Copyright 2009 by the Society for Neuro-Oncology
Bevacizumab and carboplatin increase survival and asymptomatic tumor volume in a glioma model
Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik m. S. Hämatologie und Onkologie, Berlin, Germany (K.J.); Departments of Neurology (L.L.M., S.J.L., D.F.K., E.A.N.), Cell and Developmental Biology (L.L.M.), Medical Informatics and Clinical Epidemiology (D.F.K.), Public Health and Preventive Medicine (D.F.K.), and Neurosurgery (E.A.N.), Oregon Health and Science University, Portland, OR, USA; Universitätsklinikum Würzburg, Department of Neuroradiology, Würzburg, Germany (C.G.V.); Department of Pharmacy Practice, Oregon State University, Portland, OR, USA (D.F.K.); Veterans Administration Medical Center, Portland, OR, USA (E.A.N.)
Address correspondence to Edward A. Neuwelt, Department of Neurology, Blood–Brain Barrier and Neuro-Oncology Program, Oregon Health and Science University, 3181 Sam Jackson Park Rd., L603, Portland, OR 97239-3098, USA (neuwelte{at}ohsu.edu).
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Abstract |
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To evaluate efficacy and MRI findings after intravenous bevacizumab and/or carboplatin in a human glioma animal model, we randomized male nude rats with intracerebral UW28 human glioma xenografts to four groups: (1) controls (n = 9), (2) bevacizumab 10 mg/kg (n = 6), (3) carboplatin 200 mg/m2 (n = 6), and (4) bevacizumab + carboplatin (n = 6). MRI was performed on the day of treatment (day 7–10) and 1 week later, and rats were followed for survival. Dynamic MRI was done in three controls and three rats treated with bevacizumab with or without carboplatin before and 24 h after treatment. Median overall survival (OS) was as follows: group 1, 16 days; group 2, 23 days; group 3, 22 days; group 4, 36 days. OS was significantly longer in group 4 than in group 1 (p = 0.0011), group 2 (p = 0.0014), and group 3 (p = 0.0015), and rats had significantly larger tumors. No objective tumor responses were observed on MR images at 1 week after treatment; however, after bevacizumab, dynamic MRI showed reduced gadolinium enhancement intensity and increased time to peak, consistent with decreased vascular permeability. Carboplatin + bevacizumab is effective and superior over bevacizumab or carboplatin monotherapy in this animal model. Increased survival concomitant with increased asymptomatic tumor volume is suggestive that vascular targeting with reduced peritumoral edema and mass effect contributes to the efficacy of bevacizumab. The promising survival data warrant future clinical trials using bevacizumab + carboplatin.
Keywords: bevacizumab, carboplatin, glioma, magnetic resonance imaging, rat model
Received April 18, 2008; Accepted July 22, 2008