Is deferred use of bevacizumab for glioblastoma associated with prolonged survival?

Abstract

We read with great interest the article by Piccioni et al1 which fostered the ongoing debate on the role of bevacizumab in patients with glioblastoma multiforme (GBM). After the failure of the phase III trials evaluating the upfront administration of bevacizumab in newly diagnosed GBM,2,3 the neuro-oncology community worldwide is trying to assess whether this drug is effective in selected subpopulations and what is the most appropriate timing for starting the treatment.4 This latest issue was faced by Piccioni et al1 who examined retrospectively a cohort of 468 GBM patients treated with bevacizumab at different points of the natural history of the disease: upfront (n = 80), at first recurrence (n = 264), at second recurrence (n = 88), and at third recurrence (n = 36). Their elegant statistical analysis was focused firstly on recurrent GBM: comparing the 3 groups, the authors found that progression-free survival (PFS) and overall survival (OS) from bevacizumab initiation were not different, that is, PFS and OS were independent from the time in which treatment was started. Therefore, their conclusion was that deferring the use of bevacizumab at later recurrences is not detrimental. Moreover, extending the analysis to the group of patients treated with bevacizumab upfront, the authors found no differences in the survival time after bevacizumab failure, suggesting that there is no effective treatment for GBM recurrence after bevacizumab treatment. One major issue in that work is the lack of data on OS from the diagnosis of GBM. Looking at median age of recurrent GBM patients, in fact, we noticed that time from diagnosis to the start of bevacizumab therapy was 0.8, 1.4, and 2.1 years in the groups treated at first, second, and third recurrence, respectively. As a consequence, being that OS from the start of bevacizumab therapy statistically was not different among the 3 groups, delaying bevacizumab treatment should have resulted in a prolonged OS from diagnosis; and in fact this was the finding of another recently published work.5 Data about the comparison of OS from diagnosis between patients treated with bevacizumab upfront and patients treated with bevacizumab at recurrence were also missing: having shown the post-bevacizumab survival for the whole study cohort, it is arguable that these data could have been easily derived by the authors. We recognize that probably the authors aimed at not overestimating the results of their study, due to its retrospective design. However, we believe that these data could contribute to the ongoing debate, also influencing the design of future clinical trials and orienting clinical decision making. In conclusion, we think that this is a significant issue to be addressed.