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Background: Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials., Methods: In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety., Results: A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group., Conclusions: Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.)., (Copyright © 2019 Massachusetts Medical Society.)

BackgroundNasopharyngeal carcinoma (NPC) has an extremely high incidence rate in Southern China, resulting in a severe disease burden for the local population. Current EBV serologic screening is limited by false positives, and there is opportunity to integrate polygenic risk scores for personalized screening which may enhance cost-effectiveness and resource utilization.MethodsA Markov model was developed based on epidemiological and genetic data specific to endemic areas of China, and further compared polygenic risk-stratified screening [subjects with a 10-year absolute risk (AR) greater than a threshold risk underwent EBV serological screening] to age-based screening (EBV serological screening for all subjects). For each initial screening age (30–34, 35–39, 40–44, 45–49, 50–54, 55–59, 60–64, and 65–69 years), a modeled cohort of 100,000 participants was screened until age 69, and then followed until age 79.ResultsAmong subjects aged 30 to 54 years, polygenic risk-stratified screening strategies were more cost-effective than age-based screening strategies, and almost comprised the cost-effectiveness efficiency frontier. For men, screening strategies with a 1-year frequency and a 10-year absolute risk (AR) threshold of 0.7% or higher were cost-effective, with an incremental cost-effectiveness ratio (ICER) below the willingness to pay (¥203,810, twice the local per capita GDP). Specifically, the strategies with a 10-year AR threshold of 0.7% or 0.8% are the most cost-effective strategies, with an ICER ranging from ¥159,752 to ¥201,738 compared to lower-cost non-dominated strategies on the cost-effectiveness frontiers. The optimal strategies have a higher probability (29.4–35.8%) of being cost-effective compared to other strategies on the frontier. Additionally, they reduce the need for nasopharyngoscopies by 5.1–27.7% compared to optimal age-based strategies. Likewise, for women aged 30–54 years, the optimal strategy with a 0.3% threshold showed similar results. Among subjects aged 55 to 69 years, age-based screening strategies were more cost-effective for men, while no screening may be preferred for women.ConclusionOur economic evaluation found that the polygenic risk-stratified screening could improve the cost-effectiveness among individuals aged 30–54, providing valuable guidance for NPC prevention and control policies in endemic areas of China.

Abstract Objectives The time for posttreatment tumor progression differs between nasopharyngeal carcinoma (NPC) patients. Herein, we established effective nomograms for predicting early tumor progression (ETP) and late tumor progression (LTP) in NPC patients. Methods We retrospectively enrolled 8292 NPC patients (training cohort: n = 6219; validation cohort: n = 2073). The ELP and LTP were defined as the time to tumor progression ≤24 and >24 months after treatment, respectively. Results The ETP and LTP accounted for 52.6 and 47.4% of the total patient cohort, respectively. Patients who developed ETP had markedly worse overall survival (OS) versus patients who suffered from LTP (5‐year OS: 26.2% vs. 59.7%, p

Abstract Background Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated efficacy in nasopharyngeal carcinoma (NPC). Thyroid dysfunction is among the most common immune-related adverse events. This study aimed to explore the clinical pattern of thyroid dysfunction and its relationship with survival marker in nonmetastatic NPC after immunotherapy. Methods From January 1, 2019, to December 31, 2021, 165 pairs of nonmetastatic NPC patients (165 with and 165 without anti-PD-1 immunotherapy) matched by the propensity score matching method were included in this study. Thyroid function was assessed retrospectively before the first treatment and during each immunotherapy cycle. Results The spectrum of thyroid dysfunction was different between the immunotherapy and control groups (P < 0.001). Compared with the control group, patients in the immunotherapy group developed more hypothyroidism (14.545% vs. 7.273%), less hyperthyroidism (10.909% vs. 23.636%), and a distinct pattern, biphasic thyroid dysfunction (3.030% vs. 0%). Immunotherapy also accelerates the onset of hypothyroidism, which was earlier with a median onset time difference of 32 days (P < 0.001). Patients who acquired thyroid dysfunction during immunotherapy had better complete biological response to treatment (OR, 10.980; P = 0.042). Conclusions For nonmetastatic NPC, thyroid dysfunction was associated with better response to treatment in immunotherapy but not in routine treatment. Thyroid function could be used as a predictor for survival and should be under regular and intensive surveillance in clinical practice of anti-PD-1 immunotherapy for nonmetastatic NPC.

Abstract Purpose The aims of this study focusing on Locoregionally advanced nasopharyngeal carcinoma (LANPC) were mainly two-fold: on the one hand, to establish a cut-off value to differentiate early and late failure based on prognosis after recurrence or metastasis; and on the other hand, to investigate the duration of concurrent cisplatin benefit over follow-up time. The results of our study have the potential to guide clinical practice and follow-up. Methods In total, 3123 patients with stage III-IVa NPC receiving Induction chemotherapy followed by concurrent cisplatin or not were analysed. The cut-off value of treatment failure was calculated using the minimum P-value approach. Random survival forest (RSF) model was to simulate the cumulative probabilities of treatment failure (locoregional recurrence and /or distant metastasis) over-time, as well as the monthly time-specific, event-occurring probabilities, for patients at different treatment groups. Results Based on subsequent prognosis, early locoregional failure (ELRF) should be defined as recurrence within 14 months (P = 1.47 × 10 − 3), and early distant failure (EDF) should be defined as recurrence within 20 months (P = 1.95 × 10 − 4). A cumulative cisplatin dose (CCD) > 200 mg/m2 independently reduced the risk of EDF (hazard ratio, 0.351; 95% confidence interval (CI), 0.169–0.732; P = 0.005). Better failure-free survival (FFS) and overall survival (OS) were observed in concurrent chemotherapy settings ([0 mg/m2 vs. 1-200 mg/m2 vs. >200 mg/m2]: FFS: 70.4% vs. 74.4% vs. 82.6%, all P

Abstract Background Significant intertumoral heterogeneity exists as antitumor treatment is introduced. Heterogeneous therapeutic responses are conventionally evaluated by imaging examinations based on Response Evaluation Criteria in Solid Tumors (RECIST); nevertheless, there are increasing recognitions that they do not fully capture patient clinical benefits. Currently, there is a paucity of data regarding the clinical implication of biological responses assessed by liquid biopsy of on-treatment circulating tumor DNA (ctDNA). Here, we investigated whether biological response evaluated by ctDNA kinetics added critical information to the RECIST, and whether integrating on-treatment biological response information refined risk stratification of cancer patients. Methods In this population-based cohort study, we included 821 patients with Epstein-Barr virus (EBV)-associated nasopharynx of head and neck cancer (NPC) receiving sequential neoadjuvant chemotherapy (NAC) and chemoradiotherapy (CRT), who had pretreatment and on-treatment cfEBV DNA and magnetic resonance imaging (MRI) surveillance. Biological responses evaluated by cfEBV DNA were profiled and compared with conventional MRI-based RECIST evaluation. The inverse probability weighting (IPW)-adjusted survival analysis was performed for major survival endpoints. The Cox proportional hazard regression [CpH]-based model was developed to predict the on-treatment ctDNA-based individualized survival. Results Of 821 patients, 71.4% achieved complete biological response (cBR) upon NAC completion. RECIST-based response evaluations had 25.3% discordance with ctDNA-based evaluations. IPW-adjusted survival analysis revealed that cfEBV DNApost-NAC was a preferential prognosticator for all endpoints, especially for distant metastasis. In contrast, radiological response was more preferentially associated with locoregional recurrence. Intriguingly, cfEBV DNApost-NAC further stratified RECIST-responsive and non-responsive patients; RECIST-based non-responsive patients with cBR still derived substantial clinical benefits. Moreover, detectable cfEBV DNApost-NAC had 83.6% prediction sensitivity for detectable post-treatment ctDNA, which conferred early determination of treatment benefits. Finally, we established individualized risk prediction models and demonstrated that introducing on-treatment ctDNA significantly refined risk stratification. Conclusions Our study helps advance the implementation of ctDNA-based testing in therapeutic response evaluation for a refined risk stratification. The dynamic and refined risk profiling would tailor future liquid biopsy-based risk-adapted personalized therapy.

Abstract Background The impact of radiotherapy interruption due to the Spring Festival holidays in China on the survival of patients with nasopharyngeal carcinoma (NPC) is unclear. Methods Nontrial patients with locoregionally advanced NPC receiving radiotherapy plus induction chemotherapy (IC) and/or concurrent chemotherapy (CC) were included (N = 5035) and divided into two groups based on the Spring Festival-induced radiotherapy interruption. Kaplan–Meier curves for overall survival (OS) and failure-free survival (FFS) were compared between rival groups. Impact of the timing of radiotherapy interruption (during or outside the Spring Festival) on survival was investigated in a propensity score-matched dataset. We adopted ordination correspondence analysis to determine the cut-off of radiotherapy prolongation for prognostic prediction, and accordingly performed subgroup analysis based on delayed days and chemotherapy details. Individual patient data of three phase III NPC trials (NCT00677118, NCT01245959, NCT01872962) were used for validation (N = 1465). Results Radiotherapy interruption was most frequently observed between December to January of the following year. Significantly lower OS and FFS were associated with the Spring Festival-induced interruption of radiotherapy (P = 0.009 and 0.033, respectively), but not that interruption of IC. In two matched comparison groups, the timing of radiotherapy interruption during the Spring Festival was more likely to lead to a decrease in FFS than outside the Spring Festival (P = 0.046), which was not observed in the validation using clinical trial data or in the subgroup analysis based on the 5-day delayed time. The absence of CC and the accumulated dose of cisplatin

Abstract Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor originating in the nasopharynx and has a high incidence in Southeast Asia and North Africa. To develop these comprehensive guidelines for the diagnosis and management of NPC, the Chinese Society of Clinical Oncology (CSCO) arranged a multi‐disciplinary team comprising of experts from all sub‐specialties of NPC to write, discuss, and revise the guidelines. Based on the findings of evidence‐based medicine in China and abroad, domestic experts have iteratively developed these guidelines to provide proper management of NPC. Overall, the guidelines describe the screening, clinical and pathological diagnosis, staging and risk assessment, therapies, and follow‐up of NPC, which aim to improve the management of NPC.

Abstract Background The optimal posttreatment surveillance strategy for nasopharyngeal carcinoma (NPC) remains unclear. Circulating cell-free Epstein-Barr virus (cfEBV) DNA has been recognized as a promising biomarker to facilitate early detection of NPC recurrence. Therefore, we aim to determine whether integrating circulating cfEBV DNA into NPC follow-up is cost-effective. Methods For each stage of asymptomatic nonmetastatic NPC patients after complete remission to primary NPC treatment, we developed a Markov model to compare the cost-effectiveness of the following surveillance strategies: routine follow-up strategy, i.e., (1) routine clinical physical examination; routine imaging strategies, including (2) routine magnetic resonance imaging plus computed tomography plus bone scintigraphy (MRI + CT + BS); and (3) routine 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT); cfEBV DNA-guided imaging strategies, including (4) cfEBV DNA-guided MRI + CT + BS and (5) cfEBV DNA-guided PET/CT. Clinical probabilities, utilities, and costs were derived from published studies or databases. Sensitivity analyses were performed. Results For all disease stages, cfEBV DNA-guided imaging strategies demonstrated similar survival benefits but were considerably more economical than routine imaging strategies. They only required approximately one quarter of the number of imaging studies compared with routine imaging strategies to detect one recurrence. Specifically, cfEBV DNA-guided MRI + CT + BS was most cost-effective for stage II (incremental cost-effectiveness ratio [ICER] $57,308/quality-adjusted life-year [QALY]) and stage III ($46,860/QALY) patients, while cfEBV DNA-guided PET/CT was most cost-effective for stage IV patients ($62,269/QALY). However, routine follow-up was adequate for stage I patients due to their low recurrence risk. Conclusions The cfEBV DNA-guided imaging strategies are effective and cost-effective follow-up methods in NPC. These liquid biopsy-based strategies offer evidence-based, stage-specific surveillance modalities for clinicians and reduce disease burden for patients.

Abstract Currently, there is no strong evidence of the well-established biomarkers for immune checkpoint inhibitors (ICIs) in nasopharyngeal carcinoma (NPC). Here, we aimed to reveal the heterogeneity of tumour microenvironment (TME) through virtual microdissection of gene expression profiles. An immune-enriched subtype was identified in 38% (43/113) of patients, which was characterized by significant enrichment of immune cells or immune responses. The remaining patients were therefore classified as a non-Immune Subtype (non-IS), which exhibited highly proliferative features. Then we identified a tumour immune evasion state within the immune-enriched subtype (18/43, 42%), in which high expression of exclusion- and dysfunction-related signatures was observed. These subgroups were designated the Evaded and Active Immune Subtype (E-IS and A-IS), respectively. We further demonstrated that A-IS predicted favourable survival and improved ICI response as compared to E-IS and non-IS. In summary, this study introduces the novel immune subtypes and demonstrates their feasibility in tailoring immunotherapeutic strategies.

Abstract Objectives To investigate the prognostic value of magnetic resonance imaging (MRI)‐determined cervical lymph node (CLN) size in nasopharyngeal carcinoma (NPC). Methods We retrospectively reviewed 2066 patients with NPC treated with intensity‐modulated radiotherapy, and randomly divided them into two groups, in a 1:1 ratio. One group was used for training (the training group), and the other one was for internal validation (the validation group). All patients had undergone MRI examination and the maximal axial diameters (MAD) of the axial plane of all positive nodes had been measured and recorded. Results Of 683 patients with CLN metastases in the training group (n = 1033), MAD = 4 cm was associated with worse OS (64.7% vs 84.6%, P

Background: Plasma Epstein–Barr virus (EBV) DNA load has been widely used for nasopharyngeal carcinoma (NPC) prognostic risk stratification. However, oral EBV DNA load, a non-invasive biomarker that reflects the EBV lytic replication activity, has not been evaluated for its prognostic value in NPC yet.Methods: A total number of 1,194 locoregionally advanced NPC (LA-NPC) patients from south China were included from a prospective observational cohort (GARTC) with a median follow-up of 107.3 months. Pretreatment or mid-treatment mouthwashes were collected for EBV DNA detection by quantitative polymerase chain reaction (qPCR). The difference of pre- and mid-treatment oral EBV DNA load was tested by the Wilcoxon signed-rank test. The associations of oral EBV DNA load with overall survival (OS), progression-free survival (PFS), distant metastasis–free survival (DMFS), and locoregional relapse-free survival (LRFS) were assessed using the log-rank test and multivariate Cox regression.Results: The high level of the oral EBV DNA load (>2,100 copies/mL) was independently associated with worse OS (HR = 1.45, 95% CI: 1.20–1.74, p < 0.001), PFS (HR = 1.38, 95% CI: 1.16–1.65, p < 0.001), DMFS (HR = 1.66, 95% CI: 1.25–2.21, p = 0.001), and LRFS (HR = 1.43, 95% CI: 1.05–1.96, p = 0.023). Similar and robust associations between oral EBV DNA load and prognosis were observed for patients in both the pretreatment and mid-treatment stages. The detection rate (71.7 vs. 48.6%, p < 0.001) and the median load of oral EBV DNA (13,368 vs. 382 copies/mL, p < 0.001) for patients in the pretreatment stage were significantly higher than those in the mid-treatment stage. The combination of the oral EBV DNA load and TNM staging provided a more precise risk stratification for the LA-NPC patients.Conclusion: Oral EBV DNA load was an alternative non-invasive predictor of prognosis and may facilitate risk stratification for the LA-NPC patients.

Abstract Background To identify thyroid dose‐volume thresholds for radiotherapy (RT)‐related hypothyroidism (HT) in patients with nasopharyngeal carcinoma (NPC) treated with intensity‐modulated RT (IMRT). In this way, we desired to guide the design of treatment plans and, finally, lower HT prevalence. Methods In total, 345 NPC patients treated with IMRT were evaluated retrospectively during a median follow‐up of 45.2 (range, 11.3‐64.9) months. Serum‐based assessments of thyroid function before and after IMRT were monitored periodically. Thyroid dose‐volume parameters were analyzed for their association with HT risk. Results In total, 44.1% of patients (152/345) developed primary HT. Analyses of thyroid dose‐volume parameters identified a stringent dose‐volume histogram (DVH) threshold defined by V25Gy (the percentage thyroid volume that receives >25 Gy, not the absolute volume) ≤60%, V35Gy ≤ 55%, and V45Gy ≤ 45%. Patients whose thyroid DVHs satisfied these constraints had a lower prevalence of 2‐year HT compared with the overall prevalence (13.2% vs 25.8%, P 95%, V35Gy > 90%, and V45Gy > 75%, and patients whose thyroid DVHs satisfied with these constraints had a higher prevalence of 2‐year HT than the overall incidence (36.0% vs 25.8%, P 95%, V35Gy > 90%, and V45Gy > 75% as the “inhibition” DVH line, under the precondition of not compromising the target coverage. These findings could help in the design of individual treatment plans and, eventually, to lowering of HT prevalence.

Abstract Background Immunotherapy, especially immune checkpoint inhibition, has provided powerful tools against cancer. We aimed to detect the expression of common immune checkpoints and evaluate their prognostic values in nasopharyngeal carcinoma (NPC). Methods The expression of 9 immune checkpoints consistent with 13 features was detected in the training cohort (n = 208) by immunohistochemistry and quantified by computational pathology. Then, the LASSO cox regression model was used to construct an immune checkpoint-based signature (ICS), which was validated in a validation cohort containing 125 patients. Results High positive expression of PD-L1 and B7-H4 was observed in tumour cells (TCs), whereas PD-L1, B7-H3, B7-H4, IDO-1, VISTA, ICOS and OX40 were highly expressed in tumour-associated immune cells (TAICs). Eight of the 13 immune features were associated with patient overall survival, and an ICS classifier consisting of 5 features (B7-H3TAIC, IDO-1TAIC, VISTATAIC, ICOSTAIC, and LAG3TAIC) was established. Patients with high-risk scores in the training cohort had shorter overall (P

Abstract The standard of care for patients with locoregionally advanced nasopharyngeal carcinoma is concurrent platinum-based chemoradiotherapy. Existing literature have demonstrated that the addition of gemcitabine and cisplatin as induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma may have promising efficacy but were from phase 2 clinical trials. Stronger evidence-based data in forms of phase 3 clinical trial investigating the survival benefits of adding gemcitabine and cisplatin induction chemotherapy for such patients have been urgently warranted. In one of our recent studies published in the New England Journal of Medicine, “Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma”, 480 locoregionally advanced nasopharyngeal carcinoma patients from 12 hospitals across China were randomly assigned in a 1:1 ratio to receive either chemoradiotherapy alone or gemcitabine plus cisplatin and chemoradiotherapy. Our findings evinced that, as compared to chemoradiotherapy alone, the addition of induction chemotherapy comprising of gemcitabine plus cisplatin to concurrent cisplatin-radiotherapy to patients with locoregionally advanced nasopharyngeal carcinoma was safe, demonstrated improved recurrence-free survival, overall survival, and distant recurrence-free survival, and marginally superior locoregional recurrence-free survival.

Abstract Background Intensity‐modulated radiotherapy (IMRT) provides excellent local control in nasopharyngeal carcinoma (NPC). We investigated whether simplifying 8th American Joint Committee on Cancer staging system T categories improves prognostic value. Methods We used 2191 NPC patients as a training set and 414 patients separately as an independent, external validation cohort. Results In the training set, local relapse‐free survival (LRFS), disease‐free survival (DFS), and overall survival (OS) were not significantly different between the 8th edition T2/T3 (P = 0.610, 0.380 and 0.353, respectively). Merging T2 and T3 to proposed T2 (proT2) provided significant differences in LRFS, DFS, and OS between proposed T categories. Proposed T categories had similar c‐indices for LRFS, DFS, and OS (vs the 8th edition), which was validated in the external cohorts. Moreover, for DFS, the adjusted HRs of the proT2N0 (3.8), proT1N1 (3.8), and proT2N1 (6.0) subsets were similar; the adjusted HRs of the proT3N0 (7.0), proT3N1 (11.4), proT1N2 (11.0), proT2N2 (11.6), and proT3N2 (13.3) subsets were similar; the adjusted HRs of the proT1N3 (17.8), proT2N3 (15.3), and proT3N3 (26.4) subsets were similar; the results of the adjusted HRs for OS had the same rule. Defining proT1N0 as stage I; proT1N1/proT2N0‐1 as stage II; proT3N0‐2/proT1‐2N2 as stage III; and proT1‐3N3 as stage IVa generated orderly, significant differences in DFS and OS between stages in the training set and external validation cohort. Conclusions In the IMRT era, three T categories are more reasonable (merging T2/T3 into T2) and proT3N0‐2 (the 8th edition T4N0‐2) should be down‐staged to stage III.

Abstract 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.

Abstract 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.

Purpose: The benefits of additional use of nimotuzumab (NTZ) in the treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is largely unclear. We aim to compare LA-NPC treatment outcomes in patients that received CCRT with nimotuzumab (NTZ) to patients that received CCRT only.Materials and Methods: Between October 2009 and January 2012, 31 previously untreated and newly diagnosed LA-NPC patients were administered CCRT (3 cycles of 100 mg/m2 cisplatin every third week with intensity-modulated radiotherapy) plus NTZ according to an IRB-approved institutional research protocol. A well-balanced cohort of 62 patients who received CCRT alone was created by matching each patient who received CCRT plus NTZ via propensity-matched analysis in a 2:1 ratio.Results: Compared with CCRT only, CCRT plus NTZ was significantly associated with superior overall survival (5-year OS; 96.8% vs. 82.3%; P = 0.001), superior distant metastasis-free survival (5-year DMFS; 90.3% vs. 80.6%, P = 0.012) and superior progression-free survival (5-year PFS; 83.9% vs. 71.0%, P = 0.006). In multivariate analysis, the inclusion of NTZ to CCRT was confirmed to be a favorable factor for OS (HR, 0.31; 95% CI, 0.02–0.71; P = 0.027), DMFS (HR, 0.45; 95% CI, 0.13–0.77; P = 0.034), and PFS (HR, 0.38; 95% CI, 0.11–0.89; P = 0.041). In addition, no significant differences in hematology parameters, dermatitis, nausea, vomiting, xerostomia, nephrotoxicity or neurotoxicity were found between the two arms (all P > 0.05).Conclusion: The inclusion of NTZ to CCRT is more effective for long-term survival among LA-NPC patients than CCRT only.

Abstract 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.

Abstract 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.

Abstract Background To compare the efficacy of ipsilateral lower neck sparing irradiation (ILNSI) versus ipsilateral lower neck prophylactic irradiation (ILNPI) for unilateral or bilateral neck node-negative nasopharyngeal cancer (NPC). Methods A comprehensive literature search of PubMed, EMBASE, the Cochrane Library and other public databases was conducted in October, 2017. The outcomes were 3-year overall/regional recurrence-free/disease-free/distant metastasis-free survival (OS/RRFS/DFS/DMFS) and ipsilateral lower neck (ILN) recurrence. We performed subgroup analysis of ILNSI versus ILNPI for different radiotherapy techniques. Sensitivity analysis was performed to examine the stability of the results. Results Nine head-to-head comparative studies (2, 521 patients) were included in the meta-analysis. For the comparison of ILNSI versus ILNPI, there was no significant difference in 3-year OS (HR = 1.16, 95% confidence interval [CI] = 0.85–1.58, P = 0.36), RRFS (HR = 1.37, 95% CI = 0.76–2.47, P = 0.30), DFS (HR = 1.08, 95% CI = 0.80–1.44, P = 0.62) and DMFS (HR = 1.00, 95% CI = 0.69–1.44, P = 0.99). ILNSI and ILNPI also led to equivalent ILN recurrence rates (OR = 0.98, 95% CI = 0.47–2.03, P = 0.96). No significant heterogeneity was observed for any outcome. Subgroup analysis confirmed no significant differences between ILNSI and ILNPI for any outcome, regardless of radiotherapy technique. Sensitivity analysis indicated all outcomes were highly stable in favor of the original conclusions. Conclusions ILNSI provided equivalent survival outcomes and regional control compared to ILNPI; ILNSI represents an appropriate alternative strategy for patients with unilateral or bilateral neck node-negative NPC.

We investigated the clinical characteristics, prognostic factors, and post-recurrence prognostic factors of early- and late-recurrence patients for nasopharyngeal carcinoma (NPC) after definitive intensity-modulated radiation therapy (IMRT). This was a single-center retrospective analysis of patients in China from January 2010 to December 2015. The prognostic factors for overall survival (OS) and post-recurrence OS of early- and late-recurrence patients were identified using univariate and multivariate Cox regression analyses. Of the 9,468 patients included, 409 (4.3%), 325 (3.4%), and 182(1.9%) developed purely local recurrence, purely regional recurrence, and locoregional recurrence during follow-up, respectively. In the purely local recurrence group, 192 patients (46.9%) developed early local recurrence (ETR), and 217 patients (53.1%) developed late local recurrence (LTR). Of the 192 ETR patients, multivariate Cox regression analysis revealed that age and gender were independent risk factors of OS, and post-recurrence best supportive treatment (PRBST) was associated with poorer post-recurrence OS. Of the 217 LTR patients, the results revealed that baseline value of EBV-DNA was an independent risk factor for OS, while PRBST was associated with poorer post-recurrence OS. In the purely regional recurrence group, 183 patients (56.3%) developed early regional recurrence (ENR), and 142 patients (43.7%) developed late regional recurrence (LNR). Of the 183 ENR patients, multivariate Cox regression analysis revealed that alcohol abuse and TNM stage were independent risk factors of OS, while alcohol drinkers and PRBST were associated with poorer post-recurrence OS. Of the 142 LNR patients, PRBST was associated with poorer post-recurrence OS. In the locoregional recurrence group, 87 patients (47.8%) developed early locoregional recurrence (ELR), and 95 patients (52.2%) developed late locoregional recurrence (LLR). Of the 87 ELR patients, multivariate Cox regression analysis revealed that N stage and TNM stage were independent risk factors of OS, and N2/3 stage and PRBST were associated with poorer post-recurrence OS. Of the 95 LLR patients, the results revealed that T stage was an independent risk factor for OS, while T3/4 stage and PRBST were associated with poorer post-recurrence OS. Patients with LTR/LNR/LLR demonstrate significantly better OS compared with patients with ETR/ENR/ELR, Nevertheless, post-recurrence OS between patients with ETR/ENR/ELR and LTR/LNR/LLR was not significantly different.

Purpose: The National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) provide surveillance guidelines for nasopharyngeal carcinoma (NPC). We evaluated the ability of these guidelines to capture disease recurrence.Materials and methods: All 749 NPC patients were stratified for analysis by T and N stage. We evaluated the guidelines by calculating the percentage of relapses detected when following the 2018 NCCN, 2015 NCCN, and 2012 ESMO surveillance guidelines, and related surveillance costs were compared.Results: At a median follow-up of 100.8 months, 168 patients (22.4%) had experienced recurrence. Nineteen recurrences (11.3%) were detected using the 2018 NCCN, 53 (31.5%) using the 2015 NCCN and 46 (27.4%) using the ESMO guidelines. To capture 95% recurrences, surveillance would be required for 85.57 months for T1/2, 67.45 months for T3/4, 83.57 months for N0/1, and 55.80 months for N2/3 disease. In T1/2 disease, Medicare surveillance costs per patient were US$1642.66 using 2018 NCCN or ESMO and US$2179.81 using 2015 NCCN. Costs per recurrence detected were US$42,578.64, 62,088.70, and 73,329.76 using 2018 NCCN, 2015 NCCN, and ESMO, respectively.Conclusions: If strictly followed, the NCCN and ESMO guidelines will miss more than two-thirds recurrences. Improved surveillance algorithms to balance patient benefit against costs are needed.

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.

Abstract Background Previous studies have reported radiotherapy interruption (RTI) is associated with poor local control in two-dimensional radiotherapy (2DRT) era. However, it remains unclear whether RTI still affects local control for advanced T stage (T3–4) in the intensity-modulated radiation therapy (IMRT) era. We aim to evaluate whether RTI affects local control for T3–4 NPC treated with definitive IMRT. Methods In this observational prospective study, 447 T3–4 NPC patients treated with IMRT plus concurrent chemotherapy were included. All patients completed the planned radiotherapy course, and RTI was defined as the actual time taken to finish the prescribed course of radiotherapy minus the planned radiotherapy time. Receiver operating characteristic (ROC) curve was used for determined the cutoff point of RTI. The effects of RTI on local control were analyzed in multivariate analysis. Results At 5 years, the local relapse-free survival (LRFS) and overall survival (OS) rates were 93.7 and 85.7%, respectively. The cutoff RTI for LRFS was 5.5 days by ROC curve. Compared to patients with RTI > 5 days, patients with RTI ≤ 5 days had a significantly lower rate of LRFS (97% vs. 83%; P

Abstract 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

Abstract Background To evaluate the prognostic significance of pretreatment quality of life for patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy. Methods We performed a prospective, longitudinal study on 554 newly diagnosed patients with NPC from April 2011 to January 2015. A total of 501 consecutive NPC patients were included. Patients were asked to complete the EORTC QLQ-C30 (version 3.0) and QLQ-H&N35 questionnaires before treatment. Results Global health status among QLQ-C30 correlates with EBV DNA(P = 0.019). In addition, pretreatment appetite loss was significantly correlated with EBV DNA(P = 0.02). Pretreatment teeth, opening mouth, feeding tube was significantly correlated with EBV DNA, with P value of 0.003,

(1) Purpose: This study aims to explore risk-adapted treatment for elderly patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) according to their pretreatment risk stratification and the degree of comorbidity. (2) Methods: A total of 583 elderly LA-NPC patients diagnosed from January 2011 to January 2018 are retrospectively studied. A nomogram for disease-free survival (DFS) is constructed based on multivariate Cox regression analysis. The performance of the model is evaluated by using the area under the curve (AUC) of the receiver operating characteristic curve and Harrell concordance index (C-index). Then, the entire cohort is divided into different risk groups according to the nomogram cutoff value determined by X-tile analysis. The degree of comorbidities is assessed by the Charlson Comorbidity Index (CCI). Finally, survival rates are estimated and compared by the Kaplan–Meier method and the log-rank test. (3) Results: A nomogram for DFS is constructed with T/N classification, Epstein-Barr virus DNA and albumin. The nomogram shows well prognostic performance and significantly outperformed the tumor-node-metastasis staging system for estimating DFS (AUC, 0.710 vs. 0.607; C-index, 0.668 vs. 0.585; both p < 0.001). The high-risk group generated by nomogram has significantly poorer survival compared with the low-risk group (3-year DFS, 76.7% vs. 44.6%, p < 0.001). For high-risk patients with fewer comorbidities (CCI = 2), chemotherapy combined with radiotherapy is associated with significantly better survival (p < 0.05) than radiotherapy alone. (4) Conclusion: A prognostic nomogram for DFS is constructed with generating two risk groups. Combining risk stratification and the degree of comorbidities can guide risk-adapted treatment for elderly LA-NPC patients.

