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Original Investigation
May 5, 2021

Dynamic α-Fetoprotein Response and Outcomes After Liver Transplant for Hepatocellular Carcinoma

Author Affiliations
  • 1Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Weill Cornell Medicine, New York, New York
  • 2Center for Liver Disease and Transplantation, Columbia University Medical Center, New York Presbyterian Hospital, New York
  • 3Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York, New York
  • 4Division of Gastroenterology, Department of Medicine, University of California, San Francisco
  • 5Sapienza University, Rome, Italy
  • 6Multi-Organ Transplant and HPB Surgical Oncology, Division of General Surgery, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
  • 7Center for Advanced Digestive Care, Division of Hematology and Oncology, New York–Presbyterian Hospital, Weill Cornell Medical College of Cornell University, New York
  • 8Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
  • 9Section of Abdominal Organ Transplant, Department of Surgery, Washington University School of Medicine, Washington University, St Louis, Missouri
  • 10Recanati/Miller Transplantation Institute, Department of Transplantation, Mount Sinai Medical Center, New York, New York
  • 11Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California
  • 12Institute for Experimental and Clinical Research (IREC) Université catholique de Louvain (UCL), Brussels, Belgium
  • 13Gastroenterology and Hepatology, Department of Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria
  • 14Department of Transplantation and Hepatobiliary Surgery, University of Mainz, Mainz, Germany
JAMA Surg. 2021;156(6):559-567. doi:10.1001/jamasurg.2021.0954
Key Points

Question  Can the dynamic α-fetoprotein response predict outcomes of patients undergoing liver transplant for hepatocellular carcinoma in a heterogeneous population of patients from North America and Europe?

Findings  In this multicenter international prognostic study of 2236 adults undergoing liver transplant for hepatocellular carcinoma at 4 North American and 4 European centers, the utility of the α-fetoprotein response was validated to predict recurrence and survival. In addition, the α-fetoprotein response was superior to currently available patient selection tools.

Meaning  Incorporation of a dynamic α-fetoprotein response into currently used morphometric hepatocellular carcinoma selection criteria appears to improve the ability to predict recurrence and may increase access to liver transplant for patients with hepatocellular carcinoma who would otherwise be denied potential cure.


Importance  Accurate preoperative prediction of hepatocellular carcinoma (HCC) recurrence after liver transplant is the mainstay of selection tools used by transplant-governing bodies to discern candidacy for patients with HCC. Although progress has been made, few tools incorporate objective measures of tumor biological characteristics, resulting in inclusion of patients with high recurrence rates and exclusion of others who could otherwise be cured.

Objective  To externally validate the New York/California (NYCA) score, a recently published multi-institutional US HCC selection tool that was the first model incorporating a dynamic α-fetoprotein response (AFP-R) and compare the validated score with currently accepted HCC selection tools, namely, the Milan Criteria (MC), the French-AFP (F-AFP), and Metroticket 2.0 models.

Design, Setting, and Participants  A retrospective, multicenter prognostic analysis of prospectively collected databases of 2236 adults undergoing liver transplant for HCC was conducted at 3 US, 1 Canadian, and 4 European centers from January 1, 2001, to December 31, 2013. The AFP-R was measured as the difference between maximum and final pre-liver transplant AFP level. Cox proportional hazards regression and competing risk regression analyses examined recurrence-free and overall survival. Receiver operating characteristic analyses and net reclassification index were used to compare NYCA with MC, F-AFP, and Metroticket 2.0. Data analysis was performed from June 2019 to April 2020.

Main Outcomes and Measures  The primary study outcome was 5-year recurrence-free survival; overall survival was the secondary outcome.

Results  Of 2236 patients, 1808 (80.9%) were men; mean (SD) age was 58.3 (7.96) years. A total of 545 patients (24.4%) did not meet the MC. The NYCA score proved valid on competing risk regression analysis, accurately predicting recurrence-free and overall survival (5-year cumulative incidence of recurrence risk in NYCA risk categories was 9.5% for low-, 20.5%, for acceptable-, and 40.5% for high-risk categories; P < .001 for all). The NYCA also predicted recurrence-free survival on a center-specific level: 453 of 545 patients (83.1%) who did not meet MC, 213 of 308 (69.2%) who did not meet the French-AFP, 292 of 384 (76.1%) who did not meet Metroticket 2.0 would be recategorized into NYCA low- and acceptable-risk groups (>75% 5-year recurrence-free survival). The Harrell C statistic for the validated NYCA score was 0.66 compared with 0.59 for the MC and 0.57 for the F-AFP models (P < .001). The net reclassification index for NYCA was 8.1 vs MC, 12.9 vs F-AFP, and 10.1 vs Metroticket 2.0.

Conclusions and Relevance  This study appears to externally validate the importance of AFP-R in the selection of patients with HCC for liver transplant. The AFP-R represents one of the truly objective measures of biological characteristics available before transplantation. Incorporation of AFP-R into selection criteria allows safe expansion of MC and other models, offering liver transplant to patients with acceptable tumor biological characteristics who would otherwise be denied potential cure.

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