analysis and for conducting the study. S-KM and YK were responsible for data collection, data extraction, data interpretation, and manuscript drafting. YK, WJ, HJC, and WKB were responsible for data interpretation and manuscript drafting. S-KM is the guarantor for this paper and has full responsibility for this study.
      Group name: The Korean Meta-analysis Study Group.

      discussion

      In our meta-analysis of randomized controlled trials published over >20 years, we found that there was no overall association between the consumption of antioxidant supplements and cancer risk. Further, subgroup analyses according to the type of prevention, type of antioxidant, and methodological quality of the studies also showed no preventive effect of antioxidant supplements on cancer. Our findings were consistent with those of previously published meta-analyses that evaluated the effect of antioxidant supplements on the prevention of lung cancer [
      • Caraballoso M.
      • Sacristan M.
      • Serra C.
      • Bonfill X.
      Drugs for preventing lung cancer in healthy people (Cochrane Review).
      ] and gastrointestinal cancers [
      • Bjelakovic G.
      • Nikolova D.
      • Simonetti R.G.
      • Gluud C.
      Antioxidant supplements for prevention of gastrointestinal cancer: a systematic review and meta-analysis.
      ] and on the prevention of cancers and chronic diseases [
      • Huang H.Y.
      • Caballero B.
      • Chang S.
      • et al.
      The efficacy and safety of multivitamin and mineral supplement use to prevent cancer and chronic disease in adults: a systematic review for a National Institutes of Health state-of-the-science conference.
      ] in randomized controlled trials.
      However, our findings were inconsistent with those of previous experimental studies and previous epidemiological studies regarding the association between the intake of fruits and vegetables rich in antioxidant substances or the dietary intake of antioxidant substances and the risk of cancer [
      • Tomita Y.
      • Himeno K.
      • Nomoto K.
      • et al.
      Augmentation of tumor immunity against syngeneic tumors in mice by β-carotene.
      ,
      • Glatthaar B.E.
      • Hornig D.H.
      • Moser U.
      The role of ascorbic acid in carcinogenesis.
      ,
      • Sandhu J.K.
      • Haggani A.S.
      • Birnboim H.C.
      Effect of dietary E on spontaneous or nitric oxide donor-induced mutations in a mouse tumor model.
      ,
      • Wright G.L.
      • Wang S.
      • Fultz M.E.
      • et al.
      Effect of vitamin A deficiency on cardiovascular function in the rat.
      ,
      • Hercberg S.
      • Galan P.
      • Preziosi P.
      • et al.
      The potential role of antioxidant vitamins in preventing cardiovascular diseases and cancers.
      ].
      This implies that there is a discrepancy in findings between experimental studies on animal or cancer cell lines and clinical trials for human studies with regard to the association between antioxidant substances (antioxidant supplements or fruits and vegetables rich in antioxidant substances) and the risk of cancer. The findings of experimental studies on the effects or actions of antioxidant substances should not be directly applied to humans because these substances might promote toxic effects or enhance carcinogenesis under clinical circumstances. For example, even though experimental studies showed that beta-carotene is anticarcinogenic and might play a potential protective role against cancer initiation [
      • De Flora S.
      • Bagnasco M.
      • Vainio H.
      Modulation of genotoxic and related effects by carotenoids and vitamin A in experimental models: mechanistic issues.
      ], it may act as a prooxidant in the presence of chronic oxidative stress such as that resulting from smoking; this may induce the oxidation of beta-carotene and DNA oxidative damage and eventually lead to lung cancer [
      • Cui Y.
      • Lu Z.
      • Bai L.
      • et al.
      Beta-carotene induces apoptosis and up-regulates peroxisome proliferators-activated receptor gamma expression and reactive oxygen species production in MCF-7 cancer cells.
      ,
      • Mayne S.T.
      • Handelman G.J.
      • Beecher G.
      Beta-carotene and lung cancer promotion in heavy smokers: a plausible relationship?.
      ].
      Such discrepancy is also observed between the results of observational epidemiologic studies and randomized controlled trials. Retrospective case–control studies, which investigate the relationship between diet and the risk of cancer, are susceptible to two potential biases, i.e. recall and selection: cancer patients might recall their diet differently from healthy controls, and healthy controls tend to report a healthy diet [
      • Key T.J.
      • Allen N.E.
      • Spencer E.A.
      • Travis R.C.
      The effect of diet on risk of cancer.
      ,
      • Giovannucci E.
      • Stampfer M.J.
      • Colditz G.A.
      • et al.
      A comparison of prospective and retrospective assessments of diet in the study of breast cancer.
      ]. Although cohort studies are less biased than case–control studies and indicate a relationship between antioxidant supplements and the risk of cancer, they are unable to confirm the causality [
      • Hercberg S.
      • Galan P.
      • Preziosi P.
      • et al.
      The potential role of antioxidant vitamins in preventing cardiovascular diseases and cancers.
      ]. The causality can be confirmed by repetitive, larger intervention trials (i.e. randomized controlled trials). Further, it should be noted that the consumption of antioxidant supplements in the randomized controlled trials differs from the intake of fruits and vegetables or the dietary intake of antioxidants in epidemiological studies in that the combination of several antioxidants and other micronutrients in foods or vegetables could cause unexpected consequences, and the assessment of the dietary intake for antioxidant substances could suffer from a lack of precision due to information bias or lack of validity of the questionnaire [
      • Hercberg S.
      • Galan P.
      • Preziosi P.
      • et al.
      The potential role of antioxidant vitamins in preventing cardiovascular diseases and cancers.
      ].
      In our study, we report that the use of antioxidant supplements increased the risk of bladder cancer. We are unable to confirm this relationship because the number of trials published is not sufficient to form a conclusion. In particular, further primary prevention trials are required to study the effect of antioxidant supplements on bladder cancer because three of the four studies on cancer included in this analysis were secondary prevention trials.
      Our study indicated that antioxidant supplements had no effects on either primary or secondary prevention of cancer, i.e. there was no specific difference in the effects of antioxidants between them.
      We are unable to evaluate the effect of vitamin C on the risk of cancer because there was no published study on vitamin C administered alone, although there were three studies [
      • Li J.Y.
      • Taylor P.R.
      • Li B.
      • et al.
      Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia.
      ,
      MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      ,
      • Meyer F.
      • Galan P.
      • Douville P.
      • et al.
      Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial.
      ] on vitamin C administered in combination with other antioxidants.
      With regard to the assessment of the methodological quality of the studies, there was a remarkable discrepancy between our classification of the studies as having high or low methodological quality and that in other published reports [
      • Bjelakovic G.
      • Nikolova D.
      • Guud L.L.
      • et al.
      Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.
      ,
      • Bjelakovic G.
      • Nikolova D.
      • Simonetti R.G.
      • Gluud C.
      Antioxidant supplements for prevention of gastrointestinal cancer: a systematic review and meta-analysis.
      ]. For example, the other published reports classified nine studies as studies with high methodological quality, while we classified these studies as having low methodological quality because they did not adequately report the generation of the allocation sequence (computer-generated random numbers or similar methods) and merely stated that the sequences were ‘randomly assigned’ or that ‘randomization was carried out.’ The authors of previously published meta-analyses stated that they obtained additional information on the actual design, including the randomization methods, from the authors of the individual study included in their analyses. We insist that the methodological quality of studies should be assessed on the basis of what is stated in those articles without getting additional information on the study method by direct contact with those authors.
      There are several possible limitations of our study. First, as described earlier, we are unable to clearly explain why, unlike the findings of experimental and epidemiologic studies, our study revealed that antioxidant supplements had no preventive effect on cancer. However, our findings at least imply that those of the experimental and epidemiologic studies should be interpreted cautiously and evaluated clinically.
      Secondly, our study included only synthetic antioxidants. Therefore, our findings are not applicable to the effects of fruits and vegetables. In addition, this might be a possible explanation for the discrepancy in the findings between randomized trials using synthetic antioxidants and epidemiologic studies such as case–control or cohort studies using fruits and vegetables. In other words, we think that there might be a difference between the biological activities of a synthetic antioxidant and those of an individual constituent in fruits or vegetables or whole fruits or vegetables. Even though the protective role of the individual constituent against the development of cancer was not identified in the randomized clinical trials, it is possible that the interactions and complex biological mechanisms of multiple constituents of fruits and vegetables, including antioxidants and various phytochemicals, result in the preventive effects on cancer.
      In summary, we found no overall preventive effect of antioxidant supplements on cancer in our meta-analysis of randomized controlled trials published over the past 20 years. Our findings are consistent with the other published meta-analyses and systematic reviews [
      • Huang H.Y.
      • Caballero B.
      • Chang S.
      • et al.
      The efficacy and safety of multivitamin and mineral supplement use to prevent cancer and chronic disease in adults: a systematic review for a National Institutes of Health state-of-the-science conference.
      ,
      • Bjelakovic G.
      • Nikolova D.
      • Guud L.L.
      • et al.
      Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.
      ,
      • Bjelakovic G.
      • Nikolova D.
      • Simonetti R.G.
      • Gluud C.
      Antioxidant supplements for prevention of gastrointestinal cancer: a systematic review and meta-analysis.
      ,
      • Bardia A.
      • Tleyjeh I.M.
      • Cerhan J.R.
      • et al.
      Efficacy of antioxidant supplementation in reducing primary cancer incidence and mortality: systematic review and meta-analysis.
      ,
      • World Cancer Research Fund/American Institute for Cancer Research
      Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective.
      ]. There is no clinical evidence to support the use of antioxidant supplements for primary and secondary prevention of cancer. Furthermore, even though the current study did not investigate the association between each type of antioxidant supplement and each type of cancer, the recent report from WCRF/AICR indicated that the evidence that beta-carotene supplements cause lung cancer in current smokers is convincing; that is, the use of some antioxidant supplements might be harmful. Considering that many people consume antioxidant supplements in order to improve their health and prevent cancer, we think that these findings may play a certain role in modifying these health behaviors. The potential effects (either beneficial or detrimental) of antioxidant supplements on human health, particularly in relation to cancer risk, should not be overemphasized. Our findings and explanations should be explored in future research.

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