Metastatic Patterns, Outcomes, and Prognostic Factors in De Novo Metastatic Head and Neck Cancer by Tumor HPV Status.

OBJECTIVES:To describe metastatic characteristics and outcomes in patients with de novo metastatic (cM1) head and neck squamous cell carcinoma (HNSCC). METHODS:cM1 HNSCC patients diagnosed between 2001 and 2024 were reviewed. Metastatic characteristics and management patterns were collected, including the timing of locoregional radiotherapy (LR-RT) relative to first-line systemic therapy. Overall survival (OS) was estimated using the Kaplan-Meier method, and multivariable Cox regression analyses (MVA) identified prognostic factors. RESULTS:Among 10,273 newly diagnosed HNSCC cases, 222 (2.2%) had cM1 disease (HPV-associated: 48/2593 [1.9%]; HPV-independent: 174/7680 [2.3%]). cM1 characteristics were similar between HPV-associated and HPV-independent disease, including oligometastatic presentation (1-5 lesions; 31% vs 43%, p = 0.21) and frequency of lung-only metastases (83% vs 77%, p = 0.46), although mediastinal involvement was more common in HPV-associated disease (40% vs 23%, p = 0.034). LR-RT was delivered to 191 (86%) patients: 127 (57%) as sole treatment, 55 (25%) before, and 9 (4%) after first-line systemic therapy. After median follow-up of 25 months, median OS was 7 months (6.0-8.8). On MVA, LR-RT (HR 0.49 [0.32-0.75]), HPV-associated disease (HR 0.62 [0.43-0.88]), ECOG 0-1 (HR 0.63 [0.47-0.86]), first-line immunotherapy (HR 0.52 [0.33-0.82]), and lung-only metastases (HR 0.67 [0.48-0.95]) were associated with longer OS. Among patients receiving LR-RT, a radiation dose ≥ 50 Gy was associated with improved OS (HR 0.53 [0.34-0.83]). CONCLUSIONS:cM1 HNSCC has a poor prognosis, highlighting a substantial unmet need. First-line immunotherapy and LR-RT, particularly with ≥ 50 Gy, were associated with improved OS and warrant prospective evaluation.