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Dose-Escalating and Pharmacologic Study of Oxaliplatin in Adult Cancer Patients with Impaired Hepatic Function: A National Cancer Institute Organ Dysfunction Working Group Study

Authors' Affiliations: ¹ City of Hope Comprehensive Cancer Center, Duarte, California; ² Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas; ³ University of California, Davis Cancer Center, Sacramento, California; ⁴ Albert Einstein College of Medicine, Bronx, New York; ⁵ Case Western Comprehensive Cancer Center, Cleveland, Ohio; ⁶ University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin; ⁷ New York University Cancer Institute; ⁸ Memorial Sloan-Kettering Cancer Center, New York, New York; ⁹ University of Pittsburgh Comprehensive Cancer Center, Pittsburgh, Pennsylvania; ¹⁰ University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California; ¹¹ Department of Clinical Pharmacokinetics and Drug Metabolism, Sanofi-Synthelabo, Inc., Malvern, Pennsylvania; ¹² PSI International, Inc., Vienna, Virginia; and ¹³ Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Chris H. Takimoto, Institute for Drug Development, Cancer Therapy and Research Center, 14960 Omicron Drive, San Antonio, TX 78245-3217. Phone: 210-450-3800; Fax: 210-677-0058; E-mail: ctakimot{at}idd.org.

Purpose: 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.

Experimental Design: Sixty adult cancer patients with variable hepatic function received i.v. oxaliplatin ranging from 60 to 130 mg/m² 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 upper limit of normal (ULN)], mild dysfunction group B (bilirubin ULN, ULN < AST 2.5 x ULN, or ULN < AP 5 x ULN), moderate dysfunction group C (ULN < bilirubin 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/m² 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/m² 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.

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