Age-Related Risk Stratification in HPV-Positive Oropharyngeal Cancer: Implications for Treatment De-Intensification

Although the AJCC eighth edition staging system incorporates HPV status, it remains insufficient to guide personalized treatment in HPV-positive oropharyngeal cancer (OPC). This study aimed to identify the optimal age threshold and evaluate its association with overall survival (OS) to improve risk stratification and inform individualized treatment strategies.

Data were extracted from the SEER database (2018-2021), the University Health Network (UHN), University of Toronto, and the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences (NCC). Only HPV-positive OPC cases with complete survival records were included. The optimal age threshold was identified using restricted cubic spline modeling in combination with a recursive partitioning approach. Prognostic factors beyond HPV status and AJCC eighth edition stage were evaluated using multivariable Cox proportional hazards models. Recursive partitioning analysis (RPA) was used to construct a risk stratification model. The primary endpoint was OS.

Of the 10 283 eligible patients (87.9% male; median age, 62 years), 2.7% had distant metastases at diagnosis. Restricted cubic spline analysis revealed that 62 years of age represents an important critical threshold. Multivariable Cox analysis revealed that patients younger than 62 years exhibited significantly improved OS (HR, 0.61; 95% CI, 0.54-0.70; p < 0.001). RPA stratified patients into five risk groups with distinct 2-year OS: extremely low (96.8%), low (93.7%), intermediate (86.1%), high (74.6%), and extremely high risk (47.5%). Among patients classified in the extremely low-risk group (T0-2N0-1M0 and younger than 62 years), no significant difference in OS was observed between those treated with radiotherapy alone and those treated with chemoradiotherapy. External validation in the UHN (N = 843) and NCC (N = 167) cohorts suggested that extremely low-risk patients might be spared concurrent chemotherapy.

This study developed a risk stratification model for patients with p16-positive OPC based on the AJCC eighth edition staging and age. Patients in the extremely low-risk group may derive limited benefit from concurrent chemotherapy, suggesting that its omission could be considered in selected patients and may help guide the design of future de-escalation trials.