Immunotherapy Plus Surgery Improves Survival in Microsatellite Instability-High Colon Cancer with Isolated Peritoneal Metastases

TL;DR

Adding immunotherapy and surgery improves survival for colon cancer patients with specific genetic features and peritoneal metastases.

Contribution

Combining immunotherapy and surgery is shown to be most effective for a specific type of colon cancer with peritoneal metastases.

Findings

Immunotherapy improves survival more than chemotherapy in MSI-H colon cancer with peritoneal metastases.

Surgical resection combined with immunotherapy provides the greatest survival benefit.

Prospective trials are needed to optimize treatment sequencing for this patient group.

Abstract

Microsatellite instability-high (MSI-H) colon cancer is characterized by impaired DNA mismatch repair and robust responsiveness to immune checkpoint inhibition. However, the optimal management of patients with isolated peritoneal metastases (iPM), a site of spread associated with historically poor prognosis, remains poorly defined. Leveraging national real-world data, this study demonstrates that immunotherapy is associated with significantly improved survival compared to chemotherapy in patients with MSI-H colon cancer and iPM. Importantly, the combination of immunotherapy and surgical resection resulted in the greatest survival benefit. These findings challenge conventional paradigms that discourage surgery in metastatic disease and support a multimodal treatment strategy for this biologically distinct and clinically challenging patient population. The results highlight the need for prospective trials to define optimal sequencing and integration of surgery and immunotherapy in MSI-H colorectal cancer with peritoneal involvement.

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.

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