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Background Unsatisfactory tumor response to induction chemotherapy (IC) is an adverse prognostic factor of locoregionally advanced nasopharyngeal carcinoma (LANPC). A re-induction strategy which applies additional cycles of an alternative IC regimen prior to radiotherapy (RT) has been adopted. Methods A total of 419 LANPC patients who attained suboptimal response (stable disease or disease progression) according to the Response Evaluation in Solid Tumors (RECIST) guideline after initial IC were retrospectively included. They were divided into those who received additional cycles of re-induction regimen prior to RT (re-induction group, n = 87) and those who had no additional chemotherapy (direct to RT group, n = 332). Propensity score matching (PSM) was used to adjust for potential confounders. Tumor response and long-term survival were compared between two groups. Results After receiving a second IC regimen, 39.1% of the patients in re-induction group attained partial response; however, the tumor control of subsequent RT was not significantly improved when compared with direct to RT group (patients attaining complete response after RT 55.2% vs. 52.5%, P = 0.757). Patients who received re-induction therapy showed worse locoregional relapse-free survival (LRFS) and progression-free survival (PFS) than those proceeded directly to RT (3-year LRFS 75.7% vs. 83.1%, P = 0.005; 3-year PFS 62.4% vs. 68.3%, P = 0.037). The increased hematological toxicities were observed in re-induction group that included grade 3–4 anemia, thrombocytopenia and liver enzyme increase. Conclusion Re-induction therapy decreased LRFS and PFS and increased toxicities among patients who attain suboptimal response to initial IC regimen, as compared with direct to RT strategy.

OBJECTIVES/HYPOTHESIS The routine practices of examining submucosal lesions are not suitable for deep lesions. Therefore, we evaluated the efficacy of non-real-time image-guided transnasal endoscopic fine-needle aspiration biopsy (FNAB) in diagnosing nasopharyngeal carcinoma (NPC) with submucosal lesions. STUDY DESIGN The effectiveness evaluation of diagnostic methods. METHODS Fifty suspected NPC patients who failed in conventional biopsies were enrolled in this study. The efficacy, maneuverability, and safety of FNAB in diagnosing these intractable cases were evaluated. RESULTS The definitive diagnostic results of these 50 patients were NPC (34/50, 68.0%), nasopharyngeal necrosis (1/50, 2.0%), nasopharyngeal mucositis (12/50, 24.0%), and other cancers (3/50, 6.0%), respectively. The results of the diagnostic efficacy of FNAB were sensitivity, 89.2%; specificity, 100.0%; positive predictive value, 100.0%; negative predictive value, 76.5%; and accuracy, 92.0%, respectively. The area under the receiver operating characteristic curves was 0.946 (95% confidence interval = 0.884-1.00, P

Objectives The value of using PET/CT for staging of stage I–II NPC remains unclear. Hence, we aimed to investigate the survival benefit of PET/CT for staging of early-stage NPC before radical therapy. Methods A total of 1003 patients with pathologically confirmed NPC of stages I–II were consecutively enrolled. Among them, 218 patients underwent both PET/CT and conventional workup ([CWU], head-and-neck MRI, chest radiograph, liver ultrasound, bone scintigraphy) before treatment. The remaining 785 patients only underwent CWU. The standard of truth (SOT) for lymph node metastasis was defined by the change of size according to follow-up MRI. The diagnostic efficacies were compared in 218 patients who underwent both PET/CT and CWU. After covariate adjustment using propensity scoring, a cohort of 872 patients (218 with and 654 without pre-treatment PET/CT) was included. The primary outcome was overall survival based on intention to treat. Results Retropharyngeal lymph nodes were metastatic based on follow-up MRI in 79 cases. PET/CT was significantly less sensitive than MRI in detecting retropharyngeal lymph node lesions (72.2% [62.3–82.1] vs. 91.1% [84.8–97.4], p = 0.004). Neck lymph nodes were metastatic in 89 cases and PET/CT was more sensitive than MRI (96.6% [92.8–100.0] vs. 76.4% [67.6–85.2], p < 0.001). In the survival analyses, there was no association between pre-treatment PET/CT use and improved overall survival, progression-free survival, local relapse-free survival, regional relapse-free survival, and distant metastasis-free survival. Conclusions This study showed PET/CT is of little value for staging of stage I–II NPC patients at initial imaging. Key Points • PET/CT was more sensitive than MRI in detecting neck lymph node lesions whereas it was significantly less sensitive than MRI in detecting retropharyngeal lymph node lesions. • No association existed between pre-treatment PET/CT use and improved survival in stage I–II NPC patients.

This study aimed to establish an effective nomogram to predict primary distant metastasis (DM) in patients with nasopharyngeal carcinoma (NPC) to guide the application of PET/CT. In total, 3591 patients with pathologically confirmed NPC were consecutively enrolled. The nomogram was constructed based on 1922 patients treated between 2007 and 2014. Multivariate logistical regression was applied to identify the independent risk factors of DM. The predictive value of the nomogram was evaluated using the concordance index (C-index), calibration curve, probability density functions (PDFs), and clinical utility curve (CUC). The results were validated in 1669 patients enrolled from 2015 to 2016. Net reclassification improvement (NRI) was applied to compare performances of the nomogram with other clinical factors. The best cut-off value of the nomogram chosen for clinical application was analyzed. A total of 355 patients showed primary DM among 3591 patients, yielding an incidence rate of 9.9%. Sex, N stage, EBV DNA level, lactate dehydrogenase level, and hemoglobin level were independent predictive factors for primary DM. C-indices in the training and validation cohort were 0.796 (95% CI, 0.76–0.83) and 0.779 (95% CI, 0.74–0.81), respectively. The NRI indices demonstrated that this model had better predictive performance than plasma EBV DNA level and N stage. We advocate for a threshold probability of 3.5% for guiding the application of PET/CT depending on the clinical utility analyses. This nomogram is a useful tool to predict primary DM of NPC and guide the clinical application of PET/CT individually at the initial staging.

OBJECTIVE This study aimed to select optimal candidates benefiting from the addition of induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in stage II-IVa nasopharyngeal carcinoma (NPC) based on Epstein-Barr virus (EBV) DNA and nodal maximal standardized uptake values (SUVmax-N) of [18 F]-fluorodeoxyglucose positron emission tomography. PATIENTS AND MATERIALS A total of 679 patients diagnosed with stage II-IVa (except N0) NPC were retrospectively included in this study. Overall survival was the primary endpoint. Survival differences between different groups were compared using the log-rank test. The hazard ratio (HR) and 95% confidence interval (CI) were calculated using a multivariable Cox proportional hazards model. RESULTS Both high levels of EBV DNA (>1500 copies/mL) and SUVmax-N (>12.3) indicated worse survival conditions. All patients were divided into low- and high-risk groups based on these two biomarkers. The risk group was an independent prognostic factor in OS, progression-free survival (PFS), and distant metastasis-free survival (DMFS) (all p-values

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy with a complex tumor ecosystem. How the interplay between tumor cells, EBV, and the microenvironment contributes to NPC progression and immune evasion remains unclear. Here we performed single-cell RNA sequencing on ~104,000 cells from 19 EBV(+) NPCs and 7 nonmalignant nasopharyngeal biopsies, simultaneously profiling the transcriptomes of malignant cells, EBV, stromal and immune cells. Overall, we identified global upregulation of interferon responses in the multicellular ecosystem of NPC. Notably, an epithelial–immune dual feature of malignant cells was discovered and associated with poor prognosis. Functional experiments revealed that tumor cells with this dual feature exhibited a higher capacity for tumorigenesis. Further characterization of the cellular components of the tumor microenvironment (TME) and their interactions with tumor cells revealed that the dual feature of tumor cells was positively correlated with the expression of co-inhibitory receptors on CD8(+) tumor-infiltrating T cells. In addition, tumor cells with the dual feature were found to repress IFN-γ production by T cells, demonstrating their capacity for immune suppression. Our results provide new insights into the multicellular ecosystem of NPC and offer important clinical implications.

Purpose The prognosis of nasopharyngeal carcinoma (NPC) patients with parotid lymph node (PLN) metastasis remains unclear. This study was performed to investigate the prognostic significance and optimal staging category of PLN metastasis and develop a nomogram for estimating individual risk.Materials and MethodsClinical data of 7,084 non-metastatic NPC patients were retrospectively reviewed. Overall survival (OS) was the primary endpoint. A nomogram was established based on the Cox proportional hazards regression model. The accuracy and calibration ability of this nomogram was evaluated by C-index and calibration curves with bootstrap validation.ResultTotally, 164/7,084 NPC patients (2.3%) presented with PLNs. Multivariate analyses showed that PLN metastasis was a negative prognostic factor for OS, progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS). Patients with PLN metastasis had a worse prognosis than N3 disease. Five independent prognostic factors were included in the nomogram, which showed a C-index of 0.743. The calibration curves for probability of 3- and 5-year OS indicated satisfactory agreement between nomogram-based prediction and actual observation. All results were confirmed in the validation cohort.ConclusionNPC patient with PLN metastasis had poorer survival outcome (OS, PFS, DMFS, and LRFS) than N3 disease. We developed a nomogram to provide individual prediction of OS for patients with PLN metastasis.

Background We compared the efficacy and toxicity of three IC regimens (TPF: taxanes, cisplatin, and 5-fluorouracil; TP: taxanes and cisplatin; and PF: cisplatin and 5-fluorouracil) followed by CCRT in locoregionally advanced NPC. Methods The retrospective study involved 1354 patients with newly diagnosed stage III-IVA NPC treated with IC and CCRT. The median follow-up time in our cohort was 50 months. Based on EBV DNA level, all the patients with stage IV were divided into low- (pre-EBV DNA Results A multivariate analysis revealed TPF to be more effective than TP. Among stage III patients, no significant difference in clinical outcome between the different IC regimens was showed, while TPF was associated with significantly better survival conditions in the stage IV patients. A further subgroup analysis revealed that only patients with pre-EBV DNA ≥ 1500 copies could benefit from the application of TPF among stage IV NPC. In terms of acute toxicities, PF was associated with fewer grade 3/4 acute toxicities. Conclusions In low-risk NPC patients, PF-based IC showed similar efficacy as TPF and TP but was associated with fewer grade 3/4 acute toxicities. In high-risk patients, however, the TPF regimen was superior to PF and TP, although grade 3/4 toxicities were more common with the TPF regimen.

Objective: The main aim of this study was to establish a scoring model to predict risk of progression and survival in patients with regionally recurrent nasopharyngeal carcinoma (NPC). Methods: Three hundred and forty-eight patients subjected to neck dissection from 2003 to 2017 were included for study. Clinicopathologic information for each patient was analyzed. Independent prognostic factors were selected using the Cox proportional hazards model and incorporated into the scoring model. Concordance index (C-index) and calibration curves were used to verify discrimination and calibration, respectively and the results validated using bootstrap resampling. Results: Microscopic positive lymph node > 2 [hazard ratio (HR), 2.19; 95% confidence interval (CI), 1.30-3.68; P = 0.003], extranodal extension (HR, 2.75; 95% CI, 1.69-4.47; P < 0.001), and lower neck involvement (HR, 1.78; 95% CI, 1.04-3.04; P = 0.034) were identified from multivariate analysis as independent factors for overall survival (OS). A qualitative 4-point scale was generated to stratify patients into 4 risk groups for predicting OS and progression-free survival (PFS). The novel scoring model demonstrated enhanced discrimination (C-index = 0.69; 95% CI, 0.62-0.76) relative to the original recurrent tumor-node-metastasis (rTNM) staging system (C-index = 0.56; 95% CI, 0.50-0.62), and was internally validated with a bootstrap-adjusted C-index of 0.70. The calibration curve showed good agreement between predicted probabilities and actual observations. Conclusions: The scoring system established in this study based on a large regionally recurrent NPC cohort fills a gap regarding assessment of risk and prediction of survival outcomes after neck dissection in this population and could be further applied to identify high-risk patients who may benefit from more aggressive intervention.

Patients with recurrent nasopharyngeal carcinoma (NPC) have more co-existing distant metastasis than those of no-recurrence and are more likely to suffer distant metastasis after re-irradiation than patients with newly diagnosed NPC. However, the relationship between radioresistance and distant metastasis and the mechanisms involved in radioresistance-associated metastasis are still unclear. In this study, we proved that C-C motif chemokine ligand 2 (CCL2) expression was significantly elevated in HONE1-IR cells and recurrent NPC tumour. Inhibition of CCL2 enhanced sensitivity to radiotherapy in NPC cells. Moreover, autocrine CCL2 promoted NPC cell adaptive radioresistance, metastasis and epithelial-mesenchymal transition. Additionally, p53 activated CCL2 transcription. High CCL2 expression was highly associated with poorer locoregional recurrence free survival, progression free survival and overall survival in patients with newly diagnosed NPC. Notably, high CCL2 expression was an independent prognostic factor for distant metastasis free survival in recurrent NPC patients. Our results provide insights into the autocrine signalling mechanisms of CCL2 and suggest that inhibition of autocrine CCL2 may be a candidate treatment strategy for management of radioresistant NPC.

Alpha-fetoprotein hardly increased due to nasopharyngeal cancer. In this article, we reported a 57-year-old male nasopharyngeal carcinoma patient who had posttreatment subscapular metastasis with high serum alpha-fetoprotein but negative plasma Epstein–Barr virus DNA. Pathology results indicated that the scapular mass was undifferentiated non-keratinizing carcinoma originated in the nasopharynx. Moreover, no liver lesion was detected by imaging examination. In view of the positive alpha-fetoprotein and alpha-fetoprotein messenger RNA staining result in the right scapular mass fine needle aspiration biopsy sample, we considered the diagnosis of alpha-fetoprotein-producing nasopharyngeal carcinoma that had never been reported before.

To evaluate the prognostic value of the dynamic change in absolute lymphocyte counts (ALCs) and absolute monocyte counts (AMCs) and identify patients with N stage and plasma Epstein-Barr virus (EBV) DNA levels in nasopharyngeal carcinoma (NPC) who are at risk of treatment failure.A total of 1124 eligible patients with Stage II-IVb NPC treated with concurrent chemoradiotherapy (CCRT) were enrolled. Percentage changes in the ALC (ΔALC%) and AMC (ΔAMC%) were calculated.Patients with high ΔALC% were correlated with poorer 5-year overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) rates than those with low ΔALC%. Likewise, high ΔAMC% was significantly associated with worse outcome than low ΔAMC% (OS, p = 0.001; PFS, p = 0.001; DMFS, p = 0.034). Multivariate analyses revealed that ΔALC% (p = 0.046), ΔAMC% (p = 0.019), and EBV DNA level (p 0.001) were independent prognostic factors for OS. With respect to PFS, ΔALC% (p = 0.036), ΔAMC% (p = 0.011), N classification (p = 0.016), and EBV DNA level (p 0.001) were also independent prognosticators. Based on the aforementioned independent risk factors (ΔALC% ≥ 83.33%, ΔAMC% ≥ 40.00%, Stage N2-3, EBV DNA ≥ 4000 copies/ml), patients were divided into three different risk groups (low-risk group [with1 risk factor], intermediate risk group [with 1-3 risk factors], and high-risk group [with 4 risk factors]) that correlated with disparate risks of death (p 0.001), disease progression (p 0.001), and distant metastasis (p 0.001).High ΔALC% and ΔAMC% were correlated with poor prognosis in patients with NPC. Risk stratification based on ΔALC%, ΔAMC%, N classification, and plasma EBV DNA levels could provide potential utility for risk-adapted therapeutic strategies for NPC.

