The treatment of locoregionally advanced squamous-cell carcinoma of the head and neck (hereafter called head and neck cancer) has evolved gradually from surgery as the mainstay of treatment to radiotherapy as the principal treatment.  More recently, additional benefit has been obtained with altered-fractionation radiotherapy (i.e., accelerated fractionation or hyperfractionated radiotherapy) and with radiotherapy combined with chemotherapy (chemoradiotherapy).   The value of chemoradiotherapy is, however, counterbalanced by increased and often prohibitive toxicity, particularly among patients with coexisting medical conditions and decreased performance status.

The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, is abnormally activated in epithelial cancers, including head and neck cancer. The cells of almost all such neoplasms express high levels of EGFR, a feature associated with a poor clinical outcome. Radiation increases the expression of EGFR in cancer cells, and blockade of EGFR signaling sensitizes cells to the effects of radiation.

Cetuximab (Erbitux, ImClone Systems), an IgG1 monoclonal antibody against the ligand-binding domain of EGFR, enhances the cytotoxic effects of radiation in squamous-cell carcinoma.  In a preliminary study of radiotherapy plus cetuximab in patients with locoregionally advanced head and neck cancer, the regimen was well tolerated, and all the patients who could be assessed had a complete or partial regression. Cetuximab as a single agent or combined with cisplatin was also associated with clinically significant rates of tumor regression in patients with platinum-refractory head and neck cancer.  For these reasons, we conducted a randomized, phase 3 study to determine the effect of adding cetuximab to radiotherapy in the treatment of patients with locoregionally advanced head and neck cancer.  We conducted a multinational, randomized study to compare radiotherapy alone with radiotherapy plus cetuximab, a monoclonal antibody against the epidermal growth factor receptor, in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck.

Methods Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy. The primary end point was the duration of control of locoregional disease; secondary end points were overall survival, progression-free survival, the response rate, and safety. Regarding the radiation-fractionation schemes, concomitant boost radiotherapy was selected most frequently (56 percent), followed by once-daily fractionation (26 percent) and twice-daily fractionation (18 percent). The final review of radiotherapy revealed that the mean and median doses for the once-daily, twice-daily, and concomitant-boost regimens were 67.5 and 70.0 Gy, 74.2 and 74.4 Gy, and 71.2 and 72.0 Gy, respectively, with no differences between the two treatment groups. Compliance was also balanced: overall, 44 percent of the patients were treated as stipulated, 31 percent received treatment with minor variations, and 12 percent received treatment with acceptable major variations.

Severe late effects related to radiation were reported in about 20 percent of the patients in each group. The sites most commonly affected were the esophagus, salivary glands, larynx, mucous membranes, subcutaneous tissues, bone, and skin. Twelve patients in the radiotherapy group and 11 patients in the combined-therapy group died within 60 days after the last radiotherapy or cetuximab treatment. No death was known to be related to cetuximab.

Results The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (hazard ratio for locoregional progression or death, 0.68; P=0.005). With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P=0.03). Radiotherapy plus cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P=0.006). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups.

Conclusions Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck.