title: Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results.
abstract: OBJECTIVE
  Overexpression of epidermal growth factor receptor (EGFR) has been associated with aggressive tumor phenotypes, chemotherapy, and radiation resistance, as well as poor survival in preclinical and clinical models. The EGFR inhibitor gefitinib potentiates chemotherapy and radiation tumor cytotoxicity in preclinical models, including pancreatic and colorectal cancer. We initiated two phase I trials assessing the combination of gefitinib, capecitabine, and radiation in patients with localized pancreatic and rectal cancer.
  
  
  METHODS
  Patients with pathologically confirmed adenocarcinoma of the pancreas and rectum were eligible. Pretreatment staging included computed tomography, endoscopic ultrasound, and surgical evaluation. Patients received 50.4 Gy of external-beam radiation therapy to the tumor in 28 fractions. Capecitabine and gefitinib were administered throughout the radiation course. Following completion, patients were restaged and considered for resection. Primary end points included determination of dose-limiting toxicity (DLT) and a phase II dose; secondary end points included determination of non-DLTs and preliminary radiographic and pathologic response rates.
  
  
  RESULTS
  Ten patients were entered in the pancreatic study and six in the rectal study. DLT was seen in six of 10 patients in the pancreatic study and two of six patients in the rectal study. The primary DLT in both studies was diarrhea. Two patients developed arterial thrombi.
  
  
  CONCLUSIONS
  The combination of gefitinib, capecitabine, and radiation in pancreatic and rectal cancer patients resulted in significant toxicity. A recommended phase II dose was not determined in either of our studies. Further investigation with this combination should be approached with caution.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA. czito001@mc.duke.edu
authors.forename: Brian G
authors.initials: BG
authors.lastname: Czito
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Willett
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Tyler
authors.forename: Nishan H
authors.initials: NH
authors.lastname: Fernando
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Mantyh
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Blobe
authors.forename: Wanda
authors.initials: W
authors.lastname: Honeycutt
authors.forename: Daohai
authors.initials: D
authors.lastname: Yu
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Clary
authors.forename: Theodore N
authors.initials: TN
authors.lastname: Pappas
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Ludwig
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000532:radiotherapy; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D000069287:Capecitabine; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D000077156:Gefitinib; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects*; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*
chemical_list: D000964:Antimetabolites, Antineoplastic; D011799:Quinazolines; D003841:Deoxycytidine; D000069287:Capecitabine; D066246:ErbB Receptors; D000077156:Gefitinib; D005472:Fluorouracil