Treatment Of Esophageal Cancer Patients Research Articles

Integrative Analysis of Histone Acetylation Regulated CYP4F12 in Esophageal Cancer Development.

Current therapeutic strategies for esophageal cancer (EC) patients have yielded limited improvements in survival rates. Recent research has highlighted the influence of drug metabolism enzymes on both drug response and EC development. Our study aims to identify specific drug metabolism enzymes regulated by histone acetylation and to elucidate its molecular and clinical features. CYP4F12 exhibited a notable upregulation subsequent to trichostatin A treatment as evidenced by RNA sequencing analysis conducted on the KYSE-150 cell line. The change in gene expression was associated with increased acetylation level of histone 3 K18 and K27 in the promoter. The regulation was dependent on p300. In silicon analysis of both The Cancer Genome Atlas esophageal carcinoma and GSE53624 dataset suggested a critical role of CYP4F12 in EC development, because CYP4F12 was downregulated in tumor tissues and predicted better disease-free survival. Gene ontology analysis has uncovered a robust correlation between CYP4F12 and processes related to cell migration, as well as its involvement in cytosine-mediated immune activities. Further investigation into the relationship between immune cells and CYP4F12 expression has indicated an increased level of B cell infiltration in samples with high CYP4F12 expression. CYP4F12 was also negatively correlated with the expression of inhibitory checkpoints. An accurate predictive nomogram model was established combining with clinical factors and CYP4F12 expression. In conclusion, CYP4F12 was crucial in EC development, and targeting CYP4F12 may improve the therapeutic efficacy of current treatment in EC patients. SIGNIFICANCE STATEMENT: CYP4F12 expression was downregulated in esophageal cancer (EC) patients and could be induced by trichostatin A. During EC development, CYP4F12 was linked to reduced cell migration and increased infiltration of B cells. CYP4F12 also is a biomarker as prognostic predictors and therapeutic guide in EC patients.

Near-infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts in Patient-Derived Xenografts using a Humanized anti-Fibroblast Activation Protein Antibody.

Esophageal cancer remains a highly aggressive malignancy with a poor prognosis, despite ongoing advancements in treatments such as immunotherapy. The tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), plays a crucial role in driving the aggressiveness of esophageal cancer. In a previous study utilizing human-derived xenograft models, we successfully developed a novel cancer treatment that targeted CAFs with near-infrared photoimmunotherapy (NIR-PIT), as an adjuvant therapy. In this study, we sought to translate our findings toward clinical practice by employing patient-derived xenograft (PDX) models and utilizing humanized monoclonal antibodies, specifically Sibrotuzumab, which is anti-human fibroblast activation protein (FAP) antibody and already being investigated in clinical trials as monotherapy. PDX models derived from esophageal cancer patients were effectively established, preserving the expression of key biomarkers such as EGFR and FAP, as observed in primary tumors. The application of FAP-targeted NIR-PIT using Sibrotuzumab, conjugated with the photosensitizer IR700DX, exhibited precise binding and selective elimination of FAP-expressing fibroblasts in vitro. Notably, in our in vivo investigations using both cell line-derived xenograft and PDX models, FAP-targeted NIR-PIT led to significant inhibition of tumor progression compared to control groups, all without inducing adverse events such as weight loss. Immunohistological assessments revealed a substantial reduction in CAFs exclusively within the tumor microenvironment of both models, further supporting the efficacy of our approach. Thus, our study demonstrates the potential of CAF-targeted NIR-PIT employing Sibrotuzumab as a promising therapeutic avenue for clinical treatment of esophageal cancer patients.

Chemotherapy combined with immune checkpoint inhibitors may overcome the detrimental effect of high neutrophil-to-lymphocyte ratio prior to treatment in esophageal cancer patients.

Immune checkpoint inhibitors (ICIs) have emerged as a promising treatment option for esophageal cancer (EC). Although ICIs enable long-term survival in some patients, the efficacy of ICIs varies widely among patients. Therefore, predictive biomarkers are necessary for identifying patients who are most likely to benefit from ICIs to improve the efficacy of the treatment. We retrospectively analyzed the outcomes of combination therapy, including nivolumab plus ipilimumab or chemotherapy plus anti-programmed cell death 1 (PD-1) antibodies in our institute to identify biomarkers. Twenty-seven patients received nivolumab plus ipilimumab, and thirty-six patients received chemotherapy plus anti-PD-1 antibodies were included in this study. We analyzed patient characteristics, efficacy, and safety. Multivariable analysis of biomarkers evaluated the correlation among overall survival (OS), progression-free survival (PFS), and the following variables: body mass index, performance status, neutrophil-to-lymphocyte ratio (NLR), C-reactive protein level, and albumin level before treatment. In multivariable analysis, albumin level was significantly correlated with PFS in the cisplatin plus 5-fluorouracil (CF) plus pembrolizumab group. NLR and albumin level were significantly correlated with OS in the nivolumab plus ipilimumab group. Other variables, including PS, BMI, and CRP did not correlate with any of the outcomes. High NLR in EC patients prior to treatment was significantly less effective for ICIs. In chemotherapy combined with ICIs, NLR before the treatment was not associated with treatment efficacy, suggesting combination chemotherapy may be beneficial for EC patients with high NLR. NLR may be an indicator of immunocompetence in anti-tumor immunity and a convenient predictive biomarker for selecting appropriate treatments including ICIs.

393. A RADIOMICS STRATEGY BASED ON CT INTRA-TUMORAL AND PERITUMORAL REGIONS FOR PREOPERATIVE PREDICTION OF NEOADJUVANT CHEMORADIOTHERAPY FOR ESOPHAGEAL CANCER

Abstract Background The standard treatment for esophageal cancer patients is neoadjuvant chemoradiotherapy followed by surgery. However, some of these patients do not achieve pathological complete response with this therapy, resulting in poor outcomes. The objective of this study is to develop a method for selecting patients who can achieve pathological complete response through pre-neoadjuvant therapy chest-enhanced CT scans. Methods The study enrolled 201 patients with esophageal cancer and divided them into a training set and a testing set in a 7:3 ratio. Radiomics features of intra-tumoral and peritumoral images were extracted from preoperative chest-enhanced CT scans of these patients. The features underwent dimensionality reduction in two steps, using Student’s t-test and least absolute shrinkage and selection operator. The selected intra-tumoral and peritumoral (including marginal and adjacent ROI) features were used to build models with four machine learning classifiers. The models with satisfactory accuracy and stability levels were considered to perform well. Finally, the performance of these well-performing models on the testing set was displayed using ROC curves. Results Among the 16 models, the best-performing models were the integrated (intra-tumoral and peritumoral features) -XGBoost and integrated-random forest models. In the training set, the two models had average ROC AUCs of 0.906 and 0.918 respectively, with relative standard deviations (RSDs) of 6.26 and 6.89. In the testing set, the AUCs were 0.845 and 0.871, respectively. There was no significant difference in the ROC curves between the two models. Conclusion The addition of peritumoral radiomics features to the radiomics analysis may improve the predictive performance of pathological response for esophageal cancer patients to neoadjuvant chemoradiotherapy. The integrated (intra-tumoral and peritumoral features) -XGBoost and integrated-random forest models developed in this study show potential for predicting pathological complete response in esophageal cancer patients and may help in selecting patients for neoadjuvant therapy.

Clinical characteristics and survival of esophageal cancer patients: annual report of the surgical treatment in Shanghai Chest Hospital, 2017.

Esophageal cancer remains a significant burden of lethal cancers worldwide, particularly in China. This is an annual report of Shanghai Chest Hospital (SCH) on surgical treatment for esophageal cancer patients in 2017. All patients who received surgical treatment for esophageal cancer at SCH in 2017 were given a detailed summary of clinical information based on the database of SCH. Kaplan-Meier method was used to present their survival, subgroup analyses, and multivariate Cox regression analysis were used to estimate the potential risk factors for prognosis. In 2017, a total of 663 patients received surgical treatment (628 esophagectomies and 35 endoscopic resections) for esophageal cancer at SCH. Of the patients who underwent esophagectomy, 292 patients received perioperative treatment, majority of which was postoperative treatment (47.9%). Only 69 (10.4%) patients received preoperative treatment. Minimally invasive techniques were used in 444 (70.7%) patients and robotic-assisted esophagectomies were used in 130 (20.7%) patients. Complete resection (R0) was achieved in 90.3% of esophagectomy patients. The 5-year overall survival (OS) rate after esophagectomy was 52.5%. The 5-year OS of patients with esophageal cancer can reach 52.5% after surgical treatment in 2017 at SCH. The exact beneficiaries of neoadjuvant therapy are still unclear in the 2017 cohort.

Cisplatin-induced pyroptosis is mediated via the CAPN1/CAPN2-BAK/BAX-caspase-9-caspase-3-GSDME axis in esophageal cancer

Esophageal cancer is the seventh most common cancer globally. Chemotherapy resistance remains a significant challenge in the treatment of esophageal cancer patients. Cisplatin can damage tumor cells by inducing pyroptosis. However, the underlying molecular mechanisms remain unclear. In this work, we aim to investigate pyroptosis-dependent molecular mechanisms underlying cisplatin sensitivity and find potential biomarkers to predict response to cisplatin-based chemotherapy for esophageal cancer patients. Pyroptosis-associated proteins were screened via proteomics for esophageal cancer (n = 124) and bioinformatics analysis. We observed that high calpain-1 (CAPN1) and calpain-2 (CAPN2) expression were associated with favorable clinical outcomes and prolonged survival in esophageal cancer patients. We employed immunohistochemistry to evaluate the expression of CAPN1 and CAPN2 in pretreatment tumor biopsies from 108 patients with esophageal cancer who received concurrent chemoradiotherapy (CCRT). These results suggested that esophageal cancer patients with high expression of both CAPN1 and CAPN2 are likely to experience a complete response to CCRT and have significantly better survival. Western blotting, LDH release, calpain activity and cell viability assays indicated that cisplatin could activate calpain activity, while calpain inhibition or knockout suppressed cisplatin-induced pyroptosis. Mechanistically, we uncovered a novel mechanism whereby cisplatin induced pyroptosis via activation of a CAPN1/CAPN2-BAK/BAX-caspase-9-caspase-3-GSDME signaling axis in esophageal cancer cells. Collectively, this study is the first to explore the effects of calpain on cisplatin-induced pyroptosis in esophageal cancer cells. Further, our findings also imply that the combination of CAPN1 and CAPN2 could be considered as a promising biomarker of cisplatin sensitivity and prognosis in patients with esophageal cancer, providing a possibility to guide individualized treatment.

Diagnostic and Prognostic Value of DACH1 Methylation in the Sensitivity of Esophageal Cancer to Radiotherapy.

To detect the methylation status of the cell fate determinant (DACH1) gene in esophageal cancer tissues and to explore the predictive value of methylation of DACH1 on the sensitivity to radiotherapy for esophageal cancer. Cancer tissues, corresponding paracancerous tissues, and 30 specimens of normal esophageal mucosal tissues from 70 patients admitted to the hospital after radical esophageal cancer radiotherapy from January 2016 to April 2017 were collected. The methylation status of DACH1 was detected by a methylation-specific polymerase chain reaction (MSP). The 70 esophageal cancer patients were divided into radiotherapy-sensitive and radiotherapy-insensitive groups according to the efficacy of radiotherapy, and the methylation status of DACH1 was compared between the two groups. The χ2 test was used to analyze the relationship between the methylation status of DACH1 and the clinicopathological characteristics of esophageal cancer patients. The Kaplan–Meier survival curve was used to analyze the relationship between the methylation status of DACH1 and radiotherapy sensitivity and survival of esophageal cancer patients, and the Cox proportional risk model was used to analyze the independent influencing factors affecting the radiotherapy sensitivity of esophageal cancer patients. The methylation rate of DACH1 in esophageal cancer tissues was higher than that in paracancerous tissues and normal tissues, and the differences were statistically significant (P < 0.05). 70 patients with esophageal cancer completed radiotherapy, including 46 patients with radiotherapy sensitivity and 24 patients with radiotherapy insensitivity. The DACH1 methylation rate of esophageal cancer patients in the radiotherapy-sensitive group was lower than that in the radiotherapy-insensitive group, and the difference was statistically significant (P < 0.05). The DACH1 methylation rate of esophageal cancer patients with TNM stage (III-IV), tumor differentiation degree (hypofractionation), and lymph node metastasis was higher, and the difference was statistically significant (P < 0.05). The Kaplan–Meier curve showed that the median survival time of patients with DACH1 methylation before radiotherapy was 23 months, which was shorter than that of patients with DACH1 unmethylation before radiotherapy (36 months), and the difference between the survival curves of the two groups was statistically significant (χ2 = 7.425, P < 0.05); the median survival time of patients in the radiotherapy-sensitive group was 39 months, which was longer than that of patients in the radiotherapy-insensitive group (25 months), and the difference between the two groups was statistically significant (P < 0.05). The median survival time of patients in the radiotherapy-sensitive group was 39 months, which was longer than that of patients in the radiotherapy-insensitive group (25 months), and the difference in survival curves between the two groups was statistically significant (χ2 = 7.011, P < 0.05). The results of the multifactorial Cox regression model showed that TNM stage (stage III-IV) (HR = 1.961, 95% CI: 1.125–2.768), tumor hypofractionation (HR = 1.453, 95% CI: 1.034–2.857), presence of lymph node metastasis (HR = 1.499, 95% CI: 1.025–2.851), and DACH1 methylation (HR = 1.718, 95% CI: 1.067–2.596) may increase the risk of insensitivity to radiotherapy in patients with esophageal cancer (P < 0.05). The rate of DACH1 methylation in esophageal cancer tissues was increased, and the methylation status of DACH1 was related to radiotherapy sensitivity and survival of esophageal cancer patients, which is expected to be a new target for diagnosis and treatment of esophageal cancer patients.

Exosomes Mediated Transfer of Circ_0000337 Contributes to Cisplatin (CDDP) Resistance of Esophageal Cancer by Regulating JAK2 via miR-377-3p.

Background: Chemoresistance remains a major obstacle to the treatment of esophageal cancer patients. Exosome-mediated transfer of circular RNAs (circRNAs) has been reported to be related to drug resistance in esophageal cancer. This study is designed to explore the role and mechanism of exosomal circ_0000337 on CDDP resistance in esophageal cancer.Methods: Cell viability, proliferation, colony number, apoptosis, migration, and invasion were assessed by Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and transwell assays. Circ_0000337, microRNA-377 (miR-377-3p), and Janus kinase 2 (JAK2) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Exosomes were isolated and detected by differential centrifugation and a transmission electron microscope. Protein levels of CD9, CD63, and JAK2 were tested by Western blot assay. The binding relationship between miR-377-3p and circ_0000337 or JAK2 was predicted by circinteractome or Starbase and then verified by dual-luciferase reporter assay and RNA pull-down assay. The biological role of exosomal circ_0000337 and CDDP on esophageal cancer cell growth was examined by the xenograft tumor model in vivo.Results: Circ_0000337 and JAK2 were highly expressed, and miR-377-3p was decreased in CDDP-resistant esophageal cancer tissues and cells. Moreover, circ_0000337-containing exosomes secreted by CDDP-resistant esophageal cancer cells could promote CDDP resistance, cell growth, and metastasis in CDDP-sensitive esophageal cancer cells in vitro. The mechanical analysis discovered that circ_0000337 functioned as a sponge of miR-377-3p to regulate JAK2 expression. Exosomal circ_0000337 increased the drug resistance of esophageal cancer in vivo.Conclusion: Exosomal circ_0000337 accelerated CDDP resistance of esophageal cancer cells partly by regulating the miR-377-3p/JAK2 axis, hinting a promising therapeutic target for the esophageal cancer treatment.

INDIVIDUAL PROGNOSTIC ALGORITHM FOR ESTIMATING THE RISK OF ESOPHAGEAL CANCER PROGRESSION AFTER SURGICAL TREATMENT

The development of laboratory criteria for predicting esophageal cancer (EC) prognosis is of great importance due to the need to achieve personalized approach to cancer treatment. Since the role of lymphocytic infiltration in EC remains controversial, our goal was to develop a prognostic algorithm for estimating the risk of esophageal squamous cell carcinoma progression, considering its lymphocytic microenvironment.Material and Methods. Tumor tissues were obtained from 40 EC patients during surgery; the tissues were homogenized, and lymphocyte subsets (Т-В-NK, T-reg) were determined by flow cytometry. A prognostic algorithm for calculating the risk of EC progression within 3 years was developed using discriminant analysis with the calculation of the three F functions: F0 , F6–12, F12–24, corresponding to the absence of the risk of EC progression during 3 years (F0 ); a high risk of EC progression during 6–12 months (F6–12); a high risk of EC progression during 12–24 months (F12–24) after surgery.Results. Only two factors showed the highest discriminant power, allowing us to consider the differences as statistically significant – CD3+CD4+ and T-reg cells in tumors. When dividing EC patients into groups based on the prediction of time to disease progression, coefficients were calculated and mathematical functions were determined for three discriminant functions (F0 , F6–12, F12–24) organized into a model. The F coefficient calculated for each patient allowed us to predict the risk of EC progression 6–12 and 12–24 months after surgery or the absence of disease progression within 3 years after surgery.Conclusions. The development of EC progression after surgery is apparently influenced by the lymphocytic microenvironment, predominantly by CD3+CD4+ and T-regs; their determination and inclusion in the prognostic algorithm can be important for personalized approach to the treatment of EC patients.

Development of Multiscale Transcriptional Regulatory Network in Esophageal Cancer Based on Integrated Analysis.

Objective To explore multiscale integrated analysis methods in identifying key regulators of esophageal cancer (ESCA). Methods We downloaded the ESCA dataset from The Cancer Genome Atlas (TCGA) database, which contained RNA-seq data, miRNA-seq data, methylation data, and clinical phenotype information. Then, we combined ESCA-related genes from the NCBI-GENE and OMIM databases and RNA-seq dataset from TCGA to analyze differentially expressed genes (DEGs). Meanwhile, differentially expressed miRNAs (DEmiRNAs) and genes with differential methylation levels were identified. The pivot–module pairs were established using the RAID v2.0 database and TRRUST v2 database. Next, the multifactor-regulated functional network was constructed based on the above information. Additionally, gene corresponding targeted drug information was obtained from the DrugBank database. Moreover, we further screened regulators by assessing their diagnostic value and prognostic value, especially the value of distinguishing patients at TNM I stage from normal patients. In addition, the external database from the Gene Expression Omnibus (GEO) database was used for validation. Lastly, gene set enrichment analysis (GSEA) was performed to explore the potential biological functions of key regulators. Results Our study indicated that CXCL8, CYP2C8, and E2F1 had excellent diagnostic and prognostic values, which may be potential regulators of ESCA. At the same time, the good early diagnosis ability of the three regulators also provided new insights for the diagnosis and early treatment of ESCA patients. Conclusion We develop a multiscale integrated analysis and suggest that CXCL8, CYP2C8, and E2F1 are promising regulators with good diagnostic and prognostic values in ESCA.

ASO Author Reflections: MRI-Derived Biomarker to Select Optimal Treatment for Esophageal Cancer Patients.

ASO Author Reflections: MRI-Derived Biomarker to Select Optimal Treatment for Esophageal Cancer Patients.

Channel-Attention U-Net: Channel Attention Mechanism for Semantic Segmentation of Esophagus and Esophageal Cancer

The effective segmentation of esophagus and esophageal cancer from Computed Tomography (CT) images can meaningfully assist doctors in the diagnosis and treatment of esophageal cancer patients. However, problems such as the small proportion of the esophageal region in CT images and the irregular shape of the esophagus will make the diagnosis difficult. In practical applications, not all esophagus and esophageal cancer morphology can be included in the training set, so the generalization ability of the model is very important. These are the difficulties in segmenting the esophagus and esophageal cancer. Since some adjacent tissues and organs of the esophagus are visually close to the esophagus and esophageal cancer, how to ensure that the network can extract effective distinguishing features has become the focus of research. In this paper, a novel U-Net structure - Channel-attention U-Net is proposed to segment esophagus and esophageal cancer from CT slices. This novel network combines a Channel Attention Module (CAM) that can distinguish the esophagus and surrounding tissues by emphasizing and inhibiting channel feature and Cross-level Feature Fusion Module (CFFM) which is utilized to strengthen the generalization ability of the network by using high-level features to weight low-level features. Because the high-level features represent specific organizational information, and the low-level features represent the characteristics of detailed information such as edges and contours, the network can learn specific detailed features of a definite organization. In addition, to locate the esophageal region better, a 3D semi-automatic method for segmenting esophagus and esophageal cancer is proposed. The proposed network is trained using 46,400 CT pictures as the training set and divides 11,600 CT images from the dataset at a ratio of 0.2 as the validation set. Finally, 7,250 CT images were used as the test set to test the performance of the network. The experimental results show that the IoU value of our network can reach 0.625, the dice value is 0.732 and the Hausdorff distance is 3.193.

Analysis of Homogeneous and Heterogeneous Factors for Bone Metastasis in Esophageal Cancer.

BackgroundEsophageal cancer is a common cancer worldwide. We performed the present study to assess the homogeneous and heterogeneous risk and prognostic factors of bone metastasis (BM) in esophageal cancer patients using data extracted from the Surveillance, Epidemiology, and End Results (SEER) database.Material/MethodsData from patients with esophageal cancer in the SEER database from 2010 to 2016 were extracted to reveal the risk factors for BM through univariable and multivariable logistic regression. Cox hazard regression analysis was used to evaluate the prognostic factors in esophageal cancer patients with BM from 2010 to 2015.ResultsA total of 2075 (8.0%) patients with initial bone metastasis were diagnosed from among 25 955 patients with esophageal cancer from 2010 to 2016. Male sex, T4 stage, brain metastasis, and liver metastasis were common risk factors for the occurrence and prognosis of BM. Patients with age younger than 67 years, grade III, higher N stage (N1, N2, and N3), histological subtype of esophageal adenocarcinoma or others, and lung metastasis were also more likely to experience bone metastasis, while unmarried patients were associated with shorter survival.ConclusionsThe prevalence of initial bone metastasis was approximately 8.0% in esophageal cancer patients. More attention should be paid to patients with revealed risk and prognostic factors because these factors can guide individualize bone metastasis screening and treatment of esophageal cancer patients.

Long-term effects of radiation prior to surgery and chemotherapy on survival of esophageal cancer undergoing surgery.

Esophageal cancer (EC) is one of the most common cancers in the world, with continuously growing diagnoses and morbidity. Because it is still unclear how to choose the best treatment for EC patients, a multimodal treatment is necessary to improve the prospect of the malignancy, including a sequence of surgery, chemotherapy, and radiotherapy, whether alone or combination. Therefore, this paper aims to analyze the effect of the sequence of chemotherapy, radiotherapy, and surgery on the prognosis and survival rate of patients with EC.The Surveillance, Epidemiology, and End Results (SEER) database was used to extract a dataset of patients who were diagnosed with EC from 1973 to 2015, with follow-up data for 6 years after diagnosis. The data were analyzed using correlation analysis, logistic regression Cox regression, and Kaplan–Meier analysis.EC patients who had radiation prior to surgery and chemotherapy had a better prognosis than the cases without chemotherapy. Based on univariate logistic regression, the odds radios of vital status recoded for “radiation prior to surgery combined with chemotherapy” is the lowest one among the 8 groups classified by radiation sequence with surgery and chemotherapy (P < .001). Further, radiation prior to surgery and chemotherapy is an independent prognostic factor for better survival among EC patients.In conclusion, in the treatment of EC, administering radiation prior to surgery and chemotherapy is better than no radiotherapy, perioperative radiotherapy, postoperative radiotherapy, and other combinations without chemotherapy.

A Standardized Clinical Pathway Approach to Esophageal Cancer

Clinical pathways associated with the surgical treatment of esophageal cancer patients represent an important development to maximize the opportunity for clinical and cost efficiency in patient care. The main goals implemented in standardized clinical pathways are a comprehensive preoperative workup and tumor board presentation; anesthesia management dedicated to enable enhanced recovery and standardized steps of postoperative recovery, including early mobilization; efficient removal of tubes, catheters, and lines; and early enteral feedings. Recent studies report a decreased length of hospital and intensive care unit stay and decreased costs associated with the routine application of these pathways. Some reports have also shown a decrease in postoperative morbidity and mortality related to the implementation and refinement of standardized clinical pathways. The present review is dedicated to all aspects of standardized clinical pathways for esophagectomy and aims to give an insight into key components of the clinical pathway, which have evolved over the last 20 years at our institution. This review contains 3 figures, 8 tables, and 33 tables. Key words: clinical pathway, costs, enhanced recovery, esophageal cancer, esophagectomy, hospital stay, implementation, length of stay, outcome, standardized pathway

A Standardized Clinical Pathway Approach to Esophageal Cancer

Clinical pathways associated with the surgical treatment of esophageal cancer patients represent an important development to maximize the opportunity for clinical and cost efficiency in patient care. The main goals implemented in standardized clinical pathways are a comprehensive preoperative workup and tumor board presentation; anesthesia management dedicated to enable enhanced recovery and standardized steps of postoperative recovery, including early mobilization; efficient removal of tubes, catheters, and lines; and early enteral feedings. Recent studies report a decreased length of hospital and intensive care unit stay and decreased costs associated with the routine application of these pathways. Some reports have also shown a decrease in postoperative morbidity and mortality related to the implementation and refinement of standardized clinical pathways. The present review is dedicated to all aspects of standardized clinical pathways for esophagectomy and aims to give an insight into key components of the clinical pathway, which have evolved over the last 20 years at our institution. This review contains 3 figures, 8 tables, and 33 tables. Key words: clinical pathway, costs, enhanced recovery, esophageal cancer, esophagectomy, hospital stay, implementation, length of stay, outcome, standardized pathway

Adjuvant Therapy for Node-Positive Esophageal Cancer After Induction and Surgery: A Multisite Study

The benefit of adjuvant treatment for esophageal cancer patients with positive lymph nodes after induction therapy and esophagectomy is uncertain. This in-depth multicenter study assessed the benefit of adjuvant therapy in this population. A retrospective cohort study from 9 institutions included patients who received neoadjuvant treatment, underwent esophagectomy from 2000 to 2014, and had positive lymph nodes on pathology. Factors associated with administration of adjuvant therapy were assessed using multilevel random-intercept modeling to account for institutional variation in practice. Kaplan-Meier analyses were performed based on adjuvant treatment status. Variables associated with survival were identified using Cox proportional hazards modeling. The study analyzed 1082 patients with node-positive cancer after induction therapy and esophagectomy: 209 (19.3%) received adjuvant therapy and 873 (80.7%) did not. Administration of adjuvant treatment varied significantly from 3.2% to 50.0% between sites (P<.001). Accounting for institution effect, factors associated with administration of adjuvant therapy included clinically positive and negative prognostic characteristics: younger age, higher pathologic stage, pathologic grade, noneoadjuvant radiotherapy nonsmoking status, and absence of postoperative infection. Kaplan-Meier analysis showed patients receiving adjuvant therapy had a longer median survival of 2.6 years vs 2.3 years (P= .02). Cox modeling identified adjuvant treatment as independently associated with improved survival, with a 24% reduction in mortality (hazard ratio, 0.76; P= .005). Adjuvant therapy was associated with improved overall survival. Therefore, consideration should be given to administration of adjuvant therapy to esophageal cancer patients who have persistent node-positive disease after induction therapy and esophagectomy and are able to tolerate additional treatment.

Volumetric modulated arc therapy (VMAT) in the treatment of esophageal cancer patients.

The aim of the study is to evaluate feasibility, safety, toxicity profile, and dosimetric results of volumetric modulated arc therapy (VMAT) to deliver definitive or pre-operative radiation in locally advanced esophageal cancer patients. A total of 68 patients were treated with VMAT between March 2014 and March 2018 (44% vs 56% for definitive and neoadjuvant settings, respectively). Dose prescription differed depending on the clinical scenario (54-60Gy in 30 fractions for definitive treatments; 41.4/45Gy in 23-25 fractions in the pre-operative setting). Most of the patients were given concurrent chemotherapy. Two coplanar and one non-coplanar arcs were employed for VMAT delivery. Treatment was generally well tolerated. Acute toxicity was generally mild. In patients treated with definitive intent, ≥ G3 toxicities were observed for esophagitis (30%), anorexia (26.7%), fatigue (26.7%), nausea (6.7%), and vomiting (3.3%). In patients treated within a neoadjuvant approach, ≥ G3 anorexia (21%), esophagitis (15.8%), fatigue (13.3%), nausea (5.3%), and vomiting (2.6%) were observed. Dosimetric results were consistent in term of both target coverage and normal tissue sparing. In conclusion, VMAT proved to be a feasible, safe, and effective strategy to deliver definitive or pre-operative radiation in locally advanced esophageal cancer patients.

Advanced Age is Not a Contraindication for Treatment With Curative Intent in Esophageal Cancer.

The objective of this study is to compare long-term outcomes between younger and older (70 y and above) esophageal cancer patients treated with curative intent. Overall survival (OS), disease-free survival (DFS), and locoregional recurrence-free interval were compared between older (70 y and above) and younger (below 70 y) esophageal cancer patients treated between 1998 and 2013. Treatment consisted of neoadjuvant chemoradiotherapy with surgery or definitive chemoradiotherapy: 36 to 50.4 Gy in 18 to 28 fractions combined with 5-fluorouracil/cisplatin or carboplatin/paclitaxel. The study comprised 253 patients, of whom 76 were 70 years and older. Median age was 64 years (range, 41 to 83). Most patients had stage II-IIIA disease (83%). Planned treatment was neoadjuvant chemoradiotherapy with surgery for 169 patients (41 patients aged 70 y and older) and definitive chemoradiotherapy for 84 patients (31 patients aged 70 y and older). The compliance to radiotherapy was 92%, with no difference between older and younger patients. In 33 patients (13 patients aged 70 y and older) planned surgery was not performed. Median follow-up was 4.9 years. Three-year OS was 42%. The multivariable analysis showed no statistical difference in OS or in DFS comparing older and younger patients: OS (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.61-1.28), DFS (HR, 0.87; 95% CI, 0.60-1.25). Elderly showed a longer locoregional recurrence-free interval; HR, 0.53 (95% CI, 0.30-0.92; P=0.02) and a higher pathologic complete response rate (50% vs. 25%; P=0.02). Long-term outcomes of older esophageal cancer patients (70 y and above) selected for treatment with neoadjuvant chemoradiotherapy followed by surgery or definitive chemoradiotherapy were comparable with the outcomes of their younger counterparts. Advanced age alone should not be a contraindication for potentially curative chemoradiotherapy-based treatment in esophageal cancer patients.

PS02.049: HIGH GPX1 EXPRESSION PROMOTES ESOPHAGEAL SQUAMOUS CELL CARCINOMA INVASION, MIGRATION, PROLIFERATION AND CISPLATIN-RESISTANCE BUT CAN BE REDUCED BY VITAMIN D

Abstract Background Esophageal cancer is one of the most common cancers worldwide. Despite recent progress in the devel- opment of novel therapies, esophageal carcinoma remains an aggressive cancer associated with a poor prognosis. The glutathione peroxidase 1 (GPX1) gene located on chromosome 3p21.3 is associated with the cancer of several organs. According to available information, GPX1, a gene downstream of NF-κB, is considered to exert adverse ef- fects on tumour progression and enhance malignancy in some cancers but has not been reported in esophageal cancer. It is also reported that vitamin D (Vit. D), a widely used drug in the clinical setting, could suppress GPX1 expression through the NF-κB pathway. Thus, it is speculated that Vit. D could reduce malignancy in esophageal cancer by altering the NF-κB pathway. Methods Selection GPX1 high expression EC109 and EC9706 cell line K150, and K180 low expression cell lines transfected with siRNA and vector. Using RT-PCR to detect cell transfection efficiency GPX1’s, Western blot detect the expression of uPA, MMP-2, NF-κB, and CCK-8 assay inhibition or overexpression on GPX1 on ESCC cell cisplatin resistance and proliferation. Transwell assay inhibition or over-expression of GPX1 on invasive ability of ESCC cells. Results By CCK-8 and transwell law found within the cells expressing low GPX1 ESCC can inhibit cell proliferation, cisplatin resistance, invasion and migration, high GPX1 when the opposite phenomenon can be observed. Western blot GPX1 down when found, PTEN, Bax activity rises, PDK-1, AKT, Bcl-2, uPA, MMP-2 expression decreased, vimentin, E-cadherin, ß-catenin, snail is no significant change. After Vit.D treatment, CCK-8 assay showed that cell proliferation and drug resistance was significantly inhibited; Transwell showed cell invasion and migration also decreased. Cells was detected by Western blot after transfection, cells, PTEN, Bax increased activity, p65, PDK-1, AKT, Bcl-2, uPA, MMP-2 expression decreased, vimentin, E-cadherin, ß-catenin, snail is no significant change. Conclusion Treatment with vitamin D can downregulate GPX1, thus decreasing tumour cell capacity for invasion, migration, proliferation and cisplatin resistance via the NF-κB pathway. Vitamin D, already commonly used in clinical therapy, could play a greater role in the treatment of esophageal cancer patients. Disclosure All authors have declared no conflicts of interest.