Transplant Trial Watch

Sirolimus Prolongs Survival after Living Donor Liver Transplantation for Hepatocellular Carcinoma Beyond Milan Criteria: A Prospective, Randomised, Open-Label, Multicentre Phase 2 Trial.

Lee, K. W., et al.

Journal of Clinical Medicine 2020; 9(10): 12.

The aim of this study was to compare the outcomes of sirolimus (SRL) versus tacrolimus (TAC) in patients with hepatocellular carcinoma (HCC) undergoing living donor liver transplantation (LDLT) outside of the Milan criteria.

Patients were randomised to either the SRL group or the TAC group.

42 LDLT recipients with HCC beyond the Milan criteria.

The primary endpoint was the 3-year recurrence-free survival (RFS). The secondary endpoints were the 3-year overall survival (OS) and the safety of SRL.

3 years

CET Conclusions
This report of an RCT in live donor liver transplantation compares sirolimus with tacrolimus for maintenance immunosuppression. It has some good quality indicators but overall is of moderate quality only. The study was randomised but the method for this is not described. The study is also very small, having been based on a power calculation that took into account some very different estimated survival rates (30% versus 60%). The premise is an interesting one, that recipients outside the Milan criteria would be expected to have a higher recurrence risk than standard risk patients. Therefore, the potential antitumour effect of sirolimus might show a benefit in this group of patients. Only 42 patients were included, and in univariate analysis, there was no significant difference in recurrence-free survival, or overall survival (results were 77.3% with tacrolimus and 60% with sirolimus). A multivariate analysis was done, which found that the strongest predictors of recurrence were AFP level>150 ng/mL and PET positivity. The treatment arm was not related to recurrence-free survival in this analysis. AFP level and PET positivity were also the strongest predictors of poor overall survival (HR= 35 and 28). Tacrolimus was an independent predictor poor survival in this analysis (HR= 15). As the study was so small, the confidence intervals for all of these results are very wide. mTOR inhibitors can inhibit tumour growth, but the potential improval in survival in this study is not associated with an improvement in recurrence free survival. The mechanism for this is therefore unclear.

Jadad score

Data analysis
Per protocol analysis

Allocation concealment

Trial registration - NCT01374750

Funding source
Industry funded