Nasopharyngeal Carcinoma Disease Research Articles

Radiologic extranodal extension for nodal staging in nasopharyngeal carcinoma

PurposeExtranodal extension (ENE) has the potential to add value to the current nodal staging system (N8th) for predicting outcome in nasopharyngeal carcinoma (NPC). This study aimed to incorporate ENE, as well as cervical nodal necrosis (CNN) to the current stage N3 and evaluated their impact on outcome prediction. The findings were validated on an external cohort. Methods & MaterialsPre-treatment MRI of 750 patients from the internal cohort were retrospectively reviewed. Predictive values of six modified nodal staging systems that incorporated four patterns of ENE and two patterns of CNN to the current stage N3 for disease-free survival (DFS) were compared with that of N8th using multivariate cox-regression and concordance statistics in the internal cohort. Performance of stage N3 for predicting disease recurrence was calculated. An external cohort of 179 patients was used to validate the findings. ResultsIncorporation of advanced ENE, which infiltrates into adjacent muscle/skin/salivary glands outperformed the other five modifications for predicting outcomes (p < 0.01) and achieved a significantly higher c-index for 5-year DFS (0.69 vs 0.72) (p < 0.01) when compared with that of N8th staging system. By adding advanced ENE to the current N3 increased the sensitivity for predicting disease recurrence from 22.4 % to 47.1 %. The finding was validated in the external cohort (5-year DFS 0.65 vs. 0.72, p < 0.01; sensitivity of stage N3 increased from 14.0 % to 41.9 % for disease recurrence). ConclusionResults from two centre cohorts confirmed that the radiological advanced ENE should be considered as a criterion for stage N3 disease in NPC.

Dose Painting Radiotherapy Guided by Diffusion-Weighted Magnetic Resonance vs. 18F-FDG-PET/CT in Locoregionally Advanced Nasopharyngeal Carcinoma: A Randomized, Controlled Clinical Trial

This phase II randomized controlled trial aimed at comparing the efficacy and toxicity of diffusion-weighted magnetic resonance imaging (DWI)-guided dose painting radiotherapy (DP-RT), FDG-PET/CT-guided DP-RT, and conventional MRI-based radiotherapy (RT) in locoregionally advanced nasopharyngeal carcinoma (NPC). A total of 330 patients with stage III-IVa NPC disease were randomly assigned in a 1:1:1 ratio to receive induction chemotherapy followed by concurrent chemoradiotherapy by DWI-guided DP-RT (group A, n = 110), FDG-PET/CT-guided DP-RT (group B, n = 110), or conventional MRI-based RT (group C, n = 110). All patients received volumetric modulated arc therapy (VMAT). In group A, subvolume GTVnx-DWI (gross tumor volume of nasopharynx in DWI) was defined as the areas within the GTVnx (gross tumor volume of nasopharynx) with an apparent diffusion coefficient (ADC) below the mean ADC (ADC < mean). In group B, subvolume GTVnx-PET (gross tumor volume of nasopharynx in PET images) was defined within GTVnx as the SUV50%max isocontour. The doses to GTVnx-DWI in group A and GTVnx-PET in group B were escalated to 75.2 Gy/32 fx in patients with T1-2 disease and to 77.55 Gy/33 fx in those with T3-4 disease in 2.35 Gy per fraction. In group C, planning gross tumor volume of nasopharynx (PGTVnx) was irradiated at 70.4 to 72.6 Gy/32 to 33 fx in 2.2 Gy per fraction. This trial is registered with chictr.org.cn (ChiCTR2200057476). Group A and B showed significant higher complete response (CR) rates than group C (100%, 100%, and 96.4% for group A, B and C, respectively, p = 0.036). In groups A, B and C, the 1-year local recurrence-free survival (LRFS) rates were 100%, 100%, and 94.5%, respectively (p = 0.002). The 1-year disease-free survival (DFS) rates were 100%, 99.1%, and 92.7%, respectively (p = 0.001). The 1-year distant metastasis-free survival (DMFS) rates were 100%, 99.1%, and 93.6%, respectively (p = 0.004). The 1-year overall survival (OS) rates were 100%, 100%, and 95.4%, respectively (p = 0.006). Group A and B had significantly higher 1-year LRFS, DFS, DMFS, and OS than those in group C. No significant differences were observed in LRFS, DFS, DMFS and OS between group A and B. Group B (PET/CT group) had a higher incidence of grade 3-4 acute ototoxicity (3.6%) than group A (0%) and group C (0%, p = 0.036). No significant differences in other grade 3-4 acute adverse events and late toxic effects were observed among the three groups, and no patient had grade 5 toxicities. Multivariate analysis showed that dose painting (DWI-guided DP-RT and PET/CT-guided DP-RT vs conventional MRI-based RT) was associated with improved LRFS, DFS, DMFS and OS. Both DWI-guided DP-RT and PET/CT-guided DP-RT plus chemotherapy are associated with improved LRFS, DFS, DMFS and OS compared with conventional MRI-based RT among patients with locoregionally advanced NPC. DWI-guided DP-RT does not increase toxicities, but PET/CT-guided DP-RT has higher incidence of acute ototoxicity.

The impact of the COVID-19 pandemic on nasopharyngeal carcinoma patients – a national cancer centre experience

Purpose or objectiveThe COVID-19 pandemic has resulted in significant healthcare implications, with care for cancer patients compromised due to resource diversion towards battling the pandemic. We aim to investigate the impact of the peak wave of the pandemic in 2020 on the delivery of cancer care in Singapore, specifically via our nasopharyngeal carcinoma (NPC) treatment data. This study applies real world numbers to the impact of COVID-19 on cancer care delivery in Singapore. The choice of nasopharyngeal cancer allows a good direct estimate of common treatment measures such as time to biopsy, time to staging scans, time to treatment commencement, due to its clear protocol and algorithms for staging and treatment; thus serving as an excellent surrogate for the effectiveness and timeliness of the different aspects of cancer care delivery.Materials and methodsIn this retrospective study, we included all patients with newly diagnosed NPC from 1st January to 31st May from 2017 to 2020 at our centre. This time period was chosen as it coincided with the period in 2020 during the COVID-19 pandemic where there was the most strain on healthcare resources and the most restrictions on population movement within Singapore, which may impact on healthcare seeking behaviour. Narrowing down the time period to the first 5 months of the 4 respective years also allowed us to reduce the effect of annual seasonal variation in patient numbers seen as a result of holidays and festive periods such as the Lunar New Year and scheduled school holidays. Electronic medical records (EMR) were accessed. Only newly diagnosed NPC cases were included in our analysis. Patients with second synchronous primary malignancies or NPC disease recurrence were excluded. Data analysis was carried out using a combination of SPSS and Microsoft Excel.ResultsSignificantly, there was a reduction of 37–46.3% in newly diagnosed NPC cases during the peak of the COVID-19 pandemic from January to end May 2020 compared to the preceding three years. Despite the reduction in numbers of newly diagnosed NPC, there was no statistically significant differences in delay from biopsy to the first radiation oncology visit and from biopsy to the first day of treatment in 2020 compared to the preceding years. All the patients treated in our centre also received the standard NPC treatment for their disease stage as per international guidelines.ConclusionWe recommend a heightened awareness of the dangers of delaying cancer presentation and care in healthcare policies and resource allocation and at the same time, encourage patient’s confidence in their ability to seek care. With the resurgence of new COVID-19 variants and case numbers worldwide and in Singapore, this study focuses upon the need to be aware of the exigencies of other clinical groups in resource utilization. It would be instructive to compare this study with future long term follow up to investigate the trajectory of our cancer care delivery, as well as survival outcomes.

Luteolin Isolated from Polygonum cuspidatum Is a Potential Compound against Nasopharyngeal Carcinoma.

To reveal the mechanisms by which luteolin, the major bioactive component of the Traditional Chinese Medicine (TCM) Polygonum cuspidatum, inhibits proliferation and promotes apoptosis in nasopharyngeal carcinoma (NPC) CNE2 cells. Based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), bioactive compounds of P. cuspidatum, potential target genes and NPC disease targets of TCMSP were screened, relationship networks were constructed using these potential targets of NPC, and Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. The predicted compounds, targets and pathways were corroborated using in vitro experiments, such as MTT, Cytation™ 5 real-time cell monitoring, cell cycle detection, Annexin V-FITC/PI double staining, Hoechst 33342 staining, and mitochondrial membrane potential (ΔΨm) detection. The results showed that 10 bioactive compounds (OB ≥30% and DL ≥0.18), 157 potential target genes from P. cuspidatum, and 56 common targets related to NPC were found. These included important bioactive compounds such as luteolin, quercetin, and beta-sitosterol. Key common targets included EGFR, MYC, AKT1, CASP3, CCND1, ERBB2, and common targets were enriched for the PI3K-AKT, JAK/STAT, MAPK, and C-type lectin receptor signaling pathways. The binding energy of luteolin for six common targets was less than -5.0 kcal·mol-1. After luteolin (20 μM, and 40 μM) treatment to CNE2 cells for 36 h, cell survival rates decreased, accompanied by cell morphology changes, inhibition of the cell cycle at G2/M phase, and an induction of apoptosis. The expression of the cell proliferation related protein PCNA, the antiapoptosis protein XIAP, and the PI3K-AKT pathway diagram related proteins p-ERK1/2, ERK1/2, AKT, and PI3K, all decreased. Luteolin derived from P. cuspidatum inhibited the proliferation of NPC CNE2 cells and promoted cell apoptosis through the PI3K-AKT signal pathway.

Nasopharyngeal carcinoma in children and adolescents: a literature review and our own data

Nasopharyngeal carcinoma (NPC) is one of the few epithelial tumors that regularly occur in the pediatric population. The majority of patients with localized and locally advanced NPC can be cured with current treatment protocols which include platinum-based induction therapy followed by chemoradiation therapy. The prognosis of patients with initially metastatic NPC and recurrent disease after prior curative treatment is, however, still unfavorable. Fortunately, new treatment options such as immune checkpoints inhibitors and supportive treatment with oral fluoropyrimidine give hope for better outcomes in these patients as well. It's important to note that the management of NPC diagnosed in adults and children allows for the adaptation of effective treatment approaches for either of the age groups. An analysis of our own data suggests that current treatment protocols for NPC can be successfully adopted by Russian clinics and can help to achieve treatment outcomes comparable to the results obtained in other countries. The purpose of this article is to overview current therapeutic approaches for NPC and possible ways of their improvement based on our own and literature data. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology.

Bi-amino acid functionalized biomimetic honeycomb chitosan membrane as a multifunctional hydrophilic probe for specific capture of N-linked glycopeptides in nasopharyngeal carcinoma's disease patient's serum.

In this work, a novel porous bifunctionalized composite material was synthesized via a simple method. Gold nanoparticles are uniformly dispersed on the surface of the biomimetic honeycomb chitosan membrane through the interaction between amino and Au, and then cysteine and glutathione are successfully grafted onto the surface of the Au by the Au-S bond. The modification of cysteine and glutathione makes this bifunctionalized composite material have significant advantages of superhydrophilicity and small steric hindrance simultaneously. This material manifests excellent property in glycopeptides enrichment, with high selectivity (1:5000), low detection limit (0.1fmol·μL-1 ), high recovery rate (99.4 ± 0.5%), and good repeatability. In addition, with the help of nano-flow liquid chromatography tandem mass spectrometry, this composite achieved excellent performance in efficiently enriching glycopeptides in the serum of healthy people and nasopharyngeal carcinoma's disease patient. More excitingly, further gene ontology analysis of molecular function and biological process indicated that 41 original glycoproteins of the identified glycopeptides from serum of nasopharyngeal carcinoma's disease patient significantly partake in numerous cancer-associated events, including protease binding, calcium ion binding, enzyme binding, extracellular matrix organization, cellular response to tumor necrosis factor, and inflammatory response.

Diffusion-Weighted Magnetic Resonance Imaging-Guided Dose Painting in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma Treated With Induction Chemotherapy Plus Concurrent Chemoradiotherapy: A Randomized, Controlled Clinical Trial

We hypothesized that diffusion-weighted magnetic resonance imaging (DWI)-guided dose-painting intensity modulated radiation therapy (DP-IMRT) is associated with improved local tumor control and survival in locoregionally advanced nasopharyngeal carcinoma (NPC). The purpose of this randomized study was to compare the efficacy and toxicity of DWI-guided DP-IMRT to conventional magnetic resonance imaging (MRI)-based IMRT in locoregional advanced NPC. A total of 260 patients with stage III-IVa NPC disease were randomly assigned in a 1:1 ratio to receive induction chemotherapy followed by chemoradiotherapy by DWI-guided DP-IMRT (group A, n=130) or conventional MRI-based IMRT (group B, n=130) in this prospective clinical trial. In group A, subvolume GTVnx-DWI (gross tumor volume of nasopharynx in DWI) was defined as the areas within the GTVnx (gross tumor volume of nasopharynx) with an apparent diffusion coefficient (ADC) below the mean ADC (ADC < mean) according to MRI before induction chemotherapy. The dose to GTVnx-DWI was escalated to 75.2 Gy/32 fx in patients with T1-2 disease and to 77.55 Gy/33 fx in those with T3-4 disease in 2.35 Gy per fraction. In group B, planning gross tumor volumeof nasopharynx was irradiated at 70.4 to 72.6 Gy/32 to 33 fx in 2.2 Gy per fraction. This trial is registered with chictr.org.cn (ChiCTR1800015779). A total of 260 patients were included in the trial (130 patients in group A and 130 in group B). Complete response rates after chemoradiotherapy were 99.2% (129 of 130) and 93.8% (122 of 130) in groups A and B, respectively (P=.042). At a median follow-up of 25 months, DWI-guided DP-IMRT was associated with improved 2-year disease-free survival (DFS; 93.6% [95% confidence interval {CI}, 88.1%-99.1%] vs 87.5% [95% CI, 81.4%-93.6%], P=.015), local recurrence-free survival (100% [95% CI, not applicable {NA}] vs 91.3% [95% CI, 85.4%-97.2%]), locoregional recurrence-free survival (LRRFS; 95.8% [95% CI, NA] vs 91.3% [95% CI, 85.4%-97.2%]), distant metastasis-free survival (DMFS; 97.8% [95% CI, NA] vs 90.9% [95% CI, 85.8%-96.0%]), and overall survival (100% [95% CI, NA] vs 94.5% [95% CI, 89.2%-99.8%]). Zero and 3 patients had local-only recurrences in group A and B, respectively. The most common site of first failure in each arm was distant organ failure. No statistically significant differences in acute and late toxic effects were observed. Multivariate analyses showed that DP (DWI-guided DP-IMRT vs conventional MRI-based IMRT without DP) was associated with DFS, local recurrence-free survival, LRRFS, and distant metastasis-free survival. Epstein-Barr virus DNA level was associated with DFS and LRRFS. DWI-guided DP-IMRT plus chemotherapy is associated with a disease-free survival benefit compared with conventional MRI-based IMRT among patients with locoregionally advanced NPC without increasing acute toxic effects.

Diagnostic and Prognostic Indications of Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is a disease that is highly associated with the latent infection of Epstein–Barr virus. The absence of obvious clinical signs at the early stage of the disease has made early diagnosis practically impossible, thereby promoting the establishment and progression of the disease. To enhance the stride for a reliable and less invasive tool for the diagnosis and prognosis of NPC, we synopsize biomarkers belonging to the two most implicated biological domains (oncogenes and tumor suppressors) in NPC disease. Since no single biomarker is sufficient for diagnosis and prognosis, coupled with the fact that the known established methods such as methylation-specific polymerase chain reaction (PCR), multiplex methylation-specific PCR, microarray assays, etc., can only accommodate a few biomarkers, we propose a 10-biomarker panel (KIT, LMP1, PIKC3A, miR-141, and miR-18a/b (oncogenic) and p16, RASSF1A, DAP-kinase, miR-9, and miR-26a (tumor suppressors)) based on their diagnostic and prognostic values. This marker set could be explored in a multilevel or single unified assay for the diagnosis and prognosis of NPC. If carefully harnessed and standardized, it is hoped that the proposed marker set would help transform the diagnostic and prognostic realm of NPC, and ultimately, help prevent the life-threatening late-stage NPC disease.

Soluble MICA and anti-MICA Antibodies as Biomarkers of Nasopharyngeal Carcinoma Disease

ABSTRACT The MHC class I chain-related molecule A (MICA) is a ligand for the activating natural killer (NK) cell receptor NKG2D. A part from its genetic diversity, MICA is characterized by the presence of membrane-bound and soluble isoform (sMICA) and by the propensity to elicit antibody-mediated allogeneicity (MICA Abs). Altogether such properties are important in the cancer setting. Here, we investigated whether MICA polymorphism, serum level of sMICA and MICA antibodies (Abs) may influence nasopharyngeal carcinoma (NPC) risk. 274 NPC naïve of treatment patients and 275 healthy individuals, all originating from Tunisia were included and genotyped. Among them, 160 sera from patients and 51 from controls were analyzed for the sMICA level by ELISA and were tested for the presence of MICA Abs by Luminex assay. The statistical analysis showed that: (1) we extend and confer our previous finding concerning Val/Val association with risk of NPC (p = .02, OR = 1.56; 95%CI [1.12–2.11]). (2) The higher level of sMICA characterized patients advanced stage of the disease. (3) The 18 (78%) of patients having MICA Abs exhibit all a non-advanced stage of the tumor extension at presentation. MICA129 Met /Val, sMICA and MICA Abs could be potential biomarkers of prediction, the diverse staging of NPC and hence prognostic and treatment.

Nasopharyngeal carcinoma treated with intensity-modulated radiotherapy: clinical outcomes and patterns of failure among subsets of 8th AJCC stage IVa.

The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for nasopharyngeal carcinoma (NPC) merged T4N0-2 and T1-4N3 to create stage IVa. In the present study, we aimed to assess the difference in clinical outcomes and patterns of failure between 8th AJCC T4N0-2 and T1-4N3 NPC patients treated with intensity-modulated radiotherapy (IMRT). We included 3107 patients with stage IVa NPC disease (1871 with T4N0-2 and 1236 with T1-4N3) according to the 8th AJCC staging system. Overall survival (OS) was the primary endpoint. The clinical outcomes between T4N0-2 and T1-4N3 patients were compared. T1-4N3 patients had significantly worse 3-year OS (84.1% vs. 89.2%; p < 0.001) and distant metastasis-free survival (DMFS; 78.3% vs. 85.9%; p < 0.001), but better local relapse-free survival (LRFS; 94.9% vs. 92.2%; p = 0.003), as compared with T4N0-2 patients. Multivariate analysis showed that T1-4N3 was still an independent adverse prognostic factor for both DMFS (hazard ratio [HR] = 1.517, 95% confidence interval [CI] = 1.274-1.806, p < 0.001) and OS (HR = 1.315, 95% CI = 1.100-1.572, p = 0.003), whereas T4N0-2 was an independent adverse prognostic factor for LRFS (HR = 1.581, 95% CI = 1.158-2.158, p = 0.004). In terms of the OS, T4N0-2 patients had better prognosis compared with T1-4N3 patients, and the patterns of failure differed between T4N0-2 and T1-4N3 patients. We believe that future modifications of the AJCC/UICC staging system should separate T4N0-2 from T1-4N3. • In nasopharyngeal carcinoma, T4N0-2 patients tended to develop local relapse, whereas T1-4N3 patients were more likely to develop distant metastasis. • In terms of overall survival, T4N0-2 patients had better prognosis than T1-4N3 patients. • T4N0-2 should be separated from T1-4N3 in the UICC/AJCC staging system.

Magnetic Resonance Imaging Texture Analysis Predicts Recurrence in Patients With Nasopharyngeal Carcinoma

BackgroundThe personalization of oncologic treatment using radiomic signatures is mounting in nasopharyngeal carcinoma (NPC). We ascertain the predictive ability of 3D volumetric magnetic resonance imaging (MRI) texture features on NPC disease recurrence. MethodsA retrospective study of 58 patients with NPC undergoing primary curative-intent treatment was performed. Forty-two image texture features were extracted from pre-treatment MRI in addition to clinical factors. A multivariate logistic regression was used to model the texture features. A receiver operating characteristic curve on 100 bootstrap samples was used to maximize generalizability to out-of-sample data. A Cox proportional model was used to predict disease recurrence in the final model. ResultsA total of 58 patients were included in the study. MRI texture features predicted disease recurrence with an area under the curve (AUC), sensitivity, and specificity of 0.79, 0.73, and 0.71, respectively. Loco-regional recurrence was predicted with AUC, sensitivity, and specificity of 0.82, 0.73 and 0.74 respectively while prediction for distant metastasis had an AUC, sensitivity, and specificity of 0.92, 0.79 and 0.84, respectively. Texture features on MRI had a hazard ratio of 4.37 (95% confidence interval 1.72–20.2) for disease recurrence when adjusting for age, sex, smoking, and TNM staging. ConclusionTexture features on MRI are independent predictors of NPC recurrence in patients undergoing curative-intent treatment.

Blood Cadmium Level Is Associated with Short Progression-Free Survival in Nasopharyngeal Carcinoma.

The prognosis of nasopharyngeal carcinoma (NPC) is poor with disease progression. Cadmium exposure is a risk factor for NPC. We aimed to investigate the effect of cadmium exposure, by measuring cadmium level, and clinicopathologic factors on NPC disease progression and prognosis. A total of 134 NPC cases were analyzed and venous blood samples were collected. Blood cadmium level was analyzed by graphite furnace atomic absorption spectrophotometry. Clinical data were collected at baseline for patients and tumor characteristics from medical records. Progression-free survival (PFS) was analyzed during follow-up. The effect of cadmium exposure and clinical factors on PFS was analyzed by the Kaplan–Meier method and Cox regression models. Blood cadmium level was associated with history of disease and smoking history and pack-years. On Kaplan–Meier analysis, a high blood cadmium level, male sex, smoking history and increasing pack-years, as well as advanced clinical stage were all associated with short PFS. On multivariate analysis, blood cadmium level was an independent risk factor and predictor of NPC prognosis and disease progression. Cadmium exposure and related clinical factors can affect the prognosis of NPC, which merits further study to clarify.

Molecular Targeted Therapy in the Management of Recurrent and Metastatic Nasopharyngeal Carcinoma: A Comprehensive Literature Review.

Nasopharyngeal carcinoma (NPC) is the most frequent malignancy arising in the nasopharynx. NPC, to a larger degree, substantially differs from the other malignancies of the head and neck, in terms of incidence, etiology, risk factors, molecular pathogenesis, clinical behavior, management and prognosis. Fundamentally, the management of NPC is entirely guided by the disease stage. Favorably, patients with early- stage disease have encouraging survival outcomes with stand-alone radiation therapy (RT), specifically following the emergence of intensity-modulated RT (IMRT). The reported five-year local control rates are outstanding, and they range from 70% to 90%. Unfortunately, around one-third (30%) of patients presents with loco-regional or distant recurrences, despite rigorous curative treatment in the intermediate (stage II) and advanced (stage III-IVB) NPC disease. At the present time, the management of recurrent and metastatic NPC is largely discouraging and presents significant challenges to the treating physicians. Broadly speaking, there are three management schemes utilized in the management of recurrent and metastatic NPC, namely: (i) palliative systemic chemotherapy, (ii) molecular targeted therapy, and (iii) immunotherapy. The goal of this study is to holistically review the existing body of literature on the utility and safety of molecular targeted therapy in the management of patients with recurrent and metastatic NPC, with a special focus on vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) targets.

Extranodal extension is a criterion for poor outcome in patients with metastatic nodes from cancer of the nasopharynx

PurposeExtranodal extension (ENE) is a criterion for advanced nodal staging of oropharyngeal and hypopharyngeal carcinoma. Our aim was to determine if ENE should be a staging criterion for nasopharyngeal carcinoma (NPC). Materials & methodsMRI of 546 NPC patients were reviewed retrospectively and in 404/546 (74.0%) with metastatic nodes, the nodes were assessed for ENE (grade 0 = absent; grade 1 = infiltration of surrounding fat; grade 2 = infiltration of muscle/skin), size (total volume), site (unilateral/bilateral and upper/lower neck) and necrosis. Associations between nodal features and regional relapse free survival (RRFS), distant metastases free survival (DMFS) and overall survival (OS) were assessed using cox regression. Differences of survival rates were compared using log-rank test. A p-value of < 0.05 indicates statistical significance. ResultsENE grade was the only determinant of RRFS (p = 0.014) and only independent determinant of DMFS (p = 0.003) and OS (p < 0.001). Grade 2 ENE was associated with significantly poorer RRFS, DMFS and OS compared to grade 0 and 1 (p < 0.05). Addition of grade 2 ENE to N1 and N2 disease showed similar poor RRFS, DMFS and OS to N3 disease (p > 0.05). Compared to the current stage N3 disease, inclusion of grade 2 ENE increased the number of N3 patients from 53/546 (9.7%) to 82/546 (15.0%) with similar hazard ratios for DMFS (6.855 and 7.125, respectively) and OS (3.614 and 4.085, respectively). ConclusionGrade 2 ENE (into muscle and/or skin and/or salivary glands) is an independent indicator of poor outcome and may be considered as a new criterion for N3 nodal disease in NPC.

Circulating tumor cells with karyotyping as a novel biomarker for diagnosis and treatment of nasopharyngeal carcinoma

BackgroundCirculating tumor cells (CTCs) have been considered great clinical significance in various cancers. However, it remains unknown that how is the role of CTCs in patients with nasopharyngeal carcinoma (NPC). We investigated the value of CTCs enumeration and karyotyping in NPC.MethodsIn the present study, we applied integrated subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) automatic testing system to detect and characterize CTCs of NPC patients. Enumeration and aneuploidy of chromosome 8 in CTCs were examined in various stages of patients with NPC. The changes of CTCs number and karyotyping post to chemotherapy were investigated in NPC.ResultsCTCs were detected by SE-iFISH in 46 out of 50 pre-treatment NPC patients, and performed a positive rate of 92.0%. No significant association was found between disease staging and CTCs detection rate. CTCs number constantly increased with TNM stage rising (from stage II to stage IV) no matter in newly diagnosed patients without distant metastasis (M0) and relapsed or distant metastatic patients. The number of CTCs decreased after treatment in patients with partial response (PR), while increased in patients with progressive disease or stable disease (PD/SD). More interestingly, CTCs karyotyping indicated that aneuploidy of chromosome 8 in CTCs was dramatically related to chemotherapeutic efficacy in NPC. Positive correlation was found between CTCs count and plasma EBV DNA level of NPC patients.ConclusionsCTCs could be detected in various stages of NPC patients using SE-iFISH. CTCs number could indicate the severity degree of disease in NPC. Dynamically monitoring the variations in CTCs number may predict chemotherapy efficacy during treatment. CTCs karyotyping is related to the sensibility of chemotherapy and drug resistance, and karyotyping of CTCs might predict therapeutic efficacy and evaluate chemo-resistance in NPC. CTCs could be used as a monitoring indicator in the fields of treatment, diagnosis and follow-up of NPC.

Exome and genome sequencing of nasopharynx cancer identifies NF-\u03baB pathway activating mutations

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.

48TiP - KEYNOTE-122: Phase 2 study of pembrolizumab versus standard-of-care chemotherapy in platinum-pretreated, recurrent or metastatic nasopharyngeal carcinoma

Aim/Background: Treatment for recurrent/metastatic nasopharyngeal carcinoma (NPC) that progresses on a platinum-based regimen includes gemcitabine, capecitabine, or docetaxel. Prolonged exposure to Epstein-Barr virus (EBV) in NPC leads to increased expression of PD-1, resulting in suppressed T-cell immunity and tumor surveillance. Pembrolizumab is a monoclonal anti–PD-1 antibody designed to block the interaction between PD-1 and PD-L1 and PD-L2. In the phase 1b KEYNOTE-028 study, pembrolizumab had an ORR of 22% (6/27) in heavily pretreated (≥3 lines) patients with NPC. KEYNOTE-122 (NCT02611960) is a multicenter, open-label, randomized phase 2 study designed to evaluate the efficacy and safety of pembrolizumab monotherapy versus chemotherapy in patients with platinum-pretreated, recurrent or metastatic NPC. Trial design: Key eligibility criteria include age ≥18 years, histologically confirmed nonkeratinizing differentiated NPC (WHO Class II) or undifferentiated NPC (WHO Class III), metastatic or recurrent disease, EBV positivity determined locally or centrally by EBV-encoded small RNA in situ hybridization, previous treatment with platinum-containing regimen, ECOG performance status 0-1, and measurable disease per RECIST v1.1. Patients will be randomly assigned 1:1 to receive either pembrolizumab 200 mg every 3 weeks (Q3W) or investigator’s choice of chemotherapy (capecitabine 1000 mg/m2 twice daily on days 1-14 of each 3-week cycle, gemcitabine 1250 mg/m2 once per week on days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m2 Q3W). Treatment will continue until disease progression, unacceptable toxicity, investigator decision, or 35 cycles of pembrolizumab. Response will be evaluated every 6 weeks for the first year of treatment and every 9 weeks thereafter per RECIST v1.1 by central imaging assessment. Primary end points are overall survival and progression-free survival per RECIST v1.1 by central imaging assessment; secondary end points include objective response rate and duration of response per RECIST v1.1 by central imaging assessment. Enrollment is ongoing and will continue until approximately 160 patients have enrolled. Clinical trial identification: ClinicalTrials.gov, NCT02611960 Legal entity responsible for the study: Merck & Co., Inc. Funding: Merck & Co., Inc. Disclosure: V. Lee: Received honoraria from Eli Lilly Asia Inc., and travel accommodations for international conference from Merck Sharp and Dohme. M-J. Ahn: Is on the advisory committee for AstraZeneca, ONO, Boehringer Ingelheim, Novartis, Lilly, BMS, and Merck. R.F. Swaby: I am a Merck employee and I own Merck stock. A.T.C. Chan: Research funding from Merck. All other authors have declared no conflicts of interest.

Cervical nodal necrosis is an independent survival predictor in nasopharyngeal carcinoma: an observational cohort study.

PurposeMost nasopharyngeal carcinoma (NPC) patients present with locoregionally advanced disease at the time of diagnosis; however, there is a lack of consensus on specific prognostic factors potentially improving overall survival, especially in late-stage disease. Herein, we conducted a retrospective study to evaluate various potential prognostic factors in order to provide useful information for clinical treatment of T3/T4-stage NPC.Patients and methodsA total of 189 previously untreated NPC patients were enrolled in the current study. All patients received intensity-modulated radiotherapy. Survival, death, relapse-free survival (both local and regional), and metastasis were recorded during follow-up. Factors affecting patient survival were assessed by using univariate and multivariate analyses.ResultsThe median follow-up time was 69 months. The 5-year local-regional recurrence-free survival, distant metastasis-free survival, progression-free survival (PFS), and overall survival (OS) of the entire group were 89.8%, 71.5%, 66.3%, and 68.9%, respectively. Univariate analysis revealed significant differences in the 5-year PFS (58.5% vs 72.5%, P=0.015) and OS (59.5% vs 75.8%, P=0.033) rates of patients with and without cervical nodal necrosis (CNN). Subgroup analyses revealed that CNN was associated with poorer distant metastasis-free survival and PFS among patients with N2 stage (P=0.046 and P=0.005) and with poorer PFS among patients with T3 or III stage (all P=0.022). Multivariate analysis revealed CNN to be an independent prognostic factor for PFS and OS (PFS: adjusted hazard ratio, 1.860; 95% CI: 1.134–3.051; P=0.014; OS: adjusted hazard ratio, 1.754; 95% CI: 1.061–2.899; P=0.028).ConclusionCNN is a potential independent negative prognostic factor in NPC patients. Our results suggest that stratification of NPC patients based on their CNN status should be considered as part of NPC disease management.

