title: The relevance of primary tumour location in patients with metastatic colorectal cancer: A meta-analysis of first-line clinical trials.
abstract: Retrospective subgroup analyses suggest that primary tumour location (PTL) has a prognostic importance and relates to response to targeted therapy.
  
  
  
  We conducted a meta-analysis of first-line clinical trials available up to October 2016, which assessed the relevance of PTL in patients with metastatic colorectal cancer (mCRC). Right- and left-sided colorectal cancers were differentiated (RC and LC).
  
  
  
  In 13 first-line randomised controlled trials and one prospective pharmacogenetic study, RC was associated with a significantly worse prognosis compared with LC (hazard ratio [HR] for overall survival: 1.56; 95% confidence interval [CI]: 1.43-1.70; P < 0.0001). A meta-analysis of PRIME and CRYSTAL study suggests that PTL was predictive of survival benefit from addition of anti-EGFR antibody to standard chemotherapy in patients with RAS wild-type tumour (overall survival, HR for LC: 0.69; 95% CI: 0.58-0.83; P < 0.0001 and HR for RC: 0.96; 95% CI: 0.68-1.35; P = 0.802). A meta-analysis of FIRE-3/AIO KRK0306, CALGB/SWOG 80405 and PEAK study indicates that patients with RAS wild-type LC had a significantly greater survival benefit from anti-EGFR treatment compared with anti-VEGF treatment when added to standard chemotherapy (HR 0.71; 95% CI: 0.58-0.85; P = 0.0003). By contrast, in patients with RC, benefit from standard therapy was poor and bevacizumab-based treatment was numerically associated with longer survival (HR 1.3; 95% CI: 0.97-1.74; P = 0.081).
  
  
  
  The present meta-analysis demonstrates that PTL is prognostic in mCRC. Further, it supports the conclusion that patients with left-sided RAS wild-type mCRC should be preferentially treated with an anti-EGFR antibody. In right-sided mCRC, chemotherapy plus bevacizumab is a treatment option, but optimal treatment has yet to be defined.
authors.affiliation: Department of Medical Oncology, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, 81377 Munich, Germany; Comprehensive Cancer Center, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, 81377 Munich, Germany. Electronic address: julian.holch@med.uni-muenchen.de.
authors.forename: Julian Walter
authors.initials: JW
authors.lastname: Holch
authors.affiliation: Institute of Medical Informatics, Biometry, and Epidemiology, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, 81377 Munich, Germany. Electronic address: ricard@ibe.med.uni-muenchen.de.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Ricard
authors.affiliation: Department of Medical Oncology, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, 81377 Munich, Germany; Comprehensive Cancer Center, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, 81377 Munich, Germany. Electronic address: sebastian.stintzing@med.uni-muenchen.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stintzing
authors.affiliation: Department of Medical Oncology, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, 81377 Munich, Germany; Comprehensive Cancer Center, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, 81377 Munich, Germany. Electronic address: dominik.modest@med.uni-muenchen.de.
authors.forename: Dominik Paul
authors.initials: DP
authors.lastname: Modest
authors.affiliation: Department of Medical Oncology, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, 81377 Munich, Germany; Comprehensive Cancer Center, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, 81377 Munich, Germany. Electronic address: volker.heinemann@med.uni-muenchen.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors
keywords: Anti-EGFR; Anti-VEGF; Bevacizumab; Cetuximab; Metastatic colorectal cancer; Panitumumab; Predictive biomarker; Primary tumour location; Prognostic biomarker; Sidedness