Phase I trial of gefitinib with concurrent radiotherapy and fixed dose-rate gemcitabine infusion, in locally advanced pancreatic cancer

Abstract

4105 Background: Pancreatic cancers are resistant to radiotherapy (RT) and current chemotherapy agents. Epidermal growth factor receptor (EGFR) is over-expressed in pancreatic cancer and in vitro studies have shown that EGFR inhibitors can overcome radio- and chemo-resistance. The aim of the study was to determine the maximally tolerated dose of gefitinib, in combination with RT and gemcitabine for patients with locally advanced pancreatic carcinoma (LAPC). Methods: Eighteen patients with pathological proven LAPC, due to major vascular invasion based on helical computed tomography and endoscopic ultrasound, were entered. The targeted irradiated volume included the tumor and 2 cm-margin. Prophylactic irradiation of regional nodes was not allowed. Patients with >500 cc of planned tumor volume (PTV) were excluded. An initial cohort of 6 patients was treated with RT (45 Gy/25 fractions/5 weeks) plus concomitant gefitinib (250 mg/day). Successive cohorts of patients received 100, 150 and 200 mg/m2/day of gemcitabine in a 2 hour infusion over weeks 1,2,3,4, and 5 with gefitinib (250 mg/day) and RT. Gefitinib was continued after RT until progression. A pharmacodynamic study of angiogenic markers (VEGF and IL-8) was also performed. Results: Mean PTV was 293cc (range 137–462 cc). There were no dose-limiting toxicities on study. Common toxicities were mild neutropenia, asthenia, diarrhea, cutaneous rash and nausea/vomiting. One patient showed a partial response of 13 months in duration, and 7 patients showed disease stabilization. Median progression free survival (PFS) was 3.7 months and median overall survival (OS) was 7.5 months. No patients have a reduction in VEGF levels >50%. Reduction in VEGF serum levels >25% and IL-8 levels >50% had no impact on PFS and OS. Conclusion: Our results support thatthe combination of gefitinib, RT and gemcitabine showed an acceptable toxicity but with modest activity in LAPC. [Table: see text]