Phase I trial of alpha-tocopherol effects on 13-cis-retinoic acid toxicity

Background: Retinoids are under intensive study for the treatment and prevention of cancer. Substantial dose-related toxicities of retinoids are a major obstacle to this work. In a recent retrospective analysis of combined 13-cis-retinoic acid (13cRA) and alpha-tocopherol (AT) in myelodysplasia, 13cRA toxicity was reduced significantly and 13cRA activity was enhanced. These results suggested the need for prospective testing of this new combination. This trial tested the hypotheses that AT can reduce toxicity of high-dose 13cRA. and does not interfere with 13cRA absorption/activity as reflected by reduced 13cRA serum levels. Patients and methods: This was a phase I trial design in which patients received fixed-dose 13cRA (100 mg/m(2)/d) plus escalating-dose AT (beginning at 800 IU/d, increased 400 IU/d each month until 2000 IU/d). We collected toxicity data every four weeks from self-report forms, clinical examinations and laboratory studies. AT effects on 13cRA toxicity were determined by comparing maximum toxicity at lowest AT dose with that at highest AT dose. We also measured serum levels of both agents every four weeks. Results: Of the 45 patients registered, 36 had cancer (active or prior history), 9 had premalignant lesions. Thirty-nine patients could be evaluated for initial-course toxicity; 31 for final-course toxicity. Median time on treatment (all patients) was four months (range, 1-9 months); a total of 223 month-long courses of treatment were given. Eighteen percent of patients (7/39) developed grade 3 or 4 toxicity in the initial course. The rates of increase and decrease in 13cRA toxicity associated with increasing AT doses were similar: 36% decreased (11/31), 32% increased (10/31) (P = 0.84). AT did not reduce 13cRA serum levels. After initial increases of mean AT plasma levels (17.9 mu g/ml at baseline to 45.4 mu g/ml after first four-week course), subsequent AT plasma increases (< 2-fold) did not keep pace with increased AT doses (2-3-fold). No major activity occurred in the 21 patients with active refractory cancer. The complete response rate in patients with premalignant head-and-neck or lung lesions was 77.8% (7/9), which included two patients previously refractory to 13cRA alone. Conclusions. Although escalating doses of AT did not reduce 13cRA toxicity, the rate of initial-course (including 800 IU/d of AT) high-grade toxicity was substantially lower than that typical of high-dose 13cRA-alone and similar to that typical of low-dose 13cRA-alone. Indeed, a trial of 13cRA-alone followed by 13cRA plus AT may have detected a significant toxicity difference. We did not design such a trial out of ethical concern for known side effects of high-dose 13cRA. The increase in AT serum levels was not proportional with increasing doses of AT, which may explain the lack of a dose-response effect of AT on 13cRA toxicity. Previous trials have established that 13cRA has an approximate 10% complete response rate in oral premalignancy. Our small trial's 77.8% complete response rate in premalignant lesions suggests that AT may enhance 13cRA clinical activity. Future trials of 13cRA plus AT are needed to define this combinations toxicity profile, clinical activity and pharmacokinetics.