To compare the prognosis and adverse effects of induction or adjuvant chemotherapy (IC or AC) plus concurrent chemoradiotherapy (CCRT) versus CCRT alone in paediatric nasopharyngeal carcinoma (NPC) patients in the intensity-modulated radiotherapy (IMRT) era.549 patients diagnosed from 2005 to 2021 were enrolled. Our primary endpoint was progression-free survival (PFS). The recursive partitioning analysis (RPA) was applied to derive a risk stratification system. Kaplan-Meier survival curves were used to assess the cumulative survival rates, and cox analysis was applied to evaluate the relationship between variables and endpoints.The RPA-based risk stratification identified three different risk groups. In the intermediate-risk (stage IVa and EBV4000 copies/ml) group, patients who received IC followed by CCRT achieved a significantly better 3-year PFS rate than those treated with CCRT alone (87.35% versus 75.89%; P = 0.04). But survival benefit was not obtained from the additional IC or AC in the low-risk (stage II-III and EBV4000 copies/ml) or high-risk (stage II-IVa and EBV≥4000 copies/ml) group. The most common grade 3 or 4 adverse events in patients treated with CCRT, IC + CCRT, and CCRT + AC were neutropenia (8.1%, 33.0% versus 36.9%, respectively) and leukopenia (14.1%, 26.8% versus 32.3%, respectively) with statistically significant difference.Paediatric NPC patients in the intermediate-risk group treated with IC followed by CCRT had significantly better PFS compared with patients treated with CCRT alone. And the overall incidence of acute adverse events in patients treated with IC or AC plus CCRT was higher than in patients treated with CCRT alone.

Background: Despite the development of such multiple therapeutic approaches, approximately 20% patients experience recurrence. Identification of molecular markers for stratifying the different risks of tumour recurrence and progression is considered imperative.Methods: We used a RayBio Human Cytokine Antibody Array that simultaneously detected the levels of 297 proteins and profiled the conditioned medium of HONE1 cells and the radioresistant NPC cells HONE1-IR. We found Angiogenin(ANG) expression to be significantly increased in HONE1-IR and HONE1-IR cells exposed to 4-Gy X-ray radiation.Results: We investigated the expression of ANG in NPC tissues and explored its prognostic significance in patients with NPC. We found that ANG expression was increased in recurrent NPC tissues. Elevated expression of ANG induced radio-resistance in NPC cells, in addition to being significantly associated with shorter PFS, OS, and LRFS in patients with NPC. Multivariate analysis results revealed that ANG was an independent prognostic factor that predicted PFS, OS, and LRFS. Furthermore, a nomogram model was generated to predict OS in terms of ANG expression.Conclusion: Our results found the radioresistant function of ANG and proved the clinical prognostic significance of ANG, and the results could help predict radio-sensitivity and stratify high-risk patients or tumour recurrence.

BACKGROUND: Increasing evidence indicates that radiotherapy (RT)-induced brain cortical deficits may play a critical role in developing radiation encephalopathy in patients with nasopharyngeal carcinoma (NPC). However, the evolutional processes of RT-induced cortical injury have not been sufficiently investigated. This study investigates RT-induced effects on cortical morphology using longitudinal structural magnetic resonance imaging (MRI) in NPC patients. METHODS: Using MRI-based morphometry with surface-based measures, we evaluated the longitudinal alterations of cortical volume (CV), cortical thickness (CT), and cortical surface area (CSA) in 104 NPC patients at pre-RT (n=104), within 3 months post-RT (n=92), 6 months post-RT (n=71), and 9–12 months post-RT (n=52). Twenty healthy controls were also evaluated in parallel. Linear mixed models were used to investigate the trajectories of RT-related changes in cortical brain morphology and its association with irradiation dose, with healthy controls data being used to construct a normal age-related benchmark. The level of statistical significance was set at P

This study aimed to evaluate the prognostic value of combining pretreatment Epstein‐Barr virus (EBV) DNA level and cervical node necrosis (CNN) for patients with nasopharyngeal carcinoma (NPC) receiving intensity‐modulated radiotherapy (IMRT). A total of 607 incident nonmetastatic NPC patients treated with IMRT ± chemotherapy were reviewed. Patients were divided into four groups based on EBV DNA level and CNN status. The primary endpoint was progression‐free survival (PFS). Kaplan‐Meier curves with log‐rank test were applied to compare survival outcomes and the Cox proportional model was used to identify independent prognostic factors. Pretreatment EBV DNA level and CNN status were independent prognostic factors. Patients in the low‐level EBV DNA group or non‐CNN group had significantly better 5‐year PFS. Multivariate analyses demonstrated that CNN was an independent prognostic factor for overall survival (OS) (HR = 1.927, 95% CI: 1.129‐3.290, P = .016), PFS (HR = 1.492, 95% CI: 1.005‐2.214, P = .047), distant metastasis‐free survival (DMFS) (HR = 1.661, 95% CI: 1.044‐2.644, P = .032), but not locoregional relapse‐free survival. EBV DNA levels correlated significantly with CNN with a correlation coefficient of .324 (P, It is the first retrospective study that combined pretreatment plasma EBV DNA level and cervical node necrosis (CNN) status to assess the prognosis of nasopharyngeal carcinoma patients. We observed a significant association between plasma EBV DNA level and CNN status in the IMRT era. Compared with the low‐level EBV DNA and non‐CNN group, the high‐level EBV DNA and CNN group had poorer OS, progression‐free survival, and distant metastasis‐free survival. The Kaplan–Meier survival curves showed a significant difference in survival between the different risk groups according to the optimal cut‐off.

Background This study aimed to evaluate the prognostic value of maximal standard uptake values (SUVmax) of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (PET) comparing with Epstein-Barr virus (EBV) DNA levels in de novo metastatic nasopharyngeal carcinoma (NPC) patients. Methods From December 2006 to December 2016, 253 de novo metastatic NPC patients assessed by PET/ computed tomography were involved in current study. SUVmax-T, SUVmax-N, and SUVmax-M referred to the SUVmax at the primary tumor, cervical lymph nodes, and metastatic lesions respectively. Overall survival (OS) was the primary endpoint. Result Patients who died during the follow-up had significantly higher SUVmax-N, SUVmax-M, and EBV DNA level than those in the patients who were alive. SUVmax-N and SUVmax-M were positively correlated with EBV DNA level. The cut-off values of SUVmax-T, SUVmax-N, SUVmax-M, and EBV DNA were 17.0, 12.7, and 6.9, and 13,800 copies/mL respectively, which were determined by receiver operating characteristic (ROC) curve analysis. Patients with elevated SUVmax-N, SUVmax-M, and EBV DNA levels had a lower 3-year OS rate. In multivariate analysis, the independent prognostic factors of OS included EBV DNA, metastatic site, and locoregional radiotherapy application, while SUVmax was not an independent prognostic factor. Conclusion In de novo metastatic NPC patients, higher SUVmax-N and SUVmax-M were associated with worse prognosis. However, the predictive ability of SUVmax-N and SUVmax-M was poorer than that of EBV DNA.

Objective We aimed to investigate the efficacy and safety of cetuximab (CTX) or nimotuzumab (NTZ) on the addition of palliative chemotherapy (PCT) in patients with de novo metastatic nasopharyngeal carcinoma (NPC). Materials and methods From 2007 to 2016, 451 eligible patients with de novo metastatic NPC were enrolled in the study. With propensity score matching technique, we created a well-balanced cohort by matching patients who received CTX/NTZ plus PCT (62 patients) with those receiving PCT alone (248 patients) in a ratio of 1:4. The primary endpoint was overall survival (OS). All potential prognostic factors were involved in the multivariate analysis with the Cox regression hazards model. Kaplan-Meier curves were used to compare the survival status, and log-rank test to measure the significance. Results The median follow-up time was 27.7 months (range, 1-126 months). No significant difference in survival was observed between the CTX/NTZ plus PCT group and PCT group. (3-year OS: 63.0% vs 58.1%; P=0.485). The administration of CTX/NTZ was not found to be an independent prognostic factor in multivariate analysis. With regard to toxicity, the development of a G3-4 skin reaction and mucositis was more common in patients receiving CTX plus PCT. Interaction effects analysis did not show any significant interaction effects on OS between the treatment regimen and prognostic factors (P>0.05). Conclusion The efficacy of CTX/NTZ and PCT is comparable to single PCT treatment in terms of survival outcomes among de novo metastatic NPC patients. Moreover, the application of CTX exacerbated skin reactions and mucositis.

Object To ascertain the treatment effect of concurrent chemotherapy (CCT) in stage II‐III nasopharyngeal carcinoma (NPC) patients with different Epstein‐Barr virus (EBV) DNA level in intensity‐modulated radiotherapy (IMRT) era. Methods A total of 2742 patients diagnosed with stage II‐III NPC were involved in this study. Patients received IMRT with/without CCT. Overall survival (OS) was the primary endpoint. Receiver operating characteristics curve was used to determine the cut‐off value of pre‐DNA based on OS. After propensity score matching, the role of CCT was explored in patients with different EBV DNA level. Results In our cohort, the cut‐off value of pre EBV DNA was 1460 copies/mL (area under curve [AUC], 0.695‐0.769; sensitivity, 0.766; specificity, 0.599). Patients with high EBV DNA level showed poor survival in OS, progression free survival (PFS), locoregional relapse‐free survival (LRFS) and distant metastasis‐free survival (DMFS). In patients with EBV DNA level >1460 copies/mL, the concurrent chemoradiotherapy (CCRT) group achieved higher 3‐year OS compared with IMRT groups. However, the CCRT and IMRT groups showed comparable OS in patients with EBV DNA ≤1460 copies/mL. In multivariate analyses, CCT was a protective factor for OS, PFS, and LRFS in high‐risk patients (EBV DNA level >1460 copies/mL), while not an independent prognostic factor among the low‐risk patients (EBV DNA level ≤1460 copies/mL). Conclusion Pre‐EBV DNA could be a useful tool to guide individualized treatment for stage II‐III NPC patients. Additional CCT to IMRT improved the survival for patients with high pre‐EBV DNA, while those with low pre‐EBV DNA could not.

Objective: This study aimed to establish a nomogram to predict the risk of post-radiation necrosis in nasopharyngeal carcinoma (NPC) patients. Background: This study was performed to identify influencing factors for developing post-radiation necrosis, and to establish an effective nomogram model to predict individual risks in NPC patients. Methods: 7144 NPC patients receiving radical radiotherapy from 2007 to 2012 were involved in the study, and 207 of them developed nasopharyngeal necrosis (NPN). The clinical characteristics and baseline laboratory results were collected and analyzed. Independent predictive factors were selected using the Cox proportional model and incorporated into the nomogram. The receiver operating characteristic curve and the calibration curve were used to verify discrimination and calibration. Results: The experience of re-irradiation contributed most to the occurrence of NPN (HR, 15.56, 95% CI 10.84-22.35, p

We analyzed the number of circulating tumor cells (CTCs) and Epstein-Barr virus DNA (EBV DNA) for diagnosis, monitoring and prognosis of patients with metastatic nasopharyngeal carcinoma (mNPC). The levels of CTCs and EBV DNA were measured at baseline and after first-line chemotherapy in 148 mNPC patients prospectively enrolled between December 2014 and August 2016. We also collected 122 non-mNPC cases within the same time frame for examining CTCs and EBV DNA at baseline. In 270 NPC patients, we observed improved specificity (86.0% vs. 41.0%) and inferior sensitivity (42.3% vs. 81.3%) of CTCs as compared to EBV DNA for diagnosis of distant metastasis. mNPC patients were stratified into unfavorable and favorable prognostic groups, respectively, based on CTC of 12 at baseline and 1 after first-line chemotherapy and EBV DNA of 10,000 at baseline and 4,000 after first-line chemotherapy. Conversion of baseline unfavorable CTCs and EBV DNA to favorable after first-line chemotherapy was associated with significantly longer progression-free survival (PFS) and overall survival (OS) compared to patients with unfavorable CTCs and EBV DNA at both time points. Among patients with a complete/partial response as per imaging evaluation, favorable CTCs and EBV DNA levels after first-line chemotherapy were associated with significantly longer PFS and OS. In conclusion, our data demonstrated the number of CTCs and EBV DNA before, after and during first-line chemotherapy were strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.

Background: The goal of this study was to explore the value of adding neoadjuvant chemotherapy (NACT) or adjuvant chemotherapy (ACT) to concurrent chemoradiotherapy (CCRT) in patients with nasopharyngeal carcinoma (NPC) with different risks of treatment failure. Patients and Methods: A total of 2,263 eligible patients with stage III–IVb NPC treated with CCRT ± NACT or ACT were included in this retrospective study. Distant metastasis–free survival (DMFS), overall survival, and progression-free survival were calculated using the Kaplan-Meier method and differences were compared using the log-rank test. Results: Patients in the low-risk group (stage N0–1 disease and Epstein-Barr virus [EBV] DNA P= .008). Multivariate analyses also demonstrated that additional NACT was the only independent prognostic factor for DMFS (hazard ratio, 0.42; 95% CI, 0.22–0.80; P=.009). In both the intermediate-risk group (stage N0–1 disease and EBV DNA ≥4,000 copies/mL and stage N2–3 disease and EBV DNA Conclusions: The addition of NACT to CCRT could reduce distant failure in patients with low risk of treatment failure.

Background To evaluate the clinical outcome in patients with de novo metastatic nasopharyngeal carcinoma (NPC) treated or not treated with locoregional radiotherapy (LRRT) based on plasma Epstein–Barr virus (EBV) DNA level and tumor response after palliative chemotherapy (PCT). Methods From 2007 to 2016, 502 patients with de novo metastatic NPC were included in this study. All patients were treated with PCT and 315 patients received LRRT. Our primary study endpoint was overall survival (OS). Results EBV DNA was detected in 461 patients (91.8%) before treatment but was undetectable in 249 patients (49.6%) after PCT. Three hundred and seventeen patients (63.1%) achieved satisfactory response (complete response or partial response) to PCT. Both the post-PCT EBV DNA level and tumor response were independent prognostic factors. Among low-risk patients (patients with undetectable EBV DNA and satisfactory tumor response after PCT), the 3-year OS rate was 80.4% in LRRT-treated patients and 45.3% in patients not treated with LRRT (P

Objectives: To evaluate the prognostic significance of Adult Comorbidity Evaluation-27 (ACE-27) for elderly patients (age ≥70 years) with locoregionally advanced nasopharyngeal carcinoma (NPC) treated with Intensity-Modulated Radiotherapy (IMRT), with or without chemotherapy. Methods: 206 elderly patients with locoregionally advanced NPC treated from December 2006 to December 2016 were involved into analysis as the training cohort. Besides, a separate cohort of 72 patients from the same cancer center collected between January 2003 and October 2006 served as the validation cohort. By using propensity score matching (PSM), we created a balanced cohort by matching patients who received chemoradiotherapy with patients who received IMRT alone. Treatment toxicities were calculated between CRT and RT groups using the χ2 test. The primary endpoint was cancer-specific survival (CSS). Multivariate analysis was performed to assess the relative risk for each factor by using a Cox's proportional hazards regression model. Results: The median follow-up was 39.0 months (range = 3-137 months). In the PSM cohort, patients in the CRT group achieved comparable survival compared with patients in the RT group. The 3-year CSS rate was 64.3% and 65.2%, respectively (P =0.764). In multivariate analysis, the addition of chemotherapy to IMRT was not an independent prognostic factor for CSS, whereas a high ACE-27 score was an independent risk factor. In subgroup analysis with ACE-27 score ≥ 2, the 3-year CSS rate was worse in patients from the CRT group (63.5% vs. 46.3%, P = 0.041). Conclusions: CRT is comparable to IMRT alone for elderly patients with locoregionally advanced NPC. The ACE-27 tool may help to identify high-risk subgroup for poor disease outcome and tailor individualized treatment.

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

BACKGROUND: Nutritional status is a key factor influencing the prognosis of patients with cancer. The Geriatric Nutritional Risk Index (GNRI) has been used to predict mortality risk and long-term outcomes. In this study, we aimed to evaluate the predictive value of pretreatment GNRI in patients with nasopharyngeal carcinoma (NPC). METHODS: A total of 1,065 patients with biopsy-proven non-disseminated nasopharyngeal carcinoma were included. Based on a cutoff value of pretreatment GNRI, patients were divided into two groups (low ≤107.7 and high >107.7). Combining GNRI and baseline Epstein-Barr virus (EBV) DNA, all patients were further stratified into three risk groups, namely, high-risk (high EBV DNA and low GNRI), low-risk (low EBV DNA and high GNRI), and medium-risk (except the above) groups. Multivariate analyses were performed using the Cox proportional hazards model to assess the predictive value of the GNRI. RESULTS: Among the 1,065 patients, 527 (49.5%) and 538 (50.5%) were divided into low and high GNRI groups, respectively. Within a median follow-up of 83 months, patients with a high GNRI score exhibited significantly higher overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) compared to those with low GNRI scores (P

Purpose: To improve individualized treatment of de novo metastatic nasopharyngeal carcinoma (dmNPC) patients by investigating prognostic factors and identifying patients who achieved better survival outcomes after locoregional radiotherapy (LRRT).Materials and methods: Our study included a cohort of 498 dmNPC patients. Overall survival (OS) was the primary endpoint. We analyzed the correlation of all potential prognostic factors and survival outcomes by Kaplan-Meier survival curves using log-rank test and Cox proportional hazards regression model.Results: Multivariate analysis identified three independent prognostic factors: Epstein-Barr virus (EBV) DNA, number of metastatic lesions, and number of metastatic organs. Through these factors, we successfully divided all patients into 3 subgroups: low-risk (single metastatic organ, EBV DNA ≤ 25,000 copies/ml, and ≤ 5 metastatic lesions), intermediate-risk (single metastatic organ, EBV DNA > 25,000 copies/ml, and ≤ 5 metastatic lesions), and high-risk (multiple metastatic organs or > 5 metastatic lesions or both). By comparing LRRT and non-RT groups, we found statistical differences in OS in the low-risk and intermediate-risk subgroups (p = 0.039 and p = 0.010, respectively) but no significant difference in OS in the high-risk subgroup (p = 0.076). Further multivariate analysis of different risk stratifications revealed that LRRT was a protective factor only for the low- and intermediate-risk subgroups.Conclusions: The risk stratification of dmNPC may be used as a new prognostic factor to help clinicians organize individualized LRRT treatment to improve the survival outcomes of dmNPC patients.

We aimed to compare the survival outcomes of patients with nasopharyngeal carcinoma (NPC) who had different smoking behaviors and were treated with two- or three-dimensional radiotherapy (2D/3DRT) or intensity-modulated radiotherapy (IMRT) with a long-term follow up.From 1990 to 2016, 23,325 patients with NPC were included. The primary endpoint of this study was overall survival (OS). The log-rank test and Cox proportional hazards regression model were used to assess the patients' survival outcomes.The 5-year OS rates in the entire cohort were 76.4%, 68.9%, and 79.8% in the former, current, and never smokers, respectively. In the IMRT cohort, the OS rates showed the same trend. Compared with the never smokers, the 5-year distant metastasis-free survival (DMFS) was lower in the former (P = 0.004) and current smokers (P 0.001). In the multivariate analysis of the IMRT cohort, the risk of death (P = 0.003) and recurrence (P = 0.027) was higher in the current smokers, while the risk of metastasis was higher in the former and current smokers (P = 0.031 and P = 0.019, respectively) than the never smokers. A total of 53.9% of the effect of smoking status on OS was through sex, age, and Epstein-Barr virus DNA, which were significant mediators.In the IMRT era, being a former smoker or current smoker was an independent risk factor for DMFS. The difference in OS and locoregional relapse-free survival was significant only between the current smokers and never smokers.

To explore the relationship between the Comprehensive Nutritional Index (CNI) and survival in older patients with nasopharyngeal carcinoma (NPC) and to compare the prognostic performance of three nutritional indicators (CNI, Prognostic Nutritional Index (PNI), and Nutritional Risk Index (NRI)) for overall survival (OS). This retrospective study involved 309 older NPC patients in Guangzhou (China) from November 2006 to November 2017. The CNI comprised five parameters: the body mass index (BMI), usual body weight percentage (UBW%), hemoglobin (Hb) level, albumin level, and total lymphocyte count (TLC). All single nutritional indicators were evaluated before and immediately after treatment. The principal component analysis (PCA) was used for calculation of the CNI by single nutritional indicators after treatment. The cutoff point for the CNI was evaluated and logistic regression used to explore the risk factors for the CNI. Univariable, multivariable Cox regression, and Kaplan–Meier methods were applied for OS and disease-free survival (DFS) analyses. Cox proportional hazards models were used to compare the prognostic value of the CNI, PNI, and NRI for OS. All single nutritional indicators decreased significantly after treatment (P < 0.05). The CNI cutoff point for mortality was 0.027, and the logistic regression indicated more complex treatments or higher cancer stage for NPC was associated with a low CNI (HR = 0.179; 95% CI: 0.037–0.856; 0.545, 0.367–0.811, respectively). In multivariable Cox regression, the CNI remained an independent prognostic factor of OS and DFS (HR = 0.468, 95% CI: 0.263–0.832; 0.527, 0.284–0.977, respectively). Kaplan–Meier curves showed that a low CNI was associated with worse OS and DFS (P = 0.001 and 0.013, respectively). The prognostic predictive performance of the CNI was superior to that of the PNI or NRI. The CNI can be recommended as an appropriate indicator reflecting the integrated nutritional status of older NPC patients. A low CNI predicted a poor survival outcome and the prognostic performance of CNI was superior to PNI or NRI.

To longitudinally investigate alterations in cerebral white matter volume as a function of irradiation dose and time after standard radiotherapy in nasopharyngeal carcinoma patients and to determine how these alterations are related to radiotherapy-associated neurocognitive dysfunction. A total of 120 nasopharyngeal carcinoma patients were included in the present study. Longitudinal structural magnetic resonance imaging was performed at pre-radiotherapy and 1–3, 6, and 9–12 months post-radiotherapy. Twenty healthy controls were recruited and followed up with in parallel. Structural images were processed via FreeSurfer. The Montreal Cognitive Assessment was performed to evaluate cognitive function of the participants. Linear mixed models and general linear models were used to evaluate different trajectories and the relationship between white matter volume and cognition in patients and controls within approximately 12 months of follow-up. Selective and time-dependent white matter atrophy was observed in the right parahippocampal gyrus, right inferior temporal gyrus, right middle temporal gyrus, right fusiform gyrus, and left insular cortex in post-radiotherapy patients compared to the controls. Moreover, radiotherapy-associated white matter atrophy in the right parahippocampal gyrus exhibited a dose-dependent pattern, whereas radiotherapy-associated white matter atrophy in the right inferior temporal gyrus was correlated with progressive cognitive impairment in patients. Taken together, our findings illustrate that white matter volume alterations can be used as a potential biomarker to detect radiotherapy-related subtle brain injury in nasopharyngeal carcinoma patients, which may help further elucidate the pathogenesis of radiation-induced cognitive decline and facilitate studies on cognition-sparing radiotherapy.

