Phase II trial of two different irinotecan schedules with pharmacokinetic analysis in patients with recurrent glioma: North Central Cancer Treatment Group results

Marta Santisteban, Jan C. Buckner, Joel M. Reid, Wenting Wu, Bernd W. Scheithauer, Matthew M. Ames, Sara J. Felten, Daniel A. Nikcevich, Martin Wiesenfeld, Kurt Jaeckle, Evanthia Galanis

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Abstract

Purpose: The aims of this trial were to assess the safety and efficacy of two different dosing schedules of irinotecan (CPT-11) in recurrent glioma patients, to assess irinotecan pharmacokinetics in patients on enzyme-inducing antiepileptic drugs (EIAEDs) and steroids, and to correlate with toxicity and response to treatment. Methods: Sixty-four recurrent glioma patients were included in this study. Schedule A patients received irinotecan weekly (125 mg/m2/w) for four out of six weeks. Schedule B patients received irinotecan every three weeks at a dose of 300 mg/m2. A 20% dose reduction was implemented for patients who had received prior nitrosureas. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal. Results: There was no difference in confirmed responses between the two groups (6.3%). PFS at 6 months was 6.25% (2/32 patients) on schedule A and 18.75% (6/32 patients) on schedule B but median OS (5.1 versus 5.5 months), and survival at one year (19%) was similar for both arms. The most common grade 3-4 toxicities on schedules A/B were: thrombocytopenia (15.6%/21.9%), diarrhea (6.3%/12.5%) and nausea and vomiting (0%/15.7%). One toxic death due to infection in the absence of neutropenia occurred in schedule B. EIAEDs reduced SN-38 and CPT-11 area under the curve and increased CPT-11 cleareance. This effect was more prominent in schedule A patients. Steroids did not alter CPT-11 pharmacokinetics in either schedule. Conclusions: Single agent irinotecan has modest activity in patients with recurrent gliomas, independently of the administration schedule. Irinotecan administration on an every 3 week schedule resulted in longer PFS-6, at the expense of more toxicity. EIAEDs alter CPT-11 pharmacokinetics in this group of patients, and should be taken into consideration when determining optimal dosing.

Original languageEnglish (US)
Pages (from-to)165-175
Number of pages11
JournalJournal of Neuro-Oncology
Volume92
Issue number2
DOIs
StatePublished - Jan 1 2009

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irinotecan
Glioma
Appointments and Schedules
Pharmacokinetics
Neoplasms
Therapeutics
Anticonvulsants
Enzymes
Steroids

All Science Journal Classification (ASJC) codes

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

Santisteban, Marta ; Buckner, Jan C. ; Reid, Joel M. ; Wu, Wenting ; Scheithauer, Bernd W. ; Ames, Matthew M. ; Felten, Sara J. ; Nikcevich, Daniel A. ; Wiesenfeld, Martin ; Jaeckle, Kurt ; Galanis, Evanthia. / Phase II trial of two different irinotecan schedules with pharmacokinetic analysis in patients with recurrent glioma : North Central Cancer Treatment Group results. In: Journal of Neuro-Oncology. 2009 ; Vol. 92, No. 2. pp. 165-175.
@article{2d31a66d890a4b9398fa6ac972796547,
title = "Phase II trial of two different irinotecan schedules with pharmacokinetic analysis in patients with recurrent glioma: North Central Cancer Treatment Group results",
abstract = "Purpose: The aims of this trial were to assess the safety and efficacy of two different dosing schedules of irinotecan (CPT-11) in recurrent glioma patients, to assess irinotecan pharmacokinetics in patients on enzyme-inducing antiepileptic drugs (EIAEDs) and steroids, and to correlate with toxicity and response to treatment. Methods: Sixty-four recurrent glioma patients were included in this study. Schedule A patients received irinotecan weekly (125 mg/m2/w) for four out of six weeks. Schedule B patients received irinotecan every three weeks at a dose of 300 mg/m2. A 20{\%} dose reduction was implemented for patients who had received prior nitrosureas. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal. Results: There was no difference in confirmed responses between the two groups (6.3{\%}). PFS at 6 months was 6.25{\%} (2/32 patients) on schedule A and 18.75{\%} (6/32 patients) on schedule B but median OS (5.1 versus 5.5 months), and survival at one year (19{\%}) was similar for both arms. The most common grade 3-4 toxicities on schedules A/B were: thrombocytopenia (15.6{\%}/21.9{\%}), diarrhea (6.3{\%}/12.5{\%}) and nausea and vomiting (0{\%}/15.7{\%}). One toxic death due to infection in the absence of neutropenia occurred in schedule B. EIAEDs reduced SN-38 and CPT-11 area under the curve and increased CPT-11 cleareance. This effect was more prominent in schedule A patients. Steroids did not alter CPT-11 pharmacokinetics in either schedule. Conclusions: Single agent irinotecan has modest activity in patients with recurrent gliomas, independently of the administration schedule. Irinotecan administration on an every 3 week schedule resulted in longer PFS-6, at the expense of more toxicity. EIAEDs alter CPT-11 pharmacokinetics in this group of patients, and should be taken into consideration when determining optimal dosing.",
author = "Marta Santisteban and Buckner, {Jan C.} and Reid, {Joel M.} and Wenting Wu and Scheithauer, {Bernd W.} and Ames, {Matthew M.} and Felten, {Sara J.} and Nikcevich, {Daniel A.} and Martin Wiesenfeld and Kurt Jaeckle and Evanthia Galanis",
year = "2009",
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pages = "165--175",
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Santisteban, M, Buckner, JC, Reid, JM, Wu, W, Scheithauer, BW, Ames, MM, Felten, SJ, Nikcevich, DA, Wiesenfeld, M, Jaeckle, K & Galanis, E 2009, 'Phase II trial of two different irinotecan schedules with pharmacokinetic analysis in patients with recurrent glioma: North Central Cancer Treatment Group results', Journal of Neuro-Oncology, vol. 92, no. 2, pp. 165-175. https://doi.org/10.1007/s11060-008-9749-4

