February 8, 2014

Supplemental Vitamin A May Reduce Risk of Melanoma

Study distinguishes the benefit of dietary versus supplemental forms of vitamin A
69,635 men and women aged 50-76 residing in Western Washington participated in a prospective study to find out if Vitamin A reduces the risk of melanoma.


Asgari MM, Brasky TM, White E. Association of vitamin A and carotenoid intake with melanoma risk in a large prospective cohort. J Invest Dermatol. 2012;132(6):1573-1582.


Prospective study [VITamins And Lifestyle (VITAL) cohort]


69,635 men and women aged 50–76 residing in western Washington

Key Findings

Five hundred sixty-six  incident melanomas were identified over an average of 5.84 years of follow-up. Use of retinol-containing supplements was associated with reduced risk of melanoma (HR: 0.60; 95% CI: 0.41–0.89). Separately, “high dose” retinol (>1,200 mcg/day or  >4,000 IU/day) was associated with an even greater reduction in melanoma risk (HR=0.74; 95% CI: 0.55–1.00). Protection was stronger in sun-exposed anatomical sites and in women. Dietary and total intake of retinol or carotenoids was not associated with any change in risk.

Practice Implications

The current publication is notable for distinguishing the benefit of dietary versus supplemental forms of vitamin A. Of note, neither dietary nor total intakes of vitamin A or carotenoids was associated with a reduced risk of melanoma. The only associated reduction in risk was in those who consumed vitamin A supplements.
This reduction of melanoma risk was more profound in those taking what the authors refer to as “high dose” retinol supplementation (>1,200 mcg/d = 4,000 IU/d). However, “high dose” is a relative term and most practitioners who recommend nutritional supplements would not consider 4,000 IU/day a high dose. This amount is found in many good-quality multivitamin supplements. The National Institutes of Health (NIH) Office of Dietary Supplements has determined the Recommended Daily Allowance (RDA) for vitamin A from diet be >900 mcg for men and > 700 mcg for women.1  (The RDA is based on “average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.”)  Given these levels are the minimum amount suggested to prevent deficiency, 1,200 mcg still appears a moderate dose of supplementation at best.
This is not the first study to hint at the specific role of supplemental vitamin A and reduced melanoma risk.
This is not the first study to hint at the specific role of supplemental vitamin A in reducing melanoma risk. An analysis of the cohorts of the Nurses' Health Study looked specifically at whether higher intake of vitamin C, E, retinol, individual tocopherols, or carotenoids was associated with melanoma risk. A total of 162,000 women (ages 25–77) were followed for a total of more than 1.6 million person-years. Diet was reported every 4 years and supplement usage every 2 years. The intake of vitamin C, vitamin E, and individual tocopherols and carotenoids was not associated with melanoma risk at all. However, the total intake of retinol, which includes diet and supplement, was protective in a subgroup of low-risk women (RR=0.39, 95% CI: 0.22–0.71 for ≥1,800 vs 400 mcg day(-1), P for linear trend=0.01).2
To the contrary, a study done in 2007 purported to find that antioxidant supplementation (120 mg vitamin C, 30 mg vitamin E, 6 mg beta-carotene, 100 μg selenium, and 20 mg zinc) actually increased the risk of developing melanoma, specifically in women.3 Named the Supplementation in Vitamins and Mineral Antioxidants (SU.VI.MAX) trial, it was a double-blind placebo-controlled study with 7,876 women and 5,141 men in France. The researchers found that while incident skin cancers did not differ between male placebo and intervention groups, “the incidence of melanoma was … higher in the antioxidant group for women (adjusted HR=4.31; P=0.02)” This is worth mentioning simply because this study garnered far more attention from the media and medical practitioners than the current study. However, the methodology and interpretation of the data were called into question by other researchers. In an editorial letter, one critic claimed that “The occurrence of only 2 or 3 extra cases [of melanoma] in the placebo group could have tipped the findings to nonsignificance.”4 In addition, the association of increased risk of melanoma with antioxidants in the SU.VI.MAX study prompted the researchers involved with the VITAL study to mine similar data. Usage of selenium and beta-carotene and incident melanoma was extracted from the VITAL cohort in 2008. The investigators found no association with incident melanoma and antioxidant usage.5

Study Limitations

The VITAL study is a large, ongoing, cohort study designed to assess the association of specific supplement uses and cancer risk. Participants entered the study by answering a self-reporting 24-page questionnaire on diet, supplement use, and a host of cancer risk factors. The main limitation of the VITAL study is confounding factors, although identification of major confounders has been taken into account in the design. Not surprisingly, intake of fruits and vegetables, regular physical activity, and use of non-steroidal anti-inflammatory drugs were all strongly correlated with supplement use in general. (P<0.001).6
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  1.  Dietary Supplement Fact Sheet: Vitamin A. NIH: Office of Dietary Supplements 2012; http://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/. Accessed July19, 2012.
  2.  Feskanich D, Willett WC, Hunter DJ, Colditz GA. Dietary intakes of vitamins A, C, and E and risk of melanoma in two cohorts of women. Br J Cancer. 2003;88(9):1381-1387.
  3.  Hercberg S, Ezzedine K, Guinot C, et al. Antioxidant Supplementation Increases the Risk of Skin Cancers in Women but Not in Men. The Journal of Nutrition. September 2007 2007;137(9):2098-2105.
  4.  Green AC, Hughes MC, Ibiebele TI, Williams GM, van der Pols JC, Ortonne J-P. Antioxidant Supplementation and Risk of Skin Cancers. The Journal of Nutrition. May 2008 2008;138(5):978.
  5.  Asgari Mm MSSKLHWE. Antioxidant supplementation and risk of incident melanomas: Results of a large prospective cohort study. Archives of Dermatology. 2009;145(8):879-882.
  6.  White E, Patterson RE, Kristal AR, et al. VITamins And Lifestyle Cohort Study: Study Design and Characteristics of Supplement Users. American Journal of Epidemiology. January 1, 2004 2004;159(1):83-93.