A phase I study of fludarabine combined with radiotherapy in patients with intermediate to locally advanced head and neck squamous cell carcinoma

Background and purpose: Fludarabine, 9-β-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). Materials and 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/m² per day (3 mg/m² per day in Houston) and increased by steps of 2.5 mg/m² per day (3 mg/m² 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/m², 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 μM for doses of 15 mg/m² and higher. Conclusions: This study demonstrates that fludarabine can be safely administered concurrently with radiation at a daily dose of 15 mg/m² 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.