Various antiangiogenic drugs have been

Various antiangiogenic drugs have been analyzed over the last few years; noteworthy, bevacizumab, a monoclonal antibody against VEGF-A, alone or in combination with cytotoxic agents showed interesting results in terms of radiographic response rates and progression-free survival in initial phase 2 studies (Friedman et al., 2009, Kreisl et al., 2009, Vredenburgh et al., 2007); however, these studies lacked a non-bevacizumab-containing comparator arm and overall survival was not prolonged compared to historical data. More recently, a randomized three-arm phase 2 study (BELOB) examined bevacizumab alone versus lomustine alone versus bevacizumab plus lomustine in recurrent glioblastoma (Taal et al., 2014) showing the best results for the combination arm; indeed, the 9-month overall survival rate was 38% in patients treated with bevacizumab alone, 43% in lomustine alone, 88% in lomustine with bevacizumab. GLARIUS trial evaluated the combination of bevacizumab and irinotecan versus standard temozolomide in newly diagnosed, MGMT unmethylated glioblastoma patients; this study demonstrated a longer progression-free survival with bevacizumab and irinotecan (Herrlinger et al., 2014). Notwithstanding, two subsequent randomized, placebo-controlled phase 3 trials of bevacizumab with chemoradiotherapy in patients with newly diagnosed glioblastoma showed a longer progression-free survival with bevacizumab but failed to demonstrate an improvement in overall survival (Gilbert et al., 2014, Chinot et al., 2014). Cediranib, a VEGFR TKI, and enzastaurin, an inhibitor of protein kinase C beta, also failed to demonstrate any benefit in overall survival in recurrent glioblastoma in two phase III trials. Cilengitide, an integrin receptor inhibitor, has an important and complex influence on tumor cell survival enhancing neoplastic apoptosis and blocking integrin-mediated angiogenesis and tumor migration, since integrins are widely expressed by both glioblastoma Cy3 azide and endothelial cells in tumor-associated vasculature (Gasparini et al., 2005a). Cilengitide demonstrated a modest improvement in overall survival and progression-free survival in a phase II study (CORE) (Nabors et al., 2015) enrolling patients with newly diagnosed glioblastoma with an unmethylated MGMT gene promoter, while in a phase III trial (CENTRIC) (Stupp et al., 2014) evaluating patients with newly diagnosed glioblastoma and methylated MGMT, it showed a trend for benefit in terms of overall survival. Various other drugs such as, dasatinib, vandetanib and temsirolimus were analyzed in randomized studies (Laack et al., 2015, Lee et al., 2015, Wick et al., 2010).
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Discussion Glioblastoma is the most common primary malignant brain tumor in adults and despite the use of maximal safe surgical resection, radiation therapy and alkylating agents as treatment, its prognosis still remains poor. Glioblastomas are highly vascular tumors; in particular, they have a high expression of vascular endothelial growth factor (Fischer et al., 2005). Thus, glioblastoma has emerged as an attractive tumor in which to conduct clinical trials of anti-VEGF agents such as monoclonal antibodies and tyrosine kinase inhibitors. Bevacizumab efficacy was tested in various randomized trials both as first and second-line therapy with contradictory results in terms of overall survival and progression-free survival. Other antiangiogenic drugs such as, cediranib and valatinib (VEGF receptor tyrosine kinase inhibitors), cilengitide (targeting integrins αvβ3, αvβ5 and α5β1), dasatinib (PDGF receptor tyrosine kinase inhibitor), temsirolimus (mTOR inhibitor) and enzastaurine (protein kinase C inhibitor) were studied in various randomized clinical trials. We showed, through the analysis of 14 clinical trials, that antiangiogenic treatment did not improve overall survival compared to standard cytotoxic treatment (HR=1.00, 95% CI 0.92–1.1; p=0.9); in particular, of all the trials evaluated, a single phase II trial suggested a survival benefit in favour of treatment with an antiangiogenic agent (Cilengitide; HR=0.69, 95% CI 0.48–0.97; p=0.039) (Nabors et al., 2015).