Summary of Evidence From Randomized Controlled Trials

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.

Reprints of this chapter, a related chapter (https://www.uspreventiveservicestaskforce.org) and through the National Guideline Clearinghouse™ .

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?

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).

Analysis/Synthesis

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).

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.

(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.

Beta-Carotene

Evidence from 5 randomized controlled trials^8-12 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

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

Prostate Cancer

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

Colon Cancer

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).

Breast Cancer

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

All-cause Mortality

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

Vitamin E

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.

Lung Cancer

In ATBC, vitamin E had no effect on the primary endpoint, lung cancer incidence (RR, 0.98; 95% CI, 0.86-1.12).

Prostate Cancer

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.

Other Cancers

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

All-cause Mortality

The relative risk for all-cause mortality in the vitamin E supplemented arm in ATBC was 1.02 (95% CI, 0.95-1.09).

Vitamin Combinations

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.

Colonic Polyps

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).

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.

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.

Acknowledgments

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.

Author Affiliations

[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.

Copyright and Source Information

This document is in the public domain within the United States. Requests for linking or to incorporate content in electronic resources should be sent via the USPSTF contact form.

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.

^A For more details about the trials, go to Appendix 3.
Note: ATBC indicates Alpha-Tocopherol Beta-Carotene; g, gram; mg, milligram; n, number; FU, followup; NR, not reported; CARET, Beta-Carotene and Retinol Efficacy Trial.

^A For more details about the trials, go to Appendix 3.
^B All confidence intervals .95%.
^c Unadjusted odds ratio.
Note: ATBC indicates Alpha-Tocopherol Beta-Carotene; g, gram; mg, milligram; n, number; FU, followup; NR, not reported; CARET, Beta-Carotene and Retinol Efficacy Trial.

The results of observational cohort studies that met the inclusion criteria are summarized in Appendix Table 1. Major features of each study are summarized below. Additional information about most studies is available in: Morris CD and Carson S. Vitamin supplementation to prevent cardiovascular disease, summary of the evidence for the U.S. Preventive Services Task Force available at https://www.uspreventiveservicestaskforce.org/.

1. The Netherlands Cohort Study.^A1,A2 This study was designed to examine the association between intake of vitamins C and E, retinol, and beta-carotene and risk of breast cancer. Women from the general population aged 50-69 at baseline were eligible for enrollment. Of the 62,573 women enrolled, 96% continued for 3.3 years (median) of followup. The study found no relationship between the use of vitamin C supplements and breast cancer.

2. Nurses' Health Study I.^{A3,A4,A5,A6,A7} This study was conducted in the United States and designed to determine whether vitamins A, C, E, folic acid, and multivitamin supplements are related to risk of colorectal adenomas. Female nurses aged 34-59 at baseline were eligible for enrollment. Of the 89,494 women enrolled, 96% continued for 8 years of followup participation.

3. Canadian National Breast Screening Study.^A8 This study was conducted in Canada and designed to examine the relationships of vitamins A, C, and E to risk of breast cancer. Women aged 40-59 at baseline who were involved in an ongoing breast cancer screening study were eligible for enrollment. Of the 56,837 qualified study subjects, 96% continued for 5 years of followup participation.

4. Leisure World Study.^A9,A10 This US study was designed to examine the relationships of vitamins A, C, and E to risk of lung, colon, bladder, prostate, and breast cancers. Males and females living in the Leisure World retirement community were eligible for enrollment. The average age of the 70,159 qualified study subjects (24,218 men and 45,941 women) was mid-70's. Four- to 8-year followup rates were 99% for vital status and 85% for incident cancers. Statistical adjustment was made for age and smoking but not for other confounders.

5. Health Professionals' Follow-up Study.^A11,A12 This study was conducted in the United States and designed to examine the relationships of folic acid, beta carotene and vitamins C and E to risk of colon cancer. Male dentists, osteopaths, optometrists, podiatrists, pharmacists, and veterinarians aged 40-75 were eligible for participation. Of the 43,738 qualified study subjects, 96% continued for 4 years of followup participation.

6. Iowa Women's Health Study.^A13,A14,A15 This study, conducted in the United States, was designed to investigate whether high intakes of antioxidant micronutrients (vitamins A, C, and E and beta-carotene) protect against colon and breast cancers. Women living in Iowa in 1986 who were aged 55-69 years at baseline and did not have a history of cancer were eligible for participation following completion of a dietary questionnaire. Of the 34,486 qualified study subjects, 84% continued for 5 years of followup participation.

