Simple SummaryGiven the lack of effective second-line oncotherapy and clear recommendations for surgery for regrowing tumors, the optimal treatment strategy for recurrent glioblastoma (GBM) remains controversial. We strove to identify patients with GBM who achieved survival benefits from repeated surgery, based on reoperation time. A positive but insignificant effects on postsurgical survival were found in univariate analyses for surgery that took place 6 to 16 months after diagnosis. In multivariate analyses, surgical efficacy was insignificant in the range of 6 to 24 months. Significant efficacy was proven for surgery in the 16th month after diagnosis in univariate analyses and in the 22nd month in multivariate analyses. Based on our results, the best outcomes yielded GBM reoperation in the following period after the 16th month of progression, and its efficacy increased up to the 22th month. Reoperations performed less than 6 months after diagnosis, when the tumors had progressed following oncotherapy, had no impact on survival.AbstractGlioblastoma inevitably recurs, but no standard regimen has been established for treating this recurrent disease. Several reports claim that reoperative surgery can improve survival, but the effects of reoperation timing on survival have rarely been investigated. We, therefore, evaluated the relationship between reoperation timing and survival in recurrent GBM. A consecutive cohort of unselected patients (real-world data) from three neuro-oncology cancer centers was analyzed (a total of 109 patients). All patients underwent initial maximal safe resection followed by treatment according to the Stupp protocol. Those meeting the following criteria during progression were indicated for reoperation and were further analyzed in this study: (1) The tumor volume increased by >20–30% or a tumor was rediscovered after radiological disappearance; (2) The patient’s clinical status was satisfactory (KS ≥ 70% and PS WHO ≤ gr. 2); (3) The tumor was localized without multifocality; (4) The minimum expected tumor volume reduction was above 80%. A univariate Cox regression analysis of postsurgical survival (PSS) revealed a statistically significant effect of reoperation on PSS from a threshold of 16 months after the first surgery. Cox regression models that stratified the Karnofsky score with age adjustment confirmed a statistically significant improvement in PSS for time-to-progression (TTP) thresholds of 22 and 24 months. The patient groups exhibiting the first recurrence at 22 and 24 months had better survival rates than those exhibiting earlier recurrences. For the 22-month group, the HR was 0.5 with a 95% CI of (0.27, 0.96) and ap-value of 0.036. For the 24-month group, the HR was 0.5 with a 95% CI of (0.25, 0.96) and ap-value of 0.039. Patients with the longest survival were also the best candidates for repeated surgery. Later recurrence of glioblastoma was associated with higher survival rates after reoperation.