The CancerWeb Report, What's New In Cancer: December, 1996
Lung Cancer

• Further examination of the relationship between beta-carotene and lung cancer - Among the most disheartening findings of two major studies, known as CARET and ATBC, was that supplemental beta-carotene, with or without vitamin A, increased rather than reduced the incidence of lung cancer, especially in smokers. This followed on the heels of another study of beta-carotene in 29,133 smokers in Finland which arrived at the same conclusion. On the other hand, the US Physicians' Health Study, did not find any increased risk from regular supplements of beta-carotene, even in smokers. Animal data indicating a protective action of beta-carotene against carcinogenesis, coupled with epidemiological findings in humans of the protective effect of a diet including yellow and green vegetables and fruit which are rich in beta-carotene, raised expectations that this antioxidant would have a preventive action in humans. This expectation was reinforced by the higher blood levels of beta-carotene found in those with a lower risk for lung cancer. The situation calls for an explanation. CARET and ATBC data were analyzed in more detail in the November 6, 1996 issue of the Journal of the National Cancer Institute. The CARET trial using 30 mg of beta-carotene and 25,000 IU of vitamin A daily compared with placebo in 18,314 men and women at high risk for lung cancer through exposure to asbestos or cigarette smoking was stopped in January, 1996. There was a 36% increase in the risk of lung cancer in the whole group receiving supplement, but the risk was doubled in those with the highest alcohol intake; initial blood carotene levels were unrelated to risk. No lung cancers developed in a small group of never smokers, and former smokers may also not have had any increased risk with supplementation. In the ATBC study, 29,133 male smokers were randomly assigned to placebo or a supplement of 50 mg vitamin E (alpha-tocopherol) and 20 mg beta-carotene alone or in combination. Vitamin E supplements did not affect lung cancer incidence, but beta-carotene was associated with a 16% increase in risk. Once again, this association was stronger for heavier smoking and higher alcohol intake. The clear message from these trials, emphasized by all the researchers, is that high dose beta-carotene supplements should not be taken by current smokers, especially those who smoke and drink heavily, and by asbestos workers. However, we should ask why, and an accompanying editorial in the same journal issue offers a suggestion, namely that the excess beta-carotene is being oxidized to toxic products. The gaseous products in cigarette smoke, the iron found in asbestos particles, and the products of the inflammation process occurring in asbestos-exposed lungs, are all highly oxidizing. The excess beta-carotene may undergo oxidation to damaging products. There is also a potential adverse effect of high doses of vitamin A which led to a higher cancer risk in the CARET study, and for which there is animal data suggesting such a risk. Lower levels of beta-carotene as used in the Physicians' Health study, less oxidizing action in the absence of smoke, and the presence of other protective antioxidants in vegetables, may prevent this increased risk. (J Natl Cancer Inst 88, 1996 - CARET, p. 1550; ATBC, p. 1560; editorial, p. 1513)

  Editor's Comment: - These findings may help point the way towards an explanation of what is going on in these chemoprevention studies, and how to arrive at effective cancer prevention. Simply using high-dose supplementation of the diet of a given population with a single chemopreventive' irrespective of current nutritional status, is not likely to be effective. Several factors need to be considered in developing an overall strategy. In cases where there is a known deficiency in a particular factor, dietary interventions aimed at restoring low levels of a nutrient to normal, may be the wisest approach. In all cases the overall nature of the diet needs to be considered. The antioxidant or other activity of a particular agent must be viewed in the context of the range of other active micronutrients, major components such as fat and fiber, and natural antioxidants occurring in the diet, as well as other lifestyle and occupational exposures. This is not an easy problem, and seizing on obvious' actions based on simplistic interpretations of epidemiologic findings will not solve it. Furthermore, the epidemiological findings themselves are frequently based on diet recall, 4-day food records, and food-frequency questionnaires, which may be subject to many errors (see Prentice, J Natl Cancer Inst 88:1738, 1996).