Low-dose interval radiotherapy combined with tirelizumab and SOX chemotherapy neoadjuvant therapy for locally advanced gastric/gastroesophageal junction adenocarcinoma: study protocol of a prospective, single-center, single-arm clinical trial

Low-dose interval radiotherapy combined with tirelizumab and SOX chemotherapy neoadjuvant therapy for locally advanced gastric/gastroesophageal junction adenocarcinoma: study protocol of a prospective, single-center, single-arm 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 Low-dose interval radiotherapy combined with tirelizumab and SOX chemotherapy neoadjuvant therapy for locally advanced gastric/gastroesophageal junction adenocarcinoma: study protocol of a prospective, single-center, single-arm clinical trial Liang Shang, Zhen Fang, Yan Liu, Guangying Zhao, Jin Liu, Leping Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7310982/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background： Gastroesophageal junction (G/GEJ) cancer is a global health burden with poor prognosis, especially for locally advanced or metastatic cases. While perioperative chemotherapy improves outcomes, survival remains limited. Immunotherapy combined with chemotherapy has shown promise in advanced disease, prompting investigations into neoadjuvant settings. This study evaluates a novel regimen of low-dose interval radiotherapy, tislelizumab (a PD-1 inhibitor), and SOX chemotherapy (oxaliplatin + S-1) for locally advanced G/GEJ adenocarcinoma. Methods and analysis： This is a prospective, single-center, single-arm clinical trial enrolling 32 patients with cT4N+M0 G/GEJ adenocarcinoma. The neoadjuvant regimen includes 5×3Gy radiotherapy in cycles 1 and 3, tislelizumab (200 mg IV D6), oxaliplatin (130 mg/m² IV D6), and S-1 (40 mg/m²oral BID D6–19), with 4 cycles of SOX adjuvant chemotherapy post-surgery. Primary endpoints are pathological complete response (pCR), major pathological response (MPR), and objective response rate (ORR). Secondary endpoints include R0 resection rate, safety, complications, event-free survival (EFS), and overall survival (OS). Discussion: This study explores a novel neoadjuvant regimen combining low-dose interval radiotherapy with immunotherapy and chemotherapy for locally advanced GC/GEJ. The combination is expected to significantly increase the pCR rate and improve other therapeutic outcomes while maintaining safety. Ethics and dissemination: The study was approved by the Ethical Committee of the Shandong Provincial Hospital Affiliated to Shandong First Medical University and registered with ClinicalTrials.gov (NCT06766578). Trial registration： ClinicalTrials.gov (NCT06766578) Gastroesophageal junction cancer Neoadjuvant therapy Immunotherapy Chemotherapy Radiotherapy Figures Figure 1 Introduction Gastroesophageal junction (G/GEJ) cancer, represents a major global health burden, ranking as the fifth most common cancer and the fourth leading cause of cancer-related mortality worldwide [ 1 , 2 ] . Despite surgical resection being the primary curative approach for localized disease, the prognosis remains poor, particularly for advanced-stage or type 4 GC, with 5-year survival rates below 30% after gastrectomy [ 3 ] . Perioperative chemotherapy, compared to surgery alone, has demonstrated significant survival benefits by improving R0 resection rates, reducing recurrence, and enhancing overall survival (OS). However, outcomes for locally advanced or metastatic GC remain dismal, with 5-year survival rates below 20% [ 4 – 9 ] . Currently, the treatment for advanced G/GEJ cancer has entered the era of immunotherapy. The combination of immune checkpoint inhibitors (ICIs) and chemotherapy has been shown to prolong OS and progression-free survival (PFS) compared to chemotherapy alone in the first-line setting of advanced or metastatic G/GEJ cancer patients [ 10 , 11 ] . These promising results have sparked the interest of researchers to further investigate the wide application of ICIs plus chemotherapy in the neoadjuvant setting for locally advanced G/GEJ cancer. In a single-arm, phase II clinical study conducted by Jiang et al., 36 patients with locally advanced, resectable G/GEJ cancer were enrolled to receive sintilimab plus the XELOX regimen. The pathological complete response (PCR) and R0 resection rates were 19.4% and 97.2%, respectively [ 12 ] . Another study also showed similar results. The PCR rate in patients with locally advanced G/GEJ adenocarcinoma treated with the combination of tislelizumab and SOX was 25%, and the annual recurrence-free survival (RFS) and OS were 90.0% and 91.4%, respectively [ 13 ] . These results provide new insight and suggest that chemotherapy combined with immunotherapy may represent a promising therapy for the neoadjuvant treatment of locally advanced, resectable G/GEJ adenocarcinoma. In recent years, with the advancement of radiotherapy technology and the deepening understanding of tumor biology, the role of radiotherapy in the comprehensive treatment of G/GEJ has gradually attracted attention [ 14 – 16 ] . Low-dose interval radiotherapy, as an emerging radiotherapy modality, has potential advantages [ 17 ] . Compared with traditional radiotherapy, low-dose interval radiotherapy, by adjusting the dose and time intervals of radiotherapy, may reduce damage to normal tissues while enhancing the killing effect on tumor cells. Animal experiments and some small-scale clinical studies have suggested that low-dose radiotherapy can modulate the tumor microenvironment, enhancing the ability of immune cells to recognize and attack tumors, and may have a synergistic effect with immunotherapy and chemotherapy [ 16 , 17 ] . However, research on the combination of low-dose interval radiotherapy with immunotherapy and chemotherapy in G/GEJ is still relatively limited, and further in-depth studies are needed on its specific mechanisms, optimal dosing and fractionation methods, as well as efficacy and safety. Our center has conducted a prospective, single-center, single-arm clinical trial of the PD-1 inhibitor tislelizumab combined with S-1 plus oxaliplatin: To evaluate the initial efficacy and safety of neoadjuvant low-dose interval radiotherapy combined with tirelizumab and SOX chemotherapy in locally advanced gastric/gastroesophageal junction adenocarcinoma. Methods Trial design This prospective, single-center, open-label, single-arm clinical trial aims to evaluate the efficacy and safety of low-dose interval radiotherapy combined with tirelizumab and SOX chemotherapy as neoadjuvant therapy for patients with locally advanced G/GEJ adenocarcinoma. The study design is illustrated in Fig. 1 . Inclusion and exclusion criteria The inclusion and exclusion criteria are detailed in Table 1 . Table 1 The inclusion and exclusion criteria. Inclusion Criteria Exclusion criteria • Patients voluntarily participated in the study and signed informed consent with good compliance and follow-up; • Adenocarcinoma of the gastric/gastroesophageal junction confirmed by endoscopic pathology (tumor located in the lesser bend of the stomach other than pylorus or the gastroesophageal junction) (Note: Pathology in other hospitals must be consulted by our hospital); • Patients with cT4N + M0 AJCC stage 8 combined with endoscopic, CT, MRI, or PETCT findings; • Age ≥ 18 years, ≤ 75 years, male and female; • ECOG PS score 0–1; • Presence of measurable and/or unmeasurable lesions as defined by the efficacy evaluation criteria for solid tumors (Recist 1.1); • Has not received any prior systemic antitumor therapy (including but not limited to systemic chemotherapy, radiotherapy, molecular targeted drug therapy, immunotherapy, biotherapy, topical therapy, or other investigational therapeutic drugs; • The functions of vital organs meet the following requirements (no blood components and cell growth factors are allowed to be used 2 weeks before screening) : Neutrophil absolute count (ANC) ≥ 1.5×10 9/L; Platelets ≥ 100×10 9/L; Hemoglobin ≥ 9g/dL; Serum albumin ≥ 2.8g/dL; Total bilirubin ≤ 1.5 ×ULN, ALT, AST and/or AKP ≤ 2.5 ×ULN; serum creatinine ≤ 1.5 ×ULN or creatinine clearance ≥ 60mL/min (calculated according to the Cockcroft Gault formula); International standardized ratio (INR) and activated partial thrombin time (APTT) ≤ 1.5×ULN (INR can be screened in the expected treatment range of anticoagulants for stable doses of anticoagulants such as low molecular weight heparin or warfarin); • Fertile female subjects shall perform a urine or serum pregnancy test within 72 hours prior to receiving the first study drug, prove negative, and be willing to use an effective method of contraception during the trial period up to 5 months after the last drug administration. Male subjects whose partner is a woman of reproductive age should use an effective method of contraception during the trial period and for 7 months after the last dose. • a history of surgery for gastric/esophagogastric junction tumors; • Previous history of fistula caused by primary tumor