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Importance: Nedaplatin-based concurrent chemoradiotherapy (CCRT) regimen at 2 years was noninferior to cisplatin-based regimen in patients with locoregional, stage II to IVB nasopharyngeal carcinoma (NPC) and was associated with fewer late adverse events, but longer-term outcomes and toxicity are unclear., Objective: To evaluate the 5-year outcomes and late toxicity profile of nedaplatin-based CCRT in patients with locoregional, stage II to IVB NPC., Design, Settings, and Participants: This 5-year follow-up secondary analysis of an open-label, noninferiority, multicenter randomized clinical trial enrolled patients with nonkeratinizing stage II to IVB NPC between January 16, 2012, and July 16, 2014, with a median follow-up duration of 78 months (IQR, 3-99 months). Data analysis was conducted from November 10, 2020, to July 8, 2021., Interventions: Patients were randomly assigned (1:1) to receive nedaplatin (100 mg/m2)- or cisplatin (100 mg/m2)-based chemotherapy every 3 weeks for 3 cycles concurrently with intensity-modulated radiotherapy., Main Outcomes and Measures: The primary end point was progression-free survival (PFS). Secondary end points were overall survival, distant metastasis-free survival, and locoregional relapse-free survival., Results: A total of 402 eligible participants were enrolled (median [IQR] age, 45 [18-65] years; 302 [75.1%] male). Patients were randomly assigned to receive nedaplatin- or cisplatin-based CCRT (n = 201 for each): 196 patients (97.5%) started nedaplatin-based CCRT and 197 patients (98.0%) started cisplatin-based CCRT. Intention-to-treat analysis demonstrated a 5-year progression-free survival rate of 81.4% (95% CI, 75.9%-86.9%) for the cisplatin group and 79.8% (95% CI, 74.1%-85.5%) for nedaplatin group, with a difference of 1.6% (95% CI, -6.3% to 9.5%; P = .002 for noninferiority). No significant survival differences were observed between the cisplatin and nedaplatin groups for 5-year overall survival (89.4% vs 88.8%, P = .63), distant metastasis-free survival (85.9% vs 90.4%, P = .17), and locoregional relapse-free survival (92.6% vs 89.6%, P = .17) rates. The cisplatin group had a higher incidence of grade 3 and 4 auditory toxic effects than the nedaplatin group (35 [17.7%] vs 21 [10.5%], P = .04)., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, long-term analysis confirmed that nedaplatin-based CCRT could be regarded as an alternative doublet treatment strategy to cisplatin-based CCRT in stage II to IVB NPC., Trial Registration: ClinicalTrials.gov Identifier: NCT01540136.

Purpose: This study assessed the correlation between Epstein-Barr virus (EBV) biomarkers and the eighth American Joint Committee on Cancer staging system and the prognostic values of IgG antibodies against replication and transcription activator (Rta-IgG), IgA antibodies against Epstein-Barr nuclear antigen 1, and BamH1 Z transactivator (Zta-IgA) in locoregionally advanced nasopharyngeal carcinoma (NPC) patients., Materials and Methods: Serum EBV antibody levels were measured by enzyme-linked immunosorbent assay in 435 newly diagnosed stage III-IVA NPC patients administered intensity-modulated radiation therapy±chemotherapy. The primary endpoint was progression-free survival (PFS)., Results: Rta-IgG and Zta-IgA levels were positively correlated with the N category and clinical stage. Patients with high Rta-IgG levels (> 29.07 U/mL) showed a significantly inferior prognosis as indicated by PFS (77% vs. 89.8%, p=0.004), distant metastasis-free survival (DMFS) (88.3% vs. 95.8%, p=0.021), and local recurrence-free survival (LRFS) (91.2% vs. 98.3%, p=0.009). High Rta-IgG levels were also significantly associated with inferior PFS and LRFS in multivariable analyses. In the low-level EBV DNA group (≤ 1,500 copies/mL), patients with high Rta-IgG levels had significantly inferior PFS and DMFS (both p < 0.05). However, in the high-level EBV DNA group, Rta-IgG levels were not significantly associated with PFS, DMFS, and LRFS. In the advanced T category (T3-4) subgroup, high Rta-IgG levels were also significantly associated with inferior PFS, DMFS, and LRFS (both p < 0.05)., Conclusion: Rta-IgG and Zta-IgA levels were strongly correlated with the TNM classification. Rta-IgG level was a negative prognostic factor in locoregionally advanced NPC patients, especially those with advanced T category or low EBV DNA level.

