Cancer Prevention Research High-Dose Fenretinide in Oral Leukoplakia William N. William, Jr., 1 J. Jack Lee, 2 Scott M. Lippman, 1,3 Jack W. Martin, 4 Nitin Chakravarti, 1 Hai T. Tran, 1 Anita L. Sabichi, 1,3 Edward S. Kim, 1 Lei Feng, 2 Reuben Lotan 1 and Vassiliki A. Papadimitrakopoulou 1 Abstract We previously showed that low-dose fenretinide (200 mg/d) had limited activity in retinoid- resistant oral leukoplakia (34% response rate) possibly because serum drug levels were insufficient to induce retinoid receptor–independent apoptosis. Therefore, we designed the single-arm phase II trial reported here to investigate whether higher-dose fenretinide would improve leukoplakia response over that of our previous study. Leukoplakia patients received fenretinide (900 mg/m 2 twice daily) in four 3-week cycles (1 week on drug followed by 2 weeks off). At week 12, clinical responses were determined and blood samples were collected for serum drug level assessments. A planned interim futility analysis led to early trial closure after the initial 15 (of 25 planned) patients because only 3 (20%) had a partial response (stopping rule: ≤4 responses in first 16 patients). Fenretinide was well tolerated— only one grade 3 adverse event (diarrhea) occurred. Serum fenretinide levels changed from 0 (baseline) to 0.122 ± 0.093 μmol/L (week 12). In correlative in vitro studies, high-dose fenre- tinide inhibited the growth of head and neck cancer cells more and oral leukoplakia cells less than did lower doses of fenretinide. This result is consistent with our clinical finding that high-dose fenretinide did not improve on the historical response rate of lower-dose fenreti- nide in our previous oral leukoplakia trial. Fenretinide is a synthetic retinoid [N-(4-hydroxyphenyl)reti- namide] with clinical activity in patients with the prema- lignant lesion oral leukoplakia (1, 2). It is postulated that fenretinide is active in oral premalignant lesions via modulat- ing cell growth and/or differentiation or inducing apoptosis. A dual, dose-dependant mechanism of action mediates the antineoplastic effects of fenretinide. Fenretinide induced cell differentiation at a low concentration (1 μmol/L) and apop- tosis at higher concentrations (3-10 μmol/L) in cancer cells in vitro (3–6). Of note, the induction of differentiation was not observed in mutant F9 murine embryonal carcinoma cells lacking expression of retinoic acid receptor γ and retinoid X receptor α, whereas apoptosis was shown following exposure to fenretinide in both wild-type and receptor-deleted cells (3). These collective results indicate that fenretinide-induced apoptosis is independent of retinoid receptors, whereas fenretinide- induced differentiation is not. In a previous phase II trial, we found that low-dose fenreti- nide (200 mg/d) for 12 weeks produced a 34% response rate in patients with retinoid-resistant leukoplakia (never responded or responded and then relapsed during treatment; ref. 1). The responses, however, were partial in all cases, often short lived, and correlated with previous response to natural retinoids (1). Because fenretinide serum levels (mean, 0.230 μmol/L) were at least 10-fold lower than the concentrations required in vitro for induction of apoptosis (>3 μmol/L; refs. 6–8), we hypothe- sized that the limited clinical activity of low-dose fenretinide in this trial likely was due to retinoid receptor–mediated me- chanisms and did not involve retinoid receptor–independent apoptotic effects. A previous phase I trial showed that fenretinide at 900 mg/ m 2 twice daily in 21-day cycles (7 days on drug followed by 14 days off) was tolerable and produced peak serum drug levels of 3 to 5 μmol/L (9). Based on the preclinical data (3–6), fenretinide at this dose theoretically would produce high serum levels capable of inducing retinoid receptor– independent apoptosis, eliminating premalignant clones, and thus producing sustained clinical responses in oral leu- koplakia. We hypothesized that fenretinide would have this cytotoxic-like effect of a rapid burst of apoptotic activity and that the 14-day drug holiday would minimize potential adverse effects, paralleling the rationale behind cytotoxic drug regimens. Therefore, we assessed the effects of high- dose fenretinide on oral leukoplakia in a phase II trial and correlative in vitro studies. Authors' Affiliations: Departments of 1 Thoracic/Head and Neck Medical Oncology, 2 Biostatistics, 3 Clinical Cancer Prevention, and 4 Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas Received 05/15/2008; revised 07/25/2008; accepted 07/28/2008. Grant support: National Cancer Institute, Department of Health and Human Services grants P01 CA052051 and P30 CA016672 (The University of Texas M. D. Anderson Cancer Center support grant). Requests for reprints: Vassiliki A. Papadimitrakopoulou, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 432, Houston, TX 77030.Phone:713-792-6363;Fax:713-792-1220;E-mail:vpapadim@mdanderson.org. ©2009 American Association for Cancer Research. doi:10.1158/1940-6207.CAPR-08-0100 22 Cancer Prev Res 2009;2(1) January 2009 www.aacrjournals.org Downloaded from http://aacrjournals.org/cancerpreventionresearch/article-pdf/2/1/22/2245965/22.pdf by guest on 11 June 2022