The addition of pretreatment plasma Epstein-Barr virus DNA into the eighth edition of nasopharyngeal cancer TNM stage classification.

The eighth edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage classification (TNM) for nasopharyngeal carcinoma (NPC) was launched. It remains unknown if incorporation of nonanatomic factors into the stage classification would better predict survival. We prospectively recruited 518 patients with nonmetastatic NPC treated with radical intensity-modulated radiation therapy ± chemotherapy based on the eighth edition TNM. Recursive partitioning analysis (RPA) incorporating pretreatment plasma Epstein-Barr virus (EBV) DNA derived new stage groups. Multivariable analyses to calculate adjusted hazard ratios (AHRs) derived another set of stage groups. Five-year progression-free survival (PFS), overall survival (OS) and cancer-specific survival (CSS) were: Stage I (PFS 100%, OS 90%, CSS 100%), II (PFS 88%, OS 84%, CSS 95%), III (PFS 84%, OS 84%, CSS 90%) and IVA (PFS 71%, OS 75%, CSS 80%) (p < 0.001, p = 0.066 and p = 0.002, respectively). RPA derived four new stages: RPA-I (T1-T4 N0-N2 & EBV DNA <500 copies per mL; PFS 94%, OS 89%, CSS 96%), RPA-II (T1-T4 N0-N2 & EBV DNA ≥500 copies per mL; PFS 80%, OS 83%, CSS 89%), RPA-III (T1-T2 N3; PFS 64%, OS 83%, CSS 83%) and RPA-IVA (T3-T4 N3; PFS 63%, OS 60% and CSS 68%) (all with p < 0.001). AHR using covariate adjustment also yielded a valid classification (I: T1-T2 N0-N2; II: T3-T4 N0-N2 or T1-T2 N3 and III: T3-T4 N3) (all with p < 0.001). However, RPA stages better predicted survival for PS and CSS after bootstrapping replications. Our RPA-based stage groups revealed better survival prediction compared to the eighth edition TNM and the AHR stage groups.

Lee VH ，Kwong DL ，Leung TW ，Choi CW ，O'Sullivan B ，Lam KO ，Lai V ，Khong PL ，Chan SK ，Ng CY ，Tong CC ，Ho PP ，Chan WL ，Wong LS ，Leung DK ，Chan SY ，So TH ，Luk MY ，Lee AW ... -  《-》

Proposed modifications and incorporation of plasma Epstein-Barr virus DNA improve the TNM staging system for Epstein-Barr virus-related nasopharyngeal carcinoma.

The prognosis of patients who have Epstein-Barr virus (EBV)-related nasopharyngeal carcinoma (NPC) in which the tumor tissues harbor EBV have a better prognosis than those without EBV-related NPC. Therefore, the eighth edition of the TNM staging system could be modified for EBV-related NPC by incorporating the measurement of plasma EBV DNA. In total, 979 patients with NPC who received intensity-modulated radiotherapy (IMRT) were retrospectively reviewed. Recursive partitioning analysis was conducted based on tumor (T) classification, lymph node (N) classification, and EBV DNA measurement to derive objectively the proposed stage groupings. The validity of the proposed stage groupings was confirmed in a prospective cohort of 550 consecutive patients who also received with IMRT. The pretreatment plasma EBV DNA level was identified as a significant, negative prognostic factor for progression-free survival and overall survival in univariate analysis (all P < .001) and multivariate analysis (all P < .05). Recursive partitioning analysis of the primary cohort to incorporate EBV DNA generated the following proposed stage groupings: stage RI (T1N0), RIIA (T2-T3N0 or T1-T3N1, EBV DNA ≤2000 copies/mL), stage RIIB (T2-T3N0 or T1-T3N1, EBV DNA >2000 copies/mL; T1-T3N2, EBV DNA ≤2000 copies/mL), stage RIII (T1-T3N2, EBV DNA >2000 copies/mL; T4N0-N2), and stage RIVA (any T and N3). In the validation cohort, the 5-year progression-free survival rate was 100%, 87.9%, 76.7%, 68.7%, and 50.4% for proposed stage RI, RIIA, RIIB, RIII, and RIV NPC, respectively (P < .001). Compared with the eighth edition TNM stage groupings, the proposed stage groupings incorporating EBV DNA provided better hazard consistency, hazard discrimination, outcome prediction, and sample size balance. The proposed stage groupings have better prognostic performance than the eighth edition of the TNM staging system. EBV DNA titers should be included in the TNM staging system to assess patients who have EBV-related NPC.

