SHAPE-ENDO is a single-center, open-label, pilot randomized clinical trial conducted atHospital Universitari de Bellvitge in Barcelona, Spain.The study will evaluate the feasibility, safety, and acceptability of comparing twotreatment strategies in women with atypical endometrial hyperplasia/endometrialintraepithelial neoplasia or low-risk endometrioid endometrial cancer and grade IIIobesity, defined as BMI ≥40 kg/m².Eligible participants will be randomized in a 1:1 ratio to one of two arms. The controlarm will undergo standard immediate surgery according to the institutional clinicalprotocol. The experimental arm will receive the SHAPE-ENDO multimodal pre-surgicaloptimization strategy before surgery.The SHAPE-ENDO strategy includes metabolic treatment with semaglutide/Wegovy®, localhormonal therapy with a levonorgestrel-releasing intrauterine device/Mirena® with orwithout 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 tumorprogression, the strategy may be extended up to 54 weeks before surgery.The primary objective is to evaluate the feasibility, safety, and acceptability of therandomized 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, andthe proportion of participants in the experimental arm who reach surgery without tumorprogression.Secondary outcomes include perioperative morbidity, histological response in theexperimental arm, metabolic and anthropometric changes, quality of life, treatmentadherence, safety and tolerability, and exploratory long-term oncologic outcomesincluding 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.
Drug: GLP-1 Receptor Agonist
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 Name: Semaglutide
Device: Levonorgestrel IUD (Lng-IUD)
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 Name: LNG-IUD
Drug: Oral Progestins
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 Name: Medroxyprogesterone acetate,Megestrol acetate,Progestin therapy
Behavioral: Dietetic-Nutritional intervention
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 Name: Hypocaloric diet program,Nutritional Counseling,Dietary Prehabiilitation
Behavioral: Structured Exercise and Prehabilitation Program
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 Name: Exercise Prehabilitation,Supervised Physical Activity Program,Combined Aerobic and Strength Training
Procedure: Endometrial Biopsy With or Without Hysteroscopy
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 Name: Histological Surveillance,Endometrial Sampling,Hysteroscopy
Procedure: Radiologic Surveillance (MRI and Transvaginal Ultrasound)
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 Name: Pelvic MRI,Transvaginal Ultrasound,Imaging Surveillance
Procedure: Standar upfront Surgery
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 Name: Standard Surgery,BSO,Hysterectomy,Upfront Surgery
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.
Not Provided
Jorge Garcia Fernandez, MD
+34 622595644
jorgarciafernan@gmail.com