Abstract Background Little is known about the nature of metastasis to small cervical lymph nodes (SCLNs) in the patients with nasopharyngeal carcinoma (NPC) examined by using 18-fluoro-2-deoxy-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). The present study aimed to evaluate the diagnostic values of PET/CT in identifying metastasis in SCLNs in NPC patients. Methods Magnetic resonance images (MRI) and PET/CT scans for 470 patients with newly diagnosed, non-distant metastatic NPC were analyzed. Metastatic rates of SCLNs were defined by the positive number of SCLNs on PET/CT scans and total number of SCLNs on MRI scans. Receiver operating characteristic curve was applied to compare PET/CT-determined stage with MRI-determined stage. Results In total, 2082 SCLNs were identified, with 808 (38.8%) ≥ 5 and

Abstract Background According to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system, over 50% of patients with nasopharyngeal carcinoma (NPC) have N1 disease at initial diagnosis. However, patients with N1 NPC are relatively under-researched, and the metastasis risk of this group is not well-stratified. This study aimed to evaluate the prognostic values of gross tumor volume of metastatic regional lymph node (GTVnd) and pretreatment serum copy number of Epstein–Barr virus (EBV) DNA in predicting distant metastasis of patients with N1 NPC, and to develop an integrated prognostic model that incorporates GTVnd and EBV DNA copy number for this group of patients. Methods The medical records of 787 newly diagnosed patients with nonmetastatic, histologically proven N1 NPC who were treated at Sun Yat-sen University Cancer Center between November 2009 and February 2012 were analyzed. Computed tomography-derived GTVnd was measured using the summation-of-area technique. Blood samples were collected before treatment to quantify plasma EBV DNA. The receiver operating characteristic (ROC) curve analysis was used to evaluate the cut-off point for GTVnd, and the area under the ROC curve was used to assess the predicted validity of GTVnd. The survival rates were assessed by Kaplan–Meier analysis, and the survival curves were compared using a log-rank test. Multivariate analysis was conducted using the Cox proportional hazard regression model. Results The 5-year distant metastasis-free survival (DMFS) rates for patients with GTVnd > 18.9 vs. ≤ 18.9 mL were 82.2% vs. 93.2% (P 4000 vs. ≤ 4000 copies/mL were 83.5% vs. 93.9% (P 18.9 mL and EBV DNA copy number > 4000 copies/mL were significantly associated with poor prognosis (both P

Abstract 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.

Abstract Background The 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. Methods The 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. Results Of 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

Abstract Background Epigenetic abnormalities play important roles in nasopharyngeal cancer (NPC), however, the epigenetic changes associated with abnormal cell proliferation remain unclear. Methods We detected epigenetic change of ZNF671 in NPC tissues and cell lines by bisulfite pyrosequencing. We evaluated zinc finger protein 671 (ZNF671) expression in NPC cell lines and clinical tissues using real-time PCR and western blotting. Then, we established NPC cell lines that stably overexpressed ZNF671 and knocked down ZNF671 expression to explore its function in NPC in vitro and in vivo. Additionally, we investigated the potential mechanism of ZNF671 by identifying the mitotic spindle and G2/M checkpoint pathways pathway downstream genes using gene set enrichment analysis, flow cytometry and western blotting. Results ZNF671 was hypermethylated in NPC tissues and cell lines. The mRNA and protein expression of ZNF671 was down-regulated in NPC tissues and cell lines and the mRNA expression could be upregulated after the demethylation agent 5-aza-2′-deoxycytidine treatment. Overexpression of ZNF671 suppressed NPC cell proliferation and colony formation in vitro; silencing ZNF671 using a siRNA had the opposite effects. Additionally, overexpression of ZNF671 reduced the tumorigenicity of NPC cells in xenograft model in vivo. The mechanism study determined that overexpressing ZNF671 induced S phase arrest in NPC cells by upregulating p21 and downregulating cyclin D1 and c-myc. Conclusions Epigenetic mediated zinc finger protein 671 downregulation promotes cell proliferation and enhances tumorigenicity by inhibiting cell cycle arrest in NPC, which may represent a novel potential therapeutic target.

Abstract Background This study aimed to evaluate the long-term outcome and toxicities in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated by concurrent chemoradiotherapy (CCRT) with/without adding cetuximab. Methods A total of 62 patients treated with CCRT plus cetuximab were matched with 124 patients treated with CCRT alone by age, sex, pathological type, T category, N category, disease stage, radiotherapy (RT) technique, Epstein-Barr virus (EBV) DNA levels, and Eastern Cooperative Oncology Group (ECOG). Overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed using the Kaplan–Meier method and log-rank test. Treatment toxicities were clarified and compared between two groups. Results A total of 186 well-balanced stage II to IV NPC patients were retrospectively analyzed (median follow-up, 76 months). Compared to CCRT alone, adding cetuximab resulted in more grade 3 to 4 radiation mucositis (51.6% vs. 23.4%; P

Abstract Background In the era of intensity-modulated radiotherapy (IMRT), the role of neoadjuvant chemotherapy (NACT) in treating ascending-type nasopharyngeal carcinoma (NPC) is under-evaluated. This study was to compare the efficacy of NACT followed by IMRT (NACT + RT) with the efficacy of concurrent chemoradiotherapy (CCRT) on ascending-type NPC. Methods Clinical data of 214 patients with ascending-type NPC treated with NACT + RT or CCRT between December 2009 and July 2011 were analyzed. Of the 214 patients, 98 were treated with NACT followed by IMRT, and 116 were treated with CCRT. The survival rates were assessed using Kaplan–Meier analysis, and the survival curves were compared using a log-rank test. Results The 4-year overall survival, locoregional failure-free survival, distant failure-free survival, and failure-free survival rates were not significantly different between the two groups (all P > 0.05). However, patients in the CCRT group exhibited more severe acute adverse events than did patients in the NACT + RT group during radiotherapy, including leukopenia (30.2% vs. 15.3%, P = 0.016), neutropenia (25.9% vs. 11.2%, P = 0.011), and mucositis (57.8% vs. 40.8%, P = 0.028). After radiotherapy, patients in the CCRT group exhibited significantly higher rates of xerostomia (21.6% vs. 10.2%, P = 0.041) and hearing loss (17.2% vs. 6.1%, P = 0.023). Conclusions The treatment outcomes of the NACT + RT and CCRT groups were similar; however, CCRT led to higher rates of acute and late toxicities. NACT + RT may therefore be a better treatment strategy for ascending-type NPC.

