Anxiety and depression in nasopharyngeal carcinoma patients and network analysis to identify central symptoms: A cross-sectional study from a high-incidence area.

PURPOSE: To determine the prevalence of anxiety and depression in patients with nasopharyngeal carcinoma (NPC) and to identify central symptoms and bridge symptoms among psychiatric disorders. METHODS: This cross-sectional study recruited patients with NPC in Guangzhou, China from May 2022, to October 2022. The General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) were used for screening anxiety and depression, respectively. Network analysis was conducted to evaluate the centrality and connectivity of the symptoms of anxiety, depression, quality of life (QoL) and insomnia. RESULTS: A total of 2806 respondents with complete GAD-7 and PHQ-9 scores out of 3828 were enrolled. The incidence of anxiety in the whole population was 26.5% (depression, 28.5%; either anxiety or depression, 34.8%). Anxiety was highest at caner diagnosis (34.2%), while depression reached a peak at late-stage radiotherapy (48.5%). Both moderate and severe anxiety and depression were exacerbated during radiotherapy. Coexisting anxiety and depression occurred in 58.3% of those with either anxiety or depression. The generated network showed that anxiety and depression symptoms were closely connected; insomnia was strongly connected with QoL. "Sad mood", "Lack of energy", and "Trouble relaxing" were the most important items in the network. Insomnia was the most significant bridge item that connected symptom groups. CONCLUSION: Patients with NPC are facing alarming disturbances of psychiatric disorders; tailored strategies should be implemented for high-risk patients. Besides, central symptoms (sad mood, lack of energy, and trouble relaxing) and bridge symptoms (insomnia) may be potential interventional targets in future clinical practice.

Effect of Induction Chemotherapy With Paclitaxel, Cisplatin, and Capecitabine vs Cisplatin and Fluorouracil on Failure-Free Survival for Patients With Stage IVA to IVB Nasopharyngeal Carcinoma: A Multicenter Phase 3 Randomized Clinical Trial.

Importance: Induction chemotherapy added to concurrent chemoradiotherapy significantly improves survival for patients with locoregionally advanced nasopharyngeal carcinoma, but the optimal induction regimen remains unclear. Objective: To determine whether induction chemotherapy with paclitaxel, cisplatin, and capecitabine (TPC) improves survival vs cisplatin and fluorouracil (PF) prior to chemoradiotherapy for patients with stage IVA to IVB nasopharyngeal carcinoma. Design, Setting, and Participants: This randomized, open-label, phase 3 clinical trial recruited 238 patients at 4 hospitals in China from October 20, 2016, to August 29, 2019. Patients were 18 to 65 years of age with treatment-naive, nonkeratinizing stage IVA to IVB nasopharyngeal carcinoma and an Eastern Cooperative Oncology Group performance status of 0 to 1. Interventions: Patients were randomly assigned (1:1) to receive induction chemotherapy with two 21-day cycles of TPC (intravenous paclitaxel [150 mg/m2, day 1], intravenous cisplatin [60 mg/m2, day 1], and oral capecitabine [1000 mg/m2 orally twice daily, days 1-14]) or PF (intravenous cisplatin [100 mg/m2, day 1] and fluorouracil [800 mg/m2 daily, days 1-5]), followed by chemoradiotherapy. Main Outcomes and Measures: The primary end point was failure-free survival in the intention-to-treat population. Secondary end points included distant metastasis-free survival, locoregional relapse-free survival, overall survival, tumor response, and safety. Results: Overall, 238 eligible patients (187 men [78.6%]; median age, 45 years [range, 18-65 years]) were randomly assigned to receive TPC (n = 118) or PF (n = 120). The median follow-up duration was 48.4 months (IQR, 39.6-53.3 months). Failure-free survival at 3 years was 83.5% (95% CI, 77.0%-90.6%) in the TPC group and 68.9% (95% CI, 61.1%-77.8%) in the PF group (stratified hazard ratio [HR] for recurrence or death, 0.47; 95% CI, 0.28-0.79; P = .004). Induction with the TPC regimen resulted in a significant reduction in the risk of distant metastases (stratified HR, 0.49 [95% CI, 0.24-0.98]; P = .04) and locoregional recurrence (stratified HR, 0.40 [95% CI, 0.18-0.93]; P = .03) compared with the PF regimen. However, there was no effect on early overall survival (stratified HR, 0.45 [95% CI, 0.17-1.18]; P = .10). The incidences of grade 3 to 4 acute adverse events and late-onset toxicities were 57.6% (n = 68) and 13.6% (16 of 118), respectively, in the TPC group and 65.8% (n = 79) and 17.9% (21 of 117), respectively, in the PF group. One treatment-related death occurred in the PF group. Conclusions and Relevance: This randomized clinical trial found that induction chemotherapy with 2 cycles of TPC for patients with stage IVA to IVB nasopharyngeal carcinoma improved failure-free survival compared with 2 cycles of PF, with no increase in the toxicity profile. Trial Registration: ClinicalTrials.gov Identifier: NCT02940925.

The Optimal Second-Line Systemic Treatment Model for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: A Bayesian Network Meta-Analysis.

Background: The optimal second-line systemic treatment model for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains controversial. A Bayesian network meta-analysis (NMA) was performed to address this issue with regard to efficacy and toxicity. Methods: By searching MEDLINE (via PubMed), Embase, the Cochrane Central Register of Controlled Trials and Web of Science, we extracted eligible studies. Efficacy, represented as overall survival (OS) and progression-free survival (PFS), and overall toxicity, represented as ≥ grade 3 severe acute events (sAE), were assessed to compare the following 7 treatment models through an NMA: standard-of-care therapy (SoC), single targeted therapy different from SoC (ST), double targeted therapy (DT), targeted therapy combined with chemotherapy (T+C), single immune checkpoint inhibitor therapy (SI), double immune checkpoint inhibitor therapy (DI) and single chemotherapy different from SoC (SC). Rank probabilities according to the values of the surface under the cumulative ranking curve (SUCRA) were separately determined for efficacy and toxicity. Results: In total, 5285 patients from 24 eligible studies were ultimately screened, with 5184, 4532 and 4026 involved in the NMA of OS, PFS and sAE, respectively. All qualifying studies were absent from first-line immune checkpoint inhibitor therapy. In terms of OS, SI was superior to the other treatments, followed by DI, ST, T+C, SoC, DT and SC. Other than SI and SC, all treatments tended to be consistent, with hazard ratios (HRs) close to 1 between groups. For PFS, ST ranked first, while DT ranked last. For the toxicity profiles, compared with the other models, SI resulted in the lowest incidences of sAE, with statistical significance over SoC (odds ratio [OR] 0.31, 95% credible interval [CrI] 0.11 to 0.90), ST (OR 0.23, 95% CrI 0.06 to 0.86) and DT (OR 0.11, 95% CrI 0.02 to 0.53), while DT was the worst. When the SUCRA values of OS and sAE were combined, a cluster plot illustrated the superiority of SI, which demonstrated the best OS and tolerability toward sAE. Conclusion: For R/M HNSCC patients without immune checkpoint inhibitors in the first-line setting, SI may serve as the optimal second-line systemic treatment model, demonstrating the best OS and least sAE.

Clinical value of docetaxel plus cisplatin (TP) induction chemotherapy followed by TP concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma.

Objective: To investigate the clinical value of induction chemotherapy (IC) with docetaxel plus cisplatin (TP) followed by concurrent chemoradiotherapy (CCRT) with TP in locoregionally advanced nasopharyngeal carcinoma (NPC). Methods: A total of 544 patients with locoregionally advanced NPC that was newly diagnosed from January 2009 to December 2015 were included in this study. Among these patients, 251 were treated with TP induction chemotherapy followed by CCRT with cisplatin (DDP) alone (TP + DDP group), 167 were treated with TP followed by CCRT with TP (TP + TP group), and 126 were treated with docetaxel, DDP and fluorouracil (TPF) followed by CCRT with DDP alone (TPF + DDP group). Overall survival (OS), distant metastasis-free survival (DMFS), progression-free survival (PFS) and locoregional relapse-free survival (LRRFS) were analyzed using the Kaplan-Meier method and a Cox proportional hazards model. Results: Survival analysis showed that the 5-year OS, PFS and DMFS rates in the TP + DDP group were significantly lower than those in the TP + TP group after propensity score matching (PSM). Multivariate analysis revealed that CCRT with TP was an independent prognostic factor for OS, PFS and DMFS. During CCRT, the incidence rates of grade 3/4 nausea/vomiting, oral mucositis, leukocytopenia and neutropenia were significantly increased in the TP + TP group compared with the TP + DDP group (all P < 0.05). To further explore the value of TP + TP, we performed PSM again with the TPF + DDP group. After PSM, there were 100 patients in each group. Survival analysis showed no significant differences in the 5-year OS, PFS, DMFS and LRRFS rates between the two groups. During IC and CCRT, the rate of grade 3/4 nausea/vomiting in the TPF + DDP group was higher than that in the TP+TP group (9.0% vs. 2.0%, P = 0.030; 18.0% vs. 8.0%, P = 0.036, respectively). No significant difference in the incidence of grade 3/4 hematologic toxicity was found between the two groups (all P > 0.05). Conclusion: TP + TP can reduce the distant metastasis of locoregionally advanced NPC and improve OS compared with TP + DDP; TP + TP has the same effect as TPF + DDP and is clinically feasible.

Clinical value of nedaplatin-based chemotherapy combined with radiotherapy for locoregional advanced nasopharyngeal carcinoma: a retrospective, propensity score-matched analysis.

Aims: This study aimed to investigate the clinical value of induction chemotherapy (IC) with docetaxel, 5-fluorouracil plus nedaplatin followed by concurrent chemoradiotherapy (CCRT) with nedaplatin for locoregional advanced nasopharyngeal carcinoma (NPC). Materials and Methods: In total, 269 patients diagnosed with locoregional advanced NPC between June 2012 and June 2017 were retrospectively included and divided into two groups: IC (docetaxel plus nedaplatin and 5-fluorouracil) followed by nedaplatin-based CCRT (TNF + N group, n = 146) and IC (docetaxel plus cisplatin and 5-fluorouracil) followed by cisplatin-based CCRT (TPF + P group, n = 123). The Kaplan-Meier method and Cox proportional hazards model were applied to analyse survival and prognosis. After propensity score-matched (PSM), 113 patients remained in each group. Toxicities were compared between the two groups using the Chi-square test or Fisher's exact test. Results: The overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) rates of the TNF + N and TPF + P groups were 90.7% vs. 92.3% (P = 0.315), 78.9% vs. 79.4% (P = 0.715), 82.4% vs. 85.1% (P = 0.441) and 96.1% vs. 93.3% (P = 0.414), respectively, with no significant difference in 3-year survival outcome between the two groups, and this outcome was confirmed after using PSM analyses. In the PSM cohort, a significant higher frequency of grade 3/4 vomiting was observed in the TPF + P group compared to the TNF + N group (22.1% vs. 0%, P = 0.000). However, 15.9% of patients in the TNF + N group had grade 3/4 thrombocytopenia in comparison with 6.2% in the TPF + P group (P = 0.020). Conclusions: The TNF regimen followed by CCRT with nedaplatin is an alternative treatment strategy to the standard TPF regimen followed by CCRT with cisplatin for patients with locoregional advanced NPC.

New frontiers in proton therapy: applications in cancers.

Proton therapy offers dominant advantages over photon therapy due to the unique depth-dose characteristics of proton, which can cause a dramatic reduction in normal tissue doses both distal and proximal to the tumor target volume. In turn, this feature may allow dose escalation to the tumor target volume while sparing the tumor-neighboring susceptible organs at risk, which has the potential to reduce treatment toxicity and improve local control rate, quality of life and survival. Some dosimetric studies in various cancers have demonstrated the advantages over photon therapy in dose distributions. Further, it has been observed that proton therapy confers to substantial clinical advantage over photon therapy in head and neck, breast, hepatocellular, and non-small cell lung cancers. As such, proton therapy is regarded as the standard modality of radiotherapy in many pediatric cancers from the technical point of view. However, due to the limited clinical evidence, there have been concerns about the high cost of proton therapy from an economic point of view. Considering the treatment expenses for late radiation-induced toxicities, cost-effective analysis in many studies have shown that proton therapy is the most cost-effective option for brain, head and neck and selected breast cancers. Additional studies are warranted to better unveil the cost-effective values of proton therapy and to develop newer ways for better protection of normal tissues. This review aims at reviewing the recent studies on proton therapy to explore its benefits and cost-effectiveness in cancers. We strongly believe that proton therapy will be a common radiotherapy modality for most types of solid cancers in the future.

microRNA-125b reverses the multidrug resistance of nasopharyngeal carcinoma cells via targeting of Bcl-2.

