Randomized trial of 13-cis retinoic acid compared with retinyl palmitate with or without beta-carotene in oral premalignancy

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.

Fig 1.

Flow diagram of patients screened, enrolled, observed, and analyzed. 13cRA, 13-cis retinoic acid; BC + RP, beta-carotene plus retinyl palmitate; RP, retinyl palmitate.

Fig 2.

Oral cancer–free survival in the overall population according to treatment arm. 13cRA, 13-cis retinoic acid; BC + RP, beta-carotene plus retinyl palmitate; RP, retinyl palmitate; E, number of events; N, total number of patients per arm.

Fig 3.

Oral cancer–free survival by treatment in patients with hyperplasia or dysplasia. 13cRA, 13-cis retinoic acid; BC, beta-carotene; RP, retinyl palmitate; E, number of events; N, total number of patients per arm.

Fig 4.

Oral cancer-free survival according to the 3-month clinical response (all treatment arms combined). Landmark analysis was performed by resetting the time 0 to 3 months after random assignment, which corresponds to the time of response evaluation. Note that three nonresponders had oral cancer developed within 3 months and were removed from the analysis. E, number of events; N, total number of patients per arm.