Study Design and Rationale of the ECMC-GART Phase 3 Clinical Study: Early-Stage Endometrial Cancer Based on Molecular Classification and Traditional Risk Stratification to Guide Adjuvant Radiotherapy Decisions

Background: Endometrial cancer (EC) represents a prevalent malignancy amongst women on a global scale, with adjuvant therapy strategy remaining inconsistent and controversial. Identifying subtypes integrated with molecular characteristics improves the understanding of cancer biology and consequently helps physicians make personalized therapeutic decision-making. Presented herewith is a study protocol detailing a phase III trial poised to integrate molecular profiling with traditional parameters for the stratification of early-stage EC. The ECMC-GART aims to compare the survival outcomes of integrated molecular classification with the conventional stratification system to provide evidence for further decision-making. Methods: The ECMC-GART trial is a randomized, national multicenter, Phase III, open-labeled, non-inferiority clinical study (Clinical trial registration: NCT05524389). The hypothesis is that adjuvant radiotherapy decision for early-stage endometrial cancer, which is based on molecular classification, can achieve de-escalation of adjuvant treatment without reducing local tumor control and survival, potentially further reducing radiotherapy-related toxicity and improving quality of life, compared to conventional risk stratification. The enrolled early-staged EC patients (FIGO stage I-II) will be randomized 2:1 into the experimental arm (molecular-clinicopathological classification-based treatment) and the control arm (conventional risk stratification-based treatment). The primary endpoint is the 3-year local recurrence rate. The secondary outcomes include failure-free survival, overall survival, de-escalation rate of treatment, acute and late toxicities, and Health-related cancer-specific quality of life (QLQC-30). The ECMC-GART is intended to enroll 624 EC patients to achieve the purpose of non-inferiority design ultimately. Discussion: The ECMC-GART will determine whether the molecular classification-based treatment is not inferior to the treatment based 15on previous conventional risk stratification, potentially allowing for de-escalation and individualized treatment recommendations. Trial registration: ClinicalTrails.gov, NCT05524389. Registered 23 November 2022, https://clinicaltrials.gov/study/NCT05524389