Multidrug resistance (MDR) is a major clinical obstacle in the successful treatment of patients with metastatic nasopharyngeal carcinoma (NPC). Results from previous studies suggest that microRNAs (miRNA) may be involved in promoting MDR in multiple cancer types. However, the role of miR­125b in modulating the MDR of NPC is elusive. In the present study, miR­125b expression in cisplatin (DDP) ­resistant CNE2 cells (CNE2/DDP) was compared with parental counterparts, using reverse transcription­quantitative polymerase chain reaction. A >3­fold reduction in miR­125b expression levels was observed in CNE2/DDP cells compared with parental CNE2 cells. Ectopic expression of miR­125b by transfecting CNE2/DDP cells with miR-125b mimics, increased DDP­induced cytotoxicity, apoptosis and chemosensitivity. By contrast, suppression of miR-125b by transfecting CNE2 cells with miR­125b inhibitors, reduced DDP­induced cytotoxicity and apoptosis, and facilitated cisplatin resistance. The results suggest that miR­125b may regulate the sensitivity of NPC cells to DDP by modulating the expression levels of antiapoptotic factor B-cell CLL/lymphoma 2. Collectively, the results of the present study highlight miR­125b as a potential therapeutic target for reversing MDR in NPC.

Prognostic value of kisspeptin expression in nasopharyngeal carcinoma.

OBJECTIVES/HYPOTHESIS: The KiSS-1 gene has been reported to serve as a metastasis suppressor gene in various human malignancies. However, no information is available regarding the role of the KiSS-1 gene or its gene product kisspeptin in nasopharyngeal carcinoma. STUDY DESIGN: Retrospective study. METHODS: Kisspeptin and its receptor AXOR12 expression were assessed using immunohistochemistry in paraffin-embedded tumor tissues from 140 patients diagnosed with nasopharyngeal carcinoma. Immunoreactivity was quantified, and its relationships with patients' clinical parameters and survival were analyzed. RESULTS: Using a 50% cutoff level, the immunoreactivities of kisspeptin and AXOR12 were divided into low and high expression. The expression levels of kisspeptin and AXOR12 in nasopharyngeal carcinoma were well correlated with each other (rs = 19.31, P < 0.01). Low expression of kisspeptin in nasopharyngeal carcinoma was correlated with clinical stage (P = 0.01), N stage (P = 0.03), and metastasis (P = 0.02). Patients with low kisspeptin expression had poorer distant metastasis-free survival than those with high kisspeptin expression (75.32% vs. 83.79%, P = 0.02). Although neither kisspeptin nor AXOR12 were found to be prognostic factors for overall survival, kisspeptin was determined to be an independent prognostic factor for distant metastasis-free survival (P = 0.03) using multivariate analysis. CONCLUSION: In this study, we report for the first time that low kisspeptin expression in nasopharyngeal carcinoma is correlated with poor clinical outcome; kisspeptin could serve as an independent prognostic marker for metastasis in nasopharyngeal carcinoma.

Erlotinib: An enhancer of radiation therapy in nasopharyngeal carcinoma.

The aim of this study was to explore the effects of erlotinib combined with radiation on human nasopharyngeal carcinoma (NPC) radiosensitivity using the CNE1 and CNE2 cell lines. Human NPC cells were treated with erlotinib and/or radiation. The effect of erlotinib on the radiosensitivity of the cells was detected using a clonogenic cell survival assay. The rate of apoptosis and the cell cycle were evaluated using flow cytometry. An NPC xenograft model in NOD-SCID mice was used to evaluate the efficacy of the combination therapy of erlotinib with radiation. Erlotinib enhanced the sensitivity of the CNE1 and CNE2 cells to radiation, with sensitization enhancement ratios (SERs) of 1.076 and 1.109, respectively. Erlotinib combined with radiation induced G2/M phase cell cycle arrest in the two cell lines. The mouse tumor model demonstrated a significant reduction in NPC tumor volume in mice treated with erlotinib in combination with radiation when compared with that in mice treated with radiation alone. Erlotinib combined with radiation provoked G2-M phase cell cycle arrest, thereby enhancing the sensitivity of the NPC cells to radiation.

Expression and clinical significance of Wnt-1 and beta-catenin in nasopharyngeal carcinoma.

BACKGROUND AND OBJECTIVE: As signaling molecule and key component of Wnt/beta-catenin signaling pathway respectively, Wnt-1 and beta-catenin are abnormally expressed in several malignancies and correlate with poor prognosis. This study was to investigate the expression and clinical significance of Wnt-1 and beta-catenin in nasopharyngeal carcinoma (NPC). METHODS: The expression of Wnt-1 and beta-catenin in 111 specimens of NPC was detected by SP immunohistochemistry. Their correlations to relapse-free survival (RFS), metastasis-free survival (MFS) and progression-free survival (PFS) were analyzed. RESULTS: The high expression of beta-catenin was observed in 64 (57.7%) of the 111 cases. Its high expression rate was significantly higher in advanced NPC than in early stage NPC (63.1% vs. 40.7%, p = 0.041). The RFS, MFS and PFS were lower in high beta-catenin expression group than in low beta-catenin expression group (p < 0.05). Cox regression analysis demonstrated that beta-catenin was related to poor prognosis of NPC patients. The high expression of Wnt-1 was observed in 68 (61.3%) of the 111 cases, but its expression had no effect on RFS, MFS and PFS (p > 0.05). CONCLUSIONS: Wnt/beta-catenin signaling pathway may be activated abnormally in some NPC patients. beta-catenin may be a prognostic factor of NPC.

[Occurrence and influencing factors of paranasal sinusitis in nasopharyngeal carcinoma patients after radiotherapy].

BACKGROUND & OBJECTIVE: Radiation usually results in paranasal sinusitis in nasopharyngeal carcinoma (NPC) patients, which influences patients' quality of life. This study was to explore the occurrence and influencing factors of paranasal sinusitis in NPC patients before and after radiotherapy. METHODS: Clinical data of 381 NPC patients, treated in Cancer Center of Sun Yat-sen University from Jan. 1998 to Jul. 2000, were reviewed. CT images before and after radiotherapy were compared. The occurrence and influencing factors of paranasal sinusitis were analyzed. RESULTS: Of the 381 NPC patients, 176 (46.2%) suffered from paranasal sinusitis before radiotherapy. Among the 205 NPC patients without paranasal sinusitis before radiotherapy, 103 (50.2%) developed paranasal sinusitis after radiotherapy; the occurrence rates of paranasal sinusitis at 1 month, 3 months, 6 months, and 1 year after radiotherapy were 21.0%, 33.7%, 41.5% and 29.3%, respectively (Chi(2)=20.92, P<0.001). Logistic analysis showed that T stage was related to the occurrence rate of paranasal sinusitis. CONCLUSION: The incidence of paranasal sinusitis in NPC patients after radiotherapy is high and related to T stage.

[Correlation of epidermal growth factor receptor activation to metastasis-free survival of nasopharyngeal carcinoma patients].

BACKGROUND & OBJECTIVE: Epidermal growth factor receptor (EGFR) is overexpressed in many tumors, and is correlated to poor prognosis. However, the prognostic value of EGFR expression in nasopharyngeal carcinoma (NPC) is controversial. This study was to investigate the expression of EGFR and its phosphorylated form (pEGFR) in NPC, and explore their correlations to the prognosis. METHODS: NPC samples were obtained from 110 NPC patients treated at Cancer Center of Sun Yat-sen University from Jan. 1999 to Dec. 1999. The expression of EGFR and pEGFR in 110 specimens of NPC and 20 specimens of normal nasopharyngeal tissues were detected by immunohistochemistry. The correlations of EGFR and pEGFR expression to clinical characteristics and prognosis of NPC were analyzed by univariate and multivariate analyses. RESULTS: The positive rates of EGFR and pEGFR were significantly higher in NPC than in normal tissues (100% vs. 10.0%, 60.0% vs. 15.0%, both P<0.001). High expression rate of EGFR was significantly higher in stage T3-4 tumors than in stage T1-2 tumors (63.6% vs. 43.2%, P=0.034), but it had no relationship with other clinical parameters. The 5-year metastasis-free survival rate was significantly lower in the patients with high pEGFR expression than in those with low pEGFR expression (72.2% vs. 91.0%, P=0.012). However, multivariate analysis revealed that pEGFR expression was not an independent prognostic factor for metastasis-free survival of NPC patients. CONCLUSION: Phosphorylation of EGFR is related with metastasis-free survival of NPC patients, suggesting an important role of activation of EGFR in the dissemination of NPC.