title: Magnitude of benefit of the addition of bevacizumab to first-line chemotherapy for metastatic colorectal cancer: meta-analysis of randomized clinical trials.
abstract: BACKGROUND
  Although the addition of bevacizumab to 1st line chemotherapy provides a significant survival benefit for advanced colorectal cancer, the magnitudes of both advantages and toxicities have not been extensively investigated.
  
  
  METHODS
  A literature-based meta-analysis was conducted; Hazard Ratios were extracted from randomized trials for primary end-points (Progression Free Survival, PFS, Overall Survival OS). The log of event-based risk ratio were derived for secondary endpoints (objective/partial response rate, ORR/PR; severe hypertension, bleeding and proteinuria). Absolute differences and the number needed to treat/harm (NNT/NNH) were calculated. A meta-regression analysis with clinical predictors and a sensitivity analysis according to the trial phase-design were conducted as well.
  
  
  RESULTS
  Five trials (2,728 pts) were selected. The addition of bevacizumab to 1st line chemotherapy significantly increased both PFS (although with significant heterogeneity) and OS over exclusive chemotherapy by 17.1% and 8.6% (NNT 6 and 12), regardless of the study setting (non significant interaction between phase II and III). The chance to improve PR was significantly increased by 6.5% (NNT 15), with a trend for ORR. The risk of hypertension was significantly increased by 6.2% (NNH 16). According to the meta-regression analysis, female gender and rectal primary site were significant predictors for PFS benefit.
  
  
  CONCLUSIONS
  Notwithstanding all the concerns related to costs and the significant HTN risk, the significant outcome improvement provided by bevacizumab in first-line treatment for unselected advanced colorectal cancer patients, should be considered when choosing the appropriate up-front therapy.
authors.affiliation: UO Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.forename: Vanja
authors.initials: V
authors.lastname: Vaccaro
authors.forename: Federica
authors.initials: F
authors.lastname: Cuppone
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.forename: Paolo
authors.initials: P
authors.lastname: Carlini
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.forename: Lisa
authors.initials: L
authors.lastname: Salvatore
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.forename: Paola
authors.initials: P
authors.lastname: Muti
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.forename: Diana
authors.initials: D
authors.lastname: Giannarelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D016032:Randomized Controlled Trials as Topic; D016879:Salvage Therapy; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab