David Atkins, M.D., M.P.H.a; Padma Shetty, M.D., M.P.H.a
The authors of this update are responsible for its contents, including any clinical or treatment recommendations. No statement in this update should be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Address correspondence to: David Atkins, M.D., M.P.H., Chief Medical Officer, Agency for Healthcare Research and Quality, Center for Outcomes and Evidence, Suite 6000, 540 Gaither Road, Rockville, MD 20850. Phone: (301) 427-1608; Fax: (301) 427-1639; E-mail: datkins@ahrq.gov.
* This article was prepared at AHRQ to update the evidence reviewed in the following article: Ritenbaugh C, Streit K, Helfand M. Routine vitamin supplementation to prevent cancer: A summary of the evidence from randomized controlled trials for the U.S. Preventive Services Task Force.
Reprints of this update, the chapter it updates (Routine Vitamin Supplementation to Prevent Cancer: A Summary of the Evidence From Randomized Controlled Trials for the U.S. Preventive Services Task Force), a related chapter (Routine Vitamin Supplementation To Prevent Cardiovascular Disease: A Summary of Evidence for the U.S. Preventive Services Task Force), and the USPSTF recommendations based on these two chapters (Routine Vitamin Supplementation to Prevent Cancer and Cardiovascular disease: Recommendations and Rationale) are available from the AHRQ Web site (http://www.preventiveservices.ahrq.gov) and through the National Guideline Clearinghouse™ (http://www.guideline.gov).
Background
Methods
Results
Summary
References
Notes
In 2001, the U.S. Preventive Services Task Force developed draft recommendations on the use of vitamin supplements to prevent cancer and cardiovascular disease, drawing on systematic reviews of the evidence available from randomized trials and well-conducted observational studies. The evidence pertaining to vitamin supplementation and cancer was originally summarized for the USPSTF in a manuscript covering publications through the end of 1999. To help the USPSTF finalize their draft recommendations, we updated the literature review through the end of 2002, focusing on the randomized trial evidence that was the basis of the draft recommendations.
An electronic search completed on December 23, 2002, identified relevant studies from the MEDLINE® database of publications from 1999 through December 2002. The search was limited to publications in English and studies involving human subjects. The MEDLINE® search terms included precancerous conditions, neoplasms, antioxidants, vitamins/administration and dosage, and vitamins/therapeutic use, as well as "randomized" or "controlled" or "clinical" trial (Table 1).
The search identified 197 studies; abstracts were reviewed by two independent reviewers. Studies included were original trials or supplemental analyses of primary prevention trials using vitamin or antioxidant supplements that reported cancer incidence or mortality outcomes. Studies were excluded if focus was on treatment or control of existing disease or if endpoints consisted of intermediate cancer outcomes, such as dysplasia. Of the 197 studies found in the search, 10 studies met the inclusion criteria for this review. Two studies were new randomized controlled trials not included in an earlier review, and the remaining 8 were followup studies of two large clinical trials. The excluded trials included secondary prevention trials, trials involving chemotherapy for patients with cancer, and reviews. Descriptive data was abstracted from the included trials and summarized in an evidence table (Evidence Table 1).
Two recent clinical trials reported no beneficial effect of vitamin E, vitamin C, or beta-carotene supplementation on incidence of cancer. In the MRC/BHF Heart Protection Study,1 20,536 United Kingdom hospital clinic patients at risk for heart disease were randomized to receive a combination of antioxidant nutrients (vitamin E, vitamin C, and beta-carotene) or placebo. The participants were followed for an average of 5 years and assessed for incidence of major coronary events as the primary endpoint. Incidence of new primary cancers excluding nonmelanoma skin cancers was recorded as a pre-planned secondary endpoint. The authors reported 800 new primary cancers in the nutrient group and 817 cases in the placebo group. There was no association between use of antioxidant supplementation and the incidence of cancer when compared with placebo (RR, 0.98; 95% CI, 0.89-1.08; P=.7) and no effect of supplementation on mortality caused by cancer (RR, 1.04; 95% CI, 0.90-1.21). In addition, no significant difference was found between treatment groups and controls in the incidence of any site-specific cancers.
In the second study, Green and colleagues2 investigated the association between beta-carotene supplementation and the incidence of new basal cell and squamous cell cancers in 1,621 Australian subjects recruited from the community. Subjects were randomized to one of four interventions as a part of a 2x2 factorial design: daily sunscreen application and beta-carotene supplementation, sunscreen and placebo, beta-carotene only, or placebo only. During the 4-5 years of followup, no evidence was found of a protective effect of beta-carotene on basal cell or squamous cell carcinoma of the skin (RR, 1.04; 95% CI, 0.73-1.27 and RR,1.35; 95% CI, 0.84-2.19, respectively). Similar results were reported after subjects assigned to sunscreen were excluded from the analysis.
The current search identified 3 supplemental analyses of the Physician's Health Study (PHS),3 a 12-year followup study of 22,071 apparently healthy U.S. male physicians who were randomized into one of four intervention groups as part of a 2x2 factorial design:
The aspirin component of the randomization design was discontinued six years into the study due to significant benefits on the risk for myocardial infarctions. As part of its primary analysis, the Physicians' Health Study (PHS) concluded that there was no evidence that beta-carotene supplementation was associated with the overall incidence of malignant neoplasms, cardiovascular disease, or mortality after an average of 12 years of treatment.
Two of the 3 additional analyses reviewed were consistent with the PHS in finding no association of beta-carotene supplementation with cancer incidence. Frieling and colleagues4 performed a subgroup analysis on the PHS data to assess the association of beta-carotene supplementation and the incidence of nonmelanoma skin cancer (basal cell and squamous cell carcinoma), an endpoint that was excluded from the original study. The study identified 1,786 cases of basal cell and squamous cell carcinoma in the beta-carotene group versus 1,821 cases in the placebo group. No protective or harmful effect of beta-carotene supplementation on non-melanoma skin cancer was found (RR, 0.98; 95% CI, 0.92-1.05).
In an update of the PHS analysis based on inclusion of data from additional cancer cases presenting during the trial period that were identified after publication, the authors reported no association of beta-carotene with total incidence of cancer (RR,1.0; 95% CI, 0.9-1.0; P=.41) or site-specific cancers, including prostate, colon, or lung cancers.5 A positive association was noted between beta-carotene supplementation and cancers of the bladder (103 cases; RR,1.5; 95% CI, 1.0-2.2; P=.04) and thyroid (21 cases; RR, 9.5; 95% CI, 2.2-40.7; P=.003); however, these findings are based on a small number of cases and could be due to chance because of examination of multiple endpoints. Additionally, the authors evaluated the effect of beta-carotene within subgroups defined by certain baseline characteristics. There was no significant association of beta-carotene supplementation with cancer incidence among subjects defined by several baseline factors, including age, alcohol use, smoking status, BMI, exercise, multivitamin use, or dietary beta-carotene.
A nested case-control study based on data from the 14,916 subjects of the PHS who submitted baseline blood specimens prior to randomization suggests that beta-carotene supplementation may reduce the risk for prostate cancer in those with low baseline serum beta-carotene levels.6 A total of 1,439 cases of cancer and 631 cases of prostate cancer were identified during the 12-year followup period in this subgroup. Consistent with other studies, no significant association was reported between beta-carotene supplementation and total cancer or prostate cancer incidence. When baseline plasma levels of beta-carotene were taken into account, a marginally significant protective effect of beta-carotene on prostate cancer incidence was found among participants in the lowest quartile for baseline plasma beta-carotene (RR, 0.68; 95% CI, 0.46-0.99; P=.04 and P=.01 for trend).
The ATBC study was a large clinical trial investigating the effect of alpha-tocopherol (vitamin E) and beta-carotene on lung cancer incidence and mortality among male Finnish smokers over an average 6 years of followup.7 Subjects were randomized into one of four intervention groups in a 2x2 factorial design:
The ATBC study group reported no preventive effect of vitamin E or beta-carotene supplementation on cumulative incidence of lung cancer (RR,1.02; 95% CI, .86-1.12; P=0.8 and RR,1.18; 95% CI, 1.03-1.36; P=.01, respectively). Followup studies of the ATBC trial have continued to support this finding for various subgroups and cancer endpoints.
Rautalahti and colleagues8 analyzed the ATBC data for effects of alpha-tocopherol and beta-carotene supplementation on pancreatic cancer incidence and mortality over the same followup period. No statistically significant effect on pancreatic cancer risk was found in the intervention groups that received alpha-tocopherol (RR, 1.34; 95% CI, 0.88-2.05) or in the groups receiving beta-carotene (RR, 0.75; 95% CI, 0.49-1.14).
Two recent supplementary analyses of the ATBC study investigated 2 cancer endpoints, colorectal and urinary tract cancer incidence and mortality. Albanes and colleagues9 reported no significant preventive or harmful effects of beta-carotene or alpha-tocopherol on colorectal cancer risk. Based on the cumulative incidence of colorectal cancer over the study period, the relative risk among the patients in the groups receiving alpha-tocopherol supplementation was 0.78 (95% CI, 0.55-1.09; P=.15) and in groups receiving beta-carotene, 1.05 (95% CI, 0.75-1.47; P=.78). Virtamo and colleagues10 reported similar findings with respect to urothelial (bladder, renal pelvis, and ureter) and renal cell carcinoma. In the groups receiving alpha-tocopherol supplements there was no significant effect on incidence of urothelial or renal cell cancer (RR, 1.10; 95% CI, 0.8-1.5; P=.48 and RR, 1.10; 95% CI, 0.7-1.6; P=.55, respectively). Among groups randomized to beta-carotene supplementation, there was no significant change in risk for urothelial cancers (RR, 1.0; 95% CI, 0.7-1.3; P=.92) and renal cell cancers (RR, 0.8; 95% CI, 0.6-1.30; P=.57) when compared with groups not receiving beta-carotene.
