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Importance: Concurrent chemoradiotherapy has been the standard treatment for stage II nasopharyngeal carcinoma (NPC) based on data using 2-dimensional conventional radiotherapy. There is limited evidence for the role of chemotherapy with use of intensity-modulated radiation therapy (IMRT).Objective: To assess whether concurrent chemotherapy can be safely omitted for patients with low-risk stage II/T3N0 NPC treated with IMRT.Design, Setting, and Participants: This multicenter, open-label, randomized, phase 3, noninferiority clinical trial was conducted at 5 Chinese hospitals, including 341 adult patients with low-risk NPC, defined as stage II/T3N0M0 without adverse features (all nodes <3 cm, no level IV/Vb nodes; no extranodal extension; Epstein-Barr virus DNA <4000 copies/mL), with enrollment between November 2015 and August 2020. The final date of follow-up was March 15, 2022.Interventions: Patients were randomly assigned to receive IMRT alone (n = 172) or concurrent chemoradiotherapy (IMRT with cisplatin, 100 mg/m2 every 3 weeks for 3 cycles [n = 169]).Main Outcomes and Measures: The primary end point was 3-year failure-free survival (time from randomization to any disease relapse or death), with a noninferiority margin of 10%. Secondary end points comprised overall survival, locoregional relapse-free survival, distant metastasis-free survival, adverse events, and health-related quality of life (QOL) measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference ≥10 for physical function, symptom control, or health-related QOL; higher score indicates better functioning and global health status or worse symptoms).Results: Among 341 randomized patients (mean [SD] age, 48 [10] years; 30% women), 334 (98.0%) completed the trial. Median follow-up was 46 months (IQR, 34-58). Three-year failure-free survival was 90.5% for the IMRT-alone group vs 91.9% for the concurrent chemoradiotherapy group (difference, -1.4%; 1-sided 95% CI, -7.4% to ∞; P value for noninferiority, <.001). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. The IMRT-alone group experienced a significantly lower incidence of grade 3 to 4 adverse events (17% vs 46%; difference, -29% [95% CI, -39% to -20%]), including hematologic toxicities (leukopenia, neutropenia) and nonhematologic toxicities (nausea, vomiting, anorexia, weight loss, mucositis). The IMRT-alone group had significantly better QOL scores during radiotherapy including the domains of global health status, social functioning, fatigue, nausea and vomiting, pain, insomnia, appetite loss, and constipation.Conclusions and Relevance: Among patients with low-risk NPC, treatment with IMRT alone resulted in 3-year failure-free survival that was not inferior to concurrent chemoradiotherapy.Trial Registration: ClinicalTrials.gov Identifier: NCT02633202. [ABSTRACT FROM AUTHOR]

Background: Induction chemotherapy (IC) followed by concurrent chemoradiotherapy is the mainstay treatment for patients with locoregionally advanced nasopharyngeal carcinoma. However, some patients obtain little benefit and experience unnecessary toxicities from IC. We intended to develop a gene-expression signature that can identify beneficiaries of IC.Methods: We screened chemosensitivity-related genes by comparing gene-expression profiles of patients with short-term tumor response or nonresponse to IC (n = 95) using microarray analysis. Chemosensitivity-related genes were quantified by digital expression profiling in a training cohort (n = 342) to obtain a gene signature. We then validated this gene signature in the clinical trial cohort (n = 187) and an external independent cohort (n = 240). Tests of statistical significance are 2-sided.Results: We identified 43 chemosensitivity-related genes associated with the short-term tumor response to IC. In the training cohort, a 6-gene signature was developed that was highly accurate at predicting the short-term tumor response to IC (area under the curve [AUC] = 0.87, sensitivity = 87.5%, specificity = 75.6%). We further found that IC conferred failure-free survival benefits only in patients in the benefit group (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.34 to 0.87; P = .01) and not on those in the no-benefit group (HR = 1.25, 95% CI = 0.62 to 2.51; P = .53). In the clinical trial cohort, the 6-gene signature was also highly accurate at predicting the tumor response (AUC = 0.82, sensitivity = 87.5%, specificity = 71.8%) and indicated failure-free survival benefits. In the external independent cohort, similar results were observed.Conclusions: The 6-gene signature can help select beneficiaries of IC and lay a foundation for a more individualized therapeutic strategy for locoregionally advanced nasopharyngeal carcinoma patients. [ABSTRACT FROM AUTHOR]

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

Background and Purpose: Evidence for induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) in nasopharyngeal carcinoma (NPC) was derived from landmark clinical trials excluding the T3N0, T3N1, T4N0 subgroups. This study used Epstein-Barr virus (EBV) DNA to select IC beneficiaries from the three subgroups. Materials and Methods: Significant predictors of overall survival (OS) were identified using multivariate Cox analyses. Risk stratification was generated using recursive partitioning analysis (RPA). IC+CCRT was compared with CCRT in each risk stratification and in different subgroups. Individual-level data from a clinical trial (NCT01245959) was used for validation. Results: Gender and EBV DNA were included in RPA-generated risk stratification, categorizing patients into low-risk (EBV DNA <2,000 copies/mL; female and EBV DNA ≥2,000 copies/mL) and high-risk groups (male and EBV DNA ≥2,000 copies/mL). The OS superiority of IC+CCRT over CCRT was only observed in the high-risk group (HR = 0.64, 95% CI = 0.43–0.97; P = 0.032). Subgroup analysis indicated the OS benefit was exclusively from the docetaxel–cisplatin−5-fluorouracil regimen (HR = 0.41, 95% CI = 0.22–0.78; P = 0.005). The status of the T3N1 subgroup as an IC beneficiary is more explicit than the T3N0 and T4N0 subgroups. IC+CCRT showed improved OS in the validation cohort combining high-risk cases of real-world data with clinical trial data (HR = 0.62, 95% CI = 0.42–0.94; P = 0.023). Conclusion: Patients with high-risk T3N1 NPC is the definite target population for receiving IC+CCRT in real-world practice. T3N0 and T4N0 subgroups need further investigations in future IC-related studies. [ABSTRACT FROM AUTHOR]

Objective: Twelve weeks after radiotherapy is the recommended time-point for assessing tumor response in nasopharyngeal carcinoma (NPC); however, regression after 12 weeks remains unclear. We explored NPC regression and the prognosis of patients with delayed clinical complete response (cCR).Materials and Methods: MRI images of 556 NPC patients treated with intensity-modulated radiotherapy (IMRT) between 2009 and 2012 were retrospectively reviewed. Clinical tumor response was assessed at 3-4 (assessment 1) and 6-9 months (assessment 2) after IMRT, and survival rates were compared.Results: Of the 556 patients, 463 (83.3%) had cCR at assessment 1 (early cCR). Of the 93 patients with partial response at assessment 1, 45 (48.4%) achieved cCR at assessment 2 (delayed cCR), and 48 did not have cCR at assessment 2 (non-cCR). Locoregional failure rate was lower in patients with a cCR than those without a cCR at assessment 1 (7.1% vs. 26.9%, P < .001) and assessment 2 (7.1% vs. 45.8%, P < .001). Multivariate analysis showed cCR was a favorable prognostic factor for locoregional failure-free survival (LRFFS), failure-free survival (FFS), and overall survival (OS). Early and delayed cCR groups had better 5-year LRFFS (92.6% vs. 93.3% vs. 54.2%), FFS (83.8% vs. 84.4% vs. 48.5%) and OS (92.1% vs. 90.6% vs. 65.4%) than the non-cCR group (all P < .001).Conclusions: Nearly half of the patients with partial response at 3-4 months achieve cCR by 6-9 months; delayed cCR is not a poor prognosticator. We suggest later assessment of cCR at 6-9 months after IMRT is acceptable in responding NPC. [ABSTRACT FROM AUTHOR]

Background: Tumor response to neoadjuvant chemotherapy using the regimen of cisplatin and 5-fluorouracil could define high-risk patients with locoregionally advanced nasopharyngeal carcinoma (NPC). However, the regimen of docetaxel, cisplatin, and 5-fluorouracil (TPF) appears to be more effective than the regimen of cisplatin and 5-fluorouracil. Therefore, one needs to redefine the high-risk subpopulation of patients receiving neoadjuvant chemotherapy with TPF.Methods: A total of 231 patients from a randomized phase 3 trial with American Joint Committee on Cancer/International Union Against Cancer stage III to stage IVB NPC (except T3-T4N0 disease) who were receiving treatment with the TPF regimen were enrolled. Patient survival rates between different groups were compared.Results: Of the 231 patients, the overall response to neoadjuvant chemotherapy was a complete response (CR) for 26 (11.3%), a partial response (PR) for 184 patients (79.6%), and stable disease (SD) for 21 patients (9.1%). Univariate analysis revealed the 3-year failure-free survival (FFS) rates in the CR (88.5% vs 61.9%; P =.017) and PR (81.2% vs 61.9%; P = .01) groups, and the 3-year overall survival rates for the CR (96.2% vs 76.2%; P =.048) and PR (93.4% vs 76.2%; P =.025) groups were obviously higher compared with that of the SD group. In multivariate analysis, CR was established as a favorable prognostic factor for FFS (hazard ratio [HR], 0.210; 95% confidence interval [95% CI], 0.057-0.779 [P =.02]), and PR for FFS (HR, 0.447; 95% CI, 0.213-0.936 [P =.033]) and OS (HR, 0.361; 95% CI, 0.132-0.986 [P =.047]) when compared with SD. No survival difference was observed between the CR and PR groups.Conclusions: Tumor response to TPF may be a properly powerful prognosis predictor and help to develop individualized treatment strategies for patients with locoregionally advanced NPC. Cancer 2017;123:1643-1652. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The value of adding cisplatin, fluorouracil, and docetaxel (TPF) induction chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma is unclear. We aimed to compare TPF induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone in a suitably powered trial.Methods: We did an open-label, phase 3, multicentre, randomised controlled trial at ten institutions in China. Patients with previously untreated, stage III-IVB (except T3-4N0) nasopharyngeal carcinoma, aged 18-59 years without severe comorbidities were enrolled. Eligible patients were randomly assigned (1:1) to receive induction chemotherapy plus concurrent chemoradiotherapy or concurrent chemoradiotherapy alone (three cycles of 100 mg/m2 cisplatin every 3 weeks, concurrently with intensity-modulated radiotherapy). Induction chemotherapy was three cycles of intravenous docetaxel (60 mg/m2 on day 1), intravenous cisplatin (60 mg/m2 on day 1), and continuous intravenous fluorouracil (600 mg/m2 per day from day 1 to day 5) every 3 weeks before concurrent chemoradiotherapy. Randomisation was by a computer-generated random number code with a block size of four, stratified by treatment centre and disease stage (III or IV). Treatment allocation was not masked. The primary endpoint was failure-free survival calculated from randomisation to locoregional failure, distant failure, or death from any cause; required sample size was 476 patients (238 per group). We did efficacy analyses in our intention-to-treat population. The follow-up is ongoing; in this report, we present the 3-year survival results and acute toxic effects. This trial is registered with ClinicalTrials.gov, number NCT01245959.Findings: Between March 1, 2011, and Aug 22, 2013, 241 patients were assigned to induction chemotherapy plus concurrent chemoradiotherapy and 239 to concurrent chemoradiotherapy alone. After a median follow-up of 45 months (IQR 38-49), 3-year failure-free survival was 80% (95% CI 75-85) in the induction chemotherapy plus concurrent chemoradiotherapy group and 72% (66-78) in the concurrent chemoradiotherapy alone group (hazard ratio 0·68, 95% CI 0·48-0·97; p=0·034). The most common grade 3 or 4 adverse events during treatment in the 239 patients in the induction chemotherapy plus concurrent chemoradiotherapy group versus the 238 patients in concurrent chemoradiotherapy alone group were neutropenia (101 [42%] vs 17 [7%]), leucopenia (98 [41%] vs 41 [17%]), and stomatitis (98 [41%] vs 84 [35%]).Interpretation: Addition of TPF induction chemotherapy to concurrent chemoradiotherapy significantly improved failure-free survival in locoregionally advanced nasopharyngeal carcinoma with acceptable toxicity. Long-term follow-up is required to determine long-term efficacy and toxicities.Funding: Shenzhen Main Luck Pharmaceuticals Inc, Sun Yat-sen University Clinical Research 5010 Program (2007037), National Science and Technology Pillar Program during the Twelfth Five-year Plan Period (2014BAI09B10), Health & Medical Collaborative Innovation Project of Guangzhou City (201400000001), Planned Science and Technology Project of Guangdong Province (2013B020400004), and The National Key Research and Development Program of China (2016YFC0902000). [ABSTRACT FROM AUTHOR]

Background. The objective of this study was to evaluate the prognostic value of the cumulative cisplatin dose (CCD) for long-term survival outcomes after concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (NPC). Methods. Patients were included in an open-label phase III multicenter randomized controlled trial performed at seven institutions in China, and the 298 patients receiving CCRT only were assessed. Patient survival between different CCD groups were compared. Results. Median CCD for the 298 patients was 240 mg/m² (range, 40-320 mg/m²); 113 (37.9%) patients received a CCD of <240 (≤200) mg/m², and 185(62.1%) received a CCD of ≥240 mg/m². For CCD of ≥240 mg/m² vs. <240 mg/m², the estimated 5-year overall survival, disease-free survival, locoregional relapse-free survival, and distant metastasis-free survival rates were 83.2% vs. 76.2% (p = .403), 73.5% vs. 67.8% (p = .461), 90.4% vs. 86.8% (p = .551), and 82.6% vs. 79.7% (p = .632), respectively. Multivariate analysis demonstrated that CCD (240 mg/m²) was not an independent prognostic factor in either the entire cohort or stage III/IV subgroup. Conclusion. A CCD of ≥240 mg/m² was not an independent prognostic factor in patients with locoregionally advanced NPC at high risk of distant metastasis, and 200 mg/m² cisplatin may be adequate to achieve a survival benefit. [ABSTRACT FROM AUTHOR]

Background: To compare the survival outcomes and acute toxicities of concurrent chemoradiotherapy (CCRT), induction chemotherapy (IC) plus radiotherapy (RT), and IC plus CCRT in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated using intensity-modulated radiotherapy (IMRT).Methods: Patients with stage III-IVB NPC who were treated with IMRT between 2009 and 2012 at a single institution were retrospectively reviewed. The induction regimens included PF (cisplatin and fluorouracil) and TP (docetaxel and cisplatin) every 3 weeks for 2-3 cycles; the concurrent regimen was cisplatin every three weeks for 2-3 cycles. A propensity score matching method was used to match patients from each group in a 1:1:1 ratio.Results: In total, 147 eligible patients were propensity-matched, with 49 patients in each treatment group. The median follow-up duration was 38.5 months (range, 4.5 - 56 months). The 3-year disease-free survival, overall survival, distant metastasis-free survival, and locoregional relapse-free survival rates were 82.1%, 92.8%, 87%, and 90.4% in the CCRT group; 86.3%, 91.0%, 91.6%, and 94.4% in the IC plus RT group; and 87.8%, 95.8%, 93.8%, and 93.9% in the IC plus CCRT group, respectively. No statistically significant survival differences were observed between the three treatment groups in either univariate or multivariate analyses. The incidence of grade 3-4 acute toxicities was similar among groups.Conclusions: This study suggests that CCRT, IC plus RT, and IC plus CCRT are similarly efficacious treatment strategies for patients with locoregionally advanced NPC treated using IMRT; however, long-term, large-scale randomized trials are required to confirm these findings. [ABSTRACT FROM AUTHOR]

Objective: Induction chemotherapy followed by concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). However, survival benefits from additional induction chemotherapy varied significantly among patients. This study aimed to determine the predictive value of body mass index (BMI) in induction chemotherapy in NPC.Materials and Methods: This post-hoc analysis included patients from two multicenter, randomized, phase 3 trials (NCT01245959 and NCT01872962), in which patients were randomized to receive induction chemotherapy plus concurrent chemoradiotherapy or concurrent chemoradiotherapy alone.Results: Among 960 patients participated, 957 were included in this analysis. 82 (8.6%) patients had baseline BMI < 18.5 kg/m2 (underweight) and 875 (91.4%) had BMI ≥ 18.5 kg/m2 (normal /overweight). Higher proportion of normal/overweight patients completed ≥2 cycles of induction chemotherapy than underweight patients (96.5% vs. 88.4%, p = 0.042). A strong trend for interaction was observed between BMI and induction chemotherapy regarding failure-free survival (FFS) and overall survival (OS, both pinteraction < 0.001). Normal/overweight patients benefited from induction chemotherapy regarding FFS (83.8% vs. 72.9%, p < 0.001) or OS (93.1% vs. 86.9%, p < 0.001), while underweight patients did not (p = 0.24 and p = 0.65, respectively). These results were confirmed in multivariate analysis and multiple sensitivity analyses.Conclusion: Using pooled data from two landmark phase III trials, we found that underweight patients might not benefit from additional induction chemotherapy in locoregionally advanced NPC. If confirmed in prospective studies, this could help guide individual treatment in the clinic. [ABSTRACT FROM AUTHOR]

