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Nasopharyngeal carcinoma is characterised by distinct geographical distribution and is particularly prevalent in east and southeast Asia. Epidemiological trends in the past decade have shown that its incidence has declined gradually but progressively, and mortality has been reduced substantially. These findings probably reflect lifestyle and environmental changes, enhanced understanding of the pathogenesis and risk factors, population screening, advancements in imaging techniques, and individualised comprehensive chemoradiotherapy strategies. In particular, plasma Epstein-Barr virus (EBV) DNA has been used for population screening, prognostication, predicting treatment response for therapeutic adaptation, and disease surveillance. Moreover, the widespread application of intensity-modulated radiotherapy and optimisation of chemotherapy strategies (induction, concurrent, adjuvant) have contributed to improved survival with reduced toxicities. Among the existing developments in novel therapeutics, immune checkpoint therapies have achieved breakthroughs for treating recurrent or metastatic disease and represent a promising future direction in nasopharyngeal carcinoma.

Background Findings remain unclear whether neutrophil-to-lymphocyte ratio (NLR) detrimentally affects advanced nasopharyngeal carcinoma (NPC) prognosis. We aim to evaluate the prognostic value of NLR in patients with NPC based on a large-scale cohort from an endemic area. Methods We selected patients retrospectively from a cohort examining long-term cancer outcomes following diagnosis. Neutrophil counts and lymphocyte counts were assessed prior to treatment. Kaplan–Meier method and log-rank test were used to calculate and compare survival outcomes. Additionally, Cox proportional hazards model was utilized to carry out univariate and multivariate analyses. Results Between October 2009 and August 2012, we enrolled 1550 consecutive NPC patients staged II-IVB. The median value of NLR was 2.27 (interquartile range [IQR], 1.71–3.12). Determined by operating characteristic curve using overall survival (OS) as an endpoint, the cutoff value for NLR was 2.50. At 5 years, NLR > 2.50 was associated with inferior OS (90.3% vs 82.5%; P

Purpose To evaluate the evolution of radiation-induced brain stem injury (BSI) in patients with nasopharyngeal carcinoma (NPC) treated with intensity modulated radiation therapy (IMRT) and to identify the critical dosimetric predictors of BSI. Methods and Materials A total of 6288 NPC patients treated with IMRT between 2009 and 2015 were retrospectively reviewed. Among these 6288 patients, 24 had radiation-induced BSI, which manifested as edematous lesions and contrast-enhanced lesions (CLs) on magnetic resonance imaging. Latency, symptoms, and evolution of BSI were assessed. Critical dosimetric predictors of BSI were identified using a penalized regression model with performance evaluated by receiver operating characteristic curve analysis. Results Median BSI latency was 14.5 months (range, 7.6-37.5 months), and 9 out of 24 patients (37.5%) were clinically symptomatic. Edematous lesions and CLs were both present in all patients. Necrosis was significantly more common in larger CLs (P = .007). After median follow-up of 12.5 months, 13 out of 24 patients (54.2%) had complete remission, and 5 out of 24 patients (20.8%) had partial remission. Remission was unaffected by whether or not symptomatic treatment was given. Maximum point dose (Dmax) was identified as the critical predictor of BSI (area under the receiver operating curve = 0.898), with the optimal cutoff equivalent dose in 2-Gy fractions (D2) being 67.4 Gy (sensitivity = 0.833, 20 out of 24; specificity = 0.835, 5234 out of 6264). Patients with Dmax ≥67.4 Gy (D2) were significantly more likely to develop BSI (odds ratio = 25.29; 95% CI, 8.63-74.14; P Conclusions In patients with NPC treated with IMRT, BSI generally tends to improve over time. Dmax = 67.4 Gy (D2) appears to be the dose constraint for brain stem, potentially providing clinicians with greater choice and flexibility when balancing the tumor target coverage and brain stem protection. Further studies are needed to validate our findings.

Background: To investigate the survival outcomes and update effective prognostic nomograms of nasopharyngeal carcinoma (NPC) in an endemic area. Methods: A retrospective cohort of 10126 patients who underwent radical intensity-modulated radiotherapy (IMRT) at Sun Yat-sen University Cancer Center (SYSUCC) from April 2009 to December 2015. We assigned patients into a training cohort (SYSUCC-A; n=6751) and an internal validation cohort (SYSUCC-B; n=3375) based on computer-generated random numbers. Patients collected from Wuzhou Red Cross Hospital (WZRCH) between February 2012 and July 2015 were used as the independent external validation cohort (WZRCH; n=450). Concordance index (C-index) was used to determine predictive accuracy and discriminative ability of the nomogram. Overall survival (OS) was the primary endpoint. Secondary endpoints consisted of local relapse-free survival (LRFS), regional relapse-free survival (RRFS), distant metastasis-free survival (DMFS), and disease-free survival (DFS). All statistical tests were two-sided. Findings: The three- and five-year OS, LRFS, RRFS, DMFS, and DFS rates were 92.3% and 86.5%, 95.4% and 93.4%, 96.0% and 94.3%, 89.5% and 87.0%, and 83.4% and 78.4%, respectively. Gender, age, T stage, and N stage were identified independent risk factors that predicted OS, which were all assembled into the nomogram and derived from multivariable analysis of the SYSUCC-A cohort. The nomogram c-index for OS was 0.725 (95% CI, 0.679-0.772). Calibration curve for probability of death revealed the nomogram-based predictions were in good agreement with actual observations. C-index of the nomograms for LRFS, RRFS, DMFS, and DFS were 0.684 (95% CI, 0.611-0.756), 0.650 (95% CI, 0.571-0.728), 0.680 (95% CI, 0.630-0.731), and 0.669 (95% CI, 0.629-0.710), respectively. All results were confirmed in the validation cohorts. Interpretation: Patients with NPC had satisfactory locoregional survival outcomes undergoing IMRT in an endemic area, and distant metastasis predominates as the pattern of disease relapse. These validated nomograms could serve as useful tool for predicting survival outcomes and providing patient counseling. Funding Statement: This work was supported by the Special Support Program of Sun Yat-sen University Cancer Center (16zxtzlc06), the Health & Medical Collaborative Innovation Project of Guangzhou City, China (201604020003), the Natural Science Foundation of Guang Dong Province (No. 2017A030312003), Health & Medical Collaborative Innovation Project of Guangzhou City, China (201803040003), the Innovation Team Development Plan of the Ministry of Education (No. IRT_17R110), the Overseas Expertise Introduction Project for Discipline Innovation (111 Project, B14035) and the National Natural Science Foundation of China (No. 81802707). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: All patients provided informed consent, and consent waiver for the rest of the cohort was approved by the respective ethical review boards. Patients’ clinical and demographic information were anonymized before analysis.

Objectives Induction chemotherapy (IC) now is gaining recognition for the treatment of nasopharyngeal carcinoma (NPC). The current study was conducted to examine the association between prognosis and the interval between IC and radiotherapy (RT) in NPC patients. Methods Patients with newly diagnosed, non-metastatic NPC who were treated with IC followed by RT from 2009 to 2012 were identified from an inpatient database. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LRFS) were compared between those with interval ≤ 30 and > 30 days by Kaplan-Meier and log-rank analyses; Cox modeling was used for multivariable analysis. Results A total of 668 patients met inclusion criteria with median follow-up of 64.4 months. Patients were categorized by interval: 608 patients with interval ≤ 30 days, and 60 with interval > 30 days. The 5-year OS, DFS, DMFS and LRFS rates were 86.6, 78.2, 88.0 and 89.8% for patients with interval ≤ 30 days, respectively, and 69.2, 64.5, 71.2 and 85.1% for patients with interval > 30 days, respectively. The prolonged interval was a risk factor for OS, DFS and DMFS with adjusted hazard ratios (95% confidence intervals) were 2.44 (1.48–4.01), 1.99 (1.27–3.11) and 2.62 (1.54–4.47), respectively. Conclusions Prolonged interval > 30 days was associated with a significantly higher risk of distant metastasis and death in NPC patients. Efforts should be made to avoid prolonged interval between IC and RT to minimize the risk of treatment failure. Electronic supplementary material The online version of this article (10.1186/s13014-019-1213-4) contains supplementary material, which is available to authorized users.

Background Increasing evidence support an important role for DNA methylation in nasopharyngeal carcinoma (NPC). Here, we explored the role of circadian clock gene Aryl Hydrocarbon Receptor Nuclear Translocator-Like (ARNTL) methylation in NPC. Methods We employed bisulfite pyrosequencing to determine the epigenetic change of ARNTL in NPC cell lines and tissues. ARNTL mRNA and protein expression in cell lines and tissues were detected by real-time PCR and western blotting. Then, we constructed cell lines overexpressing ARNTL and knocked down ARNTL to explore its function and effect on chemotherapy sensitivity of NPC cell lines to cisplatin in vitro and vivo. Finally, we investigated the potential molecular mechanism of ARNTL by gene set enrichment analysis (GSEA), dual Luciferase reporter assay and chromatin immunoprecipitation assay. Results ARNTL was hypermethylated, and its mRNA and protein were significantly down-regulated in NPC cell lines and tissues. When treated by 5-aza-2′-deoxycytidine, mRNA expression was up-regulated. Overexpression of ARNTL could suppress NPC cells proliferation in vitro and vivo while silencing of ARNTL using shRNA achieved opposite results. GSEA assay found that ARNTL was associated with cell cycle and ectopic ARNTL overexpression could induce G2-M phase arrest. Then, we identified and validated cyclin-dependent kinase 5 (CDK5) as the targeting gene of ARNTL by dual Luciferase reporter assay and chromatin immunoprecipitation assay. When transiently infected ARNTL-overexpression cells with PENTER-vector or PENTER-CDK5 plasmids, the later could reverse the suppressive effects of ARNTL on NPC cell proliferation. Moreover, ARNTL significantly enhanced sensitivity to cisplatin in NPC cells. Conclusions ARNTL suppresses NPC cell proliferation and enhances sensitivity to cisplatin by targeting CDK5. ARNTL may represent a novel therapeutic target for NPC.

To explore and evaluate the feasibility of radiomics in stratifying nasopharyngeal carcinoma (NPC) into distinct survival subgroups through multi-modalities MRI.A total of 658 patients (training cohort: 424; validation cohort: 234) with non-metastatic NPC were enrolled in the retrospective analysis. Each slice was considered as a sample and 4863 radiomics features on the tumor region were extracted from T1-weighted, T2-weighted, and contrast-enhanced T1-weighted MRI. Consensus clustering and manual aggregation were performed on the training cohort to generate a baseline model and classification reference used to train a support vector machine classifier. The risk of each patient was defined as the maximum risk among the slices. Each patient in the validation cohort was assigned to the risk model using the trained classifier. Harrell's concordance index (C-index) was used to measure the prognosis performance, and differences between subgroups were compared using the log-rank test.The training cohort was clustered into four groups with distinct survival patterns. Each patient was assigned to one of the four groups according to the estimated risk. Our method gave a performance (C-index = 0.827, p .004 and C-index = 0.814, p .002) better than the T-stage (C-index = 0.815, p = .002 and C-index = 0.803, p = .024), competitive to and more stable than the TNM staging system (C-index = 0.842, p = .003 and C-index = 0.765, p = .050) in the training cohort and the validation cohort.Through investigating a large one-institutional cohort, the quantitative multi-modalities MRI image phenotypes reveal distinct survival subtypes.• Radiomics phenotype of MRI revealed the subtype of nasopharyngeal carcinoma (NPC) patients with distinct survival patterns. • The slice-wise analysis method on MRI helps to stratify patients and provides superior prognostic performance over the TNM staging method. • Risk estimation using the highest risk among slices performed better than using the majority risk in prognosis.

Background The role of pretreatment Epstein-Barr virus DNA (pre-DNA) for individualized induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LA-NPC) still remains unknown. We aimed to address this clinical issue. Methods In total, data on 6218 patient with newly diagnosed LA-NPC receiving concurrent chemoradiotherapy (CCRT) with or without IC were retrospectively reviewed. Receiver operating characteristics (ROC) curve was adopted to calculate the cut-off value of pre-DNA based on disease-free survival (DFS). Propensity score matching (PSM) method was adopted to balance prognostic factors and match patients. Survival outcomes between IC + CCRT and CCRT groups were compared. Results Among the original cohort, no survival difference between IC + CCRT and CCRT groups was found. The cut-off value of pre-DNA was 4650 copies/ml (area under curve [AUC], 0.620; sensitivity, 0.6224; specificity, 0.5673). For patients with Pre-DNA ≤ 4650 copies/ml, the IC + CCRT and CCRT groups also achieved comparable survival outcomes (P > 0.05 for all rates). However, IC + CCRT was associated with significantly improved 3-year DFS (78.6% vs. 74.8%, P = 0.03), overall survival (OS; 91.4% vs. 87.5%, P = 0.002) and distant metastasis-free survival (DMFS; 86.0% vs. 82.2%, P = 0.036) for patient with pre-DNA > 4650 copies/ml. Multivariate analysis also confirm that IC + CCRT was an independent prognostic factor for DFS (HR, 0.817; 95% CI, 0.683–0.977; P = 0.027), OS (HR, 0.675; 95% CI, 0.537–0.848; P = 0.001) and DMFS (HR, 0.782; 95% CI, 0.626–0.976; P = 0.03). Conclusions Pre-DNA may be a feasible and powerful consideration for individualized IC apart from other baseline clinical characteristics in LA-NPC. Electronic supplementary material The online version of this article (10.1186/s12885-018-5177-9) contains supplementary material, which is available to authorized users.

Purpose To investigate the prognostic value of skull-base invasion (SBI) for nasopharyngeal carcinoma (NPC), propose a subclassification of SBI. Methods 792 and 433 patients with pathologically proven NPC and complete clinical and magnetic resonance imaging records at Sun Yat-sen University Cancer Center and Foshan Hospital were enrolled, and investigated using heat map/cluster, network and survival analyses. Results The results of heat map/cluster analyses and network analysis showed that T3 patients with pterygoid process and/or base of the sphenoid bone invasion (T3 slight) had better treatment outcomes than those with other SBIs (T3 severe). Significant differences were observed between T3-slight and T3-severe groups with regard to 5-year overall survival (OS) (93.0% vs. 83.5%, p = 0.014) and progression-free survival (PFS) (82.5% vs. 74.1%, p = 0.044) rates. No significant difference was observed between T3-slight group and T2 patients with regard to 5-year OS (93.0% vs. 84.7%, p = 0.062) and PFS (82.5% vs. 78.9%, p = 0.459) rates. Therefore, we downgraded patients with T3 slight to T2, yielding a new T classification sample. The survival curves of the 5-year OS and PFS rates of T2 and T3 were more reasonable after sample redistribution than those before sample redistribution. The differences in the 5-year OS and PFS rates between T2 and T3 patients after sample redistribution approached significance (p = 0.075 and 0.051, respectively). Conclusions Different types of SBIs had different effects on the prognosis for NPC. We recommend patients with T3 slight not be defined as T3 but, rather, as T2.

BACKGROUND: To identify a radiomics signature to predict local recurrence in patients with non-metastatic T4 nasopharyngeal carcinoma (NPC). METHODS: A total of 737 patients from Sun Yat-sen University Cancer Center (training cohort: n = 360; internal validation cohort: n = 120) and Wuzhou Red Cross Hospital (external validation cohort: n = 257) underwent feature extraction from the largest axial area of the tumor on pretreatment magnetic resonance imaging scans. Feature selection was based on the prognostic performance and feature stability in the training cohort. Radscores were generated using the Cox proportional hazards regression model with the selected features in the training cohort and then validated in the internal and external validation cohorts. We also constructed a nomogram for predicting local recurrence-free survival (LRFS). FINDINGS: Eleven features were selected to construct the Radscore, which was significantly associated with LRFS. For the training, internal validation, and external validation cohorts, the Radscore (C-index: 0.741 vs. 0.753 vs. 0.730) outperformed clinical prognostic variables (C-index for primary gross tumor volume: 0.665 vs. 0.672 vs. 0.577; C-index for age: 0.571 vs. 0.629 vs. 0.605) in predicting LRFS. The generated radiomics nomogram, which integrated the Radscore and clinical variables, exhibited a satisfactory prediction performance (C-index: 0.810 vs. 0.807 vs. 0.753). The nomogram-defined high-risk group had a shorter LRFS than did the low-risk group (5-year LRFS: 73.6% vs. 95.3%, P

PURPOSE To compare clinical features and survival outcomes in patients with ascending type (type A) and descending type (type D) nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era. MATERIALS AND METHODS A total of 5194 patients with type A and type D NPC treated at Sun Yat-sen University Cancer Center were randomly selected. Tumors that were mainly advanced local disease (T3-4 stage) with early stage cervical lymph node involvement (N0-1 stage) were determined as type A, while tumors with advanced lymph node disease (N2-3 stage) but early stage local invasion (T1-2 stage) were classified as type D NPC. Kaplan-Meier's analysis was used to evaluate survival rates, and log-rank test survival curves were used for comparison. In the multivariate analysis Cox proportional hazard models were developed. RESULTS There was a larger proportion of type A tumors (82%) than type D tumors (18%). Compared to patients with type A tumors, those with type D tumors had increased likelihood of distant metastasis, regional recurrence, disease recurrence, and death (P

Background Magnetic resonance images (MRI) is the main diagnostic tool for risk stratification and treatment decision in nasopharyngeal carcinoma (NPC). However, the holistic feature information of multi-parametric MRIs has not been fully exploited by clinicians to accurately evaluate patients. Objective To help clinicians fully utilize the missed information to regroup patients, we built an end-to-end deep learning model to extract feature information from multi-parametric MRIs for predicting and stratifying the risk scores of NPC patients. Methods In this paper, we proposed an end-to-end multi-modality deep survival network (MDSN) to precisely predict the risk of disease progression of NPC patients. Extending from 3D dense net, this proposed MDSN extracted deep representation from multi-parametric MRIs (T1w, T2w, and T1c). Moreover, deep features and clinical stages were integrated through MDSN to more accurately predict the overall risk score (ORS) of individual NPC patient. Result A total of 1,417 individuals treated between January 2012 and December 2014 were included for training and validating the end-to-end MDSN. Results were then tested in a retrospective cohort of 429 patients included in the same institution. The C-index of the proposed method with or without clinical stages was 0.672 and 0.651 on the test set, respectively, which was higher than the that of the stage grouping (0.610). Conclusions The C-index of the model which integrated clinical stages with deep features is 0.062 higher than that of stage grouping alone (0.672 vs 0.610). We conclude that features extracted from multi-parametric MRIs based on MDSN can well assist the clinical stages in regrouping patients.

Background: The prognostic value of C-reactive protein/albumin ratio (CRP/Alb), a novel inflammation-based marker, remains unknown in nasopharyngeal carcinoma (NPC). Methods: We conducted a retrospective review of 1572 consecutive patients with non-metastatic NPC. Patients were randomly divided into a training set (n = 514) and validation set (n = 1058). The prognostic value of the CRP/Alb ratio and the modified Glasgow prognostic score (mGPS; a well-recognized inflammation-based score) was assessed. Results: Receiver-operating characteristic analysis identified 0.05 as the optimal CRP/Alb cut-off value for disease failure in the training set. Patients with a CRP/Alb > 0.05 had poorer overall survival (OS), distant metastasis-free survival (DMFS) and disease-free survival (DFS) in the training set (all P < 0.05). These results were confirmed in the validation set (all P < 0.05) and the whole cohort (all P < 0.001). In multivariate analysis of the entire cohort, the pretreatment CRP/Alb ratio was an independent prognostic factor for OS (HR, 1.394; 95% CI, 1.004-1.937; P = 0.048) and DMFS (HR, 1.545; 95% CI, 1.124-2.122; P = 0.007), but not for DFS (P = 0.083). The mGPS had no significant independent prognostic value for any end-point. Conclusion: CRP/Alb ratio is an useful prognostic indicator in patients with NPC, independent of disease stage.

Background: The aim of this study is to investigate the prognostic value of neoadjuvant chemotherapy (NCT) in locoregionally advanced nasopharyngeal carcinoma (NPC) with low pre-treatment Epstein-Barr virus (EBV) DNA in the era of intensity-modulated radiotherapy (IMRT). Methods: Data on 1099 locoregionally advanced NPC patients treated with IMRT were retrospectively reviewed. Propensity score matching (PSM) method was adopted to balance influence of covariates. Patient survival between NCT and non-NCT groups were compared. Results: The cut-off value of pre-treatment Epstein-Barr virus DNA (pre-DNA) was 1550 copies/ml for DMFS (area under curve [AUC], 0.655; sensitivity, 0.819; specificity, 0.445). For the 145 pairs selected by PSM, the 3-year distant metastasis-free survival (DMFS), overall survival (OS), disease-free survival (DFS) and locoregional relapse-free survival (LRRFS) rates were 98.6% vs. 93.7% (P = 0.101), 95.8% vs. 94.4% (P = 0.881), 91.7% vs. 87.5% (P = 0.309) and 94.4% vs. 95.0% (P = 0.667), respectively. Multivariate analysis did not identify NCT as an independent prognostic factor (P > 0.05 for all rates), and stratified analysis based on overall stage (III and IV) and N category (N0-1 and N2-3) also got the same results. Conclusion: NCT was not established as an independent prognostic factor, and it should not be used in locoregionally advanced NPC with low pre-DNA.

// Shan-Shan Guo 1, 2, * , Lin-Quan Tang 1, 2, * , Qiu-Yan Chen 1, 2 , Lu Zhang 1, 2 , Li-Ting Liu 1, 2 , Ling Guo 1, 2 , Hao-Yuan Mo 1, 2 , Dong-Hua Luo 1, 2 , Pei-Yu Huang 1, 2 , Yan-Qun Xiang 1, 2 , Rui Sun 1, 2 , Ming-Yuan Chen 1, 2 , Lin Wang 1, 2 , Xing Lv 1, 2 , Chong Zhao 1, 2 , Xiang Guo 1, 2 , Ka-Jia Cao 1, 2 , Chao-Nan Qian 1, 2 , Mu-Shen Zeng 1 , Jin-Xin Bei 1 , Ming-Huang Hong 1, 3 , Jian-Yong Shao 1, 4 , Ying Sun 1, 5 , Jun Ma 1, 5 , Hai-Qiang Mai 1, 2 1 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China 2 Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou 510060, China 3 Good Clinical Practice center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China 4 Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou 510060, China 5 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China * These authors have contributed equally to this work Correspondence to: Hai-Qiang Mai, e-mail: maihq@sysucc.org.cn Keywords: nasopharyngeal carcinoma, induction chemotherapy, concurrent chemotherapy, IMRT, EBV DNA Received: November 22, 2015 Accepted: March 28, 2016 Published: April 18, 2016 ABSTRACT Background: The effects of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) in high-risk (stage III-IVb with EBV DNA≥4000 copies/ml) nasopharyngeal carcinoma (NPC) patients are unclear. Methods: A total of 325 high-risk NPC patients treated with IC+CCRT or CCRT alone who were treated with intensity-modulated radiation therapy (IMRT) between March 2007 and March 2013 were included. For each patient in the IC+CCRT group, a matched pair in the CCRT group was matching for: gender, age, T stage, N stage, clinical stage and WHO (World Health Organization) type. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS). Results: There were no significant differences in OS, PFS, DMFS, and LRFS between the IC+CCRT (148 patients) and CCRT (177 patients) groups. After matching, 103 paired patients were analyzed, and there were no differences between the IC+CCRT and CCRT groups regarding clinical outcomes. Based on the subgroup analysis of 156 very-high-risk patients (stage N2-3 with EBV DNA ≥4000 copies/ml), the 5-year OS of the IC+CCRT and CCRT groups was 84.3% and 67.5% (P =0.033), respectively. Based on our multivariate analysis, the treatment group was significantly associated with OS (P=0.034; HR0.451, 95%CI 0.216-0.941). Conclusions : IC+CCRT did not improve the clinical outcomes of high-risk NPC patients compared to CCRT alone. However, in very-high-risk patients, IC+CCRT treatment led to increased OS compared to patients received CCRT treatment alone.

// Lu Zhang 1, 2, * , Huai Liu 4, 5, 6, * , Lin-Quan Tang 1, 2 , Qiu-Yan Chen 1, 2 , Shan-Shan Guo 1, 2 , Li-Ting Liu 1, 2 , Ling Guo 1, 2 , Hao-Yuan Mo 1, 2 , Chong Zhao 1, 2 , Xiang Guo 1, 2 , Ka-Jia Cao 1, 2 , Chao-Nan Qian 1, 2 , Mu-Sheng Zeng 1 , Jian-Yong Shao 1, 7 , Ying Sun 1, 8 , Jun Ma 1, 8 , Ming-Huang Hong 1, 3 , Hai-Qiang Mai 1, 2 1 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China 2 Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China 3 GCP center, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China 4 Department of Radiotherapy, Hunan Cancer Hospital, Changsha, P. R. China 5 Department of Radiotherapy, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, P. R. China 6 Key Laboratory of Translational Radiation Oncology, Changsha, P. R. China 7 Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China 8 Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China * These authors contributed equally to this work Correspondence to: Ming-Huang Hong, e-mail: hongmh@sysucc.org.cn Hai-Qiang Mai, e-mail: maihq@sysucc.org.cn Keywords: nasopharyngeal carcinoma, pregnancy, prognosis, survival Received: December 10, 2015 Accepted: February 21, 2016 Published: March 09, 2016 ABSTRACT Objectives: We aimed to evaluate the prognosis of pregnancy-associated patients with nasopharyngeal carcinoma (NPC) in a young population. Methods: From June 1999 to December 2010, 51 patients aged ≤ 35 years who were diagnosed with NPC during pregnancy or within one year after delivery were admitted into the pregnancy-associated group in our institution. An additional 51 patients who were not pregnant at diagnosis were selected from 451 patients based on the matching criteria to match the pregnancy-associated female patients. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS) and distant-metastasis failure-free survival (DMFS) and locoregional failure-free survival (LRFS). Results: The advanced stage was not different between the pregnant and the non-pregnant group before matching (69.8% vs. 70.3%, P = 0.690). No difference in OS at the median follow-up time of 92 months was observed between the pregnancy-associated and the non-pregnant group (85.4% vs. 92.2%, P = 0.478); likewise, no differences were observed regarding PFS and DMFS. However, the pregnancy-associated group had worse LRFS than the non-pregnant group (84.8% vs. 95.9%, P = 0.033). When the pregnancy-associated patients were dichotomized into an early pregnancy group and a late pregnancy group, our data showed that pregnancy interval did not seem to impact the risk of death or relapse. Conclusion: Our results show that patients in the pregnant group did not seem to have more advanced stage or inferior survival than that in the non-pregnant group.

