Concomitant hyperfractionated accelerated radiotherapy (HART) with cisplatin and concurrent cetuximab for locoregionally advanced squamous cell head and neck cancer: a phase I dose escalation trial

Abstract

6029 Background: Cetuximab is a potent inhibitor of the epidermal growth factor receptor and has shown activity in squamous cell carcinoma of the head and neck (SCCHN) enhancing both radiotherapy and chemotherapy. This phase I dose-escalation clinical trial was designed to investigate the safety and tolerability of the combination of cisplatinum, cetuximab, and hyperfractionated accelerated radiotherapy. Methods: Patients (pts) with stage III or IV, M0 SCCHN were enrolled and treated with an initial dose of cetuximab (400mg/m2), followed by weekly doses of 250mg/m² during the hyperfractionated accelerated radiotherapy (HART), which started with a prescribed dose of 2.0 Gy per day for three weeks followed by 1.4 Gy twice daily to a total dose of 70.6 Gy to the gross tumor volume. Cisplatinum was administered weekly from the first day of radiotherapy until week 6 at escalating doses ranging from 20- 40 mg/m². Three patients were accrued in each cohort using a 3+3dose escalation trial design. Results: 14 patients were enrolled (median age: 53 years, range 44 to 62 years; median Karnofsky status: 90%, range 90% to 100%; cavum oris and oropharynx primary tumor: 50% of patients; T4: 71%; N2/3: 79%; stage IV disease: 93%). Three patients discontinued the study treatment. One was due to a hypersensitivity reaction after the initial dose of cetuximab, another was diagnosed with a secondary carcinoma and the third developed a stomach perforation in week 3. No dose-limiting toxicities were observed. The most common grade 3 adverse events were mucositis (46%), dysphagia (32%) and neutropenia (16%). Grade 3 cetuximab related toxicities included acne-like rash within the radiotherapy portals (38%) and hypersensitivity (7%). The objective remission rate was 91% (CR 33% and PR 58%, one patient unknown). No patients have died to date (Dec 2007). Conclusions: The trimodal regimen of cisplatinum with cetuximab and HART is active and well tolerated. The 40-mg dose of cisplatinum was chosen as the recommended phase II dose in combination with cetuximab plus HART based on acceptable toxicity when administered. No significant financial relationships to disclose.