title: 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.
abstract: BACKGROUND
  Preclinical data suggested that sustained inhibition of the anabolic enzyme, ribonucleotide reductase (RR), by hydroxyurea (HU) may be critical for the anticancer effects of the drug. A phase I trial of continuous infusion HU with concomitant hyperfractionated, accelerated radiation therapy (CHU-CHRT) was initiated to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of HU in patients with locally advanced squamous cell carcinoma (SCC) of the head and neck.
  
  
  METHODS
  Patients were required to have histologically-documented and radiographically-staged locally advanced SCC of the hypopharynx (AJC stages II, III or IV), oropharynx (AJC stage IV), or oral cavity (AJC stage IV) not amenable to reasonable surgical resection. Eligible patients had adequate bone marrow, hepatic, and renal function and had to give informed consent. Concomitant, hyperfractionated, accelerated radiation therapy (CHRT) consisted of 1.2 Gy BID (6 hour minimum interfraction interval) on weekdays and 1.2 Gy delivered daily on the weekends to a total tumor dose of 74.4 Gy. Continuous infusion hydroxyurea (CHU) was administered at 0.25-0.375 mg/m2/min as a continuous intravenous infusion daily for 5 days with weekends days off for the duration of the radiation therapy. The dose of HU was increased by 0.125 mg/m2/min between dose levels until DLT was reached in 2/6 patients. If the primary had a complete clinical response and biopsies were negative, planned neck dissections were performed.
  
  
  RESULTS
  Fifteen patients were enrolled and are evaluable. The initial dose level, 0.25 mg/m2/min was tolerated by 3/3 patients. At 0.375 mg/m2/min, 3/6 patients experienced grade 3-4 infections, with one patient having a non-fatal, subendocardial infarction. At 0.313 mg/m2/min, no patient experienced DLT.
  
  
  CONCLUSIONS
  The MTD for CHU-CHRT was 0.313 mg/m2/min. The toxicities were primarily mucosal and a phase II study is in progress.
authors.affiliation: Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467-2490, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Beitler
authors.forename: R V
authors.initials: RV
authors.lastname: Smith
authors.forename: H
authors.initials: H
authors.lastname: Haynes
authors.forename: C E
authors.initials: CE
authors.lastname: Silver
authors.forename: A
authors.initials: A
authors.lastname: Quish
authors.forename: T
authors.initials: T
authors.lastname: Kotz
authors.forename: M
authors.initials: M
authors.lastname: Serrano
authors.forename: A
authors.initials: A
authors.lastname: Brook
authors.forename: S
authors.initials: S
authors.lastname: Wadler
mesh_terms: D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D019583:Dose Fractionation, Radiation; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007275:Injections, Intravenous; D008875:Middle Aged; D009367:Neoplasm Staging
chemical_list: D006918:Hydroxyurea