7. National Health and Nutritional Examination Survey I.^A16 This US study was designed to examine the relation between vitamin C intake and cancer and all-cause mortality. Noninstitutionalized US adults aged 25-74 years at baseline who were nutritionally examined during 1971-1974 as part of an epidemiological followup study (NHANES I) were eligible for participation. Of the 14,407 qualified study subjects, 93% continued for 10 years (median) of followup participation.

8. Established Populations for Epidemiologic Studies of the Elderly.^A17 This study was conducted in the United States and designed to examine vitamin E and vitamin C supplement use in relation to mortality risk and whether vitamin C enhanced the effects of vitamin E. Residents of 4 east coast communities who were older than 65 at baseline (range 67-105) and who were involved in the Established Populations for Epidemiologic Studies of the Elderly in 1984-1993 were eligible for enrollment. Of the 11,178 qualified study subjects, 100% continued for 6 years of active participation and an additional 2-3 years for mortality followup. Adjustment was made for alcohol use, smoking history, aspirin use, and medical conditions.

9. Cancer Prevention Study II.^A18 This study was conducted in the United States and designed to determine the relation between multivitamin use and cancer and all-cause mortality. American Cancer Society volunteers recruited men and women aged 30 years and older for participation. The percentage of the 1,063,023 (453,962 men and 609,061 women) eligible study subjects who continued for the 7-year followup participation period is unclear.

10. Substudy of Polyp Prevention Study.^A19 Conducted in the United States, this study was designed to determine the relation between folate and multivitamin use and adenomatous polyp recurrence. Adults who were involved in the Polyp Prevention Study were eligible for enrollment. Eligible study subjects were 79% male and an average age of 60 years. The percentage of the 709 participants that completed the 4-year followup colonoscopy is unclear.

11. Nurses' Health Study and Health Professionals' Followup Study.^A4 This analysis was designed to measure the association of folate and methionine to risk for colorectal adenoma. Female nurses aged 34-59 from the Nurses' Health Study started in 1976. Male dentists, osteopaths, optometrists, podiatrists, pharmacists, and veterinarians aged 40-75 from the Health Professionals Followup Study, all of whom had undergone an endoscopy, were eligible for participation, started in 1986. Combined 4-year followup rates for the 9490 male subjects and 10-year followup rates for the 15,984 females subjects were 96% for standardized questionnaire completion and 91% for response to letter following adenomatous polyp recurrence.

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Note: CIN indicates cervical intraephithelial neoplasia; SU.VI.MAX, Supplementation en VItamines et Mineraux Antioxydants; SECURE, Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E; post-PTCA, post-percutaneous transluminal coronary angioplasty; CHAOS, Cambridge Heart Antioxidant Study.

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B5. Hercberg S, Preziosi P, Briancon S, Galan P, Triol I, Malvy D, et al. A primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers in a general population: the SU.VI.MAX study—design, methods, and participant characteristics. SUpplementation en VItamines et Mineraux AntioXydants. Control Clin Trials 1998;19:336-51.

B6. Lonn EM, Yusuf S, Doris CI, Sabine MJ, Dzavik V, Hutchison K, et al. Study design and baseline characteristics of the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E: SECURE. Am J Cardiol 1996;78:914-9.

B7. DeMaio SJ, King SB, di Lembo NJ, Roubin GS, Hearn JA, Bhagavan HN, et al. Vitamin E supplementation, plasma lipids and incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA). J Am Coll Nutr 1992;11:68-73.

B8. Christen WG, Gaziano JM, Hennekens CH. 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. Ann Epidemiol 2000;10:125-34.

B9. Butterworth CEJ, Hatch KD, Soong SJ, Cole P, Tamura T, Sauberlich HE, et al. Oral folic acid supplementation for cervical dysplasia: a clinical intervention trial. Am J Obstet Gynecol 1992;166:803-9.

B10. Hofstad B, Vatn M, Hoff G, Larsen S, Osnes M. Growth of colorectal polyps: design of a prospective, randomized, placebo-controlled intervention study in patients with colorectal polyps [published erratum appears in Eur J Cancer Prev 1993 Mar;2(2):189]. Eur J Cancer Prev 1992;1:415-22.

B11. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-6.

B12. Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project. Lancet 2001;357:89-95.

B13. McLarty JW. An intervention trial in high-risk asbestos-exposed persons. Adv Exp Med Biology 1992;320:141-9.

B14. Miller ER, Appel LJ, Levander OA, Levine DM. The effect of antioxidant vitamin supplementation on traditional cardiovascular risk factors. J Cardiovasc Risk 1997;4:19-24.

B15. Paganelli GM, Biasco G, Brandi G, Santucci R, Gizzi G, Villani V, et al. Effect of vitamin A, C, and E supplementation on rectal cell proliferation in patients with colorectal adenomas. J Natl Cancer Inst 1992;84:47-51.

B16. Tsubono Y, Okubo S, Hayashi M, Kakizoe T, Tsugane S. A randomized controlled trial for chemoprevention of gastric cancer in high-risk Japanese population; study design, feasibility and protocol modification. Jpn J Cancer Res 1997;88:344-9.

B17. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 1999;354:447-55.

B18. Hoogwerf BJ, Young JB. The HOPE study. Ramipril lowered cardiovascular risk, but vitamin E did not. Cleve Clin J Med 2000;67:287-93.

B19. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:154-60.

B20. Munoz N, Wahrendorf J, Bang LJ, Crespi M, Thurnham DI, Day NE, 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. Lancet 1985;2:111-4.

B21. Stich HF, Hornby AP, Mathew B, Sankaranarayanan R, Nair MK. Response of oral leukoplakias to the administration of vitamin A. Cancer Lett 1988;40:93-101.

B22. Stich HF, Rosin MP, Hornby AP, Mathew B, Sankaranarayanan R, Nair MK. Remission of oral leukoplakias and micronuclei in tobacco/betel quid chewers treated with beta-carotene and with beta-carotene plus vitamin A. Int J Cancer 1988;42:195-9.

B23. Zaridze D, Evstifeeva T, Boyle P. Chemoprevention of oral leukoplakia and chronic esophagitis in an area of high incidence of oral and esophageal cancer. Ann Epidemiol 1993;3:225-34.

B24. Wang GQ, Dawsey SM, Li JY, Taylor PR, Li B, Blot WJ, 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. Cancer Epidemiol Biomarkers Prev 1994;3:161-6.

B25. Taylor PR, Li B, Dawsey SM, Li JY, Yang CS, Guo W, et al. Prevention of esophageal cancer: the nutrition intervention trials in Linxian, China. Linxian Nutrition Intervention Trials Study Group. Cancer Res 1994;54:2029s-2031s.

B26. Dawsey SM, Wang GQ, Taylor PR, Li JY, Blot WJ, Li B, 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. Cancer Epidemiol Biomarkers Prev 1994;3:167-72.

B27. Li JY, Li B, Blot WJ, Taylor PR. [Preliminary report on the results of nutrition prevention trials of cancer and other common diseases among residents in Linxian, China] [Chinese]. Chung-Hua Chung Liu Tsa Chih [Chinese Journal of Oncology] 1993;15:165-81.

B28. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J 1999;20:725-41.

B29. Wald DS, Bishop L, Wald NJ, Law M, Hennessy E, Weir D, et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Intern Med 2001;161:695-700.

B30. Greenberg ER, Baron JA, Stukel TA, Stevens MM, Mandel JS, Spencer SK, et al. A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin. The Skin Cancer Prevention Study Group [published erratum appears in N Engl J Med 1991 Oct 31;325(18):1324]. N Engl J Med 1990;323:789-95.

B31. Green A, Williams G, Neale R, Hart V, Leslie D, Parsons P, 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;354:723-9.

B32. Ambler JS, Hirst LW, Clarke CV, Green AC. The Nambour study of ocular disease. I. Design, study population and methodology. Ophthalmic Epidemiol 1995;2:137-44.

B33. Levine N, Moon TE, Cartmel B, Bangert JL, Rodney S, Dong Q, et al. Trial of retinol and isotretinoin in skin cancer prevention: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group. Cancer Epidemiol Biomarkers Prev 1997;6:957-61.

(Supplement to Table 1)

Note: n indicates number; ATBC, Alpha-Tocopherol Beta-Carotene; MI, myocardial infarction; BC, beta-carotene; FAP, familial adenomatous polyposis; GB, gall bladder; CARET, Beta-Carotene and Retinol Efficacy Trial.