title: 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 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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Department of Surgery, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Box 3624, Durham, NC 27710, USA. reard003@mc.duke.edu
authors.forename: D A
authors.initials: DA
authors.lastname: Reardon
authors.forename: A
authors.initials: A
authors.lastname: Desjardins
authors.forename: J J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: S
authors.initials: S
authors.lastname: Gururangan
authors.forename: J H
authors.initials: JH
authors.lastname: Sampson
authors.forename: S
authors.initials: S
authors.lastname: Sathornsumetee
authors.forename: R E
authors.initials: RE
authors.lastname: McLendon
authors.forename: J E
authors.initials: JE
authors.lastname: Herndon
authors.forename: J E
authors.initials: JE
authors.lastname: Marcello
authors.forename: J
authors.initials: J
authors.lastname: Norfleet
authors.forename: A H
authors.initials: AH
authors.lastname: Friedman
authors.forename: D D
authors.initials: DD
authors.lastname: Bigner
authors.forename: H S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000032:analysis; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D017211:Treatment Failure; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D005047:Etoposide