Study Design and Rationale of the ECMC-GART Phase 3 Clinical Study: Early-Stage Endometrial Cancer Based on Molecular Classification and Traditional Risk Stratification to Guide Adjuvant Radiotherapy Decisions

Study Design and Rationale of the ECMC-GART Phase 3 Clinical Study: Early-Stage Endometrial Cancer Based on Molecular Classification and Traditional Risk Stratification to Guide Adjuvant Radiotherapy Decisions | 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 Study Design and Rationale of the ECMC-GART Phase 3 Clinical Study: Early-Stage Endometrial Cancer Based on Molecular Classification and Traditional Risk Stratification to Guide Adjuvant Radiotherapy Decisions kang ren, Wenhui Wang, Xiaoliang Liu, Shuai Sun, Ke Hu, Fuquan Zhang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3997225/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) represents a prevalent malignancy amongst women on a global scale, with adjuvant therapy strategy remaining inconsistent and controversial. Identifying subtypes integrated with molecular characteristics improves the understanding of cancer biology and consequently helps physicians make personalized therapeutic decision-making. Presented herewith is a study protocol detailing a phase III trial poised to integrate molecular profiling with traditional parameters for the stratification of early-stage EC. The ECMC-GART aims to compare the survival outcomes of integrated molecular classification with the conventional stratification system to provide evidence for further decision-making. Methods: The ECMC-GART trial is a randomized, national multicenter, Phase III, open-labeled, non-inferiority clinical study (Clinical trial registration: NCT05524389). The hypothesis is that adjuvant radiotherapy decision for early-stage endometrial cancer, which is based on molecular classification, can achieve de-escalation of adjuvant treatment without reducing local tumor control and survival, potentially further reducing radiotherapy-related toxicity and improving quality of life, compared to conventional risk stratification. The enrolled early-staged EC patients (FIGO stage I-II) will be randomized 2:1 into the experimental arm (molecular-clinicopathological classification-based treatment) and the control arm (conventional risk stratification-based treatment). The primary endpoint is the 3-year local recurrence rate. The secondary outcomes include failure-free survival, overall survival, de-escalation rate of treatment, acute and late toxicities, and Health-related cancer-specific quality of life (QLQC-30). The ECMC-GART is intended to enroll 624 EC patients to achieve the purpose of non-inferiority design ultimately. Discussion: The ECMC-GART will determine whether the molecular classification-based treatment is not inferior to the treatment based 15on previous conventional risk stratification, potentially allowing for de-escalation and individualized treatment recommendations. Trial registration: ClinicalTrails.gov, NCT05524389. Registered 23 November 2022, https://clinicaltrials.gov/study/NCT05524389 early-stage endometrial cancer molecular classification adjuvant treatment radiotherapy Figures Figure 1 Figure 2 Figure 3 Background Endometrial cancer (EC) is the most common gynecological cancer, with a rising incidence in recent years( 1 , 2 ). More than three-quarters of newly diagnosed patients are limited to FIGO I or II( 3 ). In the era of the absence of molecular testing, the decision-making of adjuvant radiotherapy mainly depends on clinicopathological risk factors. However, conventional classification and recommended treatment are inconsistent, especially in heterogeneous early-stage groups. Although the prognosis of early-stage EC is generally favorable, the prognosis deteriorates significantly once recurrence occurs. The addition of adjuvant radiotherapy is proven to reduce the recurrence by 10%-15% for patients with high-risk factors( 4 ). Based on the outcomes of a series of prospective trials, vaginal brachytherapy(VBT)has been considered the standard of adjuvant therapy for women with high-intermediate risk (HIR) EC( 5 – 7 ), for high-risk (HR) EC patients with FIGO II or FIGO Ib, grade 3(G) adjuvant pelvic external beam radiotherapy (EBRT) is recommended to reduce relapse further ( 3 , 8 ). Inaccurate clinical stratification leads to overtreatment in part of the patient population. Previous studies have estimated that about 7–10 women need to be treated with VBT to prevent one recurrence( 9 ). The internationally accepted standards for early-stage patients, such as GOG (Gynecologic Oncology Group) and PORTEC (Postoperative Radiotherapy for Endometrial Cancer) trials, are inconsistent, resulting in the same patients being classified into different risk classifications( 10 ). In 2013, the Cancer Genome Atlas (TCGA) project reclassified EC into four novel molecular groups with different biological behaviors and prognoses. ECs with p53-abnormal (p53abn) have been demonstrated to be the most aggressive and lethal group( 11 , 12 ). Although the majority of p53abn phenotypes are attributed to serous carcinomas (SECs), some G2 and G3 endometrioid endometrial cancer (EEC), and even 2%-5% of G1 EECs have p53 mutations. However, according to traditional stratification, these patients would be considered low to intermediate risk ( 13 ). Polymerase-ε mutations (POLEmut) are characterized by significantly longer survival and the least prognostically affected by clinicopathological factors, even for patients in the HR group. It's worth noting that > 10% of POLEmut ECs present at a FIGO stage > I, the adjuvant therapy remains unknown( 11 ). Several clinical trials assessing molecular classification are still underway, with the announcement of the results successively. Thus, this ECMC-GART attempts to establish an integrated classification system combining molecular assay and clinicopathological factors. The trial aims to validate the efficacy and toxicity of the integrated molecular profile in early-stage EC. This article was written according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines, and the SPIRIT checklist is provided in supplementary material 1. Methods Study Design The ECMC-GART is an open label, investigator-initiated, prospective, national multicentre, randomized, phase III, non-inferiority clinical study with approximately 13 participating centers in China. Objectives The primary objective of this study is to compare the loco-regional recurrence at three years of adjuvant therapy decisions based on integrated-molecular staging and traditional risk stratification in early-stage EC. The secondary objective aims to assess the two treatment recommendations' survival outcomes, efficacy, and tolerability. This trial hypothesizes that the decision-making based on the integrated molecular system could achieve de-escalated treatment and yield better quality-of-life results without compromising survival outcomes. Besides, patients with potentially high risks, such as p53abn, will be screened, and escalated treatment will be recommended, resulting in a better prognosis. Primary endpoint Loco-regional recurrence (LRR) is defined as the first recurrence in the vagina or pelvic cavity during follow-up, which was confirmed by imaging examination or biopsy pathology. Secondary endpoints a. Failure-free survival (FFS) FFS is defined as the time from randomization to recurrence, distant metastasis, or death from any cause, whichever is first. b. Overall survival (OS) OS is calculated from randomization to death from any cause. c. Cumulative vaginal recurrence Recurrence in the vaginal area during follow-up d. Cumulative pelvic recurrence Recurrences in the pelvic area, including the vagina, during follow-up. e. Distance metastasis (DM) DM is the presence of metastases in distant organs such as the brain, lungs, bone, or non-pelvic regional lymph node metastasis. f. De-escalation rate of treatment Comparison of the proportion of patients in two groups with the same clinicopathologic factors (FIGO, grade, LVSI, age) downgraded from EBRT to VBT or from adjuvant radiotherapy (EBRT or VBT) to observation. g. Health-related cancer-specific quality of life The general quality of life and general cancer-related symptoms are accessed by the Quality of Life Core Questionnaire (QLQC-30), scored as quite a bit/very much vs no or mild signs. QoL assessment will be performed using patient-reported questionnaires (EORTC QLQ-C30) and endometrial cancer-specific EN24 module (EORTC QLQ-EN24). h. Acute and late toxicities Toxicological outcomes will be evaluated during RT, at 1, 2 weeks, and 3, 6 months after RT, every six months for the first five years, and then annually. Acute radiation toxicity, including radiation enteritis, radiation cystitis, radiation lymphopenia, late radiation enteritis, radiation cystitis, vaginal stenosis or shortening, lymphedema, and bone marrow suppression, will be graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 5.0). Late radiation toxicity will be graded according to the Radiation Therapy Oncology Group (RTOG) / the European Organization for Research and Treatment of Cancer (EORTC) late radiation morbidity scale. i. Endometrial cancer-related health care costs The radiation, chemotherapy, and pathology review costs will be documented, including immunohistochemistry (IHC) and Next Generation Sequencing (NGS). Patients—Eligibility Criteria Staged FIGO I-II ECs who are histologically confirmed EEC after surgery with HIR or HR factors are eligible. The new FIGO classification version will be applied( 14 ). The eligibility and exclusion criteria are listed in Table 1 . Table 1 In-Exclusion criteria for ECMC-GART Inclusion Criteria: Exclusion criteria: Age of 18–75 years Residual tumor or positive margin according to the postoperative pathology Serous carcinoma or clear cell carcinoma Histologically confirmed EEC) Sarcoma or carcinosarcoma Eastern Cooperative Oncology Group(ECOG)score 0,1 or 2 History of other malignant tumors (except cured basal cell carcinoma of the skin or tumors curatively treated with no evidence of disease for ≥ 5 years.) Patients with total hysterectomy and bilateral salpingo-oophorectomy, pelvic lymphadenectomy, or sentinel lymph node biopsy, with or without para-aortic lymphadenectomy or oophorectomy. The interval between surgery and radiotherapy is more than 12 weeks. Patients with FIGO I or II and meet one of the following conditions: With serious medical complications, such as heart failure, lung disease, and other diseases that cannot tolerate the whole course of radiotherapy, a) Stage IA G1-2 with massive LVSI + or age ≥ 60 years Previous history of pelvic radiotherapy b) Stage IA G3, regardless of LVSI status c) Stage IB G1-3, regardless of LVSI status d) Stage II, regardless of tumor grade and LVSI status Randomization Randomization is performed by the Peking Union Medical College (PUMCH) stratified by center, adjuvant chemotherapy, and status of surgery (total hysterectomy + bilateral salpingo-oophorectomy, radical hysterectomy of bilateral salpingectomy with or without pelvic lymphadenectomy or sentinel lymph node mapping and dissection, with or without paraaortic lymphadenectomy), CTNNB1(yes, no) and adjuvant chemotherapy (yes, no) in a ratio of 2:1 (experimental arm versus standard arm). The random number and result of randomization will be concealed in sealed security envelopes before written informed consent is obtained. For the standard treatment arm, the HIR group is defined as patients with FIGO IA stage G1-2 with LVSI positive or age > 60 years, and patients with FIGO IA stage G3 or IB G1-2 also constitute HIR. The high-risk profile defines patients with FIGO IB G3 or II stage. Patients with POLE mutation or CTNNB1 wild-type with FIGO IA G1-3 and FIGO IB G1-2 without substantial LVSI constitute the favorable profile for the integrated-molecular group. Patients with the following three conditions will be categorized as intermediate profile: 1) MMRd with FIGO IA G1-3 or IB G1-2; 2) CTNNB1 wild-type with FIGO IB G3 or FIGO II without substantial LVSI; 3) CTNNB1 mutation with FIGO IA G1-3 or IB G1-2 and LVSI-/focal. The following patients will constitute the unfavorable profile: TP53 mutation or p53abn; CTNNB1 mutation with FIGO IB G3 or II stage; MMRd with FIGO IB G3 or II stage; Substantia LVSI. The randomization and classification processes are shown in Fig. 1 and Fig. 2 . Interventions The radiotherapy start date must not be over 12 weeks from the surgery date. In the experimental group, patients will be administered different treatment strategies according to the molecular-clinical integrated risk profile. Patients will be recommended to be exempted from postoperative adjuvant therapy if they are classified into favorable profiles. Those with an intermediate profile receive VBT, and patients with an unfavorable risk profile receive EBRT ± VBT. In the standard arm, treatment will be recommended according to the clinicopathological profile. Patients with a high-intermediate risk profile will receive VBT after surgery. Patients with high-risk profiles will be EBRT ± VBT. EBRT, including intensity-modulated radiotherapy planning (IMRT) or volumetric arc technique (VMAT), will be delivered to the pelvic area at a total dose of 45–50.4 Gy in 1.8–2 Gy daily fractions five times a week. VBT will be delivered with a vaginal cylinder to the upper half of the vagina or 3–5 cm of the upper vagina. Patients who receive VBT alone will be administrated with 6 Gy per fraction in 5 fractions or 7 Gy per fraction in 3 fractions, and those who receive a VBT boost after the completion of EBRT will be administered with doses of 4–6 Gy per fraction in 2–3 fractions. Statistics analysis The Z test will be performed to compare the recurrence rate between the two groups, and the P value will be taken as 0.05. P < 0.05 is considered a difference in the recurrence rate between the two groups; it could be concluded that the recurrence rate of the experimental group is higher than that of the standard treatment group by 3%, and the difference is statistically significant. Kaplan-Meier descriptive statistics method will be used to test the statistical difference of survival curves for OS, RFS, LRFS, etc., between the two groups, and the survival curves will be plotted. A two-sample t-test will compare QOL scores at 1-year and 3-year. Economic evaluation will be conducted in parallel with clinical trials, and a cost-utility analysis from a societal perspective will be performed. The analysis period is 48 months (from the diagnostic to the 48-month follow-up after treatment). The Markov model will be developed to compare the molecular classification and non-testing group based on medical consumption and quality of life. Quality-adjusted life years (QALY) and incremental cost-effectiveness ratios (ICERs). Deterministic and probabilistic sensitivity analyses will measure the uncertainty. The principal investigator and the protocol committee will conduct the analysis. A Data Monitoring Committee (DMC) will be established to oversee the trial and make decisions regarding whether the trial should be halted per 3 months . Sample Size and Recruitment The research hypothesis of this study is that the 3-year loco-regional recurrence rate in the integrated molecular staging group would be non-inferior to that in the standard treatment group with a noninferiority design. The locoregional recurrence rate of the HIR-HR group is estimated to be 7%. The 3-year loco-regional recurrence rate in the molecular integrated group should not be more than 3% (δ) higher than that of the standard group. The intention-to-treat will be performed for analysis using a binomial test with 80% power and alpha of 0.05. Considering a 10% dropout rate, a total of 624 cases is required, including 208 patients in the standard group and 416 patients in the molecular-clinical integrated risk profile. The study is expected to last from November 2023 through August 2027. We established an automated assisted classification decision algorithm to facilitate enrollment and the decision-making system. This software allows for random grouping and automatic stratification based on selected clinical-molecular conditions. The Fig. 4 demonstrates an example of the automated stratification algorithm. The patient was enrolled in the pilot group, and the molecular typing test indicated that POLE was wild-type, MSS, CTNNB1 mutation, stage IA, and stage G3, and these conditions were entered into the automated stratification algorithm system, which resulted in the final grouping of the patient in the "intermediate-risk group". Molecular assay The pathology review should be completed within two weeks of randomization, as radiotherapy should start within 12 weeks of surgery. The pathology review includes histological type and tumor grade, depth of invasion, presence and quantification of LVSI, MMR(MLH1、PMS2、MSH2 and MSH6),p53, β-catenin, and ER/PR status. Concurrently, a next-generation sequencing (NGS) panel including POLE(exon 1–14) ,TP53(exon 4),CTNNB1(exon 3),MSI(Microsatellite Instability) and BRCA1/2 mutations using formalin-fixed, paraffin-embedded (FFPE) tissues has been applied( 15 ). Four molecular subgroups are identified based on the results of the assay: ( 1 ) POLE hypermutant group (POLEmut); ( 2 ) MSI-H type (mismatch repair gene defective MMRd or microsatellite instability); ( 3 ) TP53 mutant type (p53abn or high copy type); ( 4 ) Microsatellite stability (MSS) or no specific molecular characterization group (NSMP). The NSMP group is further subdivided into CTNNB1 mutant and CTNNB1 wild-type subgroups based on CTNNB1 status. LVSl status is quantified by IHC into 3-tiered scoring systems according to the NCCN: no LVSI (no vessels involved), focal LVSI (< 4 vessels), and substantial LVSI (≥ four vessels)( 16 ). The results of molecular typing will be determined in the order of POLE,MMR,CTNNB1(if tested),TP53 and LVSI status. For the “multiple classifier” patients, POLEmut-p53abn EC or POLEmut-MMRd or POLEmut-MMRd / MSI-H-p53abn is categorized as single-classifier POLEmut, MMRd-p53abn EC is classified as single-classifier MMRd( 17 , 18 ).The molecular typing results will be combined with the staging and other pathologic factors to obtain the final stratification results. Trial status Recruitment started in May 2020 and is currently ongoing. Discussion There is considerable variation in practice regarding postoperative adjuvant therapy for early-stage EC. Historically, risk stratification has mainly been based on clinicopathological factors, which have the disadvantage of being poorly repeatable and can not accurately reflect tumor biology and behavior. As a result, some patients may be over-treated or under-treated, according to conventional clinical stratification methods. For patients with risk factors, the postoperative recurrence can be as high as 20%, requiring more precise identification of high-risk patients and aggressive adjuvant treatment strategies. Some studies have demonstrated that the discrepancies between the clinicopathologic and molecular classifications occurred in 6.8% (19/278) patients( 19 ). Another study reported risk groups were discordant in 6.6% (39/594) of patients classified with 2016 clinicopathologic and 2021 molecular integrated systems( 20 ). Furthermore, there is an inconsistency between subtypes due to the variety of current molecular classification methods. According to the study of Loukovaara et al., a risk-group shift occurred in 6.0% (36/604) and 7.4% (38/515) of patients classified by ProMisE and Leiden, respectively (P = 0.341)( 21 ). The ECMC-GART will address whether the integrated-molecular classification can be considered a more effective strategy. There are several trials currently underway trying to validate molecular classifications. The ECMC-GART is redesigned based on the pilot molecular trial of the PORTEC-4a( 22 ). Unlike the PORTEC-4a, which only enrolled FIGO stage I and FIGO II with microscopic infiltration, ECMC-GART recruited both FIGO I with HIR and HR factors (IA with substantial LVSI or G3, IB G1-3) and all of FIGO II patients. NCCN guideline has advised all of the HIR and HR EC to be enrolled in molecular profile–guided clinical trials to determine the most appropriate treatment strategy( 16 ). Patients with IB G3 and II have been historically considered to have a poor prognosis and be administrated with more aggressive treatment like pelvic EBRT( 23 ). However, up to 20% of high-risk patients presented with POLEmut but still had a good prognosis( 24 ). Including patients with FIGO II in the study is of great significance. The ECMC-GART tries to establish and validate an integrated molecular system. The trial will not simply divide the patients enrolled in the trial group into four categories based solely on POLE, MMR status, and p53. The NSMP-CTNNB1 wide/mut group will be further divided into four subgroups according to the FIGO stage and grade to reduce the heterogeneity within the NSMP. The 2020 ESGO/ESTRO/ESP guideline has integrated molecular subtypes into EC risk assignment and treatment algorithms( 25 ). A previous study has confirmed that the combined molecular profile and clinicopathologic features provided the highest C-index for discriminating outcome survival curves than molecular classification alone( 26 ). On the other hand, 44%-56% of early-staged EC consists of the NSMP group, which has the highest percentage and heterogeneity. CTNNB1 is not taken into the classification system according to the ESGO/ESTRO/ESP and PROBEAT algorithms yet. CTNNB1 mutation almost exclusively occurs in the NSMP profile. Patients with CTNNB1 mutation tend to have low-risk characteristics but have worse outcomes with a significantly increased rate of disease recurrence and lower overall survival( 27 ). The discriminatory power of molecular classification can be further improved by adding CTNNB1 mutation( 28 ). Furthermore, some studies proposed that β-catenin as a proxy for CTNNB1 mutations in EC showed high specificity( 29 ). Caressa Hui et al. found that adjuvant radiotherapy reduces recurrences in the NSMP group with abnormal β-catenin expression( 30 ). Thus, our center attempted to perform CTNNB1 sequencing as well as the β-catenin IHC to validate the consistency of the two methods and provide advice for adjuvant therapy. The establishment of such a stratification system that integrates molecular and clinical features seems complicated. We have tried constructing a more clinical-friendly and automatic classification decision software to facilitate clinical application. After clinical validation, we will consider establishing an automated classification system with a more user-friendly interface that is easy to operate from the palm of your hand in the future. From the molecular profile method perspective, whether IHC can completely replace gene sequencing for clinical decision-making, especially for β-catenin, is controversial. This trial carries out the IHC methods to assess the status of MMR, p53, and β-catenin and the NGS to test corresponding genes: MSI, TP53, and CTNNB1. Although IHC MMR and p53 have been demonstrated to be alternative markers for the MMR (MLH1, PMS2, MSH2, and MSH6) and TP53 genes, IHC alone missed a small number of cases. For instance, approximately 5% of TP53-mutant tumors do not show abnormalities in p53 expression by IHC( 31 ). In addition, NGS can detect additional POLE variants ( 32 ). Conclusions The ECMC-GART study, to the best of our knowledge, is the first randomized, controlled phase III trial comparing the comprehensive molecular-clinical classification and the conventional clinical system and will answer the clinically relevant question of whether the decision-making based on the integrated molecular system can achieve the de-escalation and individualized treatment. The prospective trial design will also establish an initial framework for implementing comprehensive genomic-clinical classification of ECs. In addition, through our study, evidence will be provided for adjuvant treatment options for EC with HIR and HR, and some patients can be safely exempted from unnecessary treatment. In contrast, patients with potential prognostic molecular markers of poor survival will be screened as early as possible for more aggressive treatment to improve prognosis. Declarations Author Contributions Conceptualization, K.R., X.H., and F.Z.; methodology, W.W.,B.Y., and J.Q.; validation, K.H., and F.Z.; formal analysis, X.H., S.S., and K.H.; resources, B.Y. and F.Z.; writing—original draft preparation, K.R.; writing—review and editing, X.H and S.S..; visualization, X.L.; supervision, X.H. and J.Q.; project administration, W.W.; funding acquisition, X.H. and K.H. All authors have read and agreed to the published version of the manuscript. Funding This work was supported by National High Level Hospital Clinical Research Funding (grant number: 2022-PUMCH-A-036. Availability of data and materials Data sharing is not applicable to this article as the study is still in the recruiting stage. Acknowledgments: The authors acknowledge the support from the Department of Radiation Oncology of Peking Union Medical College Hospital. Moreover, the authors are thankful to all of the researchers who contributed to this study from all of the 13 participating institutions. Declarations Ethics approval and consent to participate The trial is registered on ClinicalTrials.gov under the number NCT05524389. The protocol has been approved by the Medical Ethics Committees of Peking Union Medical College Hospital (PUMCH, I-22PJ664) and all participating centers. Written informed consent will be obtained from all participants included in the study prior to randomization. Consent for publication Not applicable. Competing interests The authors declare no conflict of interest. References Gu B, Shang X, Yan M, Li X, Wang W, Wang Q, et al. Variations in incidence and mortality rates of endometrial cancer at the global, regional, and national levels, 1990–2019. Gynecol Oncol. 2021;161(2):573–80. Crosbie EJ, Kitson SJ, McAlpine JN, Mukhopadhyay A, Powell ME, Singh N. Endometrial cancer. Lancet. 2022;399(10333):1412–28. 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Int J Gynecol Pathol. 2019;38(1):S123–31. Devereaux KA, Weiel JJ, Pors J, Steiner DF, Ho C, Charu V, et al. Prospective molecular classification of endometrial carcinomas: institutional implementation, practice, and clinical experience. Modern pathology: an official journal of the United States. and Canadian Academy of Pathology, Inc; 2021. Additional Declarations No competing interests reported. Supplementary Files SPIRITFigure.pdf 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. 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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-3997225","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":287230373,"identity":"e8daa3f2-0475-441f-99e1-c3ce63361f77","order_by":0,"name":"kang ren","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"kang","middleName":"","lastName":"ren","suffix":""},{"id":287230374,"identity":"138a7c92-6fde-4ebb-9316-3342a5a33a97","order_by":1,"name":"Wenhui Wang","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Wenhui","middleName":"","lastName":"Wang","suffix":""},{"id":287230375,"identity":"cbc48563-8247-4d03-bc56-c64ac587f001","order_by":2,"name":"Xiaoliang Liu","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Xiaoliang","middleName":"","lastName":"Liu","suffix":""},{"id":287230376,"identity":"be07a30c-77b2-4080-a6e3-cbdc9b7d4bdd","order_by":3,"name":"Shuai Sun","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Shuai","middleName":"","lastName":"Sun","suffix":""},{"id":287230377,"identity":"eb8e0919-d254-41b8-b676-7037db21805f","order_by":4,"name":"Ke Hu","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Ke","middleName":"","lastName":"Hu","suffix":""},{"id":287230378,"identity":"14f3e29d-7873-46d5-82cf-495ad8cd3a9f","order_by":5,"name":"Fuquan Zhang","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Fuquan","middleName":"","lastName":"Zhang","suffix":""},{"id":287230379,"identity":"a2abf8f4-153b-4890-8670-abadee7927e3","order_by":6,"name":"Jie Qiu","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Qiu","suffix":""},{"id":287230380,"identity":"dcf380ef-e8bf-4068-8a20-4b729070a6bc","order_by":7,"name":"Bo Yang","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Bo","middleName":"","lastName":"Yang","suffix":""},{"id":287230381,"identity":"7d62269b-7765-4096-a02c-325dd59a7be3","order_by":8,"name":"Xiaorong Hou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuUlEQVRIiWNgGAWjYBACAziDvbHx4QfStPAcbjaWIE2LRHqbAA8xWswlch8wF7ZtkzeXfNjGIMFgJ6fbQECLZc9xA+aZbbcNd85ObHtQwJBsbHaAkMOOtzEw87bdTjC4ndhuIMFwIHEbQS2H2aBabh5sk+AhSgvclhuMxGo5c4yBeca524YbziQCA9mAGL/cSGNgLii7LW9w/PjDhx8q7OQIagEC9t9IJhBWDgbMRKobBaNgFIyCkQoAUONA6FCxgxcAAAAASUVORK5CYII=","orcid":"","institution":"Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":true,"prefix":"","firstName":"Xiaorong","middleName":"","lastName":"Hou","suffix":""}],"badges":[],"createdAt":"2024-02-28 16:29:54","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3997225/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3997225/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54316630,"identity":"0ab8705f-5b0c-4152-b858-f161a023bc63","added_by":"auto","created_at":"2024-04-08 17:56:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":89590,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart of the ECMC-GART\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3997225/v1/51fae0305ef6bcb30762e19d.png"},{"id":54316628,"identity":"036c1669-91f4-4639-84cb-2d336d0eef6a","added_by":"auto","created_at":"2024-04-08 17:56:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":35529,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy design of the ECMC-GART\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3997225/v1/229e1a139f2e2e3e368d3e75.png"},{"id":54316629,"identity":"5c572cda-7799-486c-a73e-9c92a3ffa0bf","added_by":"auto","created_at":"2024-04-08 17:56:17","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":42436,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDecision tree of molecular-clinical integrated risk profile\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3997225/v1/bda882150c33184ae6f3bd4c.png"},{"id":54698490,"identity":"7739a32c-4d87-463e-ae1e-c41ca5ef3bdb","added_by":"auto","created_at":"2024-04-15 11:50:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":616321,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3997225/v1/3d0e6b4c-02dc-423a-95a7-0422f4543bc6.pdf"},{"id":54316631,"identity":"e2574a00-8c0f-4309-96fb-4c34811babdd","added_by":"auto","created_at":"2024-04-08 17:56:17","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":232309,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITFigure.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3997225/v1/e7c994c7cc226d624d4197c1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Study Design and Rationale of the ECMC-GART Phase 3 Clinical Study: Early-Stage Endometrial Cancer Based on Molecular Classification and Traditional Risk Stratification to Guide Adjuvant Radiotherapy Decisions","fulltext":[{"header":"Background","content":"\u003cp\u003eEndometrial cancer (EC) is the most common gynecological cancer, with a rising incidence in recent years(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). More than three-quarters of newly diagnosed patients are limited to FIGO I or II(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). In the era of the absence of molecular testing, the decision-making of adjuvant radiotherapy mainly depends on clinicopathological risk factors. However, conventional classification and recommended treatment are inconsistent, especially in heterogeneous early-stage groups. Although the prognosis of early-stage EC is generally favorable, the prognosis deteriorates significantly once recurrence occurs. The addition of adjuvant radiotherapy is proven to reduce the recurrence by 10%-15% for patients with high-risk factors(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Based on the outcomes of a series of