Abstract Background Nasopharyngeal carcinoma (NPC) shows a high proportion of lymph node metastasis, and treatment guidelines have been developed for positive nodes. However, no irradiation guidelines have been proposed for patients with enlarged neck lymph nodes (ENLNs) that do not meet the radiological criteria of 10 mm in diameter for positive lymph nodes. This study aimed to determine the prognostic value and radiation dose for ENLNs in N0-category NPC patients treated with intensity-modulated radiotherapy (IMRT). Methods We reviewed the medical data of 251 patients with non-metastatic, N0-category NPC treated with IMRT. Receiver operating characteristic curves were used to calculate the cut-off value of the ENLN diameter for the prediction of disease failure. The biological equivalent dose (BED) for ENLNs was calculated. Patient survival was compared between the small and large ENLN groups. Independent prognostic factors were identified using the Cox proportional hazards model. Results The estimated 4-year regional relapse-free survival rate was higher in patients with ENLNs ≥5.5 mm than in those with ENLNs 0.05 for all survival rates). In the subgroup analysis, patients receiving BED ≥72 Gy had a similar prognosis as patients receiving BED

Abstract Background The prognostic values of staging parameters require continual re-assessment amid changes in diagnostic and therapeutic methods. This study aimed to identify the prognostic factors and failure patterns of non-metastatic nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era. Methods We reviewed the data from 749 patients with newly diagnosed, biopsy-proven, non-metastatic NPC in our cancer center (South China, an NPC endemic area) between January 2003 and December 2007. All patients underwent magnetic resonance imaging (MRI) before receiving IMRT. The actuarial survival rates were estimated using the Kaplan–Meier method, and survival curves were compared using the log-rank test. Multivariate analyses with the Cox proportional hazards model were used to test for the independent prognostic factors by backward eliminating insignificant explanatory variables. Results The 5-year occurrence rates of local failure, regional failure, locoregional failure, and distant failure were 5.4, 3.0, 7.4, and 17.4%, respectively. The 5-year survival rates were as follows: local relapse-free survival, 94.6%; nodal relapse-free survival, 97.0%; distant metastasis-free survival, 82.6%; disease-free survival, 75.1%; and overall survival, 82.0%. Multivariate Cox regression analysis revealed that orbit involvement was the only significant prognostic factor for local failure (P = 0.011). Parapharyngeal tumor extension, retropharyngeal lymph node involvement, and the laterality, longest diameter, and Ho’s location of the cervical lymph nodes were significant prognostic factors for both distant failure and disease failure (all P

Abstract The value of adding induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) for the treatment of locoregionally advanced nasopharyngeal carcinoma (NPC) remains unclear. In our recent article entitled “Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial” published in the Lancet Oncology, we reported the results of a phase III, multicenter, randomized controlled trial comparing cisplatin, 5-fluorouracil, and docetaxel (TPF) IC plus CCRT versus CCRT alone in patients with T3-4N1/TxN2-3M0 NPC (ClinicalTrials.gov registration number NCT01245959). The IC-plus-CCRT group showed significantly higher 3-year failure-free survival, overall survival, and distant failure-free survival rates than the CCRT-alone group, with an acceptable toxicity profile. Our study suggests that adding TPF IC to CCRT could increase survival rates and reduce distant failure in patients with locoregionally advanced NPC. However, long-term follow-up is required to assess the eventual efficacy and toxicity of this strategy, and a more accurate method to determine prognosis is needed to enable better tailoring of treatment strategy for individual patients.

The value of post-neoadjuvant chemotherapy (NACT) tumor volume for prognostication in loco-regionally advanced nasopharyngeal carcinoma (LA-NPC) is unascertained. Here, we recruited 4109 histologically proven LA-NPC (stage III-IVA) that were treated with radical chemo-intensive-modulated radiotherapy (IMRT). Post-NACT gross primary tumor (GTVp) and lymph node (GTVnd) volumes of each patient were calculated from planning computed tomography (CT). We observed similar linear association between GTVp/GTVnd and overall survival (OS); thresholds of 52 cm3 for GTVp and 12 cm3 for GTVnd were consistent for risk discretization for OS, disease-free survival (DFS), distant metastasis-free survival (DMFS), and local relapse-free survival (LRFS). Recursive partitioning analysis (RPA) modelling incorporating T-/N-categories and GTVp/GTVnd yielded four T-N-volume (TNV) risk groupings with disparate OS (p < 0.001). TNV risk stratification outperformed GTVp/GTVnd and eighth edition TNM for predicting OS (AUC 0.643 vs. 0.541−0.591; p < 0.001), DFS (0.629 vs. 0.545−0.580; p < 0.001), and DMFS (0.652 vs. 0.522−0.621; p < 0.001). NACT + concurrent chemoradiotherapy (CCRT) over NACT + IMRT was not superior for low- and low−intermediate-risk groupings (p > 0.05 for both), but superior for intermediate- and high-risk groupings in terms of OS (HR 0.68 (95% CI 0.47−0.99) for intermediate risk, 0.73 (0.55−0.97) for high risk; both p < 0.05). Overall, GTVp/GTVnd represent effective indicators for prognostication and decision-making in LA-NPC after NACT.