A Meta-Analysis of Survival Outcomes Following Reoperation in Recurrent Glioblastoma: Time to Consider the Timing of Reoperation

Yu-Hang Zhao, Ze-Fen Wang, Zhi-Yong Pan, Dominik Péus, Juan Delgado-Fernandez, Johan Pallud, Zhi-Qiang Li, Yu-Hang Zhao, Ze-Fen Wang, Zhi-Yong Pan, Dominik Péus, Juan Delgado-Fernandez, Johan Pallud, Zhi-Qiang Li

Abstract

Background: Glioblastoma multiforme (GBM) inevitably recurs, but no standard regimen has been established for recurrent patients. Reoperation at recurrence alleviates mass effects, and the survival benefit has been reported in many studies. However, in most studies, the effect of reoperation timing on survival benefit was ignored. The aim of this meta-analysis was to investigate whether reoperation provided similar survival benefits in recurrent GBM patients when it was analyzed as a fixed or time-dependent covariate. Methods: A systematic literature search of PubMed, EMBASE, and Cochrane databases was performed to identify original articles that evaluated the associations between reoperation and prognosis in recurrent GBM patients. Results: Twenty-one articles involving 8,630 patients were included. When reoperation was considered as a fixed covariate, it was associated with better overall survival (OS) and post-progression survival (PPS) (OS: HR = 0.66, 95% CI 0.61-0.71, p < 0.001, I 2 = 0%; PPS: HR = 0.70, 95% CI 0.57-0.88, p < 0.01, I 2 = 70.2%). However, such a survival benefit was not observed when reoperation was considered as a time-dependent covariate (OS: HR = 2.19, 95% CI 1.47-3.27, p < 0.001; PPS: HR = 0.95, 95% CI 0.82-1.10, p = 0.51, I 2 = 0%). The estimate bias caused by ignoring the time-dependent nature of reoperation was further demonstrated by the re-analysis of survival data in three included studies. Conclusions: The timing of reoperation may have an impact on the survival outcome in recurrent GBM patients, and survival benefits of reoperation in recurrent GBM may be overestimated when analyzed as fixed covariates. Proper analysis methodology should be used in future work to confirm the clinical benefits of reoperation.

Keywords: glioblastoma; recurrence; reoperation; survival; time-dependent covariate.

Figures

Figure 1
Figure 1
PRISMA flow diagram of study selection.
Figure 2
Figure 2
Forest plots showing pooled results of overall survival analysis in recurrent patients with vs without reoperation (A) and when reoperation was considered as a fixed covariate vs. as a time-dependent covariate (B).
Figure 3
Figure 3
Survival curve plotted by the Kaplan-Meier and landmark methods. The survival data from the studies of Woernle et al. (25) (A), Zanello et al. (15) (B), and Delgado-Fernandez et al. (12) (C) were reanalyzed by the Kaplan-Meier (left) and landmark methods (middle and right). The Kaplan-Meier curve started at the initial diagnosis (left), and the landmark curve started at the 50th percentile (middle) and 75th percentile (right) of time between first and second surgery. In the landmark method, patients were considered to have reoperation if their reoperation occurred by the landmark time and were considered to not have reoperation if they did not undergo reoperation or their reoperation occurred after the landmark time.
Figure 4
Figure 4
Forest plots showing pooled results of post-progression survival analysis in patients with vs. without reoperation (A) and when reoperation was considered as a fixed covariate vs. as a time-dependent covariate (B).
Figure 5
Figure 5
Forest plots for post-progression survival analysis when accounting for vs. not accounting for the time to first recurrence.
Figure 6
Figure 6
Forest plots for post-progression survival analysis in patients undergoing reoperation after earlier recurrence vs. later recurrence.

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