Combining C apecitabine a nd G emcitabine i n P atients W ith Advanced P ancreatic C arcinoma: A P hase I /II T rial

Purpose: Preclinical studies indicate positive interactions between capecitabine, an oral fluorouracil precursor, and gemcitabine, the current standard treatment for advanced pancreatic carcinoma (APC). In this study, we investigated the addition of capecitabine to gemcitabine treatment for patients with APC. Patients and Methods: This multicenter study included patients naive to chemotherapy who had histologically or cytologically confirmed, nonresectable or metastatic pan- creatic carcinoma. Gemcitabine was given at a fixed dose of 1,000 mg/m 2 on days 1 and 8 of a 21-day cycle. Capecit- abine was given in increasing doses orally bid for 14 days followed by a 1-week rest. The maximum-tolerated dose (MTD) was defined as one dose level below the dose causing dose-limiting toxicity (DLT) in > one third of a cohort of six patients. We included an additional 15 patients at the MTD. Results: Thirty-six patients were included. DLT occurred at a dose of 800 mg/m 2 bid of capecitabine and consisted of myelotoxicity and mucositis. Hand-foot syndrome was not observed, and other toxic effects were mild. Thus, in this regimen, the recommended dose of capecitabine is 650 mg/m 2 bid. In 27 patients with measurable disease, we observed one complete and four partial remissions. In addition, significant drops (> 50% from baseline value) of the tumor marker CA 19 -9 occurred in 14 of 24 assess- able patients. Conclusion: The combination of capecitabine and gemcit- abine is well tolerated, with apparent efficacy in patients with APC. Therefore, it is currently being compared with gemcitabine monotherapy in a phase III study. J Clin Oncol 21:66-68. © 2003 by American Society of Clinical Oncology. C HEMOTHERAPY FOR patients with advanced pancreatic carcinoma (APC) improves clinical symptoms and overall survival. 1 Still, life expectancy for the majority of these patients is short, with a median survival between 4 and 10 months. 2-4 Until 1997, fluorouracil (5-FU) was the drug most widely used for APC, with an objective response rate of 0% to 7%. 3,5 Burris et al 3 provided evidence for better symptom control with the use of gemcitabine as a monotherapy. It is worth noting that, in this study, no objective responses were observed in the patients treated with 5-FU, but this finding may be related to the power of the study or the mode of administration of 5-FU rather than to a lack of activity of 5-FU in APC. Combination regimens of gemcitabine and 5-FU in the treat- ment of APC were found to be well tolerated and as effective as gemcitabine monotherapy in several phase I/II trials. 6-11 How- ever, adding weekly intravenous bolus 5-FU to weekly gemcit- abine did not confer a significant survival benefit in a random- ized trial, 12 but there are no randomized data on the combination of infusional 5-FU with gemcitabine in APC. Capecitabine is an oral precursor of 5-FU. It has several advantages over 5-FU, the most important of which is its easy oral administration. As conversion of capecitabine to 5-FU is dependent on an enzyme (thymidine phosphorylase) preferen- tially expressed in malignant cells, it is thought to exert its main effect locally within the tumor. 13 Phase II clinical data provided evidence for activity of capecitabine in APC, 14 and data from a xenograft model 15 indicated synergistic activity of capecitabine and gemcitabine. The aim of this study was to find the appropriate dose of capecitabine in combination with gemcitabine for patients with unresectable or metastatic pancreatic carcinoma. We also sought to evaluate the safety and efficacy of this combination.