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

Official 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

Overview

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.

Detailed description

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.

Interventions

• 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.
• 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 can
• 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, app
• 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 a
• 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 outc
• 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 experim
• 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.
• 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 approa

Primary outcome measures

• Recruitment Rate [Time frame: From study opening to end of recruitment, up to 36 months.]
• Acceptance of Randomization Rate [Time frame: At baseline, before randomization.]
• Participant Retention Rate [Time frame: From randomization to surgery and 30 days postoperatively, up to 14 months.]
• Adherence to the Assigned Intervention [Time frame: From randomization to surgery and 30 days postoperatively, up to 14 months.]
• Completion of the SHAPE-ENDO Multimodal Strategy [Time frame: From randomization to week 28 or week 54.]
• Proportion of SHAPE-ENDO Participants Reaching Surgery Without Tumor Progression [Time frame: From randomization to surgery, up to 54 weeks.]
• Incidence of Serious Adverse Events, Tumor Progression, and Study Discontinuation [Time frame: From randomization to surgery and 30 days postoperatively, up to 14 months.]

Secondary outcome measures (12)

• Perioperative Morbidity [Time frame: At surgery and up to 30 days postoperatively.]
• Surgical Approach [Time frame: At surgery.]
• Conversion to Laparotomy [Time frame: At surgery.]
• Operative Time [Time frame: At surgery.]
• Estimated Blood Loss [Time frame: At surgery.]
• Length of Hospital Stay [Time frame: From surgery to hospital discharge, up to 30 days.]
• Need for Blood Transfusion [Time frame: At surgery and up to 30 days postoperatively.]
• Sentinel Lymph Node Detection Rate [Time frame: At surgery.]
• Histological Response in the SHAPE-ENDO Arm [Time frame: Baseline to week 14, week 28, and, if applicable, week 54.]
• Time to Optimization in the SHAPE-ENDO Arm [Time frame: From randomization to week 28 or week 54]
• Rate of Surgery After SHAPE-ENDO Optimization [Time frame: From randomization to surgery, up to 54 weeks.]
• Change in Glycated Hemoglobin [Time frame: Baseline to 6 months and baseline to 12 months.]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Concin N, Matias-Guiu X, Cibula D, Colombo N, Creutzberg CL, Ledermann J, Mirza MR, Vergote I, Abu-Rustum NR, Bosse T, Chargari C, Espenel S, Fagotti A, Fotopoulou C, Gatius S, Gonzalez-Martin A, Lax S, Levy B, Lorusso D, Macchia G, Marth C, Morice P, Oaknin A, Raspollini MR, Schwameis R, Sehouli J, Sturdza A, Taylor A, Westermann A, Wimberger P, Planchamp F, Nout RA. ESGO-ESTRO-ESP guidelines for PMID 40744042
• Iavazzo C, Gkegkes ID. Conservative management of patients with endometrial intraepithelial neoplasia (EIN): Factors that could affect response and pregnancy rates. Turk J Med Sci. 2022 Jun;52(3):870. doi: 10.55730/1300-0144.5384. Epub 2022 Jun 16. No abstract available. PMID 36326317
• Cui J, Zhao YC, She LZ, Wang TJ. Comparative effects of progestin-based combination therapy for endometrial cancer or atypical endometrial hyperplasia: a systematic review and network meta-analysis. Front Oncol. 2024 May 3;14:1391546. doi: 10.3389/fonc.2024.1391546. eCollection 2024. PMID 38764577
• Laurelli G, Falcone F, Gallo MS, Scala F, Losito S, Granata V, Cascella M, Greggi S. Long-Term Oncologic and Reproductive Outcomes in Young Women With Early Endometrial Cancer Conservatively Treated: A Prospective Study and Literature Update. Int J Gynecol Cancer. 2016 Nov;26(9):1650-1657. doi: 10.1097/IGC.0000000000000825. PMID 27654262
• Fan Z, Li H, Hu R, Liu Y, Liu X, Gu L. Fertility-Preserving Treatment in Young Women With Grade 1 Presumed Stage IA Endometrial Adenocarcinoma: A Meta-Analysis. Int J Gynecol Cancer. 2018 Feb;28(2):385-393. doi: 10.1097/IGC.0000000000001164. PMID 29266019
• Marnach ML, Butler KA, Henry MR, Hutz CE, Langstraat CL, Lohse CM, Casey PM. Oral Progestogens Versus Levonorgestrel-Releasing Intrauterine System for Treatment of Endometrial Intraepithelial Neoplasia<sup/> J Womens Health (Larchmt). 2017 Apr;26(4):368-373. doi: 10.1089/jwh.2016.5774. Epub 2016 Nov 30. PMID 27901412
• Bourou MZ, Matsas A, Valsamakis G, Vlahos N, Panoskaltsis T. The Potential Role of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists as a Type of Conservative Treatment of Endometrial Cancer in Women of Reproductive Age: A Review of the Literature and a Call for Study. Cureus. 2024 Sep 18;16(9):e69678. doi: 10.7759/cureus.69678. eCollection 2024 Sep. PMID 39429275
• Toliver JC, Divino V, Ng CD, Wang J. Real-World Weight Loss Among Patients Initiating Semaglutide 2.4 mg and Enrolled in WeGoTogether, a Digital Self-Support Application. Adv Ther. 2025 Oct;42(10):5010-5022. doi: 10.1007/s12325-025-03325-1. Epub 2025 Aug 6. PMID 40768192

Identifiers

NCT: NCT07462663 · SHAPE-ENDO

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