BACKGROUND 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. METHODS 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. RESULTS 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 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. CONCLUSIONS 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.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.31741

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

The clinical utility of plasma Epstein-Barr virus DNA assays in nasopharyngeal carcinoma: the dawn of a new era?: a systematic review and meta-analysis of 7836 cases.

Purpose: Predicting prognosis and treatment outcomes for patients with for nasopharyngeal carcinoma (NPC) has been difficult due to the heterogeneous nature of the disease This study aimed to evaluate pretreatment copy number of plasma Epstein-Barr virus (EBV) DNA as an outcome marker for survival in NPC.

Methods: MEDLINE, CENTRAL and Embase databases were searched until April 7, 2015. Included studies were randomized controlled trials, two-arm prospective studies, or retrospective studies in patients with newly diagnosed NPC. The primary outcome was overall survival and secondary outcomes were progression-free, relapse-free, disease-free and distant metastasis-free survival. Sensitivity, quality and publication bias assessments were performed. 

Results: Sixteen studies were included in the meta-analysis, with a total of 7698 patients. For overall survival, pooled HR was 3.005 (95% confidence interval [CI] = 2.245–4.022; P < 0.001), indicating that higher levels of EBV DNA were associated with a greater risk of death. Pooled estimates for relapse-free, disease-free, progression-free and distant metastasis-free survival indicated that higher levels of EBV DNA were associated with an increased risk of relapse, disease recurrence, disease progression and distant metastasis in comparison with lower levels of EBV DNA (P values < 0.001). 

Conclusion: This meta-analysis found that high EBV DNA levels indicate poor prognosis and reduced long-term survival in patients with newly diagnosed NPC; hence, EBV DNA levels are highly prognostic of survival in patients with NPC. None of the included studies used the WHO standard for EBV DNA measurement, indicating a greater need for harmonization in future studies.

https://www.cimonline.ca/index.php/cim/article/download/28049/20514

Prognostic role of plasma Epstein-Barr virus DNA load for nasopharyngeal carcinoma: a meta-analysis.

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

Optimal cumulative cisplatin dose in nasopharyngeal carcinoma patients based on induction chemotherapy response.

Clinical implications of hepatitis B viral infection in Epstein–Barr virus-associated nasopharyngeal carcinoma

In this retrospective study, the correlation between pre- and post-treatment plasma Epstein–Barr virus (EBV) DNA and circulating immune subsets as well as the prognostic implications was investigated in nasopharyngeal carcinoma (NPC) patients. Patients (n = 356) were diagnosed and received comprehensive treatment at the First People’s Hospital of Foshan from 2006 to 2010. Pre- and post-treatment plasma EBV DNA load and circulating immune subsets (percentage of CD3+ T cell, CD3+ CD4+ T cells, CD3+ CD8+ T cells, CD19+ B cells and CD56+ NK cells) were analyzed by real-time PCR and flow cytometry. Patient age correlated negatively with CD3+ T cells (r = −0.264, P = 0.001) and positively with CD56+ NK cells (r = 0.272, P = 0.001). Pre-treatment plasma EBV DNA correlated negatively with CD19+ B cells (r = −0.223, P = 0.009) and CD4/CD8 ratio (r = −0.177, P = 0.047). Patients with low CD19+ B cell had poorer 5-year progression-free survival (PFS) (66.6 vs. 81.8 %, P = 0.036) and 5-year overall survival (OS) (70.5 vs. 81.5 %, P = 0.097) than patients with high CD19+ B cells. Low CD19+ B cells was identified as a negative prognostic factor for 5-year PFS (hazard ratio [HR] 0.487; P = 0.040), but not for 5-year OS (HR 0.550; P = 0.102) in multivariate analysis. Post-treatment plasma EBV DNA was the most important prognostic factor for 5-year PFS (HR 2.983; P = 0.006) and 5-year OS (HR 3.927; P < 0.001). This study demonstrates the clinical value of circulating CD19+ B cell measurements in NPC patients.

Prognostic significance of circulating CD19+ B lymphocytes in EBV-associated nasopharyngeal carcinoma

Background: We retrospectively compared the long-term efficacy of concurrent chemoradiotherapy (CCRT) regimens (docetaxel vs. cisplatin), total dose intensity of cisplatin (> 200 vs. ≤ 200 mg/m2) and pretreatment plasma levels of Epstein-Barr virus (EBV) DNA for nasopharyngeal carcinoma (NPC), and investigated the prognostic factors. Methods: We enrolled 214 patients diagnosed with NPC and treated with CCRT. 41 patients received weekly docetaxel and 173 weekly cisplatin. 62 received cumulative cisplatin of ≤ 200 mg/m2 and 111, > 200 mg/m2. Pretreatment levels of EBV DNA were available for 155 patients. Results: Patients receiving concurrent weekly docetaxel and cisplatin had similar 5-year rates for overall survival (OS) (p = 0.306), progression-free survival (PFS) (p = 0.133), distant failure-free survival (DFS) (p = 0.110), and locoregional failure-free survival (LFS) (p = 0.452). Cumulative cisplatin of > 200 mg/m2 improved the 5-year rates of PFS (p = 0.018) and DFS (p = 0.042) significantly in comparison with cumulative cisplatin of ≤ 200 mg/m2. EBV DNA levels of ≥ 1,500 copies/ml was closely associated with poor DFS (p = 0.011), PFS (p = 0.006), and OS (p = 0.004). Conclusions: Weekly cisplatin was well tolerated in CCRT, during which cumulative cisplatin of > 200 mg/m2 improved PFS and DFS. The long-term efficacy of concurrent docetaxel was similar to that of concurrent cisplatin. The EBV DNA level was the most significant prognostic factor.

Pretreatment Epstein-Barr virus DNA load and cumulative cisplatin dose intensity affect long-term outcome of nasopharyngeal carcinoma treated with concurrent chemotherapy: experience of an institute in an endemic area.

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Clinical implications of hepatitis B viral infection in Epstein–Barr virus-associated nasopharyngeal carcinoma

Prognostic significance of circulating CD19+ B lymphocytes in EBV-associated nasopharyngeal carcinoma

Pretreatment Epstein-Barr virus DNA load and cumulative cisplatin dose intensity affect long-term outcome of nasopharyngeal carcinoma treated with concurrent chemotherapy: experience of an institute in an endemic area.