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Head and neck cancer is the sixth most common cancer, representing about 5% of all cancers. Each year, more than half a million new cases are diagnosed worldwide.1–3 Over the past decade, the important role of different growth factors and their receptors and signal transduction pathways in the genesis and progression of tumours has been well recognised, and their mechanism of action and interaction is gradually being unravelled.4–10 The ErbB family comprises four members: human epidermal growth factor receptor (EFGR; HER 1), HER2 (c-erb-B2), HER3 (cerb- B3) and HER4 (c-erb-B4).
Epidermal Growth Factor Receptor
EGFR and its ligand-transforming growth factor-alpha (TGF-α) are overexpressed in the vast majority of cases of squamous cell carcinoma of the head and neck (SCCHN). EGFR overexpression is an early event in carcinogenesis and steadily increases in parallel with histological abnormalities from hyperplasia, through carcinoma in situ to invasive carcinoma.11 EGFR overexpression is the result of an enhanced transcription or a gene amplification.12,13 There is a large body of evidence indicating that EGFR overexpression is a strong, independent and unfavourable prognostic factor for loco-regional control, disease-free survival and overall survival in SCCHN.14–21 Two of the potential EGFR-targeting strategies are currently in use. Monoclonal antibodies (MAbs) are directed at the extracellular domain of the receptor and at the small-molecule and adenosine tri-phosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) (see Table 1).22–29
MAbs targeting EGFR that are under clinical development include IMC225 (cetuximab), EMD-72000 (matuzumab), ABX-EGF (panitumumab), h-R3 (nimotuzumab), 2F8 (zalutumumab) and ICR62.22 The first MAb to enter the clinic was cetuximab (IMC225). Pre-clinically, it has antitumoral activity on its own and acts synergistically with chemotherapy and radiotherapy.25,26
Cetuximab is a chimeric human/murine immunoglobulin IgG1 antibody that binds with higher affinity to the EGFR than the natural ligands EGF and tumour necrosis factor-alpha (TNF-α). The cetuximab-bound EGFR is internalised and degraded without receptor phosphorylation and activation. The availability of EGFR on the cell surface is reduced and the receptor downregulated. The most common side effects are fever, chills, asthenia, nausea, transaminase elevation and skin toxicity.25,26 A recently published large, multicentre, international phase III trial30 randomised 424 patients with stage III or IV non-metastatic squamous cell carcinoma of the oropharynx, hypopharynx or larynx to radiotherapy alone or to radiotherapy in combination with weekly cetuximab. There was a significant increase in the median duration of loco-regional control (24.4 versus 14.9 months; p=0.005) and the median duration of survival (49 versus 29.3 months; p=0.03). The only differences in grade 3/4 acute toxicity were acneiform rash and infusion reactions, which occurred in 17 and 3% of patients, respectively. In particular, the grade 3/4 radiationrelated
mucosal toxicity was no worse in the cetuximab arm (54 versus 52%). The trial was conceived before the publication of a meta-analysis that clearly established the superiority of cisplatin-based chemoradiation over radiotherapy alone as definitive treatment for loco-regionally advanced SCCHN. Thus, the control arm used in the trial can no longer be considered the current standard of care for this population.