title: Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial.
abstract: BACKGROUND
  We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC).
  
  
  METHODS
  In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint.
  
  
  RESULTS
  Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874).
  
  
  CONCLUSIONS
  Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.
authors.affiliation: 1 Department of Surgery and Section of Experimental Surgery, University Hospital Regensburg, Regensburg, Germany. 2 Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. 3 Unite d'Hepatologie et de Transplantation Hepatique, Centre Hospitalier Universitaire Henri-Mondor, Service d'Hepatologie et de Gastroenterologie, Université Paris-Est Créteil Val-de-Marne, Paris, France. 4 Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche (DiSCOG), Università degli Studi di Padova, Padova, Italy. 5 Klinik für Allgemeine, Viszeral, Transplantations- Gefäß- und Thoraxchirurgie, Klinikum der Ludwig-Maximilians-Universität München-Großhadern, München, Germany. 6 Innere Medizin IV, Sektion Lebertransplantation, Universitätsklinikum Heidelberg, Heidelberg, Germany. 7 Klinik für Allgemein-, Viszeral- und Gefässchirurgie, Universitätsklinikum Jena, Jena, Germany. 8 Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz, Germany. 9 Centro Trapianti Fegato, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico IRCCS di Milano, Milan, Italy. 10 Chirurgia Epatobiliare e Trapianto Epatico, Azienda Ospedaliera di Padova, Università di Padova, Padova, Italy. 11 Alberta Health Services Liver Transplant Program, University of Alberta, Edmonton, Alberta, Canada. 12 Centre Hépato Biliaire, Hôpital Paul Brousse, Villejuif Cedex, Paris, France. 13 Department of Gastroenterology and Hepatology, Leiden University Medical Center (LUMC), Leiden, Netherlands. 14 Service de Chirurgie Générale, Hépatique, Endocrinienne, et Transplantation, Hôpital de Hautepierre, Les Hôpitaux Universitaires de Strasbourg, Strasbourg, France. 15 Service de Néphrologie-HTA-Dialyse-Transplantation, CHU Toulouse-Rangueil, Toulouse, France. 16 Department of Surgery and Transplantation, Sahlgrenska University Hospital, Göteborg, Sweden. 17 Hepatic-Pa
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mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001315:Australia; D002170:Canada; D006528:Carcinoma, Hepatocellular / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D018450:Disease Progression; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D005060:Europe; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D016031:Liver Transplantation / Q000009:adverse effects / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus