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The Transplant Evidence Alert provides a monthly overview of the 10 most important new clinical trials in organ transplantation, selected and reviewed by the Peter Morris Centre for Evidence in Transplantation (Oxford University).
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Long-Term Effects of Everolimus-Facilitated Tacrolimus Reduction in Living-Donor Liver Transplant Recipients with Hepatocellular Carcinoma

Ann Transplant. 2022 Nov 22;27:e937988 doi: 10.12659/AOT.937988.

BACKGROUND The study objective was to evaluate the effect of everolimus (EVR) in combination with reduced tacrolimus (rTAC) compared with a standard TAC (sTAC) regimen on hepatocellular carcinoma (HCC) recurrence in de novo living-donor liver transplantation recipients (LDLTRs) with primary HCC at liver transplantation through 5 years after transplantation. MATERIAL AND METHODS In this multicenter, non-interventional study, LDLTRs with primary HCC, who were previously randomized to either everolimus plus reduced tacrolimus (EVR+rTAC) or standard tacrolimus (sTAC), and who completed the 2-year core H2307 study, were followed up. Data were collected retrospectively (end of core to the start of follow-up study), and prospectively (during the 3-year follow-up study). RESULTS Of 117 LDLTRs with HCC at LT in the core H2307 study (EVR+rTAC, N=56; sTAC, N=61), 86 patients (EVR+rTAC, N=41; sTAC, N=45) entered the follow-up study. Overall HCC recurrence was lower but statistically non-significant in the EVR+rTAC group (3.6% vs 11.5% in sTAC; P=0.136) at 5 years after LT. There was no graft loss or chronic rejection. Acute rejection and death were comparable between treatment groups. Higher mean estimated glomerular filtration rate in the EVR+rTAC group (76.8 vs 65.8 mL/min/1.73 m² in sTAC) was maintained up to 5 years. Reported adverse events were numerically lower in the EVR+rTAC group (41.0% vs 53.5% sTAC) but not statistically significant. CONCLUSIONS Although statistically not significant, early EVR initiation reduced HCC recurrence, with comparable efficacy and safety, and better long-term renal function, than that of sTAC treatment.

CET Conclusion
Reviewer: Mr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This study analysed the long-term follow-up data of patients who underwent living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC) and were enrolled in a previous RCT to receive combination everolimus/reduced tacrolimus or normal dose tacrolimus alone. The authors hypothesised that everolimus combined with reduced tacrolimus would reduce HCC recurrence and CNI-related renal dysfunction, and have similar immunosuppressive efficacy and safety. The original RCT followed the patients up for 12 months and reported similar efficacy and safety data between the 2 groups, with a reduced rate of HCC recurrence in the everolimus/reduced tacrolimus arm. This study followed these two groups of patients and analysed the same outcome measures at 5 years. Although all primary and secondary endpoints were numerically superior in the everolimus/reduced tacrolimus group, none of the differences reported achieved statistical significance. Furthermore, the all-cause 5-year overall survival was also not significantly different. This study essentially found similar outcomes to the original RCT and thus did not show compelling evidence of long-term benefit of the everolimus/reduced tacrolimus regimen in all patients who undergo LDLT. However, a sub-group analysis indicated that this regimen may benefit patients with a greater burden of HCC and who are transplanted outside of Milan criteria.
Study Details
Aims: This follow-up study aimed to report the long term outcomes of a randomised controlled trial investigating the effects of everolimus (EVR) combined with reduced tacrolimus (rTAC) versus a standard TAC (sTAC) regimen in living-donor liver transplant recipients (LDLTRs) with hepatocellular carcinoma (HCC).
Interventions: Participants were randomly assigned to receive either EVR+rTAC or sTAC.
Participants: 117 HCC patients who underwent LDLT.
Outcomes: The primary outcome was HCC recurrence. The secondary efficacy outcomes included incidences of acute and chronic rejections, graft loss, death, ‘composite of drop-out’ [death, withdrawal of consent and lost to follow-up], changes in immunosuppressive regimen, malignancies other than HCC and change in renal function.
Follow Up: 60 months
Funding: Industry funding
Publication type: Randomized Controlled Trial, Multicenter Study, Randomised Controlled Trial
Trial registration: - NCT01888432
Organ: Liver
Language: English
Author email:
MeSH terms: Humans; Living Donors; Liver Transplantation; Tacrolimus; Carcinoma, Hepatocellular; Everolimus; Follow-Up Studies; Retrospective Studies; Liver Neoplasms; Follow Up Studies; Wm0 Haq4 Wnm (Tacrolimus); 9 Hw64 Q8 G6 G (Everolimus)