Adebrelimab plus chemotherapy as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma (ESCC): a single-center, phase II, single-arm, open-label clinical trial (ADENEO) protocol

Adebrelimab plus chemotherapy as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma (ESCC): a single-center, phase II, single-arm, open-label clinical trial (ADENEO) protocol | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Adebrelimab plus chemotherapy as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma (ESCC): a single-center, phase II, single-arm, open-label clinical trial (ADENEO) protocol Peng Tang, Linrui Gao, Siyu Zuo, Ke Zhang, Tierun Wang, Jian Zheng, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6584601/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Mar, 2026 Read the published version in BMC Cancer → Version 1 posted 9 You are reading this latest preprint version Abstract Introduction: Although radical chemoradiotherpy (CRT) is the standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (LA-ESCC), the prognosis remains extremely poor. Although CRT combined with immunotherapy has a positive effect on some patients with advanced esophageal cancer, some patients still experience recurrence and metastasis after treatment. The overall response rate (ORR) of induction immunochemotherapy for advanced esophageal cancer is approximately 40%-70%. Radiotherapy or concurrent chemoradiotherapy (cCRT) after induction of chemoradiation is more effective. In this study, different patients were given different treatments according to the therapeutic effect of induction chemoimmunotherapy (ICI) in order to improve the treatment effect of locally advanced esophageal cancer. Methods and analysis: The ADENEO trial is a single center, phase II, single-arm, open-label clinical trial that will enrol 60 patients. Eligible patients will be registered, enrolled and receive 2 cycles of Adebrelimab plus albumin paclitaxel and carboplatin, and the efficacy was evaluated. The patients will divided into complete response + partial response (CR+PR) group and stable disease +progression (SD+PD) group according to the efficacy of induction therapy. In the CR+PR group, patients were treated with concurrent CRT combined with Adebrelimab. Chemoimmunotherapy was the same as that used before, the radiotherapy dose was 50.4Gy/1.8Gy/28F, and immunotherapy was maintained for one year. In the SD+PD group, the patients were treated with cCRT. To further improve the curative effect, the radiotherapy dose was PTV/PGTV: 50.4Gy/59.92Gy/28F. The chemotherapy regimen was changed and immunotherapy was not used during CRT because of tolerance to previous immunotherapy. The primary endpoint is the progression free survival (PFS) assessed by the investigators, and the secondary endpoints are ORR, overall survival (OS), duration of response (DoR), adverse event (AE) and serious adverse time (SAE). Ethics and dissemination: Written informed consent will be required from all patients enrolled, and it will be provided by them. The study protocol received approval from the independent ethical review committee of Tianjin Medical University Cancer Institude & Hospital. We will submit the finalised paper for publication on completing the analyses. Trial registration number: NCT06452602 (www.clinicaltrialsregister.eu) (ClinicalTrials.gov). locally advanced esophageal squamous cell carcinoma induction chemoimmunotherapy concurrent chemoradiotherapy Adebrelimab therapeutic effect Figures Figure 1 Introduction Esophageal cancer is a relatively common malignant tumor with poor prognosis worldwide. According to The Global Cancer Observatory (GLOBOCAN) 2022, there are 604,000 new cases per year, ranking eighth and 544,000 deaths, ranking sixth. Esophageal cancer can be divided into esophageal adenocarcinoma and esophageal squamous cell carcinoma (ESCC), according to the pathological type. China has the highest annual number of new cases and deaths from esophageal cancer, with 224,000 new cases and 187,500 deaths in 2022, of which more than 90% are ESCC [ 1 ] . Due to the hidden onset of esophageal cancer, more than half of the patients have locally advanced or advanced disease. Standard protocol for the treatment of locally advanced esophageal cancer According to the National Comprehensive Cancer Network (NCCN) guidelines and the Chinese Society of Clinical Oncology (CSCO) Guidelines, it is recommended to use "fluorouracil or taxol combined with platinum-based dual drug radical concurrent chemoradiotherapy (cCRT)" as the standard treatment for locally advanced and inoperable esophageal cancer. However, approximately 50% of patients experience recurrence or metastasis within 2 years after receiving standard cCRT, and the 5-year overall survival (OS) is only 30–40% [ 2 , 3 ] . Different chemotherapy regimens and radiotherapy doses do not improve survival [ 4 – 6 ] . Therefore, for patients with unresectable locally advanced esophageal cancer (LAEC), although cCRT is the standard treatment, the prognosis of esophageal cancer remains poor owing to its highly invasive characteristics, and more accurate combination therapy is urgently needed. Immunotherapy improves the treatment effect of esophageal cancer Immune checkpoint inhibitors play a key role in tumor therapy. Immune checkpoint inhibitors not only enhance anti-tumor immunity by restoring the function of cytotoxic T cells but also reshape the tumor microenvironment through immune-related pathways. Pembrolizumab plus chemotherapy (Keymate-590), nivolumab in combination with ipilimumab, or chemotherapy (CheckMate 648 study), camrelizumab plus chemotherapy (ESCORT 1st study), sintilimab plus chemotherapy (ORIENT-15 study), and toripalimab plus chemotherapy (JUPITER-06 study) all significantly improved OS in patients with advanced first-line esophageal cancer, compared to chemotherapy alone [ 7 – 10 ] . According to the NCCN and CSCO guidelines, chemotherapy combined with immunotherapy is the first-line standard treatment for advanced esophageal cancer. For operable esophageal cancer, the CheckMate 577 study showed that postoperative maintenance of nivolumab can significantly improve the disease-free survival (DFS) rate of patients with non-pathological complete response (pCR) after preoperative chemoradiotherapy. Immunotherapy plays an important role in postoperative maintenance of treatment [ 11 ] . Progress in the application of chemoradiotherapy combined with immunotherapy for advanced inoperable esophageal cancer According to preclinical studies, radiotherapy induces immunogenic cell death, which releases neoantigens, alters the tumor microenvironment, and ultimately activates the immune response. The combination of radiotherapy and immunotherapy may achieve synergistic anti-tumor effects, which provides a theoretical basis for the combined application of immune checkpoint inhibitors with chemoradiotherapy [ 12 , 13 ] . CRT combined with immunotherapy has shown enhanced antitumor efficacy in various solid tumors, including non-small cell lung cancer (NSCLC). CRT combined with immunotherapy may further improve the therapeutic effects in esophageal cancer. At present, multiple phase I/II single-arm small-sample clinical studies have been carried out in patients with unresectable LAEC with combined (chemo)radiotherapy and immunotherapy [ 14 – 21 ] . Zhang et al. treated 20 patients with locally advanced ESCC with camrelizumab combined with concurrent chemoradiotherapy, and the study showed that the 24-month OS and progression-free survival (PFS) rates were 69.6% and 65.0%, respectively. The incidence of ≥ grade 3 treatment-related adverse events (TRAEs) was 45%, ≥grade 3 radiation esophagitis was 20%, ≥grade 3 esophageal fistula was 10%, and no ≥ grade 3 radiation pneumonia occurred [ 16 ] . Xi et al. treated 42 untreated, unresectable stage II-IVA ESCC patients with toripalimab combined with radical chemoradiotherapy. The results showed that the 1-year OS and PFS rates were 78.4% and 54.5%, respectively [ 21 ] . In terms of current evidence, small-sample single-arm phase I/II clinical trials have shown that cCRT with immune checkpoint inhibitors is more effective than conventional CRT for the treatment of LAEC, with good tolerance and controllable toxicity. Relevant phase III randomized controlled studies (e.g., ESCORT-CRT, KEYNOTE 975, RATIONALE 311, KUNLUN) are in progress. It is urgent to find an ideal therapeutic effect prediction method Although CRT combined with immunotherapy has a positive effect on some patients with advanced esophageal cancer, some patients still experience recurrence and metastasis within 2 years after treatment. The focus of the current research is to screen effective predictive biomarkers of efficacy. Clinical biomarkers include PD-L1 expression level, tumor mutation burden (TMB), and microsatellite instability (MSI) /deficient mismatch repair (dMMR). PD-L1 expression has been extensively studied. The ESCORT study showed that patients with PD-L1 positive expression in the camrelizumab group had clinical benefits, and patients with PD-L1 positive expression TPS ≥ 10% had longer survival than patients with low expression [ 22 ] . However, the predicted effect decreased when combined with RT [ 23 ] . The efficacy of induction chemotherapy or chemoimmunotherapy can predict the effect of dCRT In addition to biomarkers, induction therapy can not only reduce tumor burden and distant metastasis but also has a very important significance in predicting the effect of CRT. A Phase II clinical study found that patients who were effectively treated with induction chemotherapy had a significant survival benefit compared with those who did not respond to induction chemotherapy after receiving two cycles of induction chemotherapy. The efficacy of induction chemotherapy can predict survival better than reported biomarkers, with 3-year OS rates of 80.0% and 10.0% and 3-year PFS rates of 55.3% and 10.0%, respectively. The difference is significant, and this result suggests that the efficacy of induction chemotherapy is an effective way to predict the efficacy of radical CRT [ 24 ] . Deng et al. carried out a study on radiotherapy after induction chemoimmunotherapy (ICI) in patients with unresectable locally advanced or metastatic esophageal cancer, and the results showed that the 2-year OS and 2-year PFS rates of the ICIs + RT and RT groups were 57.9% and 43.0% (p = 0.050), and 45.7% and 35.8% (p = 0.045), respectively. The 1-year local recurrence rate (LRR) in the ICIs + RT group than in the RT group (17.4% vs. 38.8%, p = 0.011) [ 25 ] . These results suggest that radiotherapy after ICI therapy may improve local control and survival in patients with unresectable locally advanced or metastatic esophageal cancer. Therefore, it is feasible to use chemoimmunotherapy as neoadjuvant therapy for radical CRT. For patients who were ineffective to induction immunochemotherapy, it is urgent to optimize the treatment plan. It was also shown that patients who had achieved major pathological response (MPR) had better survival, with 2-year OS rates of 91.4% and 47.7%, respectively [ 24 ] . Local recurrence and distant metastasis rates were higher in patients who were not sensitive to induction therapy than in those who were effective in induction therapy [ 26 ] . Therefore, to further improve the therapeutic effect of patients with inoperable LAEC, the therapeutic effect of LAEC should be further improved by adopting different treatment regimens for patients with different treatment sensitivities based on induction therapy stratification. Radical CRT was conducted according to different therapeutic effects by stratification. Adebrelimab is a high-affinity, humanized anti-PD-L1 monoclonal antibody that has been shown to be effective and safe against advanced ESCC, extensive small cell lung cancer (SCLC), and resectable NSCLC [ 27 , 28 ] . In the phase 1b trial of neoadjuvant debrelimab in the treatment of locally advanced resectable ESCC, the primary study endpoint was safety and feasibility. Secondary endpoints included pathological complete response (pCR) and OS. The results showed that The most common TRAEs were anorexia (32%) and fatigue (16%), with no grade 3 or greater adverse reactions. Of the 30 patients enrolled, 25 were successfully resected without surgical delay, with an MPR rate of 24%, a pCR rate of 8%, and a 2-year OS rate of 92%. Adebrelimab has demonstrated good safety and feasibility in patients with resectable LAEC [ 29 ] . Based on previous studies, this clinical trial used two cycles of ICI for locally advanced ESCC and evaluated its efficacy after the end of induction therapy. Patients with effective induction therapy (CR + PR group) were treated with concurrent CRT combined with immunotherapy, whereas patients with ineffective induction therapy (SD + PD group) were treated with different radiotherapy doses and chemotherapy regimens during concurrent CRT to improve the overall treatment effect. It is the first “induction PD-L1 inhibitor combined with chemotherapy” for inoperable locally advanced ESCC, with the aim of exploring treatment strategy for inoperable locally advanced ESCC based on the efficacy of induction immunochemotherapy. Methods and analysis Trial design This was a single-center phase II study. The study subjects were patients with inoperable, locally advanced ESCC. After two cycles of ICI, the patients were divided into CR+PR group and SD + PD group according to the efficacy of induction therapy. In the CR+PR group, patients were treated with concurrent CRT combined with immunotherapy. Chemoimmunotherapy was the same as that used before, the radiotherapy dose was 50.4Gy/1.8Gy/28F, and immunotherapy was maintained for one year. In the SD+PD group, the patients were treated with concurrent chemoradiotherapy. To further improve the curative effect, the radiotherapy dose was PTV/PGTV: 50.4Gy/59.92Gy/28F (Figure 1). The chemotherapy regimen was changed and immunotherapy was not used during CRT because of tolerance to previous immunotherapy. In this study, the combination of immune checkpoint inhibitors and radiotherapy exerted a synergistic anti-tumor effect, which is supported by theoretical feasibility and preliminary clinical research results. Induction immunotherapy can effectively stratify patients and optimize treatment plans, which may further improve PFS and prolong OS in all patients. Objectives & end points The objectives and end points of this study can be found in Table 1. Eligibility criteria See Table 2. Safety will be monitored throughout the study and 30 days after the end of the treatment. Adverse events will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Recruitment Patients are recruited and screened from Tianjin Medical University Cancer Institute & Hospital from May 2024. Oncologists will assess and evaluate patients based on the eligibility and exclusion criteria. Following this, patients will be provided with an information sheet and asked to offer written consent. Patients have the right to withdraw from the study at any time and for any reason. Interventions Induction chemotherapy combined with immunotherapy: Adebrelimab: 1200 mg intravenously, administered every 3 weeks until PD or intolerance. Adebrelimab was administered for up to 1 year. Induction chemotherapy: albumin paclitaxel: 220mg/m 2 , d1, d22. Carboplatin AUC=5, d1, d22. Concurrent chemoradiotherapy: For CR/PR patients, after concurrent chemotherapy combined with debrelimab, debrelimab was maintained for 1 year. Radiotherapy: PTV 50.4Gy/1.8Gy/28F, 5 times a week. Concurrent chemotherapy: albumin paclitaxel: 175mg/m 2 , IV, d1, d22. Carboplatin AUC=5, d1, d22. For SD/PD patients, simultaneous CRT and simultaneous integrated boost (SIB) were used. Radiotherapy: PTV 50.4Gy/1.8Gy/28F, PGTV 59.92Gy/2.14Gy/28F, 5 times a week. Concurrent chemotherapy: oxaliplatin: 85 mg/m 2 , IV, d1, d15, d29. Tetrahydrofolic acid: 400mg/m 2 , IV, d1, d15, d29. 5-FU: 400mg/m 2 , IV, d1, d15, d29. 5-FU: 1600mg/m 2 , CIV48h, d1, d15, d29. Sample size calculation This was a single-arm Phase II clinical study, and the sample size was calculated based on the primary study endpoint and investigator-assessed PFS. The sample size was calculated as follows: the median 2-year PFS of the historical control of radical CRT was 43%, the 2-year PFS of the experimental group was assumed to be 60%, HR=0.60, unilateral α=0.05, the assurance was 80%, the enrollment time was 18 months, and the follow-up time was 18 months. PASS 2021 was used to estimate that 23 cases of PFS events would be required and 53 cases would need to be enrolled. Considering 10% shedding, 60 patients were enrolled in the study. Follow-up All patients will undergo follow-up assessments every 3 month for survival/follow-up antitumour treatment within the first year after the end of treatment. Subsequently, follow-up appointments will occur every 6 months after the first year, continuing until recorded as death, loss of interview, withdrawal of informed consent, and refusal to continue providing information, or the conclusion of the entire trial. Tumour evaluation will primarily use imaging, with options for additional methods such as ultrasonic gastroscope, CT, etc, if deemed necessary. For patients who discontinue the study and treatment for reasons other than disease progression or death, tumour evaluation will follow the original plan until the disease progresses. The overall duration of this trial is anticipated to be 3 years. Statistical analysis The primary endpoint involves PFS assessed by the investigators, which will be analysed based on the intention-to-treat (ITT) population. Descriptive statistics will be used for clinicopathological characteristics and safety evaluation. Mean values and SD will be provided for continuous endpoints, while frequency and percentage distributions will be presented for discrete data. Kaplan-Meier methodology will estimate PFS and OS in the ITT population. Univariate and multivariate survival analyses will use the Cox proportional hazard model, with HRs and 95% CI calculated. Statistical analyses will employ SPSS V.25.0 software (IBM) and R software V.3.6.2. The significance level is set at p<0.05, and all statistical tests will be two sided. This study was designed to detect a 23% absolute difference in the response rate between the two arms, with 90% power and a two-sided alpha of 0.05. Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research. Ethical conduct of research The study is being conducted in full compliance with the principles of the “Declaration of Helsinki” (as amended in Tokyo, Venice, Hong Kong, and South Africa), the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, and local laws and regulations. All Investigators will ensure adherence to the ICH guidelines for Good Clinical Practice (GCP) and Clinical Safety Data Management. All subjects provided written informed consent or were included before participating in the study. The protocol was approved by a reference ethics committee (Tianjin Medical University Cancer Institute & Hospital, Tianjin, China) and was approved by E20040608. Discussion This single center, phase II clinical trial aimed to enroll 60 patients with inoperable locally advanced ESCC and to assess the efficacy and safety of Adebrelimab plus chemotherapy. It is the first “induction PD-L1 inhibitor combined with chemotherapy” for inoperable locally advanced ESCC, with the aim of exploring treatment strategy for inoperable locally advanced ESCC based on the efficacy of induction immunochemotherapy (NCT06452602). Radical CRT is the standard treatment for patients with unresectable LAEC, however, the prognosis of esophageal cancer remains poor, and more accurate combination therapy is urgently needed. CRT combined with immunotherapy may further improve the therapeutic effects in esophageal cancer. Although CRT combined with immunotherapy has a positive effect on some patients with advanced esophageal cancer, some patients still experience recurrence and metastasis within 2 years after treatment [ 16 ] . The focus of the current research is to stratify therapy with more individualized treatment for patients according to the efficacy of induction immunochemotherapy. A previous study reported that those who received two cycles of induction chemotherapy had a significant survival benefit compared with those who did not receive induction chemotherapy, and the efficacy of induction chemotherapy predicted survival better than reported biomarkers [ 24 ] . In our study, after two cycles of ICI, we re-examined endoscopic ultrasonography with bite examination, CT, and upper gastrointestinal angiography, and evaluated curative effect comprehensively according to the method reported in our previous article [ 30 ] . 18F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are considered promising tools to predict CRT response [ 31 ] . However, other studies have indicated that the prediction of pCR through PET and MRI is limited by low sensitivity and poor positive predictive value [ 32 , 33 ] . Therefore, PET-CT is not mandatory used as an evaluation method. Previous studies reported that non-responders after neoadjuvant chemotherapy (stable or progressive disease) had worse 5-year survival rates than responders (complete or partial response, 22.3% vs 45.1%) [ 26 ] . Thus, the patients were divided into CR + PR group and SD + PD groups according to the efficacy of induction therapy. FFCD 9102 study demostated that in patients with locally advanced thoracic esophageal cancers, especially epidermoid, who respond to chemoradiation, there is no benefit for the addition of surgery after chemoradiation compared with the continuation of additional chemoradiation [ 34 ] . For SD + PD group, high dose (59.4Gy) was used to improve the local control which is supported by our previous participation in NROG-001 trial. FOLFOX was used as the concurrent chemotherapy regimen based on its safety and efficacy [ 35 ] . This study has several imitations. Firstly, this study is single arm, single-center clinical trial which limited to esophageal squamous cell carcinoma. Concurrent chemoradiotherapy (cCRT) is not set as control group. Secondly, PET-CT is not mandatorily used to evalute the efficacy of induction immunochemothery. In the future, a phase III study will be carried out and cCRT group will be added if the expectation met. This will provide important basis for individualized treatment of esophageal cancer. Declarations Funding This study was funded by the National Natural Science Foundation of China (grant number 82102835 to Tian Zhang, 82272733 to Wencheng Zhang), National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine (grant number QZ23-9) to Wencheng Zhang, and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A). Author contributions Tian Zhang and Wencheng Zhang contributed to study design and protocol writing. Peng Tang and Siyu Zuo contributed to the identification and enrollment of patients in the study the treatment of patients. Tierun Wang and Jian Zheng analyzed the study samples at the central laboratory. Ke Zhang and Linrui Gao contributed to the manufacturing of the cell products. Xi Chen, Qingsong Pang and Ping Wang wrote the manuscript. All authors have read, reviewed, and approved the protocol and final manuscript. Financial disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in this manuscript. Competing interests’ disclosure The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript, apart from those disclosed. Writing disclosure No writing assistance was utilized in the production of this manuscript. References Han B,Zheng R,Zeng H,et al.Cancer incidence and mortality in China, 2022,2024[J].J Natl Cancer Cent,2024,4(1):47-53. Wang X,Bai H,Li R,et al.High versus standard radiation dose of definitive concurrent chemoradiotherapy for esophageal cancer: A systematic review and meta-analysis of randomized clinical trials,2023[J].Radiother Oncol,2023,180:109463. 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Conroy T,Galais MP,Raoul JL,et al.Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial,2014[J].Lancet Oncol,2014,15(3):305-314. Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Published Journal Publication published 13 Mar, 2026 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 15 Sep, 2025 Reviews received at journal 13 Sep, 2025 Reviewers agreed at journal 10 Sep, 2025 Reviews received at journal 22 Aug, 2025 Reviewers agreed at journal 19 Aug, 2025 Reviewers invited by journal 14 May, 2025 Editor assigned by journal 06 May, 2025 Submission checks completed at journal 06 May, 2025 First submitted to journal 03 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Gao","email":"","orcid":"","institution":"National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Linrui","middleName":"","lastName":"Gao","suffix":""},{"id":456572310,"identity":"b467e17b-ae36-442e-b70b-e78b83a78299","order_by":2,"name":"Siyu Zuo","email":"","orcid":"","institution":"National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Siyu","middleName":"","lastName":"Zuo","suffix":""},{"id":456572312,"identity":"f08bd3a8-ba51-489e-b605-0af40238504f","order_by":3,"name":"Ke Zhang","email":"","orcid":"","institution":"National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ke","middleName":"","lastName":"Zhang","suffix":""},{"id":456572314,"identity":"7a04fd75-a638-4dae-9894-d79f63e48462","order_by":4,"name":"Tierun Wang","email":"","orcid":"","institution":"National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tierun","middleName":"","lastName":"Wang","suffix":""},{"id":456572316,"identity":"6d24d7d2-acc3-4331-a8de-c476e4925a89","order_by":5,"name":"Jian Zheng","email":"","orcid":"","institution":"National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jian","middleName":"","lastName":"Zheng","suffix":""},{"id":456572317,"identity":"86114cd3-6e61-4b99-a800-63fe891f5fb1","order_by":6,"name":"Xi Chen","email":"","orcid":"","institution":"National Clinical Research Center for Cancer, Tianjin 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Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Wang","suffix":""},{"id":456572321,"identity":"ed5ba7e7-81d3-4244-b192-267d86e12d3c","order_by":10,"name":"Wencheng Zhang","email":"","orcid":"","institution":"National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wencheng","middleName":"","lastName":"Zhang","suffix":""},{"id":456572323,"identity":"a2650d80-8389-4d4a-a33f-3a13c46398e9","order_by":11,"name":"Tian Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBElEQVRIiWNgGAWjYDACCRjJ3nzwgUQFsiBeLQlAkudYsoHFGQOitYAYOWYSlW1EaJGf3fzs4dcfFvLmPGeMDW7O+xNtcID54G0eBrs8XFoY5xwzN5ZJkDDc2d5W+HDmNoPcDQfYkq15GJKLcWlhlkgwk5ZIkGDccObwZmNJsBYeM2kehgOJDTi0sEmkfwNpsd9wA6j37xyQFv5veLXwAH0t+SFBInHDjRQzCckGsC1seLVISOSUSTOkSSRvOAMMZIljxrkzD7MZW84xSMapRX5G+jbJHzZ1thuOg6KyRi6373jzwxtvKuxwagEHAQ8qF0QY4FEPBIw/8MuPglEwCkbBSAcALilYMIrYv88AAAAASUVORK5CYII=","orcid":"","institution":"National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":true,"prefix":"","firstName":"Tian","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-05-03 14:23:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6584601/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6584601/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-026-15850-5","type":"published","date":"2026-03-13T15:58:53+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83032187,"identity":"33ad933c-a8c4-4ff6-aee7-ebcc09260ba9","added_by":"auto","created_at":"2025-05-19 09:19:33","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":88565,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6584601/v1/8f846ece51a13902db116682.jpg"},{"id":104740327,"identity":"1541c867-ae6c-49f1-8da2-8457ca9f7450","added_by":"auto","created_at":"2026-03-16 16:16:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":949283,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6584601/v1/7655bb3e-5ad1-468d-9832-ecd1df90e6ed.pdf"},{"id":83032184,"identity":"b0b2be00-f8bc-4ff3-9461-c791d02d13e0","added_by":"auto","created_at":"2025-05-19 09:19:33","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18256,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6584601/v1/01118c36726c05bdaa52b938.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Adebrelimab plus chemotherapy as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma (ESCC): a single-center, phase II, single-arm, open-label clinical trial (ADENEO) protocol","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEsophageal cancer is a relatively common malignant tumor with poor prognosis worldwide. According to The Global Cancer Observatory (GLOBOCAN) 2022, there are 604,000 new cases per year, ranking eighth and 544,000 deaths, ranking sixth. Esophageal cancer can be divided into esophageal adenocarcinoma and esophageal squamous cell carcinoma (ESCC), according to the pathological type. China has the highest annual number of new cases and deaths from esophageal cancer, with 224,000 new cases and 187,500 deaths in 2022, of which more than 90% are ESCC\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Due to the hidden onset of esophageal cancer, more than half of the patients have locally advanced or advanced disease.\u003c/p\u003e\n\u003ch3\u003eStandard protocol for the treatment of locally advanced esophageal cancer\u003c/h3\u003e\n\u003cp\u003e According to the National Comprehensive Cancer Network (NCCN) guidelines and the Chinese Society of Clinical Oncology (CSCO) Guidelines, it is recommended to use \"fluorouracil or taxol combined with platinum-based dual drug radical concurrent chemoradiotherapy (cCRT)\" as the standard treatment for locally advanced and inoperable esophageal cancer. However, approximately 50% of patients experience recurrence or metastasis within 2 years after receiving standard cCRT, and the 5-year overall survival (OS) is only 30\u0026ndash;40%\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Different chemotherapy regimens and radiotherapy doses do not improve survival\u003csup\u003e[\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Therefore, for patients with unresectable locally advanced esophageal cancer (LAEC), although cCRT is the standard treatment, the prognosis of esophageal cancer remains poor owing to its highly invasive characteristics, and more accurate combination therapy is urgently needed.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eImmunotherapy improves the treatment effect of esophageal cancer\u003c/h2\u003e \u003cp\u003eImmune checkpoint inhibitors play a key role in tumor therapy. Immune checkpoint inhibitors not only enhance anti-tumor immunity by restoring the function of cytotoxic T cells but also reshape the tumor microenvironment through immune-related pathways. Pembrolizumab plus chemotherapy (Keymate-590), nivolumab in combination with ipilimumab, or chemotherapy (CheckMate 648 study), camrelizumab plus chemotherapy (ESCORT 1st study), sintilimab plus chemotherapy (ORIENT-15 study), and toripalimab plus chemotherapy (JUPITER-06 study) all significantly improved OS in patients with advanced first-line esophageal cancer, compared to chemotherapy alone\u003csup\u003e[\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. According to the NCCN and CSCO guidelines, chemotherapy combined with immunotherapy is the first-line standard treatment for advanced esophageal cancer. For operable esophageal cancer, the CheckMate 577 study showed that postoperative maintenance of nivolumab can significantly improve the disease-free survival (DFS) rate of patients with non-pathological complete response (pCR) after preoperative chemoradiotherapy. Immunotherapy plays an important role in postoperative maintenance of treatment\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProgress in the application of chemoradiotherapy combined with immunotherapy for advanced inoperable esophageal cancer\u003c/h3\u003e\n\u003cp\u003eAccording to preclinical studies, radiotherapy induces immunogenic cell death, which releases neoantigens, alters the tumor microenvironment, and ultimately activates the immune response. The combination of radiotherapy and immunotherapy may achieve synergistic anti-tumor effects, which provides a theoretical basis for the combined application of immune checkpoint inhibitors with chemoradiotherapy\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. CRT combined with immunotherapy has shown enhanced antitumor efficacy in various solid tumors, including non-small cell lung cancer (NSCLC).\u003c/p\u003e \u003cp\u003eCRT combined with immunotherapy may further improve the therapeutic effects in esophageal cancer. At present, multiple phase I/II single-arm small-sample clinical studies have been carried out in patients with unresectable LAEC with combined (chemo)radiotherapy and immunotherapy\u003csup\u003e[\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Zhang et al. treated 20 patients with locally advanced ESCC with camrelizumab combined with concurrent chemoradiotherapy, and the study showed that the 24-month OS and progression-free survival (PFS) rates were 69.6% and 65.0%, respectively. The incidence of \u0026ge;\u0026thinsp;grade 3 treatment-related adverse events (TRAEs) was 45%, \u0026ge;grade 3 radiation esophagitis was 20%, \u0026ge;grade 3 esophageal fistula was 10%, and no\u0026thinsp;\u0026ge;\u0026thinsp;grade 3 radiation pneumonia occurred\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Xi et al. treated 42 untreated, unresectable stage II-IVA ESCC patients with toripalimab combined with radical chemoradiotherapy. The results showed that the 1-year OS and PFS rates were 78.4% and 54.5%, respectively\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. In terms of current evidence, small-sample single-arm phase I/II clinical trials have shown that cCRT with immune checkpoint inhibitors is more effective than conventional CRT for the treatment of LAEC, with good tolerance and controllable toxicity. Relevant phase III randomized controlled studies (e.g., ESCORT-CRT, KEYNOTE 975, RATIONALE 311, KUNLUN) are in progress.\u003c/p\u003e\n\u003ch3\u003eIt is urgent to find an ideal therapeutic effect prediction method\u003c/h3\u003e\n\u003cp\u003eAlthough CRT combined with immunotherapy has a positive effect on some patients with advanced esophageal cancer, some patients still experience recurrence and metastasis within 2 years after treatment. The focus of the current research is to screen effective predictive biomarkers of efficacy. Clinical biomarkers include PD-L1 expression level, tumor mutation burden (TMB), and microsatellite instability (MSI) /deficient mismatch repair (dMMR). PD-L1 expression has been extensively studied. The ESCORT study showed that patients with PD-L1 positive expression in the camrelizumab group had clinical benefits, and patients with PD-L1 positive expression TPS\u0026thinsp;\u0026ge;\u0026thinsp;10% had longer survival than patients with low expression\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. However, the predicted effect decreased when combined with RT\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eThe efficacy of induction chemotherapy or chemoimmunotherapy can predict the effect of dCRT\u003c/h3\u003e\n\u003cp\u003eIn addition to biomarkers, induction therapy can not only reduce tumor burden and distant metastasis but also has a very important significance in predicting the effect of CRT. A Phase II clinical study found that patients who were effectively treated with induction chemotherapy had a significant survival benefit compared with those who did not respond to induction chemotherapy after receiving two cycles of induction chemotherapy. The efficacy of induction chemotherapy can predict survival better than reported biomarkers, with 3-year OS rates of 80.0% and 10.0% and 3-year PFS rates of 55.3% and 10.0%, respectively. The difference is significant, and this result suggests that the efficacy of induction chemotherapy is an effective way to predict the efficacy of radical CRT\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Deng et al. carried out a study on radiotherapy after induction chemoimmunotherapy (ICI) in patients with unresectable locally advanced or metastatic esophageal cancer, and the results showed that the 2-year OS and 2-year PFS rates of the ICIs\u0026thinsp;+\u0026thinsp;RT and RT groups were 57.9% and 43.0% (p\u0026thinsp;=\u0026thinsp;0.050), and 45.7% and 35.8% (p\u0026thinsp;=\u0026thinsp;0.045), respectively. The 1-year local recurrence rate (LRR) in the ICIs\u0026thinsp;+\u0026thinsp;RT group than in the RT group (17.4% vs. 38.8%, p\u0026thinsp;=\u0026thinsp;0.011)\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. These results suggest that radiotherapy after ICI therapy may improve local control and survival in patients with unresectable locally advanced or metastatic esophageal cancer. Therefore, it is feasible to use chemoimmunotherapy as neoadjuvant therapy for radical CRT. For patients who were ineffective to induction immunochemotherapy, it is urgent to optimize the treatment plan.\u003c/p\u003e \u003cp\u003eIt was also shown that patients who had achieved major pathological response (MPR) had better survival, with 2-year OS rates of 91.4% and 47.7%, respectively\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Local recurrence and distant metastasis rates were higher in patients who were not sensitive to induction therapy than in those who were effective in induction therapy\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. Therefore, to further improve the therapeutic effect of patients with inoperable LAEC, the therapeutic effect of LAEC should be further improved by adopting different treatment regimens for patients with different treatment sensitivities based on induction therapy stratification.\u003c/p\u003e \u003cp\u003e \u003cb\u003eRadical CRT was conducted according to different therapeutic effects by stratification.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAdebrelimab is a high-affinity, humanized anti-PD-L1 monoclonal antibody that has been shown to be effective and safe against advanced ESCC, extensive small cell lung cancer (SCLC), and resectable NSCLC\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. In the phase 1b trial of neoadjuvant debrelimab in the treatment of locally advanced resectable ESCC, the primary study endpoint was safety and feasibility. Secondary endpoints included pathological complete response (pCR) and OS. The results showed that The most common TRAEs were anorexia (32%) and fatigue (16%), with no grade 3 or greater adverse reactions. Of the 30 patients enrolled, 25 were successfully resected without surgical delay, with an MPR rate of 24%, a pCR rate of 8%, and a 2-year OS rate of 92%. Adebrelimab has demonstrated good safety and feasibility in patients with resectable LAEC\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBased on previous studies, this clinical trial used two cycles of ICI for locally advanced ESCC and evaluated its efficacy after the end of induction therapy. Patients with effective induction therapy (CR\u0026thinsp;+\u0026thinsp;PR group) were treated with concurrent CRT combined with immunotherapy, whereas patients with ineffective induction therapy (SD\u0026thinsp;+\u0026thinsp;PD group) were treated with different radiotherapy doses and chemotherapy regimens during concurrent CRT to improve the overall treatment effect. It is the first \u0026ldquo;induction PD-L1 inhibitor combined with chemotherapy\u0026rdquo; for inoperable locally advanced ESCC, with the aim of exploring treatment strategy for inoperable locally advanced ESCC based on the efficacy of induction immunochemotherapy.\u003c/p\u003e"},{"header":"Methods and analysis","content":"\u003cp\u003e\u003cstrong\u003eTrial design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a single-center phase II study. The study subjects were patients with inoperable, locally advanced ESCC. After two cycles of ICI, the patients were divided into CR+PR group and SD + PD group according to the efficacy of induction therapy. In the CR+PR group, patients were treated with concurrent CRT combined with immunotherapy. Chemoimmunotherapy was the same as that used before, the radiotherapy dose was 50.4Gy/1.8Gy/28F, and immunotherapy was maintained for one year. In the SD+PD group, the patients were treated with concurrent chemoradiotherapy. To further improve the curative effect, the radiotherapy dose was PTV/PGTV: 50.4Gy/59.92Gy/28F\u0026nbsp;(Figure 1). The chemotherapy regimen was changed and immunotherapy was not used during CRT because of tolerance to previous immunotherapy.\u003c/p\u003e\n\u003cp\u003eIn this study, the combination of immune checkpoint inhibitors and radiotherapy exerted a synergistic anti-tumor effect, which is supported by theoretical feasibility and preliminary clinical research results. Induction immunotherapy can effectively stratify patients and optimize treatment plans, which may further improve PFS and prolong OS in all patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives \u0026amp; end points\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe objectives and end points of this study can be found in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSee Table 2. Safety will be monitored throughout the study and 30 days after the end of the treatment. Adverse events will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients are recruited and screened from Tianjin Medical University Cancer Institute \u0026amp; Hospital from May 2024. Oncologists will assess and evaluate patients based on the eligibility and exclusion criteria. Following this, patients will be provided with an information sheet and asked to offer written consent. Patients have the right to withdraw from the study at any time and for any reason.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eInduction chemotherapy combined with immunotherapy:\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdebrelimab:\u0026nbsp;\u003c/strong\u003e1200 mg intravenously, administered every 3 weeks until PD or intolerance. Adebrelimab was administered for up to 1 year.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInduction chemotherapy:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ealbumin paclitaxel: 220mg/m\u003csup\u003e2\u003c/sup\u003e, d1, d22.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCarboplatin AUC=5, d1, d22.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eConcurrent chemoradiotherapy:\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFor CR/PR patients,\u0026nbsp;\u003c/strong\u003eafter concurrent chemotherapy combined with debrelimab, debrelimab was maintained for 1 year.\u003c/p\u003e\n\u003cp\u003eRadiotherapy: PTV 50.4Gy/1.8Gy/28F, 5 times a week.\u003c/p\u003e\n\u003cp\u003eConcurrent chemotherapy:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ealbumin paclitaxel: 175mg/m\u003csup\u003e2\u003c/sup\u003e, IV, d1, d22.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCarboplatin AUC=5, d1, d22.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFor SD/PD patients,\u0026nbsp;\u003c/strong\u003esimultaneous CRT and simultaneous integrated boost (SIB) were used.\u003c/p\u003e\n\u003cp\u003eRadiotherapy: PTV 50.4Gy/1.8Gy/28F, PGTV 59.92Gy/2.14Gy/28F, 5 times a week.\u003c/p\u003e\n\u003cp\u003eConcurrent chemotherapy:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eoxaliplatin: 85 mg/m\u003csup\u003e2\u003c/sup\u003e, IV, d1, d15, d29.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTetrahydrofolic acid: 400mg/m\u003csup\u003e2\u003c/sup\u003e, IV, d1, d15, d29.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e5-FU: 400mg/m\u003csup\u003e2\u003c/sup\u003e, IV, d1, d15, d29.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e5-FU: 1600mg/m\u003csup\u003e2\u003c/sup\u003e, CIV48h, d1, d15, d29.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size calculation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a single-arm Phase II clinical study, and the sample size was calculated based on the primary study endpoint and investigator-assessed PFS.\u003c/p\u003e\n\u003cp\u003eThe sample size was calculated as follows: the median 2-year PFS of the historical control of radical CRT was 43%, the 2-year PFS of the experimental group was assumed to be 60%, HR=0.60, unilateral α=0.05, the assurance was 80%, the enrollment time was 18 months, and the follow-up time was 18 months. PASS 2021 was used to estimate that 23 cases of PFS events would be required and 53 cases would need to be enrolled. Considering 10% shedding, 60 patients were enrolled in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients will undergo follow-up assessments every 3 month for survival/follow-up antitumour treatment within the first year after the end of treatment. Subsequently, follow-up appointments will occur every 6 months after the first year, continuing until recorded as death, loss of interview, withdrawal of informed consent, and refusal to continue providing information, or the conclusion of the entire trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTumour evaluation will primarily use imaging, with options for additional methods such as ultrasonic gastroscope, CT, etc, if deemed necessary. For patients who discontinue the study and treatment for reasons other than disease progression or death, tumour evaluation will follow the original plan until the disease progresses. The overall duration of this trial is anticipated to be 3 years.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint involves PFS assessed by the investigators, which will be analysed based on the intention-to-treat (ITT) population. Descriptive statistics will be used for clinicopathological characteristics and safety evaluation. Mean values and SD will be provided for continuous endpoints, while frequency and percentage distributions will be presented for discrete data. Kaplan-Meier methodology will estimate PFS and OS in the ITT population. Univariate and multivariate survival analyses will use the Cox proportional hazard model, with HRs and 95% CI calculated. \u0026nbsp;Statistical analyses will employ SPSS V.25.0 software (IBM) and R software V.3.6.2. The significance level is set at p\u0026lt;0.05, and all statistical tests will be two sided. This study was designed to detect a 23% absolute difference in the response rate between the two arms, with 90% power and a two-sided alpha of 0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient and public involvement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical conduct of research\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study is being conducted in full compliance with the principles of the “Declaration of Helsinki” (as amended in Tokyo, Venice, Hong Kong, and South Africa), the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, and local laws and regulations. All Investigators will ensure adherence to the ICH guidelines for Good Clinical Practice (GCP) and Clinical Safety Data Management. All subjects provided written informed consent or were included before participating in the study. The protocol was approved by a reference ethics committee (Tianjin Medical University Cancer Institute \u0026amp; Hospital, Tianjin, China) and was approved by E20040608.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis single center, phase II clinical trial aimed to enroll 60 patients with inoperable locally advanced ESCC and to assess the efficacy and safety of Adebrelimab plus chemotherapy. It is the first \u0026ldquo;induction PD-L1 inhibitor combined with chemotherapy\u0026rdquo; for inoperable locally advanced ESCC, with the aim of exploring treatment strategy for inoperable locally advanced ESCC based on the efficacy of induction immunochemotherapy (NCT06452602).\u003c/p\u003e \u003cp\u003eRadical CRT is the standard treatment for patients with unresectable LAEC, however, the prognosis of esophageal cancer remains poor, and more accurate combination therapy is urgently needed. CRT combined with immunotherapy may further improve the therapeutic effects in esophageal cancer. Although CRT combined with immunotherapy has a positive effect on some patients with advanced esophageal cancer, some patients still experience recurrence and metastasis within 2 years after treatment\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. The focus of the current research is to stratify therapy with more individualized treatment for patients according to the efficacy of induction immunochemotherapy. A previous study reported that those who received two cycles of induction chemotherapy had a significant survival benefit compared with those who did not receive induction chemotherapy, and the efficacy of induction chemotherapy predicted survival better than reported biomarkers\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn our study, after two cycles of ICI, we re-examined endoscopic ultrasonography with bite examination, CT, and upper gastrointestinal angiography, and evaluated curative effect comprehensively according to the method reported in our previous article\u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. 18F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are considered promising tools to predict CRT response\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. However, other studies have indicated that the prediction of pCR through PET and MRI is limited by low sensitivity and poor positive predictive value\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. Therefore, PET-CT is not mandatory used as an evaluation method.\u003c/p\u003e \u003cp\u003ePrevious studies reported that non-responders after neoadjuvant chemotherapy (stable or progressive disease) had worse 5-year survival rates than responders (complete or partial response, 22.3% vs 45.1%)\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. Thus, the patients were divided into CR\u0026thinsp;+\u0026thinsp;PR group and SD\u0026thinsp;+\u0026thinsp;PD groups according to the efficacy of induction therapy. FFCD 9102 study demostated that in patients with locally advanced thoracic esophageal cancers, especially epidermoid, who respond to chemoradiation, there is no benefit for the addition of surgery after chemoradiation compared with the continuation of additional chemoradiation\u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. For SD\u0026thinsp;+\u0026thinsp;PD group, high dose (59.4Gy) was used to improve the local control which is supported by our previous participation in NROG-001 trial. FOLFOX was used as the concurrent chemotherapy regimen based on its safety and efficacy\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis study has several imitations. Firstly, this study is single arm, single-center clinical trial which limited to esophageal squamous cell carcinoma. Concurrent chemoradiotherapy (cCRT) is not set as control group. Secondly, PET-CT is not mandatorily used to evalute the efficacy of induction immunochemothery. In the future, a phase III study will be carried out and cCRT group will be added if the expectation met. This will provide important basis for individualized treatment of esophageal cancer.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the National Natural Science Foundation of China (grant number 82102835 to Tian Zhang, 82272733 to Wencheng Zhang), National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine (grant number QZ23-9) to Wencheng Zhang, and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTian Zhang and Wencheng Zhang contributed to study design and protocol writing. Peng Tang and Siyu Zuo contributed to the identification and enrollment of patients in the study the treatment of patients. Tierun Wang and Jian Zheng analyzed the study samples at the central laboratory. Ke Zhang and Linrui Gao contributed to the manufacturing of the cell products. Xi Chen, Qingsong Pang and Ping Wang wrote the manuscript. All authors have read, reviewed, and approved the protocol and final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial disclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests’ disclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript, apart from those disclosed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWriting disclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo writing assistance was utilized in the production of this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHan B,Zheng R,Zeng H,et al.Cancer incidence and mortality in China, 2022,2024[J].J Natl Cancer Cent,2024,4(1):47-53.\u003c/li\u003e\n\u003cli\u003eWang X,Bai H,Li R,et al.High versus standard radiation dose of definitive concurrent chemoradiotherapy for esophageal cancer: A systematic review and meta-analysis of randomized clinical trials,2023[J].Radiother Oncol,2023,180:109463.\u003c/li\u003e\n\u003cli\u003eSolidum JGN,Rojo RD,Wo JY,et al.Proton Beam Therapy for Esophageal Cancer,2022[J].Cancers (Basel),2022,14(16).\u003c/li\u003e\n\u003cli\u003eHulshof M,Geijsen ED,Rozema T,et al.Randomized Study on Dose Escalation in Definitive Chemoradiation for Patients With Locally Advanced Esophageal Cancer (ARTDECO Study),2021[J].J Clin Oncol,2021,39(25):2816-2824.\u003c/li\u003e\n\u003cli\u003eXu Y,Dong B,Zhu W,et al.A Phase III Multicenter Randomized Clinical Trial of 60 Gy versus 50 Gy Radiation Dose in Concurrent Chemoradiotherapy for Inoperable Esophageal Squamous Cell Carcinoma,2022[J].Clin 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study,2021[J].Lancet,2021,398(10302):759-771.\u003c/li\u003e\n\u003cli\u003eLuo H,Lu J,Bai Y,et al.Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial,2021[J].JAMA,2021,326(10):916-925.\u003c/li\u003e\n\u003cli\u003eKelly RJ,Ajani JA,Kuzdzal J,et al.Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer,2021[J].N Engl J Med,2021,384(13):1191-1203.\u003c/li\u003e\n\u003cli\u003eGuo S,Yao Y,Tang Y,et al.Radiation-induced tumor immune microenvironments and potential targets for combination therapy,2023[J].Signal Transduct Target Ther,2023,8(1):205.\u003c/li\u003e\n\u003cli\u003eGao Z,Zhao Q,Xu Y,et al.Improving the efficacy of combined radiotherapy and immunotherapy: focusing on the effects of radiosensitivity,2023[J].Radiat Oncol,2023,18(1):89.\u003c/li\u003e\n\u003cli\u003eZhang W,Yan C,Gao X,et al.Safety and Feasibility of Radiotherapy Plus Camrelizumab for Locally Advanced Esophageal Squamous Cell Carcinoma,2021[J].Oncologist,2021,26(7):e1110-e1124.\u003c/li\u003e\n\u003cli\u003ePark S,Oh D,Choi YL,et al.Durvalumab and tremelimumab with definitive chemoradiotherapy for locally advanced esophageal squamous cell carcinoma,2022[J].Cancer,2022,128(11):2148-2158.\u003c/li\u003e\n\u003cli\u003eZhang W,Yan C,Zhang T,et al.Addition of camrelizumab to docetaxel, cisplatin, and radiation therapy in patients with locally advanced esophageal squamous cell carcinoma: a phase 1b study,2021[J].Oncoimmunology,2021,10(1):1971418.\u003c/li\u003e\n\u003cli\u003eWang J CY, Wu Y, Cao F, Liu Q, Gao G.1262TiP Efficacy and safety of consolidative camrelizumab following definitive concurrent chemoradiotherapy in patients with locally advanced esophageal squamous cell cancer. ,2022[J].Annals of Oncology,2022,33.\u003c/li\u003e\n\u003cli\u003eBando H KS, Kotani D, et al. .1211P A multicenter phase II study of atezolizumab monotherapy following definitive chemoradiotherapy for unresectable locally advanced esophageal squamous cell carcinoma (EPOC1802). ,2022[J].Annals of Oncology,2022,33:S1102-S1103.\u003c/li\u003e\n\u003cli\u003eJing Z DD, Zhang N, et al. .Combination of Radiation Therapy and Anti-PD-1 Antibody SHR-1210 in Treating Patients with Esophageal Squamous Cell Cancer.,2018[J].International Journal of Radiation Oncology*Biology*Physics,2018,102(3).\u003c/li\u003e\n\u003cli\u003eWang X LB.Two-Stage Phase II Study of Envafolimab Combined with Endostar and Concurrent Chemoradiotherapy in Treatment of Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma: Preliminary Results of Stage 1.,2022[J].International Journal of Radiation Oncology*Biology*Physics,2022,114(3).\u003c/li\u003e\n\u003cli\u003eZhu Y,Wen J,Li Q,et al.Toripalimab combined with definitive chemoradiotherapy in locally advanced oesophageal squamous cell carcinoma (EC-CRT-001): a single-arm, phase 2 trial,2023[J].Lancet Oncol,2023,24(4):371-382.\u003c/li\u003e\n\u003cli\u003eHuang J,Xu J,Chen Y,et al.Camrelizumab versus investigator\u0026apos;s choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study,2020[J].Lancet Oncol,2020,21(6):832-842.\u003c/li\u003e\n\u003cli\u003eJiang C,Zhu Y,Tang S,et al.High PD-L1 expression is associated with a favorable prognosis in patients with esophageal squamous cell carcinoma undergoing postoperative adjuvant radiotherapy,2019[J].Oncol Lett,2019,17(2):1626-1634.\u003c/li\u003e\n\u003cli\u003eLiu S,Luo L,Zhao L,et al.Induction chemotherapy followed by definitive chemoradiotherapy versus chemoradiotherapy alone in esophageal squamous cell carcinoma: a randomized phase II trial,2021[J].Nat Commun,2021,12(1):4014.\u003c/li\u003e\n\u003cli\u003eDeng W,Chang X,Dong X,et al.Induction immunochemotherapy followed by radiotherapy for patients with unresectable locally advanced or metastatic esophageal cancer: A propensity score-matched analysis,2023[J].Int Immunopharmacol,2023,124(Pt B):110955.\u003c/li\u003e\n\u003cli\u003eNarita K,Higaki E,Abe T,et al.Conversion from Radical Esophagectomy to Definitive Chemoradiotherapy After Neoadjuvant Chemotherapy for Advanced Esophageal Squamous Cell Carcinoma: Treatment Options Based on Chemotherapy Response,2025[J].Ann Surg Oncol,2025.\u003c/li\u003e\n\u003cli\u003eWang J,Zhou C,Yao W,et al.Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial,2022[J].Lancet Oncol,2022,23(6):739-747.\u003c/li\u003e\n\u003cli\u003eYan W,Zhong WZ,Liu YH,et al.Adebrelimab (SHR-1316) in Combination With Chemotherapy as Perioperative Treatment in Patients With Resectable Stage II to III NSCLCs: An Open-Label, Multicenter, Phase 1b Trial,2023[J].J Thorac Oncol,2023,18(2):194-203.\u003c/li\u003e\n\u003cli\u003eYin J,Yuan J,Li Y,et al.Publisher Correction: Neoadjuvant adebrelimab in locally advanced resectable esophageal squamous cell carcinoma: a phase 1b trial,2023[J].Nat Med,2023,29(9):2376.\u003c/li\u003e\n\u003cli\u003eQian D,Wang Y,Zhao G,et al.Tumor Remission and Tumor-Infiltrating Lymphocytes During Chemoradiation Therapy: Predictive and Prognostic Markers in Locally Advanced Esophageal Squamous Cell Carcinoma,2019[J].Int J Radiat Oncol Biol Phys,2019,105(2):319-328.\u003c/li\u003e\n\u003cli\u003eFang P,Musall BC,Son JB,et al.Multimodal Imaging of Pathologic Response to Chemoradiation in Esophageal Cancer,2018[J].Int J Radiat Oncol Biol Phys,2018,102(4):996-1001.\u003c/li\u003e\n\u003cli\u003eHeneghan HM,Donohoe C,Elliot J,et al.Can CT-PET and Endoscopic Assessment Post-Neoadjuvant Chemoradiotherapy Predict Residual Disease in Esophageal Cancer?,2016[J].Ann Surg,2016,264(5):831-838.\u003c/li\u003e\n\u003cli\u003eYuan H,Tong DK,Vardhanabhuti V,et al.PET/CT in the evaluation of treatment response to neoadjuvant chemoradiotherapy and prognostication in patients with locally advanced esophageal squamous cell carcinoma,2016[J].Nucl Med Commun,2016,37(9):947-955.\u003c/li\u003e\n\u003cli\u003eBedenne L,Michel P,Bouch\u0026eacute; O,et al.Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102,2007[J].J Clin Oncol,2007,25(10):1160-1168.\u003c/li\u003e\n\u003cli\u003eConroy T,Galais MP,Raoul JL,et al.Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial,2014[J].Lancet Oncol,2014,15(3):305-314.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"locally advanced esophageal squamous cell carcinoma, induction chemoimmunotherapy, concurrent chemoradiotherapy, Adebrelimab, therapeutic effect","lastPublishedDoi":"10.21203/rs.3.rs-6584601/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6584601/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e Although radical chemoradiotherpy (CRT) is the standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (LA-ESCC), the prognosis remains extremely poor. Although CRT combined with immunotherapy has a positive effect on some patients with advanced esophageal cancer, some patients still experience recurrence and metastasis after treatment. The overall response rate (ORR) of induction immunochemotherapy for advanced esophageal cancer is approximately 40%-70%. Radiotherapy or concurrent chemoradiotherapy (cCRT) after induction of chemoradiation is more effective. In this study, different patients were given different treatments according to the therapeutic effect of induction chemoimmunotherapy (ICI) in order to improve the treatment effect of locally advanced esophageal cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods and analysis:\u003c/strong\u003eThe ADENEO trial is a single center, phase II, single-arm, open-label clinical trial that will enrol 60 patients. Eligible patients will be registered, enrolled and receive 2 cycles of Adebrelimab plus albumin paclitaxel and carboplatin, and the efficacy was evaluated. The patients will divided into complete response + partial response (CR+PR) group and stable disease +progression (SD+PD) group according to the efficacy of induction therapy. In the CR+PR group, patients were treated with concurrent CRT combined with Adebrelimab. Chemoimmunotherapy was the same as that used before, the radiotherapy dose was 50.4Gy/1.8Gy/28F, and immunotherapy was maintained for one year. In the SD+PD group, the patients were treated with cCRT. To further improve the curative effect, the radiotherapy dose was PTV/PGTV: 50.4Gy/59.92Gy/28F. The chemotherapy regimen was changed and immunotherapy was not used during CRT because of tolerance to previous immunotherapy. The primary endpoint is the progression free survival (PFS) assessed by the investigators, and the secondary endpoints are ORR, overall survival (OS), duration of response (DoR), adverse event (AE) and serious adverse time (SAE).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and dissemination:\u003c/strong\u003eWritten informed consent will be required from all patients enrolled, and it will be provided by them. The study protocol received approval from the independent ethical review committee of Tianjin Medical University Cancer Institude \u0026amp; Hospital. We will submit the finalised paper for publication on completing the analyses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration number: \u003c/strong\u003eNCT06452602 (www.clinicaltrialsregister.eu) (ClinicalTrials.gov).\u003c/p\u003e","manuscriptTitle":"Adebrelimab plus chemotherapy as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma (ESCC): a single-center, phase II, single-arm, open-label clinical trial (ADENEO) protocol","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-19 09:19:28","doi":"10.21203/rs.3.rs-6584601/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-15T09:20:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-13T06:04:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"180587170332839588641944006782516036976","date":"2025-09-10T13:01:33+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-22T14:06:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"38937525577909060495851368818720159408","date":"2025-08-19T09:32:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-14T13:30:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-06T07:02:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-06T06:54:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-05-03T14:20:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a81adecf-1fc9-404d-945c-e7f58a518d68","owner":[],"postedDate":"May 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-16T16:11:54+00:00","versionOfRecord":{"articleIdentity":"rs-6584601","link":"https://doi.org/10.1186/s12885-026-15850-5","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2026-03-13 15:58:53","publishedOnDateReadable":"March 13th, 2026"},"versionCreatedAt":"2025-05-19 09:19:28","video":"","vorDoi":"10.1186/s12885-026-15850-5","vorDoiUrl":"https://doi.org/10.1186/s12885-026-15850-5","workflowStages":[]},"version":"v1","identity":"rs-6584601","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6584601","identity":"rs-6584601","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}