Efficacy of Antioxidant Supplementation in Reducing Primary Cancer Incidence and Mortality: Systematic Review and Meta-analysis

  1. Aditya Bardia, MD, MPH,
  2. Imad M. Tleyjeh, MD, MSc,
  3. James R. Cerhan, MD, PhD,
  4. Amit K. Sood, MD, MSc,
  5. Paul J. Limburg, MD, MPH,
  6. Patricia J. Erwin, MLS and
  7. Victor M. Montori, MD, MSc
  1. Knowledge and Encounter Research Unit, Department of Medicine, Mayo Clinic,
    Rochester, MN
  1. Individual reprints of this article are not available. Address address correspondence to Victor M. Montori MD, MSc, Knowledge and Encounter Research Unit, Department of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (kerunit{at}mayo.edu).
 
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Abstract

OBJECTIVE: To estimate the association between antioxidant use and primary cancer incidence and mortality and to evaluate these effects across specific antioxidant compounds, target organs, and participant subgroups.

METHODS: Multiple electronic databases (MEDLINE, Cochrane Controlled Clinical Trials Register, EMBASE, Science Citation Index) were searched from their dates of inception until August 2005 to identify eligible randomized clinical trials. Random effects meta-analyses estimated pooled relative risks (RRs) and 95% confidence intervals (CIs) that described the effect of antioxidants vs placebo on cancer incidence and cancer mortality.

RESULTS: Twelve eligible trials, 9 of high methodological quality, were identified (total subject population, 104,196). Antioxidant supplementation did not significantly reduce total cancer incidence (RR, 0.99; 95% CI, 0.94-1.04) or mortality (RR, 1.03; 95% CI, 0.92-1.15) or any site-specific cancer incidence. Beta carotene supplementation was associated with an increase in the incidence of cancer among smokers (RR, 1.10; 95% CI, 1.03-1.10) and with a trend toward increased cancer mortality (RR, 1.16; 95% CI, 0.98-1.37). Selenium supplementation was associated with reduced cancer incidence in men (RR, 0.77; 95% CI, 0.64-0.92) but not in women (RR, 1.00; 95% CI, 0.89-1.13, value for interaction, P<.001) and with reduced cancer mortality (RR, 0.78; 95% CI, 0.65-0.94). Vitamin E supplementation had no apparent effect on overall cancer incidence (RR, 0.99; 95% CI, 0.94-1.04) or cancer mortality (RR, 1.04; 95% CI, 0.97-1.12).

CONCLUSION: Beta carotene supplementation appeared to increase cancer incidence and cancer mortality among smokers, whereas vitamin E supplementation had no effect. Selenium supplementation might have anticarcinogenic effects in men and thus requires further research.

CI = confidence interval; RR = relative risk

Observational studies suggest that high intake of fruits and vegetables is associated with reduced cancer incidence and mortality.1-3 The high levels of antioxidants (particularly beta carotene and vitamin E) in fruits and vegetables are believed to contribute toward cancer prevention, possibly by inhibiting oxidative stress.4-6 In the early 1990s, the public received both encouraging7 and discouraging8-10 news about the association between antioxidant supplementation and cancer; more studies with heterogeneous findings followed.11-16 Because antioxidants are a heterogeneous group of compounds, it is unclear whether individual compounds are more beneficial (or harmful) than others. Moreover, carcinogenesis is not uniform across all anatomic sites, so specific antioxidant compounds could be associated with different effects depending on the target organ under study.17

The primary aim of this systematic review was to estimate the extent to which antioxidants affect total cancer incidence and total cancer mortality. A secondary aim included evaluation of these effects across specific antioxidant compounds, target organs, and participant subgroups.

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METHODS

This protocol-driven systematic review followed state-of-the art methods of conduct from the Cochrane Collaboration. This report follows the Quality of Reporting of Meta-analyses (QUOROM) standards for reporting systematic reviews of randomized trials.18

Eligibility Criteria

Two reviewers (A.B. and A.K.S.), working independently and in duplicate, identified and evaluated potentially eligible trials according to predefined inclusion criteria. Eligible studies were trials with a minimum of 1 year of follow-up and that randomly assigned participants—who had no history of cancer (except skin cancer) nor precancerous lesions—to receive antioxidants or placebo. Eligible antioxidants were beta carotene, selenium, zinc, vitamin C (ascorbic acid), vitamin E (α-tocopherol), and lycopene alone or in combination with other antioxidant supplements, administered by mouth or parenterally. Ineligible trials used antioxidant supplements with undisclosed components or sought antioxidant supplementation through dietary increases in vegetables, fruits, or fiber. Also, trials reporting only site-specific cancer incidence or only cancer mortality, but not overall cancer incidence, were excluded.

Literature Search

With extensive input from an expert reference librarian (P.J.E.), we designed a comprehensive search strategy. The search strategy used terms that describe key concepts (antioxidants,

FIGURE 1.
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FIGURE 1.

Diagram summarizing search strategy for eligible articles.

cancer prevention, and randomized clinical trials or population-based studies) adapted for each database (eAppendix available on www.mayoclinicproceedings.com, linked to this article). We searched Ovid MEDLINE (1966 to September 2005), Ovid EMBASE (1974 to September 2005), Institute for Scientific Information Web of Science (1993 to September 2005), and Science Citation Index (January 1972 to December 1992) and searched Scopus, Cochrane Database of Systematic Reviews, Cochrane Controlled Clinical Trials Register, and the Cumulative Index to Nursing and Allied Health (1982 to September 2005), with no language restriction. We also scanned reference lists for additional studies.

Quality Assessment

Two reviewers (A.B. and I.M.T.), working in duplicate and independently, ascertained the reported methodological quality of eligible trials19 with good chance-adjusted interrater reliability (κ=0.9). We also noted whether trials were stopped early for benefit, given recent evidence that trials stopped early for benefit can overestimate treatment effects.20 Disagreements between reviewers were resolved by discussion with a third reviewer (V.M.M.).

Data Collection

Two reviewers (A.B. and I.M.T.), working independently and in duplicate, extracted data from each eligible trial using a standardized data collection form prepared for this review. We converted international units to milligrams for vitamin E by dividing the value by 1.5. We extracted data about the number of participants, population characteristics, type of antioxidant used, and events (total cancer incidence, total cancer mortality, and site-specific cancer incidence) in antioxidant and placebo arms.

We contacted corresponding authors for missing data through e-mail messages. When the number of participants with events was not reported, we used standard algebraic equations to estimate these figures from the number of participants in each arm, the relative risks (RRs), and the 95% confidence intervals (CIs).7,21 For 1 trial that did not report RRs of cancer incidence for all antioxidants combined, we used the reported estimates comparing placebo with the arm of the trial that included beta carotene, vitamin E, and selenium (the D arm of that trial) because these supplements have received the most attention.21

Statistical Analyses

The meta-analysis was performed using the computer program Review Manager (RevMan), version 4.2 for Windows (Nordic Cochrane Centre, Copenhagen, Denmark), which was used to estimate the RR and corresponding 95% CI of the effect of antioxidants on cancer incidence and mortality. A random effects model was used to account for between-trial heterogeneity (given potentially by differences in methods, participants, antioxidant type and dose, and cancer surveillance, type, and site). Inconsistency was estimated using the I2 statistic.22

Subgroup Analyses

Planned subgroup analyses were based on type of antioxidant (beta carotene, selenium, vitamin E), type of study population (smokers or nonsmokers, male or female), and site-specific cancer (breast, lung, colorectal, proximal gastrointestinal tract [including liver], bladder, prostate, central nervous system, head and neck, hematologic, and melanoma). Treatment differences among subgroups were tested using standard tests of interactions (P<.05 was considered significant).23

Sensitivity Analysis

Sensitivity analyses were conducted to evaluate results based on study quality, trials stopped early, and choice of meta-analysis model. Finally, because patients were reexamined at various periods in the trials, we also used the log inverse method to pool results as sensitivity analyses.

