**Background:** Induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) is the standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC). However, concurrent chemotherapy (CCT) is associated with increased toxicities, poor tolerance, and low completion rates, and its value in the intensity-modulated radiotherapy (IMRT) era remains controversial. Adjuvant chemotherapy (AC) compliance is also poor. Post-IC EBV DNA is a known independent predictor of treatment outcomes, but no prior study had evaluated de-intensified treatment based on post-IC EBV DNA status. This study aimed to compare the efficacy and toxicity of IC + radiotherapy (RT) versus IC + CCRT/AC in NPC patients with negative post-IC EBV DNA.
**Methods:** A total of 547 treatment-naive, pathologically confirmed NPC patients with negative plasma EBV DNA (<500 copies/mL) after IC, treated between September 2017 and November 2020, were retrospectively reviewed. All patients received cisplatin-based IC (TP, GP, or PF regimens) followed by IMRT, with or without concurrent cisplatin (30–40 mg/m² weekly or 75–80 mg/m² every three weeks) or adjuvant chemotherapy. Patients were classified into IC + RT (n=115) and IC + CCRT/AC (n=432) groups. Propensity score matching (PSM) was performed (1:1, caliper 0.1) to balance covariates including gender, age, T category, N category, clinical stage, pre-IC EBV DNA, IC regimen, IC cycle, and targeted therapy, yielding 99 patients per group. Survival outcomes were estimated using Kaplan–Meier methods and compared with log-rank tests. Multivariate Cox regression was used for prognostic analysis.
**Key Results:** With a median follow-up of 37 months (range 8–58 months) for the original cohort and 38 months (range 12–58 months) for the PSM cohort, the 3-year LRFS, DMFS, OS, and PFS for the whole group were 92.2%, 92.4%, 96.4%, and 84.4%, respectively. Before PSM, there were no significant differences between IC + RT and IC + CCRT/AC groups: 3-year LRFS 91.1% vs. 92.6% (p=0.94), DMFS 95.6% vs. 91.5% (p=0.08), OS 95.2% vs. 96.8% (p=0.80), and PFS 85.9% vs. 84.0% (p=0.38). After PSM, results remained non-significant: LRFS 90.7% vs. 92.7% (p=0.77), DMFS 96.8% vs. 93.7% (p=0.29), OS 94.5% vs. 93.9% (p=0.57), and PFS 84.7% vs. 85.6% (p=0.96). Multivariate analysis confirmed that treatment schedule was not an independent predictor for any survival outcome. Clinical stage was an independent predictor for LRFS (HR 1.97, 95% CI 1.06–3.67, p=0.03), DMFS (HR 2.48, 95% CI 1.26–4.85, p<0.01), OS (HR 4.56, 95% CI 1.78–11.63, p<0.01), and PFS (HR 2.06, 95% CI 1.28–3.31, p<0.01). The GP regimen was associated with superior OS (HR 0.27, 95% CI 0.11–0.70, p<0.01). Cumulative incidence of locoregional relapse and distant metastasis did not differ significantly between groups. Regarding toxicities, grade 3–4 leukocytopenia (13.6% vs. 2%, p=0.017) and anemia (6.8% vs. 0%, p=0.046) were significantly more frequent in the IC + CCRT group than IC + RT. Grade 2 mucositis was also more common in the IC + CCRT group (43.2% vs. 24.2%, p=0.023). Chemotherapy completion rates were poor: 39.2% of patients receiving weekly cisplatin received only 1–3 cycles, and 25.4% of AC patients completed only 1 cycle due to intolerable toxicities or refusal.
**Clinical Implications:** This is the first study to evaluate de-intensified treatment based on post-IC EBV DNA status in NPC. The findings suggest that for patients with negative post-IC EBV DNA, omitting concurrent or adjuvant chemotherapy after IC does not compromise survival outcomes while significantly reducing acute toxicities. Post-IC EBV DNA may serve as a practical, dynamic biomarker for risk stratification to guide individualized treatment decisions. However, the retrospective, single-center design and limited follow-up are important limitations. Prospective clinical trials are needed to confirm these findings, and the emergence of low-toxicity adjuvant therapies (e.g., metronomic capecitabine, immunotherapy) warrants further investigation in combination with IC.