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Randomized trial of 13-cis retinoic acid compared with retinyl palmitate with or without beta-carotene in oral premalignancy.
Papadimitrakopoulou, VA, Lee, JJ, William, WN, Martin, JW, Thomas, M, Kim, ES, Khuri, FR, Shin, DM, Feng, L, Hong, WK, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;(4):599-604
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Abstract
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.
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Biologic correlates of a biochemoprevention trial in advanced upper aerodigestive tract premalignant lesions.
Papadimitrakopoulou, VA, Liu, DD, Mao, L, Shin, DM, El-Naggar, A, Ibarguen, H, Lee, JJ, Hong, WK, Hittelman, WN
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2002;(12):1605-10
Abstract
OBJECTIVE To identify tissue biomarkers that might be used to assess an individual's cancer risk and response to chemoprevention, we studied in dysplastic lesions of the larynx and the p.o. cavity, a series of biomarkers extensively used in previous chemoprevention trials, including chromosome polysomy (CP), proliferative status, p53 expression and gene mutations, and loss of heterozygosity at 9p, 3p, and 17p. METHOD Biopsies from 32 participants in a prospective chemoprevention trial using 13-cis-retinoic acid, IFN-alpha, and alpha-tocopherol for 12 months (20 with vocal cord and 12 with p.o. cavity lesions) were analyzed for p53 and Ki-67 expression by immunohistochemistry, loss of heterozygosity by PCR amplification, p53 mutations by PCR-based direct sequencing, and CP by in situ hybridization. RESULTS High CP (> or =4% cells with more than three chromosome copies per nucleus) was more common in p.o. (8 of 10) than laryngeal lesions (4 of 16; P = 0.01), and so was a combination of CP > or = 4% and parabasal layer p53 labeling index > or = 0.2 (P = 0.02). Low CP was a significant predictor of complete histological response (8 of 14 cases with low versus 1 of 12 cases with high CP; P = 0.01). A trend for histological progression or cancer development was observed in cases with high CP and parabasal layer p53 labeling index. CONCLUSION Low CP, more frequently observed in laryngeal lesions, appears to be a predictor of response to chemoprevention and could be used as a screening tool to identify suitable candidates for such approaches. Further investigation of biological parameters of response and cancer risk is warranted.