Do not try this at home: patterns and outcomes of radiation dose de-escalation in p16-positive oropharyngeal carcinoma.

INTRODUCTION: Radiation dose de-escalation for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has been actively investigated to reduce long-term toxicity. Following the recent failure of randomized non-inferiority trials, the real-world adoption and outcomes of de-escalated radiation remain unclear. We evaluated contemporary patterns of dose de-escalation and associated overall survival (OS) in a national cohort. METHODS: The National Cancer Database was queried for patients diagnosed from 2018-2022 with p16-positive OPSCC meeting NRG-HN005 eligibility criteria (cT1-2N1 or cT3N0-1) treated with definitive external beam radiation therapy without primary surgery. Dose-de-escalated radiation therapy (DDRT) was defined as 50.0-65.9 Gy; standard-dose radiation therapy (SDRT) as ≥66.0 Gy. Multivariable logistic regression identified predictors of DDRT. OS was estimated using Kaplan-Meier methods with log-rank testing and 2-month landmark analysis. RESULTS: Among 14,869 patients, 1,119 (7.5%) received DDRT. DDRT was more frequently delivered at academic centers (50.3% vs 40.0%, p<0.001). On multivariable analysis, academic facility type (Odds Ratio: 1.76, 95% Confidence Interval 1.31-2.43, p<0.001), more recent year of diagnosis, and geographic region were independently associated with DDRT. Three-year OS was inferior with DDRT compared with SDRT (82.1% vs 88.9%, p<0.001). Among patients receiving first-course chemotherapy, DDRT remained associated with worse OS (82.5% vs. 89.8%, p<0.001). No significant difference was observed among patients not receiving chemotherapy; however, this subgroup was small and likely underpowered to detect a meaningful difference. Landmark analysis yielded consistent findings. CONCLUSION: Radiation dose de-escalation remains infrequent in contemporary U.S. practice but is more commonly delivered at academic centers. In this population-based analysis, de-escalation was associated with inferior overall survival, aligning with recent randomized evidence. Reduced-dose radiation should remain investigational pending biomarker-guided selection strategies.