Treatment of Glioblastoma with Bevacizumab

Bevacizumab (Avastin ; Genentech/Roche, South SanFrancisco, CA,USA/Basel, Switzerland), a molecularly targeted monoclonal antibody recently approved by the US FDA for recurrent glioblastoma (GBM), presents new challenges and opportunities with respect to the treatment of these invariably fatal brain cancers. The majority of data regarding bevacizumab use in GBM is for recurrent disease, for which the drug is indicated as a single agent; however, there are now two published single-centre trials of bevacizumab use in the up-front setting for newly diagnosed GBM, as well as two large, randomized, phase III trials of up-front treatment that have been completed but not yet reported. Consequently, the scheduling of bevacizumab in the treatment of GBM is controversial, with advocates of early up-front treatment and others recommending, alternatively, delayed treatment at time of GBM recurrence. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) humanized monoclonal antibody, represents the most successful clinical application of angiogenic inhibition. All cancers require tumour-directed angiogenesis to grow beyond several microns in diameter and it was postulated many years ago by Folkman that cancers required engagement of a so-called ‘angiogenic switch’ in order to become mass-producing lesions with attendant invasion and metastasis. It was further postulated that therapy directed at cancer angiogenesis would prove of considerable utility in the treatment of cancer by blocking angiogenesis and thereby inhibiting tumour growth. These postulates have been clinically realized using agents that inhibit the VEGF signalling pathway, either by targeting the VEGF ligand (e.g. bevacizumab or aflibercept [VEGF trap]) or the VEGF receptor (e.g. the tyrosine kinase inhibitors sorafenib and sunitinib and the VEFG receptor monoclonal antibody ramucirumab). Interestingly, and with few exceptions, anti-angiogenic therapies have proven most successful when combined with chemotherapy, so-called chemosynergy. GBM is amongst the most vascular of all cancers as judged by microvascular density as well as tumour VEGF content. Consequently, angiogenic inhibition appeared a rational target for the treatment of GBM. However, because clinical experience with bevacizumab in other solid cancers (lung and colorectal, in particular) demonstrated intratumoural haemorrhage (1–2% incidence), a reluctance to use bevacizumab for brain tumours ensued. Notwithstanding this concern, Stark-Vance first used bevacizumab in combination with irinotecan (using a drug combination commonly used for colorectal cancer) for recurrent high-grade gliomas (GBM and anaplastic gliomas) in a small case series and reported remarkable radiographic response rates (40%) as well as 6-month progression-free survival (40%), prompting multiple studies of bevacizumab in recurrent GBM. Subsequently, the two GBM studies most often cited regarding bevacizumab for recurrent GBM is that of the Genentechsponsored, non-comparator randomized trial of bevacizumab with or without irinotecan (the socalled BRAIN trial) and that of the National EDITORIAL CNS Drugs 2011; 25 (10): 815-818 1172-7047/11/0010-0815/$49.95/0