Predictive values of the hemoglobin, albumin, lymphocyte and platelet score (HALP) and the modified -Gustave Roussy immune score for esophageal squamous cell carcinoma patients undergoing concurrent chemoradiotherapy.

The hemoglobin, albumin, lymphocyte and platelet (HALP) score and the Gustave Roussy immune score (GRIm⁃Score) are prognostic markers in several types of malignant tumors. The prognostic values of HALP score and GRIm⁃Score in concurrent chemoradiotherapy for unresectable esophageal cancer remain unknown. METHODS: We enrolled 150 esophageal squamous cell carcinoma (ESCC) patients who underwent concurrent chemoradiotherapy in our institution between 2013 and 2018. The cutoff values for HALP, and GRIm⁃Score were defined by using receiver's operating characteristic curves. Survival was analyzed with the Kaplan- Meier method, with differences analyzed with the log-rank test. Multivariate Cox proportional-hazards models were used to evaluate the prognostic significance of HALP and GRIm for ESCC. RESULTS: HALP was significantly associated with the Zubrod ECOG WHO performance status, tumor location, and the clinical tumor, node, metastasis stage. Modified GRIm (mGRIm) was only significantly associated with metastasis / recurrence before radiotherapy (χ2 = 6.25). Univariate Cox regression analysis showed that higher mGRIm (HR 1.9 95%CI 1.3-2.9) and lower HALP (HR 2.4 95%CI 1.6-3.7) were all associated with worse OS. Multivariate COX analysis found that higher mGRIm score (HR 1.7 95%CI 1.1-2.6), and lower HALP score (HR 2 95%CI 1.3-3.2) were both independent risk factors of overall survival. The nomogram c-index in inside validation was 0.66. CONCLUSION: Both HALP and mGRIm are independent prognostic factors for patients with unresectable ESCC.

Immune characteristics and genetic markers of esophageal cancer by single-cell analysis: implications for immunotherapy.

Background: Esophageal cancer (EC) is one of the most common cancers worldwide. The prognoses for patients with the same stage of EC can vary substantially. The progress of single-cell analysis technology has furthered the understanding of tumor heterogeneity. This paper aimed to apply single-cell analysis to explore the characteristics of the tumor environment of EC and provide a basis for personalized treatment. Methods: The latest gene expression data and clinical follow-up information of single-cell sequencing results of EC samples were downloaded from The Cancer Genome Atlas (TCGA) Genomic Data Commons (GDC) Application Programming Interface (API). A differential gene function analysis of the immune infiltration signature agents in the tumor microenvironment (TME) was performed using bioinformatics analytical methods, and potential molecular targets were sought. Results: We identified specific cell subsets in the EC and paracancerous samples, including panel cells, natural killer (NK) cells, exhausted cluster of differentiation (CD)8+ T cells, CD8+ memory T (Tcm) cells, and effector memory T (Tem) cells, including B cell enrichment in the cancer samples. Differences were detected between B cells and monocytes in stage II and III tumors, which may be related to RNA transcription and degradation. The CXCL8 protein was identified as a valid potential prognostic marker. Conclusions: Cell groups with homogenous cell surface markers exhibit intercellular variations that exert a considerable effect on cell function. Our study will contribute to the understanding of the TME and cellular heterogeneity in EC patients and serve as a valuable resource for in-depth exploration of the pathogenesis of EC and the identification of potential therapeutic targets in the future.

Effectiveness of S-1-Based Chemoradiotherapy in Patients 70 Years and Older With Esophageal Squamous Cell Carcinoma: A Randomized Clinical Trial.

Importance: Double-agent intravenous chemotherapy concurrent with radiotherapy is the standard of care for patients with inoperable esophageal cancer. However, patients tend to tolerate intravenous chemotherapy less well with age and comorbidities. It is essential to find a better treatment modality that improves survival outcomes without reducing the quality of life. Objective: To evaluate the effectiveness of simultaneous integrated boost radiotherapy (SIB-RT) with concurrent and consolidated oral S-1 chemotherapy for patients aged 70 years and older with inoperable esophageal squamous cell carcinoma (ESCC). Design, Setting, and Participants: This multicenter, phase III randomized clinical trial was conducted between March 2017 and April 2020 in 10 centers in China. Patients with inoperable, locally advanced, clinical stage II to IV ESCC were enrolled and randomized to receive SIB-RT concurrent with and followed by oral S-1 chemotherapy (CRTCT group) or SIB-RT alone (RT group). Data analysis was completed on March 22, 2022. Interventions: In both groups, the planning gross tumor volume was administered with radiation dose of 59.92 Gy and the planning target volume was administered with radiation dose of 50.4 Gy, in 28 fractions each. In the CRTCT group, concurrent S-1 was administered on radiotherapy days, and consolidated S-1 was administered at 4 to 8 weeks after SIB-RT. Main Outcomes and Measures: The primary end point was overall survival (OS) of the intent-to-treat population. Secondary end points were progression-free survival (PFS) and toxicity profile. Results: A total of 330 patients (median [IQR] age, 75.5 [72-79] years; 220 [66.7%] male patients) were included, with 146 patients randomized to the RT group and 184 randomized to the CRTCT group. A total of 107 patients (73.3%) in the RT group and 121 patients (67.9%) in the CRTCT group were clinically diagnosed with stage III to IV disease. At the time of analysis of the 330 patients in the intent-to treat-population (March 22, 2022), OS was improved in the CRTCT group compared with the RT group at 1 year (72.2% vs 62.3%) and 3 years (46.2% vs 33.9%; log-rank P = .02). PFS was similarly improved in the CRTCT group compared with the RT group at 1 year (60.8% vs 49.3%) and 3 years (37.3% vs 27.9%; log-rank P = .04). There was no significant difference in the incidence of treatment-related toxic effects higher than grade 3 between the 2 groups. Grade 5 toxic effects occurred in each group, including 1 patient who experienced myelosuppression and 4 patients with pneumonitis in the RT group and 3 patients with pneumonitis and 2 patients with fever in the CRTCT group. Conclusions and Relevance: These findings suggest that oral S-1 chemotherapy administered with SIB-RT should be considered as an alternative treatment option for patients aged 70 years and older with inoperable ESCC, since it improved survival outcomes without additional treatment-related toxic effects compared with SIB-RT alone. Trial Registration: ClinicalTrials.gov Identifier: NCT02979691.

Consolidation Chemotherapy Rather than Induction Chemotherapy Can Prolong the Survival Rate of Inoperable Esophageal Cancer Patients Who Received Concurrent Chemoradiotherapy.

Concurrent chemoradiotherapy (CRT) is regarded as the standard treatment for inoperable esophageal cancers (EC). It is still controversial whether consolidation chemotherapy (CCT) or induction chemotherapy (IC) is beneficial for the patients who received CRT. Therefore, we carried out a retrospective analysis at our institution. A total of 186 inoperable EC patients from 20 October 2017 to 7 June 2021 who have previously received CRT were included in our study. The patients were divided into IC + CRT (n = 52), CCRT (n = 64), and CRT + CCT (n = 70) groups according to whether they received induction chemotherapy, consolidation chemotherapy, or not. We used Kaplan−Meier statistics to analyze their 1-, 2-, and 3-year OS. The median follow-up time for the whole group was 14.15 months. The 1-, 2-, 3- year overall survival (OS) for the CCRT group were 72.2%, 52.5%, and 29.5%, and 50.9%, 37.5%, and 25% for the IC + CRT group (p > 0.05). For the CRT + CCT group,1-, 2-, and 3-year OS were 89.8%, 59.0%, and 42.5% (p < 0.05). Adverse reactions in the three groups were mainly graded 0−3. The difference between the three groups was not statistically significant (p > 0.05). For non-surgical EC patients who received CRT, CCT after CRT but not IC before CRT can improve 1-, 2-, and 3-year OS with a low incidence of associated severe adverse effects. As a result, the addition of consolidation chemotherapy to chemoradiotherapy has significant prognostic advantages for inoperable EC patients.

Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-ß1 positive feedback loop.

