Development of the Perihilar Cholangiocarcinoma Risk Estimation of Tumor Recurrence After Transplant (PRETREAT) Score

OBJECTIVE: To develop and validate a risk score for predicting post-transplant recurrence in perihilar cholangiocarcinoma (pCCA) patients. BACKGROUND: pCCA is an aggressive malignancy with a poor prognosis. Although neoadjuvant chemoradiation (CRT) followed by liver transplantation (LT) offers a potential cure for patients with unresectable, early-stage de novo or primary sclerosing cholangitis (PSC)-associated pCCA, post-transplant recurrence negatively impacts survival. Currently, no risk stratification tools exist. METHODS: This retrospective study included consecutive patients with unresectable de novo or PSC-associated pCCA who underwent neoadjuvant CRT followed by LT at Mayo Clinic (1993-2024). Predictors of post-transplant recurrence were identified using multivariable Cox regression with LASSO variable selection. The Perihilar Cholangiocarcinoma Risk Estimation of Tumor Recurrence after Transplant (PRETREAT) risk score was created by assigning points from model coefficients. Score performance was evaluated by discrimination (c-statistic), internally validated with 10-fold cross-validation, and externally validated in a separate cohort. Survival outcomes were compared across 3 PRETREAT risk groups and between 2 time periods. RESULTS: This study included 399 patients (development: 301; validation: 98). The 5-year cumulative incidence of post-transplant recurrence was 29.7% in the development cohort and 27.6% in the validation cohort. Multivariable analysis identified 4 independent predictors: macroscopic residual tumor on explant [hazard ratio (HR): 12.4], vascular encasement (HR: 2.18), lymphovascular invasion (HR: 2.04), and radial tumor diameter (HR: 1.02/mm). The PRETREAT score (0-22), based on these factors, demonstrated excellent performance in both internal and external validation (C-index 0.83 and 0.85, respectively). Patients were stratified into low-risk (0-7), moderate-risk (8-15), and high-risk (16-22) groups. The 5-year recurrence-free survival rates significantly differed across low-risk, moderate-risk, and high-risk groups (89.0%, 38.3%, and 15.4%, respectively; P <0.001). Over the last decade, overall survival improved significantly only in moderate-risk patients (70.4% vs 46.9%, P =0.024), without significant improvement in recurrence-free survival. CONCLUSIONS: The PRETREAT score provides a valuable tool for guiding post-transplant management of pCCA, enabling risk-stratified surveillance, and laying the foundation for future clinical trials.