A phase I trial of S-1 with concurrent radiotherapy for locally advanced pancreatic cancer

14003 Background: S-1 is a novel oral fluoropyrimidine derivative, and a phase II trial of this agent has demonstrated promising results with a response rate of 37.5% and a median survival of 8.8 months with a mild toxicity profile for patients with metastatic pancreatic cancer. This study investigated the maximum tolerated dose of S-1 based on the frequency of dose-limiting toxicities (DLT) of S-1 with concurrent radiotherapy in patients with locally advanced pancreatic cancer. Patients and Methods: Patients with locally advanced pancreatic cancer in whom adenocarcinoma had been confirmed histologically or cytologically were enrolled in this study. S-1 was administered orally in escalating doses from 50 mg/m2, which is reported to be equivalent to 200 mg/m2 intravenous 5-fluorouracil, to 80 mg/m2 bid in 10 mg/m2 increments on the day of irradiation (Monday through Friday) during radiotherapy. Radiation therapy was delivered through four fields as a total dose of 50.4 Gy in 28 fractions over 5.5 weeks. DLT was defined as grade 4 hematological toxicity and grade 3 or 4 non-hematological toxicity during chemoradiotherapy. The maximum tolerated dose was defined when three or more patients in a cohort of six patients experienced DLT. Results: Twenty-one patients (50 mg/m2 3 patients; 60 mg/m2 5 patients; 70 mg/m2 6 patients; 80 mg/m2 7 patients) were enrolled in this trial between May 2004 and November 2005. At 70 mg/m2 S-1, two of six patients demonstrated DLT involving grade 3 nausea and vomiting and grade 3 hemorrhagic gastritis, while all patients at dose levels other than 70 mg/m2 did not demonstrate any sign of dose-limiting toxicity. Of all 21 patients enrolled, 4 (19.0%) showed a partial response. More than a 50% reduction in the serum level of carbohydrate antigen 19–9 was observed in 12 (75%) of 16 patients in whom the pretreatment level was 100 U/ml or greater. Conclusion: The recommended dose of S-1 with concurrent radiotherapy is 80 mg/m2. This regimen may offer an easy alternative to intravenous 5-fluorouracil, and may be a promising treatment for locally advanced pancreatic cancer. A multicenter phase II trial of this regimen in patients with locally advanced pancreatic cancer is now underway. No significant financial relationships to disclose.