Year: 2014
Type: article
Abstract: Bevacizumab, a humanized monoclonal antibody against the vascular endothelial growth factor (VEGF) subtype A, has been extensively used for recurrent glioblastoma and has been approved for this indication in the United States on the basis of response rates. However, there have been no randomized studies that have demonstrated a survival benefit for bevacizumab in glioblastoma. Two recent phase III trials in newly diagnosed glioblastoma failed to demonstrate an overall survival benefit when bevacizumab was added to standard chemoradiation and adjuvant temozolomide, although both studies had significant crossover of patients at tumor progression amongst those randomized initially to the placebo arm. Taal and colleagues recently reported the results of a randomized phase II trial that evaluated the impact of either bevacizumab or lomustine (an oral nitrosourea alkylating agent) or their combination. They used the 9-month survival rate as the metric, setting the threshold of 55% as an indicator of success. Of the three treatment arms, only the combined bevacizumab-lomustine regimen exceeded the preset survival rate (63%). Single-agent treatment with either bevacizumab or lomustine did not reach this preset metric with 9-month survival rates of 38% and 43%, respectively. Importantly, only one patient on the single-agent lomustine arm received salvage bevacizumab at tumor recurrence, thereby limiting the issues associated with crossover and survival analysis. The toxicity profiles were within the expected spectrum for these agents. However, an intra-study dose reduction for the lomustine on the combination arm was necessary. The original dose of 110 mg/m2 every 6 weeks proved to have too much myelotoxicty, and subsequent patients were treated at 90 mg/m2 every 6 weeks. The reported data reflect the combination of patients from both lomustine dose levels. This trial provides preliminary evidence of a survival benefit for bevacizumab in a combination regimen. However, it was not powered as a definitive phase III trial; rather, it was designed with an efficacy threshold that would permit all or, conversely, none of the treatment arms to be defined as effective. Interarm comparisons are compromised by the sample size as small differences in patient prognostic characteristics may impact outcomes. These study results did stimulate interest in a fully powered, stratified randomized trial. The currently accruing EORTC 26101 study is comparing single-agent lomustine with the combination of lomustine and bevacizumab with results anticipated by the end of 2015.
Source: Neuro-Oncology
Authors: M. Gilbert, P. Wen, D. Schiff, K. Aldape
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4248116003