Two recent prospective cohort studies based on ATBC data have presented mixed results regarding the association of cancer risk and baseline serum levels of nutrient oxidants and dietary antioxidants. These studies did not examine the independent effect of supplementation on cancer risks. Malila and colleagues11 analyzed data from a cohort of 26,951 participants of the ATBC trial who had completed dietary surveys and provided serum samples prior to randomization to assess the effect on colorectal cancer risk. One hundred eighty-four cases of colorectal cancer cases were diagnosed in this cohort over an average 8-year followup period. No association was found between dietary intake of various antioxidants, including vitamin C, vitamin E, alpha-tocopherol, gamma-tocopherol, beta-carotene, and retinol, and colorectal cancer risk. After adjusting for age, BMI, smoking, supplementation assignment, and other factors, similar results were obtained when comparing the highest to the lowest quartiles of baseline serum levels of alpha-tocopherol (RR, 0.94; 95% CI, 0.57-1.57; P=.72 for trend), beta-carotene (RR,0.86; 95% CI, 0.54-1.36; P=.82 for trend), and retinol (RR,1.02; 95% CI, 0.65-1.58; P=.75 for trend). No interaction was noted between supplementation assignment and dietary or serum alpha-tocopherol and beta-carotene levels.
The second study12 examined lung cancer incidence and mortality outcomes and reported an increased risk associated with decreasing dietary and serum alpha-tocopherol levels. Among the 29,102 participants of the ATBC trial who had had serum alpha-tocopherol levels taken prior to randomization, 1,144 cases of lung cancer were diagnosed. The relative risk for lung cancer when comparing the highest quintile of baseline serum alpha-tocopherol levels to the lowest quintile was .81 (95% CI, 0.67-0.97; P=.09 for trend) after controlling for age, BMI, smoking, energy, and intervention assignment. No significant interaction was found between alpha-tocopherol supplementation assignment and baseline serum alpha-tocopherol levels. Similar results were obtained when comparing the highest and lowest quintiles of dietary alpha-tocopherol levels (RR, 0.80; 95% CI, 0.66-0.97; P=.02 for trend) and dietary vitamin E intake (RR, 0.77; 95% CI, 0.64-0.93; P=.01 for trend).
The clinical trials reviewed here spanning 1999 to 2002 do not document any consistent association between vitamin supplementation and risk for cancer. This finding is consistent with an earlier review and with prior large, randomized controlled trials of vitamin supplementation. The possibility remains of risk reduction among certain subgroups defined by cancer type or baseline characteristics. The studies that have reported an inverse relationship between supplementation of vitamins and risk for specific cancers may be affected by small case numbers and evaluation of multiple endpoints and have yet to be replicated.
1. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet. 2002;360:23-33.
2. Green AG, Williams G, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet. 1999;354:723-729.
3. Hennekens CH, Buring JE, et al. Lack of effect of long-term supplementation with beta-carotene on the incidence of malignant neoplasms and cardiovascular disease. New Eng J Med. 1996;334:1145-1149.
4. Frieling UM, Schaumberg, DA, et al. A randomized, 12-year primary-prevention trial of beta-carotene supplementation for nonmelanoma skin cancer in the Physician's Health Study. Arch Dermatol. 2000;136:179-184.
5. Cook NR, Lee I, et al. Effects of beta-carotene supplementation on cancer incidence by baseline characteristics in the Physicians' Health Study (United Sates). Cancer Causes Control. 2000;11:617-626.
6. Cook NR, Stampfer M, et al. Beta-carotene supplementation for patients with low baseline levels and decreased risks of total and prostate carcinoma. Cancer. 1999;86:1783-1792.
7. The Alpha-tocopherol Beta Carotene Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. New Eng J Med. 1994;330:1029-1035.
8. Rautalahti MT, Virtamo J, et al. The effects of supplementation with alpha-tocopherol and beta-carotene on the incidence and mortality of carcinoma of the pancreas in a randomized, controlled trial. Cancer. 1999;86:37-42.
9. Albanes D, Malila N, et al. Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: results from a controlled trial (Finland). Cancer Causes Control. 2000;11:197-205.
10. Virtamo J, Edwards BK, et al. Effects of supplemental alpha-tocopherol and beta-carotene on urinary tract cancer: Incidence and mortality in a controlled trial (Finland). Cancer Causes Control. 2000;11:933-939.
11. Malila NJ, Virtamo J, et al. Dietary and serum alpha-tocopherol, beta-carotene and retinol, and risk for colorectal cancer in male smokers. Eur J Clin Nutrition. 2002;56:615-621.
12. Woodson K, Tangrea JA, et al. Serum alpha-tocopherol and subsequent risk of lung cancer among male smokers. J Nat Cancer Instit. 1999;91:1738-1743.
[a] Atkins, Shetty: Agency for Healthcare Research and Quality, Center for Outcomes and Evidence, Suite 6000, 540 Gaither Road, Rockville, MD 20850.
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Source: Atkins D, Shetty P. Update of the Evidence From Randomized Controlled Trials, 1999-2002. Routine Vitamin Supplementation to Prevent Cancer.
Current as of June 2003
Internet Citation:
Shetty P, Atkins D. Update of the Evidence From Randomized Controlled Trials, 1999-2002. Routine Vitamin Supplementation to Prevent Cancer. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/3rduspstf/vitamins/vitupdate.htm
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