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

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.

Application of an Artificial Intelligence Algorithm to Prognostically Stratify Grade II Gliomas

“…The favorable influence on outcome of second surgery at relapse, recently suggested by van den Bent's group [16], seems to be confirmed in our independent case series and extends the indications for second surgery, so far limited to improving the control of the epileptogenic outcome and obtaining a histological assessment of the possible glioma progression [32][33][34][35][36][37][38][39][40][41][42]. A recent meta-analysis of survival outcomes following reoperation in recurrent glioblastoma suggested a possible overestimation of the positive effects of the second surgery on patient outcomes when reoperation is considered a fixed variable [43]. Although our patient population consisted of LGG patients, it would be useful in the future to evaluate the opportunity of exploring the clinical benefits of reoperation, considering this covariate both as time-dependent or fixed.…”

A Novel Comprehensive Clinical Stratification Model to Refine Prognosis of Glioblastoma Patients Undergoing Surgical Resection

“…The recurrence of GBM is inevitable, in which management often tend to be unclear and case-dependent. Although re-radiation, re-resection, bevacizumab, and chemotherapy are still the most widely used therapies for treating recurrent GBM, the clinical benefit from these treatments is still not well established [46][47][48][49][50].…”

Carmustine as a Supplementary Therapeutic Option for Glioblastoma: A Systematic Review and Meta-Analysis

“…However, the tumor inevitably recurs, and standardized strategies for the treatment of recurrent glioma are lacking. The evidences of a favorable outcome regarding re-resection and re-irradiation are still poor (3). Therefore, systemic chemotherapy has been explored as a prospective option for glioma.…”

“…Carmustine wafer implantation in GBM patients undergoing surgical resection is also thought to provide a therapeutic bridge during the period between surgical resection and onset of radiotherapy (6). Previous research assessing the effectiveness of carmustine wafer has found a significant increase in overall survival (OS) by 2-4 months in newly diagnosed GBM patients (3). Although the efficacy of carmustine administration is established in seminal trials, its safety remains controversial.…”