van Riel Johanna M G H, van Groeningen Cees J, Kedde Mark A, Gall Helen, Leisink Johanna M A, Gruia Gabriella, Pinedo Herbert M, van der Vijgh Wim J F, Giaccone Giuseppe
Department of Medical Oncology, Academic Hospital Vrije Universiteit, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.
Clin Cancer Res. 2002 Feb;8(2):405-12.
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 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.
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).
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.
通过肝动脉灌注（HAI）进行化疗的主要优势在于使肝脏中药物达到高浓度。伊立替康（CPT - 11）是治疗晚期结直肠癌和其他常转移至肝脏的肿瘤类型的活性药物。我们进行了一项I期药代动力学研究，以通过肝动脉给药方式研究CPT - 11在肝转移患者中的情况。
肝转移患者每3周通过持续HAI接受剂量范围为15至25mg/m²/天的CPT - 11，持续5天。所有患者还接受了一个周期的静脉注射CPT - 11。该研究的主要终点是确定肝动脉CPT - 11的最大耐受剂量（MTD）并研究其药代动力学。
纳入20例患者。MTD为25mg/m²/天，剂量限制性毒性为中性粒细胞减少和腹泻。与静脉给药相比，HAI给药时代谢率显著升高（P = 0.015）。总CPT - 11、CPT - 11羧酸盐和内酯的稳态浓度均低于静脉输注时（分别为P = 0.008、0.013和0.004），而总SN - 38以及SN - 38羧酸盐、内酯和葡萄糖醛酸苷的水平相似。HAI给药时CPT - 11的全身清除率显著更高（P = 0.008）。
肝动脉5天持续输注CPT - 11的MTD为25mg/m²/天。由于CPT - 11消除增加，CPT -
