Efficacy of salvage surgery versus re-irradiation for isolated regional lymph node recurrence in patients with nasopharyngeal carcinoma.

BACKGROUND: To compare the clinical characteristics and prognoses of patients with isolated regional lymph node recurrent nasopharyngeal carcinoma (irrNPC) who underwent surgery or re-irradiation treatment. METHODS: We retrospectively reviewed 124 irrNPC patients who underwent initial radiotherapy between January 2010 and December 2020. The staging of regional lymph node recurrence was as follows: 75.8% for rN1, 14.5% for rN2, and 9.7% for rN3. Fifty-five patients underwent regional lymph node surgery (Surgery group), and sixty-nine patients received salvage radiotherapy with or without chemotherapy (Re-irradiation group). The survival rate was compared using Kaplan‒Meier analysis and evaluated by the log-rank test. Cox proportional hazard models were used to analyze prognostic factors. RESULTS: The median follow-up time was 70 months, the 5-year overall survival (OS) was 74%, and the median survival time was 60.8 months. There were no significant differences in 5-year OS (75.6% vs. 72.4%, P = 0.973), regional recurrence-free survival (RRFS, 62.7% vs. 71.1%, P = 0.330) or distant metastasis-free survival (DMFS, 4.2% vs.78.7%, P = 0.677) between the Surgery group and Re-irradiation group. Multivariate analysis revealed age at recurrence, radiologic extra-nodal extension (rENE) status, and recurrent lymph node (rN) classification as independent prognostic factors for OS. The rENE status was an independent prognostic factor for DMFS. Subgroup analysis of the Surgery group revealed that the rN3 classification was an adverse prognostic factor for OS. Age at recurrence ≥ 50 years, GTV-N dose, and induction chemotherapy were found to be independent prognostic factors for OS, RRFS, and DMFS, respectively, in the Re-irradiation group. CONCLUSIONS: For NPC patients with isolated regional lymph node recurrence after initial radiotherapy, those who underwent surgery had survival prognosis similar to those who underwent re-radiotherapy with or without chemotherapy. A prospective study is needed to validate these findings.

Plasma Epstein-Barr virus microRNA BART8-3p as a potential biomarker for detection and prognostic prediction in early nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) encoded microRNA BART8-3p (miR-BART8-3p) was significantly associated with the metastasis in nasopharyngeal carcinoma (NPC). To explore the clinical values of plasma miR-BART8-3p in patients with early NPC. We retrospectively analyzed 126 patients with stage I and II NPC. A receiver operating characteristic curve was used to examine the diagnostic performance. Kaplan‒Meier analysis was applied to determine survival differences. Cox regression was used for univariate and multivariate analyses. Compared to healthy subjects, plasma EBV miR-BART8-3p was highly expressed in early NPC patients. The sensitivity, specificity, and area under the curve value of plasma miR-BART8-3p combined with plasma EBV DNA was up to 88.9%, 94.4%, and 0.931. Compared to patients with low expression of miR-BART8-3p, patients with high expression of miR-BART8-3p had poorer 5-year overall survival (OS) (98.9% vs. 91.1%, P = 0.025), locoregional recurrence-free survival (LRRFS) (100% vs. 83.9%, P < 0.001) and distant metastasis-free survival (DMFS) (98.9% vs. 88.0%, P = 0.006). Risk stratification analysis revealed that high-risk patients (with high levels of EBV DNA and miR-BART8-3p) had inferior OS, LRRFS, and DMFS than low-risk patients (without high levels of EBV DNA and miR-BART8-3p). Multivariate analysis verified that the high-risk group was an unfavorable factor for OS, LRRFS, and DMFS. A combination of plasma EBV miR-BART8-3p and EBV DNA could be a potential biomarker for the diagnosis and prognosis in early NPC.

Risk-adapted locoregional radiotherapy strategies based on a prognostic nomogram for de novo metastatic nasopharyngeal carcinoma patients treated with chemoimmunotherapy.

To develop a prognostic nomogram for individualized strategies on locoregional radiation therapy (LRRT) in patients with de novo metastatic nasopharyngeal carcinoma (dmNPC) treated with chemoimmunotherapy. Ninety patients with dmNPC treated with chemoimmunotherapy and diagnosed between 2019 and 2022 were included in our study. Cox regression analysis was performed to identify independent prognostic factors for overall survival (OS) and progression-free survival (PFS) to establish a nomogram. With a median follow-up of 17.5 months, the median PFS and OS were 24.9 months and 29.4 months, respectively. Sixty-nine patients and twenty-one patients were included in the LRRT group and without LRRT group, respectively. Multivariate analysis revealed that younger age, lower EBV DNA copy number before treatment, a single metastatic site, more cycles of chemotherapy and immunotherapy were significantly associated with better OS. A prognostic nomogram was constructed incorporating the above 5 independent factors, with a C-index of 0.894. Patients were divided into low- and high-risk cohorts based on nomogram scores. A significant improvement in OS was revealed in the LRRT group compared with the without-LRRT group for patients in the high-risk cohort (HR = 2.46, 95% CI 1.01-6.00, P = 0.049), while the OS was comparable between the two groups in the low-risk cohort. Our study indicates that LRRT may be associated with better prognosis in high-risk patients with dmNPC in the era of immunotherapy.

Selectively sparing of the supraclavicular area during intensity-modulated radiotherapy in nasopharyngeal carcinoma: A double-center observation study.

BACKGROUND AND PURPOSE: This study was aimed at evaluating the feasibility of sparing the supraclavicular area, namely levels IVb and Vc, during intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC) patients with N1-2 disease[except N1 disease with purely restropharyngeal lymph nodes(RPN) involvement], and providing a basis for the revision of International Guideline for the delineation of the clinical target volume (CTV). PATIENTS AND MATERIALS: Patients with NPC (stage TanyN1-2M0) diagnosed pathologically in Fujian Cancer Hospital (Center 1, Only Lin SJ's attending group) from January 2014 to March 2018 and Jiangxi Cancer Hospital(Center 2) from January 2014 to December 2015 were included. According to our principle, the supraclavicular area (levels IVb and Vc) were excluded from the CTVnd. Survival outcomes focused on regional recurrence-free survival (RRFS) and recurrence rates of levels IVb and Vc were analysed. RESULTS: A total of 672 eligible patients were recruited (Center 1, n = 362; Center 2, n = 310). There was no significant difference in 5-year RRFS (97.33 % vs. 97.24 %, p = 0.980), overall survival (OS) (89.14 % vs. 88.56 %, p = 0.327), local recurrence-free survival (LRFS) (94.90 % vs. 95.30 %, p = 0.593) and distant metastasis-free survival (DMFS) (89.38 % vs. 86.60 %, p = 0.130) between Center 1 and Center 2. Twenty patients developed regional failure (median: 36 months), among them, only one case (0.15 %) was recorded as levels IVb and Vc recurrence. CONCLUSION: Omitting the supraclavicular area (levels IVb and Vc) during IMRT should be safe and feasible for N1-2 disease (except N1 disease with purely RPN involvement). Well-designed multicenter prospective trials should be conducted to confirm our findings.

Lack of association between XRCC1 SNPs and acute radiation­induced injury or prognosis in patients with nasopharyngeal carcinoma.

The response to radiation therapy (RT) is closely associated with DNA damage repair. X-ray repair cross-complementing group-1 (XRCC1) is a key gene in the DNA damage repair pathway, and SNPs in this gene alter the expression and activity of its effector protein, which may in turn affect sensitivity to RT. Therefore, the course of tumor treatment and local control rate can be influenced. In the present study, a group of 158 patients with nasopharyngeal carcinoma (NPC) who received intensity-modulated RT at Fujian Cancer Hospital (Fuzhou, China) between July 2012 and October 2013 were included in retrospective chart review and followed up. Plasma was collected before treatment for genotype analysis of the three SNPs of XRCC1, namely Arg194Trp, Arg280His and Arg399Gln. Acute radiation-induced injuries sustained during treatment was graded according to the Radiation Therapy Oncology Group scoring criteria. Post-treatment follow-up was performed until August 2020. In the 158 cases of NPC, no statistically significant association was observed between the three SNPs of the XRCC1 gene and the severity of acute radiation-induced injury or prognosis. However, the AA genotype of XRCC1-Arg399Gln tended to be associated with worse progression-free survival (PFS) compared with the GA + GG genotype, although this was not significant (P=0.069). In addition, multivariate logistic analysis showed that nodal stage was significantly associated with the occurrence of acute severe radiation-induced oral mucositis (P=0.018), and there was also a trend towards an association between nodal stage and the incidence of acute severe radiation-induced pharyngitis; however, this was not statistically significant (P=0.061). Furthermore, multivariate Cox regression analysis showed that older age, distant metastasis and higher clinical stage were independent risk factors for PFS in patients with NPC. In conclusion, relying solely on the aforementioned SNPs of the XRCC1 gene may not provide a robust enough basis to predict the response to RT or prognosis in patients with NPC.

Constructing an individualized surveillance framework for nasopharyngeal carcinoma based on a dynamic risk-adapted approach.

BACKGROUND AND PURPOSE: This study aims to evaluate the dynamic survival and recurrence hazard of nasopharyngeal carcinoma(NPC) patients after definitive chemoradiotherapy utilizing conditional survival(CS) analysis, and to propose a personalized surveillance strategy at different clinical stages. MATERIALS AND METHODS: Non-metastatic NPC patients who received curative chemotherapy between June 2005 and December 2011 were included. The Kaplan-Meier method was used to calculate the CS rate. RESULTS: A total of 1616 patients were analyzed. With the prolongation of survival time, both conditional locoregional recurrence free survival and distant metastatic free survival increased gradually. Changing pattern of annual recurrence risk over time varied among different clinical stages. The annual locoregional recurrence(LRR) risk in stage I-II was always less than 2%, while in stage III-IVa, it was greater than 2% for the first three years and decreased to below 2% only after the third year. The annual distant metastases (DM) risk was always less than 2% in stage I, but higher than 2% in stage II for the first 3 years (2.5-3.8%). For those with stage III-IVa, the annual DM risk retained at a high level(>5%), and only decreased to < 5% after the third year. Based on the dynamic changes in survival probability over time, we established a surveillance plan with different follow-up intensities and frequencies for different clinical stages. CONCLUSION: The annual risk of LRR and DM decrease over time. Our individual surveillance model will provide critical prognostic information to optimize clinical decision-making, and promote to formulate surveillance counseling and help with resources allocation.

Individualized Concurrent Chemotherapy for Patients with Stage III-IVa Nasopharyngeal Carcinoma Receiving Neoadjuvant Chemotherapy Combined with Definitive Intensity-Modulated Radiotherapy.

PURPOSE: This retrospective study aimed to re-evaluate the effect of concurrent chemotherapy in patients with locally advanced nasopharyngeal carcinoma (NPC) in the era of intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: A total of 498 patients who received neoadjuvant chemotherapy (NCT) combined with concurrent chemoradiotherapy (CCRT) or IMRT were retrospectively reviewed. The distribution of baseline characteristics was balanced using propensity score matching. Additionally, the results of NCT+IMRT and NCT+CCRT were compared using Kaplan-Meier survival analysis, and differences in survival rates were analyzed using the log rank test. RESULTS: There were no significant differences in overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and local progression-free survival (LRFS) between the two groups. Patients were further categorized into risk subgroups based on pretreatment Epstein-Barr virus (EBV) DNA cutoff values using receiver operating characteristic curve analysis. There were no statistically significant differences in OS, PFS, DMFS, and LRFS between patients who received NCT+CCRT and NCT+IMRT in the high-risk group. In the low-risk group, although there were no differences between NCT+CCRT and NCT+IMRT in OS, PFS, and LRFS, patients who received NCT+CCRT had better DMFS than those who received NCT+IMRT. CONCLUSION: Pretreatment EBV DNA level can be used to individualize concurrent chemotherapy for patients with locally advanced NPC. Patients with low pretreatment EBV DNA levels may benefit from concurrent chemotherapy, whereas those with high levels may not. Other treatment modalities need to be explored for high-risk patients to improve their prognosis.

Identification of an individualized therapy prognostic signature for head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) are the most common cancers in the head and neck. Therapeutic response-related genes (TRRGs) are closely associated with carcinogenesis and prognosis in HNSCC. However, the clinical value and prognostic significance of TRRGs are still unclear. We aimed to construct a prognostic risk model to predict therapy response and prognosis in TRRGs-defined subgroups of HNSCC. METHODS: The multiomics data and clinical information of HNSCC patients were downloaded from The Cancer Genome Atlas (TCGA). The profile data GSE65858 and GSE67614 chip was downloaded from public functional genomics data Gene Expression Omnibus (GEO). Based on TCGA-HNSC database, patients were divided into a remission group and a non-remission group according to therapy response, and differentially expressed TRRGs between those two groups were screened. Using Cox regression analysis and Least absolute shrinkage and selection operator (LASSO) analysis, candidate TRRGs that can predict the prognosis of HNSCC were identified and used to construct a TRRGs-based signature and a prognostic nomogram. RESULT: A total of 1896 differentially expressed TRRGs were screened, including 1530 upregulated genes and 366 downregulated genes. Then, 206 differently expressed TRRGs that was significantly associated with the survival were chosen using univariate Cox regression analysis. Finally, a total of 20 candidate TRRGs genes were identified by LASSO analysis to establish a signature for risk prediction, and the risk score of each patient was calculated. Patients were divided into a high-risk group (Risk-H) and a low-risk group (Risk-L) based on the risk score. Results showed that the Risk-L patients had better overall survival (OS) than Risk-H patients. Receiver operating characteristic (ROC) curve analysis revealed great predictive performance for 1-, 3-, and 5-year OS in TCGA-HNSC and GEO databases. Moreover, for patients treated with post-operative radiotherapy, Risk-L patients had longer OS and lower recurrence than Risk-H patients. The nomogram involves risk score and other clinical factors had good performance in predicting survival probability. CONCLUSIONS: The proposed risk prognostic signature and Nomogram based on TRRGs are novel promising tools for predicting therapy response and overall survival in HNSCC patients.

Prioritizing sufficient dose to gross tumor volume over normal tissue sparing in intensity-modulated radiotherapy treatment of T4 nasopharyngeal carcinoma.

BACKGROUND: In intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC), priority is often given minimize dose to the critical organs at risk (OARs) to avoid potential morbid sequelae. However, in T4 NPC, dosimetric inadequacy enforced by dose constraints on OARs may significantly impact tumor control. METHODS: This was a single-institute cohort that patients diagnosed between July 2005 and December 2010 with T4 NPC treated with IMRT. All patients were re-classification according to the 7th-AJCC stage. RESULTS: Overall, the average doses such as Dmax , D1% , D2% and D1cc for various Central nervous system (CNS) OARs including brainstem, optic nerve, chiasm, temporal lobes and spinal cord were found to exceed published guidelines as RTOG0225. However, no clinical toxicities were seen during the follow-up period except for 13% patients with temporal lobe necrosis. CONCLUSION: Our retrospective review showed that its feasible to maximize gross tumor volume dose coverage while exceeding most CNS OAR constraint standards, with ideal local control and no obvious increase of craniocerebral toxicity.

Stereotactic body radiotherapy extends the clinical benefit of PD-1 inhibitors in refractory recurrent/metastatic nasopharyngeal carcinoma.

PURPOSE: Emerging evidence shows that immune checkpoint inhibitors lead to durable responses in a variety of cancers, including nasopharyngeal carcinoma (NPC), however, combination approaches (i.e., stereotactic body radiation therapy, SBRT) are required to extend this benefit beyond a subset of patients. This study retrospectively evaluated eight recurrent/metastatic NPC patients, to investigate how radiation could potentiate PD-1 checkpoint inhibition therapy. METHODS: Between September 2016 and July 2017, eight consecutive cases with histologically confirmed PDL1-positive status, for which prior standard therapy had been ineffective (five patients), were treated at our institution and Macao Clinics and two patients had disease progression within 6 months of completion of definitive chemoradiation, or one patient refused to receive chemoradiotherapy. All received PD-1 inhibitors first, seven of them accepted SBRT with an unmodified PD-1 inhibitors regimen after first evaluation as they were unresponsive to PD-1 inhibitors alone. Treatment was discontinued as long as patients were experiencing a clinical benefit in the opinion of the physicians and at least five cycles were given before stoppage. RESULTS: Median follow-up time was 56.7 months. The confirmed objective response rate based on RECIST-v1.1 at first evaluation was 12.5% (1/8). For the seven cases who received SBRT, six of them experience an objective response (6/7, 85.7%) after SBRT. Only one patient showed rapid progress and die within 95 days after the initiation of SBRT intervention. Three patients who did not have all lesions exposed to irradiation were available to evaluate the incidence of an abscopal effect, however, it did not occur as expected. Median PFS and OS for the seven patients were 8.0 and 30.8 months after SBRT intervention, respectively. Two-year OS as indicated was 71.0%. CONCLUSIONS: PD-1 inhibitors combined with SBRT demonstrated promising antitumor activity in patients with PD-L1 positive RM-NPC. Patients may benefit from continue immunotherapy beyond disease progression when SBRT was introduced.

Plasma Epstein-Barr viral DNA load after completion of two cycles of induction chemotherapy predicts outcomes for patients with advanced-stage nasopharyngeal carcinoma.

OBJECTIVES: To evaluate the prognostic value of plasma Epstein-Barr virus DNA level following the completion of two induction chemotherapy cycles (ICT; post2CICT-DNA) in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). MATERIALS AND METHODS: This retrospective study included 534 patients with LA-NPC. Recursive partitioning analysis (RPA) was applied to derive a prognostic model for risk stratification. Kaplan-Meier survival analysis was used to determine the survival results, and survival rates were compared using the log-rank test. The Cox proportional hazard model was used for univariate and multivariate analyses. RESULTS: Multivariate analyses revealed that post2CICT-DNA and N stage were independent predictors of overall survival (OS; P = 0.001 and P = 0.001, respectively), and post2CICT-DNA, pre-treatment DNA, and N stage were independent predictors of progression-free survival (PFS; P = 0.002, P = 0.001, and P = 0.021, respectively).Based on prognostic factors (pre-treatment DNA, post2CICT-DNA, and N stage), patients were stratified into three risk subgroups, with 288 patients in the low-, 213 in the intermediate-, and 33 in the high-risk group. The three-year OS rate of the low-, intermediate- and high-risk groups were 99.3% (95% CI 98.3%-100.0%), 90.0% (95% CI 85.5%-94.5%) and 67.0% (95% CI 49.9%-84.1%, P < 0.001 for each of the two groups), respectively. CONCLUSION: Plasma EBV-DNA level after two ICT cycles is a powerful predictor of prognosis in patients with LA-NPC. RPA analysis revealed that stage N3 patients with detectable post2CICT-DNA are at the highest risk of treatment failure, and future clinical trials should focus on early-treatment modification strategies for these patients.

RNF38 suppress growth and metastasis via ubiquitination of ACTN4 in nasopharyngeal carcinoma.

BACKGROUND: Accumulated evidence suggests that RING finger proteins (RNFs) are involved in the carcinogenesis of cancers. However, RNF38, a member of the RNF protein family, has not been studied in nasopharyngeal carcinoma (NPC). METHODS: RNF38 expression was analyzed by RT-PCR, Western blotting and Immunohistochemistry. Biological functions of RNF38 were evaluated by cell growth, colony formation, apoptosis, migration and invasion assays in vitro. Xenograft growth and lung metastasis models were conducted to investigate the effect of RNF38 in vivo. Liquid chromatography coupled with tandem mass spectrometry, co-immunoprecipitation, and CHX assay were implemented to detect the interaction among RNF38 and ACTN4. RESULTS: RNF38 was significantly downregulated in NPC cells and tissues. Immunohistochemistry implied that loss of RNF38 was an independent prognostic factor for poor outcomes of NPC patients. Gain- and loss-of-function experiments showed that RNF38 inhibited proliferation and metastasis in NPC in vitro and in vivo. Upregulation of RNF38 promoted apoptosis of NPC cells to etoposide but not cisplatin. ACTN4 was upregulated in NPC and negatively correlated with RNF38. Mechanistic investigations suggested that RNF38 inactivates the NF-𝛋B and ERK1/2 signaling pathways by inducing ubiquitination and degradation of ACTN4. RNF38 suppress the development of NPC by interacting with ACTN4. CONCLUSIONS: RNF38 plays a potential cancer suppressor gene role in NPC tumorigenesis and is a prognostic biomarker in NPC.

Plasma Epstein-Barr Virus MicroRNA BART8-3p as a Diagnostic and Prognostic Biomarker in Nasopharyngeal Carcinoma.

BACKGROUND: Nasopharyngeal carcinoma is an Epstein-Barr virus (EBV)-associated tumor that is highly common in southern China. Our previous sequencing data demonstrated that the EBV-encoded microRNA BART8-3p was most upregulated in nasopharyngeal carcinoma (NPC) and was closely associated with the metastasis of NPC. However, the values of plasma BART8-3p in NPC patients have not yet been well characterized. MATERIAL AND METHODS: We quantified plasma BART8-3p expression by quantitative real-time PCR in 205 newly diagnosed NPC patients. Kaplan-Meier analysis was used to compare overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) between the groups. RESULTS: Plasma pretreatment BART8-3p was highly expressed in NPC patients compared with healthy controls. Pretreatment BART8-3p yielded a 92% predictive value for detecting NPC. Importantly, BART8-3p decreased dramatically after therapy relative to pretreatment levels. High levels of pretreatment or post-treatment BART8-3p were associated with worse OS, DMFS, and LRRFS. Multivariate analysis showed that high pretreatment or post-treatment BART8-3p was an independent unfavorable prognostic marker for OS (HR 3.82, 95% CI 1.77-8.24, P = .001 or HR 2.74, 95% CI 1.27-5.91, P = .010), DMFS (HR 2.82, 95% CI 1.36-5.85, P = .005 or HR 3.27, 95% CI 1.57-6.81, P = .002), and LRRFS (HR 1.94, 95% CI 1.12-3.35, P = .018 or HR 2.03, 95% CI 1.14-3.62, P = .016) in NPC. Subgroup analysis revealed that for patients with locally advanced NPC with high levels of pretreatment BART8-3p (n = 58), more cycles of chemotherapy (≥6 cycles) tended to prolong OS (P = .070). Over 50% (6/11) patients with high levels of post-treatment BART8-3p presented distant metastasis. CONCLUSION: Plasma BART8-3p is a promising biomarker for the detection and prognosis of NPC.

Level Ib sparing intensity-modulated radiation therapy in selected nasopharyngeal carcinoma patients based on the International Guideline.

BACKGROUND AND PURPOSE: To investigate the feasibility of level Ib sparing in selected nasopharyngeal carcinoma (NPC) patients during intensity-modulated radiation therapy (IMRT) based on the International Guideline. PATIENTS AND MATERIALS: Patients with histologically-proven NPC who received definitive IMRT at our group were candidates for this analysis. Other eligibility criteria for analysis were designed according to the recommendation of International Guideline for selective coverage of level Ib. Survival outcomes focused on regional recurrence-free survival (RRFS) and level Ib recurrence rate were analyzed. RESULTS: A total of 450 patients were included, 60 of them received level Ib-covering IMRT due to the first three principles of the International Guideline according to our protocol. Of note, patients with level Ib involvement would receive ultrasound guided puncture, only those with positive pathological results would undergo level Ib-covering IMRT. For the remaining 390 patients who only fulfilled the last two criteria and/or level Ib involvement with negative pathological results, level Ib-sparing IMRT was delivered, with a median follow-up time of 112 months (range 6 to 194 months), reported 5- and 10-year RRFS were 95.4% and 92.9%, respectively. Twenty-two patients occurred regional recurrence at censorship (median 44.5 months), only 4(4/390, 1.03%) were recorded as level Ib recurrence. CONCLUSION: Level Ib-sparing IMRT should be safe and feasible for patients who only had level II involvement with ECE, and/or had a MAD of greater than 2 cm in level II, and/or level Ib involvement with negative pathological results. Further well-designed multi-center prospective trials should be conducted.

Re-evaluation of the prognostic significance of retropharyngeal node metastasis in nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy.

BACKGROUND AND PURPOSE: To investigate the prognostic value of retropharyngeal lymphadenopathy in nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy. MATERIALS AND METHODS: Retrospective studies were performed in a total of 1197 patients. We evaluated the incidence of the retropharyngeal node (RPN) metastasis and the characteristics of the metastatic RPN including laterality, size, necrosis, and extranodal neoplastic spread. RESULTS: RPN metastasis occured in 86.3% of patients. The RPN and level II metastasis shared similar survival outcomes. RPN metastasis was an independent prognostic factor for distant failure (hazard ratio = 1.615; 95% confidence interval, 1.063-2.452; P = 0.025), in which the laterality of RPN metastasis significantly influences both the distant failure (P = 0.006) and disease progression (P = 0.001). In N1 disease, the occurrence of unilateral and bilateral RPN metastasis resulted in significantly different outcomes of the disease-specific survival (P = 0.045) and progression-free survival (P = 0.049). The co-occurrence of bilateral RPN and cervical lymph nodes (CLN) metastasis was an independent adverse prognostic factor (P < 0.01) for distant failure and disease progression but not for locoregional recurrence. CONCLUSION: Both the RPN and level II are the first stations of NPC lymph node metastasis. For N1-stage NPC patients, RPN metastasis, especially co-occurrence of bilateral RPN and CLN metastasis, have an adverse influence on survival outcomes.

Comparison of radiotherapy combined with nimotuzumab vs. chemoradiotherapy for locally recurrent nasopharyngeal carcinoma.

BACKGROUND: The present study compared the effectiveness and toxicity of two treatment modalities, namely radiotherapy combined with nimotuzumab (N) and chemoradiotherapy (CRT) in patients with locally recurrent nasopharyngeal carcinoma (LR-NPC). METHODS: Patients with LR-NPC who were treated with radiotherapy were retrospectively enrolled from January 2015 to December 2018. The treatment included radiotherapy combined with N or platinum-based induction chemotherapy and/or concurrent chemotherapy. The comparison of survival and toxicity between the two treatment modalities was evaluated using the log-rank and chi-squared tests. Overall survival (OS) was the primary endpoint. RESULTS: A total of 87 patients were included, of whom 32 and 55 were divided into the N group and the CRT group, respectively. No significant differences were noted in the survival rate between the N and the CRT groups (4-year OS rates, 37.1% vs. 40.7%, respectively; P = 0.735). Mild to moderate acute complications were common during the radiation period and mainly included mucositis and xerostomia. The majority of the acute toxic reactions were tolerated well. A total of 48 patients (55.2%) demonstrated late radiation injuries of grade ≥ 3, including 12 patients (37.5%) in the N group and 36 patients (66.5%) in the CRT group. The CRT group exhibited significantly higher incidence of severe late radiation injuries compared with that of the N group (P = 0.011). CONCLUSION: Radiotherapy combined with N did not appear to enhance treatment efficacy compared with CRT in patients with LR-NPC. However, radiotherapy combined with N may be superior to CRT due to its lower incidence of acute and late toxicities. Further studies are required to confirm the current findings.

Competitive Endogenous RNA Landscape in Epstein-Barr Virus Associated Nasopharyngeal Carcinoma.

Non-coding RNAs have been shown to play important regulatory roles, notably in cancer development. In this study, we investigated the role of microRNAs and circular RNAs in Nasopharyngeal Carcinoma (NPC) by constructing a circRNA-miRNA-mRNA co-expression network and performing differential expression analysis on mRNAs, miRNAs, and circRNAs. Specifically, the Epstein-Barr virus (EBV) infection has been found to be an important risk factor for NPC, and potential pathological differences may exist for EBV+ and EBV- subtypes of NPC. By comparing the expression profile of non-cancerous immortalized nasopharyngeal epithelial cell line and NPC cell lines, we identified differentially expressed coding and non-coding RNAs across three groups of comparison: cancer vs. non-cancer, EBV+ vs. EBV- NPC, and metastatic vs. non-metastatic NPC. We constructed a ceRNA network composed of mRNAs, miRNAs, and circRNAs, leveraging co-expression and miRNA target prediction tools. Within the network, we identified the regulatory ceRNAs of CDKN1B, ZNF302, ZNF268, and RPGR. These differentially expressed axis, along with other miRNA-circRNA pairs we identified through our analysis, helps elucidate the genetic and epigenetic changes central to NPC progression, and the differences between EBV+ and EBV- NPC.

Percutaneous endoscopic gastrostomy can improve survival outcomes in patients with N3 nasopharyngeal carcinoma undergoing concurrent chemoradiotherapy.

OBJECTIVES: Our previous study revealed that percutaneous endoscopic gastrostomy (PEG) and intensive nutritional support may minimize body weight loss, maintain nutritional status, and offer better treatment tolerance for patients with locally advanced nasopharyngeal carcinoma (LA-NPC) during concurrent chemoradiotherapy (CCRT). This study aimed to further explore the potential long-term survival benefits of PEG in LA-NPC. METHODS: Between June 1, 2010 and June 30, 2014, a total of 133 consecutive LA-NPC patients who received prophylactic PEG (pPEG) feeding before the initiation of CCRT were included. Meanwhile, an additional 133 non-PEG patients, who were matched for age; sex; and tumor, node, and metastases stage, were selected as control cohort. The log-rank test was used to compare survival distributions between groups. Multivariate prognosis analysis was conducted using a Cox's proportional hazards regression model. RESULTS: After a median follow-up time of 81 months (range: 4-119 months), pPEG was not associated with significant survival benefits in the whole cohort. However, the N3 NPC patients who underwent PEG had significantly higher 5-year overall survival (OS) and progression-free survival (PFS) (84.0 and 76.0%, respectively) than those who did not undergo PEG (56.7 and 45.6%, respectively; p < 0.05). Univariate and multivariate analyses demonstrated that PEG was an independent factor for N3 survival. CONCLUSION: PEG can maintain the nutritional status and improve the rate of treatment completion for LA-NPC patients who underwent CCRT, and these advantages can transfer into survival benefits in N3 NPC. Further multicenter prospective clinical trials are warranted.

Administration of oral maintenance chemotherapy for 1 year following definitive chemoradiotherapy may improve the survival of patients with stage N3 nasopharyngeal carcinoma.

OBJECTIVES: This study aims to evaluate the effectiveness and the optimal maintenance period of oral chemotherapy using S1 following definitive chemoradiotherapy in patients with stage N3 nasopharyngeal carcinoma (N3-NPC). MATERIALS AND METHODS: A retrospective review was performed for N3-NPC treatment with maintenance chemotherapy (MC) [chemoradiotherapy (CRT)-MC] or without MC (CRT-non-MC) following definitive CRT between May 2014 and December 2017. Toxicities during MC were recorded. Overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRRFS) were compared between CRT-MC and CRT-non-MC cohorts. The optimal duration of using maintenance S1 (MC-S1) was also analyzed. RESULTS: A total of 304 patients with stage N3-NPC were identified, of whom 56 were treated with CRT-MC and 248 with CRT-non-MC. After a median follow-up of 48 months, significant differences in OS (74.9 vs. 91.7%; P = 0.003), PFS (60.7 vs. 83.7%; P = 0.001) and DMFS (68.8 vs. 85.5%; P = 0.015) were observed between the CRT-non-MC and CRT-MC groups. Skin hyperpigmentation, leukopenia and fatigue were common but not severe (grade 1-2) side effects of MC. The OS, DMFS and PFS were significantly higher for patients who received S1 administration over a period of ≥12 cycles compared with those who received <12 cycles (3-year OS, 100 vs. 87.5%, P = 0.018; 3-year PFS, 93.9 vs. 67.9%, P = 0.006; 3-year DMFS, 97.1 vs. 67.9%, P = 0.002). CONCLUSIONS: Using MC-S1 in patients with N3-NPC following definitive chemoradiotherapy achieved superior survival rate compared with the patients with non-MC. The side effects of MC-S1 were mild and tolerable. S1 should be maintained for ≥12 cycles.

Identifying the optimal candidates for locoregional radiation therapy in patients with de novo metastatic nasopharyngeal carcinoma.

BACKGROUND: To evaluate the value of locoregional radiation therapy (LRRT) in de novo metastatic nasopharyngeal carcinoma (mNPC) and identify suitable candidates for additional LRRT after palliative chemotherapy (PCT). METHODS: Patients with de novo mNPC received platinum-based chemotherapy for a minimum of four cycles with or without definitive LRRT via intensity-modulated radiation therapy (IMRT) were all candidates for this study. RESULTS: A total of 168 patients were included for this analysis. Additional LRRT was associated with significantly longer median OS (69.5 vs. 17.8 months, p < 0.001) when compared with PCT alone. However, this survival benefit of LRRT was only reflected in patients with oligometastatic diseases (90.8 vs. 17 months, p < 0.001), but not for those with polymetastatic disease (p = 0.86). CONCLUSIONS: Additional LRRT after PCT may only improve OS for oligometastatic patients. For patients with polymetastatic disease, intensive systemic treatment such as the combination of immunotherapy and adequate PCT might be necessary.