SHAPE-ENDO: Pilot Randomized Trial of Multimodal Pre-Surgical Optimization Versus Standard Surgery in Patients With Obesity and Early-Stage Endometrial Cancer

Registered clinical trial record on ClinicalTrials.gov (NCT07462663). This describes a planned, ongoing, or completed study — it is NOT peer-reviewed results. Status: not yet recruiting. Study type: interventional. Phase: Phase 4. Sponsor: Hospital Universitari de Bellvitge. Conditions: Endometrial Cancer, Endometrial Cancer Stage I, Atypical Endometrial Hyperplasia and Endometrial Carcinoma Stage I, Atypical Endometrial Hyperplasia, Endometrial Intraepithelial Neoplasia, Obesity & Overweight, BMI>40, Obesity, Obesity Grade III. Interventions: GLP-1 Receptor Agonist, Levonorgestrel IUD (Lng-IUD), Oral Progestins, Dietetic-Nutritional intervention, Structured Exercise and Prehabilitation Program, Endometrial Biopsy With or Without Hysteroscopy, Radiologic Surveillance (MRI and Transvaginal Ultrasound), Standar upfront Surgery. Summary: SHAPE-ENDO is a single-center, open-label, pilot randomized clinical trial conducted at Hospital Universitari de Bellvitge in Barcelona, Spain. The study will evaluate the feasibility, safety, and acceptability of comparing two treatment strategies in women with atypical endometrial hyperplasia/endometrial intraepithelial neoplasia or low-risk endometrioid endometrial cancer and grade III obesity, defined as BMI ≥40 kg/m². Eligible participants will be randomized in a 1:1 ratio to one of two arms. The control arm will undergo standard immediate surgery according to the institutional clinical protocol. The experimental arm will receive the SHAPE-ENDO multimodal pre-surgical optimization strategy before surgery. The SHAPE-ENDO strategy includes metabolic treatment with semaglutide/Wegovy®, local hormonal therapy with a levonorgestrel-releasing intrauterine device/Mirena® with or without oral medroxyprogesterone acetate/Progevera®, a structured nutritional program, adapted physical exercise, and scheduled oncologic surveillance with clinical evaluation, imaging, and endometrial biopsy with or without hysteroscopy. The experimental strategy will initially last 28 weeks. In participants with clinical, metabolic, or anthropometric benefit, adequate tolerance, and no evidence of tumor progression, the strategy may be extended up to 54 weeks before surgery. The primary objective is to evaluate the feasibility, safety, and acceptability of the randomized trial design. Primary feasibility outcomes include recruitment rate, acceptance of randomization, retention, adherence to the assigned intervention, completion of the SHAPE-ENDO strategy, progression during the optimization period, and the proportion of participants in the experimental arm who reach surgery without tumor progression. Secondary outcomes include perioperative morbidity, histological response in the experimental arm, metabolic and anthropometric changes, quality of life, treatment adherence, safety and tolerability, and exploratory long-term oncologic outcomes including overall survival, recurrence-free survival, and cancer-specific survival. Obesity is a major modifiable risk factor for endometrial cancer and is associated with increased surgical complexity, higher perioperative morbidity, anesthetic risk, and worse functional recovery. Although surgery remains the standard treatment for atypical endometrial hyperplasia and early-stage endometrioid endometrial cancer, patients with grade III obesity may experience a higher risk of perioperative complications. In operable patients with low-risk endometrial disease and BMI ≥40 kg/m², a structured pre-surgical optimization strategy could improve metabolic and functional status before surgery while maintaining oncologic safety through close surveillance. The SHAPE-ENDO strategy combines semaglutide-based metabolic optimization, local hormonal therapy with a levonorgestrel-releasing intrauterine device with or without oral progestins, structured nutritional support, adapted physical exercise, and scheduled histologic and radiologic monitoring. This pilot randomized trial will compare standard immediate surgery with the SHAPE-ENDO multimodal pre-surgical optimization strategy. The aim is not to replace surgery, but to evaluate whether a protocolized and closely monitored optimization window before surgery is feasible, safe, acceptable, and potentially associated with improved perioperative outcomes. Participants in both arms will undergo long-term clinical and oncologic follow-up for at least 5 years after randomization. Primary outcome measures: Recruitment Rate; Acceptance of Randomization Rate; Participant Retention Rate; Adherence to the Assigned Intervention; Completion of the SHAPE-ENDO Multimodal Strategy; Proportion of SHAPE-ENDO Participants Reaching Surgery Without Tumor Progression; Incidence of Serious Adverse Events, Tumor Progression, and Study Discontinuation. Eligibility: Inclusion Criteria: * Female participants ≥18 years old. * Histologically confirmed atypical endometrial hyperplasia/endometrial intraepithelial neoplasia (AEH/EIN) or low-risk endometrioid endometrial carcinoma, grade 1 or 2. * Disease apparently confined to the uterine corpus, assessed by expert transvaginal ultrasound and/or pelvic magnetic resonance imaging. * Low- or intermediate-risk disease according to ESGO-ESTRO-ESP 2025 criteria, including presurgical stages IA1, IA2, or IB. * Negative or focal lymphovascular space invasion, if available. * Favorable molecular profile, if available, including POLE-mutated, p53 wild-type, MMR-deficient, or NSMP estrogen receptor-positive disease. * Body mass index ≥40 kg/m² at inclusion. * Considered a candidate for surgical treatment by the multidisciplinary tumor board. * Ability to understand and sign written informed consent after receiving oral and written information about the study, including acceptance of random assignment to either standard immediate surgery or the SHAPE-ENDO multimodal pre-surgical optimization strategy. Exclusion Criteria: * FIGO stage IA3, IC, II, or higher disease. * Extensive lymphovascular space invasion, if available. * High-risk molecular profile, including p53-abnormal/mutated disease or NSMP estrogen receptor-negative disease. * Non-endometrioid histology, including serous carcinoma, clear-cell carcinoma, carcinosarcoma, mixed histology, or other high-risk histological subtypes. * Metastatic disease or suspicion of extrauterine disease. * Considered medically inoperable or "unfit" for surgery because of severe comorbidity, frailty, anesthetic contraindication, or any other clinical reason contraindicating surgical treatment. * Contraindication to GLP-1 receptor agonist therapy or progestin-based hormonal therapy, including levonorgestrel-releasing intrauterine device or oral progestins. * Previous pancreatitis, medullary thyroid carcinoma, or multiple endocrine neoplasia type 2. * Concurrent participation in another interventional pharmacological clinical trial. * Any condition that, in the investigator's judgment, may compromise participant safety, interfere with protocol compliance, or make participation inappropriate.