Correlation of enzyme-inducing anticonvulsant use with outcome of patients with glioblastoma.
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.
Jaeckle
Kurt A
KA
Mayo Clinic, Jacksonville, FL 32224, USA. jaeckle.kurt@mayo.edu
Ballman
Karla
K
Furth
Alfred
A
Buckner
Jan C
JC
D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000097:blood / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000401:mortality; D003430:Cross-Sectional Studies; D018572:Disease-Free Survival; D004790:Enzyme Induction; D005260:Female; D005909:Glioblastoma / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D012640:Seizures / Q000150:complications / Q000188:drug therapy; D016896:Treatment Outcome
D000927:Anticonvulsants; D000970:Antineoplastic Agents