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

Abstract

BACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg À1 bevacizumab biweekly and 50 mg m À2 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-2a (HIF-2a) 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 X3 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).

Therapeutic options in recurrent glioblastoma—An update

“…PFS-6 rates ranged between 28 and 50.3% and median OS between 6.7 and 9.7 months. Other experimental agents that were combined with bevacizumab are etoposide [98], the mTOR inhibitor temsirolimus [99], the EGFR-targeted tyrosine kinase inhibitor erlotinib [100], the multikinase inhibitor sorafenib [101], the histone deacetylase inhibitors panobinostat [102] or vorinostat [103].…”

Bevacizumab and glioblastoma: Scientific review, newly reported updates, and ongoing controversies

“…Several phase 2 trials of bevacizumab-based combinations have also been reported for recurrent glioblastoma (Table 1), 27,28,32, including bevacizumab with irinotecan, irinotecan plus cetuximab, irinotecan plus carboplatin, etoposide, fotemustine, sorafenib, temozolomide, erlotinib, and temsirolimus. 27,28,32,[38][39][40][41][42][43][44][45][46][47] In addition, several retrospective studies have also been reported combining bevacizumab and irinotecan; carboplatin; carboplatin and cetuximab; carboplatin, etoposide, and ifosfamide; lomustine; carmustine; etoposide; or temozolomide. [48][49][50][51][52][53][54][55][56][57][58] Although these small studies are not easily compared due to their size and various patient populations, the consensus to date has been that no combination significantly surpasses the outcomes of bevacizumab monotherapy for recurrent glioma.…”

An algorithm for chemotherapy treatment of recurrent glioma patients after temozolomide failure in the general oncology setting

“…Addition of metronomic etoposide in bevacizumab treated patients with recurrent glioma had no additional benefit compared to bevacizumab alone but resulted in increased toxicity [71].…”