The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements

Our plain-English summary of The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements, by G.E. Goodman, M.D. Thornquist, J. Balmes, et al (Journal of the National Cancer Institute, 2004).

The study

• Authors: G.E. Goodman, M.D. Thornquist, J. Balmes, M.R. Cullen, F.L. Meyskens, G.S. Omenn, B. Valanis, J.H. Williams
• Journal: Journal of the National Cancer Institute
• Published: 2004;96(23):1743-50
• Type of article: Randomized trial
• Cited by: 290 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the effect of daily beta-carotene (30 mg) and retinyl palmitate (25,000 IU) on the incidence of lung cancer, other cancers, and death in 18,314 participants who were at high risk for lung cancer because of a history of smoking or asbestos exposure. CARET was stopped ahead of schedule in January 1996 because participants who were randomly assigned to receive the active intervention were found to have a 28% increase in incidence of lung cancer, a 17% increase in incidence of death and a higher rate of cardiovascular disease mortality compared with participants in the placebo group.

Methods: After the intervention ended, CARET participants returned the study vitamins to their study center and provided a final blood sample. They continue to be followed annually by telephone and mail self-report. Self-reported cancer endpoints were confirmed by review of pathology reports, and death endpoints were confirmed by review of death certificates. All statistical tests were two-sided.

Results: With follow-up through December 31, 2001, the post-intervention relative risks of lung cancer and all-cause mortality for the active intervention group compared with the placebo group were 1.12 (95% confidence interval [CI] = 0.97 to 1.31) and 1.08 (95% CI = 0.99 to 1.17), respectively. Smoothed relative risk curves for lung cancer incidence and all-cause mortality indicated that relative risks remained above 1.0 throughout the post-intervention follow-up. By contrast, the relative risk of cardiovascular disease mortality decreased rapidly to 1.0 after the intervention was stopped. During the post-intervention phase, females had larger relative risks of lung cancer mortality (1.33 versus 1.14; P = .36), cardiovascular disease mortality (1.44 versus 0.93; P = .03), and all-cause mortality (1.37 versus 0.98; P = .001) than males.

Conclusions: The previously reported adverse effects of beta-carotene and retinyl palmitate on lung cancer incidence and all-cause mortality in cigarette smokers and individuals with occupational exposure to asbestos persisted after drug administration was stopped although they are no longer statistically significant. Planned subgroup analyses suggest that the excess risks of lung cancer were restricted primarily to females, and cardiovascular disease mortality primarily to females and to former smokers.

