title: Effectiveness of antiangiogenic drugs in glioblastoma patients: A systematic review and meta-analysis of randomized clinical trials.
abstract: BACKGROUND
  glioblastomas are highly vascularized tumors and various antiangiogenic drugs have been investigated in clinical trials showing unclear results. We performed a systematic review and a meta-analysis to clarify and evaluate their effectiveness in glioblastoma patients.
  
  
  METHODS
  we searched relevant published and unpublished randomized clinical trials analyzing antiangiogenic drugs versus chemotherapy in glioblastoma patients from January 2006 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases.
  
  
  RESULTS
  fourteen randomized clinical trials were identified (7 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) including 4330 patients. Antiangiogenic drugs showed no improvement in overall survival with a pooled HR of 1.00, a trend for an inferior outcome, in terms of overall survival, was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone (HR=1.24, p=0.056). Bevacizumab did not improve overall survival. Twelve trials (4113 patients) were analyzed for progression-free survival. Among antiangiogenic drugs, only bevacizumab demonstrated an improvement of progression-free survival (HR=0.63, p<0.001), both alone (HR=0.60, p=0.003) or in combination to chemotherapy (HR=0.63; p<0.001), both as first-line treatment (HR=0.70, p<0.001) or in recurrent disease (HR=0.52, p<0.001).
  
  
  CONCLUSIONS
  antiangiogenic drugs did not improve overall survival in glioblastoma patients, either as first or second-line treatment, and either as single agent or in combination with chemotherapy. Among antiangiogenic drugs, only bevacizumab improved progression-free survival regardless of treatment line, both as single agent or in combination with chemotherapy.
authors.affiliation: Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology, IOV - IRCCS, Padua, Italy. Electronic address: giuseppe.lombardi@ioveneto.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lombardi
authors.affiliation: Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology, IOV - IRCCS, Padua, Italy.
authors.forename: Ardi
authors.initials: A
authors.lastname: Pambuku
authors.affiliation: Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology, IOV - IRCCS, Padua, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Bellu
authors.affiliation: Clinical Trials and Biostatistics Unit, Veneto Institute of Oncology, IOV - IRCCS, Padua, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Farina
authors.affiliation: Neurosurgery Department, Azienda Ospedaliera di Padova, Padua, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Della Puppa
authors.affiliation: Neurosurgery Department, University of Padua, Padua, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Denaro
authors.affiliation: Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology, IOV - IRCCS, Padua, Italy.
authors.forename: Vittorina
authors.initials: V
authors.lastname: Zagonel
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D018572:Disease-Free Survival; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D016032:Randomized Controlled Trials as Topic
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents
keywords: Antiangiogenic drugs; Bevacizumab; Chemotherapy; Glioblastoma