Guo R ，Tang LL ，Mao YP ，Du XJ ，Chen L ，Zhang ZC ，Liu LZ ，Tian L ，Luo XT ，Xie YB ，Ren J ，Sun Y ，Ma J ... -  《-》

Comparison between the seventh and eighth edition of the AJCC/UICC staging system for nasopharyngeal cancer integrated with pretreatment plasma Epstein-Barr virus DNA level in a non-Chinese population: secondary analysis from a prospective randomized tria

To validate the eighth edition of the AJCC/UICC staging system in nasopharyngeal cancer (NPC) patients who were uniformly treated in a prospective randomized study using intensity-modulated radiation therapy and to investigate the prognostic value of plasma Epstein-Barr virus (EBV) DNA level when incorporated into the TNM staging. Between October 2010 and September 2015, non-metastatic NPC patients were treated with concurrent chemoradiation followed by adjuvant chemotherapy. Pretreatment images of 205 patients were reviewed by two radiologists to determine the TNM classification according to the seventh and eighth editions of the AJCC/UICC staging system. Overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated. Harrell's C concordance index (C-index) and Akaike information criterion (AIC) were used to compare the staging models. Recursive partitioning analysis (RPA) was conducted and incorporated with plasma EBV DNA. Overall, the eighth edition showed higher C-indexes and lower AIC values in nodal classification and stage groups, indicating a better discrimination performance and better goodness of fit, but showed similar separation for T classification compared with the seventh edition. The integration of pretreatment EBV values (<2300 vs ≥2300 copies/ml) to the eighth edition AJCC/UICC staging system allowed the classification of patients into three RPA categories and further lowered the AIC value and increased the C-index for OS. The eighth edition of the AJCC/UICC staging system had higher prognostic values in terms of OS, PFS and DMFS than the previous edition. An integration of pretreatment plasma EBV DNA into the next AJCC/UICC staging could improve the outcome prediction especially in poor risk groups who might benefit from treatment intensification.

Kitpanit S ，Jittapiromsak N ，Sriyook A ，Prayongrat A ，Kannarunimit D ，Chakkabat C ，Lertbutsayanukul C ... -  《-》

Plasma Epstein-Barr viral DNA complements TNM classification of nasopharyngeal carcinoma in the era of intensity-modulated radiotherapy.

Zhang L ，Tang LQ ，Chen QY ，Liu H ，Guo SS ，Liu LT ，Guo L ，Mo HY ，Zhao C ，Guo X ，Cao KJ ，Qian CN ，Zeng MS ，Shao JY ，Sun Y ，Ma J ，Hong MH ，Mai HQ ... -  《Oncotarget》

Individualized concurrent chemotherapy by pretreatment plasma Epstein-Barr viral DNA in II-III stage nasopharyngeal carcinoma: A propensity score matching analysis using a large cohort.

To ascertain the treatment effect of concurrent chemotherapy (CCT) in stage II-III nasopharyngeal carcinoma (NPC) patients with different Epstein-Barr virus (EBV) DNA level in intensity-modulated radiotherapy (IMRT) era. A total of 2742 patients diagnosed with stage II-III NPC were involved in this study. Patients received IMRT with/without CCT. Overall survival (OS) was the primary endpoint. Receiver operating characteristics curve was used to determine the cut-off value of pre-DNA based on OS. After propensity score matching, the role of CCT was explored in patients with different EBV DNA level. In our cohort, the cut-off value of pre EBV DNA was 1460 copies/mL (area under curve [AUC], 0.695-0.769; sensitivity, 0.766; specificity, 0.599). Patients with high EBV DNA level showed poor survival in OS, progression free survival (PFS), locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS). In patients with EBV DNA level >1460 copies/mL, the concurrent chemoradiotherapy (CCRT) group achieved higher 3-year OS compared with IMRT groups. However, the CCRT and IMRT groups showed comparable OS in patients with EBV DNA ≤1460 copies/mL. In multivariate analyses, CCT was a protective factor for OS, PFS, and LRFS in high-risk patients (EBV DNA level >1460 copies/mL), while not an independent prognostic factor among the low-risk patients (EBV DNA level ≤1460 copies/mL). Pre-EBV DNA could be a useful tool to guide individualized treatment for stage II-III NPC patients. Additional CCT to IMRT improved the survival for patients with high pre-EBV DNA, while those with low pre-EBV DNA could not.

Sun XS ，Chen WH ，Liu SL ，Liang YJ ，Chen QY ，Guo SS ，Wen YF ，Liu LT ，Xie HJ ，Tang QN ，Li XY ，Yan JJ ，Mai HQ ，Tang LQ ... -  《Cancer Medicine》