invasion; • Higher risk of gastrointestinal bleeding and perforation; • Poor nutritional status, BMI less than 18.5kg/m2, or PG-SGA score ≥ 9; • Major surgery or severe trauma within 4 weeks prior to first use of the study drug; • Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage; • has received or is currently receiving any of the following previous treatments: anti-PD-1 or anti-PD-L1 antibody therapy, chemotherapy, radiotherapy, targeted therapy; • Received any investigational drug within 4 weeks prior to first use of the investigational drug; • subjects requiring systemic treatment with corticosteroids (> 10mg prednisone equivalent daily dose) or other immunosuppressants within 2 weeks prior to initial use of the study drug, except for corticosteroids for esophageal/gastric local inflammation and for the prevention of allergy and nausea and vomiting. Other special circumstances, need to communicate with the bid. In the absence of active autoimmune disease, inhaled or topical steroids and adrenocorticosteroid replacement at doses > 10mg/ d of prednisone efficacy are permitted; • those who have received antitumor vaccine or have received live vaccine within 4 weeks prior to the first administration of the study drug; • have any active autoimmune disease or a history of autoimmune disease (such as interstitial pulmonary inflammation, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, myocarditis, nephritis, hyperthyroidism, hypothyroidism); Except patients with vitiligo or recovered asthma/ allergy of the same age without any intervention as adults; Patients with autoimmune mediated hypothyroidism treated with stable doses of thyroid hormone replacement and type 1 diabetes treated with stable doses of insulin could be included; • have a history of immunodeficiency, including HIV positive, or other acquired or congenital immunodeficiency diseases, or have a history of organ transplantation or allogeneic bone marrow transplantation; • any condition requiring systemic treatment with corticosteroids (more than 10 mg/ day of prednisone or its equivalent) or other immunosuppressant treatment within 14 days prior to treatment (except local, ocular, intraarticular, intranasal and inhaled corticosteroids with minimal systemic uptake); Prophylactic short-term (≤ 7 days) use of corticosteroids (e.g., to prevent contrast allergy) or for the treatment of non-autoimmune conditions (e.g., delayed hypersensitivity due to allergen exposure); • subjects with uncontrolled cardiac clinical symptoms or disease, such as (1) NYHA II or above heart failure (2) unstable angina pecina (3) myocardial infarction within 1 year (4) clinically significant ventricular arrhythmias or ventricular arrhythmias requiring clinical intervention; • Severe infection (CTCAE > level 2), such as severe pneumonia, bacteremia, and infectious complications requiring hospitalization, occurred within 4 weeks prior to initial use of the study drug; Chest imaging at baseline suggested active lung inflammation and signs and symptoms of infection requiring oral or intravenous antibiotic treatment within 2 weeks prior to enrollment, except for prophylactic antibiotic use; • a history of interstitial lung disease, non-infectious pneumonia, pulmonary fibrosis or other uncontrolled acute lung disease; • Patients with active pulmonary tuberculosis infection found by history or CT examination, or patients with active pulmonary tuberculosis infection history within 1 year before enrollment, or patients with active pulmonary tuberculosis infection history more than 1 year ago but without formal treatment; • Subjects with active hepatitis B (HBV DNA ≥ 2000 IU/mL or 10 4 Copies / mL), hepatitis C (positive hepatitis C antibody, and HCV-RNA higher than the lower limit of detection method); • Abnormal values of sodium, potassium and calcium greater than grade 1 in laboratory tests within 2 weeks before enrollment, which could not be improved after treatment; • known allergy to macromolecular protein preparations, or to any COMPONENT of PD-1, or allergy, hypersensitivity or contraindication to oxaliplatin or capecitabine or any component used in their preparations; • A prior diagnosis of any other malignancy, other than malignancies with a low risk of metastasis and death (5-year survival > 90%), such as adequately treated basal or squamous cell skin cancer or carcinoma in situ of the cervix; •pregnant or lactating women; Fertile subjects unwilling or unable to use effective contraception; • According to the investigator's judgment, subjects have other factors that may cause them to be forced to terminate the study, such as other serious diseases (including mental diseases) requiring combined treatment, other recent serious diseases (such as myocardial infarction and cerebrovascular accident) with high risk of recurrence, seriously abnormal laboratory test values, family or social factors, which may affect subjects' safety or the collection of test data. Treatment interventions Intravenous administration for tirelizumab 200 mg D1, intravenous administration for oxaliplatin 130 mg/m 2 D1, and oral administration twice a day for S-1 40 mg/m 2 D1 to 14. Every treatment cycle is spaced 1 week Radiation: Neoadjuvant Therapy(5×3Gy radiotherapy). Radiotherapy 5×3Gy. The preoperative radiotherapy target was outlined by radiotherapy physicians according to the NCCN Guidelines for Gastric/esophagogastric Junction Tumor 2024 edition and the surgeon's opinions. The first and third cycles were 5×3Gy. Drug Neoadjuvant Therapy (tirelizumab, oxaliplatin, S-1), The first and third cycles are 5×3Gy radiotherapy D1 to 5, intravenous administration for tirelizumab 200 mg D6, intravenous administration for oxaliplatin 130 mg/m 2 D6, and oral administration twice a day for S-1 40 mg/m 2 D6 to 19. The second and fourth cycles are apart. Procedure/Surgery Surgical treatment Surgical treatment is completed within 3–5 weeks after the end of neoadjuvant therapy. Postoperative adjuvant therapy is 4 cycles of SOX chemotherapy. Study end points Primary Outcome Measure Pathological complete response rate (pCR): Pathological complete response was defined as pT0N0M0. Secondary Outcome Measure Major pathological response rate (MPR) : The percentage of surviving tumor cells in the tumor bed after neoadjuvant therapy was ≤ 10%. Objective response rate (ORR) : Proportion of patients who achieved a complete response (CR) or a partial response (PR) as assessed by RECIST 1.1. R0 resection rate : The proportion of patients who completed R0 resection in the total enrolled patients. Treatment safety : CTCAE 5.0 was used to record grade 3 and above treatment-related adverse reactions from the beginning of neoadjuvant therapy to 30 days after the end of surgery. Postoperative complications : Clavien-Dindo criteria were used to evaluate. Event-free survival (EFS) : From the beginning of the study to the time of the first occurrence of any of the following events, disease progression beyond surgical treatment, local or distant recurrence, death from any cause, etc. Overall survival (OS) : From study inception to patient death from any cause. Biomarkers : By collecting tumor tissue and hematology samples before and after neoadjuvant therapy, scRNA-seq, WES, MRD and other techniques were used to explore biomarkers related to the efficacy of immunotherapy combined with radiotherapy and chemotherapy. Data and sample collection and management Baseline Data Demographic information, medical history, tumor staging, ECOG performance status, and other baseline characteristics will be recorded at enrollment using electronic Case Report Forms (eCRF). This includes patient demographics such as age, sex, ethnicity, height, and weight, as well as disease-specific information like the primary tumor site, TNM stage, HER2 status, and PD-L1 expression levels. Treatment Period Data Data collected during the treatment period will include details on drug dosages, radiotherapy parameters, laboratory tests (blood, urine, blood routine, blood glucose, serum electrolytes, serum proteins, coagulation tests, thyroid function, tumor markers, etc.), and imaging assessments (chest, abdomen, and pelvis CT scans, ECG). These data will be collected at regular intervals as specified in the protocol and synchronized with the eCRF through the Hospital Information System (HIS). Postoperative Data Surgical records, pathology reports, and information on complications will be provided directly by the surgical and pathology teams. This data will include details on surgical procedures, histopathological findings, and any postoperative complications encountered. Follow-Up Data Follow-up data, including survival status, time to recurrence, and adverse events, will be obtained through outpatient visits or telephone follow-ups. Follow-up assessments will be conducted every 3 months and updated in the eCRF until the end of the study. Follow-up will continue until the patient’s death, loss to follow-up, or study termination by the researchers. (Table 2 ). Table 2 Data and sample collection and management Data type Specific information Baseline Data Age, sex, ethnicity, height, and weight, the primary tumor site, TNM stage, HER2 status, and PD-L1 expression levels, ECOG performance status, and other baseline characteristics. Treatment Period Data Details on drug dosages, radiotherapy parameters, laboratory tests (blood, urine, blood routine, blood glucose, serum electrolytes, serum proteins, coagulation tests, thyroid function, tumor markers, etc.), and imaging assessments (chest, abdomen, and pelvis CT scans, ECG). Postoperative Data Surgical records, pathology reports, and information on complications. Follow-Up Data Survival status, time to recurrence, and adverse events. Sample size calculation The sample size for this study was calculated based on historical control data and the anticipated effect size. Historical data indicate a pathological complete response (pCR) rate of 15% for neoadjuvant chemoradiotherapy in G/GEJ cancer. The current study protocol is projected to increase the pCR rate to 35%. With a power of 80% and a one-sided Type I error rate of 0.05, the calculated sample size is 28 patients. Considering a dropout rate of 10%, the study plans to enroll 32 patients. Statistical analysis The primary endpoints of this study include the pathological complete response rate (pCR), major pathological response rate (MPR), and objective response rate (ORR). These metrics will be assessed using descriptive statistics, with 95% confidence intervals calculated using the Clopper-Pearson method. Secondary endpoints include event-free survival (EFS) and overall survival (OS), which will be evaluated using the Kaplan-Meier method, reporting median survival times and 95% confidence intervals. If applicable, Cox proportional hazards regression models will be used to adjust for baseline covariates. The R0 resection rate will be assessed using descriptive statistics, with 95% confidence intervals calculated. Safety analyses will focus on treatment-related adverse events (graded by CTCAE v5.0), with comparisons between severity grades performed using chi-square or Fisher’s exact tests. Postoperative complications will be evaluated using the Clavien-Dindo classification. Exploratory biomarker analyses will be conducted using tumor tissue and blood samples collected before and after neoadjuvant therapy. Techniques such as single-cell RNA sequencing (scRNA-seq), whole-exome sequencing (WES), and minimal residual disease (MRD) assessment will be employed. These analyses will utilize advanced bioinformatics tools to identify predictive and prognostic biomarkers. All statistical analyses will be conducted using R (version 4.0.3) or SPSS (version 26.0), with a two-sided significance level of P < 0.05. This study employs a two-stage design to optimize patient exposure to the experimental therapy while maintaining statistical robustness. This approach ensures rigorous evaluation of the primary and secondary endpoints while accommodating the exploratory nature of the biomarker investigations. Discussion The present research is designed to evaluate the therapeutic outcomes and safety profile of a novel neoadjuvant regimen for locally advanced gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJ). Gastric cancer ranks as the fifth most prevalent malignancy worldwide and is the third leading cause of cancer-related death, with gastroesophageal junction adenocarcinoma being a specific subtype whose incidence has been increasing in recent years. Locally advanced GC/GEJ is typically characterized by tumors that have invaded the deep layers of the gastric wall (T3 or T4) or have regional lymph node metastasis (N+), but without distant metastasis (M0). Patients with this condition generally face a poor prognosis. Traditional treatment modalities, including surgery, chemotherapy, and radiotherapy, have certain limitations in improving patient survival rates and quality of life [ 18 , 19 ] . In recent years, immunotherapy has shown great promise in the treatment of various types of cancer, especially when combined with chemotherapy and radiotherapy. Immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies, work by blocking the immune inhibitory signals between tumor cells and immune cells, thereby restoring the body's immune surveillance function against tumors. Tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody that has demonstrated good antitumor activity in various solid tumors [ 20 ] . Additionally, the SOX chemotherapy regimen (oxaliplatin + S-1) has been widely used in the treatment of gastric cancer. Low-dose interval radiotherapy is an emerging radiotherapy modality that involves inserting low-dose radiotherapy between chemotherapy cycles to enhance local control while reducing damage to normal tissues [ 21 ] . It is anticipated that the combination of low-dose interval radiotherapy with tislelizumab and SOX chemotherapy will significantly increase the pathological complete response (pCR) rate in patients [ 22 ] . Improvements in major pathological response (MPR), objective response rate (ORR), and R0 resection rate are also expected. Safety analysis will focus on the incidence and severity of treatment-related adverse events to assess the safety of the regimen. The evaluation of postoperative complications will provide insights into the safety and feasibility of the surgical procedure [ 22 ] . Analysis of event-free survival (EFS) and overall survival (OS) will offer preliminary data on long-term efficacy. Exploration of biomarkers will help identify potential markers predictive of treatment response, providing a basis for future personalized treatment strategies. Despite the rigorous design of this study, several limitations exist. First, the single-center, single-arm design lacks a randomized control group, which may affect the generalizability and external validity of the results. Second, the relatively small sample size may limit the statistical power for secondary endpoint and biomarker analyses. Additionally, the relatively short follow-up period may not fully capture long-term survival and late complications. If the results of this study are positive, future research could further validate the efficacy and safety of this regimen in a multicenter, randomized controlled trial. Moreover, the identification of biomarkers could guide future personalized treatment strategies, particularly in selecting patients most likely to benefit from immunotherapy combined with radiotherapy and chemotherapy. Long-term follow-up studies will be essential to better understand the long-term efficacy and safety of this regimen. Conclusion The innovative aspect of this study lies in the combination of low-dose interval radiotherapy with immunotherapy and chemotherapy, aiming to enhance the therapeutic efficacy for patients with locally advanced GC/GEJ. Through detailed inclusion and exclusion criteria, the reliability and reproducibility of the study results are ensured. In addition, this study will also explore biomarkers associated with the efficacy of immunotherapy combined with radiotherapy and chemotherapy, laying the foundation for future research. Declarations Competing interests The authors declare no competing interests. Ethics approval and consent to participate This study was approved by the Ethical Committee of the Shandong Provincial Hospital Affiliated to Shandong First Medical University. This study was registered with the Clinical Trials Registry ( https://clinicaltrials.gov/ , ClinicalTrials.gov: NCT06766578). We will obtain informed consent from all participants in the study, and they must be signed by the guardian and must include a date. The signed informed consent form will be kept independently by researchers and participants, and the former will be made available to project managers for monitoring and inspection. The consent form provided to participants includes provisions for the possible use of their data and biological specimens in ancillary studies. Participants are informed that their willingness to contribute data for future research is entirely voluntary, and they are under no obligation to consent to any studies beyond the scope of this one. In the course of the clinical study, any modification to the study protocol and other relevant documents shall be submitted to the ethics committee for further approval and can only be implemented with the consent of the ethics committee. Funding This paper was supported by grants from the National Natural Science Foundation of China (No. 82203854 and 82372772), Key Research and Development Program of Shandong Province (No. 2021CXGC011104), and Special Foundation for Taishan Scholars Program of Shandong Province (Nos. ts20190978 and tsqn202408363). Author Contribution L.S., Z.F., Y.L., and G.Z. contributed equally to this work. L.S. and Z.F. designed, supervised, and advanced the experiments. Y.L. analyzed the data. G.Z. prepared the figures and tables. J.L. and L.L. conceived and supervised the study, secured funding, and revised the manuscript. All authors read and approved the final manuscript. Acknowledgements Not applicable Data Availability This study was approved by the Ethical Committee of the Shandong Provincial Hospital Affiliated to Shandong First Medical University. This study was registered with the Clinical Trials Registry (https://clinicaltrials.gov/, ClinicalTrials.gov: NCT06766578). We will obtain informed consent from all participants in the study, and they must be signed by the guardian and must include a date. The signed informed consent form will be kept independently by researchers and participants, and the former will be made available to project managers for monitoring and inspection. The consent form provided to participants includes provisions for the possible use of their data and biological specimens in ancillary studies. Participants are informed that their willingness to contribute data for future research is entirely voluntary, and they are under no obligation to consent to any studies beyond the scope of this one. In the course of the clinical study, any modification to the study protocol and other relevant documents shall be submitted to the ethics committee for further approval and can only be implemented with the consent of the ethics committee. References SIEGEL R L, MILLER K D, WAGLE N S, et al. Cancer statistics, 2023 [J]. 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Front Immunol, 2024, 15: 1431957. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 10 Sep, 2025 Reviews received at journal 10 Sep, 2025 Reviews received at journal 23 Aug, 2025 Reviews received at journal 21 Aug, 2025 Reviewers agreed at journal 20 Aug, 2025 Reviewers agreed at journal 18 Aug, 2025 Reviewers agreed at journal 14 Aug, 2025 Reviewers invited by journal 14 Aug, 2025 Editor assigned by journal 06 Aug, 2025 Submission checks completed at journal 06 Aug, 2025 First submitted to journal 06 Aug, 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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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-7310982","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":503494712,"identity":"c74bb265-8cb3-4d2f-9e99-b3c66c1fd50f","order_by":0,"name":"Liang Shang","email":"","orcid":"","institution":"Shandong Provincial Hospital Affiliated to Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Liang","middleName":"","lastName":"Shang","suffix":""},{"id":503494716,"identity":"d0f903df-f8e9-407c-8868-726787eb2616","order_by":1,"name":"Zhen Fang","email":"","orcid":"","institution":"Shandong Provincial Hospital Affiliated to Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhen","middleName":"","lastName":"Fang","suffix":""},{"id":503494718,"identity":"b17f8a41-3cd1-42b9-b28b-a22824b02408","order_by":2,"name":"Yan Liu","email":"","orcid":"","institution":"Shandong Provincial Hospital Affiliated to Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Liu","suffix":""},{"id":503494719,"identity":"95e0dee1-bf88-4e9a-b39a-b4e2ac21d130","order_by":3,"name":"Guangying Zhao","email":"","orcid":"","institution":"Shandong Provincial Hospital Affiliated to Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Guangying","middleName":"","lastName":"Zhao","suffix":""},{"id":503494720,"identity":"f9ded105-822d-437e-9c34-054bb6bf138b","order_by":4,"name":"Jin Liu","email":"","orcid":"","institution":"Shandong Provincial Hospital Affiliated to Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jin","middleName":"","lastName":"Liu","suffix":""},{"id":503494721,"identity":"f617e020-f58d-45db-934f-fffae3a28543","order_by":5,"name":"Leping Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYBACPmbmBgYGAwYGfiBHAohkCGphY2aEaJFsgGjhIayFAaQFCAwOgLUwEKGFnbHxcUHBHbvN1w4fvHWjxoKHgf3w0Q0MNXfwOazZeIbBs+Rtt9OSrXOOAR3Gk5Z2g+HYM3xa2qR5DA4nm93OMZPOYQNqkeAxu8HYcBiflvbfIC3Gs/O/Sef8I05LGzNQi50B0Arp3DbitDRLzzA4nCBxO83YOrdPgocN5JeEY7i18PMfPvi54M9he/7ZyQ9v53yrk+NnP3zsxoca3FpAgBmIExvg9oKIBLwaIFrsCagZBaNgFIyCkQwA/axKVLCzasIAAAAASUVORK5CYII=","orcid":"","institution":"Shandong Provincial Hospital Affiliated to Shandong First Medical University","correspondingAuthor":true,"prefix":"","firstName":"Leping","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-08-06 14:53:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7310982/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7310982/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89655658,"identity":"1b4063f0-80d2-4d1a-8009-1e434e26a488","added_by":"auto","created_at":"2025-08-22 10:24:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":61302,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow chart. ECOG, Eastern Cooperative Oncology Group; PS, performance status; D2, D2 lymphadenectomy; MPR, Major Pathological Response; ORR, Objective Response Rate; EFS, Event-Free Survival; OS, Overall Survival.\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7310982/v1/bc17d2527075fff3cf6e9da9.png"},{"id":89657084,"identity":"072f1b63-4fc3-4d76-b4be-d2c311942744","added_by":"auto","created_at":"2025-08-22 10:32:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":891094,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7310982/v1/7f36f174-fdcc-4661-89be-e6207a49025e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Low-dose interval radiotherapy combined with tirelizumab and SOX chemotherapy neoadjuvant therapy for locally advanced gastric/gastroesophageal junction adenocarcinoma: study protocol of a prospective, single-center, single-arm clinical trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGastroesophageal junction (G/GEJ) cancer, represents a major global health burden, ranking as the fifth most common cancer and the fourth leading cause of cancer-related mortality worldwide\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Despite surgical resection being the primary curative approach for localized disease, the prognosis remains poor, particularly for advanced-stage or type 4 GC, with 5-year survival rates below 30% after gastrectomy\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Perioperative chemotherapy, compared to surgery alone, has demonstrated significant survival benefits by improving R0 resection rates, reducing recurrence, and enhancing overall survival (OS). However, outcomes for locally advanced or metastatic GC remain dismal, with 5-year survival rates below 20%\u003csup\u003e[\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eCurrently, the treatment for advanced G/GEJ cancer has entered the era of immunotherapy. The combination of immune checkpoint inhibitors (ICIs) and chemotherapy has been shown to prolong OS and progression-free survival (PFS) compared to chemotherapy alone in the first-line setting of advanced or metastatic G/GEJ cancer patients\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. These promising results have sparked the interest of researchers to further investigate the wide application of ICIs plus chemotherapy in the neoadjuvant setting for locally advanced G/GEJ cancer. In a single-arm, phase II clinical study conducted by Jiang et al., 36 patients with locally advanced, resectable G/GEJ cancer were enrolled to receive sintilimab plus the XELOX regimen. The pathological complete response (PCR) and R0 resection rates were 19.4% and 97.2%, respectively\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Another study also showed similar results. The PCR rate in patients with locally advanced G/GEJ adenocarcinoma treated with the combination of tislelizumab and SOX was 25%, and the annual recurrence-free survival (RFS) and OS were 90.0% and 91.4%, respectively\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. These results provide new insight and suggest that chemotherapy combined with immunotherapy may represent a promising therapy for the neoadjuvant treatment of locally advanced, resectable G/GEJ adenocarcinoma.\u003c/p\u003e\u003cp\u003eIn recent years, with the advancement of radiotherapy technology and the deepening understanding of tumor biology, the role of radiotherapy in the comprehensive treatment of G/GEJ has gradually attracted attention\u003csup\u003e[\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Low-dose interval radiotherapy, as an emerging radiotherapy modality, has potential advantages\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Compared with traditional radiotherapy, low-dose interval radiotherapy, by adjusting the dose and time intervals of radiotherapy, may reduce damage to normal tissues while enhancing the killing effect on tumor cells. Animal experiments and some small-scale clinical studies have suggested that low-dose radiotherapy can modulate the tumor microenvironment, enhancing the ability of immune cells to recognize and attack tumors, and may have a synergistic effect with immunotherapy and chemotherapy\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. However, research on the combination of low-dose interval radiotherapy with immunotherapy and chemotherapy in G/GEJ is still relatively limited, and further in-depth studies are needed on its specific mechanisms, optimal dosing and fractionation methods, as well as efficacy and safety.\u003c/p\u003e\u003cp\u003eOur center has conducted a prospective, single-center, single-arm clinical trial of the PD-1 inhibitor tislelizumab combined with S-1 plus oxaliplatin: To evaluate the initial efficacy and safety of neoadjuvant low-dose interval radiotherapy combined with tirelizumab and SOX chemotherapy in locally advanced gastric/gastroesophageal junction adenocarcinoma.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eTrial design\u003c/h2\u003e\u003cp\u003eThis prospective, single-center, open-label, single-arm clinical trial aims to evaluate the efficacy and safety of low-dose interval radiotherapy combined with tirelizumab and SOX chemotherapy as neoadjuvant therapy for patients with locally advanced G/GEJ adenocarcinoma. The study design is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eInclusion and exclusion criteria\u003c/h3\u003e\n\u003cp\u003eThe inclusion and exclusion criteria are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe inclusion and exclusion criteria.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInclusion Criteria\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExclusion criteria\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026bull; Patients voluntarily participated in the study and signed informed consent with good compliance and follow-up;\u003c/p\u003e\u003cp\u003e\u0026bull; Adenocarcinoma of the gastric/gastroesophageal junction confirmed by endoscopic pathology (tumor located in the lesser bend of the stomach other than pylorus or the gastroesophageal junction) (Note: Pathology in other hospitals must be consulted by our hospital);\u003c/p\u003e\u003cp\u003e\u0026bull; Patients with cT4N\u0026thinsp;+\u0026thinsp;M0 AJCC stage 8 combined with endoscopic, CT, MRI, or PETCT findings;\u003c/p\u003e\u003cp\u003e\u0026bull; Age\u0026thinsp;\u0026ge;\u0026thinsp;18 years, \u0026le;\u0026thinsp;75 years, male and female;\u003c/p\u003e\u003cp\u003e\u0026bull; ECOG PS score 0\u0026ndash;1;\u003c/p\u003e\u003cp\u003e\u0026bull; Presence of measurable and/or unmeasurable lesions as defined by the efficacy evaluation criteria for solid tumors (Recist 1.1);\u003c/p\u003e\u003cp\u003e\u0026bull; Has not received any prior systemic antitumor therapy (including but not limited to systemic chemotherapy, radiotherapy, molecular targeted drug therapy, immunotherapy, biotherapy, topical therapy, or other investigational therapeutic drugs;\u003c/p\u003e\u003cp\u003e\u0026bull; The functions of vital organs meet the following requirements (no blood components and cell growth factors are allowed to be used 2 weeks before screening) : Neutrophil absolute count (ANC)\u0026thinsp;\u0026ge;\u0026thinsp;1.5\u0026times;10 9/L; Platelets\u0026thinsp;\u0026ge;\u0026thinsp;100\u0026times;10 9/L; Hemoglobin\u0026thinsp;\u0026ge;\u0026thinsp;9g/dL; Serum albumin\u0026thinsp;\u0026ge;\u0026thinsp;2.8g/dL; Total bilirubin\u0026thinsp;\u0026le;\u0026thinsp;1.5 \u0026times;ULN, ALT, AST and/or AKP\u0026thinsp;\u0026le;\u0026thinsp;2.5 \u0026times;ULN; serum creatinine\u0026thinsp;\u0026le;\u0026thinsp;1.5 \u0026times;ULN or creatinine clearance\u0026thinsp;\u0026ge;\u0026thinsp;60mL/min (calculated according to the Cockcroft Gault formula); International standardized ratio (INR) and activated partial thrombin time (APTT)\u0026thinsp;\u0026le;\u0026thinsp;1.5\u0026times;ULN (INR can be screened in the expected treatment range of anticoagulants for stable doses of anticoagulants such as low molecular weight heparin or warfarin);\u003c/p\u003e\u003cp\u003e\u0026bull; Fertile female subjects shall perform a urine or serum pregnancy test within 72 hours prior to receiving the first study drug, prove negative, and be willing to use an effective method of contraception during the trial period up to 5 months after the last drug administration. Male subjects whose partner is a woman of reproductive age should use an effective method of contraception during the trial period and for 7 months after the last dose.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026bull; a history of surgery for gastric/esophagogastric junction tumors;\u003c/p\u003e\u003cp\u003e\u0026bull; Previous history of fistula caused by primary tumor invasion;\u003c/p\u003e\u003cp\u003e\u0026bull; Higher risk of gastrointestinal bleeding and perforation;\u003c/p\u003e\u003cp\u003e\u0026bull; Poor nutritional status, BMI less than 18.5kg/m2, or PG-SGA score\u0026thinsp;\u0026ge;\u0026thinsp;9;\u003c/p\u003e\u003cp\u003e\u0026bull; Major surgery or severe trauma within 4 weeks prior to first use of the study drug;\u003c/p\u003e\u003cp\u003e\u0026bull; Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage;\u003c/p\u003e\u003cp\u003e\u0026bull; has received or is currently receiving any of the following previous treatments: anti-PD-1 or anti-PD-L1 antibody therapy, chemotherapy, radiotherapy, targeted therapy;\u003c/p\u003e\u003cp\u003e\u0026bull; Received any investigational drug within 4 weeks prior to first use of the investigational drug;\u003c/p\u003e\u003cp\u003e\u0026bull; subjects requiring systemic treatment with corticosteroids (\u0026gt;\u0026thinsp;10mg prednisone equivalent daily dose) or other immunosuppressants within 2 weeks prior to initial use of the study drug, except for corticosteroids for esophageal/gastric local inflammation and for the prevention of allergy and nausea and vomiting. Other special circumstances, need to communicate with the bid. In the absence of active autoimmune disease, inhaled or topical steroids and adrenocorticosteroid replacement at doses\u0026thinsp;\u0026gt;\u0026thinsp;10mg/ d of prednisone efficacy are permitted;\u003c/p\u003e\u003cp\u003e\u0026bull; those who have received antitumor vaccine or have received live vaccine within 4 weeks prior to the first administration of the study drug;\u003c/p\u003e\u003cp\u003e\u0026bull; have any active autoimmune disease or a history of autoimmune disease (such as interstitial pulmonary inflammation, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, myocarditis, nephritis, hyperthyroidism, hypothyroidism); Except patients with vitiligo or recovered asthma/ allergy of the same age without any intervention as adults; Patients with autoimmune mediated hypothyroidism treated with stable doses of thyroid hormone replacement and type 1 diabetes treated with stable doses of insulin could be included;\u003c/p\u003e\u003cp\u003e\u0026bull; have a history of immunodeficiency, including HIV positive, or other acquired or congenital immunodeficiency diseases, or have a history of organ transplantation or allogeneic bone marrow transplantation;\u003c/p\u003e\u003cp\u003e\u0026bull; any condition requiring systemic treatment with corticosteroids (more than 10 mg/ day of prednisone or its equivalent) or other immunosuppressant treatment within 14 days prior to treatment (except local, ocular, intraarticular, intranasal and inhaled corticosteroids with minimal systemic uptake); Prophylactic short-term (\u0026le;\u0026thinsp;7 days) use of corticosteroids (e.g., to prevent contrast allergy) or for the treatment of non-autoimmune conditions (e.g., delayed hypersensitivity due to allergen exposure);\u003c/p\u003e\u003cp\u003e\u0026bull; subjects with uncontrolled cardiac clinical symptoms or disease, such as (1) NYHA II or above heart failure (2) unstable angina pecina (3) myocardial infarction within 1 year (4) clinically significant ventricular arrhythmias or ventricular arrhythmias requiring clinical intervention;\u003c/p\u003e\u003cp\u003e\u0026bull; Severe infection (CTCAE\u0026thinsp;\u0026gt;\u0026thinsp;level 2), such as severe pneumonia, bacteremia, and infectious complications requiring hospitalization, occurred within 4 weeks prior to initial use of the study drug; Chest imaging at baseline suggested active lung inflammation and signs and symptoms of infection requiring oral or intravenous antibiotic treatment within 2 weeks prior to enrollment, except for prophylactic antibiotic use;\u003c/p\u003e\u003cp\u003e\u0026bull; a history of interstitial lung disease, non-infectious pneumonia, pulmonary fibrosis or other uncontrolled acute lung disease;\u003c/p\u003e\u003cp\u003e\u0026bull; Patients with active pulmonary tuberculosis infection found by history or CT examination, or patients with active pulmonary tuberculosis infection history within 1 year before enrollment, or patients with active pulmonary tuberculosis infection history more than 1 year ago but without formal treatment;\u003c/p\u003e\u003cp\u003e\u0026bull; Subjects with active hepatitis B (HBV DNA\u0026thinsp;\u0026ge;\u0026thinsp;2000 IU/mL or 10 4 Copies / mL), hepatitis C (positive hepatitis C antibody, and HCV-RNA higher than the lower limit of detection method);\u003c/p\u003e\u003cp\u003e\u0026bull; Abnormal values of sodium, potassium and calcium greater than grade 1 in laboratory tests within 2 weeks before enrollment, which could not be improved after treatment;\u003c/p\u003e\u003cp\u003e\u0026bull; known allergy to macromolecular protein preparations, or to any COMPONENT of PD-1, or allergy, hypersensitivity or contraindication to oxaliplatin or capecitabine or any component used in their preparations;\u003c/p\u003e\u003cp\u003e\u0026bull; A prior diagnosis of any other malignancy, other than malignancies with a low risk of metastasis and death (5-year survival\u0026thinsp;\u0026gt;\u0026thinsp;90%), such as adequately treated basal or squamous cell skin cancer or carcinoma in situ of the cervix; \u0026bull;pregnant or lactating women; Fertile subjects unwilling or unable to use effective contraception;\u003c/p\u003e\u003cp\u003e\u0026bull; According to the investigator's judgment, subjects have other factors that may cause them to be forced to terminate the study, such as other serious diseases (including mental diseases) requiring combined treatment, other recent serious diseases (such as myocardial infarction and cerebrovascular accident) with high risk of recurrence, seriously abnormal laboratory test values, family or social factors, which may affect subjects' safety or the collection of test data.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eTreatment interventions\u003c/h3\u003e\n\u003cp\u003eIntravenous administration for tirelizumab 200 mg D1, intravenous administration for oxaliplatin 130 mg/m\u003csup\u003e2\u003c/sup\u003e D1, and oral administration twice a day for S-1 40 mg/m\u003csup\u003e2\u003c/sup\u003e D1 to 14. Every treatment cycle is spaced 1 week Radiation: Neoadjuvant Therapy(5\u0026times;3Gy radiotherapy).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eRadiotherapy\u003c/strong\u003e\u003cp\u003e5\u0026times;3Gy. The preoperative radiotherapy target was outlined by radiotherapy physicians according to the NCCN Guidelines for Gastric/esophagogastric Junction Tumor 2024 edition and the surgeon's opinions. The first and third cycles were 5\u0026times;3Gy.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eDrug\u003c/strong\u003e\u003cp\u003eNeoadjuvant Therapy (tirelizumab, oxaliplatin, S-1), The first and third cycles are 5\u0026times;3Gy radiotherapy D1 to 5, intravenous administration for tirelizumab 200 mg D6, intravenous administration for oxaliplatin 130 mg/m\u003csup\u003e2\u003c/sup\u003e D6, and oral administration twice a day for S-1 40 mg/m\u003csup\u003e2\u003c/sup\u003e D6 to 19. The second and fourth cycles are apart.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eProcedure/Surgery\u003c/strong\u003e\u003cp\u003eSurgical treatment Surgical treatment is completed within 3\u0026ndash;5 weeks after the end of neoadjuvant therapy.\u003c/p\u003e\u003c/p\u003e\u003cp\u003ePostoperative adjuvant therapy is 4 cycles of SOX chemotherapy.\u003c/p\u003e\n\u003ch3\u003eStudy end points\u003c/h3\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003ePrimary Outcome Measure\u003c/h2\u003e\u003cp\u003ePathological complete response rate (pCR): Pathological complete response was defined as pT0N0M0.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eSecondary Outcome Measure\u003c/h2\u003e\u003cp\u003e\u003cb\u003eMajor pathological response rate (MPR)\u003c/b\u003e: The percentage of surviving tumor cells in the tumor bed after neoadjuvant therapy was \u0026le;\u0026thinsp;10%. \u003cb\u003eObjective response rate (ORR)\u003c/b\u003e: Proportion of patients who achieved a complete response (CR) or a partial response (PR) as assessed by RECIST 1.1. \u003cb\u003eR0 resection rate\u003c/b\u003e: The proportion of patients who completed R0 resection in the total enrolled patients. \u003cb\u003eTreatment safety\u003c/b\u003e: CTCAE 5.0 was used to record grade 3 and above treatment-related adverse reactions from the beginning of neoadjuvant therapy to 30 days after the end of surgery. \u003cb\u003ePostoperative complications\u003c/b\u003e: Clavien-Dindo criteria were used to evaluate. \u003cb\u003eEvent-free survival (EFS)\u003c/b\u003e: From the beginning of the study to the time of the first occurrence of any of the following events, disease progression beyond surgical treatment, local or distant recurrence, death from any cause, etc. \u003cb\u003eOverall survival (OS)\u003c/b\u003e: From study inception to patient death from any cause. \u003cb\u003eBiomarkers\u003c/b\u003e: By collecting tumor tissue and hematology samples before and after neoadjuvant therapy, scRNA-seq, WES, MRD and other techniques were used to explore biomarkers related to the efficacy of immunotherapy combined with radiotherapy and chemotherapy.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eData and sample collection and management\u003c/h3\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline Data\u003c/strong\u003e\u003cp\u003eDemographic information, medical history, tumor staging, ECOG performance status, and other baseline characteristics will be recorded at enrollment using electronic Case Report Forms (eCRF). This includes patient demographics such as age, sex, ethnicity, height, and weight, as well as disease-specific information like the primary tumor site, TNM stage, HER2 status, and PD-L1 expression levels.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTreatment Period Data\u003c/strong\u003e\u003cp\u003eData collected during the treatment period will include details on drug dosages, radiotherapy parameters, laboratory tests (blood, urine, blood routine, blood glucose, serum electrolytes, serum proteins, coagulation tests, thyroid function, tumor markers, etc.), and imaging assessments (chest, abdomen, and pelvis CT scans, ECG). These data will be collected at regular intervals as specified in the protocol and synchronized with the eCRF through the Hospital Information System (HIS).\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003ePostoperative Data\u003c/strong\u003e\u003cp\u003eSurgical records, pathology reports, and information on complications will be provided directly by the surgical and pathology teams. This data will include details on surgical procedures, histopathological findings, and any postoperative complications encountered.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eFollow-Up Data\u003c/strong\u003e\u003cp\u003eFollow-up data, including survival status, time to recurrence, and adverse events, will be obtained through outpatient visits or telephone follow-ups. Follow-up assessments will be conducted every 3 months and updated in the eCRF until the end of the study. Follow-up will continue until the patient\u0026rsquo;s death, loss to follow-up, or study termination by the researchers. (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eData and sample collection and management\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eData type\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSpecific information\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBaseline Data\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAge, sex, ethnicity, height, and weight, the primary tumor site, TNM stage, HER2 status, and PD-L1 expression levels, ECOG performance status, and other baseline characteristics.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTreatment Period Data\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDetails on drug dosages, radiotherapy parameters, laboratory tests (blood, urine, blood routine, blood glucose, serum electrolytes, serum proteins, coagulation tests, thyroid function, tumor markers, etc.), and imaging assessments (chest, abdomen, and pelvis CT scans, ECG).\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePostoperative Data\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSurgical records, pathology reports, and information on complications.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFollow-Up Data\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSurvival status, time to recurrence, and adverse events.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eSample size calculation\u003c/h3\u003e\n\u003cp\u003eThe sample size for this study was calculated based on historical control data and the anticipated effect size. Historical data indicate a pathological complete response (pCR) rate of 15% for neoadjuvant chemoradiotherapy in G/GEJ cancer. The current study protocol is projected to increase the pCR rate to 35%. With a power of 80% and a one-sided Type I error rate of 0.05, the calculated sample size is 28 patients. Considering a dropout rate of 10%, the study plans to enroll 32 patients.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eThe primary endpoints of this study include the pathological complete response rate (pCR), major pathological response rate (MPR), and objective response rate (ORR). These metrics will be assessed using descriptive statistics, with 95% confidence intervals calculated using the Clopper-Pearson method. Secondary endpoints include event-free survival (EFS) and overall survival (OS), which will be evaluated using the Kaplan-Meier method, reporting median survival times and 95% confidence intervals. If applicable, Cox proportional hazards regression models will be used to adjust for baseline covariates. The R0 resection rate will be assessed using descriptive statistics, with 95% confidence intervals calculated. Safety analyses will focus on treatment-related adverse events (graded by CTCAE v5.0), with comparisons between severity grades performed using chi-square or Fisher\u0026rsquo;s exact tests. Postoperative complications will be evaluated using the Clavien-Dindo classification.\u003c/p\u003e\u003cp\u003eExploratory biomarker analyses will be conducted using tumor tissue and blood samples collected before and after neoadjuvant therapy. Techniques such as single-cell RNA sequencing (scRNA-seq), whole-exome sequencing (WES), and minimal residual disease (MRD) assessment will be employed. These analyses will utilize advanced bioinformatics tools to identify predictive and prognostic biomarkers.\u003c/p\u003e\u003cp\u003eAll statistical analyses will be conducted using R (version 4.0.3) or SPSS (version 26.0), with a two-sided significance level of P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. This study employs a two-stage design to optimize patient exposure to the experimental therapy while maintaining statistical robustness. This approach ensures rigorous evaluation of the primary and secondary endpoints while accommodating the exploratory nature of the biomarker investigations.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present research is designed to evaluate the therapeutic outcomes and safety profile of a novel neoadjuvant regimen for locally advanced gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJ). Gastric cancer ranks as the fifth most prevalent malignancy worldwide and is the third leading cause of cancer-related death, with gastroesophageal junction adenocarcinoma being a specific subtype whose incidence has been increasing in recent years. Locally advanced GC/GEJ is typically characterized by tumors that have invaded the deep layers of the gastric wall (T3 or T4) or have regional lymph node metastasis (N+), but without distant metastasis (M0). Patients with this condition generally face a poor prognosis. Traditional treatment modalities, including surgery, chemotherapy, and radiotherapy, have certain limitations in improving patient survival rates and quality of life\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn recent years, immunotherapy has shown great promise in the treatment of various types of cancer, especially when combined with chemotherapy and radiotherapy. Immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies, work by blocking the immune inhibitory signals between tumor cells and immune cells, thereby restoring the body's immune surveillance function against tumors. Tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody that has demonstrated good antitumor activity in various solid tumors\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. Additionally, the SOX chemotherapy regimen (oxaliplatin\u0026thinsp;+\u0026thinsp;S-1) has been widely used in the treatment of gastric cancer. Low-dose interval radiotherapy is an emerging radiotherapy modality that involves inserting low-dose radiotherapy between chemotherapy cycles to enhance local control while reducing damage to normal tissues\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIt is anticipated that the combination of low-dose interval radiotherapy with tislelizumab and SOX chemotherapy will significantly increase the pathological complete response (pCR) rate in patients\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Improvements in major pathological response (MPR), objective response rate (ORR), and R0 resection rate are also expected. Safety analysis will focus on the incidence and severity of treatment-related adverse events to assess the safety of the regimen. The evaluation of postoperative complications will provide insights into the safety and feasibility of the surgical procedure\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Analysis of event-free survival (EFS) and overall survival (OS) will offer preliminary data on long-term efficacy. Exploration of biomarkers will help identify potential markers predictive of treatment response, providing a basis for future personalized treatment strategies.\u003c/p\u003e\u003cp\u003eDespite the rigorous design of this study, several limitations exist. First, the single-center, single-arm design lacks a randomized control group, which may affect the generalizability and external validity of the results. Second, the relatively small sample size may limit the statistical power for secondary endpoint and biomarker analyses. Additionally, the relatively short follow-up period may not fully capture long-term survival and late complications.\u003c/p\u003e\u003cp\u003eIf the results of this study are positive, future research could further validate the efficacy and safety of this regimen in a multicenter, randomized controlled trial. Moreover, the identification of biomarkers could guide future personalized treatment strategies, particularly in selecting patients most likely to benefit from immunotherapy combined with radiotherapy and chemotherapy. Long-term follow-up studies will be essential to better understand the long-term efficacy and safety of this regimen.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe innovative aspect of this study lies in the combination of low-dose interval radiotherapy with immunotherapy and chemotherapy, aiming to enhance the therapeutic efficacy for patients with locally advanced GC/GEJ. Through detailed inclusion and exclusion criteria, the reliability and reproducibility of the study results are ensured. In addition, this study will also explore biomarkers associated with the efficacy of immunotherapy combined with radiotherapy and chemotherapy, laying the foundation for future research.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cp\u003eThis study was approved by the Ethical Committee of the Shandong Provincial Hospital Affiliated to Shandong First Medical University. This study was registered with the Clinical Trials Registry (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://clinicaltrials.gov/\u003c/span\u003e\u003cspan address=\"https://clinicaltrials.gov/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, ClinicalTrials.gov: NCT06766578). We will obtain informed consent from all participants in the study, and they must be signed by the guardian and must include a date. The signed informed consent form will be kept independently by researchers and participants, and the former will be made available to project managers for monitoring and inspection. The consent form provided to participants includes provisions for the possible use of their data and biological specimens in ancillary studies. Participants are informed that their willingness to contribute data for future research is entirely voluntary, and they are under no obligation to consent to any studies beyond the scope of this one. In the course of the clinical study, any modification to the study protocol and other relevant documents shall be submitted to the ethics committee for further approval and can only be implemented with the consent of the ethics committee.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis paper was supported by grants from the National Natural Science Foundation of China (No. 82203854 and 82372772), Key Research and Development Program of Shandong Province (No. 2021CXGC011104), and Special Foundation for Taishan Scholars Program of Shandong Province (Nos. ts20190978 and tsqn202408363).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eL.S., Z.F., Y.L., and G.Z. contributed equally to this work. L.S. and Z.F. designed, supervised, and advanced the experiments. Y.L. analyzed the data. G.Z. prepared the figures and tables. J.L. and L.L. conceived and supervised the study, secured funding, and revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eNot applicable\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThis study was approved by the Ethical Committee of the Shandong Provincial Hospital Affiliated to Shandong First Medical University. This study was registered with the Clinical Trials Registry (https://clinicaltrials.gov/, ClinicalTrials.gov: NCT06766578). We will obtain informed consent from all participants in the study, and they must be signed by the guardian and must include a date. The signed informed consent form will be kept independently by researchers and participants, and the former will be made available to project managers for monitoring and inspection. The consent form provided to participants includes provisions for the possible use of their data and biological specimens in ancillary studies. Participants are informed that their willingness to contribute data for future research is entirely voluntary, and they are under no obligation to consent to any studies beyond the scope of this one. In the course of the clinical study, any modification to the study protocol and other relevant documents shall be submitted to the ethics committee for further approval and can only be implemented with the consent of the ethics committee.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSIEGEL R L, MILLER K D, WAGLE N S, et al. Cancer statistics, 2023 [J]. CA Cancer J Clin, 2023, 73(1): 17-48.\u003c/li\u003e\n\u003cli\u003eSUNDAR R, NAKAYAMA I, MARKAR S R, et al. Gastric cancer [J]. Lancet, 2025.\u003c/li\u003e\n\u003cli\u003eYAMASHITA K, EMA A, HOSODA K, et al. Macroscopic appearance of Type IV and giant Type III is a high risk for a poor prognosis in pathological stage II/III advanced gastric cancer with postoperative adjuvant chemotherapy [J]. World journal of gastrointestinal oncology, 2017, 9(4): 166-75.\u003c/li\u003e\n\u003cli\u003eWARD Z J, GABA Q, ATUN R. Cancer incidence and survival for 11 cancers in the Commonwealth: a simulation-based modelling study [J]. The Lancet Oncology, 2024, 25(9): 1127-34.\u003c/li\u003e\n\u003cli\u003eHEGEWISCH-BECKER S, MENDEZ G, CHAO J, et al. First-Line Nivolumab and Relatlimab Plus Chemotherapy for Gastric or Gastroesophageal Junction Adenocarcinoma: The Phase II RELATIVITY-060 Study [J]. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2024, 42(17): 2080-93.\u003c/li\u003e\n\u003cli\u003eEDGE S B, COMPTON C C. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM [J]. Annals of surgical oncology, 2010, 17(6): 1471-4.\u003c/li\u003e\n\u003cli\u003eKOIZUMI W, NARAHARA H, HARA T, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial [J]. The Lancet Oncology, 2008, 9(3): 215-21.\u003c/li\u003e\n\u003cli\u003eYAMADA Y, HIGUCHI K, NISHIKAWA K, et al. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-na\u0026iuml;ve patients with advanced gastric cancer [J]. Annals of oncology : official journal of the European Society for Medical Oncology, 2015, 26(1): 141-8.\u003c/li\u003e\n\u003cli\u003eBANG Y J, VAN CUTSEM E, FEYEREISLOVA A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial [J]. Lancet (London, England), 2010, 376(9742): 687-97.\u003c/li\u003e\n\u003cli\u003eJANJIGIAN Y Y, SHITARA K, MOEHLER M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial [J]. Lancet (London, England), 2021, 398(10294): 27-40.\u003c/li\u003e\n\u003cli\u003eXU J, JIANG H, PAN Y, et al. Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial [J]. Jama, 2023, 330(21): 2064-74.\u003c/li\u003e\n\u003cli\u003eJIANG H, YU X, LI N, et al. Efficacy and safety of neoadjuvant sintilimab, oxaliplatin and capecitabine in patients with locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma: early results of a phase 2 study [J]. Journal for immunotherapy of cancer, 2022, 10(3).\u003c/li\u003e\n\u003cli\u003eYIN Y, LIN Y, YANG M, et al. Neoadjuvant tislelizumab and tegafur/gimeracil/octeracil (S-1) plus oxaliplatin in patients with locally advanced gastric or gastroesophageal junction cancer: Early results of a phase 2, single-arm trial [J]. Frontiers in oncology, 2022, 12: 959295.\u003c/li\u003e\n\u003cli\u003eSHARABI A B, LIM M, DEWEESE T L, et al. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy [J]. Lancet Oncol, 2015, 16(13): e498-509.\u003c/li\u003e\n\u003cli\u003eDEMARIA S, BHARDWAJ N, MCBRIDE W H, et al. Combining radiotherapy and immunotherapy: a revived partnership [J]. Int J Radiat Oncol Biol Phys, 2005, 63(3): 655-66.\u003c/li\u003e\n\u003cli\u003eLHUILLIER C, RUDQVIST N P, ELEMENTO O, et al. Radiation therapy and anti-tumor immunity: exposing immunogenic mutations to the immune system [J]. Genome Med, 2019, 11(1): 40.\u003c/li\u003e\n\u003cli\u003eWANG H, YAO Z, KANG K, et al. Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer [J]. Med (New York, NY), 2024, 5(10): 1237-54.e9.\u003c/li\u003e\n\u003cli\u003eNEWTON A D, DATTA J, LOAIZA-BONILLA A, et al. Neoadjuvant therapy for gastric cancer: current evidence and future directions [J]. J Gastrointest Oncol, 2015, 6(5): 534-43.\u003c/li\u003e\n\u003cli\u003eVERSCHOOR Y L, VAN DE HAAR J, VAN DEN BERG J G, et al. Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial [J]. Nat Med, 2024, 30(2): 519-30.\u003c/li\u003e\n\u003cli\u003eZHANG L, GENG Z, HAO B, et al. Tislelizumab: A Modified Anti-tumor Programmed Death Receptor 1 Antibody [J]. Cancer Control, 2022, 29: 10732748221111296.\u003c/li\u003e\n\u003cli\u003eLIU Y, ZHAO J G, ZHAO G Y. Impact of the SOX Regimen on Immune Function and Tumor Markers in Advanced Gastric Cancer [J]. Int J Gen Med, 2025, 18: 1415-22.\u003c/li\u003e\n\u003cli\u003eZHANG P F, CHEN Y, LI W K, et al. SOX combined with tislelizumab and low-dose radiation therapy for the neoadjuvant treatment of locally advanced gastric/gastroesophageal junction adenocarcinoma: study protocol for a prospective, multicenter, single-arm, phase Ib/II clinical trial [J]. Front Immunol, 2024, 15: 1431957.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"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":"Gastroesophageal junction cancer, Neoadjuvant therapy, Immunotherapy, Chemotherapy, Radiotherapy","lastPublishedDoi":"10.21203/rs.3.rs-7310982/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7310982/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground：\u003c/strong\u003eGastroesophageal junction (G/GEJ) cancer is a global health burden with poor prognosis, especially for locally advanced or metastatic cases. While perioperative chemotherapy improves outcomes, survival remains limited. Immunotherapy combined with chemotherapy has shown promise in advanced disease, prompting investigations into neoadjuvant settings. This study evaluates a novel regimen of low-dose interval radiotherapy, tislelizumab (a PD-1 inhibitor), and SOX chemotherapy (oxaliplatin + S-1) for locally advanced G/GEJ adenocarcinoma.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods and analysis：\u003c/strong\u003eThis is a prospective, single-center, single-arm clinical trial enrolling 32 patients with cT4N+M0 G/GEJ adenocarcinoma. The neoadjuvant regimen includes 5×3Gy radiotherapy in cycles 1 and 3, tislelizumab (200 mg IV D6), oxaliplatin (130 mg/m² IV D6), and S-1 (40 mg/m²oral BID D6–19), with 4 cycles of SOX adjuvant chemotherapy post-surgery. Primary endpoints are pathological complete response (pCR), major pathological response (MPR), and objective response rate (ORR). Secondary endpoints include R0 resection rate, safety, complications, event-free survival (EFS), and overall survival (OS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003eThis study explores a novel neoadjuvant regimen combining low-dose interval radiotherapy with immunotherapy and chemotherapy for locally advanced GC/GEJ. The combination is expected to significantly increase the pCR rate and improve other therapeutic outcomes while maintaining safety.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and dissemination: \u003c/strong\u003eThe study was approved by the Ethical Committee of the Shandong Provincial Hospital Affiliated to Shandong First Medical University and registered with ClinicalTrials.gov (NCT06766578).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration：\u003c/strong\u003eClinicalTrials.gov (NCT06766578)\u003c/p\u003e","manuscriptTitle":"Low-dose interval radiotherapy combined with tirelizumab and SOX chemotherapy neoadjuvant therapy for locally advanced gastric/gastroesophageal junction adenocarcinoma: study protocol of a prospective, single-center, single-arm clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-22 10:23:42","doi":"10.21203/rs.3.rs-7310982/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-10T08:44:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-10T07:03:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-23T23:06:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-21T07:14:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"62524041372259336819604972134494585491","date":"2025-08-20T10:50:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"47647620494533877688794203300871192995","date":"2025-08-18T22:38:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"242028617286580341403845528922342439384","date":"2025-08-14T22:44:21+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-14T12:35:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-07T01:53:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-07T01:52:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-08-06T14:41:25+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":"32f0acd9-4584-4cdd-9730-4e67756edb0e","owner":[],"postedDate":"August 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-19T14:08:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-22 10:23:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7310982","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7310982","identity":"rs-7310982","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}