SHAPE-ENDO: Multimodal Pre-Surgical Optimization in Patients With Obesity and Early-Stage Endometrial Cancer (Phase 1)

SHAPE-ENDO is a prospective, single-center, observational cohort study conducted at Hospital Universitari de Bellvitge (Barcelona, Spain), designed to evaluate a multimodal pre-surgical optimization strategy in women with severe obesity (BMI ≥40 kg/m²) and atypical endometrial hyperplasia or early-stage, low-risk endometrial cancer. This strategy reflects current clinical practice in selected patients in whom immediate surgery may be associated with increased perioperative risk due to obesity and comorbidities. Instead of upfront surgery, patients undergo a structured optimization program aimed at improving metabolic status while maintaining local oncologic control. The multimodal intervention includes standard-of-care treatments: * Pharmacological metabolic therapy with glucagon-like peptide-1 receptor agonists (GLP-1 RAs, e.g., semaglutide) or dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists (GIP/GLP-1 RAs, e.g., tirzepatide), according to clinical indication and availability * Local hormonal treatment with a levonorgestrel-releasing intrauterine device (LNG-IUD), with or without oral progestins * Structured nutritional intervention * Supervised physical exercise program * Scheduled clinical, imaging, and histological surveillance The study is structured in two phases: Phase 1 (prospective cohort phase): Participants are followed during a 28-54 week prehabilitation period to evaluate the proportion of patients achieving predefined optimization criteria, including significant weight loss, improved metabolic status, adequate anesthetic risk profile, and absence of tumor progression. Secondary outcomes include histological response, treatment adherence, quality of life, and feasibility of subsequent surgical management. Phase 2 (long-term follow-up and comparative phase): Participants from the prospective cohort will be followed longitudinally for a minimum of 5 years to assess overall survival, disease-specific survival, recurrence rates, long-term metabolic outcomes, and quality of life. In addition, outcomes will be compared with a historical cohort of patients with similar baseline characteristics (BMI ≥40 kg/m²) previously treated at the same institution, with particular focus on surgical morbidity and survival outcomes. All interventions are part of routine clinical care and are administered according to current clinical guidelines and physician judgment. The primary objective of the study is to evaluate whether this multimodal strategy can improve surgical eligibility and reduce perioperative risk without compromising oncologic safety, while potentially impacting long-term survival and quality of life in this high-risk population. Findings from SHAPE-ENDO may provide evidence to support a paradigm shift toward integrated metabolic and oncologic management in patients with obesity and early-stage endometrial cancer, and may inform future controlled comparative studies.

Obesity is a major modifiable risk factor for endometrial cancer and is associated with increased surgical complexity, higher perioperative morbidity, and reduced eligibility for minimally invasive surgery. In patients with severe obesity, overall mortality is frequently driven by metabolic and cardiovascular comorbidities rather than by cancer progression. Therefore, strategies aimed at improving metabolic health and functional status may have important implications for both surgical outcomes and long-term prognosis. In selected patients with atypical endometrial hyperplasia or early-stage, low-risk endometrioid carcinoma, conservative hormonal management is widely used to achieve local disease control. At the same time, pharmacological metabolic therapies-including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists (GIP/GLP-1 RAs)-have demonstrated substantial weight loss and cardiometabolic benefits in patients with obesity. Despite these advances, there is a lack of structured clinical approaches integrating oncologic control with metabolic optimization in this population. In routine clinical practice at our institution, selected patients with severe obesity and early-stage endometrial disease who are not optimal candidates for immediate surgery undergo a multimodal optimization strategy combining hormonal treatment, metabolic therapy, and lifestyle intervention, with close clinical and histological monitoring. The SHAPE-ENDO study is designed to systematically evaluate this real-world clinical approach. It aims to assess whether such a multimodal strategy can improve clinical condition and surgical eligibility without compromising oncologic control, while potentially impacting long-term outcomes such as survival and quality of life. This study may contribute to the development of integrated care models addressing both cancer and obesity-related comorbidity in patients with early-stage endometrial disease

Inclusion Criteria: * Women ≥18 years old. * Histologically confirmed Atypical Endometrial Hyperplasia / EIN or low-risk endometrioid endometrial carcinoma (G1-G2), confined to uterine body. * Classified as low/intermediate risk per ESGO-ESTRO-ESP 2025; presurgical stages IA1, IA2 or IB. * Negative or focal LVSI (if available). * Molecular subgroups: POLEmut, p53wt, MMRd or NSMP ER+. * BMI ≥35 kg/m² at inclusion. * Acceptance of temporary conservative management and ability to follow multimodal optimization strategy. * Ability to understand and sign informed consent. Exclusion Criteria: * FIGO stages IA3, IC, II or higher. * Positive lymphovascular invasion. * High-risk molecular: p53mut or NSMP ER-negative. * Non-endometrioid histologies (serous, clear cell, carcinosarcoma, mixed, etc.). * Metastatic or extra-uterine disease. * Contraindication to GLP-1RA or progestogens. * Previous pancreatitis, MEN-2, medullary thyroid carcinoma. * Participation in another pharmacological trial. * Any condition that in investigator judgment impairs safety or compliance.