Recurrence After Resection of Colorectal Liver Metastases and Its Impact on Survival: A Multistate Model-Based, Multi-institutional Observational Cohort Study

Background Conventional survival analyses cannot fully account for recurrence as an intermediate event that dynamically influences subsequent mortality. Multistate models (MSMs) enable explicit modeling of transitions between clinically relevant disease states; however, their application among patients undergoing resection for colorectal liver metastases (CRLM) remains limited. Methods An international multi-institutional database was queried to identify patients undergoing curative-intent hepatectomy for CRLM between 1998 and 2023. A four-state MSM was constructed comprising alive and recurrence-free, alive with recurrence, colorectal cancer (CRC)-related death, and non-CRC-related death. Transition probabilities and transition-specific prognostic factors were evaluated Results Among 3002 patients, 1624 (54.1%) developed recurrence and 911 (56.1%) died, predominantly from CRC-related causes (92.8%). The probability of recurrence decreased substantially the longer patients remained recurrence-free after surgery, whereas recurrence markedly worsened subsequent prognosis. High tumor burden score was independently associated with transition to recurrence (hazard ratio [HR] 1.06 per unit; 95% confidence interval 1.03–1.08; p < 0.001) but not post-recurrence mortality, suggesting that the adverse prognostic impact of tumor burden was mediated primarily through recurrence. Adjuvant chemotherapy reduced recurrence (HR 0.76; p = 0.005) and CRC-related death from the recurrence-free state (HR 0.39; p = 0.002). Conclusion MSMs provide a dynamic framework to characterize disease evolution after CRLM resection and represent recurrence as a clinically meaningful time-dependent intermediate state rather than a simple binary endpoint. Recurrence was the dominant determinant of long-term prognosis, supporting the role of MSMs for individualized prognostication and surveillance after hepatectomy for CRLM.