A PHASE-I CLINICAL-TRIAL OF PROLONGED INFUSION OF HYDROXYUREA IN COMBINATION WITH HYPERFRACTIONATED, ACCELERATED, EXTERNAL RADIATION-THERAPY IN PATIENTS WITH ADVANCED SQUAMOUS-CELL CANCER OF THE HEAD AND NECK

Background: Preclinical data suggested that sustained inhibition of th e anabolic enzyme, ribonucleotide reductase (RR), by hydroxyurea (HU) may be critical for the anticancer effects of the drug. A phase I tria l of continuous infusion HU with concomitant hyperfractionated, accele rated radiation therapy (CHU-CHRT) was initiated to determine the maxi mum tolerated dose (MTD) and dose limiting toxicities (DLT) of HU in p atients with locally advanced squamous cell carcinoma (SCC) of the hea d and neck. Methods: Patients were required to have histologically-doc umented and radiographically-staged locally advanced SCC of the hypoph arynx (AJC stages IT, III or IV), oropharynx (AJC stage IV), or oral c avity (AJC stage IV) not amenable to reasonable surgical resection. El igible patients had adequate bone marrow, hepatic, and renal function and had to give informed consent. Concomitant, hyperfractionated, acce lerated radiation therapy (CHRT) consisted of 1.2 Gy BID (6 hour minim um interfraction interval) on weekdays and 1.2 Gy delivered daily on t he weekends to a total tumor dose of 74.4 Gy. Continuous infusion hydr oxyurea (CHU) was administered at 0.25-0.375 mg/m(2)/min as a continuo us intravenous infusion daily for 5 days with weekends days off for th e duration of the radiation therapy. The dose of HU was increased by 0 .125 mg/m(2)/min between dose levels until DLT was reached in 2/6 pati ents. If the primary had a complete clinical response and biopsies wer e negative, planned neck dissections were performed. Results: Fifteen patients were enrolled and are evaluable. The initial dose level, 0.25 mg/m(2)/min was tolerated by 3/3 patients. At 0.375 mg/m(2)/min, 3/6 patients experienced grade 3-4 infections, with one patient having a n on-fatal, subendocardial infarction. At 0.313 mg/m(2)/min, no patient experienced DLT. Conclusion: The MTD for CHU-CHRT was 0.313 mg/m(2)/mi n. The toxicities were primarily mucosal and a phase II study is in pr ogress.