Concurrent chemoradiotherapy followed by adjuvant cisplatin-gemcitabine versus cisplatin-fluorouracil chemotherapy for N2-3 nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with N2-3 nasopharyngeal carcinoma have a high risk of treatment being unsuccessful despite the current practice of using a concurrent adjuvant cisplatin-fluorouracil regimen. We aimed to compare the efficacy and safety of concurrent adjuvant cisplatin-gemcitabine with cisplatin-fluorouracil in N2-3 nasopharyngeal carcinoma. METHODS: We conducted an open-label, randomised, controlled, phase 3 trial at four cancer centres in China. Eligible patients were aged 18-65 years with untreated, non-keratinising, stage T1-4 N2-3 M0 nasopharyngeal carcinoma, an Eastern Cooperative Oncology Group performance status score of 0-1, and adequate bone marrow, liver, and renal function. Eligible patients were randomly assigned (1:1) to receive concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 of intensity-modulated radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 3 weeks or fluorouracil (4 g/m2 in continuous intravenous infusion for 96 h) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 4 weeks, for three cycles. Randomisation was done using a computer-generated random number code with a block size of six, stratified by treatment centre and nodal category. The primary endpoint was 3-year progression-free survival in the intention-to-treat population (ie, all patients randomly assigned to treatment). Safety was assessed in all participants who received at least one dose of chemoradiotherapy. This study was registered at ClinicalTrials.gov, NCT03321539, and patients are currently under follow-up. FINDINGS: From Oct 30, 2017, to July 9, 2020, 240 patients (median age 44 years [IQR 36-52]; 175 [73%] male and 65 [27%] female) were randomly assigned to the cisplatin-fluorouracil group (n=120) or cisplatin-gemcitabine group (n=120). As of data cutoff (Dec 25, 2022), median follow-up was 40 months (IQR 32-48). 3-year progression-free survival was 83·9% (95% CI 75·9-89·4; 19 disease progressions and 11 deaths) in the cisplatin-gemcitabine group and 71·5% (62·5-78·7; 34 disease progressions and seven deaths) in the cisplatin-fluorouracil group (stratified hazard ratio 0·54 [95% CI 0·32-0·93]; log rank p=0·023). The most common grade 3 or worse adverse events that occurred during treatment were leukopenia (61 [52%] of 117 in the cisplatin-gemcitabine group vs 34 [29%] of 116 in the cisplatin-fluorouracil group; p=0·00039), neutropenia (37 [32%] vs 19 [16%]; p=0·010), and mucositis (27 [23%] vs 32 [28%]; p=0·43). The most common grade 3 or worse late adverse event (occurring from 3 months after completion of radiotherapy) was auditory or hearing loss (six [5%] vs ten [9%]). One (1%) patient in the cisplatin-gemcitabine group died due to treatment-related complications (septic shock caused by neutropenic infection). No patients in the cisplatin-fluorouracil group had treatment-related deaths. INTERPRETATION: Our findings suggest that concurrent adjuvant cisplatin-gemcitabine could be used as an adjuvant therapy in the treatment of patients with N2-3 nasopharyngeal carcinoma, although long-term follow-up is required to confirm the optimal therapeutic ratio. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Major Project of Basic and Applied Basic Research, Sci-Tech Project Foundation of Guangzhou City, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, Natural Science Foundation of Guangdong Province, Postdoctoral Innovative Talent Support Program, Pearl River S&T Nova Program of Guangzhou, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, the Rural Science and Technology Commissioner Program of Guangdong Province, and Fundamental Research Funds for the Central Universities.

Radiomic signatures reveal multiscale intratumor heterogeneity associated with tissue tolerance and survival in re-irradiated nasopharyngeal carcinoma: a multicenter study.

BACKGROUND: Post-radiation nasopharyngeal necrosis (PRNN) is a severe adverse event following re-radiotherapy for patients with locally recurrent nasopharyngeal carcinoma (LRNPC) and associated with decreased survival. Biological heterogeneity in recurrent tumors contributes to the different risks of PRNN. Radiomics can be used to mine high-throughput non-invasive image features to predict clinical outcomes and capture underlying biological functions. We aimed to develop a radiogenomic signature for the pre-treatment prediction of PRNN to guide re-radiotherapy in patients with LRNPC. METHODS: This multicenter study included 761 re-irradiated patients with LRNPC at four centers in NPC endemic area and divided them into training, internal validation, and external validation cohorts. We built a machine learning (random forest) radiomic signature based on the pre-treatment multiparametric magnetic resonance images for predicting PRNN following re-radiotherapy. We comprehensively assessed the performance of the radiomic signature. Transcriptomic sequencing and gene set enrichment analyses were conducted to identify the associated biological processes. RESULTS: The radiomic signature showed discrimination of 1-year PRNN in the training, internal validation, and external validation cohorts (area under the curve (AUC) 0.713-0.756). Stratified by a cutoff score of 0.735, patients with high-risk signature had higher incidences of PRNN than patients with low-risk signature (1-year PRNN rates 42.2-62.5% vs. 16.3-18.8%, P < 0.001). The signature significantly outperformed the clinical model (P < 0.05) and was generalizable across different centers, imaging parameters, and patient subgroups. The radiomic signature had prognostic value concerning its correlation with PRNN-related deaths (hazard ratio (HR) 3.07-6.75, P < 0.001) and all causes of deaths (HR 1.53-2.30, P < 0.01). Radiogenomics analyses revealed associations between the radiomic signature and signaling pathways involved in tissue fibrosis and vascularity. CONCLUSIONS: We present a radiomic signature for the individualized risk assessment of PRNN following re-radiotherapy, which may serve as a noninvasive radio-biomarker of radiation injury-associated processes and a useful clinical tool to personalize treatment recommendations for patients with LANPC.

Nasopharyngeal necrosis contributes to overall survival in nasopharyngeal carcinoma without distant metastasis: a comprehensive nomogram model.

OBJECTIVES: This study focused on developing and validating a nomogram to predict the overall survival (OS) of patients with nasopharyngeal carcinoma (NPC) without distant metastasis based on their clinical characteristics, serum biomarkers, and presence of nasopharyngeal (NP) necrosis. METHODS: This study included 9298 patients with NPC. Patients from January 2009 to December 2014 were randomly categorized into the training cohort and validation cohort A. Validation cohort B, whose data were collected from January 2015 to December 2017, was also included. OS was the primary endpoint of this study. Cox regression analysis was used to detect independent risk variables. Decision curve analysis, calibration curve, time-dependent receiver operating characteristic (ROC) curve, and concordance index (C-index) were used to evaluate the performance of the nomogram model. RESULTS: A total of 267 patients developed NP necrosis after the first routine radiotherapy. After radiotherapy, patients with NP necrosis had significantly lower OS than other patients in all three cohorts (p < 0.001). Eleven factors, including NP necrosis, were involved in the nomogram, which had favorable discrimination and calibration with a C-index of 0.768 in the training cohort, 0.749 in validation cohort A, and 0.739 in validation cohort B. The nomogram exhibited a significantly larger area under the ROC curve for predicting OS than the TNM stage and Epstein-Barr virus (EBV) DNA (p < 0.001). CONCLUSION: Compared with the TNM system and EBV DNA, we established a nomogram model with an accurate prognostic prediction for patients with NPC, which might help with patient management in NPC. KEY POINTS: • This study included 9298 patients with NPC, and 11 factors were involved in the final model. • The nomogram had a significantly higher C-index and area under the ROC curve than the TNM stage and EBV DNA. • We established the first nomogram model for NPC involving the occurrence of NP necrosis, which was valuable for providing individual counseling and clinical assessments.

Nomogram for the prediction of primary distant metastasis of nasopharyngeal carcinoma to guide individualized application of FDG PET/CT.

PURPOSE: This study aimed to establish an effective nomogram to predict primary distant metastasis (DM) in patients with nasopharyngeal carcinoma (NPC) to guide the application of PET/CT. METHODS: In total, 3591 patients with pathologically confirmed NPC were consecutively enrolled. The nomogram was constructed based on 1922 patients treated between 2007 and 2014. Multivariate logistical regression was applied to identify the independent risk factors of DM. The predictive value of the nomogram was evaluated using the concordance index (C-index), calibration curve, probability density functions (PDFs), and clinical utility curve (CUC). The results were validated in 1669 patients enrolled from 2015 to 2016. Net reclassification improvement (NRI) was applied to compare performances of the nomogram with other clinical factors. The best cut-off value of the nomogram chosen for clinical application was analyzed. RESULTS: A total of 355 patients showed primary DM among 3591 patients, yielding an incidence rate of 9.9%. Sex, N stage, EBV DNA level, lactate dehydrogenase level, and hemoglobin level were independent predictive factors for primary DM. C-indices in the training and validation cohort were 0.796 (95% CI, 0.76-0.83) and 0.779 (95% CI, 0.74-0.81), respectively. The NRI indices demonstrated that this model had better predictive performance than plasma EBV DNA level and N stage. We advocate for a threshold probability of 3.5% for guiding the application of PET/CT depending on the clinical utility analyses. CONCLUSION: This nomogram is a useful tool to predict primary DM of NPC and guide the clinical application of PET/CT individually at the initial staging.

Low value of whole-body dual-modality [18f]fluorodeoxyglucose positron emission tomography/computed tomography in primary staging of stage I-II nasopharyngeal carcinoma: a nest case-control study.

OBJECTIVES: The value of using PET/CT for staging of stage I-II NPC remains unclear. Hence, we aimed to investigate the survival benefit of PET/CT for staging of early-stage NPC before radical therapy. METHODS: A total of 1003 patients with pathologically confirmed NPC of stages I-II were consecutively enrolled. Among them, 218 patients underwent both PET/CT and conventional workup ([CWU], head-and-neck MRI, chest radiograph, liver ultrasound, bone scintigraphy) before treatment. The remaining 785 patients only underwent CWU. The standard of truth (SOT) for lymph node metastasis was defined by the change of size according to follow-up MRI. The diagnostic efficacies were compared in 218 patients who underwent both PET/CT and CWU. After covariate adjustment using propensity scoring, a cohort of 872 patients (218 with and 654 without pre-treatment PET/CT) was included. The primary outcome was overall survival based on intention to treat. RESULTS: Retropharyngeal lymph nodes were metastatic based on follow-up MRI in 79 cases. PET/CT was significantly less sensitive than MRI in detecting retropharyngeal lymph node lesions (72.2% [62.3-82.1] vs. 91.1% [84.8-97.4], p = 0.004). Neck lymph nodes were metastatic in 89 cases and PET/CT was more sensitive than MRI (96.6% [92.8-100.0] vs. 76.4% [67.6-85.2], p < 0.001). In the survival analyses, there was no association between pre-treatment PET/CT use and improved overall survival, progression-free survival, local relapse-free survival, regional relapse-free survival, and distant metastasis-free survival. CONCLUSIONS: This study showed PET/CT is of little value for staging of stage I-II NPC patients at initial imaging. KEY POINTS: • PET/CT was more sensitive than MRI in detecting neck lymph node lesions whereas it was significantly less sensitive than MRI in detecting retropharyngeal lymph node lesions. • No association existed between pre-treatment PET/CT use and improved survival in stage I-II NPC patients.

Efficacy of controlled-release oxycodone for reducing pain due to oral mucositis in nasopharyngeal carcinoma patients treated with concurrent chemoradiotherapy: a prospective clinical trial.

BACKGROUND: Pain due to oral mucositis (OM) is a major problem during concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients. METHODS: We enrolled 56 NPC patients receiving CCRT and allocated them into two groups: moderate pain group (n = 27) and a severe pain group (n = 29) according to the degree of pain reported (moderate = numerical rating scale (NRS) score 4-6 or severe = NRS score 7-10) at initiation of controlled-release oxycodone (CRO) treatment. RESULTS: Total dose of CRO was significantly higher in severe pain patients than in moderate pain patients (791.60 ± 332.449 mg vs. 587.27 ± 194.940 mg; P = 0.015). Moderate pain patients had significantly better quality of life (P = 0.037), lower weight loss (P = 0.030) and more active CCRT response (90.9% vs. 64.0%; P = 0.041). Although 24-h pain control rate was comparable in the two groups (85.2% vs. 86.2%; P = 0.508), the moderate pain group score eventually stabilized at ~ 2 vs. 3 in the severe pain group (P < 0.001); the titration time to reach bearable pain (NRS ≤ 3) was also significantly shorter in moderate pain patients (2.45 ± 0.60 days vs. 3.60 ± 1.98 days; P = 0.012). Incidence of adverse events was comparable in both groups. CONCLUSIONS: The study findings suggest that early introduction of low-dose CRO at the moderate pain stage could help reduce the total dose required, provide better pain control, improve quality of life, and enhance CCRT response.

Concurrent chemoradiotherapy with nedaplatin versus cisplatin in stage II-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised phase 3 trial.

BACKGROUND: Cisplatin-based concurrent chemoradiotherapy is currently considered to be the standard treatment regimen for patients with advanced nasopharyngeal carcinoma, but has well known side-effects such as gastrointestinal reactions, nephrotoxicity, and ototoxicity. Nedaplatin was developed to decrease the toxic effects induced by cisplatin, and in this trial we assessed whether a nedaplatin-based concurrent chemoradiotherapy regimen was non-inferior to a cisplatin-based regimen in patients with locoregional, stage II-IVB nasopharyngeal carcinoma. METHODS: We did an open-label, non-inferiority, phase 3, randomised, controlled trial at two centres in China. Patients aged 18-65 years with non-keratinising stage II-IVB (T1-4N1-3 or T3-4N0) nasopharyngeal carcinoma, a Karnofsky score of at least 70, and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either nedaplatin 100 mg/m2 or cisplatin 100 mg/m2 on days 1, 22, and 43 for three cycles concurrently with intensity-modulated radiotherapy. Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre and clinical stage. Patients and clinicians were not masked to treatment allocation. The primary endpoint was progression-free survival at 2 years; non-inferiority was shown if the upper limit of the 95% CI for the difference in 2-year progression-free survival between the two groups did not exceed 10%. Analyses were by both intention to treat and per protocol, including all patients who received at least one complete cycle of chemotherapy. This trial is registered with ClinicalTrials.gov, number NCT01540136, and is currently in follow-up. FINDINGS: Between Jan 16, 2012, and July 16, 2014, we randomly assigned 402 patients to nedaplatin-based (n=201) or cisplatin-based (n=201) concurrent chemoradiotherapy. In the intention-to-treat population, 2-year progression-free survival was 89·9% (95% CI 85·8-94·0) in the cisplatin group and 88·0% (83·5-94·5) in the nedaplatin group, with a difference of 1·9% (95% CI -4·2 to 8·0; pnon-inferiority=0·0048). In the per-protocol analysis (cisplatin group, n=197; nedaplatin group, n=196), 2-year progression-free survival was 89·7% (95% CI 85·4-94·0) in the cisplatin group and 88·7% (84·2-94·5) in the nedaplatin group, with a difference of 1·0% (95% CI -5·2 to 7·0; pnon-inferiority=0·0020). A significantly higher frequency of grade 3 or 4 vomiting (35 [18%] of 198 in the cisplatin group vs 12 [6%] of 200 in the nedaplatin group, p<0·0001), nausea (18 [9%] vs four [2%], p=0·0021), and anorexia (53 [27%] vs 26 [13%], p=0·00070) was observed in the cisplatin group compared with the nedaplatin group. 11 (6%) patients in the nedaplatin group had grade 3 or 4 thrombocytopenia compared with four (2%) in the cisplatin group (p=0·065). Patients in the cisplatin group had a higher frequency of any grade or grade 3 or 4 late auditory or hearing toxicities than did patients in the nedaplatin group (grade 3 or 4: three [2%] in the nedaplatin group vs 11 [6%] in the cisplatin group, p=0·030). No patients died from treatment-related causes. INTERPRETATION: Our findings show that nedaplatin-based concurrent chemoradiotherapy represents an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy for patients with locoregional, advanced nasopharyngeal carcinoma. Further investigations are needed to explore the potential use of this treatment as induction or adjuvant chemotherapy or in combination with other agents. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, Sun Yat-sen University Clinical Research 5010 Program, Sci-Tech Project Foundation of Guangzhou City, National Key Basic Research Program of China, Special Support Plan of Guangdong Province, Sci-Tech Project Foundation of Guangdong Province, Health & Medical Collaborative Innovation Project of Guangzhou City, National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, PhD Start-up Fund of Natural Science Foundation of Guangdong Province, Cultivation Foundation for the Junior Teachers in Sun Yat-sen University, and Fundamental Research Funds for the Central Universities.

The elevated pretreatment platelet-to-lymphocyte ratio predicts poor outcome in nasopharyngeal carcinoma patients.

The aim of this study was to evaluate whether the platelet-to-lymphocyte ratio (PLR) could be used to predict the prognosis of patients with nasopharyngeal carcinoma (NPC). Patients (n = 1261) who were diagnosed with nonmetastatic NPC between January 2008 and December 2010 were recruited. The peripheral platelet and lymphocyte counts were retrieved, and the PLR was calculated. Univariate and multivariate Cox proportional hazards analyses were used to assess their association with PLR: overall survival (OS), cancer-specific survival (CSS), and distant metastasis-free survival (DMFS). The elevated PLR, using the third quartile values (153.64) as the optimal cutoff values, was found to be associated with the significant decline in CSS (hazard ratio [HR] 1.83, 95 % confidence interval [CI] 1.27-2.63, P < 0.001), OS (HR 1.81, 95 % CI 1.28-2.56, P < 0.001), and DMFS (HR 1.60, 95 % CI 1.15-2.23, P = 0.005) that remained significant during the multivariable analyses (CCS HR 1.84, 95 % CI 1.26-2.67, P < 0.001; OS HR 1.83, 95 % CI 1.28-2.61, P < 0.001; DMFS HR 1.56, 95 % CI 1.11-2.19, P = 0.011). Subgroup analyses indicated that the PLR could be used to stratify prognosis effectively for patients with early- or advanced-stage NPC, and Epstein-Barr virus DNA levels of ≥1500 copies/mL. In conclusions, elevated PLR values were associated with poor CSS, OS, and DMFS for patients with NPC; this easily accessed variable based on a large amount of cases multivariate analysis is valuable for predicting prognosis in patients with NPC.

Expression of Aurora-B and FOXM1 predict poor survival in patients with nasopharyngeal carcinoma.

PURPOSE: The purpose of this work was to investigate the relationship between Aurora-B, FOXM1, and clinical outcomes in patients with nasopharyngeal carcinoma (NPC) who were treated with a combination of induction chemotherapy and radiotherapy. PATIENTS AND METHODS: The expression of Aurora-B and FOXM1 were investigated by immunohistochemistry using a tissue microarray (TMA) containing samples from 166 NPC patients who were treated with cisplatin (DDP) + fluorouracil (5-FU) induction chemotherapy and radiotherapy between 1999 and 2005. The relationship of Aurora-B, FOXM1, and survival of these NPC patients was analyzed. RESULTS: Informative TMA results were obtained in 91 tumor cases for Aurora-B and 93 tumor cases for FOXM1. The 8-year failure-free survival rate (FFS) for the Aurora-B-negative and Aurora-B-positive group was 65.6 and 37.3%, respectively (p = 0.024), and the 8-year distant FFS (D-FFS) rate was 65.6 and 41.5%, respectively (p = 0.047). The 8-year overall survival (OS) in the FOXM1-negative group was moderately higher than in the FOXM1-positive group (58.4 vs 39.1%, p = 0.081). Cox regression analysis revealed that for FFS, Aurora-B expression was a significant prognostic factor (p = 0.025), while for D-FFS, Aurora-B expression was a marginally significant prognostic factor (p = 0.056). When FOXM1 expression was analyzed, the Cox regression analyses showed that FOXM1 expression was a marginally significant prognostic factor (p = 0.056) for OS. Correlation analysis showed that Aurora-B and FOXM1 expression had no significant correlation. CONCLUSION: Aurora-B and FOXM1 were both adverse prognostic markers for NPC patients treated with chemoradiotherapy. However, the two markers had no significant correlation.

The impact of the cumulative dose of cisplatin during concurrent chemoradiotherapy on the clinical outcomes of patients with advanced-stage nasopharyngeal carcinoma in an era of intensity-modulated radiotherapy.

BACKGROUND: The impact of cumulative dose of cisplatin on clinical outcomes of nasopharyngeal carcinoma (NPC) patients who received intensity-modulated radiotherapy (IMRT) was evaluated. METHODS: This study included 491 consecutive patients with histologically confirmed NPC who were treated with concurrent chemoradiotherapy with IMRT. The patients were divided into three groups: low- (cumulative dose≤100 mg/m2), medium- (cumulative dose>100 mg/m2 and ≤200 mg/m2), and high- (cumulative dose>200 mg/m2) dose groups. Subgroups of patients included pre-treatment levels of Epstein-Barr Virus DNA (EBV DNA)<4000 copies/ml and pre-treatment EBV DNA≥4000 copies/ml. To test for independent significance, the Kaplan-Meier with the log-rank test and the Cox proportional hazards model were used. RESULTS: The 5-year overall survival (OS) rates of the low-, medium-, and high-dose groups were 64.1%, 91.1%, and 89.4%, respectively (P=0.002). Based on multivariate analysis, patients who were in the medium- and high-dose groups had compared with the low-dose group, with an odds ratio of 0.135 (95% CI 0.045-0.405, P<0.001) and 0.225 (95% CI 0.069-0.734, P=0.013), respectively. For the low-risk patients, the cumulative dose of cisplatin significantly associated with a lower OS (P<0.001). The medium-dose group had reduced odds of death compared with the low-dose group, with an odds ratio of 0.062 (95% CI 0.001-0.347, P=0.002), according to multivariate analysis. CONCLUSIONS: The cumulative dose of cisplatin is associated with OS and distant metastasis-free survival (DMFS) among NPC patients who received IMRT.

Elevated peripheral blood lymphocyte-to-monocyte ratio predicts a favorable prognosis in the patients with metastatic nasopharyngeal carcinoma.

INTRODUCTION: Patients with metastatic nasopharyngeal carcinoma (NPC) have variable survival outcomes. We have previously shown that an elevated peripheral blood lymphocyte-to-monocyte ratio (LMR) is associated with an increased metastatic risk in patients with primary NPC. The present study aimed to investigate the prognostic value of pretreatment LMR in a large cohort of metastatic NPC patients. METHODS: Clinical data of 672 patients with metastatic NPC diagnosed between January 2003 and December 2009 were analyzed. The peripheral lymphocyte and monocyte counts were retrieved, and LMR was calculated. Receiver operating characteristic (ROC) curve analysis and univariate and multivariate COX proportional hazards analyses were performed to evaluate the association of LMR with overall survival (OS). RESULTS: Univariate analysis revealed that an elevated absolute lymphocyte count (≥1.390×10(9)/L) and LMR (≥2.475) as well as a decreased monocyte count (<0.665×10(9)/L) were significantly associated with prolonged OS. Multivariate Cox proportional hazard analysis showed that LMR (hazard ratio [HR]=0.50, 95% confidence interval [CI]=0.41-0.60, P<0.001), absolute lymphocyte count (HR=0.77, 95% CI=0.64-0.93, P=0.007), and monocyte count (HR=1.98, 95% CI=1.63-2.41, P<0.001) were independent prognostic factors. By stratification analyses, only LMR remained a significant predictor of prognosis. CONCLUSION: We identified pretreatment LMR as an independent prognostic factor for patients with metastatic NPC. Independent validation of our findings is needed.

A new T classification based on masticator space involvement in nasopharyngeal carcinoma: a study of 742 cases with magnetic resonance imaging.

BACKGROUND: The aim of this study was to investigate the prognostic significance and various classifications for anatomic masticator space involvement (MSI) in patients with nasopharyngeal carcinoma (NPC). METHODS: This study retrospectively analyzed 742 patients with untreated nondisseminated NPC who underwent magnetic resonance imaging (MRI) scan of the nasopharynx and neck. The MSI was graded according to different anatomic features. The overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) of the patients with different MSI grades were analyzed using the Kaplan-Meier method and log-rank tests. RESULTS: The frequency of MSI was 24.1% (179/742). The 5-year OS, LRFS, DMFS, DFS for NPC patients with versus without MSI were 70.9% versus 82.5% (P = 0.001), 94.1% versus 91.4% (P = 0.511), 81.4% versus 88.7% (P = 0.021), and 78.0% versus 83.5% (P = 0.215), respectively. Significant differences in OS were also found among different MSI groups. In the patients with MSI, the OS of the group with medial and/or lateral pterygoid involvement (MLPI) NPC was 73.9% compared to 51.3% (P < 0.0001) in the patients with infratemporal fossa involvement (IFI). CONCLUSIONS: MSI was an independent prognostic factor for OS and DMFS. NPCs invading the masticator space should be separately categorized into MLPI and IFI prognostic groups. We suggest that MLPI should be staged as T3 while IFI is staged as T4 disease in future TNM staging revision.

Phase I dose-escalation study of nab-paclitaxel combined with cisplatin and capecitabin as induction chemotherapy followed by concurrent chemoradiotherapy in patients with nasopharyngeal carcinoma.

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

The independent, unfavorable prognostic factors endothelin A receptor and chemokine receptor 4 have a close relationship in promoting the motility of nasopharyngeal carcinoma cells via the activation of AKT and MAPK pathways.

BACKGROUND: Recent studies have indicated that the expression of endothelin A receptor (ETAR) and chemokine receptor 4 (CXCR4) could be used as an indicator of the metastatic potential of nasopharyngeal carcinoma (NPC). The aim of this study was to determine the prognostic value of ETAR and CXCR4 in NPC patients and to reveal the interplay of the endothelin-1 (ET-1)/ETAR and stromal-derived factor-1(SDF-1)/CXCR4 pathways in promoting NPC cell motility. METHODS: Survival analysis was used to analyze the prognostic value of ETAR and CXCR4 expression in 153 cases of NPC. Chemotaxis assays were used to evaluate alterations in the migration ability of non-metastatic 6-10B and metastatic 5-8F NPC cells. Real-time PCR, immunoblotting, and flow cytometric analyses were used to evaluate changes in the expression levels of CXCR4 mRNA and protein induced by ET-1. RESULTS: The expression levels of ETAR and CXCR4 were closely related to each other and both correlated with a poor prognosis. A multivariate analysis showed that the expression levels of both ETAR and CXCR4 were independent prognostic factors for overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). The migration of 6-10B and 5-8F cells was elevated by ET-1 in combination with SDF-1α. The knockdown of ETAR protein expression by siRNA reduced CXCR4 protein expression in addition to ETAR protein expression, leading to a decrease in the metastatic potential of the 5-8F cells. ET-1 induced CXCR4 mRNA and protein expression in the 6-10B NPC cells in a time- and concentration-dependent fashion and was inhibited by an ETAR antagonist and PI3K/AKT/mTOR and MAPK/ERK1/2 pathway inhibitors. CONCLUSIONS: ETAR and CXCR4 expression levels are potential prognostic biomarkers in NPC patients. ETAR activation partially promoted NPC cell migration via a mechanism that enhanced functional CXCR4 expression.

Randomized study of sinusoidal chronomodulated versus flat intermittent induction chemotherapy with cisplatin and 5-fluorouracil followed by traditional radiotherapy for locoregionally advanced nasopharyngeal carcinoma.

Neoadjuvant chemotherapy plus radiotherapy is the most common treatment regimen for advanced nasopharyngeal carcinoma (NPC). Whether chronomodulated infusion of chemotherapy can reduce its toxicity is unclear. This study aimed to evaluate the toxic and therapeutic effects of sinusoidal chronomodulated infusion versus flat intermittent infusion of cisplatin (DDP) and 5-fluorouracil (5-FU) followed by radiotherapy in patients with locoregionally advanced NPC. Patients with biopsy-diagnosed untreated stages III and IV NPC (according to the 2002 UICC staging system) were randomized to undergo 2 cycles of sinusoidal chronomodulated infusion (Arm A) or flat intermittent constant rate infusion (Arm B) of DDP and 5-FU followed by radical radiotherapy. Using a "MELODIE" multi-channel programmed pump, the patients were given 12-hour continuous infusions of DDP (20 mg/m2) and 5-FU (750 mg/m2) for 5 days, repeated every 3 weeks for 2 cycles. DDP was administered from 10:00 am to 10:00 pm, and 5-FU was administered from 10:00 pm to 10:00 am each day. Chronomodulated infusion was performed in Arm A, with the peak deliveries of 5-FU at 4:00 am and DDP at 4:00 pm. The patients in Arm B underwent a constant rate of infusion. Radiotherapy was initiated in the fifth week, and both arms were treated with the same radiotherapy techniques and dose fractions. Between June 2004 and June 2006, 125 patients were registered, and 124 were eligible for analysis of response and toxicity. The major toxicity observed during neoadjuvant chemotherapy was neutropenia. The incidence of acute toxicity was similar in both arms. During radiotherapy, the incidence of stomatitis was significantly lower in Arm A than in Arm B (38.1% vs. 59.0%, P = 0.020). No significant differences were observed for other toxicities. The 1-, 3-, and 5-year overall survival rates were 88.9%, 82.4%, and 74.8% for Arm A and 91.8%, 90.2%, and 82.1% for Arm B. The 1-, 3-, and 5-year progression-free survival rates were 91.7%, 88.1%, and 85.2% for Arm A and 100%, 94.5%, and 86.9% for Arm B. The 1-, 3-, and 5-year distant metastasis-free survival rates were 82.5%, 79.1%, and 79.1% for Arm A and 90.2%, 85.2%, and 81.7% for Arm B. Chronochemotherapy significantly reduced stomatitis but was not superior to standard chemotherapy in terms of hematologic toxicities and therapeutic response.

The map of bone metastasis in nasopharyngeal carcinoma: A real-world study.

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

Paclitaxel liposome, cisplatin and 5-fluorouracil-based induction chemotherapy followed by de-escalated intensity-modulated radiotherapy with concurrent cisplatin in stage IVA-IVB childhood nasopharyngeal carcinoma in endemic area: a phase II, single-arm trial.

Background: Previous studies demonstrated that induction chemotherapy (IC) followed by de-escalated chemoradiotherapy adapted to tumor response was effective in treating childhood nasopharyngeal carcinoma (NPC), but the toxicity profile of this treatment strategy, and whether childhood patients with advanced stages can obtain enough benefits from it requires further investigation. Methods: We conducted a single-center phase II trial (NCT03020329). All participants received 3 cycles of paclitaxel liposome, cisplatin and 5-fluorouracil (TPF)-based IC. Patients who showed complete or partial response received de-escalated radiotherapy of 60 Gy with 3 cycles of concurrent cisplatin, and those who showed stable or progressive disease received standard-dose radiotherapy of 70 Gy with concurrent cisplatin. The primary endpoint was the complete response (CR) rate at the end of concurrent chemoradiotherapy (CCRT). Findings: From November 2016 to March 2021, 44 patients were recruited in the cohort. The CR rate was 80% (35/44, 95% CI, 65-90) of the whole cohort. All patients achieved CR 3 months after CCRT. By the last follow-up, the 3-year progression-free survival and overall survival were 91% (95% CI, 82-99) and 100% respectively. Dry mouth was the most common late toxicity, with an incidence of 41% (18/44), followed by skin fibrosis and hearing impairment. No patient suffered from severe late toxicity and growth retardation. Interpretation: Our results proved the efficacy and safety of TPF regimen followed by de-escalated radiotherapy with concurrent cisplatin in treating stage IVa-b childhood NPC patients. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

A phase II randomised controlled trial of adjuvant tumour-infiltrating lymphocytes for pretreatment Epstein-Barr virus DNA-selected high-risk nasopharyngeal carcinoma patients.

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

Reduced-dose radiotherapy for Epstein-Barr virus DNA selected staged III nasopharyngeal carcinoma: A single-arm, phase 2 trial.

BACKGROUND: Radiotherapy-related toxicities of nasopharyngeal carcinoma (NPC) caused by a standard dose of 70 Gy remain a critical issue. Therefore, we assessed whether a radiotherapy dose of 60 Gy was non-inferior to the standard dose in patients with low-risk stage III NPC with a favourable response to induction chemotherapy (IC). PATIENTS AND METHODS: We did a single-arm, single-centre, phase II clinical trial in China. Patients with low-risk (Epstein-Barr virus [EBV] DNA level <4000 copies/ml) stage III NPC were treated with two cycles IC. Patients with complete/partial response and undetectable EBV DNA level were assigned 60 Gy intensity-modulated radiotherapy concurrently with three cycles of cisplatin. The primary end-point was 2-year progression-free survival (PFS). This trial is registered with ClinicalTrials.gov, number NCT03668730. RESULTS: One patient quit because of withdrawal of informed consent after IC. In total, 215 patients completed two cycles of IC, after which 116 (54.0%) and 99 (46.0%) patients were assigned 60 and 70 Gy radiotherapy, respectively. For 215 patients, the 2-year PFS was 90.7% (95% CI, 86.8%-94.6%) with a median follow-up of 43.9 months (interquartile range [IQR], 39.8-46.2). For patients treated with 60 Gy radiotherapy, the 2-year PFS rate was 94.8% (95%CI 90.7%-98.9%) with a median follow-up of 43.9 months (IQR 40.2-46.2). The most common late toxicity was grade 1-2 dry mouth (incidence rate: 54.3%). No grade 3+ long-term adverse event was observed, and most quality-of-life items, domains, and symptom scores returned to baseline by 6 months. CONCLUSION: Reduced-dose radiation (60 Gy) is associated with favourable survival outcomes and limited treatment-related toxicities in patients with low-risk stage III NPC sensitive to IC.

Camrelizumab combined with apatinib in patients with first-line platinum-resistant or PD-1 inhibitor resistant recurrent/metastatic nasopharyngeal carcinoma: a single-arm, phase 2 trial.

Immunotherapy combined with antiangiogenic targeted therapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for refractory recurrent/metastatic nasopharyngeal carcinoma (RM-NPC). We conducted a phase 2 trial to evaluate the safety and activity of camrelizumab plus apatinib in platinum-resistant (cohort 1, NCT04547088) and PD-1 inhibitor resistant NPC (cohort 2, NCT04548271). Here we report on the primary outcome of objective response rate (ORR) and secondary endpoints of safety, duration of response, disease control rate, progression-free survival, and overall survival. The primary endpoint of ORR was met for cohort 1 (65%, 95% CI, 49.6-80.4, n = 40) and cohort 2 (34.3%; 95% CI, 17.0-51.8, n = 32). Grade ≥ 3 treatment-related adverse events (TRAE) were reported in 47 (65.3%) of 72 patients. Results of our predefined exploratory investigation of predictive biomarkers show: B cell markers are the most differentially expressed genes in the tumors of responders versus non-responders in cohort 1 and that tertiary lymphoid structure is associated with higher ORR; Angiogenesis gene expression signatures are strongly associated with ORR in cohort 2. Camrelizumab plus apatinib combination effectiveness is associated with high expression of PD-L1, VEGF Receptor 2 and B-cell-related genes signatures. Camrelizumab plus apatinib shows promising efficacy with a measurable safety profile in RM-NPC patients.