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


Authors: Omuro, A.; Beal, K.; Gutin, P.; Karimi, S.; Correa, D. D.; Kaley, T. J.; Deangelis, L. M.; Chan, T. A.; Gavrilovic, I. T.; Nolan, C.; Hormigo, A.; Lassman, A. B.; Mellinghoff, I.; Grommes, C.; Reiner, A. S.; Panageas, K. S.; Baser, R. E.; Tabar, V.; Pentsova, E.; Sanchez, J.; Barradas Panchal, R.; Zhang, J.; Faivre, G.; Brennan, C. W.; Abrey, L. E.; Huse, J. T.
Article Title: Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma
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.
Keywords: adolescent; adult; cancer survival; clinical article; treatment outcome; aged; overall survival; bevacizumab; drug withdrawal; cancer radiotherapy; temozolomide; nuclear magnetic resonance imaging; progression free survival; quality of life; multiple cycle treatment; tumor volume; kidney failure; lung embolism; glioblastoma; patient safety; neuropsychological test; clinical effectiveness; stereotactic treatment; brain ischemia; brain blood volume; thrombotic thrombocytopenic purpura; hypofractionated stereotactic radiotherapy; diffusion coefficient; chemoradiotherapy; human; male; female; article
Journal Title: Clinical Cancer Research
Volume: 20
Issue: 19
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2014-10-01
Start Page: 5023
End Page: 5031
Language: English
DOI: 10.1158/1078-0432.ccr-14-0822
PROVIDER: scopus
PUBMED: 25107913
PMCID: PMC4523080
DOI/URL:
Notes: Export Date: 1 December 2014 -- Source: Scopus
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MSK Authors
  1. Anne S Reiner
    248 Reiner
  2. Timothy Chan
    317 Chan
  3. Raymond E Baser
    133 Baser
  4. Denise D Correa
    83 Correa
  5. Viviane S Tabar
    225 Tabar
  6. Philip H Gutin
    163 Gutin
  7. Cameron Brennan
    226 Brennan
  8. Andrew Lassman
    111 Lassman
  9. Antonio Marcilio Padula Omuro
    204 Omuro
  10. Kathryn Beal
    221 Beal
  11. Sasan Karimi
    115 Karimi
  12. Adilia Hormigo
    49 Hormigo
  13. Thomas Kaley
    154 Kaley
  14. Elena Pentsova
    132 Pentsova
  15. Christian Grommes
    150 Grommes
  16. Lauren E Abrey
    278 Abrey
  17. Katherine S Panageas
    512 Panageas
  18. Jason T Huse
    143 Huse
  19. Craig Nolan
    59 Nolan
  20. Jianan Zhang
    7 Zhang
  21. Geraldine M Faivre
    7 Faivre