A time-adapted risk stratification framework guided by longitudinal post-radiotherapy EBV DNA clearance for high-risk nasopharyngeal carcinoma patients

Abstract Purpose Patients with nasopharyngeal carcinoma (NPC) exhibiting persistent EBV DNA positivity throughout treatment (a “D-D-D” trajectory) represent a high-risk group with undefined management strategies. This study aimed to define critical post-radiotherapy timepoints to establish a precision surveillance strategy for these patients. Methods In a longitudinal cohort of non-metastatic “D-D-D” NPC patients, plasma Epstein-Barr virus (EBV) DNA was quantified at 1.5, 3, 6, 9, and 12 months post-radiotherapy. A time-dependent Cox model was employed to evaluate the dynamic prognostic value of EBV DNA status. Model performance was rigorously compared using Harrell’s C-index, the Akaike information criterion, and net reclassification improvement. Classification metrics, including sensitivity, specificity, and predictive values, were analyzed to identify clinically actionable decision points. Results Among 295 patients, early clearance by 1.5 months (10.5% of the cohort) conferred favorable survival, comparable to the “D-D-U” subgroup from our previous analysis. The 12-month EBV DNA status emerged as the strongest independent predictor of disease progression (adjusted HR = 2.804, 95% CI: 2.273–3.460, P < 0.001), offering high specificity (98.6%) but delayed intervention. In contrast, the 1.5-month timepoint, while highly sensitive (95.0%), generated an unactionable alert rate (89.0%). The 3-month assessment optimally balanced these parameters, maintaining substantial sensitivity (76.7%) within a clinically actionable alert rate (65.5%). Conclusions We propose a time-adapted risk stratification framework wherein the 3-month assessment identifies patients for intensified surveillance, while persistent EBV DNA at 12 months identifies a population at high risk of progression. The clinical benefit of timepoint-guided interventions warrants prospective randomized investigation. Clinical trial number Not applicable