Dose-escalating and pharmacologic study of oxaliplatin in adult cancer patients with impaired hepatic function

A national cancer institute organ dysfunction working group study

Timothy W. Synold, Chris H. Takimoto, James H. Doroshow, David Gandara, Sridhar Mani, Scot C. Remick, Daniel L. Mulkerin, Anne Hamilton, Sunil Sharma, Ramesh K. Ramanathan, Heinz Josef Lenz, Martin Graham, Jeffrey Longmate, Bennett M. Kaufman, Percy Ivy

Research output: Contribution to journalArticle

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Abstract

Purpose: To determine the toxicities, pharmacokinetics, and maximally tolerated doses of oxaliplatin in patientswith hepaticimpairment 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 to130 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 hepaticdy sfunction: control group A [bilirubin, AST, and AP ≤ upper limit of normal (ULN)], mild dysfunction group B (bilirubin V ULN, ULN ≤ AST V 2.5 x ULN, or ULN < AP ≤ 5 x ULN), moderate dysfunction group C (ULN < 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 patientswith 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.

Original languageEnglish (US)
Pages (from-to)3660-3666
Number of pages7
JournalClinical Cancer Research
Volume13
Issue number12
DOIs
StatePublished - Jun 15 2007

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oxaliplatin
National Cancer Institute (U.S.)
Aspartate Aminotransferases
Bilirubin
Alkaline Phosphatase
Liver
Neoplasms
Platinum
Maximum Tolerated Dose
Liver Function Tests
Liver Transplantation
Adenocarcinoma
Research Design
Pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / Synold, Timothy W.; Takimoto, Chris H.; Doroshow, James H.; Gandara, David; Mani, Sridhar; Remick, Scot C.; Mulkerin, Daniel L.; Hamilton, Anne; Sharma, Sunil; Ramanathan, Ramesh K.; Lenz, Heinz Josef; Graham, Martin; Longmate, Jeffrey; Kaufman, Bennett M.; Ivy, Percy.

In: Clinical Cancer Research, Vol. 13, No. 12, 15.06.2007, p. 3660-3666.

Research output: Contribution to journalArticle

Synold, TW, Takimoto, CH, Doroshow, JH, Gandara, D, Mani, S, Remick, SC, Mulkerin, DL, Hamilton, A, Sharma, S, Ramanathan, RK, Lenz, HJ, Graham, M, Longmate, J, Kaufman, BM & Ivy, P 2007, 'Dose-escalating and pharmacologic study of oxaliplatin in adult cancer patients with impaired hepatic function: A national cancer institute organ dysfunction working group study', Clinical Cancer Research, vol. 13, no. 12, pp. 3660-3666. https://doi.org/10.1158/1078-0432.CCR-06-2385
Synold, Timothy W. ; Takimoto, Chris H. ; Doroshow, James H. ; Gandara, David ; Mani, Sridhar ; Remick, Scot C. ; Mulkerin, Daniel L. ; Hamilton, Anne ; Sharma, Sunil ; Ramanathan, Ramesh K. ; Lenz, Heinz Josef ; Graham, Martin ; Longmate, Jeffrey ; Kaufman, Bennett M. ; Ivy, Percy. / Dose-escalating and pharmacologic study of oxaliplatin in adult cancer patients with impaired hepatic function : A national cancer institute organ dysfunction working group study. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 12. pp. 3660-3666.
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abstract = "Purpose: To determine the toxicities, pharmacokinetics, and maximally tolerated doses of oxaliplatin in patientswith hepaticimpairment 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 to130 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 hepaticdy sfunction: control group A [bilirubin, AST, and AP ≤ upper limit of normal (ULN)], mild dysfunction group B (bilirubin V ULN, ULN ≤ AST V 2.5 x ULN, or ULN < AP ≤ 5 x ULN), moderate dysfunction group C (ULN < 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 patientswith 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.",
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T1 - Dose-escalating and pharmacologic study of oxaliplatin in adult cancer patients with impaired hepatic function

T2 - A national cancer institute organ dysfunction working group study

AU - Synold, Timothy W.

AU - Takimoto, Chris H.

AU - Doroshow, James H.

AU - Gandara, David

AU - Mani, Sridhar

AU - Remick, Scot C.

AU - Mulkerin, Daniel L.

AU - Hamilton, Anne

AU - Sharma, Sunil

AU - Ramanathan, Ramesh K.

AU - Lenz, Heinz Josef

AU - Graham, Martin

AU - Longmate, Jeffrey

AU - Kaufman, Bennett M.

AU - Ivy, Percy

PY - 2007/6/15

Y1 - 2007/6/15

N2 - Purpose: To determine the toxicities, pharmacokinetics, and maximally tolerated doses of oxaliplatin in patientswith hepaticimpairment 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 to130 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 hepaticdy sfunction: control group A [bilirubin, AST, and AP ≤ upper limit of normal (ULN)], mild dysfunction group B (bilirubin V ULN, ULN ≤ AST V 2.5 x ULN, or ULN < AP ≤ 5 x ULN), moderate dysfunction group C (ULN < 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 patientswith 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.

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