A phase II study of concurrent radiation therapy, temozolomide and the histone deacetylase inhibitor Valproic Acid for newly diagnosed patients with Glioblastoma
Mené sur 37 patients atteints d'un glioblastome récemment diagnostiqué et traités entre 2006 et 2013, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression et de la survie globale à 6, 12 et 24 mois, et la toxicité de l'ajout de l'acide valproïque, un inhibiteur des histones désacétylases, à un traitement combinant de manière concomitante une radiothérapie et le témozolomide
Purpose : Valproic Acid (VPA) is an antiepileptic agent with HDACi (histone deacetylase inhibitor) activity shown to radiosensitize glioblastoma (GBM) cells in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed GBM. Methods and Materials : 37 patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients were administered VPA 25 mg/kg orally divided into two daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA and TMZ related acute toxicities were evaluated using the Cancer Therapy and Evaluation Program Common Toxicity Criteria (CTC) Version 3.0 for toxicity and adverse event reporting as well as the RTOG/EORTC Radiation Morbidity Scoring Scheme. Results : 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (21- 63.8), median progression free survival (PFS) was 10.5 (6.8 – 51.2). OS at 6, 12, 24 months was 97%, 86%, 56% respectively. PFS at 6, 12, 24 months was 70%, 43%, 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ were blood/ bone marrow toxicity (32%), neurological (11%), metabolic/laboratory (8%). Younger age and class V RPA were significant for both OS and PFS. VPA levels were not correlated to grade 3/4 toxicity. Conclusions : The addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes as compared to historical data and merits further study.
http://www.redjournal.org/article/S0360-3016(15)00442-3/abstract