Locoregionally Advanced Nasopharyngeal Carcinoma Research Articles

Adjuvant Capecitabine Following Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma

Induction 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. To investigate the efficacy and safety of adjuvant capecitabine with CCRT for the treatment of patients with LA-NPC. This 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. Patients 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). Failure-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. There 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). In 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. ClinicalTrials.gov Identifier: NCT02143388.

Long-term results of the phase II dose and volume de-escalation trial for locoregionally advanced nasopharyngeal carcinoma

ObjectivePatients with locoregionally advanced nasopharyngeal carcinoma (LANPC) were assigned to dose and volume de-escalated intensity-modulated radiation therapy (IMRT) based on response to induction chemotherapy (IC) to limit treatment related toxicity while preserving efficacy. Methods and materialsA single-arm de-escalated phase II trial was performed in this study. Patients with LANPC received two cycles of IC with docetaxel 60 mg/m2 d1, cisplatin 25 mg/m2/day d1-3 and 5-fluorouracil 500 mg/m2/day d1-5 q21d, followed by IMRT. The gross tumor volume of the primary intracavity nasopharyngeal tumor and involved lymph nodes were delineated based on the post-IC tumor extension. Part of the prescribed doses were reduced from 70.4 Gy to 66 Gy for T3-4 diseases. The primary end point was 5-year progression-free survival (PFS) in stage III and IVA-B NPC compared with historical controls of 50% and 35%. ResultsBetween January 2010 and November 2013, 48 and 83 eligible patients with stage III and IVA-B NPC were accrued to this trial. With a median follow-up of 92 months, the 5-year and 8-year estimated PFS were 89.6% and 76.0%, 63.9% and 58.0% for patients with stage III and IVA-B disease, which were all improved in comparison with historical controls. Grade 3 acute mucositis were developed in 27.5% patients. Cranial neuropathy and asymptomatic temporal lobe necrosis were found in 2.3% and 1.5% patients. ConclusionDose and volume de-escalated IMRT was associated with high PFS and mild late neurological toxicities for IC responders. Further exploration of de-escalation strategies in appropriate patients is needed.Clinical trial registration: Clinical trials.gov identifier: NCT03389295.

Individualized number of induction chemotherapy cycles for locoregionally advanced nasopharyngeal carcinoma patients based on early tumor response.

The optimal number of cycles of induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LANPC) is unclear. We aimed to combine the tumor response during IC and tumor stage to individualize the number of IC cycles. Totally, 498 LANPC patients who received IC plus CCRT between 2014 and 2018 were reviewed. Tumor response during IC was used to stratify patients with different risks. All patients were classified into those who received two cycles of IC and those who were treated with three cycles. Propensity score matching methods were performed to compare the treatment efficiency. After two cycles of IC, 340/498 (68.3%) cases showed complete tumor response (CR)/partial response (PR) and 158 (31.7%) achieved stable disease (SD)/disease progression (PD). Unfavorable responders (SD/PD) exhibited poor survival outcomes. The three-cycle IC regimen was correlated with better OS and PFS than the two-cycle regimen for N2-3 patients in the CR/PR group. However, the use of different IC cycle strategies achieved similar survival outcomes for SD/PD or N0-1 patients. The incidences of acute toxicities were higher in the IC=3 group. Tumor response during IC could be a powerful predictor of LANPC and could be used to guide the individualized number of IC cycles. A three-cycle IC regimen seemed to be preferable for N2-3 patients who received CR/PR during IC. However, an additional cycle of IC could not benefit N0-1 or SD/PD patients, and the optimal treatment strategies for these patients require further consideration.

Induction chemotherapy regimen of docetaxel plus cisplatin versus docetaxel, cisplatin plus fluorouracil followed by concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: Preliminary results of an open-label, noninferiority, multicentre, randomised, controlled phase 3 trial.

SummaryBackgroundInduction chemotherapy regimens of docetaxel and cisplatin plus fluorouracil (TPF) are currently clinically used for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) but have well-known side effects, such as myelosuppression and diarrhea. A docetaxel plus cisplatin (TP) regimen was developed to decrease the toxic effects induced by fluorouracil. In this trial, we assessed whether the TP induction chemotherapy regimen was noninferior to the TPF regimen.MethodsWe performed an open-label, noninferiority, phase 3, multicentre, randomised, controlled trial at six centres in China. Eligible patients with NPC (stage III-IVA (excluding T3-4N0), Karnofsky's Performance Scoring ≥70) were randomly assigned (1:1) to receive either TP (docetaxel (75 mg per square meter, d1, intravenous infusion) and cisplatin (75 mg per square meter of body-surface area, d1, intravenous infusion)) or TPF (docetaxel (60 mg per square meter, d1, intravenous infusion) plus cisplatin (60 mg per square meter, d1, intravenous infusion) and 5-fluorouracil (600 mg per square meter, d1-d5, intravenous 120-hour infusion)) administered every 3 weeks for 3 cycles followed by concurrent chemoradiotherapy. The primary endpoint was failure-free survival at 2 years. Secondary endpoints included overall survival, safety, and treatment compliance. The trial was stopped early because of strong evidence for noninferiority (margin was -10%) of TP in failure-free survival. Efficacy analyses were performed in both the intention-to-treat and per-protocol trial populations and we included the patients who started treatment in each group for the safety analysis. The study was registered with chictr.org.cn, ChiCTR1800016337.FindingsBetween June 1, 2018 and October 31, 2021, we randomly assigned 361 patients to the TP (n = 181) or TPF (n = 180) induction chemotherapy group. The 2-year failure-free survival was 91·3% (95% CI 86·2-96·4) in the TP group and 82·4% (84·8-88·9) in the TPF group (P = 0·029). Patients in the TPF group had a higher frequency of grade 1 or 2 neutropenia (53 (30·0%) vs. 28 (15·7%); P = 0·0010), grade 1 or 2 diarrhea (20 (11·3%) vs. 9 (5·1%); P = 0·032), and grade 3 or 4 neutropenia (43 (24·3%) vs. 25 (14·0%); P = 0·014) in the induction chemotherapy period. There was no treatment-related death.InterpretationThe preliminary results revealed that TP induction chemotherapy regimen was found to be clearly non-inferior compared to the TPF regimen in failure-free survival, with a lower frequency of neutropenia, anaemia and diarrhoea. The more convenient and beneficial survival regimen of the TP regimen should be recommended in patients with LA-NPC.FundingThis study was supported by grants from the Natural Science Foundation of Guangdong Province, China [grant number 2021A1515011182], Natural Science Foundation of Guangdong Province, China [grant number 2022A1515012272], National Natural Science Foundation of China [grant number 82072029] and National Natural Science Foundation of China [grant number 81903037].

Induction versus adjuvant chemotherapy combined with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: a retrospective cohort study.

Background: Currently available evidence favors the combination of chemotherapy with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma (LANPC). However, the optimal timing for additional chemotherapy is unclear. This study was conducted to compare the efficacy and toxicity of induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) versus concurrent chemoradiotherapy plus adjuvant chemotherapy (CCRT+AC).Methods: Two medical centers in China enrolled patients with LANPC (stage III-IVB) between January 2009 and May 2020. Through the use of propensity score matching (PSM), baseline characteristics were balanced. The primary endpoint was overall survival (OS), which was evaluated by the Kaplan-Meier method and log-rank test. Potential independent prognostic factors were identified using univariate and multivariate Cox proportional hazard analyses. Based on the chi-squared test, we compared the adverse events associated with treatment between the groups.Results: After the implementation of PSM, 159 patients treated with IC+CCRT and 72 patients treated with CCRT+AC were eventually enrolled in this study. There was no significant difference between patients treated with IC+CCRT and CCRT+AC in terms of 3-year OS (94.7% versus 90.9%, p=0.816), progression-free survival (PFS) (91.2% versus 83.1%, p=0.588), locoregional recurrence-free survival (LRFS) (92.5% versus 81.8%, p=0.478), or distant metastasis-free survival (DMFS) (93.4% versus 88.2%, p=0.783). There was no prognostic significance of the treatment for OS, PFS, LRFS, or DMFS (all p > 0.05) in the univariate and multivariate analyses. Patients treated with CCRT+AC had a higher incidence of grade 3 to 4 leucopenia (p=0.001) and neutropenia (p=0.001) than those treated with IC+CCRT.Conclusions: IC plus CCRT achieved comparable survival outcomes to CCRT plus AC and had a lower incidence of toxicity.

Prognostic significance of AKR1C4 and the advantage of combining EBV DNA to stratify patients at high risk of locoregional recurrence of nasopharyngeal carcinoma

BackgroundDistinguishing patients at a greater risk of recurrence is essential for treating locoregional advanced nasopharyngeal carcinoma (NPC). This study aimed to explore the potential of aldo–keto reductase 1C4 (AKR1C4) in stratifying patients at high risk of locoregional relapse.MethodsA total of 179 patients with locoregionally advanced NPC were grouped by different strategies; they were: (a) divided into two groups according to AKR1C4 expression level, and (b) classified into three clusters by integrating AKR1C4 and Epstein-Barr virus (EBV) DNA. The Kaplan–Meier method was used to calculate locoregional relapse-free survival (LRFS), overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). The Cox proportional hazards model was used to determine potential prognostic factors, and a nomogram was generated to predict 3-year and 5-year LRFS.ResultsA significant difference in the 5-year LRFS was observed between the high and low AKR1C4 expression groups (83.3% vs. 92.7%, respectively; p = 0.009). After integrating AKR1C4 expression and EBV DNA, the LRFS (84.7%, 84.5%, 96.9%, p = 0.014) of high-, intermediate-, and low- AKR1C4 and EBV DNA was also significant. Multivariate analysis indicated that AKR1C4 expression (p = 0.006) was an independent prognostic factor for LRFS. The prognostic factors incorporated into the nomogram were AKR1C4 expression, T stage, and EBV DNA, and the concordance index of the nomogram for locoregional relapse was 0.718.ConclusionsIn conclusion, high AKR1C4 expression was associated with a high possibility of relapse in NPC patients, and integrating EBV DNA and AKR1C4 can stratify high-risk patients with locoregional recurrence.

Efficacy and safety of a treatment in patients with locoregionally advanced nasopharyngeal carcinoma (LANC) involving carotid artery invasion.

Locally advanced nasopharyngeal carcinoma (LANC) often invades the parapharyngeal space and internal carotid artery. Are patients with LANC invading carotid artery are at risk of massive neck hemorrhage after radiotherapy? This retrospective study included 130 LANC patients with carotid artery invasion admitted to our hospital between January 2012 and September 2019. All patients were treated with induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) ± epidermal growth factor receptor (EGFR) inhibitor. Univariate and multivariate analysis of risk factors were conducted for the prognosis and the occurrence of massive neck hemorrhage of LANC patients with carotid artery invasion. The 5-year progression-free survival (PFS), distant metastasis-free survival (DMFS), local nodal recurrence-free survival (LNRFS), local recurrence-free survival (LRFS), nodal recurrence-free survival (NRFS) and overall survival (OS) of the 130 patients were 75.2%, 76.8%, 90.0%, 93.9%, 95.8% and 87.2%, respectively. The incidence of fatal bleeding after radiotherapy was 2.3% (3/130). The primary site of the three cases were all the pharyngeal recess, with more than 270° carotid artery invasion, suffering nasopharyngeal necrosis after radiotherapy (2 of which were diabetics and 1 received re-radiation after recurrence). Univariate analysis showed that clinical stage was negatively correlated with DMFS and PFS (P < 0.05). The induction chemotherapy TP regimen, platinum-based concurrent chemotherapy and EGFR inhibitors (Nituzumab/Cetuximab) significantly improved PFS and DMFS (P < 0.05). Patients with hemoglobin levels > 110g/L had significantly inferior PFS, DMFS and OS than those with hemoglobin levels ≤ 110g/L (P < 0.05). Multivariate analysis showed that the EGFR inhibitor was an independent risk factor for PFS and DMFS, while the lowest hemoglobin level was an independent risk factor for OS. In LANC patients whose carotid artery invasion was < 270°, induction chemotherapy (IC) followed by helical tomotherapy (HT) and concurrent chemoradiotherapy (CCRT) with EGFR (epidermal growth factor receptor) inhibitor had mild and tolerable side effects, better PFS and DMFS, with no massive hemorrhage. In patients whose primary tumor was pharyngeal recess with carotid artery invasion ≥ 270°, poorly controlled diabetes or re-radiotherapy led to a higher risk of massive hemorrhage after radiotherapy.

MRI-based random survival Forest model improves prediction of progression-free survival to induction chemotherapy plus concurrent Chemoradiotherapy in Locoregionally Advanced nasopharyngeal carcinoma

BackgroundThe present study aimed to explore the application value of random survival forest (RSF) model and Cox model in predicting the progression-free survival (PFS) among patients with locoregionally advanced nasopharyngeal carcinoma (LANPC) after induction chemotherapy plus concurrent chemoradiotherapy (IC + CCRT).MethodsEligible LANPC patients underwent magnetic resonance imaging (MRI) scan before treatment were subjected to radiomics feature extraction. Radiomics and clinical features of patients in the training cohort were subjected to RSF analysis to predict PFS and were tested in the testing cohort. The performance of an RSF model with clinical and radiologic predictors was assessed with the area under the receiver operating characteristic (ROC) curve (AUC) and Delong test and compared with Cox models based on clinical and radiologic parameters. Further, the Kaplan-Meier method was used for risk stratification of patients.ResultsA total of 294 LANPC patients (206 in the training cohort; 88 in the testing cohort) were enrolled and underwent magnetic resonance imaging (MRI) scans before treatment. The AUC value of the clinical Cox model, radiomics Cox model, clinical + radiomics Cox model, and clinical + radiomics RSF model in predicting 3- and 5-year PFS for LANPC patients was [0.545 vs 0.648 vs 0.648 vs 0.899 (training cohort), and 0.566 vs 0.736 vs 0.730 vs 0.861 (testing cohort); 0.556 vs 0.604 vs 0.611 vs 0.897 (training cohort), and 0.591 vs 0.661 vs 0.676 vs 0.847 (testing cohort), respectively]. Delong test showed that the RSF model and the other three Cox models were statistically significant, and the RSF model markedly improved prediction performance (P < 0.001). Additionally, the PFS of the high-risk group was lower than that of the low-risk group in the RSF model (P < 0.001), while comparable in the Cox model (P > 0.05).ConclusionThe RSF model may be a potential tool for prognostic prediction and risk stratification of LANPC patients.

Novel Plasma Proteomic Biomarkers for Early Identification of Induction Chemotherapy Beneficiaries in Locoregionally Advanced Nasopharyngeal Carcinoma.

BackgroundInduction chemotherapy (IC) can alleviate locoregionally advanced nasopharyngeal carcinoma (LA-NPC), but effectiveness differs between patients, toxicity is problematic, and effective blood-based IC efficacy predictors are lacking. Here, we aimed to identify biomarkers for early identification of IC beneficiaries.MethodsSixty-four pairs of matched plasma samples collected before and after IC from LA-NPC patients including 34 responders and 30 non-responders, as well as 50 plasma samples of healthy individuals, were tested using data-independent acquisition mass spectrometry. The proteins associated with clinical traits or IC benefits were investigated by weighted gene co-expression network analysis (WGCNA) and soft cluster analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional annotations were performed to determine the potential function of the identified proteins. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of candidate biomarkers in predicting IC beneficiaries.ResultsCompared with healthy individuals, 1027 differentially expressed proteins (DEPs) were found in the plasma of LA-NPC patients. Based on feedback from IC outcomes, 463 DEPs were identified in the pre-IC plasma between responders and non-responders. A total of 1212 DEPs represented the proteomic changes before and after IC in responders, while 276 DEPs were identified in post-IC plasma between responders and non-responders. WGCNA identified nine protein co-expression modules correlated with clinical traits. Soft cluster analysis identified four IC benefits-related protein clusters. Functional enrichment analysis showed that these proteins may play a role in IC via immunity, complement, coagulation, glycosaminoglycan and serine. Four proteins differentially expressed in all group comparisons, paraoxonase/arylesterase 1 (PON1), insulin-like growth factor-binding protein 3 (IGFBP-3), rheumatoid factor D5 light chain (v-kappa-3) and RNA helicase (DDX55), were associated with clinical traits or IC benefits. A four-protein model accurately identified potential IC beneficiaries (AUC=0.95) while diagnosing LA-NPC (AUC=0.92), and the prediction performance was verified using the models to confirm the effective IC (AUC=0.97) and evaluate IC outcome (AUC=0.94).ConclusionThe plasma protein profiles among IC responders and non-responders were different. PON1, IGFBP3, v-kappa-3 and DDX55 could serve as potential biomarkers for early identification of IC beneficiaries for individualised treatment of LA-NPC.

Optimal induction chemotherapy regimen for locoregionally advanced nasopharyngeal carcinoma: an update Bayesian network meta-analysis.

Induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) has been established as standard of care for locoregionally advanced nasopharyngeal carcinoma (LANPC). No direct comparison between different IC regimens has been performed. We conducted Bayesian network meta-analysis to evaluate the efficacy and safety of IC regimens in LANPC. We systematically searched studies comparing different regimens of IC plus CCRT versus CCRT alone for LANPC. Pairwise meta-analysis and Bayesian network meta-analysis were conducted using Review Manger, Stata and R software. Eight eligible studies with a total of 2382 patients were involved. Compared with CCRT alone, IC + CCRT significantly improved PFS (HR = 0.68 [95% CI 0.59-0.79]) and OS (HR = 0.72 [95% CI 0.61-0.86]) in conventional meta-analysis. In Bayesian network meta-analysis, GP (gemcitabine and cisplatin) had advantage in prolonging PFS, OS and DMFS. GP had adverse but manageable impacts on hemoglobin and platelet. Meanwhile, treatment compliance of GP was higher than that of other regimens. Based on existing evidences, GP could likely to be recommended as an optimal IC regimen for LANPC.

Plasma Epstein-Barr viral DNA load after completion of two cycles of induction chemotherapy predicts outcomes for patients with advanced-stage nasopharyngeal carcinoma

ObjectivesTo evaluate the prognostic value of plasma Epstein-Barr virus DNA level following the completion of two induction chemotherapy cycles (ICT; post2CICT-DNA) in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Materials and methodsThis retrospective study included 534 patients with LA-NPC. Recursive partitioning analysis (RPA) was applied to derive a prognostic model for risk stratification. Kaplan-Meier survival analysis was used to determine the survival results, and survival rates were compared using the log-rank test. The Cox proportional hazard model was used for univariate and multivariate analyses. ResultsMultivariate analyses revealed that post2CICT-DNA and N stage were independent predictors of overall survival (OS; P = 0.001 and P = 0.001, respectively), and post2CICT-DNA, pre-treatment DNA, and N stage were independent predictors of progression-free survival (PFS; P = 0.002, P = 0.001, and P = 0.021, respectively).Based on prognostic factors (pre-treatment DNA, post2CICT-DNA, and N stage), patients were stratified into three risk subgroups, with 288 patients in the low-, 213 in the intermediate-, and 33 in the high-risk group. The three-year OS rate of the low-, intermediate- and high-risk groups were 99.3% (95% CI 98.3%-100.0%), 90.0% (95% CI 85.5%-94.5%) and 67.0% (95% CI 49.9%-84.1%, P < 0.001 for each of the two groups), respectively. ConclusionPlasma EBV-DNA level after two ICT cycles is a powerful predictor of prognosis in patients with LA-NPC. RPA analysis revealed that stage N3 patients with detectable post2CICT-DNA are at the highest risk of treatment failure, and future clinical trials should focus on early-treatment modification strategies for these patients.

Abstract 5128: Identification and characterization of nasopharyngeal carcinoma prognostic subtypes based on a circRNA classifier: Implications of stratified treatment

Abstract Accurate risk stratification for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is crucial for treatment decisions and prognosis. Here, we introduce a circRNA-based classifier that could improve the prognostic stratification of LA-NPC patients. The circRNAs are identified by microarray profiling, followed by qRT-PCR validation and selection using a machine learning method in the training cohort (n = 170). Based on the proposed classifier, two prognostic-distinctive NPC subtypes are identified, namely the high-risk subtype (subtype H) and low-risk subtype (subtype L), which have significantly different disease-free survival (HR 2.99, 95% CI 1.58-5.67, P &amp;lt; 0.001). Validation in the internal cohort (n = 170) and external cohort (n = 150) yield similar results and the circRNA-based classifier is an independent risk factor of posttreatment relapse. Meanwhile, multiple interdependent features of different subtypes are observed, including relatively higher immune cell infiltration and immune-related pathways activation in subtype L; and predominant stromal, immunosuppressive and tumor-promoting components with moderate immune activation in subtype H. With a less aggressive and more immune-active tumor microenvironment, patients of subtype L could benefit from the addition of induction chemotherapy. In contrast, patients of subtype H, who are vulnerable to chemoresistance, display a strong tendency to benefit from additional immunotherapy. Overall, we define two NPC prognostic subtypes based on a circRNA classifier across multiple cohorts, which exhibit distinct biological ecosystems and suggest opportunities for the personalization of therapeutic regimens. Citation Format: Yelin Liang, Yuheng Zhao, Qian Li, Wei Jiang, Jun Ma, Na Liu, Yingqin Li. Identification and characterization of nasopharyngeal carcinoma prognostic subtypes based on a circRNA classifier: Implications of stratified treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5128.

Neoadjuvant chemotherapy plus tislelizumab followed by concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: A single-arm, phase II trial.

6068 Background: Neoadjuvant treatment with gemcitabine plus cisplatin (GP) prior to concurrent chemoradiotherapy (CCRT) has favorable survival outcomes with acceptable toxicity in patients with locoregionally advanced nasopharyngeal carcinoma (LANPC), 10% of whom achieved complete response (CR) after neoadjuvant treatment. Immune checkpoint blockade therapy plus GP regimen has been shown to improve the survival in recurrent or metastatic NPC. We investigated the efficacy and safety of neoadjuvant treatment with GP plus tislelizumab, an anti-PD-1 monoclonal antibody, in previously untreated LANPC. Methods: In this phase II, single-armed Simon two-stage study, eligible patients are of age 18-70, with adequate haematological, renal, and hepatic function, diagnosed with staged III-IVa（AJCC 8th） non-keratinizing LANPC. Enrolled patients received intravenous gemcitabine (1000 mg/m2) on days 1 and 8, cisplatin (80 mg/m2) on day 1, and tislelizumab (200mg) on day 1 every 3 weeks for 3 cycles followed by standard CCRT. The primary endpoint was CR rate after neoadjuvant treatment, using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator. The secondary endpoints included pathology complete response (pCR) rate, 2-year progress-free survival (PFS), overall survival (OS), locoregional failure-free survival (LRRFS), distant metastasis-free survival (DMFS), and toxicity. This study is registered with ClinicalTrials.gov, NCT04833257, all enrolled patients have finished their treatment and the follow-up is ongoing. Results: From April 14th 2021 to August 5th, 2021, a total of 63 patients (median age 46y, 74.6% male) were enrolled at Sun Yat-sen University Cancer Center. As of January 31st, 2022, the median follow-up is 7.37 months, no patients had disease progression. The CR rate after neoadjuvant treatment was 41.3% (95% CI, 28.8% to 53.8%). The ORR and pCR rate were 88.9% (95% CI, 80.9% to 96.9%) and 75.8% (95% CI, 64.8% to 86.8%), respectively. The incidence of acute treatment-related AEs (trAEs) and immune-related adverse events (irAEs) of grade 3 or 4 was 69.8% and 3.2%, respectively. All of irAEs for grade 3 or 4 were hepatotoxicity and skin rash. Long-term efficacy is awaited. Conclusions: Neoadjuvant treatment with GP plus tislelizumab achieved impressive CR rate and pCR rate with manageable toxicities. Further follow-up is needed to confirm the long-term efficacy. Clinical trial information: NCT04833257.

Recombinant human endostatin combined with intensity-modulated radiotherapy in low-risk locoregionally advanced nasopharyngeal carcinoma: A phase II, randomized, multicenter clinical trial.

6061 Background: Concurrent chemoradiotherapy (CCRT) is currently considered to be the standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC), accompanied with non-neglectable toxicity and unsatisfactory compliance. Therefore, it is highly warranted to explore an alternative regimen for LA-NPC. This trial aimed to assess and investigate the efficacy and safety of recombinant human endostatin ( Rh-endostatin) with intensity-modulated radiotherapy (IMRT) for low-risk LA-NPC. Methods: Patients with low-risk LA-NPC were randomly assigned into ERT group (n=60, receiving Rh-endostatin plus radiotherapy) and CCRT group (n=60, receiving cisplatin plus radiotherapy). The primary endpoint was the 5-year overall survival (OS). Non-inferiority was shown if the upper limit of the 95% CI for the difference in 5-year OS between the ERT group and CCRT group did not exceed 15%. The secondary endpoint was 3-year progression-free survival (PFS). Results: A total of 120 patients were included in the trial. After a median follow-up of 71 months (IQR 62-75), the 5-year OS rate was 88.1% in the ERT group and 77.6% in the CCRT group, with a difference of 10.5% (95% CI: -0.03 to 0.24; Pnon-inferiority = 0.002). Patients in the ERT group had better 3-year PFS than that in the CCRT group (89.8% vs 70.6%; HR = 0.362; 95% CI: 0.150-0.873; Plog-rank = 0.018). The overall all-grade toxicity burdens were heavier in CCRT group. No patients died of treatment-related causes. Conclusions: Rh-endostatin combined with IMRT had favorable efficacy, fewer toxic effects and more improved quality of life, which might be a promising alternative regimen to CCRT for low-risk LA-NPC in clinic. Clinical trial information: NCT02237924. [Table: see text]

TIRA study: A phase III, multicenter, randomized controlled study of toripalimab plus radical chemoradiotherapy with or without concurrent cisplatin in patients with high-risk locoregionally advanced nasopharyngeal carcinoma.

TPS6101 Background: Patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) suffer a high risk of distant metastasis and require guideline-recommended multimodality therapy. However, cisplatin-based concurrent chemotherapy leads to a high incidence of severe toxicities and low patient compliance, consequently limiting survival improvement. Toripalimab, an immune checkpoint inhibitor targeting programmed cell death 1 (PD-1), has a novel anti-cancer mechanism and mild toxicity spectrum. Robust evidence showed that given toripalimab + gemcitabine-cisplatin (GP) chemotherapy regimen, the median progression-free survival could be markedly improved in patients with recurrent and metastatic NPC. Besides, PD-1 antibody + radiotherapy is also regarded as a promising therapeutic strategy due to the synergistic effect. Therefore, we hypothesized that the de-intensification strategy using toripalimab + induction chemotherapy (IC) followed by radiotherapy alone would obtain equivalent survival and low toxicity in patients with LA-NPC compared with toripalimab + IC followed by concurrent chemoradiotherapy. Methods: TheTIRA study is a multicenter, randomized, controlled, open-label, phase III study. Since August 2021, we have been recruiting high-risk LA-NPC patients (stage III-IVa, except T3-4N0M0 &amp; T3N1M0) from 12 Chinese centers. Our target sample size is temporarily set at 494 patients with 247 for each arm. Patients will be 1:1 ratio randomized to the experimental or control arm. Patients in the experimental arm will receive induction-concurrent toripalimab (240 mg, d1, Q3W × 6 cycle) with IC (gemcitabine 1000 mg/m2, d1 &amp; d8 + cisplatin 80 mg/m2, d1, Q3W × 3 cycle) + intensity-modulated radiotherapy (IMRT, 70 Gy in 33 fractions), and thereafter adjuvant toripalimab (240 mg, d1, Q3W × 11 cycle). Patients in the controlled arm will receive an additional concurrent cisplatin (100 mg/m2, d1, Q3W × 2 cycle). The primary endpoint is the 3-year failure-free survival. Secondary endpoints include 3-year overall survival, 3-year distant metastasis-free survival, 3-year locoregional recurrence-free survival, quality-of-life assessment according to the systems of the European Organization for Research and Treatment of Cancer and the Functional Assessment of Cancer Therapy, and safety profile. Exploratory analysis will be performed for potential biomarkers of survival prediction including PD-L1 expression and tumor-infiltrating lymphocytes. Clinical trial information: NCT04907370.

A lncRNA signature associated with tumor immune heterogeneity predicts distant metastasis in locoregionally advanced nasopharyngeal carcinoma

Increasing evidence has revealed the roles of long noncoding RNAs (lncRNAs) as tumor biomarkers. Here, we introduce an immune-associated nine-lncRNA signature for predicting distant metastasis in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). The nine lncRNAs are identified through microarray profiling, followed by RT–qPCR validation and selection using a machine learning method in the training cohort (n = 177). This nine-lncRNA signature classifies patients into high and low risk groups, which have significantly different distant metastasis-free survival. Validations in the Guangzhou internal (n = 177) and Guilin external (n = 150) cohorts yield similar results, confirming that the signature is an independent risk factor for distant metastasis and outperforms anatomy-based metrics in identifying patients with high metastatic risk. Integrative analyses show that this nine-lncRNA signature correlates with immune activity and lymphocyte infiltration, which is validated by digital pathology. Our results suggest that the immune-associated nine-lncRNA signature can serve as a promising biomarker for metastasis prediction in LA-NPC.

Nomogram Based on Inflammatory Biomarkers and Nutritional Indicators for Predicting Overall Survival in Locoregionally Advanced Nasopharyngeal Carcinoma.

PurposeTo establish and validate a nomogram to predict overall survival in locoregionally advanced nasopharyngeal carcinoma (LA-NPC) based on inflammatory biomarkers and nutritional indicators.Patients and MethodsA total of 1304 patients who underwent concurrent chemoradiotherapy (CCRT) with or without induction chemotherapy (IC) or adjuvant chemotherapy (AC) were included in the study. The prognosis factors of overall survival (OS) were selected by Cox regression analysis to establish the nomogram. Concordance index (C-index), calibration curves, decision curve analysis (DCA) and Kaplan–Meier curves were used to evaluate the nomogram.ResultsUsing multivariate Cox analysis of clinically important variables, the following variables were incorporated in the prediction of OS: age, gender, T stage, N stage, pre-treatment plasma Epstein–Barr virus (EBV) DNA, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), lactic dehydrogenase-to-albumin ratio (LAR) and prognostic nutritional index (PNI). The discriminative ability, clinical usefulness and calibration of the nomogram revealed good predictive ability as indicated by the C-index (0.717 in nomogram and 0.602 in the 8th AJCC staging system), decision curves, calibration curves and K-M curves.ConclusionInflammatory biomarkers and nutritional indicators of survival for LA-NPC were selected to create a nomogram predicting OS. The proposed nomogram resulted in more accurate prognostic prediction than 8th AJCC staging system.

MRI-based radiomics to compare the survival benefit of induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy plus adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma: A multicenter study

Background and purposeIt remains uncertain whether induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) or CCRT plus adjuvant chemotherapy (AC) is more effective in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). This study aimed to develop and validate a joint radiomic and clinical signature (RCS) for the prognostic stratification of LA-NPCs and to identify patients who might benefit more from IC + CCRT or CCRT + AC. Materials and methodsOverall, 893 LA-NPC patients who received IC + CCRT or CCRT + AC were enrolled from four hospitals. RCS based on pretreatment magnetic resonance images and clinical data was constructed for predicting 5-year progression-free survival (PFS). The predictive ability of the RCS and TNM staging system for 5-year PFS, locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were compared by Harrell’s concordance indices (C-indices). Patients were divided into high- and low-risk subgroups based on RCS scores. The survival benefit of IC + CCRT vs. CCRT + AC in different subgroups was compared by Kaplan–Meier survival curves. ResultsThe RCS combining the radiomic signature, TNM stage and EBV DNA demonstrated significantly higher C-indices than TNM stage for predicting 5-year PFS, LRRFS, DMFS and OS in the training and validation cohorts. In the high-risk group (RCS score ≥ 0.25), CCRT + AC achieved significantly better PFS, LRRFS, DMFS and OS than IC + CCRT. In the low-risk group (RCS score < 0.25), IC + CCRT yielded significantly better outcomes than CCRT + AC. ConclusionThe RCS provides a noninvasive way to predict the outcomes of LA-NPC and helps identify patients who may benefit more from IC + CCRT vs. CCRT + AC.

A Bayesian network meta-analysis of the primary definitive therapies for locoregionally advanced nasopharyngeal carcinoma: IC+CCRT, CCRT+AC, and CCRT alone.

The major aim of this Bayesian network analysis was to determine the optimal treatment strategy for locoregionally advanced nasopharyngeal carcinoma (LANPC). We systematically searched databases and extracted data from randomized clinical trials involving LANPC patients randomly assigned to receive induction chemotherapy followed by concurrent chemoradiotherapy (IC+CCRT), CCRT followed by adjuvant chemotherapy (CCRT+AC), or CCRT. In the network analysis, IC+CCRT was significantly better than CCRT alone for 5-year FFS (odds ratio [OR]: 1.63, 95% credible interval [CrI] 1.16-2.29), DMFS (OR: 1.56, 95% CrI 1.08-2.22), and LFRS (OR: 1.62, 95% CrI 1.02-2.59), but not OS (OR: 1.35, 95% CrI 0.92-2.00). Rank probabilities showed that IC+CCRT was ranked the best followed by CCRT+AC and CCRT for all 5-year outcomes. Although compared to IC+CCRT and CCRT, CCRT+AC did not significantly improve survival but had the highest 5-year survival rates. IC+CCRT could be recommended as a front-preferred primary definitive therapy for patients with LANPC.

Prognostic significance of wait time for radical radiotherapy in locoregionally advanced nasopharyngeal carcinoma.

The prognostic significance of wait time between definite diagnosis and initial radical radiotherapy is not well established in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) receiving both induction chemotherapy (IC) and concurrent chemoradiotherapy (CCRT). From 2010 to 2018, 648 patients with LA-NPC treated with IC followed by CCRT were included. A total of 172 pairs of patients with LA-NPC were selected by propensity score matching (PSM). Compared to patients with an acceptable wait time (≤75 days), patients with a prolonged wait time (>75 days) had a significant lower 5-year DMFS rate (86.6% vs. 74.1%, p=0.006). Subgroup analyses indicated that the unfavorable effects of longer waiting times were mainly seen among stage IVa patients. A prolonged wait time (>75 days) between definite diagnosis and initial radical radiotherapy has negative prognostic effects on patients with LA-NPC receiving IC plus CCRT, particularly those with IVa stage.