Additional factors associated with better prognosis in HPV-positive patients are nonsmoking status, node count (N0–2a), higher expression of p16, low/no EGFR expression, and high HPV copy numbers.5 The presence of wild-type p53 rather than mutant p53 may explain the improved response to CRT regimens; individual immune responses also may play a role. It should be noted that within the set of HPV-positive OPC is also a subset not driven primarily by HPV (ie, HPV has infected an already-mutated cancer cell); molecular analysis showing HPV-driven tumor characteristics can identify those with the best prognosis.5

At present, HPV status does not figure into recommended treatment strategies. Treatment is based on various CT/CRT and CRT strategies, as well as surgery—for those with resectable tumors. CRT has demonstrated survival and locoregional control benefits while preserving function and anatomic structures.12 For stage I and II OPC, surgery or RT are equally effective but RT may allow preservation of function.12 For stages III and IV, recommended options for multimodality treatment are surgery (where possible) followed by RT or CT; neoadjuvant CT followed by surgery and/or RT; or CRT.12

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In HNSCC, cetuximab added to platinum-based CT has shown promise in small studies, but response appears unrelated to HPV status. A study (n=39) with cetuximab as part of CT/CRT in mostly stage IV patients (64% HPV positive) found no difference in response based on HPV status. Three-year OS was 74%.19 In an open-label trial, bevacizumab added to CT/CRT for stage III-IVB HNSCC had acceptable additional toxicities and produced 2-year PFS of 75.9% and OS of 88%. About half of the patients were HPV-positive.20

Because E6/E7 are directly involved in oncogenesis and not found on normal cells, they make attractive targets for immunotherapy designed to enhance response to their specific antigens. Following positive results with a monoclonal antibody to HPV16 E6 in a mouse tumor model, phase 1 trials are planned or under way.5

The differential response of HPV-positive tumors to RT/CRT offers possible implications for treatment planning. O’Sullivan and colleagues identified a subgroup of patients with oropharyngeal cancer at low risk for distant metastases (HPV-positive, T1–3, N0–2a). The distant control rate in these patients was 93% (vs. 76% for patients with T4/N2b–3 disease) and was similar for RT or CRT.21 Further research is needed to determine whether some patients can receive less intensive therapy without increasing their risk of recurrence or treatment failure. 


The incidence of HPV-positive OPC, almost entirely related to high-risk serotype 16, has increased, and the number of cases is expected to surpass that of cervical cancers later this decade. It is apparent that HPV-positive OPC represents a distinct cancer type with specific risk factors, tumor biology, presentation, and response to treatment.7,17 Patients who are diagnosed with oropharyngeal cancer or HNSCC of unknown primary should be tested for HPV.5