Safety and Efficacy of NOM and OPFS Versus RO for dMMR/MSI-H or POLE-Mutated Gastrointestinal Cancers

Overview

Purpose: The purpose of this study is to evaluate the safety and efficacy of Non-Operative Management (NOM) and Organ Preservation First Strategy (OPFS) compared with Radical Operation (RO) in patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or POLE-mutated gastrointestinal cancers. Background \& Design: With the remarkable efficacy of neoadjuvant immunotherapy in dMMR/MSI-H or POLE-mutated gastrointestinal tumors, organ preservation has become a promising alternative to highly invasive surgeries. The NOR-MP trial is a single-center, bidirectional registry study consisting of two parts: a retrospective cohort study and a prospective observational registry. Intervention Group (NOM/OPFS): Patients who achieve a clinical complete response (cCR) or near-cCR after neoadjuvant immunotherapy will undergo a "Watch \& Wait" (W\&W) strategy. Patients with near-cCR or non-cCR who are eligible for organ preservation will undergo local excision (LE) or endoscopic resection (including ESD or EMR). Comparison Group (Radical Operation): Patients who undergo standard radical surgical resection after neoadjuvant immunotherapy. The study aims to determine whether an organ-preserving approach can achieve comparable oncological outcomes and safety profiles while significantly improving patients' quality of life compared to radical surgery.

The NOR-MP trial is a single-center, bidirectional registry study designed to compare the clinical outcomes of Organ Preservation First Strategy (OPFS) / Non-Operative Management (NOM) against standard Radical Operation (RO) for patients diagnosed with dMMR/MSI-H or POLE-mutated gastrointestinal cancers. The study is divided into two sequential parts based on the nature of data collection: Part 1: Retrospective Cohort Study This part retrospectively reviews the medical records of eligible patients with dMMR/MSI-H or POLE-mutated gastrointestinal cancers who previously completed neoadjuvant immunotherapy. Patients are allocated into two historical cohorts: Experimental Cohort (NOM/OPFS): Patients who achieved cCR/near-cCR after neoadjuvant immunotherapy and entered the "Watch \& Wait" (W\&W) program, as well as those with near-cCR or non-cCR who underwent local excision (LE) or endoscopic resection (including Endoscopic Submucosal Dissection \[ESD\] or Endoscopic Mucosal Resection \[EMR\]). Control Cohort (RO): Patients who underwent radical surgical operation after neoadjuvant immunotherapy. Pathological outcomes (including the proportions of ypCR, ypTisN0, and ypT1-2N0) and surgical safety data will be collected and analyzed. Part 2: Prospective Registry Study This part prospectively enrolls newly diagnosed patients with dMMR/MSI-H or POLE-mutated gastrointestinal cancers receiving neoadjuvant immunotherapy. Following treatment evaluation by the multi-disciplinary NOR-MP research team, patients are enrolled into two parallel observational tracks: Experimental Cohort (NOM/OPFS): Patients eligible for and consenting to NOM or OPFS. This includes the W\&W strategy for those achieving cCR/near-cCR, and LE or endoscopic resection (ESD/EMR) for those with near-cCR or non-cCR. Control Cohort (RO): Patients who proceed to standard radical operation. Pathological response distribution (proportions of ypCR, ypTisN0, ypT1-2N0, and ypT3+ diseases) and short-to-long-term surgical safety endpoints will be prospectively documented. By comparing the retrospective and prospective cohorts, this study evaluates whether the omission of radical surgery is oncologically safe and preserves organ function without compromising long-term survival.