Pretreatment Epstein-Barr Virus Research Articles

Combined pre-treatment and middle-treatment Epstein-Barr virus DNA load contributes to prognostication and treatment modification in nasopharyngeal carcinoma patients.

To investigate whether pre-treatment and middle-treatment plasma Epstein-Barr virus (EBV) DNA loads are useful predictors of prognosis and indicators of therapy modification in nasopharyngeal carcinoma (NPC) patients undergoing radical concurrent chemoradiotherapy (CCRT). Plasma EBV DNA load was measured by quantitative polymerase chain reaction before treatment (pre-DNA) and during the second cycle of DDP (mid-DNA). The primary endpoint was 5-year progression-free survival (PFS). A total of 775 NPC patients treated with CCRT were included. In total, 553 patients with pre-DNA <4000 copies/mL and 222 with ⩾4000 copies/mL. A total of 559 patients had mid-DNA undetectable and 216 had detectable. Multivariate analysis showed that pre- and mid-DNA were independent prognostic predictors of PFS [hazard ratio (HR), 2.035; 95% confidence interval (CI), 1.406-2.944; p < 0.001; HR, 1.597; 95% CI, 1.101-2.316; p = 0.014]. The area under the curve of the combination of pre-DNA and mid-DNA for 5-year PFS was higher than that of pre-DNA, mid-DNA, and tumor node metastasis (TNM) stage (0.679 versus 0.622, 0.608, 0.601). In the low-risk group (pre-DNA <4000 copies/mL and undetectable mid-DNA), patients receiving ⩽200 mg/m2 showed similar efficacy as those receiving >200 mg/m2 cumulative cisplatin dose (CCD) but were associated with fewer all-grade late toxicities. However, in the high-risk group (pre-DNA ⩾4000 copies/mL or detectable mid-DNA), patients receiving >200 mg/m2 CCD showed a higher 5-year PFS (73.1% versus 58.6%, p = 0.027) and locoregional relapse-free survival (88.5% versus 76.1%, p = 0.028) than those receiving ⩽200 mg/m2 CCD. The combination of pre-DNA and mid-DNA could be particularly useful for guiding risk stratification and early treatment modification for NPC treated with CCRT. A total of 200 mg/m2 cisplatin seemed to be the optimal dose for the low-risk patients, while >200 mg/m2 cisplatin may be adequate to achieve satisfactory survival outcomes in the high-risk group.

Oral chemotherapy versus observation alone in nasopharyngeal carcinoma patients with persistently detected circulating cell-free Epstein-Barr virus DNA during follow-up

AimDespite the high risk of tumor recurrence, patients with nasopharyngeal carcinoma (NPC) with persistently (at least twice) detected circulating cell-free Epstein-Barr virus (EBV) DNA levels during follow-up are routinely recommended to keep observation. For these patients, whether administering more aggressive treatment could improve survival outcomes remains unknown. Materials and methodsWe retrospectively included 431 patients with nonmetastatic NPC with persistently detected EBV DNA during follow-up, who do not have clinical or imaging evidence of recurrence. Among these patients, 79 were administered oral chemotherapy, and the remaining 352 underwent observation alone. Baseline characteristics were balanced with propensity score matching (PSM) analysis. The primary endpoint was modified disease-free survival (mDFS), defined as time from detectable EBV DNA result to tumor recurrence or death. The secondary endpoints were disease-free survival (DFS) and overall survival (OS). ResultsOne-to-three PSM resulted in 251 eligible patients (oral chemotherapy group, 73; observation group, 178). In the matched cohort, the oral chemotherapy group had higher median mDFS (12.9 months [95 % confidence interval [CI] 9.6–16.3] vs. 6.8 months [95 % CI 5.8–7.8], p = 0.009) and DFS (24.1 months [95 % CI 18.5–29.7] vs. 16.7 months [95 % CI 14.4–19.1], p = 0.035) than the observation group. The median OS was numerically higher in the oral chemotherapy group than in the observation group (57.9 months [95 % CI 42.5–73.3] vs. 50.8 months [95 % CI 39.7–61.9], p = 0.71). A consistent benefit favoring oral chemotherapy was observed for mDFS in all subgroups analyses for male, <45 years, stage III-IVa disease, pretreatment EBV DNA load ≥ 4,000 copies/mL, no induction chemotherapy, or a detectable EBV DNA load ≥ 1,200 copies/mL. After adjusting for other confounders in the multivariate analysis, oral chemotherapy remained a significantly favorable factor for both mDFS (hazard ratio [HR] 0.67, 95 % CI 0.50–0.89; p = 0.006) and DFS (HR 0.68, 95 % CI 0.51–0.91; p = 0.01), but not a significant factor for OS (HR 0.89, 95 % CI 0.62–1.27; p = 0.52). ConclusionsIn patients with NPC having persistently detected EBV DNA levels but without clinical or imaging evidence of recurrence during follow-up, oral chemotherapy significantly prolongs mDFS and DFS. Employing oral chemotherapy as a more aggressive treatment option, as opposed to mere observation, could potentially benefit these patients, although further prospective validation is necessitated.

Prognostic value of metastatic cervical lymph node stiffness in nasopharyngeal carcinoma: A prospective cohort study

ObjectivesExtracellular matrix stiffness plays an important role in tumorigenesis. In this study, we assessed the prognostic value of metastatic cervical lymph node (CLN) stiffness measured using ultrasound shear wave elastography (SWE) in patients with nasopharyngeal carcinoma (NPC). MethodsA total of 325 consecutive patients with NPC and CLN metastases were prospectively enrolled in this study. The association between the CLN stiffness and patient characteristics was also evaluated. Survival analysis was performed for 307 patients with stage M0 disease. Distant metastasis-free survival (DMFS) was the primary endpoint. Log-rank test and multivariate analysis were used to explore the prognostic value of CLN stiffness. ResultsEighteen patients developed distant metastases before treatment (stage M1) and had significantly higher CLN stiffness (Pt-test < 0.001) than the other patients (stage M0). For stage M0 patients, those in the high-stiffness group had lower 3-year DMFS (83.3% vs. 91.7%, P = 0.013) and 3-year progression-free survival (PFS) (78.2% vs. 87.9%, P = 0.015) than those in the low-stiffness group. Multivariate analysis identified CLN stiffness and pretreatment Epstein–Barr virus (EBV) DNA as independent prognostic factors for DMFS and PFS. We further established stiffness-EBV risk stratification based on these two factors. The concordance index, receiver operating characteristic curve, and decision curve analyses showed that our risk stratification outperformed the TNM classification for predicting metastasis. ConclusionThe stiffness of metastatic CLN is closely associated with the prognosis of patients with NPC. SWE can be used as a pretreatment examination for CLN-positive patients. A multicenter study is required to verify our results.

Delta-Radiomics Guides Adaptive De-Intensification after Induction Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma in the IMRT Era

In the setting of intensity-modulated radiotherapy (IMRT) and induction chemotherapy (IC), the benefits from concurrent chemotherapy remained controversial for locoregionally advanced nasopharyngeal carcinoma (LANPC). This study aimed to construct a delta-radiomics model for benefit prediction and patient selection for omitting concurrent chemotherapy. Between December 2009 and December 2015, a total of 718 patients with LANPC treated with IC+IMRT or IC+concurrent chemoradiotherapy (CCRT) were retrospectively enrolled and randomly assigned to a training set (n = 503) and a validation set (n = 215). Radiomic features were extracted from magnetic resonance images of pre-IC and post-IC. Interclass correlation coefficients and Pearson correlation coefficients were calculated to select robust radiomic features. After univariate Cox analysis, a delta-radiomics signature was built using the LASSO-Cox regression. A nomogram incorporating the delta-radiomics signature and clinical prognostic factors was then developed and evaluated for calibration and discrimination. Risk stratification by the nomogram was evaluated by Kaplan-Meier methods. The primary outcome was overall survival (OS). The delta-radiomics signature, which comprised 19 selected features, was independently associated with prognosis. It yielded an area under the receiver operating characteristic curve (AUC) of 0.77 (95% confidence interval [CI] 0.71 to 0.82) for the training set and 0.71 (95% CI 0.61 to 0.81) for the validation set. The nomogram composed of the delta-radiomic signature, age, T category, N category, pre-treatment Epstein-Barr virus DNA, and treatment showed great calibration and discrimination performance with an AUC of 0.80 (95% CI 0.75 to 0.85) for the training set and 0.75 (95% CI 0.64 to 0.85) for the validation set. Risk stratification by the nomogram excluding the treatment variable resulted in two risk groups with distinct OS. Significant better outcomes were observed in the high-risk patients with IC+CCRT compared to those with IC+IMRT (5-year OS: 73.8% vs. 61.4% in the training set and 85.8% vs. 65.6% in the validation set; all log-rank p < 0.05), while comparable outcomes between IC+CCRT and IC+IMRT were shown for the low-risk patients (95.8% vs. 95.8% in the training set and 92.2% vs. 88.3% in the validation set; all log-rank p > 0.05). The delta-radiomics signature was identified as an independent indicator of LANPC. Integrating clinical predictors with the delta-radiomics signature, the radiomics-based nomogram could predict individual's survival outcomes and benefits from concurrent chemotherapy after IC for LANPC. Low-risk patients with LANPC determined by the nomogram may be potential candidates for omission of concurrent chemotherapy following IC in the IMRT era.

Integrating pretreatment MRI-detected nodal features and Epstein-Barr virus DNA to identify optimal candidates for intensity-modulated radiotherapy alone in patients with stage II nasopharyngeal carcinoma

ObjectivesTo develop and validate a prognostic nomogram based on MRI-detected features of retropharyngeal and cervical lymph nodes and Epstein–Barr virus (EBV) DNA in patients with stage II nasopharyngeal carcinoma (NPC) to distinguish low-risk patients for whom intensity-modulated radiotherapy (IMRT) alone is sufficient. MethodsThis retrospective study enrolled 894 patients with stage II NPC (596 and 298 in the training and validation cohorts, respectively) with pretreatment MRI between August 2010 and May 2019. All patients received IMRT with or without additional chemotherapy. We identified independent risk factors using univariate and multivariate Cox regression analyses. Survival was compared using Kaplan–Meier curves with the log-rank test. ResultsIndependent factors derived from the multivariate analysis include cervical nodal necrosis (CNN), the extracapsular spread (ECS) of cervical and retropharyngeal lymph nodes, and gamma-glutamyl transferase (γ-GGT). Nomograms A, B, and C were established based on the clinical [tumor-node-metastasis (TNM) stage + Epstein–Barr virus (EBV) DNA], the clinical-radiological [all independent predictors] and the combined models [the clinical-radiological model + EBV DNA], respectively. Nomogram C (C-index 0.769 [0.718–0.820]) demonstrated better risk discrimination than nomogram B (0.762 [0.715–0.809]), nomogram A (0.619 [0.564–0.674]), and the TNM stage (0.560 [0.509–0.611]). In the low-risk group divided by nomogram C, no significant survival differences were observed between patients treated with radiotherapy (RT) alone and other regimens including additional chemotherapy. ConclusionsThe nomogram combining MRI-detected retropharyngeal and cervical lymph node features with pretreatment EBV-DNA improved the prognostic risk stratification for stage II NPC.

A phase II randomised controlled trial of adjuvant tumour-infiltrating lymphocytes for pretreatment Epstein-Barr virus DNA-selected high-risk nasopharyngeal carcinoma patients

PurposeThe safety and objective clinical responses were observed in the phase I study using adjuvant autologous tumour-infiltrating lymphocytes (TILs) following concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients. Methods and materialsOne hundred fifty-six patients with stage III–IVb and pretreatment Epstein–Barr virus DNA levels of ≥4000 copies/ml were randomly assigned to receive CCRT combined with TIL infusion (n = 78) or CCRT alone (n = 78). All patients received CCRT and patients assigned to the TIL group received TIL infusion within 1 week after CCRT. The primary endpoint was investigator-assessed progression-free survival (PFS) at 3 years. ResultsAfter a median follow-up of 62.3 months, no significant difference was observed in the 3-year PFS rate between the CCRT plus TIL infusion group and CCRT alone group (75.6% versus 74.4%, hazard ratios, 1.08; 95% confidence intervals, 0.62–1.89). TIL infusion was safe without grade 3 or 4 adverse events and all the high-grade adverse effects were associated with myelosuppression caused by CCRT. Exploratory analysis showed that a potential survival benefit was observed with TILs in patients with lower levels of circulating CD8+TIM3+ cells, serum IL-8 or PD-L1. The infused TIL products in patients with favourable outcomes were associated with increased transcription of interferon-γ and a series of inflammatory related genes and a lower exhausted score. ConclusionThe primary objective of prolonging PFS with CCRT plus TILs in high-risk NPC patients was not met. These findings may provide evidence for the design of future trials investigating the combination of TILs plus immune checkpoint inhibitors based on CCRT in high-risk NPC patients. Trial registration numberNCT02421640

Prognostic effect of residual plasma Epstein-Barr viral DNA after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma.

To assess the prognostic effect of plasma Epstein-Barr virus (EBV) DNA load after induction chemotherapy (postIC -EBV DNA) on survival outcomes in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Patients who were diagnosed with LA-NPC between August 2017 and October 2021 were included. The chi-squared test, receiver operating characteristic, Kaplan-Meier survival analysis, and Cox proportional hazard model were used for statistical analysis. We included 172 patients with EBV DNA-positive LA-NPC in this study. There were 35.5% (n = 61) of patients had plasma residual EBV DNA after induction chemotherapy (IC). Patients with higher EBV DNA before IC (p < 0.001) and advanced nodal stage (p = 0.031) were significantly related to a higher rate of residual postIC -EBV DNA. Patients with detectable postIC -EBV DNA had inferior 3-year locoregional relapse-free survival (LRFS) (86.7% vs. 96.9%, p = 0.020), distant metastasis-free survival (DMFS) (76.8% vs. 94.2%, p < 0.001), disease-free survival (DFS) (68.2% vs. 91.1%, p < 0.001), and overall survival (OS) (87.8% vs. 97.9%, p = 0.044) compared to those with undetectable postIC -EBV DNA. The multivariate prognostic analyses showed that detectable postIC -EBV DNA was the independent prognostic factor related to LRFS (p = 0.032), DMFS (p = 0.010), and DFS (p = 0.004) than those with undetectable postIC -EBV DNA. Pretreatment EBV DNA load had no prognostic effect in the multivariate analyses. The monitoring of plasma postIC -EBV DNA has improved prognostication in LA-NPC. Our findings suggest that postIC -EBV DNA may be a robust indicator to identify the optimal candidate for intensive treatment.

Individualized Concurrent Chemotherapy for Patients with Stage III-IVa Nasopharyngeal Carcinoma Receiving Neoadjuvant Chemotherapy Combined with Definitive Intensity-Modulated Radiotherapy.

This retrospective study aimed to re-evaluate the effect of concurrent chemotherapy in patients with locally advanced nasopharyngeal carcinoma (NPC) in the era of intensity-modulated radiotherapy (IMRT). A total of 498 patients who received neoadjuvant chemotherapy (NCT) combined with concurrent chemoradiotherapy (CCRT) or IMRT were retrospectively reviewed. The distribution of baseline characteristics was balanced using propensity score matching. Additionally, the results of NCT+IMRT and NCT+CCRT were compared using Kaplan-Meier survival analysis, and differences in survival rates were analyzed using the log rank test. There were no significant differences in overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and local progression-free survival (LRFS) between the two groups. Patients were further categorized into risk subgroups based on pretreatment Epstein-Barr virus (EBV) DNA cutoff values using receiver operating characteristic curve analysis. There were no statistically significant differences in OS, PFS, DMFS, and LRFS between patients who received NCT+CCRT and NCT+IMRT in the high-risk group. In the low-risk group, although there were no differences between NCT+CCRT and NCT+IMRT in OS, PFS, and LRFS, patients who received NCT+CCRT had better DMFS than those who received NCT+IMRT. Pretreatment EBV DNA level can be used to individualize concurrent chemotherapy for patients with locally advanced NPC. Patients with low pretreatment EBV DNA levels may benefit from concurrent chemotherapy, whereas those with high levels may not. Other treatment modalities need to be explored for high-risk patients to improve their prognosis.

Tumor residue in patients with stage II–IVA nasopharyngeal carcinoma who received intensity-modulated radiation therapy: development and validation of a prediction nomogram integrating postradiotherapy plasma Epstein–Barr virus deoxyribonucleic acid, clinical stage, and radiotherapy dose

BackgroundTo develop and validate a predictive nomogram for tumor residue 3–6 months after treatment based on postradiotherapy plasma Epstein–Barr virus (EBV) deoxyribonucleic acid (DNA), clinical stage, and radiotherapy (RT) dose in patients with stage II–IVA nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT).MethodsIn this retrospective study, 1050 eligible patients with stage II–IVA NPC, who completed curative IMRT and underwent pretreatment and postradiotherapy (-7 to +28 days after IMRT) EBV DNA testing, were enrolled from 2012 to 2017. The prognostic value of the residue was explored using Cox regression analysis in patients (n=1050). A nomogram for predicting tumor residues after 3–6 months was developed using logistic regression analyses in the development cohort (n=736) and validated in an internal cohort (n=314).ResultsTumor residue was an independent inferior prognostic factor for 5-year overall survival, progression-free survival, locoregional recurrence-free survival and distant metastasis-free survival (all P<0.001). A prediction nomogram based on postradiotherapy plasma EBV DNA level (0 vs. 1–499 vs. ≥500 copies/ml), clinical stage (II vs. III vs. IVA), and RT dose (68.00–69.96 vs. 70.00–74.00 Gy) estimated the probability of residue development. The nomogram showed better discrimination (area under the curve (AUC): 0.752) than either the clinical stage (0.659) or postradiotherapy EBV DNA level (0.627) alone in the development and validation cohorts (AUC: 0.728).ConclusionsWe developed and validated a nomogram model integrating clinical characteristics at the end of IMRT for predicting whether tumor will residue or not after 3–6 months. Thus, high-risk NPC patients who might benefit from immediate additional intervention could be identified by the model, and the probability of residue can be reduced in the future.

Can the prognosis of individual patients with nasopharyngeal carcinoma be predicted using a routine blood test at admission?

