Background: Increasing use of transoral robotic surgery (TORS) for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is likely to impact recurrence patterns and outcomes. Profiling HPV+ HNSCC recurrences after TORS and identifying features predictive of lethal outcome would facilitate tailoring adjuvant therapy and guide surveillance post-therapy. This study uses long term follow-up of patients at the first institution to bring TORS into clinical use to describe the recurrence patterns, distinguish outcomes associated with distinct patterns, and create a risk model for lethal recurrence. Methods: This retrospective cohort study at a single academic tertiary center analyzed 634 consecutive, treatment-naïve HPV+ HNSCC patients receiving TORS and neck dissection for clinical features at presentation and pathologic traits identified by surgical resection. The main outcomes were distant metastatic recurrence (DMR) and locoregional recurrence (LRR). Multivariate logistic regression with backward stepwise elimination was used to identify features associated with recurrence. Results: 6.5% of patients developed DMR at a median of 12.4 months after surgery and had a 5-year overall survival (OS) of 52.5% (95% CI, 33.9%-68.2%), whereas the 6.2% patients developing LRR alone had 5-year OS of 83.3% (95% CI, 66.2%-92.2%; P =.01). After recurrence, 5-year progression-free survival was 24.7% (95% CI, 11.4%-40.7%) for DMR cases and 85.7% (95% CI, 65.1-94.6%) for cases with LRR alone (P <.001). Comparing recurrent cases to recurrence-free controls showed DMR to be independently associated with positive surgical margins (AOR 5.7; 95% CI, 2.1-15.7) and advanced clinical stage at presentation (AOR 6.5; 95% CI, 1.9-23.0). Positive margins increased DMR risk by 4.2-fold and reduced 5-year disease-free survival (P <.001) in early-stage cases (Table), which comprised 95% of the cohort. By contrast, isolated LRR was associated with failure to receive indicated adjuvant therapy and was usually controllable by salvage therapy. Conclusions: Based on the largest single institution cohort reported to date, long term oncologic outcomes for HPV+ HNSCCs after TORS are excellent overall. While DMR is often fatal, LRR is salvageable with durable disease control. In addition to standard staging criteria, positive margins indicate substantially higher risk of DMR but not LRR. A risk model for DMR that incorporates margin status after TORS is relevant for guiding clinical trial design and whole-body surveillance.

a. Coefficient in logistic regression model. Intercept is -2.2