title: Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression.
abstract: OBJECTIVE
  This phase II trial was designed to assess the efficacy and safety of cetuximab, gemcitabine, and oxaliplatin followed by cetuximab, capecitabine, and radiation therapy in locally advanced pancreatic cancer (LAPC).
  
  
  METHODS
  Treatment-naive eligible patients (n = 69) received intravenous gemcitabine (1,000 mg/m(2)) and oxaliplatin (100 mg/m(2)) every 2 weeks for four doses, followed by radiation (50.4 Gy to the gross tumor only) with concurrent capecitabine (825 mg/m(2) twice daily on radiation treatment days). Cetuximab (500 mg/m(2)) was started on day 1 of chemotherapy and was continued every 2 weeks during chemotherapy and chemoradiotherapy. Diagnostic cytology specimens were immunostained for Smad4(Dpc4) expression.
  
  
  RESULTS
  Median overall survival time was 19.2 months (95% CI, 14.2 to 24.2 months), and 1-year, 2-year, and 4-year actuarial overall survival rates were 66.0%, 25.02%, and 11.3%, respectively. Acneiform rash correlated with improved survival (P = .001), but initial CA19-9, borderline resectable initial stage, and surgical resection (n = 7) did not. The 1-year and 2-year radiographic local progression rates were 22.8% and 61.0%, respectively. The worst acute toxic effects were GI toxicity (32% and 10% for grades 2 and 3, respectively); fatigue (26% and 6% for grades 2 and 3, respectively); sensory neuropathy (9% and 1% for grades 2 and 3, respectively); and acneiform rash (54% and 3% for grades 2 and 3, respectively). Smad4(Dpc4) expression correlated with a local rather than a distant dominant pattern of disease progression (P = .016).
  
  
  CONCLUSIONS
  This regimen appears effective and has acceptable toxicity. The primary end point (1-year overall survival rate > 45%) was met, with encouraging survival duration. Smad4(Dpc4) immunostaining correlated with the pattern of disease progression. Prospective validation of Smad4(Dpc4) expression in cytology specimens as a predictive biomarker is warranted and may lead to personalized treatment strategies for patients with localized pancreatic cancer.
authors.affiliation: Dept of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX. ccrane@mdanderson.org
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Crane
authors.forename: Gauri R
authors.initials: GR
authors.lastname: Varadhachary
authors.forename: John S
authors.initials: JS
authors.lastname: Yordy
authors.forename: Gregg A
authors.initials: GA
authors.lastname: Staerkel
authors.forename: Milind M
authors.initials: MM
authors.lastname: Javle
authors.forename: Howard
authors.initials: H
authors.lastname: Safran
authors.forename: Waqar
authors.initials: W
authors.lastname: Haque
authors.forename: Bridgett D
authors.initials: BD
authors.lastname: Hobbs
authors.forename: Sunil
authors.initials: S
authors.lastname: Krishnan
authors.forename: Jason B
authors.initials: JB
authors.lastname: Fleming
authors.forename: Prajnan
authors.initials: P
authors.lastname: Das
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lee
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wolff
mesh_terms: D000206:Actuarial Analysis; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000068818:Cetuximab; D017024:Chemotherapy, Adjuvant; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D018579:Patient Selection; D018714:Radiotherapy, Adjuvant; D012074:Remission Induction; D012107:Research Design; D051901:Smad4 Protein / Q000378:metabolism*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000068818:Cetuximab; D000093542:Gemcitabine