Phase I-II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer

Purpose: To determine the maximum-tolerated dose (MTD), dose-limiting toxic ities, and efficacy of gemcitabine combined with fluorouracil (5-FU) in pat ients with pancreatic cancer. Patients and Methods: patients with measurable,locally advanced, nonresecta ble or metastatic pancreatic cancer were candidates for the study 5-FU was given via protracted venous infusion (PVI) at a fixed dosage of 200 mg/m(2) /d, and gemcitabine was administered weekly for 3 consecutive weeks every 4 weeks. The initial dose of gemcitabine was 700 mg/m(2) and was escalated i n increments of 100 mg/m(2)/wk until the appearance of severe toxicity. Mea surements of efficacy included the following: response rate; clinical benef it response, which is a composite measurement of pain, performance status, and weight loss; time to disease progression; and survival. Results: Twenty-six patients received a total of 109 courses. Dose-limiting toxicity, which consisted of grade 4 neutropenia with fever (one patient) and grade 4 thrombocytopenia (one patient), was observed in two of three pa tients treated with 1,100 mg/m(2)/wk of gemcitabine. On the basis of these results, the MTD of gemcitabine with 5-FU via PVI on this schedule was 1,00 0 mg/m(2). Sixteen patients developed grade 3-4 neutropenia, and three pati ents developed grade 3-4 thrombocytopenia. Grade 3-4 nonhematologic toxicit y consisted of diarrhea (two patients) and cutaneous toxicity, asthenia, ed ema, mucositis, and nausea and vomiting (one patient each). The delivered d ose-intensity of gemcitabine was similar at the 1,000 mg/m(2) dose level (5 99 mg/m(2)/wk) as at the 900 mg/m(2) (601 mg/m(2)/wk) dose level. For this reason, the recommended dose of gemcitabine for phase II evaluation on this schedule was 900 mg/m(2). Five patients held objective responses (one comp lete response and four partial responses; response rate, 19.2%; 95% confide nce interval [CI], 6.5 to 39.3), and 10 patients had improvement of disease -related symptoms (45%; 95% CI, 24 to 67). After a median follow-up of 17.7 months (range, 7.8 to 24.8 months), the median progression-free survival a nd overall survival times were 7.4 months (95% CI, 3.3 to 11.4) and 10.3 mo nths (95% CI, 8.1 to 12.5), respectively. Conclusion: The MTD of gemcitabine when combined with 5-FU via PVI on this schedule was 1,000 mg/m(2)/wk; however, on the basis of administered dose-i ntensity, the recommended dose for additional investigation is 900 mg/m(2). This combination chemotherapy regimen was well tolerated and showed promis ing antitumor activity in the treatment of pancreatic cancer. (C) 1999 by A merican Society of Clinical Oncology.