Carotene and Retinol Efficacy Trial

The a-tocopherol, P-carotene (ATBC) Cancer Prevention study was a randomised-controlled trial that tested the effects of daily doses of either 50 mg (50 lU) vitamin E (all-racemic a-tocopherol acetate), or 20 mg of P-carotene, or both with that of a placebo, in a population of more than 29,000 male smokers for 5-8 years. No reduction in lung cancer or major coronary events was observed with any of the treatments. What was more startling was the unexpected increases in risk of death from lung cancer and ischemic heart disease with P-carotene supplementation (ATBC Cancer Prevention Study Group, 1994). Increases in the risk of both lung cancer and cardiovascular disease mortality were also observed in the P-carotene and Retinol Efficacy Trial (CARET), which tested the effects of combined treatment with 30 mg/d P-carotene and retinyl pahnitate (25,000 lU/d) in 18,000 men and women with a history of cigarette smoking or occupational exposure to asbestos (Hennekens et al, 1996). 

ATBC = Alpha Tocopherol Beta Carotene Prevention Study CARET = The Beta Carotene and Retinol Efficacy Trial PHYS = Physicians Health Study. 

OMENN G s, GOODMAN G E, THORNQUIST M, et al., (1996) Risk factors for limg cancer and for intervention effects in CARET, the beta-carotene and retinol efficacy trial. J Natl Cancer Inst. 88 1550-59. 

However, intervention trials investigating the effects of P-carotene and lycopene supplementation on CVD have not reported convincing results (Table 3.1.3). Among the seven studies reviewed herein, four primary prevention trials, namely the Multicenter Skin Cancer Prevention Study, the Beta Carotene and Retinol Efficacy Trial, the ATBC cancer prevention study, " and the Physicians Health Study have shown no association between a supplementation of P-carotene and risk of death from CVD or fatal and non-fatal MI. 

Goodman GE, Thomquist MD, Balmes J, Cullen MR, Meyskens FL, Omenn GS, Valanis B and Williams JH. 2004. The (1-carotene and retinol efficacy trial incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping (5-carotene and retinol supplements. J Natl Cancer Inst 96(23) 1743—1750. 

Thornquist, M.D., "Streamlining IRB review in multisite trials through single-study IRB Cooperative Agreements experience of the p-Carotene and Retinol Efficacy Trial (CARET)," Controlled Clinical Trials, 23, 80-86 (2002). 

However, in the skin, vitamin D is also activated by oxidation, and an excess of quenching of this oxidation, due to high concentrations of /3-carotene in the skin, may reduce the amount of vitamin D availability. This is not only important for bone construction, but also because vitamin D represents a powerful natural anticancer agent. This can be an explanation why an increase of lung cancer was found in Finland (country with relative lack of sun), where smoking people and subjects with asbestosis were treated with /3-Carotene and Retinol Efficacy Trial. Concomitantly in ATBC, ischemic episodes were more severe due to the very high dosage of /3-carotene, which can become pro-oxidant. 

Neuhouser ML, Patterson RE, Thornquist MD, et al, Fruits and vegetables are associated with lower lung cancer risk only in the placebo arm of the beta-carotene and retinol efficacy trial (CARET). Cancer Epidemiol Biomarkers Prev 2003 12 350-358. 

Omenn GS, Goodman G, Thornquist M, Barnhart S, Balmes J, Cherniack M, Cullen M, Glass A, Keogh J, Liu D, Meyskens F Jr, Perloff M, Valanis B, and Williams J Jr (1996a) Chemoprevention of lung cancer the beta-Carotene and Retinol Efficacy Trial (CARET) in high-risk smokers and asbestos-exposed workers. lARC Scientific Publication 136, 67-85. 

Brodkin CA, McCullough J, Stover B, et al. 1997. Lobe of origin and histologic type of lung cancer associated with asbestos exposure in the carotene and retinol efficacy trial (CARET). Am J Ind Med 32 582-591. 

Goodman GE, Omenn GS. 1992. Carotene and retinol efficacy trial Lung cancer chemoprevention trial in heavy cigarette smokers and asbestos-exposed workers. CARET Coinvestigators and Staff. Adv Exp Med Biol 320 137-40. 

Omenn GS, Goodman G, Thomquist M, et al. 1994. The beta-carotene and retinol efficacy trial (CARET) for chemoprevention of lung cancer in high risk populations Smokers and asbestos-exposed workers. Cancer Res 54(Suppl 7) 2038s-2043s. 

In contrast to retinoids, carotenoids were considered non-toxic, even when taken chronically in large amounts, until recently, when it was found that ethanol interacts with carotenoids, interfering with their conversion to retinol. In baboons, the consumption of ethanol together with beta-carotene resulted in more striking hepatic injury than consumption of either compound alone (98). This interaction occurred at a total dose of 7.2-10.8 mg of beta-carotene per Joule of diet. This dose is common in people who take supplements and is the same order of magnitude used in the Beta-Carotene and Retinol Efficacy Trial (CARET) (30 mg/day) (99) and in another study (20 mg/day for 12 weeks) (100). The amount of alcohol given to the baboons was equivalent to that taken by an average alcohohc. The well-known toxicity... 

Brodkin, C.A., and Hammar, S., Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial, J. Natl. Cancer Inst., 88,1550, 1996. 

Goodman, G.E. et al.. The association between lung and prostate cancer risk, and serum micronutrients results and lessons learned from beta-carotene and retinol efficacy trial. Cancer Epidemiol. BiomarkersPrev., 12, 518,2003. 

L. Berglund. 1999. Effect of long-term beta-carotene and vitamin A on serum cholesterol and triglyceride levels among participants in the Carotene and Retinol Efficacy Trial (CARET). 143 427-434. 

Omenn, G.S. (2007) Chemoprevention of lung cancers lessons from CARET, the beta-carotene and retinol efficacy trial, and prospects for the future. Eur J Cancer Prev 16 (3), 184-191... 

ATBC, Alpha Tocopherol Beta Carotene Prevention Study CARET, Beta Carotene and Retinol Efficacy Trial LCPS, Linxian Cancer Prevention Study PHS, Physicians Health Study PPP, Primary Prevention Project SCPS, Skin Cancer Prevention Study VACP, Vitamin A and Cancer Prevention WHS, Women s Health Study CHD, Coronary Heart Disease CVD, Cardiovascular disease. 

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