Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. Clinical article

Abstract

Object: The authors assessed the safety and maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of bevacizumab after osmotic disruption of the blood-brain barrier (BBB) with mannitol in patients with recurrent malignant glioma.

Methods: A total of 30 patients with recurrent malignant glioma were included in the current study.

Results: The authors report no dose-limiting toxicity from a single dose of SIACI of bevacizumab up to 15 mg/kg after osmotic BBB disruption with mannitol. Two groups of patients were studied; those without prior bevacizumab exposure (naïve patients; Group I) and those who had received previous intravenous bevacizumab (exposed patients; Group II). Radiographic changes demonstrated on MR imaging were assessed at 1 month postprocedure. In Group I patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 34.7%, a median reduction in the volume of tumor enhancement of 46.9%, a median MR perfusion (MRP) reduction of 32.14%, and a T2-weighted/FLAIR signal decrease in 9 (47.4%) of 19 patients. In Group II patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 15.2%, a median volume reduction of 8.3%, a median MRP reduction of 25.5%, and a T2-weighted FLAIR decrease in 0 (0%) of 11 patients.

Conclusions: The authors conclude that SIACI of mannitol followed by bevacizumab (up to 15 mg/kg) for recurrent malignant glioma is safe and well tolerated. Magnetic resonance imaging shows that SIACI treatment with bevacizumab can lead to reduction in tumor area, volume, perfusion, and T2-weighted/FLAIR signal.

Fig. 1

A: Sagittal Gd-enhanced T1-weighted MR image showing a large right posterior temporal GBM (arrow). B: The microcatheter tip (arrow) adjacent to the craniotomy site on an unsubtracted digital subtraction angiography study delineates the point of chemotherapy injection. C: Digital subtraction angiogram showing contrast infusion into the distal branch of the right middle cerebral artery (arrowhead) supplying the neoplasm demonstrates the distribution of IA infusion of mannitol and bevacizumab.

Fig. 2

Contiguous Gd-enhanced T1-weighted MR images demonstrating a marked interval decrease in the size of the enhancing component (A and B) and the associated T2-weighted/FLAIR images (C and D) of the patient’s recurrent posterior right temporal GBM before (panels A and C) and 1 month after (panels B and D) IA bevacizumab treatment.

Fig. 3

Gadolinium-enhanced T1-weighted images (A and B) obtained pre- and post-IA bevacizumab infusion demonstrating a 29.6% interval decrease in the area of the targeted enhancing component of a recurrent left frontal GBM. The 3D volumetric measurements (C and D) of the targeted left frontal component (arrows) demonstrate an interval decrease of 66.8% in the volume of the neoplasm. The patient had marked clinical improvement in speech and comprehension 4 days after the procedure. Functional regional cerebral blood volume maps (E and F) on the corresponding MRP image, with regions of interest placed within the enhancing component, showing a 43% decrease in the regional cerebral blood volume values from 3.58 to 2.04 ml/100 g of brain tissue.

Fig. 4

Selected axial and coronal FDG-PET brain images obtained in a patient immediately before (A) and approximately 1 month after (B) SIACI therapy demonstrate a qualitative diminution of metabolic activity in the left frontal and deep thalamic lesions. The images were acquired at a 3-hour delay after radiotracer administration to increase tumor-to-background conspicuity.