Purpose: Previous studies suggest that a cumulative cisplatin dose of 200 mg/m 2 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/m 2 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/m 2 for two cycles or once-a-week cisplatin at 40 mg/m 2 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; P noninferiority = 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., (©2021 The Authors; Published by the American Association for Cancer Research.)

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<0.05). The addition of IC to CCRT was associated with survival improvement in OS, PFS, and DMFS in high-risk patients, while no survival difference was found between CCRT and IC+CCRT in low-risk patients., Conclusions: Our study can help clinicians select stage II-IVa NPC patients who benefit from IC, which is important in guiding individual treatment., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The tumor immune microenvironment has clinicopathological significance in predicting prognosis and therapeutic efficacy. We aimed to develop an immune signature to predict distant metastasis in patients with nasopharyngeal carcinoma (NPC)., Methods: Using multiplexed quantitative fluorescence, we detected 17 immune biomarkers in a primary screening cohort of 54 NPC tissues presenting with/without distant metastasis following radical therapy. The LASSO (least absolute shrinkage and selection operator) logistic regression model used statistically significant survival markers in the training cohort (n=194) to build an immune signature. The prognostic and predictive accuracy of it was validated in an external independent group of 304 patients., Results: Eight statistically significant markers were identified in the screening cohort. The immune signature consisting of four immune markers (PD-L1+ CD163+, CXCR5, CD117) in intratumor was adopted to classify patients into high and low risk in the training cohort and it showed a high level of reproducibility between different batches of samples (r=0.988 for intratumor; p<0.0001). High-risk patients had shorter distant metastasis-free survival (HR 5.608, 95% CI 2.619 to 12.006; p<0.0001) and progression-free survival (HR 2.798, 95% CI 1.498 to 5.266; p=0·001). The C-indexes which reflected the predictive capacity in training and validation cohort were 0.703 and 0.636, respectively. Low-risk patients benefited from induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) (HR 0.355, 95% CI 0.147 to 0.857; p=0·021), while high-risk patients did not (HR 1.329, 95% CI 0.543 to 3.253; p=0·533). To predict the individual risk of distant metastasis, nomograms with the integration of both immune signature and clinicopathological risk factors were developed., Conclusions: The immune signature provided a reliable estimate of distant metastasis risk in patients with NPC and might be applied to identify the cohort which benefit from IC+CCRT., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: This study aimed to elucidate the optimal cumulative cisplatin dose (CCD) for concurrent chemoradiotherapy (CCRT) according to the post-induction chemotherapy (IC) plasma Epstein-Barr virus (EBV) DNA level., Results: EBV DNA was detected and undetected in 179 and 370 patients, respectively. Of the entire cohort, 73/549 (13.3%) patients received a total CCD ≥ 160 mg/m 2 and 476/549 (86.7%) patients, <160 mg/m 2 . CCD enhancement was not associated with a survival benefit in patients with undetected EBV DNA after IC. However, among patients with post-IC detectable EBV DNA, higher 3-year PFS and locoregional relapse-free survival (LRFS) rates were observed in those who received a CCD ≥ 160 mg/m 2 . Multivariate analysis also showed CCD was an independent prognostic factor for PFS and LRFS in patients with post-IC detectable EBV DNA., Conclusions: CCD enhancement was not associated with a survival benefit in patients with undetected EBV DNA after IC. However, among patients with post-IC detectable EBV DNA, those receiving ≥160 mg/m 2 CCD showed significantly improved 3-year PFS and LRFS., Methods: NPC patients (549) treated with IC and CCRT were included. Prognosis was assessed using a multivariate Cox proportional hazards model. Furthermore, grade 1-4 toxicities were compared between different CCD groups.

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 < .001). Compared with low-level EBV DNA and non-CNN grouping, high-level EBV DNA and CNN grouping had poor PFS. The combined classification was an independent prognostic factor for OS (P < .001), PFS (P = .001), and DMFS (P = .018). Pretreatment plasma EBV DNA level and CNN status both closely correlated with prognosis of NPC patients in the IMRT era. Combined EBV DNA level and CNN status improves risk stratification and prognostic value., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: We aim to examine nasopharyngeal carcinoma (NPC) characteristics and survival outcomes in patients aged 70 years and older in the intensity-modulated radiotherapy (IMRT) era., Methods and Materials: From 2006 to 2013, 126 non-metastatic NPC patients aged ≥ 70 years who were treated with IMRT +/‒ chemotherapy were included. Adult Comorbidity Evaluation 27 (ACE-27) was used to measure patient comorbidities. The overall survival (OS) and cancer-specific survival (CSS)were calculatedwith the Kaplan-Meier method, and differenceswere compared using the log-rank test. The Cox proportional hazards model was used to carry out multivariate analyses., Results: For the entire group, only two patients (1.6%) presented stage I disease, and up to 84.1% patients had stage III-IVB disease. All patients had a comorbidity score of 0 in 24 (19.0%), 1 in 45 (35.7%), 2 in 42 (33.3%), and 3 in 15 (11.9%) patients. The main acute grade during radiotherapy was 3-4 adverse events consisting of mucositis (25.4%), bone marrow suppression (16.7%), and dermatitis (8.7%). After treatment, four patients (3.2%) developed temporal lobe injury. Five-year CSS and OS rates were 67.3% (95% confidence interval [CI], 58.6% to 77.4%) and 54.0% (95% CI, 45.6% to 63.9%), respectively. Five-year OS was significantly higher for ACE-27 score 0-1 than ACE-27 score 2-3 (72.9% and 39.9%, respectively; p < 0.001). Multivariate analyses showed ACE-27 score 0-1 was significantly associated with superior OS (hazard ratio [HR], 3.02; 95% CI, 1.64 to 5.55; p < 0.001). In addition, the rate of OS was higher for stage I-III than that of stage IV, with borderline significance (HR, 1.67; 95% CI, 0.99 to 2.82; p=0.053). But no significant advantage was observed in OS when chemotherapy was used (p > 0.05)., Conclusion: Our findings suggest IMRT +/- chemotherapy has a manageable toxicity and provides an acceptable survival in patients aged ≥ 70 years with NPC. ACE-27 score was significantly associated with survival outcomes in this group population.

Purpose: To evaluate the efficacy of induction chemotherapy in the treatment of stage II nasopharyngeal carcinoma (NPC) in era of intensity modulated radiotherapy (IMRT)., Methods and Materials: A total of 173 patients with American Joint Committee on Cancer (AJCC) 7th stage II NPC from two institutions were included. All patients were divided into two groups: induction chemotherapy + concurrent chemoradiotherapy group (ICRT) group and concurrent chemoradiotherapy group (CCRT). Induction chemotherapy was consisted of one to three cycles of cisplatin plus fluorouracil (PF) or paclitaxel plus cisplatin (TP). Concurrent chemotherapy included one to three cycles of cisplatin. We retrospectively assessed overall survival (OS), progression-free survival (PFS), locoregional failure free survival (LRFFS) and distant metastasis free survival (DMFS) in patients of both groups. T-test, Chi-square test, Kaplan-Meier methodology and Cox proportional hazards model were used to analyze., Results: With a median follow up of 64.7 months, no significant difference was found in grade 3-4 hematologic toxicity, liver dysfunction and renal impairment between ICRT and CCRT group. Univariable analyses shown adding induction chemotherapy to CCRT significantly decreased 5-year OS (87.9% vs 95.5%, P = 0.033), 5-year PFS (74.0% vs 86.1%, P = 0.035), 5-year LRFFS (80.0% vs 91.2%, P = 0.016), but there was no statistically significant difference in 5-year DMFS (87.1% vs 94.7%, P = 0.095). In multivariable analyses, we found the consistent results that induction chemotherapy was a negative factor associated with OS (HR of death = 3.768, 95% CI = 1.117-12.709; P = 0.032), PFS (HR of progression = 2.156, 95% CI = 1.060-4.386; P = 0.034), LRFFS (HR of locoregional relapse = 2.435, 95% CI = 1.009-5.874; P = 0.048) and also DMFS (HR of metastasis = 2.873, 95% CI = 1.005-8.211; P = 0.049), in stage II NPC patients., Conclusion: In present study, we found that induction chemotherapy caused deleterious effect on stage II NPC patients. However, this is a retrospective study and the adverse effects of induction chemotherapy has not been previously reported. It warrants further investigation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: CLCA2 was reported as a tumor suppressor and disregulated in breast cancer. However, its function in tumor growth and metastasis in NPC has rarely been reported. In this study, we investigated the functional and molecular mechanisms by which CLCA2 influences NPC., Methods: CLCA2 expression in human NPC cell lines and tissues was examined via real-time PCR (RT-PCR), Western blot and IHC. The biological roles of CLCA2 in proliferative, migration and invasion of NPC cell lines was evaluated in 5-8F, S18, S26 and SUNE-1 cells. Cell viability, migration and invasion were assessed in vitro by MTS, colony formation and transwell assay, respectively. CLCA2 in growth and metastasis of NPC were evaluated in vivo through NPC xenograft tumor growth, lung metastatic mice model and popliteal lymph node (LN) metastasis model., Results: Overexpression of CLCA2 significantly decreased proliferation, migration and invasion of NPC cells. In contrast, knockdown of CLCA2 elicited the opposite effects. CLCA2 overexpression suppressed xenograft tumor growth and lung, popliteal lymph node (LN) metastasis in vivo. CLCA2 inhibited tumor metastasis through suppressing epithelial-Mesenchymal transition (EMT) and in-activating FAK/ERK1/2 signaling pathway in NPC cells. Immunohistochemical staining of 143 NPC samples revealed that CLCA2 expression was an independent, favorable prognostic factor for overall survival and distant metastasis-free survival of patients. In addition, inhibition of FAK and ERK1/2 reversed CLCA2 silencing-induced tumor cell migration. Furthermore, inhibitors against chloride channels suppressed NPC cellular migration which could have been enhanced by the presence of CLCA2., Conclusion: CLCA2 suppress NPC proliferation, migration, invasion and epithelial-mesenchymal transition through inhibiting FAK/ERK signaling.

