Bevacizumab and carboplatin increase survival and asymptomatic tumor volume in a glioma model

¹ Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik m. S. Hämatologie und Onkologie, Berlin, Germany
² Department of Neurology, Oregon Health and Science University, Portland, OR; Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR; USA
³ Universitätsklinikum Würzburg, Dept. of Neuroradiology, Würzburg, Germany
⁴ Department of Neurology, Oregon Health and Science University, Portland, OR; USA
⁵ Department of Neurology, Oregon Health and Science University, Portland, OR; Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR; Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, OR; Department of Pharmacy Practice, Oregon State University, Portland, OR; USA
⁶ Department of Neurology, Oregon Health and Science University, Portland, OR; Department of Neurosurgery, Oregon Health and Science University, Portland, OR; Veterans Administration Medical Center, Portland, OR; USA

^* To whom correspondence should be addressed. E-mail: jneuwelte{at}ohsu.edu.

	Abstract

Purpose: To evaluate efficacy and magnetic resonance imaging (MRI) after intravenous bevacizumab and/or carboplatin in a human glioma animal model.

Experimental Design: Male nude rats with intracerebral UW28 human glioma xenografts were randomized to four groups: (1) controls (n = 9) ; (2) bevacizumab 10 mg/kg (n = 6) ; (3) carboplatin 200 mg/m2 (n = 6); and (4) bevacizumab plus carboplatin (n = 6) . MRI was performed on the day of treatment (day 7-10) and one week later, and rats were followed for survival. Dynamic MRI was done in three controls and three rats treated with bevacizumab ± carboplatin before and 24 hours after treatment.

Results: Median overall survival (OS) was: (1) controls, 16 days; (2) bevacizumab, 23 days; (3) carboplatin, 22 days; (4) bevacizumab plus carboplatin, 36 days. OS of group 4 was significantly longer than 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 MRI at one week after treatment; however, after bevacizumab dynamic MRI showed reduced gadolinium enhancement intensity and increased time to peak, consistent with decreased vascular permeability.

Conclusions: Carboplatin plus 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 plus carboplatin.

Key Words: bevacizumab, carboplatin, glioma, magnetic resonance imaging, rat model

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