Phase I trial of all-trans retinoic acid in patients with treated head andneck squamous carcinoma

Although retinoids show promise for prevention of second primary upper aero digestive tract tumors, the optimum retinoid, dose, and schedule are unknow n, All-trans retinoic acid (ATRA) has greater affinity for retinoic acid re ceptors and may be more active than other retinoids but has a shorter plasm a half life and may up-regulate its own metabolism, We defined the maximum long-term tolerable dose, dosing frequency, pharmacokinetics, and toxicity of ATRA in patients with treated squamous cell carcinoma of the head and ne ck (SCCHN), Twenty-one patients were randomized to 45, 90, or 150 mg/m(2) A TRA either once daily, or as divided doses every 8 h, for 1 year. Pharmacok inetics were assessed periodically, Fourteen men and seven women with previ ous SCCHN of initial stage I-IV were treated. Grade greater than or equal t o 3 toxicities (reversible) included headache and hypertriglyceridemia in 5 and 6 patients each, mucositis in 2 patients, and hyperbilirubinemia, elev ated alkaline phosphatase, colitis, lipasemia, xerostomia, eczema, and arth ritis in 1 patient each, The 150-mg/m(2) dose was not tolerable. Doses were reduced for grade greater than or equal to 3 toxicity in seven of eight pa tients at 90 mg/m2 daily. Three of nine patients at 45 mg/m(2)/day required dose reduction, two at the once-daily dose. Day 1 ATRA area under the plas ma concentration versus time curve (AUC) increased with dose, and after 1-2 months of continued dosing, the AUC declined in 7 of 13 patients (54%) stu died. ATRA AUC did not correlate with toxicity severity or frequency. Fifte en mg/m2/day every 8 h is a tolerable dose for 1 year in patients with trea ted SCCHN, ATRA pharmacokinetics did not correlate with toxicity.