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      Prognostic Impact of Plasma Epstein-Barr Virus DNA in Patients with Nasopharyngeal Carcinoma Treated using Intensity-Modulated Radiation Therapy

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          Abstract

          The prognostic value of plasma Epstein-Barr virus (EBV) DNA remains unknown in nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). We retrospectively reviewed medical records of 584 newly diagnosed patients with nonmetastatic and biopsy-proven NPC treated using IMRT. Plasma EBV DNA concentration was measured before therapy (pre-DNA) and within 1 month of completing therapy (post-DNA) using real-time quantitative polymerase chain reaction. Receiver operating characteristic (ROC) curves were generated to identify pre-DNA and post-DNA cut-off values. Prognostic value was assessed using a multivariate Cox proportional hazards model .Three-year disease-free survival (DFS), overall survival (OS), loco-regional relapse-free survival (LRRFS) and distant metastasis-free (DMFS) for pre-DNA >2010 vs.≤2010 were 78.1% vs. 93.6% ( P < 0.001), 92.3% vs. 98.9% ( P < 0.001), 90.9% vs. 96.6% ( P = 0.004) and 85.5% vs. 96.6% ( P < 0.001), respectively. Three-year DFS, OS, LRRFS and DMFS for post-DNA >0 vs. = 0 were 49.9% vs. 88.5% ( P < 0.001), 72.1% vs. 97.5% ( P < 0.001), 86.6% vs. 94.3% ( P= 0.019), and 60.5% vs. 93.3% ( P < 0.001), respectively. Plasma EBV DNA remains a prognostic factor in IMRT era and should be incorporated into TNM staging to guide individualized treatment strategies in NPC.

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          How does intensity-modulated radiotherapy versus conventional two-dimensional radiotherapy influence the treatment results in nasopharyngeal carcinoma patients?

          To compare the results of intensity-modulated radiotherapy (IMRT) with those of two-dimensional conventional radiotherapy (2D-CRT) in the treatment of patients with nasopharyngeal carcinoma (NPC). A retrospective review of data from 1,276 patients with biopsy-proven, nonmetastatic NPC was performed. All patients had undergone magnetic resonance imaging and were staged according to the sixth edition of the American Joint Committee on Cancer staging criteria. Radiotherapy was the primary treatment for all patients. Of the 1,276 patients, 512 were treated with IMRT and 764 with 2D-CRT. The 5-year actuarial local relapse-free survival (LRFS), the nodal relapse-free survival (NRFS), the distant metastasis-free survival (DMFS), and the disease-free survival (DFS) rates were 92.7%, 97.0%, 84.0%, and 75.9%, respectively, for the IMRT group, and 86.8%, 95.5%, 82.6%, and 71.4%, respectively, for the 2D-CRT group. In stage T1 patients, improvement of LRFS in the IMRT group was even significantly higher than in the 2D-CRT group (100% vs. 94.4%; p = 0.016). A trend of improvement of DFS was observed in the IMRT group compared with the 2D-CRT group but without reaching statistical significance. NRFS and DMFS rates were similar in the two groups. A greater improvement of treatment results with IMRT than with 2D-CRT was demonstrated primarily by achieving a higher local tumor control rate in NPC patients, especially in the early T stage patients. The goal of better control of both local failure in advanced, nonmetastatic NPC patients and of distant failure should be addressed in future studies. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Neoplastic Characteristics of the DNA Found in the Plasma of Cancer Patients

            About one third of patients with various malignant diseases were found to have extractable amounts of DNA in their plasma whereas no DNA could be detected in normal controls. Using the test established by one of us (M. B.), which is based on decreased strand stability of cancer cell DNA, we have found that several plasma DNA originate from cancer cells.
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              Plasma Epstein-Barr virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma.

              Epstein-Barr virus (EBV) DNA can be detected and quantified in the plasma of patients with EBV-related tumors, such as nasopharyngeal carcinoma (NPC). Although NPC at early stages can be cured by radical radiotherapy, there is a high recurrence rate in patients with advanced NPC. The pretreatment level of circulating EBV DNA is a prognostic factor for NPC, but the prognostic value of post-treatment EBV DNA has not been studied. We designed a prospective study in Hong Kong, China, to investigate the value of plasma EBV DNA as a prognostic factor for NPC. One hundred seventy NPC patients, without metastatic disease at presentation, were treated with a uniform radiotherapy protocol. Circulating EBV DNA was measured by real-time quantitative polymerase chain reaction before treatment and 6-8 weeks after radiotherapy was completed. Risk ratios (RRs) were determined with a Cox regression model, and associations of various factors with progression-free and overall survival and recurrence rates were determined with a stepwise Cox proportional hazards model. All statistical tests were two-sided. Ninety-nine percent of patients achieved complete clinical remission. Levels of post-treatment EBV DNA dominated the effect of levels of pretreatment EBV DNA for progression-free survival. The RR for NPC recurrence was 11.9 (95% confidence interval [CI] = 5.53 to 25.43) for patients with higher post-treatment EBV DNA and 2.5 (95% CI = 1.14 to 5.70) for patients with higher pretreatment EBV DNA. Higher levels of post-treatment EBV DNA were statistically significantly associated with overall survival (P<.001; RR for NPC recurrence = 8.6, 95% CI = 3.69 to 19.97). The positive and negative predictive values for NPC recurrence for a higher level of post-treatment EBV DNA were 87% (95% CI = 58% to 98%) and 83% (95% CI = 76% to 89%), respectively. Levels of post-treatment plasma EBV DNA in patients with NPC appear to strongly predict progression-free and overall survival and to accurately reflect the post-treatment residual tumor load.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                29 February 2016
                2016
                : 6
                : 22000
                Affiliations
                [1 ]Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine , People’s Republic of China
                [2 ]Imaging Diagnosis and Interventional Center, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine , People’s Republic of China
                [3 ]Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University , People’s Republic of China
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                srep22000
                10.1038/srep22000
                4770420
                26924234
                2b17a8f5-095e-4d25-9598-62614c20b4e2
                Copyright © 2016, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 01 October 2015
                : 03 February 2016
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