// Li Lin 1, * , Ji-Jin Yao 1, * , Guan-Qun Zhou 1 , Rui Guo 1 , Fan Zhang 1 , Yuan Zhang 1 , Lin Xu 1 , Lu-Lu Zhang 1 , Ai-Hua Lin 2 , Jun Ma 1 , Ying Sun 1 1 Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China 2 Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Ying Sun, e-mail: sunying@sysucc.org.cn Keywords: nasopharyngeal carcinoma, intensity modulated radiotherapy, individualized clinical target volume, clinical outcome, toxicities Received: October 10, 2015 Accepted: February 18, 2016 Published: March 09, 2016 ABSTRACT Background: To evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) using individualized clinical target volumes (CTVs) based on the loco-regional extension patterns of nasopharyngeal carcinoma (NPC). Methods: From December 2009 to February 2012, 220 patients with histologically-proven, non-disseminated NPC were prospectively treated with IMRT according to an individualized delineation protocol. CTV1 encompassed the gross tumor volume, entire nasopharyngeal mucosa and structures within the pharyngobasilar fascia with a margin. CTV2 encompassed bilateral high risk anatomic sites and downstream anatomic sites adjacent to primary tumor, bilateral retropharyngeal regions, levels II, III and Va, and prophylactic irradiation was gave to one or two levels beyond clinical lymph nodes involvement. Clinical outcomes and toxicities were evaluated. Results: Median follow-up was 50.8 (range, 1.3–68.0) months, four-year local relapse-free, regional relapse-free, distant metastasis-free, disease-free and overall survival rates were 94.7%, 97.0%, 91.7%, 87.2% and 91.9%, respectively. Acute severe (≥ grade 3) mucositis, dermatitis and xerostomia were observed in 27.6%, 3.6% and zero patients, respectively. At 1 year, xerostomia was mild, with frequencies of Grade 0, 1, 2 and 3 xerostomia of 27.9%, 63.3%, 8.3% and 0.5%, respectively. Conclusions: IMRT using individualized CTVs provided high rates of local and regional control and a favorable toxicity profile in NPC. Individualized CTV delineation strategy is a promising one that may effectively avoid unnecessary or missed irradiation, and deserve optimization to define more precise individualized CTVs.

// Jia-Wei Lv 1, * , Yu-Pei Chen 1, * , Guan-Qun Zhou 1, * , Ling-Long Tang 1 , Yan-Ping Mao 1 , Wen-Fei Li 1 , Rui Guo 1 , Ai-Hua Lin 2 , Jun Ma 1 , Ying Sun 1 1 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China 2 Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Ying Sun, e-mail: sunying@sysucc.org.cn Key words: baseline plasma EBV DNA, cigarette smoking, intensity-modulated radiation therapy, nasopharyngeal carcinoma, prognostication Received: December 12, 2015 Accepted: February 11, 2016 Published: February 23, 2016 ABSTRACT We evaluated the combined prognostic value of cigarette smoking and baseline plasma Epstein-Barr virus deoxyribonucleic acid (EBV DNA) in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). Of consecutive patients, 1501 with complete data were eligible for retrospective analysis. Smoking index (SI; cigarette packs per day times smoking duration [years]), was used to evaluate the cumulative effect of smoking. Primary end-point was overall survival (OS); progression-free survival (PFS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRFS) were secondary end-points. Both cigarette smoking and baseline plasma EBV DNA load were associated with poorer survival ( P

The aim of this study was to determine the prognostic value of wait time from histological diagnosis to primary treatmen for nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). Between October 2009 and February 2012, a total of 1672 NPC patients were retrospectively analyzed. A cutoff value of > 4 weeks was used to define prolonged wait time. Matched patients according to the wait time were identified using propensity score matching (PSM), which was also used to identify matched patients for subsequent stratified analyses. Differences in progression-free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS) were estimated using the Kaplan-Meier method and Cox proportional hazards models. In total, 407 pairs of NPC patients were selected by PSM. The 3-year PFS rate was significantly lower for patients with a prolonged wait time (> 4 weeks) than for those with an acceptable wait time (P = 0.035). Stratified analyses revealed that the negative effects of a prolonged wait time occurred primarily in patients with advanced NPC without neoadjuvant chemotherapy (NACT; PFS:P = 0.040; DMFS:P = 0.028). In multivariate analysis, a prolonged wait time was found to be an independent unfavorable prognostic factor for PFS and DMFS in advanced-staged patients without NACT. These results suggest that a prolonged time (> 4 weeks) between diagnosis and primary radical radiotherapy is a disadvantage for NPC patients, particularly those with advanced disease receiving no NACT. Thus, it is necessary to optimize resources for decreasing this wait time, although additional studies are warranted to further clarify our findings.

// Yuan Zhang 1, * , Wen-Fei Li 1, * , Yan-Ping Mao 1 , Rui Guo 1 , Ling-Long Tang 1 , Hao Peng 1 , Ying Sun 1 , Qing Liu 2 , Lei Chen 1 , Jun Ma 1 1 Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, People’s Republic of China 2 Department of Cancer Prevention Research, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Jun Ma, e-mail: majun2@mail.sysu.edu.cn Lei Chen, e-mail: chenlei@sysucc.org.cn Keywords: nasopharyngeal neoplasms, tumor markers, biological, Epstein-Barr virus, DNA Received: August 21, 2015 Accepted: January 13, 2016 Published: January 30, 2016 ABSTRACT Background: Nasopharyngeal carcinoma is associated with Epstein-Barr virus (EBV). The current study investigated change in the plasma EBV DNA load in the first 3 months after treatment and its clinical significance in NPC. Methods: A total of 273 patients with non-metastatic, histologically-proven NPC treated with radiotherapy or chemoradiotherapy were retrospectively reviewed. Results: EBV DNA was detectable in 19/273 (7.0%) patients at the end of therapy (end-DNA). Three months later, 16/273 (5.9%) patients had detectable EBV DNA (3-month-DNA). To investigate risk stratified by the pattern of change in post-treatment EBV-DNA, we divided patients into four subgroups: Group 1, undetectable end-DNA and 3-month-DNA ( n = 244); Group 2, detectable end-DNA and undetectable 3-month-DNA ( n = 13); Group 3, undetectable end-DNA and detectable 3-month-DNA ( n = 7); and Group 4, detectable end-DNA and 3-month-DNA ( n = 2). Patients with delayed remission of EBV DNA after treatment (Group 2) had significantly poorer 3-year DFS (48.6% vs. 89.7%, P < 0.001), DMFS (48.6% vs. 94.6%, P < 0.001) and OS (91.7% vs. 97.5%, P < 0.001) than those with persistently undetectable EBV DNA post-treatment (Group 1). Five of the seven patients with re-emergent EBV DNA (Group 3) and both patients with persistent EBV DNA post-treatment (Group 4) developed disease failure. Conclusion: Plasma EBV DNA load continues to change during the first 3 months after treatment. The pattern of change in EBV DNA load post-treatment could help identify patients with different prognoses.

Background: The development of intensity-modulated radiotherapy (IMRT) has revolutionized the management of nasopharyngeal carcinoma (NPC). The purpose of this study was to investigate the impact of clinical stage on radiation doses to organs at risk (OARs) in NPC. Material and Methods: One hundred and forty-eight patients with newly diagnosed and untreated NPC were prospectively enrolled. Based on the anatomic definition and pathogenesis of radiation induced injury, a total of 28 OARs surrounding the nasopharynx were contoured on axial computed tomography (CT) planning images in each patient. Dose-volume histograms, as well as the mean and maximal doses for each structure, were calculated. Results: Radiation doses to 15 OARs (including the brain stem, temporal lobe and eye) were positively correlated with T stage, the radiation doses to 13 OARs (including the brachial plexus, parotid and thyroid) increased significantly with N stage, and the radiation doses to the spinal cord and mandible had no association with T or N stage. Based on the characteristic of excess rates, 9 OARs (e.g. spinal cord, eye, trachea, and et al.) met tolerance doses easily in all stages, 9 OARs (e.g. brain stem, temporal lobe, brachial plexus, and et al.) easily in early stages but with difficulty in advanced stages, and 10 OARs (e.g. cochlea, parotid, thyroid, and et al.) with difficulty in all stages. Conclusions: The radiation doses to most of OARs are associated with T or N stage, and there are three kinds of patterns for them: 1) meet tolerance doses easily in all stages; 2) meet tolerance doses easily in early stages but with difficulty in advanced stages; and 3) meet tolerance doses with difficulty in all stages.

Background: To identify predictors for development of mastoiditis after intensity-modulated radiation therapy (IMRT) in nasopharyngeal carcinoma (NPC). Methods: Data for 146 NPC patients treated with IMRT was retrospectively reviewed under institutional ethics committee approval. Clinical factors associated with mastoiditis were analyzed. Dose-volume histogram analysis was performed for the Eustachian tube, tympanic cavity, mastoid air cells, cochlea, internal auditory canal and vestibular apparatus to relate doses to radiographic changes in the mastoid. Mastoiditis was assessed using magnetic resonance imaging and was classified as Grade 0 (none), 1 (mild), 2 (moderate) or 3 (severe); Grade 3 mastoiditis was the study end-point. Results: Eighty-eight ears (36%) had radiation-induced mastoiditis: 38/244 (15.6%) mastoid complexes had Grade 1-2 mastoiditis and 50/244 (20.5%) mastoid complexes had Grade 3 mastoiditis. Multivariate analysis revealed a mastoid mean dose > 35.93 Gy (odds ratio [OR]=4.22, P=.003), Eustachian tube mean dose > 53.43 Gy (OR=2.16, P=.034) and advanced T category (T3 and T4; OR=10.33, P=.032) were negative prognostic factors for Grade 3 mastoiditis. Conclusions: Radiation-induced mastoiditis remains a common late toxicity in NPC after radiotherapy. The mean dose to the mastoid air cells and Eustachian tube should be limited to reduce the risk of radiation-induced mastoiditis.

