Phase II Study of Bevacizumab, Temozolomide and Hypofractionated Stereotactic Radiotherapy for Newly Diagnosed Glioblastoma

PURPOSE: Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly-diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab. EXPERIMENTAL DESIGN: Patients with tumor volume ≤60cc were treated with HFSRT (6x6Gy to contrast-enhancement and 6x4Gy to FLAIR hyperintensity with dose painting) combined with concomitant/ adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall-survival (OS): Promising=70%; non-promising=50%; α=0.1; β=0.1. RESULTS: Forty patients were enrolled (median age: 55y; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% (95%CI 84-100) and median OS was 19m. The median progression-free survival was 10m, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of TCGA glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR=14%, versus 77% for other subclasses; p=0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in rCBV over time (p<0.0001) but had no prognostic value, whereas higher baseline ADC ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (p=0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT. CONCLUSIONS: This aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable to historical controls. Analysis of advanced neuro-imaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non-IDH-1 mutated glioblastoma.