Purpose: Previous studies suggest that a cumulative cisplatin dose of 200 mg/m2 might be adequate in the intensity-modulated radiation therapy (IMRT) era for locoregionally advanced nasopharyngeal carcinoma (LANPC). However, two cycles of once-every-3-weeks cisplatin at 100 mg/m2 has never been prospectively compared with standard once-a-week cisplatin regimen. Patients and Methods: This trial was conducted at three hospitals from 2011 to 2016. Patients who met the eligibility criteria were recruited (ChiCTR-TRC-12001979) and randomly assigned (1:1) via a computer-generated sequence to receive once-every-3-weeks cisplatin at 100 mg/m2 for two cycles or once-a-week cisplatin at 40 mg/m2 for six cycles concurrently with IMRT. Primary endpoint was failure-free survival and between-group absolute difference of 10% as the noninferiority margin. Results: A total of 510 patients were enrolled. Median follow-up time was 58.3 months with 85.4% of 3-year failure-free survival in the once-every-3-weeks group and 85.6% in the once-a-week group. An absolute difference of −0.2% (95% confidence interval, −6.3 to 5.9; Pnoninferiority = 0.0016). Acute toxicities of grade 3 or higher occurred in 55.8% in the once-every-3-weeks group and 66.3% in the once-a-week group (P = 0.015). The most common acute toxicities were hematologic abnormalities, including leukopenia (16% vs. 27%; P = 0.0022) and thrombocytopenia (1% vs. 5%; P = 0.015). The late grade 3–4 auditory loss rate was significantly lower in the once-every-3-weeks group than the once-a-week group (6% vs. 13%; P = 0.0039). Conclusions: Once-every-3-weeks cisplatin as concurrent chemoradiotherapy is noninferior to once-a-week cisplatin in the treatment efficacy in the LANPC. Although both regimens are well tolerated, severe acute toxicities and late-onset auditory loss are higher in the once-a-week group.

Background To compare the efficacy of induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) versus induction chemotherapy plus radiotherapy (IC+RT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Patients and Methods One thousand three hundred twenty four patients with newly-diagnosed NPC treated with IC+CCRT or IC+RT were enrolled. Progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), locoregional relapse-free survival (LRFS), and acute toxicities during radiotherapy were compared using propensity score matching (PSM). A nomogram was developed to predict the 3- and 5-year PFS with or without concurrent chemotherapy (CC). Results PSM assigned 387 patients to the IC+CCRT group and IC+RT group, respectively. After 3 years, no significant difference in PFS (84.7 vs. 87.5%, P = 0.080), OS (95.5 vs. 97.6%, P = 0.123), DMFS (89.7 vs. 92.8%, P = 0.134), or LRFS (94.0 vs. 94.1%, P = 0.557) was noted between the groups. Subgroup analysis indicated comparable survival outcomes in low-risk NPC patients (II-III with EBV DNA

Purpose Curative radiotherapy for nasopharyngeal carcinoma (NPC) can lead to acquired nasal cavity stenosis and atresia (ANCSA). As the first study to investigate risk factors of ANCSA in a large cohort of NPC patients, this article aims to develop and validate a multivariate normal tissue complication probability (NTCP) model to predict the development of ANCSA and to establish a nomogram for clinical use. Methods and materials The retrospective cohort was comprised of 548 NPC patients treated with radical radiotherapy. The cohort was randomly divided into training and validation groups. Least absolute shrinkage and selection operator regression was performed for variable selection from the clinical and dosimetric characteristics in the training group. A multivariate NTCP model and a nomogram were established for the prediction of ANCSA development. Discrimination and calibration were tested using receiver operating characteristic (ROC) curves and calibration tests, respectively, for both groups. Results ANCSA was observed in 132 (24.1%) of 548 patients with NPC who underwent radical radiotherapy. The median time to ANCSA detection after treatment was 2.8 months (range, 0.0–57.7 months). Five potential predictors, including choanal invasion, low white blood cell count, high C-reactive protein level, high serum amyloid A level, and high V70Gy of the nasal cavity, were selected to develop the NTCP model based on 365 patients in the training group. The model had a fairly good discriminative power according to the ROC analysis in both the training (area under ROC curve = 0.79, 95%CI: 0.73–0.84) and validation (0.73, 0.64–0.82) groups. The calibration power was tested using the calibration test in the training (E-max = 0.069, E-avg = 0.015, p = 0.977) and validation (E-max = 0.057, E-avg = 0.032, p = 0.747) groups. Conclusions We developed and successfully validated an NTCP model for early prediction of ANCSA in patients with NPC after radical radiotherapy. This could help clinicians assess the risk of ANCSA before the initiation of follow-ups and ensure appropriate and timely management of this complication.

Objectives: To investigate the optimal treatment pattern in patients with de novo metastatic nasopharyngeal carcinoma (NPC). Methods: We assessed 502 consecutive and unselected de novo metastatic NPC patients in Sun Yat-sen University Cancer Center (SYSUCC) from November 2006 to October 2016 in our study. All patients were treated with palliative chemotherapy (PCT) and 308 patients received locoregional radiotherapy (LRRT) subsequently. Our primary study endpoint was overall survival (OS). Results: The patients treated with LRRT were associated with improved survival on univariate analysis (3-year OS rate 63.7% vs. 31.8%, P < 0.001) and multivariate analysis (HR 0.52, 95%CI 0.40–0.68, P < 0.001). The overall survival benefit of more than 4 PCT cycles was significant in female (HR 0.45, 95% CI 0.24-0.86, P = 0.016) and patients with multiple metastatic sites (HR 0.42, 95% CI 0.26-0.66, P < 0.001). The application of concurrent chemotherapy (CCT) was not associated with better survival among patients receiving LRRT (HR 1.31, 95% CI 0.92-1.86, P = 0.141). Conclusion: LRRT prolonged survival in de novo metastatic NPC. For patients treated with multiple metastatic sites, more than 4 cycles of PCT is necessary. CCT does not improve survival in de novo metastatic NPC patients.

Background and Aims: To investigate the longitudinal trend of health-related quality of life (HRQOL) from the start to the end of concurrent chemoradiotherapy and survival in patients with advanced nasopharyngeal carcinoma (NPC).Methods: A total of 145 patients with stage II–IVb NPC, who were a subsample of a randomized phase III clinical trial, were recruited in this study. HRQOL was measured weekly for a total of 6 weeks during concurrent chemoradiotherapy by the Chinese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30. Longitudinal trends of HRQOL domains over time were analyzed using mixed models. Survival rates were estimated using Kaplan-Meier method.Results: During a median follow-up of 45 months, the 3-year progression-free survival rate, overall survival rate, and distant metastasis-free survival rate were highly at 86.8% (95% CI: 80.1%, 91.4%), 95.1% (95% CI: 90.1%, 97.6%), and 91.0% (95% CI: 84.9%, 94.6%), respectively. The average weekly declines of five functioning domains were 1.83–3.52 points during the treatment period, with role functioning having the largest decline rate (−2.52 points per week, 95% CI: −4.50, −2.55; p < 0.001). Loss of appetite is the most affected symptom, with severe appetite loss ranging from 35.9 to 61.1%. The average increases of symptoms were 0.63–5.16 points per week during treatment period (all p-values for time

Purpose This study aimed to establish an effective prognostic nomogram to predict the risk of early metastasis (EM) in nasopharyngeal carcinoma (NPC) patients, as a guide for intensive treatment. Materials and methods A total of 9021 patients with biopsy-confirmed NPC at our institute were enrolled in this study between December 2006 to December 2016. We randomized these patients using a proportion of 2/3 and 1/3 and selected 6044 and 2977 patients as the training and validation cohorts, respectively. All patients received radiotherapy with or without chemotherapy. Univariate and multivariate logistical regressions were used to identify independent risk factors. The nomogram’s predictive value was evaluated by concordance indexes (C-indexes), calibration curves, probability density functions (PDFs), and clinical utility curves (CUCs). ROC analysis using Delong test was used to compare efficiency between the nomogram and other risk factors. Results In total, 174 (2.9%) and 81 (2.7%) patients in training and validation cohorts, respectively, had EM. Pretreatment plasma EBV DNA, N stage, LDH, ALP, BMI, and sex were independent predictive factors of EM. The C-indexes of nomogram were 0.756 (95% CI = 0.719–0.793) and 0.766 (95% CI = 0.720–0.813), in the training and validation cohorts, respectively. The C-index of the nomogram was significantly superior to any one of independent factors. According to the PDFs and CUCs and considering the balance of the true positive EM patients and true positive non-EM patients, we chose 5.0% as a threshold probability for clinical decision-making, which could distinguish about 85% and 48% of non-EM and EM patients, respectively. Conclusion Our nomogram had good accuracy in predicting EM incidence, and a 5.0% threshold was appropriate for clinical decision-making.

Metabolic reprogramming plays important roles in development and progression of nasopharyngeal carcinoma (NPC), but the underlying mechanism has not been completely defined. In this work, we found INSL5 was elevated in NPC tumor tissue and the plasma of NPC patients. Plasma INSL5 could serve as a novel diagnostic marker for NPC, especially for serum VCA‐IgA‐negative patients. Moreover, higher plasma INSL5 level was associated with poor disease outcome. Functionally, INSL5 overexpression increased, whereas knockdown of its receptor GPCR142 or inhibition of INSL5 reduced cell proliferation, colony formation, and cell invasion in vitro and tumorigenicity in vivo. Mechanistically, INSL5 enhanced phosphorylation and nuclear translocation of STAT5 and promoted glycolytic gene expression, leading to induced glycolysis in cancer cells. Pharmaceutical inhibition of glycolysis by 2‐DG or blockade of INSL5 by a neutralizing antibody reversed INSL5‐induced proliferation and invasion, indicating that INSL5 can be a potential therapeutic target in NPC. In conclusion, INSL5 enhances NPC progression by regulating cancer cell metabolic reprogramming and is a potential diagnostic and prognostic marker as well as a therapeutic target for NPC., This study reveals that INSL5 promotes tumor progression by regulating cancer cell metabolic reprogramming. INSL5 is a potential diagnostic and prognostic marker as well as a therapeutic target for nasopharyngeal carcinoma (NPC).

Objective: Our study aimed to compare the efficacy and toxicity of two chemotherapy regimens, gemcitabine plus cisplatin (GP) vs. docetaxel plus, fluorouracil plus cisplatin (TPF), in metastatic nasopharyngeal carcinoma (NPC) patients. Methods: We retrospectively enrolled metastatic NPC patients between July 2006 and December 2016 who were treated with TPF or GP palliative chemotherapy (PCT). The association between the PCT regimens and survival conditions was evaluated by log-rank tests and the Cox proportional hazards model. A cohort was created using propensity score matching with the ratio of 1:1 to clarify the results of the multivariable Cox regression analyses. Overall survival (OS) was the primary endpoint. Results: Of 266 eligible patients, 186 and 80 patients, respectively, received TPF and GP regimen. No significant difference was demonstrated in the survival rate between the GP and TPF groups (3-year OS: 52.6 vs. 50.3%; P = 0.929). However, multivariable analysis suggested receiving GP as an independent protective factor (hazard ratio, 0.864; 95% confidence interval, 0.753-0.992; P = 0.042). In the matched cohort, treatment with GP was also associated with a significantly higher OS (3-year OS: 52.6 vs. 35.6%, P = 0.042). Subgroup analysis indicated that the superiority of GP reflected in patients with secondary metastases rather than primary metastases. The incidence of grade 3 to 4 treatment-related toxicity was more common in the TPF group than in the GP group. Conclusion: Our study suggested that GP might be superior to TPF for metastatic NPC patients, especially those with secondary distant metastases. Further studies are necessary to validate our results.

Novel strategies to treat late-stage nasopharyngeal carcinoma that often develop resistance to chemotherapy remains an unmet clinical demand. In this study, we identify the multi-kinase inhibitor pacritinib as capable of resensitizing the response to paclitaxel in an acquired resistance model. Transcriptome analysis of paclitaxel-sensitive and -resistant cell lines, as well as chemorefractory clinical samples, identified S100A9 as the top candidate gene suppressed by pacritinib and whose overexpression was significantly associated with paclitaxel resistance and poor clinical outcome. Moreover, both paclitaxel-resistant nasopharyngeal carcinoma cells and relapsed/metastatic clinical samples exhibited increased IRAK1 phosphorylation and demonstrated that pacritinib could abolish the IRAK1 phosphorylation to suppress S100A9 expression. Functional studies in both in vitro and in vivo models showed that genetic or pharmacologic blockade of IRAK1 overcame the resistance to paclitaxel, and combined treatment of pacritinib with paclitaxel exhibited superior antitumor effect. Together, these findings demonstrate an important role for the IRAK1–S100A9 axis in mediating resistance to paclitaxel. Furthermore, targeting of IRAK1 by pacritinib may provide a novel therapeutic strategy to overcome chemoresistance in nasopharyngeal carcinoma.Significance:Deregulation of the IRAK1–S100A9 axis correlates with poor prognosis, contributes to chemoresistance in nasopharyngeal carcinoma, and can be targeted by pacritinib to overcome chemoresistance in nasopharyngeal carcinoma.

Background: This study aimed to investigate the efficiency and toxicities of concurrent chemoradiotherapy (CCRT) and induction chemotherapy (IC) followed by radiotherapy (RT) in different risk locoregionally advanced nasopharyngeal carcinoma (NPC). Methods: A total of 1814 eligible patients with stage II–IVB disease treated with CCRT or IC plus RT were included. The overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated using the Kaplan–Meier method, and the differences were compared using the log-rank test. Results: Nomograms were developed to predict OS, PFS and DMFS (C-index: 0.71, 0.70 and 0.71, respectively). Patients were then divided into three different risk groups based on the scores calculated by the nomogram for OS. In the low and intermediate-risk group, no significant survival differences were observed between patients treated with IC plus RT alone and CCRT (5-year OS, 97.3% versus 95.6%, p = 0.642 and 87.6% versus 89.7%, p = 0.381, respectively; PFS, 95.9% versus 95.6%, p = 0.325 and 87.6% versus 89.0%, p = 0.160, respectively; DMFS, 97.2% versus 94.8%, p = 0.339 and 87.2% versus 89.3%, p = 0.628, respectively). However, in the high-risk group, IC plus RT displayed an unfavorable 5-year OS (71.0% versus 77.2%, p = 0.022) and PFS (69.4.0% versus 75.4%, p = 0.019) compared with CCRT. A significantly higher incidence of grade 3 and 4 adverse events was documented in patients treated with CCRT than in those treated with IC plus RT in all risk groups ( p = 0.040). Conclusion: IC followed by RT represents an alternative treatment strategy to CCRT for patients with low and intermediate-risk NPC, but it is not recommended for patients with high-risk NPC.

Objective:In this study, we aimed to establish an integrated prognostic model for local recurrence nasopharyngeal carcinoma (lrNPC) patients, and evaluate the benefit of re-radiotherapy (RT) in patients with different risk levels.Materials and methods:In total, 271 patients with lrNPC were retrospectively reviewed in this study. Overall survival (OS) was the primary endpoint. Multivariate analysis was performed to select the significant prognostic factors (PResults:Three independent prognostic factors (age, relapsed T [rT] stage, and Epstein-Barr virus [EBV] DNA) were identified from multivariable analysis. Five prognostic groups were derived from an RPA model that combined rT stage and EBV DNA. After further pair-wise comparisons of survival outcome in each group, three risk groups were generated. We investigated the role of re-RT in different risk groups, and found that re-RT could benefit patients in the low (PConclusion:Age, rT stage and EBV DNA were identified as independent predictors for lrNPC. We established an integrated RPA-based prognostic model for OS incorporating rT stage and EBV DNA, which could guide individual treatment for lrNPC.

