Phase i trial of radiotherapy concurrent with twice-weekly gemcitabine for head and neck cancer: Translation from preclinical investigations aiming to improve the therapeutic ratio

BACKGROUND: Once-weekly gemcitabine concurrent with radiotherapy was highly effective in the treatment of head and neck cancer (HNC) but limited by high mucosal toxicity. Pre-clinical investigations suggested that delivering gemcitabine at substantially lower doses twice weekly during radiotherapy improved the therapeutic ratio. We sought to translated these preclinical findings to a phase I trial. METHODS: Twenty-five patients with non-resectable HNC were scheduled to receive gemcitabine twice weekly during the last 2 weeks (total 5 infusions) of hyperfractionated radiotherapy delivering 1.2 Gy twice daily to total 76.8 Gy. Tumor biopsies to measure active intracellular (phosphorylated) gemcitabine were planned after the first drug delivery. Patients were assigned to escalating dose cohorts using the Continuous Reassessment Method. RESULTS: Twenty-one patients evaluable for toxicity were divided into cohorts receiving twice weekly treatment with 10, 20, 33, or 50 mg/m² gemcitabine. Dose-limiting toxicity was grade 3-4 confluent mucositis/pharyngitis, and the maximally tolerated dose (MTD) was 20 mg/m². Median survival was 20 months, with no difference between cohorts receiving lower (10, 20 mg/m²) or higher (33, 50 mg/m²) gemcitabine doses. Tumor biopsies after the first drug delivery showed only a minority of tumor cells in the specimens. CONCLUSION: These findings validate preclinical models that show that gemcitabine is radiation sensitizer at doses far below those used for systemic chemotherapy. However, the improvement in the therapeutic ratio predicted from the preclinical study did not translate into a substantial relative increase in the MTD of the drug in the clinical phase I trial.