The landscape of hepatocellular carcinoma recurrence after liver transplantation: a nationwide 14-year study

Background & Aims Recurrence of hepatocellular carcinoma (r-HCC) remains a major determinant of post-transplant (LT) outcomes. The 2024 ILTS-ILCA consensus highlighted the need for contemporary data assessing how evolving selection criteria and therapeutic strategies over the past 15 years have influenced prognosis. Methods We conducted a retrospective study including all patients diagnosed with r-HCC following LT between 2008 and 2020 across 15 French transplant centres. Recurrence patterns, post-recurrence survival, and overall transplant outcomes were analysed, including temporal trends and the impact of AFP model implementation in 2013. Results We analysed 388 patients with r-HCC, median time to recurrence was 19.1 months, with 26.3% occurring beyond 3 years. Earlier recurrence was associated with tumour-related factors (AFP and Milan criteria, αFP kinetics), and later recurrence with patient-related factors (HCV recurrence, alcohol relapse, grade 2 obesity). Following AFP model implementation, time to recurrence shortened (p<0.001). Surgical/ablative treatments improved survival in r-HCC in a subgroup of patients with single organ involvement of liver, lung or lymph nodes. Survival did not improve between patients diagnosed before 2016, between 2016 and 2018, or after 2018 (p=0.09). Calcineurin inhibitors or mycophenolate mofetil had no impact on survival, whereas mTOR inhibitor use was associated with significantly longer survival (20.7 vs 13.2 months, p=0.001). Conclusions r-HCC is a heterogeneous disease distinct from HCC in non-transplanted patients. Earlier recurrences following extended selection criteria implementation warrant caution. Surgical/ablative approaches should be prioritized even for extrahepatic disease. Despite expanded TKI options since 2016, outcomes of systemic treatment did not show statistical improvement. Post-recurrence mTOR inhibitors should be evaluated in clinical trials. IMPACT AND IMPLICATIONS This nationwide cohort study provides updated data on recurrence of hepatocellular carcinoma (HCC) after liver transplantation in the modern era, a special population excluded from major HCC trials, highlighting major heterogeneity in patients' trajectories before and after recurrence, variations across eras of selection criteria and systemic therapies, and an urgent unmet need as the approval of second-generation TKIs after 2016 did not incrementally improve survival. The study results are important for transplant hepatologists and liver oncologists to optimize patient selection for liver transplantation, to individualize prolongation of surveillance beyond the current ILTS-ILCA 3-year window recommendation based on patient-related risk factors for late recurrences, and prioritize radical treatments with curative intent for selected patients with single organ involvement of liver, lungs or lymph nodes, rather than a blanket systemic-only approach. The retrospective design of the analysis does not allow for formal demonstration of superiority of therapeutic strategies, but provide evidence to design clinical trials on newer systemic agents such as immune-checkpoint inhibitors.