Concomitant gemcitabine (Gemzar) and extended nodes irradiation in the treatment of pancreatic and biliary carcinoma: a phase I study

Background: The rationale for combining cytotoxic agents, such as gemcitabine, and radiotherapy is based on their ability to act as radiation sensitizers and to improve overall response rate. Several studies on pancreatic or biliary carcinoma evaluated the maximum tolerated dose (MTD) of gemcitabine when combined with irradiation of the macroscopic tumor. However, most of these neoplasms metastasize to the regional lymph nodes. Aim of this report is to determine the MTD of weekly gemcitabine when combined with extended field irradiation (tumor plus nodal irradiation). Patients and Method: 15 patients entered the study. Of these 5 patients were treated with chemoradiation after radical surgical resection. External beam radiation (ERT) was delivered to the tumor (or tumor bed) and regional lymph nodes by using a three-field technique. The initial dose of gemcitabine was 100 mg/m(2) administered as short intravenous infusion once a week. At each dose level 3 patients were treated, and if no grade 3-4 toxicity (considered as dose-limiting toxicity, DLT) was recorded, dose escalation was applied with 50 mg/m(2) increments until the MTD was established. Results: All patients were evaluable for acute toxicity. There were no treatment-related deaths. No DLT occurred at the first 4 dose levels (100-250 mg/m(2)). At the 5th dose level (300 mg/m(2)), 3 patients experienced DLT. 1 had grade 3 gastrointestinal toxicity (painful erosion of gastric mucosa), 1 had uncomplicated grade 3 leukopenia and 1 grade 3 change in liver biochemistry tests. In addition, all 10 unresected patients were evaluated for response, 4 of whom had progressive disease (1 local; 2 distant; 1 local and distant) and 6 had no change. The median follow-up was 21 months. Conclusion: Based on this study, the recommended dose for weekly short infusional gemcitabine combined with radiation therapy to the tumor and lymph nodes is 250 mg/m(2). This value is suggestive of a correlation between acute toxicity and inclusion of lymph nodes in the irradiated volume. Moreover, different infusion modalities, as continuous infusion gemcitabine, should be tested more accurately.