CRD summary

This well-conducted review found that beta carotene supplementation appeared to increase cancer incidence and mortality among smokers; vitamin E supplementation had no effect. Selenium supplementation might have anticarcinogenic effects in men. These conclusions are likely to be reliable.

Authors' objectives

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

Searching

MEDLINE (1966 to September 2005), EMBASE (1974 to September 2005), Web of Science (1993 to September 2005), Science Citation Index (1972 to December 2005), CINAHL (1982 to September 2005), Scopus, Cochrane Central Register of Controlled Trials (CENTRAL) and Cochrane Database of Systematic Reviews were searched without language restrictions. Details of the search strategies were available as a web appendix. Reference lists were screened for additional studies.

Study selection

Randomised controlled trials (RCTs) that compared antioxidants to placebo in patients who had no history of cancer (except skin cancer) and that had at least one year follow-up were eligible for inclusion. Studies had to report overall cancer incidence to be included. Eligible antioxidants were beta carotene, selenium, zinc, vitamin C, vitamin E and lycopene alone or in combination with other antioxidants administered orally or parenterally. Studies that included fewer than 10 events per arm were excluded.

All trials evaluated oral antioxidants that included beta carotene (15 to 30mg/day), vitamin C (120 to 250mg/day), vitamin E (30 to 900 IU/day) and selenium (100 to 200ug/day). Most trials included both men and women; two included only men and two included only women. Most studies enrolled the general population; two were conducted in high risk populations (smokers). Studies were conducted in China, Europe and USA. Two studies were stopped early because of evidence of harm.

Two reviewers independently assessed studies for inclusion.

Assessment of study quality

Two reviewers independently assessed study quality according to the criteria: generation of allocation sequence; allocation concealment; blinding; follow-up; and intention-to-treat analysis. Studies were rated adequate or inadequate for each item and were classed as high quality if all items were rated adequate. Studies were also assessed according to whether they were stopped early for benefit/harm. Disagreements were resolved through discussion with a third reviewer.

Data extraction

Two reviewers independently extracted data to calculate relative risks (RR) together with 95% confidence intervals (CI) using a standardised form. International units were converted to micrograms. Authors were contacted for additional data where necessary.

Methods of synthesis

Summary relative risks together with 95% CIs were estimated using random-effects models. Heterogeneity was quantified using the I² statistic. Prespecified subgroup analyses based on type of antioxidant, population and site-specific cancer were conducted. Treatment differences among subgroups were tested using standard tests of interactions. Sensitivity analyses were conducted to evaluate the effects of study quality, trials stopped early and choice of meta-analysis model.

Results of the review

Twelve RCTs were included (n=104,196, range 1,312 to 39,876). Nine studies fulfilled all quality criteria and were judged to be of high quality.

Overall, antioxidants did not reduce total cancer incidence (12 RCTs, p=0.77) or cancer mortality (11 RCTS, p=0.59). There was evidence of heterogeneity (I²=46% for incidence and 67% for mortality). Exclusion of low-quality trials and trials stopped early for harm did not alter the results.

Beta-carotene was associated with a small increase in cancer incidence (RR 1.06, 95% CI 1.00 to 1.12; four RCTs). When stratified according to smoking status, the association was significant for smokers (RR 1.10, 95% CI 1.03 to 1.18; four RCTs), but not for non-smokers (two RCTs, p=0.94). There was no association between beta-carotene and cancer mortality (four RCT, p=0.24). Results did not differ according to gender.

Selenium was associated with decreased cancer incidence (RR 0.88, 95% CI 0.77 to 1.00; four RCTs) and cancer mortality (RR 0.78, 95% CI 0.65 to 0.94; three RCTs). When stratified on gender the result for cancer incidence was significant for men (RR 0.77, 95% CI 0.64 to 0.92; four RCTs), but not for women (four RCTs, p=0.099). Appropriate data were not reported to stratify the mortality data on gender. Results did not differ according to smoking status.

Vitamin E alone or combined with beta-carotene was not associated with cancer incidence or cancer mortality.

There was no significant effect of antioxidants on any site-specific cancers. There was an increased risk of smoking related cancers with beta carotene supplementation (RR 1.14, 95% CI 1.06 to 1.24; five RCTs).

Authors' conclusions

Beta carotene supplementation appeared to increase cancer incidence and mortality among smokers; vitamin E supplementation had no effect. Selenium supplementation might have anticarcinogenic effects in men.

CRD commentary

The review addressed a clear question supported by defined inclusion criteria. The literature search was extensive. No specific attempts were made to locate unpublished studies and so there was a possibility of publication bias. Appropriate steps were taken to minimise bias and errors at all stages of the review process. Study quality was assessed with appropriate criteria and the results were clearly presented and considered in the analysis. The methods of analysis were appropriate and included assessment and investigation of heterogeneity.

This was a well-conducted review and the authors' conclusions are likely to be reliable.

Implications of the review for practice and research

Practice: The authors stated that beta-carotene supplementation should be avoided by tobacco users.

Research: The authors stated that further investigation of the effects of selenium supplementation in men were required.

Funding

Not stated.

Bibliographic details

Bardia A, Tleyjeh IM, Cerhan JR , Sood AK , Limburg PJ, Erwin PJ, Montori VM. Efficacy of antioxidant supplementation in reducing primary cancer incidence and mortality: systematic review and meta-analysis. Mayo Clinic Proceedings 2008; 83(1): 23-34. [PubMed: 18173999]

Original Paper URL

http://www.mayoclinicproceedings.com/content/83/1/23.abstract

Indexing Status

Subject indexing assigned by NLM

MeSH

Antioxidants /therapeutic use; Dietary Supplements; Female; Humans; Incidence; Male; Neoplasms /mortality /prevention & control; Survival Rate; Treatment Outcome

AccessionNumber

12008000209

Database entry date

27/10/2010

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.