Imaging-Detected Extranodal Extension in p16-Positive Oropharyngeal Cancer: Secondary Analysis of RTOG 1016.

Importance: Imaging-detected extranodal extension (iENE) has been included in the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) protocol tumor-node-metastasis 9th edition staging system (TNM9) for human papillomavirus (HPV)-mediated (p16-positive) oropharyngeal cancer (HPV-positive OPC). Objective: To confirm the new TNM9 staging system on a prospective dataset. Design, Setting, and Participants: This prognostic study included patients with HPV-positive OPC with clinically node-positive disease treated at 182 health care centers in the US and Canada and enrolled in the NRG Radiation Therapy Oncology Group (RTOG) 1016 trial between 2011 and 2014 were included. Deidentified images were reviewed between September and December 2021. Data were analyzed between May and September 2023. Exposure: Computed tomography simulation scans were reviewed by 2 expert head and neck radiologists documenting the presence of iENE. Main Outcomes and Measures: Kaplan-Meier analysis was used to estimate overall survival (OS) and progression-free survival (PFS). Cumulative incidence curves were generated for locoregional failure (LRF) and distant metastasis. Univariate (UVA) and multivariate analyses (MVA) were performed incorporating iENE with other known prognostic factors. The TNM9 clinical nodal schema incorporating iENE was compared with the previous TNM8. Model goodness of fit and comparison of models was done using Akaike information criterion (AIC) and Harrell concordance statistic (C index). Results: Of the 987 patients enrolled in NRG RTOG 1016, 586 met inclusion criteria (median age, 58 years [range, 33-83 years]; 534 male [91.1%]), 350 (60%) of whom had iENE. Median (IQR) follow-up was 4.2 (3.3-5.0) years. Patients with iENE had inferior 5-year OS (79.2% vs 87.0%; difference, 7.8% [95% CI, 1.2%-14.4%]) and 5-year PFS (68.8% vs 80.4%; difference, 11.6% [95% CI, 4.1%-19.2%]) compared with those without iENE. On MVA, iENE was independently associated with inferior OS (HR, 1.63; 95% CI, 1.04-2.56) and PFS (HR, 1.78; 95% CI, 1.24-2.57). TNM9 and TNM8 clinical nodal schemas had similar performance in terms of C index and AIC (TNM8: C, 0.73 [95% CI, 0.68-0.78]; AIC = 1109.34 vs TNM9: C, 0.72 [95% CI, 0.67-0.77]; AIC = 1112.70). Conclusions and Relevance: This study showed that the updated TNM9 clinical nodal schema, in which patients with iENE-positive disease are upstaged 1 stratum from their TNM8 clinical N category, discriminates better than the TNM8 category between patients. Trial Registration: ClinicalTrials.gov Identifier: NCT01302834.