Pilot phase I study of gefitinib (GEF) in combination with paclitaxel (PAC) and radiation therapy (RT) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) and effects on epidermal growth factor receptor (EGFR) signaling pathway

Abstract

16526 Background: The over expression of EGFR in HNSCC stimulates tumor cell proliferation, inhibits apoptosis, and increases resistance to chemotherapy and radiation. We examined the toxicity and maximum tolerated dose (MTD), and the downstream signaling and cellular effects in tumor biopsies in locally advanced HNSCC patients (Pts.) treated with GEF+PAC and RT. Methods: Pilot phase I dose escalation study initiated at GEF 250 mg/d + PAC 45 mg/m2 weekly x 6 with concurrent RT to 72 Gy. Eligibility: Stage III-IVB HNSCC, age=18 years, no prior RT or chemotherapy, ECOG =2, adequate organ function and informed consent. Endpoints: MTD determination, analysis of tumor biopsies for treatment effect on phospho-EGFR, Akt, Erk1/2, STAT3, NF-κB p65, Ki67 expression, TUNEL assay, serial measurement of serum IL-6, IL-8, VEGF, HGF and GROa. Results: 10 Pts., median age 60.7 yrs. (range, 41–83), 7 men and 3 women were treated. The MTD was GEF 250 mg/d + PAC 36 mg/m2 weekly x 6 with concurrent RT. Grade 3/4 toxicities included prolonged (>8 wk duration) mucositis in 7 Pts., infection (1) and interstitial pneumonitis (1). Two Pts. experienced protracted painful oral dysesthesia. There were 5 CR's and 1 PR. Of 7 Pts. undergoing serial biopsy, 1 Pt. showed a significant decrease in phosphorylated-EGFR expression, decreased downstream phosphoprotein signaling and cellular proliferation within 8 days of initiating GEF. Conclusions: Severe and prolonged mucositis was dose-limiting for this schedule of GEF+PAC and RT in locally advanced HNSCC. Inhibition of EGFR activation and downstream signaling by GEF was observed in a minority of Pts. on serial tumor biopsy specimens obtained during treatment. No significant financial relationships to disclose.