title: Surrogate Endpoints in Second-Line Trials of Targeted Agents in Metastatic Colorectal Cancer: A Literature-Based Systematic Review and Meta-Analysis.
abstract: The purpose of this study was to evaluate progression-free survival (PFS) and objective response rate (ORR) as surrogate endpoints of overall survival (OS) in modern clinical trials investigating the efficacy of targeted agents in the second-line treatment of metastatic colorectal cancer (mCRC).
  
  
  
  A systematic search of literature pertaining to randomized phase II and III trials evaluating targeted agents as second-line treatments for mCRC was performed. The strength of the correlation between both PFS and ORR and OS was assessed based on the Pearson's correlation coefficient (R) and the coefficient of determination (R2).
  
  
  
  Twenty trials, including a total of 7,571 patients, met the search criteria. The median duration of post-progression survival (PPS) was 7.6 months. The median differences between experimental and control arms were 0.65 months (range, -2.4 to 3.4) for the median PFS and 0.7 months (range, -5.8 to 3.9) for the median OS. PFS and ORR showed moderate (R=0.734, R2=0.539, p < 0.001) and poor correlation (R=0.169, R2=0.029, p=0.476) with OS, respectively. No differences between anti-angiogenic agents and other drugs were evident.
  
  
  
  Targeted agents investigated in the second-line treatment of mCRC provided minimal PFS gains translating into modest OS improvements. Considering both the moderate correlation between PFS and OS and the short duration of PPS, the OS should remain the preferred primary endpoint for randomized clinical trials in the second-line treatment of mCRC.
authors.affiliation: Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.affiliation: Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Antoniotti
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Pietrantonio
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Berenato
authors.affiliation: Department of Oncology, University of Turin, A.O.U. San Luigi Gonzaga, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tampellini
authors.affiliation: Department of Oncology, University of Turin, A.O.U. San Luigi Gonzaga, Turin, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Baratelli
authors.affiliation: Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Salvatore
authors.affiliation: Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Marmorino
authors.affiliation: Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Borelli
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Nichetti
authors.affiliation: Department of Oncology, University of Turin, A.O.U. San Luigi Gonzaga, Turin, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bironzo
authors.affiliation: Department of Oncology, University of Turin, A.O.U. San Luigi Gonzaga, Turin, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sonetto
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maria Di
authors.initials: MD
authors.lastname: Bartolomeo
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Filippo de
authors.initials: F
authors.lastname: Braud
authors.affiliation: Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.affiliation: Department of Oncology, University of Turin, A.O. Ordine Mauriziano, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Di Maio
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D015415:Biomarkers; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D016017:Odds Ratio; D016016:Proportional Hazards Models; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers
keywords: Biomarkers; Colorectal neoplasms; Molecular targeted therapy