Bevacizumab versus alkylating chemotherapy in recurrent glioblastoma

Abstract

Background: The use of alkylating chemotherapy versus bevacizumab for recurrent glioblastoma remains controversial. Here, we tested the hypothesis that the activity of alkylators, but not that of bevacizumab, would be associated with the O⁶-methylguanine DNA methyltransferase (MGMT) promoter methylation status.

Methods: We analyzed a cohort of patients treated at centers of the German Glioma Network or the University Hospital Zurich with alkylating agent-based chemotherapy (n = 260) or bevacizumab without or with irinotecan (n = 84) for first recurrence of glioblastoma. Outcome was stratified for O⁶-methylguanine DNA methyltransferase (MGMT) status and crossover to bevacizumab or alkylators at further progression.

Results: Median post-recurrence survival-1 (PRS-1) for patients receiving alkylating agents at first recurrence was longer than with bevacizumab (11.1 versus 7.4 months, p < 0.001). The use of alkylators was associated with longer PRS-1 for patients with a methylated versus unmethylated MGMT promoter (p = 0.017). For patients receiving bevacizumab, PRS-1 was not different with or without MGMT promoter methylation. PRS-1 was longer in patients receiving alkylating chemotherapy compared to bevacizumab for patients with methylated (p < 0.001) or unmethylated MGMT promoter (p = 0.034). For patients with alkylators at first recurrence receiving bevacizumab at any further recurrence, PRS-1 was longer than in patients receiving bevacizumab first and alkylators thereafter (p = 0.002).

Conclusions: This study confirms limited value of bevacizumab in recurrent glioblastoma independent of MGMT status. Alkylating agents have activity in recurrent glioblastoma, especially in the context of MGMT promoter methylation.

Keywords: Bevacizumab; Chemotherapy; Glioblastoma; Nitrosourea; Temozolomide.

Fig. 1

Outcome stratified for treatment at first recurrence. Outcome for the entire patient cohort (left) or the subgroup of patients with known IDH status and exclusion of patients with IDH-mutant tumors (right) treated with alkylating agents (blue curve) or bevacizumab alone or in combination with irinotecan (red curve) at first recurrence: Post-recurrence survival-1 (PRS-1) (a, b), progression-free survival from initial diagnosis (PFS-1) (c, d), overall survival (OS) from initial diagnosis (e, f), and median PFS-1 and median PRS-1 (g, h)

Fig. 2

Outcome stratified by treatment and MGMT status. Outcome data for the entire patient cohort (left) or the subgroup of patients with known IDH status and exclusion of patients with IDH-mutant tumors (right) treated at first recurrence with either alkylating agents (blue curves) or bevacizumab (red curves) stratified for methylated (continuous line) or unmethylated (dashed line) MGMT promoter: post-recurrence survival-1 (PRS-1) (a, b), progression-free survival from initial diagnosis (PFS-1) (c, d), overall survival (OS) from initial diagnosis (e, f), and median PFS-1 and median PRS-1 (g, h)

Fig. 3

Outcome stratified for further salvage therapies. Outcome data for the entire patient cohort (left) or the subgroup of patients with known IDH status and exclusion of patients with IDH-mutant tumors (right) treated at first recurrence with alkylating agents followed by a bevacizumab-containing regimen at any further recurrence (blue continuous line) or never received bevacizumab at any further salvage therapy (blue dashed line) or treated with a bevacizumab-containing regimen at first recurrence followed by treatment with alkylators at any further recurrence (red continuous line) or never receiving alkylators at any further salvage therapy (red dashed curve): post-recurrence survival-1 (PRS-1) (a, b), progression-free survival from initial diagnosis (PFS-1) (c, d), overall survival (OS) from initial diagnosis (e, f), median PFS-1 and median PRS-1 (g, h). In the subgroup of patients receiving further systemic therapy after second recurrence, median PFS-1, median time from initiation of systemic treatment for first recurrence until the initiation of any salvage therapy for second recurrence (PFS-2) and survival from systemic treatment for second recurrence to death (PRS-2) was also assessed (i, j)