BACKGROUND: Radiation-induced bystander effect (RIBE) can promote tumor metastasis contributing to the failure of radiotherapy for esophageal squamous cell carcinoma (ESCC). Aberrant expression of DJ-1 has been identified in ESCC; however, the relationship between DJ-1 and RIBE in ESCC remains unknown. METHODS: We detected DJ-1 in the serum and cell supernatants by enzyme-linked immunosorbent assay (ELISA) and evaluated tumor metastasis by phenotypic experiments in vivo and in vitro. RNA-seq, mass spectrometry, western blot (WB), immunoprecipitation (IP), and dual-luciferase reporter assays were performed to explore the underlying mechanisms. RESULTS: DJ-1 was highly expressed in the serum of patients with ESCC receiving radiotherapy and was significantly overexpressed in the medium of ESCC cells receiving irradiation. DJ-1 promoted tumor metastasis via the TGF-ß1 pathway. Mechanistic studies revealed that DJ-1 bound to HSC70 to promote Smad3 phosphorylation and nuclear aggregation in a protein-interaction manner, which activated the transcription of Thrombospondin-1 (TSP1). Subsequently, the activation of TGF-ß1 by TSP1 re-promoted Smad3 phosphorylation and nuclear aggregation, constituting a positive feedback loop to strengthen the metastasis of ESCC cells, which was effectively blocked by LY2109761 and LSKL. Moreover, higher levels of serum DJ-1 in patients with ESCC were related to a poorer prognosis of radiotherapy. CONCLUSIONS: Irradiation can induce ESCC cells secreting DJ-1. Secreted DJ-1 enters bystander cells to initiate activation of the TGF-ß1 pathway via the DJ-1/HSC70/Smad3 signaling axis. The TSP1/TGF-ß1/Smad3 positive feedback pathway constitutes the core pathway that promotes ESCC metastasis. DJ-1 is a useful biomarker for predicting the efficacy of radiotherapy and a potential therapeutic target for reversing RIBE in ESCC. Schematic diagram showing the underlying mechanism that irradiation-induced secretion of DJ-1 accelerates the metastasis of bystander ESCC cells.

Dose escalation based on 18F-FDG PET/CT response in definitive chemoradiotherapy of locally advanced esophageal squamous cell carcinoma: a phase III, open-label, randomized, controlled trial (ESO-Shanghai 12).

INTRODUCTION: Definitive chemoradiotherapy has established the standard non-surgical treatment for locally advanced esophageal cancer. The standard dose of 50-50.4 Gy has been established decades ago and been confirmed in modern trials. The theorical advantage of better local control and technical advances for less toxicity have encouraged clinicians for dose escalation investigation. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) have the potential to tailor therapy for esophageal patients not showing response to CRT and pioneers the PET-based dose escalation. METHODS AND ANALYSIS: The ESO-Shanghai 12 trial is a prospective multicenter randomized phase 3 study in which patients are randomized to either 61.2 Gy or 50.4 Gy of radiation dose by PET response. Both groups undergo concurrent chemoradiotherapy with paclitaxel/cisplatin regimen for 2 cycles followed by consolidation chemotherapy for 2 cycles. Patients with histologically confirmed ESCC [T1N1-3M0, T2-4NxM0, TxNxM1 (Supraclavicular lymph node metastasis only), (AJCC Cancer Staging Manual, 8th Edition)] and without any prior treatment of chemotherapy, radiotherapy or surgery against esophageal cancer will be eligible. The primary endpoints included overall survival in PET/CT non-responders (SUVmax > 4.0) and overall survival in total population. Patients will be stratified by standardized uptake volume, gross tumor volume and tumor location. The enrollment could be ended, when the number of PET/CT non-responder reached 132 and the total population reached 646 for randomization. ETHICS AND DISSEMINATION: This trial has been approved by the Fudan University Shanghai Cancer Center Institutional Review Board. Trial results will be disseminated via peer reviewed scientific journals and conference presentations. Trial registration The trial was initiated in 2018 and is currently recruiting patients. Trial registration number NCT03790553.

Addition of roxadustat to erythropoiesis-stimulating agent (ESA) effectively corrects ESA-hyporesponsive anaemia in patients on peritoneal dialysis.

WHAT IS KNOWN AND OBJECTIVE: Erythropoiesis-stimulating agent (ESA) hyporesponsiveness is an important cause for the undertreatment of anaemia. A decrease in haemoglobin (Hb) levels was observed during the initial stage of the conversion from ESA to roxadustat. The study aims to investigate the effectiveness and safety of adding roxadustat to an ESA for the treatment of ESA-hyporesponsive anaemia in patients on peritoneal dialysis (PD). METHODS: Patients on PD with ESA-hyporesponsive anaemia were enrolled from January 2020 to April 2020 with a 24-week follow-up period. Patients were treated with roxadustat at a starting dose of 50 or 100 mg thrice weekly without changing the ESA dose. Roxadustat and ESA dose adjustments were made as needed to maintain Hb levels within 11.0 to 13.0 g/dl. Efficacy outcomes and safety were assessed. RESULTS AND DISCUSSION: Nine patients were recruited in the study. Both the cumulative responsive rate and maintenance rate of Hb > 11 g/dl were 100%. Six patients required ESA dose reduction from ≥15,000 UI/week to ≤7000 IU/week at week 24. No drug-related severe adverse events were observed in this study. WHAT IS NEW AND CONCLUSION: The addition of roxadustat effectively and smoothly corrected anaemia in patients who were hyporesponsive to ESA, and permitted reduction of the ESA dose.

Circulating Tumor Cells in Esophageal Squamous Cell Carcinoma - Mini Review.

Esophageal cancer has high incidence and mortality rates and a low five-year survival rate of <15% owing to its strong capabilities of invasion, relapse and metastasis. The classic view holds that metastasis and diffusion is an advanced event during cancer progression, but recent studies show that distant diffusion of primary cancer cells may actually be an early event. Detection of circulating tumor cells (CTCs) in the circulation may indicate tumor spread, so CTCs are considered to be the key factor of metastatic cascade. In recent years, despite research progress on CTCs, there is a lack of systematic and important evidence to confirm the diagnostic, monitoring and prognostic values of CTCs in esophageal squamous cell carcinoma (ESCC). In this review, we clarify the relationship between CTC values and ESCC and provide more reliable evidence to improve the management and treatment of ESCC.

Clinicopathological analysis of 67 cases of esophageal neuroendocrine carcinoma and the effect of postoperative adjuvant therapy on prognosis.

ABSTRACT: The clinicopathological properties of esophageal neuroendocrine carcinoma (ENEC) and its optimal therapy have not been widely studied, as the disease is not common. Consequently, we conducted a retrospective study to analyze the clinical features as well as the prognosis of patients with surgically resected ENEC.The clinicopathological data of patients with ENEC who underwent esophagostomy with regional lymphadenectomy at Jiangsu Province People's Hospital and Jiangsu Provincial Tumor Hospital starting January 2008 until December 2014 were collected.Ninety-two cases of ENEC were part of this study. However, only 67 patients were analyzed and followed up. A univariate model for the Cox proportional hazards revealed that prognosis was associated with postoperative adjuvant therapy, age, and lymph node metastasis (P < .05); a multivariate Cox proportional hazards model showed that postoperative adjuvant therapy was a significant independent prognostic factor. Postoperative adjuvant therapy directly affected overall survival, with a significant disparity noted between the groups (P = .022). In this study, patients who received adjuvant therapy had an average time of survival of 39 months (interquartile range: 27.068-50.932 months), while those who did not receive adjuvant therapy had an average survival time of 13 months (interquartile range: 10.129-15.871 months). The survival time was longer in the treated group than in the untreated group (hazard ratio = 0.47; 95% confidence interval: 0.23-0.94; P = .034).ENEC is a heterogeneous tumor with a very poor prognosis. Combining surgery with adjuvant and/or chemotherapy significantly prolongs the survival of patients, and the optimal treatment for ENEC should be determined with future prospective studies.

Chemoradiotherapy Is Superior to Radiotherapy Alone in Esophageal Cancer Patients Older Than 65 Years: A Propensity Score-Matched Analysis of the SEER Database.

INTRODUCTION: Radiotherapy (RT) is the main treatment for unoperated esophageal cancer (EC) patients. It is controversial whether adding chemotherapy (CT) to RT is beneficial for elderly EC patients. The purpose of our study was to compare the efficacy of chemoradiotherapy (CRT) with RT alone for non-surgical elderly esophageal cancer patients. METHODS: A total of 7,101 eligible EC patients older than 65 years diagnosed between 2000 and 2018 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. All the samples were divided into the radiotherapy group and the chemoradiotherapy group. After being matched by propensity score matching (PSM) at a 1:1 ratio, 3,020 patients were included in our analysis. The Kaplan-Meier method and log-rank test were applied to compare overall survival (OS) and cancer-specific survival (CSS). RESULTS: After PSM, the clinical characteristics of patients between the RT and CRT groups were comparable. For EC patients older than 65 years, the 3-year OS and CSS in the CRT group were 21.8% and 27.4%, and the 5-year OS and CSS in the CRT group were 12.7% and 19.8%, respectively. The 3-year OS and CSS in the RT group were 6.4% and 10.4%, and the 5-year OS and CSS in the RT group were 3.5% and 7.2%, respectively. Next, these patients were divided into five subgroups based on the age stratification (ages 65-69; 70-74; 75-79; 80-84; ≥85). In each subgroup analysis, the 3- and 5-year OS and CSS showed significant benefits in the CRT group rather than in the RT group (all p < 0.05). We were unable to assess toxicities between the two groups due to a lack of correlated information. CONCLUSIONS: CRT could improve OS and CSS for non-surgical EC patients older than 65 years. Adding chemotherapy to radiation showed a significant prognostic advantage for elderly esophageal cancer patients.

Robust rank aggregation and cibersort algorithm applied to the identification of key genes in head and neck squamous cell cancer.

OBJECTIVE: Although multiple hub genes have been identified in head and neck squamous cell cancer (HNSCC) in recent years, because of the limited sample size and inconsistent bioinformatics analysis methods, the results are not reliable. Therefore, it is urgent to use reliable algorithms to find new prognostic markers of HNSCC. METHOD: The Robust Rank Aggregation (RRA) method was used to integrate 8 microarray datasets of HNSCC downloaded from the Gene Expression Omnibus (GEO) database to screen differentially expressed genes (DEGs). Later, Gene Ontology (GO) functional annotation together with Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was carried out to discover functions of those discovered DEGs. According to the KEGG results, those discovered DEGs showed tight association with the occurrence and development of HNSCC. Then cibersort algorithm was used to analyze the infiltration of immune cells of HNSCC and we found that the main infiltrated immune cells were B cells, dendritic cells and macrophages. A protein-protein interaction (PPI) network was established; moreover, key modules were also constructed to select 5 hub genes from the whole network using cytoHubba. 3 hub genes showed significant relationship with prognosis for TCGA-derived HNSCC patients. RESULT: The potent DEGs along with hub genes were selected by the combined bioinformatic approach. AURKA, BIRC5 and UBE2C genes may be the potential prognostic biomarker and therapeutic targets of HNSCC. CONCLUSIONS: The Robust Rank Aggregation method and cibersort algorithm method can accurately predict the potential prognostic biomarker and therapeutic targets of HNSCC through multiple GEO datasets.

Interobserver variability in target volume delineation in definitive radiotherapy for thoracic esophageal cancer: a multi-center study from China.

PURPOSE: To investigate the interobserver variability (IOV) in target volume delineation of definitive radiotherapy for thoracic esophageal cancer (TEC) among cancer centers in China, and ultimately improve contouring consistency as much as possible to lay the foundation for multi-center prospective studies. METHODS: Sixteen cancer centers throughout China participated in this study. In Phase 1, three suitable cases with upper, middle, and lower TEC were chosen, and participants were asked to contour a group of gross tumor volume (GTV-T), nodal gross tumor volume (GTV-N) and clinical target volume (CTV) for each case based on their routine experience. In Phase 2, the same clinicians were instructed to follow a contouring protocol to re-contour another group of target volume. The variation of the target volume was analyzed and quantified using dice similarity coefficient (DSC). RESULTS: Sixteen clinicians provided routine volumes, whereas ten provided both routine and protocol volumes for each case. The IOV of routine GTV-N was the most striking in all cases, with the smallest DSC of 0.37 (95% CI 0.32-0.42), followed by CTV, whereas GTV-T showed high consistency. After following the protocol, the smallest DSC of GTV-N was improved to 0.64 (95% CI 0.45-0.83, P = 0.005) but the DSC of GTV-T and CTV remained constant in most cases. CONCLUSION: Variability in target volume delineation was observed, but it could be significantly reduced and controlled using mandatory interventions.

M5C regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in lung adenocarcinoma.

BACKGROUND: In recent years, immunotherapy has made great progress, and the regulatory role of epigenetics has been verified. However, the role of 5-methylcytosine (m5C) in the tumor microenvironment (TME) and immunotherapy response remains unclear. METHODS: Based on 11 m5C regulators, we evaluated the m5C modification patterns of 572 lung adenocarcinoma (LUAD) patients. The m5C score was constructed by principal component analysis (PCA) algorithms in order to quantify the m5C modification pattern of individual LUAD patients. RESULTS: Two m5C methylation modification patterns were identified according to 11 m5C regulators. The two patterns had a remarkably distinct TME immune cell infiltration characterization. Next, 226 differentially expressed genes (DEGs) related to the m5C phenotype were screened. Patients were divided into three different gene cluster subtypes based on these genes, which had different TME immune cell infiltration and prognosis characteristics. The m5C score was constructed to quantify the m5C modification pattern of individual LUAD patients. We found that the high m5C score group had a better prognosis. The role of the m5C score in predicting prognosis was also verified in the dataset GSE31210. CONCLUSIONS: Our study revealed that m5C modification played a significant role in TME regulation of LUAD. Investigation of the m5C regulation mode may have some implications for tumor immunotherapy in the future.

Outcomes and Prognostic Factors of Salvage Radiation for Postoperative Lymph Node Recurrence of Esophageal Squamous Cell Carcinoma.

Purpose: Recurrence of esophageal squamous cell carcinoma (ESCC) in regional lymph nodes (LNs) after surgical section can be treated with salvage resection, radiotherapy (RT) or chemoradiotherapy (CRT). RT or CRT is more widely used in clinic. This paper investigates the effects, toxicities and prognostic risk factors of salvage RT or CRT on patients with LN recurrence. Methods: We retrospectively analyzed the clinical outcomes of 103 patients receiving salvage RT or CRT for LN recurrence after ESCC resection. In total, 39 patients received RT alone and 64 received concurrent CRT. All the patients received intensity modulated radiation therapy (IMRT), administered with a median dose of 62 Gy (range, 50-70 Gy). Results: The median follow-up time was 44.5 months, and median survival was 22.5 months (5.5-99.5 months). One-, 3-, and 5-year overall survival (OS) were 80.6, 37.0, and 25.8%, respectively. One- and 2-year progression free survival (PFS) were 57.3 and 34.0%, respectively. Grade 3 or above toxicity was low (16.5%) and no treatment-related deaths occurred. In univariate analysis of OS, pN0 (p = 0.039), smaller LN volume (≤25 cm3, p = 0.019), combined chemotherapy (p = 0.041) and single LN recurrence (p = 0.001) were associated with prolonged OS. And pT1-2 (p = 0.044), pN0 (p = 0.042), irradiation dose (>60 Gy, p = 0.044), combined chemotherapy (p = 0.019) and single LN recurrence (p = 0.002) were associated with prolonged PFS. In multivariate analysis, the patients with only one recurrent node had a significant better OS (HR = 0.556, 95% CI 0.324-0.956, p = 0.034) and PFS (HR = 0.528, 95% CI 0.339-0.847, p = 0.008). Conclusions: Salvage RT or CRT for regional LN recurrence is effective and acceptable. Fewer recurrent nodes may indicate a better long-term survival.

Prognostic Factors for Patients with Esophageal Cancer Receiving Definitive Radiotherapy Alone: A Retrospective Analysis.

PURPOSE: Intensity-modulated radiotherapy (IMRT) can improve the prognosis of patients with esophageal cancer. This study aimed to evaluate clinical factors relevant to the prognosis of patients with esophageal cancer who received intensity-modulated radiotherapy (IMRT) alone. PATIENT AND METHODS: Data of 103 patients with pathologically confirmed esophageal cancer who were admitted to our hospital between October 2011 and November 2017 were retrospectively reviewed. All patients had squamous cell carcinoma. All patients received IMRT. Patients with stage I-IVA tumors were included to represent the real-world clinical practice. We performed univariate and multivariate analyses to identify prognostic factors for overall survival (OS) and progression-free survival (PFS). In univariate analyses, the Kaplan-Meier method was used to estimate OS and PFS for various subgroups. In multivariate analyses, hazard ratios were calculated. RESULTS: Single-factor analysis revealed that T stage (P=0.019), N stage (P =0.047), and lesion length (P =0.000) were associated with the prognosis of esophageal cancer patients who received IMRT. Cox regression analysis revealed that T stage (odds ratio [OR] = 4.68; P < 0.05), N stage (OR = 0.28; P < 0.05), and lesion length (OR = 0.09; P < 0.05) were independent factors relevant to prognosis. CONCLUSION: T stage, N stage, and lesion length influenced the long-term curative effects of IMRT for esophageal cancer and were prognostic factors for patients with esophageal cancer receiving definitive radiotherapy alone. The higher the stage and the longer the tumor, the lower the survival rate.

Diagnostic, Prognostic, and Recurrence Monitoring Value of Plasma CYFRA21-1 and NSE Levels in Patients With Esophageal Squamous Cell Carcinoma.

This study was aimed to evaluate the clinical values of single markers and combination in the diagnosis, short-term efficacy and recurrence risk assessment of esophageal squamous cell carcinoma (ESCC). METHODS: Totally 50 patients with I-IVa stage ESCC, 50 healthy controls and 11 patients with recurrent esophageal cancer after comprehensive treatment were enrolled. Serum biomarkers were collected and evaluated. Serum concentrations of carcinoembryonic antigen (CEA), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) and neuron specific enolase (NSE) were measured by enzyme-linked immunosorbent assay before and after treatment. RESULTS: The diagnostic efficacy ROC curve area of CEA, CYFRA21-1 and NSE in esophageal cancer was 0.70, 0.71 and 0.64(all P <0.05), respectively, the sensitivity was 80%, 88.89% and 60% respectively, and the specificity was 53%, 58.5% and 58% respectively. The sensitivity and specificity of the combined detection were 68% and 78% respectively. The area under ROC curve was 0.75. CEA, CYFRA21-1 and NSE were significantly higher than the healthy control group and thus can be used as diagnostic markers of esophageal cancer (all P <0.05). After standard treatment, the clinical CR and PR rate of patients with positive CYFRA21-1 or NSE before treatment was significantly lower than that of patients with negative CYFRA21-1 or NSE (X2 = 4.52,P =0.03). A significant negative correlation was found between N stage and clinical efficacy (HR 2.48, 95%CI 1.07-5.73). After comprehensive treatment, the serum CYFRA21-1 and NSE levels in recurrent patients also increased significantly(all P<0.05), indicating these two markers play obvious roles in recurrence monitoring. CONCLUSION: CYFRA21-1 and NSE may help to predict the response of ESCC to CRT, and play important roles in the diagnosis and recurrence monitoring of esophageal cancer. These markers have a diagnostic value of esophageal cancer when combined with CEA.

Age plays an important role in the decision of definitive concurrent chemoradiotherapy (CCRT) for esophageal squamous cell carcinoma (ESCC): a propensity-score matched analysis of multicenter data (3JECROG R-02A).

BACKGROUND: To examine the survival benefit of definitive concurrent chemoradiotherapy (CCRT) compared to radiotherapy alone in patients with esophageal squamous cell carcinoma (ESCC) using a real-world patient population. METHODS: This retrospective study included 2,762 patients with ESCC across ten medical centers in China from 2001 to 2017. A total of 1,133 patients received radiotherapy alone and 815 patients were treated with CCRT. The patient survival rates were assessed by propensity-score matching (PSM) and subgroup analysis. RESULTS: The baseline characteristics were significantly different between the two groups, with the CCRT group showing a higher proportion of males, younger patients, cervical/upper thoracic cancers, and worse T and N stages. There were no significant differences in the clinical characteristics between the two groups after PSM. Before PSM, the median overall survival (OS) rates were 31.2 and 24.1 months in the CCRT and RT alone groups, respectively, demonstrating the superior therapeutic effects (TEs) of the CCRT. However, the median OS rates were not significantly different between the two groups after PSM (32.6 and 39.4 months in the CCRT and radiotherapy alone groups, respectively). The subgroup analyses revealed that the median OS was significantly better in the CCRT group compared to the radiotherapy alone group (37.5 vs. 25.1 months, respectively) in patients less than 70 years of age [hazard ratio (HR) 0.782, 95% confidence interval (CI): 0.657 to 0.932]. In contrast, in patients 70 years of age and older, the 5-year survival rate was poorer in the CCRT group (34.8%) compared to the radiotherapy alone group (73.4%). Therefore, CCRT was an independent poor prognostic risk factor (HR 3.206, 95% CI: 2.168 to 4.740). CONCLUSIONS: CCRT may not be suitable for all patients with localized ESCC. Younger patients less than 70 years of age might benefit significantly from CCRT. However, in patients aged 70 years and older, the potential survival benefit of CCRT and the optimal combination treatment regimens require further investigation.

Dose escalation of 3D radiotherapy is effective for esophageal squamous cell carcinoma: a multicenter retrospective analysis (3JECROG R-03).

BACKGROUND: To evaluate the impact of radiation dose escalation on overall survival (OS) in patients with non-metastatic esophageal squamous cell carcinoma (ESCC) treated with radical radiotherapy. METHODS: The clinical data of ESCC patients treated with three-dimensional (3D) radiotherapy alone or chemoradiotherapy were collected from multiple institutes and retrospectively analyzed. Patients who received radiation dose ≥40 Gy were included. Radiation dose as a continuous variable was entered into the Cox regression model by using penalized spline regression to allow for a nonlinear relationship between radiation dose and OS to be identified. Patients were stratified into five groups according to EQD2. The Kaplan-Meier method was used to assess the OS in different dose groups. Univariate and multivariate analyses were performed to evaluate the factors associated with OS. RESULTS: A total of 2,469 patients were included from 10 institutes across China. The median follow-up time was 58.3 months [95% confidence interval (CI): 56.4-60.2 months]. The median OS and PFS time were 24.3 months (95% CI: 22.5-26.2 months) and 18.0 months (95% CI: 16.4-19.6 months), respectively. The risk of death decreased sharply with a dose up to 60 to 62 Gy, before increasing slightly after the dose was elevated beyond 62 Gy. Multivariate analysis indicated that the chance of death was significantly decreased in patients who received radiotherapy doses of 60-62 Gy [P=0.028, hazard ratio (HR) 0.85, 95% CI: 0.73-0.98)], compared with those who received radiotherapy doses of 40-60 Gy. CONCLUSIONS: Our results reveal radiation dose is a significant prognostic factor of survival for ESCC patients. Higher radiation dose contributes to much more favorable survival outcomes for ESCC patients receiving radical radiotherapy by modern techniques, and 60 Gy or above might be the most optimal radiation dose.

Stage III Esophageal Squamous Cell Carcinoma Patients With Three-Dimensional Conformal or Intensity-Modulated Radiotherapy: A Multicenter Retrospective Study.

Aim: To evaluate long-term outcome and prognostic factors of stage III esophageal cancer after definitive radiotherapy using three dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) techniques. Methods: Patients with T3N1M0/T4N0-1M0 esophageal squamous cell carcinoma (ESCC) treated with definitive radiotherapy from 2002 to 2016 in 10 Chinese medical centers were retrospectively analyzed. Overall survival (OS) and progression-free survival (PFS) rates were calculated. Prognostic factors were analyzed by Log-rank test and multivariable Cox model. Results: Survival data of 1,450 patients were retrospectively collected. With a median follow-up time of 65.9 months, 1-, 3-, and 5-year OS rates were 69.3, 36.7, and 27.7%, respectively, and PFS rates were 58.6, 32.7, and 27.4%, respectively. Univariable analyses showed that gender, age, lesion location, lesion length, largest tumor diameter, lymph node metastasis, gross tumor volume, EQD2, short-term response, and concurrent chemotherapy were prognostic factors for OS. Multivariable analyses showed that lesion location, T-classification, GTV size, EQD2, and short-term response to RT were independent prognostic factors for OS, and tumor diameter, GTV size, and short-term response were independent prognostic factors for PFS. Conclusions: This study demonstrated that definitive radiotherapy using 3DCRT and IMRT provides promising outcomes for locally advanced ESCC.