Regarding progression free survival analyzing clinical
Regarding progression free-survival, analyzing 12 clinical trials, we demonstrated that the use of antiangiogenic treatment results in a statistically longer PFS with a pooled HR of 0.76 (95% CI 0.65–0.89, p<0.001). However, a high heterogeneity in the effect of antiangiogenic drugs on the hazard risk for progression-free survival was observed across studies, as confirmed by the significant test for heterogeneity (Q=58.4, p<0.001; =76.04). And so, this benefit was confirmed only for bevacizumab, both in newly diagnosed glioblastoma patients and in recurrent disease; indeed, when the analysis was limited to the 7 trials using bevacizumab as antiangiogenic agent, there was no heterogeneity (Q=15.3, p=0.06); likely, this could reflect the different antiangiogenic mechanism of bevacizumab versus the other antiangiogenic drugs. Moreover, the high heterogeneity could be due to different criteria of radiological evaluation used in the clinical trials such as, Macdonald criteria (Macdonald et al., 1990) or RANO criteria (Wen et al., 2010) or Levin criteria (Levin et al., 1977). Nevertheless, the sensitivity analysis accounting for the progression-free survival results were largely unchanged. The improvement of PFS and the lack of survival benefit regarding bevacizumab might be due to the cross over design of various studies, which allowed patients to receive salvage bevacizumab after placebo and it may have masked any potential survival advantage; indeed, a recent post-hoc, exploratory analysis examining outcomes for patients enrolled in the AVAglio trial who received only a single line of therapy suggests that the addition of bevacizumab to standard glioblastoma treatment prolongs both PFS and OS (Chinot et al., 2016). Another diacerein of improvement of PFS only is that after antiangiogenic therapy glioblastomas appear to became more aggressive: in a preclinical study, bevacizumab has been capable of inducing an invasive tumor phenotype expressing matrix metalloprotease-2 (Hartmann et al., 2010); moreover, in vivo administration of antiangiogenic drugs has been demonstrated to promote a transition from the proneural to the mesenchymal gene signature subset, having a worse prognosis (Piao et al., 2013). However, improved progression-free survival may potentially delay deterioration of neurological and cognitive functions and improve the extent of time spent with a better quality of life; in the AVAglio study, because patients receiving bevacizumab had longer progression-free periods, the median duration of stable or improved health-related quality of life was consistently longer in the bevacizumab arm versus the standard treatment (Chinot et al., 2014). The improvement of quality of life may also be due to lower corticosteroid dose and, therefore, less corticosteroid-related toxicity in patients treated with bevacizumab; indeed, studies including the AVAglio trial, have shown that bevacizumab has a steroid-sparing effect, due to improved tumor control as well as alleviation of vasogenic brain edema (Chinot et al., 2014, Jakobsen et al., 2011, Gallego Perez-Larraya et al., 2012, Corroyer-Dulmont et al., 2013). However, all these data are similar to those of a prior meta-analysis which evaluated 7 randomized clinical studies, 5 as first-line and 2 as second-line therapy (2987 patients) (Khasraw et al., 2014); we confirmed these results in a larger meta-analysis including 14 randomized studies. Moreover, in our study, a high homogeneity was observed among the studies analyzed for overall survival (Q=20.3, p=0.12; =21.2), and even in all subgroups. The future of antiangiogenic therapy remains unclear; moreover, with the advent of immunotherapy, its association with antiangiogenic drugs may be interesting for glioblastoma patients; indeed, it is hypothesized that combining immunotherapy with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments (Manegold et al., 2017). This combination remains to be validated in large trials for glioblastoma patients.