Background: Plasma Epstein–Barr virus DNA (EBV-DNA) is an established prognostic biomarker in nasopharyngeal carcinoma (NPC). While baseline EBV-DNA reflects tumour burden, increasing interest has focused on on-treatment EBV-DNA dynamics as a marker of early molecular response (EMR), but heterogeneity in timepoints, EMR definitions and study designs limits clinical translation.
Objective: To systematically review and qualitatively synthesise the prognostic significance of plasma EBV-DNA dynamics measured during curative-intent therapy in locoregionally advanced, non-metastatic NPC.
Methods: This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement. PubMed/Medical Literature Analysis and Retrieval System Online, Embase, Scopus and Web of Science were searched (January 2004 to December 4, 2025). Eligible studies included prospective and observational designs reporting serial plasma EBV-DNA measurements during treatment and survival outcomes. Owing to heterogeneity in sampling timepoints, EMR constructs and EBV-DNA assays, no quantitative meta-analysis was performed. Risk of bias was assessed using design-appropriate tools.
Results: Twenty-one eligible reports, representing 20 analytically distinct study cohorts, met the inclusion criteria. Across treatment strategies and analytical approaches, unfavourable on-treatment EBV-DNA dynamics (persistent detectability, delayed clearance or adverse kinetic patterns) were consistently associated with inferior survival outcomes, particularly distant metastasis-free and event-free survival. In reports providing hazard ratios for distant metastasis-related endpoints, effect sizes were generally greater than 2. EBV-DNA rebound after initial clearance was also associated with unfavourable prognosis, although prospective validation remains required.
Conclusion: On-treatment and early post-radiotherapy EBV-DNA dynamics show consistent prognostic associations in locoregionally advanced NPC, but heterogeneous assays, sampling windows and response definitions preclude validated clinical decision thresholds. These measures should not guide treatment adaptation outside clinical trials; prospective standardisation and validation are required.
