VPA superior to EIAEDs for glioblastoma treatment during TMZ
MedWire News: Valproic acid (VPA) is superior to enzyme-inducing anti-epileptic drugs (EIAEDs) for treating patients with glioblastoma during temozolomide (TMZ)-based chemoradiotherapy, suggest study findings showing improvements in overall survival.
In addition, the study showed that VPA-treated glioblastoma patients showed better outcomes than those receiving no AED at all. The findings are of importance, given that seizures occur in approximately 30-50% of patients with glioblastomas.
"These results suggest that the choice of AED in patients with brain tumors should be carefully considered because it may affect survival… and further support a recent trend to favor a non-EIAED for patients with a malignancy to allow administration of modern chemotherapy and targeted agents that often show increased hepatic metabolism if patients are given an EIAED," say Michael Weller (University Hospital Zurich, Switzerland) and co-authors.
Using data from the European Organization for Research and Treatment of Cancer (EORTC) 26981-22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy with or without TMZ for newly diagnosed glioblastoma, Weller and team retrospectively analyzed the use of AEDs in 573 glioblastoma patients to assess the impact of AED use and chemoradiotherapy on survival.
When treatment began, 30.5% of patients were not taking AEDs, 48.3% were taking an EIAED, and 23.4% were taking any non-EIAED. At baseline, the overall survival of patients who were receiving AEDs was similar to those who were not receiving any AED (12.78 and 13.19 months for VPA only and EIAED only vs 1.52 months for no AED, respectively).
Conversely, patients who were taking VPA alone showed an increased survival benefit from treatment with radiation therapy and TMZ compared with patients receiving EIAED only or those not receiving any AED (median survival 17.3 vs 14.4 and 14.0 months, respectively). Corresponding hazard ratios (HRs) associated with each group were 0.38, 0.69, and 0.67, respectively.
The researchers found that the use of VPA did not confer any survival benefit among patients who received radiation therapy alone without TMZ, although many of these patients received salvage TMZ treatment at tumor progression.
Patients who received VPA only had more grade 3 and 4 thrombocytopenia and leucopenia than patients without an AED or those taking an EIAED only. Weller and team say the reasons for the potential benefit of VPA remain unclear, but suggest that VPA may increase TMZ bioavailability, act as a histone deacetylase (HDAC) inhibitor, or induce autophagy in vivo.
"Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo," conclude the authors in the journal Neurology.
In an associated editorial, Patrick Wen (Dana Farber/Brigham and Women's Cancer Center, Boston, Massachusetts, USA) and David Schiff (University of Virginia Medical Center, Charlottesville, USA) say that until data from ongoing studies further investigating TMZ and the HDAC inhibitor vorinostat for treating glioblastoma become available, "it is unclear whether the potential survival benefit of VPA outweighs the definite increase in hematologic toxicity."
By Ingrid Grasmo