The metastatic rate of nasopharyngeal carcinoma (NPC) is the highest among head and neck tumours. Additionally, distant metastasis is the main cause of therapy failure and mortality in NPC. Thus, novel biomarkers are needed for designing new therapeutic strategies to improve the prognosis of this disease. In this study, qRT-PCR and western blotting revealed that the expression of the WD repeat domain phosphoinositide interacting 1 (WIPI-1) was markedly decreased in NPC cells and tissues. Furthermore, low WIPI-1 expression closely correlated with poor prognosis in NPC patients. In vitro functional experiments revealed that overexpression or knockdown of WIPI-1 repressed or facilitated the migration, colony formation, and proliferation of NPC cells. Consistent with the in vitro studies, WIPI-1 significantly inhibited tumour growth, invasion and metastasis in popliteal lymph node metastasis, lung metastasis, and xenograft mouse models in vivo. Mechanistically, WIPI-1 directly interacted with tripartite motif containing 21 (TRIM21) and enhanced starvation-induced autophagy by interacting with TRIM21 in NPC cells. Moreover, MYC gene expression was markedly increased in the WIPI-1 knockdown group, as demonstrated by RNA-seq analysis and qRT-PCR validation. Altogether, WIPI-1 acts as a tumour suppressor gene in NPC that inhibits tumour growth and metastasis. Targeting WIPI-1 may be a novel treatment approach for NPC. [ABSTRACT FROM AUTHOR]

• N2-3 or T4 patients were ideal candidates for locoregionally advanced NPC trials. • Patients with pre-treatment EBV DNA ≥4,000 copies/mL might be eligible for trials. • Patients with detectable post-treatment EBV DNA are candidates for adjuvant trials. This study aims to identify the optimal high-risk candidates for clinical trials in locoregionally advanced nasopharyngeal carcinoma (NPC). Non-metastatic NPC patients (n = 9,468) were included. Recursive partitioning analyses (RPA) were performed to generate risk stratification. Receiver operating characteristics curve was used to determine the cut-off value of pre-treatment Epstein-Barr virus (EBV) DNA for progression-free survival (PFS). Individual-level data from two clinical trials were used for validation. Anatomic stratification based on T and N category (eighth edition TNM, TNM-8) classified the N2-3 or T4 as an anatomic high-risk group with 5-year PFS of 69% (95% confidence interval: 68–71%). Prognostic stratification identified patients with pre-treatment EBV DNA ≥4000 copies/mL as a prognostic high-risk group with 5-year PFS of 69% (67–70%). The c-index was significantly higher for anatomic stratification (0.621, p < 0.001) and prognostic stratification (0.585, p < 0.001) compared with existing TNM-8 stage groups (0.562). The validation cohorts based on clinical trials data showed greater PFS benefit than the results of the original trials [Hazard ratio: NCT01245959, 0.64 vs. 0.67; NCT01872962, 0.42 vs. 0.52]. Moreover, detectable post-treatment EBV DNA indicated a high risk of progression with 5-year PFS of 38.7% and was the most adverse independent factor for all endpoints. N2-3 or T4 NPC patients were ideal candidates for multicenter clinical trials in locoregionally advanced NPC. Patients with detectable post-treatment EBV DNA are suitable candidates for adjuvant trials. [ABSTRACT FROM AUTHOR]

Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18–65 years with newly diagnosed high-risk non-metastatic stage III–IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3–4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0–44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81–90] vs 76% [70–81]; stratified hazard ratio 0·59 [0·38–0·92]; p=0·019). Grade 3–4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3–4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. For the Chinese translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

Objective: In nasopharyngeal carcinoma (NPC), the staging category of parotid lymph node (PLN) metastasis is not explicitly defined, resulting in varied classifications and treatment strategies in clinical practice. This study aimed to determine the prognostic value and optimal staging category of PLN metastasis in NPC.Materials and Methods: With the NPC database from a big-data platform, 10,126 patients with primarily diagnosed, non-metastatic NPC and treated with intensity modulated radiotherapy at our center from 2009 to 2015 were analyzed in this study.Results: In total, 43/10126 patients (0.4%) were diagnosed with histologically verified PLN metastasis at initial diagnosis. Of these, 88.4% (38/43) had enlarged lymph nodes in level II and 34.9% (15/43) in level Ib. Compared with patients without PLN metastasis, those with PLN metastasis had higher risk of disease failure (adjusted hazard ratio [HR], 1.770), distant metastasis (HR, 1.907), and regional recurrence (HR, 3.649), with similar 3-year disease-free survival (70.0% vs. 71.1%) and distant metastasis-free survival (74.8% vs. 77.4%) with patients with N3 disease. Of note, 10/43 patients had regional recurrence: six had recurrent lymph nodes in level Ib; and four of these six patients had no identifiable level Ib lymph nodes on pretreatment imaging.Conclusion: PLN metastasis was associated with high risk of distant metastasis and regional recurrence, and patients with PLN metastasis had similar outcome compared with patients with N3 disease. Regional recurrences in rare levels, such as level Ib, were common in patients with PLN metastasis at initial diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the feasibility of contralateral lower neck sparing intensity modulation radiated therapy (IMRT) for nasopharyngeal carcinoma patients (NPC) with unilateral cervical lymph node metastasis.Materials and Methods: Retrospective review of 546 patients with unilateral cervical lymph node metastasis treated between November 2009 and February 2012 at one institution. All patients were staged using magnetic resonance imaging and received radical IMRT. Patients were classified into two groups: the inferior border of the negative neck irradiation field only covered Levels III to Va in Group 1; the inferior border covered entire neck down to Levels IV to Vb in Group 2.Results: Median follow-up was 49.9months (range, 1.3-69.2months). Four-year overall survival (OS:89.3% vs. 88.9%, P=0.91), disease-free survival (DFS:81.7% vs. 81.0%, P=0.91), distant metastasis-free survival (DMFS:88.2% vs. 87.9%, P=0.95), local relapse-free survival (LRFS:96.7% vs. 94.7%, P=0.70) and nodal relapse-free survival (NRFS: 96.1% vs. 95.9%, P=0.94) were not significantly different between Group 1 and Group 2. Twenty-two patients developed cervical lymph node relapse; of whom 20/22 (91.0%) developed unilateral relapse within pretreatment positive neck. Only one patient developed out-of-field relapse, though this patient also relapsed within the neck irradiation field (Level II). No clinicopathological feature tested had significant prognostic value for NRFS in multivariate analysis.Conclusions: In the IMRT and MRI era, contralateral lower neck sparing IMRT seems to be feasible for NPC patients with unilateral cervical lymph node metastasis. [ABSTRACT FROM AUTHOR]

