title: Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma.
abstract: OBJECTIVE
  The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGFalpha).
  
  
  METHODS
  One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome.
  
  
  RESULTS
  Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% +/- 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance.
  
  
  CONCLUSIONS
  Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.
authors.affiliation: Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232-6307, USA. mace.rothenberg@vanderbilt.edu
authors.forename: Mace L
authors.initials: ML
authors.lastname: Rothenberg
authors.forename: Bonnie
authors.initials: B
authors.lastname: LaFleur
authors.forename: Donna E
authors.initials: DE
authors.lastname: Levy
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Morgan-Meadows
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Berlin
authors.forename: Al B
authors.initials: AB
authors.lastname: Benson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use*; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077156:Gefitinib