International study on the outcome of locoregional therapy for liver transplant in hepatocellular carcinoma beyond Milan criteria

Background & Aims: Good outcomes after liver transplantation (LT) have been reported after successfully downstaging to Milan criteria in more advanced hepatocellular carcinoma (HCC). We aimed to compare post-LT outcomes in patients receiving locoregional therapies (LRT) before LT according to Milan criteria and University of California San Francisco downstaging (UCSF-DS) protocol and 'all-comers'. Methods: This multicentre cohort study included patients who received any LRT before LT from Europe and Latin America (2000-2018). We excluded patients with alpha-foetoprotein (AFP) above 1,000 ng/ml. Competing risk regression analysis for HCC recurrence was conducted, estimating subdistribution hazard ratios (SHRs) and corresponding 95% CIs. Results: From 2,441 LT patients, 70.1% received LRT before LT (n = 1,711). Of these, 80.6% were within Milan, 12.0% within UCSF-DS, and 7.4% all-comers. Successful downstaging was achieved in 45.2% (CI 34.8-55.8) and 38.2% (CI 25.4-52.3) of the UCSF-DS group and all-comers, respectively. The risk of recurrence was higher for all-comers (SHR 6.01 [p <0.0001]) and not significantly higher for the UCSF-DS group (SHR 1.60 [p = 0.32]), compared with patients remaining within Milan. The allcomers presented more frequent features of aggressive HCC and higher tumour burden at explant. Among the UCSF-DS group, an AFP value of QO ng/ml at listing was associated with lower recurrence (SHR 2.01 [p = 0.006]) and better survival. However, recurrence was still significantly high irrespective of AFP 520 ng/ml in all-comers. Conclusions: Patients within the UCSF-DS protocol at listing have similar post-transplant outcomes compared with those within Milan when successfully downstaged. Meanwhile, all-comers have a higher recurrence and inferior survival irrespective of response to LRT. Additionally, in the UCSF-DS group, an ALP of 520 ng/ml might be a novel tool to optimise selection of candidates for LT. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). Lay summary: Patients with more extended HCC (within the UCSF-DS protocol) successfully downstaged to the conventional Milan criteria do not have a higher recurrence rate after LT compared with the group remaining in the Milan criteria from listing to transplantation. Moreover, in the UCSF-DS patient group, an ALP value equal to or below 20 ng/ml at listing might be a novel tool to further optimise selection of candidates for LT. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).

Automated summary

Successful downstaging of more advanced hepatocellular carcinoma (HCC) within the UCSF-DS protocol to the conventional Milan criteria does not result in a higher recurrence rate after liver transplantation (LT) compared to patients remaining within Milan criteria. Additionally, in the UCSF-DS group, an ALP value equal to or below 20 ng/ml at listing might be a novel tool to further optimize selection of candidates for LT.