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Therapeutics

Combination β-carotene and vitamin A was harmful in patients at risk for lung cancer

ACP J Club. 1996 Sept-Oct;125:40. doi:10.7326/ACPJC-1996-125-2-040


Source Citation

Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996 May 2;334:1150-5. [PubMed ID: 8602180]


Abstract

Objective

To determine the effects of a combination of β-carotene and vitamin A on the incidence of lung cancer on persons at risk for developing lung cancer.

Design

Randomized, double-blind, placebo-controlled trial with mean 4-year follow-up (β-carotene and Retinol Efficacy Trial [CARET]). CARET was initiated in 1985 with 2 pilot studies: 1 enrolled 816 men who were exposed to asbestos, the other was a 2 × 2 factorial design in which 1029 men and women who were heavy smokers were enrolled. Beginning in 1988, the trial was expanded to > 18 000 participants.

Setting

6 study centers in the United States.

Participants

The asbestos workers were 4060 men (mean age 57 y) who were exposed to asbestos on the job at least 15 years before enrollment. 14 254 heavy smokers were aged 50 to 69 years (mean age 58 y, 56% women), had ≥ 20 pack-years of smoking, and were either current smokers or had quit smoking in the past 6 years. 98% of participants were followed up.

Intervention

In 1988, the active treatment groups of the 2 studies were consolidated. 9420 participants who were allocated to the active treatment groups received β-carotene, 30 mg/d, plus vitamin A (retinol), 25 000 IU, and 8894 participants received placebo. Compliance was assessed by weighing returned pill bottles and by patient self-reports. The active intervention was terminated 21 months ahead of schedule to protect the participants from possible harm.

Main outcome measures

Incidence of lung cancer and death from all causes and from cardiovascular causes.

Main results

Analysis was by intention to treat. The incidence of lung cancer was higher in participants who received β-carotene and vitamin A compared with participants who received placebo (5.92 vs 4.69 cases/1000 person-y, P = 0.02; relative risk [RR] for lung cancer in participants receiving β-carotene and vitamin A 1.28, 95% CI 1.04 to 1.57). The incidence of death from all causes was also higher in participants who received β-carotene and vitamin A (14.45 vs 11.91 deaths/1000 person-y, P = 0.02; RR for death 1.17, CI 1.03 to 1.33), as was the risk for death from lung cancer (RR 1.46, CI 1.07 to 2.00). The relative risk for death from cardiovascular causes was 1.26 (CI 0.99 to 1.61).

Conclusion

Supplemental combined β-carotene and vitamin A not only did not confer any benefit, it was associated with an increased risk for lung cancer and death from all causes in persons at high risk for developing lung cancer.

Source of funding: National Cancer Institute.

For article reprint: Dr. G.S. Omenn, Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, 1124 Columbia-MP859, Seattle, WA 98104, USA. FAX 734-647-9739.


Commentary

Long-term supplementation with beta-carotene did not affect the incidence of cancer or cardiovascular disease in men

The CARET trial is 1 of a series of important randomized trials that tests the efficacy of dietary supplements. The study design is exemplary, although follow-up is relatively short (median 3.7 y). Patients in the target group (men exposed to asbestos and long-term smokers, 44% of whom were women) were at high risk for lung cancer and cardiovascular disease.

The finding that patients who were randomized to β-carotene and vitamin A had an increase in overall mortality and lung cancer deaths, plus an increase in cardiovascular mortality, is contrary to the observational studies that show a lower mortality rate with higher intake of fruits and vegetables (1). Intriguingly, the baseline serum β-carotene levels in this study were inversely correlated with subsequent development of lung cancer. Because supplements had no beneficial effect on survival, this finding needs to be elucidated. One explanation for the effect is that β-carotene is a marker for a different protective component in fruit and vegetables or for another separate confounding factor. Further, the supplementation may have been pharmacologically inappropriate.

The study by Hennekens and colleagues is a double-blind placebo-controlled trial of β-carotene in over 22 000 male physicians. Only 11% were current smokers, although 39% were former smokers. The result showed no benefit for men who were randomized to β-carotene. As with the CARET trial, and again in contrast with observational studies, no decrease was observed in the mortality rate from lung cancer or heart disease.

Unlike the CARET trial and 1 other study (2) that showed increased death rates for patients who received β-carotene and other supplements, no apparent detrimental effects from β-carotene occurred. This could be the play of chance, or perhaps the choice of patients at high risk for these diseases in the other studies was important. High serum levels of β-carotene, retinyl-palmate, and vitamin E may have interacted negatively in the process of carcinogenesis and formation of atheroma. No evidence existed, however, indicating that those with the highest β-carotene levels were at greatest risk.

The fact that trials have failed to show any advantage for nutritional supplements underlines the dictum that positive associations in observational studies must be tested in randomized controlled trials. The observation that a high intake of fruit and vegetables and serum levels of β-carotene are correlated with a low risk for lung cancer and cardiovascular death remains unexplained. The only study that showed a modest benefit for β-carotene, vitamins, and selenium only recruited patients who were vitamin and mineral depleted (3).

If all the studies are taken into account, no support exists for the use of supplementation, although a diet high in fruits and vegetables is still recommended. Stopping smoking remains the best way to decrease the risk for lung cancer and cardiovascular disease. Research is needed to find out why high intake of fruits and vegetables is apparently beneficial.

Chris J. Williams, DM
Institute of Health SciencesOxford, England, UK


References

1. Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer. 1992;18:1-29.

2. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alph-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994; 330:1029-35.

3. Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China. J Natl Cancer Inst. 1993;85:1483-92.