Background: Currently, there is no uniform consensus regarding the appropriate staging for invasion of the paranasal sinuses in nasopharyngeal carcinoma (NPC). In the current AJCC staging system for NPC, paranasal sinus invasion is defined within the T3 classification. However, according to the Chinese 2008 staging system, which is also widely used in the regions where NPC is endemic in China, paranasal sinus invasion is classified as T4 disease. Methods: Patients (n = 1811) with non-metastatic, histologically-proven NPC treated with intensity-modulated radiotherapy (IMRT) were retrospectively analyzed. Results: Paranasal sinus invasion was identified in 289/1811 patients (16.0%). Multivariate analysis revealed ethmoid sinus invasion (HR, 2.889; 95% CI, 1.362-6.131; P = 0.006) and maxillary sinus invasion (HR, 3.110; 95% CI, 1.439-6.721; P = 0.004) were independent prognostic factors for local relapse-free survival (LRFS). T3 patients with ethmoid sinus or maxillary sinus invasion had similar 3-year LRFS (83.6% vs. 92.2%, P = 0.132) as T4 patients, and had poorer LRFS (83.6% vs. 98.3%, P = 0.006) than T3 patients with sphenoid sinus invasion alone. Also, T3 patients with sphenoid sinus invasion alone had similar 3-year LRFS (98.3 vs. 96.4%, P = 0.391) as T3 patients without paranasal sinus invasion, and a trend toward higher LRFS (98.3% vs. 92.2%, P = 0.065) than T4 patients. Conclusion: In patients underwent IMRT, tumors with ethmoid sinus or maxillary sinus invasion had a higher risk of local failure than those with sphenoid sinus invasion alone. Sphenoid sinus invasion alone should be classified as T3 disease and ethmoid sinus or maxillary sinus involvement as T4 disease in the current AJCC staging system for NPC.

Background: The optimal treatment for early-stage nasopharyngeal carcinoma (NPC) remains controversial. Identification of prognostic factors for metastasis and tumor progression is urgently required to improve clinical decision-making for patients with American Joint Committee on Cancer (AJCC) 2009 stage II NPC from the endemic area. Methods: Consecutive newly-diagnosed patients (n=296) with non-disseminated, biopsy-proven stage II NPC were retrospectively reviewed; all patients received intensity-modulated radiotherapy and MRI follow-up. Plasma EBV DNA level, serum lactate dehydrogenase, serum albumin, serum globulin and leukocyte counts were measured before therapy. Survival rates were analyzed using the Kaplan-Meier method and log-rank test and multivariate Cox proportional hazards model. Results: Median follow-up was 50.2 months (range, 8-69.5 months). Multivariate analysis demonstrated a plasma Epstein-Barr virus (EBV) DNA level ≥ 4000 copies/mL, maximal axial diameter (MAD) of the cervical lymph nodes ≥ 30 mm and serum globulin level < 29.5 g/L were independent predictors of poor DMFS (P = 0.018; P = 0.019; P = 0.006, respectively). On the basis of these parameters, a prognostic model was developed as follows: 1) patients with no risk factors; 2) one risk factor; and 3) two or three risk factors. The 3-year distant metastasis-free survival rates for groups 1, 2 and 3 were 100%, 94.6% and 84.3%, respectively (P = 0.001). Conclusion: The prognostic model based on EBV DNA, serum globulin and nodal size may facilitate individualized treatment of patients with stage II NPC at high risk of distant metastasis.

To evaluate the survival benefit of intensity-modulated radiotherapy (IMRT) compared with conventional two-dimensional radiotherapy (2D-CRT) in nasopharyngeal carcinoma (NPC) using a large cohort with long follow-up.We retrospectively analysed 7081 non-metastatic NPC patients who received curative IMRT or 2D-CRT from February 2002 to December 2011.Of the 7081 patients, 2245 (31.7%) were administered IMRT, while 4836 (68.3%) were administered 2D-CRT. At 5 years, the patients administered IMRT had significantly higher local relapse-free survival (LRFS), loco-regional relapse-free survival (LRRFS), progression-free survival (PFS) and overall survival (OS) (95.6%, 92.5%, 82.1% and 87.4%, respectively) than those administered 2D-CRT (90.8%, 88.5%, 76.7% and 84.5%, respectively; p0.001). The distant metastasis-free survival (DMFS) was higher for IMRT than 2D-CRT, with borderline significance (87.6% and 85.7%, respectively; p=0.056). However, no difference was observed between IMRT and 2D-CRT in nodal relapse-free survival (NRFS; 96.3% and 97.4%, respectively; p=0.217). Multivariate analyses showed that IMRT was an independent protective prognostic factor for LRFS, LRRFS and PFS, but not NRFS, DMFS or OS.IMRT provided an improved LRFS, LRRFS and PFS in both the early and advanced T classifications and overall stage for non-disseminated NPC compared with 2D-CRT. However, no significant advantage was observed in NRFS, DMFS or OS when IMRT was used.

Objectives To explore the role of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) and CCRT plus adjuvant chemotherapy (AC) in locoregionally advanced nasopharyngeal carcinoma (LANPC). Materials and methods The propensity score-matched (PSM) method was adopted to balance variables. We identified independent prognostic factors using Cox regression analysis and compared outcomes between two chemotherapy treatment combinations for patients in different subgroups. Results A total of 550 patients were selected by one-to-two PSM. Survival outcomes for the matched data set indicated that the IC + CCRT group achieved higher 5-year overall survival (OS; 89.3% vs 85.3%, P = 0.119), failure-free survival (FFS; 80.2% vs 79.0%, P = 0.722) and distant metastasis-free survival (DMFS; 87.4% vs 84.4%, P = 0.322) compared with CCRT + AC, although this was statistically non-significant. Subgroup analysis revealed that IC + CCRT was associated with significantly improved OS (Hazard ratio [HR] = 2.68, 95% Confidence interval [CI] = 1.16–6.22, P = 0.017), FFS (HR = 1.94, 95% CI = 1.06–3.57, P = 0.029) and locoregional relapse-free survival (LRRFS; HR = 2.63, 95% CI = 1.04–6.68, P = 0.034) in T3 disease. Moreover, this combination of treatment could significantly prolong OS (HR = 3.72, 95% CI = 1.41–9.80, P = 0.004) in N2 disease. However, the superiority of CCRT + AC was only observed in LRRFS (HR = 0.18, 95% CI 0.04–0.79, P = 0.010) for the T4 subgroup. Conclusion IC + CCRT should be strongly considered by patients with LANPC, especially those with T3 or N2 disease.

6522 Background: Induction chemotherapy (IC) followed by concurrent chemoradiotherapy is the mainstay treatment for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). However, some patients obtain little benefit and experience unnecessary toxicities from IC. We intended to develop a gene expression signature that can identify patients who will benefit from IC. Methods: We screened chemoresistance-related genes by comparing gene expression profiles of patients with short-term tumor response or non-response to IC (n = 95) using microarray analysis. Chemoresistance-related genes were quantified by digital expression profiling in a training cohort (n = 342) to obtain a gene signature. We then validated this gene signature in the clinical trial cohort (n = 187) and an external independent cohort (n = 240). Results: We identified 43 chemoresistance-related genes associated with the short-term tumor response to IC. In the training cohort, a 6-gene signature was developed that was highly accurate at predicting the short-term tumor response to IC (area under the curve [AUC] 0.87, sensitivity = 87.5%, specificity = 75.6%). We then apply the 6-gene signature to classify patients into the benefit group and the no-benefit group. In the benefit group, patients could benefit from IC in terms of failure-free survival (hazard ratio [HR] 0.54 [95% confidence interval 0.34-0.87]; p = 0.01), while patients in the no-benefit group could not (HR 1.25 [95%CI 0.62-2.51]; p = 0.53). In the clinical trial cohort, the developed 6-gene signature was also highly accurate at predicting the response to IC (AUC = 0.82; sensitivity = 87.5%; specificity = 71.8%). Additionally, IC conferred failure-free survival benefits only on patients in the benefit group (HR 0.37 [95%CI 0.18-0.75], p = 0.004) and not on those in the no-benefit group (HR 0.70 [95%CI 0.27-1.82]; p = 0.46). In the external independent cohort, similar results were observed. Conclusions: The 6-gene signature can help select patients who will benefit from IC and thus lay a foundation for a more individualized therapeutic strategy for LA-NPC patients.

Objectives Definitive concurrent chemoradiotherapy (CCRT) is the standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). The cumulative cisplatin dose (CCD) during radiotherapy is an important prognostic factor; however, the optimal CCD is undetermined. Materials and methods In this retrospective analysis, patients with locoregionally advanced NPC treated with single-agent cisplatin-based CCRT or RT alone from 2009 through 2015 were identified. CCD was entered into a multivariate Cox regression model as a continuous variable using natural cubic splines to allow for a nonlinear relationship between CCD and outcomes. The primary endpoint was overall survival, and the secondary endpoints were locoregional relapse‐free survival and distant metastasis‐free survival. Results A total of 2 924 patients were included in our study, with a median CCD of 160 mg/m2 (range, 0–300 mg/m2). As the CCD increased, the risk of death remained steady until 180 mg/m2, then decreased sharply until 250 mg/m2, and then increased until 300 mg/m2. The optimal CCD of 230–270 mg/m2 was associated with the lowest risk of death and disease relapse. However, the CCD had less prognostic value for disease control, especially for distant control among high-risk patients (N2–3 or T4). Conclusions A CCD dose of 230–270 mg/m2 (240 mg/m2 is recommended) is optimal for patients with locoregionally advanced NPC, especially for those at low risk (T1–3 and N0–1). For high-risk patients (N2–3 or T4), additional chemotherapy should be administered before or after CCRT.

