title: Phase I trial of all-trans retinoic acid in patients with treated head and neck squamous carcinoma.
abstract: 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 > or =3 toxicities (reversible) included headache and hypertriglyceridemia 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 > or =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.
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore 21201, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Park
authors.forename: W C
authors.initials: WC
authors.lastname: Gray
authors.forename: I
authors.initials: I
authors.lastname: Hernandez
authors.forename: M
authors.initials: M
authors.lastname: Jacobs
authors.forename: R A
authors.initials: RA
authors.lastname: Ord
authors.forename: M
authors.initials: M
authors.lastname: Sutharalingam
authors.forename: R G
authors.initials: RG
authors.lastname: Smith
authors.forename: D A
authors.initials: DA
authors.lastname: Van Echo
authors.forename: S
authors.initials: S
authors.lastname: Wu
authors.forename: B A
authors.initials: BA
authors.lastname: Conley
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D005500:Follow-Up Studies; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006261:Headache / Q000139:chemically induced; D006801:Humans; D015228:Hypertriglyceridemia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa; D009367:Neoplasm Staging; D013280:Stomatitis / Q000139:chemically induced; D016896:Treatment Outcome; D014212:Tretinoin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D014212:Tretinoin