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Head and Neck Cancer EGFR Inhibition in the Treatment of Squamous Cell Carcinoma of the Head and Neck Mersiha Hadziahmetovic, MD 1 and Mitchell Machtay, MD 2 1. Assistant Professor of Radiation Oncology, University Hospitals Seidman Cancer Center, Firelands Regional Medical Center, Sandusky, Ohio, US; 2. Chairman, Department of Radiation Oncology, UH Case Medical Center and Professor, Radiation Oncology, CWRU School of Medicine, Cleveland, Ohio, US Abstract Squamous cell carcinoma of the mucosal surfaces in the head and neck (SCCHN) remains a therapeutic challenge in much of the world. Most patients present with locally and/or regionally advanced disease, and are offered curative (definitive) therapy in the form of external beam radiotherapy with a concurrent radiosensitizing systemic agent, most commonly platinum-based or targeting an epidermal growth factor receptor (EGFR). In this review, we will cover the literature and published data evaluating the use of EGFR inhibitors as part of the concurrent or postoperative regimen in the context of definitive treatment for patients with SCCHN, as well as its use in patients with recurrent or distantly metastatic disease. Keywords Cetuximab, EGFR inhibitor, CRT, squamous cell carcinoma of the head and neck Disclosure: Mersiha Hadziahmetovic, MD, and Mitchell Machtay, MD, have no conflicts of interest to declare. No funding was received in the publication of this article. Received: October 6, 2014 Accepted: October 29, 2014 Citation: Oncology & Hematology Review, 2014;10(2):152–6 Correspondence: Mersiha Hadziahmetovic, MD, University Hospitals Seidman Cancer Center at Firelands Regional Medical Center, 701 Tyler Street, Sandusky, OH 44870, US. E: Head and neck cancer (HNC) will affect more than an estimated 55,000 individuals in the US in 2014, the vast majority of these being squamous cell carcinoma (SCC), with 12,000 estimated deaths. 1 Worldwide, the figures for incidence and mortality are approximately 560,000 and 300,000, respectively. 2 The current standard of care for local-regionally advanced SCC of the pharynx and larynx is chemoradiotherapy with a platinum- based agent, most commonly high-dose cisplatin (100 mg/m 2 q 3 weeks), and increasingly weekly cisplatin (30–40 mg/m 2 ). In the last decade or so, targeted therapies against EGFR have also been studied in this patient population. EGFR is a receptor tyrosine kinase (TK), a member of the ErbB family of receptors, and is activated by binding of an epidermal growth factor and other specific ligands. Once activated, EGFR transitions from an inactive monomer to an active homo- or heterodimer, and thereby stimulates the downstream intracellular protein-TK activity, which can ultimately result in hallmarks of carcinogenesis, namely cell proliferation, blocked apoptosis, invasion and metastasis, and tumor-induced neovascularization. 3 It is now well-known that mutations that lead to constitutive activation and ultimately overexpression of EGFR are associated with several distinct malignancies. 4,5 Heretofore, six EGFR inhibitors have been approved by the US Food and Drug Administration (FDA) for use in non-small cell lung carcinoma; pancreatic carcinoma; HER2-overexpressing breast cancer; metastatic colorectal carcinoma (EGFR-overexpressing); and SCC of the head and neck. The inhibitors belong to one of two categories— 152 monoclonal antibodies (e.g., panitumumab and cetuximab) are intravenous agents whose mechanism of action is through extracellular binding of the EGFR with subsequent inhibition of downstream signaling pathways, whereas the TK inhibitors (e.g., erlotinib, gefitinib, and lapatinib) are oral agents whose mechanism of action is through intracellular binding and subsequent inhibition of downstream signaling pathways. The first EGFR inhibitor approved in 2004 by the FDA for use in SCCHN is a monoclonal antibody agent cetuximab (Erbitux ® ImClone, Bristol-Myers Squibb). Besides its proven in vitro and in vivo radiosensitization, its toxicity profile is also relatively and comparably favorable: it effects varying degrees of dermatologic toxicity, modest gastrointestinal toxicity with electrolyte abnormalities, and is also nonemetogenic. 6– 8 EGFR Inhibition in Combination with Radiotherapy as Definitive Treatment of SCCHN Concurrent chemoradiotherapy (CRT) improves survival and organ preservation for patients with local-regionally advanced SCCHN. 9–13 The National Comprehensive Cancer Network (NCCN) Guidelines maintain that the standard CRT approach for fit patients with locally advanced disease is upfront concurrent high-dose cisplatin and radiotherapy (Category 1 recommendation based upon high-level evidence and with uniform NCCN consensus). Due to toxicity with high-dose cisplatin, other concurrent systemic agents that have a more favorable toxicity profile, and are thereby © Tou c h ME d ica l ME d ia 2014