Epidermal growth factor receptor inhibitor gefitinib added to chemoradiotherapy in locally advanced head and neck cancer

Abstract

Purpose: Assess efficacy and toxicity of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, added to, and in maintenance after, concurrent chemoradiotherapy (CCRT) in locally advanced head and neck cancer (LA-HNC) and correlate outcomes with EGFR gene copy number alterations.

Patients and methods: Patients with stage III to IV LA-HNC received two cycles of carboplatin/paclitaxel induction chemotherapy (IC) followed by split-course CCRT with fluorouracil, hydroxyurea, twice daily radiotherapy (FHX), and gefitinib (250 mg daily) followed by continued gefitinib for 2 years total. The primary end point was complete response (CR) rate after CCRT. EGFR gene copy number was assessed by fluorescent in situ hybridization.

Results: Sixty-nine patients (66 with stage IV disease, 37 with oropharynx primary tumors, and 67 with performance status 0 to 1) were enrolled with a median age of 55 years. Predominant grade 3 or 4 toxicities during IC and CCRT were neutropenia (n = 20) and in-field mucositis (n = 59) and dermatitis (n = 23), respectively. CR rate after CCRT was 90%. After median follow-up of 3.5 years, 4-year overall, progression-free, and disease-specific survival rates were 74%, 72%, and 89%, respectively. To date, one patient has developed a second primary tumor in the aerodigestive tract. In 31 patients with available tissue, high EGFR gene copy number was associated with worse overall survival (P = .02).

Conclusion: Gefitinib can be administered with FHX and as maintenance therapy for at least 2 years, demonstrating CR and survival rates that compare favorably with prior experience. High EGFR gene copy number may be associated with poor outcome in patients with LA-HNC treated with this regimen.

Fig 1.

Flow diagram of all patients who signed informed consent. IC, induction chemotherapy; CRT, chemoradiotherapy.

Fig 2.

Mean toxicity grade of (A) acute in-volume mucositis and (B) dermatitis over time. The planned duration of chemoradiotherapy was 7 to 9 weeks. Toxicities were graded on a weekly basis starting from initiation of concurrent chemoradiotherapy to at least 4 weeks after completing chemoradiotherapy. Common Terminology Criteria of Adverse Events (CTCAE) version 3.0 was used to grade toxicity. Error bars represent standard deviation.

Fig 3.

Kaplan-Meier survival curves. Survival estimates of (A) overall survival, (B) progression-free survival, and (C) disease-specific survival for all patients.

Fig 4.

Photomicrographs (×1,200) for EGFR (red) and CEP7 (green). (A) Disomy. (B) EGFR trisomy in 15% (arrow) and tetrasomy in 2% of cells (arrowhead), classified EGFR fluorescent in situ hybridization (FISH) negative. (C) Cells are trisomic (arrow) or highly polysomic (arrowhead), classified EGFR FISH positive. (D) High polysomy in 83% (arrowhead), classified EGFR FISH positive. (E, F) Low and high EGFR amplification, classified EGFR FISH positive.

Fig A1.

Survival differences in patients with oropharynx and non-oropharynx primary tumors. Kaplan-Meier survival estimates of (A) overall survival, (B) progression-free survival, and (C) disease-specific survival for patients with oropharynx (gold line) and non-oropharynx (blue line) primary tumors. Corresponding P values using the log-rank test are shown.