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NEUROLOGY 2009;73:1207-1213
© 2009 American Academy of Neurology

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

Kurt A. Jaeckle, MD, Karla Ballman, PhD, Alfred Furth, MS and Jan C. Buckner, MD

From Mayo Clinic Florida (K.A.J.), Jacksonville, FL; and Mayo Clinic Rochester (K.B., A.F., J.C.B.), Rochester, MN.

Address correspondence and reprint requests to Dr. Kurt A. Jaeckle, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224 jaeckle.kurt{at}mayo.edu

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.

Abbreviations: CI = confidence interval; CYP = cytochrome P450; EIAC = enzyme-inducing anticonvulsant; GBM = glioblastoma; HR = hazard ratio; MTD = maximum tolerated dose; NCCTG = North Central Cancer Treatment Group; OR = odds ratio; OS = overall survival; PFS = progression-free survival.

Supported by grants NIH/NCI U10 CA25224 and U24 CA114740.

Disclosure: Author disclosures are provided at the end of the article.

Received November 10, 2008. Accepted in final form July 21, 2009.






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