Most patients with head and neck cancers present with advanced disease stages during their first hospital visit. For patients with advanced head and neck cancers, surgery is a common definitive therapy. After surgery, a pathological evaluation is necessary to decide upon additional therapy. The pathological risk factors for recurrence and/or distant metastases after surgery are as follows: positive surgical margins, T3 and T4 pathologies, positive perineural invasions and/or vascular tumor embolism of the primary site, and extranodal extension (ENE) and/or multiple positive metastasis to lymph nodes. Patients with these results are recommended to undergo postoperative radiotherapy [1,2]. Among these risk factors, microscopically involved surgical margins of the primary site and ENE are considered to be core high-risk factors that indicate a poor prognosis. The outcome for patients with these core high-risk factors could be improved by concurrent chemotherapy during postoperative radiotherapy [3].

The standard protocol for postoperative chemoradiotherapy is the concurrent use of cis-platinum (CDDP; 100 mg/m² once every 3 weeks) during radiotherapy (total dose of 66 Gy) for patients with core high-risk factors [1-3]. However, many of these patients are intolerant to CDDP due to advanced age, poor renal function, hearing impairment, and/or poor general condition. One option to overcome these problems is the combined administration of cetuximab (Cmab) and docetaxel (DTX) during postoperative radiotherapy. This regimen has been shown to afford favorable outcomes with improved disease-free survival (DFS) and overall survival (OS) and less toxicity compared to high-dose CDDP administration [4]. A phase 2/3 trial (RTOG 1216) of this regimen is ongoing. Focusing on the reduced toxicity of this regimen, we administered the combination of Cmab and DTX during postoperative radiotherapy for a limited number of patients with CDDP-intolerant core high-risk head and neck cancer, and established the safety of this procedure [5]. Here, we propose a multicenter, single-arm phase 2 trial to confirm the efficacy of postoperative bio-chemoradiotherapy (B-CRT) using Cmab and DTX for patients with CDDP-intolerant core high-risk head and neck cancer (Figure 1).

The University Hospital Medical Information Network Clinical Trials Registry (UMIN000031835) was completed on March 22, 2018. Patient enrollment started on April 1, 2018, and enrollment will close on March 31, 2021. The observation period will end on March 31, 2023. The expected schedule is shown in Figure 2.

Head and neck cancers account for approximately 5% of all malignancies in Japan, and both the incidences and mortality rates are increasing, especially in patients aged over 50 years [9,10]. The risk factors of head and neck cancer are smoking and alcohol consumption, and older patients have a longer history of these habits. Aging and a long history of smoking or alcohol consumption can induce cardiovascular disorders, pulmonary diseases, hepatic disorders, synchronous malignancies, and poor general condition. Additionally, Japanese patients with head and neck cancer show poorer renal functions with age [11], which limits the use of platinum-based drugs, especially CDDP. Such disadvantages restrict ideal treatment and are risk factors for complications during treatment.

Approximately 60% of patients with head and neck cancer present with advanced stage disease at their first visit, and surgery has been the definitive therapy for patients with advanced stage head and neck cancer despite recent improvements in treatment and diagnostic instruments. Although surgery is a fundamental treatment for locoregional control, multidisciplinary approaches, including radiotherapy and chemotherapy, are improving prognoses. Postoperative radiotherapy has been the standard adjuvant therapy for patients with high risks of locoregional recurrences or distant metastases [12,13], but radiotherapy does not show dramatic prognostic improvements. After the report of Bernier et al [3], the concurrent use of high-dose CDDP with postoperative radiotherapy has become the standard therapy for patients with core high-risk factors (eg, microscopically involved surgical margins of the primary site and ENE). Although the accepted standard regimen is CDDP administration at the dose of 100 mg/m² once every 3 weeks during radiotherapy, many patients with core high-risk head and neck cancer are not suited to receive this regimen due to advanced age, poor renal function, hearing impairment, or poor general status.

Cmab is an immunoglobulin G subclass 1 monoclonal antibody that inhibits ligand binding to the epidermal growth factor receptor (EGFR) and stimulates antibody-dependent cell-mediated cytotoxicity. One of the mechanisms of Cmab is that EGFR inhibition will result in decreased proliferation via mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways [14]. It has been shown that Cmab has synergistic effects with radiotherapy by modification of the radiation response through EGFR and its signal transduction pathways [15-17]. DTX is a taxane drug with a cytotoxic effect that is attributed to the inhibition of microtubule stabilization during cell divisions [18]. DTX has radiosensitizing effects by increasing G2/M phase cell fraction, reoxygenation of radioresistant hypoxic cells, radiation-induced apoptosis, and other synergistic antiangiogenetic effects [19-21]. Cmab and DTX have synergistic chemotherapeutic and radiosensitizing effects both in vivo and in vitro [22].

In a randomized phase 2 trial, Harari et al [4] reported superior 2-year OS and DFS with less toxicity in patients with core high-risk factors who received postoperative radiotherapy with Cmab and DTX compared with those who received high-dose CDDP. The 2-year OS was 79% for the Cmab plus DTX arm and 69% for the CDDP arm, and the 2-year DFS was 66% and 57%, respectively. Grade 3/4 myelosuppression was observed in 14% of patients in the Cmab plus DTX arm and 28% of patients in the CDDP arm. Regarding hematological adverse events, a small number of grade 3/4 events (3% of lymphopenia and 0.5% of anemia [23,24]) were reported with radiotherapy with Cmab alone, and an 8% rate of leukopenia, 4% to 4.8% rate of neutropenia, 56% rate of lymphopenia, and 4.8% rate of thrombocytopenia [25,26] were reported with radiotherapy with DTX alone in patients with advanced head and neck cancer. Although the combined use of Cmab and DTX with radiotherapy tends to result in a high incidence of severe myelosuppression, in our experience it was a low percentage and was controllable compared to the myelosuppression events in patients who were administered CDDP. Following this report, we applied this regimen as postoperative B-CRT in a small number of patients (11) with CDDP-intolerant core high-risk head and neck cancer and confirmed the efficacy and safety [5]. The 2-year DFS was 55%, which was the same as the expected 2-year DFS that was calculated from previous reports in this trial. No grade 4 adverse events were observed, and the grade 3 adverse events included oral mucositis (45%), aspiration (27%), radiation dermatitis (18%), leucopenia (9%), neutropenia (9%), lung infection (9%), and hyponatremia (9%). These adverse events were controllable and tolerable. Both Cmab and DTX are considered to have less usage restrictions compared with CDDP. We consider that these merits make the combined use of Cmab and DTX as postoperative B-CRT suitable for patients with CDDP-intolerant core high-risk head and neck cancer. We will clarify the efficacy of this regimen in this phase 2 trial. A limitation to this study is that it has a single arm with a limited number of patients.