| Trial Type | Study | Design/ Intervention |
Endpoints | Number of Subjects/ Followup Period |
Results (95% CI) |
Conclusions |
|---|---|---|---|---|---|---|
| New Trials | Heart Protection Study Collaborative Group.1 | RCT; intention-to-treat; subjects randomized to receive antioxidant nutrients (600mg vit E, 250mg vit C, and 20mg beta-carotene) or placebo; Followup visits at 4,8,12m and then every six months for 5yr; Population: men and women 40-80 y.o. with non-fasting cholesterol of at least 3.5 mmol/L having substantial 5-yr risk of heart disease based on past history of CHD, occipital arterial disease, DM, or HTN; recruited from clinics at 69 UK hospitals. | Primary-Incidence of major coronary events ( non-fatal MI and death from coronary disease); secondary-major vascular events (major coronary events, strokes, coronary or non-coronary revascularizations; site-specific cancer, cerebral hemorrhage, vascular procedures, hospitalization. | 63,603 screened; 32,145 had prerandomization testing; 20,536 subjects randomized; average 5 year followup. | All-cause mortality (1446 deaths in vitamin group vs 1389 in placebo) RR 1.04 (CI .97 - 1.12; P=.3); Major vascular events (2306 in vitamin group vs 2312 in placebo) RR 1.00 (CI .94 - 1.06; P=>.9); New primary cancers excluding NMSC (800 cases in vitamin group, 817 cases in placebo) RR .98 (CI .89 - 1.08; p=.7); no significant difference between treatment groups in incidence of any site- specific cancer. | Supplementation of vit E, vit C, and beta-carotene found to be safe but showed no benefit among individuals at high risk or low risk for vascular events or cancer. |
| Green A, et al.2 | RCT; intention-to-treat; Subjects from Queensland, Australia, community randomized to one of four groups: daily sun screen and 30 mg beta carotene, daily sun screen and placebo, beta carotene only, or placebo only, ages 20-69 yrs. | Incidence of basal cell carcinoma and squamous cell carcinoma and number of tumors among subjects with newly diagnosed skin cancer. Cancers diagnosed within first year of study were excluded. | 1,621 subjects randomized; followup 4-5 years. | Basal cell CA (102 cases in beta carotene groups vs. 93 cases in placebo) - RR 1.04 (CI .73 - 1.27); Squamous cell CA (40 cases in beta carotene groups vs. 28 cases in placebo) - RR 1.35 (CI .84 - 2.19; not significant); Number similar with subjects receiving sunscreen excluded from analysis. | Beta carotene supplementation found to have no protective or harmful effect on incidence of basal cell or squamous cell carcinoma. | |
| Physician's Health Study | PRIMARY RESULTS Hennekens CH, et al.3 |
RCT, double-blinded, 2x2 factorial design; Intervention - 4 groups: 1) aspirin + beta-carotene placebo; 2) beta carotene + aspirin placebo; 3) both active agents; 4) both placebos; Aspirin component terminated in 1988. | Cases of malignant neoplasms excluding nonmelanoma skin cancer; lung cancer; malignant cancer mortality; Cardiovascular events - MI, strokes, cardiovascular mortality, all cause mortality; all important cardiovascular events. | 22,071 U.S. male physicians aged 40-84 in 1982 with no hx of cancer, MI, stroke, or transient cerebral ischemia; beta-carotene (11,036) and placebo (11,035); Followup average 12 years. | All CA (1,273 cases in beta-carotene group vs. 1293 in placebo) - RR .98 (95% CI .91-1.06); no statistically significant effect of beta-carotene on incidence of lung, colorectal, prostate, stomach, pancreas, or brain cancer or melanoma, leukemia, or lymphoma; no effect of beta-carotene on CA mortality (386 in beta-carotene group vs, 380 in placebo) - RR 1.02 (.89-1.18). | No statistically significant benefit or harm of 12 years of supplementation of beta-carotene on incidence of malignant neoplasms, cardiovascular disease or death among current smokers or nonsmokers. |
| Frieling UM, et al.4 | Subgroup analysis of PHS; excluded data from 187 subjects with diagnosis of NMSC at time of randomization. | Incidence of first nonmelanoma skin cancer (basal cell carcinoma and squamous cell carcinoma); new endpoint. | See above. | NMSC (1,786 cases in beta-carotene group vs. 1821 in placebo) - RR .98 (CI .92-1.05); BCC (1,574 cases vs. 1598 cases) - RR .99 (CI .92-1.06); SCC (340 cases vs. 352 cases) - RR .97 (CI .84-1.13). | No effect of beta-carotene supplementation on incidence of NMSC (basal cell carcinoma or squamous cell carcinoma). | |
| Cook, NR, et al.6 | Nested case-control study among the 14,916 subjects of the Physicians' Health Study who submitted baseline blood specimens prior to randomization; 1439 total cancer cases were compared to 2204 controls matched on smoking status and age. | Incidence of total and prostate CA among subjects differing by baseline blood levels of beta-carotene. | See above. | 1,439 CA cases: 631 prostate, 169 colon, 93 melanoma, 85 lung, 94 lymphoma, and less than 50 other; Total CA in beta-carotene supplementation group - RR .96 (CI .83 - 1.10) and prostate CA - RR .91 (CI .75 - 1.11); Total cancer in beta-carotene group in lowest baseline plasma beta-carotene quartile - RR .83 (CI .63 - 1.09) and in highest quartile. RR 1.14 (CI .86 - 1.52) [nonsignificant]; Prostate cancer in beta-carotene group in lowest baseline plasma beta-carotene quartile - RR .68 (CI .46 - .99; p= .04) and in highest quartile - RR 1.33 (CI .91 - 1.96 P=.14 |
Beta-carotene supplementation may reduce risk of prostate CA in those with low baseline levels. | |
| Cook, NR, et al.5 | Update of PHS analysis including primary cancers occurring during trial period but not identified until after publication. Also, subgroup analysis of PHS defined by baseline characteristics of subjects. | Any malignant neoplasm except non-melanoma skin, primary-lung cancer. | See above. | 2,667 confirmed cases of cancer with 1,314 in beta carotene group and 1353 in placebo; Total cancer: RR 1.0 (CI .9-1.0; P=.41) No association with prostate (1,117 cases) RR 1.0 (CI .9 - 1.1), colon (267 cases): RR .9 (CI .7-1.2) Positive association of supplementation with bladder CA (103 cases): RR 1.5 (CI 1.0 - 2.2; P=.04 and thyroid (21 cases): RR 9.5 (CI 2.2-40.7; P=.003); No significant association of beta-carotene assignment with baseline cancer risk factors (inc. age, smoking status, BMI, exercise, multivitamin use, or dietary beta carotene) with cancer incidence; Colon CA among those who drink alcohol daily (86 cases) RR .5 (CI .3-.8). | No effect of beta carotene on total cancer or prostate colon or lung CA specifically Positive association with bladder and thyroid cancer, but may be due to methodology and not consistent with previous findings. | |
| ATBC Trial | PRIMARY RESULTS The ATBC Cancer Prevention Study Group.7 |
RCT; Male smokers from southwestern Finland aged 50 through 69; Subjects with history of cancer or serious illness, taking anticoagulants, or taking Vit E, A or beta-carotene supplements in excess were excluded; Subjects were randomized into 1 of 4 groups: 50 mg alpha-tocopherol daily, 50 mg alpha-tocopherol and 20 mg beta-carotene daily, 20 mg beta-carotene daily, or placebo. | Primary-lung cancer incidence and mortality; secondary-cancers other than lung cancer. | 29,133 subjects randomized; followup 5-8 years (median 6.1 years). | Lung cancer incidence in alpha-tocopherol groups (433 cases vs. 443 in non-tocopherol) - RR .98 (CI .86-1.12; P=.8); Lung cancer incidence in beta-carotene groups (474 cases v, 402 in non-betacarotene) - RR 1.18 (CI 1.03 - 1.36; P=.01); Overall mortality in alpha-tocopherol groups - RR 1.02 (CI .95 - 1.09; P= .6); in beta carotene groups - RR 1.08 (CI 1.01 - 1.16; P= .02). | No effect of Vitamin E or beta-carotene supplementation in the prevention of lung cancer incidence or mortality. |
| Rautalahti MT, et al.8 | Supplemental analysis of ATBC data on effect of alpha-tocopherol and beta-carotene supplementation on pancreatic cancer incidence. | Pancreatic cancer incidence and mortality. | See above. | Pancreatic carcinoma: 25 cases in AT group, 12 cases in BC, 26 cases in ATBC, and 26 cases in placebo; Incidence in BC and ATBC groups - RR .75 (CI .49 - 1.14); Incidence in AT and ATBC groups - RR 1.34 (CI .88 - 2.05); Pancreatic CA mortality in BC and ATBC groups - RR .81 (.53 - 1.26); Pancreatic CA mortality in AT and ATBC groups - RR 1.10 (CI .72 - 1.72). |
Neither supplement had a statistically significant on pancreatic cancer incidence; suggests benefit of BC. | |
| Albanes D, et al.9 | Supplemental analysis of ATBC data on effect of alpha-tocopherol and beta-carotene supplementation on colorectal cancer incidence. | Colorectal cancer incidence and mortality. | See above. | Colorectal carcinoma: 29 cases in AT group, 39 cases in BC group, 30 in ATBC, and 37 in placebo; Cumulative incidence in BC and ATBC groups - RR 1.05 (CI .75 - 1.47, P= .78); Cumulative incidence in AT and ATBC groups - RR .78 (CI .55 - 1.09; P= .15); Colorectal CA mortality in BC and ATBC groups: RR 1.01 (.56 - 1.79); Colorectal CA mortality in AT and ATBC groups: RR .92 (CI .51- 1.64). | No beneficial or harmful effect of beta-carotene but found a nonsignificant preventive effect of alpha-tocopherol on colorectal CA. | |
| Virtamo J, et al.10 | Supplemental analysis of ATBC data on effect of alpha-tocopherol and beta-carotene supplementation on urinary tract cancer. | Urothelial cancer (bladder, renal pelvis, ureter) and renal cell cancer incidence. | See above. | Urothelial carcinoma: 47 cases in AT group, 43 in BC; 42 cases in ATBC; 37 in placebo. Cumulative Incidence of: urothelial cancers in BC and ATBC groups:- RR 1.0 (CI .7 - 1.3; p=.92); urothelial cancers in AT and ATBC groups: RR 1.1 (CI .8 - 1.5; p=.48); renal cell cancer - 27 cases in AT group , 21 in BC, 27 in ATBC, and 27 in placebo; cumulative incidence of renal cell cancer in AT and ATBC: RR 1.1 (CI .7-1.6; p=.55); Cumulative incidence of renal cell cancer in BC and ATBC: RR .8 (CI .6 - 1.3; P=.57). | No effect of alpha-tocopherol or beta-carotene supplementation on the incidence of urothelial or renal cell cancer. | |
| Malila N, et al.11 | Nested prospective cohort study using data from ATBC trial to study association between dietary and serum levels of antioxidants at baseline. | Colorectal cancer incidence. | 26,951 participants of ATBC study with all baseline data including baseline serum samples and complete baseline dietary history available; Median followup, 8.0 yrs. | 184 colorectal cases were diagnosed by end of followup; no association described between dietary antioxidant nutrients (Vit C, Vit E, alpha-tocopherol, beta-carotene, retinol, lycopene, or lutein + zeaxanthin) and colorectal CA incidence; no association between highest and lowest quartiles of serum alpha-tocopherol (RR=.94; 95% CI, 0.57-1.57; P=.72 for trend), beta-carotene (RR=.86; 95% CI, 0.54-1.36; P=.82 for trend) or retinol (RR=1.02; 95% CI, 0.65-1.58; P=.75 for trend) and colorectal CA incidence; adjusted for supplementation assignment. | No effect of dietary alpha-tocopherol or beta carotene on colorectal cancer risk; No association between serum levels of antioxidants and colorectal cancer risk. | |
| Woodson K, et al. 12 | Nested prospective cohort study using data from ATBC trial to study association between baseline serum alpha-tocopherol levels and incidence of lung cancer. | Lung cancer incidence and mortality. | 29, 102 participants of ATBC study with baseline serum alpha-tocopherol levels taken prior to randomization; median followup = 7.7 years. | 1144 cases of lung cancer diagnosed in cohort; nonsignificant inverse association (P=.09 for trend) with baseline alpha-tocopherol and lung cancer risk, RR=.81 (95% CI, 0.67-0.97) highest quintile compared to lowest quintile; dietary alpha-tocopherol showed inverse association (P=.02 for trend) for lung cancer risk, RR=.80 (95% CI, 0.66-0.97) highest quintile compared to lowest quintile; adjusted for supplementation assignment. | Baseline serum alpha-tocopherol and dietary serum alpha-tocopherol found to be inversely associated with lung cancer risk. |
Note: AT indicates alpha-tocopherol; ATBC, Alpha-Tocopherol Beta-Carotene study; BC, beta carotene; CA indicates cancer; CHD, coronary heart disease; CI, confidence interval; DM, diabetes mellitus; HTN, hypertension; MI, myocardial infarction; NMSC, nonmelanoma skin cancer; P, probability; PHS, Physicians Health Study; RCT, randomized controlled trial; RR, relative risk; UK, United Kingdom; vit, vitamin.