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Phase I Trial of All-Trans Retinoic Acid in Patients with Treated Head and Neck Squamous Carcinoma¹

Division of Hematology-Oncology, Department of Medicine [S. H. P., R. G. S., D. A. V. E., B. A. C.], and Department of Radiation Oncology [M. J., M. S.], University of Maryland School of Medicine and Program of Oncology; Division of Developmental Therapeutics, Program of Oncology [S. H. P., S. W., B. A. C.]; and Department of Oral and Maxillofacial Surgery, University of Maryland School of Dentistry and Program of Oncology [R. A. O.], Greenebaum Cancer Center at the University of Maryland, Baltimore, Maryland 21201; Division of Otolaryngology-Head/Neck Surgery, Department of Surgery, University of Maryland School of Medicine [W. C. G.], Baltimore, Maryland 21201; and Division of Hematology-Oncology, Department of Medicine, Baltimore Veterans Administration Medical Center, Baltimore, Maryland 21201 [I. H.]

Although retinoids show promise for prevention of second primary upper aerodigestive tract tumors, the optimum retinoid, dose, and schedule are unknown. All-trans retinoic acid (ATRA) has greater affinity for retinoic acid receptors and may be more active than other retinoids but has a shorter plasma 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 neck (SCCHN). Twenty-one patients were randomized to 45, 90, or 150 mg/m² ATRA either once daily, or as divided doses every 8 h, for 1 year. Pharmacokinetics were assessed periodically. Fourteen men and seven women with previous SCCHN of initial stage I–IV were treated. Grade 3 toxicities (reversible) included headache and hypertri-glyceridemia in 5 and 6 patients each, mucositis in 2 patients, and hyperbilirubinemia, elevated alkaline phosphatase, colitis, lipasemia, xerostomia, eczema, and arthritis in 1 patient each. The 150-mg/m² dose was not tolerable. Doses were reduced for grade 3 toxicity in seven of eight patients at 90 mg/m² daily. Three of nine patients at 45 mg/m²/day required dose reduction, two at the once-daily dose. Day 1 ATRA area under the plasma 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%) studied. ATRA AUC did not correlate with toxicity severity or frequency. Fifteen mg/m²/day every 8 h is a tolerable dose for 1 year in patients with treated SCCHN. ATRA pharmacokinetics did not correlate with toxicity.

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