Detectable Plasma Epstein-Barr Virus Research Articles

Patterns and Prognosis of Local Recurrence of Nasopharyngeal Carcinoma after Intensity-modulated Radiotherapy.

Objective: To investigate the patterns of local failure and prognosis in patients with locally recurrent nasopharyngeal carcinoma (rNPC) after primary intensity-modulated radiotherapy (IMRT). Methods: The data of 298 patients with locally rNPC after IMRT were retrospectively analyzed. Magnetic resonance images of the initial and recurrent tumors were reviewed and, for patients with extra-nasopharyngeal local recurrence, the gross tumor volume of local recurrence was transferred to the original IMRT plan for dosimetry analysis. Significant prognostic factors for overall survival (OS) were selected by multivariate Cox regression analysis. Results: The commonest recurrence sites were the nasopharynx (93%, 277/298) and skull base (53.7%, 160/298). Of the 21 patients with extra-nasopharyngeal recurrence (19 cases valid), 12 had in-field failures, 4 had marginal failures, and 3 had out-field failures. The ethmoid sinus (57.1%, 4/7) and nasal cavity (28.6%, 2/7) were the most frequent sites of marginal and out-field failures. After median follow-up of 37 months, the 3-year and estimated 5-year OS rates were 57.3% and 41.7%, respectively. Multivariate analysis showed that age, recurrence interval, plasma Epstein-Barr virus (EBV) DNA level, and recurrent T stage were independent prognostic factors for OS. Conclusions: Local failure after IMRT occurs most commonly in the nasopharynx and skull base. In patients with extra-nasopharyngeal recurrence, in-field failure remains the main failure pattern, and marginal and out-field failures mainly occur in the ethmoid sinus and nasal cavity. Elder age, shorter recurrence interval, detectable plasma EBV DNA, and advanced recurrent T stage are negative predictors of OS in patients with rNPC.

Plasma Epstein–Barr Virus DNA and Risk of Future Nasopharyngeal Cancer

BackgroundWe previously conducted a prospective study to show that nasopharyngeal cancer (NPC) screening with circulating Epstein–Barr virus (EBV) DNA analysis can improve survival. However, the long-term significance of positive results in individuals without cancer was unclear.MethodsWe conducted a second-round screening at a median of 43 months after the initial screening. Participants with detectable plasma EBV DNA were retested in 4 weeks, and those with persistently positive results were investigated with nasal endoscopy and magnetic resonance imaging.ResultsOf the 20,174 volunteers who participated in the first-round screening, 17,838 (88.6%) were rescreened. Among them, 423 (2.37%) had persistently detectable plasma EBV DNA. Twenty-four patients were identified as having NPC. A significantly higher proportion of patients had stage I/II cancer than in a historical cohort (67% vs. 20%; chi-square test, P<0.001), and they had superior 3-year progression-free survival (100% vs. 78.8%). Compared with participants with undetectable plasma EBV DNA in the first round of screening, participants with transiently and persistently positive results in the first round were more likely to have a cancer identified in the second round, with relative risks of 4.4 (95% confidence interval, 1.3 to 15.0) and 16.8 (95% confidence interval, 5.7 to 49.6), respectively.ConclusionsIndividuals with detectable plasma EBV DNA but without an immediately identifiable NPC were more likely to have the cancer identified in another round of screening performed 3 to 5 years later. (Funded by Kadoorie Charitable Foundation and others; ClinicalTrials.gov number, NCT02063399.)

Prospective study of integrating post-radiotherapy [18F] fluorodeoxyglucose-positron emission tomography/computed tomography scan and plasma Epstein-Barr virus DNA in surveillance of locoregionally advanced nasopharyngeal carcinoma.

6072 Background: To evaluate the role of [18F] fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan at 12-weeks after the end of Radiotherapy (RT) integrated with plasma EBV DNA in surveillance and standardized implementation of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Methods: This prospective study was conducted in patients with stage III-IVa LA-NPC. FDG-PET/CT examination and plasma Epstein-Barr virus (EBV) DNA measurements was performed pretreatment and at 12-weeks after the end RT. The primary study endpoint was the negative predictive value (NPV) and other supporting diagnostic test characteristics of 12-weeks FDG-PET/CT for the surveillance of residual locoregional disease and new distant metastasis. Results: From June 2018 to December 2019, 506 eligible patients were enrolled and entered follow-up (median,45 months). At 12 weeks after the end of RT, there were 22 (4.3%) patients have residual locoregional disease, 30 (5.9%) patients developed distant metastasis and 6 (1.2%) patients presented both residual locoregional disease and distant metastasis. The NPV of 12-weeks FDG-PET/CT for overall residual diseases and distant metastasis was 96.3% (95% confidence interval [CI], 94.0%-97.8%) with sensitivity of 72.4% (95%CI, 58.9%-83.0%), specificity of 93.3% (95%CI, 90.5%-95.4%), positive predictive value (PPV) of 58.3% (95%CI, 46.1%-69.6%) and accuracy of 90.9% (95%CI, 88.4%-93.4%). In EBV DNA-based risk subgroups, the NPV of 12-weeks PDG-PET/CT was 96.8% (95%CI, 94.5%-98.2%) in patients with undetectable 12-weeks plasma EBV DNA and 87.0% (95%CI, 65.3%-96.5%) in patients with detectable 12-weeks plasma EBV DNA. Conclusions: 12-weeks PDG-PET/CT was reliable in the surveillance of LA-NPC and could help optimize the follow-up strategy and provide implications for timely and effective therapeutic regimen, especially for patients in different EBV DNA-based risk groups. Clinical trial information: NCT03601390 .

Response-adapted therapy for locally advanced nasopharyngeal carcinoma based on clinical response and circulating Epstein-Barr virus DNA level post induction chemotherapy.

TPS6112 Background: For locally advanced nasopharyngeal carcinoma (NPC), the mainstay treatment is cisplatin-based concurrent chemoradiation (CCRT). Recent phase III clinical trials have demonstrated that induction chemotherapy (ICT) plus CCRT, compared with CCRT alone, further improved progression-free survival (PFS). However, not every patient has good response to ICT. Evidence has accumulated that those with poor response to ICT, or those with detectable Epstein-Barr Virus (EBV) DNA post ICT, correlated with poorer PFS. In addition, real-time monitoring of plasma EBV DNA response adds prognostic information, and has the potential utility for risk-adapted treatment intensification in NPC. The aim of this study is to clarify whether response-adapted strategy based on clinical efficacy and EBV DNA response confers survival benefit to patients with locally advanced NPC. Methods: This is an open-label, 3-arm, phase II study. Patients with pathologically confirmed, locally advanced NPC (III-IVA, excluding T3N0M0, 8th AJCC staging system), with pretreatment detectable plasma EBV DNA level and ECOS PS 0-1 were eligible. Patients will receive one cycle of GP-based ICT. After one cycle of ICT, plasma EBV DNA and head and neck MR are performed. Based on clinical efficacy (evaluated per RECIST 1.1 criteria) and changes of plasma EBV DNA after one cycle, patients will be divided into three arms. Patients with good response (Arm A: Early Responders, undetectable EBV DNA level and CR/PR) will directly receive CCRT. Patients with intermediate response (Arm B: Intermediate Responders, detectable EBV DNA and CR/PR/decreased SD; or undetectable EBV DNA yet without CR/PR) will be randomized to experiment subgroup (GP combined with Toripalimab for two additional cycles then CCRT and maintenance Toripalimab treatment) and standard subgroup (GP for two additional cycles then CCRT). Patients with poor response (Arm C: Treatment Resistant, increased EBV DNA level, or PD/enlarged SD) will be switched to TP regimen combined with Toripalimab, followed by CCRT and maintenance Toripalimab treatment. Sample size calculation is based on 2-year PFS rate for arm B as the primary endpoint (one-sided α = 0.10, power = 0.80). Our target sample size is estimated to be 198-240, among them 168 for arm B. Secondary endpoints include adverse events determined by CTCAE v5.0, ORR at 3 months post-CRT, 2-year locoregional recurrence-free survival (LRFS) rate, 2-year distant metastasis-free survival (DMFS) rate, 2-year overall survival (OS) rate, as well as quality of Life for arm B. Exploratory endpoints include 2-year PFS rate, LRFS rate, DMFS rate, OS rate, ORR at 3 months post-CRT, adverse effects, and quality of life for arm A and arm C. This trial opened to accrual in July 2022 and the recruitment is ongoing. Clinical trial information: NCT05628922 .

Frequency of Peripheral CD8+ T Cells Expressing Chemo-Attractant Receptors CCR1, 4 and 5 Increases in NPC Patients with EBV Clearance upon Radiotherapy

Radiotherapy (RT) is the standard-of-care for Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC), where the post-RT clearance of plasma EBV DNA is prognostic. Currently, it is not known whether the post-RT clearance of plasma EBV DNA is related to the presence of circulating T-cell subsets. Blood samples from NPC patients were used to assess the frequency of T-cell subsets relating to differentiation, co-signaling and chemotaxis. Patients with undetectable versus detectable plasma EBV DNA levels post-RT were categorized as clearers vs. non-clearers. Clearers had a lower frequency of PD1+CD8+ T cells as well as CXCR3+CD8+ T cells during RT compared to non-clearers. Clearers exclusively showed a temporal increase in chemo-attractant receptors CCR1, 4 and/or 5, expressing CD8+ T cells upon RT. The increase in CCR-expressing CD8+ T cells was accompanied by a drop in naïve CD8+ T cells and an increase in OX40+CD8+ T cells. Upon stratifying these patients based on clinical outcome, the dynamics of CCR-expressing CD8+ T cells were in concordance with the non-recurrence of NPC. In a second cohort, non-recurrence associated with higher quantities of circulating CCL14 and CCL15. Collectively, our findings relate plasma EBV DNA clearance post-RT to T-cell chemotaxis, which requires validation in larger cohorts.

227MO Characterization of minimal residual disease (MRD) post-radiotherapy (RT) in nasopharyngeal carcinoma (NPC) patients identifies a favorable subgroup with low risk of relapse

Detectable plasma Epstein-Barr virus (EBV) DNA post-RT implies a poor prognosis, but Hui et al. reported a model that could sub-stratify these patients by an EBV DNA cut-off of 500 copies/mL. Detection limits however vary between different EBV DNA assays, which could lead to false positives at low EBV DNA levels. We investigated the EBV DNA kinetics and survival in patients harboring a detectable, but non-quantifiable EBV DNA post-RT (≤265 copies/mL; termed as MRD).

Significance of boost dose for T4 nasopharyngeal carcinoma with residual primary lesion after intensity-modulated radiotherapy.

Previous studies showed poorer survival in T4 disease with residual lesion. To evaluate the efficacy and toxicity of a boost dose for T4 nasopharyngeal carcinoma (NPC), patients with a residual primary lesion after intensity-modulated radiotherapy (IMRT). 398 T4 NPC patients with residual primary lesions after radical IMRT were retrospectively reviewed. An IMRT boost dose of 4-6.75Gy was delivered to the residual lesions in 2-3 fractions. Propensity score matching (PSM) was applied to balance potential confounders between groups (ratio, 1:2). The presence of Epstein-Barr virus (EBV) DNA in plasma after IMRT was used for risk stratification. Patients who received boost radiation had significantly improved overall survival (OS) and local recurrence-free survival (LRFS) compared with those who did not (all P < 0.05). In the matched cohort, 3-year OS was 86.6% in the boost radiation group and 72.7% in the non-boost group (P = 0.022). Three-year LRFS was 93.4% in the boost radiation group and 83.5% in the non-boost group (P = 0.022). In the subgroup analysis, boost dose was shown to significantly improve 3-year OS (88.0% vs. 74.1%, P = 0.021) in the low-risk group (with undetectable plasma EBV DNA after IMRT). The administration of a boost dose also improved 3-year OS in the high-risk group (with detectable plasma EBV DNA after IMRT) (66.7% vs. 60.0%, P = 0.375). Multivariate analysis demonstrated that boost dose was the only protective prognostic factor. The addition of a boost dose for T4 NPC patients with residual primary lesion after radical IMRT provides satisfactory tumor control and clinical benefit. Additional timely and effective strengthening treatments are recommended for patients with detectable levels of plasma EBV DNA after radiotherapy.

Combination of Oral Nanatinostat (Nstat), a Novel Histone Deacetylase Inhibitor (HDACi), and the Oral Anti-Viral, Valganciclovir (VGCV), Is Active in Relapsed/Refractory (R/R) Epstein-Barr Virus (EBV)-Positive B-Cell, T-Cell, and Hodgkin Lymphoma: Interim Safety and Efficacy Results from a Phase 1b/2a Study

Combination of Oral Nanatinostat (Nstat), a Novel Histone Deacetylase Inhibitor (HDACi), and the Oral Anti-Viral, Valganciclovir (VGCV), Is Active in Relapsed/Refractory (R/R) Epstein-Barr Virus (EBV)-Positive B-Cell, T-Cell, and Hodgkin Lymphoma: Interim Safety and Efficacy Results from a Phase 1b/2a Study

The diagnostic and prognostic values of plasma Epstein-Barr virus DNA for residual cervical lymphadenopathy in nasopharyngeal carcinoma patients: a retrospective study

BackgroundCurrently, the diagnosis and treatment of nasopharyngeal carcinoma (NPC) patients with residual cervical lymphadenopathy following radical radiotherapy with or without chemotherapy are challenging. We investigated the prognosis of NPC patients with residual cervical lymphadenopathy and assessed the diagnostic and prognostic values of Epstein-Barr virus (EBV) DNA in these patients.MethodsThis study included 82 NPC patients who were diagnosed with suspected residual cervical lymphadenopathy following completion of antitumor therapy. Their plasma EBV DNA levels were measured using quantitative polymerase chain reaction (qPCR) before the initiation of treatment and before neck dissection. Fine needle aspiration cytology (FNAC) was performed in 21 patients. All patients had undergone neck dissection and postoperative pathological examination to identify the nature of residual cervical lymphadenopathy. The overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) were calculated using the Kaplan–Meier method and compared using the log-rank test. The Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Multivariable analysis was used to estimate the effect of potential prognostic factors on survival.ResultsFollowing a median follow-up of 52.6 months, compared with patients with negative postoperative pathological findings for residual cervical lymphadenopathy, the patients with positive findings had a significantly lower 3-year PFS rate (49.9% vs. 83.3%, P = 0.008). Among NPC patients with residual cervical lymphadenopathy, the patients with preoperative plasma EBV DNA > 0 copy/mL had a lower 3-year PFS rate than did those with no detectable EBV DNA (43.7% vs. 61.1%, P = 0.031). In addition, combining FNAC with preoperative EBV DNA detection improved the diagnostic sensitivity. Multivariable analysis demonstrated that residual cervical lymphadenopathy with positive postoperative pathological result was an independent prognostic factor for PFS and that detectable preoperative plasma EBV DNA was an independent prognostic factor for OS.ConclusionsUsing FNAC combined with preoperative EBV DNA detection improves the sensitivity in diagnosing NPC with residual cervical lymphadenopathy. Compared with patients with undetectable EBV DNA, patients with detectable preoperative plasma EBV DNA have worse prognosis and may require a more aggressive treatment strategy.

Spontaneous remission of residual post-therapy plasma Epstein-Barr virus DNA and its prognostic implication in nasopharyngeal carcinoma: A large-scale, big-data intelligence platform-based analysis.

Detectable post-therapy plasma Epstein-Barr virus (EBV) DNA predicts poor survival in non-metastatic nasopharyngeal carcinoma (NPC). However, some patients subsequently experience spontaneous remission of residual EBV DNA during follow-up and it was unclear whether these patients were still at high risk of disease failure. Using the NPC database from an established big-data intelligence platform, 3269 NPC patients who had the plasma EBV DNA load measured at the end of therapy (± 1 week) were identified. In total, 93.0% (3031/3269) and 7.0% (238/3269) of patients had undetectable and detectable (> 0 copy/ml) plasma EBV DNA at the end of therapy (EBV DNAend ), respectively. Detectable EBV DNAend was a prognostic factor for poorer 3-year disease-free survival (DFS), overall survival (OS), distant metastasis-free survival (DMFS), and loco-regional recurrence-free survival (LRRFS) in both univariate and multivariate analyses. Of 238 patients with residual EBV DNAend , 192 underwent EBV DNA assay 3 months after and spontaneous remission occurred in 72.4% (139/192). However, these patients still had poorer 3-year DFS (55.1% vs. 89.8%), OS (79.1% vs. 96.2%), DMFS (68.4% vs. 94.1%) and LRRFS (84.5% vs. 95.0%) than patients with undetectable EBV DNAend (all p < 0.001). And patients with persistent detectable post-therapy EBV DNA had the worst outcomes. These results were confirmed in multivariate analysis. In conclusion, residual EBV DNA post therapy was a robust biomarker for NPC prognosis. Although residual post-therapy EBV DNA could spontaneous remit during follow-up, these patients were still at high risk of disease failure and such patients may benefit from adjuvant therapy.

Human cytomegalovirus and Epstein-Barr virus infections increase the risk of death in patients with head and neck cancers receiving radiotherapy or radiochemotherapy.

Viral infections, including cytomegalovirus (CMV) and Epstein-Barr virus (EBV), play an important role in carcinogenesis and can influence patients’ prognosis and condition during cancer treatment.The goal of this study was to investigate CMV and EBV infections in patients receiving radiotherapy or radiochemotherapy due to head and neck cancers to determine the influence of these infections on the risk of death. The observation period was 2 years.Of 41 patients enrolled, 11 received radiotherapy (simultaneous-integrated boost intensity-modulated radiation therapy [SIB-IMRT], 2.25 Gy/fraction, 30 fractions, [n = 7] or IMRT, 2 Gy per fraction, 35 fractions, [n = 4]) and 30 received radiochemotherapy (cisplatin 100 mg/m2 and SIB-IMRT [n = 13] or IMRT [n = 17]). Plasma CMV and EBV DNA levels were assessed using real-time PCR before or during treatment or 4 weeks posttreatment.The risk of death in the group positive for plasma CMV or EBV deoxyribonucleic acid (DNA) was significantly higher compared to the group without detectable plasma CMV (odd ratio [OR]: 7.5, 95% confidence interval [CI]: 1.11–50.67) or EBV DNA (OR: 10.91, 95% CI: 1.135–104.8). Results were confirmed using the Bayesian method. Plasma positivity for CMV or EBV DNA was associated with a higher risk of death (both P = .04).Viral infections negatively affect the survival of patients with head and neck cancers. Diagnosing and treating these viral infections in patients with positive results should be considered.

Relationship between pretreatment concentration of plasma Epstein-Barr virus DNA and tumor burden in nasopharyngeal carcinoma: An updated interpretation.

BackgroundPretreatment plasma Epstein‐Barr virus (EBV) DNA is an important tumor marker and prognostic factor in nasopharyngeal carcinoma (NPC). This study aimed to clarify the relationship between plasma EBV DNA level and tumor burden.Materials and MethodsPretreatment tumor burden was measured by radiologically delineated volumes, including nasopharynx tumor volume (GTVnx) and malignant nodes volume (GTVnd); pretreatment level of plasma EBV DNA was quantified by quantitative polymerase chain reaction. The relationship between natural logarithm of EBV DNA (ln‐DNA) and square root of tumor volume (sq‐GTV) was analyzed by Pearson correlation coefficient and partial correlation coefficient. Correlations in subgroups of tumor and nodal stages were also analyzed. A linear regression model was constructed to evaluate the contribution of tumor volumes to plasma EBV DNA. The prognostic effects of EBV DNA independent of tumor burden were evaluated.ResultsTwo thousand two hundred and forty nine nonmetastatic NPC patients with detectable plasma EBV DNA were included in correlation analyses. Ln‐DNA showed significant correlation with sq‐GTVnx (r = 0.171) and sq‐GTVnd (r = 0.339) separately. Together, sq‐GTVnx and sq‐GTVnd could only explain 12.9% of the ln‐DNA. Tumor and nodal stages of disease could clearly influence the strength of relationship in subgroup analysis. After excluding confounding volume information, EBV DNA still can predict death and distant metastasis, but not locoregional relapse.ConclusionThis study suggests that plasma EBV DNA is not only an index of tumor burden, but may also reflect other tumor features, such as accessibility to circulation, angiogenesis, tumor cell kinetics, metabolic activity, and metastatic potential, among others.

Analysis of Plasma Epstein-Barr Virus DNA in Nasopharyngeal Cancer After Chemoradiation to Identify High-Risk Patients for Adjuvant Chemotherapy: A Randomized Controlled Trial.

Purpose The contribution of adjuvant chemotherapy after chemoradiation therapy (CRT) in nasopharyngeal cancer (NPC) remains controversial. Plasma Epstein-Barr virus (EBV) DNA is a potential biomarker of subclinical residual disease in NPC. In this prospective, multicenter, randomized controlled trial, we used plasma EBV DNA to identify patients with NPC at a higher risk of relapse for adjuvant chemotherapy. Patients and Methods Eligible patients with histologically confirmed NPC of Union for International Cancer Control stage IIB to IVB, adequate organ function, and no locoregional disease or distant metastasis were screened by plasma EBV DNA at 6 to 8 weeks after radiotherapy (RT). Patients with undetectable plasma EBV DNA underwent standard surveillance. Patients with detectable plasma EBV DNA were randomly assigned to either adjuvant chemotherapy with cisplatin and gemcitabine for six cycles (arm 1) or observation (arm 2). Patients were stratified for primary treatment (RT v CRT) and stage (II/III v IV). The primary end point was relapse-free survival (RFS). Results Seven hundred eighty-nine patients underwent EBV DNA screening. Plasma EBV DNA was undetectable in 573 (72.6%) and detectable in 216 (27.4%); 104 (13.2%) with detectable EBV DNA were randomly assigned to arms 1 (n = 52) and 2 (n = 52). After a median follow-up of 6.6 years, no significant difference was found in 5-year RFS rate between arms 1 and 2 (49.3% v 54.7%; P = .75; hazard ratio for relapse or death, 1.09; 95% CI, 0.63 to 1.89). The level of post-RT plasma EBV DNA correlated significantly with the hazards of locoregional failure, distant metastasis, and death. Conclusion In patients with NPC with detectable post-RT plasma EBV DNA, adjuvant chemotherapy with cisplatin and gemcitabine did not improve RFS. Post-RT plasma EBV DNA level should be incorporated as the selection factor in future clinical trials of adjuvant therapy in NPC.

Plasma Epstein-Barr Virus Load as an Early Biomarker and Prognostic Factor of Human Immunodeficiency Virus-related Lymphomas.

Epstein-Barr virus (EBV) has been implicated in lymphomagenesis and can be found infecting tumor cells and in plasma at lymphoma diagnosis, especially in human immunodeficiency virus (HIV)-infected patients. Our aim was to evaluate the usefulness of plasma EBV load as biomarker and prognostic factor in HIV-positive patients with lymphomas. EBV loads were measured by polymerase chain reaction in plasma samples of 81 HIV-positive patients' lymphomas at different moments: within 1 year before lymphoma diagnosis, at diagnosis, and at complete response (CR). Control samples included HIV-negative patients with lymphomas and HIV-positive patients without neoplasia or opportunistic infections. HIV-positive patients with lymphomas had more frequently-detectable EBV load at lymphoma diagnosis (53%) than either HIV-negative patients with the same lymphoma type (16%; P < .001) or HIV-positive individuals without neoplasia or opportunistic infection (1.2%; P < .001). HIV-positive lymphoma patients with detectable EBV load in plasma at lymphoma diagnosis had statistically significant decrease of EBV load at CR. High EBV load (>5000 copies/mL) at lymphoma diagnosis was an independent negative prognostic factor for overall survival and progression-free survival in HIV-positive patients with lymphomas. Detectable plasma EBV loads identified HIV-positive subjects that would eventually develop lymphoma (area under the curve, 82%; 95% CI: 0.67-0.96). Plasma EBV load can be used as a biomarker and as a prognostic factor in HIV-positive patients with lymphomas. The presence of the EBV load in the plasma of an HIV-positive patient can be an early predictor of lymphoma development.

Clinical Significance of Plasma Epstein-Barr Virus DNA in Pulmonary Lymphoepithelioma-like Carcinoma (LELC) Patients

Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a histologically distinctive subtype of NSCLC and an Epstein-Barr virus (EBV)-associated epithelial neoplasm. We investigated the clinical significance of plasma concentrations of EBV DNA in patients with pulmonary LELC. Two independent sets of plasma samples from a total of 429 patients with patients with pulmonary LELC (287 initial and 142 confirmatory) were available for EBV DNA determination. Plasma samples from the patients were subjected to a real-time quantitative polymerase chain reaction before treatment and 3 months after radical resection. Cutoff points were determined for pretreatment plasma EBV DNA concentration (low <4000 copies/mL versus high ≥4000 copies/mL) on the basis of a measure of heterogeneity with the log-rank test statistic with respect to overall survival (OS). The Kaplan-Meier method and Cox regression were used to evaluate the relationship between plasma EBV DNA concentrations and clinical outcome. Among patients with advanced-stage pulmonary LELC who underwent sequential blood draws, we evaluated the relationship between change in disease status and change in EBV DNA concentrations by using nonparametric tests. High EBV DNA concentration was associated with shorter OS in the initial, confirmatory, and combined data sets (combined data set hazard ratio= 3.67, 95% confidence interval: 2.72-4.38, p < 0.001). These findings persisted after multivariable adjustment. Compared with low EBV DNA concentration, high EBV DNA concentration was associated with shorter OS in patients with any stage of disease. High EBV DNA concentration was also associated with shorter disease-free survival (DFS) in patients with stage I/II disease. Patients with persistently detectable plasma EBV DNA had significantly poorer OS (p < 0.001) and DFS (p < 0.001) than did patients with undetectable EBV DNA 3 months after radical resection. In patients who underwent sequential evaluation of EBV DNA, an association was identified between an increase in EBV DNA concentration and a poor response to treatment and disease progression of pulmonary LELC. High baseline EBV DNA concentration is an independent poor prognostic marker in patients with pulmonary LELC. These results should be confirmed in larger prospective trials.

Prognostic value of plasma Epstein\u2013Barr virus DNA level during posttreatment follow-up in the patients with nasopharyngeal carcinoma having undergone intensity-modulated radiotherapy

BackgroundThe value of Epstein–Barr virus (EBV) DNA assay during posttreatment follow-up of the patients with nasopharyngeal carcinoma (NPC) presenting with different pretreatment plasma EBV DNA levels remains unclear. In the present study, we aimed to evaluate the prognostic value of plasma EBV DNA assay during posttreatment follow-up in the patients with NPC who have undergone intensity-modulated radiotherapy.MethodsThe medical records of 385 NPC patients treated with intensity-modulated radiotherapy between November 2009 and February 2012 were reviewed. All patients underwent plasma EBV DNA assays before treatment, within 3 months after treatment, and then every 3–12 months during posttreatment follow-up period. The recurrence rates for patients with different pretreatment and posttreatment follow-up plasma EBV DNA levels were analyzed.ResultsOf the 385 patients, 267 (69.4%) had detectable pretreatment plasma EBV DNA (> 0 copy/mL) and 93 (24.2%) had detectable posttreatment EBV DNA during a median follow-up of 52.8 months (range 9.3–73.8 months). Detectable EBV DNA during posttreatment follow-up was found in 14.4% (17/118) and 28.5% (76/267) of patients with undetectable and detectable pretreatment EBV DNA, respectively, and was significantly associated with tumor recurrence in both patient groups. EBV DNA was detectable in 12.8% (40/313) of patients who remained disease-free, 56.4% (22/39) of patients with locoregional recurrence alone, and 93.9% (31/33) of patients with distant metastasis as the first recurrence event (P < 0.001); 6.5% (19/292) of patients with undetectable EBV DNA and 57.0% (53/93) of patient with detectable EBV DNA during posttreatment follow-up experienced tumor recurrence. Compared with other cut-off values, the cut-off value of 0 copy/mL for EBV DNA during posttreatment follow-up had the highest area under the ROC curve (AUC) value (0.804, 95% confidence interval 0.741–0.868) for predicting tumor recurrence (sensitivity, specificity, and accuracy: 73.6%, 87.2%, and 84.7%, respectively).ConclusionPlasma EBV DNA level during posttreatment follow-up is a good marker for predicting distant metastasis but not locoregional recurrence in the patients with NPC irrespective of the pretreatment EBV DNA levels.

P3.02-001 Clinical Significance of Plasma Epstein-Barr Virus DNA in Pulmonary Lymphoepithelioma-Like Carcinoma (LELC) Patients

Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare subtype of non-small-cell lung cancer (NSCLC) and an Epstein-Barr virus (EBV)-associated epithelial neoplasm. We investigated the clinical significance of plasma concentrations of EBV DNA in pulmonary LELC patients. Two independent sets of plasma samples from a total of 429 patients with pulmonary LELC patients (287 initial and 142 confirmatory) were available for EBV DNA determination. Plasma samples from the patients were subjected to a real-time quantitative polymerase chain reaction (qPCR) before treatment and three months after radical resection. Cutoff points were determined for pretreatment plasma EBV DNA (low, <4000 copies/mL; high, ≥4000 copies/mL) on the basis of a measure of heterogeneity with the log-rank test statistic with respect to overall survival. Kaplan-Meier method and Cox regression were used to evaluate the relationship between plasma EBV DNA concentrations and clinical outcome. Among advanced stage pulmonary LELC patients who underwent sequential blood draws, we evaluated the relationship between change in disease status and change in EBV DNA concentrations using nonparametric tests. High EBV DNA concentration was associated with poor OS in the initial, confirmatory, and combined data sets (combined data set: hazard ratio (HR), 3.67; 95% CI, 2.72 to 4.38; P <0.001). These findings persisted after multivariable adjustment. Compared with low EBV DNA concentration, high EBV DNA concentration was associated with poor OS in patients with any stage. High EBV DNA concentration was also associated with poor disease-free survival (DFS) in patients with stage I/II disease. Patients with persistently detectable plasma EBV DNA had significantly poor OS (P <0.001) and DFS (P <0.001) than patients with undetectable EBV DNA three months after radical resection. In patients who underwent sequential evaluation of EBV DNA, an association was identified between an increase in EBV DNA concentration and a poor response to treatment and disease progression of pulmonary LELC. High baseline EBV DNA concentration is an independent poor prognostic marker in pulmonary LELC patients. These results should be confirmed in larger prospective trials.

Early detection of nasopharyngeal carcinoma by plasma Epstein‐Barr virus DNA analysis in a surveillance program

Nasopharyngeal carcinoma (NPC) is prevalent in Southeast Asia. Over the last decade, plasma Epstein-Barr virus (EBV) DNA has been developed as a tumor marker for NPC. In this study, the authors investigated whether plasma EBV DNA analysis is useful for NPC surveillance. In total, 1318 volunteers ages 40 to 60 years were prospectively recruited. Plasma EBV DNA and serology for viral capsid antigen immunoglobulin A (IgA) were measured. Participants who had detectable plasma EBV DNA or positive IgA serology underwent nasal endoscopic examination and a follow-up plasma EBV DNA analysis in approximately 2 weeks. All participants were followed for 2 years to record the development of NPC. Three individuals with NPC were identified at enrolment. All of them were positive for EBV DNA and remained positive in follow-up analysis. Only 1 of those patients was positive for EBV serology. In 1 patient who had NPC with a small tumor confined to the mucosa, the tumor was not detectable on endoscopic examination. Because of a 2-fold increase in plasma EBV DNA on the follow-up analysis, that patient underwent magnetic resonance imaging, which revealed the tumor. Among the participants who did not have NPC but had initially positive plasma EBV DNA results, approximately 66% had negative EBV DNA results after a median of 2 weeks. Plasma EBV DNA analysis proved useful for detecting early NPC in individuals without a clinical suspicion of NPC. Repeating the test in those who had initially positive results differentiated those with NPC from those who had false-positive results. Cancer 2013. © 2013 American Cancer Society.

Plasma Epstein-Barr virus DNA level strongly predicts survival in metastatic/recurrent nasopharyngeal carcinoma treated with palliative chemotherapy

Plasma Epstein-Barr virus (EBV) DNA is widely used in screening, monitoring, and prediction of relapse in nonmetastatic nasopharyngeal carcinoma (NPC). However, data regarding utility of plasma EBV DNA in metastatic NPC are rare. The current study was to test the prognostic implication of plasma EBV DNA level in metastatic/recurrent NPC patients treated with palliative chemotherapy. Plasma EBV DNA level was measured at baseline and thereafter at the start of each treatment cycle in 127 histologically proven metastatic/recurrent NPC patients treated with palliative chemotherapy. Correlations of pre-treatment and post-treatment plasma EBV DNA levels to survival and response were analyzed. Patients with a low pre-treatment plasma EBV DNA level (<median) had significantly better survival than those with a high pre-treatment plasma EBV DNA level (≥median). Patients with a post-treatment plasma EBV DNA decline to an undetectable level had better survival and better tumor response compared with those with a sustained detectable post-treatment plasma EBV DNA level. The early decrease of post-treatment plasma EBV DNA to an undetectable level after 1 cycle of chemotherapy was associated with significantly increased survival. Patients with low pre-treatment plasma EBV DNA level and undetectable post-treatment plasma EBV DNA showed a favorable prognosis (5-year overall and progression-free survival of 50.6% and 21.7%, respectively). Plasma EBV DNA is of predictive value for prognosis in metastatic/recurrent NPC patients undergoing palliative chemotherapy. The pre-treatment plasma EBV DNA level as well as the early decrease of plasma EBV DNA after chemotherapy enabled easy and early discrimination between patients who will and those who will not benefit from continued treatment.

Use of Plasma Epstein-Barr virus DNA Monitoring as a Tumor Marker in follow-up of Patients with Nasopharyngeal Carcinoma: Preliminary Results and Report of two Cases

Recent studies suggest that plasma Epstein-Barr virus (EBV) DNA may reflect tumor burden in patients with nasopharyngeal cancer. A prospective study was initiated to investigate this correlation in 125 patients (34 pretreatment [Group A], 78 in remission [Group B] and 13 relapsed [Group C]) and 19 healthy controls. In group A, EBV DNA was detected in plasma samples of 24 (70%) patients. In Group B, EBV DNA was detected in 7 patients (range 77-13,731 copies/mL) and further imaging in all but one of these patients revealed active disease confirmed by ultrasound-guided fine-needle biopsy. There was only one false-positive case; this patient is currently under follow-up. Here we describe 2 of the 7 patients with detectable plasma EBV DNA in whom recurrence was documented by PET scan during follow-up. Our results showed that in group B the positive predictive value of quantitative analysis of plasma EBV DNA was 85%. Quantitative analysis of EBV DNA in plasma seems to become an integral part of screening, staging, monitoring, and prediction of relapse in patients with nasopharyngeal carcinoma. However, previous studies cannot be considered definitive and more reports on the use of this technique are urgently needed from both endemic and non-endemic regions.