Oropharynx SCC (p16/HPV−): Definitive Treatment

Oropharynx SCC (p16/HPV−): Definitive Treatment: overview

This algorithm covers definitive treatment of p16/HPV negative oropharyngeal squamous cell carcinoma, divided first by extent of disease. Early disease (T1 to T2, N0 to N1) can be treated with resection plus ipsilateral or bilateral neck dissection, which is single-modality therapy if the neck is pN0 to pN1, or with definitive radiotherapy; concurrent chemoradiation is the alternative for T1 to T2 N1 disease. Resectable locally advanced disease (T3 to T4 or N2 to N3) is managed with surgery and neck dissection, or with definitive concurrent cisplatin-based chemoradiation. For PD-L1 CPS 1 or higher (except N0), the chart adds neoadjuvant pembrolizumab, then surgery, then radiotherapy with pembrolizumab (plus cisplatin for extranodal extension or a positive margin), then adjuvant pembrolizumab, based on KEYNOTE-689.

Adjuvant therapy after surgery follows pathologic risk. pN0 without adverse features is observed, and pN1 without other risk factors may receive radiotherapy. Extranodal extension, with or without a positive margin, calls for cisplatin chemoradiation, supported by RTOG 9501. An isolated positive margin is managed with re-resection or radiotherapy or chemoradiation, and other risk features with radiotherapy with or without concurrent chemotherapy.

Step by step

• Early disease (T1 to T2, N0 to N1): resection plus ipsilateral or bilateral neck dissection (single modality if pN0 to pN1), or definitive radiotherapy.
• Early disease with T1 to T2 N1: concurrent chemoradiation as an alternative.
• Resectable locally advanced disease (T3 to T4 or N2 to N3): surgery plus neck dissection, or definitive concurrent chemoradiation with cisplatin.
• Locally advanced disease with PD-L1 CPS 1 or higher (except N0): neoadjuvant pembrolizumab, then surgery, then radiotherapy plus pembrolizumab (plus cisplatin if extranodal extension or positive margin), then adjuvant pembrolizumab (KEYNOTE-689).
• After surgery, pN0 without adverse features: observation; pN1 without other risk features: consider radiotherapy.
• Extranodal extension with or without a positive margin: adjuvant cisplatin chemoradiation (RTOG 9501).
• Positive margin alone: re-resection, or radiotherapy or chemoradiation; other risk features: radiotherapy with or without concurrent chemotherapy.

Trials behind this algorithm

• MACH-NC mena-analysis Lacas B et al, J of Radiother Oncol, 2021, PMID: 33515668
• KEYNOTE-689 Uppaluri R et al, NEJM, 2025; PMID: 40532178
• RTOG 9501 Cooper JS et al, N Engl J Med, 2004; PMID: 15128893