EGFR Inhibition in the Treatment of Squamous Cell Carcinoma of the Head and Neck

& Hematology Review, 2014;10(2):152–6

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 06, 2014 Accepted October 29, 2014 Citation & 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: Mersiha.Hadziahmetovic@uhhospitals.org

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 platinumbased agent, most commonly high-dose cisplatin (100 mg/m2 q 3 weeks), and increasingly weekly cisplatin (30–40 mg/m2). 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— 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 easier for patients to tolerate, have been studied.14,15 Results of several phase II and III trials testing cetuximab as part of an intensified treatment approach for patients with SCCHN, whether as an addition to induction chemotherapy (IC) or to the concurrent CRT, have been published in recent years. The best known of these trials is a phase III study conducted by Bonner and colleagues that demonstrated that cetuximab in combination with radiotherapy also improves survival compared with radiation alone for patients with SCCHN.16,17 In this trial, 424 patients with stage III–IV SCC of the oropharynx, hypopharynx, or larynx were randomized to radiotherapy with or without cetuximab. The original publication reported that after a median follow-up of 4.5 years, a 10 % absolute overall survival (OS) benefit was observed in the concurrent cetuximab arm (45 % versus 55 %). Local-regional control was also significantly better with cetuximab (47 % versus 34 %). Of note, the patients who benefitted the most from receiving cetuximab were also treated with a concomitant boost radiation course, an accelerated fractionation approach that has been shown in a phase III randomized trial (RTOG 9003) to effect significantly improved local-regional control compared with the standard once-daily fractionation for locally advanced HNC.18 Moreover, the subgroup analysis favored radiotherapy alone in patients with a Karnofsky Performance Status (KPS) 60–80, and in patients 65 years or older. The highly anticipated RTOG (1016) trial comparing CRT with high-dose cisplatin versus bioradiotherapy (BRT) with cetuximab in patients with human papilloma virus (HPV)-related SCC of the oropharynx just completed accrual. The primary objective of this trial is to determine whether substitution of cisplatin with cetuximab will result in comparable 5-year OS.19

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Keywords: Cetuximab, EGFR inhibitor, CRT, squamous cell carcinoma of the head and neck