Development of a risk classification system combining TN-categories and circulating EBV DNA for non-metastatic NPC in 10,149 endemic cases

Fo-Ping Chen; Li Lin; Jin-Hui Liang; Sze Huey Tan; Enya H W Ong; Ying-Shan Luo; Luo Huang; Adelene Y L Sim; Hai-Tao Wang; Tian-Sheng Gao; Bin Deng; Guan-Qun Zhou; Jia Kou; Melvin L K Chua; Ying Sun

doi:10.1177/17588359211052417

Development of a risk classification system combining TN-categories and circulating EBV DNA for non-metastatic NPC in 10,149 endemic cases

Ther Adv Med Oncol. 2021 Oct 26:13:17588359211052417. doi: 10.1177/17588359211052417. eCollection 2021.

Authors

Fo-Ping Chen¹, Li Lin¹, Jin-Hui Liang², Sze Huey Tan³, Enya H W Ong⁴, Ying-Shan Luo¹, Luo Huang⁴, Adelene Y L Sim⁴, Hai-Tao Wang⁴, Tian-Sheng Gao², Bin Deng², Guan-Qun Zhou¹, Jia Kou¹, Melvin L K Chua⁵, Ying Sun⁶

Affiliations

¹ Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
² Department of Radiation Oncology, Wuzhou Red Cross Hospital, Wuzhou, China.
³ Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore.
⁴ Division of Radiation Oncology, National Cancer Centre Singapore, Singapore.
⁵ Division of Radiation Oncology, Department of Head and Neck and Thoracic Cancers, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610.
⁶ Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, No. 651 Dongfeng Eastern Road, Guangzhou 510060, Guangdong, China.

Abstract

Background: The objective of this study was to construct a risk classification system integrating cell-free Epstein-Barr virus (cfEBV) DNA with T- and N- categories for better prognostication in nasopharyngeal carcinoma (NPC).

Methods: Clinical records of 10,149 biopsy-proven, non-metastatic NPC were identified from two cancer centers; this comprised a training (N = 9,259) and two validation cohorts (N = 890; including one randomized controlled phase 3 trial cohort). Adjusted hazard ratio (AHR) method using a two-tiered stratification by cfEBV DNA and TN-categories was applied to generate the risk model. Primary clinical endpoint was overall survival (OS). Performances of the models were compared against American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) 8th edition TNM-stage classification and two published recursive partitioning analysis (RPA) models, and were validated in the validation cohorts.

Results: We chose a cfEBV DNA cutoff of ⩾2,000 copies for optimal risk discretization of OS, disease-free survival (DFS) and distant metastasis-free survival (DMFS) in the training cohort. AHR modeling method divided NPC into six risk groups with significantly disparate survival (p < 0.001 for all): AHR1, T1N0; AHR2A, T1N1/T2-3N0 cfEBV DNA < 2,000 (EBV_low); AHR2B, T1N1/T2-3N0 cfEBV DNA ⩾ 2,000 (EBV_high) and T1-2N2/T2-3N1 EBV_low; AHR3, T1-2N2/T2-3N1 EBV_high and T3N2/T4N0 EBV_low; AHR4, T3N2/T4 N0-1 EBV_high and T1-3N3/T4N1-3 EBV_low; AHR5, T1-3N3/T4 N2-3 EBV_high. Our AHR model outperformed the published RPA models and TNM stage with better hazard consistency (1.35 versus 3.98-12.67), hazard discrimination (5.29 versus 6.69-13.35), explained variation (0.248 versus 0.164-0.225), balance (0.385 versus 0.438-0.749) and C-index (0.707 versus 0.662-0.700). In addition, our AHR model was superior to the TNM stage for risk stratification of OS in two validation cohorts (p < 0.001 for both).

Conclusion: Herein, we developed and validated a risk classification system that combines the AJCC/UICC 8th edition TN-stage classification and cfEBV DNA for non-metastatic NPC. Our new clinicomolecular model provides improved OS prediction over the current staging system.

Keywords: Epstein-Barr virus DNA; TNM stage; adjusted hazard ratio; nasopharyngeal carcinoma; risk stratification.