title: A Systematic Review and Network Meta-Analysis of Biologic Agents in the First Line Setting for Advanced Colorectal Cancer.
abstract: BACKGROUND
  Epithelial growth factor receptor inhibitors (EGFRis) and bevacizumab (BEV) are used in combination with chemotherapy for the treatment of metastatic colorectal cancer (mCRC). However, few randomized controlled trials (RCTs) have directly compared their relative efficacy on progression-free survival (PFS) and overall survival (OS).
  
  
  METHODS
  We conducted a systematic review of first-line RCTs comparing (1) EGFRis vs. BEV, with chemotherapy in both arms (2) EGFRis + chemotherapy vs. chemotherapy alone, or (3) BEV + chemotherapy vs. chemotherapy alone, using Cochrane methodology. Data on and PFS and OS were extracted using the Parmar method. Pairwise meta-analyses and Bayesian network meta-analyses (NMA) were conducted to estimate the direct, indirect and combined PFS and OS hazard ratios (HRs) comparing EGFRis to BEV.
  
  
  RESULTS
  Seventeen RCTs contained extractable data for quantitative analysis. Combining direct and indirect data using an NMA did not show a statistical difference between EGFRis versus BEV (PFS HR = 1.11 (95% CR: 0.92-1.36) and OS HR = 0.91 (95% CR: 0.75-1.09)). Direct meta-analysis (3 RCTs), indirect (14 RCTs) and combined (17 RCTs) NMA of PFS HRs were concordant and did not show a difference between EGFRis and BEV. Meta-analysis of OS using direct evidence, largely influenced by one trial, showed an improvement with EGFRis therapy (HR = 0.79 (95% CR: 0.65-0.98)), while indirect and combined NMA of OS did not show a difference between EGFRis and BEV Successive inclusions of trials over time in the combined NMA did not show superiority of EGFRis over BEV.
  
  
  CONCLUSIONS
  Our findings did not support OS or PFS benefits of EGFRis over BEV in first-line mCRC.
authors.affiliation: Faculty of Medicine, University of Toronto, Toronto Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kumachev
authors.affiliation: Faculty of Medicine, University of Toronto, Toronto Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Yan
authors.affiliation: Faculty of Medicine, University of Toronto, Toronto Canada; Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: Berry
authors.affiliation: Faculty of Medicine, University of Toronto, Toronto Canada; Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Canada.
authors.forename: Yoo-Joung
authors.initials: YJ
authors.lastname: Ko
authors.affiliation: Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Canada.
authors.forename: Maria C R
authors.initials: MC
authors.lastname: Martinez
authors.affiliation: Faculty of Medicine, Queens University, Kingston, Canada.
authors.forename: Keya
authors.initials: K
authors.lastname: Shah
authors.affiliation: Faculty of Medicine, University of Toronto, Toronto Canada; Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Canada; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
authors.forename: Kelvin K W
authors.initials: KK
authors.lastname: Chan
mesh_terms: D001499:Bayes Theorem; D001685:Biological Factors / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D006801:Humans
chemical_list: D001685:Biological Factors