RESUMEN
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.
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Neoplasias Nasofaríngeas , Neutropenia , Adolescente , Masculino , Humanos , Femenino , Adulto , Cisplatino , Carcinoma Nasofaríngeo/tratamiento farmacológico , Gemcitabina , China , Desoxicitidina , Quimioradioterapia , Fluorouracilo , Neutropenia/inducido químicamente , Neoplasias Nasofaríngeas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia AdyuvanteRESUMEN
OBJECTIVE: We compared the clinical characteristics and survival outcomes after radical radiotherapy between nasopharyngeal carcinoma (NPC) with early and late metastases based on a relatively large cohort, which provides valuable data for the planning of clinical surveillance strategies. METHODS: This was a single-center retrospective analysis of 10,566 patients who received radical radiotherapy in China from January 2000 to December 2016. Overall survival was the primary endpoint. Kaplan-Meier survival analysis and log-rank tests were applied to investigate the association between early or late metastasis and the endpoints. The prognostic value of clinicopathological features was identified using univariate and multivariate Cox proportional hazards models. RESULTS: The cutoff value for time to metastasis was based on ROC analysis. A total of 559 (5.3%) patients developed distant metastases, 297 (53.1%) of which developed early metastatic disease, with the rest (46.9%) developing late metastatic disease. The K-M analysis showed that the patients with late metastatic foci had significantly better post-metastatic OS (P = 0.0056). Multivariate analysis indicated that age, liver metastasis, the number of metastatic foci and time to metastasis (P = 0.013) are independent prognostic factors for OS. After analyzing the impact of different treatment methods, we found that local treatment was an independent protective factor for LM, while local treatment was not associated with a survival benefit for EM disease. CONCLUSIONS: The time to metastasis after radical radiotherapy affected the prognosis of NPC patients and local treatment was an independent protective factor that could improve the survival of late metastatic NPC patients.
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Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/patología , Pronóstico , Neoplasias Nasofaríngeas/patología , Estudios Retrospectivos , Estadificación de NeoplasiasRESUMEN
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.
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Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Nomogramas , Carcinoma Nasofaríngeo/patología , Estadificación de Neoplasias , Infecciones por Virus de Epstein-Barr/patología , Neoplasias Nasofaríngeas/patología , Herpesvirus Humano 4/genética , Pronóstico , Necrosis/patologíaRESUMEN
PURPOSE: To analyze the clinical outcomes of patients with regional persistent/recurrent nasopharyngeal carcinoma (NPC) who received neck dissection, and to evaluate the clinical benefit of postoperative adjuvant therapy (PAT) based on patients' positive lymph node counts (PLNs), extracapsular spread (ECS) and preoperative plasma EBV DNA levels. METHODS: From 2003 to 2017, 342 patients with regional persistent/recurrent NPC were included in this study. All patients were treated with neck dissection and 76 patients received PAT. Progression-free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRFS) were compared between groups using propensity score matching (PSM). RESULTS: 152 patients without PAT treatment and 76 patients with PAT treatment were selected by the PSM. There was no significant difference in 2-year PFS (52.4% vs. 61.3%, P = 0.371), 2-year OS (91.9% vs. 90.5%, P = 0.097) or 2-year LRFS (66.3% vs. 67.9%, P = 0.872) between the two groups. However, the application of PAT brought survival benefits to patients in terms of 2-year DMFS (76.5% vs. 84.7%, P = 0.020). PLN, ECS and preoperative EBV DNA level remained independent risk factors for poorer PFS. Accordingly, patients were divided into low-risk and high-risk groups using receiver operating characteristic (ROC) curve; the 2-year PFS rates for two risk groups were 73.4% and 59.1% (P < 0.0001) respectively. The results showed that low-risk patients didn't benefit from the addition of PAT. However, the 2-year DMFS rate was significantly improved in high-risk PAT-treated patients than those treated by neck dissection alone (83.7% vs. 71.7%, P = 0.023). CONCLUSIONS: PLNs, ECS and preoperative EBV DNA level are associated with the prognosis of patients with regional persistent/recurrent NPC. High-risk patients identified by PLNs, ECS and preoperative EBV DNA level may benefit from the addition of PAT after neck dissection.
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Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/cirugía , Disección del Cuello , Herpesvirus Humano 4/genética , ADN Viral , Recurrencia Local de Neoplasia , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: The combined use of immune checkpoint inhibitors (ICIs) with palliative chemotherapy (PCT) is a promising first-line treatment for de novo metastatic nasopharyngeal carcinoma (mNPC). However, the efficacy of ICIs with PCT vs PCT with definitive radiation therapy (DRT) remain unclear. METHODS: Patients with mNPC who received first-line immunochemotherapy (ICI + PCT) or PCT + DRT were included. Propensity score matching (PSM) was applied to balance potential confounders between patients who did and did not undergo DRT (at a ratio of 1:1). Progression free survival (PFS) and overall survival (OS) were compared between the 2 groups using a log-rank test and Cox proportional hazard model. RESULTS: Among all participants, 149 received ICI + PCT. After PSM, 149 patients were included in the PCT + DRT group. First-line immunochemotherapy was associated with significantly improved PFS (median 9.0 months vs 12.0 months, P < .001) and OS (median 12.5 months vs 19.9 months, P < .001). Subgroup analysis revealed that tumor response to immunochemotherapy, metastatic organs, and number of metastatic sites potentially affected the efficacy of DRT after first-line immunochemotherapy. CONCLUSION: Compared with PCT + DRT, first-line immunochemotherapy was associated with improved PFS and OS in patients with mNPC but not in patients with unfavorable tumor response and metastasis involving the liver, distant nodes, or multiple sites.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Nasofaríngeas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios de Cohortes , Humanos , Estimación de Kaplan-Meier , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Estudios RetrospectivosRESUMEN
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.
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Neoplasias Nasofaríngeas , Nomogramas , Fluorodesoxiglucosa F18 , Humanos , Carcinoma Nasofaríngeo/diagnóstico por imagen , Neoplasias Nasofaríngeas/diagnóstico por imagen , Estadificación de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , PronósticoRESUMEN
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.
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Neoplasias Nasofaríngeas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios de Casos y Controles , Fluorodesoxiglucosa F18 , Humanos , Ganglios Linfáticos/patología , Carcinoma Nasofaríngeo/diagnóstico por imagen , Neoplasias Nasofaríngeas/diagnóstico por imagen , Neoplasias Nasofaríngeas/patología , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Radiofármacos , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: We compared the efficacy and toxicity of three IC regimens (TPF: taxanes, cisplatin, and 5-fluorouracil; TP: taxanes and cisplatin; and PF: cisplatin and 5-fluorouracil) followed by CCRT in locoregionally advanced NPC. METHODS: The retrospective study involved 1354 patients with newly diagnosed stage III-IVA NPC treated with IC and CCRT. The median follow-up time in our cohort was 50 months. Based on EBV DNA level, all the patients with stage IV were divided into low- (pre-EBV DNA < 1500 copies) and high-risk group (pre-EBV DNA ≥ 1500 copies). Progression free survival (PFS), overall survival (OS), locoregional relapse free survival (LRFS), distant metastasis free survival (DMFS) and grade 3-4 toxicities were compared among different IC regimens. The survival rates were compared using log-rank test and a Cox proportional hazards model was used to perform multivariate analyses. RESULTS: A multivariate analysis revealed TPF to be more effective than TP. Among stage III patients, no significant difference in clinical outcome between the different IC regimens was showed, while TPF was associated with significantly better survival conditions in the stage IV patients. A further subgroup analysis revealed that only patients with pre-EBV DNA ≥ 1500 copies could benefit from the application of TPF among stage IV NPC. In terms of acute toxicities, PF was associated with fewer grade 3/4 acute toxicities. CONCLUSIONS: In low-risk NPC patients, PF-based IC showed similar efficacy as TPF and TP but was associated with fewer grade 3/4 acute toxicities. In high-risk patients, however, the TPF regimen was superior to PF and TP, although grade 3/4 toxicities were more common with the TPF regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , ADN Viral/genética , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Carcinoma Nasofaríngeo/virología , Neoplasias Nasofaríngeas/virología , Estudios Retrospectivos , Taxoides/administración & dosificación , Taxoides/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Early diagnosis is critical to reduce the mortality caused by nasopharyngeal carcinoma (NPC). MicroRNAs (miRNAs) are dysregulated and play important roles in carcinogenesis. Therefore, this study aimed to identify diagnostically relevant circulating miRNA signatures in patients with NPC. METHODS: Total RNA was extracted from whole blood samples obtained from 120 patients with NPC, 30 patients with head-neck tumors (HNT), and 30 healthy subjects (HSs), and examined by using a custom microarray. The expression levels of four miRNAs identified by using the microarray were validated with quantitative real-time reverse transcription polymerase chain reaction. The 120 patients with NPC and 30 HSs were randomly assigned to training group-1 and validation group-1, respectively. By using significance analysis of microarray (SAM), the specific miRNA expression profiles in whole blood from patients with NPC are obtained. By using lasso regression and adaptive boosting, a diagnostic signature was identified in training group-1, and its accuracy was verified in validation group-1. By using the same methods, another signature to distinguish patients with NPC from those with HNT and HSs was identified in training group-2 and confirmed in validation group-2. RESULTS: There were 117 differentially expressed miRNAs (upregulated and downregulated fold change ≥ 1.5) between the patients with NPC and HSs, among which an 8-miRNA signature was identified with 96.43% sensitivity and 100% specificity [area under the curve (AUC) = 0.995] to diagnose NPC in training group-1 and 86.11% sensitivity and 88.89% specificity (AUC = 0.941) in validation group-1. Compared with traditional Epstein-Barr virus (EBV) seromarkers, this signature was more specific for NPC. Furthermore, a 16-miRNA signature to differentiate NPC from HNT and HS (HNT-HS) was established from 164 differentially expressed miRNAs, which diagnosed NPC and HNT-HS with 100% accuracy (AUC = 1.000) in training group-2 and 87.04% (AUC = 0.924) in validation group-2. CONCLUSIONS: The present study identified two miRNA signatures for the highly accurate diagnosis and differential diagnosis of patients with NPC from HSs and patients with HNT. The identified miRNAs might represent novel serological biomarkers and potential therapeutic targets for NPC.
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Biomarcadores de Tumor , MicroARNs/sangre , MicroARNs/genética , Carcinoma Nasofaríngeo/diagnóstico , Neoplasias Nasofaríngeas/diagnóstico , Transcriptoma , Adulto , Anciano , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , MicroARN Circulante/análisis , MicroARN Circulante/sangre , MicroARN Circulante/genética , Detección Precoz del Cáncer , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Carcinoma Nasofaríngeo/sangre , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/sangre , Neoplasias Nasofaríngeas/genéticaRESUMEN
BACKGROUND: This study aimed to evaluate the prognostic value of maximal standard uptake values (SUVmax) of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (PET) comparing with Epstein-Barr virus (EBV) DNA levels in de novo metastatic nasopharyngeal carcinoma (NPC) patients. METHODS: From December 2006 to December 2016, 253 de novo metastatic NPC patients assessed by PET/ computed tomography were involved in current study. SUVmax-T, SUVmax-N, and SUVmax-M referred to the SUVmax at the primary tumor, cervical lymph nodes, and metastatic lesions respectively. Overall survival (OS) was the primary endpoint. RESULT: Patients who died during the follow-up had significantly higher SUVmax-N, SUVmax-M, and EBV DNA level than those in the patients who were alive. SUVmax-N and SUVmax-M were positively correlated with EBV DNA level. The cut-off values of SUVmax-T, SUVmax-N, SUVmax-M, and EBV DNA were 17.0, 12.7, and 6.9, and 13,800 copies/mL respectively, which were determined by receiver operating characteristic (ROC) curve analysis. Patients with elevated SUVmax-N, SUVmax-M, and EBV DNA levels had a lower 3-year OS rate. In multivariate analysis, the independent prognostic factors of OS included EBV DNA, metastatic site, and locoregional radiotherapy application, while SUVmax was not an independent prognostic factor. CONCLUSION: In de novo metastatic NPC patients, higher SUVmax-N and SUVmax-M were associated with worse prognosis. However, the predictive ability of SUVmax-N and SUVmax-M was poorer than that of EBV DNA.
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Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/virología , Fluorodesoxiglucosa F18 , Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/etiología , Tomografía de Emisión de Positrones , Adulto , Anciano , ADN Viral , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/mortalidad , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/etiología , Neoplasias Nasofaríngeas/mortalidad , Estadificación de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Curva ROCRESUMEN
BACKGROUND: To evaluate the clinical outcome in patients with de novo metastatic nasopharyngeal carcinoma (NPC) treated or not treated with locoregional radiotherapy (LRRT) based on plasma Epstein-Barr virus (EBV) DNA level and tumor response after palliative chemotherapy (PCT). METHODS: From 2007 to 2016, 502 patients with de novo metastatic NPC were included in this study. All patients were treated with PCT and 315 patients received LRRT. Our primary study endpoint was overall survival (OS). RESULTS: EBV DNA was detected in 461 patients (91.8%) before treatment but was undetectable in 249 patients (49.6%) after PCT. Three hundred and seventeen patients (63.1%) achieved satisfactory response (complete response or partial response) to PCT. Both the post-PCT EBV DNA level and tumor response were independent prognostic factors. Among low-risk patients (patients with undetectable EBV DNA and satisfactory tumor response after PCT), the 3-year OS rate was 80.4% in LRRT-treated patients and 45.3% in patients not treated with LRRT (P < 0.001). Multivariate analyses demonstrated that LRRT was an independent prognostic factor of OS in the low-risk patients (P < 0.001). However, among the high-risk patients (patients with detectable EBV DNA and/or unsatisfactory response after PCT), no statistically significant survival differences were observed between the LRRT and non-LRRT groups. CONCLUSIONS: EBV DNA level and tumor response after PCT both correlate with the prognosis of de novo metastatic NPC. In such cases, LRRT may benefit the patients with undetectable EBV DNA levels and satisfactory tumor response after PCT.
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Infecciones por Virus de Epstein-Barr/terapia , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Cuidados Paliativos/métodos , Adulto , Quimioradioterapia/métodos , ADN Viral/sangre , Infecciones por Virus de Epstein-Barr/sangre , Infecciones por Virus de Epstein-Barr/virología , Femenino , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/fisiología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/sangre , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/sangre , Neoplasias Nasofaríngeas/patología , Metástasis de la Neoplasia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
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.
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Antineoplásicos/uso terapéutico , Carcinoma/terapia , Quimioradioterapia , Cisplatino/uso terapéutico , Neoplasias Nasofaríngeas/terapia , Compuestos Organoplatinos/uso terapéutico , Adolescente , Adulto , Anciano , Anorexia/inducido químicamente , Antineoplásicos/efectos adversos , Carcinoma/secundario , Cisplatino/efectos adversos , Femenino , Trastornos de la Audición/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/patología , Náusea/inducido químicamente , Compuestos Organoplatinos/efectos adversos , Supervivencia sin Progresión , Dosificación Radioterapéutica , Trombocitopenia/inducido químicamente , Vómitos/inducido químicamente , Adulto JovenRESUMEN
BACKGROUND: Despite increasing use, symptomatic venous thromboembolism (VTE) associated with peripherally inserted central catheter (PICC) is a common complication in nonmetastatic nasopharyngeal carcinoma (NPC) patients. METHODS: A total of 3012 nonmetastatic NPC patients were enrolled in this retrospective study, and we applied Cox regression and log-rank tests to assess the association between PICC-VTE and survival using the propensity score method (PSM) to adjust for gender, age, radiotherapy technique, tumor stage, node stage, UICC clinical stage and pre-treatment EBV DNA. RESULTS: 217 patients developed PICC-VTE, with an incidence of 7.20%. PSM identified 213 patients in the cohort with VTE and 852 in that without. Patients who developed PICC-VTE had a shorter 5-year PFS (77.5% vs 87.6%, p < 0.001), DMFS (85.0% vs 91.2%, p < 0.001), LRRFS (93.9% vs 97.7%, p < 0.001) and OS (85.4% vs 87.6%, p < 0.001). Subgroup analyses indicated that no significant survival difference was found between PICC-related superficial venous thrombosis and deep vein thrombosis, nor did different anticoagulant treatment methods. CONCLUSIONS: PICC-VTE was associated with a worse survival outcome in nonmetastatic NPC patients. A prospective randomized clinical trial is required to verify the results.
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Anticoagulantes/uso terapéutico , Cateterismo Periférico/efectos adversos , Carcinoma Nasofaríngeo/mortalidad , Neoplasias Nasofaríngeas/mortalidad , Tromboembolia Venosa/epidemiología , Adulto , Cateterismo Periférico/instrumentación , Catéteres Venosos Centrales/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/complicaciones , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/complicaciones , Neoplasias Nasofaríngeas/terapia , Puntaje de Propensión , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Tasa de Supervivencia , Tromboembolia Venosa/tratamiento farmacológico , Tromboembolia Venosa/etiologíaRESUMEN
BACKGROUND: We wished to evaluate the efficacy and safety of liposomal paclitaxel and docetaxel for induction chemotherapy (IC) for nasopharyngeal carcinoma (NPC). METHODS: A total of 1498 patients with newly-diagnosed NPC between 2009 and 2017 treated with IC plus concurrent chemotherapy were included in our observational study. Overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS) and grade-3-4 toxicities were compared between groups using propensity score matching (PSM). RESULTS: In total, 767 patients were eligible for this study, with 104 (13.6%) and 663 (86.4%) receiving a liposomal paclitaxel-based and docetaxel-based taxanes, cisplatin and 5-fluorouracil (TPF) regimen, respectively. PSM identified 103 patients in the liposomal-paclitaxel group and 287 patients in the docetaxel group. There was no significant difference at 3 years for OS (92.2% vs. 93.9%, P = 0.942), PFS (82.6% vs. 81.7%, P = 0.394), LRFS (94.7% vs. 93.3%, P = 0.981) or DMFS (84.6% vs. 87.4%, P = 0.371) between the two groups after PSM. Significant interactions were not observed between the effect of chemotherapy regimen and sex, age, T stage, N stage, overall stage, or Epstein-Barr virus DNA level in the subgroup multivariate analysis. The prevalence of grade-3-4 leukopenia and neutropenia in the liposomal-paclitaxel group was significantly lower than that of the docetaxel group (P < 0.05 for all). CONCLUSIONS: Compared with docetaxel, liposomal paclitaxel has identical anti-tumor efficacy, but causes fewer and milder adverse reactions in IC for NPC.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/fisiopatología , Carcinoma Nasofaríngeo/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neutropenia/fisiopatología , Adolescente , Adulto , Anciano , Línea Celular Tumoral , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Supervivencia sin Enfermedad , Docetaxel/administración & dosificación , Docetaxel/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Herpesvirus Humano 4/genética , Humanos , Liposomas/química , Liposomas/farmacología , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/epidemiología , Carcinoma Nasofaríngeo/patología , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Neutropenia/inducido químicamente , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Taxoides/administración & dosificación , Taxoides/efectos adversosRESUMEN
Acylglycerol kinase (AGK) has been reported to promote a malignant phenotype and enhance the development of cancer stem cells. However, the clinical value of AGK in cancer remains unclear. This study aimed to investigate the expression and clinicopathological significance of AGK in nasopharyngeal carcinoma (NPC). AGK was significantly upregulated in NPC cell lines and clinical specimens as indicated by real-time PCR and Western blotting. Among the AGK-positive cases, 52/114 (45.6 %) of the archived human NPC specimens expressed high levels of AGK. High expression of AGK was associated with significantly shorter overall and disease-free survival (P < 0.001 and P = 0.002; log-rank test) and was an independent prognostic factor for overall survival (P = 0.041; multivariate Cox analysis). High AGK expression was associated with lymph node metastasis (P < 0.001; chi-squared test) and was an independent predicted factor for lymph node metastasis in NPC (P = 0.032; multivariate logistic analysis). AGK is overexpressed and associated with disease progression and lymph node metastasis in NPC. AGK has potential as a novel prognostic factor for overall survival in NPC.
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Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Neoplasias Nasofaríngeas/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Adulto , Western Blotting , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Modelos Logísticos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Nasofaríngeas/enzimología , Neoplasias Nasofaríngeas/patología , Estadificación de Neoplasias , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia ArribaRESUMEN
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.
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Albúminas , Neoplasias Nasofaríngeas , Enfermedades del Sistema Nervioso Periférico , Humanos , Cisplatino , Carcinoma Nasofaríngeo/tratamiento farmacológico , Capecitabina , Quimioterapia de Inducción/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Paclitaxel/efectos adversos , Quimioradioterapia/efectos adversos , Neoplasias Nasofaríngeas/patología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológicoRESUMEN
OBJECTIVE: To investigate the prognostic value of tumor response (TR) for locoregionally recurrent nasopharyngeal carcinoma (lrNPC) patients at the end of re-radiotherapy (re-RT) and develop a risk score model to predict patient's radiosensitivity to re-RT. MATERIALS AND METHODS: A total of 594 patients with lrNPC from 2010 to 2020 were retrospectively reviewed as the total cohort. Among these, 310 patients with complete first-line treatment data were reviewed as a secondary cohort. Overall survival (OS) was the primary endpoint. Locoregional control (LRC) was the secondary endpoint. Multivariate Cox analysis was performed to investigate the prognostic value of TR at the end of re-RT (rTR). A risk score model for predicting rTR was obtained by logistic regression analysis, and its effectiveness was compared using receiver operating characteristic (ROC) analysis. RESULTS: Patients with complete response (CR) to rTR had higher 5-year OS and LRC rate than non-CR patients in both the total and secondary cohort. rTR was an independent prognostic factor for OS (P = 0.002) and LRC (P = 0.008). We developed a risk score model including four significant risk factors (relapse T stage, relapse gross tumor volume, time to recurrence, and initial TR). The area under the curve of the risk score model was 0.73 (95% CI: 0.678 to 0.780), which was significantly higher than that of each variable alone. Patients with the highest risk scores may be insensitive to re-RT and had a residual tumor risk of 89.9% after rRT. CONCLUSION: rTR was an independent prognostic factor for OS and LRC in lrNPC patients. We developed a risk score model for predicting patients' sensitivity to re-RT to screen for radiosensitive patients. This can serve as a treatment decision-making tool for clinicians.
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Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/radioterapia , Pronóstico , Estudios Retrospectivos , Neoplasias Nasofaríngeas/patología , Recurrencia Local de Neoplasia/patología , Factores de Riesgo , Imagen por Resonancia MagnéticaRESUMEN
OBJECTIVES: About 17.7-34.0 % of patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) responded well to anti-PD-1 monotherapy. We sought to establish a nomogram to estimate the progression-free survival (PFS) of RM-NPC patients receiving subsequent-line anti-PD-1 monotherapy. MATERIALS AND METHODS: This cohort study investigated consecutive RM-NPC patients undergoing anti-PD-1 monotherapy. A nomogram was developed in the training cohort (n = 161), using a Cox multivariate model with backward stepwise inclusion, and was validated in the validation cohort (n = 69). Its predictive accuracy was assessed using a concordance index (C-index) and calibration curve. The primary endpoint was PFS. Secondary endpoints included the objective response rate (ORR), disease control rate (DCR), and overall survival (OS). RESULTS: Liver metastasis, albumin, lactate dehydrogenase, monocyte-to-lymphocyte ratio, and plasma Epstein-Barr virus DNA were used to develop a nomogram that could separate patients into favourable- and unfavourable-prognosis groups. The C-index in the training and validation cohort were 0.70 and 0.68, respectively, which was confirmed by calibration curves. Median PFS (mPFS) was lower for the unfavourable-prognosis than for the favourable-prognosis group (1.80 vs 4.93; hazard ratio 2.49 [95 % confidence interval: 1.78-3.49]; p < 0.001), across all subgroups. OS exhibited the same pattern. The ORR and DCR were markedly lower in the unfavourable-prognosis than in the favourable-prognosis group. All results were confirmed in the validation cohort. CONCLUSION: Our model is a reliable prognostic indicator of PFS in RM-NPC patients undergoing anti-PD-1 monotherapy, allowing robust estimation of the immunotherapy benefit an individual might derive.
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Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Pronóstico , Carcinoma Nasofaríngeo/patología , Estudios de Cohortes , Estadificación de Neoplasias , Recurrencia Local de Neoplasia/patología , Herpesvirus Humano 4 , Neoplasias Nasofaríngeas/patologíaRESUMEN
BACKGROUND AND PURPOSE: We sought to determine the prognostic value of a pre-treatment peripheral blood signature and the peripheral blood signature-based nomogram for patients with non-metastatic nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: We retrospectively collected 21 peripheral blood indicators from patients with NPC between 2004 and 2015. Data were randomly divided into a training and a validation set (ratio: 6:4). The peripheral blood signature was constructed based on candidate biomarkers using the least absolute shrinkage and selection operator Cox regression model. Multivariable logistic regression was applied to identify the independent risk factors of overall survival to build the nomogram. The predictive value of the peripheral blood nomogram was evaluated using time-dependent area under the curve, decision curve analysis, and calibration curve. RESULTS: In total, 6668 patients were enrolled with 4000 and 2668 in the training and validation cohorts, respectively. Four peripheral blood indicators, (white blood cell count, lymphocyte percentage, haemoglobin, and mean platelet volume), were included to construct the peripheral blood signature. Patients were divided into low- and high-risk groups using an optimal cut-off value of - 1.71142. Patients in the high-risk group had significantly lower overall, distant metastasis-free, and progression-free survival than patients in the low-risk group in both cohorts (P < 0.05). We constructed and validated a peripheral blood signature-based nomogram in combination with five vital clinical characteristics, (age, sex, tumour stage, nodal stage, and pre-treatment Epstein-Barr virus DNA), which showed favourable performance. CONCLUSION: Patients with NPC with different outcomes could be distinguished based on their peripheral blood signature score; the proposed peripheral blood signature-based nomogram offers individualised risk estimation.
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Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patología , Estudios Retrospectivos , Herpesvirus Humano 4 , Pronóstico , Nomogramas , Factores de Riesgo , Pruebas Hematológicas , Neoplasias Nasofaríngeas/patologíaRESUMEN
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.