title: Magnitude of risks and benefits of the addition of bevacizumab to chemotherapy for advanced breast cancer patients: Meta-regression analysis of randomized trials.
abstract: BACKGROUND
  Although the addition of bevacizumab significantly improves the efficacy of chemotherapy for advanced breast cancer, regulatory concerns still exist with regard to the magnitude of the benefits and the overall safety profile.
  
  
  METHODS
  A literature-based meta-analysis to quantify the magnitude of benefit and safety of adding bevacizumab to chemotherapy for advanced breast cancer patients was conducted. Meta-regression and sensitivity analyses were also performed to identify additional predictors of outcome and to assess the influence of trial design.
  
  
  RESULTS
  Five trials (3,841 patients) were gathered. A significant interaction according to treatment line was found for progression-free survival (PFS, p = 0.027); PFS was significantly improved for 1(st) line (Hazard Ratio, HR 0.68, p < 0.0001), with a 1-yr absolute difference (AD) of 8.4% (number needed to treat, NNT 12). A non-significant trend was found in overall survival (OS), and in PFS for 2(nd) line. Responses were improved with the addition of bevacizumab, without interaction between 1(st) line (Relative Risk, RR 1.46, p < 0.0001) and 2(nd) line (RR 1.58, p = 0.05). The most important toxicity was hypertension, accounting for a significant AD of 4.5% against bevacizumab (number needed to harm, NNH 22). Other significant, although less clinically meaningful, adverse events were proteinuria, neurotoxicity, febrile neutropenia, and bleeding. At the meta-regression analysis for 1(st)-line, more than 3 metastatic sites (p = 0.032), no adjuvant chemotherapy (p = 0.00013), negative hormonal receptor status (p = 0.009), and prior anthracyclines-exposure (p = 0.019), did significantly affect PFS.
  
  
  CONCLUSIONS
  Although with heterogeneity, the addition of bevacizumab to 1st-line chemotherapy significantly improves PFS, and overall activity. Hypertension should be weighted with the overall benefit on the individual basis.
authors.affiliation: Department of Medical Oncology, Regina Elena National Cancer Institute, Roma, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Cuppone
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.forename: Vanja
authors.initials: V
authors.lastname: Vaccaro
authors.forename: Fabio
authors.initials: F
authors.lastname: Puglisi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fabi
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.forename: Paolo
authors.initials: P
authors.lastname: Carlini
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nisticò
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Russillo
authors.forename: Paola
authors.initials: P
authors.lastname: Papaldo
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Ferretti
authors.forename: Matti
authors.initials: M
authors.lastname: Aapro
authors.forename: Diana
authors.initials: D
authors.lastname: Giannarelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D005260:Female; D006801:Humans; D009367:Neoplasm Staging; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068258:Bevacizumab