Dose-escalating and pharmacological study of oxaliplatin in adult cancer patients with impaired renal function: A National Cancer Institute Organ Dysfunction Working Group Study

Purpose: This study was undertaken to determine the toxicities, phormacokinetics, and maximum tolerated doses of oxaliplatin in patients with renal impairment and to develop formal guidelines for oxaliplatin dosing in this patient population. Patients and Methods: Thirty-seven adult cancer patients with variable renal function received intravenous oxaliplatin at 60 to 130 mg/m(2) every 3 weeks. Patients were stratified by 24-hour creatinine clearance (CrCL) into four cohorts: group A (controls, CrCL greater than or equal to60 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/m(2) was well tolerated in all patient groups with a CrCl greater than or equal to20 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 (r(2) = 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. Conclusion: Oxaliplatin at 130 mg/m(2) 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. (C) 2003 by American Society of Clinical Oncology.