beta-Carotene and Cancer

The provitamin beta-Carotene is a plant pigment that converts to the active forms of vitamin A (ie, retinal or retinoic acid) intracellularly.¹ Vitamin A is critical for immune function, cell signaling, reproduction, vision, and formation/maintenance of many organs.

Although higher intake of carotenoids via fruits and vegetables is associated with reduced cancer risk, findings from several large, randomized, controlled trials in the 1990s indicated that beta-Carotene supplementation may increase the risk of certain cancers. This fact sheet focuses on studies evaluating the effect of beta-Carotene supplementation on cancer incidence and outcomes.

No Benefit of beta-Carotene Supplementation

alpha-Tocopherol beta-Carotene Cancer (ATBC) Prevention Study

The ATBC study randomly assigned 29,133 male smokers aged 50 to 69 living in Finland between 1985 to 1988 to receive beta-Carotene (20 mg daily), alpha-tocopherol (50 mg daily), beta-Carotene (20 mg daily) plus alpha-tocopherol (50 mg daily), or placebo for a median follow-up of 6.1 years.² Compliance was excellent, with a median 99% of capsules taken across intervention groups.

There was a significantly higher incidence of lung cancer among men who received beta-Carotene supplementation compared with placebo after 18 months of intervention (difference, 18%; 95% CI, 3-36%; P = .01; relative risk [RR], 1.16; 95% CI, 1.02-1.33; P = .02).^2,3 This association trended toward being stronger among men who smoked 20 or more cigarettes a day (RR, 1.25; 95% CI, 1.07-1.46).²

The beta-Carotene group also had a greater incidence of prostate (difference, 20%; 95% CI, -13% to 66%) and stomach cancers compared with the placebo group.^2,4 There was no difference in incidence of colorectal cancer, colorectal adenoma recurrence, pancreatic cancer, urinary tract cancers, or liver cancer among those who received beta-Carotene compared with placebo.^5-9

Overall mortality was 8% higher in the beta-Carotene group compared with those who did not receive beta-Carotene during the trial (95% CI, 1-16%; P = .02). Lung cancer–associated mortality was also higher in the beta-Carotene group, though not significantly (P = .08).³

An 18-year follow-up analysis, however, found no significant difference in overall mortality or lung or prostate cancer–associated mortality between the beta-Carotene group compared with others.¹⁰

beta-Carotene and Retinol Efficacy Trial (CARET)

The CARET study randomly assigned 18,314 smokers, former smokers, and asbestos-exposed participants aged 46 to 74 living in the United States to receive beta-Carotene (30 mg daily) plus retinol (25,000 IU daily) or placebo beginning in 1985.¹¹ The asbestos cohort included subjects with occupational exposure starting at least 15 years prior to enrollment.

beta-Carotene plus retinol was associated with an increased incidence of lung cancer compared with placebo among the entire cohort (RR, 1.28; 95% CI, 1.04-1.57; P = .02), with nonsignificant increases among asbestos-exposed subjects (RR, 1.40; 95% CI, 0.95-2.07; P = .08) and heavy smokers (RR, 1.23; 95% CI, 0.96-1.56; P = .09).¹¹ There was no increased risk of prostate cancer with beta-Carotene plus retinol supplementation compared with placebo.¹²

The risk of all-cause mortality was also significantly higher in the beta-Carotene plus retinol group compared with the placebo group for the entire cohort (RR, 1.17; 95% CI, 1.03-1.33; P = .02) and the asbestos-exposed cohort (RR, 1.25; 95% CI, 1.01-1.56; P = .04), but not in the heavy smokers cohort (RR, 1.13; 95% CI, 0.96-1.32; P = .14).¹¹

Lung cancer–associated mortality was significantly higher with beta-Carotene plus retinol supplementation compared with placebo (RR, 1.46; 95% CI, 1.07-2.00). The increased risk of mortality and lung cancer–associated mortality diminished within 6 years after beta-Carotene and retinol discontinuation.¹³

The CARET intervention was halted early in January 1996 when an interim analysis detected excess mortality, and in consideration of the ATBC trial results.