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

Official title

Safety and Efficacy of Nonoperative Management (NOM) and Organ Preservation First Strategy (OPFS) Versus Radical Operation (RO) for dMMR/MSI-H or POLE-Mutated Gastrointestinal Cancers: A Single-Center, Bidirectional Registry Study

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.

Detailed description

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.

Interventions

• Other 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.

Primary outcome measures

• Organ Preservation Rate (for OPFS/NOM group) [Time frame: Up to 3 years after the completion of neoadjuvant immunotherapy.]

Secondary outcome measures (5)

• Surgical Safety and Postoperative Complications [Time frame: Within 30 days and 90 days post-surgery.]
• Pathological Response Distribution (for RO group) [Time frame: At the time of radical surgery (typically within 4-12 weeks post-immunotherapy).]
• Local Regrowth / Recurrence Rate [Time frame: Followed up at regular intervals (every 3-6 months) up to 3 years.]
• Overall Survival (OS) [Time frame: Up to 5 years.]
• Disease-Free Survival (DFS) / Disease-Specific Survival (DSS) [Time frame: From enrollment/treatment initiation up to 5 years.]

Eligibility criteria

Inclusion criteria

• Histologically confirmed primary gastrointestinal adenocarcinoma or squamous cell carcinoma (e.g., colorectal cancer, gastric cancer, gastroesophageal junction cancer).
• Confirmed as deficient mismatch repair (dMMR) by immunohistochemistry (IHC), high microsatellite instability (MSI-H) by polymerase chain reaction (PCR) or next-generation sequencing (NGS), or harboring POLE exonuclease domain mutations.
• Received neoadjuvant/conversion immunotherapy (immune checkpoint inhibitors, either monotherapy or combination therapy) prior to treatment response evaluation.
• For the Retrospective Cohort (Part 1): Patients treated between \[Start Month/Year\] and \[End Month/Year\] who completed evaluation and subsequent strategy (NOM/OPFS or RO).
• For the Prospective Cohort (Part 2): Newly diagnosed patients who consent to long-term follow-up and multi-disciplinary team (MDT) assessment for organ preservation or radical surgery.
• Age ≥ 18 years at the time of diagnosis.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Exclusion criteria

• Concurrently diagnosed with other active malignant tumors within the past 5 years.
• Patients with proficient mismatch repair (pMMR) / microsatellite stable (MSS) tumors, or wild-type POLE status.
• Evidence of untreatable distant metastasis or systemic disease that precludes local tumor management (NOM/OPFS or radical operation).
• Inability to undergo regular endoscopic, radiological (MRI/CT), or clinical follow-up due to compliance or geographic reasons.
• Refusal to sign the informed consent form (applicable to the prospective cohort).

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

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07642323 · PKUCH-NORMP trial

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