The lack of benefit in terms of overall survival
The lack of benefit in terms of overall survival for antiangiogenic treatment was similar when antiangiogenic drug was used both as first and second-line therapy, and both in association with cytotoxic treatment or alone. Noteworthy, a trend for an inferior outcome was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone (HR=1.24, p=0.056); indeed, in the BELOB study, patients receiving bevacizumab plus lomustine reported a longer median overall survival than patients treated with bevacizumab alone (12 versus 8 months, respectively) (Taal et al., 2014). Yet, patients treated with cediranib alone had an inferior outcome than patients treated with cediranib plus lomustine (median OS: 8 versus 9.4 months, respectively) (Batchelor et al., 2013a). This finding is consistent with data on the use of bevacizumab in other tumors such as colorecatal cancer, where bevacizumab is active only when combined with cytotoxic treatment (Giantonio et al., 2007). AVAPERL trial, a randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin and pemetrexed in advanced nonsquamous non-small-cell lung cancer, showed that bevacizumab plus pemetrexed was associated with significant outcome compared with bevacizumab alone (Barlesi et al., 2013). These combined regimens may produce additive or synergistic antitumor activity related to increased access into the tumor mass of cytotoxic drugs or to enhanced oxygen pressure, as a result of the enhanced permeability induced by antiangiogenic drugs (Gasparini et al., 2005b). Moreover, in our meta-analysis we showed that bevacizumab did not improve overall survival, neither as first nor second-line treatment. Noteworthy, in the two large randomized phase III study analyzing bevacizumab in association with Afatinib dimaleate therapy and temozolomide in newly diagnosed glioblastoma (Gilbert et al., 2014, Chinot et al., 2014), the results were negative, showing bevacizumab does not prolong OS in any subgroup (HR=1.13, 95% CI 0.93–1.37; p=0.2; HR=0.88, 95% CI 0.76–1.02; p=0.10; respectively) (Gilbert et al., 2014, Chinot et al., 2014); AVAglio enrolled 921 patients and OS showed no difference between arms (median 16.8 versus 16.7 months) but found that bevacizumab significantly prolonged PFS (10.6 versus 6.2 months, p<0.001) (Chinot et al., 2014); on the other hand, the RTOG 0825 trial enrolled 637 patients obtaining similar results with regards to OS and PFS. PFS was also extended for patients receiving bevacizumab in addition to standard treatment but this did not reach the preset level of statistical significance (Gilbert et al., 2014). On the other hand, all randomized studies analyzing bevacizumab as second-line treatment failed to demonstrate a statistically significant benefit in terms of OS (Taal et al., 2014, Brandes et al., 2014, Wick et al., 2015) (see Table 2). However, some studies suggested that early treatment with bevacizumab may be associated with a better PFS but not with superior OS and so, bevacizumab treatment may be safely delayed to a subsequent line of therapy (Schaub et al., 2016). The lack of increase in overall survival could be due to poor patient selection; indeed, no predictive biomarker for longer OS in patients treated with antiangiogenic drugs are known. Among several studies evaluating tumor tissue biomarkers, Sathornsumetee et al. showed that high expression of VEGF correlates with a longer PFS but not increased survival in patients with recurrent GBM treated with bevacizumab and irinotecan (Sathornsumetee et al., 2008). Likewise, in another prospective study of GBM, patients treated with cediranib in association with chemoradiotherapy as first line treatment, no tyrosine kinase receptors such as EGFR and PDGFR were associated with better outcome (Batchelor et al., 2013b). Similar results were shown for circulating blood biomarkers; Various studies analyzed pretreatment plasma VEGF and sVEGFR2 in patients treated with antiangiogenic drugs such as bevacizumab, cediranib, valatinib and vandetanib and found no association with outcome (Lu-Emerson et al., 2015). Labussiere et al. (Labussiere et al., 2016) observed an increase of angiotensin-2 at recurrence in patients treated with bevacizumab while no biomarker at baseline was associated with response, PFS and OS. In another two retrospective French studies, metalloproteinase 2 and metalloproteinase 9 were associated with response and survival in patients treated with bevacizumab for recurrent high-grade glioma (Tabouret et al., 2015, Tabouret et al., 2014). Moreover, several single nucleotide polymorphisms (SNP) in the VEGF and VEGFR-2 promoters were analyzed; Di Stefano et al., showed that the SNP rs2010963 is associated with longer PFS and higher risk of vascular events in recurrent GBM treated with bevacizumab (Di Stefano et al., 2015). Finally, a retrospective analysis of AVAglio data showed that only patients with IDH1 wild-type proneural glioblastoma had a longer OS (Sandmann et al., 2015). However, all currently identified markers have not been replicated from one trial to the other and so, this work remains to be done.