A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

Abstract

BackgroundThe potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.Methods/DesignThe study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.DiscussionIf our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC.Trial RegisterTrial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36)

Strategies to improve outcome of patients with hepatocellular carcinoma receiving a liver transplantation

“…There are no randomized controlled trials evaluating the role of mTOR inhibitors in preventing HCC recurrence. The SILVER study is a multicentre randomized controlled trial which preliminary results are expected to be available in 2016, and may shed some light in the actual role of sirolimus in LT patients with HCC [132] . The major concern with sirolimus relies in its safety profile.…”

Place of liver transplantation in the treatment of hepatocellular carcinoma in the normal liver

“…Adjuvant chemotherapy and optimized immunosuppression (probably including rapamycin) should be further explored in order to improve the outcomes of LT in these particular recipients. [49][50][51] We hope that the results of the ongoing SILVER study 52 will confirm the experimentally proven antitumor properties of mammalian target of rapamycin inhibitors in the clinical transplant setting.…”

Liver Transplantation for HCC: A Review

“…The Silver trial-an open-label, multicenter-randomized control trial designed to compare sirolimus containing immunosuppression with mTOR inhibitor-free regimen in patients undergoing liver transplantation for HCC-is in the recruitment phase [130]. The outcome of this trial is expected to clarify the controversy.…”