Summary of Evidence From Randomized Controlled Trials
Routine Vitamin Supplementation to Prevent Cancer
Cheryl Ritenbaugh, Ph.D., M.PH.a; Kelly Streit, M.S., R.D.b; Mark Helfand, M.D., M.S.b
The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position from the Agency for Healthcare Research and Quality, or the U.S. Department of Health and Human Services.
Address correspondence to: Cheryl Ritenbaugh, Ph.D., M.P.H., Senior Investigator, Kaiser Permanente Center for Health Research, 3800 N. Interstate Avenue, Portland OR, 97227-1110; E-mail: Cheryl.Ritenbaugh@kp.org.
Select for copyright and reprint information.
Reprints of this chapter, a related chapter (Routine Vitamin Supplementation to Prevent Cardiovascular Disease: A Summary of the Evidence for the U.S. Preventive Services Task Force) and the USPSTF recommendations based on the two chapters (Routine Vitamin Supplementation to Prevent Cancer and Cardiovascular Disease: Recommendations and Rationale) are available on the AHRQ Web Site (www.preventiveservices.ahrq.gov) and through the National Guideline Clearinghouse (www.guideline.gov). They are also available from the AHRQ Publications Clearinghouse in print or through subscription to the Guide to Clinical Preventive Services, Third Edition: Periodic Updates. To order, contact the Clearinghouse at 1-800-358-9295 or E-mail firstname.lastname@example.org.
Role of the Funding Source
Recommendations for Future Research
Cancer is the second leading cause of death in the United States, accounting for 1 of every 4 deaths.1 Nutritional status has long been speculated to play a significant role in certain cancers. One theory holds that oxidative damage to cells contributes to carcinogenesis. In laboratory experiments, the antioxidant vitamins, vitamin C, vitamin E (alpha-tocopherol), and beta-carotene, counteract damage to biomolecules due to oxidants,2 raising the possibility that increased intake of these vitamins might prevent cancer. Vitamin A (retinol), which acts within the cell to control gene expression, and folic acid,3 which is involved in DNA methylation and purine and pyrimidine synthesis, may also have a role in preventing cancer.4
In epidemiological studies, low dietary intake and blood levels of certain antioxidant vitamins have been associated with a higher incidence of certain cancers and higher cancer mortality.5 Several randomized controlled trials designed to test the efficacy of vitamin supplements in the primary prevention of cancer have also been undertaken. These randomized trials have examined the effect of vitamin supplements on cancer biomarkers, on the incidence and progression of precancerous lesions, on the incidence of invasive cancer, and on cancer-specific and all-cause mortality.
Most of the trials that examined cancer incidence and mortality have been published in the last decade. In light of the large body of new evidence, the U.S. Preventive Services Task Force decided that it was timely to review the benefits of vitamin supplementation. This summary reviews randomized trials that addressed this question, posed by the Task Force:
Do antioxidant vitamin supplements reduce all-cause mortality, cancer mortality, or the incidence of cancer or certain precancerous lesions in the general adult population of the United States?
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Literature Search and Study Selection
The criteria for inclusion in the review were developed in consultation with members of the USPSTF. English-language randomized controlled trials and prospective cohort studies concerning adults in developed countries were eligible for inclusion. Case-control studies were excluded unless they were performed in the context of a prospective cohort study (i.e., a nested case-control study). Studies of supplementation with vitamin A, vitamin C, vitamin E, beta-carotene, folic acid, combinations of these vitamins, or a multiple vitamin were eligible if they reported a) the incidence of or mortality from any invasive cancer other than nonmelanoma skin cancer or b) the incidence of colonic polyps. Studies of other precancerous lesions, carcinoma in situ, and regression of cancer or of precancerous lesions were excluded.
This summary reports the results of our review of randomized trials that address this question. The results of the cohort studies were presented to the USPSTF, but they are excluded from this report because they did not contribute to the Task Force's recommendations. Appendix 1 summarizes the results of the included cohort studies. We searched the Cochrane Controlled Trials Registry (December 2001) and the MEDLINE® database from 1966 to December 2001 using terms for the 5 nutrients (A, C, E, beta-carotene, and folate) as well as multivitamin and antioxidant supplements and terms for cancer and precancerous lesions. We also searched the reference lists of review articles and, in several rounds of review of earlier manuscripts, asked experts for additional references. Finally, we searched MEDLINE® again (December 2001) using the acronyms or full titles of the major trials and cohort studies to identify additional publications. Two reviewers applied the eligibility criteria listed above after reviewing the titles and abstracts of retrieved citations and again after selecting full-text articles for closer review.
