Radiation concurrent with gemcitabine for locally advanced head and neck cancer: A phase I trial and intracellular drug incorporation study

Purpose: To examine the feasibility and dose-limiting toxicity (DLT) of onc e-weekly gemcitabine at doses predicted in preclinical studies to produce r adiosensitization, concurrent with a standard course of radiation for local ly advanced head and neck cancer. Tumor incorporation of gemcitabine tripho sphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level. Patients and Methods: twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) c oncurrent with weekly infusions of low-dose gemcitabine. tumor biopsies wer e performed after the first gemcitabine infusion (before radiation started) , and the intracellular concentrations of dFdCTP were measured. Results: Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving d ose levels of 300 mg/m(2)/wk, 150 mg/m(2)/wk, and 50 mg/m(2)/wk. No DLT was observed at 10 mg/m(2)/wk. The rate of endoscopy- and biopsy assessed comp lete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP lev els were similar in patients receiving 50 to 300 mg/m(2) (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m(2). Conclusion: A high rate of acute and late mucosa-related DLT and a high rat e of complete tumor response were observed in this regimen at the dose leve ls of 50 to 300 mg/m(2), which also resulted in similar, subcytotoxic intra cellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different re gimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio. (C) 2001 by American Society of Clinical Oncology.