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RESULTS

The literature search identified 599 trials, of which 33 were potentially eligible. After reviewing full texts of articles, we selected 12 eligible trials.7-9,11-14,21,24-27 Trials were excluded (Figure 1) if they were not randomized (n=4),28-31 included participants with baseline cancer or precancerous lesions (n=7),32-38 included fewer than 10 events per arm, or did not measure the outcome of interest (n=10).39-48

Study Characteristics

Table 1 describes the baseline characteristics of the included trials. Eight trials enrolled both men and women; 2, only women; and 2, only men. All but 3 trials enrolled more

View this table:
TABLE 1.

General Characteristics of Eligible Trialsa

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TABLE 2.

Study Quality of Eligible Trialsa

than 10,000 participants. All trials evaluated antioxidants as oral supplements, but dosage of the antioxidants varied (beta carotene, 15-30 mg/d; vitamin C, 120-250 mg/d; vitamin E, 30-900 IU/d; and selenium, 100-200 μg/d). Two trials involved only high-risk populations (smokers or former smokers), and the rest (10) of the 12 trials involved general populations, although 1 of the 10 studies included patients with baseline skin cancers.7 Two trials originated in China, 1 was an international collaboration, and others originated either in Europe (n=4) or in the United States (n=5). Two trials were stopped early because of evidence of harm.8,25

On the basis of available data, 9 trials fulfilled our (or standard) criteria for high methodological quality (Table 2). Three trials did not report generation of allocation sequence and intention-to-treat analysis.7,21,27 Loss to follow-up was generally low (<1% in most studies), but 3 studies did not report data about loss to follow-up.7,8,21

Meta-analysis of Cancer Incidence

The 12 studies had a combined population of 104,196 (randomized or analyzable) participants. Overall, antioxidants did not significantly reduce total cancer incidence (RR, 0.99; CI, 0.94-1.04; I2, 45.7%; P=.77) (Figure 2).

Results remained similar after we excluded the trials with low quality (RR, 1.00; 95% CI, 0.95-1.05; P=.99), after we excluded trials stopped early for harm (RR, 0.98; 95% CI, 0.93-1.02; P=.25), or after we used the fixed effects (log inverse) method to pool results (RR, 1.00; 95% CI, 0.97-1.03; P=.92).

Meta-analysis of Cancer mortality

Antioxidants did not significantly reduce total cancer mortality (RR, 1.03; 95% CI, 0.92-1.15; I2, 66.9%; P=.59) (Figure 2). Results remained similar after we excluded the trials with low quality (RR, 1.04; 95% CI, 0.92-1.16; P=.53) and trials that were stopped early for harm (RR, 0.99; 95% CI, 0.90-1.09; P=.86). Results showed significant increases in cancer mortality with antioxidants when we used the fixed effects (log inverse) method to pool results (RR, 1.06; 95% CI, 1.00-1.13; P=.04).

Subgroup Analysis of Antioxidant Subgroup

On the basis of the type of antioxidant, trials were pooled into 3 broad subgroups: beta carotene, vitamin E, and selenium. When trials had antioxidant combinations and when data for effect of individual antioxidants were available, they were used accordingly; in other cases they were treated separately.

Beta carotene. Beta carotene was associated with a slight increase in cancer incidence (RR, 1.06; 95% CI, 1.00-1.12; I2, 0%; P=.03). This became more apparent when stratified by smoking status. Beta carotene was found to be associated with an increased incidence of cancer among smokers (RR, 1.10; 95% CI, 1.03-1.18; I2, 0%; P=.01) but not among nonsmokers (RR, 1.00; 95% CI, 0.92-1.10; I2, 0%; P=.94), as illustrated in Figure 3. Results of the test of interaction assessing the effect of beta carotene among smokers and nonsmokers on cancer incidence were significant (P=.01). For other antioxidants (vitamin E, selenium), no such interaction with cancer incidence was observed. We also conducted a formal test of interaction between beta carotene and vitamin E on cancer incidence, which was found to be nonsignificant.

Finally, beta carotene supplementation showed a trend toward increased cancer mortality (RR, 1.10; 95% CI, 0.94-1.29; I2, 73.7%; P=.24); however, 1 trial assessed a combination

FIGURE 2.
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FIGURE 2.

Effect of antioxidants on cancer incidence (top) and cancer mortality (bottom). ATBC = Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group; CARET = Beta Carotene and Retinol Efficacy Trial; CI = confidence interval; GISSI-Prevenzione = Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (Italian Group for the Study of Survival of Myocardial Infarction); HOPE = Heart Outcomes Prevention Evaluation; HPS = Heart Protection Study Collaborative Group; NPCT = Nutritional Prevention of Cancer Trial; PHS = Physicians' Health Study; RR = relative risk; SU.VI.MAX = SUpplémention en VItamines et Minéraux AntioXydants (Antioxidant Vitamin and Mineral Supplements); WHS = Women's Health Study.

of beta carotene, selenium, and vitamin E.7 Excluding this trial (as selenium could have a chemopreventive effect; see next paragraph), beta carotene showed a trend toward increased cancer mortality (RR, 1.16; 95% CI, 0.98-1.37; I2, 71.6%), and this was marginally significant (P=.08) (Figure 3). However, the latter result had substantial heterogeneity, possibly because of differences in the study populations, particularly by smoking status. In fact, a higher RR was observed in the 2 trials that comprised smokers and former smokers8,9 (Figure 3). This adds further weight to the observation that beta carotene might be more harmful among smokers, but unfortunately, we could not confirm this because mortality results were not stratified by smoking status (as the trials did not report the relevant data).

FIGURE 3.
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FIGURE 3.

Effect of beta carotene on cancer incidence (top) and cancer mortality (bottom). For expansion of abbreviations, please see footnote to Figure 2.

Selenium. Selenium supplementation reduced total cancer incidence (RR, 0.88; 95% CI, 0.77-1.00; I2, 52.7%; P=.05). However, when stratified by sex (Figure 4), selenium supplementation was found to have a beneficial effect in reducing cancer incidence among men (RR, 0.77; 95% CI, 0.64-0.92; I2, 54.1%; P=.004) but not women (RR, 1.00; 95% CI, 0.89-1.13; I2, 0%; P=.099), and the interaction by sex was statistically significant (P<.001). For other antioxidants (beta carotene, vitamin E), no such effect on cancer incidence was observed between the sexes.

Selenium was found to be associated with reduced cancer mortality (RR, 0.78; CI, 0.65-0.94; I2, 20.4%; P=.01) as outlined in Figure 4. These results come from pooling results of 4 trials, 1 of which had low methodological quality,7,21 and 2 of which assessed the combination of beta carotene, vitamin E, and selenium.7,13 Excluding the last 2 trials lowered the heterogeneity and strengthened the inverse effect of selenium on cancer incidence (RR, 0.69; 95% CI, 0.56-0.85; I2, 0%; P<.01) as well as cancer mortality (RR, 0.61; 95% CI, 0.42-0.89; I2, 0%; P=.01). We were

FIGURE 4.
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FIGURE 4.

Effect of selenium on cancer incidence (top) and cancer mortality (bottom). For expansion of abbreviations, please see footnote to Figure 2.

unable to stratify the mortality results by sex (as the trials did not report the relevant data).

Vitamin E. Vitamin E was found to have no effect on cancer incidence (RR, 0.99; 95% CI, 0.94-1.04; I2, 0%; P=.71) or cancer mortality (RR, 1.04; 95% CI, 0.97-1.12; I2, 0%; P=.29), as evident in Figure 5. Similarly, for 4 trials reporting data on the combination of vitamin E and beta carotene, the results remained nonsignificant for cancer incidence (RR, 0.95; 95% CI, 0.90-1.01; P=.10) and cancer mortality (RR, 0.98; 95% CI, 0.86-1.12; P=.79).

Subgroup Analysis by Specific Cancer Sites and Types

There was no significant effect of antioxidants on any site-specific cancer incidence (Table 3). Given the increased risk of cancer incidence among smokers consuming beta carotene, we investigated the effect of beta carotene (alone or in combination with other supplements) on smoking-related cancer (lung, head and neck, upper gastrointestinal tract, and bladder) and found an increased risk of these cancers with beta carotene supplementation (RR, 1.14; 95% CI, 1.06-1.24; I2, 0%; P<.01), as outlined in Figure 6.

FIGURE 5.
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FIGURE 5.