Purpose: To comprehensively assess the reporting quality of randomized, controlled trials (RCTs) in nasopharyngeal carcinoma (NPC), and to identify significant predictors of quality.Methods and Materials: Two investigators searched MEDLINE and EMBASE for RCTs published between January 1988 and December 2015 that assessed the effect of combined chemoradiotherapy for NPC. The overall quality of each report was assessed using a 28-point overall quality score (OQS) based on the 2010 Consolidated Standards of Reporting Trials (CONSORT) statement. To provide baseline data for further evaluation, we also investigated the reporting quality of certain important issues in detail, including key methodologic items (allocation concealment, blinding, intention-to-treat principle), endpoints, follow-up, subgroup analyses, and adverse events.Results: We retrieved 24 relevant RCTs including 6591 patients. Median 2010 OQS was 15.5 (range, 10-24). Half of the items in the 2010 OQS were poorly reported in at least 40% of trials. Multivariable regression models revealed that publication after 2010 and high impact factor were significant predictors of improved 2010 OQS. Additionally, many issues that we consider significant were not reported adequately.Conclusions: Despite publication of the CONSORT statement more than a decade ago, overall reporting quality for RCTs in NPC was unsatisfactory. Additionally, substantial selectivity and heterogeneity exists in reporting of certain crucial issues. This survey provides the first prompt for NPC trial investigators to improve reporting quality according to the CONSORT statement; increased scrutiny and diligence by editors and peer reviewers is also required. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study is to optimize the cycle for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) receiving neoadjuvant chemotherapy (NCT) in the era of intensity-modulated radiotherapy (IMRT).Materials and Methods: Data on 569 locoregionally advanced NPC patients treated with IMRT were retrospectively reviewed. Propensity score matching (PSM) method was adopted to balance prognostic factors and match patients. Survival outcomes of matched patients between different NCT cycle groups were compared.Results: The median cycle of NCT was 2 (range, 2-4 cycles) for the whole cohort, and patients were therefore stratified as low cycle (=2) and high cycle (>2) groups. In total, 247 pairs of NPC patients were selected by PSM. Univariate analysis found no significantly prognostic difference between the low cycle and high cycle groups, and multivariate analysis did not establish NCT cycle as an independent factor. However, stratified analysis revealed patients in the low cycle group had better OS than those of patients in the high cycle group (92.4% vs. 80.8%, P=0.029), and NCT was identified as an independent prognostic factor for OS in patients with N2-3 category (HR, 2.252; 95% CI, 1.024-4.953; P=0.043).Conclusion: Two cycles of NCT may be enough and additional more cycles are not associated with improved survival outcomes for patients with locoregionally advanced NPC in the era of IMRT. [ABSTRACT FROM AUTHOR]

• CCRT after IC reduced hazard of failure and death in advanced NPC in the IMRT era. • CCRT after IC did not benefit patients with unfavorable tumor response. • CCRT after IC benefited patients with favorable tumor response. • Unfavorable responders deserve intensification of concurrent chemotherapy. • Omission of concurrent chemotherapy in low-risk favorable responders is reasonable. In the intensity-modulated radiotherapy (IMRT) era, the role of concurrent chemoradiotherapy (CCRT) after induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LANPC) is undetermined, while concerns exist about CCRT-associated excessive toxicity. We aimed to combine tumor response and risk assessment to guide decisions about concurrent chemotherapy. From April 2009 to December 2015, 744 LANPC patients treated with CCRT/IMRT after IC were included. Matching techniques were performed for treatment effect evaluation. Tumor response to IC was used for patient stratification. A nomogram was built based on multivariable Cox regression analysis to predict overall survival (OS). After IC, 508 patients (68.3%) had favorable tumor response (complete or partial response), among whom IC + CCRT achieved significantly superior 5-year disease-free survival and OS than IC + IMRT (82.2% vs. 72.5%, P = 0.025; 89.2% vs. 79.9%, P = 0.025). However, no significant difference was found in patients with unfavorable response (both P > 0.05). For favorable responders, a nomogram was built integrating age, smoking, T category, N category, pretreatment Epstein-Barr virus DNA and treatment modality. The concordance index was 0.713 and calibration was good. The nomogram determined three risk groups with distinct OS. High-risk patients benefited from CCRT after IC regarding disease-free survival, OS and distant metastasis-free survival, whereas low- and intermediate-risk patients did not. For LANPC patients with unfavorable response to IC, subsequent CCRT seems inadequate, rendering intensification necessary. For favorable responders with low risk, IC + IMRT represents a reasonable de-intensification approach, although confirmation by prospective data is needed. [ABSTRACT FROM AUTHOR]

• Clinical trials and real-world studies on NPC were differed in stage and treatment. • Stage details, year of treatment, and EBV DNA were related to survival disparity. • Assessing whether the trial pragmatism deviates from real practice was necessary. • Pragmatic features related to the study setting mainly affected the control group. Prognosis often differs between trial participants and nontrial (pragmatic) patients in similar clinical scenarios, raising a concern that results of trials may not represent those in real-world practice. Individual patient data were extracted from three phase III randomized controlled trials and a big-data real-world database (n = 10,126). Patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy (CCRT [control]: 2438 vs. 519) or induction chemotherapy plus CCRT (experimental) were included. Propensity score matching and correspondence analysis were used for data mining. Compared with the real-world CCRT cohort, clinical trials preferred to include cases with T4 (25.3–43.3% vs. 18.8%) and N2 (44.4–60.7% vs. 38.9%) categories. Real-world patients were more likely to undergo shorter irradiation time (44 vs. 46–49 days), inadequate chemotherapy cycles (70.6% vs. 25.2–43.9%), other chemotherapy (36.4% vs. 0.0%), and flexible regimens (≥3 vs. 1). Although real-world patients had better survival than trial participants, the survival disparities disappeared in the matched cohorts, except for in one trial with the lowest pragmatism assessment caused by stringent eligibility criteria and low flexibility of delivery. Stage specification, year of treatment, and Epstein-Barr virus DNA were related to survival disparities (all P ≤ 0.034). The influence of pragmatic features on survival mainly affected the control (all P ≤ 0.043) rather than the experimental group. Special attention should be paid to the control group when interpreting trial results. Assessing whether the pragmatic features of studies deviate from routine practice will lead to better conversion of trial findings into clinical guidelines. [ABSTRACT FROM AUTHOR]

Objective: In cancer trials, prior cancer is a common exclusion criterion. We evaluated the characteristics of prior cancer exclusion criteria in nasopharyngeal carcinoma (NPC) trials and determined its prognostic effect on patients with NPC.Methods: We reviewed NPC trials for prior cancer exclusion criteria. Then we estimated the effect of prior cancer among NPC patients using the Surveillance, Epidemiology, and End Results database.Propensity score-matching was used to compensate for differences in baseline characteristics between patients with and without prior cancer.Results: There were 109 clinical trials involving 10,437 patients; 49 trials (45%) excluded patients with prior cancer. Prior cancer exclusion was more common in recent or phase III trials. We identified 10,195 NPC patients; 6.2% had prior cancer. More than 70% of these cancers were in situ/localized/regional and diagnosed relatively close to the NPC diagnosis (median 3.3 years). Patients with certain prior cancer type (prostate, breast, gynecological, hematological), time of diagnosis (>5 years ago), or stage (in situ/localized) did not have inferior survival compared with patients with no prior cancer. We tested one form of prior cancer exclusion criteria in an NPC cohort resembling a modern trial population: it did not adversely affect overall and NPC-specific survival.Conclusions: Many NPC trials excluded patients with prior cancer, whichimpacts trialaccrual and generalizability. Our findings suggest that broader inclusion in trials of patients with NPC with prior cancer might not affect trial outcomes. More research is needed to understand the appropriateness of this exclusion policy across cancer types and trials. [ABSTRACT FROM AUTHOR]

Objectives: The subgroups of patients with nasopharyngeal carcinoma (NPC) who benefit from induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) remain unclear.Materials and Methods: We established prognostic nomograms for overall survival (OS) and disease-free survival (DFS), and validated the nomograms in 1230 patients with NPC and subgroup of 923 patients with locoregionally advanced NPC (LANPC). Three well-matched risk groups (i.e., low, intermediate and high risk) were created via recursive partitioning and 1-to-1 propensity score matching; IC+CCRT was compared with CCRT in each risk group.Results: Histological type, T category, N category, plasma Epstein-Barr virus deoxyribonucleic acid (and the same factors plus age and neutrophil-lymphocyte ratio) were included in the nomograms for DFS (and OS). Both nomograms had higher c-indexes than the 7th edition staging system in both NPC/LANPC (all P-values≤0.010). The nomogram for OS also had a higher c-index in LANPC than the 8th edition staging system (P-value=0.052). OS was significantly different between all three risk groups in the individualized risk stratification (all P-values<0.001), while the 7th and 8th edition staging systems failed to clearly separate OS for stage II and III disease (P-value=0.415 and 0.347, respectively). IC+CCRT improved OS in intermediate and high risk patients with LANPC compared to CCRT alone (P-value<0.001 and P-value=0.002, respectively).Conclusion: These prognostic nomograms could accurately guide treatment of individual patients with NPC. IC+CCRT could improve OS for patients with LANPC at intermediate to high risk. [ABSTRACT FROM AUTHOR]