The searches identified 932 citations, of which 102 were reports from 36 randomized controlled trials. Ten of these trials were included in this review. The excluded trials either had no eligible cancer endpoints, combined included with excluded nutrients, or had not yet reported results (Appendix 2).
Two reviewers independently abstracted descriptive data from the included trials, using one form for abstraction of information about the study design and another form for results. To assess study quality, we used the system developed by the USPSTF, which includes a set of 6 criteria to rate the internal validity of each study as "good," "fair," or "poor."6 For clinical trials we also assessed study quality using the Jadad score.7 We summarized the results of studies in evidence tables organized by type of study, nutrient, and outcome. For supplement/outcome combinations with sufficient evidence, we assessed heterogeneity among studies and conducted meta-analyses using a pairwise, sequential procedure based on maximum likelihood methods (M. Aickin, Ph.D., and M. Helfand, M.D., M.P.H., unpublished data, 2000).
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Role of the Funding Source
This research was funded by AHRQ under a contract to support the work of the USPSTF. AHRQ staff and USPSTF members participated in the initial design of the study and reviewed interim analyses and the final manuscript.
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(Table 1) summarizes the characteristics of the 9 randomized controlled trials that met the criteria for inclusion. Beta-carotene supplementation has been studied in 5 controlled trials (Appendix 3 provides more details about the trials). Only 1 trial examined the effect of vitamin E supplementation on cancer incidence and mortality. For these outcomes, no studies of vitamin A or vitamin C alone versus placebo have been completed. Vitamin C has been studied only in combination with other vitamins. None of the included trials addressed supplementation with folic acid. Six studies examined vitamin combinations; 4 did so as part of a factorial design and 2 did not.
Evidence from 5 randomized controlled trials8-12 indicates that beta-carotene supplementation increases lung cancer incidence in smokers and has no effect on cancer incidence in nonsmokers. These trials were designed to test beta-carotene at levels above those that could be achieved through food, approximately 10 times the average U.S. intake.13 They achieved substantially higher blood levels of beta-carotene than those associated with benefit in epidemiological studies.
Lung cancer was the primary endpoint in the Alpha-Tocopherol Beta-Carotene (ATBC) trial.9 In ATBC, 29,133 male smokers were randomized in geographically defined blocks to vitamin E, beta-carotene, both, or neither.9 Baseline characteristics were similar in the 4 groups. There were only 113 exclusions after randomization, 97 of whom were excluded because Finnish cancer registry records or a chest x-ray showed that cancer was present prior to randomization. Analysis was by intention-to-treat. The study was terminated early for a significant adverse effect of beta-carotene on lung cancer incidence among heavy smokers (relative risk [RR], 1.19; 95% confidence interval [CI], 1.03-1.35). Total mortality was 8% higher (RR, 1.08; 95% CI, 1.01-1.16) among the participants who received beta-carotene than among those who did not, primarily because there were more deaths from lung cancer and ischemic heart disease.
The Beta-Carotene and Retinol Efficacy Trial (CARET)14 was designed to test the combination of beta-carotene (30 mg/d) and vitamin A (retinyl palmitate 25,000 IU/d) to prevent lung cancer in 18,000 high-risk participants—asbestos workers and heavy smokers. After 4 years, there were statistically significant increases in the incidence of lung cancer (RR, 1.28; 95% CI, 1.04 to 1.57; P=.02), mortality from lung cancer (RR, 1.46; 95% CI, 1.07 to 2.00), and all-cause mortality (RR, 1.17; 95% CI, 1.03 to 1.33).
A randomized controlled trial among 1,024 asbestos workers in Australia15 compared a group receiving beta-carotene (30 mg) with a group receiving vitamin A (25,000 IU/d retinol) without a placebo group. The vitamin A group had lower total mortality than the beta-carotene group, largely due to a significantly lower risk for developing mesothelioma (RR, 0.24; 95% CI, 0.07-0.86; 3 vs 12 cases). Incidence of lung cancer, however, was not significantly lower in the subjects randomized to vitamin A (RR, 0.66; 95% CI,0. 19-2.32). Without untreated controls, it is uncertain whether these findings indicate a harmful effect of beta-carotene or a beneficial effect of vitamin A, but they confirm the findings of other trials of a lack of benefit of beta-carotene.
