The Efficacy and Safety of Adding Teniposide to Temozolomide Plus Bevacizumab in Recurrent Grade 4 Glioma: A Real-World Exploratory Single-Center Study.

Background: Salvage options for recurrent grade 4 glioma (GBM) remain limited and no single standard of care has been established after recurrence. Teniposide (VM-26) has been reintroduced into clinical practice, but its benefit when added to temozolomide (TMZ) plus bevacizumab (Bev) in recurrent grade 4 glioma remains unclear. Methods: This single-center, real-world exploratory study retrospectively enrolled 53 patients with recurrent grade 4 glioma who received either teniposide plus TMZ and Bev (VM26 + TMZ + Bev, n = 26) or TMZ plus Bev (TMZ + Bev, n = 27). The control group combined patients treated before teniposide became available again in China (2020-2022) with those treated concurrently with the triplet (2023-2026). Safety was assessed using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0; tumor response was evaluated according to the Response Assessment in Neuro-Oncology (RANO) criteria on an intention-to-treat basis, and survival was estimated by the Kaplan-Meier method. Results: Median progression-free survival (PFS) was 7.8 months (95% confidence interval (CI), 4.9-10.9) in the VM26 + TMZ + Bev group versus 5.1 months (95% CI, 4.4-6.8) in the TMZ + Bev group (log-rank p = 0.037; unadjusted hazard ratio (HR) 0.50, 95% CI, 0.25-0.97), and median overall survival (OS) was 12.7 months (95% CI, 8.4-15.4) versus 8.5 months (95% CI, 7.3-9.7) (log-rank p = 0.042; unadjusted HR 0.47, 95% CI, 0.23-0.98). Multivariable adjustment strengthened these estimates, whereas propensity score weighting and matching gave estimates of the same direction that did not reach significance. The objective response rate (ORR) was 26.9% (7/26) versus 14.8% (4/27) (p = 0.327) and the disease control rate (DCR) was 80.8% versus 77.8% (p = 1.000). Grade ≥ 3 adverse events (AEs) occurred in 11.5% versus 7.4% of patients (p = 0.669); leukopenia and neutropenia were more frequent with teniposide (26.9% vs. 3.7%; p = 0.024) but lost significance after Benjamini-Hochberg correction (q = 0.122). No unexpected toxicity types were observed, although any-grade leukopenia and neutropenia were more frequent with teniposide and should be anticipated in clinical use. Conclusions: In this exploratory real-world cohort, adding teniposide to TMZ plus Bev was associated with longer PFS and OS and a numerically higher ORR, without a significant increase in grade ≥ 3 toxicity, although any-grade leukopenia and neutropenia were more frequent and should be anticipated; however, treatment era could not be fully separated from treatment effect: in an era-matched analysis restricted to the concurrently treated cohorts, the direction of the effect was preserved but did not reach significance. The survival differences rested on a small number of events and were not robust to reclassification of individual patient outcomes. These findings warrant confirmation in prospective randomized studies.