title: Dual blockade of the EGFR and COX-2 pathways: a phase II trial of cetuximab and celecoxib in patients with chemotherapy refractory metastatic colorectal cancer.
abstract: OBJECTIVE
  The epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways play key and often complementary roles in the pathogenesis of colorectal cancer (CRC). This study explores the clinical and biological effects of combined blockade of these pathways.
  
  
  METHODS
  Cetuximab-naive patients with refractory CRC were treated with cetuximab (400 mg/m loading dose followed by weekly cetuximab at 250 mg/m) and celecoxib (200 mg orally twice daily). Urinary PGE-M, a stable metabolite of PGE2 that correlates with in vivo COX-2 activity, and serum TGF-α, a ligand that binds to EGFR, were measured serially to assess the biological effect of COX-2 and EGFR blockade.
  
  
  RESULTS
  Seventeen patients accrued in this study. Of the 13 patients evaluable for response, 2 (15.4%) had confirmed partial responses, 4 (30.8%) had stable disease, and 7 (53.8%) had progressive disease. The median progression-free survival for all evaluable patients was 55 days (95% confidence interval, 45-112; range, 10-295 d). This study was terminated early owing to lack of sufficient clinical activity. There were no statistically significant differences in serum TGF-α or urinary PGE-M between cycles in responders or nonresponders.
  
  
  CONCLUSIONS
  This regimen resulted in response rates similar to those published for cetuximab monotherapy in patients with recurrent CRC. Apart from a higher than expected rate of infusion reactions, no other unexpected toxicities were observed. No differences in serum TGF-α or urinary PGE-M between cycles were seen, suggesting that the appropriate targets may not have been hit.
authors.affiliation: Vanderbilt University Medical Center, Department of Veterans Affairs, Nashville, TN, USA. emily.chan@vanderbilt.edu
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Bonnie
authors.initials: B
authors.lastname: Lafleur
authors.forename: Mace L
authors.initials: ML
authors.lastname: Rothenberg
authors.forename: Nipun
authors.initials: N
authors.lastname: Merchant
authors.forename: Albert Craig
authors.initials: AC
authors.lastname: Lockhart
authors.forename: Bakula
authors.initials: B
authors.lastname: Trivedi
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Berlin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068579:Celecoxib; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068579:Celecoxib; D000068818:Cetuximab