title: The importance of optimal drug sequencing in metastatic colorectal cancer: biological rationales for the observed survival benefit conferred by first-line treatment with EGFR inhibitors.
abstract: BACKGROUND
  Use of both the vascular endothelial growth factor (VEGF) inhibitor bevacizumab and the epidermal growth factor receptor (EGFR) inhibitors cetuximab and panitumumab as potential first-line therapies for patients with RAS-wild-type metastatic colorectal cancer presents clinicians with an important decision. We review clinical data evaluating first-line treatment with EGFR inhibitors. Additionally, by undertaking an integrated 'bench-to-bedside' approach, we provide potential models, testable hypotheses and biological rationales that might account for these clinical observations.
  
  
  METHODS
  A literature search encompassing PubMed and the ASCO/ESMO websites was undertaken in October 2014. Search terms included 'colorectal cancer', 'cetuximab', 'panitumumab' and 'bevacizumab'.
  
  
  CONCLUSIONS
  A number of clinical studies indicate a survival benefit for patients receiving EGFR inhibitors in combination with chemotherapy in the first-line setting, relative to both chemotherapy alone and VEGF inhibitors plus chemotherapy. Existing preclinical and clinical data suggest that a biological basis exists for providing RAS-wild-type patients with first-line EGFR inhibitors, followed by second-line VEGF inhibitors. More specifically, first-line treatment with EGFR inhibitors may elicit unique biological changes that sensitize tumors to subsequent lines of therapy; conversely, first-line treatment with VEGF inhibitors may elicit biological changes that desensitize tumors to subsequent lines of therapy.
authors.affiliation: UCLA's Jonsson Comprehensive Cancer Center, Department of Hematology/Oncology , 8-684 Factor Building, Box 951781, Los Angeles, CA 90095-1781 , USA ZWainberg@mednet.ucla.edu.
authors.forename: Zev A
authors.initials: ZA
authors.lastname: Wainberg
authors.forename: Alexandra
authors.initials: A
authors.lastname: Drakaki
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000494:pharmacology / Q000627:therapeutic use; D000068818:Cetuximab / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic / Q000379:methods; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D000077544:Panitumumab; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: bevacizumab; cetuximab; colorectal cancer; panitumumab