Annals of Oncology Advance Access originally published online on October 3, 2008
Annals of Oncology 2009 20(2):239-243; doi:10.1093/annonc/mdn640
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gastrointestinal tumors |
A phase I study of full-dose gemcitabine and regional arterial infusion of nafamostat mesilate for advanced pancreatic cancer
1 Department of Surgery
2 Department of Radiology, The Jikei University School of Medicine, Tokyo, Japan
* Correspondence to: Dr T. Uwagawa, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. Tel: +81-3-3433-1111 ext. 3401; Fax: +81-3-5472-4140; E-mail: uwatadashi{at}msn.com
Background: The primary end points of this study were to determine the dose-limiting toxic effects (DLTs), maximum tolerated dose, and a recommended phase II dose of a synthetic serine protease inhibitor, nafamostat mesilate, in combination with full-dose gemcitabine in patients with unresectable locally advanced or metastatic pancreatic cancer. The secondary end point was to assess therapeutic response.
Patients and methods: Patients with previously untreated pancreatic cancer received gemcitabine (1 000 mg/m2 i.v. for 30 min) on days 1, 8, and 15, with nafamostat mesilate (continuous regional arterial infusion for 24 h through a port-catheter system) on days 1, 8, and 15; this regimen was repeated at 28-day intervals. The initial dose of nafamostat mesilate was 2.4 mg/kg and was escalated in increments of 1.2 mg/kg until a dose of 4.8 mg/kg was achieved. A standard ‘3+3’ phase I dose-escalation design was used. Therapeutic response and clinical benefit response were assessed.
Results: Twelve patients were enrolled in this study. None of the patients experienced DLTs, and nafamostat mesilate was well tolerated at doses up to 4.8 mg/kg in combination with full-dose gemcitabine. This combination chemotherapy yielded a reduction of a high serum level of the tumor marker CA19-9. Pain was reduced in three of seven patients without oral morphine sulfate. Overall survival was 7.1 months for all patients.
Conclusion: This phase I study was carried out safely. This combination chemotherapy showed beneficial improvement in health-related quality of life. The recommended phase II dose of nafamostat mesilate in combination with full-dose gemcitabine is 4.8 mg/kg.
Key words:
chemoresistance, gemcitabine, nafamostat mesilate, NF-
B, pancreatic cancer
Received for publication August 3, 2008. Accepted for publication August 25, 2008.