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Precise detection of recurrence in patients with treated nasopharyngeal carcinoma (NPC) facilitates timely intervention and prolongs survival. However, there is no compelling tool realizing real-time precise recurrence detection as scale hitherto. Here we present a deep learning-based sequential scan model called RAIN, harnessing 10,212 time-series follow-up head and neck magnetic resonance (MR) scans of 1,808 patients with treated NPC in a multicenter observational study (Blinded ID). The RAIN yields larger area under the receiver operating curve (AUC) values than single scan model (internal: 0.916 vs 0.855, p = 0.004; external: 0.900 vs 0.709, p

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

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Purpose This study was aimed to investigate long-term survivals and toxicities of early-stage nasopharyngeal carcinoma (NPC) in endemic area, evaluating the role of chemotherapy in stage II patients.Materials and Methods Totally 187 patients with newly diagnosed NPC and restaged American Joint Committee on Cancer/ International Union Against Cancer 8th T1-2N0-1M0 were retrospectively recruited. All received intensity-modulated radiotherapy (IMRT)±chemotherapy (CT) from 2001 to 2010.Results With 15.7-year median follow-up, 10-year locoregional recurrence-free survival, distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS) were 93.3%, 93.5%, 92.9% and 88.2%, respectively. Multivariable analyses showed cervical lymph nodes positive and pre-treatment prognostic nutritional index ≥ 52.0 could independently predict DMFS (p=0.036 and p=0.011), DSS (p=0.014 and p=0.026), and OS (p=0.002 and p < 0.001); Charlson comorbidity index < 3 points could predict DSS (p=0.011); age > 45 years (p=0.002) and pre-treatment lactate dehydrogenase ≥ 240 U/L (p < 0.001) predicted OS. No grade 4 late toxicity happened; grade 3 late toxicities included subcutaneous fibrosis (4.3%), deafness or otitis (4.8%), skin dystrophy (2.1%), and xerostomia (1.1%). No differences on survivals were shown between IMRT+CT vs. IMRT alone in stage II patients, even in T2N1M0 (p > 0.05). Unsurprising, patients in IMRT+CT had more acute gastrointestinal reaction, myelosuppression, mucositis, late ear toxicity, and cranial nerve injury (all p < 0.05) than IMRT alone group.Conclusion Superior tumor control and satisfying long-term outcomes could be achieved with IMRT in early-stage NPC with mild late toxicities. As CT would bring more toxicities, it should be carefully performed to stage II patients.

Shu-Hui Lv,1– 3,* Wang-Zhong Li,1,2,* Hu Liang,1,2 Guo-Ying Liu,1,2 Wei-Xiong Xia,1,2 Yan-Qun Xiang1,2 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, China; 2Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China; 3Medical Affairs Office, The Fifth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan-Qun Xiang; Wei-Xiong XiaDepartment of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, ChinaTelFax +86-1866-6096-623 Email xiangyq@sysucc.org.cn; xiawx@sysucc.org.cnPurpose: We sought to assess the prognostic and predictive value of a circulating inflammation signature (CISIG) and develop CISIG-based tools for predicting prognosis and guiding individualized induction chemotherapy (ICT) in non-metastatic nasopharyngeal carcinoma (NPC).Patients and Methods: We retrospectively collected a candidate inflammatory biomarker panel from patients with NPC treated with definitive radiotherapy between 2012 and 2017. We developed the CISIG using candidate biomarkers identified by a least absolute shrinkage and selection operator (LASSO) Cox regression model. The Cox regression analyses were used to evaluate the CISIG prognostic value. A CISIG-based prediction model was constructed, validated, and assessed. Potential stratified ICT treatment effects were examined.Results: A total of 1149 patients were analyzed. Nine biomarkers selected by LASSO regression in the training cohort were used to construct the CISIG, including hyaluronidase, laminin, procollagen III, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, high-density lipoprotein, lactate dehydrogenase, and C-reactive protein-to-albumin ratio. CISIG was an independent prognostic factor for disease-free survival (DFS; hazard ratio: 2.65, 95% confidence interval: 1.93– 3.64; P < 0.001). High CISIG group (>− 0.2) was associated with worse 3-year DFS than low CISIG group in both the training (67.5% vs 88.3%, P < 0.001) and validation cohorts (72.3% vs 85.1%, P < 0.001). We constructed and validated a CISIG-based nomogram, which showed better performance than the clinical stage and Epstein–Barr virus DNA classification methods. A significant interaction between CISIG and the ICT treatment effect was observed (P for interaction = 0.036). Patients with high CISIG values did not benefit from ICT, whereas patients with low CISIG values significantly benefited from ICT.Conclusion: The developed CISIG, based on a circulating inflammatory biomarker panel, adds prognostic information for patients with NPC. The proposed CISIG-based tools offer individualized risk estimation to facilitate suitable ICT candidate identification.Keywords: nasopharyngeal carcinoma, inflammatory biomarkers, circulating inflammation signature, prognostic value, predictive value, induction chemotherapy

Purpose Current guideline recommends a uniform method of delineation of subclinical disease within the primary clinical target volume (CTVp) for all stages of nasopharyngeal carcinoma (NPC). We performed a prospective observational study to investigate the outcomes with a reduced CTVp and radiation dose for early-stage NPC. Methods and Materials Patients with newly diagnosed, biopsy-proven World Health Organization type II-III and American Joint Committee on Cancer/Union for International Cancer Control sixth edition stage T1-2N0-1 disease were enrolled. All patients were treated with intensity modulated radiation therapy alone. We categorized CTVp into CTVp1 (high risk) and CTVp2 (low risk). CTVp1 comprised of gross tumor (on magnetic resonance imaging or contrast-enhanced computed tomography) plus a 5-mm margin (3-mm posteriorly) and was prescribed to 60 Gy in 30 fractions (fr). CTVp2 was generated from CTVp1 plus a 5-mm margin (3 mm posteriorly), excluding the maxillary and cavernous sinuses, and was prescribed to 54 Gy in 30 fr. The prescribed doses to the primary and nodal gross tumor volume (GTVp and GTVn) were 68 Gy in 30 fr and 60 to 66 Gy in 30 fr, respectively. Primary endpoint was local recurrence-free survival. This study was registered in ClinicalTrials.gov , number NCT03839602 . Results From May 2001 to August 2006, 103 patients were recruited and completed IMRT. With a median follow-up of 15.2 years (range, 2.1-18.1 years), only 1 patient had local failure. Ten-year local recurrence-free survival, regional recurrence-free survival, distant metastasis-free survival, and overall survival were 90.3%, 88.3%, 90.3%, and 91.2%, respectively. Among late IMRT-related adverse events, we recorded 2 patients with G1 cranial nerve injury, 3 patients with G3 hearing loss, and 3 patients with G3 subcutaneous fibrosis. No patients had temporal lobe necrosis, brain stem injury, or trismus. Conclusions Decreased CTV margins and radiation doses can achieve long-term tumor control with mild late toxicities for patients with early-stage NPC.

Background To explore the prognostic value and the role for treatment decision of pathological microscopic features in patients with nasopharyngeal carcinoma (NPC) using the method of deep learning. Methods The pathological microscopic features were extracted using the software QuPath (version 0.1.3. Queen's University) in the training cohort (Guangzhou training cohort, n = 843). We used the neural network DeepSurv to analyze the pathological microscopic features (DSPMF) and then classified patients into high‐risk and low‐risk groups through the time‐dependent receiver operating characteristic (ROC). The prognosis accuracy of the pathological feature was validated in a validation cohort (n = 212). The primary endpoint was progression‐free survival (PFS). Results We found 429 pathological microscopic features in the H&E image. Patients with high‐risk scores in the training cohort had shorter 5‐year PFS (HR 10.03, 6.06‐16.61; P, The research of this paper is time‐effective, innovative, and practical. It may help clinician to judge the prognosis of the patients with NPC and guide the treatment decision.

IMPORTANCE: Capecitabine maintenance therapy improves survival outcomes in various cancer types, but data are limited on the efficacy and safety of capecitabine maintenance therapy in metastatic nasopharyngeal carcinoma (NPC). OBJECTIVE: To investigate the efficacy and safety of capecitabine maintenance therapy in metastatic NPC. DESIGN, SETTING, AND PARTICIPANTS: This randomized phase 3 clinical trial was conducted at Sun Yat-sen University Cancer Center from May 16, 2015, to January 9, 2020, among 104 patients with newly diagnosed metastatic NPC who had achieved disease control after 4 to 6 cycles of induction chemotherapy with paclitaxel, cisplatin, and capecitabine. The final follow-up date was May 30, 2021. All efficacy analyses were conducted in the intention-to-treat population. INTERVENTIONS: Eligible patients were randomly assigned (1:1) to receive either capecitabine maintenance therapy (1000 mg/m(2) orally twice daily on days 1-14) every 3 weeks plus best supportive care (BSC) (capecitabine maintenance group) or BSC alone after 4 to 6 cycles of induction chemotherapy. MAIN OUTCOMES AND MEASURES: Progression-free survival (PFS). Secondary end points were objective response rate, duration of response, overall survival, and safety. RESULTS: This study included 104 patients (84 men [80.8%]; median age, 47 years [IQR, 38-54 years]), with 52 assigned to the capecitabine maintenance group and 52 assigned to the BSC group. After a median follow-up of 33.8 months (IQR, 22.9-50.7 months), there were 23 events (44.2%) of progression or death in the capecitabine maintenance group and 37 events (71.2%) of progression or death in the BSC group. Median PFS survival was significantly higher in the capecitabine maintenance group (35.9 months [95% CI, 20.5 months-not reached]) than in the BSC group (8.2 months [95% CI, 6.4-10.0 months]), with a hazard ratio of 0.44 (95% CI, 0.26-0.74; P = .002). Higher objective response rates and longer median duration of response were observed in the capecitabine maintenance group (25.0%; 40.0 months) compared with the BSC group (objective response rate, 25.0% [n = 13] vs 11.5% [n = 6]; and median duration of response, 40.0 months [95% CI, not reached-not reached] vs 13.2 months [95% CI, 9.9-16.5 months]). The most common grade 3 or 4 adverse events during maintenance therapy were anemia (6 of 50 [12.0%]), hand-foot syndrome (5 of 50 [10.0%]), nausea and vomiting (3 of 50 [6.0%]), fatigue (2 of 50 [4.0%]), and mucositis (2 of 50 [4.0%]). No deaths in the maintenance group were deemed treatment-related. CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, capecitabine maintenance therapy significantly improved PFS for patients with newly diagnosed metastatic NPC who achieved disease control after capecitabine-containing induction chemotherapy. Capecitabine exhibited manageable toxic effects. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02460419

Background To explore the prognostic value of early radiological response (ERR) to first‐line platinum‐containing chemotherapy in patients with metastatic nasopharyngeal carcinoma (mNPC), as well as its correlation with the best radiological response (BRR). Patients and methods A total of 756 mNPC patients with measurable lesions who received first‐line platinum‐containing chemotherapy were enrolled in this study. ERR was defined as complete or partial response after 6 weeks of chemotherapy according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. We performed survival analyses according to the radiological response after repeated chemotherapy. Log‐rank test and Cox regression were used to analyze the survival data. Results About 470 patients achieved ERR and 78 patients achieved subsequent response (objective response after repeated chemotherapy). ERR patients had better OS (P, The radiological response to chemotherapy is a critical feature in the clinical evaluation of antitumor effects and associated with survival outcome. Our study suggested that early radiological response is helpful in giving prognostic information for both physicians and patients, and also valuable in selecting patients for more intensive multidisciplinary treatments.

ImportanceInduction or adjuvant chemotherapy with concurrent chemoradiotherapy (CCRT) are first-line treatment options for treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Adjuvant platinum regimens are, however, poorly tolerated, highlighting the unmet need for an efficacious, tolerable adjuvant regimen.ObjectiveTo investigate the efficacy and safety of adjuvant capecitabine with CCRT for the treatment of patients with LA-NPC.Design, Setting, and ParticipantsThis open-label randomized clinical trial recruited patients from March 31, 2014, to July 27, 2018, at 3 institutions in China, with at least 3 years of follow-up. The data collection cutoff date was February 9, 2022. Eligibility included stage III-IVb nasopharyngeal carcinoma and at least 1 of the following: T3-4N2 or T1-4N3; plasma Epstein-Barr virus DNA titer higher than 20 000 copies/mL; primary gross tumor volume larger than 30.0 cm3; fluorodeoxyglucose F 18 positron emission tomography/computed tomography maximum standard uptake value of the primary gross tumor volume larger than 10.0; or multiple nodal metastases and any larger than 4.0 cm.InterventionsPatients were randomly assigned 1:1 to receive either capecitabine (1000 mg/m2 twice daily for 14 days every 3 weeks for 8 cycles) or observation following CCRT (100 mg/m2 cisplatin every 3 weeks for 2 to 3 cycles, depending on duration of radiotherapy).Main Outcomes and MeasuresFailure-free survival in the intention-to-treat cohort was assessed using Kaplan-Meier survival curves compared with the log-rank test. Unstratified Cox proportional hazards regression models were used to estimate hazard ratios, with corresponding 95% CIs based on the Wald test.ResultsThere were 180 patients enrolled (median [IQR] age, 47 [40-55] years; 143 [79.4%] men). Among 90 patients in the capecitabine group, 76 (84.4%) had at least 2 high-risk factors; among 90 patients in the control group, 80 (88.9%) had at least 2 high-risk factors. All patients completed CCRT, except 1 patient in the capecitabine group who received 1 cycle of cisplatin. Of the 90 patients in the capecitabine group, 85 (94.4%) received capecitabine, with 71 (78.9%) completing 8 cycles. With a median (IQR) follow-up of 58.0 (49.5-80.1) months, 18 events were recorded in the capecitabine group vs 31 events in the control group. Failure-free survival was improved with adjuvant capecitabine (3 years, 83.3% vs 72.2%; 5 years, 78.5% vs 65.9%; hazard ratio, 0.53 [95% CI, 0.30-0.94]; P = .03). The incidence of grade 3 treatment-related adverse events (TRAEs) was higher in the capecitabine group than in the control group (54 of 90 patients [60.0%] vs 46 of 90 patients [51.1%]). Treatment-related adverse events included xerostomia (17 [18.9%] vs 9 [10.0%] patients), mucositis (21 [23.3%] vs 15 [16.7%] patients), and anorexia (8 [8.9%] vs 4 [4.4%] patients). The incidence of grade 3 delayed treatment-related adverse events was comparable in both groups (9 of 83 [10.8%] vs 7 of 81 [8.6%] patients).Conclusions and RelevanceIn this randomized clinical trial, adjuvant capecitabine at the full dose following CCRT was well tolerated and improved failure-free survival among patients with LA-NPC and high-risk factors. Further investigations assessing optimal dose and duration are warranted.Trial RegistrationClinicalTrials.gov Identifier: NCT02143388

Wang-Zhong Li,1,2,* Xin Hua,3,* Shu-Hui Lv,1,2,* Hu Liang,1,2 Guo-Ying Liu,1,2 Nian Lu,1,2 Wei-Xin Bei,1,2 Wei-Xiong Xia,1,2 Yan-Qun Xiang1,2 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 2Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 3Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan-Qun Xiang; Wei-Xiong XiaDepartment of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of ChinaTel +86-1866-6096-623Email xiangyq@sysucc.org.cn; xiawx@sysucc.org.cnPurpose: We aimed to develop a simple scoring system based on baseline inflammatory and nutritional parameters to predict the efficacy of first-line chemotherapy and survival outcomes for de novo metastatic nasopharyngeal carcinoma (mNPC).Patients and Methods: We retrospectively collected ten candidate inflammatory and nutritional parameters from de novo mNPC patients who received platinum-based first-line chemotherapy treatment. We examined the effects of these ten candidate variables on progression-free survival (PFS) using the Cox regression model. We built a risk-scoring system based on the regression coefficients associated with the identified independent prognostic factors. The predictive accuracy of the scoring system was evaluated and independently validated.Results: A total of 460 patients were analyzed. Four independent prognostic factors were identified in a training cohort and were used to construct the scoring system, including nutritional risk index, C-reactive protein level, alkaline phosphatase level, and lactate dehydrogenase level. Based on the score obtained from the scoring system, we stratified patients into three prognostic subgroups (low: 0– 1 point, intermediate: 2– 3 points, and high: 4 points) associated with significantly different disease control rates (94.7% vs. 92.5% vs. 66.0%, respectively) and survival outcomes (3-year PFS: 55.8% vs. 29.1% vs. 11.9%, respectively). The scoring system had a good performance for the prediction of short-term disease control (area under the receiver operating characteristic curve [AUC]: 0.701) and long-term survival outcomes (time-dependent AUC for 5-year PFS: 0.713). The results were internally validated using an independent cohort (AUC for predicting disease control: 0.697; time-dependent AUC for 5-year PFS: 0.713).Conclusion: We developed and validated a clinically useful risk-scoring system that could predict the efficacy of first-line chemotherapy and survival outcomes in de novo mNPC patients. This system may help clinicians to design personalized treatment strategies.Keywords: metastatic nasopharyngeal carcinoma, nutritional status, cancer-related inflammation, chemotherapy efficacy, survival outcomes

Background The mortality of nasopharyngeal carcinoma (NPC) is usually lower in females than in males, but the underlying mechanism remains largely unknown. We sought to describe the age-dependent patterns of gender disparities in NPC survival and explore the extent to which the confounder or mediation effects could explain these differences. Methods A total of 11,980 patients with NPC were reviewed. The effect of gender on cancer-specific survival (CSS) was assessed using Cox regression analyses. Two propensity score methods were conducted to control the confounding bias between genders. Restricted cubic spline regression was used to model the association of gender and age with mortality flexibly. Multiple mediation analysis was applied to estimate the direct or indirect effect of gender on CSS. Results Overall, 7026 males and 2320 females were analyzed. The crude CSS was significantly higher for females than males (10-year CSS 78.4% vs 70.3%; P < 0.001). Similar results were observed after adjusting for confounding bias. Gender disparities in NPC-specific mortality were age-dependent, where they would increase with age until peaking at age 55–60 years and decline rapidly afterward. Subgroup analyses revealed that females’ survival advantage was observed in the 18–45 age group and was more prominent in the 46–55 age group, but vanished in the > 55 age group. Either confounder or mediation effects only accounted for approximately 20% of the gender differences. Conclusions Gender disparities in cancer-specific mortality for patients with NPC were age-dependent. The differences mostly cannot be explained by confounder or mediation effects.

Background: No consensus in sequence selection for artificial intelligence model development has been achieved, we aimed to explore whether contrast-enhanced magnetic resonance imaging (ceMRI) could be substituted in the identification and segmentation of nasopharyngeal carcinoma (NPC) with the aid of deep learning models in a large-scale cohort. Methods: A total of 4,478 eligible individuals were randomly split into training, validation and test sets. The diagnostic performance between NPC and benign hyperplasia and segmentation efficacy in NPC were compared among self-constrained 3D DenseNet models developed using axial T1-weighted imaging (T1WI), T2WI or enhanced T1WI (T1WIC) images separately. Findings: All developed models exhibited similar satisfactory diagnostic performance in discriminating NPC from benign hyperplasia, attaining over accuracy over 99.00% in all T stages of NPC. However, the T1WIC model yielded a significantly higher dice similarity coefficient (DSC) and lower average surface distance (ASD) than either the T1WI model or T2WI model in the test set of NPC cohort (DSC, 0.768±0.070 vs 0.759±0.065 and 0.755±0.071, p < 0.001; ASD, 1.573±0.954 mm vs 1.661±0.898 mm and 1.722±1.133 mm, p < 0.01).Interpretation: Unenhanced MRI could substitute ceMRI in discriminating NPC from benign hyperplasia but not in the segmentation for NPC with the aid of deep learning models and ceMRI remained the optimal sequence for developing segmentation models for NPC , indicating the feasibility of reducing the use of MR contrast in screening program. Funding: This work was supported by the National Natural Science Foundation of China [Grant No. 31900461, 81702873, 81872375, 81572665, 81802712]. Declaration of Interest: Nothing to disclose. Ethical Approval: The ethics committee of the authors’ institution approved the study protocol and patient consent was waived due to the retrospective nature of the study.

Background There is no clinically applicable prognostic model designed for patients with de novo metastatic nasopharyngeal carcinoma (mNPC) treated with chemotherapy followed by locoregional radiotherapy (LRRT). We sought to develop a predictive tool of overall survival for individualized prediction and risk stratification in this heterogeneous patient population. Patients and methods A total of 244 eligible patients with de novo mNPC, who were treated with platinum-based first-line chemotherapy followed by LRRT, were included in this retrospective study. We divided patients into the training and validation sets based on the date of initial treatment, with 152 patients treated between 2008 and 2013 comprising the training set for model development and 92 patients treated at a later time (2014 to 2015) forming the validation set. We applied Cox proportional hazards model to examine factors associated with overall survival (OS). We developed and subsequently validated a prognostic model to predict OS. We assessed the performance of this prognostic model and stratified patients based on prognostic scores obtained from this proposed model. Results The median OS of the entire cohort was 60.9 months. C-creative protein, number of metastatic sites, liver metastasis, post-treatment Epstein–Barr virus DNA, and response of metastasis were significantly associated with OS. A prognostic model for individual survival prediction was developed and graphically represented as a nomogram. The model showed favorable discrimination (C-index: 0.759), predictive accuracy [time dependent area under the curve (tAUC) at 5 years: 0.800], and calibration, and was further validated in an independent dataset. A risk stratification derived from the model can stratify these patients into three prognostic subgroups with significantly different survival. Conclusion We developed and validated a prognostic model that exhibited adequate performance in individualized prediction and risk stratification for patients with de novo mNPC treated with chemotherapy followed by LRRT., Highlights • We developed and validated a prognostic model for patients with de novo mNPC treated with chemotherapy followed by LRRT. • The prognostic model exhibited adequate performance in individualized prediction and risk stratification. • The prognostic model can stratify patients into three prognostic subgroups with distinctly different survival. • The prognostic model could be helpful in making individualized treatment recommendations in clinical practice.

Objectives We aimed to build a survival system by combining a highly-accurate machine learning (ML) model with explainable artificial intelligence (AI) techniques to predict distant metastasis in locoregionally advanced nasopharyngeal carcinoma (NPC) patients using magnetic resonance imaging (MRI)-based tumor burden features. Materials and methods 1643 patients from three hospitals were enrolled according to set criteria. We employed ML to develop a survival model based on tumor burden signatures and all clinical factors. Shapley Additive exPlanations (SHAP) was utilized to explain prediction results and interpret the complex non-linear relationship among features and distant metastasis. We also constructed other models based on routinely used cancer stages, Epstein-Barr virus (EBV) DNA, or other clinical features for comparison. Concordance index (C-index), receiver operating curve (ROC) analysis and decision curve analysis (DCA) were executed to assess the effectiveness of the models. Results Our proposed system consistently demonstrated promising performance across independent cohorts. The concordance indexes were 0.773, 0.766 and 0.760 in the training, internal validation and external validation sets. SHAP provided personalized protective and risk factors for each NPC patient and uncovered some novel non-linear relationships between features and distant metastasis. Furthermore, high-risk patients who received induction chemotherapy (ICT) and concurrent chemoradiotherapy (CCRT) had better 5-year distant metastasis-free survival (DMFS) than those who only received CCRT, whereas ICT + CCRT and CCRT had similar DMFS in low-risk patients. Conclusions The interpretable machine learning system demonstrated superior performance in predicting metastasis in locoregionally advanced NPC. High-risk patients might benefit from ICT.

Nasopharyngeal carcinoma (NPC) is highly incident in southern China. Distant metastasis is the leading cause of death in NPC patients. However, the phenotypical feature of this patient population is largely undefined. The current study aimed to categorize metastatic NPC patients into novel subgroups based on their EBV DNA trajectories. In this retrospective study, 446 eligible patients with metastatic NPC treated at Sun Yat-Sen University Cancer Center between 2012 and 2016 were analyzed. Using a mixture model analysis, we identified distinct trajectories based on longitudinal EBV DNA measurements. We evaluated their associations with metastatic NPC mortality using Cox regression analysis. The two-class trajectory model provided the best fit, in which 272 patients were classified as non-sustained EBV DNA class and 174 patients as sustained EBV DNA class. After a median follow-up of 60.8 months, the median OS was 61.7 months in the sustained EBV DNA clearance class versus 20.0 months in the non-sustained EBV DNA clearance class (P

Induction chemotherapy added to concurrent chemoradiotherapy significantly improves survival for patients with locoregionally advanced nasopharyngeal carcinoma, but the optimal induction regimen remains unclear.To determine whether induction chemotherapy with paclitaxel, cisplatin, and capecitabine (TPC) improves survival vs cisplatin and fluorouracil (PF) prior to chemoradiotherapy for patients with stage IVA to IVB nasopharyngeal carcinoma.This randomized, open-label, phase 3 clinical trial recruited 238 patients at 4 hospitals in China from October 20, 2016, to August 29, 2019. Patients were 18 to 65 years of age with treatment-naive, nonkeratinizing stage IVA to IVB nasopharyngeal carcinoma and an Eastern Cooperative Oncology Group performance status of 0 to 1.Patients were randomly assigned (1:1) to receive induction chemotherapy with two 21-day cycles of TPC (intravenous paclitaxel [150 mg/m2, day 1], intravenous cisplatin [60 mg/m2, day 1], and oral capecitabine [1000 mg/m2 orally twice daily, days 1-14]) or PF (intravenous cisplatin [100 mg/m2, day 1] and fluorouracil [800 mg/m2 daily, days 1-5]), followed by chemoradiotherapy.The primary end point was failure-free survival in the intention-to-treat population. Secondary end points included distant metastasis-free survival, locoregional relapse-free survival, overall survival, tumor response, and safety.Overall, 238 eligible patients (187 men [78.6%]; median age, 45 years [range, 18-65 years]) were randomly assigned to receive TPC (n = 118) or PF (n = 120). The median follow-up duration was 48.4 months (IQR, 39.6-53.3 months). Failure-free survival at 3 years was 83.5% (95% CI, 77.0%-90.6%) in the TPC group and 68.9% (95% CI, 61.1%-77.8%) in the PF group (stratified hazard ratio [HR] for recurrence or death, 0.47; 95% CI, 0.28-0.79; P = .004). Induction with the TPC regimen resulted in a significant reduction in the risk of distant metastases (stratified HR, 0.49 [95% CI, 0.24-0.98]; P = .04) and locoregional recurrence (stratified HR, 0.40 [95% CI, 0.18-0.93]; P = .03) compared with the PF regimen. However, there was no effect on early overall survival (stratified HR, 0.45 [95% CI, 0.17-1.18]; P = .10). The incidences of grade 3 to 4 acute adverse events and late-onset toxicities were 57.6% (n = 68) and 13.6% (16 of 118), respectively, in the TPC group and 65.8% (n = 79) and 17.9% (21 of 117), respectively, in the PF group. One treatment-related death occurred in the PF group.This randomized clinical trial found that induction chemotherapy with 2 cycles of TPC for patients with stage IVA to IVB nasopharyngeal carcinoma improved failure-free survival compared with 2 cycles of PF, with no increase in the toxicity profile.ClinicalTrials.gov Identifier: NCT02940925.

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

Summary Background Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma. Methods In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18–60 years with previously untreated, non-keratinising stage III–IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1–5 and 22–26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1–5 and 22–26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68–70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62–68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30–32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed. Findings From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9–81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7–80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio [HR] 0·98, 95% CI 0·69–1·39; log-rank p=0·92), with a difference of 0·5% (95% CI −7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (−6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3–4 adverse events were mucositis (102 [41%] of 252 in the lobaplatin-based group vs 99 [40%] of 249 in the cisplatin-based group), leucopenia (39 [16%] vs 56 [23%]), and neutropenia (25 [10%] vs 59 [24%]). No treatment-related deaths were reported. Interpretation Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma. Funding National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. Translation For the Chinese translation of the abstract see Supplementary Materials section.

We aimed to develop a nomogram integrating MRI-based tumor burden features (MTBF), nodal necrosis, and some clinical factors to forecast the distant metastasis-free survival (DMFS) of patients suffering from non-metastatic nasopharyngeal carcinoma (NPC). A total of 1640 patients treated at Sun Yat-sen University Cancer Center (Guangzhou, China) from 2011 to 2016 were enrolled, among which 1148 and 492 patients were randomized to a training cohort and an internal validation cohort, respectively. Additionally, 200 and 257 patients were enrolled in the Foshan and Dongguan validation cohorts, respectively, which served as independent external validation cohorts. The MTBF were developed from the stepwise regression of six multidimensional tumor burden variables, based on which we developed a nomogram also integrating nodal necrosis and clinical features. This model divided the patients into high- and low-risk groups by an optimal cutoff. Compared with those of patients in the low-risk group, the DMFS [hazard ratio (HR): 4.76, 95% confidence interval (CI): 3.39–6.69; p < 0.0001], and progression-free survival (PFS; HR: 4.11, 95% CI: 3.13–5.39; p < 0.0001) of patients in the high-risk group were relatively poor. Furthermore, in the training cohort, the 3-year DMFS of high-risk patients who received induction chemotherapy (ICT) combined with concurrent chemoradiotherapy (CCRT) was better than that of those who were treated with CCRT alone (p = 0.0340), whereas low-risk patients who received ICT + CCRT had a similar DMFS to those who only received CCRT. The outcomes we obtained were all verified in the three validation cohorts. The survival model can be used as a reliable prognostic tool for NPC patients and is helpful to determine patients who will benefit from ICT.

Objectives We aimed to develop a dual-task model to detect and segment nasopharyngeal carcinoma (NPC) automatically in magnetic resource images (MRI) based on deep learning method, since the differential diagnosis of NPC and atypical benign hyperplasia was difficult and the radiotherapy target contouring of NPC was labor-intensive. Materials and methods A self-constrained 3D DenseNet (SC-DenseNet) architecture was improved using separated training and validation sets. A total of 4100 individuals were finally enrolled and split into the training, validation and test sets at a proximate ratio of 8:1:1 using simple randomization. The diagnostic metrics of the established model against experienced radiologists was compared in the test set. The dice similarity coefficient (DSC) of manual and model-defined tumor region was used to evaluate the efficacy of segmentation. Results Totally, 3142 nasopharyngeal carcinoma (NPC) and 958 benign hyperplasia were included. The SC-DenseNet model showed encouraging performance in detecting NPC, attained a higher overall accuracy, sensitivity and specificity than those of the experienced radiologists (97.77% vs 95.87%, 99.68% vs 99.24% and 91.67% vs 85.21%, respectively). Moreover, the model also exhibited promising performance in automatic segmentation of tumor region in NPC, with an average DSC at 0.77 ± 0.07 in the test set. Conclusions The SC-DenseNet model showed competence in automatic detection and segmentation of NPC in MRI, indicating the promising application value as an assistant tool in clinical practice, especially in screening project.

We aimed to develop an accurate prognostic model to identify suitable candidates for definitive radiation therapy (DRT) in addition to palliative chemotherapy (PCT) among patients with de novo metastatic nasopharyngeal carcinoma (mNPC).Patients with de novo mNPC who received first-line PCT with or without DRT were included. Overall survival for patients who received PCT alone versus PCT plus DRT was estimated using inverse probability of treatment weighting-adjusted survival analyses. We developed and validated a prognostic model to predict survival and stratify risks in de novo mNPC. A model-based trees approach was applied to estimate stratified treatment effects using prognostic scores obtained from the prognostic model and to identify suitable DRT candidates. Dominance analysis was used to determine the relative importance of each predictor of receiving DRT.A total of 460 patients were enrolled; 244 received PCT plus DRT and 216 received PCT alone. The 6-month conditional landmark, inverse probability of treatment weighting-adjusted Cox regression analysis showed that PCT plus DRT was associated with a significant survival benefit (hazard ratio: 0.516; 95% confidence interval, 0.403-0.660; P.001). A prognostic model based on 5 independent prognostic factors, including serum lactate dehydrogenase, number of metastatic sites, presence of liver metastasis, posttreatment Epstein-Barr virus DNA level, and response of metastases to chemotherapy was developed and subsequently validated. Prognostic scores obtained from the prognostic model were used for risk stratification and efficacy estimation. High-risk patients identified using the proposed model would not benefit from additional DRT, whereas low-risk patients experienced significant survival benefits. Socioeconomic factors, including insurance status and education level, played an important role in receipt of DRT.Additional DRT after PCT was associated with increased overall survival in patients with de novo mNPC, especially low-risk patients identified with a newly developed prognostic model.

There were few studies focused on the cervical lymph necrosis (CNN) of nasopharyngeal carcinoma (NPC) patients to develop a nomogram and guide the treatment decision at the era of intensity modulated radiation therapy (IMRT).The prognostic accuracy of CNN in the training cohort (n = 1940) was validated in Guangzhou internal validation cohort (n = 832) and two external validation cohorts (Dongguan, n = 232; Foshan, n = 134).The primary end point was progression-free survival (PFS), calculated using the Kaplan-Meier method. After a median 60.0 months' follow-up, patients with CNN in the training cohort had worse 5-year PFS (70.8% vs. 89.1%, P 0.001) than patients without CNN, which was validated in the validation cohorts. The nomogram based on CNN predicted an individual PFS risk (training: C-index 0.733; Guangzhou validation: C-index 0.736; Foshan: C-index 0.722; Dongguan: C-index 0.756). Stage N2 patients in the CNN group and stage IV patients no matter the status of CNN, PFS was better with induction chemotherapy (ICT) and CCRT than CCRT (P 0.05).Taken together, CNN reliably predicts survival risk in NPC patients. N2 patients in the CNN group and stage IV patients may receive survival benefit from ICT.

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

To retrospectively investigate the optimal regimen of concurrent chemotherapy for nasopharyngeal carcinoma (NPC) by comparing clinical outcomes of patients who received platinum-based and non-platinum-based concurrent chemoradiotherapy (CCRT) regimens. Based on a prospectively maintained database from 1998 to 2013 in an endemic area, a total of 4608 newly diagnosed, biopsy-proven, and non-disseminated NPC patients were identified and allocated into three cohorts based on concurrent chemotherapy regimens: cisplatin-based (CP) chemotherapy cohort, other platinum-based (OP) chemotherapy cohort, and non-platinum-based (NP) chemotherapy cohort. Overall survival (OS) and disease-free survival (DFS) were estimated using the Cox proportional hazards model and propensity score analysis of treatment using an inverse probability weighting model (PSA/IPTW). Finally, sensitivity analysis estimated the effects of potential unmeasured confounders. The median follow-up time was 68.5 months (range 2–194 months). The multivariate Cox model showed that NP regimens were significantly related with worse survival compared with CP or OP regimens (OS: HR 1.51, 95% CI 1.16–2.00, P = 0.002; HR 1.68, 95% CI 1.24–2.27, P = 0.001; DFS: HR 1.31, 95% CI 1.03–1.66, P = 0.031; HR 1.50, 95% CI 1.14–1.97, P = 0.004, respectively). Meanwhile, no significant survival difference was found between OP and CP regimens. The PSA/IPTW method, CCRT-specific and III–IVB NPC cohort subgroup analysis showed similar results. Sensitivity analysis confirmed the robustness of our results. Platinum-based concurrent chemotherapy, including both CP and OP regimens, yields better survival benefits for non-metastatic NPC patients than the NP regimen and remains the optimal regimen for these patients.

This abstract was not presented at the symposium.

Purpose: To date, no guidelines exist for elderly nasopharyngeal carcinoma (NPC) patients (60 years of age or older) due to a lack of prospective clinical trials. This study evaluated the efficacy of concurrent chemotherapy (CCRT) for NPC in elderly patients treated with intensity-modulated radiotherapy (IMRT). Methods: Patients were identified from a prospectively maintained database. A total of 198 consecutive cases of elderly patients with NPC receiving IMRT, including 103 patients treated with IMRT plus CCRT and 95 patients treated with IMRT alone, were analysed from January 2002 to December 2013. Multivariate analysis (MVA) using the Cox proportional hazards model and propensity score analysis (PSA) were performed for overall survival (OS) and disease-free survival (DFS). Finally, sensitivity analysis was performed. Results: The median follow-up time was 55.3 months (range, 3-135.6 months). In the entire cohort, both MVA and PSA models showed that compared with IMRT alone, IMRT plus CCRT significantly improved survival (hazard ratio [HR] 2.143, 95% confidence interval [95% CI] 1.180-3.890; HR 1.961, 95% CI, 1.117-3.443, for OS and DFS, respectively). Similar results were found in the subgroups with high levels of Epstein-Barr virus (EBV) DNA, except in the low-EBV-DNA cohort. The total rates of severe acute toxicity, including leukopenia, neutropenia, stomatitis, and emesis, were significantly higher in the IMRT+CCRT group than in the IMRT-alone group (P < 0.001) but were similar to the rates of severe late toxicity (P = 0.818). Sensitivity analysis confirmed the robustness of our analysis. Conclusions: In the era of IMRT, CCRT retained survival benefits at high EBV DNA levels but not at low EBV DNA levels for elderly NPC patients. Randomized clinical trials are needed to confirm our findings.

