Bevacizumab versus alkylating chemotherapy in recurrent glioblastoma



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.


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.


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).


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.

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The authors would like to thank the patients and their families and acknowledge the contributions of all health care providers involved in the care of the patients.


There was no funding for the current study. The German Glioma Network was supported by the Deutsche Krebshilfe.

Author information

KS, SL, DG, UH, MaW, GS, NT, US, MT, WW contributed patient data, KS, BH and MiW wrote the manuscript, BH performed statistical analyses, GR, FL and TP were involved in molecular analysis of tumors for a subset of patients. MiW designed the project and supervised the study. All authors discussed the results and reviewed the manuscript.

Correspondence to Katharina Seystahl.

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Conflict of interest

KS has received honoraria for board participation from Roche. GR has received honoraria from advisory boards from Abbvie. UH reports grants and personal fees from Roche, personal fees and non-financial support from Medac, personal fees and non-financial support from Bristol-Myers Squibb, personal fees from Novocure, personal fees from Novartis, personal fees from Daichii-Sankyo, personal fees from Riemser, personal fees from Noxxon, personal fees from AbbVie, personal fees from Bayer. MiW has received research grants from Abbvie, Adastra, Dracen, Merck, Sharp & Dohme (MSD), Merck (EMD), Novocure, Piqur and Roche, and honoraria for lectures or advisory board participation or consulting from Abbvie, Basilea, Bristol Meyer Squibb (BMS), Celgene, Merck, Sharp & Dohme (MSD), Merck (EMD), Novocure, Orbus, Roche and Tocagen. The other authors report no conflicts of interest.

Availability of data and material

The datasets of the study are available from the corresponding author on reasonable request and provided that the request is in line with the regulations of the review committees.

Ethical approval

This study was approved by the responsible review committees of the participating centers of the German Glioma Network in Germany ( (353/2003 V) and the University Hospital Zurich, Switzerland (2015-0437). The study was performed in accordance with the Declaration of Helsinki.

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Seystahl, K., Hentschel, B., Loew, S. et al. Bevacizumab versus alkylating chemotherapy in recurrent glioblastoma. J Cancer Res Clin Oncol (2019) doi:10.1007/s00432-019-03086-9

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  • Chemotherapy
  • Temozolomide
  • Nitrosourea
  • Bevacizumab
  • Glioblastoma