Tracking the evolution of esophageal squamous cell carcinoma under dynamic immune selection by multi-omics sequencing.

Intratumoral heterogeneity (ITH) has been linked to decreased efficacy of clinical treatments. However, although genomic ITH has been characterized in genetic, transcriptomic and epigenetic alterations are hallmarks of esophageal squamous cell carcinoma (ESCC), the extent to which these are heterogeneous in ESCC has not been explored in a unified framework. Further, the extent to which tumor-infiltrated T lymphocytes are directed against cancer cells, but how the immune infiltration acts as a selective force to shape the clonal evolution of ESCC is unclear. In this study, we perform multi-omic sequencing on 186 samples from 36 primary ESCC patients. Through multi-omics analyses, it is discovered that genomic, epigenomic, and transcriptomic ITH are underpinned by ongoing chromosomal instability. Based on the RNA-seq data, we observe diverse levels of immune infiltrate across different tumor sites from the same tumor. We reveal genetic mechanisms of neoantigen evasion under distinct selection pressure from the diverse immune microenvironment. Overall, our work offers an avenue of dissecting the complex contribution of the multi-omics level to the ITH in ESCC and thereby enhances the development of clinical therapy.

Sarcopenia is associated with higher toxicity and poor prognosis of nasopharyngeal carcinoma.

BACKGROUND: Given the growing evidence that sarcopenia is associated with toxicity and survival in various cancers, we investigated its significance in patients with nasopharyngeal carcinoma (NPC) receiving concurrent chemoradiotherapy (CCRT). METHODS: In this retrospective analysis, we studied 862 NPC patients who had received CCRT between 2010 and 2014. Sarcopenia was determined using routine pre-radiotherapy computed tomography (CT) simulation scans at the third cervical vertebral level. Receiver-operating characteristic curve analyses were used to determine the optimal cutoff values. Propensity score matching (PSM) was applied to develop comparable cohorts of patients with or without sarcopenia. RESULTS: A total of 862 patients were included as the primary cohort, and 308 patients were matched and regarded as the matched cohort. In the primary cohort, the 5-year overall survival (OS), locoregional recurrence-free survival, and distant metastasis-free survival (DMFS) rates for the sarcopenia group versus non-sarcopenia group were 78.2% versus 93.6% (p < 0.001), 89.4% versus 87.9% (p = 0.918), and 82.5% versus 89.0% (p = 0.007), respectively. Univariate and multivariate survival analyses revealed that sarcopenia was an independent predictor of OS (p < 0.001 and p < 0.001) and DMFS (p = 0.009, p = 0.034). Patients with sarcopenia experienced significantly higher rates of treatment-related toxicities compared with patients without sarcopenia (p = 0.032). In addition, patients with sarcopenia also experienced significantly worse treatment response than those without sarcopenia (p = 0.004). Similar results were found in a PSM cohort. CONCLUSION: The current findings support that sarcopenia is a promising indicator for predicting clinical outcomes in NPC patients receiving CCRT. A simple and rapid analysis on CT simulation images can provide information about the therapeutic toxicity and survival prognosis, consequently guiding personalized multi-modality interventions during CCRT.

Correction to: Concurrent chemoradiotherapy with weekly docetaxel versus cisplatin in the treatment of locoregionally advanced nasopharyngeal carcinoma: a propensity score matched analysis.

In the original publication of this article [1], the first affiliation name in the Author details section should be updated to 'Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China' because the affiliation has been renamed from Jun. 15th, 2019.

Long-Term Survival and Prognostic Factors in Locoregionally Advanced Nasopharyngeal Carcinoma Patients Treated with TPF Induction Chemotherapy followed by Cisplatin-Combined Concurrent Chemoradiotherapy.

Purpose: The objective of this study was to report long-term results of docetaxel, cisplatin, and 5-fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and identify prognostic factors for this group of patients. Materials and Methods: From December 2010 to January 2015, 109 patients with locoregionally advanced (III-IVB) NPC were included. Patients were scheduled to complete TPF induction chemotherapy followed by cisplatin based CCRT. Failure-free survival (FFS), overall survival (OS), locoregional failure-free survival (LRFFS) and distant failure-free survival (DFFS) served as clinical outcomes. Kaplan-Meier method, Cox proportional hazards model and receiver operating characteristic (ROC) curves were used for analyzing. Results: With a median follow-up of 60.2 months (range, 7.9-91.6 months), 3-year FFS, OS, LRFFS, and DFFS were 76.8%, 85.1%, 88.3%, and 84.1%, respectively. The highest incidence rate of recurrence and metastasis were in the first year after treatment. Multivariate analyses showed that age, total time of radiation therapy (RTT), and total time of therapy (TTT) were independent prognostic factors for FFS and OS. Body mass index (BMI), RTT and TTT were significant variables predicting DFFS. TTT was the only independent prognostic factor for LRFFS. Conclusion: This study indicated that TPF regimen produced encouraging results in Asian patients with locoregionally advanced nasopharyngeal carcinoma. Toxicity was tolerable and reversible. However, overall treatment time is an important factor that we should take into consideration when make plans of induction chemotherapy related treatment.

Concurrent chemoradiotherapy with weekly docetaxel versus cisplatin in the treatment of locoregionally advanced nasopharyngeal carcinoma: a propensity score-matched analysis.

BACKGROUND: Promising efficacy and manageable toxicity of docetaxel-based concurrent chemoradiotherapy (CCRT) were reported in head and neck cancer. In addition, the effect of CCRT in combination with cisplatin and/or 5-fluorouracil on both locoregionally advanced and metastatic/recurrent nasopharyngeal carcinoma (NPC) was verified. However, CCRT with docetaxel for locoregionally advanced NPC are not well studied. This study aimed to compare effectiveness and toxicities of CCRT with weekly docetaxel versus tri-weekly cisplatin for locoregionally advanced NPC. METHODS: Clinical data of patients with locoregionally advanced NPC newly diagnosed between January 2010 and December 2014 receiving CCRT with either weekly docetaxel (15 mg/m2) or tri-weekly cisplatin (80-100 mg/m2) were reviewed. Propensity score matching at a 1:1 ratio was performed to balance baseline characteristics. Adverse events and survival were compared between the two groups. RESULTS: A total of 962 patients were included as the whole cohort, and 448 patients were matched and were regarded as the matched cohort. The median follow-up duration was 48 months for the whole cohort. The 3-year nodal recurrence-free survival rate was significantly increased for patients treated with docetaxel in both the whole (hazard ratio [HR] = 0.37, 95% confidence interval [CI] 0.19-0.72, P = 0.030) and matched cohorts (HR = 0.33, 95% CI 0.14-0.79, P = 0.023). However, no significant differences were observed in overall survival, local recurrence-free survival, and distant metastasis-free survival between the two groups in both cohorts. Significantly higher rates of grade 3 radiodermatitis (6.7% vs. 1.8%, P = 0.001), mucositis (74.5% vs. 37.9%, P < 0.001), and leucopenia (2.2% vs. 11.6%, P < 0.001) were observed in the docetaxel group, but any grade of renal injury (1.8% vs. 15.1%, P < 0.001), vomiting (18.8% vs. 88.3%, P < 0.001), and ALT elevation (19.2% vs. 31.3%, P = 0.027) were more common in the cisplatin group. CONCLUSIONS: CCRT with weekly low-dose docetaxel is an effective and tolerable therapeutic regimen for locally advanced NPC. It provides a survival benefit mainly by improving the control of regional lymph node metastases, especially for patients with low pretreatment EBV DNA levels.

When the Loss Costs Too Much: A Systematic Review and Meta-Analysis of Sarcopenia in Head and Neck Cancer.

Purpose: Whether or not skeletal muscle mass (SMM) depletion, known as sarcopenia, has significant negative effects on the prognosis of patients with head and neck cancer (HNC) is both new and controversial. In this meta-analysis, we aimed to determine the prognostic significance of sarcopenia in HNC. Methods: We searched PubMed, the Cochrane Library, Embase, and Web of Science, which contain trial registries and meeting proceedings, to identify related published or unpublished studies. We used the Newcastle-Ottawa Scale (NOS) to appraise the risk of bias of the included retrospective studies. Pooled hazard ratios (HR) and the I 2 statistic were estimated for the impact of sarcopenia on overall survival (OS) and relapse-free survival (RFS). Results: We analyzed data from 11 studies involving 2,483 patients (39.4% on average of whom had sarcopenia). Based on the univariate analysis data, the sarcopenia group had significantly poorer OS compared to the non-sarcopenia group [HR = 1.97, 95% confidence interval (CI): 1.71-2.26, I 2 = 0%]. In the cutoff value subgroup, group 1, defined as skeletal muscle index (SMI) of 38.5 cm2/m2 for women and 52.4 cm2/m2 for men (HR = 2.41, 95% CI: 1.72-3.38, I 2 = 0%), had much poorer OS. In the race subgroup, the results were consistent between the Asia (HR = 2.11, 95% CI: 1.59-2.81) and non-Asia group (HR = 1.92, 95% CI: 1.64-2.25). The sarcopenia group also had significantly poorer RFS (HR = 1.74, 95% CI: 1.43-2.12, I 2 = 0%). Conclusions: Presence of pre-treatment sarcopenia has a significant negative impact on OS and RFS in HNC compared with its absence. Further well-conducted studies with detailed stratification are needed to complement our findings.

Low Skeletal Muscle Mass Impairs Quality of Life in Nasopharyngeal Carcinoma Patients Treated With Concurrent Chemoradiotherapy.

Background: Nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT) frequently develop low skeletal muscle mass (SMM), but, little is known about the impacts of low SMM on health-related quality of life (QOL). Methods: We retrospectively assessed 56 patients with locoregionally advanced NPC enrolled in a prospective trial. Low SMM was determined on routine computed tomography simulation (CT-sim) scans taken before radiotherapy, at the third cervical (C3) vertebral level with validated sex-specific cutoffs. QOL was assessed using the World Health Organization Quality of Life Questionnaire-100 at baseline and after 3 weeks. Pain was scored every 24 h using a numerical rating scale (NRS). Characteristics related to low SMM were identified by logistic regression. The chi-square test was used to examine the association of low SMM with QOL and pain. Results: Of the 56 participants (mean age 44.20 ± 10.93 years), over half (60.71%) developed low SMM. Patients with low SMM were more likely to be older (P = 0.035), male (P = 0.066), have a lower body-mass index (BMI; P = 0.091), and have a higher pain score (P = 0.001). Older age (hazard ratio [HR] = 1.788, P = 0.016), being male (HR = 3.145, P = 0.010), lower BMI (HR = 0.761, P = 0.033), and lower prognostic nutritional index (HR = 0.186, P = 0.034) were associated with higher risk of low SMM. Low SMM was associated with poorer baseline QOL scores (P = 0.072), especially in the physical domain (P = 0.002) and its three facets: pain (P = 0.003), energy (P = 0.021), and sleep (P = 0.007). Low SMM was also associated with significantly worse QOL scores (P = 0.006) at 3 weeks, especially in the physical (P = 0.002), psychological (P = 0.046), independence (P = 0.003), social domains (P = 0.023), and in general health condition (P = 0.043). For pain score, low SMM group had worse overall changes from baseline to week 3 (P = 0.011). Conclusions: The incidence of low SMM, as evaluated using routine CT-sim scans, is high in patients receiving CCRT for locoregionally advanced NPC. Low SMM results in poorer QOL and higher pain scores, which underscores the requirement for nutritional and functional interventions to address low SMM early in the treatment course.

Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in nasopharyngeal carcinoma patients with cervical nodal necrosis.

The effectiveness of neoadjuvant chemotherapy (NACT) followed by concurrent chemoradiotherapy (CCRT) compared with CCRT alone in nasopharyngeal carcinoma (NPC) patients who presented with cervical nodal necrosis (CNN) is unknown. A total of 792 patients with stage T1-4N1-3M0 NPC and presented with CNN based on magnetic resonance imaging were retrospectively reviewed. Propensity score matching method was used to balance treatment arms for baseline characteristics. Eventually, 508 patients were propensity-matched on a 1:1 basis to create two groups (NACT + CCRT and CCRT groups). Survival rates were calculated by Kaplan-Meier method and differences were compared by using the log-rank test. The 5-year disease specific survival, disease-free survival and distant metastasis-free survival were significantly higher in NACT + CCRT group relative to the matched CCRT group (82.1% vs. 72.5%, P = 0.021; 70.3% vs. 54.1%, P < 0.001; 81.9% vs. 67.3%, P < 0.001, respectively). Although the rates of grade 3-4 leucopenia and mucositis were higher in NACT + CCRT group than CCRT group, compliance with the combined treatment was good and no significant difference was observed between two groups. NACT followed by CCRT was relatively safe and could achieve better survival than CCRT alone in NPC patients with CNN by reducing the risk of death, tumor progression and distant metastasis.

Elevated plasma fibrinogen level shows superior prognostic value than Epstein-Barr virus DNA load for stage IVA/B nasopharyngeal carcinoma patients in the intensity-modulated radiotherapy era.

PURPOSE: Effective prognostic factors for patients with stage IVA/B nasopharyngeal carcinoma (NPC) who are susceptible to distant metastases are limited. We aim to investigate the prognostic value of pretreatment plasma fibrinogen (FIB) level and Epstein-Barr virus DNA (EBV-DNA) load in these patients in the era of intensity-modulated radiotherapy (IMRT). RESULTS: The 5-year DSS, DFS and DMFS rates of the entire cohort were 72.7%, 66.8%, 80.0%, respectively. High FIB level was identified as a negative prognostic factor for survival: the 5-year DSS, DFS and DMFS rates for patients with high FIB (> 4.0 g/L) and normal FIB (≤ 4.0 g/L) were 60.3% vs. 76.0%, 56.0% vs. 69.9%, and 59.4% vs. 85.5%, respectively (all P < 0.001). Subgroup analysis demonstrated that DSS, DFS and DMFS decreased as FIB gradually increased, even within the normal range. The risk of distant metastasis in patients with high FIB was over 3-fold than patients with normal FIB. EBV-DNA was not an independent prognostic factor for any survival outcomes in multivariate analysis. CONCLUSION: High pretreatment FIB level shows superior prognostic value than EBV-DNA load for stage IVA/B NPC patients in the era of IMRT. MATERIALS AND METHODS: A total of 755 patients with newly-diagnosed stage IVA/B NPC treated with definitive IMRT between January 2007 and December 2011 were enrolled. Plasma FIB and EBV-DNA were measured before treatment. Disease-specific survival (DSS), disease-free survival (DFS) and distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method; differences were compared using the log-rank test.

Prognostic Value of Cavernous Sinus Invasion in Patients with Nasopharyngeal Carcinoma Treated with Intensity-Modulated Radiotherapy.

PURPOSE: To investigate the prognostic value of cavernoussinus invasion (CSI) in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). PATIENTS AND METHODS: Retrospective review of data from 1,087 patients with biopsy-proven, non-metastatic NPC. All patients were diagnosed using magnetic resonance imaging (MRI) scans and received IMRT as the primary treatment. RESULTS: The incidence of cavernoussinus invasion in this cohort was 12.1%. In univariate analysis, 5-year overall survival (OS) (70.6% vs. 88.5%, P < 0.001) and distant metastasis-free survival (DMFS) (71.4% vs. 87.7%, P < 0.001), but not locoregional relapse-free survival (LRFS) (93.9% vs. 93.7%, P = 0.341), were significantly different between patients with and without cavernoussinus invasion. In the T4 subgroup, the 5-year OS, DMFS, and LRFS of patients with and without cavernoussinus extension were 70.6% vs. 81.9% (P = 0.011), 71.4% vs. 84.1% (P = 0.011), and 91.2% vs. 89.7% (P = 0.501), respectively. In multivariate analysis, cavernoussinus invasion was an independent prognostic factor for poorer OS (HR = 1.782; P = 0.013) and DMFS (HR = 1.771; P = 0.016), but not LRFS (HR = 0.632; P = 0.294). In patients with lymph node metastasis, the DMFS rates of patients with and without cavernoussinus invasion were significantly different (P < 0.001). Preliminaryanalysis indicated that neoadjuvant chemotherapy led to better DMFS and OS in patients with cavernoussinus invasion than concurrent chemotherapy or radiotherapy alone; however, the differences were not significant. CONCLUSIONS: In the IMRT era, cavernoussinus invasion remains a prognostic factor for poor DMFS and OS in NPC, even in patients with T4 disease.