Failure pattern and salvage in head and neck cancer of unknown primary: A national study by DAHANCA

Background: Failure patterns in patients with head and neck squamous cell carcinoma of unknown primary (HNSCCUP) depend on disease etiology and treatment type and extent. Treatment strategies may include radiotherapy to address any potential mucosal tumor sites, or alternatively, the omission of mucosal irradiation to permit targeted intervention should a primary tumor subsequently emerge. The Danish 2013 guidelines employed both strategies based on N-classification and Epstein-Barr Virus status, but not Human Papilloma Virus (HPV) status. The present study aimed to analyze failure patterns in a complete, nationwide Danish cohort of patients with HNSCCUP, with a focus on HPV status, treatment targets, and salvage outcomes. Materials & Methods: All HNSCCUP patients treated in the period 2014 to 2020, were identified in the DAHANCA database. An image-based pattern of failure analysis was conducted to evaluate the extent of primary treatment coverage at sites of recurrence. Results: In a consecutive cohort of 254 HNSCCUP patients, 43 % had HPV-associated disease (p16 positivity). Treatment modalities included definitive neck dissection (dND) (n = 60) and treatment regiments involving intensity modulated radiotherapy (IMRT, n = 194); either postoperative or primary IMRT with or without adjuvant chemotherapy. 71 patients (28 %) experienced failure within 5 years. Anatomical localization of emerging primaries depended on HPV status and primary treatment modality. Higher rates of emerging primaries were seen in the dND group (35 %) compared to the IMRT group (6 %), with salvage treatment resulting in cure rates of 78 % and 27 %, respectively. Most regional failures in the IMRT group originated within elective clinical target volumes (89 %). No significant difference in loco-regional failure was observed when comparing the dND group with the IMRT group, when including salvage effects. Conclusion: The study findings support a personalized treatment strategy guided by HPV status and highlight the importance of including salvage outcomes in treatment efficacy analyses.