Management of HPV+ head and neck squamous cell carcinoma with unknown primary in the era of treatment de-escalation

Background: Management of HPV+ HNSCC with unknown primary (SCCUP) remains controversial. A transoral surgery (TOS) for SCCUP with concurrent neck dissection (ND) has excellent rates of primary lesion detection and removal. This approach allows pathologic staging, directed adjuvant radiation therapy (RT), reduced radiation doses, and decreased rates of chemotherapy. De-escalation trials have largely excluded patients with SCCUP. Methods: Single-center retrospective cohort analysis of patients with p16+ SCCUP between July 2012 and December 2021. Only patients without evidence of a primary tumor on physical or PET-CT exams were included. Kaplan-Meier estimates were computed for both disease-free survival (DFS) and overall survival (OS) for patients treated with standard of care versus on-trial. Details of demographics, tumor staging, treatment modalities, recurrence, and rates of gastrostomy tube placement were also analyzed. Results: 66 patients were included, with 13 patients treated on a de-escalation trial. The primary lesion was detected in 57 patients (86.4%). 5-year OS for the on-trial and standard-of-care groups were 100% and 94.7%, respectively, and 5-year DFS estimates were 100% and 92.8%. Patients treated on-trial had lower radiation doses to the ipsilateral pharyngeal constrictor, ipsilateral salivary glands, oral cavity, and mandible. Conclusion: Patients with HPV+ SCCUP treated with TOS and risk-directed adjuvant therapy have excellent OS and DFS, including patients enrolled in de-escalation trials. The majority of primary lesions are found intra-operatively with adequate margin clearance, allowing these patients to be treated similar to other early-stage HPV+ SCC patients. Patients on de-escalation trials received less radiation to organs at risk.