Key Points Question Can incorporating Epstein-Barr virus DNA status into analysis of the tumor-node-metastasis framework improve cancer staging quality in nasopharyngeal carcinoma? Findings In this multicenter prognostic study of 2354 patients in China, a recursive partitioning analysis (RPA)–based staging system that divided nonmetastatic nasopharyngeal carcinoma cases into 3 groups with distinctly different prognoses was developed and validated. The RPA stage system outperformed the current TNM staging and 2 reported RPA staging schemes. Meaning These results suggest that an RPA-based staging system can outperform conventional TMN staging groups for predicting survival rates., This prognostic study describes the development and validation of a novel staging system for nonmetastatic nasopharyngeal carcinoma based on recursive partitioning analysis of Epstein-Barr virus status., Importance Nonanatomic prognostic factors complement the traditional anatomic staging system and could be incorporated into the tumor-node-metastasis (TNM) framework. Several diseases have incorporated nonanatomic prognostic factors into the determination of TNM staging groups. Objective To refine TNM staging groups for Epstein-Barr virus (EBV)–related nonmetastatic nasopharyngeal carcinoma (NPC) by incorporating EBV DNA status. Design, Setting, and Participants This multicenter prognostic study included patients with NPC treated with radiotherapy at 2 hospitals in China from January 2008 to December 2016. Progression-free survival and overall survival according to EBV DNA status and the TNM staging system were compared. Recursive partitioning analysis (RPA) combined with supervised clustering was applied to derive prognostic groupings, and then a refined RPA staging schema was developed, validated, and compared with existing staging schemes. Statistical analyses were conducted from October 1, 2020, to June 15, 2021. Exposures Curative intensity-modulated radiotherapy with or without platinum-based chemotherapy. Main Outcomes and Measures The primary end point was progression-free survival. The performance of the staging system was assessed using the time-dependent area under the receiver operating characteristic curves and the TNM stage system’s evaluation methodology. Results A total of 2354 patients (1709 men [72.6%]; median [interquartile range] age, 45 [38-53] years) were split into training (1372 [58.3%]), internal validation (672 [28.5%]), and external validation (310 [13.2%]) cohorts. Pretreatment EBV DNA was detected in 1338 (56.8%) patients. EBV DNA status was an independent prognostic factor: lower survival probability by higher TNM stage was evident in EBV DNA–positive patients but not in those with EBV DNA–negative disease. After integrating EBV DNA status and TNM stage, nonmetastatic NPC cases were categorized into RPA-I (T1-3N0 or EBV DNA–negative T1-3N1 cancers), RPA-II (EBV DNA–positive T1-3N1-2 or EBV DNA–negative T1-3N2-3/T4N0-3 cancers), and RPA-III (EBV DNA–positive T4N0-3/T1-3N3 cancers) groups, each with distinctly different prognosis. This system of RPA staging outperformed the current TNM stage system and 2 reported RPA staging schemes. These results were internally and externally validated. Conclusions and Relevance An RPA-based staging system for EBV-related NPC cases was associated with improved outcomes. This staging system may facilitate prognostic stratification and clinical trial designs.

Objective To compare the effectiveness of concurrent cisplatin chemoradiotherapy plus cetuximab with that of concurrent chemoradiotherapy (CCRT) alone in locoregionally advanced nasopharyngeal carcinoma (LRANPC) patients. Materials and methods A total of 3257 LRANPC patients from a prospectively maintained database were included in this observational study to examine the effectiveness of adding cetuximab to CCRT. We compared overall survival (OS), disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) using the propensity score method. Results In this cohort, 131 patients received CCRT plus cetuximab. Cetuximab-treated patients were more likely to receive intensity-modulated radiation therapy and were less likely to receive induction chemotherapy or adjuvant chemotherapy. The addition of cetuximab was associated with increased DMFS compared with CCRT alone based on univariable and multivariable analyses (5-year OS, 94.1% vs. 87.3%; P = 0.044), but not with increased OS, DFS, or LRRFS. Propensity score matching identified 96 patients in each cohort and confirmed that a DMFS benefit was associated with the addition of cetuximab (HR, 0.38; 95% CI, 0.15–0.99, P = 0.044). Subgroup analyses demonstrated a significant DMFS benefit with CCRT plus cetuximab in patients with N2-N3 stage disease compared with N2-N3 patients receiving CCRT alone (87.9% and 66.2%, respectively; P = 0.045). Conclusions In conclusion, the addition of cetuximab to first-line chemoradiotherapy is associated with an improvement in DMFS in patients with LRANPC. A prospective randomized clinical trial will be necessary to validate this result.