SHAPE-ENDO (Strategic Hormonal Approach & Prehabilitation in Endometrial Cancer): An Open-Label, Pilot Randomized Clinical Trial Comparing Standard Immediate Surgery Versus a Multimodal Metabolic Optimization and Prehabilitation Strategy Before Surgery in Patients With Atypical Endometrial Hyperplasia or Low-Risk Endometrioid Endometrial Cancer and BMI ≥40 kg/m²
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 80
- 主要终点
- Proportion of patients achieving predefined metabolic and clinical optimization criteria
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
No masking will be performed because of the nature of the interventions. Participants and investigators will know the assigned treatment strategy..
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Female participants ≥18 years old.
- •Histologically confirmed atypical endometrial hyperplasia/endometrial intraepithelial neoplasia (AEH/EIN) or low-risk endometrioid endometrial carcinoma, grade 1 or
- •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.
排除标准
- •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
- •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.
研究组 & 干预措施
Arm A - Standard Immediate Surgery
Participants randomized to the control arm will undergo standard immediate surgical treatment according to the institutional protocol of Hospital Universitari de Bellvitge. Surgery will usually include hysterectomy with bilateral salpingo-oophorectomy, sentinel lymph node assessment when indicated and feasible, and minimally invasive or robotic approach whenever technically possible according to clinical judgment.
Intervention: Procedure/Surgery - Standard Immediate Surgery Standard surgical management according to institutional practice for atypical endometrial hyperplasia/endometrial intraepithelial neoplasia or early-stage low-risk endometrioid endometrial cancer. Perioperative outcomes, surgical approach, conversion to laparotomy, estimated blood loss, operative time, hospital stay, transfusion, sentinel lymph node detection, intraoperative complications, and 30-day postoperative complications graded according to Clavien-Dindo will be recorded.
干预措施: Standar upfront Surgery (Procedure)
Arm B - Experimental: SHAPE-ENDO Multimodal Strategy Before Surgery
Participants randomized to the experimental arm will receive the SHAPE-ENDO multimodal pre-surgical optimization strategy before surgery. The strategy includes semaglutide/Wegovy®, levonorgestrel-releasing intrauterine device/Mirena® with or without oral medroxyprogesterone acetate/Progevera®, structured nutritional intervention, adapted physical exercise, and scheduled oncologic surveillance. The strategy will last 28 weeks initially and may be extended up to 54 weeks if there is clinical, metabolic, or anthropometric benefit, adequate tolerance, and no tumor progression.
Intervention: Drug - Semaglutide / Wegovy® Weekly subcutaneous semaglutide administered according to approved labeling, clinical indication, tolerance, and endocrinology assessment, with standard dose escalation up to the tolerated therapeutic dose. Dose, adherence, tolerability, adverse events, and reasons for dose modification or discontinuation will be recorded.
Intervention: Device - Levonorgestrel-Releasing I
干预措施: GLP-1 Receptor Agonist (Drug)
Arm B - Experimental: SHAPE-ENDO Multimodal Strategy Before Surgery
Participants randomized to the experimental arm will receive the SHAPE-ENDO multimodal pre-surgical optimization strategy before surgery. The strategy includes semaglutide/Wegovy®, levonorgestrel-releasing intrauterine device/Mirena® with or without oral medroxyprogesterone acetate/Progevera®, structured nutritional intervention, adapted physical exercise, and scheduled oncologic surveillance. The strategy will last 28 weeks initially and may be extended up to 54 weeks if there is clinical, metabolic, or anthropometric benefit, adequate tolerance, and no tumor progression.
Intervention: Drug - Semaglutide / Wegovy® Weekly subcutaneous semaglutide administered according to approved labeling, clinical indication, tolerance, and endocrinology assessment, with standard dose escalation up to the tolerated therapeutic dose. Dose, adherence, tolerability, adverse events, and reasons for dose modification or discontinuation will be recorded.
Intervention: Device - Levonorgestrel-Releasing I
干预措施: Oral Progestins (Drug)
Arm B - Experimental: SHAPE-ENDO Multimodal Strategy Before Surgery
Participants randomized to the experimental arm will receive the SHAPE-ENDO multimodal pre-surgical optimization strategy before surgery. The strategy includes semaglutide/Wegovy®, levonorgestrel-releasing intrauterine device/Mirena® with or without oral medroxyprogesterone acetate/Progevera®, structured nutritional intervention, adapted physical exercise, and scheduled oncologic surveillance. The strategy will last 28 weeks initially and may be extended up to 54 weeks if there is clinical, metabolic, or anthropometric benefit, adequate tolerance, and no tumor progression.
Intervention: Drug - Semaglutide / Wegovy® Weekly subcutaneous semaglutide administered according to approved labeling, clinical indication, tolerance, and endocrinology assessment, with standard dose escalation up to the tolerated therapeutic dose. Dose, adherence, tolerability, adverse events, and reasons for dose modification or discontinuation will be recorded.
