Molecular and clinical responses in a pilot study of gefitinib with paclitaxel and radiation in locally advanced head-and-neck cancer.
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.
Van Waes
Carter
C
Head and Neck Surgery Branch, National Institute of Deafness and Communication Disorders, National Institutes of Health, Bethesda, MD, USA.
Allen
Clint T
CT
Citrin
Deborah
D
Gius
David
D
Colevas
A Dimetrios
AD
Harold
Nancy A
NA
Rudy
Susan
S
Nottingham
Liesl
L
Muir
Christine
C
Chen
Zhong
Z
Singh
Anurag K
AK
Dancey
Janet
J
Morris
John C
JC
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
D009363:Neoplasm Proteins; D011799:Quinazolines; D066246:ErbB Receptors; D017239:Paclitaxel; D000077156:Gefitinib