Effect of vitamin E on cancer incidence (top) and cancer mortality (bottom). For expansion of abbreviations, please see footnote to Figure 2.

Similar increases were not seen for other antioxidants. Antioxidants showed a slight decrease in prostate cancer (RR, 0.87; 95% CI, 0.74-1.02; I2, 63.5%; P=.08). This result had a high heterogeneity, and further sensitivity analysis revealed that the results varied by antioxidant type. Vitamin E in particular was associated with a reduced risk of prostate cancer (RR, 0.82; 95% CI, 0.67-0.99; I2, 46.5%; P=.04), but the number of trials was small (n=3). One trial reported a decreased incidence of prostate cancer with selenium.12

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DISCUSSION

This systematic review suggests that antioxidant supplementation, particularly with beta carotene and vitamin E, does not prevent cancer. Further, beta carotene can increase the risk of smoking-related cancers (lung, head and neck, upper gastrointestinal tract, and bladder cancer) and can increase cancer mortality. However, selenium supplementation can help prevent cancer, particularly among men; this preventive effect requires confirmation by further research.

Limitations

Our study has several limitations. First, antioxidants are a heterogeneous group of compounds, and different studies used different combinations and doses of antioxidants. Also, some trials did not measure or report overall cancer incidence, introducing reporting bias. We tried to overcome this limitation by contacting authors and were able to garner relevant data for trials evaluating beta carotene. Second, results indicating site-specific cancer incidence need to be interpreted with caution because we did not include trials reporting only site-specific outcomes, and because not all trials classified these cancers (particularly gastrointestinal and genitourinary cancers) similarly.49 Third, publication bias could have affected this review; however, the likelihood of publication bias is lower in systematic reviews of prevention trials that tend to have large sample sizes. Fourth, the observers were not blinded to the names of the authors, institutions, names of journals, sources of funding, nor any acknowledgments. However, the authors had no conflict of interest, and data were obtained in duplication. Finally, it is possible that the trials were of short duration and thus did not observe any beneficial

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TABLE 3.

Effect of Antioxidants on Site-Specific Cancer Incidencea

effects from antioxidants. This is unlikely to be a major factor, given that some trials had as much as 7 years of follow-up. Indeed, postintervention results of some of these studies also fail to show any beneficial effects from these antioxidants.28

Comparison With Other Systematic Reviews

Of the other 5 systematic reviews of antioxidants and cancer incidence or mortality,15,16,50-52 none comprehensively assessed primary prevention of overall cancer incidence or cancer mortality. One meta-analysis found no significant preventive effect of antioxidants on gastrointestinal cancers (RR, 0.9; 95% CI, 0.8-1.1; I2, 52%), except for selenium (RR, 0.49; 95% CI, 0.36-0.67; I2, 0%).15 Another recent meta-analysis reported a dose-response relationship between vitamin E (150 IU/d) and risk of all-cause mortality (RR, 1.04; 95% CI, 1.01-1.07).16 Similarly, a recent systematic review found that beta carotene (given singly) increased mortality (RR, 1.06; 95% CI, 1.01-1.11), vitamin E had no effect on mortality (RR, 1.02; 95% CI, 0.98-1.05), and selenium seemed to decrease mortality (RR, 0.85; 95% CI, 0.68-1.07).50 The last effect diminished when trials with high bias were excluded (RR, 0.91; 95% CI, 0.81-1.02). However, neither of these systematic reviews16,50 reported the effect of antioxidants on cancer mortality. Two similar reviews by Coulter et al51 and Huang et al52 found no preventive effects of vitamin C or vitamin E supplementation on overall cancer incidence. However, our review was different from those reviews: (1) we focused on trials of primary prevention and looked at the effect of antioxidants during the intervention period without including posttrial follow-up, a period with fewer protections against bias; (2) we performed meta-analyses of eligible trials that were not reviewed by Coulter et al51; (3) we included other commonly used antioxidants, such as beta carotene and selenium, which were not included in their reviews; (4) we conducted sensitivity analyses based on smoking status; and (5) we included 8 additional trials (until mid-2005) not included in the earlier reviews. All these factors allowed us to identify novel findings in this review.

Implications for Practice, Research, and Policy

Our review of trials apparently contradicts the inference from observational studies linking antioxidants with reduced risk of cancer. There are multiple possible explanations for this contradiction. Fruits and vegetables are a complex mixture of antioxidants, as well as other potentially beneficial micronutrients and macronutrients. The interaction of antioxidants, rather than high doses of individual compounds, could yield benefit.53,54 However, other antioxidants besides beta carotene and vitamin E (such as selenium, lycopene, xanthine, or unidentified compounds) could account for the beneficial effects of fruits and vegetables.55 Our systematic review suggests that selenium might account for some of the beneficial effects. Finally, subtypes of antioxidants might account for the beneficial effects. For example, there are multiple forms of vitamin E (such as α, β, γ) and beta carotene, and each could be associated with various outcomes.

Another likely explanation relates to the discrepancy seen between cohort studies and randomized trials of dietary risk factors and risk of cancer.56 Participants favoring diets rich in fruits and vegetables might also engage in other lifestyles measures that reduce the risk of cancer. When these confounders are accounted for by randomization, the putative effect essentially disappears.

Our study suggested that antioxidants, particularly beta carotene, might increase risk of cancers that are related to smoking. This is possibly because, under exposure to certain conditions, such as smoking, antioxidants can have a pro-oxidant effect and might enhance carcinogenesis.57,58 A

FIGURE 6.
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FIGURE 6.

Effect of beta carotene on smoking-related cancers. For expansion of abbreviations, please see footnote to Figure 2.

recent study found that carotenoids could increase the oxidative stress induced by smoking and promote toxic effects in tissues.59 Other systematic reviews have also reported that beta carotene might increase overall mortality as well as cardiovascular mortality.15,50,60 Thus, it might be prudent to avoid beta carotene supplementation, especially for people with high risk for cancer, such as smokers.

With the compelling evidence already available, it is very unlikely that additional randomized trials of beta carotene and vitamin E as chemopreventive agents will yield positive results. However, vitamin E might protect against prostate cancer, and a large trial assessing the effect of vitamin E on prostate cancer is currently under way.61

Selenium supplementation might provide cancer prevention among men. However, these results need to be interpreted with caution because the number of trials was small. Two trials were of low quality and had other compounds (1 had garlic) that could contribute toward the beneficial effects seen. Nevertheless, 1 trial with adequate protection against bias did show beneficial effects of selenium, and the effects were also confirmed by serum levels of selenium.13 The possible mechanisms by which selenium is postulated to decrease the incidence of cancer include inhibition of oxidative damage to DNA, recharging of cellular proliferation, modulation of apoptosis, and alteration of cellular gene expression.62 It should also be noted that most of the selenium trials were conducted in areas where residents were likely to be nutritionally deficient in selenium. Thus, it is possible that beneficial effects are restricted to those who are nutritionally deficient in selenium.

Epidemiological studies have also associated selenium with reduced cancer risk,63-66 particularly among men.67,68 In one of the randomized trials, the authors measured the selenium levels after intervention and found that men had a higher level of selenium after supplementation than women had.13 This sex effect has been attributed to differences in tissue response to selenium, selenium metabolism, hormones, and tumor biology between men and women.69 Only 1 study in this systematic review reported the effect of selenium on prostate cancer, and it found a protective effect,12 as seen in other epidemiological studies.70-72 Two large randomized trials assessing the role of selenium as a chemopreventive agent for prostate cancer are currently under way.60,73 Similar trials of selenium supplementation for prevention of cancer in general, particularly among men, could be warranted, as suggested by this systematic review.

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CONCLUSION

Antioxidant supplementation, particularly with beta carotene and vitamin E, does not reduce primary cancer incidence or cancer mortality. Beta carotene supplementation might increase the risk of smoking-related cancers, as well as cancer mortality, and should be avoided by tobacco users. Selenium supplementation might reduce cancer incidence, especially in men. Further research is needed to confirm the chemopreventive effect of selenium.

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Footnotes

  • Dr Tleyjeh is now with the King Fahd Medical City, Riyadh, Saudi Arabia.

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