Table 1.

Clinical Trials Examining Vitamins and Minerals as Chemoprevention Agents

First Author Year, Study Name*	Number (n)	Population (Country)	Intervention	Duration	End Point	Results
Multivitamins and combinations
Blot 1993 15 Nutrition Intervention Trial	29,584	Health individuals aged 40–69 with no history of esophageal or stomach cancer (China)	Participants were randomized to receive either two of the four following combinations, all four combinations, or a placebo: zinc and retinol; riboflavin and niacin; vitamin C and molybdenum; beta-carotene, vitamin E and selenium.. Doses of each nutrient ranged from one to two times U.S. Recommended Daily Allowances (RDAs).	5.25 years	Cancer incidence (esophagus, gastric cardia, stomach, and other cancers), cancer mortality, and total mortality.	Those receiving beta carotene, vitamin E, and selenium experienced a significant reduction in overall mortality (RR=0.91; 95% CI=0.84–0.99), total cancer incidence (RR=0.87; 95% CI= 0.75–1.00), and stomach cancer incidence (RR=0.79; 95% CI=0.64–0.99). Supplementation with retinol and zinc, riboflavin and niacin, or vitamin C and molybdenum did not significantly cancer mortality, or cancer incidence.
Meyer 2005 16 SU.VI.MAX Trial	5,141	Healthy men aged 45–60 (Canada)	Randomized, double-blind placebo controlled trial. Participants received either a placebo or a capsule containing acombination of 120 mg vitamin C, 30 mg alpha-tocopherol, 6 mg beta-carotene, 100 μg selenium and 20 mg zinc every day for 8 years.	8 years	Prostate cancer incidence	Nonsignificant reduction of the rate of prostate cancer overall. Stratified analysis showed that among men with normal PSA levels, the rate of prostate cancer was significantly lower in those who received supplementation, (HR = 0.52; 95% CI = 0.29–0.92). In men with elevated PSA levels at baseline, selenium supplementation increased prostate cancer incidence although this result was only borderline statistically significant (HR = 1.54; 95% CI = 0.87–2.72).
Vitamin C
Moertel 1985 19	100	100 men and women with advanced colorectal cancer (United States)	Participants received either 10g of vitamin C or placebo daily	Median duration was 2.5 months with vitamin C and 3.6 months with placebo	Progression of advanced colorectal cancer and survival	Vitamin C supplementation did not result in any significant difference in disease progression or survival. No patients with measurable disease experience improvement after treatment with Vitamin C.
Gaziano 2009 20 The Physician’s Health Study II	14,641	Male physicians aged 50 years or older (United States)	Randomized, double-blind, placebo controlled factorial trail. Participants randomized to receive either 1) 400 IU of vitamin E every other day and 500 mg/dl of vitamin C daily; 2) 400 IU of vitamin E every other day and placebo vitamin C daily; 3) placebo vitamin E every other day and 500 mg/dl of vitamin C placebo daily; or 4) placebo Vitamin E and C.	Mean follow up 8 years	Total prostate cancer, total cancer, for vitamin E component; total cancer, incident colorectal cancer for vitamin C component. Total mortality and cancer mortality for both.	Vitamin E did not significantly affect the incidence of prostate cancer (active vs. placebo vitamin E HR=0.97; 95% CI=0.85–1.09), or total cancer (active vs. placebo vitamin E HR=1.04; 95% CI=0.95–1.13), There was no significant effect of vitamin C supplementation on total cancer incidence (active vs. placebo vitamin CHR = 1.01; 95% CI = 0.92–1.10; P = .86) or prostate cancer incidence (active vs. placebo vitamin C HR = 1.02; 95% CI = 0.90–1.15; P = .80). Neither vitamin E nor vitamin C had a significant effect on colorectal, lung, or other site-specific cancers.
Vitamin E
Lonn 2005 24 Heart Outcomes Prevention Evaluation (HOPE); HOPE – The Ongoing Outcomes (HOPE-TOO)	HOPE: 9,541 HOPE-TOO: 7,030	Men and women at least 55 years old with vascular disease or diabetes mellitus (International)	Randomized placebo controlled trial. Participants randomized to receive 400 IU/day of Vitamin E or placebo.	Mean duration of follow-up was 7 years.	Cancer incidence and cancer mortality.	There were no significant differences in incident cancers between the Vitamin E group and the placebo group (RR = 0.94; 95% CI = 0.84–1.06; P = 0.30) or in cancer mortality (RR=0.88; 95% CI: 0.71–1.09)
Lee 2005 25 The Women’s Health Study	39,876	Healthy women aged 45 years or older (United States)	Randomized placebo controlled trial. Participants were given either 600 IU of vitamin E or placebo on alternate days.	Average follow-up of 10.1 years	Total invasive cancer incidence; breast, lung and colon cancer incidence; cancer mortality	There were no significant differences between the two groups on the incidences of total cancer (RR = 1.01; 95% CI = 0.94–1.08; P = .87), breast cancer (RR = 1.00; 95% CI = 0.90–1.12; P = .95), lung cancer (RR = 1.09; 95% CI = 0.83–1.44; P = .52), or colon cancers (RR = 1.00; 95% CI = 0.77–1.31; P = .99). Vitamin E supplementation had no significant effect on cancer mortality (RR= 1.12, 95% CI 0.95–1.32).
Lipmann (2009)21 Selenium and Vitamin E Cancer Prevention Trial (SELECT)	35,533	Healthy men age 55 and older (age 50 and older if African American) with normal digital rectal exams and prostate specific antigens <4 ng/ml (United States, Canada, Puerto Rico)	Randomized, placebo-controlled trial. Participants were randomized into four groups 1) 200 μg/day of selenium, 2) 400 IU/day vitamin E, 3) Vitamin E and selenium supplements, or 4) placebo	Median follow up 5.5 years	Prostate cancer incidence, lung, colorectal, and overall primary cancer.	Supplementation with Vitamin E and/or selenium did not result in any significant differences in the incidence of prostate cancer (HR: 1.13 (99% CI, 0.95–1.35 for vitamin E; 1.04 (99% CI, 0.87–1.24) for selenium; and 1.05 (99% CI, 0.88–1.25) for selenium and _ vitamin E all vs placebo. There were no significant differences) in any other prespecified cancer end points.
Klein (2011) Selenium and Vitamin E Cancer Prevention Trial (SELECT)23	35, 533	Healthy men age 55 and older (age 50 and older if African American) with normal digital rectal exams and prostate specific antigens <4 ng/ml (United States, Canada, Puerto Rico)	Randomized, placebo-controlled trial. Participants were randomized into four groups 1) 200 μg/day of selenium, 2) 400 IU/day vitamin E, 3) Vitamin E and selenium supplements, or 4) placebo	Median 7 years	Prostate cancer incidence	Supplementation with Vitamin E resulted in an increased of risk prostate cancer (HR: 1.17; 99% CI: 1.004–1.36 P=0.008). Supplementation with both selenium and combination selenium and vitamin E resulted in a nonsignificant increase in prostate cancer risk. (HR: 1.09; 99% CI: 0.93–1.27, P=0.18 for selenium; HR: 1.05; 99% CI: 0.89–1.22, p=0.46 for selenium and Vitamin E respectively).
Selenium
Yu 1991 26	2,474	Male and female first-degree relatives of liver cancer patients (China)	Participants were randomized to receive 200 μg selenium or placebo daily.	2 years	Liver cancer incidence	Ten cases in the selenium and 13 cases in the placebo group were observed (RR = 0.55; 95% CI = 0.24 – 1.25).
Yu 199727	226	Male and female Hepatitis B Surface Antigen (HBsAg)-carriers between the ages of 21 and 63 years (China)	Participants either were randomized to receive 200 μg of selenium or placebo for 4 years	8 years	Liver cancer incidence	Eleven cases were detected in the placebo group and four cases in the selenium group (RR = 0.36; 95% CI = 0.12 – 1.11).
Clark 1996 Nutrition Prevention of Cancer Trial (NPCT)30	1312	Men and women 18–80 year with a history of basal cell or squamous cell skin carcinomas (United States).	A multicenter, double-blind, randomized, placebo-controlled trial. Participants were randomized to receive 200 μg of selenium or placebo. Patients were treated for a mean (SD) of 4.5 (2.8) years	A mean of 6.5 years	Incidence of basal and squamous cell carcinomas of the skin, prostate, lung, and colorectal cancer. all-cause mortality, total cancer mortality, and total cancer incidence.	Selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer: relative risk(RR):1.10,95% CI:, 0.95–1.28),;(RR: 1.14; 95% CI, 0.93–1.39) for basal and squamous cell carcinoma, respectively. Patients treated with selenium had a significant reductions in total cancer mortality (RR, 0.50; 95% CI, 0.31–0.80), total cancer incidence, (RR, 0.63; 95% CI, 0.47–0.85]), and incidences of lung, colorectal, and prostate cancers. The trial was stopped early because of the reductions in total cancer mortality and cancer incidence in the group treated with selenium,
Clark 199831 Nutrition Prevention of Cancer Trial (NPCT)	974	Men with a history of either a basal cell or squamous cell carcinoma.. (United States)	A multicenter, double-blind, randomized, placebo-controlled trial. Participants were randomized to receive 200 μg of selenium or placebo. Patients were treated for a mean (SD) of 4.5 (2.8) years	A mean of 6.5 years	Prostate cancer incidence	Lower risk of prostate cancer experienced among the intervention group than the placebo group (RR = 0.37; P = 0.002).
Li 2000 28	2,065	Male HBs-Ag carriers (China)	Participants were randomized to receive 0.5 mg sodium selenite or placebo daily.	3 years	Liver cancer incidence	Liver cancer incidence was significantly lower in the group treated with selenium than in the placebo group (RR = 0.51, 95% CI = 0.34 – 0.77).
Duffield-Lillico 200332 Nutritional Prevention of Cancer Trial (NPCT)	927	Men with no history of prostate cancer (United States)	200 μg/day of selenium in 0.5-g high-selenium or placebo	Mean follow-up 7.5 years	Prostate cancer incidence	Selenium supplementation significantly decreased the risk of prostate cancer incidence (RR = 0.51; 95% CI = 0.29–0.87, P = 0.002). The protective effect of selenium supplementation on risk of prostate cancer incidence is greatest among those with a PSA ≤ 4 ng/mL (RR = 0.35; 95% CI = 0.13–0.87, P = 0.01) and among those with a selenium baseline plasma level of ≤ 106.4 ng/mL (RR = 0.14; 95% CI = 0.02–0.59, P = 0.002).
Reid 200833 Nutritional Prevention of Cancer (NPCT)	424	High risk dermatology patients with confirmed histories of nonmelanoma skin cancer (NMSC) (United States)	Participants were randomized into three treatment groups: 400 μg/selenium), 200 μg of selenium, or placebo	6 years	Total NMSC, total squamous cell carcinoma, total basal cell carcinoma and total cancer incidence	The risk of NMSC increased among those who took the 200 μg selenium (HR = 1.51; 95% CI = 1.13–2.04, P < 0.006). No difference in risk of NMSC was shown at the 400 mcg group (HR = 0.95; 95% CI = 0.69–1.20, P = 0.51). Treatment with 200 μg of selenium decreased total cancer incidence (RR= 0.75 = 95% CI: 0.56–0.99)
Beta-Carotene
Greenberg 1990 38	1,805	Patients who had had a recent nonmelanoma skin cancer (United States)	Participants randomized to receive either 50 mg beta-carotene or placebo daily	Up to 5 years of follow-up	First occurrence of a new basal cell or squamous cell skin cancer	After five years of follow-up, there was no difference between the groups in the rate of occurrence a new nonmelanoma skin cancer in (RR = 1.04; 95 % CI = 0.89 – 1.21, P = 0.63). No significant difference between treatment and control groups in the mean number of new nonmelanoma skin cancers per patient-year (RR = 1.07; 95% CI = 0.91 – 1.24; P = 0.42).
Heinonen 1994 35 ATBC Trial	29,133	Male smokers 50 to 69 years of age (Finland)	Participants randomized to receive either 50 mg alpha-tocopherol, 20 mg beta-carotene, both agents, or placebo daily	Median 6.1 years of follow up	Lung cancer incidence, cancer incidence	Higher incidence of lung cancer among the men who received beta carotene than among those who did not (change in incidence, 18%; 95 percent confidence interval, 3 to 36 %). No significant change in lung cancer incidence among men receiving alpha-tocopherol. Supplementation with beta carotene and alphatocopherol did not significantly impact total cancer incidence.
Omenn 1996 36 The Beta-Carotene and Retinol Efficacy Trial (CARET)	18,314	Smokers, former smokers, and workers exposed to asbestos (United States)	Participants were randomized to receive 30 mg beta-carotene and 25,000 IU retinol or placebo daily	Mean of 4 years	Lung cancer incidence; cancer incidence, mortality	The active-treatment group had an increased risk of lung cancer as compared with the placebo group (RR = 1.28; 95% CI = 1.04 – 1.57;P = 0.02). There were no statistically significant differences in the risks of other types of cancer. Study was stopped 21 months early because of findings.
