© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 3, 206-214,
February 5, 2003
© 2003 Oxford University Press
ARTICLE |
Treatment of Former Smokers With 9-cis-Retinoic Acid Reverses Loss of Retinoic Acid Receptor-
Expression in the Bronchial Epithelium: Results From a Randomized Placebo-Controlled Trial
Affiliations of authors: J. M. Kurie, R. Lotan, J. S. Lee, F. R. Khuri, W. K. Hong (Department of Thoracic/Head and Neck Medical Oncology), J. J. Lee, D. D. Liu (Department of Biostatistics), R. C. Morice (Department of Pulmonary Medicine), X.-C. Xu (Department of Cancer Prevention), J. Y. Ro (Department of Pathology), W. N. Hittelman (Department of Experimental Therapeutics), G. L. Walsh, J. A. Roth (Department of Thoracic and Cardiovascular Surgery), The University of Texas M. D. Anderson Cancer Center, Houston; J. D. Minna, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas.
Correspondence to: Waun Ki Hong, M.D., Box 432, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: whong{at}mdanderson.org).
Background: Loss of retinoic acid receptor beta (RAR-
) expression in the bronchial epithelium is considered a biomarker of preneoplasia. Retinoids can restore expression of this receptor and, presumably, halt the progression of carcinogenesis. This study was designed to investigate whether either of two retinoid-based regimens, 9-cis-retinoic acid (RA) or 13-cis-RA plus 
-tocopherol (AT), could reverse RAR- expression loss in former smokers after 3 months of treatment. Methods: Individuals (n = 226) who had smoked at least 20 pack-years and had ceased smoking for at least 12 months were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) + AT (1200 IU), or placebo. Bronchoscopy and biopsy at six predetermined sites of the bronchial tree were performed before treatment and at 3 and 6 months thereafter. Specimens were evaluated for squamous metaplasia, dysplasia, and RAR- expression. McNemar’s test was used to test changes in RAR- expression and squamous metaplasia within each treatment group, and a generalized estimating equations model was applied to model the treatment effect, adjusting for covariates. All statistical tests were two-sided. Results: A total of 177 assessable subjects completed at least 3 months of therapy and underwent at least the baseline and 3-month bronchoscopic evaluations with biopsies. RAR- was detected in 69.7% of all baseline biopsy samples, and metaplasia was evident in 6.9% of all baseline samples from 240 subjects. Restoration of RAR- expression (P = .03) and reduction of metaplasia (P = .01) were found in the 9-cis-RA group. After adjustment for years of smoking, packs/day smoked, and metaplasia, treatment with 9-cis-RA, but not with 13-cis-RA + AT, led to a statistically significant increase in RAR- expression compared with placebo (P = .03). Conclusion: 9-cis-RA treatment can restore RAR- expression in the bronchial epithelium of former smokers, raising the possibility that this retinoid has potential chemopreventive properties in former smokers.
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