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1.
Cancer Res ; 79(18): 4612-4626, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31331909

RESUMO

Long noncoding RNAs (lncRNA) play important roles in the tumorigenesis and progression of cancers. However, the clinical significance of lncRNAs and their regulatory mechanisms in nasopharyngeal carcinogenesis (NPC) are largely unknown. Here, based on a microarray analysis, we identified 384 dysregulated lncRNAs, of which, FAM225A was one of the most upregulated lncRNAs in NPC. FAM225A significantly associated with poor survival in NPC. N(6)-Methyladenosine (m6A) was highly enriched within FAM225A and enhanced its RNA stability. FAM225A functioned as an oncogenic lncRNA that promoted NPC cell proliferation, migration, invasion, tumor growth, and metastasis. Mechanistically, FAM225A functioned as a competing endogenous RNA (ceRNA) for sponging miR-590-3p and miR-1275, leading to the upregulation of their target integrin ß3 (ITGB3), and the activation of FAK/PI3K/Akt signaling to promote NPC cell proliferation and invasion. In summary, our study reveals a potential ceRNA regulatory pathway in which FAM225A modulates ITGB3 expression by binding to miR-590-3p and miR-1275, ultimately promoting tumorigenesis and metastasis in NPC. SIGNIFICANCE: These findings demonstrate the clinical significance of the lncRNA FAM225A in nasopharyngeal carcinoma (NPC) and the regulatory mechanism involved in NPC development and progression, providing a novel prognostic indicator and promising therapeutic target.

2.
N Engl J Med ; 381(12): 1124-1135, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31150573

RESUMO

BACKGROUND: Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials. METHODS: In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety. RESULTS: A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group. CONCLUSIONS: Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Quimioterapia de Indução , Carcinoma Nasofaríngeo/tratamento farmacológico , Adolescente , Adulto , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Humanos , Quimioterapia de Indução/efeitos adversos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/terapia , Análise de Sobrevida , Adulto Jovem
3.
Radiother Oncol ; 137: 137-144, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102988

RESUMO

PURPOSE: To compare clinical features and survival outcomes in patients with ascending type (type A) and descending type (type D) nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era. MATERIALS AND METHODS: A total of 5194 patients with type A and type D NPC treated at Sun Yat-sen University Cancer Center were randomly selected. Tumors that were mainly advanced local disease (T3-4 stage) with early stage cervical lymph node involvement (N0-1 stage) were determined as type A, while tumors with advanced lymph node disease (N2-3 stage) but early stage local invasion (T1-2 stage) were classified as type D NPC. Kaplan-Meier's analysis was used to evaluate survival rates, and log-rank test survival curves were used for comparison. In the multivariate analysis Cox proportional hazard models were developed. RESULTS: There was a larger proportion of type A tumors (82%) than type D tumors (18%). Compared to patients with type A tumors, those with type D tumors had increased likelihood of distant metastasis, regional recurrence, disease recurrence, and death (P < 0.001 for all), however, not for local recurrence (P < 0.001). The HR (hazard ratio) for death following recurrence of disease for type D tumors were 1.6 compared to type A tumors. Multivariate analysis revealed that elevated EBV DNA, elevated lactate dehydrogenase, alcohol consumption, and no family history of cancer attributed to the development of type D tumors. Annual hazard rate in type A patients increased, peaking at 12-18 months after initial treatment and downward thereafter. Similar trend also occurred in type D during the first 5 years following treatment. Notably, a minor peak was also observed 7-8 years post treatment. CONCLUSIONS: In the IMRT era, recurrence patterns differed across tumor types. Type D NPC had a more aggressive clinical course and worse outcomes compared with type A NPC.

4.
Int J Radiat Oncol Biol Phys ; 105(1): 124-131, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31075310

RESUMO

PURPOSE: To evaluate the evolution of radiation-induced brain stem injury (BSI) in patients with nasopharyngeal carcinoma (NPC) treated with intensity modulated radiation therapy (IMRT) and to identify the critical dosimetric predictors of BSI. METHODS AND MATERIALS: A total of 6288 NPC patients treated with IMRT between 2009 and 2015 were retrospectively reviewed. Among these 6288 patients, 24 had radiation-induced BSI, which manifested as edematous lesions and contrast-enhanced lesions (CLs) on magnetic resonance imaging. Latency, symptoms, and evolution of BSI were assessed. Critical dosimetric predictors of BSI were identified using a penalized regression model with performance evaluated by receiver operating characteristic curve analysis. RESULTS: Median BSI latency was 14.5 months (range, 7.6-37.5 months), and 9 out of 24 patients (37.5%) were clinically symptomatic. Edematous lesions and CLs were both present in all patients. Necrosis was significantly more common in larger CLs (P = .007). After median follow-up of 12.5 months, 13 out of 24 patients (54.2%) had complete remission, and 5 out of 24 patients (20.8%) had partial remission. Remission was unaffected by whether or not symptomatic treatment was given. Maximum point dose (Dmax) was identified as the critical predictor of BSI (area under the receiver operating curve = 0.898), with the optimal cutoff equivalent dose in 2-Gy fractions (D2) being 67.4 Gy (sensitivity = 0.833, 20 out of 24; specificity = 0.835, 5234 out of 6264). Patients with Dmax ≥67.4 Gy (D2) were significantly more likely to develop BSI (odds ratio = 25.29; 95% CI, 8.63-74.14; P < .001) than those with Dmax <67.4 Gy (D2). CONCLUSIONS: In patients with NPC treated with IMRT, BSI generally tends to improve over time. Dmax = 67.4 Gy (D2) appears to be the dose constraint for brain stem, potentially providing clinicians with greater choice and flexibility when balancing the tumor target coverage and brain stem protection. Further studies are needed to validate our findings.

5.
Radiology ; 291(3): 677-686, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30912722

RESUMO

Background Nasopharyngeal carcinoma (NPC) may be cured with radiation therapy. Tumor proximity to critical structures demands accuracy in tumor delineation to avoid toxicities from radiation therapy; however, tumor target contouring for head and neck radiation therapy is labor intensive and highly variable among radiation oncologists. Purpose To construct and validate an artificial intelligence (AI) contouring tool to automate primary gross tumor volume (GTV) contouring in patients with NPC. Materials and Methods In this retrospective study, MRI data sets covering the nasopharynx from 1021 patients (median age, 47 years; 751 male, 270 female) with NPC between September 2016 and September 2017 were collected and divided into training, validation, and testing cohorts of 715, 103, and 203 patients, respectively. GTV contours were delineated for 1021 patients and were defined by consensus of two experts. A three-dimensional convolutional neural network was applied to 818 training and validation MRI data sets to construct the AI tool, which was tested in 203 independent MRI data sets. Next, the AI tool was compared against eight qualified radiation oncologists in a multicenter evaluation by using a random sample of 20 test MRI examinations. The Wilcoxon matched-pairs signed rank test was used to compare the difference of Dice similarity coefficient (DSC) of pre- versus post-AI assistance. Results The AI-generated contours demonstrated a high level of accuracy when compared with ground truth contours at testing in 203 patients (DSC, 0.79; 2.0-mm difference in average surface distance). In multicenter evaluation, AI assistance improved contouring accuracy (five of eight oncologists had a higher median DSC after AI assistance; average median DSC, 0.74 vs 0.78; P < .001), reduced intra- and interobserver variation (by 36.4% and 54.5%, respectively), and reduced contouring time (by 39.4%). Conclusion The AI contouring tool improved primary gross tumor contouring accuracy of nasopharyngeal carcinoma, which could have a positive impact on tumor control and patient survival. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Chang in this issue.

6.
Oral Oncol ; 91: 7-12, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30926066

RESUMO

OBJECTIVES: Epstein-Barr virus (EBV)-positive cervical lymph node (CLN) metastasis of unknown primary origin is classified as nasopharyngeal carcinoma (NPC) T0 by the American Joint Committee on Cancer staging manual (8th edition). We aimed to investigate the possible primary sites and patterns of EBV-positive CLN metastases and to provide implications for the management of NPC T0 classification. MATERIALS AND METHODS: We retrospectively reviewed 269 patients with newly diagnosed EBV-positive CLN metastatic disease who underwent EBV detection via EBV-encoded RNA in situ hybridization. Fifteen patients with unknown primary tumors underwent follow-up after initial treatment. RESULTS: In patients with EBV-positive CLNs, the most common primary sites after the nasopharynx (51.7%) were the salivary gland (24.5%), lung (7.8%), oropharynx (3.3%), nasal cavity/maxillary (3.3%), oral cavity (2.2%), orbit (1.1%), and liver (0.4%). No primary site was found in 15 patients (5.6%). For salivary gland malignancies, level II and I were the most frequently involved regions. Tumors arising from the lung or liver metastasized to the lower neck (level IV, V, and VI) rather than the upper neck. After initial treatment, 2/15 patients with EBV-positive CLNs of unknown primary exhibited primary NPC and oropharyngeal tumor, respectively. Further, even without prophylactic irradiation to the nasopharynx, only one of 13 unknown primary patients developed NPC. CONCLUSIONS: The origins of EBV-positive CLNs may not be restricted to the nasopharynx alone, and are likely to involve the head and neck or non-head and neck regions. NPC T0 classification should be cautiously assigned to such tumors.

7.
BMC Cancer ; 19(1): 37, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30621619

RESUMO

BACKGROUND: Findings remain unclear whether neutrophil-to-lymphocyte ratio (NLR) detrimentally affects advanced nasopharyngeal carcinoma (NPC) prognosis. We aim to evaluate the prognostic value of NLR in patients with NPC based on a large-scale cohort from an endemic area. METHODS: We selected patients retrospectively from a cohort examining long-term cancer outcomes following diagnosis. Neutrophil counts and lymphocyte counts were assessed prior to treatment. Kaplan-Meier method and log-rank test were used to calculate and compare survival outcomes. Additionally, Cox proportional hazards model was utilized to carry out univariate and multivariate analyses. RESULTS: Between October 2009 and August 2012, we enrolled 1550 consecutive NPC patients staged II-IVB. The median value of NLR was 2.27 (interquartile range [IQR], 1.71-3.12). Determined by operating characteristic curve using overall survival (OS) as an endpoint, the cutoff value for NLR was 2.50. At 5 years, NLR > 2.50 was associated with inferior OS (90.3% vs 82.5%; P < 0.001), distant metastasis-free survival (DMFS, 89.4% vs 85.0%; P = 0.014), and progression-free survival (PFS, 80.9% vs 76.5%; P = 0.031) than NLR ≤2.50. In multivariate analysis, NLR was found to be a significant prognostic factor for OS (HR, 1.72; 95% CI, 131-2.24; P < 0.001), DMFS (HR, 1.45; 95% CI, 1.10-1.92; P = 0.009), and PFS (HR, 1.29; 95% CI, 1.04-1.59; P = 0.021). CONCLUSION: Pretreatment NLR independently affects survival. Our findings suggest that NLR measurements will be of great clinical significance in the management of NPC.


Assuntos
Linfócitos/patologia , Carcinoma Nasofaríngeo/patologia , Neutrófilos/patologia , Prognóstico , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/sangue
8.
J Pineal Res ; 66(3): e12557, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30638277

RESUMO

We performed comprehensive genomic analyses of the melatonergic system within the tumor microenvironment and their clinical relevance across a broad spectrum of solid tumors. RNA-seq data from The Cancer Genome Atlas (TCGA) of 14 solid tumors representing 6658 human samples were analyzed. The tumor melatonergic system was characterized by the rates of melatonin synthesis and metabolism using a two-gene expression model (melatonin synthesis/metabolism Index). We calculated three indexes according to different melatonin metabolism isoenzymes (Index-I [ASMT:CYP1A1], Index-II [ASMT:CYP1A2], and Index-III [ASMT:CYP1B1]). Samples of each cancer type were classified into two subgroups (high vs low) based on median values. Clinical outcomes, mutational burden, and neoepitope abundance were analyzed and compared. We found that the ability of the tumor microenvironment to synthesize and accumulate melatonin varied across cancer types and negatively correlated with tumor burden. Kaplan-Meier survival analyses and multivariable modeling showed that the three indexes played different roles across different cancers and harbored prognostic values in breast cancer (adjusted hazard ratio [AHR]Index-II  = 0.65 [0.44-0.97]; P = 0.03), cervical cancer (AHRIndex-I  = 0.62 [0.39-0.98]; P = 0.04), lung squamous cell carcinoma (AHRIndex-III  = 0.75 [0.56-0.99]; P = 0.04), melanoma (AHRIndex-I  = 0.74 [0.55-0.98]; P = 0.04), and stomach adenocarcinoma (AHRIndex-III  = 0.68 [0.41-0.94]; P = 0.02). We further investigated its clinical relevance with tumor immunogenic features (mutational burden and neoantigen abundance), which may predict immunotherapy benefits. We observed significant negative correlations with mutational burden in the majority of tumors (P < 0.05), except cervical cancer, pancreatic adenocarcinoma, and thyroid carcinoma. Our study provides a systematic overview of the oncostatic values of the melatonergic system and highlights the utilization of this simple and promising gene signature as a prognosticator and potential predictor of response to immunotherapy.


Assuntos
Melatonina/metabolismo , Neoplasias/genética , Neoplasias/imunologia , Microambiente Tumoral/fisiologia , Genômica , Humanos , Estimativa de Kaplan-Meier , Neoplasias/mortalidade , Prognóstico , Transcriptoma
9.
BMJ ; 363: k4226, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30409774

RESUMO

OBJECTIVE: To provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched to include relevant studies published in English between January 2007 and February 2018. REVIEW METHODS: Only head-to-head phase II and III randomised controlled trials comparing any two or three of the following treatments or different doses of the same ICI drug were included: nivolumab, pembrolizumab, ipilimumab, tremelimumab, atezolizumab, conventional therapy (chemotherapy, targeted therapy, and their combinations), two ICI drugs, or one ICI drug with conventional therapy. Eligible studies must have reported site, organ, or system level data on treatment related adverse events. High quality, single arm trials and placebo controlled trials on ICI drugs were selected to establish a validation group. RESULTS: 36 head-to-head phase II and III randomised trials (n=15 370) were included. The general safety of ICI drugs ranked from high to low for all adverse events was as follows: atezolizumab (probability 76%, pooled incidence 66.4%), nivolumab (56%, 71.8%), pembrolizumab (55%, 75.1%), ipilimumab (55%, 86.8%), and tremelimumab (54%, not applicable). The general safety of ICI drugs ranked from high to low for severe or life threatening adverse events was as follows: atezolizumab (49%, 15.1%), nivolumab (46%, 14.1%), pembrolizumab (72%, 19.8%), ipilimumab (51%, 28.6%), and tremelimumab (28%, not applicable). Compared with conventional therapy, treatment-related adverse events for ICI drugs occurred mainly in the skin, endocrine, hepatic, and pulmonary systems. Taking one ICI drug was generally safer than taking two ICI drugs or one ICI drug with conventional therapy. Among the five ICI drugs, atezolizumab had the highest risk of hypothyroidism, nausea, and vomiting. The predominant treatment-related adverse events for pembrolizumab were arthralgia, pneumonitis, and hepatic toxicities. The main treatment-related adverse events for ipilimumab were skin, gastrointestinal, and renal toxicities. Nivolumab had a narrow and mild toxicity spectrum, mainly causing endocrine toxicities. Integrated evidence from the pooled incidences, subgroup, and sensitivity analyses implied that nivolumab is the best option in terms of safety, especially for the treatment of lung cancer. CONCLUSIONS: Compared with other ICI drugs used to treat cancer, atezolizumab had the best safety profile in general, and nivolumab had the best safety profile in lung cancer when taking an integrated approach. The safety ranking of treatments based on ICI drugs is modulated by specific treatment-related adverse events. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017082553.

10.
Radiother Oncol ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30448002

RESUMO

PURPOSE: To evaluate the effect of radiotherapy interruption (RTI) in patients with nasopharyngeal carcinoma (NPC) receiving intensity-modulated radiotherapy (IMRT). PATIENTS AND METHODS: A total of 7826 patients using the well-established big-data intelligence platform were identified. Computer-generated random numbers were used to assign these patients into a training cohort (n = 3913 patients) and an internal validation cohort (n = 3913 patients). RTI was defined as the difference between radiation treatment time and planned radiation time (assuming a Monday start). Survival analysis was performed using the Kaplan-Meier method for survival, and log-rank test to evaluate difference. Optimal RTI threshold was identified using the recursive partitioning analyses (RPAs). Multivariate analysis was performed using the Weibull model. The primary endpoint was overall survival (OS). RESULTS: The optimal threshold of RTI with respect to OS in the training cohort was 6.5 d based on RPAs. Therefore, a uniform threshold of 7 d (<7 vs. ≥7 d) was selected to classify both training and validation cohorts into high and low RTI groups for survival analysis. RTI of ≥7 d showed significant detrimental effects on OS in both training (5-y OS, 82.4% vs 86.5%; P = 0.001) and validation cohorts (5-y OS, 85.2% vs 86.7%; P = 0.013) than those patients with RTI of <7 d. Consistent with results of the univariate analysis, RTI of ≥7 d was found to be an independent unfavorable prognostic factor for OS in both training (HR, 1.49; 95% CI, 1.14-1.95; P = 0.003) and validation cohort (HR, 1.37; 95% CI, 1.07-1.65; P = 0.031). Subgroup analysis showed that RTI of ≥7 d had significant adverse effects on prognosis of NPC patients receiving IMRT, regardless of TNM stage and chemotherapy (P < 0.05 for all). CONCLUSIONS: In the IMRT era, RTI independently influences survival. Raising RTI ≥ 7 d was consistently unfavorable for NPC survival. Medical practitioners must remind patients on the importance of minimizing RT interruptions.

11.
Radiother Oncol ; 129(2): 389-395, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30270098

RESUMO

BACKGROUND AND PURPOSE: Lacking quantitative evaluations of competing risk data of nasopharyngeal carcinoma (NPC), we aimed to evaluate the probability of NPC- and other cause-specific mortality (NPC-SM; OCSM) and develop competing risk nomograms to quantify survival differences. MATERIAL AND METHOD: Using the institutional big-data intelligence platform, 7251 NPC patients undergoing intensity-modulated radiotherapy between 2009-2014 were identified to establish nomograms based on Fine and Gray's competing risk analysis. RESULTS: The 5-year NPC-SM and OCSM of the cohort were 13.1% and 1.2%, respectively, and elevated 5-year OCSMs were observed in patients aged ≥65 years (5.5%) or with severe comorbidities (4.3%). Age was most predictive of OCSM: patients aged 55-64 and ≥65 years exhibited subdistribution hazard ratios (SHRs) of 2.70 (95% confidence interval [CI], 1.64-4.4; P < .001) and 5.78 (95% CI, 3.32-10.08; P < .001), respectively. Comorbidity measured using the Charlson Comorbidity Index (CCI) was also strongly predictive of OCSM: patients with CCI scores of 1 and ≥2 exhibited SHRs of 2.33 (95% CI, 1.46-3.71; P < .001) and 2.58 (95% CI, 1.16-5.73; P = .020), respectively. All validated factors were integrated into the competing nomograms: age, sex, histology type, tumor and node stages, plasma Epstein-Barr virus-DNA level, lactate dehydrogenase level, and C-reactive protein (CRP) level into the NPC-SM model (concordance [c]-index = 0.743); and age, CCI, Albumin level, and CRP level into the OCSM model (c-index = 0.793). CONCLUSION: OCSM represents a significant competing event for NPC-SM in elderly patients and patients with comorbidities. We present the first prognostic nomograms to quantify competing risks, which may help to tailor individualized treatment.

12.
Cancer Biol Ther ; : 1-6, 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30081714

RESUMO

PURPOSE: The benefits of additional use of nimotuzumab (NTZ) in the treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is largely unclear. We aim to compare LA-NPC treatment outcomes in patients that received CCRT with nimotuzumab (NTZ) to patients that received CCRT only. MATERIALS AND METHODS: Between October 2009 and January 2012, 31 previously untreated and newly diagnosed LA-NPC patients were administered CCRT (3 cycles of 100 mg/m2 cisplatin every third week with intensity-modulated radiotherapy) plus NTZ according to an IRB-approved institutional research protocol. A well-balanced cohort of 62 patients who received CCRT alone was created by matching each patient who received CCRT plus NTZ via propensity-matched analysis in a 2:1 ratio. RESULTS: Compared with CCRT only, CCRT plus NTZ was significantly associated with superior overall survival (5-year OS; 96.8% vs. 82.3%; P = 0.001), superior distant metastasis-free survival (5-year DMFS; 90.3% vs. 80.6%, P = 0.012) and superior progression-free survival (5-year PFS; 83.9% vs. 71.0%, P = 0.006). In multivariate analysis, the inclusion of NTZ to CCRT was confirmed to be a favorable factor for OS (HR, 0.31; 95% CI, 0.02-0.71; P = 0.027), DMFS (HR, 0.45; 95% CI, 0.13-0.77; P = 0.034), and PFS (HR, 0.38; 95% CI, 0.11-0.89; P = 0.041). In addition, no significant differences in hematology parameters, dermatitis, nausea, vomiting, xerostomia, nephrotoxicity or neurotoxicity were found between the two arms (all P > 0.05). CONCLUSION: The inclusion of NTZ to CCRT is more effective for long-term survival among LA-NPC patients than CCRT only.

13.
Radiat Oncol ; 13(1): 141, 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30081932

RESUMO

BACKGROUND: To compare the efficacy of ipsilateral lower neck sparing irradiation (ILNSI) versus ipsilateral lower neck prophylactic irradiation (ILNPI) for unilateral or bilateral neck node-negative nasopharyngeal cancer (NPC). METHODS: A comprehensive literature search of PubMed, EMBASE, the Cochrane Library and other public databases was conducted in October, 2017. The outcomes were 3-year overall/regional recurrence-free/disease-free/distant metastasis-free survival (OS/RRFS/DFS/DMFS) and ipsilateral lower neck (ILN) recurrence. We performed subgroup analysis of ILNSI versus ILNPI for different radiotherapy techniques. Sensitivity analysis was performed to examine the stability of the results. RESULTS: Nine head-to-head comparative studies (2, 521 patients) were included in the meta-analysis. For the comparison of ILNSI versus ILNPI, there was no significant difference in 3-year OS (HR = 1.16, 95% confidence interval [CI] = 0.85-1.58, P = 0.36), RRFS (HR = 1.37, 95% CI = 0.76-2.47, P = 0.30), DFS (HR = 1.08, 95% CI = 0.80-1.44, P = 0.62) and DMFS (HR = 1.00, 95% CI = 0.69-1.44, P = 0.99). ILNSI and ILNPI also led to equivalent ILN recurrence rates (OR = 0.98, 95% CI = 0.47-2.03, P = 0.96). No significant heterogeneity was observed for any outcome. Subgroup analysis confirmed no significant differences between ILNSI and ILNPI for any outcome, regardless of radiotherapy technique. Sensitivity analysis indicated all outcomes were highly stable in favor of the original conclusions. CONCLUSIONS: ILNSI provided equivalent survival outcomes and regional control compared to ILNPI; ILNSI represents an appropriate alternative strategy for patients with unilateral or bilateral neck node-negative NPC.

14.
Cell Physiol Biochem ; 48(1): 285-292, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30011397

RESUMO

BACKGROUND/AIMS: Lipoproteins have been reported to be associated with prognosis in various cancers; however, the prognostic value of lipoproteins in patients with nasopharyngeal carcinoma (NPC) remains largely unknown. We aim to asses the role of circulating lipoproteins in locoregionally advanced NPC patients. METHODS: Between October 2009 and August 2012, a total of 1,081 patients with stage III-IVB NPC were included in the analysis. Circulating high-density lipoprotein (HDL) and low-density lipoprotein (LDL) are the two key lipoproteins, which were measured at baseline. Receiver operating characteristic (ROC) curve analysis was used to evaluate different cut-off points for lipoproteins. Actuarial rates were performed using Kaplan-Meier methods and the log-rank test. RESULTS: The cutoff points of HDL, LDL, and LDL/HDL ratio were 1.17 mmol/L, 3.75 mmol/L, and 2.73, respectively. At 5 years, high HDL (> 1.17 mmol/L) was significantly associated with better overall survival (OS, 86.6% vs. 78.9%; P=0.004), distant metastasis-free survival (DMFS, 86.9% vs. 80.8%; P=0.004), locoregional relapse-free survival (LRFS, 90.8% vs. 85.4%; P=0.010), and progression-free survival (PFS, 79.1% vs. 70.2%; P= 0.001) than low HDL (≤1.17 mmol/L). In contrast, high LDL (> 3.75 mmol/L) tend to be inferior OS (79.1% vs. 84.9%; P= 0.016) in compassion with low LDL (≤3.75 mmol/L). Likewise, patients with high LDL/HDL ratio (> 2.73) tend to be inferior OS (79.3% vs. 86.9%; P=0.001), DMFS (81.9% vs. 86.5%; P=0.030), and PFS (72.6% vs. 77.8%; P= 0.034) than those of low LDL/HDL ratio (≤2.73). In multivariate analysis, baseline HDL was found to be a significant prognostic factor for LRFS (HR= 0.65; 95% CI, 0.45-0.93; P= 0.019) and PFS (HR=0.75; 95% CI, 0.58-0.98; P= 0.034). CONCLUSIONS: Circulating HDL is significantly associated with treatment outcomes in patients with locoregionally advanced NPC. We suggest that HDL measurements will be of great clinical significance in the management of NPC.


Assuntos
Carcinoma/patologia , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Neoplasias Nasofaríngeas/patologia , Adulto , Área Sob a Curva , Carcinoma/metabolismo , Carcinoma/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/mortalidade , Estadiamento de Neoplasias , Prognóstico , Curva ROC
15.
BMC Cancer ; 18(1): 740, 2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30012115

RESUMO

BACKGROUND: Previous studies have reported radiotherapy interruption (RTI) is associated with poor local control in two-dimensional radiotherapy (2DRT) era. However, it remains unclear whether RTI still affects local control for advanced T stage (T3-4) in the intensity-modulated radiation therapy (IMRT) era. We aim to evaluate whether RTI affects local control for T3-4 NPC treated with definitive IMRT. METHODS: In this observational prospective study, 447 T3-4 NPC patients treated with IMRT plus concurrent chemotherapy were included. All patients completed the planned radiotherapy course, and RTI was defined as the actual time taken to finish the prescribed course of radiotherapy minus the planned radiotherapy time. Receiver operating characteristic (ROC) curve was used for determined the cutoff point of RTI. The effects of RTI on local control were analyzed in multivariate analysis. RESULTS: At 5 years, the local relapse-free survival (LRFS) and overall survival (OS) rates were 93.7 and 85.7%, respectively. The cutoff RTI for LRFS was 5.5 days by ROC curve. Compared to patients with RTI >  5 days, patients with RTI ≤ 5 days had a significantly lower rate of LRFS (97% vs. 83%; P < 0.001). In multivariate analysis, RTI was a risk factor independently associated with LRFS (HR = 9.64, 95% CI, 4.10-22.65), but not for OS (HR = 1.09, 95% CI, 0.84-1.64). CONCLUSIONS: The current analysis demonstrates a significant correlation between prolonged RTI and local control in NPC, even when concurrent chemotherapy is used. We consider that attention to RTI seems to be warranted for patients with advanced T-stage NPC in the era of IMRT.

16.
Clin Chim Acta ; 484: 314-319, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29860034

RESUMO

BACKGROUND: We evaluated the prognostic value of serum bilirubin in advanced nasopharyngeal carcinoma (NPC) patients. METHODS: Seven-hundred fifty-nine advanced NPC patients treated with definitive chemoradiotherapy were retrospectively analyzed. Serum indirect bilirubin (IBIL) and direct bilirubin (DBIL) were measured before treatment. To evaluate different cutoff points for serum bilirubin, we utilized ROC curves. The Kaplan-Meier method and log-rank test were adopted to calculate and compare survival outcomes. Cox proportional hazard models were used to perform univariate and multivariate analyses. RESULTS: At 5 y, IBIL >7.15 µmol/l were significantly associated with superior progression-free survival (PFS, 83.6% vs 70.3%; P < .001), overall survival (OS, 88.6% vs 80.5%; P = .012), distant metastasis-free survival (DMFS, 90.3% vs 82.8%; P = .006), and locoregional relapse-free survival (LRFS, 92.1% vs 86.4%; P = .048) than IBIL ≤7.15 µmol/l. Similarly, patients with DBIL >2.65 µmol/l had better prognosis across all outcomes than those of patients with DBIL ≤2.65 µmol/l (all P < .05), except no difference was observed in LRFS (90.5% vs. 87.3%, P = .195). Multivariate analyses showed that IBIL >7.15 µmol/l was an independent protective prognostic factor for PFS (HR, 0.57; 95% CI, 0.40-0.81; P = .002), OS (HR, 0.67; 95% CI, 0.43-0.92; P = .041), and DMFS (HR, 0.63; 95% CI, 0.40-0.98; P = .034); while serum DBIL only remained significant for PFS (HR, 0.63; 95% CI, 0.44-0.89; P = .009). CONCLUSIONS: Pretreatment IBIL and DBIL are potentially independent prognostic factors for patients with advanced NPC.


Assuntos
Bilirrubina/sangue , Biomarcadores Tumorais/sangue , Carcinoma/diagnóstico , Neoplasias Nasofaríngeas/diagnóstico , Adulto , Carcinoma/sangue , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/sangue , Prognóstico , Estudos Retrospectivos
17.
Int J Radiat Oncol Biol Phys ; 102(4): 1382-1391, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29804816

RESUMO

PURPOSE: To estimate the clinical benefit and cost-effectiveness of routine head and neck magnetic resonance imaging (MRI) in the follow-up of patients with nasopharyngeal carcinoma after definitive intensity modulated radiation therapy. PATIENTS AND METHODS: Two Markov models were developed to compare the cost and effectiveness of 3 strategies: routine clinical surveillance without serial imaging and routine annual and biannual MRI surveillance in the first 5 years. Two hypothetical cohorts of patients with primary stage T1-2 or T3-4 nasopharyngeal carcinoma who achieved complete remission after radical treatment and remained asymptomatic were analyzed. Baseline probabilities, transition probabilities, utilities, and costs were derived from published studies. Markov models were used to calculate life-time costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Model robustness was addressed via univariable and probabilistic sensitivity analyses. RESULTS: In T1-2 patients, surveillance strategies utilizing routine MRI provided few QALYs compared with non-MRI clinical follow-up (annual MRI, 0.022 QALYs; biannual MRI, 0.035 QALYs), whereas the costs associated with MRI surveillance were considerable. Compared with clinical follow-up, the ICERs for annual and biannual MRI strategies were $328,389 and $403,857 per QALY. In T3-4 patients, annual and biannual MRI surveillance provided 0.052 and 0.088 incremental QALYs, with ICERs of $156,204 and $169,772 per QALY, respectively. Model conclusions were robust and remained stable in 1-way and probabilistic sensitivity analyses. CONCLUSIONS: Routine MRI surveillance was not cost-effective owing to the high cost of MRI coupled with low rates of failure in T1-2 patients, whereas annual MRI surveillance was the dominant and possibly a cost-effective strategy for T3-4 patients, depending on the social willingness to pay.

18.
Oral Oncol ; 78: 37-45, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29496056

RESUMO

OBJECTIVES: To investigate the role of sequential chemoradiotherapy (SCRT; induction chemotherapy [IC] followed by intensity-modulated radiotherapy [IMRT]) in stage II and low-risk stage III-IV nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Four well-matched groups were individually generated using propensity score matching in patients (n = 689) with stage II (SCRT vs. concurrent chemoradiotherapy [CCRT], SCRT vs. IMRT alone) and low-risk stage III-IV NPC (SCRT vs. CCRT, SCRT vs. IC + CCRT). Five-year overall/disease-free/locoregional relapse-free/distant metastasis-free survival (OS/DFS/LRRFS/DMFS) and acute hematological toxicities were compared between groups. The value of SCRT was further investigated in multivariate analysis and subgroup analysis by adjusting for covariates and limiting IC-to-IMRT time interval, respectively. RESULTS: SCRT led to equivalent survival outcomes compared to CCRT/IMRT alone and CCRT/IC + CCRT in stage II and low-risk stage III-IV NPC, respectively (all P > .050). In multivariate analysis, patients with stage II NPC treated by SCRT obtained higher DMFS (AHR = 0.22, 95% CI = 0.05-1.00, P = .050), but not OS, DFS or LRRFS, compared to patients receiving CCRT; non-significant differences were observed between SCRT and other treatments. SCRT with short IC-to-IMRT time interval (≤70 days) achieved higher 5-year survival rates than IMRT alone (DMFS: P = .046), CCRT (stage II NPC; OS: P = .047; DMFS: P = .020) and IC + CCRT (DFS: P = .041). Moreover, SCRT was associated with higher, equivalent and lower frequencies of acute hematological toxicities than IMRT alone, CCRT and IC + CCRT, respectively. CONCLUSION: SCRT is mainly beneficial in stage II NPC, leading to better DMFS and/or equivalent acute hematological toxicities compared to CCRT/IMRT alone. CCRT is still the best choice for low-risk stage III-IV NPC.

19.
Int J Radiat Oncol Biol Phys ; 100(4): 891-902, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29485068

RESUMO

PURPOSE: To establish the regional lymph node (LN) distribution probability map and draw the neck clinical target volume specific to nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: One thousand patients with pathologically proven NPC were enrolled from January 2010 to December 2011. The center point of the LNs with a minimal axial diameter of ≥4 mm was marked on a single treatment planning computed tomography scan. The neck LN levels I to X using the 2013 updated international consensus guidelines were also contoured. LN distribution probability maps and distribution curves were established. The relationships between the LN distribution and consensus guidelines were analyzed to propose modifications for clinical target volume boundaries specific to NPC. RESULTS: A total of 10,651 LNs from 959 patients were marked. Based on the distribution of LNs and consensus guidelines, most of the LN levels defined in the 2013 updated consensus guidelines were confirmed to be comprehensive and applicable for NPC. However, for level Vb, 13.3% of cases (11 of 83) had LNs beyond the posteromedial border. For level VIIa (retropharyngeal LN), 1.5% of cases (12 of 819) had LNs above the cranial boundary, and 5 cases had LNs that emerged in the medial group. Moreover, we confirmed that no LN had been detected in certain areas of levels Ib, II, IVa, and Vc. Accordingly, a new level VIIc was proposed to include the medial group of retropharyngeal LNs, moderately extended boundaries for levels Vb and VIIa were recommended, and reduced boundaries are possibly adaptable for levels Ib, II, IV, and Vc. CONCLUSIONS: Most LN levels in the 2013 updated consensus guidelines are comprehensive and applicable for NPC. We have proposed a new level VIIc to include a medial group of retropharyngeal LNs, recommended moderate extended boundaries for levels Vb and VIIa, and suggested that the boundaries for levels Ib, II, IV, and Vc might be reduced.

20.
Cancer Res Treat ; 50(4): 1084-1095, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29141396

RESUMO

PURPOSE: Local relapse-free survival (LRFS) differs widely among patients with T4 category nasopharyngeal carcinoma (NPC). We aimed to build a nomogram incorporating clinicopathological information to predict LRFS in T4 NPC after definitive intensity-modulated radiation therapy (IMRT). Materials and Methods: Retrospective study of 415 Chinese patients with non-metastatic T4 NPC treated with definitive IMRT with or without chemotherapy at our cancer center between October 2009 and September 2013. The nomogram for LRFS at 3 and 5 years was generated based on multivariate Cox proportional hazards regression, and validated using bootstrap resampling, assessing discriminative performance using the concordance index (C-index) and determining calibration ability via calibration curves. RESULTS: Five-year LRFS was 88.8%. We identified and incorporated four independent prognostic factors for LRFS: ethmoid sinus invasion, primary gross tumor volume, age, and pretreatment body mass index. The C-index of the nomogram for local recurrence was 0.732 (95% confidence interval, 0.726 to 0.738), indicating excellent predictive accuracy. The calibration curve revealed excellent agreement between nomogram-predicted and observed LRFS probabilities. Risk subgroups based on total point score cutoff values enabled effective discrimination of LRFS. CONCLUSION: This pretreatment nomogram enables clinicians to accurately predict LRFS in T4 NPC after definitive IMRT, and could help to facilitate personalized patient counselling and treatment strategies.

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