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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
80
Weekly subcutaneous semaglutide/GLP-1 receptor agonist therapy administered according to approved labeling, clinical indication, patient tolerance, and endocrinology assessment, with standard dose escalation up to the tolerated therapeutic dose. The intervention is used for weight loss and metabolic optimization in participants with severe obesity. Dose, adherence, tolerability, and reasons for dose modification or discontinuation will be recorded prospectively.
Local hormonal therapy using a 52-mg levonorgestrel-releasing intrauterine system placed at baseline or within 14 days after baseline, with ultrasound confirmation of correct placement. The LNG-IUD is used within the protocolized SHAPE-ENDO strategy according to clinical indication, approved labeling, current guidelines, and physician judgment, for local disease control in atypical endometrial hyperplasia/endometrial intraepithelial neoplasia or early-stage, low-risk endometrioid endometrial cancer. Tolerability, continuation, adverse events, and local histological response will be recorded prospectively.
Systemic hormonal therapy prescribed according to clinical criteria to support local disease control in atypical endometrial hyperplasia or early-stage endometrioid carcinoma. Typical regimens include medroxyprogesterone acetate (400-600 mg/day) or megestrol acetate (160-320 mg/day). Therapy is initiated or escalated when indicated based on tumor burden or suboptimal response to LNG-IUD. Oral progestins may be used within the protocolized SHAPE-ENDO strategy according to clinical indication, approved labeling, current guidelines, and physician judgment. Use, dosing, tolerance, and outcomes will be recorded prospectively.
Personalized hypocaloric diet plan supervised by the clinical nutrition team as part of standard obesity and metabolic management. The program includes caloric restriction based on basal metabolic requirements, with the option of very low-calorie diets (VLCD) for 4-6 weeks in selected cases. Follow-up occurs at regular outpatient visits with recording of weight, BMI, waist circumference, and adherence. This intervention is part of routine clinical care and not assigned experimentally; outcomes are recorded prospectively.
A structured physical exercise program designed to improve functional capacity, aerobic tolerance, and surgical fitness. Program includes supervised or semi-supervised weekly sessions combining aerobic and strength training, typically 3 sessions per week for 30-45 minutes, adapted to baseline performance. The intervention is part of routine clinical care for patients with obesity undergoing surgical preparation and is not assigned experimentally. Data on adherence, tolerance, and functional outcomes are collected prospectively
Scheduled histological surveillance performed at baseline and at follow-up intervals (typically 14 and 28-54 weeks) to assess local tumor status, including complete response, stability, or progression. Procedures include outpatient endometrial biopsy with optional hysteroscopy based on clinical indication. These evaluations form part of standard clinical care in patients managed conservatively for atypical endometrial hyperplasia or early-stage endometrioid carcinoma and are not assigned experimentally. Data are recorded prospectively to assess disease evolution and surgical eligibility.
Radiologic evaluation using pelvic MRI and transvaginal ultrasound performed as part of routine clinical care to assess uterine disease, myometrial invasion, adnexal status, and treatment response. Imaging is typically performed at baseline to confirm staging and during follow-up when clinically indicated. These imaging modalities are used per standard clinical guidelines and are not assigned experimentally; results are collected prospectively to evaluate disease stability and surgical planning.
Standard surgical treatment according to the institutional protocol of Hospital Universitari de Bellvitge for atypical endometrial hyperplasia/endometrial intraepithelial neoplasia or early-stage low-risk endometrioid endometrial cancer. Surgery will usually include hysterectomy with bilateral salpingo-oophorectomy, sentinel lymph node assessment when indicated and feasible, and a minimally invasive or robotic approach whenever technically possible according to clinical judgment. Surgical approach, operative time, estimated blood loss, conversion to laparotomy, transfusion, hospital stay, intraoperative complications, 30-day postoperative complications, readmission, and sentinel lymph node detection will be recorded.
Recruitment Rate
Number of participants enrolled per month during the active recruitment period. This outcome will assess the feasibility of recruiting eligible participants with atypical endometrial hyperplasia/endometrial intraepithelial neoplasia or low-risk endometrioid endometrial cancer and BMI ≥40 kg/m² into a pilot randomized clinical trial.
Time frame: From study opening to end of recruitment, up to 36 months.
Acceptance of Randomization Rate
Proportion of eligible participants who agree to participate in the trial and accept random assignment to either standard immediate surgery or the SHAPE-ENDO multimodal pre-surgical optimization strategy.
Time frame: At baseline, before randomization.
Participant Retention Rate
Proportion of randomized participants who complete the planned follow-up required for the main pilot analysis, including surgical treatment and 30-day postoperative assessment, or completion of the assigned intervention period when applicable.
Time frame: From randomization to surgery and 30 days postoperatively, up to 14 months.
Adherence to the Assigned Intervention
Proportion of randomized participants who comply with the main procedures planned in their assigned arm. In the control arm, this includes undergoing standard immediate surgery and postoperative follow-up. In the SHAPE-ENDO arm, this includes adherence to the multimodal strategy, scheduled visits, oncologic surveillance, and planned reassessment.
Time frame: From randomization to surgery and 30 days postoperatively, up to 14 months.
Completion of the SHAPE-ENDO Multimodal Strategy
Proportion of participants randomized to the SHAPE-ENDO arm who complete the planned multimodal pre-surgical optimization strategy until the week 28 reassessment and, when applicable, until week 54.
Time frame: From randomization to week 28 or week 54.
Proportion of SHAPE-ENDO Participants Reaching Surgery Without Tumor Progression
Proportion of participants randomized to the SHAPE-ENDO arm who undergo surgery after the pre-surgical optimization period without histological, radiological, or clinical evidence of tumor progression.
Time frame: From randomization to surgery, up to 54 weeks.
Incidence of Serious Adverse Events, Tumor Progression, and Study Discontinuation
Frequency of serious adverse events, tumor progression during the optimization period, and reasons for discontinuation or withdrawal from the study. Adverse events will be recorded prospectively and classified according to CTCAE v5.0 when applicable. These events will be described overall and by randomized arm when applicable.
Time frame: From randomization to surgery and 30 days postoperatively, up to 14 months.
Perioperative Morbidity
Proportion of participants with intraoperative complications and/or clinically relevant postoperative complications within 30 days after surgery, compared between the standard immediate surgery arm and the SHAPE-ENDO arm. Postoperative complications will be classified according to the Clavien-Dindo classification, with clinically relevant complications defined as Clavien-Dindo grade ≥II
Time frame: At surgery and up to 30 days postoperatively.
Surgical Approach
Proportion of participants undergoing minimally invasive surgery, robotic surgery, conventional laparoscopy, or laparotomy, compared between the standard immediate surgery arm and the SHAPE-ENDO arm.
Time frame: At surgery.
Conversion to Laparotomy
Proportion of participants requiring conversion from minimally invasive surgery to laparotomy, compared between the standard immediate surgery arm and the SHAPE-ENDO arm.
Time frame: At surgery.
Operative Time
Duration of surgery measured in minutes, from skin incision to skin closure, compared between the standard immediate surgery arm and the SHAPE-ENDO arm.
Time frame: At surgery.
Estimated Blood Loss
Estimated intraoperative blood loss measured in milliliters, compared between the standard immediate surgery arm and the SHAPE-ENDO arm.
Time frame: At surgery.
Length of Hospital Stay
Number of days from surgery to hospital discharge, compared between the standard immediate surgery arm and the SHAPE-ENDO arm.
Time frame: From surgery to hospital discharge, up to 30 days.
Need for Blood Transfusion
Proportion of participants requiring perioperative blood transfusion, compared between the standard immediate surgery arm and the SHAPE-ENDO arm
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Time frame: At surgery and up to 30 days postoperatively.
Sentinel Lymph Node Detection Rate
Proportion of participants in whom sentinel lymph node mapping is successful, including unilateral and bilateral detection rates when sentinel lymph node assessment is performed. Detection rates will be described and compared between the standard immediate surgery arm and the SHAPE-ENDO arm.
Time frame: At surgery.
Histological Response in the SHAPE-ENDO Arm
Proportion of participants in the SHAPE-ENDO arm with complete response, stable disease, or tumor progression during the pre-surgical optimization period. Complete response is defined as absence of endometrioid carcinoma or atypical hyperplasia in endometrial biopsy. Stable disease is defined as persistence of the lesion without progression in grade or stage. Progression is defined as progression from atypical endometrial hyperplasia/endometrial intraepithelial neoplasia to endometrioid endometrial carcinoma, increase to grade 3, high-risk histology, or extension beyond the uterine corpus.
Time frame: Baseline to week 14, week 28, and, if applicable, week 54.
Time to Optimization in the SHAPE-ENDO Arm
Time from randomization to multidisciplinary committee decision indicating that sufficient clinical, metabolic, anthropometric, and oncologic optimization has been achieved to proceed to surgery.
Time frame: From randomization to week 28 or week 54
Rate of Surgery After SHAPE-ENDO Optimization
Proportion of participants randomized to the SHAPE-ENDO arm who undergo surgery after the pre-surgical optimization strategy.
Time frame: From randomization to surgery, up to 54 weeks.
Change in Glycated Hemoglobin
Change from baseline in glycated hemoglobin, measured as HbA1c percentage using standard clinical laboratory assays. Changes over time will be described within each arm and compared between the standard immediate surgery arm and the SHAPE-ENDO arm.
Time frame: Baseline to 6 months and baseline to 12 months.
Change in Fasting Plasma Glucose
Change from baseline in fasting plasma glucose concentration, measured in mg/dL using standard laboratory assays. Changes over time will be described within each arm and compared between both randomized arms.
Time frame: Baseline to 6 months and baseline to 12 months.
Change in Insulinemia and HOMA-IR
Change from baseline in fasting insulin concentration and HOMA-IR, when available. Changes over time will be described within each arm and compared between both randomized arms.
Time frame: Baseline to 6 months and baseline to 12 months.
Change in FIB-4 Index
Change from baseline in fibrosis-4 index, calculated using age, AST, ALT, and platelet count. Changes over time will be described within each arm and compared between both randomized arms.
Time frame: Baseline to 6 months and baseline to 12 months.
Change in Lipid Profile
Change from baseline in triglycerides, LDL cholesterol, and HDL cholesterol measured using standard laboratory lipid panel testing. Changes over time will be described within each arm and compared between both randomized arms.
Time frame: Baseline to 6 months and baseline to 12 months.
Change in Blood Pressure
Change from baseline in systolic and diastolic blood pressure, measured in mmHg during scheduled clinical visits. Changes over time will be described within each arm and compared between both randomized arms.
Time frame: Baseline to 6 months and baseline to 12 months.
Change in C-Reactive Protein
Change from baseline in serum C-reactive protein concentration, measured in mg/L using standard laboratory assays. Changes over time will be described within each arm and compared between both randomized arms.
Time frame: Baseline to 6 months and baseline to 12 months.
Change in Body Weight and BMI
Absolute and percentage change from baseline in body weight and body mass index. Changes over time will be described within each arm and compared between both randomized arms.
Time frame: Baseline to 6 months and baseline to 12 months.
Change in Waist Circumference
Change from baseline in waist circumference, measured in centimeters. Changes over time will be described within each arm and compared between both randomized arms.
Time frame: Baseline to 6 months and baseline to 12 months.
Change in Visceral Adiposity by MRI
Absolute and percentage change from baseline in visceral adiposity measured by pelvic MRI according to the predefined radiologic measurement protocol. Changes over time will be described within each arm and compared between both randomized arms.
Time frame: Baseline to week 28 and, if applicable, week 54.
Change in Body Composition by Bioelectrical Impedance Analysis
Change from baseline in body composition parameters measured by bioelectrical impedance analysis. Changes over time will be described within each arm and compared between both randomized arms.
Time frame: Baseline to week 28 and, if applicable, week 54.
Change in Health-Related Quality of Life Score - SF-36
Change from baseline in health-related quality of life assessed using the Short Form-36 Health Survey. Scores range from 0 to 100, with higher scores indicating better health-related quality of life. Changes over time will be described within each arm and compared between both randomized arms.
Time frame: Baseline to 6 months, 12 months, and during long-term follow-up up to 5 years.
Change in Quality of Life Score - EORTC QLQ-C30
Change from baseline in quality of life assessed using the EORTC QLQ-C30 questionnaire. Scores range from 0 to 100 according to EORTC scoring guidelines. Changes over time will be described within each arm and compared between both randomized arms.
Time frame: Baseline to 6 months, 12 months, and during long-term follow-up up to 5 years.
Overall Survival
Time from randomization to death from any cause. Participants alive at the end of follow-up will be censored at the date of last contact.
Time frame: From randomization up to 5 years.
Cancer-Specific Survival
Time from randomization to death from endometrial cancer. Participants alive or deceased from causes unrelated to endometrial cancer will be censored according to the statistical analysis plan.
Time frame: From randomization up to 5 years.
Recurrence-Free Survival
Time from randomization to first documented recurrence of endometrial cancer. Recurrence may be defined by histological, radiological, or clinical evidence according to standard follow-up criteria. Participants without recurrence will be censored at the date of last available follow-up.
Time frame: From randomization up to 5 years.