title: Dose-escalating and pharmacological study of oxaliplatin in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study.
abstract: OBJECTIVE
  This study was undertaken to determine the toxicities, pharmacokinetics, and maximum tolerated doses of oxaliplatin in patients with renal impairment and to develop formal guidelines for oxaliplatin dosing in this patient population.
  
  
  METHODS
  Thirty-seven adult cancer patients with variable renal function received intravenous oxaliplatin at 60 to 130 mg/m2 every 3 weeks. Patients were stratified by 24-hour creatinine clearance (CrCL) into four cohorts: group A (controls, CrCL > or =60 mL/min), group B (mild dysfunction, CrCL 40 to 59 mL/min), group C (moderate dysfunction, CrCL 20 to 39 mL/min), and group D (severe dysfunction, CrCL <20 mL/min). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations.
  
  
  RESULTS
  No dose-limiting toxicities were observed in any patient group during the first cycle of therapy. Escalation of oxaliplatin to the maximum dose of 130 mg/m2 was well tolerated in all patient groups with a CrCL > or =20 mL/min (groups A, B, and C). Pharmacokinetic analysis showed that patients with decreased CrCL had a corresponding decrease in the clearance of plasma ultrafiltrable platinum (r2 = 0.765). However, oxaliplatin-induced side effects were not more common or severe in patients with mild to moderate renal dysfunction, despite the decrease in ultrafiltrable platinum clearance.
  
  
  CONCLUSIONS
  Oxaliplatin at 130 mg/m2 every 3 weeks is well tolerated by patients with mild to moderate degrees of renal dysfunction. These data strongly support the recommendation that dose reductions of single-agent oxaliplatin are not necessary in patients with a CrCL greater than 20 mL/min.
authors.affiliation: University of Texas Health Science Center at San Antonio, Cancer Therapy and Research Center, 7979 Wurzbach Rd, Room Z415, San Antonio, TX 78229, USA. ctakimot@idd.org.
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Scot C
authors.initials: SC
authors.lastname: Remick
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: James
authors.initials: J
authors.lastname: Doroshow
authors.forename: Anne
authors.initials: A
authors.lastname: Hamilton
authors.forename: Daniel
authors.initials: D
authors.lastname: Mulkerin
authors.forename: Martin
authors.initials: M
authors.lastname: Graham
authors.forename: Graham F
authors.initials: GF
authors.lastname: Lockwood
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.forename: Merrill
authors.initials: M
authors.lastname: Egorin
authors.forename: Barbara
authors.initials: B
authors.lastname: Schuler
authors.forename: Denis
authors.initials: D
authors.lastname: Greenslade
authors.forename: Andrew
authors.initials: A
authors.lastname: Goetz
authors.forename: Ronald
authors.initials: R
authors.lastname: Knight
authors.forename: Rebecca
authors.initials: R
authors.lastname: Thomas
authors.forename: Brian P
authors.initials: BP
authors.lastname: Monahan
authors.forename: William
authors.initials: W
authors.lastname: Dahut
authors.forename: Jean L
authors.initials: JL
authors.lastname: Grem
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D007674:Kidney Diseases / Q000503:physiopathology*; D007677:Kidney Function Tests; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009316:National Institutes of Health (U.S.); D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000077150:Oxaliplatin; D011336:Probability; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D016019:Survival Analysis; D016896:Treatment Outcome; D014481:United States
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin