title: mTOR inhibitor therapy: Does it prevent HCC recurrence after liver transplantation?
abstract: Prevention of hepatocellular carcinoma (HCC) recurrence after liver transplantation is a clinical priority. The importance of the mammalian target of rapamycin (mTOR) pathway in cell growth and survival makes it a logical target for antitumor strategies, as borne out by clinical data in various types of malignancy. A number of studies have indicated that the mTOR inhibitors everolimus and sirolimus suppress cell proliferation and tumor growth in animal models of HCC. Coadministration of an mTOR inhibitor could permit lower dosing of chemotherapeutic agents in HCC management, and trials in non-transplant HCC population are exploring combined used with various agents including sorafenib, the vascular endothelial growth factor inhibitor bevacizumab and conventional agents. In terms of a preventive effect after liver transplantation for HCC, data from retrospective studies and non-randomized prospective analyses in which patients received an mTOR inhibitor with concomitant calcineurin inhibitor therapy have indicated that HCC recurrence rates and overall survival may be improved compared to a standard calcineurin inhibitor regimen. Meta-analyses have supported these findings, but controlled trials are required before any firm conclusions can be drawn. In two of the three randomized trials which have assessed de novo mTOR inhibitor therapy after liver transplantation, there was a numerically lower rate of HCC recurrence by one year post-transplant in patients given an mTOR inhibitor versus the control arm, but absolute numbers were low. Overall, based on the available data from retrospective studies, meta-analyses, and post-hoc assessments of randomized trials, it appears advisable to consider mTOR inhibition-based immunosuppression after transplantation for HCC, particularly in patients who exceed the Milan criteria. Prospective data are awaited.
authors.affiliation: Department of Hepatology and Liver Transplant Unit Henri Mondor Hospital, Paris Est University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva, Switzerland. Electronic address: christophe.duvoux@hmn.aphp.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Duvoux
authors.affiliation: Department of Hepatology and Liver Transplant Unit Henri Mondor Hospital, Paris Est University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Toso
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000601:surgery*; D000068338:Everolimus / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000601:surgery*; D016031:Liver Transplantation / Q000009:adverse effects* / Q000379:methods; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000517:prevention & control*; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus