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
Altmetric Score
MSK Authors
  1. Anne S Reiner
    122 Reiner
  2. Timothy Chan
    222 Chan
  3. Raymond E Baser
    65 Baser
  4. Denise D Correa
    65 Correa
  5. Viviane S Tabar
    123 Tabar
  6. Philip H Gutin
    153 Gutin
  7. Cameron Brennan
    156 Brennan
  8. Andrew Lassman
    107 Lassman
  9. Antonio Marcilio Padula Omuro
    177 Omuro
  10. Kathryn Beal
    157 Beal
  11. Sasan Karimi
    97 Karimi
  12. Adilia Hormigo
    48 Hormigo
  13. Thomas Kaley
    90 Kaley
  14. Christian Grommes
    57 Grommes
  15. Lauren E Abrey
    272 Abrey
  16. Katherine S Panageas
    331 Panageas
  17. Jason T Huse
    127 Huse
  18. Craig Nolan
    44 Nolan
  19. Jianan Zhang
    7 Zhang
  20. Geraldine M Faivre
    7 Faivre