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Background The standard treatment for elderly patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is definitive chemoradiotherapy with S-1. However, the 3-year overall survival (OS) is limited to approximately 40%. Tislelizumab is the first- and second-line standard treatment for advanced ESCC with tolerable toxicity. In this study, we aimed to explore a new curative strategy for locally advanced unresectable ESCC in the elderly by combining tislelizumab with chemoradiotherapy. Methods This study is an open-label, multicenter, investigator-initiated phase II clinical trial in older patients with inoperable locally advanced ESCC evaluating tislelizumab plus concurrent chemoradiotherapy compared with concurrent chemoradiotherapy. The main inclusion criteria were pathological confirmation of locally advanced inoperable ESCC at clinical cT1N2-3M0 or cT2-4bN0-3M0 (stage II–IVA), age ≥ 70 years, absence of previous systemic anti-tumor therapy, and adequate organ function. A total of 136 patients will be recruited from approximately seven centers (in Tianjin, Chengdu, Taiyuan, Zhengzhou, Shijiazhuang, Changsha, Nanjing) over a period of 18 months and randomized in a 1:1 ratio to receive tislelizumab in combination with concurrent chemoradiotherapy (tislelizumab + S-1 + radiotherapy) or concurrent chemoradiotherapy (S-1 + radiotherapy). The efficacy and safety of the treatment will be evaluated during the therapy and follow-up period until disease progression, death, or the end of the trial. The primary study endpoint was investigator-assessed progression-free survival (PFS), and secondary study endpoints were OS, objective response rate (ORR), duration of remission (DOR), and safety. Fresh or archival tumor tissues and peripheral blood samples will be used in exploratory studies. Discussion This study is the first “programmed death-1 (PD-1) inhibitor combined with concurrent chemoradiotherapy” for elderly patients with inoperable locally advanced ESCC (NCT06061146). The synergistic efficacy of combined definitive concurrent chemoradiotherapy with tislelizumab is expected to result in survival benefits for elderly patients with inoperable locally advanced ESCC. Because S-1 plus concurrent radiotherapy is the standard treatment option for locally advanced ESCC in older patients, the combination of definitive concurrent chemoradiotherapy and tislelizumab has the potential to change the standard ESCC therapeutic strategy with comparable safety. Trial registration ClinicalTrials.gov NCT06061146.Registered 9/10/2023.

Background In locally advanced, operable esophageal squamous cell carcinoma (ESCC), neoadjuvant immunochemotherapy (nICT) has shown results that are somewhat comparable to those of standard neoadjuvant chemoradiotherapy (nCRT). The impact of these neoadjuvant treatments on survival outcomes, however, has yet to be elucidated. Methods This study included 489 patients with locally advanced ESCC who underwent surgery at Sichuan Cancer Hospital after receiving neoadjuvant treatment between June 2017 and September 2023. Patients were categorized into nCRT and nICT groups based on whether they received neoadjuvant treatment. To mitigate potential biases and balance covariates between the two cohorts, 1:2 propensity score matching (PSM) was conducted using a caliper width of 0.05. Results After PSM, the baseline characteristics of the 360 patients remained balanced between the two groups. The findings indicated a superior pathological response in the nCRT group, as evidenced by significantly greater rates of complete response (32.87% vs 14.58%, P  < 0.001) and favorable tumor regression grade (TRG), as well as reduced ypT stages and less perineural and angioinvasion, despite comparable ypN stages. Despite the improvement in complete pathological response (pCR) in the nCRT group, the 3-year disease-free survival (DFS) and overall survival (OS) rates did not significantly differ between the groups (DFS: 58.32% vs 56.16%, P  = 0.67; OS: 69.96% vs 71.99%, P = 0.99). Crucially, The nICT group showed a lower incidence of grade 3 and 4 adverse events in Leukopenia (2.8% vs 29%; P  < 0.001) and Neutropenia (2.8% vs 24%; P  < 0.001) during neoadjuvant treatment, comparing with nCRT group. Conclusions Our preliminary findings suggest that nICT followed by surgery offers comparable survival rates to nCRT, despite being less effective in pathologic outcomes. Nonetheless, nICT is a safe and feasible strategy for locally advanced ESCC, warranting further exploration to understand its impact on long-term survival.

We aimed to determine whether monitoring tumor-derived exosomal microRNAs (miRNAs) could be used to assess radiotherapeutic sensitivity in patients with locally advanced esophageal squamous cell carcinoma (ESCC). RNA sequencing was employed to conduct a comparative analysis of miRNA expression levels during radiotherapy, focusing on identifying miRNAs associated with progression. Electron microscopy confirmed the existence of exosomes, and co-cultivation assays and immunofluorescence validated their capacity to infiltrate macrophages. To determine the mechanism by which exosomal miR-143-3p regulates the interplay between ESCC cells and M2 macrophages, ESCC cell-derived exosomes were co-cultured with macrophages. Serum miR-143-3p and miR-223-3p were elevated during radiotherapy, suggesting resistance to radiation and an unfavorable prognosis for ESCC. Increased levels of both miRNAs independently predicted shorter progression-free survival (p = 0.015). We developed a diagnostic model for ESCC using serum microRNAs, resulting in an area under the curve of 0.751. Radiotherapy enhanced the release of miR-143-3p from ESCC cell-derived exosomes. Immune cell infiltration analysis at the Cancer Genome Atlas (TCGA) database revealed that ESCC cell-derived miR-143-3p triggered M2 macrophage polarization. Mechanistically, miR-143-3p upregulation affected chemokine activity and cytokine signaling pathways. Furthermore, ESCC cell exosomal miR-143-3p could be transferred to macrophages, thereby promoting their polarization. Serum miR-143-3p and miR-223-3p could represent diagnostic and prognostic markers for patients with ESCC undergoing radiotherapy. Unfavorable prognosis could be linked to the increased levels of ESCC cell-derived exosomal miR-143-3p, which might promote tumor progression by interacting with macrophages.

Background Postoperative radiotherapy (PORT) is crucial for patients with thoracic locally advanced esophageal squamous cell carcinoma (LA-ESCC, pT3-4aN0-3M0) following esophagectomy. However, the appropriate radiation volume has not been well established. This study aimed to determine the optimal PORT volume for LA-ESCC patients. Methods LA-ESCC patients post-esophagectomy were randomly assigned to either the large-field irradiation (LFI, primary lesion and lymph node tumor bed plus elective nodal irradiation) group or the small-field irradiation (SFI, primary lesion and lymph node tumor bed alone) group. Stratification was based on T stage and the number of lymph node metastases. The primary endpoint was disease-free survival (DFS), while the secondary endpoints included overall survival (OS), adverse events, and patterns of initial failure. Results A total of 401 patients were randomly assigned to the intention-to-treat analysis(LFI group, n  = 210; SFI group, n  = 191). The median DFS of patients in the LFI group was 47.9 months and 48.1 months in the SFI group (HR = 0.87, 95%CI, 0.65 to 1.16; p  = 0.32). The estimated one-year and three-year OS rates were 89.2% and 63.2% for patients in the LFI group, compared to 86.6% and 60.7% for the SFI group, respectively. The difference of OS between the two groups was not significant (HR = 0.86, 95%CI, 0.63 to 1.16; p  = 0.35). Fewer patients in the LFI group experienced locoregional recurrence compared to the SFI group (12.9% vs 20.4%, p  = 0.013). Additionally, locoregional recurrence-free survival of the LFI group was significantly longer than that of SFI group (HR = 0.54, 95%CI, 0.34–0.87; p  = 0.01). The most common toxicity was grade 2 esophagitis, observed in 22.9% of the LFI group and 16.8% of the SFI group. Grade 3 adverse events occurred in 6.7% of the LFI group and 2.6% of the SFI group. No grade 4 or 5 toxicities were observed. Adverse events did not significantly differ between the two groups. Conclusions Postoperative radiotherapy, with the specified radiation volume shows encouraging survival outcomes that are comparable to those of neoadjuvant chemoradiotherapy in patients with thoracic LA-ESCC. Both postoperative irradiation fields were found to be feasible and safe.

Background This study aims to delineate the long-term outcomes and recurrence patterns of locally advanced thoracic esophageal squamous cell carcinoma (TESCC) patients managed with or without postoperative radiotherapy (PORT). Methods A retrospective cohort from two academic centers, encompassing patients who initially underwent esophagectomy and were pathologically staged T3-4, was analyzed. Survival outcomes were constructed using Kaplan–Meier method, with survival significance was evaluated using the log-rank test. Propensity score matching (PSM) was utilized to balance potential selection bias. Results Among the 506 patients, 251 underwent surgery alone and 255 received radiotherapy following radical surgery. With a median follow-up of 49.1 months, PORT significantly improved 5-year overall survival (53.8% vs. 25.3%; p  < 0.001) and 5-year disease-free survival rates (45.3% vs. 8.5%; p  < 0.001) compared to surgery alone. These differences in survival outcomes persisted even after PSM ( p  < 0.001 for both). Treatment failure was significantly less frequent in the PORT group (46.7%) compared to the surgery-only group (90.0%; p  < 0.001), with corresponding reductions in locoregional recurrence (9.4% vs. 54.1%; p  < 0.001). This underscores the significant association between PORT and disease control. Conclusion The absence of neoadjuvant chemoradiotherapy highlights the importance of PORT in improving survival and reducing recurrence in advanced T3-4 TESCC patients. This study underscores the importance of PORT as a salvage treatment for locally advanced TESCC patients without neoadjuvant chemoradiotherapy.

The aim of this study was to explore the high-risk factors for recurrence in patients with locally advanced esophageal squamous cell carcinoma (ESCC) undergoing definitive chemoradiotherapy or radiotherapy (dCRT or dRT). Conditional survival (CS) was used to evaluate the dynamic survival and recurrence risk of patients after treatment, and individualized monitoring strategies were developed for patients. Logistic regression analysis was performed to determine independent recurrence risk factors. Calibration curves and receiver operating characteristic (ROC) curve were used to evaluate nomogram models. Kaplan–Meier curves were used to compare survival rates in different groups and to calculate CS rate. A total of 677 patients were included. Multivariate logistic analyses demonstrated that chemotherapy cycles, tumor length, body mass index (BMI), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR) were independent recurrence risk factors (p < 0.05). Subsequently, we constructed nomogram models to predict recurrence and risk stratification. Kaplan–Meier curves showed that conditional locoregional recurrence-free survival and distant metastasis-free survival of patients in different risk groups and clinical stages progressively increased with survival time, whereas local recurrence and distant metastasis annual recurrence rates decreased yearly with increasing survival time. Finally, we developed an individualized follow-up strategy based on CS at different frequencies. Individualized follow-up strategies developed on the basis of CS can better monitor the changes in patients’ conditions and contribute to timely salvage treatment and rational allocation of healthcare resources.

Background Neoadjuvant chemoimmunotherapy (NCIT) for locally advanced esophageal squamous cell carcinoma (ESCC) is supported by increasing data, but the sample size is limited, and the findings are not completely consistent. We conducted a real‐world study and a meta‐analysis to evaluate the efficacy and safety of NCIT in locally advanced ESCC. Methods We retrospectively assessed the outcomes of patients with locally advanced ESCC who completed NICT and subsequent esophagectomy at our hospital between January 2019 and December 2022, including pathological complete response (pCR) rate, major pathological response (MPR) rate, 1‐, 2‐, and 3‐year overall survival (OS) rates, disease control rate (DCR), objective response rate (ORR), 1‐year recurrence rate, R0 resection rate and adverse events. Moreover, a meta‐analysis of 27 published literatures was also conducted for comparison. Results In the analysis, 128 patients were studied, with 25% achieving pCR, 46.1% MPR, and 99.2% R0 resection. The 1‐, 2‐, and 3‐year OS rates were 91.41% (95% CI: 85.15%–95.63%), 75.00% (95% CI: 66.58%–82.23%) and 64.84% (95% CI: 55.91%–73.07%).ORR and DCR were 31.2% (95% CI: 23.31–39.99) and 64.1% (95% CI: 55.15%–72.38%), and the 1‐year recurrence rate was 26.7% (95% CI: 22.5%–38.1%). Treatment‐related events occurred in 96.1% but were acceptable. In a meta‐analysis of 27 studies with 1734 patients, pooled rates for pCR, MPR, ORR, DCR, and R0 resection were 29%, 52%, 71%, 97%, and 98%, respectively, with a 1‐year recurrence rate of 12%. Conclusion NCIT is safe and provides potential survival benefits for patients with locally advanced ESCC. However, randomized phase 3 trial data is still needed. The efficacy and safety of Neoadjuvant chemoimmunotherapy for locally advanced ESCC.

ABSTRACT Background The method of lymph node (LN) irradiation for locally advanced esophageal squamous cell carcinoma (LA‐ESCC) is still a topic of debate. We investigated the efficacy, toxicity, and rate of out‐of‐field LNs in irradiation across different target areas in patients with LA‐ESCC undergoing neoadjuvant chemoradiotherapy (nCRT). Methods We retrospectively reviewed patient records from June 2017 to August 2022 and divided patients into elective nodal irradiation (ENI) and involved‐field irradiation (IFI) groups. The differences in hematological and non‐hematological toxicities of the out‐of‐field LNs were analyzed between the two groups. The log‐rank test was used to evaluate the Kaplan–Meier curves for overall and progression‐free survival. Results Among the 306 included patients, 202 (66.0%) received ENI and 104 (34.0%) received IFI. At the 3‐year follow‐up, the survival rate did not differ significantly between the groups (p > 0.05). Although the occurrence of radiation‐induced pneumonia did not differ (p > 0.05), the incidence of radiation‐induced esophagitis and the degree of leukopenia differed significantly (p < 0.05). While the average heart irradiation dose or heart V20, V30, and V40 did not differ significantly (p > 0.05), we observed significant differences in the clinical target volume, average lung irradiation dose, and lung V20, V30, and V40 (p < 0.05). Among all patients, 29 cases (9.5%) experienced out‐of‐field LNs with 26 (93.1%) in abdominal LNs, whereas only 3 cases (6.9%) with out‐of‐field LNs were in the upper esophagus. There was no statistical significance between out‐of‐field LNs and LN irradiation methods (p = 0.724). Conclusions Under similar prognostic conditions, IFI resulted in mild toxicity compared to ENI. Therefore, for patients with ESCC undergoing nCRT, IFI is the preferred irradiation approach for the lymphatic drainage area. Our study boasts the largest sample size among existing research on ESCC patients who have undergone nCRT treatment. For LA‐ESCC patients who have undergone nCRT, IFI is the preferred method of lymph node irradiation.

Definitive chemoradiotherapy with cisplatin (CDDP) plus 5-fluorouracil is the standard treatment for locally advanced esophageal squamous cell carcinoma (LA-ESCC); however, CDDP is unsuitable for patients with cardiac and/or renal dysfunction. Based on the results of the PRODIGE5/ACCORD17 trial, 5-fluorouracil and leucovorin with oxaliplatin plus radiotherapy (FOLFOX-RT) has been recognized as a treatment option. However, the efficacy and safety of FOLFOX-RT is still unclear in Japan. Medical records were reviewed for patients with LA-ESCC who received FOLFOX-RT between April 2019 and July 2021 at our institution. We evaluated complete response rate, progression-free survival (PFS), overall survival (OS), and adverse events. Fifteen patients were analyzed and median age was 72.5 years (range=51-83 years). All patients completed three courses of FOLFOX and the planned radiotherapy. The complete response rate was 40.0%. With a median follow-up of 10.6 months, the 6-month PFS rate was 63.0% (95%CI=32.3-82.8%), and the 6-month OS rate was 85.7% (95%CI=53.9-96.2%). Common adverse events were esophagitis (80.0%), leukopenia (53.3%), fatigue (53.3%), and neutropenia (46.7%). Only one patient had grade 4 esophageal perforation. FOLFOX-RT for LA-ESCC was well tolerated and could be a treatment option for CDDP-intolerant patients.

Background and purpose We evaluated and compared the efficacy and safety of chemotherapy with paclitaxel plus cisplatin (TP) or carboplatin (TC) in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC) who underwent neoadjuvant chemoradiotherapy (NCRT). Materials and methods This single-center retrospective study assessed patients with LA-ESCC (cT2N + M0, cT3-4aNanyM0) receiving NCRT plus curative-intent esophagectomy with TP or TC regimen. The primary endpoints were grade ≥ 3 adverse events (AEs) and overall survival (OS). AEs were compared using a t-test according to CTCAE 4.0. The Kaplan–Meier survival curves were compared using the log-rank test; the treatment effect was measured using hazard ratios and 95% confidence intervals. Results We included 151 and 50 patients in the TC and TP groups, respectively. Baseline demographic and clinical characteristics were well balanced between groups. The TP group exhibited significantly higher hematologic and non-hematologic AEs than the TC group, and the noticeable difference was the incidence of febrile neutropenia of grade 3 or higher ( P  = 0.011). No significant intergroup differences were noted considering postoperative complications, resection margins, or pathological complete remission rate (all P  > 0.05). OS and progression-free survival (PFS) did not significantly differ between groups. The estimated 3-year OS and PFS rates were 65.1% versus 69.4% and 58.4% versus 53.5% for TP and TC groups, respectively. Conclusion In patients with LA-ESCC, we recommend TC, not TP, as an optimal chemotherapy regimen for NCRT, given its superiorsafety profile and comparable efficacy.