Survival analyses of populations and the establishment of prognoses for individual patients are important activities in the practice of medicine. Standard survival models, such as the Cox proportional hazards model, require extensive feature engineering or prior knowledge to model at an individual level. Some survival analysis models can avoid these problems by using machine learning extended the CPH model, and higher performance has been reported. In this paper, we propose an innovative loss function that is defined as the sum of an extended mean squared error loss and a pairwise ranking loss based on ranking information on survival data. We apply this loss function to optimize a deep feed-forward neural network (RankDeepSurv), which can be used to model survival data. We demonstrate that the performance of our model, RankDeepSurv, is superior to that of other state-of-the-art survival models based on an analysis of 4 public medical clinical datasets. When modelling the prognosis of nasopharyngeal carcinoma (NPC), RankDeepSurv achieved better prognostic accuracy than the CPH established by clinical experts. The difference between high and low risk groups in the RankDeepSurv model is greater than the difference in the CPH. The results show that our method has considerable potential to model survival data in medical settings.

Human nasopharyngeal carcinoma (NPC) has the highest metastatic rate in head and neck. However, the mechanisms underlying NPC metastasis remain unclear. Here using propensity-score-matched miRNA microarray analysis, miR-142-3p is identified to be the most correlated with distant-metastasis-free survival and downregulated in paraffin-embedded NPC with distant metastasis, which is validated in both internal cohort and external GEO dataset from Canada. miR-142 locus hypermethylation was observed and found to be associated with miR-142-3p downregulation in metastatic NPC. Furthermore, miR-142-3p was epigenetically silenced by EZH2-recruited DNMT1 and suppressed NPC cell metastasis and EMT. Intersecting PCR array gene profiling with bioinformatic prediction, we identify ZEB2 as a direct and functional target of miR-142-3p in NPC. Reversal of miR-142-3p silencing efficiently suppresses NPC cell invasion and metastasis. Moreover, epigenetic miR-142 hypermethylation is correlated with unfavorable prognosis in both training and validation cohorts. This study identifies miR-142-3p as a key suppressive regulator in NPC metastasis and reveals a DNMT1-mediated epigenetic mechanism for miR-142-3p silencing, providing a potential prognostic marker and therapeutic target to combat NPC metastasis.

Purpose Our previous results showed survival benefits of concurrent chemoradiotherapy (CCRT) in treating stage II nasopharyngeal carcinoma (NPC) compared with radiotherapy (RT) alone. Here, we present the updated 10-year survival results and late toxicity profile to assess the ultimate effectiveness of concurrent chemotherapy. Methods Patients with stage II NPC were randomly assigned to RT arm (n = 114) or to CCRT arm (n = 116) with a concurrent weekly cisplatin regimen. The primary end-point was overall survival (OS). Results With a median follow-up of 125 months, significant improvements in OS (83.6% vs 65.8%, P = 0.001), progression-free survival (76.7% vs 64.0%, P = 0.014), cancer-specific survival (86.2% vs 71.9%, P = 0.002), distant-metastasis free survival (94.0% vs 83.3%, P = 0.007) were observed in CCRT arm. In point of locoregional-relapse free survival, the impact of CCRT was not remarkable. The findings were in accordance with our previous report. The survival benefits earned by CCRT mainly reflected in T2N1 population. Although CCRT brought more acute toxic effects (P = 0.001), as presented in previous report, the late toxicities and treatment-associated deaths events were comparable between two arms. Conclusions Ten-year outcomes confirmed that CCRT could improve the OS of stage II patients without adding late toxicities compared with conventional RT.

Objectives Induction chemotherapy (IC) is gaining recognition for the treatment of nasopharyngeal carcinoma (NPC). We aimed to develop a model to predict benefit from additional IC to concurrent chemoradiotherapy (CCRT). Materials and methods From an NPC-specific database, 7413 patients with stage II–IVa disease who received CCRT with or without IC were included. Distant metastasis-free survival (DMFS) was the primary outcome and benefit from IC was evaluated by adjusted hazard ratio. Interaction terms between IC and other prognostic factors were identified in multivariate Cox model, and IC benefit score (ICBS) was calculated based on β coefficients from the Cox model. Results Nodal category, overall stage, and pre-treatment plasma Epstein–Barr virus DNA (log transformed as continuous variable) interacted with IC and determined ICBS. ICBS could discriminate patients who benefited differently from IC in terms of DMFS well, especially for patients with high and low ICBS. As for patients with medium ICBS, predictive performance of ICBS seemed reduced. Conclusions Based on the ICBS model, we proposed a decision-making process to help in clinical practice. Multi-institutional and prospective studies are warranted to further validate our findings.

PURPOSE The incidence, risk factors and survival impact of secondary primary malignancies (SPMs) among survivors of nasopharyngeal carcinoma (NPC) treated with definitive intensity-modulated radiation therapy (IMRT) with or without chemotherapy are poorly characterized. METHODS AND MATERIALS Consecutive patients (n=6,377) from the big-data intelligence platform at Sun Yat-sen University Cancer Center, China (in a high-incidence area) with newly diagnosed non-metastatic pathologically proven non-keratinizing undifferentiated NPC treated with IMRT±chemotherapy between January 2003 and June 2013 were retrospectively analyzed. Cumulative incidence of SPMs was calculated using the Kaplan-Meier method. Cox proportional hazards model was used to identify potential risk factors for SPMs and assess whether SPMs affect overall survival. RESULTS Of the 6,377 patients, 189 (3.0%) suffered SPMs (median follow-up, 62 months). One-, 2-, 3-, 4-, and 5-cumulative risks of SPMs were 0.4%, 0.9%, 1.6%, 2.2%, and 2.6%, respectively. Latency from start of IMRT to SPMs diagnosis was 37 months (range, 6 to 102 months). In patients with SPMs, 14.3% suffered SPMs within 1 year post-IMRT: 1-3 years, 38.1%; 3-5 years, 33.9%; and >5 years, 13.7%. Lung cancer was the most common SPM (50/6,377, 0.78%). Multivariate analysis demonstrated sex (male, 64% increase), age (≥50 years, 68% increase), and smoking history (41% increase) were significant risk factors for SPMs, and SPMs were associated with poorer overall survival. CONCLUSION This large cohort study confirms SPMs a dreadful complication for long-term survivors of NPC treated with IMRT. SPMs negatively impact overall survival in NPC. Close follow-up is recommended for older male survivors with a smoking history.

Purpose To establish effective prognostic nomograms using clinical features and detailed magnetic resonance imaging (MRI) findings for primary tumor and regional lymph nodes after intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma. Method The nomogram for overall survival (OS) was based on a retrospective study of 595 patients who underwent IMRT at Sun Yat-sen University Cancer Center from 2010 to 2012. The predictive accuracy and discriminative ability of our nomogram models were determined by concordance index and calibration curve, and were compared with the nomogram models combining clinical features with tumor-node-metastasis (TNM) classification. The results were validated using bootstrap resampling and a cohort study of 241 patients. The same data cohort was used to predict the progress-free survival (PFS) of nasopharyngeal carcinoma with 3:1 training cohort (N = 558) and validation cohort (N = 278). Results The following factors were assembled into our prognostic survival nomogram models: Age, Epstein–Barr virus DNA copy number before treatment (EBV_DNA_CN), tensor veli palatini (TVP) involvement, musculus pterygoideus lateralis (MPL) involvement, prestyloid space (PS) involvement, prevertebral space (PVS) involvement, base of sphenoid bone (BOSB) involvement, paranasal sinus (PNS) involvement, the laterality of Ⅱ (Ⅱ_laterality), the laterality of retropharyngeal lymph node (RPLN_laterality), nodal grouping (NG), extranodal neoplastic spread (ENS), contrast-enhancing rim (CER) and Nodal_number. The calibration curves showed good agreement between nomogram-predicted and actual survival. Our nomogram models for OS and PFS, provided better results than the nomogram models combining clinical features with TNM classification. Results were further confirmed in the validation set. Conclusion Detailed MRI findings of primary tumor and regional lymph nodes can improve the performance of prognostic nomograms for patients with nasopharyngeal carcinoma.

Background Alternative polyadenylation (APA) is a widespread phenomenon in the posttranscriptional regulation of gene expression that generates mRNAs with alternative 3′-untranslated regions (3’UTRs). APA contributes to the pathogenesis of various diseases, including cancer. However, the potential role of APA in the development of nasopharyngeal carcinoma (NPC) remains largely unknown. Methods A strategy of sequencing APA sites (SAPAS) based on second-generation sequencing technology was carried out to explore the global patterns of APA sites and identify genes with tandem 3’UTRs in samples from 6 NPC and 6 normal nasopharyngeal epithelial tissue (NNET). Sequencing results were then validated using quantitative RT-PCR in a larger cohort of 16 NPC and 16 NNET samples. Results The sequencing data showed that the use of tandem APA sites was prevalent in NPC, and numerous genes with APA-switching events were discovered. In total, we identified 195 genes with significant differences in the tandem 3’UTR length between NPC and NNET; including 119 genes switching to distal poly (A) sites and 76 genes switching to proximal poly (A) sites. Several gene ontology (GO) terms were enriched in the list of genes with switched APA sites, including regulation of cell migration, macromolecule catabolic process, protein catabolic process, proteolysis, small conjugating protein ligase activity, and ubiquitin-protein ligase activity. Conclusions APA site-switching events are prevalent in NPC. APA-mediated regulation of gene expression may play an important role in the development of NPC, and more detailed studies targeting genes with APA-switching events may contribute to the development of novel future therapeutic strategies for NPC. Electronic supplementary material The online version of this article (10.1186/s12929-018-0477-6) contains supplementary material, which is available to authorized users.

