Tislelizumab plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy for elderly patients with inoperable locally advanced esophageal squamous cell carcinoma: a multicenter, randomized, parallel-controlled, phase II clinical trial

Tislelizumab plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy for elderly patients with inoperable locally advanced esophageal squamous cell carcinoma: a multicenter, randomized, parallel-controlled, phase II clinical trial | 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 Tislelizumab plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy for elderly patients with inoperable locally advanced esophageal squamous cell carcinoma: a multicenter, randomized, parallel-controlled, phase II clinical trial Ke Zhang, Qifeng Wang, Jianzhong Cao, Chengcheng Fan, Wenbin Shen, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3972285/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 May, 2024 Read the published version in Journal of Clinical Oncology → Version 1 posted You are reading this latest preprint version Abstract Background The standard treatment for elderly patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is definitive chemoradiotherapy based on S-1. However, 3-year overall survival (OS)is limited about 40%. Tislelizumab has been the first-line and second-line standard treatment for advanced ESCC with tolerable toxicity. In the study we aimed to explore a new curative strategy for locally advanced unresectable elderly ESCC by combining tislelizumab with chemoradiotherapy. Methods The 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 to concurrent chemoradiotherapy. The main inclusion criteria are pathological confirmation of locally advanced inoperable ESCC at clinical cT1N2-3M0 or cT2-4bN0-3M0(stage II–IVA), aged ≥ 70 years, without any previous systemic anti-tumor therapy, and adequate organ function. A total of 136 patients will be recruited from approximately 6 centers over a period of 1 year 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 treatment will be evaluated during the therapy and follow-up period until disease progression or death or the end of the trial. The primary study endpoint is investigator-assessed progression free survival (PFS), and the secondary study endpoints are OS, objective response rate (ORR), duration of remission (DOR), and safety. Fresh or archival tumor tissues and peripheral blood samples will be used in the exploratory studies. Discussion The synergistic efficacies of combined definitive concurrent chemoradiotherapy with tislelizumab are expected to result in survival benefit for elderly patients with inoperable locally advanced ESCC. As S-1 plus concurrent radiotherapy is the standard treatment option for locally advanced ESCC 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 Concurrent chemoradiotherapy Immunotherapy Locally advanced esophageal squamous cell carcinoma Older patients Tislelizumab Figures Figure 1 1. Background Esophageal cancer (EC) is a common malignant tumor with poor prognosis worldwide, and the morbidity and mortality of esophageal cancer in China was 224,000 and 178,500 in 2022[ 1 ]. Esophageal squamous cell carcinoma (ESCC) is the main histologic subtype of EC in China. The proportion of elderly patients with ESCC over the age of 70 years is as high as 30–40% [ 2 ], which is still increasing due to the aging trend of the society. However, neither consensus nor guidelines is available for these patients. It urgently needs clinical trials focusing on elderly ESCC. As far, definitive radiotherapy is the main treatment for elderly patients with locally advanced ESCC because these patients are intolerable to surgery. While, the radiation field and dose are still controversial. Several studies recently showed the survival was not different between ESCC patients receiving involved field irradiation (IFI) and elective nodal irradiation (ENI)[ 3 , 4 ]. In a retrospective analysis that enrolled 137 elderly ESCC patients who aged 70 years or older, although there was no difference of median overall survival (OS) and 3-year OS rates between the IFI and ENI group, the incidence of grade ≥ 3 radiation esophagitis was lower in the IFI group[ 5 ]. In the exploration of radiation dose, 50.4 Gy is widely used in the concurrent chemoradiotherapy (CCRT) which is the standard care for locally advanced inoperable ESCC according to the results of RTOG94-05 study [ 6 ]. With application of modern radiation techniques, several prospective randomized clinical studies revealed that high dose (60 Gy) did not improve survival compared with 50 Gy, but increased the grade ≥ 3 treatment-related adverse effects (TRAEs) [ 7 – 10 ]. Therefore, 50 Gy in IFI might be preferred for elderly ESCC. Recent studies with small sample sizes demonstrated the completion of dual-agent chemoradiotherapy(CRT) was limited in elderly ESCC patients over 75 years old because of the higher incidence of toxicities[ 11 , 12 ]. S-1 is a new oral fluoropyrimidine derivative consisting of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate in a molar ratio of 1:0.4:1. S-1 may show a superior radiosensitizing effect than fluorouracil due to its stable high-level plasma concentration[ 13 ]. 5-chloro-2,4-dihydroxypyridine inhibited the DNA repair resulted from radiation-induced damage, enhancing the sensitivity of tumor cells to radiotherapy[ 14 ]. The results of multicenter phase II/ III randomized controlled studies in elderly ESCC manifested, compared with radiotherapy alone, combining S-1 with radiotherapy not only benefit survival, but also had tolerable toxicities[ 14 – 16 ]. Since S-1 is given orally, which is far more convenient than intravenous administration, particularly for elderly patients and patients required nasal administration. Combining S-1 and radiotherapy probably has become the standard treatment strategy in elderly patients with locally advanced inoperable ESCC. However, the survival was suboptimal, with a 3-year OS rate of about 40% [ 14 – 16 ]. New strategies are still required to further improve the treatment outcome for elderly patients. Emerging studies indicated promising synergistic effects of combining immunotherapy with CRT, presenting a novel treatment avenue for ESCC. Tislelizumab, an anti-programmed death-1(PD-1) antibody, has recently been proved in the first- and second-line standard treatment for advanced ESCC[ 17 , 18 ]. The RATIONALE-302 study showed that tislelizumab had a good survival benefit in the second-line treatment of advanced metastatic ESCC. Patients in tislelizumab group showed prolonged median OS(8.6 months) and reduced TRAEs(73.3%) compared with patients in chemotherapy group[ 18 ].. The RATIONALE-306 study also showed that tislelizumab in combination with chemotherapy achieved an ultra-long survival benefit in the first-line treatment of advanced metastatic ESCC. The median OS and progression free survival (PFS) are 17.2 months and 7.3 months, respectively[ 17 ]. Tislelizumab exhibited mild toxicities[ 17 , 18 ] and might be well tolerated in elderly. But, tislelizumab combined with radiotherapy applied in elderly ESCC patients remains unknown. Herein, we conduct the first clinical trial to assess the efficacy and safety of tislelizumab plus concurrent S-1 combined with radiotherapy versus concurrent S-1 combined with radiotherapy for elderly patients with inoperable locally advanced ESCC. 2. Methods/design 2.1 Study design This trial is a multicenter, phase II study to assess the efficacy and safety of tislelizumab plus concurrent S-1 combined with radiotherapy versus concurrent S-1 combined with radiotherapy for elderly patients with inoperable locally advanced ESCC. The inclusion and exclusion criteria are shown as following. Eligible patients will be randomized in a 1:1 ratio in the investigation and control group. The CCRT is S-1 (40–60 mg, orally administered from day 1 to 14 and from day 22 to 35) and radiotherapy (IFI) at 50.4 Gy/1.8 Gy/28 fractions (5 times per week). In the investigation group, tislelizumab will be given from the first day of radiotherapy in Q3W for one year. Figure 1 showed the diagram of study design. 