title: A phase I study of fludarabine combined with radiotherapy in patients with intermediate to locally advanced head and neck squamous cell carcinoma.
abstract: OBJECTIVE
  Fludarabine, 9-beta-D-arabinofuranosyl-2-fluoroadenine, is an adenine nucleoside analogue that has significant activity in hematological malignancies and has shown promising activity in combination with radiation in preclinical solid tumor models. In this framework, we designed two phase I trials (one conducted at M.D. Anderson Cancer Center in Houston, and the other conducted in two Belgian hospitals) exploring concurrent fludarabine and radiotherapy in patients with intermediate to locally advanced head and neck squamous cell carcinomas (HNSCC).
  
  
  METHODS
  Fludarabine was administered i.v. daily 3-4 h before the last 10 fractions of a standard radiation fractionation regimen (70 Gy in 7 weeks). The main objective of the trials was to determine the maximum tolerated dose (MTD) of fludarabine in this particular setting. Twenty-eight patients with stage T2-T4, any N, M0 were included in the study. Fludarabine doses started at 7.5 mg/m(2) per day (3 mg/m(2) per day in Houston) and increased by steps of 2.5 mg/m(2) per day (3 mg/m(2) per day in Houston).
  
  
  RESULTS
  The addition of fludarabine at increasing doses to radiation did not result in increased intensity or duration of skin (18% grade 3 dermatitis) or mucosal (60% grade 3 mucositis) radiotoxicity compared to what was expected for radiation alone. At a daily dose of 17.5 mg/m(2), two patients out of five (40%) developed a grade 4 neutropenia, of whom one developed a neutropenic fever. This dose was set as the MTD. All patients developed a fludarabine dose-dependant lymphocytopenia. The plasma F-ara-A concentration peaked after the 30-min infusion in a dose-dependent fashion and reached an average peak concentration of approximately 2 microM for doses of 15 mg/m(2) and higher.
  
  
  CONCLUSIONS
  This study demonstrates that fludarabine can be safely administered concurrently with radiation at a daily dose of 15 mg/m(2) during the final 2 weeks of radiotherapy. A phase II trial will be required to establish the potential role of concurrent fludarabine and radiotherapy in the treatment of moderately to locally advanced HNSCC.
authors.affiliation: Department of Radiation Oncology, Université Catholique de Louvain, St-Luc University Hospital, 10 Avenue Hippocrate, Brussels, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Grégoire
authors.forename: K Kian
authors.initials: KK
authors.lastname: Ang
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Rosier
authors.forename: Marc
authors.initials: M
authors.lastname: Beauduin
authors.forename: Adam S
authors.initials: AS
authors.lastname: Garden
authors.forename: Marc
authors.initials: M
authors.lastname: Hamoir
authors.forename: Walter N
authors.initials: WN
authors.lastname: Hittelman
authors.forename: Yves
authors.initials: Y
authors.lastname: Humblet
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Luka
authors.initials: L
authors.lastname: Milas
authors.forename: Carine
authors.initials: C
authors.lastname: Mitine
authors.forename: Pierre
authors.initials: P
authors.lastname: Scalliet
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D010039:Otorhinolaryngologic Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D011832:Radiation Injuries; D014740:Vidarabine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D014740:Vidarabine; C024352:fludarabine