ANTICONVULSANTS INCRESE GBM SURVIVAL!

NEW YORK (Reuters Health) Oct 28 - Glioblastoma patients treated for seizures with enzyme-inducing anticonvulsant (EIAC) drugs survive longer and have slower disease progression than patients treated with other anticonvulsants.

This paradoxical finding, reported in the October issue of Neurology, comes from a cross-sectional analysis of data from three nonsimultaneous trials involving glioblastoma patients, all administered by the Mayo Clinic.

As the researchers explain in their report, EIACs - such as phenobarbital, phenytoin, carbamazepine, and primidone -- induce P450 microsomal enzymes, leading to enhanced metabolism of many common chemotherapeutic drugs. Oncologists have long believed that these drugs restrict the achievement of effective chemotherapeutic levels.

"We were worried, originally," that the EIACs would make cancer drugs less effective, Dr. Kurt Jaeckle of the Mayo Clinic in Jacksonville, Florida, told Reuters Health.

With this hypothesis, he and his colleagues studied database records on 620 newly diagnosed glioblastoma patients who entered the treatment trials between 1994 and 2002. Treatments and anticonvulsant use were dictated by the three trial protocols and treating physicians.

At enrollment, 432 patients were being treated with EIACs, 14 were on a non-EIAC, and 159 were not taking any anticonvulsant. Fifteen subjects had missing data on anticonvulsant use. There was no significant difference in EIAC use between the three trials (p=0.28). The study did not consider changes in EIAC administration that occurred after enrollment. All but 48 patients had died by the time of the analysis.

Compared to non-EIAC patients, those on EIACs were on average slightly younger (median 55 vs 58 years, p=0.0057), had slightly higher Mini-Mental State Examination scores (median 29 vs 28, p=0.045), were less likely to have had only a biopsy (13.4% vs 27.8%, p<0.0001),>

Median overall survival was 12.3 months for patients on EIACs and 10.7 months in those not on EIACs (p=0.0002). The projected hazards ratio on multivariate analysis was 0.75.

Median progression-free survival was also significantly longer in the EIAC group: 5.6 months vs 4.8 months in the no-EIAC group (p=0.003).

Seizure history had no clear bearing on overall survival or progression-free survival.

"What we found, to our amazement, was that people who were on enzyme-inducing anticonvulsants were actually living longer than the ones that were not," Dr. Jaeckle said.

He and his co-authors point out that trials in 2005 and 2006 found EIACs to be an independent predictor of progression-free survival in glioblastoma and to be correlated with better outcome in anaplastic glioma. But, the researchers add, while they are not the first to challenge conventional wisdom about EIACs, they are the first to use the effect of these drugs as their primary end point.

They admit, however, that while they have correlated EIAC use with longer survival and slower progression, "a cause-and-effect relationship for this association cannot be derived from this analysis."

If a direct etiology is uncovered, Dr. Jaeckle suspects it will be a drug metabolite with anti-tumor activity. He added that other groups are already using in vitro methods to understand how anticonvulsants and their metabolites may affect tumor cells.

Neurology 2009;73:1207-1213.