Long-term Use of β-Carotene, Retinol, Lycopene, and Lutein Supplements and Lung Cancer Risk: Results from the VITamins And Lifestyle (VITAL) Study

Jessie A. Satia; Alyson Littman; Christopher G. Slatore; Joseph A. Galanko; Emily White


Am J Epidemiol. 2009;169(7):815-828. 

In This Article

Abstract and Introduction


High-dose β-carotene supplementation in high-risk persons has been linked to increased lung cancer risk in clinical trials; whether effects are similar in the general population is unclear. The authors examined associations of supplemental β-carotene, retinol, vitamin A, lutein, and lycopene with lung cancer risk among participants, aged 50–76 years, in the VITamins And Lifestyle (VITAL) cohort Study in Washington State. In 2000–2002, eligible persons (n = 77,126) completed a 24-page baseline questionnaire, including detailed questions about supplement use (duration, frequency, dose) during the previous 10 years from multivitamins and individual supplements/mixtures. Incident lung cancers (n = 521) through December 2005 were identified by linkage to the Surveillance, Epidemiology, and End Results cancer registry. Longer duration of use of individual β-carotene, retinol, and lutein supplements (but not total 10-year average dose) was associated with statistically significantly elevated risk of total lung cancer and histologic cell types; for example, hazard ratio = 2.02, 95% confidence interval: 1.28, 3.17 for individual supplemental lutein with total lung cancer and hazard ratio = 3.22, 95% confidence interval: 1.29, 8.07 for individual β-carotene with small-cell lung cancer for > 4 years versus no use. There was little evidence for effect modification by gender or smoking status. Long-term use of individual β-carotene, retinol, and lutein supplements should not be recommended for lung cancer prevention, particularly among smokers.


Lung cancer is the second most common cancer in the United States and the leading cause of cancer deaths.[1,2] It was estimated that 215,020 new cases of lung cancer would be diagnosed in the United States in 2008, constituting 15% of all cancer diagnoses.[1,2] Cigarette smoking is the most significant contributor to lung cancer development, accounting for as many as 90% of all lung cancers.[1–3] Nonetheless, there are other, less prominent risk factors, including environmental exposure to secondhand smoke; occupational exposure to certain metals, radon, and asbestos; genetic susceptibility; and diet.[1–8]

Vegetables and fruits have been repeatedly shown to be associated with reduced risk of lung cancer.[1,3–8] Carotenoids, red and yellow pigments found in many fruits and vegetables, are among the components of fruits and vegetables believed to confer protection, largely because of their antioxidant properties.[9,10] In principle, antioxidants should be associated with reduced lung cancer risk because they may protect against oxidative damage.[9–11]

The observation that fruits and vegetables may reduce lung cancer risk led to implementation of 2 large, randomized clinical trials in which high doses of β-carotene were used: the Beta-Carotene And Retinol Efficacy Trial (CARET) in the United States and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial in Finland. The CARET intervention tested the efficacy of 30 mg of β-carotene plus 25,000 IU of retinyl palmitate daily in male and female heavy smokers and in men exposed to asbestos.[12] The ATBC trial tested 20 mg of β-carotene plus 50 IU of vitamin E daily in male heavy smokers.[13] Both trials found that β-carotene, alone or in combination with vitamin E or retinyl palmitate, increased the incidence of lung cancers by 36% (in CARET) and 16% (in the ATBC trial) compared with placebo.

The paradoxical findings between the observational studies and clinical trials may be attributable to several factors, including the fact that fruits and vegetables contain numerous substances (other than β-carotene) that may affect lung cancer risk, the interactions of nutrients within foods, and possible differential metabolism of nutrients from foods compared with those that are manufactured.[12–16] Given the low likelihood of new randomized trials evaluating these associations, carefully designed observational studies are critical to untangling the potential associations of dietary supplement use with lung cancer risk.

These results also led to concern about the millions of Americans using supplements, because the doses of β-carotene and other carotenoids in dietary supplements are much higher than would typically be acquired from diet.[17,18] Most Americans' supplemental intakes of retinol and major carotenoids are from multivitamins; some people also ingest these nutrients by using individual supplements or other nonmultivitamin mixtures.[17,18] However, there are very few published studies on associations between supplement use of retinol and carotenoids and risk of lung cancer.

We used data from the VITamins And Lifestyle (VITAL) Study, the only known large cohort investigation focused on dietary supplement use and cancer risk, to rigorously examine associations of supplemental intakes of β-carotene, retinol, total vitamin A, lutein, and lycopene with lung cancer risk. We have previously shown that multivitamins do not increase lung cancer risk.[19] Therefore, this study focused on use of the individual supplements and at higher doses than would be obtained from most common formulations of multivitamins.


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