Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative and HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion. Traditional staging of HNSCC using the tumour-node-metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where comorbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies.

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Background Patients with HPV-positive oropharyngeal squamous cell carcinoma (OPC) have high survival rates when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab, an antibody against the epidermal growth factor receptor, can preserve high survival rates and reduce treatment toxicity is unknown. Methods In a randomized, non-inferiority, multicenter trial, patients with locoregionally-advanced p16-positive OPC were stratified by American Joint Committee on Cancer T (T1-T2 vs. T3-T4) and N (N0-N2a vs. N2b-N3), Zubrod Performance Status (0 vs. 1), and tobacco smoking history (≤ vs. >10 pack-years) and randomized 1:1 to radiotherapy plus cetuximab 400 milligrams per square meter of body surface area (mg/m2), followed by 250 mgs/m2 for seven weekly doses or cisplatin 100 mgs/m2 for two doses, 21 days apart. The sample size was 800 eligible patients. The primary endpoint was overall survival (OS) with non-inferiority margin 1.45 (hazard ratio). Findings From June 2011 through July 2014, 849 patients (805 eligible; 399 cetuximab; 406 cisplatin) were randomized at 182 centers in the United States and Canada. With median follow-up 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criterion for OS. Estimated 5-year OS was 77·9% (95% confidence interval [CI] 73·4-82·5) in cetuximab group versus 84·6% (95%CI=80·6-88·6) in cisplatin group (hazard ratio [HR], 1·45, 1-sided 95% upper CI, 1·94; non-inferiority p=0·5056; 1-sided log-rank p=0.0163). PFS was significantly lower in cetuximab group than in cisplatin group (HR 1·72, 95%CI=1·29-2·29; 5-year rates, 67·3% vs. 78·4%), and LRF was significantly higher (HR 2·05, 95%CI=1·35-3·10; 5-year rates, 17·3% vs. 9·9%). The rate of moderate-to-severe toxicity that was acute (77·4% vs. 81·7%, p=0·1586) and late (16·5 vs. 20·4%, p=0·1904) was similar in the cetuximab and cisplatin groups, respectively. Interpretation For patients with HPV-positive OPC, radiotherapy plus cetuximab demonstrated inferior OS and PFS compared to radiotherapy plus cisplatin; toxicity rates were similar (NCT01302834). Funding National Cancer Institute USA, Eli Lilly and The Oral Cancer Foundation