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NCT Number: NCT07462663

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

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.

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Key information

Conditions

Endometrial Cancer Atypical Endometrial Hyperplasia Atypical Endometrial Hyperplasia and Endometrial Carcinoma Stage I BMI>40 Body Weight Endometrial Cancer Stage I Endometrial Hyperplasia Endometrial Intraepithelial Neoplasia Endometrial Neoplasms Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Genital Diseases Genital Diseases, Female Genital Neoplasms, Female Neoplasms Neoplasms by Site Nutrition Disorders Nutritional and Metabolic Diseases Obesity Obesity & Overweight Obesity Grade III Overnutrition Overweight Pathological Conditions, Signs and Symptoms Signs and Symptoms Urogenital Diseases Urogenital Neoplasms Uterine Diseases Uterine Neoplasms

Age range

18 year and older

Sex eligibility

Female

Study type

Interventional

Phase

Phase 4

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

GLP-1 receptor agonist

Drug

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.

Other names: Semaglutide

Levonorgestrel IUD (Lng-IUD)

Device

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.

Other names: LNG-IUD

Oral Progestins

Drug

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.

Other names: Medroxyprogesterone acetate, Megestrol acetate, Progestin therapy

Dietetic-Nutritional intervention

Behavioral

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.

Other names: Hypocaloric diet program, Nutritional Counseling, Dietary Prehabiilitation

Structured Exercise and Prehabilitation Program

Behavioral

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

Other names: Exercise Prehabilitation, Supervised Physical Activity Program, Combined Aerobic and Strength Training

Endometrial Biopsy With or Without Hysteroscopy

Procedure

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.

Other names: Histological Surveillance, Endometrial Sampling, Hysteroscopy

Radiologic Surveillance (MRI and Transvaginal Ultrasound)

Procedure

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.

Other names: Pelvic MRI, Transvaginal Ultrasound, Imaging Surveillance

Standar upfront Surgery

Procedure

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.

Other names: Standard Surgery, BSO, Hysterectomy, Upfront Surgery

Primary outcomes

  1. Recruitment Rate

    Time frame: 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.

  2. Acceptance of Randomization Rate

    Time frame: 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.

  3. Participant Retention Rate

    Time frame: 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.

  4. Adherence to the Assigned Intervention

    Time frame: 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.

  5. Completion of the SHAPE-ENDO Multimodal Strategy

    Time frame: 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.

  6. Proportion of SHAPE-ENDO Participants Reaching Surgery Without Tumor Progression

    Time frame: 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.

  7. Incidence of Serious Adverse Events, Tumor Progression, and Study Discontinuation

    Time frame: 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.

Secondary outcomes

  1. Perioperative Morbidity

    Time frame: At surgery and up to 30 days postoperatively.

    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

  2. Surgical Approach

    Time frame: At surgery.

    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.

  3. Conversion to Laparotomy

    Time frame: At surgery.

    Proportion of participants requiring conversion from minimally invasive surgery to laparotomy, compared between the standard immediate surgery arm and the SHAPE-ENDO arm.

  4. Operative Time

    Time frame: At surgery.

    Duration of surgery measured in minutes, from skin incision to skin closure, compared between the standard immediate surgery arm and the SHAPE-ENDO arm.

  5. Estimated Blood Loss

    Time frame: At surgery.

    Estimated intraoperative blood loss measured in milliliters, compared between the standard immediate surgery arm and the SHAPE-ENDO arm.

  6. Length of Hospital Stay

    Time frame: From surgery to hospital discharge, up to 30 days.

    Number of days from surgery to hospital discharge, compared between the standard immediate surgery arm and the SHAPE-ENDO arm.

  7. Need for Blood Transfusion

    Time frame: At surgery and up to 30 days postoperatively.

    Proportion of participants requiring perioperative blood transfusion, compared between the standard immediate surgery arm and the SHAPE-ENDO arm

  8. Sentinel Lymph Node Detection Rate

    Time frame: At surgery.

    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.

  9. Histological Response in the SHAPE-ENDO Arm

    Time frame: Baseline to week 14, week 28, and, if applicable, week 54.

    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.

  10. Time to Optimization in the SHAPE-ENDO Arm

    Time frame: From randomization to week 28 or week 54

    Time from randomization to multidisciplinary committee decision indicating that sufficient clinical, metabolic, anthropometric, and oncologic optimization has been achieved to proceed to surgery.

  11. Rate of Surgery After SHAPE-ENDO Optimization

    Time frame: 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 strategy.

  12. Change in Glycated Hemoglobin

    Time frame: Baseline to 6 months and baseline to 12 months.

    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.

  13. Change in Fasting Plasma Glucose

    Time frame: Baseline to 6 months and baseline to 12 months.

    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.

  14. Change in Insulinemia and HOMA-IR

    Time frame: Baseline to 6 months and baseline to 12 months.

    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.

  15. Change in FIB-4 Index

    Time frame: Baseline to 6 months and baseline to 12 months.

    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.

  16. Change in Lipid Profile

    Time frame: Baseline to 6 months and baseline to 12 months.

    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.

  17. Change in Blood Pressure

    Time frame: Baseline to 6 months and baseline to 12 months.

    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.

  18. Change in C-Reactive Protein

    Time frame: Baseline to 6 months and baseline to 12 months.

    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.

  19. Change in Body Weight and BMI

    Time frame: Baseline to 6 months and baseline to 12 months.

    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.

  20. Change in Waist Circumference

    Time frame: Baseline to 6 months and baseline to 12 months.

    Change from baseline in waist circumference, measured in centimeters. Changes over time will be described within each arm and compared between both randomized arms.

  21. Change in Visceral Adiposity by MRI

    Time frame: Baseline to week 28 and, if applicable, week 54.

    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.

  22. Change in Body Composition by Bioelectrical Impedance Analysis

    Time frame: Baseline to week 28 and, if applicable, week 54.

    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.

  23. Change in Health-Related Quality of Life Score - SF-36

    Time frame: Baseline to 6 months, 12 months, and during long-term follow-up up to 5 years.

    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.

  24. Change in Quality of Life Score - EORTC QLQ-C30

    Time frame: Baseline to 6 months, 12 months, and during long-term follow-up up to 5 years.

    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.

  25. Overall Survival

    Time frame: From randomization up to 5 years.

    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.

  26. Cancer-Specific Survival

    Time frame: From randomization up to 5 years.

    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.

  27. Recurrence-Free Survival

    Time frame: From randomization up to 5 years.

    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.

Study contacts

Contact information is provided by the study sponsor or research team.

Jorge Garcia Fernandez, MD

CONTACT

[email protected]

+34 622595644

Sponsors and collaborators

Lead sponsor

Hospital Universitari de Bellvitge

Other

Collaborators

  • University of Barcelona

Registry information

Official study title

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

Acronym: SHAPE-ENDO

Important dates

Study start
2027
Primary completion
2031
Study completion
2035
First posted
Mar 10, 2026
Registry last updated
Jun 10, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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