Abstract and Introduction
Abstract
The majority of the head and neck cancers are squamous cell carcinomas, which commonly overexpress the EGF receptor (EGFR). Cetuximab is a chimeric monoclonal antibody that binds with high affinity to the extracellular domain of EGFR, and in addition induces antibody-dependent cellular cytoxicity. In a randomized Phase III trial in patients with locoregionally advanced squamous cell carcinoma of the head and neck, the addition of cetuximab to radiotherapy prolonged the median time of locoregional control from 14.9 to 24.4 months and increased the median overall survival from 29.3 to 49.0 months. In patients with platinum-refractory recurrent and/or metastatic disease, the objective response and disease-control rates in various studies ranged from 10 to 13% and from 46 to 56%, respectively. In the EXTREME trial, the addition of cetuximab to platinum/5-fluorouracil as first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck not only led to significant improvements in survival, response rate and disease control, but also induced a better symptom control in comparison with that observed with platinum/5-fluorouracil alone.
Introduction
More than 90% of head and neck cancers are of squamous cell histology and originate in the lip/oral cavity, nasopharynx, oropharynx, hypopharynx and the larynx. Head and neck cancer is the sixth most common cancer type worldwide and there has been a significant increase in the global incidence of squamous cell carcinoma of the head and neck (SCCHN) over the past decade. At present, more than 650,000 new cases of SCCHN are diagnosed each year worldwide. In Europe alone, it is estimated that there are approximately 143,000 new cases and more than 68,000 deaths due to the disease each year. In total, 85% of SCCHN are linked to tobacco use. Frequent and heavy consumption of alcohol also increases the risk of SCCHN, and this is particularly true when tobacco and alcohol are used together.
During the past two decades, numerous studies have shown that human papillomavirus is a risk factor for the development of oropharyngeal carcinoma. This virus-related tumor frequently occurs in individuals in their thirties or even twenties, is not necessarily associated with tobacco or alcohol exposure, and is associated with a better prognosis.
For the 60% of patients who present with locally advanced SCCHN at diagnosis, combined-modality therapy is generally recommended. For patients with unresectable disease, the current standard treatment is concurrent cisplatin-based chemoradiation. Despite such an approach, the majority of these patients develop local and/or regional recurrences, and distant metastases occur in 20–30% of the patients. Moreover, approximately 10% of patients present with distant metastases at diagnosis.
Cetuximab (Erbitux®; Merck KgaA, Darmstadt, Germany; Imclone) is a chimeric monoclonal antibody of the IgG1 class that is directed against the human EGF receptor (EGFR). It binds with high affinity to the extracellular domain of the human EGFR. Cetuximab binds to the EGFR with an affinity that is approximately five- to ten-fold higher than that of endogenous ligands. Cetuximab blocks binding of endogenous EGFR ligands, resulting in inhibition of the function of the receptor. It further induces the internalization of EGFR, which can lead to downregulation of EGFR. Cetuximab also targets cytotoxic immune effector cells towards EGFR-expressing tumor cells (antibody-dependent cell-mediated cytotoxicity). The EGFR family (Her family) consists of four closely related protein tyrosine kinase receptors: EGFR (erbB-1, Her-1), erbB-2/neu (Her-2/neu), erbB-3 (Her-3) and erbB-4 (Her-4). EGFR signaling in tumor cells is responsible for regulating a diverse network of cellular functions that influence neoplastic growth, including proliferation, survival, DNA damage repair, adhesion, migration and neovascularization. EGFR is expressed at various levels in a number of human cancers of epithelial origin. It is almost invariably overexpressed in SCCHN. Specific ligands of EGFR are EGF and EGF-related peptides including TGF, amphiregulin and HB-EGF.