Continuous administration of irinotecan by hepatic arterial infusion: a phase I and pharmacokinetic study.
OBJECTIVE
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.


METHODS
Patients with liver metastases received CPT-11 at doses ranging from 15 to 25 mg/m(2)/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/m(2)/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/m(2)/day. HAI of CPT-11 resulted in a higher metabolic ratio because of increased elimination of CPT-11. We recommend 20 mg/m(2)/day for additional Phase II studies.
van Riel
Johanna M G H
JM
Department of Medical Oncology, Academic Hospital Vrije Universiteit, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.
van Groeningen
Cees J
CJ
Kedde
Mark A
MA
Gall
Helen
H
Leisink
Johanna M A
JM
Gruia
Gabriella
G
Pinedo
Herbert M
HM
van der Vijgh
Wim J F
WJ
Giaccone
Giuseppe
G
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D005260:Female; D005965:Glucuronates / Q000494:pharmacology; D006499:Hepatic Artery / Q000473:pathology; D006801:Humans; D007261:Infusions, Intra-Arterial; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D013997:Time Factors
C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; D000972:Antineoplastic Agents, Phytogenic; D005965:Glucuronates; D000077146:Irinotecan; D002166:Camptothecin