Vincenzo Mazzaferro1, Davide Citterio2, Sherrie Bhoori2, Marco Bongini2, Rosalba Miceli3, Luciano De Carlis4, Michele Colledan5, Mauro Salizzoni6, Renato Romagnoli6, Barbara Antonelli7, Marco Vivarelli8, Giuseppe Tisone9, Massimo Rossi10, Salvatore Gruttadauria11, Stefano Di Sandro4, Riccardo De Carlis4, Maria Grazia Lucà5, Massimo De Giorgio5, Stefano Mirabella6, Luca Belli4, Stefano Fagiuoli5, Silvia Martini6, Massimo Iavarone12, Gianluca Svegliati Baroni8, Mario Angelico9, Stefano Ginanni Corradini10, Riccardo Volpes11, Luigi Mariani3, Enrico Regalia2, Maria Flores2, Michele Droz Dit Busset2, Carlo Sposito13. 1. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy. Electronic address: vincenzo.mazzaferro@istitutotumori.mi.it. 2. HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy. 3. Clinical Epidemiology and Trial Organization, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy. 4. General Surgery and Abdominal Transplantation Unit, Hepatology, University of Milano-Bicocca andNiguarda-CàGranda Hospital, Milan, Italy. 5. Department of Organ Failure and Transplantation, Gastroenterology, Hepatology and Liver Transplantation, Ospedale Papa Giovanni XXIII, Bergamo, Italy. 6. General Surgery 2U and Liver Transplantation Center, University of Turin, AOU Cittàdella Salute e della Scienza di Torino, Turin, Italy. 7. General and Liver Transplant Surgery Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 8. Hepatobiliary and Abdominal Transplantation Surgery, Hepatology, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy. 9. Department of Surgical Sciences and Medical Sciences University of Rome-Tor Vergata, Rome, Italy. 10. Department of General Surgery and Organ Transplantation, Sapienza University, Rome, Italy. 11. Abdominal Surgery and Organ Transplantation Unit, Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, ISMETT, Palermo, Italy. 12. Division of Gastroenterology and Hepatology, CRC A M and A Migliavacca Center for Liver Disease, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 13. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy.
Abstract
BACKGROUND: Indications for liver transplantation for hepatocellular carcinoma are evolving and so-called expanded criteria remain debated. Locoregional therapies are able to downstage hepatocellular carcinoma from beyond to within the Milan criteria. We aimed to investigate the efficacy of liver transplantation after successful hepatocellular carcinoma downstaging. METHODS: We did an open-label, multicentre, randomised, controlled trial designed in two phases, 2b and 3, at nine Italian tertiary care and transplantation centres. Patients aged 18-65 years with hepatocellular carcinoma beyond the Milan criteria, absence of macrovascular invasion or extrahepatic spread, 5-year estimated post-transplantation survival of at least 50%, and good liver function (Child-Pugh A-B7) were recruited and underwent tumour downstaging with locoregional, surgical, or systemic therapies according to multidisciplinary decision. After an observation period of 3 months, during which sorafenib was allowed, patients with partial or complete responses according to modified Response Evaluation Criteria in Solid Tumors were randomly assigned (1:1) by an interactive web-response system to liver transplantation or non-transplantation therapies (control group). A block randomisation (block size of 2), stratified by centre and compliance to sorafenib treatment, was applied. Liver transplantation was done with whole or split organs procured from brain-dead donors. The control group received sequences of locoregional and systemic treatment at the time of demonstrated tumour progression. The primary outcomes were 5-year tumour event-free survival for phase 2b and overall survival for phase 3. Analyses were by intention to treat. Organ allocation policy changed during the course of the study and restricted patient accrual to 4 years. This trial is registered with ClinicalTrials.gov, NCT01387503. FINDINGS:Between March 1, 2011, and March 31, 2015, 74 patients were enrolled. Median duration of downstaging was 6 months (IQR 4-11). 29 patients dropped out before randomisation and 45 were randomly assigned: 23 to the transplantation group versus 22 to the control group. At data cutoff on July 31, 2019, median follow-up was 71 months (IQR 60-85). 5-yeartumour event-free survival was 76·8% (95% CI 60·8-96·9) in the transplantation group versus 18·3% (7·1-47·0) in the control group (hazard ratio [HR] 0·20, 95% CI 0·07-0·57; p=0·003). 5-yearoverall survival was 77·5% (95% CI 61·9-97·1) in the transplantation group versus 31·2% (16·6-58·5) in the control group (HR 0·32, 95% CI 0·11-0·92; p=0·035). The most common registered grade 3-4 serious adverse events were hepatitis C virus recurrence (three [13%] of 23 patients) and acute transplant rejection (two [9%]) in the transplantation group, and post-embolisation syndrome (two [9%] of 22 patients) in the control group. Treatment-related deaths occurred in four patients: two (8%) of 23 patients in the transplantation group (myocardial infarction and multi-organ failure) versus two (9%) of 22 patients in the control group (liver decompensation). INTERPRETATION: Although results must be interpreted with caution owing to the early closing of the trial, after effective and sustained downstaging of eligible hepatocellular carcinomas beyond the Milan criteria, liver transplantation improved tumour event-free survival and overall survival compared with non-transplantation therapies Post-downstaging tumour response could contribute to the expansion of hepatocellular carcinoma transplantation criteria. FUNDING: Italian Ministry of Health.
