Development and validation of a risk model integrating plasma Epstein-Barr virus DNA (EBV DNA) level and TNM stage for stratification of nasopharyngeal cancer (NPC) to adjuvant therapy

Abstract

Background: Clinical guidelines for treatment decision in NPC are mainly based on the anatomical classification by UICC TNM staging. The concentration of plasma EBV DNA measured after radiotherapy (RT) or chemoradiation (CRT) is highly prognostic and independent of UICC stage, which may be useful in risk stratification of NPC patients to adjuvant therapy. Method(s): For model development, we used the prospective multi-center 0502 EBV DNA screening cohort (recruitment period 2006 - 2015; n = 745). Eligible patients had histologically confirmed NPC of stage II-IVB (UICC 7th Edition) and post-RT EBV DNA measured in plasma, no loco-regional disease or distant metastasis after RT/CRT and received no adjuvant therapy. Primary endpoint was overall survival (OS). We used recursive-partitioning analysis (RPA) to classify patients into groups of low-, intermediate- and high-risk of death. For internal validation, we pooled independent patient cohorts from previous published biomarker studies (1997-2006; n = 340). For external validation, we used external cohort of NPC patients treated at Sun Yat-sen University Cancer Center (2009-2012; n=837) using SYSU EBV DNA test. Result(s): RPA classified NPC patients based on the post-RT plasma EBV DNA level and UICC stage into three distinct prognostic groups (Table). RPA low risk group shared similar 5-yr OS (89.4%; 95% CI = 86.4-92.5%) as UICC stage II (88.5%; 84.0-93.1%) but included 2.3x number of patients that could be potentially spared of adjuvant therapy toxicity. The overall C-index of OS was 0.7118 for RPA risk group, compared to 0.6042 for TNM stage and 0.6747 for EBV DNA (both p<0.01). RPA risk group has improved hazard discrimination and calibration than either TNM stage or plasma EBV DNA level. The result was validated in both internal and external cohorts. Conclusion(s): Incorporation ofpost-RT plasmaEBV DNA level into UICC TNM stage improved risk stratification of NPC patients to adjuvant therapy.