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Original Investigation
July 14, 2021

Evaluation of the Intention-to-Treat Benefit of Living Donation in Patients With Hepatocellular Carcinoma Awaiting a Liver Transplant

Author Affiliations
  • 1Institut de Recherche Clinique, Université Catholique de Louvain, Brussels, Belgium
  • 2General Surgery and Organ Transplantation Unit, Department of General 3 Surgery and Organ Transplantation, Sapienza University of Rome, Rome, Italy
  • 3Abdominal Transplant and HPB Surgical Oncology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
  • 4Liver Transplantation and Hepatobiliary Surgery, Padua University Hospital, University of Padua, Padua, Italy
  • 5Center for Liver Disease and Transplantation, Columbia University Medical Center, New York Presbyterian Hospital, New York
  • 6Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Weill Cornell Medicine, New York, New York
  • 7Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria
  • 8Institute of Liver Transplantation and Regenerative Medicine, Medanta-The Medicity, Guragram, Delhi, India
  • 9Department of Surgery, The University of Hong Kong, Hong Kong, China
  • 10Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  • 11Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
  • 12Klinik für Allgemein-, Viszeral- und Transplantationschirurgie Universitätsmedizin Mainz, Mainz, Germany
  • 13Department of Surgery and Science, Kyushu University, Fukuoka, Japan
  • 14Department of Hepatobiliary and Pancreatic Surgery Shulan Hospital, Shulan Health Zhejiang University Hospital, Hangzhou, China
  • 15Biostatistics Unit, University of Padua, Padua, Italy
JAMA Surg. Published online July 14, 2021. doi:10.1001/jamasurg.2021.3112
Key Points

Question  Can the intention-to-treat survival benefit of a potential live donor be evaluated in a patient with hepatocellular carcinoma (HCC) who is on the waiting list for a liver transplant?

Findings  In this cohort study of nearly 4000 patients with HCC who were on a waiting list at transplant centers in Europe, Asia, the US, and Canada, living-donor liver transplant (LDLT) was an independent protective factor, reducing the risk of intention-to-treat death in 4 different settings. When LDLT was incorporated in the mathematical models, their discriminatory ability further improved.

Meaning  Findings from this study suggest that LDLT could potentially decrease the risk of death, by 33% to 49%, for patients with HCC awaiting a liver transplant.


Importance  Living-donor liver transplant (LDLT) offers advantages over deceased-donor liver transplant (DDLT) of improved intention-to-treat outcomes and management of the shortage of deceased-donor allografts. However, conflicting data still exist on the outcomes of LDLT in patients with hepatocellular carcinoma (HCC).

Objective  To investigate the potential survival benefit of an LDLT in patients with HCC from the time of waiting list inscription.

Design, Setting, and Participants  This multicenter cohort study with an intention-to-treat design analyzed the data of patients aged 18 years or older who had an HCC diagnosis and were on a waiting list for a first transplant. Patients from 12 collaborative centers in Europe, Asia, and the US who were on a transplant waiting list between January 1, 2000, and December 31, 2017, composed the international cohort. The Toronto cohort comprised patients from 1 transplant center in Toronto, Ontario, Canada who were on a waiting list between January 1, 2000, and December 31, 2015. The international cohort centers performed either an LDLT or a DDLT, whereas the Toronto cohort center was selected for its capability to perform both LDLT and DDLT. The benefit of LDLT was tested in the 2 cohorts before and after undergoing an inverse probability of treatment weighting (IPTW) analysis. Data were analyzed from February 1 to May 31, 2020.

Main Outcomes and Measures  Intention-to-treat death was defined as a patient death that occurred for any reason and was calculated from the time of waiting list inscription for liver transplant to the last follow-up date (December 31, 2019). Four multivariable Cox proportional hazards regression models for intention-to-treat death were created.

Results  A total of 3052 patients were analyzed in the international cohort, of whom 2447 were men (80.2%) and the median (IQR) age at first referral was 58 (53-63) years. The Toronto cohort comprised 906 patients, of whom 743 were men (82.0%) and the median (IQR) age at first referral was 59 (53-63) years. In all the settings, LDLT was an independent protective factor, reducing the risk of overall death by 49% in the pre-IPTW analysis for the international cohort (HR, 0.51; 95% CI, 0.36-0.71; P < .001), 33% in the post-IPTW analysis for the international cohort (HR, 0.67; 95% CI, 0.53-0.85; P = .001), 43% in the pre-IPTW analysis for the Toronto cohort (HR, 0.57; 95% CI, 0.45-0.73; P < .001), and 48% in the post-IPTW analysis for the Toronto cohort (HR, 0.52; 95% CI, 0.42 to 0.65; P < .001). The discriminatory ability of the mathematical models further improved in all of the cases in which LDLT was incorporated.

Conclusions and Relevance  This study suggests that having a potential live donor could decrease the intention-to-treat risk of death in patients with HCC who are on a waiting list for a liver transplant. This benefit is associated with the elimination of the dropout risk and has been reported in centers in which both LDLT and DDLT options are equally available.

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