Advanced Esophageal Research Articles

Palliative Care for Advanced Esophageal Cancer: Solomon Islands and Fiji Perspective

Palliative Care for Advanced Esophageal Cancer: Solomon Islands and Fiji Perspective

A Comparison of Clinicopathologic Outcomes and Patterns of Lymphatic Spread Across Neoadjuvant Chemotherapy, Neoadjuvant Chemoradiotherapy, and Neoadjuvant Immunochemotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma.

Neoadjuvant chemoradiotherapy (NCRT) is recommended as the treatment standard for locally advanced esophageal squamous cell carcinoma (ESCC). The use of immunotherapy in the neoadjuvant setting has gained attention. Multiple, clinical trials have explored the efficacy and safety of neoadjuvant immunochemotherapy (NICT). We evaluated the differences in clinicopathologic outcomes and the patterns of lymphatic spread among patients receiving neoadjuvant chemotherapy (NCT), NCRT, and NICT before esophagectomy for locally advanced ESCC. A total of 702 patients with ESCC who completed transthoracic esophagectomy followed neoadjuvant therapy were included. Pathological characteristics, including pathologic complete response (pCR), tumor regression grade (TRG) score and patterns of lymphatic spread, were evaluated. Compared with the NCT group, the NCRT group and NICT group had an advantage in pathological response (P < 0.05). The pCR rate was 8.1% in the NCT group, 29.9% in the NCRT group, and 23.6% in the NICT group. The TRG score (P < 0.05) and pathologic T stage (P < 0.05) in the NCT group were significantly higher. Compared with NICT, NCRT can significantly reduce the rate of lymph node metastasis rate in station 1R (0 vs. 3.4%, P < 0.05) and 2R (1.1% vs. 6.8%, P < 0.05). Subgroup analysis according to the tumor location distribution showed that NICT group had higher lymph node metastasis rate in station 2R (9.1%) in middle thoracic cases (P < 0.05) and in station 18 (7.5%) (P < 0.05) in lower thoracic cases. NCRT or NICT followed by surgery may result in a promising pCR rate and show a better performance in therapeutic response of primary lesion. For patients with lymph node metastasis in station 1R and 2R, NCRT should be the optimal preoperative treatment strategy.

External Beam Radiotherapy for Dysphagia Palliation in Advanced Esophageal Cancer: A Prospective Study

Background: Esophageal cancer is a highly aggressive malignancy often associated with a poor prognosis because of locoregional failure and distant metastases. About 60–70 percent of the patients present at an advanced stage, have a median survival in the range of 6-10 months, and are not amenable to definitive treatment. Dysphagia is the most common complaint, seen in 80%–90% of patients. The priority for managing patients with advanced disease is dysphagia control, which in turn can improve nutritional intake and quality of life. External-beam radiotherapy (EBRT) is one of the major means of palliation. Objective: The primary goal of our study was to assess the efficacy of external beam radiotherapy in alleviating dysphagia in patients with esophageal cancer.Materials and method: This was a single arm prospective clinical study conducted in a tertiary care hospital in northeast India. The study comprised of 57 esophageal cancer patients, ineligible for definitive treatment. The patients received EBRT of 30 Gy in 10 fractions over two weeks. Dysphagia was graded using Modified Takita’s grading system. Patients were followed up at one-month intervals after treatment to assess dysphagia and acute toxicity. Results: Out of 57 patients in the study, subjective dysphagia relief was seen in 82.45%. The median dysphagia score decreased from 3 to 2 at the end of the 3-month post treatment period. (p &lt; .001). In terms of treatment-related toxicity, treatment was well tolerated. No grade 4-5 toxicity was encountered. The most commonly encountered toxicity was radiation esophagitis, which affected 15 patients (26.31%).Conclusion: Radiation significantly improves dysphagia in esophageal cancer patients. It is an effective, non-invasive, and well-tolerated way to treat dysphagia in selected individuals with incurable esophageal cancer.

Clinicopathological Characteristics and Survival Outcomes in Patients with Advanced Esophageal Squamous Cell Carcinoma Who Were Intraoperatively Diagnosed Non-Curative

Introduction: Curative esophagectomy is not always possible in patients with locally advanced esophageal cancer. However, few studies have investigated patients who underwent non-curative surgery with intraoperative judgment. This study aimed to investigate patient characteristics and clinical outcomes for patients undergoing non-curative surgery and compare them between non-resectional and non-radical surgery. Methods: Among 989 consecutive patients with thoracic esophageal squamous cell carcinoma who were preoperatively expected for curative esophagectomy, 66 who were eligible for non-curative surgery were included in this study. Results: Intraoperative diagnosis of T4b accounted for 93% of the reasons for the failure of curative surgery. In those patients, esophageal cancer locally invaded into the aortobronchial constriction (70%), trachea (25%), or pulmonary vein (5%). Lymph node metastasis mainly invaded into the trachea (50%) or bronchus (28%). The overall survival of patients with non-curative surgery was 51.5%, 25.7%, and 10.4% at 6, 12, and 24 months after surgery, respectively. Although there were no differences in preoperative patient characteristics between non-resectional and non-radical surgery, distant metastasis, especially pleural dissemination, was significantly observed in T4b patients due to esophageal cancer with non-radical surgery than those with non-resectional surgery (35% vs. 15%, p = 0.002). Even in patients with non-curative surgery, R1 resection and postoperative chemoradiotherapy were identified as independent factors for survival 1 year after surgery (p = 0.047, and 0.019). Conclusions: T4b tumor located in aortobronchial constriction or trachea/bronchus makes it difficult to diagnose whether it is resectable or unresectable. Moreover, surgical procedures and perioperative treatment were deeply associated with the clinical outcomes.

Intraoperative Blood Loss Impacts Recurrence and Survival in Patients With Locally Advanced Esophageal Cancer.

Intraoperative blood loss (IBL) has been reported to decrease survival after surgical resection of some malignancies; however, there are few reports on the effects of IBL on recurrence and survival in locally advanced esophageal cancer. Therefore, we investigated the relationship between IBL and postoperative recurrence and overall survival in patients who underwent surgery for esophageal cancer. One hundred and ninety-eight patients with locally advanced esophageal cancer who underwent preoperative adjuvant chemotherapy and curative resection as standard treatment were included in this study. Based on a defined cut-off value for IBL, 27 and 171 patients were classified into the high and low IBL groups, respectively. The relationship between each group and clinicopathological factors, postoperative recurrence, and overall survival were investigated. In terms of the relationship between IBL and clinicopathological factors, the high IBL group had significantly more patients with pathological T4, longer operative time, and higher incidence of postoperative complications than the low IBL group. Both recurrence-free and overall survival were significantly worse in the high IBL group than in the low IBL group. Furthermore, multivariate analysis identified high IBL as an independent factor for predicting poor reference free survival and overall survival. Heavy IBL in patients with locally advanced esophageal cancer may be a useful predictor of postoperative recurrence and overall survival.

The Use of Trimodality Treatment in Patients With Locally Advanced Oesophageal Squamous Cell Carcinoma: An Experience From a Large Cancer Centre in Pakistan.

Introduction Esophageal cancer is one of the most common cancers worldwide. Neoadjuvant chemoradiotherapy followed by surgery is the standard treatment for locally advanced squamous cell carcinoma (SCC). Pathological complete response (pCR) after surgery is associated with better outcomes in terms of overall survival and disease-free survival. We aim to determine the effectiveness of neoadjuvant chemoradiotherapy in patients with locally advanced SCC at our institute, the largest purpose-built cancer center in Pakistan. We also aim to identify various factors influencing pCR, such as chemotherapy regimen, total radiation dose, clinical stage at presentation, and gender. Materials and methods This is a retrospective review of all patients with esophageal SCCpresented between January 2019 and 2021 to the institute for treatment. Patients received neoadjuvant chemoradiotherapy (nCRT) as per the CROSS trial protocol, followed by surgery. We assessed the pCR rate. Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 22 (Released 2013; IBM Corp., Armonk, New York). pCR was studied alongside associated factors such as age, gender, stage of disease, chemotherapy regimen, and total dose of radiotherapy. A p-value of <0.05 was considered statistically significant. The chi-square test was used to compare categorical variables. Univariate and multivariate logistic regression was employed to evaluate factors affecting pCR. Results A total of 218 patients were included in the study. pCR was achieved in 64.2% of the patients. The female gender was associated with better outcomes, as 70.4% (n=81) of female patients achieved a complete pathological response, compared to 57.3% (n=59) of males, with a p-value of 0.03. On univariate analysis, the complete pathological response was 69.6% (n=94) in the age group of 45 years and below, whereas it was 55.4% (n=46) in the age group above 45 years, with a p-value of 0.024. Though statistically insignificant, outcomes were slightly better for those with node-negative disease, as 67.2% (n=41) achieved complete pathological response compared to those with node-positive disease at 63.1% (n=99). Univariate logistic regression analysis identified gender (p=0.044, OR=1.77, 95% CI:1.016-3.108) and age group (p=0.034, OR=1.844, 95% CI: 1.046-3.252) as significantly associated with pCR. Female patients were 77% more likely to achieve pCR compared to male patients (OR=1.77, 95% CI:1.016-3.108). Younger patients (≤45 years) were 84.4% more likely to achieve pCR compared to the older age group (OR=1.844, 95% CI:1.046-3.252). However, these did not maintain significance in multivariate logistic regression analysis. Conclusion Our study indicated a high rate of pCR with nCRT in patients with esophageal SCC compared to other studies. The achievement of pCR was higher among females and younger patients, which was statistically significant on univariate logistic regression analysis. Our study also concluded that a higher dose of RT (50Gy/25#) is not superior to a lower dose (45Gy/25#) in terms of pCR achievement but was statistically insignificant. Similarly, CARBO/PAC was not superior to CIS/CAP in terms of pCR achievement and was also statistically insignificant.

Neoadjuvant Chemoradiation Followed by Surgery for Locally Advanced Squamous Cell Carcinoma Esophagus: Demographics and Evaluation of Prognostic Factors at a Tertiary Care Center in India.

Neoadjuvant chemoradiation followed by surgery has been the standard of care for locally advanced carcinoma esophagus. We present our experience and inference of various factors associated with the same treatment and the prognostic influence of the same. A retrospective analysis of a cohort of 132 squamous cell carcinoma esophagus patients post neoadjuvant chemoradiation operated with curative intentwas carried out. The 2-year overall survival rate was 64.5%. A pathological complete response was achieved in 32.5% of patients and was the only factor that significantly determined overall survival (p = 0.048). Neoadjuvant chemoradiation before surgery for locally advanced squamous cell cancer of the esophagus remains the standard of care with a pathological complete response being a significant factor in predicting overall survival. More prospective randomized studies are necessary to analyze factors affecting and predicting a pathological complete response which would help organ preservation in patients with a complete response.

Radiotherapy for Advanced Esophageal Cancer: from Palliation to Curation.

Esophageal cancer is a global health problem, which is 7th most common and 6th most deadly cancer. It has been the era of immuno-oncology for esophageal cancer management. Radiation therapy has been one of the key local therapeutic approaches for esophageal cancer treatment, while its role in advanced disease is challenging and debatable. There have been emerging clinical and translational studies of radiation therapy in recurrent or metastatic esophageal cancer. Immunotherapy has been established the standard care of 1st and 2nd line systemic therapies of advanced esophageal cancer, and the development of tumor immunity has opened a new chapter for the esophageal cancer radiation therapy. The current review will summarize the classic radiation therapy research in advanced esophageal cancer, as well as the most recent key findings. The subtitles will cover palliative radiotherapy for dysphagia, re-radiation for recurrent disease, oligo-focal disease management and stereotactic radiation therapy, and radiotherapy with immunotherapy. Radiotherapy plays vital role in multidisciplinary management of advanced EC. External or intratumoral irradiation has been used for palliation of dysphagia and improving QOL in esophageal cancer patients traditionally, while recent clinical and technical advance enables radiotherapy to be considered in recurrent or metastatic disease for curation attention. Novel clinical and translational investigation is opening a new chapter of radiotherapy with immunotherapy for benefiting advanced EC patients.

ASO Visual Abstract: Radiomics Nomogram with Added Nodal Features Improves Treatment Response Prediction in Locally Advanced Esophageal Squamous Cell Carcinoma-A Multicenter Study.

ASO Visual Abstract: Radiomics Nomogram with Added Nodal Features Improves Treatment Response Prediction in Locally Advanced Esophageal Squamous Cell Carcinoma-A Multicenter Study.

Radiotherapy for Patients with Locally Advanced Esophageal Squamous Cell Carcinoma Receiving Neoadjuvant Immunotherapy Combined with Chemotherapy

With the success of immunotherapy in advanced esophageal cancer, neoadjuvant chemo-immunotherapy (CIT) is being increasingly used for local staged esophageal cancer, especially in the context of clinical trials, which brings similar pCR with neoadjuvant chemoradiotherapy and shows promising results. However, there is still a part of potentially operable patients can't undergo surgery after neoadjuvant chemo-immunotherapy. The follow-up treatment and prognosis of this population remain unclear. Patients pathologically diagnosed with ESCC, clinical stage T1-3N+M0 or T3-4aNanyM0(AJCC 8th), PS 0-1 were retrospectively enrolled from 1/2020 to 6/2021 in Zhejiang Cancer Hospital. All patients firstly received PD-1 inhibitors (Camrelizumab, Sintilimab or Tislelizumab) plus chemotherapy (albumin paclitaxel,260 mg/m²on day 1 plus carboplatin AUC = 5 on day 1) every 3 weeks for 2-4 cycles. For those patients who did not receive surgery, definitive radiotherapy with 50.4Gy/28F or 50Gy/25F was adopted using VMAT, concurrent with chemotherapy or alone. The concurrent chemotherapy regimens included weekly TC (paclitaxel 50 mg/m 2, d1, carboplatin AUC = 2, d1) or S1 (60mg bid d1-14,29-42). The survival outcomes and treatment toxicity were recorded and analyzed. A total of 56 eligible patients were finally identified from 558 patients who were treated in department of thoracic surgery, 31 patients showed no response to neoadjuvant CIT (6 with PD and 25 with SD), 25 patients achieved PR but did not receive surgery due to poor performance status or refuse to operation. Median age was 66(IQR 56-72) and 55(98.2%) were males. 12(19.6%) were stage II and 44(80.4%) were stage III. Among all the patients,25 (44.6%) received radiotherapy alone, and 31 (55.4%) received chemoradiotherapy after neoadjuvant CIT. The median follow-up was 11.8 months (IQR 8.6-20.1). The median PFS and OS were 16.5 months (95CI 12.9-21.4) and 18.6 months (95CI 11.2-NA), respectively. In the subgroup analysis, the median PFS for patients with PR to CIT was 20.2 moths (95CI:17.23-NA), and 12.9 moths (95CI: 0.68-20.4) for patients with SD or PD, HR was 0.45 (95CI:0.22- 0.93, P = 0.027). No significant difference was observed for patients received radiotherapy alone or chemoradiotherapy with HR = 1.36(95CI:0.69-2.71, P = 0.37). The most common AEs observed during this study were anemia (98.2%), Leukopenia (83.9%), Thrombocytopenia (53.6%). Adverse events of grade≥3 radiation-induced pneumonitis and esophagitis were 12.5% and 32.1%, especially, 6 patients (10.7%) died from esophageal fistula and 2 patients (3.6%) died from grade 5 pneumonitis. For local advanced ESCC patients after neoadjuvant CIT who did not receive surgery, definitive radiotherapy was an optional treatment strategy. However, those patients with no response to CIT also showed poor response to radiotherapy, and particular attention should be paid to treatment related toxicity, especially esophageal fistula.

