Prolonged fixed dose rate infusion of gemcitabine with autologous haemopoietic support in advanced pancreatic adenocarcinoma

摘要

This study aimed to define the maximum-tolerated dose (MTD) of fixed dose rate (FDR) of gemcitabine (2′-2′-difluorodeoxycitidine) infusion with circulating haemopoietic progenitor support and to evaluate the activity of the treatment. Secondary end points were pharmacokinetic of gemcitabine and difluorodeoxyuridina (dFdU) measured at first course and the activity andexpression profile of cytidine deaminase (CdA) on circulating mononuclear cells. Patients with advanced pancreatic carcinoma received escalating dose of gemcitabine 10?mg?m?2?min?1 every 2 weeks with circulating haemopoietic progenitor support. First dose level was 3000?mg?m?2 and the doses were increased by 500?mg?m?2 until MTD. In all, 23 patients were enrolled. Toxicities were mild or moderate; the only patient treated at 7000?mg?m?2 died because of toxicity; therefore; the MTD was established at 6500?mg?m?2. The overall response rate was 22.2%. The AUC of gemcitabine showed a dose-dependent increase, while the AUC of dFdU reached a plateau at 4500?mg?m?2. A significant relationship was found between the AUC of dFdU and CdA expression and activity (P<0.05). Moreover, progression rate and survival were significantly related to CdA expression and activity levels. The activity of high-dose gemcitabine is not superior to that reported with less intensive FDR schedules. The predictive role of CdA expression and activity on outcome deserves further investigation.