Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma

Antonio Omuro, Kathryn Beal, Philip Gutin, Sasan Karimi, Denise D. Correa, Thomas J. Kaley, Lisa M. DeAngelis, Timothy A. Chan, Igor T. Gavrilovic, Craig Nolan, Adilia Hormigo, Andrew B. Lassman, Ingo Mellinghoff, Christian Grommes, Anne S. Reiner, Katherine S. Panageas, Raymond E. Baser, Viviane Tabar, Elena Pentsova, Juan SanchezRenata Barradas-Panchal, Jianan Zhang, Geraldine Faivre, Cameron W. Brennan, Lauren E. Abrey, Jason T. Huse

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

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 ≤60 cc were treated with HFSRT (6 x 6 Gy to contrast enhancement and 6 x 4 Gy 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%; nonpromising = 50%; α = 0.1; β = 0.1. Results: Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84-100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P < 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (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 with historical controls. Analysis of advanced neuroimaging 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.

Original languageEnglish (US)
Pages (from-to)5023-5031
Number of pages9
JournalClinical Cancer Research
Volume20
Issue number19
DOIs
StatePublished - Oct 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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