Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial

Our plain-English summary of Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial, by G.S. Omenn, G.E. Goodman, M.D. Thornquist, et al (Journal of the National Cancer Institute, 1996).

The study

• Authors: G.S. Omenn, G.E. Goodman, M.D. Thornquist, J. Balmes, M.R. Cullen, A. Glass, J.P. Keogh, F.L. Meyskens, B. Valanis, J.H. Williams, S. Barnhart, M.G. Cherniack, C.A. Brodkin, S. Hammar
• Journal: Journal of the National Cancer Institute
• Published: 1996;88(21):1550-9
• Type of article: Randomized trial
• Cited by: 850 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in beta-carotene (a violet to yellow plant pigment that acts as an antioxidant and can be converted to vitamin A by enzymes in the intestinal wall and liver) and retinol (an alcohol chemical form of vitamin A), and people having higher serum beta-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate). Promptly after the January 18, 1996, announcement that the CARET active intervention had been stopped, we published preliminary findings from CARET regarding cancer, heart disease, and total mortality.

Purpose: We present for the first time results based on the pre-specified analytic method, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the intervention.

Methods: CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial, initiated with a pilot phase and then expanded 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Serum was collected from the participants at base line and periodically after randomization and was analyzed for beta-carotene concentration. An Endpoints Review Committee evaluated endpoint reports, including pathologic review of tissue specimens. The primary analysis is a stratified logrank test for intervention arm differences in lung cancer incidence, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were estimated by use of Cox regression models; tests were performed for quantitative and qualitative interactions between the intervention and smoking status or alcohol intake. O'Brien-Fleming boundaries were used for stopping criteria at interim analyses. Statistical significance was set at the .05 alpha value, and all P values were derived from two-sided statistical tests.

Results: According to CARET's pre-specified analysis, there was an RR of 1.36 (95% confidence interval [CI] = 1.07-1.73; P = .01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% CI = 1.13-2.23; P = .01) for weighted lung cancer mortality. All subgroups, except former smokers, had a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associations of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity of RR among quartiles of alcohol intake has P = .01, unadjusted for multiple comparisons) and with large-cell histology (RR = 1.89; 95% CI = 1.09-3.26; test for heterogeneity among histologic categories has P = .35), but not with base-line serum beta-carotene concentrations.

Conclusions: CARET participants receiving the combination of beta-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for beta-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study in 29133 male smokers in Finland.

In plain English

This article reported detailed results from CARET, a randomized, double-blinded, placebo-controlled trial at six study centers. It tested a daily combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate (vitamin A) against placebo in 18,314 people at high risk of lung cancer: 14,254 heavy smokers and 4,060 male workers with occupational asbestos exposure. Through December 15, 1995, lung cancer incidence was 5.9 per 1000 persons per year in the active group versus 4.6 in the placebo group (weighted relative risk 1.36, 95% CI 1.07 to 1.73). Lung cancer mortality was also higher in the active group (weighted relative risk 1.59, 95% CI 1.13 to 2.23). Among asbestos-exposed participants, the weighted relative risk for lung cancer was 1.82 (95% CI 1.16 to 2.84). Of 23 mesothelioma cases, 14 were in the active group and nine in the placebo group, a difference that was not statistically significant. The authors treated links with alcohol intake and with former smoking as only suggestive or hypothesis-raising. The authors concluded that the combination gave no chemopreventive benefit and was followed by excess lung cancer incidence and mortality.

