Systematic review with meta-analysis: sirolimus-or everolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma

Background: Calcineurin-inhibitor immunosuppressants (tacrolimus and ciclosporin) have been associated with an exposure-related increase in tumour recurrence following liver transplantation for hepatocellular carcinoma (HCC). Conversely, mechanistic target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) have been suggested to reduce recurrence rates and improve survival in this patient group. Aim: To clarify the potential benefit of mTOR-inhibitors in HCC transplant patients by comparing recurrence and survival outcomes with calcineurin-inhibitor-based immunosuppression. Methods: A systematic review and meta-analysis was performed. The inclusion criteria were observational or interventional studies reporting the effect of early-initiated (< 6 months post-transplant) mTOR-inhibitor-based immunosuppression on survival or tumour recurrence in patients transplanted with HCC, compared to a control of calcineurin-inhibitor-based therapy. Results: Meta-analysis demonstrated that compared with calcineurin-inhibitor controls, recurrence-free-survival was significantly increased with mTOR-inhibitor-based therapy at 1-year (Risk-Ratio (RR): 1.09, 95% CI: 1.01-1.18) and 3-years (RR: 1.1, 95% CI: 1.01-1.21) post-transplant, with a nonsignificant increase at 5-years (RR: 1.15, 95% CI: 0.99-1.35). Overall survival was improved at 1-year (RR: 1.07, 95% CI: 1.02-1.12), 3-years (RR: 1.1, 95% CI: 1.02-1.19), and 5-years (RR: 1.18, 95% CI: 1.08-1.29). Recurrence-rate was lower in the mTOR-inhibitor arm (RR: 0.67, 95% CI: 0.56-0.82), with no significant increase in acute rejection (RR: 1.1, 95% CI: 0.94-1.28). Conclusions: mTOR-inhibitor-based immunosuppression may be a preferable option in patients transplanted with HCC. It improves recurrence-free-survival over at least three years and reduces the recurrence rate compared with standard calcineurin-inhibitor- based therapy, with no significant increase in the rate of acute rejection. Future research should clarify the effect in higher vs lower risk cohorts.