Pretreatment EBV ‐ DNA / TLG ‐Based Risk Stratification Is Associated With Survival Outcomes in Nonmetastatic Nasopharyngeal Carcinoma: An Exploratory Study

ABSTRACT Whether combining pretreatment plasma Epstein–Barr virus DNA (EBV‐DNA) with 18F‐FDG PET/CT‐derived total lesion glycolysis (TLG) improves prognostic stratification in nonmetastatic nasopharyngeal carcinoma (NPC) is unclear, particularly in nonendemic populations. We retrospectively analyzed 86 eligible nonmetastatic NPC patients treated with definitive radiotherapy (2010–2024) at a single nonendemic‐region institution. EBV‐DNA (prespecified cutoff 3500 copies/mL) and TLG (cutoff 200, ROC‐derived within this cohort) were dichotomized. Both were available in 59/86 patients (68.6%), who differed from the rest in nodal and overall stage and in RT technique. Baseline PET/CT was in‐house in 57 of 86 patients, and a robustness analysis in that subgroup is reported. Given limited events (13 PFS, 9 OS), Cox analyses are exploratory and were supplemented with penalized regression and bootstrap validation. At a median follow‐up of 75.5 months, 5‐year PFS and OS for the whole cohort ( n = 86) were 81.1% and 85.9%. The EBV‐DNA high /TLG high subgroup remained associated with inferior PFS after adjustment in an exploratory model (adjusted HR = 3.97, 95% CI: 1.32–11.93) and, in a single‐variable model, with inferior OS (HR = 4.13, 95% CI: 1.10–15.52). Discrimination was comparable to the individual‐biomarker model for PFS and lower for OS. Five‐year PFS fell monotonically across the four risk groups in the complete‐case cohort ( n = 59; 89.7%–58.3%). OS differed across groups (log‐rank p = 0.044) but was not strictly monotonic, with wide, overlapping confidence intervals. This two‐biomarker model is hypothesis‐generating and needs prospective, multicenter validation before any consideration of risk‐adapted treatment.