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Dietary intervention trials of lung cancer using supplements

Alpha-tocopherol, beta-carotene cancer prevention study (ATBCCPS)

  • 29,000 male smokers in Finland.
  • Daily supplements with 20 mg beta carotene, 50 mg alpha tocopherol, both or placebo.
  • After 6 years, 876 new cases of lung cancer.
  • RR of lung cancer = 1.18 (p = 0.01) in beta carotene group.
  • RR of total mortality = 1.08 (p= 0.02) in beta carotene group.
  • No effect of vitamin E

Physicians’ Health Study (PHS)

  • 22,000 physicians.
  • 50 mg beta carotene every 2nd day, or placebo.
  • After 12 years of follow-up: 170 new cases of lung cancer.
  • RR of lung cancer = 0.9 (95% CI 0.6-1.4) RR of total mortality = 1.05 (0.9-1.3).
  • (NOTE: 11% current, 39% former smokers).
  • RR similar when restricted to current smokers (RR=0.9, 95% CI 0.6-1.4)

Beta-carotene and Retinol Efficacy Trial (CARET)

  • 18,000 men and women at high risk of lung ca (smokers or exposed to asbestos).
  • 30 mg beta-carotene and 25,000 IU retinol daily.
  • Trial stopped 21 months early, after average of 4 years follow-up.
  • RR of lung cancer in supplement group = 1.28 (95% CI 1.04-1.57).
  • Effect of supplements worse in asbestos workers and in heavy smokers.
  • RR for total mortality = 1.17 (95% CI 1.03-1.33) for supplement group.

COMBINED from the 3 trials:

  • No evidence that beta-carotene, vitamin E or retinol supplements protect against lung cancer in well nourished populations
  • Some evidence that beta carotene and possibly retinol increase risk, particularly in people at high risk of lung cancer, such as smokers.

Possible reasons for the unexpected results from the dietary supplement trials

  • Chance unlikely explanation for increased risks
  • Length of supplement (4-12 years) not sufficient?
  • Beneficial effects may be difficult to obtain in presence of carcinogenic compounds in smokers?
  • Disequilibrium induced by excess beta-carotene?
  • could interfere with absorption or metabolism of one or more of the other carotenoids or other plant constituents
  • beta carotene may have pro-oxidant effects under certain non-physiological conditions
  • Beta carotene may interfere with the normal apoptotic death of abnormal cells (high doses could mimic bcl-2, an inhibitor of apoptosis) – especially among smokers?