Correlation of enzyme-inducing anticonvulsant use with outcome of patients with glioblastoma

Kurt A. Jaeckle, Karla Ballman, Alfred Furth, Jan C. Buckner

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

BACKGROUND: Clinical trials involving patients with glioblastoma (GBM) distinguish cohorts who are treated with enzyme-inducing anticonvulsants (EIAC). Such anticonvulsants induce hepatic P450 microsomal enzymes, which accelerate the metabolism of certain chemotherapy and molecular targeted agents. However, the resultant effect of such induction on patient outcome has received limited study. METHODS:: We performed a correlative analysis of baseline EIAC use with outcome, using a cross-sectional database of 620 patients with newly diagnosed GBM treated prospectively on North Central Cancer Treatment Group trials. RESULTS: At registration, 72% were receiving treatment with EIAC; 2% were receiving non-EIACs, and the 26% were not receiving anticonvulsants (26%). Surprisingly, in the multivariable Cox model, overall survival (OS) and progression-free survival (PFS) showed a positive correlation with EIAC use (hazard ratio [HR] = 0.75, p = 0.0028 and HR = 0.80, p = 0.022), even after adjustment for the known prognostic factors of age, performance status, extent of resection, steroid use, and baseline neurocognitive function. Specifically, the median OS was longer in EIAC compared with non-EIAC patients (12.3 vs 10.7 months, p = 0.0002). Similarly, PFS was longer in EIAC patients (5.6 vs 4.8 months, p = 0.003). No differences in median OS or PFS were observed when comparing patients with or without a history of seizures at baseline. CONCLUSIONS:: Paradoxically, enzyme-inducing anticonvulsant (EIAC) use correlated with superior outcome of patients with glioblastoma. These results suggest that in comparative clinical trials testing agents metabolized by P450 microsomal enzymes, treatment arms may need stratification for the proportion of patients receiving EIAC.

Original languageEnglish (US)
Pages (from-to)1207-1213
Number of pages7
JournalNeurology
Volume73
Issue number15
DOIs
StatePublished - Oct 2009

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Glioblastoma
Anticonvulsants
Enzymes
Disease-Free Survival
Cytochrome P-450 Enzyme System
Survival
Clinical Trials
Proportional Hazards Models
Seizures
Therapeutics
Steroids
Databases
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Jaeckle, Kurt A. ; Ballman, Karla ; Furth, Alfred ; Buckner, Jan C. / Correlation of enzyme-inducing anticonvulsant use with outcome of patients with glioblastoma. In: Neurology. 2009 ; Vol. 73, No. 15. pp. 1207-1213.
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abstract = "BACKGROUND: Clinical trials involving patients with glioblastoma (GBM) distinguish cohorts who are treated with enzyme-inducing anticonvulsants (EIAC). Such anticonvulsants induce hepatic P450 microsomal enzymes, which accelerate the metabolism of certain chemotherapy and molecular targeted agents. However, the resultant effect of such induction on patient outcome has received limited study. METHODS:: We performed a correlative analysis of baseline EIAC use with outcome, using a cross-sectional database of 620 patients with newly diagnosed GBM treated prospectively on North Central Cancer Treatment Group trials. RESULTS: At registration, 72{\%} were receiving treatment with EIAC; 2{\%} were receiving non-EIACs, and the 26{\%} were not receiving anticonvulsants (26{\%}). Surprisingly, in the multivariable Cox model, overall survival (OS) and progression-free survival (PFS) showed a positive correlation with EIAC use (hazard ratio [HR] = 0.75, p = 0.0028 and HR = 0.80, p = 0.022), even after adjustment for the known prognostic factors of age, performance status, extent of resection, steroid use, and baseline neurocognitive function. Specifically, the median OS was longer in EIAC compared with non-EIAC patients (12.3 vs 10.7 months, p = 0.0002). Similarly, PFS was longer in EIAC patients (5.6 vs 4.8 months, p = 0.003). No differences in median OS or PFS were observed when comparing patients with or without a history of seizures at baseline. CONCLUSIONS:: Paradoxically, enzyme-inducing anticonvulsant (EIAC) use correlated with superior outcome of patients with glioblastoma. These results suggest that in comparative clinical trials testing agents metabolized by P450 microsomal enzymes, treatment arms may need stratification for the proportion of patients receiving EIAC.",
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Correlation of enzyme-inducing anticonvulsant use with outcome of patients with glioblastoma. / Jaeckle, Kurt A.; Ballman, Karla; Furth, Alfred; Buckner, Jan C.

In: Neurology, Vol. 73, No. 15, 10.2009, p. 1207-1213.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Correlation of enzyme-inducing anticonvulsant use with outcome of patients with glioblastoma

AU - Jaeckle, Kurt A.

AU - Ballman, Karla

AU - Furth, Alfred

AU - Buckner, Jan C.

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N2 - BACKGROUND: Clinical trials involving patients with glioblastoma (GBM) distinguish cohorts who are treated with enzyme-inducing anticonvulsants (EIAC). Such anticonvulsants induce hepatic P450 microsomal enzymes, which accelerate the metabolism of certain chemotherapy and molecular targeted agents. However, the resultant effect of such induction on patient outcome has received limited study. METHODS:: We performed a correlative analysis of baseline EIAC use with outcome, using a cross-sectional database of 620 patients with newly diagnosed GBM treated prospectively on North Central Cancer Treatment Group trials. RESULTS: At registration, 72% were receiving treatment with EIAC; 2% were receiving non-EIACs, and the 26% were not receiving anticonvulsants (26%). Surprisingly, in the multivariable Cox model, overall survival (OS) and progression-free survival (PFS) showed a positive correlation with EIAC use (hazard ratio [HR] = 0.75, p = 0.0028 and HR = 0.80, p = 0.022), even after adjustment for the known prognostic factors of age, performance status, extent of resection, steroid use, and baseline neurocognitive function. Specifically, the median OS was longer in EIAC compared with non-EIAC patients (12.3 vs 10.7 months, p = 0.0002). Similarly, PFS was longer in EIAC patients (5.6 vs 4.8 months, p = 0.003). No differences in median OS or PFS were observed when comparing patients with or without a history of seizures at baseline. CONCLUSIONS:: Paradoxically, enzyme-inducing anticonvulsant (EIAC) use correlated with superior outcome of patients with glioblastoma. These results suggest that in comparative clinical trials testing agents metabolized by P450 microsomal enzymes, treatment arms may need stratification for the proportion of patients receiving EIAC.

AB - BACKGROUND: Clinical trials involving patients with glioblastoma (GBM) distinguish cohorts who are treated with enzyme-inducing anticonvulsants (EIAC). Such anticonvulsants induce hepatic P450 microsomal enzymes, which accelerate the metabolism of certain chemotherapy and molecular targeted agents. However, the resultant effect of such induction on patient outcome has received limited study. METHODS:: We performed a correlative analysis of baseline EIAC use with outcome, using a cross-sectional database of 620 patients with newly diagnosed GBM treated prospectively on North Central Cancer Treatment Group trials. RESULTS: At registration, 72% were receiving treatment with EIAC; 2% were receiving non-EIACs, and the 26% were not receiving anticonvulsants (26%). Surprisingly, in the multivariable Cox model, overall survival (OS) and progression-free survival (PFS) showed a positive correlation with EIAC use (hazard ratio [HR] = 0.75, p = 0.0028 and HR = 0.80, p = 0.022), even after adjustment for the known prognostic factors of age, performance status, extent of resection, steroid use, and baseline neurocognitive function. Specifically, the median OS was longer in EIAC compared with non-EIAC patients (12.3 vs 10.7 months, p = 0.0002). Similarly, PFS was longer in EIAC patients (5.6 vs 4.8 months, p = 0.003). No differences in median OS or PFS were observed when comparing patients with or without a history of seizures at baseline. CONCLUSIONS:: Paradoxically, enzyme-inducing anticonvulsant (EIAC) use correlated with superior outcome of patients with glioblastoma. These results suggest that in comparative clinical trials testing agents metabolized by P450 microsomal enzymes, treatment arms may need stratification for the proportion of patients receiving EIAC.

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