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: Randomized, double-blinded, placebo-controlled chemoprevention trial (CARET), begun as pilot studies and then expanded 10-fold at six study centers; analysis by intention to treat
• Who was studied: 18,314 men and women at high risk of lung cancer: 14,254 heavy smokers (44% women, mean age 58) and 4,060 asbestos-exposed male workers (mean age 57; 3% never smokers, 58% former smokers, 38% current smokers). Recruitment was completed in September 1994, and follow-up for this report ran through December 15, 1995.
• Exposure: Daily 30 mg beta-carotene plus 25,000 IU retinyl palmitate versus placebo. Pilot participants were first given other doses and were switched to this regimen in 1988. The asbestos-exposed workers had on average 35 years since first asbestos exposure and 27 years of asbestos exposure on the job, and about two thirds had chest x-rays positive for asbestos-related disease. Fiber types were not reported.
• Main results:
  • All participants: lung cancer incidence was 5.9 per 1000 persons per year in the active group versus 4.6 in the placebo group (229/9420 active vs 159/8894 placebo).
  • All participants: weighted relative risk of lung cancer for active versus placebo was 1.36 (95% CI 1.07 to 1.73; P = .01). The unweighted relative risk was 1.28 (95% CI 1.04 to 1.57; P = .02).
  • Asbestos-exposed participants: 62/2044 lung cancers in the active group vs 44/2016 in the placebo group. Weighted relative risk was 1.82 (95% CI 1.16 to 2.84; P = .008). Unweighted relative risk was 1.40 (95% CI 0.95 to 2.07; P = .08).
  • All participants: lung cancer mortality relative risk was 1.59 (95% CI 1.13 to 2.23; P = .01) with 2-year linear weighting, and 1.46 (95% CI 1.07 to 2.00; P = .02) unweighted.
  • Former smokers in the heavy-smoker population (no asbestos exposure): relative risk 0.80 (unweighted 95% CI 0.48 to 1.31; P = .37). The authors said this only raises a hypothesis, because many tests were performed.
  • Highest quartile of alcohol intake: relative risk 1.99 (95% CI 1.28 to 3.09), compared with 1.07 (95% CI 0.76 to 1.51) in nondrinkers. The authors considered this only suggestive.
  • Large-cell lung cancer: relative risk 1.89 (95% CI 1.09 to 3.26). The test for heterogeneity across histologic types was not statistically significant (P = .35).
  • Baseline serum beta-carotene was inversely associated with later lung cancer (all participants RR 0.69, 95% CI 0.54 to 0.88), but it did not modify the elevated risks associated with the active vitamins.
  • Mesothelioma (all participants): 23 cases, 14 active vs 9 placebo; 21 were among the asbestos-exposed and 2 in the smoker population. Relative risk was 1.52 (95% CI 0.66 to 3.52; P = .32).
  • No statistically significant differences between groups for any of eight common cancer types other than lung cancer (including mesothelioma) or for their aggregate.
• The authors' conclusion: The authors concluded that CARET participants receiving beta-carotene plus vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. They wrote that the results were highly consistent with the Finnish ATBC study.
• Limitations the authors state:
  • The subgroup findings (former smokers, alcohol) were based on many tests without adjustment for multiple comparisons.
  • The design did not allow the authors to tell whether giving retinyl palmitate together with beta-carotene affected the risk.
  • The alcohol finding lacked a consistent dose-response pattern.

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, Relative Risk, Statistical Significance, confidence interval, Histology.

Related studies

• 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)
• Lobe of origin and histologic type of lung cancer associated with asbestos exposure in the Carotene and Retinol Efficacy Trial (CARET) — C.A. Brodkin, J. McCullough, et al. (1997)
• 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 — G.E. Goodman, M.D. Thornquist, et al. (2004)
• CARET, the beta-carotene and retinol efficacy trial to prevent lung cancer in asbestos-exposed workers and in smokers — G.S. Omenn, G. Goodman, et al. (1991)
• Recruitment for the beta-carotene and retinol efficacy trial (CARET) to prevent lung cancer in smokers and asbestos-exposed workers — G.S. Omenn, G. Goodman, et al. (1992)
• Changes in cholesterol and triglyceride concentrations in the Vanguard population of the Carotene and Retinol Efficacy Trial (CARET) — B. Cartmel, J. Dziura, et al. (2005)

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