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Background: A series of randomized controlled trials (RCTs) have demonstrated the promising prospect of immunotherapy in operable non-small cell lung cancer (NSCLC) and further changed the clinical practice. However, current studies still yet to answer which immunotherapy mode is the optimal strategy, and there is currently a lack of direct comparison between neoadjuvant immunochemotherapy and perioperative immunotherapy ("sandwich mode", including neoadjuvant immunochemotherapy and adjuvant immunotherapy). Thus, we conducted a network meta-analysis (NMA) to evaluate the efficacy between neoadjuvant immunochemotherapy and perioperative immunotherapy., Methods: We performed a Bayesian NMA (PROSPERO registration number: CRD42024495955) by retrieving relevant eligible studies from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences until December 31, 2023. Phase II or III RCTs that evaluated the efficacy of different strategies of immunotherapy in operable NSCLC, including neoadjuvant immunochemotherapy and perioperative immunotherapy ("sandwich mode"), were retrieved for analysis. The patients were grouped into neoadjuvant chemotherapy alone (arm A), neoadjuvant immunotherapy plus chemotherapy (arm B); neoadjuvant immunotherapy plus chemotherapy followed by surgery and adjuvant immunotherapy (arm C), respectively. The endpoint was event-free survival (EFS) in different subgroups., Results: Seven studies of 2,934 patients were selected for this NMA finally. Compared with neoadjuvant chemotherapy, both neoadjuvant immunochemotherapy [hazard ratio (HR) 0.61, 95% confidence interval (CI): 0.36-0.98] and perioperative immunotherapy (HR 0.56, 95% CI: 0.42-0.71) significantly improved the EFS in intention-to-treat population, but there was no statistical difference between these two treatments (HR 1.1, 95% CI: 0.62-1.9). There was no statistical difference between perioperative immunotherapy and neoadjuvant immunochemotherapy in all subgroup analysis of EFS. However, in patients with non-squamous disease, programmed cell death-ligand 1 (PD-L1) expression more than 50%, or stage III disease, both neoadjuvant immunotherapy [(HR 0.50, 95% CI: 0.26-0.97), (HR 0.24, 95% CI: 0.061-0.96), (HR 0.50, 95% CI: 0.39-0.63)] and perioperative immunotherapy [(HR 0.64, 95% CI: 0.46-0.87), (HR 0.40, 95% CI: 0.21-0.71), (HR 0.54, 95% CI: 0.34-0.85)] improved EFS significantly compared with neoadjuvant chemotherapy., Conclusions: Both neoadjuvant immunochemotherapy and perioperative immunotherapy significantly increased EFS compared with neoadjuvant chemotherapy. There is no evidence that perioperative immunotherapy is better than neoadjuvant immunochemotherapy in EFS. Patients with non-squamous disease, PD-L1 expression more than 50%, or stage III disease can try the neoadjuvant immunochemotherapy mode., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-287/coif). All authors report that this study was supported by the Youth Project of the Natural Science Foundation of Guangdong Province (No. 2022A1515110399), and the National Key R&D Program of China (No. 2022YFE0133100). The authors have no other conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Background: There is currently no consensus on whether intensive cycles of neoadjuvant immunochemotherapy provide greater benefit than do less intensive cycles (two cycles) in esophageal cancer (EC). Therefore, in this study, we assessed the efficacy and safety of three to four cycles of neoadjuvant immunochemotherapy compared to two cycles for treating patients with locally advanced esophageal squamous cell carcinoma (ESCC)., Methods: This is a retrospective study of patients enrolled on previous clinical studies involving locally/regionally advanced ESCC (St. II-IVA) who received preoperative immunochemotherapy at the Department of Thoracic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine from 2019 to 2021. In this study, patients were planned to receive 2-4 cycles of chemoimmunotherapy. In this secondary analysis, patients who received three to four cycles of neoadjuvant immunochemotherapy were compared to those receiving two cycles in terms of safety and oncologic outcomes. The follow-up duration required for inclusion was at least one year following surgery, or until the patient died or independently elected to cease treatment if less than one year., Results: Our study identified a total of 142 participants, who were categorized into two groups based on the number of neoadjuvant treatment cycles: the two cycles group (2 cycles) (n=65) and the three to four cycles group (3-4 cycles) (n=77). Regarding the rate of major pathologic response (MPR), the rates for the 3-4 cycles and 2 cycles groups were 22.1% and 20.0%, respectively, although this difference was not statistically significant (P=0.25). Similarly, the rate of pathologic complete remission (pCR) was higher in the 3-4 cycles group at 14.3% compared to 7.7% in the 2 cycles group, but the difference did not reach statistical significance (P=0.07). However, the incidence of adverse events (AEs) classified as grade 3 or 4 was significantly higher in the 3-4 cycles group than in the 2 cycles group (36.4% vs. 18.5%; P=0.02). The median disease-free survival (DFS) for the 3-4 cycles group was 30.8 months [95% confidence interval (CI): not reached to not reached] and was not reached in the 2 cycles group (hazard ratio 2.35, 95% CI: 1.134-4.86; P=0.02). The 2 cycles group did not reach the median overall survival (OS) (hazard ratio 2.47, 95% CI: 1.08-5.53; P=0.045), with that in the 3-4 cycles group 34.9 months (95% CI: 24.5 to not reached). Interestingly, the survival outcomes were more favorable in the 2 cycles group for certain subgroups of patients: those who were male, those with a history of smoking, those with a history of drinking, and those who did not achieve MPR., Conclusions: Two cycles of neoadjuvant immunochemotherapy can be considered in locally advanced ESCC at high risk of developing toxicity with 3-4 cycles with similar oncologic outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1365/coif). J.M.P. received honoraria from ASTELLAS and J&J Worldwide, and payment for participation in Advisory Board from Ferranova, and serves as the Chair of the Florida Chapter of the American College of Surgeons (FCACS) Surgical Education Committee. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Background: Esophageal squamous cell cancer (ESCC) patients with the potentially resectable disease most would experience relapse after surgery. Immunotherapy has been reported to improve the prognosis of advanced esophageal cancer and may be a new strategy to prevent this urgent condition's recurrence. We first evaluated the efficacy and safety of neoadjuvant chemotherapy combined with immunotherapy in patients with resectable ESCC., Methods: All patients with resectable locally advanced ESCC (clinical stage III-IVB). Received at least 1 cycle of neoadjuvant chemotherapy combined with immunotherapy (NACI), and the interval between each cycle and the operation should be at least 3 weeks. All patients were treated with standard surgery. The tumor imaginations were obtained at baseline and within a week before surgery. The efficacy endpoint was the rate of major pathologic response (MPR, 10% viable tumor cells). Expression of immunohistochemical-related molecules was investigated in surgical samples., Results: A total of 38 patients with ESCC were included (36 males, median age 61 years), and most of them used Pembrolizumab (55.26%) and Camrelizumab (31.58%). We analyzed 19 patients and found that 13 patients (68.42%) achieved radiological partial response (PR) by CT images. R0 resection was performed in 35 patients (92.11%), and 10 patients (26.32%) developed postoperative complications. Through postoperative pathology, we found 13 (34.21%) patients had complete pathologic response (cPR), and 16 (42.11%) patients achieved MPR. We also found that none of the factors had a statistically significant impact on MPR. Still, the regression rate of Sum of lesion diameter (SLD) was significantly positively correlated with the pathological remission rate (P=0.012, r=0.565)., Conclusions: The rate of MPR in ESCC patients reached 42.11%. The use of the NACI regimen did not increase the occurrence of complications in neoadjuvant treatment and operation, and the SLD regression rate has a certain guiding significance for the effect of immunotherapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-21-340). The authors have no conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

Background: Neoadjuvant chemotherapy (NAC) and neoadjuvant chemoradiotherapy (NACR) are the standard treatments for esophageal squamous cell carcinoma (ESCC). However, the 5-year overall survival (OS) rate is still far from satisfactory. In recent years, immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of ESCC. More than 20 phase II clinical trials have been launched to explore combinations of ICIs in the neoadjuvant setting for ESCC. Based on our phase II clinical trial, a two-arm phase III trial was launched in Henan Cancer Hospital. ICIs combined with NAC may usher in a new era and may benefit locally advanced, resectable ESCC patients., Methods: A two-arm phase III trial was launched in April 2020 in Henan Cancer Hospital. Patient recruitment will be completed within 18 months. The primary endpoint is event-free survival (EFS). The secondary endpoints include pathologic complete response (pCR), disease-free survival (DFS) rate, overall response rate (ORR), R0 resection rate, major pathologic response (MPR), adverse events (AEs), complication rate and quality of life (QOL). A biobank of pretreatment, resected tumor tissue and paired blood samples will be built for translational research in the future., Discussion: This RCT directly compares NAC with neoadjuvant toripalimab plus chemotherapy in terms of EFS for locally advanced ESCC. The results may usher in a new era of resectable ESCC treatment., Trial Registration: NCT04280822 (https://www.clinicaltrials.gov/ct2/show/NCT04280822). Registered title: "A Phase III, Randomized Controlled Study of Neo-adjuvant Toripalimab (JS001) in Combination with Chemotherapy versus Neo-adjuvant Chemotherapy for Resectable Esophageal Squamous Cell Carcinoma". Version 1.0/Nov. 21, 2019., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5404). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: Esophageal squamous cell carcinoma (ESCC) remains a challenging malignancy with poor prognosis and limited therapeutic methods. However, recent clinical trials of immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of lethal malignancies. The second-line treatment of late-stage ESCC was approved based on the results of KEYNOTE-180, KEYNOTE-181 and ATTRACTION-1, ATTRACTION-3. Combining ICIs with chemotherapy in neoadjuvant therapy may benefit patients with locally advanced, resectable ESCC., Methods: A two-arm phase II trial was launched in July 2019 in Henan Cancer Hospital. The primary outcome measure will be completed within 21 months. The pathological complete response (pCR) rate is the primary endpoint, and the secondary endpoints include overall survival (OS), disease-free survival (DFS), the toxicities of the neoadjuvant toripalimab plus chemotherapy, the relationship between combined positivity score (CPS) of specimen and the treatment response, the relationship between lymphocyte infiltration and the treatment response, the progression-free survival (PFS) rate, and adverse events (AEs). It was assumed that the pCR rate of this trial might be 25%. Therefore, the 30 enrolled patients could reject the hypothesis at 75% (α=0.1)., Discussion: The study will determine the safety and efficacy of neoadjuvant immunochemotherapy for ESCC and provide enough evidence for phase III clinical trials., Trial Registration: Clinical Trials.gov, NCT03985670, Registered: October 24, 2019, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0008Z9D&selectaction=Edit&uid=U0002MIY&ts=2&cx=-i71o4q. Registry name: "Teripalimab Plus Chemotherapy in Local Advanced Esophageal Cancer"., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-2198). The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)