Objectives: The aim of this study was to compare the metastatic patterns of synchronous bone metastasis (SBM) and metachronous bone metastasis (MBM) in nasopharyngeal carcinoma (NPC). Methods: This study included bone metastases in NPC patients from 2005 to 2016 in a Chinese hospital. Cohort 1 was collected from 2005 to 2010 for discovery, and Cohort 2 from 2011 to 2016 for validation. The chi‐squared test, Wilcoxon rank sum test, and Kaplan–Meier technique were used to compare site, time, and survival between cohorts 1 and 2. Prognostic factors were analyzed using univariate or multivariate Cox regression. Results: Cohort 1 had 112 individuals with SBM and 394 with MBM, and cohort 2 had 328 with SBM and 307 with MBM. The thoracic vertebra was the most frequently affected site of metastasis. Patients with SBM more often had metastasis to the cervical vertebrae compared with patients with MBM (34.5% vs. 22.3%, p < 0.05). Patients with SBM had better overall survival (42.2 months, 95% CI: 33.9–50.7) than patients with MBM (24.9 months, 95% CI: 22.2–28.7). Age at bone metastasis detection, metastasis to other organs, and more bone metastasis locations were associated with worse prognosis. The majority of MBMs occurred at 7 to 18 months after NPC diagnosis. Conclusion: Radiotherapy does not modify the metastatic patterns of NPC bone metastases. Patients with SBM tend to have metastasis to the cervical vertebra, which is close to the nasopharynx. Paying more attention to bone metastases during follow‐up in the first 2 years after an NPC diagnosis. [ABSTRACT FROM AUTHOR]

Purpose: Radiotherapy is the most important primary treatment for patients with nasopharyngeal carcinoma. Generally, the treatment duration of radiotherapy takes six or six and half weeks with 30 to 33 fractions. The current study was conducted to evaluate the association between prognosis and the duration of radiotherapy in nasopharyngeal carcinoma patients. Methods: Patients with primary nasopharyngeal carcinoma who were treated with intensity-modulated radiotherapy and concurrent cisplatin-based chemotherapy, with or without induction chemotherapy between January, 2008 and December, 2013 at a single institution were retrospectively reviewed. Results: In total, 1292 patients were included. At a median follow-up of 71.0 months (range 2.0–126.0 months), locoregional recurrence, distant failure and death were observed in 8.8%, 12.2% and 15.6% of all patients, respectively. Estimated 5-year locoregional relapse–free survival, distant metastasis–free survival, progression-free survival and overall survival in patients with radiation ≤ 7 weeks versus patients with radiation >7 weeks were: 93.2% versus 87.0% (P < 0.001), 89.4% versus 84.4% (P = 0.016), 79.8% versus 70.6% (P < 0.001) and 87.2% versus 78.4% (P < 0.001), respectively. Conclusions: Prolonged duration of radiotherapy with a significantly higher risk of distant metastasis and death in nasopharyngeal carcinoma patients. Understanding this point, healthcare providers should make efforts to avoid prolonged duration of radiotherapy to minimize the risk of treatment failure. [ABSTRACT FROM AUTHOR]

Purpose: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

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 [18F]‐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<0.05). The addition of IC to CCRT was associated with survival improvement in OS, PFS, and DMFS in high‐risk patients, while no survival difference was found between CCRT and IC+CCRT in low‐risk patients. Conclusions: Our study can help clinicians select stage II–IVa NPC patients who benefit from IC, which is important in guiding individual treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To evaluate the prognostic value of serum endostatin levels in patients with advanced-stage nasopharyngeal carcinoma (NPC). Materials and methods: Between August 2003 and March 2005, 218 patients with advanced-stage NPC were enrolled in this study, including 70 patients in the training cohort and 148 in the validation cohort. The pre-treatment serum endostatin and vascular endothelial growth factor (VEGF) levels were measured using competitive enzyme immunoassays. For the normal control, serums samples from 20 healthy individuals were also collected. Results: Serum endostatin levels in the patients with advanced-stage NPC were significantly higher than those of controls, but VEGF levels were similar in the two groups. Univariate analysis revealed significant differences between the high and low endostatin level groups regarding 5 year overall survival (63.9% versus 90.5%; P = 0.003), progression-free survival (PFS) (50.2% versus 79.3%; P = 0.003) and distant metastasis-free survival (DMFS) (59.1% versus 85.3%; P = 0.01) in the training cohort. Using the same cut-off value generated from the training cohort, there were also significant unfavourable correlations between serum endostatin levels and overall survival (P = 0.001), PFS (P = 0.001) and DMFS (P = 0.002) in the second independent validation cohort. Multivariate analysis using the entire group (n = 218) revealed that the serum endostatin level was an independent unfavourable prognostic factor for overall survival (hazard ratio 4.8; 95% confidence interval 2.48–9.23; P < 0.0001), PFS (hazard ratio 3.44; 95% confidence interval 2.06–5.74; P < 0.0001) and DMFS (hazard ratio 3.65; 95% confidence interval 1.92–6.94; P < 0.0001) in patients with advanced-stage NPC. No associations were observed between the outcomes and the serum VEGF levels in patients with advanced-stage NPC. Conclusions: High endostatin levels are associated with poor survival and this knowledge may improve the risk stratification of patients with advanced-stage NPC. [Copyright &y& Elsevier]

Background Endoscopic nasopharyngectomy is a new salvage treatment for locally recurrent nasopharyngeal carcinoma (NPC). However, how to resurface the nasopharyngeal defects in endoscopic endonasal approaches to avoid persistent postoperative headache, to the best of our knowledge, has not been reported. Methods From September 2009 to August 2010, we used a modified posterior pedicle nasal septum and floor mucoperiosteum flap (nasal septum and floor flap, NSFF) after endoscopic nasopharyngectomy in 12 patients with locally recurrent NPC. Most of the nasal septum and floor mucoperiosteum, except for the posterior pedicle, was harvested to cover the nasopharyngeal defects. Results All NSFFs successfully covered the entire nasopharyngeal defects and relined the nasopharynx with good functional recovery. The nasopharyngeal wounds recovered in 28 days (range, 14 to 56 days), and the donor-site wounds recovered in 46.5 days (range, 24-84 days). No reconstruction-related complications or disease recurrences were observed. Conclusion The NSFF is a safe and promising reconstructive option to resurface the nasopharyngeal defect after endoscopic nasopharyngectomy in patients with locally recurrent NPC. © 2011 Wiley Periodicals, Inc. Head Neck, 2011 [ABSTRACT FROM AUTHOR]

• From 1990 to 2016, the smoking rate of patients showed a downward trend, while the overall survival improved over time. • The 5-year OS rates in the entire cohort were 76.4%, 68.9%, and 79.8% in the former, current, and never smokers. • In the multivariate analysis of the IMRT cohort, the risk of death and metastasis was higher in the current smokers. • Heavy smoking increases the risk of death and metastasis. 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. [ABSTRACT FROM AUTHOR]