Intervention: Device - Levonorgestrel-Releasing I
干预措施: Dietetic-Nutritional intervention (Behavioral)
Arm B - Experimental: SHAPE-ENDO Multimodal Strategy Before Surgery
Participants randomized to the experimental arm will receive the SHAPE-ENDO multimodal pre-surgical optimization strategy before surgery. The strategy includes semaglutide/Wegovy®, levonorgestrel-releasing intrauterine device/Mirena® with or without oral medroxyprogesterone acetate/Progevera®, structured nutritional intervention, adapted physical exercise, and scheduled oncologic surveillance. The strategy will last 28 weeks initially and may be extended up to 54 weeks if there is clinical, metabolic, or anthropometric benefit, adequate tolerance, and no tumor progression.
Intervention: Drug - Semaglutide / Wegovy® Weekly subcutaneous semaglutide administered according to approved labeling, clinical indication, tolerance, and endocrinology assessment, with standard dose escalation up to the tolerated therapeutic dose. Dose, adherence, tolerability, adverse events, and reasons for dose modification or discontinuation will be recorded.
Intervention: Device - Levonorgestrel-Releasing I
干预措施: Structured Exercise and Prehabilitation Program (Behavioral)
Arm B - Experimental: SHAPE-ENDO Multimodal Strategy Before Surgery
Participants randomized to the experimental arm will receive the SHAPE-ENDO multimodal pre-surgical optimization strategy before surgery. The strategy includes semaglutide/Wegovy®, levonorgestrel-releasing intrauterine device/Mirena® with or without oral medroxyprogesterone acetate/Progevera®, structured nutritional intervention, adapted physical exercise, and scheduled oncologic surveillance. The strategy will last 28 weeks initially and may be extended up to 54 weeks if there is clinical, metabolic, or anthropometric benefit, adequate tolerance, and no tumor progression.
Intervention: Drug - Semaglutide / Wegovy® Weekly subcutaneous semaglutide administered according to approved labeling, clinical indication, tolerance, and endocrinology assessment, with standard dose escalation up to the tolerated therapeutic dose. Dose, adherence, tolerability, adverse events, and reasons for dose modification or discontinuation will be recorded.
Intervention: Device - Levonorgestrel-Releasing I
干预措施: Endometrial Biopsy With or Without Hysteroscopy (Procedure)
Arm B - Experimental: SHAPE-ENDO Multimodal Strategy Before Surgery
Participants randomized to the experimental arm will receive the SHAPE-ENDO multimodal pre-surgical optimization strategy before surgery. The strategy includes semaglutide/Wegovy®, levonorgestrel-releasing intrauterine device/Mirena® with or without oral medroxyprogesterone acetate/Progevera®, structured nutritional intervention, adapted physical exercise, and scheduled oncologic surveillance. The strategy will last 28 weeks initially and may be extended up to 54 weeks if there is clinical, metabolic, or anthropometric benefit, adequate tolerance, and no tumor progression.
Intervention: Drug - Semaglutide / Wegovy® Weekly subcutaneous semaglutide administered according to approved labeling, clinical indication, tolerance, and endocrinology assessment, with standard dose escalation up to the tolerated therapeutic dose. Dose, adherence, tolerability, adverse events, and reasons for dose modification or discontinuation will be recorded.
Intervention: Device - Levonorgestrel-Releasing I
干预措施: Radiologic Surveillance (MRI and Transvaginal Ultrasound) (Procedure)
Arm B - Experimental: SHAPE-ENDO Multimodal Strategy Before Surgery
Participants randomized to the experimental arm will receive the SHAPE-ENDO multimodal pre-surgical optimization strategy before surgery. The strategy includes semaglutide/Wegovy®, levonorgestrel-releasing intrauterine device/Mirena® with or without oral medroxyprogesterone acetate/Progevera®, structured nutritional intervention, adapted physical exercise, and scheduled oncologic surveillance. The strategy will last 28 weeks initially and may be extended up to 54 weeks if there is clinical, metabolic, or anthropometric benefit, adequate tolerance, and no tumor progression.
Intervention: Drug - Semaglutide / Wegovy® Weekly subcutaneous semaglutide administered according to approved labeling, clinical indication, tolerance, and endocrinology assessment, with standard dose escalation up to the tolerated therapeutic dose. Dose, adherence, tolerability, adverse events, and reasons for dose modification or discontinuation will be recorded.
Intervention: Device - Levonorgestrel-Releasing I
干预措施: Levonorgestrel IUD (Lng-IUD) (Device)
结局指标
主要结局
Proportion of patients achieving predefined metabolic and clinical optimization criteria
时间窗: Up to 12 months
Optimization is defined as achieving ≥12-15% total body weight loss and/or reduction to BMI \<35 without evidence of tumor progression on histologic or radiologic assessment, enabling eligibility for minimally invasive surgery. Metabolic parameters (weight, BMI, waist circumference, HbA1c, blood pressure, and lipid profile) are recorded longitudinally. Progression is assessed through scheduled endometrial biopsy and imaging.
Recruitment Rate
时间窗: From study opening to end of recruitment, up to 36 months.
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.
Acceptance of Randomization Rate
时间窗: At baseline, before randomization.
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.
Participant Retention Rate
时间窗: From randomization to surgery and 30 days postoperatively, up to 14 months.
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.
Adherence to the Assigned Intervention
时间窗: From randomization to surgery and 30 days postoperatively, up to 14 months.
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.
Completion of the SHAPE-ENDO Multimodal Strategy
时间窗: From randomization to week 28 or week 54.
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.
Proportion of SHAPE-ENDO Participants Reaching Surgery Without Tumor Progression
时间窗: From randomization to surgery, up to 54 weeks.
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.
Incidence of Serious Adverse Events, Tumor Progression, and Study Discontinuation
时间窗: From randomization to surgery and 30 days postoperatively, up to 14 months.
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.
次要结局
- Perioperative Morbidity(At surgery and up to 30 days postoperatively.)
- Surgical Approach(At surgery.)
- Conversion to Laparotomy(At surgery.)
- Operative Time(At surgery.)
- Estimated Blood Loss(At surgery.)
- Length of Hospital Stay(From surgery to hospital discharge, up to 30 days.)
- Need for Blood Transfusion(At surgery and up to 30 days postoperatively.)
- Sentinel Lymph Node Detection Rate(At surgery.)
- Histological Response in the SHAPE-ENDO Arm(Baseline to week 14, week 28, and, if applicable, week 54.)
- Time to Optimization in the SHAPE-ENDO Arm(From randomization to week 28 or week 54)
- Rate of Surgery After SHAPE-ENDO Optimization(From randomization to surgery, up to 54 weeks.)
- Change in Glycated Hemoglobin(Baseline to 6 months and baseline to 12 months.)
- Change in Fasting Plasma Glucose(Baseline to 6 months and baseline to 12 months.)
- Change in Insulinemia and HOMA-IR(Baseline to 6 months and baseline to 12 months.)
- Change in FIB-4 Index(Baseline to 6 months and baseline to 12 months.)
- Change in Lipid Profile(Baseline to 6 months and baseline to 12 months.)
- Change in Blood Pressure(Baseline to 6 months and baseline to 12 months.)
- Change in C-Reactive Protein(Baseline to 6 months and baseline to 12 months.)
- Change in Body Weight and BMI(Baseline to 6 months and baseline to 12 months.)
- Change in Waist Circumference(Baseline to 6 months and baseline to 12 months.)
- Change in Visceral Adiposity by MRI(Baseline to week 28 and, if applicable, week 54.)
- Change in Body Composition by Bioelectrical Impedance Analysis(Baseline to week 28 and, if applicable, week 54.)
- Change in Health-Related Quality of Life Score - SF-36(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(Baseline to 6 months, 12 months, and during long-term follow-up up to 5 years.)
- Overall Survival(From randomization up to 5 years.)
- Cancer-Specific Survival(From randomization up to 5 years.)
- Recurrence-Free Survival(From randomization up to 5 years.)
- Change in Glycated Hemoglobin (HbA1c)(Baseline to 6 months and Baseline to 12 months)
- Histological Complete Response Rate of Endometrial Lesion(Baseline to 6 months and 12 months)
- Proportion of patients reaching eligibility for minimally invasive surgery(Up to 12 months)
- Change in Health-Related Quality of Life Score (SF-36)(Baseline to 12 months)
- Change in Serum Triglycerides(Baseline to 6 months and Baseline to 12 months)
- Incidence of adverse events related to standard-of-care treatments(Baseline to 12 months)
- Perioperative outcomes following minimally invasive surgery(At time of surgery and 30 days postoperatively)
- Changes in anthropometric measures (BMI, waist circumference, visceral adiposity)(Up to 12 months)
- Adherence to GLP-1 therapy, hormonal therapy, diet, and exercise interventions(Baseline to 12 months)
- Change in Fasting Plasma Glucose(Baseline to 6 months and Baseline to 12 months)
- Change in HDL Cholesterol(Baseline to 6 months and Baseline to 12 months)
- Change in LDL Cholesterol(Baseline to 6 months and Baseline to 12 months)
- Change in Blood Pressure(Baseline to 6 months and Baseline to 12 months)
- Change in C-Reactive Protein (CRP)(Baseline to 6 months and Baseline to 12 months)
- Change in Quality of Life Score (EORTC QLQ-C30)(Baseline to 12 months)
- Change in Functional Capacity(Baseline to 12 months)
研究者
Jorge García Fernández
Specialist in Gynaecology and Obstetrics
Hospital Universitari de Bellvitge