Tumor cell-derived exosomal miR-193b-3p promotes tumor-associated macrophage activation to facilitate nasopharyngeal cancer cell invasion and radioresistances.

Background: Communication between cancer cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) plays a crucial role in accelerating nasopharyngeal cancer (NPC) metastasis and radioresistance. However, the mechanisms through which NPC cells regulate the properties and activation of TAMs during NPC progression are not yet fully understood. Methods: A high-metastatic NPC subclone (HMC) and a low-metastatic NPC subclone (LMC) were screened from the CNE-2 cell line and exosomes were collected from HMCs and LMCs, respectively. The effects of HMC- and LMC-derived exosomes (HMC-Exos and LMC-Exos) on the regulation of TAM activation were evaluated by assessing the levels of inflammation-related or immunosuppression-related genes. The role of miRNA-193b-3p (miR-193b) in mediating communication between NPCs and TAMs was assessed using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot analysis, Transwell assays, and clonogenic survival assays. Results: HMCs and HMC-Exos exhibited a greater capacity to facilitate macrophage protumorigenic activation than LMCs and LMC-Exos. miR-193b levels derived from HMC-Exos were higher than those from LMC-Exos, and miR-193b levels were higher in metastatic NPC tissue-derived TAMs than in non-metastatic NPC tissue-derived TAMs. The upregulated miR-193b was packaged into exosomes and transferred to macrophages. Functionally, miR-193b up-regulation accelerated TAM activation by directly targeting mitogen-activated protein/ERK kinase kinase 3 (MEKK3). As a result, miR-193b-overexpressed macrophages facilitated NPC cell invasion and radioresistance. Conclusions: These data revealed a critical role for exosomal miR-193b in mediating intercellular communication between NPC cells and macrophages, providing a potential target for NPC treatment.

Survival outcomes and toxicity profiles among patients with nonmetastatic nasopharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT) versus IMRT + carbon-ion radiotherapy: A propensity score-matched analysis.

OBJECTIVES: To compare survival outcomes and toxic effects among patients with newly diagnosed nonmetastatic nasopharyngeal carcinoma (NPC) when treated with intensity-modulated radiotherapy (IMRT) versus IMRT + carbon-ion radiotherapy (CIRT). METHODS: We performed a retrospective propensity score matching analysis (1:1) of patients treated with IMRT and IMRT + CIRT. Descriptive statistics were used to examine the baseline characteristics of the patients. Survival was estimated using the Kaplan-Meier method. Univariate and multivariable logistic regression analysis were used to identify the independent predictors of survival. We examined the association between risk factors and adverse events (AEs) using chi-square tests. Cox model and logistic regression were used to analyze AEs. RESULTS: Hundred and nine patients who received IMRT + CIRT were included and the median follow-up time was 20.6 months (range: 4.6-82 months). There were no statistically significant differences in locoregional failure-free survival, distant metastasis-free survival, disease-free survival, or overall survival between the two groups, but potentially better in IMRT + CIRT group (p > 0.05, respectively). Nodal boost was the only significant factor associated with LRFS and DFS on multivariable analysis. Thirty-seven patients (34.0%) developed grade 3 acute OMs and no grade 4 acute OMs were observed in IMRT + CIRT group. All patients in IMRT + CIRT group developed grade 1 dermatitis; while in the match group, 76 patients developed grade 1 dermatitis, 27 patients developed grade 2 dermatitis, 5 patients developed grade 3 dermatitis, 1 patient developed grade 4 dermatitis. IMRT + CIRT treatment was associated with a significant trend of lower grades of OM and dermatitis (p < 0.05, respectively). Any severe (i.e., grade 3) chronic AEs, such as xerostomia, skin fibrosis, temporal lobe necrosis, osteoradionecrosis, or radiation-induced optic neuropathy, was not observed. CONCLUSIONS: In this study, IMRT + CIRT was associated with significantly reduced acute toxicity burden compared with full course of IMRT, with excellent survival outcomes. Patients with persistent disease after treatment and treated with nodal boost had a worse outcome. More accurate assessments of IMRT + CIRT to primary nonmetastatic NPC patients will be imperative.

PICK1 inhibits the malignancy of nasopharyngeal carcinoma and serves as a novel prognostic marker.

Although many important advances have been made in the treatment of nasopharyngeal carcinoma (NPC) in recent years, local recurrence and distant metastasis remain the main factors affecting NPC prognosis. Biomarkers for predicting the prognosis of NPC need to be urgently identified. Here, we used whole-exon sequencing (WES) to determine whether PICK1 mutations are associated with the prognosis of NPC. Functionally, PICK1 inhibits the proliferation and metastasis of NPC cells both in vivo and in vitro. Mechanistically, PICK1 inhibited the expression of proteins related to the Wnt/ß-catenin signaling pathway. PICK1 restrained the nuclear accumulation of ß-catenin and accelerated the degradation of ß-catenin through the ubiquitin-proteasome pathway. The reduced PICK1 levels were significantly associated with poor patient prognosis. Hence, our study findings reveal the mechanism by which PICK1 inactivates the Wnt/ß-catenin signaling pathway, thereby inhibiting the progression of NPC. They support PICK1 as a potential tumor suppressor and prognostic marker for NPC.

Deletion of concurrent chemotherapy on the basis of sequential chemoradiotherapy for non-metastatic stage T4 nasopharyngeal carcinoma in IMRT era.

PURPOSE: Intensity-modulated radiotherapy (IMRT) combined with concurrent chemotherapy is deemed as the mainstay treatment in locoregionally advanced nasopharyngeal carcinoma (NPC). Nevertheless, the tolerance of severe acute toxicity of concurrent chemotherapy was unsatisfied. In addition, T4 is the predicting factor of poor prognosis for NPC patients. In this retrospective analysis, the long-term outcomes IMRT combined by induction chemotherapy deleting concurrent chemotherapy with or without adjuvant chemotherapy for T4 non-metastatic NPC were analyzed. MATERIALS AND METHODS: From January 2005 to November 2016, a total of 145 biopsy-proven non-metastatic T4 NPC was treated with IMRT combined by induction chemotherapy with or without adjuvant chemotherapy. The survival and side effects of the patients were analyzed. RESULTS: Median follow-up time was 74 months (ranges, 8-186 months). 10.0%, 61.3%, 27.3%, and 1.3% developed grade 1, 2, 3, and 4 mucositis during IMRT, respectively. 5.5% and 2.0% patients experienced grade 1 and 2 nausea and vomiting; no patients developed grade 3 or 4 nausea and vomiting. Of 145 patients enrolled, 5-year and 10-year overall survival(OS) rates were 73.7% and 53.9%, local progression-free survival(LPFS) rates were 86.1% and 71.6%, regional progression-free survival(RPFS) rates were 96.7% and 92.8%, distant metastasis-free survival (DMFS) rates were 86.7%, 78.2%, respectively. At the last follow-up, five patients developed cranial nerve injury, one patient developed mandibular bone necrosis, four patients developed temporal lobe injury, four patients developed nasopharyngeal massive hemorrhage (three cases after recurrence and one case without recurrence), and five patients developed second primary tumor. CONCLUSION: The survival outcomes of treating T4 NPC IMRT combined by induction chemotherapy deleting concurrent chemotherapy with or without adjuvant chemotherapy are encouraging. Moreover, mucosal reaction, nausea, and vomiting reaction were reduced during IMRT.

Prognostic value of lymph node-to-primary tumor ratio of PET standardized uptake value for nasopharyngeal carcinoma: a recursive partitioning risk stratification analysis.

Background: Induction chemotherapy (IC) combined with concurrent chemoradiotherapy has become the standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Data on the prognostic value of the lymph node-to-primary tumor ratio (NTR) of positron emission tomography (PET) standardized uptake value (SUV) for patients treated with IC were limited. Objectives: To evaluate the prognostic value of the SUV NTR for patients with LA-NPC treated with IC. Design: In all, 467 patients with pretreatment 18F-fluorodeoxyglucose PET/computed tomography (CT) scans between September 2017 and November 2020 were retrospectively reviewed. Methods: The receiver operating characteristic (ROC) analysis was used to determine the optimal cut-off value of SUV NTR. Kaplan-Meier method was used to evaluate survival rates. The recursive partitioning analysis (RPA) was performed to construct a risk stratification model. Results: The optimal cutoff value of SUV NTR was 0.74. Multivariate analyses showed that SUV NTR and overall stage were independent predictors for distant metastasis-free survival (DMFS) and regional recurrent-free survival (RRFS). Therefore, an RPA model based on the endpoint of DMFS was generated and categorized the patients into three distinct risk groups: RPA I (low risk: SUV NTR < 0.74 and stage III), RPA II (medium risk: SUV NTR < 0.74 and stage IVa, or SUV NTR ⩾ 0.74 and stage III), and RPA III (high risk: SUV NTR ⩾ 0.74 and stage IVa), with a 3-year DMFS of 98.9%, 93.4%, and 84.2%, respectively. ROC analysis showed that the RPA model had superior predictive efficacy than the SUV NTR or overall stage alone. Conclusion: SUV NTR was an independent prognosticator for distant metastasis and regional recurrence in locoregionally advanced NPC. The RPA risk stratification model based on SUV NTR provides improved DMFS and RRFS prediction over the eighth edition of the TNM (Tumor Node Metastasis) staging system.

Optimizing Cervical Target Volume in Patients with Nasopharyngeal Cancer Based On Nodal Drainage Distance.

PURPOSE: To determine the potential nodal drainage distances of nasopharyngeal carcinoma (NPC) by investigating spatial distribution of metastatic lymph nodes (LN). EXPERIMENTAL DESIGN: Patients with NPC harboring at least two ipsilateral metastatic LNs were enrolled. LN spreading distances were analyzed in nonrestricted direction, cranial-to-caudal direction, and between the two most caudal LNs. Euclidean distance (ED) and vertical distance (VD) between any two LNs were computed. The nearest-neighbor ED and VD covering 95% of LNs or patients (p95-ED and p95-VD) were considered drainage distances, and were further validated by independent internal and external cohorts with recurrent LNs. RESULTS: In all, 5,836 metastatic LNs in 948 patients were contoured. Corresponding to the three scenarios, per-LN level, the p95-EDs were 2.83, 3.28, and 3.55 cm, and p95-VDs were 2.17, 2.32, and 2.63 cm, respectively. Per-patient level, the p95-EDs were 3.25, 3.95, and 3.81 cm, and p95-VDs were 2.67, 2.81, and 2.73 cm, respectively. In internal validation, over 95% of recurred LNs occurred within ED of 2.91 cm and VD of 0.82 cm to the neighbor LN, and the corresponding distances in external validation were 2.77 and 0.67 cm, respectively. CONCLUSIONS: In NPC, the maximum LN drainage distance was 3.95 cm without considering the direction. Specifically, in cranial-to-caudal direction, the sufficient vertical drainage distance was 2.81 cm, indicating that a 3-cm extension from the most inferior node may be rational as caudal border of the prophylactic clinical target volume (CTV). These findings promote in-depth understanding of nodal spreading patterns, uncovering paramount evidence for individualized CTV.

Effects of Marital Status on Hypopharynx Squamous Cell Carcinoma Survival Stratified by Demographic and Pathological Factors: A Retrospective Study.

Objectives: Understanding the interaction between marital status and gender, race, and age is important for developing tailored interventions aimed at improving socio-emotional support for patients. Therefore, the objective of this study is to explore the correlation between marital status and hypopharynx squamous cell carcinoma (SCC) and whether the association varied by age, race, and gender. Methods: We examined the clinicopathological variables using chi-squared tests and we evaluated the association between survival and different variables using the methods of Kaplan-Meier. Univariate and multivariate analyses were performed to determine the effects of each variable on survival. Results: A total of 1686 patients were analyzed. The rate of being married was lower among African American, and this rate decreased with higher tumor stage. While both married male and female survivors benefit from their marital status, subgroups analysis shows a differential in overall survival (OS) based on gender, with males benefiting more than females. Patients who were divorced/separated [male hazard ratio (HR) = 1.214, 95% confidence interval (CI): 0.985-1.495; female HR = 1. 159, 95% CI: 0.691-1.945], never married (male HR = 1.476, 95% CI: 1.234-1.765; female HR = 1.422, 95% CI: 0.901-2.245), and widowed (male HR = 1.795, 95% CI: 1.390-2.317; female HR = 1.663, 95% CI: 1.081-2.559) had increased hazard of OS compared with married/partnered patients. The effect of marital status was significantly associated with treatment outcome only in Caucasian patients who harbored well/moderately differentiated and nonmetastatic disease (P < .001). Conclusion: While there are survival benefits for married patients with hypopharynx SCC, married/partnered males may benefit more than females. Age, race, and gender could affect the correlation between marital status and survival.

Induction Toripalimab and Chemotherapy for Organ Preservation in Locally Advanced Laryngeal and Hypopharyngeal Cancer: A Single-Arm Phase II Clinical Trial.

PURPOSE: The aim of this study was to assess the efficacy, toxicities, and potential role of larynx preservation of induction chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitor in locally advanced laryngeal and hypopharyngeal cancer. PATIENTS AND METHODS: This is a single-arm phase II study. Patients with histopathologically confirmed, resectable locally advanced laryngeal/hypopharyngeal squamous cell carcinoma and Eastern Cooperative Oncology Group Performance Status 0-1 were eligible. Three cycles of induction chemotherapy (paclitaxel 175 mg/m2 d1, cisplatin 25 mg/m2 d1-3) combined with PD-1 inhibitor (toripalimab 240 mg d0) were administered. Response assessment was performed after induction chemoimmunotherapy using RECIST 1.1 criteria. Patients with a complete/partial response of the primary tumor received concurrent chemoradiation, followed by maintenance therapy of toripalimab. Otherwise, patients were referred to surgery, followed by adjuvant (chemo) radiation and maintenance therapy of toripalimab. The primary endpoint is a larynx preservation rate at 3 months postradiation. RESULTS: Twenty-seven patients were enrolled. Most cases exhibited stage IV disease (81.5%), with T4 representing 37.0%. Five patients underwent pretreatment tracheostomy because of impaired larynx function. Overall response rate of induction chemoimmunotherapy was 85.2%. At 3 months postradiation, the larynx preservation rate was 88.9%. With a median follow-up of 18.7 months, the 1-year overall survival rate, progression-free survival rate, and larynx preservation rate were 84.7%, 77.6%, and 88.7%, respectively. When excluding those with pretreatment tracheostomy, the 1-year larynx preservation rate was 95.5%. Exploratory analysis revealed that relapse correlated with enrichment of RNA signature of hypoxia and M2 macrophage-associated genes. CONCLUSIONS: Induction toripalimab combined with chemotherapy provided encouraging activity, promising larynx preservation rate and acceptable toxicity in this cohort of extensively locally advanced laryngeal and hypopharyngeal cancer.

Radiation-induced nasopharyngeal ulcers after re-irradiation with intensity-modulated radiotherapy in locoregional recurrent nasopharyngeal carcinoma patients: a dose-volume-outcome analysis.

OBJECTIVE: To analyze the interrelation between radiation dose and radiation-induced nasopharyngeal ulcer (RINU) in locoregional recurrent nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). METHODS: Clinical data were collected from 363 patients with locoregional recurrent NPC who received re-irradiated with definitive IMRT from 2009 to 2017. Twenty-nine patients were diagnosed with RINU. Univariate and multivariate analyses were used to re-evaluate the first and second radiotherapy plans and to identify predictive dosimetric factors. RESULTS: All dosimetric parameters were notably associated with the progression to RINU (p < 0.01) using paired samples Wilcoxon signed rank tests. Multivariate analysis showed that EQD2_ [Formula: see text]D80 (dose for 80 percent volume of the unilateral nasopharynx lesion) was an independent prognostic factor for RINU (p = 0.001). The area under the ROC curve for EQD2_ [Formula: see text]D80 was 0.846 (p < 0.001), and the cutoff point of 137.035 Gy could potentially be the dose tolerance of the nasopharyngeal mucosa. CONCLUSIONS: The sum of equivalent dose in 2 Gy fractions (EQD2) in the overlapping volumes between initial and re-irradiated nasopharyngeal mucosal tissue can be effective in predicting the hazard of developing RINU in NPC patients undergoing radical re­irradiation with IMRT and we propose a EQD2_ [Formula: see text]D80 threshold of 137.035 Gy for the nasopharynx.

Radiomic signatures reveal multiscale intratumor heterogeneity associated with tissue tolerance and survival in re-irradiated nasopharyngeal carcinoma: a multicenter study.

BACKGROUND: Post-radiation nasopharyngeal necrosis (PRNN) is a severe adverse event following re-radiotherapy for patients with locally recurrent nasopharyngeal carcinoma (LRNPC) and associated with decreased survival. Biological heterogeneity in recurrent tumors contributes to the different risks of PRNN. Radiomics can be used to mine high-throughput non-invasive image features to predict clinical outcomes and capture underlying biological functions. We aimed to develop a radiogenomic signature for the pre-treatment prediction of PRNN to guide re-radiotherapy in patients with LRNPC. METHODS: This multicenter study included 761 re-irradiated patients with LRNPC at four centers in NPC endemic area and divided them into training, internal validation, and external validation cohorts. We built a machine learning (random forest) radiomic signature based on the pre-treatment multiparametric magnetic resonance images for predicting PRNN following re-radiotherapy. We comprehensively assessed the performance of the radiomic signature. Transcriptomic sequencing and gene set enrichment analyses were conducted to identify the associated biological processes. RESULTS: The radiomic signature showed discrimination of 1-year PRNN in the training, internal validation, and external validation cohorts (area under the curve (AUC) 0.713-0.756). Stratified by a cutoff score of 0.735, patients with high-risk signature had higher incidences of PRNN than patients with low-risk signature (1-year PRNN rates 42.2-62.5% vs. 16.3-18.8%, P < 0.001). The signature significantly outperformed the clinical model (P < 0.05) and was generalizable across different centers, imaging parameters, and patient subgroups. The radiomic signature had prognostic value concerning its correlation with PRNN-related deaths (hazard ratio (HR) 3.07-6.75, P < 0.001) and all causes of deaths (HR 1.53-2.30, P < 0.01). Radiogenomics analyses revealed associations between the radiomic signature and signaling pathways involved in tissue fibrosis and vascularity. CONCLUSIONS: We present a radiomic signature for the individualized risk assessment of PRNN following re-radiotherapy, which may serve as a noninvasive radio-biomarker of radiation injury-associated processes and a useful clinical tool to personalize treatment recommendations for patients with LANPC.

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.

Risk Factors for Synchronous Lung Metastasis in Squamous Cell Carcinoma of Hypopharynx.

Background: The objective of this study is to assess the risk factors for synchronous lung metastases (LM) in patients with hypopharynx squamous cell carcinomas (HPSCC). Methods: HPSCC patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2013. We examined the association between risk factors and synchronous LM using chi-squared tests. Predictors of survival rates were assessed using univariate and multivariate analyses. Results: A total of 1683 patients were analyzed, including 70 patients (4.2%) with synchronous LM, and 1613 patients without synchronous LM (95.8%). Multivariate logistic regression analysis showed that Caucasian (P = .038), lower T (P = .026) or N classification (P = .000), and highly differentiated disease (P = .002) were associated with a significantly lower risk of LM. Elderly not married patients with higher T or N classification, multiple sites of metastases, and no surgical therapy to the primary tumors were more likely to reduce life expectancy. Conclusion: By analyzing data from a large cohort, Caucasian, lower T or N classification, and highly differentiated disease were associated with a significantly lower risk of LM. Elderly not married patients with advanced T or N classification, no surgical therapy to the primary tumors, and multiple sites of metastases were more likely to reduce life expectancy. More accurate assessments of LM will be imperative for early diagnosis and treatment in non-Caucasian patients who harbored higher T or N classification and poorly differentiated disease.

Is radical radiotherapy with/without surgery an effective treatment in the lymphoepithelial carcinoma of the salivary gland？.

BACKGROUND: There is limited information of radical radiotherapy (RT) on lymphoepithelial carcinoma of salivary gland (LECSG) regarding to the rarity of the disease. We conducted this retrospective study that evaluated the feasibility and efficacy of radical RT with/without surgery in LECSG. METHODS: We retrospectively reviewed patients that were pathologically diagnosed of LECSG and had definite or suspicious residual disease. The prescribed dose given to P-GTV and/or P-GTV-LN was 66 to 70.4 Gy. The clinical target volume (CTV) involved ipsilateral salivary gland and corresponding lymph node drainage area. RESULTS: A total of 56 patients were included. With a median follow-up of 60 months (range: 8 to 151 months), the 1-, 5-, and 10-year progression-free survival (PFS) rates were 94.6%, 84.7% and 84.7%; locoregional progression-free survival (LRPFS) rates were 98.2%, 87.4% and 87.4%; distance metastasis-free survival (DMFS) rates were 94.6%, 86.7% and 86.7%; and overall survival (OS) rates were 98.2%, 92.4% and 89.0%, respectively. A total of 7 patients without surgery were included. All patients were alive and only one patient experienced failure of distant metastasis four months after RT. The results of univariate analysis showed that compared with N stage, the number of positive lymph nodes (2 positive lymph nodes) was better prognostic predictor especially in PFS. There were no treatment-related deaths and most toxicities of RT were mild. CONCLUSIONS: Radical RT with/without surgery in LECSG for definite or suspicious residual disease is feasibility and efficacy. Most toxicities of RT were mild due to the target volume involved ipsilateral area.

Induction chemotherapy plus re-irradiation versus re-irradiation alone in locally recurrent nasopharyngeal carcinoma: A model-based analysis.

OBJECTIVE: To investigate the role of additional induction chemotherapy (IC) prior to re-irradiation in locally recurrent nasopharyngeal carcinoma (lrNPC). METHODS: A total of 480 patients from three cancer treatment centers who received re-irradiation between 2012 and 2020 were retrospectively analyzed. Overall survival (OS) was determined using the Kaplan-Meier method and compared with log-rank method. Inverse probability of treatment weighting (IPTW) was performed to match the patients in pairwise treatment groups. Multivariate analysis using the Cox proportional hazards regression method identified predictors of OS. The risk stratification model was defined by the risk score calculated with the sum of coefficients. RESULTS: In the entire cohort, the addition of IC was associated with similar OS compared with radiotherapy alone (P = 0.58) or with concomitant chemoradiation (P = 0.76). A risk stratification model was constructed and validated based on significant prognostic factors (coefficient) including male (0.6), age ≥ 60 years (0.9), volume of recurrence gross tumor volume ≥ 16 cc (0.7), and lactate dehydrogenase (LDH)-ratio ≥ 0.5 (0.4). In the intermediate-risk group (sum of coefficient: 0.9---1.6), patients with IC plus re-irradiation had a significantly better OS than those who received re-irradiation (P = 0.03). After adjustments for several potentially confounding variables with IPTW, survival benefit of IC was also observed (P = 0.031). However, no significant difference in OS for the additional IC prior to re-irradiation was demonstrated in the low- (sum of coefficient: <0.9) and high-risk group (sum of coefficient: > 1.6). CONCLUSION: Additional IC prior to re-irradiation was associated with improved OS in the intermediate-risk group of lrNPC, whereas there was no difference for the low-risk and high-risk group. Prospective validation is required to validate these findings.

Early Death Incidence and Prediction Among Patients With Hypopharynx Squamous Cell Carcinomas.

Background: The objective of this study is to evaluate the incidence and associated factors for early death (ED) in hypopharynx squamous cell carcinomas (SCC) patients. Materials and Methods: Patients were extracted from the Surveillance, Epidemiology and End Results database between 2004 and 2014. The ED (survival time ≤3 months) rate was calculated, and associated risk factors were evaluated by the logistic regression models. Results: A total of 2659 patients were analyzed and 307 (11.5%) patients died within 3 months after cancer diagnosis, among whom 243 (79.2%) patients died from cancer-specific cause. In univariate analyses, advanced age, divorced/single/widowed (DSW), non-Caucasian, advanced T classification, distant metastasis, and no surgery were significantly associated with ED (P < .05, respectively). Multivariate analyses showed that advanced age, DSW, advanced T classification, distant metastasis, and no surgery were significantly associated with all-cause and cancer-specific ED. Conclusion: Our results showed that a total of 11.5% patients with hypopharynx SCC suffered ED, among whom 79.2% patients died from cancer-specific cause. Predictors of ED are primarily related to age ≥62 years, advanced T classification, distant metastasis, and no surgery but also include unmarried status; better prognostic and predictive tools for select ED patients in larger sample size are needed.

