title: Controversies in antiepidermal growth factor receptor therapy in metastatic colorectal cancer.
abstract: The randomized first-line trials, including the CRYSTAL trial, the OPUS trial, and the PRIME trial, have demonstrated the significant efficacy of cetuximab or panitumumab in patients with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type tumors. The addition of an antiepidermal growth factor receptor (anti-EGFR)-directed monoclonal antibody to chemotherapy for these patients significantly improved progression-free survival, response rates, and R0 resection rates to a greater extent than overall survival compared with patients who received chemotherapy alone. However, 2 recent randomized phase 3 trials, the MRC COIN trial and the Nordic VII trial, reported an unexpected lack of benefit from the addition of cetuximab to chemotherapy in the first-line setting. In addition, recent retrospective analyses performed on a pooled data set from major clinical trials added more complexity, reporting an unexpected association of KRAS G13D mutation with a better clinical outcome compared with patients who had other KRAS mutations in the first-line and salvage settings, whereas the other independent analysis failed to demonstrate a benefit from panitumumab in patients with the same KRAS G13D mutation. The anti-EGFR monoclonal antibody-associated skin toxicity and the controversial strategies of management also are discussed. In this review, the authors analyze the previous randomized clinical trials and more critically re-evaluate recent trials and subgroup analyses to derive 3 factors that need to be taken into consideration regarding the addition of EGFR-directed monoclonal antibodies to chemotherapy: the preclinical data on mechanisms of action between chemotherapy and anti-EGFR antibodies along with mechanisms of resistance to anti-EGFR antibodies, the role of cross-over events in overall survival data, and the significant dose reductions of chemotherapeutic agents when combined with anti-EGFR agents.
authors.affiliation: Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA 19141, USA. woojangh@einstein.edu
authors.forename: Janghee
authors.initials: J
authors.lastname: Woo
authors.forename: Neil
authors.initials: N
authors.lastname: Palmisiano
authors.forename: William
authors.initials: W
authors.lastname: Tester
authors.forename: John C
authors.initials: JC
authors.lastname: Leighton
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068818:Cetuximab; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D000068818:Cetuximab