Prognostication of Half-Life Clearance of Plasma EBV DNA in Previously Untreated Non-metastatic Nasopharyngeal Carcinoma Treated With Radical Intensity-Modulated Radiation Therapy

Abstract

Introduction: The prognostic role of plasma Epstein-Barr virus (EBV) DNA clearance when intensity-modulated radiotherapy (IMRT) and the 8th edition of American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM Staging Classification are fully implemented remains undeciphered. We investigated if its half-life clearance during radical treatment for non-metastatic nasopharyngeal carcinoma (NPC) was an early prognosticator. Patients and methods: Patients with previously untreated non-metastatic NPC were prospectively treated with radical IMRT and concurrent chemotherapy +/induction/adjuvant chemotherapy from 2014 to 2018. Their plasma EBV DNA was measured immediately before treatment followed by weekly schedules until 0 copy/ml in two consecutive measurements. Cox regression models were employed to identify prognostic factors. Results: Forty-five patients were prospectively recruited and analyzed. After a median follow-up of 30.3 months, 2 (4.5%), 1 (2.3%), and 6 (13.6%) patients experienced local, regional, and distant relapses, respectively. The median half-life clearance of plasma EBV DNA was 7.92 days. Those with half-life clearance of >15 days had a worse 3-years progression-free survival (PFS) (79.5 vs. 25.0%, p = 0.005), distant metastasis-free survival (DMFS) (85.0 vs. 31.3%, p = 0.009), and overall survival (OS) (91.3 vs. 75.0%, p = 0.024) when compared to those with a shorter half-life. Multivariable analyses demonstrated that only half-life (>15 days) was prognostic of DMFS [HR (95% CI): 4.91 (1.31; 18.39), p = 0.01] and OS [HR (95% CI): 5.24 (1.06; 26.05)] while half-life (>15 days) [HR (95% CI): 5.14 (1.28; 22.73), p = 0.02] and sum of pretreatment gross tumor volumes of the primary nasopharyngeal tumor and the radiologically positive neck nodes (GTV_P+N) [HR (95% CI): 1.01 (1.00; 1.03), p = 0.02] were prognostic of PFS. Chan et al. Kinetics of Plasma EBV DNA Conclusion: The half-life clearance of plasma EBV DNA was prognostic in non-metastatic NPC staged and treated in the contemporary era. Earlier biomarker surveillance during treatment should be considered. Clinical Trial Registration: This study has been registered with ClinicalTrials.gov (Identifier: NCT03830996).

The Most Efficacious Induction Chemotherapy Regimen for Locoregionally Advanced Nasopharyngeal Carcinoma: A Network Meta-Analysis

“…In particular, early responders with more rapid clearance of plasma EBV DNA during IC had a significantly longer OS. Similarly, our another recently published prospective study also demonstrated that the half-life clearance rate of plasma EBV DNA of 15 days, which is during the very early phase of radical treatment, was prognostic of distant metastasis-free survival (DMFS), PFS and OS ( 30 ). These two studies indicated the potential utility of real-time monitoring of plasma EBV DNA during IC for risk-adapted treatment intensity modification.…”

Monitoring and adapting cancer treatment using circulating tumor DNA kinetics: Current research, opportunities, and challenges

“…Subsequently, most patients who undergo definitive radiotherapy demonstrate a steady decline in ctDNA concentration over the course of treatment, measurable by weeks 2 and 3. The median half-life of this decline has been estimated at 3 to 8 days ( 89 , 90 ). Most of the patients clear ctDNA completely, and residual ctDNA at the end of treatment is a poor prognostic marker ( 52 , 53 , 91 , 92 ).…”

“…Increasing sampling allows for more granular observation of ctDNA kinetics and more precise estimation of the decay half-life. The importance of half-life was illustrated in a study of nonmetastatic NPC receiving radical intensity modulated radiotherapy with concurrent chemotherapy wherein clearance half-life was predictive of PFS ( 90 ). While postradiotherapy EBV DNA levels represent a more specific poor prognostic marker than mid-radiotherapy levels ( 93 ), persistent mid-radiotherapy EBV DNA could be a sensitive early predictor of recurrence risk.…”

A systematic review and recommendations on the use of plasma EBV DNA for nasopharyngeal carcinoma

“…Patients with more rapid clearance of plasma EBV DNA reflected a better tumour response and subsequently showed better survival outcomes. A recent prospective study by Chan et al on patients treated with radical intensity-modulated radiation therapy revealed that half-time clearance of plasma EBV DNA >15 days was associated with lower distant metastasis-free survival, PFS and OS [95]. (3) at the baseline before treatment; (4) before and during induction chemotherapy; (5) during concurrent chemoradiation (e.g.…”