Heinonen 1998 37 Alpha-Tocopherol and Beta-Carotene (ATBC) Trial	29,133	Male smokers aged 50–69 years (Finland)	Participants received 50 mg alpha-tocopherol, 20 mg beta-carotene, both agents, or placebo daily	Median 6.1 years of follow up	Total cancer incidence; prostate cancer incidence and prostate cancer mortality	Prostate cancer incidence decreased by 32% (95% CI= −47% to −12%) in the group receiving alpha-tocopherol compared with those not receiving it. Mortality from prostate cancer was 41% lower (95% CI = −65% to −1%) among men receiving alpha-tocopherol. Supplementation with beta carotene did not significantly impact prostate cancer incidence or prostate cancer mortality.
Lee 1999 78 The Women’s Health Study	39,876	Women aged 45 years or older (United States)	Participants were given either 600 IU of natural source vitamin E, 100 mg aspirin, 50 mg beta-carotene, all three agents, all three placebos, two agents and one placebo, or one agent and two placebos. All treatment given on alternate days.	Mean 4.1 years	Invasive cancer incidence	Among women randomly assigned to receive β-carotene or placebo, there were no statistically significant differences in incidence of cancer (RR = 1.03; 95% CI = 0.89 – 1.18; P = 0.73) Beta-carotene component of study was stopped early after median treatment of 2.1 years due to findings from previous studies.
Albanes 2000 39 ATBC Trial	29,133	Male smokers aged 50–69 years (Finland)	Participants received 50 mg alpha-tocopherol, 20 mg beta-carotene, both agents, or placebo daily	Median 6.1 years of follow up	Colorectal cancer incidence	Relative to control group, neither beta carotene nor alpha-tocopherol had a significant effect on colorectal cancer incidence Beta carotene (RR = 1.05, 95% CI 0.75–1.47; log-rank test p = 0.78): Alpha-tocopherol (RR = 0.78; 95% CI = 0.55–1.09).
Vitamin D
Trivedi 200346	2,686	Healthy men and women aged 65–85 (United Kingdom)	100,000 IU oral vitamin D3 supplementation or placebo every four months	5 years	Cancer incidence	Vitamin D3 supplementation had no significant effect on cancer incidence (any cancer age-adjusted RR = 1.09; 95% CI = 0.86 – 1,36), even when stratified by sex (Males: any cancer age-adjusted RR = 1.11; 95% CI = 0.87 – 1.42; Females: any cancer age-adjusted RR = 0.95; 95% CI = 0.54 – 1.68).
Wactawski-Wende 2006 48 Women’s Health Initiative	36,282	Healthy postmenopausal women 50 to 79 years of age (United States)	Participants randomized into one of two arms. The intervention arm received 1,000 mg of elemental calcium with 400 IU vitamin D3 or placebo.	7 years	Colorectal cancer incidence	The incidence of invasive colorectal cancer did not differ significantly between women receiving calcium plus vitamin D supplementation and those assigned to placebo (HR = 1.08; 95% CI = 0.86–1.34, P = 0.51).
Lappe 200747	1,179	Healthy postmenopausal women over 55 living in a rural area (United States)	Population-based, double-blind, randomized placebo-controlled trial. Participants were randomized to receive 1400–1500 mg supplemental calcium alone, supplemental calcium plus 1100 IU vitamin D3/d (Ca + D), or placebo	4 years	Cancer incidence	Cancer incidence was lower in the Ca + D women than in the placebo control subjects (P < 0.03). Unadjusted relative risks (RR) of incident cancer in the Ca + D and Ca− only groups were 0.402 (P = 0.01) and 0.532 (P = 0.06), respectively. Treatment and serum 25-hydroxy vitamin D concentrations were significant, independent predictors of cancer risk.
Brunner 2011 Women’s Health Initiative49	36,282	Healthy postmenopausal women 50 to 79 years of age (United States)	Participants randomized into one of two arms. The intervention arm received 1,000 mg of elemental calcium with 400 IU vitamin D3 or placebo.	7 years	Cancer incidence and mortality	Incidence of invasive cancer did not differ between the two groups (HR = 0.98; CI = 0.90, 1.05, unweighted P = 0.54]. Mortality did not differ between the two groups (HR = 0.90 (0.77, 1.05).

^*Study Names included if applicable

Abbreviations: RR: Risk Ratio, CI: Confidence Interval, HR: Hazard Ratio NMSC: Nonmelanoma skin cancer,