• A total of 531 patients with local recurrence nasopharyngeal carcinoma (lrNPC) were retrospectively reviewed. • We established and validated an integrated prognostic model for lrNPC patients. • Three risk groups were derived from an RPA model that combined rT stage and EBV DNA. • Re-radiotherapy could benefit patients in the low and intermediate-risk subgroups. • No association between re-RT and survival benefit was found in the high-risk. subgroup. In this study, we aimed to establish and validate an integrated prognostic model for locally recurrent nasopharyngeal carcinoma (lrNPC) patients, and evaluate the benefit of re-radiotherapy (re-RT) in patients with different risk levels. In total, 531 patients with lrNPC were retrospectively reviewed in this study, including 271 patients from 2006 to 2012 as the training cohort and 260 patients from 2013 to 2016 as the validation cohort. Overall survival (OS) was the primary endpoint. Multivariate analysis was performed to select the significant prognostic factors (P < 0.05). A prognostic model for OS was derived by recursive partitioning analysis (RPA) combining independent predictors using the algorithm of optimized binary partition. Three independent prognostic factors (age, relapsed T [rT] stage, and Epstein-Barr virus [EBV] DNA) were identified from multivariate 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 (P < 0.001) and intermediate-risk subgroups (P = 0.017), while no association between re-RT and survival benefit was found in the high-risk subgroup (P = 0.328). The results of risk stratification and re-RT efficacy were verified in the validation cohort. 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. [ABSTRACT FROM AUTHOR]

• The combination of nab-paclitaxel, cisplatin and capecitabin (TPC) as induction chemotherapy followed by cisplatin concurrent chemoradiotherpay showed good tolarance and anti-tumor effecacy in patients with advanced nasopharyngeal carcinoma. • The MTD of nab-paclitaxel is 225 mg/m2, that combined with cisplatin and capecitabine as induction chemotherapy, followed by concurrent chemoradiotherapy. • The RP2D of nab-paclitaxel is 200 mg/m2. Nab-paclitaxel is a promising albumin-bound paclitaxel with a therapeutic index superior to that of docetaxel, but the optimal dose of nab-paclitaxel combined with cisplatin and capecitabine as induction chemotherapy followed by concurrent chemoradiotherapy for patients with locally advanced nasopharyngeal carcinoma remains unknown. This was an open-label, single-arm study investigating the safety and efficacy of nab-paclitaxel + cisplatin + capecitabin as IC for three cycles, followed by cisplatin CCRT, conducted by using the standard "3 + 3" design in LA-NPC. If more than one-third of the patients in a cohort experienced dose-limiting toxicity (DLT), the dose used in the previous cohort was designated the maximum tolerated dose (MTD). The recommended phase 2 dose (RP2D) was defined as one level below the MTD. From 29 May 2021 to 17 March 2022, 19 patients with LA-NPC were enrolled, one patient withdrew informed consent. Two DLTs occurred in cohort 4 (grade 4 febrile neutropenia and grade 3 peripheral neuropathy), and an MTD was established as 225 mg/m2. The most frequent grade 3 or 4 adverse events were neutropenia (16.7 %), hypertriglyceridemia (16.7 %), leukopenia (5.6 %) and peripheral neuropathy (5.6 %) during IC. The RP2D is nab-paclitaxel 200 mg/m2 on day 1, combined with cisplatin 75 mg/mg2 on day 1 and capecitabin1000 mg/m2 on days 1–14, twice a day, every 3 weeks, for three cycles as an IC regimen prior to CCRT. Trial registration: ClinicalTrials.gov Identifier: NCT04850235. [ABSTRACT FROM AUTHOR]

Radiotherapy-related toxicities of nasopharyngeal carcinoma (NPC) caused by a standard dose of 70 Gy remain a critical issue. Therefore, we assessed whether a radiotherapy dose of 60 Gy was non-inferior to the standard dose in patients with low-risk stage III NPC with a favourable response to induction chemotherapy (IC). We did a single-arm, single-centre, phase II clinical trial in China. Patients with low-risk (Epstein-Barr virus [EBV] DNA level <4000 copies/ml) stage III NPC were treated with two cycles IC. Patients with complete/partial response and undetectable EBV DNA level were assigned 60 Gy intensity-modulated radiotherapy concurrently with three cycles of cisplatin. The primary end-point was 2-year progression-free survival (PFS). This trial is registered with ClinicalTrials.gov , number NCT 03668730. One patient quit because of withdrawal of informed consent after IC. In total, 215 patients completed two cycles of IC, after which 116 (54.0%) and 99 (46.0%) patients were assigned 60 and 70 Gy radiotherapy, respectively. For 215 patients, the 2-year PFS was 90.7% (95% CI, 86.8%–94.6%) with a median follow-up of 43.9 months (interquartile range [IQR], 39.8–46.2). For patients treated with 60 Gy radiotherapy, the 2-year PFS rate was 94.8% (95%CI 90.7%–98.9%) with a median follow-up of 43.9 months (IQR 40.2–46.2). The most common late toxicity was grade 1–2 dry mouth (incidence rate: 54.3%). No grade 3+ long-term adverse event was observed, and most quality-of-life items, domains, and symptom scores returned to baseline by 6 months. Reduced-dose radiation (60 Gy) is associated with favourable survival outcomes and limited treatment-related toxicities in patients with low-risk stage III NPC sensitive to IC. • A total of 216 patients with low-risk stage III NPC were enroled in this study. • One hundred and sixteen patients had CR/PR and undetectable EBV DNA after IC. • Sixty Gy RT is non-inferior to the 70 Gy RT in low-risk stage III NPC. • No grade 3+ long-term adverse event was found in 60 Gy cohort. • The 2-year PFS rate of the whole cohort was 90.7%. [ABSTRACT FROM AUTHOR]

