Efficacy and safety of adding PD-1 Inhibitors to standard therapies in advanced and recurrent endometrial cancer: A single-center retrospective case-control study

Efficacy and safety of adding PD-1 Inhibitors to standard therapies in advanced and recurrent endometrial cancer: A single-center retrospective case-control study | 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 Research Article Efficacy and safety of adding PD-1 Inhibitors to standard therapies in advanced and recurrent endometrial cancer: A single-center retrospective case-control study Wala Abduljabbar Mohammed Al-duais, Nafiza Martini, Majd Hanna, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6499385/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Endometrial cancer (EC) is the most prevalent gynecological malignancy in developed nations, with a poor prognosis for advanced or metastatic cases. Immune checkpoint inhibitors targeting PD-1/PD-L1 have emerged as promising therapies, but their efficacy as part of combination regimens remains underexplored. Objective This retrospective cohort study evaluates the clinical outcomes and safety of adding PD-1 inhibitors to standard therapies (chemotherapy, radiotherapy, and targeted therapy) for recurrent and metastatic EC. Methods Ninety-four patients treated for recurrent/metastatic EC between January 2018 and January 2022 were divided into two groups: a treatment group (n = 46) receiving combination therapy with PD-1 inhibitors and a control group (n = 48) receiving standard therapies alone. Clinical tumor markers (CA125, HE4, ROMA scores), disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and adverse events were analyzed. Statistical methods included Kaplan-Meier survival analysis and Cox regression. Results The treatment group demonstrated significantly improved outcomes compared to the control group. Median PFS was 39 months versus 16 months (p < 0.001), DCR was 89.13% versus 72.92% (p = 0.046), and ORR showed a trend toward significance at 65.22% versus 45.83% (p = 0.059). Tumor markers such as CA125 and HE4 were significantly reduced in the treatment group post-therapy (p < 0.05). Adverse events were comparable between groups, with most reactions being mild to moderate and manageable. Conclusion PD-1 inhibitor-based combination therapy significantly improves survival outcomes and disease control in recurrent/metastatic EC without increasing severe adverse events. These findings suggest that this approach is both effective and safe, warranting further investigation in larger clinical trials to refine treatment strategies and expand personalized care options for EC patients. Oncology Women's studies Obstetrics & Gynecology Immunology Endometrial cancer PD-1 Inhibitors Combination therapy Immune Checkpoint Blockade Figures Figure 1 Figure 2 Introduction Endometrial cancer (EC) is considered the most predominant gynecological cancer in developed nations, carrying a lifetime risk of 2.8 ( 1 ). The majority of EC cases, approximately 80%, are diagnosed at an early stage within the uterus, resulting in a five-year survival rate exceeding 95% ( 2 ). However, the prognosis significantly worsens when the cancer spreads regionally or to distant sites, with corresponding survival rates of 68% and 17% ( 3 ). Despite advances in medical and surgical treatments, survival rates for advanced or metastatic endometrial cancer have not significantly improved in recent years, highlighting the urgent need for more effective therapeutic strategies. Immune checkpoint blockade (ICI) has emerged as a promising approach for treating various cancers ( 4 ). In the era of targeted therapy, significant progress has been made in understanding the upregulation of programmed death-ligand 1 (PD-L1) in cancer cells, which contributes to immune evasion by tumors ( 2 ). This has sparked growing interest in immune checkpoint inhibitors as a promising strategy for managing challenging solid malignancies, including endometrial cancer. Numerous clinical trials have investigated the efficacy and safety of ICI in EC, leading to the approval of Pembrolizumab, an anti-programmed cell death protein 1 (anti-PD-1) antibody, as a viable alternative for selected patients with unresectable or metastatic disease ( 2 ). However, due to the limitations of checkpoint inhibitor monotherapy, identifying additional targets has become an urgent need ( 5 ). Research studies have shown that combining chemotherapy, radiation therapy, and immunotherapy leads to improved outcomes compared to using any of these treatments alone. The rationale behind this combined approach is that chemotherapy and radiation help expose more tumor antigens, which can then be targeted by the activated immune system in the presence of immunotherapy checkpoint inhibitors. This strategy is believed to generate long-lasting antitumor immune responses with reduced toxicity compared to chemotherapy or radiation alone, applicable to various cancer types ( 5 , 6 ). Consequently, Current clinical trials are assessing combination approaches using immunotherapy with chemotherapy, radiation, or other targeted treatments ( 7 – 9 ). Thus, our study aims to evaluate the efficacy of this combination therapy compared to standard treatment. Methods and Materials Participants and Study Design: This retrospective cohort study was conducted at Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China. The study population included patients who received treatment for Recurrent and metastatic Endometrial Cancer between January 1st 2018 and January 1st 2022. This study was done to evaluate whether adding immunotherapy to other standard therapies would improve the outcomes. Thus, Cases were divided into a treatment group of 46 cases and a control group of 48 cases based on whether PD-1 inhibitors were used during treatment. The treatment and control groups were respectively treated with or without PD-1 inhibitors in addition to chemotherapy, targeted therapy, or radiotherapy. Inclusion & exclusion criteria: Only those meeting the inclusion criteria were enrolled: age 18–70 years, Eastern Cooperative Oncology Group (ECOG) score of 2 points or better at first treatment, and pathologically or cytologically confirmed diagnosis of recurrent or metastatic endometrial cancer. The patients in the treatment group included who received PD-1 inhibitors. The control group included cases who did not receive PD-1 inhibitors. Both groups received various combinations of chemotherapy, targeted therapy, and radiation therapy as part of their treatment regimens. Exclusion criteria involved concurrent malignant tumors, history of autoimmune disease, prior anti-PD-1/PD-L1 or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody therapy, or any other antibody or drug with T-cell co-stimulation or checkpoint pathway as a specific target. Data collection and Follow-up: Relevant demographic and clinical information were retrospectively collected for each patient from electronic medical records, including age in years, weight, histological type of cancer, FIGO staging, the Eastern Cooperative Oncology Group (ECOG) Performance Status, tumor diagnosis date, recurrence time, site of recurrence and metastasis before treatment, PD-1 inhibitor use type, radiotherapy and chemotherapy and targeted treatment. In addition, Data of the following serum tumor markers that were recorded before and after treatment application were also collected: CA125, HE4, CA-724, and CA19-19. Besides, the Risk of Ovarian Malignancy Algorithm (ROMA) scores were collected before and after treatment in both groups. Furthermore, adverse reactions that occurred as a result of the treatment were also documented in both groups. Finally, we collected patients’ overall health status, progress of the combination therapy, date of the most recent follow-up examination; recurrence details (if applicable) including the time of recurrence, the location and the treatment approaches implemented, and mortality information (if applicable) including the cause and time of death. Based on the collected data, we measured disease control rate (DCR) and Overall response rate (ORR) as well as progression-free survival (PFS) for both groups. All follow-up data was collected up to and including January 1, 2023. Treatment Methods - Immunotherapy Patients in the treatment group received combination therapy that included immunotherapy along with chemotherapy, radiotherapy, or targeted therapy. The immunotherapy regimen consisted of one of the following PD-1 inhibitors, administered every 3 weeks at a dose of 200 mg: Sintilimab, Tislelizumab, or Camrelizumab. The immunotherapy treatment was continued until one of the following occurred: Disease progression, Unacceptable toxicity, or Patient's decision to discontinue treatment (Tables 1 & 2). - Combination Therapy Chemotherapy : Chemotherapy regimens primarily included the administration of the following drugs, every 3 weeks: Paclitaxel at a dose of 135 ~ 175mg/m2, Abraxane at a dose of 260mg/m2, carboplatin (AUC 4-5mg⋅m − 2⋅min − 1), Nedaplatin at a dose of 80 ~ 100 mg/m2, docetaxel at a dose of 75 mg/m2, Oxaliplatin at a dose of 100mg/m2, Doxorubicin Hydrochloride Liposome at a dose of 20 mg/m2 (Table 1). Targeted therapy : Targeted therapy options included: Bevacizumab at a dose of 7.5mg/kg every 3 weeks. Apatinib at a dose of 125 or 250mg orally on a daily basis. Anlotinib at a dose of 12mg orally daily for 2 weeks followed by a 1-week break (Table 1). Radiation therapy Patients were evaluated for localized radiation therapy to sites of recurrence/metastases. Eligible patients received external beam pelvic radiation ± intravaginal radiation, or intravaginal radiation alone, five days a week with a two-day interval between treatments. Strict limitations were imposed to minimize exposure to normal tissues (Table 1). Statistical Methods: The data analysis was conducted using IBM SPSS Statistics version 26.0. For normally distributed measurement data, results were presented as mean ± standard deviation (x̄ ± s) and analyzed using the chi-square (χ2) test. Counting data were expressed as frequencies and percentages (n, %) and evaluated using the t-test. Survival analysis was performed using the Kaplan-Meier method to generate survival curves. The log-rank test was employed to compare survival curves between groups. To identify factors influencing disease progression in patients with recurrent endometrial cancer treated with PD-1 inhibitors, Cox regression analysis was utilized. Statistical significance was set at p < 0.05 for all analyses. Ethics: The study protocol underwent a thorough review and received approval from the Shengjing Hospital of China Medical University, Shenyang, Liaoning, China ethics committee. Results Patients' baseline characteristics in both groups (Case and Control): A total of 94 patients were enrolled in this study. The treatment group (combined therapy) (n = 46) had a median age of 52.01 ± 6.9 years. In terms of FIGO staging, 22 participants were classified as stages I-II, and 24 participants were classified as stages III-IV. Regarding ECOC grading, thirty-three participants had a grade of 0, ten participants had a grade of 1, and three participants had a grade of 2. For histological types, 23 participants had Endometrioid Adenocarcinoma, 17 participants had Endometrial Clear Cell Carcinoma (ECCC), and 6 participants had Uterine Serous Carcinoma (USC) (Table 3). The non-immunotherapy group (control group) (n = 48) had a median age of 54.21 ± 7.3 years. In terms of FIGO staging, 25 participants were classified as stages I-II, and 23 participants were classified as stages III-IV. Regarding ECOC grading, 34 participants had a grade of 0, 8 participant had a grade of 1, and 6 participant had a grade of 2. For histological types, 28 participants had Endometrioid Adenocarcinoma, 12 participants had Endometrial Clear Cell Carcinoma (ECCC), 8 participants had Uterine Serous Carcinoma (USC) (Table 3) . Clinical tumor markers (HE4, CA125, CA724, and CA19-9) & ROMA Score before and after treatment in both groups (Table 4) : Before treatment, there were no significant differences in tumor marker levels between the treatment group and the control group. However, after treatment, the levels of CA125, HE4, ROMA scores in the case group (combined therapy) were significantly lower compared to the control group (non-immunotherapy), with statistical significance (P < 0.05). For example, the investigation observed a marked reduction in CA125 levels among participants who underwent combined therapy. Specifically, CA125 concentrations decreased from an initial measurement of 80.34 to a final value of 22.47 in the treatment group. In contrast, the control group exhibited a less pronounced decline, with CA125 levels lowering from 97.64 at baseline to 43.70 upon completion of the treatment regimen. The between-group difference in CA125 outcome was found to be statistically significant with a p-value of 0.034. However, there were no significant differences in CA19-9 and CA-724 levels between both groups after treatment. Treatment response and comparison between treatment and control groups (Table 5): In treatment group (treated with added immunotherapy), results showed that out of 46 patients, eleven patients (23.91%) achieved complete response, 19 (41.30%) patients achieved partial response, and 11 patients (23.91%) had stable disease while only 5 patients (10.87%%) experienced disease progression. While in the control group treated with standard chemotherapy, out of 48 patients, 7 patients (14.58%) achieved complete response, 15 (31.25%) achieved partial response, 13 (27.08%) had stable disease, and 13 (27.08%) experienced disease progression. In treatment group, ORR reached 65.22% compared to 45.83% in control group with a p value of 0.059 suggesting a trend toward significance but does not reach the conventional threshold of P < 0.05. DCR in treatment group was 89.13% vs 72.92% in control group with a p value of 0.046 indicating a statistically significant difference between the treatment and control groups. The Progress Free Survival of patients in the treatment group and the control group after treatment (Table 6, Fig. 1) : The time of progression-free survival refers to the period between the beginning of treatment for patients with tumor diseases and the observation of disease progress or death for any reason. Our results found that the median progression-free survival (PFS) in the treatment group was 39 months (23–54 months), while in the control group it was 16 months (14–17 months). The difference in PFS between the two groups was statistically significant (P < 0.001). Analysis of the influencing factors of combined PD-1 inhibitor treatment on the progress of the patient's disease (Table 7, Fig. 2) : Cox regression analysis did not reveal any independent risk factors (age over 60 years, ECOG score of 1, or an interval of more than 6 months between recurrence and the last treatment)) affecting disease progression after combined immunotherapy for recurrent and metastatic endometrial cancer(P greater than 0.05). Besides, Treatment factors (chemotherapy, radiotherapy, and targeted therapy) appeared to reduce risk (HR 0.05). Treatment-related adverse reactions in both groups (Table 8): The incidence of adverse reactions was generally similar between the case and control groups. Among the 94 patients included in the study, a total of 91 individuals (96.8%) experienced adverse events during treatment. There were no statistically significant differences in the incidence of adverse reactions between the groups (P > 0.05), and there was also no statistically significant difference in the incidence of grade 3 or above adverse reactions leading to treatment discontinuation between the groups (P = 0.642). Discussion Our case-control study confirms that adding immunotherapy to first-line treatment in advanced and recurrent endometrial cancer significantly improves outcomes. This aligns with major phase III trials (RUBY, NRG-GY018, AtTEnd, DUO-E), where pooled data from 2,320 patients showed a substantial progression-free survival (PFS) benefit (HR: 0.70 [95% CI: 0.62–0.79]) ( 10 ). Our study found a median PFS of 39 months in patients treated with combined immunotherapy versus 16 months in controls who were treated with other standard therapies. Compared to patients who did not receive PD-1 inhibitors, the method of PD-1 inhibitor combined adjuvant therapy significantly reduced the levels of clinical tumor markers, particularly HE4, which decreased from 168 to 77 in the immunotherapy group while increasing in other standard therapies group. HE4 and CA125 have been shown to be valuable predictors of recurrence risk and overall survival in EC patients ( 11 – 13 ). Besides, the addition of PD-1 inhibitors to other treatment resulted in a notable increase in disease control rate (DCR) to 89.13% and objective response rate (ORR) to 65.22% in patients with recurrent and metastatic EC. The significant reduction in tumor markers and improved DCR suggest that PD-1 inhibitor combination therapy could be a promising approach for managing recurrent and metastatic EC. Our study found no significant difference in treatment-related side effects between groups. The PD-1 inhibitor combination therapy group experienced a 76% incidence of adverse reactions, mostly grade 1–2 and manageable. Common side effects included myelosuppression, liver and kidney function abnormalities. Grade ≥ 3 reactions were less frequent but required treatment suspension and symptomatic management. While generally safe, PD-1 inhibitor combination therapy necessitates close monitoring and timely adjustments to minimize side effects. Moreover, Cox regression analysis revealed no single factor independently influenced disease progression in relapsed endometrial cancer patients receiving PD-1 inhibitor combination therapy. This suggests balanced baseline data and consistent clinical parameters across the study population. The observed improvements in progression-free survival (PFS) can thus be attributed to the combination therapy's efficacy. This finding indicates that PD-1 inhibitor combination treatment may be effective across diverse patient groups, regardless of traditional prognostic factors, potentially expanding personalized treatment options for a broader range of patients. Several studies have indeed shown that combining radiation therapy and immunotherapy can produce synergistic effects in cancer treatment. Immunotherapy enhances the visibility of tumors to the immune system; this synergy occurs through several mechanisms: Radiation promotes the translocation of calreticulin to the cell surface, enhancing phagocytosis of tumor cells by antigen-presenting cells. It also downregulates CD47, an anti-phagocytosis signal ( 14 ). In addition, Radiation increases the expression of MHC-I on tumor surfaces, improving tumor recognition by cytotoxic T cells ( 15 ). Furthermore, Radiation-induced DNA damage may create neoantigens, triggering immune surveillance ( 14 ). Moreover, Radiation can induce systemic antitumor immunity, potentially affecting untreated distant tumors through the Abscopal effect ( 14 , 16 ). Also, Radiation activates the cGAS-STING pathway, boosting anti-tumor immunity, but it can also sometimes cause immunosuppression ( 14 ). In short, the combination of radiation therapy and immunotherapy not only improves the control of local tumors, but also strengthens the systemic immune response, provides a counter strategy for distant metastasis, shows the mutual promotion effect of the two treatments, and provides patients with a more comprehensive and effective treatment plan. The combination of chemotherapy and immunotherapy exhibits synergistic mechanisms through multiple pathways. Chemotherapy enhances immunotherapy by increasing tumor antigen presentation and immunogenicity through stress responses and apoptosis, which exposes new tumor antigens and stimulates dendritic cell activation ( 17 ). Additionally, chemotherapeutic agents upregulate PD-L1 expression in tumor tissues, creating a more favorable environment for PD-1/L1 inhibitors to function effectively ( 17 – 19 ). Furthermore, Effector T cells play a critical role in overcoming stromal-mediated chemoresistance. CD8 + T cells abrogate fibroblast-induced resistance to platinum-based chemotherapy by altering glutathione and cysteine metabolism in stromal cells through interferon gamma (IFNγ) signaling ( 20 ). This mechanism reduces chemoresistance while enhancing cytotoxic T lymphocyte activity in the tumor microenvironment. Targeted therapies can significantly enhance the effects of immunotherapy by reshaping the tumor microenvironment and boosting the immune system's ability to attack cancer. These drugs work in several key ways: First, they disrupt immunosuppressive networks by reducing regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which normally block immune responses ( 21 – 23 ). Second, they make tumors more recognizable to the immune system by increasing the expression of tumor antigens and decreasing immunosuppressive signals ( 23 , 24 ). Third, they help reprogram the tumor microenvironment—for example, VEGF inhibitors normalize blood vessels to improve immune cell infiltration, while CSF1R inhibitors shift macrophages from a pro-tumor to an anti-tumor state ( 23 , 25 ). Additionally, targeted therapies like BRAF or MEK inhibitors can directly enhance T-cell function when combined with immune checkpoint inhibitors. This synergy explains why combinations of targeted therapy and immunotherapy—such as BRAF/MEK inhibitors with PD-1 blockers in melanoma or trastuzumab with immune therapies in HER2 + breast cancer—often produce stronger and more durable responses than either treatment alone ( 23 , 24 ). By breaking down the tumor's defenses and boosting immune recognition, targeted therapies effectively "prime" tumors for immunotherapy, leading to more effective cancer control. In summary, this study demonstrates the effectiveness of combined PD-1 inhibitors in the treatment of recurrent and metastatic endometrial cancer, which is of great clinical significance. First of all, the research results support the addition of PD-1 inhibitors as an effective treatment method in the treatment strategy of recurrent or metastatic endometrial cancer. Compared with traditional chemotherapy, radiotherapy or targeted therapy, combined PD-1 inhibitor therapy can significantly improve total efficiency (ORR) and disease control rate (DCR), as well as extend the survival period without progress (PFS).This means that patients can expect a better treatment response and a longer disease-free survival time, thereby improving their quality of life. Conclusion In conclusion, this study demonstrates that the addition of PD-1 inhibitors to standard therapies, including chemotherapy, radiotherapy, and targeted therapy, significantly improves clinical outcomes in patients with recurrent and metastatic endometrial cancer. The combination therapy group exhibited superior progression-free survival (PFS), disease control rate (DCR), and reductions in tumor markers such as CA125 and HE4 compared to the control group receiving standard treatments alone. Furthermore, the incidence of adverse events was comparable between the two groups, with most side effects being mild to moderate and manageable. This underscores the safety profile of PD-1 inhibitor combination therapy. Future studies should focus on optimizing treatment regimens and identifying predictive biomarkers to further personalize therapy and maximize patient outcomes. Abbreviations ECOG Eastern Cooperative Oncology Group CA125 Cancer Antigen 125 HE4 Human Epididymis Protein 4 CA-724 Cancer Antigen 724 CA19-9 Cancer Antigen 19 − 9 ROMA Risk of Ovarian Malignancy Algorithm FIGO International Federation of Gynecology and Obstetrics DCR Disease Control Rate ORR Objective/overall response rate CR Complete response PR Partial Response SD Stable Disease EC Endometrial Cancer Declarations Ethics: The study protocol underwent a thorough review and received approval from the Shen gjing Hospital of China Medical University, Shenyang, Liaoning, China ethics committee. Availability of data and materials: The datasets collected and analyzed during the current study are not publicly available. Some restrictions apply to the availability of these data but are available from the corresponding author on reasonable request. Competing interests: The authors declare no financial or non-financial conflicts of interest. Funding: The project was supported by Department of Obstetrics and Gynecology, China Medical University, Shenyang, Liaoning, China. The funding bodies had no rule in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. References Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424 Musacchio L, Boccia SM, Caruso G, Santangelo G, Fischetti M, Tomao F et al (2020) Immune Checkpoint Inhibitors: A Promising Choice for Endometrial Cancer Patients? J Clin Med. ;9(6) Colombo N, Creutzberg C, Amant F, Bosse T, González-Martín A, Ledermann J et al (2016) ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment and follow-up. Ann Oncol. ;27(1):16–41 Gómez-Raposo C, Merino Salvador M, Aguayo Zamora C, García de Santiago B (2021) Casado Sáenz E. 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Front Immunol 10:990 Wen Y, Zhu Y, Zhang C, Yang X, Gao Y, Li M et al (2022) Chronic inflammation, cancer development and immunotherapy. Front Pharmacol 13:1040163 Tables Table 1 to 8 are available in the Supplementary Files section. Additional Declarations The authors declare no competing interests. Supplementary Files Tables.docx Cite Share Download PDF Status: Posted 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. 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Martini","email":"","orcid":"https://orcid.org/0000-0002-9289-0674","institution":"Faculty of Medicine, Damascus University, Damascus, Syrian Arab Republic.","correspondingAuthor":false,"prefix":"","firstName":"Nafiza","middleName":"","lastName":"Martini","suffix":""},{"id":446006432,"identity":"de1a7916-3f91-4d8c-b557-8d0af5d559d8","order_by":2,"name":"Majd Hanna","email":"","orcid":"https://orcid.org/0000-0003-3173-5256","institution":"Faculty of Medicine, Damascus University, Damascus, Syrian Arab Republic.","correspondingAuthor":false,"prefix":"","firstName":"Majd","middleName":"","lastName":"Hanna","suffix":""},{"id":446006433,"identity":"44e18d06-f0ad-4f6c-a459-9ccce853d25d","order_by":3,"name":"Imad-Addin Almasri","email":"","orcid":"https://orcid.org/0000-0002-4741-3721","institution":"Damascus University, Faculty of Economics, Statistics Department, Damascus, Syrian Arab Republic.","correspondingAuthor":false,"prefix":"","firstName":"Imad-Addin","middleName":"","lastName":"Almasri","suffix":""},{"id":446006434,"identity":"6d3de6ae-b876-41db-b456-5495fc807ee5","order_by":4,"name":"Zhenhua Dua","email":"","orcid":"","institution":"Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.","correspondingAuthor":false,"prefix":"","firstName":"Zhenhua","middleName":"","lastName":"Dua","suffix":""}],"badges":[],"createdAt":"2025-04-22 02:04:19","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6499385/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6499385/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":81199226,"identity":"7b296a21-04bf-4aa8-88eb-61afc2ed49bd","added_by":"auto","created_at":"2025-04-23 10:54:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":28572,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison between the combined PD-1 inhibitor group and the unapplied PD-1 inhibitor group (log-rank P=0.001).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6499385/v1/a9775948f9fcc0c8ffd53207.png"},{"id":81198348,"identity":"2b211d83-f832-4f8b-a7b3-e0ea2667a5bc","added_by":"auto","created_at":"2025-04-23 10:46:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":165310,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLegend not included with this version\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6499385/v1/4f548a9219914f87ac1a9396.png"},{"id":81199559,"identity":"1766c59b-9dd9-4c41-b04f-f5b6238cbc3a","added_by":"auto","created_at":"2025-04-23 11:02:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1052831,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6499385/v1/b540e054-493a-481b-9c77-279e2f8dde4f.pdf"},{"id":81198347,"identity":"19cebc78-e6b8-4a63-855b-0e33b4e71223","added_by":"auto","created_at":"2025-04-23 10:46:44","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":36672,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6499385/v1/6cfef8695eca1b3fe54ad5e0.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEfficacy and safety of adding PD-1 Inhibitors to standard therapies in advanced and recurrent endometrial cancer: A single-center retrospective case-control study\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndometrial cancer (EC) is considered the most predominant gynecological cancer in developed nations, carrying a lifetime risk of 2.8 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The majority of EC cases, approximately 80%, are diagnosed at an early stage within the uterus, resulting in a five-year survival rate exceeding 95% (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). However, the prognosis significantly worsens when the cancer spreads regionally or to distant sites, with corresponding survival rates of 68% and 17% (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Despite advances in medical and surgical treatments, survival rates for advanced or metastatic endometrial cancer have not significantly improved in recent years, highlighting the urgent need for more effective therapeutic strategies.\u003c/p\u003e \u003cp\u003eImmune checkpoint blockade (ICI) has emerged as a promising approach for treating various cancers (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In the era of targeted therapy, significant progress has been made in understanding the upregulation of programmed death-ligand 1 (PD-L1) in cancer cells, which contributes to immune evasion by tumors (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). This has sparked growing interest in immune checkpoint inhibitors as a promising strategy for managing challenging solid malignancies, including endometrial cancer. Numerous clinical trials have investigated the efficacy and safety of ICI in EC, leading to the approval of Pembrolizumab, an anti-programmed cell death protein 1 (anti-PD-1) antibody, as a viable alternative for selected patients with unresectable or metastatic disease (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, due to the limitations of checkpoint inhibitor monotherapy, identifying additional targets has become an urgent need (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Research studies have shown that combining chemotherapy, radiation therapy, and immunotherapy leads to improved outcomes compared to using any of these treatments alone. The rationale behind this combined approach is that chemotherapy and radiation help expose more tumor antigens, which can then be targeted by the activated immune system in the presence of immunotherapy checkpoint inhibitors. This strategy is believed to generate long-lasting antitumor immune responses with reduced toxicity compared to chemotherapy or radiation alone, applicable to various cancer types (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Consequently, Current clinical trials are assessing combination approaches using immunotherapy with chemotherapy, radiation, or other targeted treatments (\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Thus, our study aims to evaluate the efficacy of this combination therapy compared to standard treatment.\u003c/p\u003e"},{"header":"Methods and Materials","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants and Study Design:\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study was conducted at Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China. The study population included patients who received treatment for Recurrent and metastatic Endometrial Cancer between January 1st 2018 and January 1st 2022. This study was done to evaluate whether adding immunotherapy to other standard therapies would improve the outcomes. Thus, Cases were divided into a treatment group of 46 cases and a control group of 48 cases based on whether PD-1 inhibitors were used during treatment. The treatment and control groups were respectively treated with or without PD-1 inhibitors in addition to chemotherapy, targeted therapy, or radiotherapy.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInclusion \u0026 exclusion criteria:\u003c/h3\u003e\n\u003cp\u003eOnly those meeting the inclusion criteria were enrolled: age 18\u0026ndash;70 years, Eastern Cooperative Oncology Group (ECOG) score of 2 points or better at first treatment, and pathologically or cytologically confirmed diagnosis of recurrent or metastatic endometrial cancer. The patients in the treatment group included who received PD-1 inhibitors. The control group included cases who did not receive PD-1 inhibitors. Both groups received various combinations of chemotherapy, targeted therapy, and radiation therapy as part of their treatment regimens.\u003c/p\u003e \u003cp\u003eExclusion criteria involved concurrent malignant tumors, history of autoimmune disease, prior anti-PD-1/PD-L1 or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody therapy, or any other antibody or drug with T-cell co-stimulation or checkpoint pathway as a specific target.\u003c/p\u003e\n\u003ch3\u003eData collection and Follow-up:\u003c/h3\u003e\n\u003cp\u003eRelevant demographic and clinical information were retrospectively collected for each patient from electronic medical records, including age in years, weight, histological type of cancer, FIGO staging, the Eastern Cooperative Oncology Group (ECOG) Performance Status, tumor diagnosis date, recurrence time, site of recurrence and metastasis before treatment, PD-1 inhibitor use type, radiotherapy and chemotherapy and targeted treatment. In addition, Data of the following serum tumor markers that were recorded before and after treatment application were also collected: CA125, HE4, CA-724, and CA19-19. Besides, the Risk of Ovarian Malignancy Algorithm (ROMA) scores were collected before and after treatment in both groups. Furthermore, adverse reactions that occurred as a result of the treatment were also documented in both groups. Finally, we collected patients\u0026rsquo; overall health status, progress of the combination therapy, date of the most recent follow-up examination; recurrence details (if applicable) including the time of recurrence, the location and the treatment approaches implemented, and mortality information (if applicable) including the cause and time of death. Based on the collected data, we measured disease control rate (DCR) and Overall response rate (ORR) as well as progression-free survival (PFS) for both groups. All follow-up data was collected up to and including January 1, 2023.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTreatment Methods\u003c/b\u003e \u003c/p\u003e\n\u003ch3\u003e- Immunotherapy\u003c/h3\u003e\n\u003cp\u003ePatients in the treatment group received combination therapy that included immunotherapy along with chemotherapy, radiotherapy, or targeted therapy. The immunotherapy regimen consisted of one of the following PD-1 inhibitors, administered every 3 weeks at a dose of 200 mg: Sintilimab, Tislelizumab, or Camrelizumab. The immunotherapy treatment was continued until one of the following occurred: Disease progression, Unacceptable toxicity, or Patient's decision to discontinue treatment \u003cb\u003e(Tables\u0026nbsp;1 \u0026amp; 2).\u003c/b\u003e\u003c/p\u003e\n\u003ch3\u003e- Combination Therapy\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003e \u003cb\u003eChemotherapy\u003c/b\u003e: Chemotherapy regimens primarily included the administration of the following drugs, every 3 weeks: Paclitaxel at a dose of 135\u0026thinsp;~\u0026thinsp;175mg/m2, Abraxane at a dose of 260mg/m2, carboplatin (AUC 4-5mg\u0026sdot;m\u0026thinsp;\u0026minus;\u0026thinsp;2\u0026sdot;min\u0026thinsp;\u0026minus;\u0026thinsp;1), Nedaplatin at a dose of 80\u0026thinsp;~\u0026thinsp;100 mg/m2, docetaxel at a dose of 75 mg/m2, Oxaliplatin at a dose of 100mg/m2, Doxorubicin Hydrochloride Liposome at a dose of 20 mg/m2 \u003cb\u003e(Table\u0026nbsp;1).\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eTargeted therapy\u003c/b\u003e: Targeted therapy options included: Bevacizumab at a dose of 7.5mg/kg every 3 weeks. Apatinib at a dose of 125 or 250mg orally on a daily basis. Anlotinib at a dose of 12mg orally daily for 2 weeks followed by a 1-week break \u003cb\u003e(Table\u0026nbsp;1).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eRadiation therapy\u003c/strong\u003e \u003cp\u003ePatients were evaluated for localized radiation therapy to sites of recurrence/metastases. Eligible patients received external beam pelvic radiation\u0026thinsp;\u0026plusmn;\u0026thinsp;intravaginal radiation, or intravaginal radiation alone, five days a week with a two-day interval between treatments. Strict limitations were imposed to minimize exposure to normal tissues \u003cb\u003e(Table\u0026nbsp;1).\u003c/b\u003e\u003c/p\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Methods:\u003c/h2\u003e \u003cp\u003eThe data analysis was conducted using IBM SPSS Statistics version 26.0. For normally distributed measurement data, results were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (x̄ \u0026plusmn; s) and analyzed using the chi-square (χ2) test. Counting data were expressed as frequencies and percentages (n, %) and evaluated using the t-test. Survival analysis was performed using the Kaplan-Meier method to generate survival curves. The log-rank test was employed to compare survival curves between groups. To identify factors influencing disease progression in patients with recurrent endometrial cancer treated with PD-1 inhibitors, Cox regression analysis was utilized. Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for all analyses.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthics:\u003c/h3\u003e\n\u003cp\u003e The study protocol underwent a thorough review and received approval from the Shengjing Hospital of China Medical University, Shenyang, Liaoning, China ethics committee.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePatients' baseline characteristics in both groups (Case and Control):\u003c/h2\u003e \u003cp\u003eA total of 94 patients were enrolled in this study. The treatment group (combined therapy) (n\u0026thinsp;=\u0026thinsp;46) had a median age of 52.01\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9 years. In terms of FIGO staging, 22 participants were classified as stages I-II, and 24 participants were classified as stages III-IV. Regarding ECOC grading, thirty-three participants had a grade of 0, ten participants had a grade of 1, and three participants had a grade of 2. For histological types, 23 participants had Endometrioid Adenocarcinoma, 17 participants had Endometrial Clear Cell Carcinoma (ECCC), and 6 participants had Uterine Serous Carcinoma (USC) \u003cb\u003e(Table\u0026nbsp;3).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe non-immunotherapy group (control group) (n\u0026thinsp;=\u0026thinsp;48) had a median age of 54.21\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3 years. In terms of FIGO staging, 25 participants were classified as stages I-II, and 23 participants were classified as stages III-IV. Regarding ECOC grading, 34 participants had a grade of 0, 8 participant had a grade of 1, and 6 participant had a grade of 2. For histological types, 28 participants had Endometrioid Adenocarcinoma, 12 participants had Endometrial Clear Cell Carcinoma (ECCC), 8 participants had Uterine Serous Carcinoma (USC) \u003cb\u003e(Table\u0026nbsp;3)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eClinical tumor markers (HE4, CA125, CA724, and CA19-9) \u0026amp; ROMA Score before and after treatment in both groups (Table\u0026nbsp;4)\u003c/b\u003e:\u003c/p\u003e \u003cp\u003eBefore treatment, there were no significant differences in tumor marker levels between the treatment group and the control group. However, after treatment, the levels of CA125, HE4, ROMA scores in the case group (combined therapy) were significantly lower compared to the control group (non-immunotherapy), with statistical significance (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). For example, the investigation observed a marked reduction in CA125 levels among participants who underwent combined therapy. Specifically, CA125 concentrations decreased from an initial measurement of 80.34 to a final value of 22.47 in the treatment group. In contrast, the control group exhibited a less pronounced decline, with CA125 levels lowering from 97.64 at baseline to 43.70 upon completion of the treatment regimen. The between-group difference in CA125 outcome was found to be statistically significant with a p-value of 0.034. However, there were no significant differences in CA19-9 and CA-724 levels between both groups after treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eTreatment response and comparison between treatment and control groups (Table\u0026nbsp;5):\u003c/h2\u003e \u003cp\u003eIn treatment group (treated with added immunotherapy), results showed that out of 46 patients, eleven patients (23.91%) achieved complete response, 19 (41.30%) patients achieved partial response, and 11 patients (23.91%) had stable disease while only 5 patients (10.87%%) experienced disease progression. While in the control group treated with standard chemotherapy, out of 48 patients, 7 patients (14.58%) achieved complete response, 15 (31.25%) achieved partial response, 13 (27.08%) had stable disease, and 13 (27.08%) experienced disease progression.\u003c/p\u003e \u003cp\u003eIn treatment group, ORR reached 65.22% compared to 45.83% in control group with a p value of 0.059 suggesting a trend toward significance but does not reach the conventional threshold of P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. DCR in treatment group was 89.13% vs 72.92% in control group with a p value of 0.046 indicating a statistically significant difference between the treatment and control groups.\u003c/p\u003e \u003cp\u003e \u003cb\u003eThe Progress Free Survival of patients in the treatment group and the control group after treatment (Table\u0026nbsp;6, Fig.\u0026nbsp;1)\u003c/b\u003e:\u003c/p\u003e \u003cp\u003eThe time of progression-free survival refers to the period between the beginning of treatment for patients with tumor diseases and the observation of disease progress or death for any reason. Our results found that the median progression-free survival (PFS) in the treatment group was 39 months (23\u0026ndash;54 months), while in the control group it was 16 months (14\u0026ndash;17 months). The difference in PFS between the two groups was statistically significant (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cb\u003eAnalysis of the influencing factors of combined PD-1 inhibitor treatment on the progress of the patient's disease (Table\u0026nbsp;7, Fig.\u0026nbsp;2)\u003c/b\u003e:\u003c/p\u003e \u003cp\u003eCox regression analysis did not reveal any independent risk factors (age over 60 years, ECOG score of 1, or an interval of more than 6 months between recurrence and the last treatment)) affecting disease progression after combined immunotherapy for recurrent and metastatic endometrial cancer(P greater than 0.05). Besides, Treatment factors (chemotherapy, radiotherapy, and targeted therapy) appeared to reduce risk (HR\u0026thinsp;\u0026lt;\u0026thinsp;1), but none showed statistical significance (all P-values\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eTreatment-related adverse reactions in both groups (Table\u0026nbsp;8):\u003c/h2\u003e \u003cp\u003eThe incidence of adverse reactions was generally similar between the case and control groups. Among the 94 patients included in the study, a total of 91 individuals (96.8%) experienced adverse events during treatment. There were no statistically significant differences in the incidence of adverse reactions between the groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05), and there was also no statistically significant difference in the incidence of grade 3 or above adverse reactions leading to treatment discontinuation between the groups (P\u0026thinsp;=\u0026thinsp;0.642).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur case-control study confirms that adding immunotherapy to first-line treatment in advanced and recurrent endometrial cancer significantly improves outcomes. This aligns with major phase III trials (RUBY, NRG-GY018, AtTEnd, DUO-E), where pooled data from 2,320 patients showed a substantial progression-free survival (PFS) benefit (HR: 0.70 [95% CI: 0.62\u0026ndash;0.79]) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Our study found a median PFS of 39 months in patients treated with combined immunotherapy versus 16 months in controls who were treated with other standard therapies.\u003c/p\u003e \u003cp\u003eCompared to patients who did not receive PD-1 inhibitors, the method of PD-1 inhibitor combined adjuvant therapy significantly reduced the levels of clinical tumor markers, particularly HE4, which decreased from 168 to 77 in the immunotherapy group while increasing in other standard therapies group. HE4 and CA125 have been shown to be valuable predictors of recurrence risk and overall survival in EC patients (\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Besides, the addition of PD-1 inhibitors to other treatment resulted in a notable increase in disease control rate (DCR) to 89.13% and objective response rate (ORR) to 65.22% in patients with recurrent and metastatic EC. The significant reduction in tumor markers and improved DCR suggest that PD-1 inhibitor combination therapy could be a promising approach for managing recurrent and metastatic EC.\u003c/p\u003e \u003cp\u003eOur study found no significant difference in treatment-related side effects between groups. The PD-1 inhibitor combination therapy group experienced a 76% incidence of adverse reactions, mostly grade 1\u0026ndash;2 and manageable. Common side effects included myelosuppression, liver and kidney function abnormalities. Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 reactions were less frequent but required treatment suspension and symptomatic management. While generally safe, PD-1 inhibitor combination therapy necessitates close monitoring and timely adjustments to minimize side effects.\u003c/p\u003e \u003cp\u003eMoreover, Cox regression analysis revealed no single factor independently influenced disease progression in relapsed endometrial cancer patients receiving PD-1 inhibitor combination therapy. This suggests balanced baseline data and consistent clinical parameters across the study population. The observed improvements in progression-free survival (PFS) can thus be attributed to the combination therapy's efficacy. This finding indicates that PD-1 inhibitor combination treatment may be effective across diverse patient groups, regardless of traditional prognostic factors, potentially expanding personalized treatment options for a broader range of patients.\u003c/p\u003e \u003cp\u003eSeveral studies have indeed shown that combining radiation therapy and immunotherapy can produce synergistic effects in cancer treatment. Immunotherapy enhances the visibility of tumors to the immune system; this synergy occurs through several mechanisms: Radiation promotes the translocation of calreticulin to the cell surface, enhancing phagocytosis of tumor cells by antigen-presenting cells. It also downregulates CD47, an anti-phagocytosis signal (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In addition, Radiation increases the expression of MHC-I on tumor surfaces, improving tumor recognition by cytotoxic T cells (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Furthermore, Radiation-induced DNA damage may create neoantigens, triggering immune surveillance (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Moreover, Radiation can induce systemic antitumor immunity, potentially affecting untreated distant tumors through the Abscopal effect (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Also, Radiation activates the cGAS-STING pathway, boosting anti-tumor immunity, but it can also sometimes cause immunosuppression (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In short, the combination of radiation therapy and immunotherapy not only improves the control of local tumors, but also strengthens the systemic immune response, provides a counter strategy for distant metastasis, shows the mutual promotion effect of the two treatments, and provides patients with a more comprehensive and effective treatment plan.\u003c/p\u003e \u003cp\u003eThe combination of chemotherapy and immunotherapy exhibits synergistic mechanisms through multiple pathways. Chemotherapy enhances immunotherapy by increasing tumor antigen presentation and immunogenicity through stress responses and apoptosis, which exposes new tumor antigens and stimulates dendritic cell activation (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Additionally, chemotherapeutic agents upregulate PD-L1 expression in tumor tissues, creating a more favorable environment for PD-1/L1 inhibitors to function effectively (\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Furthermore, Effector T cells play a critical role in overcoming stromal-mediated chemoresistance. CD8\u0026thinsp;+\u0026thinsp;T cells abrogate fibroblast-induced resistance to platinum-based chemotherapy by altering glutathione and cysteine metabolism in stromal cells through interferon gamma (IFNγ) signaling (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). This mechanism reduces chemoresistance while enhancing cytotoxic T lymphocyte activity in the tumor microenvironment.\u003c/p\u003e \u003cp\u003eTargeted therapies can significantly enhance the effects of immunotherapy by reshaping the tumor microenvironment and boosting the immune system's ability to attack cancer. These drugs work in several key ways: First, they disrupt immunosuppressive networks by reducing regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which normally block immune responses (\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Second, they make tumors more recognizable to the immune system by increasing the expression of tumor antigens and decreasing immunosuppressive signals (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Third, they help reprogram the tumor microenvironment\u0026mdash;for example, VEGF inhibitors normalize blood vessels to improve immune cell infiltration, while CSF1R inhibitors shift macrophages from a pro-tumor to an anti-tumor state (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Additionally, targeted therapies like BRAF or MEK inhibitors can directly enhance T-cell function when combined with immune checkpoint inhibitors. This synergy explains why combinations of targeted therapy and immunotherapy\u0026mdash;such as BRAF/MEK inhibitors with PD-1 blockers in melanoma or trastuzumab with immune therapies in HER2\u0026thinsp;+\u0026thinsp;breast cancer\u0026mdash;often produce stronger and more durable responses than either treatment alone (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). By breaking down the tumor's defenses and boosting immune recognition, targeted therapies effectively \"prime\" tumors for immunotherapy, leading to more effective cancer control.\u003c/p\u003e \u003cp\u003eIn summary, this study demonstrates the effectiveness of combined PD-1 inhibitors in the treatment of recurrent and metastatic endometrial cancer, which is of great clinical significance. First of all, the research results support the addition of PD-1 inhibitors as an effective treatment method in the treatment strategy of recurrent or metastatic endometrial cancer. Compared with traditional chemotherapy, radiotherapy or targeted therapy, combined PD-1 inhibitor therapy can significantly improve total efficiency (ORR) and disease control rate (DCR), as well as extend the survival period without progress (PFS).This means that patients can expect a better treatment response and a longer disease-free survival time, thereby improving their quality of life.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, this study demonstrates that the addition of PD-1 inhibitors to standard therapies, including chemotherapy, radiotherapy, and targeted therapy, significantly improves clinical outcomes in patients with recurrent and metastatic endometrial cancer. The combination therapy group exhibited superior progression-free survival (PFS), disease control rate (DCR), and reductions in tumor markers such as CA125 and HE4 compared to the control group receiving standard treatments alone. Furthermore, the incidence of adverse events was comparable between the two groups, with most side effects being mild to moderate and manageable. This underscores the safety profile of PD-1 inhibitor combination therapy. Future studies should focus on optimizing treatment regimens and identifying predictive biomarkers to further personalize therapy and maximize patient outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eECOG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEastern Cooperative Oncology Group\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCA125\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCancer Antigen 125\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHE4\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHuman Epididymis Protein 4\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCA-724\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCancer Antigen 724\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCA19-9\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCancer Antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROMA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRisk of Ovarian Malignancy Algorithm\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFIGO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Federation of Gynecology and Obstetrics\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDisease Control Rate\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/overall 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\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStable Disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEndometrial Cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics:\u0026nbsp;\u003cbr\u003e\u003c/strong\u003eThe study protocol underwent a thorough review and received approval from the \u003cspan dir=\"RTL\"\u003eShen\u003c/span\u003egjing Hospital of China Medical University, Shenyang, Liaoning, China ethics committee.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets collected and analyzed during the current study are not publicly available. Some restrictions apply to the availability of these data but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no financial or non-financial conflicts of interest. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003eThe project was supported by Department of Obstetrics and Gynecology, China Medical University, Shenyang, Liaoning, China. The funding bodies had no rule in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394\u0026ndash;424\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMusacchio L, Boccia SM, Caruso G, Santangelo G, Fischetti M, Tomao F et al (2020) Immune Checkpoint Inhibitors: A Promising Choice for Endometrial Cancer Patients? J Clin Med. ;9(6)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColombo N, Creutzberg C, Amant F, Bosse T, Gonz\u0026aacute;lez-Mart\u0026iacute;n A, Ledermann J et al (2016) ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment and follow-up. Ann Oncol. ;27(1):16\u0026ndash;41\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eG\u0026oacute;mez-Raposo C, Merino Salvador M, Aguayo Zamora C, Garc\u0026iacute;a de Santiago B (2021) Casado S\u0026aacute;enz E. Immune checkpoint inhibitors in endometrial cancer. Crit Rev Oncol Hematol 161:103306\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarrueto L, Caminero F, Cash L, Makris C, Lamichhane P, Deshmukh RR (2020) Resistance to Checkpoint Inhibition in Cancer Immunotherapy. Transl Oncol 13(3):100738\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang Y, Chen M, Nie H, Yuan Y (2019) PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum Vaccin Immunother 15(5):1111\u0026ndash;1122\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCetin B, Gumusay O (2023) PD-1 and PD-L1 Blockade plus Chemotherapy in Endometrial Cancer. N Engl J Med 389(9):866\u0026ndash;867\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePolak P, Fu L, Foulkes WD (2023) PD-1 and PD-L1 Blockade plus Chemotherapy in Endometrial Cancer. N Engl J Med 389(9):866\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonk BJ, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R et al (2023) Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 24(4):392\u0026ndash;402\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBogani G, Monk BJ, Powell MA, Westin SN, Slomovitz B, Moore KN et al (2024) Adding immunotherapy to first-line treatment of advanced and metastatic endometrial cancer. Ann Oncol 35(5):414\u0026ndash;428\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQuan Q, Liao Q, Yin W, Zhou S, Gong S, Mu X (2021) Serum HE4 and CA125 combined to predict and monitor recurrence of type II endometrial carcinoma. Sci Rep 11(1):21694\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbbink K, Zusterzeel PL, Geurts-Moespot AJ, Herwaarden AEV, Pijnenborg JM, Sweep FC et al (2018) HE4 is superior to CA125 in the detection of recurrent disease in high-risk endometrial cancer patients. Tumour Biol 40(2):1010428318757103\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCymbaluk-Płoska A, Gargulińska P, Bulsa M, Kwiatkowski S, Chudecka-Głaz A, Michalczyk K (2021) Can the Determination of HE4 and CA125 Markers Affect the Treatment of Patients with Endometrial Cancer? Diagnostics (Basel). ;11(4)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Y, Deng W, Li N, Neri S, Sharma A, Jiang W et al (2018) Combining Immunotherapy and Radiotherapy for Cancer Treatment: Current Challenges and Future Directions. Front Pharmacol 9:185\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSharma A, Bode B, Wenger RH, Lehmann K, Sartori AA, Moch H et al (2011) γ-Radiation promotes immunological recognition of cancer cells through increased expression of cancer-testis antigens in vitro and in vivo. PLoS ONE 6(11):e28217\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCushman TR, Gomez D, Kumar R, Likacheva A, Chang JY, Cadena AP et al (2018) Combining radiation plus immunotherapy to improve systemic immune response. J Thorac disease 10(Suppl 3):S468\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTian Z, Yao W (2022) PD-1/L1 inhibitor plus chemotherapy in the treatment of sarcomas. Front Immunol 13:898255\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Y, Pattarayan D, Huang H, Zhao Y, Li S, Wang Y et al (2024) Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer. Nat Commun 15(1):3178\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCubas R, Moskalenko M, Cheung J, Yang M, McNamara E, Xiong H et al (2018) Chemotherapy combines effectively with anti\u0026ndash;PD-L1 treatment and can augment antitumor responses. J Immunol 201(8):2273\u0026ndash;2286\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang W, Kryczek I, Dost\u0026aacute;l L, Lin H, Tan L, Zhao L et al (2016) Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell 165(5):1092\u0026ndash;1105\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlizadeh D, Larmonier N (2014) Chemotherapeutic targeting of cancer-induced immunosuppressive cells. Cancer Res 74(10):2663\u0026ndash;2668\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKersh AE, Ng S, Chang YM, Sasaki M, Thomas SN, Kissick HT et al (2018) Targeted therapies: immunologic effects and potential applications outside of cancer. J Clin Pharmacol 58(1):7\u0026ndash;24\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVanneman M, Dranoff G (2012) Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer 12(4):237\u0026ndash;251\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu C, Liu X, Yang J, Zhang M, Jin H, Ma X et al (2019) Combination of immunotherapy with targeted therapy: theory and practice in metastatic melanoma. Front Immunol 10:990\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWen Y, Zhu Y, Zhang C, Yang X, Gao Y, Li M et al (2022) Chronic inflammation, cancer development and immunotherapy. Front Pharmacol 13:1040163\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 8 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"China Medical University, Shenyang, Liaoning, China","isAcceptedByJournal":false,"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":"Endometrial cancer, PD-1 Inhibitors, Combination therapy, Immune Checkpoint Blockade","lastPublishedDoi":"10.21203/rs.3.rs-6499385/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6499385/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEndometrial cancer (EC) is the most prevalent gynecological malignancy in developed nations, with a poor prognosis for advanced or metastatic cases. Immune checkpoint inhibitors targeting PD-1/PD-L1 have emerged as promising therapies, but their efficacy as part of combination regimens remains underexplored.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study evaluates the clinical outcomes and safety of adding PD-1 inhibitors to standard therapies (chemotherapy, radiotherapy, and targeted therapy) for recurrent and metastatic EC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eNinety-four patients treated for recurrent/metastatic EC between January 2018 and January 2022 were divided into two groups: a treatment group (n\u0026thinsp;=\u0026thinsp;46) receiving combination therapy with PD-1 inhibitors and a control group (n\u0026thinsp;=\u0026thinsp;48) receiving standard therapies alone. Clinical tumor markers (CA125, HE4, ROMA scores), disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and adverse events were analyzed. Statistical methods included Kaplan-Meier survival analysis and Cox regression.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe treatment group demonstrated significantly improved outcomes compared to the control group. Median PFS was 39 months versus 16 months (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), DCR was 89.13% versus 72.92% (p\u0026thinsp;=\u0026thinsp;0.046), and ORR showed a trend toward significance at 65.22% versus 45.83% (p\u0026thinsp;=\u0026thinsp;0.059). Tumor markers such as CA125 and HE4 were significantly reduced in the treatment group post-therapy (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Adverse events were comparable between groups, with most reactions being mild to moderate and manageable.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePD-1 inhibitor-based combination therapy significantly improves survival outcomes and disease control in recurrent/metastatic EC without increasing severe adverse events. These findings suggest that this approach is both effective and safe, warranting further investigation in larger clinical trials to refine treatment strategies and expand personalized care options for EC patients.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of adding PD-1 Inhibitors to standard therapies in advanced and recurrent endometrial cancer: A single-center retrospective case-control study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-23 10:46:39","doi":"10.21203/rs.3.rs-6499385/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":"310f91d4-2b3b-4ebc-82ab-8a546976713a","owner":[],"postedDate":"April 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":47473094,"name":"Oncology"},{"id":47473095,"name":"Women's studies"},{"id":47473096,"name":"Obstetrics \u0026 Gynecology"},{"id":47473097,"name":"Immunology"}],"tags":[],"updatedAt":"2025-04-23T10:46:39+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-23 10:46:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6499385","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6499385","identity":"rs-6499385","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}