Impact of Age, Race, and Gender on the Association Between Marital Status and Treatment Outcomes in Oral Tongue Squamous Cell Carcinomas.

Background: The objective of this study is to assess whether the impact of marital status on oral tongue squamous cell carcinomas (OTSCC) prognosis varied by gender, age, and race. Methods: We examined the clinicopathological variables using chi-squared tests, and we evaluated the association between survival and different variables using the methods of Kaplan-Meier. Univariate and multivariate analyses were performed to determine the effects of each variable on survival. Results: A total of 5282 patients were analyzed. The rate of being married was higher among Asian or Caucasian, and this rate decreased with higher tumor stage. While both married male and female survivors benefit from their marital status, we found a differential in OS based on gender, with females benefiting more than males (male P = .038; female P = .009, respectively). Patients who were divorced/separated/widowed (male HR = 1.275, 95% CI: 1.085-1.499; female HR = 1.313, 95% CI: 1.083-1.593) and never married (male HR = 1.164, 95% CI: 0.983-1.378; female HR = 1.224, 95% CI: 0.958-1.565) had increased hazard of OS compared with married/partnered patients (male P = .038; female P = .009). Subgroups analysis shows that the effect of marital status was significantly associated with treatment outcome only in Caucasian patients aged 50 years or older who harbored non-metastatic disease and received surgery (P < .001). Conclusion: While there are survival benefits for married patients with OTSCC, married/partnered females may benefit more than males. Age, race, and gender could affect the correlation between marital status and survival.

Prognostic nomograms for nasopharyngeal carcinoma with nodal features and potential indication for N staging system: Validation and comparison of seven N stage schemes.

PURPOSE: To identify the prognostic value of the nodal features, propose a nomogram-based N stage system and evaluate the performance of seven N stage schemes of nasopharyngeal carcinoma (NPC) patients. METHODS: Data from 1638 non-distant metastatic NPC patients were used to develop nomograms predicting 3-year and 5-year overall survival (OS) and distant metastasis-free survival (DMFS). Based on nomogram and multivariate analyses, a new N-stage scheme was proposed. The performance of the nomogram-based N staging system was assessed against five newly proposed N staging systems and the current 8th N staging system using a quantitative model to compare hazard consistency, discrimination, outcome prediction, and sample size balance. The Kaplan-Meier method with log-rank tests was used to compare survival differences. RESULTS: Nomograms to predict OS and DMFS were constructed using extranodal extension infiltrating the surrounding structures (ENEmax), maximal axial diameter (MAD), large retropharyngeal lymph nodes (RLN, minimal axial diameter > 1.5 cm), multiple central nodal necrosis (CNN), and total lymph node (LN) number and level. Multivariate analysis showed the independent prognostic value of ENEmax and MAD > 3 cm for all selected survival endpoints (p < 0.05). Large RLN and lower neck involvement were independently associated with OS (p < 0.05). We proposed using a large RLN and MAD > 3 cm as N2 factors, and ENEmax and lower neck involvement as N3 factors. Among the seven N-stage schemes, our nomogram-based N scheme and ENEmax to N3 scheme (ENE3) ranked in the top two in the overall comparison with the elevated outcome predicting value (highest c-index). However, between the N0, N1, N1, and N2 subgroups, the ENE3 scheme showed no difference in OS or DMFS (p > 0.05). CONCLUSION: The predictive model highlighted the independent prognostic value of ENEmax, cervical lymph node, MAD, and large RLN, which can be used as criteria for future N staging.

Detection of the high-risk factors for synchronous bone metastasis in tonsillar squamous cell carcinoma.

BACKGROUND: To analyze the risk factors for synchronous bone metastases (BM) in patients with tonsillar squamous cell carcinomas. METHODS: Tonsillar carcinomas patients were extracted from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2013. We examined the association between risk factors and synchronous BM using Chi-squared tests. Predictors of survival rates were assessed using univariate and multivariate analyses. RESULTS: A total of 5752 patients were analyzed, which including 35 patients (0.6%) with synchronous BM, and 5717 patients without synchronous BM (99.4%). Multivariate logistic regression analysis showed that Caucasian, lower T or N classification were associated with a significantly lower risk of BM (P < 0.05, respectively). Elderly not married non-Caucasian patients with highly differentiated disease, higher T or N classification, multiple sites of metastases and no surgical therapy to primary tumor were more likely to reduce life expectancy. CONCLUSIONS: By analyzing data from a large cohort, Caucasian, lower T or N classification were associated with a significantly lower risk of BM. Elderly not married non-Caucasian patients with highly differentiated disease, higher T or N classification, multiple sites of metastases and no surgical therapy to primary tumor were more likely to reduce life expectancy. More accurate assessments of BM will be imperative for early diagnosis and treatment in non-Caucasian tonsillar carcinoma patients who harbored with higher T or N classification.

Prognostic value of circulating Epstein-Barr virus DNA level post-induction chemotherapy for patients with nasopharyngeal carcinoma: A recursive partitioning risk stratification analysis.

BACKGROUND: To evaluate the prognostic value of plasma Epstein-Barr virus (EBV) DNA level post-induction chemotherapy (IC) for patients with nasopharyngeal carcinoma (NPC). METHODS: A total of 893 newly diagnosed NPC patients treated with IC were retrospectively reviewed. The recursive partitioning analysis (RPA) was performed to construct a risk stratification model. The receiver operating characteristic (ROC) analysis was applied to determine the optimal cut-off value of post-IC EBV DNA. RESULTS: Post-IC EBV DNA levels and overall stage were independent predictors for distant metastasis-free survival (DMFS), overall survival (OS), and progression-free survival (PFS). The RPA model base on post-IC EBV DNA and overall stage categorized the patients into three distinct risk groups: RPA I (low-risk: stage II-III and post-IC EBV DNA < 200 copies/mL), RPA II (median-risk: stage II-III and post-IC EBV DNA ≥ 200 copies/mL, or stage IVA and post-IC EBV DNA < 200 copies/mL), and RPA III (high-risk: stage IVA and post-IC EBV DNA ≥ 200 copies/mL), with 3-year PFS of 91.1%, 82.6%, and 60.2%, respectively (p < 0.001). The DMFS and OS rates in different RPA groups were also distinct. The RPA model showed better risk discrimination than either the overall stage or post-RT EBV DNA alone. CONCLUSIONS: Plasma EBV DNA level post-IC was a robust prognostic biomarker for NPC. We developed an RPA model that provides improved risk discrimination over the 8th edition of the TNM staging system by integrating the post-IC EBV DNA level and the overall stage.

Tislelizumab plus chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal cancer: A multicenter phase 3 trial (RATIONALE-309).

Checkpoint inhibitors are effective in recurrent/metastatic nasopharyngeal cancer (R/M NPC). RATIONALE-309 (NCT03924986) randomized 263 treatment-naive R/M NPC patients to tislelizumab or placebo every 3 weeks (Q3W), plus chemotherapy (Q3W for 4-6 cycles). At interim analysis, progression-free survival (PFS) was significantly longer with tislelizumab-chemotherapy versus placebo-chemotherapy (hazard ratio: 0.52; 95% confidence interval: 0.38, 0.73; p < 0.0001). PFS benefit for tislelizumab-chemotherapy versus placebo-chemotherapy was observed regardless of programmed death-ligand 1 expression. PFS after next line of treatment and overall survival showed favorable trends for tislelizumab-chemotherapy versus placebo-chemotherapy. The safety profile was similar between arms. Gene expression profiling (GEP) identified immunologically "hot" tumors, and showed an activated dendritic cell (DC) signature was associated with tislelizumab-chemotherapy PFS benefit. Our results support that tislelizumab-chemotherapy should be considered as first-line treatment for R/M NPC, and GEP and activated DC signature results may help identify patients who might benefit most from immunochemotherapy treatment. VIDEO ABSTRACT.