title: Pharmacology of oxaliplatin in solid tumor patients with hepatic dysfunction: a preliminary report of the National Cancer Institute Organ Dysfunction Working Group.
abstract: Oxaliplatin, which was recently approved by the US Food and Drug Administration for the treatment of advanced colorectal cancer, is often administered to patients with altered liver function caused by hepatic metastases. Because of the absence of data on the clearance of oxaliplatin in patients with liver dysfunction, and to develop dosing recommendations for the safe use of oxaliplatin in this clinical setting, the Organ Dysfunction Working Group of the National Cancer Institute performed a phase I and pharmacokinetic trial of this drug in patients displaying a wide range of liver function abnormalities. Sixty patients grouped into five classes of liver function were enrolled in this study, including a 12-patient control group with normal liver function, 15 patients with "mild," 16 patients with "moderate," and 16 with "severe" liver dysfunction, as well as one patient who had undergone liver transplantation. The patients had a median age of 62 years and a Eastern Cooperative Oncology Group performance status of 0. All patients had received prior systemic chemotherapy, and 70% had a diagnosis of a gastrointestinal malignancy. The control patients were treated with 130 mg/m(2) oxaliplatin intravenously every 21 days; the starting doses for patients with mild, moderate, or severe liver dysfunction or post-liver transplantation were 105, 80, or 60 mg/m(2), respectively. Cohorts of three or more patients were escalated from these starting doses to 130 mg/m(2) if dose-limiting toxicities were not observed, and pharmacokinetic evaluations were performed at each dose level for every category of liver dysfunction. We found that oxaliplatin was well tolerated at its recommended dose and schedule of 130 mg/m(2) every 21 days in patients with all levels of liver dysfunction, and that there was no apparent alteration in the clearance of either total or ultrafilterable platinum species from plasma, even in patients with severe hepatic functional abnormalities.
authors.affiliation: Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Synold
authors.forename: David
authors.initials: D
authors.lastname: Gandara
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
authors.forename: Scot C
authors.initials: SC
authors.lastname: Remick
authors.forename: Daniel
authors.initials: D
authors.lastname: Mulkerin
authors.forename: Anne
authors.initials: A
authors.lastname: Hamilton
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Heinz Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: Martin
authors.initials: M
authors.lastname: Graham
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Longmate
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007262:Infusions, Intravenous; D008107:Liver Diseases / Q000150:complications*; D008113:Liver Neoplasms / Q000150:complications / Q000556:secondary; D016031:Liver Transplantation; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000077150:Oxaliplatin
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin