Bevacizumab and recurrent malignant gliomas: a European perspective.

TO THE EDITOR: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF; Avastin, Genentech, South San Francisco, CA, and Roche, Basel, Switzerland), was approved in 2009 by the US Food and Drug Administration for the treatment of recurrent glioblastoma. The basis for this accelerated approval was uncontrolled phase II trials with a total of 215 patients; a single-arm phase II trial of bevacizumab with irinotecan added at progression and a randomized phase II trial of the same regimen or first-line treatment with the combination of bevacizumab and irinotecan. Even before US Food and Drug Administration approval, bevacizumab was widely used in this indication in the United States and in some European countries, and is currently given off-label for patients with newly diagnosed high-grade glioma. The marketing application to the European Medicines Agency was rejected November 2009. European Medicines Agency felt that the still existing question about activity in recurrent glioblastoma prevented registration with the given data. It is remarkable that over the 3 years since the first report on the efficacy of bevacizumab in recurrent glioblastoma only a few hundred patients with recurrent glioblastoma were accrued into reported prospective clinical trials, while already thousands of patients have been treated off-label. Despite the rapid US Food and Drug Administration approval, numerous questions with regard to dosing, timing, and efficacy remain. Opportunities to adequately test this promising agent were missed or avoided. This has already led to considerable national differences with respect to access and reimbursement of bevacizumab for patients with glioma. Based on these reports and our own clinical experience, bevacizumab is without doubt a useful drug in recurrent glioma. However, the uncontrolled trials that evaluated bevacizumab and irinotecan versus bevacizumab alone (and the addition of irinotecan at progression) leave many questions unanswered. Was the right end point used? The primary end point was the rate of patients alive and free of progression at 6 months, a surrogate end point that had been considered valuable for cytotoxic agents, but is inappropriate when studying antiangiogenic agents that will modify vascular permeability and thus the imaging response assessment based on contrast enhancement. VEGF was initially also referred to as vascular permeability factor and it is well recognized that VEGF is a major mediator of blood-brain barrier disturbance. Inhibiting VEGF signaling decreases tumor enhancement even without an intrinsic antitumor effect. Indeed, clinical progression has been observed in the absence of evident tumor progression on T1-gadolinium–enhanced magnetic resonance imaging with T2-weighted sequences showing tumor extension without disruption of the blood-brain barrier. The substantial differences in response rates when independently assessed by the investigators (39% and 46% for bevacizumab and bevacizumab with irinotecan, respectively), by a sponsor-mandated central radiologic review (28% and 38%), and finally by the US Food and Drug Administration (20% and 26%), illustrate the difficulties and limitations of objective response as the primary end point for outcome to treatment with antiangiogenic agents. Of note, an international panel is currently revisiting the response criteria for brain tumors, and has judged the response rate and progression-free survival inappropriate end points for anti-VEGF signaling treatments. Does treatment with bevacizumab increase survival? The reported survival times of 8 to 9 months correspond to what had been reported as median survival after progression for patients treated with radiotherapy alone, or radiotherapy and concomitant temozolomide before the availability of bevacizumab, and needs to be compared with 6 to 7 months in many bluntly negative trials on recurrent glioblastoma. The disappointing disparity between the high response rates reported for bevacizumab in recurrent glioblastoma and the modest at best survival benefit may partly be explained by the limited effect on the tumor mass itself. The obvious question is whether the effects of bevacizumab by and large resemble that of dexamethasone and should therefore be named pseudoresponse. The duration of a response, and ultimately overall survival, are probably more accurate indicators of the therapeutic activity of a compound. The data reported in Journal of Clinical Oncology remain immature, with a minimum follow-up of only 6 months and just half of the patients having died at the time of analysis in September 2007, 2 years before publication. No update has been made available yet. Do we know the optimal bevacizumab dose? Stark-Vance’s initial experience of high response rates in recurrent glioma with bevacizumab used a dose of 5 mg/kg every 2 weeks; nevertheless, the dose of bevacizumab in subsequent trials was doubled without further investigations or justification. One cannot rule out that the higher dose of bevacizumab actually increases toxicity and complication rate, this not even considering the economical impact. Should bevacizumab be given as a single agent or in combination? In most indications, anti-VEGF agents had to be combined with classical cytotoxic drugs to demonstrate activity. Based on overall survival, this trial shows no added benefit of irinotecan when looking at overall survival, and a marginal improvement in response rate. Yet, irinotecan is largely responsible for the toxicity of the regimen. AntiVEGF signaling drugs may increase the penetration of co-medication into tumors by reducing the intratumoral pressure and through normalization of abnormal and nonfunctional capillary networks. As a severe unwanted effect, drug penetration might be decreased by restoring the blood-brain barrier. Examples of the importance of welldesigned trials included Randomized Phase III Study of Capecitabine, Oxaliplatin, and Bevacizumab With or Without Cetuximab in Advanced Colorectal Cancer (CAIRO 2), where the use of bevacizumab in the adjuvant setting did not translate into improved outcome, and the simultaneous administration of both bevacizumab and cetuximab even seemed to be detrimental. Do we know the best timing of bevacizumab? A source of concern is the rebound edema after discontinuation of bevacizumab. Because of this, salvage therapy after failure of bevacizumab has been particularly challenging, and no drug or regimen either alone or in JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C E