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.