phase I study of gemcitabine given via intrahepatic pump for primary or metastatic hepatic malignancies

Purpose To determine the maximum tolerated dose and duration of hepatic arterial infusion (HAI) gemcitabine in patients with unresectable hepatic metastases from colorectal cancer or primary hepatic malignancies. Methods Patients received weekly gemcitabine via the side-port of an implantable HAI pump for 3 weeks in a 28-day cycle. During the dose escalation phase, increasing doses of HAI gemcitabine (800, 1,000, 1,200, and 1,500 mg/m²) were given at a fixed dose-rate of 10 mg/(m² min). This was followed by the infusion duration escalation (IDE) phase, in which HAI gemcitabine at 1,000 mg/m² was given over increasing lengths of time (200, 300, and 400 min). To estimate hepatic drug extraction, the pharmacokinetics of HAI gemcitabine was compared with those of intravenous gemcitabine given at the same dose-rate to the same patient in the IDE phase. Results Twenty-eight of 30 patients were evaluable. HAI gemcitabine was well tolerated up to 1,500 mg/m² given at 10 mg/(m² min) and up to 1,000 mg/m² infused over 400 min. There were no protocol-defined dose-limiting toxicities. One patient with cholangiocarcinoma had a partial response. Hepatic extraction of gemcitabine seems highly variable among patients and does not correlate with the length of HAI infusion. Conclusions Hepatic arterial infusion of gemcitabine given at doses higher or longer than the recommended systemic dose of 1,000 mg/m² over 30 min is well tolerated. For future studies, we recommend an infusion of 1,500 mg/m² at a fixed dose-rate of 10 mg/(m² min).