In plain English

This article reported follow-up of CARET, a randomized trial at six United States centers. It gave 18,314 people at high risk of lung cancer daily 30 mg beta-carotene plus 25,000 IU retinyl palmitate, or placebo. Participants were heavy current or recent former smokers, or men with occupational asbestos exposure. The trial was stopped early in January 1996 because of adverse findings. The authors then followed participants through December 31, 2001, by annual self-report checked against pathology reports and death certificates. After the supplements stopped, relative risks for the active versus placebo group were 1.12 (95% CI 0.97 to 1.31) for lung cancer and 1.08 (0.99 to 1.17) for death from any cause. The cardiovascular death relative risk was 1.02 (0.88 to 1.19). In the 3,693 asbestos-exposed men, the post-intervention lung cancer relative risk was 0.92 (0.65 to 1.30). Women had higher relative risks than men. The authors concluded that the earlier excess risks of lung cancer and all-cause mortality persisted at lower, not statistically significant levels. They cautioned that the subgroup findings may be spurious because of multiple testing.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Post-intervention follow-up of a randomized, placebo-controlled chemoprevention trial (CARET); relative risks estimated with Cox proportional hazards models
• Who was studied: 18,314 participants randomized at six U.S. centers (Seattle, Portland, San Francisco, Irvine, Baltimore, New Haven): male and female current and recent former heavy smokers, and male asbestos-exposed workers. 8,744 active and 8,396 placebo participants were in the post-intervention analysis (smoker cohort 13,447; asbestos-exposed cohort 3,693, all male). Follow-up ran from January 12, 1996 to December 31, 2001. 1,174 enrolled participants did not contribute: 1,092 died during the intervention phase and 82 were lost to follow-up.
• Exposure: Daily 30 mg beta-carotene plus 25,000 IU retinyl palmitate versus placebo, stopped January 11, 1996. Asbestos exposure was an entry criterion for the asbestos-exposed men: at least 5 years in a high-risk trade, completed at least 10 years before randomization, and at least 15 years since first exposure. No fiber types are named.
• Main results:
  • All participants, post-intervention phase: lung cancer incidence relative risk for active versus placebo was 1.12 (95% CI 0.97 to 1.31; P .13), with 376 versus 311 cases. During the intervention phase it had been 1.28 (1.04 to 1.57).
  • All participants: the smoothed lung cancer relative risk was greater than 1.1 for the first 4 years after the intervention ended. The pointwise 95% confidence intervals excluded 1.0 between November 1997 and August 1999.
  • All participants, post-intervention: death from any cause relative risk 1.08 (95% CI 0.99 to 1.17; P .07), with 1225 versus 1047 deaths. The authors described this as suggestive of, but not definitive for, a continued modestly elevated risk.
  • All participants, post-intervention: lung cancer mortality relative risk 1.20 (95% CI 1.01 to 1.43), with 294 versus 227 deaths.
  • All participants, post-intervention: cardiovascular disease mortality relative risk 1.02 (95% CI 0.88 to 1.19), down from 1.26 (0.99 to 1.61) during the intervention phase.
  • Asbestos-exposed cohort (3,693 men), post-intervention: lung cancer incidence relative risk 0.92 (95% CI 0.65 to 1.30), with 61 active versus 66 placebo cases. All-cause mortality relative risk was 0.96 (0.81 to 1.13). There were no statistically significant differences in relative risks between asbestos-exposed participants and males in the smoker cohort.
  • Smoker cohort, post-intervention: lung cancer incidence relative risk was 1.33 (95% CI 1.01 to 1.75) in females. The difference from males was not statistically significant (P 0.09).
  • Post-intervention, females versus males: lung cancer mortality relative risk 1.33 versus 1.14. Cardiovascular disease mortality relative risk 1.44 (95% CI 1.02 to 2.04) in females versus 0.93 in males (P .03). All-cause mortality relative risk 1.37 in females (P .001 for the difference); the male figure is printed inconsistently.
  • Post-intervention: former smokers had a cardiovascular disease mortality relative risk of 1.44, compared with 0.87 in current smokers (nominal P .01).
• The authors' conclusion: The authors concluded that the excess risks of lung cancer and all-cause mortality seen at the end of the intervention persisted over 6 years of follow-up, but at lower and not statistically significant levels. They wrote that planned subgroup analyses suggest the excess lung cancer risk was mainly in females, and the excess cardiovascular mortality mainly in females and former smokers. They said further follow-up is needed to confirm or refute these trends.
• Limitations the authors state:
  • The results for the primary endpoints in the full study population were not statistically significant.
  • Secondary endpoint and subgroup findings may be spurious because many statistical tests were performed.
  • The very high smoothed relative risks for females early in the intervention period reflect unstable estimates from very few events before 1990.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Lung Cancer, Asbestos Exposure, Pathology Report, Death Certificate, Relative Risk, confidence interval, Occupational Exposure.

Related studies

• Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial — G.S. Omenn, G.E. Goodman, et al. (1996)
• Evidence for excess colorectal cancer incidence among asbestos-exposed men in the Beta-Carotene and Retinol Efficacy Trial — O.A. Aliyu, M.R. Cullen, et al. (2005)
• Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease — G.S. Omenn, G.E. Goodman, et al. (1996)
• Predictors of lung cancer among asbestos-exposed men in the {beta}-carotene and retinol efficacy trial — M.R. Cullen, M.J. Barnett, et al. (2005)
• Research cost analyses to aid in decision making in the conduct of a large prevention trial, CARET. Carotene and Retinol Efficacy Trial — M.D. Thornquist, N. Urban, et al. (1993)
• Vitamin A and cancer prevention II: comparison of the effects of retinol and beta-carotene — N.H. de Klerk, A.W. Musk, et al. (1998)

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