Locoregionally Advanced Nasopharyngeal Carcinoma Research Articles

Abstract 3272: PJA1 inhibits docetaxel-induced pyroptosis and results in chemoresistance in nasopharyngeal carcinoma

Abstract Background: Nasopharyngeal carcinoma (NPC) is highly prevalent in South China. More than 70% of patients are diagnosed with locoregionally advanced NPC (LA-NPC) at initial presentation, and the addition of induction chemotherapy (IC) to concurrent chemoradiotherapy is recommended for these patients. However, chemoresistance is a main reason for treatment failure in NPC patients, and the exact regulatory mechanism underlying chemoresistance in NPC remains to be elucidated. Methods: A gene expression dataset and STRING database were used to identify core module and gene that are related to the efficacy of docetaxel-cisplatin-5-fluorouracil (TPF) IC in NPC patients. In vitro and in vivo functional experiments were used to test the effects of PJA1 on docetaxel chemoresistance of NPC cells. The flow cytometric analysis, western blot, and lactate dehydrogenase (LDH) release assays were performed to determine the effects of PJA1 on GSDME-mediated cell pyroptosis. Co-immunoprecipitation, mass spectrometry, immunofluorescence staining, and ubiquitination assays were performed to explore the regulatory manners between PJA1 and PGAM5-DRP1 axis. Finally, multiplex immunofluorescence and immunohistochemical staining were used to evaluate the clinical significance of PJA1 -PGAM5-DRP1 axis in patients with NPC. Results: PJA1 was identified as a key E3 ligase of the top-ranked module ubiquitin-proteasome system dysregulation that involved in NPC chemoresistance, which was highly expressed in NPC patients with nonresponse to the TPF IC. PJA1 facilitated the docetaxel resistance of NPC cells through inhibiting the GSDME-mediated pyroptosis. Mechanistically, PJA1 promoted the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, further increasing the phosphorylation of DRP1 at S637 and reducing the mitochondrial reactive oxygen species (ROS) production, in turn resulting in a suppressive of GSDME-mediated pyroptosis. PGAM5 knockdown fully restored the docetaxel sensitization effect of PJA1 knockdown. Moreover, RTA402, a pharmacological inhibitor of PJA1, enhanced the docetaxel sensitivity of NPC cells. Clinically, high PJA1 expression indicated resistance to TPF IC an inferior survival in NPC patients. Conclusions: Our study emphasizes the essential role of E3 ligase PJA1 in regulating chemoresistance in NPC and provides new therapeutic strategies for NPC patients based on targeting the ubiquitin-proteasome system. Citation Format: Na Liu, Ying-Qing Li, Sheng-Yan Huang. PJA1 inhibits docetaxel-induced pyroptosis and results in chemoresistance in nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3272.

Metronomic S-1 Adjuvant Chemotherapy Improves Survival in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma.

This study aimed to investigate the efficacy and safety of using metronomic S-1 adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma (LANPC). We retrospectively collected data on patients diagnosed with LANPC between January 2016 and December 2021. All patients were treated with induction chemotherapy and concurrent chemoradiotherapy with or without metronomic chemotherapy (MC). Toxicities during MC were recorded. The chi-square test, Kaplan-Meier methods, propensity score matching (PSM), and Cox proportional hazards model were used for statistical analyses. A total of 474 patients were identified, including 64 (13.5%) and 410 (83.5%) patients with or without receiving MC, respectively. Patients who received metronomic S-1 had significantly better 3-year locoregional recurrence-free survival (LRFS) (100% vs. 90.9%, p=0.038), distant metastasis-free survival (DMFS) (98.5% vs. 84.1%, p=0.002), disease-free survival (DFS) (98.4% vs. 77.5%, p < 0.001), and overall survival (OS) (98.0% vs. 87.7%, p=0.008) compared to those without metronomic S-1. The multivariate prognostic analysis revealed that metronomic S-1 was identified as an independent prognostic factor associated with better DMFS (hazard ratio [HR], 0.074; p=0.010), DFS (HR, 0.103; p=0.002) and OS (HR, 0.127; p=0.042), but not in LRFS (p=0.071). Similar results were found using PSM. Common adverse events observed in the metronomic S-1 group included leukopenia, neutropenia, increased total bilirubin, anorexia, rash/desquamation, and hyperpigmentation. All patients with adverse events were grade 1-2. It is worth conducting a randomized controlled trial to assess the effect of metronomic S-1 on survival outcomes and toxicities of LANPC.

CT-based peritumoral radiomics nomogram on prediction of response and survival to induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma

PurposeThe study aims to harness the value of radiomics models combining intratumoral and peritumoral features obtained from pretreatment CT to predict treatment response as well as the survival of LA-NPC(locoregionally advanced nasopharyngeal carcinoma) patients receiving multiple types of induction chemotherapies, including immunotherapy and targeted therapy.Methods276 LA-NPC patients (221 in the training and 55 in the testing cohort) were retrospectively enrolled. Various statistical analyses and feature selection techniques were applied to identify the most relevant radiomics features. Multiple machine learning models were trained and compared to build signatures for the intratumoral and each peritumoral region, along with a clinical signature. The performance of each model was evaluated using different metrics. Subsequently, a nomogram model was constructed by combining the best-performing radiomics and clinical models.ResultsIn the testing cohort, the nomogram model exhibited an AUC of 0.816, outperforming the other models. The nomogram model’s calibration curve showed good agreement between predicted and observed outcomes in both the training and testing sets. When predicting survival, the model’s concordance index (C-index) was 0.888 in the training cohort and 0.899 in the testing cohort, indicating its robust predictive ability.ConclusionIn conclusion, the combined nomogram model, incorporating radiomics and clinical features, outperformed other models in predicting treatment response and survival outcomes for LA-NPC patients receiving induction chemotherapies. These findings highlight the potential clinical utility of the model, suggesting its value in individualized treatment planning and decision-making.

Prognostic value of lymph node-to-primary tumor ratio of PET standardized uptake value for nasopharyngeal carcinoma: a recursive partitioning risk stratification analysis.

Induction chemotherapy (IC) combined with concurrent chemoradiotherapy has become the standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Data on the prognostic value of the lymph node-to-primary tumor ratio (NTR) of positron emission tomography (PET) standardized uptake value (SUV) for patients treated with IC were limited. To evaluate the prognostic value of the SUV NTR for patients with LA-NPC treated with IC. In all, 467 patients with pretreatment 18F-fluorodeoxyglucose PET/computed tomography (CT) scans between September 2017 and November 2020 were retrospectively reviewed. The receiver operating characteristic (ROC) analysis was used to determine the optimal cut-off value of SUV NTR. Kaplan-Meier method was used to evaluate survival rates. The recursive partitioning analysis (RPA) was performed to construct a risk stratification model. The optimal cutoff value of SUV NTR was 0.74. Multivariate analyses showed that SUV NTR and overall stage were independent predictors for distant metastasis-free survival (DMFS) and regional recurrent-free survival (RRFS). Therefore, an RPA model based on the endpoint of DMFS was generated and categorized the patients into three distinct risk groups: RPA I (low risk: SUV NTR < 0.74 and stage III), RPA II (medium risk: SUV NTR < 0.74 and stage IVa, or SUV NTR ⩾ 0.74 and stage III), and RPA III (high risk: SUV NTR ⩾ 0.74 and stage IVa), with a 3-year DMFS of 98.9%, 93.4%, and 84.2%, respectively. ROC analysis showed that the RPA model had superior predictive efficacy than the SUV NTR or overall stage alone. SUV NTR was an independent prognosticator for distant metastasis and regional recurrence in locoregionally advanced NPC. The RPA risk stratification model based on SUV NTR provides improved DMFS and RRFS prediction over the eighth edition of the TNM (Tumor Node Metastasis) staging system.

Delta-Radiomics Guides Adaptive De-Intensification after Induction Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma in the IMRT Era

In the setting of intensity-modulated radiotherapy (IMRT) and induction chemotherapy (IC), the benefits from concurrent chemotherapy remained controversial for locoregionally advanced nasopharyngeal carcinoma (LANPC). This study aimed to construct a delta-radiomics model for benefit prediction and patient selection for omitting concurrent chemotherapy. Between December 2009 and December 2015, a total of 718 patients with LANPC treated with IC+IMRT or IC+concurrent chemoradiotherapy (CCRT) were retrospectively enrolled and randomly assigned to a training set (n = 503) and a validation set (n = 215). Radiomic features were extracted from magnetic resonance images of pre-IC and post-IC. Interclass correlation coefficients and Pearson correlation coefficients were calculated to select robust radiomic features. After univariate Cox analysis, a delta-radiomics signature was built using the LASSO-Cox regression. A nomogram incorporating the delta-radiomics signature and clinical prognostic factors was then developed and evaluated for calibration and discrimination. Risk stratification by the nomogram was evaluated by Kaplan-Meier methods. The primary outcome was overall survival (OS). The delta-radiomics signature, which comprised 19 selected features, was independently associated with prognosis. It yielded an area under the receiver operating characteristic curve (AUC) of 0.77 (95% confidence interval [CI] 0.71 to 0.82) for the training set and 0.71 (95% CI 0.61 to 0.81) for the validation set. The nomogram composed of the delta-radiomic signature, age, T category, N category, pre-treatment Epstein-Barr virus DNA, and treatment showed great calibration and discrimination performance with an AUC of 0.80 (95% CI 0.75 to 0.85) for the training set and 0.75 (95% CI 0.64 to 0.85) for the validation set. Risk stratification by the nomogram excluding the treatment variable resulted in two risk groups with distinct OS. Significant better outcomes were observed in the high-risk patients with IC+CCRT compared to those with IC+IMRT (5-year OS: 73.8% vs. 61.4% in the training set and 85.8% vs. 65.6% in the validation set; all log-rank p < 0.05), while comparable outcomes between IC+CCRT and IC+IMRT were shown for the low-risk patients (95.8% vs. 95.8% in the training set and 92.2% vs. 88.3% in the validation set; all log-rank p > 0.05). The delta-radiomics signature was identified as an independent indicator of LANPC. Integrating clinical predictors with the delta-radiomics signature, the radiomics-based nomogram could predict individual's survival outcomes and benefits from concurrent chemotherapy after IC for LANPC. Low-risk patients with LANPC determined by the nomogram may be potential candidates for omission of concurrent chemotherapy following IC in the IMRT era.

The Short-Term Efficacy and Safety of Induction Chemotherapy Combined with PD-1 Inhibitor or Anti-EGFR in Locoregionally Advanced Nasopharyngeal Carcinoma

This study aimed to investigate the short-term efficacy and safety of induction chemotherapy (IC) combined with PD-1 inhibitor or anti-EGFR in the treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). We retrospectively reviewed the clinical data of 206 patients with LA-NPC, including IC combined with anti-PD1 (57 patients), IC combined with anti-EGFR (28 patients), and IC alone (121 patients). The short-term efficacy was assessed at the end of IC and one month after overall treatment. According to the RECIST v1.1, the short-term efficacy of cervical lymph nodes and primary nasopharynx foci was divided into complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). The overall response (ORR) was defined as the sum of CR and PR. Acute toxicities were graded according to the CTCAE v5.0. One-way analysis of variance (ANOVA) was used to compare differences in the numerical variables among groups. Fisher Freeman-Halton test or Pearson Chi-square test was used to compare classified variables. The ORR rates of primary nasopharynx foci in IC, anti-EGFR, and anti-PD1 group were 68.60%, 67.9%, and 94.7%, respectively, and the corresponding rates of ORR in cervical lymph nodes were 78.5%, 71.4%, and 93.0%, respectively. There was a statistical difference in the ORR between the three groups. Further analysis showed that after IC or overall treatment, the CR rate of primary nasopharynx foci in the anti-PD1 group was significantly higher than the other two groups. The most common adverse effects were hematotoxicity, gastrointestinal toxicity, and transaminase elevation. However, there were no statistical differences in the frequency of any common adverse effects between the three groups. The addition of anti-PD1 based on IC significantly improved the short-term efficacy of LA-NPC and toxicities were tolerable.

Radiotherapy Alone vs. Concurrent or Adjuvant Chemoradiotherapy for Nasopharyngeal Carcinoma Patients with Negative Epstein-Barr Virus DNA Post-Induction Chemotherapy

Induction chemotherapy (IC) plus concurrent chemoradiotherapy has been recommended as the standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC). However, concurrent chemotherapy was associated with increased toxicities, poor tolerance, and low completion rates. The aim of this study was to compare the efficacy and toxicity of IC+ radiotherapy (RT) and IC+ concurrent or adjuvant chemoradiotherapy (IC+CCRT/AC) in patients with negative post-IC EBV DNA. A total of 547 NPC patients with negative plasma EBV DNA post-IC were included. Patients were classified into the IC+RT group and the IC+ concurrent or adjuvant chemoradiotherapy (IC+CCRT/AC) group. Locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), overall survival (OS), and progression-free survival (PFS) were estimated and compared using the Kaplan-Meier method. Propensity-score matching (PSM) was performed to balance the variables. The median follow-up time was 37 months. The 3-year LRFS, DMFS, OS, and PFS rates for the whole group were 92.2%, 92.4%, 96.4%, and 84.4%, respectively. There was no significant difference in LRFS, DMFS, OS, and PFS between the IC+RT and the IC+CCRT/AC group both before PSM (3-year rates of 91.1% vs. 92.6%, p = 0.94; 95.6% vs. 91.5%, p = 0.08; 95.2% vs. 96.8%, p = 0.80; 85.9% vs. 84.0%, p = 0.38) and after PSM (90.7% vs. 92.7%, p = 0.77; 96.8% vs. 93.7%, p = 0.29; 94.5% vs. 93.9%, p = 0.57; 84.7% vs. 85.6%, p = 0.96). Multivariate analysis demonstrated that treatment schedule was not an independent predictor for survival rates. Patients in the IC+RT group had fewer treatment-related acute toxicities and better tolerance. IC+RT displayed similar survival outcomes as IC+CCRT/AC for NPC patients with negative post-IC EBV DNA. Our current data seems not to support the routine use of concurrent or adjuvant chemotherapy after IC for unselected patients.

Concurrent chemoradiotherapy plus anlotinib vs. concurrent chemoradiotherapy alone in locally advanced nasopharyngeal carcinoma: An interim analysis of a multicenter randomized controlled trial.

Despite the use of intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy (CCRT), the treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is not satisfactory. EGFR and VEGFR are highly expressed in 60-80% of patients with LA-NPC and this is associated with a poor prognosis, which suggests the potential effectiveness of an inhibitor targeting tumor angiogenesis for treating LA-NPC. The present study aimed to assess the safety and effectiveness of CCRT combined with anlotinib in patients with LA-NPC. The study involved patients with LA-NPC (stage III-IVA) from four institutions in Guangxi, China. Patients were randomized to receive CCRT + anlotinib (n=36) or CCRT alone (n=37). Acute toxicity and short-term efficacy were evaluated. The most common grade 3 or 4 adverse events were leucopenia [10 (27.7%) vs. 8 (21.6%)], neutropenia [6 (16.7%) vs. 5 (13.5%)] and mucositis [13 (36.1%) vs. 11 (29.7%)] in the CCRT + anlotinib vs. CCRT cohort but there were no significant differences between the two cohorts (P=0.54, P=0.70 and P=0.56, respectively). Two patients (5.6%) displayed grade 1/2 hemorrhage in the CCRT + anlotinib cohort. No patient displayed grade 3/4 hemorrhages or adverse event-associated deaths in any cohort. Complete response rates in the CCRT + anlotinib arm at 1 week and 3 and 6 months post-radiotherapy were 60.0, 91.4, and 97.1%, respectively, compared with 40.5, 81.1 and 91.9% in the CCRT arm but there was no significant difference (P=0.10, P=0.35 and P=0.65, respectively). This interim analysis of the ongoing trial showed that administration of CCRT + anlotinib has acceptable toxicity profiles, good compliance and promising results in patients with LA-NPC. A larger study cohort and a longer follow-up period are needed to confirm therapeutic effectiveness and late toxicity.

Survival after induction chemotherapy in locoregional advanced nasopharyngeal carcinoma: An updated systematic review and meta-analysis.

Induction chemotherapy (ICT) augmentation is a common strategy for standard concurrent chemoradiotherapy (CCRT) of locoregionally advanced nasopharyngeal carcinoma (NPC). The survival condition is a crucial issue for patients with locoregionally advanced NPC. The survival of ICT patients with CCRT treatment versus standard CCRT alone should be elucidated via a systemic review and meta-analysis of randomized clinical trials. We compared ICT with CCRT and CCRT alone treatment to determine if ICT with CCRT can be associated with a significant benefit of survival conditions versus CCRT. Different survival indicators were analyzed for the ICT with CCRT. Twelve studies with a total of 3711 patients with locoregionally advanced NPC were enrolled. The focused outcome was the overall survival, progression-free survival, distant metastasis-free survival, and locoregional recurrence-free survival. Our results showed that ICT with CCRT is associated with a significant benefit for the overall survival status versus CCRT treatment. Similar significant benefits in the survival condition were seen in progression-free survival, distant metastasis-free survival, and locoregional recurrence-free survival. The updated meta-analysis results suggest that the ICT with CCRT might be associated with significant benefits of survival in overall, progression-free, distant metastasis-free, as well as locoregional recurrence-free dimensions versus CCRT treatment. However, the bias of different kinds, doses, and regimens of chemotherapy agents and radiotherapy should not be ignored.

Multi-task deep learning-based radiomic nomogram for prognostic prediction in locoregionally advanced nasopharyngeal carcinoma

PurposePrognostic prediction is crucial to guide individual treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) patients. Recently, multi-task deep learning was explored for joint prognostic prediction and tumor segmentation in various cancers, resulting in promising performance. This study aims to evaluate the clinical value of multi-task deep learning for prognostic prediction in LA-NPC patients.MethodsA total of 886 LA-NPC patients acquired from two medical centers were enrolled including clinical data, [18F]FDG PET/CT images, and follow-up of progression-free survival (PFS). We adopted a deep multi-task survival model (DeepMTS) to jointly perform prognostic prediction (DeepMTS-Score) and tumor segmentation from FDG-PET/CT images. The DeepMTS-derived segmentation masks were leveraged to extract handcrafted radiomics features, which were also used for prognostic prediction (AutoRadio-Score). Finally, we developed a multi-task deep learning-based radiomic (MTDLR) nomogram by integrating DeepMTS-Score, AutoRadio-Score, and clinical data. Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were used to evaluate the discriminative ability of the proposed MTDLR nomogram. For patient stratification, the PFS rates of high- and low-risk patients were calculated using Kaplan–Meier method and compared with the observed PFS probability.ResultsOur MTDLR nomogram achieved C-index of 0.818 (95% confidence interval (CI): 0.785–0.851), 0.752 (95% CI: 0.638–0.865), and 0.717 (95% CI: 0.641–0.793) and area under curve (AUC) of 0.859 (95% CI: 0.822–0.895), 0.769 (95% CI: 0.642–0.896), and 0.730 (95% CI: 0.634–0.826) in the training, internal validation, and external validation cohorts, which showed a statistically significant improvement over conventional radiomic nomograms. Our nomogram also divided patients into significantly different high- and low-risk groups.ConclusionOur study demonstrated that MTDLR nomogram can perform reliable and accurate prognostic prediction in LA-NPC patients, and also enabled better patient stratification, which could facilitate personalized treatment planning.

A contrast-enhanced CT radiomics-based model to identify candidates for deintensified chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma patients.

To develop a contrast-enhanced CT (CECT) radiomics-based model to identify locoregionally advanced nasopharyngeal carcinoma (LA-NPC) patients who would benefit from deintensified chemoradiotherapy. LA-NPC patients who received low-dose concurrent cisplatin therapy (cumulative: 150mg/m2), were randomly divided into training and validation groups. 107 radiomics features based on the primary nasopharyngeal tumor were extracted from each pre-treatment CECT scan. Through Cox regression analysis, a radiomics model and patients' corresponding radiomics scores were created with predictive independent radiomics features. T stage (T) and radiomics score (R) were compared as predictive factors. Combining the N stage (N), a clinical model (T + N), and a substitution model (R + N) were constructed. Training and validation groups consisted of 66 and 33 patients, respectively. Three significant independent radiomics features (flatness, mean, and gray level non-uniformity in gray level dependence matrix (GLDM-GLN)) were found. The radiomics score showed better predictive ability than the T stage (concordance index (C-index): 0.67 vs. 0.61, AUC: 0.75 vs. 0.60). The R + N model had better predictive performance and more effective risk stratification than the T + N model (C-index: 0.77 vs. 0.68, AUC: 0.80 vs. 0.70). The R + N model identified a low-risk group as deintensified chemoradiotherapy candidates in which no patient developed progression within 3years, with 5-year progression-free survival (PFS) and overall survival (OS) both 90.7% (hazard ratio (HR) = 4.132, p = 0.018). Our radiomics-based model combining radiomics score and N stage can identify specific LA-NPC candidates for whom de-escalation therapy can be performed without compromising therapeutic efficacy. Our study shows that the radiomics-based model (R + N) can accurately stratify patients into different risk groups, with satisfactory prognosis in the low-risk group when treated with low-dose concurrent chemotherapy, providing new options for individualized de-escalation strategies. • A radiomics score, consisting of 3 predictive radiomics features (flatness, mean, and GLDM-GLN) integrated with the N stage, can identify specific LA-NPC populations for deintensified treatment. • In the selection of LA-NPC candidates for de-intensified treatment, radiomics score extracted from primary nasopharyngeal tumors based on CECT can be superior to traditional T stage classification as a predictor.

The value of integrating tumor volume and plasma Epstein-Barr virus DNA load during sequential chemoradiotherapy for prognostic prediction and therapeutic guidance in high-risk locoregionally advanced nasopharyngeal carcinoma

ObjectivesTo investigate the value of integrating primary gross tumor volume (GTVp) and gross tumor volume of nodes (GTVn) after induction chemotherapy (IC) and dynamic changes in plasma cell-free Epstein-Barr virus DNA (cfEBV DNA) during sequential chemoradiotherapy (CRT) in high-risk locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Materials and methodsWe retrospectively reviewed 988 patients with LA-NPC undergoing IC plus concurrent chemoradiotherapy (CCRT) between 2014 and 2018. The entire cohort was divided into four subgroups according to tumor volume and the cfEBV DNA load. Using a supervised statistical clustering approach, we stratified the subgroups into three clusters. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRRFS) were calculated using Kaplan-Meier analysis and inter-group differences were compared using the log-rank test. ResultsWe observed that GTVp & GTVn and cfEBV DNApostIC & cfEBV DNApostCRT were powerful prognostic factors for OS (p = 0.004, p < 0.001, p < 0.001, and p < 0.001, respectively). The survival curves of the three clusters were significantly different. The 5-year OS for the low-risk, intermediate-risk and high–risk clusters were 97.0%, 86.2% and 77.1% (all P values < 0.001), respectively. The risk stratification system showed better predictive performance than the current tumor-node-metastasis (TNM) classification for OS (area under curve [AUC]: 0.653 versus 0.560, p < 0.001), DFS (AUC: 0.639 versus 0.540, p < 0.001), DMFS (AUC: 0.628 versus 0.535, p < 0.001) and LRRFS (AUC: 0.616 versus 0.513, p < 0.001). ConclusionBoth tumor volume and the cfEBV DNA level during sequential CRT are effective prognostic indicators for patients with high-risk LA-NPC. The developed risk stratification system incorporating above factors improved survival prediction and demonstrated potential value in decision-making.

A single center retrospective study assessing the prognostic significance of pre-treatment neutrophil/lymphocyte ratio in locally advanced nasopharyngeal carcinoma.

In light of the growing evidence suggesting the impact of inflammatory parameters on the survival of individuals with cancer, this research assessed the prognostic significance of the neutrophil-to-lymphocyte ratio (NLR) in individuals diagnosed with locally advanced nasopharyngeal carcinoma (NPC) prior to undergoing intensity-modulated radiation therapy (IMRT). A total of 163 individuals diagnosed with locally advanced NPC treated with IMRT at our hospital between January 2012 and December 2017 were included in this research. For each patient, the absolute counts of neutrophils and lymphocytes were recorded, and the NLR was calculated at the first diagnosis. To determine the optimal cut-off values for NLR, receiver operating characteristic (ROC) curve analysis was conducted. The effects of the determined cut-off value on local failure-free survival (LFFS), overall survival (OS), progression-free survival (PFS), and distant failure-free survival (DFFS) were evaluated employing the Cox regression model. The median follow-up duration for the individuals in this study was 15 months (ranging from 6 to 79 months). According to the determined NLR cut-off value of 3.27, individuals were classified into two groups (high NLR and low NLR). Individuals in the high-NLR group had remarkably poorer 3-year OS (62.8% vs. 91.7%), PFS (51.4% vs. 82.4%), and DFFS (70.7% vs. 89.6%) compared to the low-NLR group. Furthermore, the outcomes of univariate and multivariate survival analyses revealed that NLR served as an independent predictor of DFFS (HR: 2.81, 95% CI: 1.195-6.608, P=0.018), OS (HR: 3.1, 95% CI: 1.211-7.935, P=0.018), and PFS (HR: 2.21, 95% CI: 1.133-4.292, P=0.02). Elevated NLR exhibited a significant correlation with reduced OS, DFFS, and PFS. These findings suggest that NLR holds promise as a cost-effective and reliable marker for the prediction of clinical outcomes among patients with locoregionally advanced nasopharyngeal carcinoma (LANPC). Furthermore, incorporating NLR into clinical decision-making regarding LANPC treatment strategies may contribute to a more targeted approach aimed at reducing the risk of distant failure.

Widely targeted quantitative lipidomics and prognostic model reveal plasma lipid predictors for nasopharyngeal carcinoma

BackgroundDysregulation of lipid metabolism is closely associated with cancer progression. The study aimed to establish a prognostic model to predict distant metastasis-free survival (DMFS) in patients with nasopharyngeal carcinoma (NPC), based on lipidomics.MethodsThe plasma lipid profiles of 179 patients with locoregionally advanced NPC (LANPC) were measured and quantified using widely targeted quantitative lipidomics. Then, patients were randomly split into the training (125 patients, 69.8%) and validation (54 patients, 30.2%) sets. To identify distant metastasis-associated lipids, univariate Cox regression was applied to the training set (P < 0.05). A deep survival method called DeepSurv was employed to develop a proposed model based on significant lipid species (P < 0.01) and clinical biomarkers to predict DMFS. Concordance index and receiver operating curve analyses were performed to assess model effectiveness. The study also explored the potential role of lipid alterations in the prognosis of NPC.ResultsForty lipids were recognized as distant metastasis-associated (P < 0.05) by univariate Cox regression. The concordance indices of the proposed model were 0.764 (95% confidence interval (CI), 0.682–0.846) and 0.760 (95% CI, 0.649–0.871) in the training and validation sets, respectively. High-risk patients had poorer 5-year DMFS compared with low-risk patients (Hazard ratio, 26.18; 95% CI, 3.52–194.80; P < 0.0001). Moreover, the six lipids were significantly correlated with immunity- and inflammation-associated biomarkers and were mainly enriched in metabolic pathways. ConclusionsWidely targeted quantitative lipidomics reveals plasma lipid predictors for LANPC, the prognostic model based on that demonstrated superior performance in predicting metastasis in LANPC patients.

PD-1 blockade with sintilimab plus induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT) versus IC-CCRT in locoregionally-advanced nasopharyngeal carcinoma (LANPC): A multicenter, phase 3, randomized controlled trial (CONTINUUM).

LBA6002 Background: Despite the success of PD-1 blockade plus chemotherapy in recurrent/metastatic NPC, its role in LANPC is unproven. This trial evaluated the efficacy and safety of adding sintilimab (a PD-1 inhibitor) to IC-CCRT in LANPC. Methods: Patients with non-metastatic high-risk LANPC (stage III-IVA, excluding T3-4N0/T3N1) were enrolled at 9 centers in China, and randomized (1:1; stratified by center and stage with block size four) to the Standard Arm (gemcitabine and cisplatin IC plus cisplatin CCRT), or Sintilimab Arm (sintilimab plus IC-CCRT). Sintilimab 200mg was given intravenously once every 3 weeks for up to 12 cycles (3 induction, 3 concurrent, and 6 adjuvant). The primary endpoint was event-free survival (EFS) (i.e. freedom from local/regional/distant failure or death). It is estimated that approximately 417 patients would provide 80% power to detect a hazard ratio (HR) of 0.52 with a two-sided type 1 error of 0.05. Quality of life (QoL) was assessed by EORTC-C30. Biomarkers including tertiary lymphoid structure (TLS), PD-L1, and gene expression were also analyzed. Results: Between December 2018, and March 2020, 425 patients were randomized to the Sintilimab Arm (n = 210) and Standard Arm (n = 215). After a median follow-up of 42 months (94% alive patients ≥36 months), the intention-to-treat analysis showed that 3-year EFS was 86.1% in the Sintilimab Arm and 76.0% in the Standard Arm (stratified HR, 0.59; 95% confidence interval [CI], 0.38-0.92; stratified log-rank p = 0.019). Grade 3-4 adverse events (AEs) occurred in 155 (74.2%) and 140 (65.4%) patients, including immune-related AEs in 20 (9.6%) and 2 (0.9%) patients and grade 5 AEs in 2 (0.95%) and 1 (0.5%) patients in the Sintilimab and Standard Arm, respectively (Table). No minimum clinically important differences in QoL were observed. The benefit of the addition of sintilimab was observed in patients with TLS (HR 0.18; 95% CI, 0.04-0.81; p = 0.011) but not in patients without TLS (HR 0.94; 95% CI, 0.50-1.76; p = 0.85). Conclusions: The addition of sintilimab to standard IC-CCRT results in significant improvement of EFS, manageable safety profile, and comparable QoL in high-risk LANPC. TLS appears to be a predictive biomarker for benefit of sintilimab. Clinical trial information: NCT03700476 . [Table: see text]

Explainable machine learning via intra-tumoral radiomics feature mapping for patient stratification in adjuvant chemotherapy for locoregionally advanced nasopharyngeal carcinoma.

This study aimed to discover intra-tumor heterogeneity signature and validate its predictive value for adjuvant chemotherapy (ACT) following concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). 397 LA-NPC patients were retrospectively enrolled. Pre-treatment contrast-enhanced T1-weighted (CET1-w) MR images, clinical variables, and follow-up were retrospectively collected. We identified single predictive radiomic feature from primary gross tumor volume (GTVnp) and defined predicted subvolume by calculating voxel-wised feature mapping and within GTVnp. We independently validate predictive value of identified feature and associated predicted subvolume. Only one radiomic feature, gldm_DependenceVariance in 3mm-sigma LoG-filtered image, was discovered as a signature. In the high-risk group determined by the signature, patients received CCRT + ACT achieved 3-year disease free survival (DFS) rate of 90% versus 57% (HR, 0.20; 95%CI, 0.05-0.94; P = 0.007) for CCRT alone. The multivariate analysis showed patients receiving CCRT + ACT had a HR of 0.21 (95%CI: 0.06-0.68, P = 0.009) for DFS compared to those receiving CCRT alone. The predictive value can also be generalized to the subvolume with multivariate HR of 0.27 (P = 0.017) for DFS. The signature with its heterogeneity mapping could be a reliable and explainable ACT decision-making tool in clinical practice.

A randomized, controlled trial to investigate cognitive behavioral therapy in prevention and treatment of acute oral mucositis in patients with locoregional advanced nasopharyngeal carcinoma undergoing chemoradiotherapy.

Oral mucositis is a common side effect of concurrent chemoradiotherapy (CCRT). This study aimed to determine whether cognitive behavioral therapy (CBT) could help prevent oral mucositis during chemoradiation therapy for locoregional advanced nasopharyngeal carcinoma (LA-NPC). Between July 15, 2020, and January 31, 2022, a randomized controlled phase II trial was conducted. Eligible patients (N=282, 18-70 years old) with pathologically diagnosed LA-NPC were randomly assigned to receive CBT or treatment as usual (TAU) during CCRT (computer-block randomization, 1:1). The primary endpoints were the incidence and latency of oral mucositis. The incidence of oral mucositis was significantly lower in the CBT group (84.8%; 95% confidence interval [CI], 78.7%-90.9%) than in the TAU group (98.6%; 95% CI, 96.6%-100%; P<0.001). The median latency period was 26 days and 15 days in the CBT and TAU groups, respectively (hazard ratio, 0.16; 95% CI, 0.12-0.22; P<0.001). CBT significantly reduced ≥ grade 3 oral mucositis (71.9% vs. 22.5%, P<0.001), dry mouth (10.8% vs. 3.7%, P=0.021), dysphagia (18% vs. 5.1%, P=0.001), and oral pain (10% vs. 3.6%, P=0.034) compared with TAU. Patients receiving CBT and TAU during CCRT had similar short-term response rates. CBT reduced the occurrence, latency, and severity of oral mucositis in patients with LA-NPC during CCRT.

Induction chemotherapy with nedaplatin, docetaxel and 5-fluorouracil followed by concurrent nedaplatin and radiotherapy in locoregionally advanced nasopharyngeal carcinoma: A single arm, open label, phase II clinical trial.

6067 Background: To evaluate the efficacy of induction chemotherapy with nedaplatin, docetaxel and 5-fluorouracil followed by concurrent nedaplatin combined with radical radiotherapy in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Methods: This is a prospective, single-arm, open-label, phase II trial. Patients with aged 18-65 years, newly diagnosed stage III-IVa (except T3-4N0) nasopharyngeal carcinoma were enrolled. Eligible patients received induction chemotherapy with docetaxel (60 mg/m² intravenously on days (D) 1, 22 and 43), Nedaplatin (60 mg/m² intravenously on D 1, 22 and 43) and fluorouracil (600 mg/m² per day as a continuous 120 hours (h) infusion on D 1-5, 22-26 and 43-47) every three weeks for three cycles, thereafter received intensity-modulated radiotherapy (IMRT) concurrently with nedaplatin (100mg/m2 intravenously on D 1, 22 and (or) 43) every three weeks for two or three cycles. The primary end point was objective response rate (ORR). The secondary end points included overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS) and local recurrence-free survival (LRFS). Results: Between March 2020 and June 2021, a total of 32 patients with LA-NPC were enrolled. With a median follow-up duration of 14.0 months (IQR 11.7-16.3), 32 patients (100%) achieved ORR at three months after treatment. The 12-month PFS was 95.7% (95% CI 87.3% to 100%) and the 12-month OS was 100%. The most common grade 3 or 4 adverse events during induction chemotherapy were neutropenia (3 [9.4%]), diarrhea (3 [9.4%]) and hepatoxicity (3 [9.4%]), followed by leucopenia (2 [6.3%]) and fatigue (1 [3.1%]). The most common grade 3 or 4 adverse events during concurrent chemotherapy were mucositis (3 [9.4%]), leucopenia (1 [3.1%]), neutropenia (1 [3.1%]) and thrombocytopenia (1 [3.1%]). All of these adverse events were manageable. Conclusions: Induction chemotherapy with nedaplatin, docetaxel and 5-fluorouracil followed by concurrent nedaplatin combined with radical radiotherapy showed promising antitumor activity and manageable toxicities in patients with LA-NPC. Further phase III randomized controlled trials are warranted to validate our findings. Clinical trial information: NCT04834206 .

Prospective study of integrating post-radiotherapy [18F] fluorodeoxyglucose-positron emission tomography/computed tomography scan and plasma Epstein-Barr virus DNA in surveillance of locoregionally advanced nasopharyngeal carcinoma.

6072 Background: To evaluate the role of [18F] fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan at 12-weeks after the end of Radiotherapy (RT) integrated with plasma EBV DNA in surveillance and standardized implementation of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Methods: This prospective study was conducted in patients with stage III-IVa LA-NPC. FDG-PET/CT examination and plasma Epstein-Barr virus (EBV) DNA measurements was performed pretreatment and at 12-weeks after the end RT. The primary study endpoint was the negative predictive value (NPV) and other supporting diagnostic test characteristics of 12-weeks FDG-PET/CT for the surveillance of residual locoregional disease and new distant metastasis. Results: From June 2018 to December 2019, 506 eligible patients were enrolled and entered follow-up (median,45 months). At 12 weeks after the end of RT, there were 22 (4.3%) patients have residual locoregional disease, 30 (5.9%) patients developed distant metastasis and 6 (1.2%) patients presented both residual locoregional disease and distant metastasis. The NPV of 12-weeks FDG-PET/CT for overall residual diseases and distant metastasis was 96.3% (95% confidence interval [CI], 94.0%-97.8%) with sensitivity of 72.4% (95%CI, 58.9%-83.0%), specificity of 93.3% (95%CI, 90.5%-95.4%), positive predictive value (PPV) of 58.3% (95%CI, 46.1%-69.6%) and accuracy of 90.9% (95%CI, 88.4%-93.4%). In EBV DNA-based risk subgroups, the NPV of 12-weeks PDG-PET/CT was 96.8% (95%CI, 94.5%-98.2%) in patients with undetectable 12-weeks plasma EBV DNA and 87.0% (95%CI, 65.3%-96.5%) in patients with detectable 12-weeks plasma EBV DNA. Conclusions: 12-weeks PDG-PET/CT was reliable in the surveillance of LA-NPC and could help optimize the follow-up strategy and provide implications for timely and effective therapeutic regimen, especially for patients in different EBV DNA-based risk groups. Clinical trial information: NCT03601390 .

Induction chemotherapy plus radiotherapy alone versus cisplatin-based concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: An open-label, non-inferiority, randomized phase 3 trial.

6001 Background: Cisplatin-based concurrent chemoradiotherapy (CCRT) has long been regarded as standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) due to its favorable local control. However, concurrent platinum is associated with intolerable toxicities and ineffective in preventing distant metastasis. Since IMRT enhances the local control and induction chemotherapy (IC) decreases the risk of distant failure, it is worth exploring whether IC plus IMRT alone regimen could replace CCRT for patients with LA-NPC. Methods: This open-label, phase 3, non-inferiority clinical trial was conducted from June 12, 2015 to April 30, 2019. Patients with stage T1-4N2-3 or T3-4N0-1 M0 NPC were randomly assigned (1:1) to receive gemcitabine (1000 mg/m²) and cisplatin (80 mg/m²) IC for 2 cycles followed by IMRT alone or IMRT plus concomitant weekly cisplatin (40 mg/m²) up to 7 cycles. 2-year failure-free survival was set as primary endpoint and non-inferiority margin of 10% was established. Efficacy analysis and safety analysis were dividedly performed in the intention-to-treat and safety population. Results: A total of 249 patients were enrolled, including 124 patients in IC group and 125 patients in CCRT group. Median follow-up time was 60 months (IQR, 48-71). 2-year failure-free survival was 90.2% in IC group versus 86.3% in CCRT group, with an HR of 0.818 (95% CI, 0.479-1.397) and absolute difference of 3.9% (1-sided 95%CI, -4.2 to 11.9). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. Compared with CCRT group, fewer grade ≥3 AEs occurred in IC group (47.5% vs 61.5%, p = 0.015), including leucopenia, anemia, mucositis, nausea and dysphagia. The IC group had significantly better QoL during and short periods after IMRT, including domains of global health status, physical functioning, fatigue, nausea and vomiting, pain, and appetite loss. Conclusions: For LA-NPC, gemcitabine and cisplatin induction chemotherapy plus IMRT alone was not inferior in 2-year failure-free survival to concurrent chemoradiotherapy. Clinical trial information: NCT02460887 .