Integrating post-radiotherapy plasma Epstein-Barr virus DNA and TNM stage for risk stratification of nasopharyngeal carcinoma to adjuvant therapy

Abstract Background After curative radiotherapy (RT) or chemoradiation (CRT), there is no validated tool to accurately identify patients for adjuvant therapy in nasopharyngeal carcinoma (NPC). Post-radiotherapy circulating plasma Epstein-Barr virus (EBV) DNA can detect minimal residual disease and is associated with recurrence and survival independent of TNM stage. We aimed to develop and validate a risk model for stratification of NPC patients after completion of RT/CRT to observation or adjuvant therapy. Patients and methods The prospective multi-center 0502 EBV DNA screening cohort enrolled from 2006-2015 (n=745) was used for model development. For internal validation, we pooled independent patient cohorts from prospective clinical studies enrolled from 1997-2006 (n=340). For external validation, we used retrospective cohort of NPC patients treated at Sun Yat-sen University Cancer Center from 2009-2012 (n=837). Eligible patients had histologically confirmed NPC of UICC 7th Edition stage II-IVB who completed curative RT/CRT with or without neoadjuvant chemotherapy, had post-radiotherapy EBV DNA tested within 120 days after RT, and received no adjuvant therapy. The 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. Results Combining post-radiotherapy EBV DNA level (0, 1-49, 50-499, >=500 copies/ml) and TNM stage (II, III, IVAB), RPA model classified patients into low-, intermediate- and high-risk groups with 5-year OS of 89.4%, 78.5% and 37.2% respectively. The RPA low-risk group had comparable OS to TNM stage II (5-year OS 88.5%) but identified more patients (64.8% versus stage II 28.1%) that could potentially be spared adjuvant therapy toxicity. RPA model (c-index 0.712) showed better risk discrimination than either TNM stage (0.604) or post-RT EBV DNA alone (0.675) with improved calibration and consistence. These results were validated in both internal and external cohorts. Conclusion Combining post-radiotherapy EBV DNA and TNM stage improved risk stratification in NPC.