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Dose-Escalating and Pharmacological Study of Oxaliplatin in Adult Cancer Patients With Impaired Renal Function: A National Cancer Institute Organ Dysfunction Working Group Study

Chris H. Takimoto, Scot C. Remick, Sunil Sharma, Sridhar Mani, Ramesh K. Ramanathan, James Doroshow, Anne Hamilton, Daniel Mulkerin, Martin Graham, Graham F. Lockwood, Percy Ivy, Merrill Egorin, Barbara Schuler, Denis Greenslade, Andrew Goetz, Ronald Knight, Rebecca Thomas, Brian P. Monahan, William Dahut, Jean L. Grem

From the Medicine Branch at Navy, National Naval Medical Center, and the Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Centers, National Cancer Institute, Bethesda, MD; Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX; Comprehensive Cancer Center at University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH; Memorial Sloan Kettering Cancer Center, and New York University, New York, and Montefiore Hospital, Albert Einstein College of Medicine, Bronx, NY; University of Pittsburgh Cancer Institute, Pittsburgh, PA; City of Hope, Duarte, CA; University of Wisconsin, Madison, WI; Department of Clinical Metabolism and Pharmacokinetics, Sanofi-Synthelabo, Inc, Malvern, PA, and Alnwick, UK; National Cancer Institute, Bethesda, MD.

Address reprint requests to Chris H. Takimoto, MD, PhD, University of Texas Health Science Center at San Antonio, Cancer Therapy and Research Center, 7979 Wurzbach Rd, Room Z415, San Antonio, TX 78229; email: ctakimot{at}idd.org.

Purpose: 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.

Patients and 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 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 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.

Conclusion: 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.

Supported in part by National Cancer Institute (Bethesda, MD) grants U01CA069853, U01CA062502, U01CA069856, U01CA076642, U01CA062505, U01CA062491, and U01CA069855.

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