title: A phase II study of gefitinib monotherapy in advanced esophageal adenocarcinoma: evidence of gene expression, cellular, and clinical response.
abstract: OBJECTIVE
  At presentation, most cases of adenocarcinoma of the esophagus (ACE) are inoperable. Although chemotherapy can prolong survival, patients eventually die as a result of refractory disease. Epidermal growth factor receptor (EGFR) is almost universally expressed in ACE and is a negative prognostic factor.
  
  
  METHODS
  This open-label, two-center, noncomparative, two-part phase II trial assessed the EGFR tyrosine kinase inhibitor gefitinib (500 mg/d) in patients with advanced, inoperable ACE. The primary end point was tumor response. The effect of EGFR inhibition was also evaluated by gene expression analysis of tumor biopsies taken before gefitinib treatment and 28 days after.
  
  
  RESULTS
  Twenty-seven patients were recruited and evaluable for tumor response and safety. Three patients had a partial response and seven had stable disease, giving a disease control rate (partial response + stable disease) of 37%. Drug-related adverse events were generally mild: diarrhea in 19 (grade 3 in three) and rash in 19 (grade 3 in five) patients, and there were no grade 4 drug-related adverse events. Microarray experiments on tumor biopsies showed that gefitinib also down-regulated oncogenes associated with tumor progression. Ki67 (a marker of tumor growth) expression decreased in five of seven biopsies taken before and after treatment.
  
  
  CONCLUSIONS
  Gefitinib (500 mg/d) is an active and generally well-tolerated treatment for ACE. Studies on endoscopic biopsies are feasible and indicate that gefitinib inhibits both gene expression and cellular biology at 500 mg/d, and these may provide surrogate end points for predictive biomarkers. Further trials of gefitinib are warranted, particularly as patient response seems to be durable and current second-line chemotherapy options have no proven ability to prolong life.
authors.affiliation: Department of Oncology, New Cross Hospital, Wolverhampton, United Kingdom. drf@ferryd.freeserve.co.uk
authors.forename: David R
authors.initials: DR
authors.lastname: Ferry
authors.forename: Mark
authors.initials: M
authors.lastname: Anderson
authors.forename: Kate
authors.initials: K
authors.lastname: Beddard
authors.forename: Simon
authors.initials: S
authors.lastname: Tomlinson
authors.forename: Paul
authors.initials: P
authors.lastname: Atherfold
authors.forename: Jolanta
authors.initials: J
authors.lastname: Obszynska
authors.forename: Rebecca
authors.initials: R
authors.lastname: Harrison
authors.forename: Janusz
authors.initials: J
authors.lastname: Jankowski
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001706:Biopsy; D066246:ErbB Receptors / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011799:Quinazolines / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D019394:Ki-67 Antigen; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib