title: Molecular and clinical responses in a pilot study of gefitinib with paclitaxel and radiation in locally advanced head-and-neck cancer.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR) overexpression in head-and-neck squamous cell carcinoma (HNSCC) stimulates tumor cell proliferation, inhibits apoptosis, and increases chemotherapy and radiation resistance. We examined the toxicity, safety and the effects on EGFR signaling in tumor biopsy samples from patients with locally advanced HNSCC treated with the EGFR signaling inhibitor gefitinib (GEF) combined with weekly intravenous paclitaxel (PAC) and radiation therapy (RT).
  
  
  METHODS
  This was a pilot Phase I dose-escalation study. Eligibility included Stage III to IVB HNSCC, age >or=18 years, no prior RT or chemotherapy, adequate organ function, and informed consent. Endpoints included determination of maximum tolerated dose (MTD) and analysis of treatment effect on EGFR signaling, tumor cell proliferation, and apoptosis in biopsy samples.
  
  
  RESULTS
  Ten patients were treated. The MTD of this combination was GEF 250 mg/d with PAC 36 mg/m(2) intravenously weekly x 6 with concurrent RT. Grade 3/4 toxicities included prolonged (>8 weeks) stomatitis (7 patients), infection (2 patients), and interstitial pneumonitis (1 patient). There were five complete responses (CR) and two partial responses (PR). Of 7 patients undergoing serial biopsies, only 1 patient demonstrated a reduction in phosphorylated EGFR, decreased downstream signaling, and reduced cellular proliferation after initiating GEF.
  
  
  CONCLUSIONS
  Inhibition of EGFR by GEF was observed in only one of seven tumors studied. The addition of GEF to PAC and RT did not appear to improve the response of locally advanced HNSCC compared with our prior experience with PAC and RT alone. This treatment appeared to delay recovery from stomatitis.
authors.affiliation: Head and Neck Surgery Branch, National Institute of Deafness and Communication Disorders, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Carter
authors.initials: C
authors.lastname: Van Waes
authors.forename: Clint T
authors.initials: CT
authors.lastname: Allen
authors.forename: Deborah
authors.initials: D
authors.lastname: Citrin
authors.forename: David
authors.initials: D
authors.lastname: Gius
authors.forename: A Dimetrios
authors.initials: AD
authors.lastname: Colevas
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Harold
authors.forename: Susan
authors.initials: S
authors.lastname: Rudy
authors.forename: Liesl
authors.initials: L
authors.lastname: Nottingham
authors.forename: Christine
authors.initials: C
authors.lastname: Muir
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: Anurag K
authors.initials: AK
authors.lastname: Singh
authors.forename: Janet
authors.initials: J
authors.lastname: Dancey
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D049109:Cell Proliferation; D003131:Combined Modality Therapy / Q000009:adverse effects / Q000379:methods; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D007239:Infections / Q000209:etiology; D017563:Lung Diseases, Interstitial / Q000209:etiology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D010865:Pilot Projects; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D011879:Radiotherapy Dosage; D012074:Remission Induction; D013280:Stomatitis / Q000209:etiology
chemical_list: D009363:Neoplasm Proteins; D011799:Quinazolines; D066246:ErbB Receptors; D017239:Paclitaxel; D000077156:Gefitinib