title: Dose-escalating and pharmacologic study of oxaliplatin in adult cancer patients with impaired hepatic function: a National Cancer Institute Organ Dysfunction Working Group study.
abstract: OBJECTIVE
  To determine the toxicities, pharmacokinetics, and maximally tolerated doses of oxaliplatin in patients with hepatic impairment and to develop formal guidelines for oxaliplatin dosing in this patient population.
  
  
  METHODS
  Sixty adult cancer patients with variable hepatic function received i.v. oxaliplatin ranging from 60 to 130 mg/m(2) every 3 weeks. Patients were stratified by levels of total bilirubin, aspartate aminotransferase (AST), and alkaline phosphatase (AP) into five cohorts based on the degree of hepatic dysfunction: control group A [bilirubin, AST, and AP < or = upper limit of normal (ULN)], mild dysfunction group B (bilirubin < or = ULN, ULN < AST < or = 2.5 x ULN, or ULN < AP < or = 5 x ULN), moderate dysfunction group C (ULN < bilirubin < or = 3.0 mg/dL, AST > 2.5 x ULN, or AP > 5 x ULN), severe dysfunction group D (bilirubin > 3.0 mg/dL, any AST, and any AP), and liver transplantation group E (any bilirubin, any AST, and any AP). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations.
  
  
  RESULTS
  Dose escalation of single-agent oxaliplatin to 130 mg/m(2) was well tolerated in all cohorts. Platinum clearance did not correlate with any liver function test. Two of 56 assessable patients with a diagnosis of laryngeal carcinoma and cervical adenocarcinoma experienced partial responses lasting 3 and 5.5 months.
  
  
  CONCLUSIONS
  Oxaliplatin at 130 mg/m(2) every 3 weeks was well tolerated in all patients with impaired liver function. Dose reductions of single-agent oxaliplatin are not indicated in patients with hepatic dysfunction.
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Synold
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
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 L
authors.initials: DL
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: Bennett M
authors.initials: BM
authors.lastname: Kaufman
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000150:complications; D008111:Liver Function Tests; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000378:metabolism / Q000494:pharmacology*; D000077150:Oxaliplatin
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin