Multicenter, phase 1, dose escalation study of hypofractionated stereotactic radiation therapy with bevacizumab for recurrent glioblastoma and anaplastic astrocytoma Journal Article


Authors: Clarke, J.; Neil, E.; Terziev, R.; Gutin, P.; Barani, I.; Kaley, T.; Lassman, A. B.; Chan, T. A.; Yamada, J.; DeAngelis, L.; Ballangrud, A.; Young, R.; Panageas, K. S.; Beal, K.; Omuro, A.
Article Title: Multicenter, phase 1, dose escalation study of hypofractionated stereotactic radiation therapy with bevacizumab for recurrent glioblastoma and anaplastic astrocytoma
Abstract: Purpose To establish the maximum tolerated dose of a 3-fraction hypofractionated stereotactic reirradiation schedule when delivered with concomitant bevacizumab to treat recurrent high-grade gliomas. Methods and Materials Patients with recurrent high-grade glioma with Karnofsky performance status ≥60, history of standard fractionated initial radiation, tumor volume at recurrence ≤40 cm3, and absence of brainstem or corpus callosum involvement were eligible. A standard 3+3 phase 1 dose escalation trial design was utilized, with dose-limiting toxicities defined as any grade 3 to 5 toxicities possibly, probably, or definitely related to radiation. Bevacizumab was given at a dose of 10 mg/kg every 2 weeks. Hypofractionated stereotactic reirradiation was initiated after 2 bevacizumab doses, delivered in 3 fractions every other day, starting at 9 Gy per fraction. Results A total of 3 patients were enrolled at the 9 Gy × 3 dose level cohort, 5 in the 10 Gy × 3 cohort, and 7 in the 11 Gy × 3 cohort. One dose-limiting toxicity of grade 3 fatigue and cognitive deterioration possibly related to hypofractionated stereotactic reirradiation was observed in the 11 Gy × 3 cohort, and this dose was declared the maximum tolerated dose in combination with bevacizumab. Although no symptomatic radionecrosis was observed, substantial treatment-related effects and necrosis were observed in resected specimens. The intent-to-treat median overall survival was 13 months. Conclusions Reirradiation using a 3-fraction schedule with bevacizumab support is feasible and reasonably well tolerated. Dose-escalation was possible up to 11 Gy × 3, which achieves a near doubling in the delivered biological equivalent dose to normal brain, in comparison with our previous 6 Gy × 5 schedule. Promising overall survival warrants further investigation. © 2017 Elsevier Inc.
Keywords: adult; clinical article; controlled study; middle aged; cancer surgery; overall survival; fatigue; neutropenia; bevacizumab; hypertension; multimodality cancer therapy; cancer patient; nuclear magnetic resonance imaging; glioma; neurosurgery; prospective study; progression free survival; infection; multiple cycle treatment; tumor volume; leukopenia; cohort analysis; radiation injury; necrosis; drug dose escalation; lymphocytopenia; hyponatremia; karnofsky performance status; tumors; radiation dose fractionation; multicenter study; tumor recurrence; glioblastoma; muscle weakness; radiation hazard; maximum tolerated dose; phase 1 clinical trial; mental deterioration; toxicity; stereotactic body radiation therapy; brain ischemia; radiation dose distribution; brain stem; meningitis; radiation necrosis; chemoradiotherapy; skin infection; hypofractionated; corpus callosum; dose limiting toxicity; dose-escalation study; high-grade gliomas; re-irradiation; anaplastic astrocytoma; hypofractionated radiotherapy; methods and materials; intention to treat analysis; human; male; female; priority journal; article; infestation; hypofractionated stereotactic radiation therapy
Journal Title: International Journal of Radiation Oncology, Biology, Physics
Volume: 99
Issue: 4
ISSN: 0360-3016
Publisher: Elsevier Inc.  
Date Published: 2017-11-15
Start Page: 797
End Page: 804
Language: English
DOI: 10.1016/j.ijrobp.2017.06.2466
PROVIDER: scopus
PMCID: PMC5654655
PUBMED: 28870792
DOI/URL:
Notes: Article -- Export Date: 1 November 2017 -- Source: Scopus
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MSK Authors
  1. Timothy Chan
    206 Chan
  2. Robert J Young
    106 Young
  3. Yoshiya Yamada
    353 Yamada
  4. Philip H Gutin
    148 Gutin
  5. Andrew Lassman
    101 Lassman
  6. Antonio Marcilio Padula Omuro
    167 Omuro
  7. Kathryn Beal
    153 Beal
  8. Thomas Kaley
    77 Kaley
  9. Katherine S Panageas
    312 Panageas
  10. Elizabeth Catherine Neil
    4 Neil