Phase II trial of two different irinotecan schedules with pharmacokinetic analysis in patients with recurrent glioma : North Central Cancer Treatment Group results. / Santisteban, Marta; Buckner, Jan C.; Reid, Joel M.; Wu, Wenting; Scheithauer, Bernd W.; Ames, Matthew M.; Felten, Sara J.; Nikcevich, Daniel A.; Wiesenfeld, Martin; Jaeckle, Kurt; Galanis, Evanthia.

In: Journal of Neuro-Oncology, Vol. 92, No. 2, 01.01.2009, p. 165-175.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase II trial of two different irinotecan schedules with pharmacokinetic analysis in patients with recurrent glioma

T2 - North Central Cancer Treatment Group results

AU - Santisteban, Marta

AU - Buckner, Jan C.

AU - Reid, Joel M.

AU - Wu, Wenting

AU - Scheithauer, Bernd W.

AU - Ames, Matthew M.

AU - Felten, Sara J.

AU - Nikcevich, Daniel A.

AU - Wiesenfeld, Martin

AU - Jaeckle, Kurt

AU - Galanis, Evanthia

PY - 2009/1/1

Y1 - 2009/1/1

N2 - Purpose: The aims of this trial were to assess the safety and efficacy of two different dosing schedules of irinotecan (CPT-11) in recurrent glioma patients, to assess irinotecan pharmacokinetics in patients on enzyme-inducing antiepileptic drugs (EIAEDs) and steroids, and to correlate with toxicity and response to treatment. Methods: Sixty-four recurrent glioma patients were included in this study. Schedule A patients received irinotecan weekly (125 mg/m2/w) for four out of six weeks. Schedule B patients received irinotecan every three weeks at a dose of 300 mg/m2. A 20% dose reduction was implemented for patients who had received prior nitrosureas. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal. Results: There was no difference in confirmed responses between the two groups (6.3%). PFS at 6 months was 6.25% (2/32 patients) on schedule A and 18.75% (6/32 patients) on schedule B but median OS (5.1 versus 5.5 months), and survival at one year (19%) was similar for both arms. The most common grade 3-4 toxicities on schedules A/B were: thrombocytopenia (15.6%/21.9%), diarrhea (6.3%/12.5%) and nausea and vomiting (0%/15.7%). One toxic death due to infection in the absence of neutropenia occurred in schedule B. EIAEDs reduced SN-38 and CPT-11 area under the curve and increased CPT-11 cleareance. This effect was more prominent in schedule A patients. Steroids did not alter CPT-11 pharmacokinetics in either schedule. Conclusions: Single agent irinotecan has modest activity in patients with recurrent gliomas, independently of the administration schedule. Irinotecan administration on an every 3 week schedule resulted in longer PFS-6, at the expense of more toxicity. EIAEDs alter CPT-11 pharmacokinetics in this group of patients, and should be taken into consideration when determining optimal dosing.

AB - Purpose: The aims of this trial were to assess the safety and efficacy of two different dosing schedules of irinotecan (CPT-11) in recurrent glioma patients, to assess irinotecan pharmacokinetics in patients on enzyme-inducing antiepileptic drugs (EIAEDs) and steroids, and to correlate with toxicity and response to treatment. Methods: Sixty-four recurrent glioma patients were included in this study. Schedule A patients received irinotecan weekly (125 mg/m2/w) for four out of six weeks. Schedule B patients received irinotecan every three weeks at a dose of 300 mg/m2. A 20% dose reduction was implemented for patients who had received prior nitrosureas. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal. Results: There was no difference in confirmed responses between the two groups (6.3%). PFS at 6 months was 6.25% (2/32 patients) on schedule A and 18.75% (6/32 patients) on schedule B but median OS (5.1 versus 5.5 months), and survival at one year (19%) was similar for both arms. The most common grade 3-4 toxicities on schedules A/B were: thrombocytopenia (15.6%/21.9%), diarrhea (6.3%/12.5%) and nausea and vomiting (0%/15.7%). One toxic death due to infection in the absence of neutropenia occurred in schedule B. EIAEDs reduced SN-38 and CPT-11 area under the curve and increased CPT-11 cleareance. This effect was more prominent in schedule A patients. Steroids did not alter CPT-11 pharmacokinetics in either schedule. Conclusions: Single agent irinotecan has modest activity in patients with recurrent gliomas, independently of the administration schedule. Irinotecan administration on an every 3 week schedule resulted in longer PFS-6, at the expense of more toxicity. EIAEDs alter CPT-11 pharmacokinetics in this group of patients, and should be taken into consideration when determining optimal dosing.

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