The prognosis of patients who have Epstein-Barr virus (EBV)-related nasopharyngeal carcinoma (NPC) in which the tumor tissues harbor EBV have a better prognosis than those without EBV-related NPC. Therefore, the eighth edition of the TNM staging system could be modified for EBV-related NPC by incorporating the measurement of plasma EBV DNA.In total, 979 patients with NPC who received intensity-modulated radiotherapy (IMRT) were retrospectively reviewed. Recursive partitioning analysis was conducted based on tumor (T) classification, lymph node (N) classification, and EBV DNA measurement to derive objectively the proposed stage groupings. The validity of the proposed stage groupings was confirmed in a prospective cohort of 550 consecutive patients who also received with IMRT.The pretreatment plasma EBV DNA level was identified as a significant, negative prognostic factor for progression-free survival and overall survival in univariate analysis (all P.001) and multivariate analysis (all P.05). Recursive partitioning analysis of the primary cohort to incorporate EBV DNA generated the following proposed stage groupings: stage RI (T1N0), RIIA (T2-T3N0 or T1-T3N1, EBV DNA ≤2000 copies/mL), stage RIIB (T2-T3N0 or T1-T3N1, EBV DNA2000 copies/mL; T1-T3N2, EBV DNA ≤2000 copies/mL), stage RIII (T1-T3N2, EBV DNA2000 copies/mL; T4N0-N2), and stage RIVA (any T and N3). In the validation cohort, the 5-year progression-free survival rate was 100%, 87.9%, 76.7%, 68.7%, and 50.4% for proposed stage RI, RIIA, RIIB, RIII, and RIV NPC, respectively (P.001). Compared with the eighth edition TNM stage groupings, the proposed stage groupings incorporating EBV DNA provided better hazard consistency, hazard discrimination, outcome prediction, and sample size balance.The proposed stage groupings have better prognostic performance than the eighth edition of the TNM staging system. EBV DNA titers should be included in the TNM staging system to assess patients who have EBV-related NPC.

Little is known about the value of the nutritional risk screening 2002 (NRS2002) scale in nasopharyngeal carcinoma (NPC). We conducted a large-scale study to address this issue. We employed a big-data intelligence database platform at our center and identified 3232 eligible patients treated between 2009 and 2013. Of the 3232 (12.9% of 24 986) eligible patients, 469 (14.5%), 13 (0.4%), 953 (29.5%), 1762 (54.5%) and 35 (1.1%) had NRS2002 scores of 1, 2, 3, 4 and 5, respectively. Survival outcomes were comparable between patients with NRS20023 and ≥3 (original scale). However, patients with NRS2002 ≤3 vs3 (regrouping scale) had significantly different 5-year disease-free survival (DFS; 82.7% vs 75.0%, P .001), overall survival (OS; 88.8% vs 84.1%, P = .001), distant metastasis-free survival (DMFS; 90.2% vs 85.9%, P = .001) and locoregional relapse-free survival (LRRFS; 91.6% vs 87.2%, P = .001). Therefore, we proposed a revised NRS2002 scale, and found that it provides a better risk stratification than the original or regrouping scales for predicting DFS (area under the curve [AUC] = 0.530 vs 0.554 vs 0.577; P .05), OS (AUC = 0.534 vs 0.563 vs 0.582; P .05), DMFS (AUC = 0.531 vs 0.567 vs 0.590; P .05) and LRRFS (AUC = 0.529 vs 0.542 vs 0.564; P .05 except scale A vs B). Our proposed NRS2002 scale represents a simple, clinically useful tool for nutritional risk screening in NPC.

We evaluated the prognostic value of serum bilirubin in advanced nasopharyngeal carcinoma (NPC) patients.Seven-hundred fifty-nine advanced NPC patients treated with definitive chemoradiotherapy were retrospectively analyzed. Serum indirect bilirubin (IBIL) and direct bilirubin (DBIL) were measured before treatment. To evaluate different cutoff points for serum bilirubin, we utilized ROC curves. The Kaplan-Meier method and log-rank test were adopted to calculate and compare survival outcomes. Cox proportional hazard models were used to perform univariate and multivariate analyses.At 5 y, IBIL7.15 μmol/l were significantly associated with superior progression-free survival (PFS, 83.6% vs 70.3%; P .001), overall survival (OS, 88.6% vs 80.5%; P = .012), distant metastasis-free survival (DMFS, 90.3% vs 82.8%; P = .006), and locoregional relapse-free survival (LRFS, 92.1% vs 86.4%; P = .048) than IBIL ≤7.15 μmol/l. Similarly, patients with DBIL2.65 μmol/l had better prognosis across all outcomes than those of patients with DBIL ≤2.65 μmol/l (all P .05), except no difference was observed in LRFS (90.5% vs. 87.3%, P = .195). Multivariate analyses showed that IBIL7.15 μmol/l was an independent protective prognostic factor for PFS (HR, 0.57; 95% CI, 0.40-0.81; P = .002), OS (HR, 0.67; 95% CI, 0.43-0.92; P = .041), and DMFS (HR, 0.63; 95% CI, 0.40-0.98; P = .034); while serum DBIL only remained significant for PFS (HR, 0.63; 95% CI, 0.44-0.89; P = .009).Pretreatment IBIL and DBIL are potentially independent prognostic factors for patients with advanced NPC.

Background Little is known about the prognostic difference of anti-EGFR therapy, cetuximab (CTX) or nimotuzumab (NTZ), concurrently with induction chemotherapy (IC, investigational arm) or RT (control arm) for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). We conducted this retrospective study to address this. Methods We identified 296 patients with newly diagnosed LA-NPC at Sun Yat-Sen University Cancer Center between January 2012 and May 2015. Patients were treated by IC with CCRT or RT and CTX/NTZ was delivered during IC or radiotherapy. Survival outcomes and toxicities between different arms were compared. Results In total, there were 149 patients in the investigational arm and 147 in control arm. The 3-year disease-free survival, overall survival, distant metastasis-free survival and locoregional relapse-free survival rates for investigational arm vs. control arm were 84.3% vs. 74.3% (P = 0.027), 94.0% vs. 92.1% (P = 0.673), 88.0% vs. 81.8% (P = 0.147) and 93.3% vs. 88.0% (P = 0.093). Multivariate analysis revealed patients in the control arm achieved significantly worse disease-free survival (HR, 1.497; 95% CI, 1.016–2.206; P = 0.026) compared with those in the investigational arm; however, no significant difference was identified for other endpoints. Patients in the investigational arm experienced more grade 3–4 skin reaction (15.4% vs. 2.0%, P

Little is known about the efficacy and toxicity of anti-epidermal growth factor receptor therapy concurrently with induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). The present study aimed to address this question. We identified 2848 patients with newly diagnosed LA-NPC receiving IC between January 2012 and May 2015. The propensity score matching (PSM) method was used to balance various factors and to match patients. Survival outcomes and toxicities between different groups were compared. In total, 596 patients were selected at a 1:3 ratio, with 149 in the IC + CTX/NTZ group and 447 in the IC alone group. The 3-year disease-free survival, overall survival, distant metastasis-free survival and locoregional relapse-free survival rates for IC + CTX/NTZ vs IC alone were 84.3% vs 75.2% (P = .059), 94.0% vs 87.9% (P = .053), 88.0% vs 84.9% (P = .412) and 93.3% vs 88.2% (P = .242). Multivariate analysis established a treatment group (IC vs IC + CTX/NTZ) as a prognostic predictor for DFS (hazard ratio [HR], 1.497; 95% confidence interval [CI], 1.016-2.206; P = .041) and OS (HR, 1.984; 95%, CI, 1.023-3.848; P = .043). Grade 3-4 skin reaction (15.4% vs 0.4%, P < .001) and mucositis (10.1% vs 2.7%, P < .001) were more common in the IC + CTX/NTZ group than that in the IC alone group. Our findings suggested that CTX/NTZ in combination with IC may be a more effective and promising strategy for patients with LA-NPC treated with intensity-modulated radiotherapy.

Background/Aims: Lipoproteins have been reported to be associated with prognosis in various cancers; however, the prognostic value of lipoproteins in patients with nasopharyngeal carcinoma (NPC) remains largely unknown. We aim to asses the role of circulating lipoproteins in locoregionally advanced NPC patients. Methods: Between October 2009 and August 2012, a total of 1,081 patients with stage III-IVB NPC were included in the analysis. Circulating high-density lipoprotein (HDL) and low-density lipoprotein (LDL) are the two key lipoproteins, which were measured at baseline. Receiver operating characteristic (ROC) curve analysis was used to evaluate different cut-off points for lipoproteins. Actuarial rates were performed using Kaplan–Meier methods and the log-rank test. Results: The cutoff points of HDL, LDL, and LDL/HDL ratio were 1.17 mmol/L, 3.75 mmol/L, and 2.73, respectively. At 5 years, high HDL (> 1.17 mmol/L) was significantly associated with better overall survival (OS, 86.6% vs. 78.9%; P=0.004), distant metastasis-free survival (DMFS, 86.9% vs. 80.8%; P=0.004), locoregional relapse-free survival (LRFS, 90.8% vs. 85.4%; P=0.010), and progression-free survival (PFS, 79.1% vs. 70.2%; P= 0.001) than low HDL (≤1.17 mmol/L). In contrast, high LDL (> 3.75 mmol/L) tend to be inferior OS (79.1% vs. 84.9%; P= 0.016) in compassion with low LDL (≤3.75 mmol/L). Likewise, patients with high LDL/HDL ratio (> 2.73) tend to be inferior OS (79.3% vs. 86.9%; P=0.001), DMFS (81.9% vs. 86.5%; P=0.030), and PFS (72.6% vs. 77.8%; P= 0.034) than those of low LDL/HDL ratio (≤2.73). In multivariate analysis, baseline HDL was found to be a significant prognostic factor for LRFS (HR= 0.65; 95% CI, 0.45-0.93; P= 0.019) and PFS (HR=0.75; 95% CI, 0.58-0.98; P= 0.034). Conclusions: Circulating HDL is significantly associated with treatment outcomes in patients with locoregionally advanced NPC. We suggest that HDL measurements will be of great clinical significance in the management of NPC.

