Case Report Bevacizumab as First-Line Therapy for Patients With Brain Metastases From Renal Carcinoma: A Case Series Fable Zustovich, Alessandra Ferro, Patrizia Farina Clinical Genitourinary Cancer, Vol. 12, No. 3, e107-10 ª 2014 Elsevier Inc. All rights reserved. Keywords: Antiangiogenic, Cerebral, Kidney, Target therapy, VEGF Introduction Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). This protein is highly expressed in kidney cancer and it has been shown to be increased beginning with start of the disease. 1 Most clear-cell kidney tumors are driven by dysfunction of the von Hippel-Lindau (VHL) gene: loss of VHL function causes upregulation of hypoxia-inducible factor, which results in increased VEGF. 2 This dysfunction of the VHL gene is thought to be a very early event in clear-cell kidney tumor development. 3 Because of the role of VHL gene dysfunction, VEGF is a primary disease driver in renal carcinoma. Bevacizumab has been approved since 2007 by the European Medi- cines Agency and 2009 by the US Food and Drug Administration for metastatic kidney carcinoma when used in combination with a-interferon (IFN). 4,5 The efficacy of this protocol was proven in 2 large randomized phase III studies published in 2008: the AVOREN (Avastin for renal cell cancer) and Cancer and Leukemia Group B (CALGB) 90206 trials. The AVOREN study 6 is a large, multicenter, randomized, double-blind, placebo-controlled Phase III trial study. Patients with previously untreated metastatic predominantly clear-cell kidney carcinoma were randomized to receive bevacizumab at 10 mg/kg every 2 weeks with a-IFN starting at 9 million international units or placebo with a-IFN. The AVOREN protocol allowed for a-IFN dose escalation, reduction, or discontinuation to manage its toxicity, but bevacizumab was continued until disease progression or unac- ceptable toxicity. The progression-free survival (PFS) benefit of bevacizumab with a-IFN was observed as early as 2 months and was sustained throughout the duration of the study: bevacizumab with a-IFN improved median PFS by 89% over placebo with a-IFN (10.2 vs. 5.4 months; hazard ratio [HR], 0.60 [95% confidence interval (CI), 0.49-0.72]; P < .0001). Median overall survival (OS) with bevacizumab and a-IFN was 23 months, a nonsignificant increase versus placebo with a-IFN (21 months; HR, 0.86 [95% CI, 0.72-1.04]; P ¼ .1291). Bevacizumab with a-IFN more than doubled overall response rate (ORR) versus placebo with a-IFN (30% vs. 12%; P < .0001). Moreover, duration of response was longer with bevacizumab with a-IFN (13.5 months) compared with placebo with a-IFN (11.1 months). The open-label, phase III CALGB 90206 trial, 7 which compared treatment using bevacizumab and a-IFN with a-IFN alone, also showed significant PFS and ORR benefits for bevacizumab with a-IFN (median PFS, 8.4 vs. 4.9 months, respectively; HR, 0.71; P < .001, stratified; ORR, 25.5% vs. 13.1%, respectively, strati- fied). OS was not statistically different in both groups (18.3 months for the combination vs. 17.4 months for a-IFN alone). With regard to the toxicity of the protocol, the most common adverse reactions observed for bevacizumab were: fatigue, proteinuria, Clinical Practice Points  Bevacizumab has been approved by the European Medicines Agency and the US Food and Drug Admin- istration for metastatic kidney carcinoma (mRCC) when used in combination with a-interferon (IFN).  The efficacy of the protocol was proven in 2 large randomized phase III studies published in 2008: the AVOREN (Avastin for renal cell cancer) and Cancer and Leukemia Group B 90206 trials.  Bevacizumab can safely be administered to patients with mRCC with cerebral lesions, and a-IFN can be reduced or discontinued to manage its toxicity.  In our case series, bevacizumab was proven to reduce dimension and perilesional edema of cranial metas- tases, and provide relief of symptoms and prolonga- tion of progression-free and overall survival. Istituto Oncologico Veneto e IRCCS, Padova, Italy Submitted: Nov 7, 2013; Revised: Dec 27, 2013; Accepted: Dec 27, 2013; Epub: Jan 2, 2014 Address for correspondence: Fable Zustovich, MD, Istituto Oncologico Veneto e IRCCS, Via Gattamelata, 64, 35127 Padova, Italy Fax: þ390498215904; e-mail contact: fable.zustovich@ioveneto.it 1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.12.005 Clinical Genitourinary Cancer June 2014 - e107