2.2 Eligibility criteria for the trial 2.2.1 Inclusion Criteria Patients with histologically confirmed cT1N2-3M0 or cT2-4bN0-3M0 or cT1-4bN0-3M1 (supraclavicular lymph node metastasis) locally advanced ESCC (according to the 8th edition of American Joint Committee on Cancer); clinically staged as II-IVb inoperable locally advanced ESCC (including contraindications to or refusal of surgery). Patients aged ≥ 70 years, included male and female. Patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. Patients without any previous systemic anti-tumor therapy (including systemic chemotherapy, radiotherapy, molecular targeted therapy, immunotherapy, biologic therapy, topical therapy and other investigational therapeutic agents, etc.). Patients agreed to provide fresh or archival tumor tissues within 6 months (fresh samples preferred) for biomarker analysis such as programmed death ligand 1(PD-L1). Tissue specimens are formalin-fixed, paraffin-embedded (FFPE) for exploration study. Patients with life expectancy longer than 3 months. Patients with adequate hematologic function, defined as ANC ≥1500/μL, platelet count ≥100,000/μL and hemoglobin count ≥9.0 g/dL or ≥5.6 mmol/L. Patients with adequate renal function, defined as creatinine ≤1.5× ULN or measured or calculated creatinine clearance ≥60 mL/min for those with creatinine levels >1.5× ULN (Calculated from the Cockcroft-Gault formula). Patients with adequate hepatic function, defined as total bilirubin ≤1.5× ULN and ALT/AST/AKP levels ≤2.5× ULN and albumin ≥2.8 g/dL. Patients with adequate coagulation function, defined as INR ≤1.5× ULN and APTT≤1.5× ULN unless the patient is receiving anticoagulant therapy as long as INR is within the therapeutic range. Patients who sign written informed consent. 2.2.2 Exclusion Criteria Patients receiving surgery for ESCC. Patients with esophageal fistulae due to invasion of the primary tumor. Patients with risk of gastrointestinal bleeding, esophageal fistula or esophageal perforation. Patients with poor nutritional status, weight loss of ≥10% in the previous 2 months, with no significant improvement after nutritional intervention. Patients receiving major operation or severe trauma within 4 weeks prior to enrollment. Patients with uncontrollable pleural effusion, pericardial effusion, or ascites that requires repeated drainage. Patients with active multiple primary cancers (synchronous multiple primary cancers and multiple cancers with a progression-free period of ≤5 years from the time of enrollment), carcinoma in situ or intramucosal carcinoma curable by local resection are not included in the definition of active multiple primary cancers. Patients previously received or are receiving any of the following treatments: Anti-PD-1 or anti-PD-L1 antibody therapy, chemotherapy, radiotherapy or targeted therapy. Participation in a study of an investigational agent or device within 4 weeks before the first dose of study treatment. Systemic treatment with corticosteroids (>10 mg prednisone equivalent per day) or other immunosuppressive agents is required for 2 weeks before the first dose of study treatment. Patients using corticosteroids for local inflammation or for prevention of allergy, nausea and vomiting can be included. Received anti-tumor vaccine or any live vaccine within 4 weeks before the first dose of study treatment. Patients with any active autoimmune disease or history of autoimmune disease (e.g. interstitial pneumonitis, uveitis, enteritis, hepatitis, pituitary gland inflammation, vasculitis, myocarditis, nephritis, hyperthyroidism and hypothyroidism). Patients with vitiligo or those who had asthma or allergies in childhood but did not need any intervention as adults; patients with autoimmune-mediated hypothyroidism treated with stable doses of thyroid replacement hormone and type I diabetes mellitus treated with stable doses of insulin are not included in the definition of active autoimmune disease or history of autoimmune disease. Patients diagnosed HIV infection or other acquired/congenital immunodeficiency diseases, or history of organ/ allogeneic transplantation. Patients diagnosed uncontrolled cardiac clinical symptoms or disease (such as NYHA II or above heart failure, unstable angina, myocardial infarction within 1 year or clinically significant supraventricular or ventricular arrhythmias requiring clinical intervention). Patients with severe infections (Common Terminology Criteria for Adverse Events Grade >2), such as severe pneumonia, bacteremia, infectious complications, etc., within 4 weeks before the first use of study treatment; active lung inflammation requiring oral or intravenous antibiotic treatment within 2 weeks before the first use of study treatment. Patients with history interstitial lung disease, non-infectious pneumonia, or pulmonary insufficiency ≥ grade 3 as confirmed by pulmonary function tests. Patients with active tuberculosis infection. Patients with active hepatitis B (HBV DNA ≥2000 IU/mL or 104 copies/mL), hepatitis C (hepatitis C antibody positive and HCV-RNA above the lower limit of detection); Patients with abnormal sodium, potassium, and calcium laboratory test values (>Grade 1) that do not improve after treatment within 2 weeks prior to randomization. 2.3 Planned sample size The open label, multicenter, parallel-controlled, investigator-initiated phase II clinical trial was expected to take 18 months to enroll all participants, with an additional follow-up period of 24 months after the last patient randomization. Considering the median PFS is 16 months in elderly ESCC receiving concurrent S-1 combined with radiotherapy in history studies[ 14 – 16 ], we expect the median PFS would be 28 months at the hazard ratio of 0.57. The final sample size consists in 136 patients by 1:1 randomized in the two groups with 80% power and one-sided alpha and calculating for a 10% dropout rate. The study uses the following stratification factors: tumor staging II/III and IV, age 70–79 and ≥ 80. Allocation to either arm will be decided by a computer-generated randomization schedule. 2.4 Study procedures 2.4.1 Evaluation and randomization Patient participation in this study need sign the informed consent before any study-specific screening or evaluation. Screening examinations and assessments will be performed within 28 days prior to enrollment. Routine blood tests and blood biochemistry performed prior to the start of the first cycle of treatment need be completed within 7 days prior to randomization. Patients must be restaged within 4 weeks prior to randomization, including undergoing computed tomography (CT) scan cervical, thoracic and abdominal (including pelvic) CT or magnetic resonance imaging (all contrast-enhanced, replaced by routine CT scan if contrast is prohibited). Magnetic resonance imaging (MRI) of the brain is required when brain metastasis is suspected and diagnosed (replaced by contrast-enhanced CT if MRI is prohibited). And Bone scan/Positron Emission Tomography (PET) is only carried out when there are clinical indications with time to test relaxed to within 42 days prior to the first dose of medication. 2.4.2 Intervention In the treatment group, patients will receive tislelizumab combined with concurrent S-1 and radiotherapy. Tislelizumab is given via intravenous infusion from the first day of radiotherapy every 3 weeks until progressive disease or intolerable combined with concurrent chemoradiotherapy. Tislelizumab will maintain for a maximum of 1 year. In the control group, patients will receive concurrent S-1 and radiotherapy. 2.4.2.1 Chemotherapy S-1 is orally administered from day 1 to day 14 and day 22 to 35. The dose is based on the patient's body surface area (BSA): 40 mg twice daily for BSA < 1.25 m 2 ; 50 mg twice daily for 1.25 m 2 ≤ BSA < 1.50 m 2 ; 60 mg twice daily for BSA ≥ 1.50 m 2 . If grade 3 or above hematologic, gastrointestinal, or dermal toxicity occurs during S-1 treatment, the dose need be decreased from 60, 50 to 40 mg, and S-1 will be discontinued immediately if a grade 4 adverse event (AE) occurs. 2.4.2.2 Radiotherapy Prior to patient enrollment, the radiation oncologist evaluates the patient's thoracic CT or PET-CT to ensure that the treatment area does not significantly exceed the prescribed normal tissue limits and that the 50.4 Gy irradiation dose is appropriate for the patient. Radiotherapy is delivered by standardized intensity-modulated radiotherapy (IMRT) or volumetric rotational intensity-modulated radiotherapy (VMAT). The prescribed dose is total 50.4 Gy, with 1.8 Gy per fraction and 5 times per week. IFI is used in determining the radiation field. Cone Beam CT verification is required once a week during the treatment to ensure the accuracy of the treatment. For a subject develops severe esophagitis or other serious radiotherapy-induced AEs, the subject may continue to receive radiotherapy if in the opinion of the investigator. Intensified supportive therapy is allowed to help the subject continue to receive radiotherapy without increased risk. 2.4.2.3 Immunotherapy Tislelizumab is administered on the first day of radiotherapy at the dose of 200 mg intravenously for 30 min (not less than 20 min and not more than 60 min) per infusion and repeated every 21 days until progression disease or intolerance, or up to a maximum of 1 year. If tislelizumab-related AEs occur during treatment, the investigator may suspend tislelizumab treatment according to the protocol based on the subject's AEs profile. 2.4.3 Follow-up The subject's blood routine examination, blood biochemistry and thyroid function are rechecked 30 days after the last dose. Survival status and tumor imaging will be evaluated every 3 months from the end of treatment during 2 years and 6 months after 2 years. 2.5 Outcome measures/endpoints 2.5.1 Primary objective PFS is measured from the date of randomization until progression (as per RECIST 1.1 assessment, regardless of continued treatment) or death from any cause. Subjects who neither experience disease progression nor death will be censored at the date of their last evaluable tumor assessment. 2.5.2 Secondary objectives OS is the time from randomization to the date of death from any cause. For subjects that are alive, their survival time will be censored at the date of last contact (“last known alive date”). OS is censored for subjects at the date of last confirmed survival if they are loss in follow up. Objective response rate (ORR) is the proportion of randomized subjects who achieve a best response of complete response (CR) or partial response (PR) using the RECIST 1.1 criteria. Best objective response (BOR) is the best investigator-rated designation for the period between the date of enrollment and the date of objectively documented progression according to RECIST 1.1 criteria or to the initiation of subsequent anti-tumor therapy, whichever occurs first. For subjects with no progression and no initiation of subsequent anti-tumor therapy, the BOR will be determined based on all response evaluation. Duration of Objective Response (DOR) is the time between the date of first documented response (CR or PR) to the date of the first documented progression as determined by RECIST 1.1, or death due to any cause, whichever occurs first. For subjects who neither progress nor die, the DOR will be censored. Severity of AEs is assessed using Common Terminology Criteria for Adverse Events v5.0. All AEs are recorded from randomization until 90 days after the end of treatment, regardless of relatedness to study medication. For TRAEs, investigators should follow up until resolution, remission, or to baseline levels, or ≤ grade 1, or to steady state, or with a reasonable explanation (e.g. loss to follow-up, death). The investigators assess quality of life of the elderly subjects in a multidimensional manner through a series of questionnaires, such as European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30&OES18, Charlson comorbidity index, Barthel Index, Instrumental Activities of Daily Living Scale, Mini-Nutritional Assessment, Mini-Mental State Examination, Geriatric Depression Scale, and Medical Outcomes Study Social Support Survey. 2.6 Biomarker analysis and translational research We will collect serial biopsies from the primary site and blood collections at 3 time points if possible (before treatment, after 40 Gy of radiotherapy, and progression). Using the collected samples, we will investigate biomarkers for efficacy or resistance to the treatment. We will also analyze phenotype of immune-competent cells using both immunohistochemistry and flowcytometry, PD-L1 status. 2.7 Statistical analysis Time to event distributions (i.e. PFS and OS)will be estimated using the Kaplan–Meier method, and log-rank tests will be used to determine the significance. A Cox multivariable regression will be used to determine prognostic factors for survival benefit. In terms of safety, we will finally tabulate the incidence of each AE. 3. Discussion The multicenter, randomized, parallel-controlled, Phase II clinical trial aims to enroll 136 elderly patients with inoperable locally advanced ESCC and to assess the efficacy and safety of tislelizumab plus concurrent S-1 and radiotherapy versus concurrent S-1 and radiotherapy. It is the first "PD-1 inhibitor combined with concurrent chemoradiotherapy" for elderly patients with inoperable locally advanced ESCC, aiming to explore a novel treatment strategy for elderly ESCC (NTC06061146). This study addresses the special population of elderly ESCC patients with multidimensional assessment and nutritional support therapy for pre-treatment, under treatment and maintenance therapy, which will be accomplished by a multidisciplinary collaboration including radiation oncology department, medical oncology department, nutrition department and endoscopy department. Moreover, if tislelizumab plus concurrent S-1 and radiotherapy significantly improve the PFS of elderly ESCC patients, further confirmatory phase III trial will be planned. And the results of our study may inform the optimization of treatment of combing immunotherapy and concurrent chemoradiotherapy for the elderly patients with inoperable locally advanced ESCC. Abbreviations EC Esophageal cancer ESCC Esophageal squamous cell carcinoma IFI Involved field irradiation ENI Elective nodal irradiation CCRT Concurrent chemoradiotherapy TRAEs Treatment-related advent events CRT Chemoradiotherapy PD-1 Programmed death-1 PFS Progression free survival ECOG PS Eastern Cooperative Oncology Group Performance Status PD-L1 Programmed death ligand 1 FFPE Formalin fixed paraffin embedded CT computed tomography MRI Magnetic resonance imaging PET Positron Emission Tomography BSA Body surface area AE Adverse event IMRT Intensity-modulated radiotherapy VMAT Volumetric Modulated Arc Therapy ORR Objective response rate CR Complete response PR Partial response BOR Best objective response DOR duration of remission EORTC QLQ European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Declarations Acknowledgements We thank all participating patients, all participating sub-centers and investigators who devote their time and passion in implementation of the study. Funding The investigator-initiated trial is supported by national natural science foundation of China (82272733, 82273083). BeiGene provides insurance costs for participating patients, but have no role in study design, data collection, data analysis, data interpretation and writing the manuscript. Availability of data and materials The datasets during the current study can be obtained from the corresponding author upon reasonable request. Authors’ contributions All authors participated in writing, reviewing and approving the manuscript for submission. Study concepts and design: WZ; Data acquisition: KZ, QW, JC, CF, WS, QX, XG, XL, TZ, XC, ZL, ZZ, CY, WZ; Quality control of data and algorithms: KZ, QW, JC, CF, WS, QX, XG, XL, TZ, XC, ZL, ZZ, CY, WZ; Manuscript preparation: KZ, WZ and CY; Manuscript editing: KZ, WZ and CY; Manuscript review: KZ, QW, JC, CF, WS, QX, XG, XL, TZ, XC, JD, ZL, ZZ, CY, PW, QP, WZ. Ethics approval and consent to participate Institutional review board approval was obtained for the trial from the ethical committee of Tianjin Cancer Hospital (E20230954) in August 2023. The trial was published under NCT06061146 on ClinicalTrials.gov. All participants have signed the informed consent form. Consent for publication Not applicable. Competing interests No competing interests are declared by all authors. Authors’ information 1 Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China 2 Radiation Oncology Key Laboratory of Sichuan Province, Department of Radiation Oncology, Sichuan Cancer Hospital Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. 3 Department of Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030013, China 4 The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China 5 Radiotherapy Department of the Fourth Hospital of Hebei Medical University 6 Thoracic Radiotherapy Department Hunan Cancer Hospital the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University 7 Department of Radiation Oncology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, 300, Guangzhou Road, Nanjing, Jiangsu, China. 8 Department of Nutrition Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin’s Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China 9 Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin’s Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China References Han B, Zheng R, Zeng H, Wang S, Sun K, Chen R, Li L, Wei W, He J. 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Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 31 May, 2024 Read the published version in Journal of Clinical Oncology → Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3972285","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":274449663,"identity":"e41d623c-243b-4f2e-bb97-127e055e0d17","order_by":0,"name":"Ke Zhang","email":"","orcid":"","institution":"Department of Radiation Oncology, Tianjin Medical University Cancer Institute \u0026 Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin","correspondingAuthor":false,"prefix":"","firstName":"Ke","middleName":"","lastName":"Zhang","suffix":""},{"id":274449665,"identity":"f12a2413-239f-4192-9414-92c6b151f4a8","order_by":1,"name":"Qifeng Wang","email":"","orcid":"","institution":"Department of Radiation Oncology, Sichuan Cancer Hospital Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science, Chengdu","correspondingAuthor":false,"prefix":"","firstName":"Qifeng","middleName":"","lastName":"Wang","suffix":""},{"id":274449666,"identity":"5f6bbc4f-e429-49b1-af75-dad9976857cd","order_by":2,"name":"Jianzhong Cao","email":"","orcid":"","institution":"Department of Radiotherapy, Shanxi Province Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University,Taiyuan","correspondingAuthor":false,"prefix":"","firstName":"Jianzhong","middleName":"","lastName":"Cao","suffix":""},{"id":274449667,"identity":"28cf1c6f-b4d7-4fd2-8111-73146f4c0274","order_by":3,"name":"Chengcheng Fan","email":"","orcid":"","institution":"The Affiliated Cancer Hospital of Zhengzhou University \u0026 Henan Cancer Hospital, Zhengzhou","correspondingAuthor":false,"prefix":"","firstName":"Chengcheng","middleName":"","lastName":"Fan","suffix":""},{"id":274449668,"identity":"6acb7f59-b406-4360-b97d-d7161164905a","order_by":4,"name":"Wenbin Shen","email":"","orcid":"","institution":"Radiotherapy Department of the Fourth Hospital of Hebei Medical University,Shijiazhuang","correspondingAuthor":false,"prefix":"","firstName":"Wenbin","middleName":"","lastName":"Shen","suffix":""},{"id":274449669,"identity":"168c68d0-7204-4223-808a-250b2b5dc0f8","order_by":5,"name":"Qin Xiao","email":"","orcid":"","institution":"Thoracic Radiotherapy Department Hunan Cancer Hospital the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University,Changsha","correspondingAuthor":false,"prefix":"","firstName":"Qin","middleName":"","lastName":"Xiao","suffix":""},{"id":274449670,"identity":"185a3cb0-52b0-4eb6-95dc-fae9033e4406","order_by":6,"name":"Xiaolin Ge","email":"","orcid":"","institution":"Department of Radiation Oncology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, 300, Guangzhou Road, Nanjing","correspondingAuthor":false,"prefix":"","firstName":"Xiaolin","middleName":"","lastName":"Ge","suffix":""},{"id":274449671,"identity":"ff86ce4d-3666-4176-a26a-cdc01b7f297d","order_by":7,"name":"Tian Zhang","email":"","orcid":"","institution":"Department of Radiation Oncology, Tianjin Medical University Cancer Institute \u0026 Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin","correspondingAuthor":false,"prefix":"","firstName":"Tian","middleName":"","lastName":"Zhang","suffix":""},{"id":274449672,"identity":"cd980c32-074b-49e9-a974-4eff22bcf555","order_by":8,"name":"Xiao Liu","email":"","orcid":"","institution":"The Affiliated Cancer Hospital of Zhengzhou University \u0026 Henan Cancer Hospital, Zhengzhou","correspondingAuthor":false,"prefix":"","firstName":"Xiao","middleName":"","lastName":"Liu","suffix":""},{"id":274449673,"identity":"6e22fdb9-6ce4-44f3-a6b2-d14e366cb55e","order_by":9,"name":"Xi Chen","email":"","orcid":"","institution":"Department of Radiation Oncology, Tianjin Medical University Cancer Institute \u0026 Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin","correspondingAuthor":false,"prefix":"","firstName":"Xi","middleName":"","lastName":"Chen","suffix":""},{"id":274449674,"identity":"78600c31-7c73-4978-a578-df371e996076","order_by":10,"name":"Jie Dong","email":"","orcid":"","institution":"Department of Nutrition Therapy, Tianjin Medical University Cancer Institute \u0026 Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Dong","suffix":""},{"id":274449675,"identity":"fa6d18a6-0ddb-42fb-a2b7-2eefb71840ff","order_by":11,"name":"Zewei Li","email":"","orcid":"","institution":"Department of Radiation Oncology, Tianjin Medical University Cancer Institute \u0026 Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin","correspondingAuthor":false,"prefix":"","firstName":"Zewei","middleName":"","lastName":"Li","suffix":""},{"id":274449676,"identity":"2c872198-94c9-40be-908f-ff528e691787","order_by":12,"name":"Zhunhao Zheng","email":"","orcid":"","institution":"Department of Radiation Oncology, Tianjin Medical University Cancer Institute \u0026 Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin","correspondingAuthor":false,"prefix":"","firstName":"Zhunhao","middleName":"","lastName":"Zheng","suffix":""},{"id":274449677,"identity":"fbab30b0-db3d-40ae-8e8d-a001ab5d5d96","order_by":13,"name":"Cihui Yan","email":"","orcid":"","institution":"Department of Immunology, Tianjin Medical University Cancer Institute \u0026 Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin","correspondingAuthor":false,"prefix":"","firstName":"Cihui","middleName":"","lastName":"Yan","suffix":""},{"id":274449678,"identity":"9f11c6d2-4746-441d-b854-82a1bd30cfb2","order_by":14,"name":"Ping Wang","email":"","orcid":"","institution":"Department of Radiation Oncology, Tianjin Medical University Cancer Institute \u0026 Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin","correspondingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Wang","suffix":""},{"id":274449679,"identity":"6b4d6333-08c5-4466-8d4a-0f25b1ec1286","order_by":15,"name":"Qingsong Pang","email":"","orcid":"","institution":"Department of Radiation Oncology, Tianjin Medical University Cancer Institute \u0026 Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin","correspondingAuthor":false,"prefix":"","firstName":"Qingsong","middleName":"","lastName":"Pang","suffix":""},{"id":274449680,"identity":"00e7cea0-a2aa-453d-a79c-5b8e63554fd1","order_by":16,"name":"Wencheng Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxUlEQVRIiWNgGAWjYHACNhAhh8QmUosxD8laEnuI1mJw/PizBz931KbvFztjwPCh7DAD/+wGAlrOJKQb9p45ntsjnWPAOOPcYQaJOwfwazG7wXBMgrftGFgLM2/bYQYDiQRCWhjbJP+2HUvnAWn5S5wWZjZp3raaBLAWRmK02J9JY5OWbTtg2HM7reBgz7l0HokbBLRIth9/Jvm2rU6efXbyxgc/yqzl+GcQ0AIFh8HkASDmIUo9ENQRq3AUjIJRMApGIgAAUtE/1wFnvTYAAAAASUVORK5CYII=","orcid":"","institution":"Department of Radiation Oncology, Tianjin Medical University Cancer Institute \u0026 Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin","correspondingAuthor":true,"prefix":"","firstName":"Wencheng","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2024-02-20 08:59:53","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3972285/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3972285/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1200/JCO.2024.42.16_suppl.TPS4183","type":"published","date":"2024-06-01T00:36:07+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":51714928,"identity":"93b604b9-9298-45d9-a05b-55e4cea81fb0","added_by":"auto","created_at":"2024-02-27 20:45:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":152322,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design. Elderly patients with locally advanced ESCC will be randomly divided into two groups: tislelizumab combined with CCRT group (N = 68) and CCRT group (N = 68).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3972285/v1/8c43d977abaa098c65a4367d.png"},{"id":59617403,"identity":"27dc12f8-0037-47cc-b4de-4674146d501c","added_by":"auto","created_at":"2024-07-04 00:36:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":587335,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3972285/v1/dfd39405-75be-422b-93aa-9ac8173a8e60.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Tislelizumab plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy for elderly patients with inoperable locally advanced esophageal squamous cell carcinoma: a multicenter, randomized, parallel-controlled, phase II clinical trial","fulltext":[{"header":"1. Background","content":"\u003cp\u003eEsophageal cancer (EC) is a common malignant tumor with poor prognosis worldwide, and the morbidity and mortality of esophageal cancer in China was 224,000 and 178,500 in 2022[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Esophageal squamous cell carcinoma (ESCC) is the main histologic subtype of EC in China. The proportion of elderly patients with ESCC over the age of 70 years is as high as 30\u0026ndash;40% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], which is still increasing due to the aging trend of the society. However, neither consensus nor guidelines is available for these patients. It urgently needs clinical trials focusing on elderly ESCC.\u003c/p\u003e \u003cp\u003eAs far, definitive radiotherapy is the main treatment for elderly patients with locally advanced ESCC because these patients are intolerable to surgery. While, the radiation field and dose are still controversial. Several studies recently showed the survival was not different between ESCC patients receiving involved field irradiation (IFI) and elective nodal irradiation (ENI)[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In a retrospective analysis that enrolled 137 elderly ESCC patients who aged 70 years or older, although there was no difference of median overall survival (OS) and 3-year OS rates between the IFI and ENI group, the incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 radiation esophagitis was lower in the IFI group[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In the exploration of radiation dose, 50.4 Gy is widely used in the concurrent chemoradiotherapy (CCRT) which is the standard care for locally advanced inoperable ESCC according to the results of RTOG94-05 study [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. With application of modern radiation techniques, several prospective randomized clinical studies revealed that high dose (60 Gy) did not improve survival compared with 50 Gy, but increased the grade\u0026thinsp;\u0026ge;\u0026thinsp;3 treatment-related adverse effects (TRAEs) [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Therefore, 50 Gy in IFI might be preferred for elderly ESCC.\u003c/p\u003e \u003cp\u003eRecent studies with small sample sizes demonstrated the completion of dual-agent chemoradiotherapy(CRT) was limited in elderly ESCC patients over 75 years old because of the higher incidence of toxicities[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. S-1 is a new oral fluoropyrimidine derivative consisting of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate in a molar ratio of 1:0.4:1. S-1 may show a superior radiosensitizing effect than fluorouracil due to its stable high-level plasma concentration[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. 5-chloro-2,4-dihydroxypyridine inhibited the DNA repair resulted from radiation-induced damage, enhancing the sensitivity of tumor cells to radiotherapy[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The results of multicenter phase II/ III randomized controlled studies in elderly ESCC manifested, compared with radiotherapy alone, combining S-1 with radiotherapy not only benefit survival, but also had tolerable toxicities[\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Since S-1 is given orally, which is far more convenient than intravenous administration, particularly for elderly patients and patients required nasal administration. Combining S-1 and radiotherapy probably has become the standard treatment strategy in elderly patients with locally advanced inoperable ESCC. However, the survival was suboptimal, with a 3-year OS rate of about 40% [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. New strategies are still required to further improve the treatment outcome for elderly patients.\u003c/p\u003e \u003cp\u003eEmerging studies indicated promising synergistic effects of combining immunotherapy with CRT, presenting a novel treatment avenue for ESCC. Tislelizumab, an anti-programmed death-1(PD-1) antibody, has recently been proved in the first- and second-line standard treatment for advanced ESCC[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The RATIONALE-302 study showed that tislelizumab had a good survival benefit in the second-line treatment of advanced metastatic ESCC. Patients in tislelizumab group showed prolonged median OS(8.6 months) and reduced TRAEs(73.3%) compared with patients in chemotherapy group[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].. The RATIONALE-306 study also showed that tislelizumab in combination with chemotherapy achieved an ultra-long survival benefit in the first-line treatment of advanced metastatic ESCC. The median OS and progression free survival (PFS) are 17.2 months and 7.3 months, respectively[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Tislelizumab exhibited mild toxicities[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] and might be well tolerated in elderly. But, tislelizumab combined with radiotherapy applied in elderly ESCC patients remains unknown.\u003c/p\u003e \u003cp\u003eHerein, we conduct the first clinical trial to assess the efficacy and safety of tislelizumab plus concurrent S-1 combined with radiotherapy versus concurrent S-1 combined with radiotherapy for elderly patients with inoperable locally advanced ESCC.\u003c/p\u003e"},{"header":"2. Methods/design","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design\u003c/h2\u003e \u003cp\u003eThis trial is a multicenter, phase II study to assess the efficacy and safety of tislelizumab plus concurrent S-1 combined with radiotherapy versus concurrent S-1 combined with radiotherapy for elderly patients with inoperable locally advanced ESCC. The inclusion and exclusion criteria are shown as following. Eligible patients will be randomized in a 1:1 ratio in the investigation and control group. The CCRT is S-1 (40\u0026ndash;60 mg, orally administered from day 1 to 14 and from day 22 to 35) and radiotherapy (IFI) at 50.4 Gy/1.8 Gy/28 fractions (5 times per week). In the investigation group, tislelizumab will be given from the first day of radiotherapy in Q3W for one year. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e showed the diagram of study design.\u003c/p\u003e\u003cp\u003e2.2 Eligibility criteria for the trial\u003c/p\u003e\n\u003cp\u003e2.2.1 Inclusion Criteria\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003ePatients with histologically confirmed cT1N2-3M0 or cT2-4bN0-3M0 or cT1-4bN0-3M1 (supraclavicular lymph node metastasis) locally advanced ESCC (according to the 8th edition of American Joint Committee on Cancer); clinically staged as II-IVb inoperable locally advanced ESCC (including contraindications to or refusal of surgery).\u003c/li\u003e\n \u003cli\u003ePatients aged \u0026ge; 70 years, included male and female.\u003c/li\u003e\n \u003cli\u003ePatients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.\u003c/li\u003e\n \u003cli\u003ePatients without any previous systemic anti-tumor therapy (including systemic chemotherapy, radiotherapy, molecular targeted therapy, immunotherapy, biologic therapy, topical therapy and other investigational therapeutic agents, etc.).\u003c/li\u003e\n \u003cli\u003ePatients agreed to provide fresh or archival tumor tissues within 6 months (fresh samples preferred) for biomarker analysis such as programmed death ligand 1(PD-L1). Tissue specimens are formalin-fixed, paraffin-embedded (FFPE) for exploration study.\u003c/li\u003e\n \u003cli\u003ePatients with life expectancy longer than 3 months.\u003c/li\u003e\n \u003cli\u003ePatients with adequate hematologic function, defined as ANC \u0026ge;1500/\u0026mu;L, platelet count \u0026ge;100,000/\u0026mu;L and hemoglobin count \u0026ge;9.0 g/dL or \u0026ge;5.6 mmol/L.\u003c/li\u003e\n \u003cli\u003ePatients with adequate renal function, defined as creatinine \u0026le;1.5\u0026times; ULN or measured or calculated creatinine clearance \u0026ge;60 mL/min for those with creatinine levels \u0026gt;1.5\u0026times; ULN (Calculated from the Cockcroft-Gault formula).\u003c/li\u003e\n \u003cli\u003ePatients with adequate hepatic function, defined as total bilirubin \u0026le;1.5\u0026times; ULN and ALT/AST/AKP levels \u0026le;2.5\u0026times; ULN and albumin \u0026ge;2.8 g/dL.\u003c/li\u003e\n \u003cli\u003ePatients with adequate coagulation function, defined as INR \u0026le;1.5\u0026times; ULN and APTT\u0026le;1.5\u0026times; ULN unless the patient is receiving anticoagulant therapy as long as INR is within the therapeutic range.\u003c/li\u003e\n \u003cli\u003ePatients who sign written informed consent.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e2.2.2 Exclusion Criteria\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003ePatients receiving surgery for ESCC.\u003c/li\u003e\n \u003cli\u003ePatients with esophageal fistulae due to invasion of the primary tumor.\u003c/li\u003e\n \u003cli\u003ePatients with risk of gastrointestinal bleeding, esophageal fistula or esophageal perforation.\u003c/li\u003e\n \u003cli\u003ePatients with poor nutritional status, weight loss of \u0026ge;10% in the previous 2 months, with no significant improvement after nutritional intervention.\u003c/li\u003e\n \u003cli\u003ePatients receiving major operation or severe trauma within 4 weeks prior to enrollment.\u003c/li\u003e\n \u003cli\u003ePatients with uncontrollable pleural effusion, pericardial effusion, or ascites that requires repeated drainage.\u003c/li\u003e\n \u003cli\u003ePatients with active multiple primary cancers (synchronous multiple primary cancers and multiple cancers with a progression-free period of \u0026le;5 years from the time of enrollment), carcinoma in situ or intramucosal carcinoma curable by local resection are not included in the definition of active multiple primary cancers.\u003c/li\u003e\n \u003cli\u003ePatients previously received or are receiving any of the following treatments:\u003col style=\"list-style-type: lower-alpha;\"\u003e\n \u003cli\u003eAnti-PD-1 or anti-PD-L1 antibody therapy, chemotherapy, radiotherapy or targeted therapy.\u003c/li\u003e\n \u003cli\u003eParticipation in a study of an investigational agent or device within 4 weeks before the first dose of study treatment.\u003c/li\u003e\n \u003cli\u003eSystemic treatment with corticosteroids (\u0026gt;10 mg prednisone equivalent per day) or other immunosuppressive agents is required for 2 weeks before the first dose of study treatment. Patients using corticosteroids for local inflammation or for prevention of allergy, nausea and vomiting can be included.\u003c/li\u003e\n \u003cli\u003eReceived anti-tumor vaccine or any live vaccine within 4 weeks before the first dose of study treatment.\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n \u003cli\u003ePatients with any active autoimmune disease or history of autoimmune disease (e.g. interstitial pneumonitis, uveitis, enteritis, hepatitis, pituitary gland inflammation, vasculitis, myocarditis, nephritis, hyperthyroidism and hypothyroidism). Patients with vitiligo or those who had asthma or allergies in childhood but did not need any intervention as adults; patients with autoimmune-mediated hypothyroidism treated with stable doses of thyroid replacement hormone and type I diabetes mellitus treated with stable doses of insulin are not included in the definition of active autoimmune disease or history of autoimmune disease.\u003c/li\u003e\n \u003cli\u003ePatients diagnosed HIV infection or other acquired/congenital immunodeficiency diseases, or history of organ/ allogeneic transplantation.\u003c/li\u003e\n \u003cli\u003ePatients diagnosed uncontrolled cardiac clinical symptoms or disease (such as NYHA II or above heart failure, unstable angina, myocardial infarction within 1 year or clinically significant supraventricular or ventricular arrhythmias requiring clinical intervention).\u003c/li\u003e\n \u003cli\u003ePatients with severe infections (Common Terminology Criteria for Adverse Events Grade \u0026gt;2), such as severe pneumonia, bacteremia, infectious complications, etc., within 4 weeks before the first use of study treatment; active lung inflammation requiring oral or intravenous antibiotic treatment within 2 weeks before the first use of study treatment.\u003c/li\u003e\n \u003cli\u003ePatients with history interstitial lung disease, non-infectious pneumonia, or pulmonary insufficiency \u0026ge; grade 3 as confirmed by pulmonary function tests.\u003c/li\u003e\n \u003cli\u003ePatients with active tuberculosis infection.\u003c/li\u003e\n \u003cli\u003ePatients with active hepatitis B (HBV DNA \u0026ge;2000 IU/mL or 104 copies/mL), hepatitis C (hepatitis C antibody positive and HCV-RNA above the lower limit of detection);\u003c/li\u003e\n \u003cli\u003ePatients with abnormal sodium, potassium, and calcium laboratory test values (\u0026gt;Grade 1) that do not improve after treatment within 2 weeks prior to randomization.\u003c/li\u003e\n\u003c/ol\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Planned sample size\u003c/h2\u003e \u003cp\u003eThe open label, multicenter, parallel-controlled, investigator-initiated phase II clinical trial was expected to take 18 months to enroll all participants, with an additional follow-up period of 24 months after the last patient randomization. Considering the median PFS is 16 months in elderly ESCC receiving concurrent S-1 combined with radiotherapy in history studies[\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], we expect the median PFS would be 28 months at the hazard ratio of 0.57. The final sample size consists in 136 patients by 1:1 randomized in the two groups with 80% power and one-sided alpha and calculating for a 10% dropout rate. The study uses the following stratification factors: tumor staging II/III and IV, age 70\u0026ndash;79 and \u0026ge;\u0026thinsp;80. Allocation to either arm will be decided by a computer-generated randomization schedule.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Study procedures\u003c/h2\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003e2.4.1 Evaluation and randomization\u003c/h2\u003e \u003cp\u003ePatient participation in this study need sign the informed consent before any study-specific screening or evaluation. Screening examinations and assessments will be performed within 28 days prior to enrollment. Routine blood tests and blood biochemistry performed prior to the start of the first cycle of treatment need be completed within 7 days prior to randomization. Patients must be restaged within 4 weeks prior to randomization, including undergoing computed tomography (CT) scan cervical, thoracic and abdominal (including pelvic) CT or magnetic resonance imaging (all contrast-enhanced, replaced by routine CT scan if contrast is prohibited). Magnetic resonance imaging (MRI) of the brain is required when brain metastasis is suspected and diagnosed (replaced by contrast-enhanced CT if MRI is prohibited). And Bone scan/Positron Emission Tomography (PET) is only carried out when there are clinical indications with time to test relaxed to within 42 days prior to the first dose of medication.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e2.4.2 Intervention\u003c/h2\u003e \u003cp\u003eIn the treatment group, patients will receive tislelizumab combined with concurrent S-1 and radiotherapy. Tislelizumab is given via intravenous infusion from the first day of radiotherapy every 3 weeks until progressive disease or intolerable combined with concurrent chemoradiotherapy. Tislelizumab will maintain for a maximum of 1 year. In the control group, patients will receive concurrent S-1 and radiotherapy.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section4\"\u003e \u003ch2\u003e2.4.2.1 Chemotherapy\u003c/h2\u003e \u003cp\u003eS-1 is orally administered from day 1 to day 14 and day 22 to 35. The dose is based on the patient's body surface area (BSA): 40 mg twice daily for BSA\u0026thinsp;\u0026lt;\u0026thinsp;1.25 m\u003csup\u003e2\u003c/sup\u003e; 50 mg twice daily for 1.25 m\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026le;\u0026thinsp;BSA\u0026thinsp;\u0026lt;\u0026thinsp;1.50 m\u003csup\u003e2\u003c/sup\u003e; 60 mg twice daily for BSA\u0026thinsp;\u0026ge;\u0026thinsp;1.50 m\u003csup\u003e2\u003c/sup\u003e. If grade 3 or above hematologic, gastrointestinal, or dermal toxicity occurs during S-1 treatment, the dose need be decreased from 60, 50 to 40 mg, and S-1 will be discontinued immediately if a grade 4 adverse event (AE) occurs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section4\"\u003e \u003ch2\u003e2.4.2.2 Radiotherapy\u003c/h2\u003e \u003cp\u003ePrior to patient enrollment, the radiation oncologist evaluates the patient's thoracic CT or PET-CT to ensure that the treatment area does not significantly exceed the prescribed normal tissue limits and that the 50.4 Gy irradiation dose is appropriate for the patient. Radiotherapy is delivered by standardized intensity-modulated radiotherapy (IMRT) or volumetric rotational intensity-modulated radiotherapy (VMAT). The prescribed dose is total 50.4 Gy, with 1.8 Gy per fraction and 5 times per week. IFI is used in determining the radiation field. Cone Beam CT verification is required once a week during the treatment to ensure the accuracy of the treatment. For a subject develops severe esophagitis or other serious radiotherapy-induced AEs, the subject may continue to receive radiotherapy if in the opinion of the investigator. Intensified supportive therapy is allowed to help the subject continue to receive radiotherapy without increased risk.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section4\"\u003e \u003ch2\u003e2.4.2.3 Immunotherapy\u003c/h2\u003e \u003cp\u003eTislelizumab is administered on the first day of radiotherapy at the dose of 200 mg intravenously for 30 min (not less than 20 min and not more than 60 min) per infusion and repeated every 21 days until progression disease or intolerance, or up to a maximum of 1 year. If tislelizumab-related AEs occur during treatment, the investigator may suspend tislelizumab treatment according to the protocol based on the subject's AEs profile.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e2.4.3 Follow-up\u003c/h2\u003e \u003cp\u003eThe subject's blood routine examination, blood biochemistry and thyroid function are rechecked 30 days after the last dose. Survival status and tumor imaging will be evaluated every 3 months from the end of treatment during 2 years and 6 months after 2 years.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Outcome measures/endpoints\u003c/h2\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003e2.5.1 Primary objective\u003c/h2\u003e \u003cp\u003ePFS is measured from the date of randomization until progression (as per RECIST 1.1 assessment, regardless of continued treatment) or death from any cause. Subjects who neither experience disease progression nor death will be censored at the date of their last evaluable tumor assessment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section3\"\u003e \u003ch2\u003e2.5.2 Secondary objectives\u003c/h2\u003e \u003cp\u003eOS is the time from randomization to the date of death from any cause. For subjects that are alive, their survival time will be censored at the date of last contact (\u0026ldquo;last known alive date\u0026rdquo;). OS is censored for subjects at the date of last confirmed survival if they are loss in follow up.\u003c/p\u003e \u003cp\u003eObjective response rate (ORR) is the proportion of randomized subjects who achieve a best response of complete response (CR) or partial response (PR) using the RECIST 1.1 criteria. Best objective response (BOR) is the best investigator-rated designation for the period between the date of enrollment and the date of objectively documented progression according to RECIST 1.1 criteria or to the initiation of subsequent anti-tumor therapy, whichever occurs first. For subjects with no progression and no initiation of subsequent anti-tumor therapy, the BOR will be determined based on all response evaluation.\u003c/p\u003e \u003cp\u003eDuration of Objective Response (DOR) is the time between the date of first documented response (CR or PR) to the date of the first documented progression as determined by RECIST 1.1, or death due to any cause, whichever occurs first. For subjects who neither progress nor die, the DOR will be censored.\u003c/p\u003e \u003cp\u003eSeverity of AEs is assessed using Common Terminology Criteria for Adverse Events v5.0. All AEs are recorded from randomization until 90 days after the end of treatment, regardless of relatedness to study medication. For TRAEs, investigators should follow up until resolution, remission, or to baseline levels, or \u0026le;\u0026thinsp;grade 1, or to steady state, or with a reasonable explanation (e.g. loss to follow-up, death).\u003c/p\u003e \u003cp\u003eThe investigators assess quality of life of the elderly subjects in a multidimensional manner through a series of questionnaires, such as European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30\u0026amp;OES18, Charlson comorbidity index, Barthel Index, Instrumental Activities of Daily Living Scale, Mini-Nutritional Assessment, Mini-Mental State Examination, Geriatric Depression Scale, and Medical Outcomes Study Social Support Survey.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Biomarker analysis and translational research\u003c/h2\u003e \u003cp\u003eWe will collect serial biopsies from the primary site and blood collections at 3 time points if possible (before treatment, after 40 Gy of radiotherapy, and progression). Using the collected samples, we will investigate biomarkers for efficacy or resistance to the treatment. We will also analyze phenotype of immune-competent cells using both immunohistochemistry and flowcytometry, PD-L1 status.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e2.7 Statistical analysis\u003c/h2\u003e \u003cp\u003eTime to event distributions (i.e. PFS and OS)will be estimated using the Kaplan\u0026ndash;Meier method, and log-rank tests will be used to determine the significance. A Cox multivariable regression will be used to determine prognostic factors for survival benefit. In terms of safety, we will finally tabulate the incidence of each AE.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eThe multicenter, randomized, parallel-controlled, Phase II clinical trial aims to enroll 136 elderly patients with inoperable locally advanced ESCC and to assess the efficacy and safety of tislelizumab plus concurrent S-1 and radiotherapy versus concurrent S-1 and radiotherapy. It is the first \"PD-1 inhibitor combined with concurrent chemoradiotherapy\" for elderly patients with inoperable locally advanced ESCC, aiming to explore a novel treatment strategy for elderly ESCC (NTC06061146). This study addresses the special population of elderly ESCC patients with multidimensional assessment and nutritional support therapy for pre-treatment, under treatment and maintenance therapy, which will be accomplished by a multidisciplinary collaboration including radiation oncology department, medical oncology department, nutrition department and endoscopy department.\u003c/p\u003e \u003cp\u003eMoreover, if tislelizumab plus concurrent S-1 and radiotherapy significantly improve the PFS of elderly ESCC patients, further confirmatory phase III trial will be planned. And the results of our study may inform the optimization of treatment of combing immunotherapy and concurrent chemoradiotherapy for the elderly patients with inoperable locally advanced ESCC.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEsophageal cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eESCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEsophageal squamous cell carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIFI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInvolved field irradiation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eENI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eElective nodal irradiation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCCRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConcurrent chemoradiotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTRAEs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTreatment-related advent events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChemoradiotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD-1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgrammed death-1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgression free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eECOG PS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEastern Cooperative Oncology Group Performance Status\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD-L1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgrammed death ligand 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFFPE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFormalin fixed paraffin embedded\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomputed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMagnetic resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePET\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePositron Emission Tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBSA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBody surface area\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAdverse event\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIMRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntensity-modulated radiotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVMAT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVolumetric Modulated Arc Therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eORR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eObjective response rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eComplete response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePartial response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBest objective response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eduration of remission\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEORTC QLQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEuropean Organization for Research and Treatment of Cancer Quality of Life Questionnaire\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eWe thank all participating patients, all participating sub-centers and investigators who devote their time and passion in implementation of the study.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThe investigator-initiated trial is supported by national natural science foundation of China (82272733, 82273083). BeiGene provides insurance costs for participating patients, but have no role in study design, data collection, data analysis, data interpretation and writing the manuscript.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe datasets during the current study can be obtained from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003eAuthors’ contributions\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors participated in writing, reviewing and approving the manuscript for submission. Study concepts and design: WZ; Data acquisition: KZ, QW, JC, CF, WS, QX, XG, XL, TZ, XC, ZL, ZZ, CY, WZ; Quality control of data and algorithms: KZ, QW, JC, CF, WS, QX, XG, XL, TZ, XC, ZL, ZZ, CY, WZ; Manuscript preparation: KZ, WZ and CY; Manuscript editing: KZ, WZ and CY; Manuscript review: KZ, QW, JC, CF, WS, QX, XG, XL, TZ, XC, JD, ZL, ZZ, CY, PW, QP, WZ.\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eInstitutional review board approval was obtained for the trial from the ethical committee of Tianjin Cancer Hospital (E20230954) in August 2023. The trial was published under NCT06061146 on ClinicalTrials.gov. All participants have signed the informed consent form.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eNo competing interests are declared by all authors.\u003c/p\u003e\n\u003cp\u003eAuthors’ information\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute \u0026amp; Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003eRadiation Oncology Key Laboratory of Sichuan Province, Department of Radiation Oncology, Sichuan Cancer Hospital Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u003c/sup\u003eDepartment of Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030013, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e4\u003c/sup\u003eThe Affiliated Cancer Hospital of Zhengzhou University \u0026amp; Henan Cancer Hospital, Zhengzhou, Henan 450008, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e5\u003c/sup\u003eRadiotherapy Department of the Fourth Hospital of Hebei Medical University\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e6\u003c/sup\u003eThoracic Radiotherapy Department Hunan Cancer Hospital the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e7\u003c/sup\u003eDepartment of Radiation Oncology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, 300, Guangzhou Road, Nanjing, Jiangsu, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e8\u003c/sup\u003eDepartment of Nutrition Therapy, Tianjin Medical University Cancer Institute \u0026amp; Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin’s Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e9\u003c/sup\u003eDepartment of Immunology, Tianjin Medical University Cancer Institute \u0026amp; Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin’s Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHan B, Zheng R, Zeng H, Wang S, Sun K, Chen R, Li L, Wei W, He J. 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Randomized Study on Dose Escalation in Definitive Chemoradiation for Patients With Locally Advanced Esophageal Cancer (ARTDECO Study). J Clin Oncol. 2021;39(25):2816\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYou J, Zhu S, Li J, Li J, Shen J, Zhao Y, Li X, Jia L, Li Q, Yang J, et al. High-Dose Versus Standard-Dose Intensity-Modulated Radiotherapy With Concurrent Paclitaxel Plus Carboplatin for Patients With Thoracic Esophageal Squamous Cell Carcinoma: A Randomized, Multicenter, Open-Label, Phase 3 Superiority Trial. Int J Radiat Oncol Biol Phys. 2023;115(5):1129\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang H, Li G, Chen L, Duan Y, Zou C, Hu C. Definitive concurrent chemoradiotherapy with S-1 and cisplatin in elderly esophageal squamous cell carcinoma patients. J Thorac Dis. 2017;9(3):646\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXing L, Liang Y, Zhang J, Wu P, Xu D, Liu F, Yu X, Jiang Z, Song X, Zang Q, et al. Definitive chemoradiotherapy with capecitabine and cisplatin for elder patients with locally advanced squamous cell esophageal cancer. J Cancer Res Clin Oncol. 2014;140(5):867\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Groeningen CJ, Peters GJ, Schornagel JH, Gall H, Noordhuis P, de Vries MJ, Turner SL, Swart MS, Pinedo HM, Hanauske AR, et al. Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors. J Clin Oncol. 2000;18(14):2772\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJi Y, Du X, Zhu W, Yang Y, Ma J, Zhang L, Li J, Tao H, Xia J, Yang H, et al. Efficacy of Concurrent Chemoradiotherapy With S-1 vs Radiotherapy Alone for Older Patients With Esophageal Cancer: A Multicenter Randomized Phase 3 Clinical Trial. JAMA Oncol. 2021;7(10):1459\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang X, Han W, Zhang W, Wang X, Ge X, Lin Y, Zhou H, Hu M, Wang W, Liu K, et al. Effectiveness of S-1-Based Chemoradiotherapy in Patients 70 Years and Older With Esophageal Squamous Cell Carcinoma: A Randomized Clinical Trial. JAMA Netw Open. 2023;6(5):e2312625.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Y, Zheng Z, Li M, Zhang Y, Zhao F, Gong H, Lin H, Huang W, Chen X, Xu Z, et al. Comparison of concurrent chemoradiotherapy with radiotherapy alone for locally advanced esophageal squamous cell cancer in elderly patients: A randomized, multicenter, phase II clinical trial. Int J Cancer. 2022;151(4):607\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023;24(5):483\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShen L, Kato K, Kim SB, Ajani JA, Zhao K, He Z, Yu X, Shu Y, Luo Q, Wang J, et al. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 2022;40(26):3065\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Concurrent chemoradiotherapy, Immunotherapy, Locally advanced esophageal squamous cell carcinoma, Older patients, Tislelizumab","lastPublishedDoi":"10.21203/rs.3.rs-3972285/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3972285/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe standard treatment for elderly patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is definitive chemoradiotherapy based on S-1. However, 3-year overall survival (OS)is limited about 40%. Tislelizumab has been the first-line and second-line standard treatment for advanced ESCC with tolerable toxicity. In the study we aimed to explore a new curative strategy for locally advanced unresectable elderly ESCC by combining tislelizumab with chemoradiotherapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe 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 to concurrent chemoradiotherapy. The main inclusion criteria are pathological confirmation of locally advanced inoperable ESCC at clinical cT1N2-3M0 or cT2-4bN0-3M0(stage II\u0026ndash;IVA), aged\u0026thinsp;\u0026ge;\u0026thinsp;70 years, without any previous systemic anti-tumor therapy, and adequate organ function. A total of 136 patients will be recruited from approximately 6 centers over a period of 1 year and randomized in a 1:1 ratio to receive tislelizumab in combination with concurrent chemoradiotherapy(tislelizumab\u0026thinsp;+\u0026thinsp;S-1\u0026thinsp;+\u0026thinsp;radiotherapy) or concurrent chemoradiotherapy (S-1\u0026thinsp;+\u0026thinsp;radiotherapy). The efficacy and safety of treatment will be evaluated during the therapy and follow-up period until disease progression or death or the end of the trial. The primary study endpoint is investigator-assessed progression free survival (PFS), and the secondary study endpoints are OS, objective response rate (ORR), duration of remission (DOR), and safety. Fresh or archival tumor tissues and peripheral blood samples will be used in the exploratory studies.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThe synergistic efficacies of combined definitive concurrent chemoradiotherapy with tislelizumab are expected to result in survival benefit for elderly patients with inoperable locally advanced ESCC. As S-1 plus concurrent radiotherapy is the standard treatment option for locally advanced ESCC older patients, the combination of definitive concurrent chemoradiotherapy and tislelizumab has the potential to change the standard ESCC therapeutic strategy with comparable safety.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eClinicalTrials.gov NCT06061146.Registered 9/10/2023\u003c/p\u003e","manuscriptTitle":"Tislelizumab plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy for elderly patients with inoperable locally advanced esophageal squamous cell carcinoma: a multicenter, randomized, parallel-controlled, phase II clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-27 20:45:11","doi":"10.21203/rs.3.rs-3972285/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f63241f3-be0a-4322-accd-d038bcae1ef8","owner":[],"postedDate":"February 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-02-13T22:08:09+00:00","versionOfRecord":{"articleIdentity":"rs-3972285","link":"https://doi.org/10.1200/JCO.2024.42.16_suppl.TPS4183","journal":{"identity":"journal-of-clinical-oncology","isVorOnly":true,"title":"Journal of Clinical Oncology"},"publishedOn":"2024-06-01 00:36:07","publishedOnDateReadable":"June 1st, 2024"},"versionCreatedAt":"2024-02-27 20:45:11","video":"","vorDoi":"10.1200/JCO.2024.42.16_suppl.TPS4183","vorDoiUrl":"https://doi.org/10.1200/JCO.2024.42.16_suppl.TPS4183","workflowStages":[]},"version":"v1","identity":"rs-3972285","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3972285","identity":"rs-3972285","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}