The safety and objective clinical responses were observed in the phase I study using adjuvant autologous tumour-infiltrating lymphocytes (TILs) following concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients. One hundred fifty-six patients with stage III–IVb and pretreatment Epstein–Barr virus DNA levels of ≥4000 copies/ml were randomly assigned to receive CCRT combined with TIL infusion (n = 78) or CCRT alone (n = 78). All patients received CCRT and patients assigned to the TIL group received TIL infusion within 1 week after CCRT. The primary endpoint was investigator-assessed progression-free survival (PFS) at 3 years. After a median follow-up of 62.3 months, no significant difference was observed in the 3-year PFS rate between the CCRT plus TIL infusion group and CCRT alone group (75.6% versus 74.4%, hazard ratios, 1.08; 95% confidence intervals, 0.62–1.89). TIL infusion was safe without grade 3 or 4 adverse events and all the high-grade adverse effects were associated with myelosuppression caused by CCRT. Exploratory analysis showed that a potential survival benefit was observed with TILs in patients with lower levels of circulating CD8+TIM3+ cells, serum IL-8 or PD-L1. The infused TIL products in patients with favourable outcomes were associated with increased transcription of interferon-γ and a series of inflammatory related genes and a lower exhausted score. The primary objective of prolonging PFS with CCRT plus TILs in high-risk NPC patients was not met. These findings may provide evidence for the design of future trials investigating the combination of TILs plus immune checkpoint inhibitors based on CCRT in high-risk NPC patients. NCT02421640 • Adoptive immunotherapy with autologous TILs following CCRT was safe. • Additional TIL infusion does not improve PFS in high-risk NPC patients. • A potential survival benefit was observed with CCRT plus TILs in selected patients. • Provide evidence for trials investigating the TILs plus immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Summary: The aim of this randomized study was to compare the efficacy of induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) versus induction chemotherapy plus radiotherapy (IC+RT) for patients with locoregionally advanced nasopharyngeal carcinoma. From August 2002 to April 2005, 408 patients were randomly divided into two groups: an IC+CCRT group and an IC+RT group. Patients in both groups received the same induction chemotherapy: two cycles of floxuridine (FuDR)+carboplatin (FuDR, 750mg/m2, d1-5; carboplatin, area under the curve [AUC]=6). The patients received radiotherapy 1week after they finished the induction chemotherapy. The patients in the IC+CCRT group also received carboplatin (AUC=6) on days 7, 28, and 49 of radiotherapy. Eight patients did not meet the inclusion criteria, and the remaining 400 cases were analyzed. Grade III or IV toxicity was found in 28.4% of the patients in the IC+CCRT group and 13.1% of those in the IC+RT group (P <.001). Five-year overall survival rates were 70.3% and 71.7% (P =0.734) in the IC+CCRT and IC+RT groups, respectively. No significant differences in failure-free survival, locoregional control, and distant control were found between the two groups. Compared with the IC+RT program, the IC+CCRT program used in the present study did not improve the overall survival and failure-free survival in patients with locoregionally advanced nasopharyngeal carcinoma. Using carboplatin in the concurrent chemoradiotherapy was not suitable for nasopharyngeal carcinoma. [Copyright &y& Elsevier]

Objective: 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.Materials and Methods: 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.Results: 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).Conclusion: 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. [ABSTRACT FROM AUTHOR]