title: Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 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.
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York. OmuroA@mskcc.org.
authors.forename: Antonio
authors.initials: A
authors.lastname: Omuro
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Beal
authors.affiliation: Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Philip
authors.initials: P
authors.lastname: Gutin
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Sasan
authors.initials: S
authors.lastname: Karimi
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Denise D
authors.initials: DD
authors.lastname: Correa
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kaley
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: DeAngelis
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York. Department of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Igor T
authors.initials: IT
authors.lastname: Gavrilovic
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Craig
authors.initials: C
authors.lastname: Nolan
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Adilia
authors.initials: A
authors.lastname: Hormigo
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Lassman
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York. Department of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Ingo
authors.initials: I
authors.lastname: Mellinghoff
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Christian
authors.initials: C
authors.lastname: Grommes
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Reiner
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Panageas
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Baser
authors.affiliation: Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Viviane
authors.initials: V
authors.lastname: Tabar
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Elena
authors.initials: E
authors.lastname: Pentsova
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Juan
authors.initials: J
authors.lastname: Sanchez
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Renata
authors.initials: R
authors.lastname: Barradas-Panchal
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Jianan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Faivre
authors.affiliation: Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York. Department of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Cameron W
authors.initials: CW
authors.lastname: Brennan
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Abrey
authors.affiliation: Department of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D001706:Biopsy; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000601:surgery*; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005909:Glioblastoma / Q000175:diagnosis / Q000188:drug therapy* / Q000601:surgery*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D016634:Radiosurgery / Q000009:adverse effects / Q000379:methods; D000077204:Temozolomide; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D003606:Dacarbazine; D000077204:Temozolomide
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