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

1569-8041

phase I trial ; retinoid ; solid tumors ; vitamin E

Springer Online Journal Archives 1860-2000

Medicine

Abstract Background: Retinoids are under intensive study for the treatment andprevention of cancer. Substantial dose-related toxicities of retinoids are amajor obstacle to this work. In a recent retrospective analysis of combined13-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 newcombination. This trial tested the hypotheses that AT can reduce toxicity ofhigh-dose 13cRA and does not interfere with 13cRA absorption/activity asreflected by reduced 13cRA serum levels. Patients and methods: This was a phase I trial design in whichpatients received fixed-dose 13cRA (100 mg/m2/d) plusescalating-dose AT (beginning at 800 IU/d, increased 400 IU/d each month until2000 IU/d). We collected toxicity data every four weeks from self-reportforms, clinical examinations and laboratory studies. AT effects on 13cRAtoxicity were determined by comparing maximum toxicity at lowest AT dose withthat at highest AT dose. We also measured serum levels of both agents everyfour weeks. Results: Of the 45 patients registered, 36 had cancer (active orprior history), 9 had premalignant lesions. Thirty-nine patients could beevaluated for initial-course toxicity; 31 for final-course toxicity. Mediantime on treatment (all patients) was four months (range, 1–9 months);a total of 223 month-long courses of treatment were given. Eighteen percentof patients (7/39) developed grade 3 or 4 toxicity in the initial course. Therates of increase and decrease in 13cRA toxicity associated with increasingAT doses were similar: 36% decreased (11/31), 32% increased(10/31) (P = 0.84). AT did not reduce 13cRA serum levels. After initialincreases of mean AT plasma levels (17.9 µg/ml at baseline to 45.4µg/ml after first four-week course), subsequent AT plasma increases(〈2-fold) did not keep pace with increased AT doses (2–3-fold). Nomajor activity occurred in the 21 patients with active refractory cancer. Thecomplete response rate in patients with premalignant head-and-neck or lunglesions was 77.8% (7/9), which included two patients previouslyrefractory to 13cRA alone. Conclusion: Although escalating doses of AT did not reduce 13cRAtoxicity, the rate of initial-course (including 800 IU/d of AT) high-gradetoxicity was substantially lower than that typical of high-dose 13cRA-aloneand similar to that typical of low-dose 13cRA-alone. Indeed, a trial of13cRA-alone followed by 13cRA plus AT may have detected a significant toxicitydifference. We did not design such a trial out of ethical concern for knownside effects of high-dose 13cRA. The increase in AT serum levels was notproportional with increasing doses of AT, which may explain the lack of adose-response effect of AT on 13cRA toxicity. Previous trials have establishedthat 13cRA has an approximate 10% complete response rate in oralpremalignancy. Our small trial's 77.8% complete response rate inpremalignant lesions suggests that AT may enhance 13cRA clinical activity.Future trials of 13cRA plus AT are needed to define this combinationåstoxicity profile, clinical activity and pharmacokinetics.

Electronic Resource