Objective: To compare the survival outcomes brought by different radiation dose schedules to bone lesions and different chemotherapy regimens in bone metastatic nasopharyngeal carcinoma (NPC). Background: The current treatment strategy for bone metastatic NPC patients was empirically given and poorly studied before. It is of necessity to optimize the treatment for bone metastasis to enhance the therapeutic effect and increase the proportion of long-term survived patients. Methods: Three hundred patients who received chemoradiotherapy from 2002 to 2018 were involved in the study. Demographics, laboratory results, and detailed treatment plans were recorded. Radiotherapy plans were classified into three categories based on the intensity, and the survival analysis was performed using log-rank test. Multivariable analysis was made by the Cox proportional regression model. Results: Patients who received 60–75 Gy/30–35 fractions of radiation to the metastatic bones had significantly longer bone relapse-free survival (BRFS) (HR, 0.53, 95% CI, 0.37–0.78, P = 0.003), overall survival (OS) (HR, 0.63, 95% CI, 0.46–0.84, P = 0.007), and progression-free survival (PFS) (HR, 0.80, 95% CI, 0.67–0.95, P = 0.041). The administration of paclitaxel, cisplatin and 5-fluorouracil regimen was also associated with better BRFS (HR, 0.27, 95% CI, 0.10–0.75, P = 0.007), PFS (HR, 0.60, 95% CI, 0.42–0.87, P = 0.007), and OS with borderline significance (HR, 0.54, 95% CI, 0.29–1.03, P = 0.058). In multivariable analysis, the post-treatment EBV DNA level and radical radiation dose were proved as independent prognostic factors for both BRFS and OS. Conclusions: Radiotherapy to metastatic bones with palliative dose prescription should not be considered in bone metastatic NPC patients. TPF chemotherapy regimen might help to improve the survivals in NPC patients but failed to be an independent protective factor.

Purpose The purpose of this study was to evaluate the long-term clinical outcome and toxicity of induction chemotherapy (IC) followed by concomitant chemoradiotherapy (CCRT) compared with CCRT alone for the treatment of children and adolescent locoregionally advanced nasopharyngeal carcinoma (LACANPC). Materials and methods A total of 194 locoregionally advanced nasopharyngeal carcinoma patients youngerthan 21 years who received CCRT with or without IC before were included in the study population. Overall survival (OS) rate, progression-free survival (PFS) rate, locoregional recurrence-free survival (LRFS) rate, and distant metastasis-free survival (DMFS) rate were assessed by the Kaplan-Meier method and a log-rank test. Treatment toxicities were clarified and compared between two groups. Results One hundred and thiry of 194 patients received IC+CCRT. Patients who were younger and with more advanced TNM stage were more likely to receive IC+CCRT and intensive modulated radiotherapy. The addition of IC before CCRT failed to improve survival significantly. The matched analysis identified 43 well-balanced patients in both two groups. With a median follow-up of 51.5 months, no differences were found between the IC+CCRT group and the CCRT group in 5-year OS (83.7% vs. 74.6%, p=0.153), PFS (79.2% vs. 73.4%, p=0.355), LRFS (97.7% vs. 88.2%, p=0.083), and DMFS (81.6% vs. 81.6%, p=0.860). N3 was an independent prognostic factor predicting poorer OS, PFS, and DMFS. The addition of IC was associated with increased rates of grade 3 to 4 neutropenia. Conclusion This study failed to demonstrate that adding IC before CCRT could provide a significant additional survival benefit for LACANPC patients. Further investigations are warranted.

Purpose: To directly compare the efficacy and acute toxicities of intensity-modulated radiotherapy (IMRT) concurrent with weekly cisplatin (40 mg/m2) to high-dose concurrent cisplatin (100 mg/m2) at three-week intervals. Materials and Methods: A total of 3,799 patients diagnosed with locally advanced nasopharyngeal carcinoma (NPC) at Sun Yat-Sen University Cancer Center between January 2010 and December 2013 were retrospectively reviewed. Propensity score analysis was conducted to balance the baseline characteristics between the groups, which allowed us to draw reliable conclusions. The efficacy and safety profiles were then assessed in the well-balanced large cohort. Results: The risk of distant metastasis was lower among the patients treated with weekly concurrent cisplatin than among those treated with the triweekly regimen (hazard ratio [HR], 0.45; P = .028). However, the disease-free survival, loco-regional relapse-free survival and overall survival rates were similar. The weekly group showed significantly higher rates of grade 3-4 thrombocytopenia, but lower rates of grade 3-4 mucositis, nausea and vomiting than the triweekly group. Conclusion: IMRT concurrent with a weekly cisplatin regimen was associated with significantly improved distant metastasis-free survival in locally advanced NPC. Differences in the selected acute toxicities between the weekly and triweekly concurrent cisplatin regimens were noted.

Background Due to the occult anatomic location of the nasopharynx and frequent presence of adenoid hyperplasia, the positive rate for malignancy identification during biopsy is low, thus leading to delayed or missed diagnosis for nasopharyngeal malignancies upon initial attempt. Here, we aimed to develop an artificial intelligence tool to detect nasopharyngeal malignancies under endoscopic examination based on deep learning. Methods An endoscopic images-based nasopharyngeal malignancy detection model (eNPM-DM) consisting of a fully convolutional network based on the inception architecture was developed and fine-tuned using separate training and validation sets for both classification and segmentation. Briefly, a total of 28,966 qualified images were collected. Among these images, 27,536 biopsy-proven images from 7951 individuals obtained from January 1st, 2008, to December 31st, 2016, were split into the training, validation and test sets at a ratio of 7:1:2 using simple randomization. Additionally, 1430 images obtained from January 1st, 2017, to March 31st, 2017, were used as a prospective test set to compare the performance of the established model against oncologist evaluation. The dice similarity coefficient (DSC) was used to evaluate the efficiency of eNPM-DM in automatic segmentation of malignant area from the background of nasopharyngeal endoscopic images, by comparing automatic segmentation with manual segmentation performed by the experts. Results All images were histopathologically confirmed, and included 5713 (19.7%) normal control, 19,107 (66.0%) nasopharyngeal carcinoma (NPC), 335 (1.2%) NPC and 3811 (13.2%) benign diseases. The eNPM-DM attained an overall accuracy of 88.7% (95% confidence interval (CI) 87.8%–89.5%) in detecting malignancies in the test set. In the prospective comparison phase, eNPM-DM outperformed the experts: the overall accuracy was 88.0% (95% CI 86.1%–89.6%) vs. 80.5% (95% CI 77.0%–84.0%). The eNPM-DM required less time (40 s vs. 110.0 ± 5.8 min) and exhibited encouraging performance in automatic segmentation of nasopharyngeal malignant area from the background, with an average DSC of 0.78 ± 0.24 and 0.75 ± 0.26 in the test and prospective test sets, respectively. Conclusions The eNPM-DM outperformed oncologist evaluation in diagnostic classification of nasopharyngeal mass into benign versus malignant, and realized automatic segmentation of malignant area from the background of nasopharyngeal endoscopic images.

Thus far, there is no final conclusion on the treatment of local recurrent nasopharyngeal carcinoma (lrNPC) patients. Herein, we developed a nomogram which combined prognostic biomarkers to predict clinical outcome and guide individual treatment.From 2006 to 2016, 303 patients with lrNPC were retrospectively reviewed. Overall survival (OS) was the primary endpoint. The nomogram was established with the significant prognostic factors (P 0.05) selected by multivariate analysis using Cox regression model. Harrell Concordance Index (C-index), calibration curves, and decision curve analysis (DCA) were applied to evaluate this model.Four independent prognostic factors (age, hypertension, relapsed T (rT) stage, and Epstein-Barr virus DNA) identified from multivariable analysis were included into the nomogram. The C-index of the nomogram was 0.687. The calibration curves for 1-, 3-, and 5-year OS rate showed satisfactory agreements between the predicted and actual values. The decision curve analysis also exhibited a preferable net benefit of this model. All patients were subdivided into three risk groups based on the nomogram. Local treatment was associated with higher OS than palliative chemotherapy alone in the low (P 0.001) and intermediate-risk groups (P = 0.001). However, no significant difference was observed between different treatment methods in the high-risk group (P = 0.176).We established the nomogram for patients with lrNPC to predict OS and guide individual treatment, which showed satisfactory performance in accuracy, discrimination capability, and clinical utility.