Oral chemotherapy versus observation alone in nasopharyngeal carcinoma patients with persistently detected circulating cell-free Epstein-Barr virus DNA during follow-up

Aim Despite the high risk of tumor recurrence, patients with nasopharyngeal carcinoma (NPC) with persistently (at least twice) detected circulating cell-free Epstein-Barr virus (EBV) DNA levels during follow-up are routinely recommended to keep observation. For these patients, whether administering more aggressive treatment could improve survival outcomes remains unknown. Materials and methods We retrospectively included 431 patients with nonmetastatic NPC with persistently detected EBV DNA during follow-up, who do not have clinical or imaging evidence of recurrence. Among these patients, 79 were administered oral chemotherapy, and the remaining 352 underwent observation alone. Baseline characteristics were balanced with propensity score matching (PSM) analysis. The primary endpoint was modified disease-free survival (mDFS), defined as time from detectable EBV DNA result to tumor recurrence or death. The secondary endpoints were disease-free survival (DFS) and overall survival (OS). Results One-to-three PSM resulted in 251 eligible patients (oral chemotherapy group, 73; observation group, 178). In the matched cohort, the oral chemotherapy group had higher median mDFS (12.9 months [95 % confidence interval [CI] 9.6–16.3] vs. 6.8 months [95 % CI 5.8–7.8], p = 0.009) and DFS (24.1 months [95 % CI 18.5–29.7] vs. 16.7 months [95 % CI 14.4–19.1], p = 0.035) than the observation group. The median OS was numerically higher in the oral chemotherapy group than in the observation group (57.9 months [95 % CI 42.5–73.3] vs. 50.8 months [95 % CI 39.7–61.9], p = 0.71). A consistent benefit favoring oral chemotherapy was observed for mDFS in all subgroups analyses for male, <45 years, stage III-IVa disease, pretreatment EBV DNA load ≥ 4,000 copies/mL, no induction chemotherapy, or a detectable EBV DNA load ≥ 1,200 copies/mL. After adjusting for other confounders in the multivariate analysis, oral chemotherapy remained a significantly favorable factor for both mDFS (hazard ratio [HR] 0.67, 95 % CI 0.50–0.89; p = 0.006) and DFS (HR 0.68, 95 % CI 0.51–0.91; p = 0.01), but not a significant factor for OS (HR 0.89, 95 % CI 0.62–1.27; p = 0.52). Conclusions In patients with NPC having persistently detected EBV DNA levels but without clinical or imaging evidence of recurrence during follow-up, oral chemotherapy significantly prolongs mDFS and DFS. Employing oral chemotherapy as a more aggressive treatment option, as opposed to mere observation, could potentially benefit these patients, although further prospective validation is necessitated.