RCT Entities:
BACKGROUND: Indications for liver transplantation for hepatocellular carcinoma are evolving and so-called expanded criteria remain debated. Locoregional therapies are able to downstage hepatocellular carcinoma from beyond to within the Milan criteria. We aimed to investigate the efficacy of liver transplantation after successful hepatocellular carcinoma downstaging. METHODS: We did an open-label, multicentre, randomised, controlled trial designed in two phases, 2b and 3, at nine Italian tertiary care and transplantation centres. Patients aged 18-65 years with hepatocellular carcinoma beyond the Milan criteria, absence of macrovascular invasion or extrahepatic spread, 5-year estimated post-transplantation survival of at least 50%, and good liver function (Child-Pugh A-B7) were recruited and underwent tumour downstaging with locoregional, surgical, or systemic therapies according to multidisciplinary decision. After an observation period of 3 months, during which sorafenib was allowed, patients with partial or complete responses according to modified Response Evaluation Criteria in Solid Tumors were randomly assigned (1:1) by an interactive web-response system to liver transplantation or non-transplantation therapies (control group). A block randomisation (block size of 2), stratified by centre and compliance to sorafenib treatment, was applied. Liver transplantation was done with whole or split organs procured from brain-dead donors. The control group received sequences of locoregional and systemic treatment at the time of demonstrated tumour progression. The primary outcomes were 5-year tumour event-free survival for phase 2b and overall survival for phase 3. Analyses were by intention to treat. Organ allocation policy changed during the course of the study and restricted patient accrual to 4 years. This trial is registered with ClinicalTrials.gov, NCT01387503. FINDINGS: Between March 1, 2011, and March 31, 2015, 74 patients were enrolled. Median duration of downstaging was 6 months (IQR 4-11). 29 patients dropped out before randomisation and 45 were randomly assigned: 23 to the transplantation group versus 22 to the control group. At data cutoff on July 31, 2019, median follow-up was 71 months (IQR 60-85). 5-year tumour event-free survival was 76·8% (95% CI 60·8-96·9) in the transplantation group versus 18·3% (7·1-47·0) in the control group (hazard ratio [HR] 0·20, 95% CI 0·07-0·57; p=0·003). 5-year overall survival was 77·5% (95% CI 61·9-97·1) in the transplantation group versus 31·2% (16·6-58·5) in the control group (HR 0·32, 95% CI 0·11-0·92; p=0·035). The most common registered grade 3-4 serious adverse events were hepatitis C virus recurrence (three [13%] of 23 patients) and acute transplant rejection (two [9%]) in the transplantation group, and post-embolisation syndrome (two [9%] of 22 patients) in the control group. Treatment-related deaths occurred in four patients: two (8%) of 23 patients in the transplantation group (myocardial infarction and multi-organ failure) versus two (9%) of 22 patients in the control group (liver decompensation). INTERPRETATION: Although results must be interpreted with caution owing to the early closing of the trial, after effective and sustained downstaging of eligible hepatocellular carcinomas beyond the Milan criteria, liver transplantation improved tumour event-free survival and overall survival compared with non-transplantation therapies Post-downstaging tumour response could contribute to the expansion of hepatocellular carcinoma transplantation criteria. FUNDING: Italian Ministry of Health.
Authors: Maria Reig; Alejandro Forner; Jordi Rimola; Joana Ferrer-Fàbrega; Marta Burrel; Ángeles Garcia-Criado; Robin K Kelley; Peter R Galle; Vincenzo Mazzaferro; Riad Salem; Bruno Sangro; Amit G Singal; Arndt Vogel; Josep Fuster; Carmen Ayuso; Jordi Bruix Journal: J Hepatol Date: 2021-11-19 Impact factor: 30.083
Authors: Xi Xu; Xingyu Pu; Li Jiang; Yang Huang; Lunan Yan; Jiayin Yang; Tianfu Wen; Bo Li; Hong Wu; Wentao Wang Journal: J Cancer Res Clin Oncol Date: 2020-08-27 Impact factor: 4.553