Background and purposeWe sought to determine the prognostic value of a pre-treatment peripheral blood signature and the peripheral blood signature-based nomogram for patients with non-metastatic nasopharyngeal carcinoma (NPC). Materials and methodsWe retrospectively collected 21 peripheral blood indicators from patients with NPC between 2004 and 2015. Data were randomly divided into a training and a validation set (ratio: 6:4). The peripheral blood signature was constructed based on candidate biomarkers using the least absolute shrinkage and selection operator Cox regression model. Multivariable logistic regression was applied to identify the independent risk factors of overall survival to build the nomogram. The predictive value of the peripheral blood nomogram was evaluated using time-dependent area under the curve, decision curve analysis, and calibration curve. ResultsIn total, 6668 patients were enrolled with 4000 and 2668 in the training and validation cohorts, respectively. Four peripheral blood indicators, (white blood cell count, lymphocyte percentage, haemoglobin, and mean platelet volume), were included to construct the peripheral blood signature. Patients were divided into low- and high-risk groups using an optimal cut-off value of − 1.71142. Patients in the high-risk group had significantly lower overall, distant metastasis-free, and progression-free survival than patients in the low-risk group in both cohorts (P < 0.05). We constructed and validated a peripheral blood signature-based nomogram in combination with five vital clinical characteristics, (age, sex, tumour stage, nodal stage, and pre-treatment Epstein–Barr virus DNA), which showed favourable performance. ConclusionPatients with NPC with different outcomes could be distinguished based on their peripheral blood signature score; the proposed peripheral blood signature-based nomogram offers individualised risk estimation.

Prognostic significance of circulating Epstein-Barr virus DNA in pulmonary lymphoepithelioma-like carcinoma: A meta-analysis and validation study.

In small-scale studies, circulating Epstein-Barr virus (EBV) DNA levels have prognostic value in patients with pulmonary lymphoepithelioma-like carcinoma (LELC). Therefore, we performed a comprehensive meta-analysis to evaluate the prognostic significance of circulating EBV DNA levels in patients with pulmonary LELC. Studies that discussed the prognostic significance of circulating EBV DNA detection in pulmonary LELC were eligible for inclusion in this study. The overall survival (OS) and progression-free survival (PFS) were the primary outcomes. Pooled hazard ratio (HR), 95% confidence intervals (CIs), and pvalue were calculated to estimate the prognostic significance of EBV DNA levels. Additionally, we conducted a further observation using an independent cohort. The pooled HR and 95% CI of pretreatment EBV DNA levels for OS and PFS were 3.63 (95% CI: 2.90-4.55) and 2.88 (95% CI: 1.90-4.38), respectively. The pooled HR and 95% CI for Posttreatment EBV DNA levels for OS and PFS were 3.77 (95% CI: 2.96-4.80) and 3.52 (95% CI: 1.91-6.51, p < 0.001), respectively. The independent cohort showed similar results that patients with high pretreatment EBV DNA or positive posttreatment EBV DNA had significantly inferior PFS. Circulating EBV DNA levels provide prognostic values of survival and treatment response in pulmonary LELC patients.

Combination of smoking and Epstein-Barr virus DNA is a predictor of poor prognosis for nasopharyngeal carcinoma: a long-term follow-up retrospective study

BackgroundThis retrospective study was performed to determine the prognostic potential of smoking and its combination with pre-treatment plasma Epstein-Barr virus (EBV) DNA levels in patients with nasopharyngeal carcinoma (NPC).MethodsMedical records of 1080 non-metastatic NPC patients who received intensity-modulated radiotherapy were reviewed. Male patients were categorized as never and ever smokers, and the smoking amount, duration, and cumulative consumption were used to evaluate dose-dependent effects. Survival outcomes were assessed using Kaplan-Meier survival analysis and the multivariate Cox regression analysis. Propensity score matching (PSM) was constructed.ResultsThe 5-year overall survival (OS) was worse for ever smokers than never smokers, and significantly decreased with the increase of smoking amount, duration, and cumulative consumption. Compared with never smokers, the multivariate-adjusted hazard ratio (HR) of death was higher in ever smokers (HR = 1.361, P = 0.049), those smoked ≥20 cigarettes/day (HR = 1.473, P = 0.017), those smoked for ≥30 years (HR = 1.523, P = 0.023), and those cumulative smoked for ≥30 pack-years (HR = 1.649, P = 0.005). The poor prognostic effects of smoking was also confirmed in the PSM analysis. The combination of cumulative smoking consumption and pre-treatment EBV DNA levels was proven to be an independent poor prognostic factor for male NPC, and the risk of death, progression, and distant metastases gradually increased with both factors (P < 0.001).ConclusionsCombination of smoking and pre-treatment EBV DNA levels as a predictor of poor prognosis could further improve the risk stratification and prognostication for NPC.

Utilization of the lymph node-to-primary tumor ratio of PET standardized uptake value and circulating Epstein–Barr virus DNA to predict distant metastasis in nasopharyngeal carcinoma

Background and purposeTo determine the clinical impact of integrating Epstein–Barr virus (EBV) DNA and lymph node-to-primary tumor ratio (NTR) of positron emission tomography (PET) standardized uptake value (SUV) in predicting distant metastasis, such as distant metastasis-free survival (DMFS), in patients with nasopharyngeal carcinoma (NPC). Materials and methodsWe retrospectively reviewed patients diagnosed with non-disseminated NPC between 2010 and 2017. The optimal cut-off values of EBV DNA and SUV NTR were determined using receiver operating characteristic analysis. The prognostic values of SUV NTR and EBV DNA on DMFS and overall survival were evaluated using the Kaplan–Meier method. Univariate and multivariable analyses were performed using the Wald Chi-squared test and Cox proportional hazards regression, respectively. ResultsA total of 488 patients were included in the analysis. The median follow-up period was 61.6 months. The optimal cut-off values of EBV DNA and SUV NTR were 3377.5 copies per mL and 0.64, respectively. The five-year DMFS for patients with high vs low EBV DNA and SUV NTR levels were 64.9% vs 86.6% (p < 0.001) and 78.7% vs 87.4% (p = 0.021), respectively. In subgroup analysis, the high-risk group with high levels of pretreatment EBV DNA and SUV NTR had worse DMFS in either American Joint Committee on Cancer (AJCC) stage I–III or IVA–B (p = 0.001 and <0.001, respectively). Univariate and multivariable analyses showed the statistical significance of EBV DNA, SUV NTR, and their composite in DMFS (p < 0.001 for EBV DNA; p = 0.022 for SUV NTR; p < 0.001 for their composite). ConclusionThis study showed that EBV DNA and SUV NTR have independent and additive values as prognosticators for distant metastasis in patients with NPC, suggesting that these two individual factors, except the AJCC staging system, should be included in future studies.

Value of Diffusion-Weighted Imaging and Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Prediction of Treatment Outcomes in Nasopharyngeal Carcinoma

Magnetic resonance imaging (MRI) parameters that reflect the tumor microenvironment of nasopharyngeal carcinoma (NPC) may predict treatment response and facilitate treatment planning. This study aimed to evaluate the diffusion-weighted imaging and dynamic contrast-enhanced MRI (DCE-MRI) values for predicting the treatment outcomes in NPC patients. Eighty-three patients with NPC underwent pretreatment MRI simulation with diffusion-weighted imaging and dynamic contrast-enhanced MRI. Average values of the apparent diffusion coefficient (ADC), Ktrans, Kep, Ve, Vp, and tumor volume of the primary tumors were measured. Other potential clinical characteristics (age, sex, staging, pathology, pretreatment Epstein-Barr virus level, and treatment type) were analyzed. Patients underwent follow-up imaging 6 months after treatment initiation. Treatment responses were assigned according to the Response Evaluation Criteria in Solid Tumors guideline (version 1.1). Fifty-one patients showed complete response (CR), whereas 32 patients did not (non-CR). Univariable logistic regression with variables dichotomized by optimal cutoff values showed that ADC ≥1.45 × 10 -3 mm 2 /s, Vp ≥0.14, tumor volume of ≥14.05 mL, high stage (stages III and IV), and Epstein-Barr virus level of ≥2300 copies/mL were predictors of non-CR ( P = 0.008, 0.05, 0.01, 0.009, and 0.04, respectively). The final multivariable model, consisting of a combination of ADC ≥1.45 × 10 -3 mm 2 /s, Vp ≥0.14, and high stage, could predict non-CR with a good discrimination ability (area under the receiver operating characteristic curve, 0.76 [95% confidence interval, 0.66-0.87]; sensitivity, 62.50%; specificity, 80.39%; and accuracy 73.49%). A multivariable prediction model using a combination of ADC ≥1.45 × 10 -3 mm 2 /s, Vp ≥0.14, and high stage can be effective for treatment response prediction in NPC patients.

A nomogram based on tumor response to induction chemotherapy may predict survival in locoregionally advanced nasopharyngeal carcinoma.

To evaluate the clinical significance of tumor response to induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LANPC) patients and further to develop a nomogram for predicting survival prognosis. A total of 498 patients with stage III-IVA NPC applying IC and concurrent chemotherapy were reviewed (training cohort, n=376; validation cohort, n=122). Tumor response was an independent predictor for clinical outcomes. The nomogram included age, N stage, pretreatment Epstein-Barr virus DNA, lymphocyte-to-monocyte ratio, and tumor response achieved an ideal C-index of 0.703 (95% CI 0.655-0.751) in the validation cohort for predicting overall survival (OS), which outperformed than that of the TNM system alone (C-index, 0.670, 95% CI: 0.622-0.718). In addition, the nomogram could successfully classified patients into different risk groups. We established and validated a precise and convenient nomogram based on tumor response for predicting the OS of LANPC patients.

M1 stage subdivisions based on 18F-FDG PET-CT parameters to identify locoregional radiotherapy for metastatic nasopharyngeal carcinoma.

Purpose:To establish a risk classification of de novo metastatic nasopharyngeal carcinoma (mNPC) patients based on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET-CT) radiomics parameters to identify suitable candidates for locoregional radiotherapy (LRRT).Methods:In all, 586 de novo mNPC patients who underwent 18F-FDG PET-CT prior to palliative chemotherapy (PCT) were involved. A Cox regression model was performed to identify prognostic factors for overall survival (OS). Candidate PET-CT parameters were incorporated into the PET-CT parameter score (PPS). Recursive partitioning analysis (RPA) was applied to construct a risk stratification system.Results:Multivariate Cox regression analyses revealed that total lesion glycolysis of locoregional lesions (LRL-TLG), the number of bone metastases (BMs), metabolic tumor volume of distant soft tissue metastases (DSTM-MTV), pretreatment Epstein–Barr virus DNA (EBV DNA), and liver involvement were independent prognosticators for OS. The number of BMs, LRL-TLG, and DSTM-MTV were incorporated as the PPS. Eligible patients were divided into three stages by the RPA-risk stratification model: M1a (low risk, PPSlow + no liver involvement), M1b (intermediate risk, PPSlow + liver involvement, PPShigh + low EBV DNA), and M1c (high risk, PPShigh + high EBV DNA). PCT followed by LRRT displayed favorable OS rates compared to PCT alone in M1a patients (p < 0.001). No significant survival difference was observed between PCT plus LRRT and PCT alone in M1b and M1c patients (p > 0.05).Conclusions:The PPS-based RPA stratification model could identify suitable candidates for LRRT. Patients with stage M1a disease could benefit from LRRT.

Identifying optimal clinical trial candidates for locoregionally advanced nasopharyngeal carcinoma: Analysis of 9468 real-world cases and validation by two phase 3 multicentre, randomised controlled trial

Background and purposeThis study aims to identify the optimal high-risk candidates for clinical trials in locoregionally advanced nasopharyngeal carcinoma (NPC). Materials and methodsNon-metastatic NPC patients (n = 9,468) were included. Recursive partitioning analyses (RPA) were performed to generate risk stratification. Receiver operating characteristics curve was used to determine the cut-off value of pre-treatment Epstein-Barr virus (EBV) DNA for progression-free survival (PFS). Individual-level data from two clinical trials were used for validation. ResultsAnatomic stratification based on T and N category (eighth edition TNM, TNM-8) classified the N2-3 or T4 as an anatomic high-risk group with 5-year PFS of 69% (95% confidence interval: 68–71%). Prognostic stratification identified patients with pre-treatment EBV DNA ≥4000 copies/mL as a prognostic high-risk group with 5-year PFS of 69% (67–70%). The c-index was significantly higher for anatomic stratification (0.621, p < 0.001) and prognostic stratification (0.585, p < 0.001) compared with existing TNM-8 stage groups (0.562). The validation cohorts based on clinical trials data showed greater PFS benefit than the results of the original trials [Hazard ratio: NCT01245959, 0.64 vs. 0.67; NCT01872962, 0.42 vs. 0.52]. Moreover, detectable post-treatment EBV DNA indicated a high risk of progression with 5-year PFS of 38.7% and was the most adverse independent factor for all endpoints. ConclusionsN2-3 or T4 NPC patients were ideal candidates for multicenter clinical trials in locoregionally advanced NPC. Patients with detectable post-treatment EBV DNA are suitable candidates for adjuvant trials.

Assessment of Survival Model Performance Following Inclusion of Epstein-Barr Virus DNA Status in Conventional TNM Staging Groups in Epstein-Barr Virus–Related Nasopharyngeal Carcinoma

Nonanatomic prognostic factors complement the traditional anatomic staging system and could be incorporated into the tumor-node-metastasis (TNM) framework. Several diseases have incorporated nonanatomic prognostic factors into the determination of TNM staging groups. To refine TNM staging groups for Epstein-Barr virus (EBV)-related nonmetastatic nasopharyngeal carcinoma (NPC) by incorporating EBV DNA status. This multicenter prognostic study included patients with NPC treated with radiotherapy at 2 hospitals in China from January 2008 to December 2016. Progression-free survival and overall survival according to EBV DNA status and the TNM staging system were compared. Recursive partitioning analysis (RPA) combined with supervised clustering was applied to derive prognostic groupings, and then a refined RPA staging schema was developed, validated, and compared with existing staging schemes. Statistical analyses were conducted from October 1, 2020, to June 15, 2021. Curative intensity-modulated radiotherapy with or without platinum-based chemotherapy. The primary end point was progression-free survival. The performance of the staging system was assessed using the time-dependent area under the receiver operating characteristic curves and the TNM stage system's evaluation methodology. A total of 2354 patients (1709 men [72.6%]; median [interquartile range] age, 45 [38-53] years) were split into training (1372 [58.3%]), internal validation (672 [28.5%]), and external validation (310 [13.2%]) cohorts. Pretreatment EBV DNA was detected in 1338 (56.8%) patients. EBV DNA status was an independent prognostic factor: lower survival probability by higher TNM stage was evident in EBV DNA-positive patients but not in those with EBV DNA-negative disease. After integrating EBV DNA status and TNM stage, nonmetastatic NPC cases were categorized into RPA-I (T1-3N0 or EBV DNA-negative T1-3N1 cancers), RPA-II (EBV DNA-positive T1-3N1-2 or EBV DNA-negative T1-3N2-3/T4N0-3 cancers), and RPA-III (EBV DNA-positive T4N0-3/T1-3N3 cancers) groups, each with distinctly different prognosis. This system of RPA staging outperformed the current TNM stage system and 2 reported RPA staging schemes. These results were internally and externally validated. An RPA-based staging system for EBV-related NPC cases was associated with improved outcomes. This staging system may facilitate prognostic stratification and clinical trial designs.

Prognostic Value of Regression Rate of Plasma EBV DNA After Induction Chemotherapy for Stage II-IVA Nasopharyngeal Carcinoma.

Background/ObjectiveWe aimed to explore the prognostic value of regression rate (RR) of plasma Epstein–Barr virus (EBV) DNA after induction chemotherapy (IC) in patients with stages II–IVA nasopharyngeal carcinoma (NPC).MethodsEligible patients receiving IC followed by concurrent chemoradiotherapy were included. The cut-off value of pre-treatment EBV DNA (pre-IC DNA) and RR were identified by receiver operating curve (ROC). Recursive partitioning analysis (RPA) was applied to create new staging. Harrell’s c-index and time-independent ROC were employed to compare different RPA staging.ResultsIn total, 1,184 patients were included. The cut-off values of pre-IC DNA and RR were 16,200 copies/ml and 95.127% for patients receiving two cycles, and 5,520 copies/ml and 99.994% for those receiving three cycles. Notably, we only focused on patients receiving two cycles of IC. Patients with a RR >95.127% had significantly better 5-year overall survival (OS) than those with a RR ≤95.127% (86.2% vs. 54.3%, P <0.001). Then, RPA1 (pre-IC DNA + TNM staging + RR) and RPA2 (pre-IC DNA + TNM staging + post-IC EBV DNA [post-IC DNA]) staging systems were created. RPA1 staging achieved stronger power in OS prediction than RPA2 staging and TNM staging (c-index: 0.763 [0.714–0.812] vs. 0.735 [0.684–0.786] vs. 0.677 [0.604–0.749]; AUC: 0.736 vs. 0.714 vs. 0.628), indicating that RR had stronger prognostic power than post-IC DNA. Moreover, patients with stages III–IVRPA1 could benefit from high concurrent cumulative platinum dose (≥160 mg/m2).ConclusionRR in conjunction with current TNM staging could better conduct risk stratification, prognosis prediction and help to guide precise concurrent chemotherapy.

Subdivision of de-novo metastatic nasopharyngeal carcinoma based on tumor burden and pretreatment EBV DNA for therapeutic guidance of locoregional radiotherapy

BackgroundNasopharyngeal carcinoma (NPC) is a malignancy predominantly associated with infection by the Epstein-Barr virus (EBV). Approximately 12,900 new cases of NPC occur each year, with more than 70% of cases occurring in the east and southeast Asia. NPC is different from ordinary head and neck squamous cell carcinoma due to its particular biological properties and it is highly sensitive to radiotherapy. With the development of RT technology, the 3-year local control rate and survival rates of non-metastatic NPC reached 80–90% in the intensity-modulated RT (IMRT) era. However, whether distant metastatic NPC (de novo mNPC, dmNPC) should receive locoregional RT (LRRT) needs to be clarified.ResultsMultivariate analysis identified three independent prognostic factors: Epstein-Barr virus (EBV) DNA, number of metastatic lesions, and number of metastatic organs. Through these factors, all patients were successfully divided into 3 subgroups: low-risk (single metastatic organ, EBV DNA ≤ 25,000 copies/ml, and ≤ 5 metastatic lesions), intermediate-risk (single metastatic organ, EBV DNA > 25,000 copies/ml, and ≤ 5 metastatic lesions), and high-risk (multiple metastatic organs or > 5 metastatic lesions or both). By comparing LRRT and non-LRRT groups, statistical differences were found in OS in the low-risk and intermediate-risk subgroups (p = 0.039 and p = 0.010, respectively) but no significant difference was found in OS in the high-risk subgroup (p = 0.076). Further multivariate analysis of different risk stratifications revealed that LRRT can improve OS of low- and intermediate-risk subgroups.ConclusionsThe risk stratification of dmNPC may be used as a new prognostic factor to help clinicians organize individualized LRRT treatment to improve the survival outcomes of dmNPC patients.