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, Ramesk 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

Research output: Contribution to journalArticle

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Abstract

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/m 2 was well tolerated in all patient groups with a CrCL ≥20 mL/min (groups A, B, and C). Pharmaeokinetic 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.

Original languageEnglish (US)
Pages (from-to)2664-2672
Number of pages9
JournalJournal of Clinical Oncology
Volume21
Issue number14
DOIs
StatePublished - Jul 15 2003
Externally publishedYes

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oxaliplatin
National Cancer Institute (U.S.)
Pharmacology
Kidney
Creatinine
Neoplasms
Platinum

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dose-escalating and pharmacological study of oxaliplatin in adult cancer patients with impaired renal function : A National Cancer Institute organ dysfunction working group study. / Takimoto, Chris H.; Remick, Scot C.; Sharma, Sunil; Mani, Sridhar; Ramanathan, Ramesk K; Doroshow, James; Hamilton, Anne; Mulkerin, Daniel; Graham, Martin; Lockwood, Graham F.; Ivy, Percy; Egorin, Merrill; Schuler, Barbara; Greenslade, Denis; Goetz, Andrew; Knight, Ronald; Thomas, Rebecca; Monahan, Brian P.; Dahut, William; Grem, Jean L.

In: Journal of Clinical Oncology, Vol. 21, No. 14, 15.07.2003, p. 2664-2672.

Research output: Contribution to journalArticle

Takimoto, CH, Remick, SC, Sharma, S, Mani, S, Ramanathan, RK, Doroshow, J, Hamilton, A, Mulkerin, D, Graham, M, Lockwood, GF, Ivy, P, Egorin, M, Schuler, B, Greenslade, D, Goetz, A, Knight, R, Thomas, R, Monahan, BP, Dahut, W & Grem, JL 2003, 'Dose-escalating and pharmacological study of oxaliplatin in adult cancer patients with impaired renal function: A National Cancer Institute organ dysfunction working group study', Journal of Clinical Oncology, vol. 21, no. 14, pp. 2664-2672. https://doi.org/10.1200/JCO.2003.11.015
Takimoto, Chris H. ; Remick, Scot C. ; Sharma, Sunil ; Mani, Sridhar ; Ramanathan, Ramesk K ; Doroshow, James ; Hamilton, Anne ; Mulkerin, Daniel ; Graham, Martin ; Lockwood, Graham F. ; Ivy, Percy ; Egorin, Merrill ; Schuler, Barbara ; Greenslade, Denis ; Goetz, Andrew ; Knight, Ronald ; Thomas, Rebecca ; Monahan, Brian P. ; Dahut, William ; Grem, Jean L. / Dose-escalating and pharmacological study of oxaliplatin in adult cancer patients with impaired renal function : A National Cancer Institute organ dysfunction working group study. In: Journal of Clinical Oncology. 2003 ; Vol. 21, No. 14. pp. 2664-2672.
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abstract = "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/m 2 was well tolerated in all patient groups with a CrCL ≥20 mL/min (groups A, B, and C). Pharmaeokinetic 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.",
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T1 - Dose-escalating and pharmacological study of oxaliplatin in adult cancer patients with impaired renal function

T2 - A National Cancer Institute organ dysfunction working group study

AU - Takimoto, Chris H.

AU - Remick, Scot C.

AU - Sharma, Sunil

AU - Mani, Sridhar

AU - Ramanathan, Ramesk K

AU - Doroshow, James

AU - Hamilton, Anne

AU - Mulkerin, Daniel

AU - Graham, Martin

AU - Lockwood, Graham F.

AU - Ivy, Percy

AU - Egorin, Merrill

AU - Schuler, Barbara

AU - Greenslade, Denis

AU - Goetz, Andrew

AU - Knight, Ronald

AU - Thomas, Rebecca

AU - Monahan, Brian P.

AU - Dahut, William

AU - Grem, Jean L.

PY - 2003/7/15

Y1 - 2003/7/15

N2 - 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/m 2 was well tolerated in all patient groups with a CrCL ≥20 mL/min (groups A, B, and C). Pharmaeokinetic 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.

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