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

Clinical article

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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.

Abbreviations used in this paper: BBB = blood-brain barrier; DLT = dose-limiting toxicity; FDG = [18F]fluorodeoxyglucose; GBM = glioblastoma multiforme; IA = intraarterial; IV = intravenous; KPS = Karnofsky Performance Scale; MRP = MR perfusion; MTD = maximum tolerated dose; PE = pulmonary embolism; SIACI = superselective intraarterial cerebral infusion; SUV = standard uptake value; VEGF = vascular endothelial growth factor.

Article Information

Address correspondence to: John A. Boockvar, M.D., Department of Neurological Surgery, Weill Medical College of Cornell University, 510 East 70th Street, New York, New York 10021. email: jab2029@med.cornell.edu.

Please include this information when citing this paper: published online October 22, 2010; DOI: 10.3171/.2010.9.JNS101223

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    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.

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    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.

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    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.

  • View in gallery

    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.

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