Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study

D A Reardon, A Desjardins, J J Vredenburgh, S Gururangan, J H Sampson, S Sathornsumetee, R E McLendon, J E Herndon 2nd, J E Marcello, J Norfleet, A H Friedman, D D Bigner, H S Friedman, D A Reardon, A Desjardins, J J Vredenburgh, S Gururangan, J H Sampson, S Sathornsumetee, R E McLendon, J E Herndon 2nd, J E Marcello, J Norfleet, A H Friedman, D D Bigner, H S Friedman

Abstract

Background: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial.

Methods: A total of 59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg(-1) bevacizumab biweekly and 50 mg m(-2) etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2alpha (HIF-2alpha) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome.

Results: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade > or = 3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism.

Conclusion: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).

Figures

Figure 1
Figure 1
Kaplan–Meier plots of progression-free survival (A) and overall survival (B) for grade 3 malignant glioma and glioblastoma patients.
Figure 2
Figure 2
Baseline and post-treatment magnetic resonance imaging of a representative, responding glioblastoma patient including post-contrast axial T1-weighted and fluid-attenuated inversion recovery (FLAIR) images. [18F]fluorodeoxyglucose positron-emission tomography imaging at the completion of 12 cycles of therapy shows no evidence of hypermetabolic activity (arrow). (A) Baseline and off-study magnetic resonance imaging showing worsened FLAIR signal abnormality, indicating an infiltrative, microscopic pattern of treatment failure (arrows) involving the isolateral hemisphere (B) and the contralateral hemisphere (C), despite improved contrast enhancement.

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