Originally published as JCO Early Release 10.1200/JCO.2008.17.1850 on December 15 2008

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Randomized Trial of 13-cis Retinoic Acid Compared With Retinyl Palmitate With or Without Beta-Carotene in Oral Premalignancy

From the Departments of Thoracic/Head and Neck Medical Oncology, Biostatistics and Dental Oncology, and Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX; and the Department of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA.

Corresponding author: Vassiliki Papadimitrakopoulou, MD, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 432, Houston, TX 77030; e-mail: vpapadim{at}mdanderson.org.

Purpose To investigate whether retinyl palmitate (RP) alone or plus beta-carotene (BC) would be as effective and less toxic than low-dose 13-cis retinoic acid (13cRA) in treating oral premalignant lesions (OPLs) and reducing the risk of oral cancer.

Patients and Methods Initially, patients were randomly assigned to receive low-dose 13cRA or BC plus RP for 3 years (plus 2 years follow-up). After other randomized trials established an adverse effect of BC on lung cancer incidence/mortality, BC was dropped (patients randomly assigned to 13cRA or RP alone). The primary end point was OPL clinical response at 3 months.

Results We randomly assigned 162 eligible patients. The 3-month clinical response rate of the combined BC plus RP and RP alone arm (32.5%) was not statistically equivalent to that of 13cRA (48.1%). The clinical response rate of RP alone (20.0%) was significantly lower than that of BC plus RP (42.9%; P = .03). Similar oral cancer–free survival rates were observed across all arms. There was no significant association between 3-month OPL response and subsequent oral cancer development (P = .11). Grades 2 and higher adverse events were more common in the 13cRA than other groups (P < .0001).

Conclusion This large chemoprevention trial did not establish the equivalence of RP plus BC or RP alone with low-dose 13cRA in reducing the long-term risk of oral cancer. At present, 13cRA, BC plus RP, and RP alone cannot be recommended for chemoprevention, and new, better agents are needed in this setting. Our results did not establish short-term OPL response as a surrogate end point for oral cancer–free survival.

Supported by Grants No. P01 CA052051 and P30 CA016672 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services (The University of Texas M. D. Anderson Cancer Center support grant).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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