Background: Microsatellite instability-high (MSI-H) colon cancer with isolated peritoneal metastases (iPM) represents a molecularly and anatomically distinct clinical subset with limited evidence to guide treatment. Given the unique immunogenic profile of MSI-H tumors and the historically poor prognosis of peritoneal dissemination, we evaluated the association of immunotherapy, chemotherapy, and surgery with survival outcomes in this population. Methods: Using the National Cancer Database, we identified patients with MSI-H colon cancer and iPM diagnosed between 2016–2021. Patients were stratified by systemic therapy type (immunotherapy, chemotherapy, combination) and surgical resection status. Kaplan–Meier and multivariable Cox regression analyses were used to assess overall survival (OS). Results: Among 598 patients, 22% received systemic treatment with immunotherapy and 76% underwent surgical resection. Immunotherapy was associated with significantly longer median OS compared to chemotherapy (33 vs. 18 months, p < 0.001). On multivariable analysis, immunotherapy remained independently associated with improved survival (HR: 0.46; p < 0.001). Surgical resection of the primary tumor with (HR: 0.40; p < 0.001) or without metastatectomy (HR: 0.41; p < 0.001) was associated with longer survival, and the combination of surgery and immunotherapy yielded the greatest survival benefit. Conclusions: Patients with MSI-H colon cancer and iPM treated with immunotherapy had significantly improved survival, compared to chemotherapy. Surgical resection combined with immunotherapy is associated with the greatest survival benefit, supporting a multimodal approach. These findings provide real-world evidence supporting integration of immunotherapy and surgery in this molecularly and anatomically distinct population.

PAST Risk stratification for adjuvant treatment of colon cancer primarily relies on clinicopathologic variables. 1 Decisions regarding adjuvant therapy are often guided by these factors; however, 15-20% of stage II patients who forgo adjuvant treatment experience recurrence. 2 Identifying high-risk, node-negative colon cancer patients remains a significant challenge. With the advent of routine molecular testing, genomic data could complement clinicopathologic features to guide treatment decisions, particularly for early-stage disease.