Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas

Abstract

Purpose: Preclinical studies suggest that inhibition of vascular endothelial growth factor (VEGF) improves glioma response to radiotherapy. Bevacizumab, a monoclonal antibody against VEGF, has shown promise in recurrent gliomas, but the safety and efficacy of concurrent bevacizumab with brain irradiation has not been extensively studied. The objectives of this study were to determine the safety and activity of this combination in malignant gliomas.

Methods and materials: After prior treatment with standard radiation therapy patients with recurrent glioblastoma (GBM) and anaplastic gliomas (AG) received bevacizumab (10 mg/kg intravenous) every 2 weeks of 28-day cycles until tumor progression. Patients also received 30 Gy of hypofractionated stereotactic radiotherapy (HFSRT) in five fractions after the first cycle of bevacizumab.

Results: Twenty-five patients (20 GBM, 5 AG; median age 56 years; median Karnofsky Performance Status 90) received a median of seven cycles of bevacizumab. One patient did not undergo HFSRT because overlap with prior radiotherapy would exceed the safe dose allowed to the optic chiasm. Three patients discontinued treatment because of Grade 3 central nervous system intratumoral hemorrhage, wound dehiscence, and bowel perforation. Other nonhematologic and hematologic toxicities were transient. No radiation necrosis was seen in these previously irradiated patients. For the GBM cohort, overall response rate was 50%, 6-month progression-free survival was 65%; median overall survival was 12.5 months, and 1-year survival was 54%.

Discussion: Bevacizumab with HFSRT is safe and well tolerated. Radiographic responses, duration of disease control, and survival suggest that this regimen is active in recurrent malignant glioma.

Trial registration: ClinicalTrials.gov NCT00595322.

Figure 1

Baseline (A) and post-treatment (B) gadolinium enhanced brain MRI in a patient with glioblastoma showing a partial response.

Figure 2

Progression-free and overall survival curves for all patients (n=25).

Figure 3

The upper panel shows pre-treatment perfusion MRI studies and the lower panel shows the perfusion MRI studies after one cycle of bevacizumab for a left frontal lobe glioblastoma patient. There are increased ratios of transfer coefficient (Ktrans) (A), fractional blood volume (fBV) (B) and relative cerebral blood volume (rCBV) (C) before treatment; Ktrans (D), fBV (E) and rCBV (F) normalized after the first cycle of bevacizumab.