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Continuous Administration of Irinotecan by Hepatic Arterial Infusion

A Phase I and Pharmacokinetic Study

Department of Medical Oncology, Academic Hospital Vrije Universiteit, 1081 HV Amsterdam, the Netherlands [J. M. G. H. v. R., C. J. v. G., M. A. K., H. G., J. M. A. L., H. M. P., W. J. F. v. d. V., G. Gi.], and Aventis, Anthony Cedex, France [G. Gr.]

Purpose: The main advantage of administering chemotherapy by means of hepatic arterial infusion (HAI) is the achievement of a high concentration of the drug in the liver. Irinotecan (CPT-11) is an active agent for the treatment of advanced colorectal cancer and other tumor types, which frequently metastasize in the liver. We performed a Phase I and pharmacokinetic study to investigate CPT-11 by hepatic arterial administration in patients with liver metastases.

Patients and Methods: Patients with liver metastases received CPT-11 at doses ranging from 15 to 25 mg/m²/day for 5 days every 3 weeks by continuous HAI. All of the patients also received one cycle CPT-11 i.v. Primary end points of the study were to define the maximum tolerated dose (MTD) of hepatic arterial CPT-11 and to study its pharmacokinetics.

Results: Twenty patients were included. The MTD was 25 mg/m²/day and the dose-limiting toxicities were neutropenia and diarrhea. The metabolic ratio was significantly increased with HAI compared with i.v. administration (P = 0.015). The steady-state concentrations of total CPT-11 and CPT-11 carboxylate and lactone were all lower than those during i.v. infusion (P = 0.008, 0.013, and 0.004, respectively), whereas the levels of total SN-38, and SN-38 carboxylate, lactone, and glucuronide were similar. The total body clearance of CPT-11 was significantly higher with HAI (P = 0.008).

Conclusions: The MTD of CPT-11 given by hepatic 5-day continuous infusion was 25 mg/m²/day. HAI of CPT-11 resulted in a higher metabolic ratio because of increased elimination of CPT-11. We recommend 20 mg/m²/day for additional Phase II studies.

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