Abstract CT136: Therapeutic and prophylactic AdE1-LMPpoly-based adoptive T-cell immunotherapy for Epstein-Barr virus-associated nasopharyngeal carcinoma

Abstract Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is endemic in regions of South-East Asia, with incidence as high as 25-50 cases per 100,000 people in southern China. While current standard therapy is curative for a subset with stage I or II disease, a high proportion of patients relapse and many patients are still initially diagnosed with advanced stage III or IV disease, where overall 5-year survival is significantly reduced. EBV-specific immunotherapy has been successfully used in the treatment of post-transplant lymphomas and may have the potential application to improve outcomes in NPC patients. We have designed the AdE1-LMPpoly vector to promote rapid expansion of CD8+ T cells specific for the latent membrane proteins (LMP) 1&amp;2 and EBV nuclear antigen 1 (EBNA1) expressed in NPC. We recruited a total of 52 NPC patients, including 42 patients with refractory stage IV NPC disease and 11 at-risk patients with no or minimal residual disease (referred to as N/MRD patients). Of these, 6 patients with refractory disease were withdrawn prior to the commencement of T cell manufacture. Using AdE1-LMpoly, we successfully expanded autologous EBV-specific T cells from 35 NPC patients, while 11 patients showed no or minimal expansion of antigen-specific T cells. Thirty patients, including 21 patients with active disease and nine N/MRD patients, successfully completed autologous T cell therapy defined by the administration of at least two cycles of immunotherapy. None of these patients showed treatment-related grade 3, 4, or 5 adverse events as per the NCI Common Terminology Criteria for Adverse Events. The time to progression in patients with refractory stage IV NPC disease ranged from 6 to 456 days from the time of first T cell infusion, with a median time to progression of 63 days, while median progression-free survival in N/MRD patients was 527 days. Refractory patients showed a median survival of 478 days following recruitment, while all N/MRD patients remain alive. The median overall survival for a corresponding refractory stage IV disease cohort during the study period from the same institute was 309 days. Our study suggests that autologous EBV-specific T cells are a safe novel treatment option for NPC patients, and may offer better clinical benefit for patients, particularly when T cell therapy is administered during the early stages of the disease. Citation Format: Corey Smith, Andrea Schuessler, Janice Tsang, Leone Beagley, Victor Lee, Ben Panizza, Sandro Porceddu, John Nicholls, Dora Kwong, Rajiv Khanna. Therapeutic and prophylactic AdE1-LMPpoly-based adoptive T-cell immunotherapy for Epstein-Barr virus-associated nasopharyngeal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT136.

Prognostic significance of residual or recurrent lymph nodes in the neck for patients with nasopharyngeal carcinoma after radiotherapy.

Nasopharyngeal carcinoma is the most frequently diagnosed primary tumor originating from the nasopharynx, and the preferred treatment modality is radiotherapy. To identify nasopharyngeal carcinoma prognostic factors in patients with residual or recurrent cervical lymph node metastases after radiotherapy. The clinicopathologic characteristics and prognoses of 67 nasopharyngeal carcinoma patients with residual or recurrent cervical lymph node metastases who were diagnosed and treated were analyzed retrospectively. The Chi-squared test and Cox proportional hazard regression model were used to investigate associations between survival and clinicopathological features. Cumulative survival plots were obtained using the Kaplan-Meier method. Data analysis using the Cox proportional hazard regression model revealed that the size of residual or recurrent lymph node metastases, level V lymph node involvement, number of involved levels, surgical procedure performed, and distant metastases were significantly associated with overall survival. Chi-squared analysis only determined a significant correlation between distant metastases and patient survival. Furthermore, the Kaplan-Meier analysis demonstrated that the 1-, 3-, and 5-year survival rates for patients were 86.6%, 52.2%, and 38.6%, respectively. Radical neck dissection resulted in substantially longer overall survival than modified neck dissection. The size of residual or recurrent lymph node metastases, level V lymph node involvement, number of involved levels, surgical procedure performed, and presence of distant metastases were prognostic factors for nasopharyngeal carcinoma patients with residual or recurrent cervical lymph node metastases after radiotherapy, with distant metastases being the most important determinant. Classical radical neck dissection is recommended for treating recurrent nodal disease in nasopharyngeal carcinoma.