Assessing the role of everolimus in reducing hepatocellular carcinoma recurrence after living donor liver transplantation for patients within the UCSF criteria: re-inventing the role of mammalian target of rapamycin inhibitors

Abstract

Backgrounds/AimsThe protective effect of everolimus (EVR) in hepatocellular carcinoma (HCC) patients who receive liver transplantation in terms of reducing the recurrence has not been sufficiently investigated in clinical trials. In this second stage of our ongoing study, we intend to analyze the effects of EVR as an immunosuppressant, when it is started in the early phase after living donor liver transplantation (LDLT), on HCC recurrence in patients with HCC within the University of California at San Francisco (UCSF) criteria.MethodsFrom January 2011 to June 2013, a total of 250 patients underwent LDLT for HCC at our institute. The patients with HCC within the UCSF criteria were included in the study and divided in two groups depending upon the postoperative immunosuppression. Group A: HCC patients that received EVR+TAC based immunosuppressive regimen (n=37). Group B: HCC patients that received standard TAC based immunosuppressive regimen without EVR (n=29). The target trough level for EVR was 3 to 5 ng/ml while for TAC it was 8–10 ng/ml.ResultsFor group A patients, the mean trough level of the EVR was 3.47±1.53 ng/ml (range, 1.5–11.2) with a daily dose of 1.00±0.25 mg/day. For group A and B, the average TAC trough levels were 6.97±3.98 ng/ml (range, 2.50 to 11.28 ng/ml) and 6.93±2.58 (range, 2–16.30), respectively. The 1-year, 3-year and 4-year overall survival achieved for Group A patients was 94.95%, 86.48% and 86.48%, respectively while for Group B patients it was 82.75%, 68.96%, and 62.06%, respectively (p=0.0217).ConclusionsEVR use in liver transplant recipients in the early stage after transplantation reduces the HCC recurrence rates in HCC patients within the UCSF criteria.

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

“…One further study had an intervention arm containing mTOR‐inhibitors and another experimental anti‐oncogenic agent, and was excluded due to the potential confounding effect. Therefore, 23 studies were included in the quantitative analysis …”

The Effect of Immunosuppression on Coagulation After Liver Transplantation

“…In this study, we aimed to evaluate whether conversion of IS to an EVR‐based regimen for LT patients could induce coagulation disorders and promote thrombosis or other thromboembolic events. Currently, EVR is commonly used after LT because of its beneficial nephroprotective, antiviral, and antiproliferative effects . Sirolimus has received black‐box warnings related to death and graft loss in LT, and concerns have thus been raised about mTOR inhibitors regarding thromboembolic complications mainly on the basis of studies showing an increased thromboembolic risk for sirolimus .…”

“…Currently, EVR is commonly used after LT because of its beneficial nephroprotective, antiviral, and antiproliferative effects. (1,2,6,11,29) Sirolimus has received black-box warnings related to death and graft loss in LT, and concerns have thus been raised about mTOR inhibitors regarding thromboembolic complications mainly on the basis of studies showing an increased thromboembolic risk for sirolimus. (15)(16)(17) In lung transplant recipients, sirolimus caused an increased risk for venous thromboembolism, (15) whereas in LT patients, sirolimus was responsible for a higher incidence of artery and portal vein thrombosis.…”

“…Furthermore, EVR had been shown to exert antiproliferative effects and antitumor activity on hepatoma cells in vitro . However, in either clinical or in vivo trials, clear evidence is still missing confirming that the application of EVR could reduce recurrence rates of hepatocellular carcinoma (HCC) after LT . New evidence suggests that EVR protects LT patients from the development of donor‐specific antibodies, which may complicate longterm graft viability .…”

“…(1)(2)(3) Furthermore, EVR had been shown to exert antiproliferative effects and antitumor activity on hepatoma cells in vitro. (4,5) However, in either clinical or in vivo trials, clear evidence is still missing confirming that the application of EVR could reduce recurrence rates of hepatocellular carcinoma (HCC) after LT. (6)(7)(8) New evidence suggests that EVR protects LT patients from the development of donor-specific antibodies, which may complicate longterm graft viability. (9,10) Moreover, the administration of EVR is related to a reduction in the risk of cytomegalovirus infections among immunosuppressed patients (11)(12)(13) and has been shown to reduce the viral load of LT patients infected with hepatitis C virus genotypes 2a and 3.…”