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

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 - 2009

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irinotecan
Glioma
Appointments and Schedules
Pharmacokinetics
Neoplasms
Therapeutics
Anticonvulsants
Enzymes
Steroids

Keywords

  • Dexamethasone
  • Enzyme-inducing antiepileptic drugs
  • Irinotecan
  • Pharmacokinetics
  • Recurrent gliomas

ASJC Scopus subject areas

  • Clinical Neurology
  • Cancer Research
  • Oncology
  • Neurology

Cite this

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 Craig; Reid, Joel M; Wu, Wenting; Scheithauer, Bernd W.; Ames, Matthew M.; Felten, Sara J.; Nikcevich, Daniel A.; Wiesenfeld, Martin; Jaeckle, Kurt A.; Galanis, Evanthia.

In: Journal of Neuro-Oncology, Vol. 92, No. 2, 2009, p. 165-175.

Research output: Contribution to journalArticle

Santisteban, Marta ; Buckner, Jan Craig ; Reid, Joel M ; Wu, Wenting ; Scheithauer, Bernd W. ; Ames, Matthew M. ; Felten, Sara J. ; Nikcevich, Daniel A. ; Wiesenfeld, Martin ; Jaeckle, Kurt A. ; 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.
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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.",
keywords = "Dexamethasone, Enzyme-inducing antiepileptic drugs, Irinotecan, Pharmacokinetics, Recurrent gliomas",
author = "Marta Santisteban and Buckner, {Jan Craig} 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 Jaeckle, {Kurt A.} and Evanthia Galanis",
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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 Craig

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 A.

AU - Galanis, Evanthia

PY - 2009

Y1 - 2009

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.

KW - Dexamethasone

KW - Enzyme-inducing antiepileptic drugs

KW - Irinotecan

KW - Pharmacokinetics

KW - Recurrent gliomas

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