Endoscopic Ultrasonography-Derived Maximum Tumor Thickness and Tumor Shrinkage Rate as Independent Prognostic Factors in Locally Advanced Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemoradiotherapy

Neoadjuvant chemoradiotherapy (NCRT) is increasingly used in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). Endoscopic ultrasonography (EUS)-derived maximum tumor thickness (MTT) before and after standard NCRT for LA-ESCC indicates treatment response. However, the accuracy of predicting long-term survival remains uncertain. This study aimed to investigate the association between EUS-derived MTT pre- and post-NCRT and tumor shrinkage rate as well as long-term survival in patients with LA-ESCC receiving NCRT. We retrospectively enrolled patients with LA-ESCC who underwent EUS examination pre- and post-NCRT from 2017 to 2021. MTT was measured using EUS. Tumor shrinkage rate was the ratio of the difference between pre- and post-MTT to pre-MTT. The most fitted cut-off value defining the EUS response was determined by the receiver operating characteristic curve. Univariate and multivariate Cox regression analyses and Kaplan-Meier (KM) curves were used to calculate overall survival (OS) and progression-free survival (PFS). Data from another center were also used for external validation testing. The median follow-up period was 30.6 months.230 patients with LA-ESCC who underwent EUS pre- or post-NCRT were enrolled. Of the patients, 178 completed the first EUS pre-NCRT and obtained pre-MTT, 200 completed the re-examined EUS post-NCRT and obtained post-MTT, and 148 completed both EUS and achieved tumor shrinkage. In the whole group the 1-year and 3-year OS rates were 93.9% and 67.9%, and PFS rates were 77.7% and 54.1%, respectively. Thinner post-MTT (≤8.8 mm) and EUS-responders (tumor shrinkage rate≥52%) were independently associated with better OS. The result of EUS-respond was an independent prognostic factor could be confirmed in the external validation group. Among LA-ESCC patients with initial ultrasonic T2-3 staging and T4 staging, no statistically differences were observed between the responder and non-responder groups (P = 0.082; P = 0.190). EUS-derived MTT and tumor shrinkage post-NCRT are independent prognostic factors for long-term survival and may be an alternative method for evaluating tumor response in patients with LA-ESCC after NCRT. Initial tumor infiltration beyond esophageal adventitial layer on ultrasound effect could not, however, predict the long-term prognosis.

Treatment Response Prediction Using a Combination of Hematological Biomarkers and CT Deep Learning Radiomics in Locally Advanced Esophageal Squamous Cell Carcinoma

To assess the complementary value of hematological biomarkers to deep learning-radiomic models for assessing esophageal squamous cell carcinoma (ESCC) pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT), which will help to provide a reference for the following clinical study of esophageal preservation. A total of 157 patients with ESCC were enrolled and divided into a training cohort (n = 111) and a validation cohort (n = 47). Computed tomography (CT) was performed for all patients 2 weeks before and 6 weeks after nCRT. In addition, clinicopathological factors and hematological parameters before nCRT were collected. Deep learning and handcrafted radiomic features were extracted from segmented regions of interest (ROIs) from pretreatment (ROI1) and posttreatment (ROI2) CT, which represented the features of the pre- and posttreatment tumors, respectively. The minimum redundancy maximum relevance (mRMR) and least absolute shrinkage and selection operator (LASSO) algorithms were used for feature selection, and logistic regression (LR) was used as the classifier. The deep learning radiomic nomogram (DLRN) was then developed based on the rad-scores and independent clinicopathological risk factors. The model was assessed using area under the receiver operating characteristic (ROC) curve analysis, calibration curve analysis and decision curve analysis and verified with both 10-fold cross-validation and internal validation using bootstrap resampling with 1000 replicates. Rad-scores were constructed with 8 features, which were finally selected as the most predictive features from ROI 1 and ROI 2. The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), albumin and rad-scores were incorporated into the DLRN, which achieved good prediction performance, with areas under the ROC curve of 0.888 (95% CI, 0.824-0.951, p <0.05) for the training cohort and 0.873 (95% CI, 0.772-0.974, p <0.05) for the validation cohort. On the training set, the DLRN achieved an AUC of 0.882 in 10-fold cross-validation, and after internal validation, the area under the ROC curve still reached 0.884. The DLRN performed significantly better than the clinical model and radiomics models (p<0.05). IDI and continuous NRI showed significant improvement for the DLRN when incorporating radiomics features and hematological parameters (IDI = 0.3399, P <0.001; continuous NRI = 1.141, P <0.001; categorical NRI = 0.3836, P <0.001). Calibration curves (p > 0.05) and DCA demonstrated that the DLRN was useful for pCR prediction and produced a greater net benefit than the clinical model and radiomics models. Incorporation of radiomics features and hematological parameters into the DLRN improved pCR prediction after nCRT in ESCC. Enhanced pCR predictability may improve patient selection before surgery, providing clinical application value for the use of active surveillance.

Neoadjuvant Chemoradiotherapy Combined with Nimotuzumab and Camrelizumab in Initially Inoperable Patients with Locally Advanced Esophageal Cancer: A Prospective, One-Arm, Phase II Study

The neoadjuvant chemoradiotherapy combined with surgery has become the standard treatment model for operable locally advanced esophageal cancer. This present study was aimed to explore the feasibility and safety of neoadjuvant chemoradiotherapy combined with nimotuzumab and camrelizumab in initially inoperable patients with locally advanced esophageal cancer (NCT0535168). Patients with initially inoperable locally advanced esophageal cancer were enrolled. All patients were supposed to receive neoadjuvant chemoradiotherapy (40.85-41.4Gy/19-23f plus albumin paclitaxel (0.05g qw) and cisplatin (30mg qw)). The nimotuzumab (EGFR antibody targeting extracellular domain) was administrated 200mg weekly and the camrelizumab was taken 200mg every 3 weeks. The primary endpoints were safety and the surgical conversion rate. The second endpoints were pathological response, 1, 2 and 3-years disease free survival, and alteration of the immune microenvironment after neoadjuvant therapy. From December 2021 to now, 20 initially inoperable patients with locally advanced esophageal cancer were enrolled in this study, including 16 males and 4 females. The median age was 65 years. 19 patients were squamous cell carcinoma, and 1 patient was adenocarcinoma. The surgical conversion rate was 70% (14/20). The pathological complete response rate was 35.7% (5/14). The main AEs were radiation esophagitis and hematological toxicity. 4 patients developed over Grade III myelosuppression (3 for Grade Ⅲ (15%) and 1 for Grade Ⅳ (5%). 1(5%) patient developed Grade III atopic dermatitis. No patients died or with disease progression in patients who underwent surgery up to now. Compare to pre-treatment baseline, CD8+T cell and IFN-γ were significantly increased, IL-8 was significantly decreased in peripheral blood after neoadjuvant therapy. The neoadjuvant chemoradiotherapy combined with nimotuzumab and camrelizumab was with high surgical conversion rate and acceptable safety in initially inoperable patients with locally advanced esophageal cancer.

A Comparison of Clinicopathologic Outcomes and Patterns of Lymphatic Spread across Neoadjuvant Chemotherapy, Neoadjuvant Chemoradiotherapy and Neoadjuvant Immunochemotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma

To evaluate the differences in pathologic complete response (pCR) rates, TRG score, pathologic T stage and the pattern of lymphatic spread among patients receiving neoadjuvant chemotherapy (NCT) or neoadjuvant chemoradiotherapy (NCRT) or neoadjuvant immunochemotherapy (NICT) prior to esophagectomy for locally advanced esophageal squamous cell carcinoma (ESCC). A total of 702 patients with ESCC who completed transthoracic esophagectomy followed neoadjuvant therapy at three cancer centers from January 2017 to December 2022 were enrolled. Among the included patients, 382 patients were treated with NCR, 172 with NCRT, and 148 with NICT. Inverse probability of treatment weighting (IPTW) was performed to control potential confounding factors. Pathological response of primary tumor was evaluated using the Chirieac modified tumor regression grade (TRG) system. The complete regression of primary lesion and nodal metastases were considered pCR. Lymph node classification system used the 8th edition of AJCC. Specimens were assessed for pattern of lymphatic spread. After adjusting for baseline characteristics, the R0 resection rate did not significantly differ between the patients receiving NCT or NCRT or NICT (99.48% vs.100% vs.98.65%, P = 0.273). Compared with the NCT group, the NCRT group and NICT group had an advantage in pathological response (P<0.05). The pCR rate was 7.07% in the NCT group, 30.23% in the NCRT group, and 22.30% in the NICT group. Compared to the other two groups, the TRG score (P<0.05) and pathologic T stage (P<0.05) in the NCT group were significantly higher. In the NCT group, 9.97% had ypT0 disease, compared with 35.76% in the NCRT group and 25.68% in the NICT group. And in the NCT group, 9.71% had TRG1 disease, compared with 32.76% in the NCRT group and 25% in the NICT group. Compared with NICT, NCRT can significantly reduce the rate of LNM in station 1R (0 vs 3.38%, P<0.05) and 2R (1.15% vs 6.76%, P<0.05). Subgroup analysis according to the tumor location distribution showed that in upper thoracic cases, there was no statistical difference in LNM rates among stations no matter whether patients received NCT or NCRT or NICT. NICT group had higher LNM rates in station 2R (9.1%) in middle thoracic cases (P<0.05) and in station 18 (7.5%) (P<0.05) in lower thoracic cases, compared with the NCRT group and NCT group. NCRT or NICT followed by surgery may result in a promising pCR rate and show a better performance in therapeutic response of primary lesion. No matter whether patients received NCT or NCRT or NICT, multiple level and skip node metastases are common, and adequate lymphadenectomy should be achieved to ensure the complete removal of metastatic lymph nodes.

A Prospective Study of Bevacizumab and Neoadjuvant Concurrent Chemoradiation in Locally Advanced Esophageal Squamous Cell Carcinoma: Paradoxical Increase in Circulating Vascular Endothelial Growth Factor-A and Effect on Outcome

In the prior prospective biomarker study, high serum vascular endothelial growth factor-A (VEGF-A) was associated with a poor prognosis. We conducted a prospective phase II trial of adding Bevacizumab, an anti-VEGF-A monoclonal antibody, to neoadjuvant concurrent chemoradiation (neoCCRT) for patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). This prospective biomarker study aims to evaluate the expressions of angiogenesis-associated circulating biomarkers before and after neoCCRT and compare clinical outcomes for patients receiving platinum/5-fluorouracil (PF) with or without Bevacizumab. Patients with biopsy-proven resectable non-T4 LA-ESCC were enrolled for the prospective phase II trial investigating PF-neoCCRT plus Bevacizumab (BPF group). A parallel patient cohort enrolled in a prospective biomarker study receiving PF-neoCCRT was included in the present analysis as the control group (PF group). Radiotherapy was delivered with 40 Gy in 20 fractions. All patients had restaging workups after enoCCRT and underwent radical esophagectomy if the disease remained resectable. Serums were collected before and after neoCCRT. The serum concentrations of angiogenesis-associated biomarkers were determined by the multiplex enzyme-linked immunosorbent assay. Survival analyses were performed by the Kaplan-Meier method. The t-test and log-rank test were used to compare differences in biomarker expression and survival between groups. From 2016 to 2019, 43 patients (BPF/PF group: 21/22) were enrolled in the study. Twenty patients in each group had serum samples available for biomarker analysis. 15 out of 21 patients in the BPF group and 20 out of 22 patients in the PF group underwent radical esophagectomy. Six patients in the BPF group and nine patients in the PF group achieved pathological complete responses. The median overall survival for the BPF and PF group was 20.8 months and not-reached, respectively (hazard ratio = 1.33, long rank p = 0.58). In the BPF group, the serum VEGF-A level was significantly increased from an average value of 446 pg/mL to 723 pg/mL after neoCCRT (p = 0.037), while its level was decreased from 815 ng/mL to 380 pg/mL in the PF group (p = 0.104). In addition, the expression value of circulating Angiopoietin-1 was not changed in the BPF group (before neoCCRT, mean value = 828 pg/mL; after neoCCRT, mean value 762 pg/mL, p = 0.67). In contrast, serum Angiopoietin-1 level was reduced from an average value of 659 pg/mL before neoCCRT to 271 pg/mL after neoCCRT (p = 0.002) in the PF group. The addition of Bevacizumab to PF-neoCCRT did not improve pathological or survival outcomes in patients with resectable LA-ESCC. Adding a single dose of Bevacizumab paradoxically increases circulating VEGF-A while maintaining the Angiopoietin-1 serum level after neoCCRT. Further investigation by using additional VEGF-A inhibition may be required to achieve sustained angiogenesis blocked for tumor control.

The Predictive Value of Changes in Basal Myocardial F-18 Fluorodeoxyglucose Uptake for Cardiotoxicity in Locally Advanced Esophageal Cancer Patients Receiving Definitive Radiotherapy

To investigate the predictive value of changes in myocardial 18F-FDG uptake for major adverse cardiac events (MACEs) in locally advanced esophageal cancer patients receiving definitive radiotherapy. Between August 2012 and January 2018, 400 patients with stage II-III esophageal cancer receiving definitive radiotherapy at two institutions were divided into the training (n = 240) and external validation cohorts (n = 160). All patients underwent FDG-PET imaging within 1 week before treatment and 3 months after treatment. Myocardium delineation was performed by Carimas software (version 2.10) based on the AHA 17-segment model. When contouring the left ventricle, the myocardium was automatically divided into basal (segments 1-6), middle (segments 7-12), and apical (segments 13-16) regions, and the mean dose and FDG uptake parameters of each region were obtained by Carimas. Our primary endpoint was MACEs. Patient clinicopathologic factors, dosimetric parameters for the whole heart and cardiac substructures, and myocardial changes within the three regions on 18F-FDG PET were utilized to seek the best predictive models for cardiotoxicity. To avoid multicollinearity between dose-volume histogram (DVH) parameters, we selected the variables with the lowest Akaike Information Criterion (AIC) value from the DVH parameters of the same cardiac structure for the actual modeling procedure. Competing risk analysis and Cox regressions analysis were performed. The predictive performance of the models was evaluated using the area under the receiver operating characteristic curve (AUC) and Brier score. At a median follow-up interval of 78 months, 28 patients (11.7%) developed MACEs. The basal region of the myocardium received the highest radiation dose, followed by the middle and the apex region. The basal myocardial SUVmax and SUVmean significantly increased after radiotherapy while the apical and middle myocardial SUVmax and SUVmean not significantly increased. In univariate analysis, age, pre-existing cardiac disease, changes in pre- and post-treatment basal myocardial SUVmax and SUVmean (∆SUVmax and ∆SUVmean), and dosimetric parameters for MHD, mean LCX, mean LAD, and mean LV dose were associated with an increased hazard of MACEs. Multivariate analysis showed that basal ∆SUVmean retained significance after adjusting for age, pre-existing cardiac disease, and dosimetric parameters for whole heart and cardiac substructures. The AUCs and Brier scores demonstrated favorable predictive accuracies of the model's integrating variables with significant difference in multivariate analysis when predicting MACEs in the training and validation cohorts. ∆SUVmean was an independent indicator of MACE in locally advanced esophageal cancer patients receiving definitive radiotherapy. Changes in basal myocardial FDG uptake is a promising biomaker for predicting radiation-induced cardiotoxicity.

Comparison of Pathologic Response and Survival Outcomes between Neoadjuvant Immunochemotherapy (nICT) and Neoadjuvant Chemoradiotherapy (nCRT) in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma: A Propensity Score-Matched Analysis

The neoadjuvant immunochemotherapy (nICT) is a novel treatment, which is likely to be safer for locally advanced, surgically resectable Esophageal squamous cell carcinoma (ESCC) that comparing with the traditional neoadjuvant therapy. However, the efficacy of nICT was controversial and the survival benefit remain unknown. This study included 313 patients with locally advanced ESCC who underwent surgery following neoadjuvant therapy at Sichuan Cancer Hospital from June 2017 and September 2021. The patients were divided into nICT group and neoadjuvant chemoradiotherapy (nCRT) group according to the neoadjuvant strategy. A 1:2 propensity score matching (PSM) was used to balance potential bias across several covariates between two groups with a caliper 0.05. Among the 146 patients after PSM, the baseline factors were comparable between two groups. Compared with the nCRT group, the nICT group shown a lower pathologic complete response(pCR) rate (11.54% vs 35.11%; P = 0.0039) and lymph nodes uninvolved rate (ypN0: 44.23% vs 62.77%; P = 0.0154), but a higher perineural invasion (32.69% vs 12.77%; P = 0.0075) and angioinvasion rate (40.38% vs 10.64%; P = 0.0001). However, the 2-year OS and DFS rates were similar between the nICT group and the nCRT group in overall study cohort, and these data were confirmed in the matched samples (2-year OS, 78.2% vs 77.2% [p = 0.95]; DFS, 56.9% vs 58.0% [p = 0.69]). Our preliminary findings indicate that, for individuals with locally advanced ESCC, nICT followed by surgery appears to be less effective in pathologic outcomes, while having a comparable survival rate to nRCT. These results imply a complicated and possibly multifaceted link between the kind of neoadjuvant therapy, the pathologic outcomes, and the final survival.

Grade 4 Lymphopenia Might Associate with Pericardial Irradiation Dose and Worse Prognosis in Patients with Locally Advanced Esophageal Cancer Receiving Concurrent Chemo-Radiotherapy

The immune system may influence prognosis, and lymphopenia is a frequent side effect of concurrent chemo-radiotherapy (CCRT). Radical irradiation for locally advanced esophageal cancer (LA-EC) exposes significant vascular and heart volumes, and we hypothesized that lymphopenia is linked to cardiac and pericardial doses and affects patient prognosis. We identified 190 LA-EC patients who received radical CCRT between 2011 and 2019. Cardiac, pericardial, and lung dosimetric parameters were obtained and multivariate analysis (MVA) was performed to correlate clinical factors and dosimetric parameters with overall survival (OS). Absolute lymphocyte count (ALC), absolute platelet count (PLT), absolute white blood cell count (WBC), absolute neutrophil count (ANC), neutrophil-lymphocyte ratio (NLR = ANC/ALC), and platelet-lymphocyte ratio (PLR = PLT/ALC) were collected before and during CRT. Grade 4 (G4) lymphopenia was defined as Lymphocyte count nadir <0.2 103/mL during CRT and it was used to dichotomize the lymphocyte count nadir. MVA was performed to correlate hematologic toxicity with OS. Logistic stepwise regression was performed to determine the relationship between dosimetric parameters and G4 lymphopenia. Finally, a nomogram of G4 lymphopenia was developed and validated externally. Median follow-up time for all patients was 27.5 months (range 12-118 months). On MVA for OS (n = 190), higher pericardial V30 (PV30) was linked to worse survival (HR = 1.013, 95% CI 1.001-1.026, p = 0.039). The median OS stratified by PV30>55.3% and PV30≤55.3% was 24 months and 54 months, respectively (p = 0.004). G4 lymphopenia was shown to be linked with worse OS in the MVA of hematological toxicity (n = 161) with OS (HR = 2.042, 95% CI 1.335-3.126, p = 0.001). 24 (24%) of the 100 patients in the training set had G4 lymphopenia. Our final model comprised Stage-IVA (p = 0.017), PLR during CRT (p = 0.008), Heart V50 (p = 0.046), and PV30 (p = 0.048). External validation 26 of 90 patients (29%) had grade 4 lymphocytopenia. The ROC curve displays an AUC for internal validation of 0.775 and external validation of 0.843. Higher doses of pericardial radiation might affect LA-EC patients' prognosis by inducing G4 lymphopenia in CCRT process. Further prospective studies are warranted to confirm these findings, especially in the era of immune-checkpoint inhibitor treatment.

Prospective Trial of Using Imaging to Predict Pathologic Response and Clinical Outcomes in Locally Advanced Esophageal Cancer

Trimodality therapy with chemoradiation (CRT) followed by esophagectomy is the standard of care for locally advanced esophageal cancer. An unresolved question is whether pathologic complete response (pCR) can be assessed non-invasively for patients post-CRT. In this study, we assessed whether diffusion-weighted imaging (DWI) with MRI or PET can be used as predictors of pCR and other clinical outcomes after CRT. Patients were enrolled on a single-arm institutional trial (PA13-0380) assessing the role of imaging in predicting outcomes in potentially resectable esophageal patients undergoing trimodality therapy. All patients received neoadjuvant CRT, and 29 patients had subsequent surgery. DWI MRI and PET scans were obtained at baseline, 2 weeks after the start of CRT (interim) and 4 to 6 weeks after completion of CRT (follow up). Apparent diffusion coefficients (ADCs) were calculated based on DWI images. Circulating tumor DNA was obtained for 27 patients post-radiation using CAPP-Seq. Mann-Whitney tests compared imaging changes associated with pCR. Discrimination of pCR by imaging changes was quantified by received operating characteristics. Youden's index was applied to select optimal thresholds. Kaplan-Meier analysis was performed to assess differences in overall survival (OS) and progression-free survival (PFS) by changes in DWI, PET, and ctDNA parameters. Our cohort of 60 patients had a median follow up of 42.7 months, age of 65.4 yrs, and ECOG of 1 at completion of CRT. 90% were male, 58% had a history of smoking, and 85% were white. 83% had adenocarcinoma with the rest squamous cell carcinoma. Stages of the patients ranged from IIA to IIIB. All had moderately (47%) or poorly (53%) differentiated disease. All received 41.4-50.4 Gy in 1.8 Gy fractions with the majority receiving 50.4 Gy (95%). 29 patients underwent surgery after CRT of which 8 (27.6%) had pCR. Mean ΔADC from baseline to mid-treatment was most associated with pCR (AUC = 0.98, p<0.001) for patients undergoing surgery. Max ΔADC from baseline to first follow-up was most associated with OS (p = 0.002) and PFS (p<0.001) for the whole cohort. 27 patients had ctDNA analyzed after RT with the presence of ctDNA significantly associated with worse OS (HR = 0.12, p = 0.05) and PFS (HR = 0.10, p = 0.002). Combining ctDNA and max ΔADC generated a model that was more predictive of OS and PFS than either alone. We found that neither the PET parameters of TLG or SUV max at baseline or changes in these parameters from baseline to mid-treatment or first follow-up were as predictive as DWI. We show that changes in DWI is associated with pCR, OS, and PFS in resectable esophageal cancer patients undergoing CRT. DWI was more predictive than PET and a model combining DWI and ctDNA was the most predictive of clinical outcomes. This study shows the significant promise of using DWI in potentially guiding treatment decisions in esophageal cancer patients and will require validation in a larger cohort.

Advances in Neoadjuvant Immunotherapy for Locally Advanced Esophageal Cancer

Abstract: Esophageal cancer is one of the common malignant tumors in China with a high mortality rate. Neoadjuvant chemoradiotherapy (nRCT) is currently the primary treatment method for locally advanced esophageal cancer. However, nRCT has not been not widely applied in China due to several reasons. First, the radiotherapy equipment and technology vary in different regions, and the learning curve for these technologies is steep, making rapid implementation difficult. Furthermore, the combined toxicity of radiotherapy and chemotherapy can counteract the survival benefits of preoperative treatment. In recent years, a promising approach involves combining neoadjuvant chemotherapy with immunotherapy for patients with locally advanced esophageal cancer. This article offers an overview of the progress in neoadjuvant therapy for this condition.