Objectives This study aimed at identifying the optimal induction chemotherapy regimen for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated by intensity-modulated radiotherapy. Materials and methods We identified eligible patients with newly-diagnosed stage III-IVA NPC (excluding T3N0) between September 2009 and May 2015. Survival outcomes and grade 3–4 toxicities were compared between different IC regimen groups. Results In total, 3738 patients were eligible for this study, with 1572 (42.1%), 1085 (29.0%) and 1081 (28.9%) receiving TPF, PF and TP, respectively. In the whole population, multivariate analysis found that TPF seems to be better than PF and TP. Howerver, subgroup analysis revealed TPF and TP had same effectiveness in patients receiving a cumulative cisplatin dose (CCD) ≥ 200 mg/m2 in concurrent chemotherapy, while TPF shows relatively better survival benefit in patients receiving CCD Conclusions Our study concluded that induction TP regimen may be enough for patients receiving a CCD ≥ 200 mg/m2, while TPF may be superior to TP and PF for patients receiving a CCD

Background: To construct a clinicomolecular index integrating circulating Epstein-barr virus DNA (cfEBV DNA) with T- and N- categories for prognostication in nasopharyngeal carcinoma (NPC). Methods: We utilised medical records of 9,160 biopsy-proven, non-metastatic NPC cases who underwent intensity-modulated radiotherapy (IMRT) with or without chemotherapy. Decision tree modeling (DTM) and adjusted hazard ratio (AHR) methods were used to generate risk models incorporating T- and N-categories and pre-treatment cfEBV DNA load. Predictive accuracy and discrimination of the models were compared against UICC/AJCC 8th edition TNM stage and a RPA-based model. Cox regression was used for survival outcome analyses. Findings: We observed linearity between cfEBV DNA and DFS; cfEBV DNA of >2,000 copies was consistent for risk discretisation (HR >1·0) for DFS, OS and DMF in our cohort of 9,160 patients. DTM and AHR modelling using a two-tiered stratification by cfEBV DNA (≤2,000 and >2,000 copies) and Tand N- categories yielded six RGs with significantly disparate DFS (P

Background To evaluate the incidence of neck muscle spasm in nasopharyngeal carcinoma (NPC) patients that received intensity-modulated radiotherapy (IMRT), and to analyse the patient- and treatment-related risk factors associated with neck muscle spasm. Methods A sample of 152 IMRT-treated, biopsy-proven, nondisseminated NPC patients were retrospectively analysed. All had documented IMRT treatment plans and had returned for follow-up review at 4 years post-radiotherapy. Spasm of the sternocleidomastoid (SCM) muscle was graded from 0 to 3 (absent to severe) and this grade served as the clinical endpoint. Risk factors were identified using logistic regression analysis. Results Within 4 years of radiotherapy, neck muscle spasm developed in 23.68% of the patients; Grades 0, 1, 2 and 3 were respectively assigned to 83.55, 7.57, 6.58 and 2.30% of assessed SCMs. Multivariate analysis indicated that gender, N stage, V60 (percentage of SCM volume that received >60 Gy) were independent prognostic variables, and that the optimal threshold for using V60 to predict neck muscle spasm was 61.92% (sensitivity = 0.900, specificity = 0.953). Conclusions Gender, N stage and V60 were independent predictive factors for post-radiotherapy neck muscle spasm, and a V60 of ≤61.92% in the SCM was relatively safe.

Distant metastasis remains the predominant mode of treatment failure in nasopharyngeal carcinoma (NPC). Unfortunately, the molecular events underlying NPC metastasis remain poorly understood. Secreted frizzled-related protein 1 (SFRP1) plays an important role in tumorigenesis and progression. However, little is known about the function and mechanism of SFRP1 in NPC. Immunohistochemistry was used to determine SFRP1 expression levels in patients with NPC. SFRP1 function was evaluated using MTT, colony formation, wound-healing, Transwell assays, and in vivo models. The methylation level of SFRP1 in NPC cells was examined using bisulfate pyrosequencing; the Wnt/β-catenin signaling pathway genes were studied using Western blotting. Compared with patients with high SFRP1 expression, patients with low SFRP1 expression had worse overall survival [HR, 2.32; 95% confidence interval (CI), 1.36–3.94; P = 0.002], disease-free survival (HR, 1.98; 95% CI, 1.23–3.18; P = 0.005), and distant metastasis-free survival (HR, 2.07; 95% CI, 1.19–3.59; P = 0.009). Multivariate Cox regression analysis indicated that SFRP1 was an independent prognostic factor. Furthermore, SFRP1 was significantly downregulated in NPC cell lines. SFRP1 overexpression suppressed NPC cell proliferation, migration, and invasion in vitro and lung colonization in vivo. SFRP1 expression was restored after treatment with a demethylation agent, and the SFRP1 promoter region was hypermethylated in NPC cells. β-Catenin, c-Myc, and cyclin D1 were downregulated after SFRP1 restoration, which suggested that SFRP1 suppressed growth and metastasis by inhibiting the Wnt/β-catenin signaling pathway in NPC. SFRP1 provides further insight into NPC progression and may provide novel therapeutic targets for NPC treatment. Cancer Prev Res; 8(10); 968–77. ©2015 AACR.

// Yu-Pei Chen 1, * , Wen-Na Zhang 1, * , Lei Chen 1, * , Ling-Long Tang 1 , Yan-Ping Mao 1 , Wen-Fei Li 1 , Xu Liu 1 , Guan-Qun Zhou 1 , Ying Sun 1 , Tie-Bang Kang 1 , Mu-Sheng Zeng 1 , Na Liu 1 , Jun Ma 1 1 Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Na Liu, e-mail: liun1@sysucc.org.cn Jun Ma, e-mail: majun2@mail.sysu.edu.cn Keywords: LMP1, EBV, cancer, survival, meta-analysis Received: May 20, 2015 Accepted: August 07, 2015 Published: August 18, 2015 ABSTRACT Latent membrane protein 1 (LMP1) is identified as the main transforming oncoprotein of Epstein-Barr virus (EBV). LMP1 is frequently expressed in a variety of EBV-associated cancers, including nasopharyngeal carcinoma (NPC), non-Hodgkin lymphoma (NHL), Hodgkin disease (HD), and gastric cancer (GC). However, due to conflicting results, the prognostic value of LMP1 expression on clinical outcomes in EBV-associated cancers remains unclear. We performed a meta-analysis on 32 studies with a total of 3752 patients to explore the association between LMP1 expression and overall survival (OS) in EBV-associated cancers. Overall, LMP1 expression was significantly associated with poorer OS (hazard ratio, HR = 1.51, 95% confidence interval, CI, 1.13–2.03), irrespective of cancer type. Further analyses showed that LMP1 expression correlated with poorer OS in NPC (HR = 2.48, 95% CI, 1.77–3.47) and NHL patients (HR = 1.83, 95% CI, 1.07–3.15), but not in HD patients (HR = 0.98, 95% CI, 0.60–1.62) or GC patients (HR = 0.70, 95% CI, 0.44–1.12). Subgroup analyses indicated that the age and geographical factors seemed to have an effect on the clinical outcomes of HD patients with positive LMP1 expression. In conclusion, LMP1 expression can be used as a prognostic biomarker in NPC, NHL, and certain HD patients. This data suggests that novel therapies targeting LMP1 may improve clinical outcomes for EBV-associated cancer patients.

Background and purpose We used a literature-based meta-analysis to assess whether failure-free survival (FFS) or progression-free survival (PFS) could be reliable surrogate endpoints for overall survival (OS) in trials of combined chemotherapy and radiotherapy for nasopharyngeal carcinoma (NPC). Methods and materials We identified randomised trials that evaluated combined chemoradiotherapy strategies, and reported FFS or PFS and OS in NPC. We analysed the treatment effects on FFS or PFS, and OS. We used the coefficient of determination ( R 2 ), and the surrogate threshold effect (STE) to assess the trial-level correlation. Results Twenty-one trials (5212 patients), with sixteen treatment-control comparisons for FFS, and nine for PFS, were analysed. FFS was strongly correlated with OS ( R 2 =0.88, STE=0.84), as was PFS ( R 2 =0.90, STE=0.88). Moreover, FFS and PFS at 3years were still strongly correlated with 5-year OS ( R 2 =0.80, STE=0.83; R 2 =0.85, STE=0.84). Conclusions Both FFS and PFS could be valid surrogate endpoints for OS in trials of combined chemotherapy and radiotherapy for NPC; PFS may be a more acceptable surrogate endpoint compared with FFS.