Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: The JUPITER-02 Randomized Clinical Trial.

Importance: There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC). Objective: To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone. Design, Setting, and Participants: JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers. Interventions: Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment. Main Outcome: Progression-free survival as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival, progression-free survival assessed by investigator, duration of response, and safety. Results: Among the 289 patients enrolled (median age, 46 [IQR, 38-53 years; 17% female), at the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo (median, 21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37-0.73]). With a median survival follow-up of 36.0 months, a significant improvement in overall survival was identified with toripalimab over placebo (hazard ratio [HR], 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008). The median overall survival was not reached in the toripalimab group, while it was 33.7 months in the placebo group. A consistent effect on overall survival, favoring toripalimab, was found in subgroups with high and low PD-L1 (programmed death-ligand 1) expression. The incidence of all adverse events, grade 3 or greater adverse events, and fatal adverse events were similar between the 2 groups. However, adverse events leading to discontinuation of toripalimab or placebo (11.6% vs 4.9%), immune-related adverse events (54.1% vs 21.7%), and grade 3 or greater immune-related adverse events (9.6% vs 1.4%) were more frequent in the toripalimab group. Conclusions and Relevance: The addition of toripalimab to chemotherapy as first-line treatment for RM-NPC provided statistically significant and clinically meaningful progression-free survival and overall survival benefits compared with chemotherapy alone, with a manageable safety profile. These findings support the use of toripalimab plus gemcitabine-cisplatin as the new standard of care for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT03581786.

Integrin α5 mediates intrinsic cisplatin resistance in three-dimensional nasopharyngeal carcinoma spheroids via the inhibition of phosphorylated ERK /caspase-3 induced apoptosis.

Nasopharyngeal carcinoma (NPC) originates in the nasopharynx epithelium. Although concurrent chemoradiation therapy followed by chemotherapy is considered as an effective treatment, there is substantial drug resistance in locally advanced NPC patients. One major contributor to the chemoresistance includes aberrant expression of cell adhesion molecules, such as integrin α and ß subunits, giving rise to cell adhesion-mediated drug resistance. Thus, the aim of this study was to investigate the effect of integrin α5 on the development of intrinsic cisplatin resistance in NPC and the associated underlying mechanisms using in vitro three-dimensional (3D) spheroid models, as well as induced cisplatin-resistant NPC (NPCcisR). We demonstrated that established 3D highly- (5-8F) and lowly- (6-10B) metastatic NPC spheroids overexpressed integrin α5 and aggravated their resistance to cisplatin. Besides, enhanced integrin α5 resulted in substantially reduced growth, corresponding to G0/G1 and G2/M cell cycle arrest. In addition, 5-8FcisR and 6-10BcisR cells in 3D forms synergistically strengthened endurance of their spheroids to cisplatin treatment as observed by increased resistance index (RI) and decreased apoptosis. Mechanistically, the aberrantly expressed integrin α5 decreased drug susceptibility in NPC spheroids by inactivating ERK and inhibition of caspase-3 inducing apoptosis. Furthermore, the effect of integrin α5 inducing intrinsic resistance was verified via treatment with ATN-161, a peptide inhibitor for integrin α5ß1. The results showed dramatic reduction in integrin α5 expression, reversal of ERK phosphorylation and caspase-3 cleavage, together with elevated cisplatin sensitivity, indicating regulation of innate drug resistance via integrin α5. Taken together, our findings suggest that integrin α5 could act as a promising target to enhance the chemotherapeutic sensitivity in NPC.

EGFR-PKM2 signaling promotes the metastatic potential of nasopharyngeal carcinoma through induction of FOSL1 and ANTXR2.

Nasopharyngeal carcinoma (NPC) is notorious for its aggressiveness and high metastatic potential. NPC patients with distant metastasis have a particularly poor prognosis; however, evaluating metastatic potential by expression profiles of primary tumors is challenging. This study aimed to investigate the association between activation of epidermal growth factor receptor (EGFR) signaling and NPC metastasis and the underlying mechanisms. We found an association between EGFR protein overexpression and intense EGFR immunostaining in NPC samples with advanced tumor node metastasis stage, clinical stage, and distant metastasis in NPC patients. Exogenous EGF stimulates NPC mobility and invasiveness in vitro. Activation of EGFR signaling prompted PKM2 translocation to the nucleus. Silencing either EGFR or PKM2 attenuates NPC cell aggressiveness in vitro and in vivo. Blocking EGFR signaling with cetuximab suppressed NPC cell invasiveness in vitro and metastatic potential in vivo. Comprehensive analyses of transcriptome profiles indicated that the EGFR-PKM2 axis activates a number of novel metastasis promoters, including F3, FOSL1, EPHA2, ANTXR2, and AKR1C2. Finally, we found that the metastasis-promoting function of the EGFR-PKM2 axis is dependent on nuclear PKM2 regulation of the transcription of metastasis-related genes, including FOSL1 and ANTXR2. Our study indicates that EGFR-PKM2 signaling promotes NPC cell invasion and metastasis through induction of FOSL1 and ANTXR2 and identifies EGFR as a promising biomarker for predicting the risk of distant metastasis.

Molecular subtyping of nasopharyngeal carcinoma (NPC) and a microRNA-based prognostic model for distant metastasis.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic cancer, with diverse molecular characteristics and clinical outcomes. This study aims to dissect the molecular heterogeneity of NPC, followed by the construction of a microRNA (miRNA)-based prognostic model for prediction of distant metastasis. METHODS: We retrieved two NPC datasets: GSE32960 and GSE70970 as training and validation cohorts, respectively. Consensus clustering was employed for cluster discovery, and support vector machine was used to build a classifier. Finally, Cox regression analysis was applied to constructing a prognostic model for predicting risk of distant metastasis. RESULTS: Three NPC subtypes (immunogenic, classical and mesenchymal) were identified that are molecularly distinct and clinically relevant, of which mesenchymal subtype (~ 36%) is associated with poor prognosis, characterized by suppressing tumor suppressor miRNAs and the activation of epithelial--mesenchymal transition. Out of the 25 most differentially expressed miRNAs in mesenchymal subtype, miR-142, miR-26a, miR-141 and let-7i have significant prognostic power (P < 0.05). CONCLUSIONS: We proposed for the first time that NPC can be stratified into three subtypes. Using a panel of 4 miRNAs, we established a prognostic model that can robustly stratify NPC patients into high- and low- risk groups of distant metastasis.

Epstein-Barr virus-specific adoptive immunotherapy for recurrent, metastatic nasopharyngeal carcinoma.

BACKGROUND: Early-stage and intermediate-stage nasopharyngeal cancer (NPC) generally carry a good prognosis, but for patients with recurrent, metastatic disease, options are limited. In the current study, the authors present a phase 1/2 study to evaluate the efficacy of Epstein-Barr virus (EBV)-stimulated cytotoxic T-lymphocyte (EBV-CTL) immunotherapy in this patient population. METHODS: Screening for patients with active, recurrent, metastatic EBV-associated NPC began in February 2007, and the study was closed to accrual in January 2012. After informed consent was obtained, patients had their blood drawn to initiate manufacturing of the EBV-CTL product. During product manufacturing, patients were placed on interim standard-of-care chemotherapy, and only after disease progression on the interim chemotherapy did patients receive investigational immunotherapy. Patients were restaged every 2 months until disease progression and then followed for survival. RESULTS: A total of 28 patients were enrolled, and 21 patients were treated. There was 1 complete response achieved, and at the time of last follow-up, the patient had been in remission for >8 years since treatment. The median progression-free survival was 2.2 months, and the median overall survival was 16.7 months. Two other patients, after failing EBV-CTL immunotherapy, unexpectedly demonstrated strong responses to the chemotherapy regimens they had previously failed. Patient EBV viral load and EBV-CTL specificity for tumor-associated viral antigens did not appear to correlate with clinical response. CONCLUSIONS: A durable response was observed with EBV-CTL immunotherapy, but the overall response rate for patients with recurrent, metastatic NPC was low. Further research is necessary to increase the efficacy of EBV-specific immunotherapy in patients with incurable NPC, and to characterize mechanisms for refacilitation to chemotherapy. Cancer 2017;123:2642-50. © 2017 American Cancer Society.

Addition of Definitive Radiotherapy to Chemotherapy in Patients With Newly Diagnosed Metastatic Nasopharyngeal Cancer.

Background: Management of metastatic (M1) nasopharyngeal cancer (NPC) is controversial; data suggest high overall survival (OS) rates with definitive chemoradiotherapy (CRT). Herein, we evaluated OS in patients with M1 NPC undergoing chemotherapy alone versus CRT. Methods: The National Cancer Data Base was queried for M1 NPC cases. Patients undergoing no/unknown chemotherapy and/or with unknown/nondefinitive radiotherapy (RT) doses (<60 Gy) were excluded. Logistic regression analysis ascertained clinical factors associated with RT administration. Kaplan-Meier analysis evaluated OS between both cohorts; Cox proportional hazards modeling assessed factors associated with OS. Survival was then evaluated between matched populations using inverse-probability-weighted regression adjustment. OS between groups was also measured in patients surviving ≥1 and ≥3 years to address bias from poor-prognostic subsets (eg, widely disseminated disease), and those receiving CRT ≤30 and ≤60 days of each other (surrogates for concurrent CRT) versus >30 and >60 days (sequential) of each other. Results: Of 555 patients, 296 (53%) received chemotherapy alone and 259 (47%) underwent CRT. Patients undergoing CRT more often had private insurance (P=.001) and lived in areas with higher education levels (P=.028). Median OS in the chemotherapy-only and CRT cohorts were 13.7 and 25.8 months, respectively (P<.001); differences persisted between matched populations (P<.001). On multivariate analysis, receipt of additional RT independently predicted for improved OS (P<.001). OS differences between cohorts remained apparent when evaluating patients surviving for ≥1 (P<.001) and ≥3 (P=.002) years. Patients who received concurrent or sequential CRT displayed improved OS over those receiving chemotherapy alone, for both the 30-day (P<.001) and 60-day cutoffs (P<.001). Conclusions: Patients with M1 NPC undergoing definitive RT and chemotherapy experienced higher survival than those receiving chemotherapy alone. Risk stratification and patient selection for such combined modality interventions is critical.

Diffusion-weighted imaging of nasopharyngeal carcinoma to predict distant metastases.

Our study aimed to identify diffusion-weighted imaging (DWI) parameters obtained from primary nasopharyngeal carcinoma (NPC) at initial presentation, that can predict patients at risk of distant metastases. One hundred and sixty-four patients underwent pretreatment magnetic resonance imaging and DWI. The apparent diffusion coefficient (ADC)mean, ADCskewness, and ADCkurtosis were obtained by histogram analysis. Univariate and multivariate analyses of these ADC parameters together with primary volume (PV), nodal volume (NV), T stage, N stage and presence of locoregional relapse (LRR) were compared between patients with distant metastases (DM+) and patients without distant metastases (DM-) at 5 years using logistic regression. Twenty-eight out of 164 patients (17.1 %) were DM+ (2.5-60 months) and 136/164 patients were DM- (61.2-119.4 months). Compared to DM- patients, the primary tumour of DM+ patients showed significantly lower ADCskewness (ADC values with the greatest frequency were higher) (p = 0.041), and higher PV (p = 0.022), NV (p < 0.01), T stage (p = 0.023), N stage (p < 0.01) and LRR (p < 0.01). On multivariate analysis the ADCskewness was no longer significant (p = 0.120) and only NV and LRR were independent predictors for DM+ (p = 0.023 and 0.021, respectively). DWI showed that compared to DM- patients, DM+ patients had a significantly lower primary tumour ADCskewness, but at initial presentation NV was the only independent predictor of DM.

Cervical metastasis of gingival carcinoma misdiagnosed as branchiogenic carcinoma, a rare entity - report of a case and review of literature.

BACKGROUND: A cervical cystic mass is associated with a number of pathologies that present with similar symptoms. These conditions are difficult to differentiate using fine-needle aspiration (FNA), ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI). Another dilemma in the differential diagnosis of cervical cystic masses is due to the controversies associated with the existence of branchiogenic carcinoma (BC). BC is an extremely rare disease that must be differentiated from other conditions presenting with cervical cystic masses, especially cystic metastasis from occult primary lesions. CASE PRESENTATION: We present a case report of a right cervical cystic metastasis from a significantly small squamous cell carcinoma primary gingival lesion misdiagnosed as BC by histopathology. A 62-year-old female presented with a painless progressively enlarging cervical mass at the anterior edge of the sternocleidomastoid muscle in the right submandibular region. Preoperative MRI and US revealed a well-defined cystic round mass. Postoperative histological examination indicated BC. Positron emission tomography/computed tomography (PET/CT) revealed high 18F-FDG (18F 2-fluoro-2-deoxy-D-glucose) uptake in surgical regions with a SUV (standard uptake value) max 4.0 and ipsilateral nasopharynx with a SUVmax 4.4, without any distant metastasis. Pathologic results revealed nasopharyngeal lymphadenosis. Considering the low incidence of BC and the limitation of diagnosis in one institution, the patient was referred to another hospital. Physical examination detected a significantly small neoplasm (~3 mm diameter) in the right lower gingiva. Histopathological examination of the neoplasm revealed a well-differentiated squamous cell carcinoma. Surgery, including a partial mandibulectomy and modified neck dissection (neck level I-V and submental lymph nodes) were undertaken. Postoperative histopathological results revealed a well-differentiated squamous cell carcinoma of right lower gingiva and two metastatic lymph nodes in the 18 lymph nodes of level II. A month later, recurrence occurred in the right cervical level II. The patient was placed on postoperative concurrent chemo-radiotherapy and supportive care. The patient suffered from cachexia and survived for only six months after surgery. CONCLUSIONS: In cases of cervical cystic masses that appear after the age of 40, clinicians should bear in mind that occult primary lesions should be excluded and examination of the gingiva should be undertaken. PET/CT has a limited role in identifying small occult primary lesions and a comprehensive physical examination must be carefully performed.

Overexpression of IGFBP3 is associated with poor prognosis and tumor metastasis in nasopharyngeal carcinoma.

Insulin-like growth factor-binding protein-3 (IGFBP3) is an N-linked glycosylated, phosphorylated protein, which has been reported to regulate cancer progression and metastasis. However, the role of IGFBP3 in tumor metastasis remains under debate. Nasopharyngeal carcinoma (NPC) is a highly metastatic head and neck cancer. And it fails to achieve the desired therapeutic efficacy in patients with metastasis, while the role of IGFBP3 in NPC is still unclear. In this study, we first used immunohistochemistry to explore the expression of IGFBP3 in NPC tissues. We found that IGFBP3 was significantly elevated in NPC and its expression level was correlated with N classification, distant metastasis, and TNM clinical stage (all P < 0.05). Patients with high expression of IGFBP3 had poorer survival rate (P < 0.05). In addition, we found that downregulation of IGFBP3 inhibited cell migration and adhesion by Transwell migration assay, wounding healing assay, and cell adhesion assays in vitro. Besides, NPC cells stimulated with recombinant IGFBP3 accelerated migration and adhesion. These data suggest overexpression of IGFBP3 promotes tumor metastasis in NPC, which makes it a potential therapeutic target.

Solitary splenic metastasis from nasopharyngeal carcinoma: a case report and systematic review of the literature.

BACKGROUND: Solitary splenic metastases are a rare occurrence, and the nasopharyngeal carcinoma represents one of the most uncommon primary sources. The present study aimed to describe a rare case of a solitary single splenic metastasis from nasopharyngeal carcinoma and to assess the number of cases of isolated nasopharyngeal carcinoma metastases to the spleen reported in the literature. MAIN BODY: We describe the case of a 56-year-old man with a history of nasopharyngeal carcinoma and complete remission after chemo-radiotherapy. Three months after complete remission, positron emission tomography/computed tomography scan revealed a hypermetabolic splenic lesion without increased metabolic activity in other areas. After laparoscopic splenectomy, the pathology report confirmed a single splenic metastasis from undifferentiated carcinoma of the nasopharyngeal type. The postoperative period was uneventful. We also performed a systematic review of the literature using MEDLINE and Google Scholar databases. All articles reporting cases of splenic metastases from nasopharyngeal carcinoma, with or without histologic confirmation, were evaluated. The literature search yielded 15 relevant articles, which were very heterogeneous in their aims and methods and described only 25 cases of splenic metastases from nasopharyngeal carcinoma. CONCLUSION: The present review shows that solitary splenic metastases from nasopharyngeal carcinoma are a rare event, but it should be considered in patients presenting with splenic lesions at imaging and a history of primary or recurrent nasopharyngeal carcinoma. No evidence supports a negative impact of splenectomy in patients with solitary splenic metastasis from nasopharyngeal carcinoma.

Analysis of setup error based on CTVision for nasopharyngeal carcinoma during IGRT.

The aim of the present study was to investigate the role of CTVision in interfractional setup errors during intensity-modulated radiation therapy (IMRT) in 12 nasopharyngeal carcinoma (NPC) patients. The trend of setup errors as a function of time during a fractionated radiotherapy course was investigated, and the influence of reconstructive thickness on image reconstruction for setup errors was analyzed. The appropriate planning target volume (PTV) margin and planning risk volume (PRV) margin were defined to provide a reference for the design of IMRT for NPC. Based on CTVision, online CT was performed weekly for each patient. Setup errors were measured by registration between the CT reconstructed image and reference image. Mean of setup errors, estimated population systematic (Σ), and population random (σ) errors were calculated using SPSS (v15.0). Optimum PTV and PRV margins were calculated. In the clinical data, for the LR (left-right), SI (superior-inferior), and AP (anterior-posterior) directions, Σ was 0.8, 0.8, and 1.0 mm, respectively, and σ was 1.0, 1.3, and 0.8 mm, respectively. In the LR, SI, and AP directions, PTV margins were at least 2.7, 2.9, and 3.0 mm, respectively, and PRV margins were at least 1.5, 1.7, and 1.7 mm, respectively. No significant differences in setup errors were observed during the fractionated radiotherapy course (p > 0.05). However, CT image reconstruction with different thicknesses affected the accuracy of measurements for setup errors, particularly in the SI direction. The application of CTVision to correct setup errors is important and can provide reasonable margins to guarantee the coverage of PTVs and spare organs at risk. A thickness of 3 mm in the reconstructed image is appropriate for the measurement of setup errors by image registration.

Prognostic Value of Cervical Nodal Necrosis in Nasopharyngeal Carcinoma: Analysis of 1800 Patients with Positive Cervical Nodal Metastasis at MR Imaging.

PURPOSE: To evaluate the prognostic value of cervical nodal necrosis (CNN) in patients with nasopharyngeal carcinoma (NPC) with magnetic resonance (MR) imaging. MATERIALS AND METHODS: This was an institutional review board-approved retrospective study of 1800 patients with newly diagnosed stage T1, 4N1, 3M0 NPC who were treated with definitive radiation therapy, with or without chemotherapy, between January 2007 and December 2009; the requirement to obtain informed consent was waived. MR images were reviewed to assess lymph node status, and patients were divided into CNN and non-CNN groups. The overall survival, disease-free survival, regional relapse-free survival (RRFS), and distant metastasis-free survival (DMFS) were calculated with the Kaplan-Meier method, and differences were compared by using the log-rank test. RESULTS: The incidence of CNN was 44.0% (792 of 1800). After the median follow-up period of 53 months, the 5-year overall survival, disease-free survival, RRFS, and DMFS rates of the CNN and non-CNN groups were 78.8% and 91.8%, 78.2% and 91.2%, 78.6% and 91.8%, and 78.4% and 91.6%, respectively (for all rates, P < .001). The distant metastasis rate was 18.7% (148 of 792) for the CNN group versus 4.6% (46 of 1008) for the non-CNN group (P < .01). Subgroup analysis revealed similar survival outcomes between stage N1 disease with CNN and stage N2 disease without CNN, stage N2 disease with CNN, and stage N3 disease regardless of CNN. CNN, T stage, N stage, age older than 44 years, and male sex were significant independent negative prognostic factors for overall survival, disease-free survival, RRFS, and DMFS. CONCLUSION: CNN is an independent negative prognostic factor in patients with NPC, and it may be appropriate to investigate whether N stage should be upgraded by one level in patients with CNN.

Nasopharyngeal carcinoma with paranasal sinus invasion: the prognostic significance and the evidence-based study basis of its T-staging category according to the AJCC staging system.

BACKGROUND: To evaluate the prognostic significance of paranasal sinus invasion for patients with NPC and to provide empirical proofs for the T-staging category of paranasal sinus invasion according to the AJCC staging system for nasopharyngeal carcinoma. METHODS: The clinical records and imaging studies of 770 consecutive patients with newly diagnosed, untreated, and nondisseminated NPC were reviewed retrospectively. The overall survival, distant metastasis-free survival, and local relapse-free survival of these patients were analyzed using the Kaplan-Meier method, and the differences were compared using the log-rank test. RESULTS: The incidence of paranasal sinus invasion was 23.6%, with the rate of incidence of sphenoid sinus invasion being the highest. By multivariate analysis, paranasal sinus invasion was shown to be an independent prognostic factor for overall survival, distant metastasis-free survival, and local relapse-free survival (p < 0.05 for all). No significant differences in overall survival, distant metastasis-free survival, and local relapse-free survival were observed between patients with sphenoid sinus invasion alone and those with maxillary sinus and ethmoid sinus invasion (p = 0.87, p = 0.80, and p = 0.37, respectively). The overall survival, distant metastasis-free survival, and local relapse-free survival for patients with stage T3 disease with paranasal sinus invasion were similar to the survival rates for patients with stage T3 disease without paranasal sinus invasion (p = 0.22, p = 0.15, and p = 0.93, respectively). However, the rates of overall survival and local relapse-free survival were better for patients with stage T3 disease with paranasal sinus invasion than for patients with stage T4 disease (p < 0.01, and p = 0.03, respectively). CONCLUSIONS: Paranasal sinus invasion is an independent negative prognostic factor for NPC, regardless of which sinus is involved. Our results confirm that it is scientific and reasonable for the AJCC staging system for nasopharyngeal carcinoma to define paranasal sinus invasion as stage T3 disease.

Partial hepatectomy for liver metastases from nasopharyngeal carcinoma: a comparative study and review of the literature.

BACKGROUND: The management of liver metastases from nasopharyngeal carcinoma (NPC) has not been extensively investigated. This study aimed to compare the long-term outcome of patients with liver metastases from NPC who were treated by a partial hepatectomy or transcatheter hepatic artery chemoembolization (TACE). METHODS: Between January 1993 and December 2010, 830 patients were diagnosed with liver metastases from NPC and exhibited a complete response to the primary cancer of the nasopharynx and regional lymph nodes. Fifteen patients with intrahepatic metastasis underwent R0 partial hepatectomy. As a parallel control group, another 15 patients with a resectable liver metastasis who underwent TACE were selected. Prior to the resection and TACE that were performed on patients in these two groups, radical radiotherapy with or without adjuvant chemotherapy was administered. Clinicopathological data and treatment outcomes were compared retrospectively. RESULTS: No significant differences were observed between the two groups in terms of the clinicopathological features, which include gender ratio, liver function, accompanying cirrhosis, rate of infection with the hepatitis B virus, tumor size, tumor number, pathological type and preoperative comorbidities. The 1-, 3- and 5-year overall survival rates from the time of hepatectomy were 85.7%, 64.2% and 40.2%, respectively, with a median survival of 45.2 months, whereas the 1-, 3- and 5-year overall survival rates were 53.3%, 26.6% and 20.0% for patients in the control group (P = 0.039), respectively, with a median survival of 14.1 months. The actuarial median progression-free survival (PFS) of the patients in the resection group was 21.2 months, and the 1-, 3- and 5-year PFS rates were 70%, 53% and 18%, respectively. In the control group, the 1-, 3- and 5-year PFS rates were 27%, 7% and 0.0% (P = 0.007), respectively, with a median survival of 4.2 months. Thus far, 5 patients have survived for more than 5 years, and the longest survival time is 168.1 months. CONCLUSIONS: For patients with limited liver metastases from NPC, hepatectomy provides a survival advantage over TACE. Due to the limited treatment options for patients with liver metastasis from NPC, hepatectomy should be recommended as an optimal treatment. Moreover, perioperative chemotherapy may be associated with an improved prognosis.

Lung squamous cell carcinoma metastasizing to the nasopharynx following bronchoscopy intervention therapies: a case report.

Metastatic carcinoma to the nasopharynx is extremely rare, and few cases have been reported in the literature. In the present report, we describe the case of a patient with a mass in the nasopharynx found by bronchoscopy. Our patient was a 61-year-old man receiving multiple bronchoscopy intervention therapies for advanced lung squamous cell carcinoma (SCC), which was histopathologically confirmed. The SCC metastasized to the nasopharynx following the bronchoscopy intervention therapies. The lesion was considered metastatic from lung cancer on the basis of clinical and histological clues. The exact mechanism of lung cancer metastasis to the nasopharynx in this case remains unclear because either implantation or hematogenous and lymphatic spread is possible. A thorough head and neck examination should be undertaken during bronchoscopic evaluation, especially in patients receiving bronchoscopy intervention therapies. The early detection of a silent nasopharyngeal metastasis is important to choosing from among the multiple treatment options available.

Patterns of regional lymph node metastasis of nasopharyngeal carcinoma: a meta-analysis of clinical evidence.

BACKGROUND: The characteristics of cervical lymphatic metastasis in nasopharyngeal carcinoma (NPC) are not completely understood. As such, radiotherapy to the entire lymphatic of the neck bilaterally has been empirically practiced even in early stage disease, although not supported by clinical evidence. We studied the pattern and probability of nodal metastasis through a meta-analysis of published evidences, with an aim to establish an evidence-based guideline for selecting and delineation of clinical target volume of neck lymphatics for conformation radiation for NPC. METHODS: A literature search yielded an initial 411 original articles, and 13 studies with 2920 NPC cases staged via MRI were included in this analysis. The occurrence of nodal metastasis was calculated and analyzed according to the respective regional nodal levels. RESULTS: 85% of NPC cases presented with lymphadenopathy. The most commonly involved regions include retropharyngeal (69%) and level II lymph nodes (70%). The overall probability of levels III, IV, and V nodal involvement are 45%, 11%, and 27%, respectively. Low-risk node groups included the supraclavicular, levels IA/IB and VI nodes, and parotid nodes with involvement rates at 3%, 0%, 3%, 0%, and 1%, respectively. Nodal metastases followed an orderly pattern and the probability of "skip" metastasis between levels varied between 0.5-7.9%. CONCLUSIONS: Lymph node metastasis in NPC follows a predictable and orderly pattern. The rarity of metastasis in certain nodal groups and "skip" metastasis suggest that reduced treatment volume is feasible in conformal radiotherapy for NPC.

Promising treatment outcomes of intensity-modulated radiation therapy for nasopharyngeal carcinoma patients with N0 disease according to the seventh edition of the AJCC staging system.

BACKGROUND: Intensity-modulated radiation therapy (IMRT) provides excellent locoregional control for nasopharyngeal carcinoma (NPC), and has gradually replaced two-dimensional conventional radiotherapy as the first-line radiotherapy technique. Furthermore, in the new seventh edition of the American Joint Committee on Cancer (AJCC) staging system, retropharyngeal lymph nodes were upgraded from N0 to N1 disease as a result of their negative impact on the distant metastasis-free survival (DMFS) rates of NPC. This retrospective study was conducted in order to review the treatment outcomes and patterns of failure in NPC patients with N0 disease after IMRT in order to effectively guide treatment in the future. METHODS: We retrospectively reviewed data from 506 biopsy-proven nonmetastatic NPC patients. There were 191 patients with negative cervical lymph node involvement. According to the seventh edition of the American Joint Committee on Cancer (AJCC) staging system, 110 patients (21.7%) were staged with N0 disease, and 81 patients (16.0%) were reclassified with N1 disease due to the presence of RLN metastasis. All patients received IMRT as the primary treatment. RESULTS: In patients with negative cervical lymph node involvement, distant metastasis-free survival (DMFS) was significantly higher in patients without retropharyngeal lymph node (RLN) metastasis than those with RLN metastasis (95.9% vs. 88.1% respectively, P = 0.04). For N0 disease, the 5-year overall survival (OS), local relapse-free survival (LRFS), nodal relapse-free survival (NRFS) and DMFS rates were 93.8%, 97.1%, 99.1% and 95.9%, respectively. For T1N0, T2N0, T3N0 and T4N0, OS was 97.8%, 100%, 93.8% and 76.9%, LRFS was 100%, 92.9%, 100% and 88.9% and DMFS was 96.6%, 90.9%, 100% and 93.3%, respectively. OS and LRFS were higher in T1-3 N0 patients than T4N0 patients (P < 0.01 and P = 0.01, respectively). CONCLUSIONS: The seventh edition of the AJCC N-staging system improves prognostic accuracy by upgrading RLN metastasis to N1 disease. IMRT produces excellent survival rates in T1-3 N0 disease; however, T4N0 disease remains a challenge and additional improvements are required to achieve a favorable prognosis for these NPC patients.

Long-term monitoring of dynamic changes in plasma EBV DNA for improved prognosis prediction of nasopharyngeal carcinoma.

BACKGROUND: This study was performed to investigate whether long-term monitoring of dynamic changes in plasma Epstein-Barr virus (EBV) DNA could improve prognosis prediction of nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: About 1077 nonmetastatic NPC patients were recruited to retrospectively analyze the prognostic value of plasma EBV DNA load pretreatment and 3, 12, 24, and 36 months posttreatment. We also examined the prognostic value of dynamic changes in plasma EBV DNA at various time points. RESULTS: Patients with plasma EBV DNA load above optimal pre- and posttreatment cut-offs had significantly worse five-year progression-free survival, distant metastasis-free survival, locoregional relapse-free survival, and overall survival (OS) at all-time points, excluding only OS at 36 months posttreatment due to limited mortalities. Patients with persistently undetectable plasma EBV DNA at the first four time points had the best prognosis, followed by those with positive detection pretreatment and consistently negative detection posttreatment, those with negative detection pretreatment and positive detection at one time point posttreatment, and those with positive detection pretreatment and at one time point posttreatment, whereas patients with positive detection at ≥2 time points posttreatment had the worst prognosis. Cox proportional hazard models identified the dynamic change pattern as an independent prognostic factor, and receiver operating characteristic curve analysis demonstrated that the dynamic change at four time point was more valuable than any single time point for predicting disease progression, distant metastasis, locoregional relapse, and mortality. CONCLUSIONS: Dynamic changes in plasma EBV DNA pre- and posttreatment could predict the long-term survival outcome and provide accurate risk stratification in NPC.