prospective trials, vaginal brachytherapy(VBT)has been considered the standard of adjuvant therapy for women with high-intermediate risk (HIR) EC(\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), for high-risk (HR) EC patients with FIGO II or FIGO Ib, grade 3(G) adjuvant pelvic external beam\u003c/p\u003e \u003cp\u003eradiotherapy (EBRT) is recommended to reduce relapse further (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Inaccurate clinical stratification leads to overtreatment in part of the patient population. Previous studies have estimated that about 7\u0026ndash;10 women need to be treated with VBT to prevent one recurrence(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The internationally accepted standards for early-stage patients, such as GOG (Gynecologic Oncology Group) and PORTEC (Postoperative Radiotherapy for Endometrial Cancer) trials, are inconsistent, resulting in the same patients being classified into different risk classifications(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn 2013, the Cancer Genome Atlas (TCGA) project reclassified EC into four novel molecular groups with different biological behaviors and prognoses. ECs with p53-abnormal (p53abn) have been demonstrated to be the most aggressive and lethal group(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Although the majority of p53abn phenotypes are attributed to serous carcinomas (SECs), some G2 and G3 endometrioid endometrial cancer (EEC), and even 2%-5% of G1 EECs have p53 mutations. However, according to traditional stratification, these patients would be considered low to intermediate risk (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Polymerase-ε mutations (POLEmut) are characterized by significantly longer survival and the least prognostically affected by clinicopathological factors, even for patients in the HR group. It's worth noting that \u0026gt;\u0026thinsp;10% of POLEmut ECs present at a FIGO stage\u0026thinsp;\u0026gt;\u0026thinsp;I, the adjuvant therapy remains unknown(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Several clinical trials assessing molecular classification are still underway, with the announcement of the results successively.\u003c/p\u003e \u003cp\u003eThus, this ECMC-GART attempts to establish an integrated classification system combining molecular assay and clinicopathological factors. The trial aims to validate the efficacy and toxicity of the integrated molecular profile in early-stage EC. This article was written according to the Standard Protocol Items: Recommendations for Interventional Trials\u003c/p\u003e \u003cp\u003e(SPIRIT) guidelines, and the SPIRIT checklist is provided in supplementary material 1.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThe ECMC-GART is an open label, investigator-initiated, prospective, national multicentre, randomized, phase III, non-inferiority clinical study with approximately 13 participating centers in China.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eThe primary objective of this study is to compare the loco-regional recurrence at three years of adjuvant therapy decisions based on integrated-molecular staging and traditional risk stratification in early-stage EC.\u003c/p\u003e \u003cp\u003eThe secondary objective aims to assess the two treatment recommendations' survival outcomes, efficacy, and tolerability. This trial hypothesizes that the decision-making based on the integrated molecular system could achieve de-escalated treatment and yield better quality-of-life results without compromising survival outcomes. Besides, patients with potentially high risks, such as p53abn, will be screened, and escalated treatment will be recommended, resulting in a better prognosis.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003ePrimary endpoint\u003c/h2\u003e \u003cp\u003eLoco-regional recurrence (LRR) is defined as the first recurrence in the vagina or pelvic cavity during follow-up, which was confirmed by imaging examination or biopsy pathology.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSecondary endpoints\u003c/b\u003e \u003c/p\u003e \u003cp\u003ea. Failure-free survival (FFS)\u003c/p\u003e \u003cp\u003eFFS is defined as the time from randomization to recurrence, distant metastasis, or death from any cause, whichever is first.\u003c/p\u003e \u003cp\u003eb. Overall survival (OS)\u003c/p\u003e \u003cp\u003eOS is calculated from randomization to death from any cause.\u003c/p\u003e \u003cp\u003ec. Cumulative vaginal recurrence\u003c/p\u003e \u003cp\u003eRecurrence in the vaginal area during follow-up\u003c/p\u003e \u003cp\u003ed. Cumulative pelvic recurrence\u003c/p\u003e \u003cp\u003eRecurrences in the pelvic area, including the vagina, during follow-up.\u003c/p\u003e \u003cp\u003ee. Distance metastasis (DM)\u003c/p\u003e \u003cp\u003eDM is the presence of metastases in distant organs such as the brain, lungs, bone, or non-pelvic regional lymph node metastasis.\u003c/p\u003e \u003cp\u003ef. De-escalation rate of treatment\u003c/p\u003e \u003cp\u003eComparison of the proportion of patients in two groups with the same clinicopathologic factors (FIGO, grade, LVSI, age) downgraded from EBRT to VBT or from adjuvant radiotherapy (EBRT or VBT) to observation.\u003c/p\u003e \u003cp\u003eg. Health-related cancer-specific quality of life\u003c/p\u003e \u003cp\u003eThe general quality of life and general cancer-related symptoms are accessed by the Quality of Life Core Questionnaire (QLQC-30), scored as quite a bit/very much vs no or mild signs. QoL assessment will be performed using patient-reported questionnaires (EORTC QLQ-C30) and endometrial cancer-specific EN24 module (EORTC QLQ-EN24).\u003c/p\u003e \u003cp\u003eh. Acute and late toxicities\u003c/p\u003e \u003cp\u003eToxicological outcomes will be evaluated during RT, at 1, 2 weeks, and 3, 6 months after RT, every six months for the first five years, and then annually. Acute radiation toxicity, including radiation enteritis, radiation cystitis, radiation lymphopenia, late radiation enteritis, radiation cystitis, vaginal stenosis or shortening, lymphedema, and bone marrow suppression, will be graded according to the National Cancer Institute\u0026rsquo;s Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 5.0). Late radiation toxicity will be graded according to the Radiation Therapy Oncology Group (RTOG) / the European Organization for Research and Treatment of Cancer (EORTC) late radiation morbidity scale.\u003c/p\u003e \u003cp\u003ei. Endometrial cancer-related health care costs\u003c/p\u003e \u003cp\u003eThe radiation, chemotherapy, and pathology review costs will be documented, including immunohistochemistry (IHC) and Next Generation Sequencing (NGS).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003ePatients\u0026mdash;Eligibility Criteria\u003c/h2\u003e \u003cp\u003eStaged FIGO I-II ECs who are histologically confirmed EEC after surgery with HIR or HR factors are eligible. The new FIGO classification version will be applied(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The eligibility and exclusion criteria are listed 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\u003eIn-Exclusion criteria for ECMC-GART\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\u003eAge of 18\u0026ndash;75 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResidual tumor or positive margin according to the postoperative pathology\u003c/p\u003e \u003cp\u003eSerous carcinoma or clear cell carcinoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistologically confirmed EEC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSarcoma or carcinosarcoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEastern Cooperative Oncology Group(ECOG)score 0,1 or 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHistory of other malignant tumors \u0026nbsp;\u0026nbsp;(except cured basal cell carcinoma of the skin or tumors curatively treated with no evidence of disease for \u0026ge;\u0026thinsp;5 years.)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with total hysterectomy and bilateral salpingo-oophorectomy, pelvic lymphadenectomy, or sentinel lymph node biopsy, with or without para-aortic lymphadenectomy or oophorectomy.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThe interval between surgery and radiotherapy is more than 12 weeks.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with FIGO I or II and meet one of the following conditions:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWith serious medical complications, such as heart failure, lung disease, and other diseases that cannot tolerate the whole course of radiotherapy,\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ea) Stage IA G1-2 with massive LVSI\u0026thinsp;+\u0026thinsp;or age\u0026thinsp;\u0026ge;\u0026thinsp;60 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrevious history of pelvic radiotherapy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eb) Stage IA G3, regardless of LVSI status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec) Stage IB G1-3, regardless of LVSI status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ed) Stage II, regardless of tumor grade and LVSI status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003eRandomization\u003c/h2\u003e \u003cp\u003eRandomization is performed by the Peking Union Medical College (PUMCH) stratified by center, adjuvant chemotherapy, and status of surgery (total hysterectomy\u0026thinsp;+\u0026thinsp;bilateral salpingo-oophorectomy, radical hysterectomy of bilateral salpingectomy with or without pelvic lymphadenectomy or sentinel lymph node mapping and dissection, with or without paraaortic lymphadenectomy), CTNNB1(yes, no) and adjuvant chemotherapy (yes, no) in a ratio of 2:1 (experimental arm versus standard arm). The random number and result of randomization will be concealed in sealed security envelopes before written informed consent is obtained. For the standard treatment arm, the HIR group is defined as patients with FIGO IA stage G1-2 with LVSI positive or age\u0026thinsp;\u0026gt;\u0026thinsp;60 years, and patients with FIGO IA stage G3 or IB G1-2 also constitute HIR. The high-risk profile defines patients with FIGO IB G3 or II stage. Patients with POLE mutation or CTNNB1 wild-type with FIGO IA G1-3 and FIGO IB G1-2 without substantial LVSI constitute the favorable profile for the integrated-molecular group. Patients with the following three conditions will be categorized as intermediate profile:\u003c/p\u003e \u003cp\u003e1) MMRd with FIGO IA G1-3 or IB G1-2;\u003c/p\u003e \u003cp\u003e2) CTNNB1 wild-type with FIGO IB G3 or FIGO II without substantial LVSI;\u003c/p\u003e \u003cp\u003e3) CTNNB1 mutation with FIGO IA G1-3 or IB G1-2 and LVSI-/focal.\u003c/p\u003e \u003cp\u003eThe following patients will constitute the unfavorable profile:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTP53 mutation or p53abn;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCTNNB1 mutation with FIGO IB G3 or II stage;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eMMRd with FIGO IB G3 or II stage;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSubstantia LVSI.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eThe randomization and classification processes are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003eInterventions\u003c/h2\u003e \u003cp\u003eThe radiotherapy start date must not be over 12 weeks from the surgery date. In the experimental group, patients will be administered different treatment strategies according to the molecular-clinical integrated risk profile.\u003c/p\u003e \u003cp\u003ePatients will be recommended to be exempted from postoperative adjuvant therapy if they are classified into favorable profiles. Those with an intermediate profile receive VBT, and patients with an unfavorable risk profile receive EBRT\u0026thinsp;\u0026plusmn;\u0026thinsp;VBT.\u003c/p\u003e \u003cp\u003eIn the standard arm, treatment will be recommended according to the clinicopathological profile. Patients with a high-intermediate risk profile will receive VBT after surgery. Patients with high-risk profiles will be EBRT\u0026thinsp;\u0026plusmn;\u0026thinsp;VBT.\u003c/p\u003e \u003cp\u003eEBRT, including intensity-modulated radiotherapy planning (IMRT) or volumetric arc technique (VMAT), will be delivered to the pelvic area at a total dose of 45\u0026ndash;50.4 Gy in 1.8\u0026ndash;2 Gy daily fractions five times a week. VBT will be delivered with a vaginal cylinder to the upper half of the vagina or 3\u0026ndash;5 cm of the upper vagina. Patients who receive VBT alone will be administrated with 6 Gy per fraction in 5 fractions or 7 Gy per fraction in 3 fractions, and those who receive a VBT boost after the completion of EBRT will be administered with doses of 4\u0026ndash;6 Gy per fraction in 2\u0026ndash;3 fractions.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistics analysis\u003c/h2\u003e \u003cp\u003eThe Z test will be performed to compare the recurrence rate between the two groups, and the P value will be taken as 0.05. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 is considered a difference in the recurrence rate between the two groups; it could be concluded that the recurrence rate of the experimental group is higher than that of the standard treatment group by 3%, and the difference is statistically significant. Kaplan-Meier descriptive statistics method will be used to test the statistical difference of survival curves for OS, RFS, LRFS, etc., between the two groups, and the survival curves will be plotted. A two-sample t-test will compare QOL scores at 1-year and 3-year. Economic evaluation will be conducted in parallel with clinical trials, and a cost-utility analysis from a societal perspective will be performed. The analysis period is 48 months (from the diagnostic to the 48-month follow-up after treatment). The Markov model will be developed to compare the molecular classification and non-testing group based on medical consumption and quality of life. Quality-adjusted life years (QALY) and incremental cost-effectiveness ratios (ICERs). Deterministic and probabilistic sensitivity analyses will measure the uncertainty. The principal investigator and the protocol committee will conduct the analysis. A Data Monitoring Committee (DMC) will be established to oversee the trial and make decisions regarding whether the trial should be halted per 3 months .\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eSample Size and Recruitment\u003c/h2\u003e \u003cp\u003eThe research hypothesis of this study is that the 3-year loco-regional recurrence rate in the integrated molecular staging group would be non-inferior to that in the standard treatment group with a noninferiority design. The locoregional recurrence rate of the HIR-HR group is estimated to be 7%. The 3-year loco-regional recurrence rate in the molecular integrated group should not be more than 3% (δ) higher than that of the standard group. The intention-to-treat will be performed for analysis using a binomial test with 80% power and alpha of 0.05. Considering a 10% dropout rate, a total of 624 cases is required, including 208 patients in the standard group and 416 patients in the molecular-clinical integrated risk profile. The study is expected to last from November 2023 through August 2027.\u003c/p\u003e \u003cp\u003eWe established an automated assisted classification decision algorithm to facilitate enrollment and the decision-making system. This software allows for random grouping and automatic stratification based on selected clinical-molecular conditions.\u003c/p\u003e \u003cp\u003eThe Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e demonstrates an example of the automated stratification algorithm. The patient was enrolled in the pilot group, and the molecular typing test indicated that POLE was wild-type, MSS, CTNNB1 mutation, stage IA, and stage G3, and these conditions were entered into the automated stratification algorithm system, which resulted in the final grouping of the patient in the \"intermediate-risk group\".\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eMolecular assay\u003c/h2\u003e \u003cp\u003eThe pathology review should be completed within two weeks of randomization, as radiotherapy should start within 12 weeks of surgery.\u003c/p\u003e \u003cp\u003eThe pathology review includes histological type and tumor grade, depth of invasion, presence and quantification of LVSI, MMR(MLH1、PMS2、MSH2 and MSH6),p53, β-catenin, and ER/PR status. Concurrently, a next-generation sequencing (NGS) panel including POLE(exon 1\u0026ndash;14) ,TP53(exon 4),CTNNB1(exon 3),MSI(Microsatellite Instability) and BRCA1/2 mutations using formalin-fixed, paraffin-embedded (FFPE) tissues has been applied(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Four molecular subgroups are identified based on the results of the assay: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) POLE hypermutant group (POLEmut); (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) MSI-H type (mismatch repair gene defective MMRd or microsatellite instability); (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) TP53 mutant type (p53abn or high copy type); (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Microsatellite stability (MSS) or no specific molecular characterization group (NSMP). The NSMP group is further subdivided into CTNNB1 mutant and CTNNB1 wild-type subgroups based on CTNNB1 status. LVSl status is quantified by IHC into 3-tiered scoring systems according to the NCCN: no LVSI (no vessels involved), focal LVSI (\u0026lt;\u0026thinsp;4 vessels), and substantial LVSI (\u0026ge;\u0026thinsp;four vessels)(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe results of molecular typing will be determined in the order of POLE,MMR,CTNNB1(if tested),TP53 and LVSI status. For the \u0026ldquo;multiple classifier\u0026rdquo; patients, POLEmut-p53abn EC or POLEmut-MMRd or POLEmut-MMRd / MSI-H-p53abn is categorized as single-classifier POLEmut, MMRd-p53abn EC is classified as single-classifier MMRd(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).The molecular typing results will be combined with the staging and other pathologic factors to obtain the final stratification results.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eTrial status\u003c/h2\u003e \u003cp\u003eRecruitment started in May 2020 and is currently ongoing.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThere is considerable variation in practice regarding postoperative adjuvant therapy for early-stage EC. Historically, risk stratification has mainly been based on clinicopathological factors, which have the disadvantage of being poorly repeatable and can not accurately reflect tumor biology and behavior. As a result, some patients may be over-treated or under-treated, according to conventional clinical stratification methods. For patients with risk factors, the postoperative recurrence can be as high as 20%, requiring more precise identification of high-risk patients and aggressive adjuvant treatment strategies. Some studies have demonstrated that the discrepancies between the clinicopathologic and molecular classifications occurred in 6.8% (19/278) patients(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Another study reported risk groups were discordant in 6.6% (39/594) of patients classified with 2016 clinicopathologic and 2021 molecular integrated systems(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Furthermore, there is an inconsistency between subtypes due to the variety of current molecular classification methods. According to the study of Loukovaara et al., a risk-group shift occurred in 6.0% (36/604) and 7.4% (38/515) of patients classified by ProMisE and Leiden, respectively (P\u0026thinsp;=\u0026thinsp;0.341)(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). The ECMC-GART will address whether the integrated-molecular classification can be considered a more effective strategy.\u003c/p\u003e \u003cp\u003eThere are several trials currently underway trying to validate molecular classifications. The ECMC-GART is redesigned based on the pilot molecular trial of the PORTEC-4a(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Unlike the PORTEC-4a, which only enrolled FIGO stage I and FIGO II with microscopic infiltration, ECMC-GART recruited both FIGO I with HIR and HR factors (IA with substantial LVSI or G3, IB G1-3) and all of FIGO II patients. NCCN guideline has advised all of the HIR and HR EC to be enrolled in molecular profile\u0026ndash;guided clinical trials to determine the most appropriate treatment strategy(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Patients with IB G3 and II have been historically considered to have a poor prognosis and be administrated with more aggressive treatment like pelvic EBRT(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). However, up to 20% of high-risk patients presented with POLEmut but still had a good prognosis(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Including patients with FIGO II in the study is of great significance. The ECMC-GART tries to establish and validate an integrated molecular system. The trial will not simply divide the patients enrolled in the trial group into four categories based solely on POLE, MMR status, and p53. The NSMP-CTNNB1 wide/mut group will be further divided into four subgroups according to the FIGO stage and grade to reduce the heterogeneity within the NSMP. The 2020 ESGO/ESTRO/ESP guideline has integrated molecular subtypes into EC risk assignment and treatment algorithms(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). A previous study has confirmed that the combined molecular profile and clinicopathologic features provided the highest C-index for discriminating outcome survival curves than molecular classification alone(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). On the other hand, 44%-56% of early-staged EC consists of the NSMP group, which has the highest percentage and heterogeneity. CTNNB1 is not taken into the classification system according to the ESGO/ESTRO/ESP and PROBEAT algorithms yet. CTNNB1 mutation almost exclusively occurs in the NSMP profile. Patients with CTNNB1 mutation tend to have low-risk characteristics but have worse outcomes with a significantly increased rate of disease recurrence and lower overall survival(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). The discriminatory power of molecular classification can be further improved by adding CTNNB1 mutation(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Furthermore, some studies proposed that β-catenin as a proxy for CTNNB1 mutations in EC showed high specificity(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Caressa Hui et al. found that adjuvant radiotherapy reduces recurrences in the NSMP group with abnormal β-catenin expression(\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Thus, our center attempted to perform CTNNB1 sequencing as well as the β-catenin IHC to validate the consistency of the two methods and provide advice for adjuvant therapy.\u003c/p\u003e \u003cp\u003eThe establishment of such a stratification system that integrates molecular and clinical features seems complicated. We have tried constructing a more clinical-friendly and automatic classification decision software to facilitate clinical application. After clinical validation, we will consider establishing an automated classification system with a more user-friendly interface that is easy to operate from the palm of your hand in the future.\u003c/p\u003e \u003cp\u003eFrom the molecular profile method perspective, whether IHC can completely replace gene sequencing for clinical decision-making, especially for β-catenin, is controversial. This trial carries out the IHC methods to assess the status of MMR, p53, and β-catenin and the NGS to test corresponding genes: MSI, TP53, and CTNNB1. Although IHC MMR and p53 have been demonstrated to be alternative markers for the MMR (MLH1, PMS2, MSH2, and MSH6) and TP53 genes, IHC alone missed a small number of cases. For instance, approximately 5% of TP53-mutant tumors do not show abnormalities in p53 expression by IHC(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). In addition, NGS can detect additional POLE variants (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe ECMC-GART study, to the best of our knowledge, is the first randomized, controlled phase III trial comparing the comprehensive molecular-clinical classification and the conventional clinical system and will answer the clinically relevant question of whether the decision-making based on the integrated molecular system can achieve the de-escalation and individualized treatment. The prospective trial design will also establish an initial framework for implementing comprehensive genomic-clinical classification of ECs. In addition, through our study, evidence will be provided for adjuvant treatment options for EC with HIR and HR, and some patients can be safely exempted from unnecessary treatment. In contrast, patients with potential prognostic molecular markers of poor survival will be screened as early as possible for more aggressive treatment to improve prognosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, K.R., X.H., and F.Z.; methodology, W.W.,B.Y., and J.Q.; validation, K.H., and F.Z.; formal analysis, X.H., S.S., and K.H.; resources, B.Y. and F.Z.; writing\u0026mdash;original draft preparation, K.R.; writing\u0026mdash;review and editing, X.H and S.S..; visualization, X.L.; supervision, X.H. and J.Q.; project administration, W.W.; funding acquisition, X.H. and K.H. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by National High Level Hospital Clinical Research Funding (grant number: 2022-PUMCH-A-036.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing is not applicable to this article as the study is still in the\u0026nbsp;recruiting stage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge the support from the Department of Radiation Oncology of Peking Union Medical College Hospital. Moreover, the authors are thankful to all of the researchers who contributed to this study from all of the 13 participating institutions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial is registered on ClinicalTrials.gov under the number NCT05524389. The protocol has been approved by the Medical Ethics Committees of Peking Union Medical College Hospital (PUMCH, I-22PJ664) and all participating centers. Written informed\u0026nbsp;consent will be obtained from all participants included in the study prior to\u0026nbsp;randomization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGu B, Shang X, Yan M, Li X, Wang W, Wang Q, et al. Variations in incidence and mortality rates of endometrial cancer at the global, regional, and national levels, 1990\u0026ndash;2019. Gynecol Oncol. 2021;161(2):573\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCrosbie EJ, Kitson SJ, McAlpine JN, Mukhopadhyay A, Powell ME, Singh N. Endometrial cancer. 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Br J Cancer. 2015;113(2):299\u0026ndash;310.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLedinek Ž, Sobočan M, Knez J. The Role of CTNNB1 in Endometrial Cancer. Dis Markers. 2022;2022:1442441.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamon-Patino JL, Ruz-Caracuel I, Heredia-Soto V, Garcia de la Calle LE, Zagidullin B, Wang Y et al. Prognosis Stratification Tools in Early-Stage Endometrial Cancer. Could We Improve Their Accuracy? Cancers. 2022;14(4).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTravaglino A, Raffone A, Saccone G, De Luca C, Mollo A, Mascolo M, et al. Immunohistochemical Nuclear Expression of β-Catenin as a Surrogate of CTNNB1 Exon 3 Mutation in Endometrial Cancer. Am J Clin Pathol. 2019;151(5):529\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHui C, Mendoza MG, Snyder J, Dorigo O, Litkouhi B, Renz M, et al. Adjuvant radiation therapy in early-stage endometrial cancer with abnormal beta-catenin expression is associated with improved local control. Gynecol Oncol. 2023;174:42\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eK\u0026ouml;bel M, Ronnett BM, Singh N, Soslow RA, Gilks CB, McCluggage WG. Interpretation of P53 Immunohistochemistry in Endometrial Carcinomas: Toward Increased Reproducibility. Int J Gynecol Pathol. 2019;38(1):S123\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDevereaux KA, Weiel JJ, Pors J, Steiner DF, Ho C, Charu V, et al. Prospective molecular classification of endometrial carcinomas: institutional implementation, practice, and clinical experience. Modern pathology: an official journal of the United States. and Canadian Academy of Pathology, Inc; 2021.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"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":"early-stage endometrial cancer, molecular classification, adjuvant treatment, radiotherapy","lastPublishedDoi":"10.21203/rs.3.rs-3997225/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3997225/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eEndometrial cancer (EC) represents a prevalent malignancy amongst women on a global scale, with adjuvant therapy strategy remaining inconsistent and controversial. Identifying subtypes integrated with molecular characteristics improves the understanding of cancer biology and consequently helps physicians make personalized therapeutic decision-making. Presented herewith is a study protocol detailing a phase III trial poised to integrate molecular profiling with traditional parameters for the stratification of early-stage EC. The ECMC-GART aims to compare the survival outcomes of integrated molecular classification with the conventional stratification system to provide evidence for further decision-making.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe ECMC-GART trial is a randomized, national multicenter, Phase III, open-labeled, non-inferiority clinical study (Clinical trial registration: NCT05524389). The hypothesis is that adjuvant radiotherapy decision for early-stage endometrial cancer, which is based on molecular classification, can achieve de-escalation of adjuvant treatment without reducing local tumor control and survival, potentially further reducing radiotherapy-related toxicity and improving quality of life, compared to conventional risk stratification. The enrolled early-staged EC patients (FIGO stage I-II) will be randomized 2:1 into the experimental arm (molecular-clinicopathological classification-based treatment) and the control arm (conventional risk stratification-based treatment). The primary endpoint is the 3-year local recurrence rate. The secondary outcomes include failure-free survival, overall survival, de-escalation rate of treatment, acute and late toxicities, and Health-related cancer-specific quality of life (QLQC-30). The ECMC-GART is intended to enroll 624 EC patients to achieve the purpose of non-inferiority design ultimately.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003eThe ECMC-GART will determine whether the molecular classification-based treatment is not inferior to the treatment based 15on previous conventional risk stratification, potentially allowing for de-escalation and individualized treatment recommendations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eClinicalTrails.gov, NCT05524389. Registered 23 November 2022, \u0026nbsp;https://clinicaltrials.gov/study/NCT05524389\u003c/p\u003e","manuscriptTitle":"Study Design and Rationale of the ECMC-GART Phase 3 Clinical Study: Early-Stage Endometrial Cancer Based on Molecular Classification and Traditional Risk Stratification to Guide Adjuvant Radiotherapy Decisions","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-08 17:56:13","doi":"10.21203/rs.3.rs-3997225/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":"ab3015dd-c225-44b9-bf24-af3fe752a53b","owner":[],"postedDate":"April 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-15T11:42:04+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-08 17:56:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3997225","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3997225","identity":"rs-3997225","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}