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

Clinical article

John A. BoockvarDepartments of Neurosurgery,

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 M.D.
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Apostolos J. TsiourisNeuroradiology,

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 M.D.
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Christoph P. HofstetterDepartments of Neurosurgery,

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 M.D., Ph.D.
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Ilhami KovanlikayaNeuroradiology,

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 M.D.
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Sherese FralinDepartments of Neurosurgery,

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 M.S.N.
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Kartik KesavabhotlaDepartments of Neurosurgery,

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 B.S.
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Stephen M. SeedialNeuroradiology,

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 B.S.
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Susan C. PannulloDepartments of Neurosurgery,

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Theodore H. SchwartzDepartments of Neurosurgery,

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Philip StiegDepartments of Neurosurgery,

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 Ph.D., M.D.
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Robert D. ZimmermanNeuroradiology,

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 M.D.
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Jared KnopmanDepartments of Neurosurgery,

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 M.D.
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Ronald J. ScheffMedical Oncology,

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Paul ChristosBiostatistics and Epidemiology, Weill Cornell Brain Tumor Center, Weill Cornell Medical College of Cornell University, New York, New York

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 Dr.P.H., M.S.
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Shankar VallabhajosulaNuclear Medicine, and

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 M.D.
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Howard A. RiinaDepartments of Neurosurgery,

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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.
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