The Physicians' Health Study found no impact of beta-carotene on lung cancer incidence in an average-risk population with a low prevalence of smokers (RR, 0.93; 95% CI, 0.69-1.25).8 There was also no significant increase in lung cancer incidence in the beta-carotene arm of the Women's Health Study (RR, 1.43; 95% CI, 0.82-2.48).10 However, this arm was terminated early after a median duration of treatment of only 2.1 years due to the lack of benefits of beta-carotene (and suggestion of possible adverse effects) observed in the other trials discussed above.10
For prostate cancer, there was no significant effect of beta-carotene on the incidence of prostate cancer in ATBC (RR, 1.23; 95% CI, 0.95-1.60).16 In the Physicians' Health Study, there was no effect on lung cancer incidence among all men randomized to beta-carotene (RR, 0.99; 95% CI, 0.88-1.11).8 However, among subjects in the lower quartile of serum beta-carotene at baseline, the incidence of prostate cancer was significantly reduced among subjects who received beta-carotene compared with those receiving placebo.17,18
Beta-carotene supplementation had no effect on the incidence of colon cancer in ATBC21, (RR, 1.05; 95% CI, 0.75-1.47), in the Physicians' Health Study8 (RR, 0.96; 95% CI, 0.78-1.18), or in the Women's Health Study (RR, 0.99; 95% CI, 0.62-1.60).10
Two studies tested the impact of beta-carotene on the recurrence of adenomatous polyps. A U.S. trial11 found no effect on the relative risk for recurrence in subjects randomized to beta-carotene vs placebo (adjusted RR, 1.01; 95% CI, 0.85 to 1.20), while an Australian trial12 was terminated after 2 years because of a trend toward an increased incidence of recurrent polyps in the beta-carotene group (unadjusted odds ratio, 1.5; 95% CI, 0.9-2.5).
The Women's Health Study found no effect of beta-carotene supplementation on breast cancer (RR, 1.01; 95% CI, 0.81-1.24).10
Beta-carotene supplementation had no effect on all-cause mortality in the ATBC (RR, 1.08; 95% CI, 1.01-1.16),9 the Physicians' Health Study (RR, 1.01; 95% CI, 0.93-1.10),8 the Women's Health Study (RR, 1.07; 95% CI, 0.74-1.56),10 and a skin cancer prevention study (RR, 1.03; 95% CI, 0.82-1.30).20
The only randomized controlled trial data on vitamin E supplementation and cancer risk come from the ATBC trial, which included only male smokers. No studies in women have been completed.
In ATBC, vitamin E had no effect on the primary endpoint, lung cancer incidence (RR, 0.98; 95% CI, 0.86-1.12).
In ATBC, the effect of vitamin E supplementation on incidence and mortality from several cancers was examined as part of a planned secondary endpoint analysis.21 Patients who took supplemental vitamin E had a lower incidence of prostate cancer than those who did not (RR, 0.66; 95% CI, 0.44-0.94; number of cases 99/14,564 compared with 151/14,569) and also had lower mortality from prostate cancer (RR, 0.59; 95% CI, 0.35-0.99).16,22 Protection against prostate cancer was greater among men with more pack-years of smoking, differing from the lung cancer result.
How valid is this result likely to be? The examination of multiple individual cancers as secondary endpoints raises the possibility that this is a chance finding. Comparability between groups in the baseline risk for prostate cancer was only partially ascertainable; this is a concern because baseline differences in risk cannot be ruled out in a trial that used geographically defined blocks as the unit of randomization. Geographic differences in rates of prostate procedures, such as transurethral resection of the prostate, could also result in spurious differences in incidence. This ascertainment bias could also affect the likelihood that a death was attributed to prostate cancer. These biases cannot be ruled out, but, if they are present, one would expect them to affect the results of beta-carotene as well as vitamin E. As noted earlier, beta-carotene had no protective effect on prostate cancer incidence or mortality in ATBC; in fact, there was a trend toward harm.
Colon Cancer and Polyps
In 2 reports from the ATBC trial, vitamin E supplementation did not reduce colon cancer incidence significantly (RR, 0.78; 95% CI, 0.55-1.09).19 Vitamin E supplementation increased the risk for adenomatous polyps (RR, 1.66; 95% CI, 1.19-2.32).23 This finding might have been due to differences in rates of detection because the patients diagnosed to have polyps who received vitamin E supplement were more likely to have pre-diagnosis rectal bleeding and intestinal pain, symptoms which may have led to higher rates of colonoscopy.
In ATBC, vitamin E supplementation was not associated with a significant difference in the incidence of stomach cancer (70/14,564 in those receiving vitamin E compared with 56/14,569; P=0.21).21 It had no effect on pancreatic cancer incidence (RR, 1.34; 95% CI, 0.88-2.05) or mortality.24
The relative risk for all-cause mortality in the vitamin E supplemented arm in ATBC was 1.02 (95% CI, 0.95-1.09).
Three of the studies described above, CARET, ATBC, and the Polyp Prevention Study,11 and 2 additional trials of polyp prevention, randomized at least 1 arm to a vitamin combination. The results from CARET (beta-carotene plus vitamin A) were discussed above. In ATBC, there was no benefit in the combined antioxidant (beta-carotene plus vitamin E) arm for any cancer, and there were no interactions between beta-carotene and vitamin E.
Studies of the efficacy of vitamin combinations to prevent colonic neoplasia had mixed results. The Polyp Prevention Study, a U.S. multi-center trial, used a factorial design to evaluate beta-carotene (described above) and vitamin C plus vitamin E.11 After 4 years on study (3 years between colonoscopies), the relative risk for polyp recurrence for the vitamin C plus vitamin E supplement vs placebo was 1.08 (95% CI, 0.91 to 1.29).
Two other trials examined the effect of vitamin combinations on colon polyps. In Canada, a randomized trial compared vitamin C plus vitamin E to lactulose and placebo.25 After 2 years of followup, there was no significant effect on polyp recurrence in the group randomized to vitamins C plus E compared with placebo (RR, 0.86; 95% CI, 0.51-1.45). A small Italian trial evaluated a daily dose of vitamin A plus vitamin C plus vitamin E vs. placebo in 150 participants.26 After a 3-year followup, the relative risk for polyp recurrence in the intervention group compared with the control group was RR, 0.16 (95% CI, 0.04-0.46).
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The main findings of this review are summarized in Table 2. The strongest finding is that beta-carotene supplements and combinations including beta-carotene are harmful in smokers and others at high risk for lung cancer. Another strong finding is that supplemental beta-carotene appears to have no effect on mortality or cancer incidence in the general population.
Historically, the results of randomized trials of vitamin supplements have not always confirmed those of epidemiological cohort studies. Even for well-designed, well-conducted cohort studies, it is never possible to be certain that the results do not reflect the influence of unrecognized confounders. Uncertainty about the adequacy of control for the "healthy user effect" and other potential confounders makes it difficult to decide how much weight to place on consistent results from cohort studies.
Limitations of the randomized trials may also be responsible for the discrepancy between trials and observational studies. The timeframe for prevention of chronic diseases may be longer than the followup period in the trials, or the trials may have examined the efficacy of supplements at the wrong time in the natural history of the disease. The trials of beta-carotene, for example, recruited subjects at high risk for developing lung cancer in order to increase statistical power. The subjects had smoked tobacco or been exposed to asbestos for many years before the efficacy of supplements was tested. This raises the possibility that the cohort studies observed a benefit from using beta-carotene earlier in the course of carcinogenesis, at a period that the trials have not examined.
The trials in nonsmokers may have the opposite problem: the subjects included in the trials may have been at lower risk than those observed to benefit in the cohort studies. In some of the epidemiological studies, supplements were associated with a reduced risk for cancer only in the subgroup of subjects who had low baseline intake or serum levels of antioxidant vitamins.5,27,28 As noted earlier, a similar observation was made in the Physicians' Health Study, in which beta-carotene supplementation was associated with a reduced incidence of prostate cancer in subjects who were relatively deficient in beta-carotene at baseline.17,18 The trials may have limited the chance of finding a benefit by focusing on relatively well-nourished subjects selected by profession rather than by baseline nutritional measures.
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Recommendations for Future Research
Among the vitamin-cancer combinations that have evidence from randomized trials, the most promising finding was that smokers who took vitamin E had a lower incidence of prostate cancer and lower mortality from prostate cancer than those who did not. A large U.S. trial is underway to confirm the finding that vitamin E might reduce mortality from prostate cancer.
Among the vitamin-cancer combinations that do not yet have evidence from randomized trials, the strongest evidence from observational studies is for a possible beneficial effect of vitamin A for breast cancer (go to Appendix 1). The cohort studies also raise the possibility that vitamin A reduces the risk for colon cancer in women.
The cohort studies evaluating B vitamin supplementation in relation to breast cancer and colon cancer also show some evidence of benefit. A randomized controlled trial of the effect of long-term B vitamin supplementation on polyp recurrence is currently underway.
Three other trials are also in progress. The Physicians' Health Study II has re-randomized many of the original Physicians' Health Study participants and has recruited additional participants to a 2x2x2 factorial randomized controlled trial comparing vitamin C, vitamin E, and a multivitamin (100% of RDA type) with placebo.29 The Women's Health Study, focusing on health professionals, is a factorial study of beta-carotene, vitamin E, and aspirin; the beta-carotene arm has been closed, but the vitamin E and aspirin arms continue. Finally, the "SUpplementation en VItamines et Mineraux AntioXydants" study is a population-based, randomized trial of over 12,000 subjects. The SU.VI.MAX study is designed to test the efficacy of a daily supplementation with antioxidant vitamins (vitamin C, 120 mg; vitamin E, 30 mg; and beta-carotene, 6 mg) and minerals (selenium, 100 microg; and zinc, 20 mg) at nutritional doses in reducing mortality from cancers and cardiovascular diseases.30,31
Epidemiological cohort studies will continue to be extremely important in providing guidance regarding the role of vitamin supplementation in the prevention of chronic disease. The largest established cohorts (Nurses' Health Study, Health Professionals' Follow-up Study, Iowa Women's Study, and Leisure World Study) are now reaching a stage of maturity in which they can provide information on risks and benefits associated with behaviors taking place early in the carcinogenesis process. A problem that will continue to plague the epidemiological studies, however, is the degree to which supplement users differ in other ways from non-users, ways that may not be fully accounted for in the multivariate analyses. Attempts by scientists to analyze the large cohort studies in ways that replicate, to the extent possible, clinical trial designs would be extremely useful in elucidating the sources of the differences in findings between clinical trials and cohort studies. Understanding the sources of these differences will permit us to better use the cohort study data and to better design long-term clinical trials.
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The study on which this summary is based was conducted by the Oregon Health & Science University Evidence-based Practice Center, under contract to the Agency for Healthcare Research and Quality (Contract No. 290-97-0018, Task Order No. 2).
The authors wish to thank Janet Allan, Ph.D., R.N., and Steven Woolf, M.D., M.P.H., of the U.S. Preventive Services Task Force and Susan Carson, M.P.H., and Kim Peterson, M..S, of the Oregon Health & Science University Evidence-based Practice Center, for their contributions to this project. The corresponding author confirms that the above acknowledgments include everyone who has contributed significantly to this work.
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[a] Ritenbaugh: Kaiser Permanente Center for Health Research, Portland, OR.
[b] Helfand, Streit: Oregon Evidence-based Practice Center, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, OR.
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Source: 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 are available from the AHRQ Web site at http://www.preventiveservices.ahrq.gov and through the National Guideline Clearinghouse (http://www.guideline.gov). Print copies of this evidence summary, along with other summaries and Recommendations and Rationale statements, are available by subscription to the Guide to Clinical Preventive Services, Third Edition: Periodic Updates. The cost of a subscription is $60 (PDF file, 230 KB; Text Version) and can be ordered through the AHRQ Publications Clearinghouse (call 1-800-358-9295 or E-mail firstname.lastname@example.org).
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Current as of June 2003
Ritenbaugh C, Streit K, Helfand M. Routine Vitamin Supplementation to Prevent Cancer: Summary of Evidence From Randomized Controlled Trials . Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/3rduspstf/vitamins/vitasum.htm