Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial

被引：375

作者：

Geissler, Edward K. ^{[1
,2
]}

Schnitzbauer, Andreas A. ^{[1
,2
,3
]}

Zuelke, Carl ^{[1
,2
]}

Lamby, Philipp E. ^{[1
,2
]}

Proneth, Andrea ^{[1
,2
]}

Duvoux, Christophe ^{[4
]}

Burra, Patrizia ^{[5
]}

Jauch, Karl-Walter ^{[6
]}

Rentsch, Markus ^{[6
]}

Ganten, Tom M. ^{[7
]}

Schmidt, Jan ^{[7
]}

Settmacher, Utz ^{[8
]}

Heise, Michael ^{[8
,9
]}

Rossi, Giorgio ^{[10
]}

Cillo, Umberto ^{[11
]}

Kneteman, Norman ^{[12
]}

Adam, Rene ^{[13
]}

van Hoek, Bart ^{[14
]}

Bachellier, Philippe ^{[15
]}

Wolf, Philippe ^{[15
]}

Rostaing, Lionel ^{[16
]}

Bechstein, Wolf O. ^{[3
]}

Rizell, Magnus ^{[17
]}

Powell, James ^{[18
,19
]}

Hidalgo, Ernest ^{[18
,19
]}

Gugenheim, Jean ^{[20
]}

Wolters, Heiner ^{[21
]}

Brockmann, Jens ^{[21
]}

Roy, Andre ^{[22
]}

Mutzbauer, Ingrid ^{[1
,2
]}

Schlitt, Angela ^{[1
,2
]}

Beckebaum, Susanne ^{[23
]}

Graeb, Christian ^{[6
]}

Nadalin, Silvio ^{[24
]}

Valente, Umberto ^{[25
]}

Sanchez Turrion, Victor ^{[26
]}

Jamieson, Neville ^{[27
]}

Scholz, Tim ^{[28
]}

Colledan, Michele ^{[29
]}

Faendrich, Fred ^{[30
]}

Becker, Thomas ^{[30
]}

Soderdahl, Gunnar ^{[31
]}

Chazouilleres, Olivier ^{[32
]}

Makisalo, Heikki ^{[33
]}

Pageaux, Georges-Philippe ^{[34
]}

Steininger, Rudolf ^{[35
]}

Soliman, Thomas ^{[35
]}

de Jong, Koert P. ^{[36
]}

Pirenne, Jacques ^{[37
]}

Margreiter, Raimund ^{[38
]}

机构：

[1] Univ Hosp Regensburg, Dept Surg, Regensburg, Germany

[2] Univ Hosp Regensburg, Sect Expt Surg, Regensburg, Germany

[3] Univ Frankfurt Klinikum, Klin Allgemein & Viszeralchirurg, Frankfurt, Germany

[4] Univ Paris Est Creteil Val de Marne, CHU Henri Mondor, Serv Hepatol & Gastroenterol, Unite Hepatol & Transplantat Hepat, Paris, France

[5] Univ Padua, Dipartimento Sci Chirurg Oncol & Gastroenterol Di, Padua, Italy

[6] Univ Munich, Klinikum, Klin Allgemeine Viszeral Transplantat Gefass & Th, Munich, Germany

[7] Univ Klinikum Heidelberg, Sekt Lebertransplantat, Innere Med 4, Heidelberg, Germany

[8] Univ Klinikum Jena, Klin Allgemein Viszeral & Gefasschirurg, Jena, Germany

[9] Johannes Gutenberg Univ Mainz, Univ Med, Klin Allgemein Viszeral & Transplantat Chirurg, Mainz, Germany

[10] Policlin IRCCS Milano, Osped Maggiore, Fondazione IRCCS Ca Granda, Ctr Trapianti Fegato, Milan, Italy

[11] Univ Padua, Azienda Osped Padova, Chirurg Epatobiliare & Trapianto Epatico, Padua, Italy

[12] Univ Alberta, Alberta Hlth Serv, Liver Transplant Program, Edmonton, AB, Canada

[13] Hop Paul Brousse, Ctr Hepato Biliaire, Paris, France

[14] Leiden Univ, Med Ctr, Dept Gastroenterol & Hepatol, Leiden, Netherlands

[15] Hop Univ Strasbourg, Hop Hautepierre, Serv Chirurg Gen Hepat Endocrinienne & Transplant, Strasbourg, France

[16] CHU Toulouse Rangueil, Serv Nephrol HTA Dialyse Transplantat, Toulouse, France

[17] Sahlgrens Univ Hosp, Dept Surg & Transplantat, S-41345 Gothenburg, Sweden

[18] Royal Infirm Edinburgh NHS Trust, Hepat Pancreat Biliary Surg Serv, Edinburgh, Midlothian, Scotland

[19] Royal Infirm Edinburgh NHS Trust, Edinburgh Transplant Unit, Edinburgh, Midlothian, Scotland

[20] CHU Nice, Hop ARCHET 2, Ctr Transplantat Hepat, Serv Chirurg Digest, F-06202 Nice, France

[21] Univ Klinikum Munster, Klin Allgemein & Viszeralchirur, Munster, Germany

[22] CHU Montreal, Hop St Luc, Hepatobiliary & Pancreat Surg Unit, Montreal, PQ, Canada

[23] Univ Klinikum Essen, Klin Allgemein Viszeral & Transplantat Chirurg, Essen, Germany

[24] Klinikum Univ Tubingen, Klin Allgemeine Viszeral & Transplantat Chirurg, Tubingen, Germany

[25] Univ Genoa, Azienda Ospedal Univ San Martino Genova, Chirurg Generale & Trapianti Organo, Genoa, Italy

[26] Hosp Univ Puerta Hierro Majadahonda, Dept Cirugia, Unidad Transplante Hepat, Madrid, Spain

[27] Cambridge Univ Hosp, Addenbrookes Hosp, NHS Fdn Trust, Dept Surg, Cambridge, England

[28] Oslo Univ Hosp, Dept Transplantat Med, Clin Canc Surg & Transplantat, Sect Transplant Surg, N-0450 Oslo, Norway

[29] Azienda Ospedaliera Papa Giovanni XXIII, Chirurg Terza & Chirurg Torac, Bergamo, Italy

[30] Univ Klinikum Schleswig Holstein, Klin Allgemeine Chirurg Viszeral Thorax Transplan, Kiel, Germany

[31] Karolinska Univ Hosp, Dept Transplantat Surg, Stockholm, Sweden

[32] Hop St Antoine, Serv Hepatol, Federat Hepatogastroenterol, F-75571 Paris, France

[33] Univ Helsinki, Cent Hosp, Div Transplantat & Liver Surg, Helsinki, Finland

[34] Hop Saint Eloi, APEMAD, CHRU Montpellier, Serv Hepatogastroenterol & Transplantat Hepat, Montpellier, France

[35] Med Univ Wien, AKH Wien, Univ Klin Chirurg, Abt Transplantat, Vienna, Austria

[36] Univ Groningen, Univ Med Ctr Groningen, Dept Surg, Div Hepatopancreaticobiliary Surg & Liver Tranpl, Groningen, Netherlands

[37] UZ Leuven, Abdominale Transplantatiechirurg, Leuven, Belgium

[38] Med Univ Innsbruck, Univ Klin Visceral Transplantat Throaxchirurg, A-6020 Innsbruck, Austria

[39] Univ Bologna, Chirurg Generale & Trapianti, Policlin S Orsola Malpighi, Bologna, Italy

[40] Univ Klinikum Leipzig, Klin Visceral Transplantat Thorax & Gefasschirurg, Leipzig, Germany

[41] Royal Prince Alfred Hosp, AW Morrow Gastroenterol, Sydney, NSW, Australia

[42] Royal Prince Alfred Hosp, Ctr Liver, Sydney, NSW, Australia

[43] Royal Prince Alfred Hosp, Liver Transplant Unit, Sydney, NSW, Australia

[44] Hannover Med Sch, Klin Allgemein Viszeral & Transplantat Chirurg, D-30623 Hannover, Germany

[45] Ghent Univ Hosp & Med Sch, Hepatobiliary & Pancreat Surg, Ghent, Belgium

[46] Natl Canc Inst, IRCCS, Ist Nazl Tumori, Dept Surg,Transplantat & Hepatobiliary Canc Unit, I-20133 Milan, Italy

[47] St Luc Univ Hosp, UCL Transplant Ctr, Dept Abdominal & Transplantat Surg SCTA, Brussels, Belgium

[48] Hosp Univ Vall Hebron, Serv Cirugia Gen, Unidad Trasplante Hepat, Barcelona, Spain

[49] Univ Hosp Birmingham, NHS Fdn Trust, Queen Elizabeth Hosp, Liver & Hepatopancreato Biliary HPB Unit, Birmingham, W Midlands, England

[50] Univ Med Berlin, Klin Allgemein Visceral & Transplantat Chirurg, Berlin, Germany

来源：

TRANSPLANTATION | 2016年 / 100卷 / 01期

关键词：

RENAL-CELL CARCINOMA; RAPAMYCIN INHIBITORS; IMMUNOSUPPRESSION; RECURRENCE; SURVIVAL; TARGET; CANCER; METAANALYSIS; PROGRESSION; EVEROLIMUS;

D O I：

10.1097/TP.0000000000000965

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：116 / 125

页数：10

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