Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab

Abstract

Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, a phase II trial that evaluated efficacy of bevacizumab alone or in combination with irinotecan, using the Cox regression models adjusted for age, baseline Karnofsky performance score, first vs second relapse, and treatment arm. Hazard ratios (HRs) and P-values for survival between responders and nonresponders were calculated. Additional analyses were performed to test robustness, validity, fit, and accuracy of the models. The relationships between progression-free survival (PFS) and survival and between OR and PFS were also explored. There were 55 responders and 112 nonresponders across the 2 treatment arms in BRAIN. OR status at 9, 18, and 26 weeks was a statistically significant predictor of survival (HR ≤ 0.52, P < .01). PFS was also a statistically significant predictor of survival at each landmark (HR ≤ 0.25, P < .0001). The association between OR and PFS was not statistically significant, likely due to inadequate statistical power for the analysis. Clarifying the relationship of OR and survival is important for determining whether OR can be a reliable predictor of the benefit of a therapeutic agent in patients with recurrent GBM.

The Impact of T2/FLAIR Evaluation per RANO Criteria on Response Assessment of Recurrent Glioblastoma Patients Treated with Bevacizumab

“…The value of earlier detection of nonenhancing radiographic progression needs to be evaluated in the context of residual survival benefit. While prior studies demonstrating that progression determined by the Macdonald criteria correlate with survival (6,9,20), our landmark analyses demonstrate that progression determined by RANO criteria at 2, 4, and 6 months following bevacizumab treatment also correlate with OS. Comparing the two criteria in the same analyses, however, the inclusion of T2/FLAIR evaluation in determining progression did not significantly improve or reduce the correlation of progression status with survival.…”

The role of bevacizumab in recurrent glioblastoma: new insights from randomized trials

“…These results are consistent with those reported in previous retrospective analyses in which imaging-based end points (response rate or PFS), obtained with bevacizumab were found to correlate with survival [11,12].…”

Recurrent glioblastoma: Volumetric assessment and stratification of patient survival with early posttreatment magnetic resonance imaging in patients treated with bevacizumab

“…9,24 Another phase 2 trial of bevacizumab among heavily pretreated patients with recurrent glioblastoma indicated that early response at 4 weeks based on the Levin criteria is associated with a longer PFS, whereas early response based on objective Macdonald criteria did not demonstrate the same association. 3,25 Our study indicates that early treatment response, assessed by percentage change in enhancing tumor volume before and after treatment, may serve as a predictor for both OS and PFS.…”