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.