title: Progression-free survival as a surrogate endpoint for median overall survival in metastatic colorectal cancer: literature-based analysis from 50 randomized first-line trials.
abstract: OBJECTIVE
  To evaluate progression-free survival (PFS) as a potential surrogate endpoint (SEP) for overall survival (OS) in metastatic colorectal cancer (mCRC) with a focus on applicability to trials containing targeted therapy with anti-VEGF- or anti-EGF receptor (EGFR)-directed monoclonal antibodies.
  
  
  METHODS
  A systematic literature search of randomized trials of first-line chemotherapy for mCRC reported from January 2000 to January 2012 was conducted. Adjusted weighted linear regression was used to calculate correlations within PFS and OS (endpoints; R(EP)) and between treatment effects on PFS and on OS (treatment effects; R(TE)).
  
  
  RESULTS
  Fifty trials reflecting 22,736 patients met the inclusion criteria. Correlation between treatment effects on PFS and OS and between the endpoints PFS and OS was high across all studies (R(TE) = 0.87, R(EP) = 0.86). This was also observed in chemotherapy-only trials (R(TE) = 0.93, R(EP) = 0.81) but less so for trials containing monoclonal antibodies (R(TE) = 0.47; R(EP) = 0.52). Limiting the analysis to bevacizumab-based studies (11 trials, 3,310 patients) again yielded high correlations between treatment effects on PFS and on OS (R(TE) = 0.84), whereas correlation within PFS and OS was low (R(EP) = 0.45). In 7 trials (1,335 patients) investigating cetuximab- or panitumumab-based studies, contrasting correlations with very wide confidence intervals were observed (R(TE) = 0.28; R(EP) = 0.96).
  
  
  CONCLUSIONS
  PFS showed consistently high correlation with OS of an order that would justify its use as an SEP in chemotherapy regimens. For validation of surrogacy in anti-VEGF and anti-EGFR-directed therapies, further research and a larger set of trials is needed.
authors.affiliation: Department of Medical Oncology, Klinikum Grosshadern and Comprehensive Cancer Center, Ludwig Maximilian University of Munich, Munich, Germany. clemens.giessen@med.uni-muenchen.de
authors.forename: Clemens
authors.initials: C
authors.lastname: Giessen
authors.forename: Ruediger Paul
authors.initials: RP
authors.lastname: Laubender
authors.forename: Donna Pauler
authors.initials: DP
authors.lastname: Ankerst
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stintzing
authors.forename: Dominik Paul
authors.initials: DP
authors.lastname: Modest
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mansmann
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology*; D006801:Humans; D009362:Neoplasm Metastasis; D016032:Randomized Controlled Trials as Topic
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents