Retrospective Cohort Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 28, 2018; 24(12): 1321-1331
Published online Mar 28, 2018. doi: 10.3748/wjg.v24.i12.1321
Model combining pre-transplant tumor biomarkers and tumor size shows more utility in predicting hepatocellular carcinoma recurrence and survival than the BALAD models
Nicha Wongjarupong, Gabriela M Negron-Ocasio, Roongruedee Chaiteerakij, Benyam D Addissie, Essa A Mohamed, Kristin C Mara, William S Harmsen, J Paul Theobald, Brian E Peters, Joseph G Balsanek, Melissa M Ward, Nasra H Giama, Sudhakar K Venkatesh, Denise M Harnois, Michael R Charlton, Hiroyuki Yamada, Alicia Algeciras-Schimnich, Melissa R Snyder, Terry M Therneau, Lewis R Roberts
Nicha Wongjarupong, Gabriela M Negron-Ocasio, Benyam D Addissie, Essa A Mohamed, Nasra H Giama, Michael R Charlton, Lewis R Roberts, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
Nicha Wongjarupong, Roongruedee Chaiteerakij, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10400, Thailand
Gabriela M Negron-Ocasio, University of Puerto Rico Medical Sciences Campus, San Juan 00921, Puerto Rico
Kristin C Mara, William S Harmsen, Terry M Therneau, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, United States
J Paul Theobald, Brian E Peters, Joseph G Balsanek, Melissa M Ward, Alicia Algeciras-Schimnich, Melissa R Snyder, Division of Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
Sudhakar K Venkatesh, Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
Denise M Harnois, Department of Transplantation, Mayo Clinic Florida, Jacksonville, FL 32224, United States
Hiroyuki Yamada, Wako Life Sciences, Incorporated, Mountain View, CA 94043, United States
Author contributions: Wongjarupong N, Chaiteerakij R and Roberts LR designed research; Wongjarupong N, Chaiteerakij R, Negron-Ocasio GM, Addissie BD, Mohamed EA, Giama NH, Venkatesh SK, Harnois DM and Charlton MR performed research; Theobald JP, Peters BE, Balsanek JG, Ward MM, Yamada H, Algeciras-Schimnich A and Synder MR contributed new reagents and analytic tools; Mara KC, Harmsen WS, Therneau TM analyzed data; Wongjarupong N, Negron-Ocasio GM, Roberts LR wrote the paper.
Supported by Mayo Clinic Center for Clinical and Translational Science (CCATS), No. NCATS 1UL1TR002377-01; Mayo Clinic Center for Cell Signaling in Gastroenterology, No. NIDDK P30DK084567-09; and Wako Life Sciences, Inc.
Institutional review board statement: This study was approved by Mayo Clinic Institutional Review Board (IRB 17-001912).
Informed consent statement: The IRB waived the requirement written informed consent for this minimal risk retrospective study.
Conflict-of-interest statement: Roberts LR has received grant funding from BTG, Gilead Sciences and Wako Life Sciences; Yamada H is an employee of Wako Life Sciences. There are no other potential conflicts of interest for the rest of the authors.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Lewis R Roberts, MB ChB, PhD, Professor of Medicine, Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, 200 First Street SW Rochester, MN 55905, United States. roberts.lewis@mayo.edu
Telephone: +1-507-2664720 Fax: +1-507-2840762
Received: December 3, 2017
Peer-review started: December 4, 2017
First decision: December 13, 2017
Revised: March 10, 2018
Accepted: March 18, 2018
Article in press: March 18, 2018
Published online: March 28, 2018
Processing time: 112 Days and 11.6 Hours
ARTICLE HIGHLIGHTS
Research background

Liver transplant is one of the curative treatments for hepatocellular carcinoma (HCC). However, with the limited availability of donor organs, it is essential to select patients who will derive the most benefit from transplant. The alpha-fetoprotein (AFP) model has been widely used for this purpose. In the development cohort of the BALAD model by Toyoda et al, liver transplant patients were excluded. In the validation cohort in four countries by Chan et al, there were only 21 transplant patients included, and in the Japan Nationwide study from Toyoda et al, an unknown number of transplant patients were classified in the other treatment group. There is therefore very limited data on the utility of the BALAD model in patients with liver transplant.

Research motivation

The BALAD model has been shown to be a promising predictor of outcome in hepatocellular carcinoma patients receiving most treatment modalities, but there is very limited data on its performance in hepatocellular carcinoma patients receiving liver transplants. The BALAD model incorporates three tumor biomarkers which represent the underlying biology of hepatocellular carcinomas, as well as the serum bilirubin and albumin, which reflect the extent of the underlying liver dysfunction in patients with chronic liver disease. Individually, the AFP, AFP-L3, and des-gamma-carboxyprothrombin (DCP) have been shown to predict the recurrence and survival of hepatocellular carcinoma patients receiving liver transplants. However, presumably due to replacement of the diseased liver during transplantation, it has been shown that the serum bilirubin and albumin are not predictive of patient outcomes post liver transplant.

Research objectives

We aimed to assess the performance of the discontinuous BALAD and continuous BALAD-2 scores in patients who underwent liver transplant for HCC. Further, we assessed the performance of each component of the BALAD in predicting outcomes and propose a more effective model for liver transplant patients.

Research methods

We included patients with hepatocellular carcinoma receiving liver transplants between 2000 and 2008 for whom blood samples were available to allow testing and calculation of the BALAD scores. Patient characteristics, the components of the BALAD model, BALAD score, and BALAD-2 class were analyzed to calculate hazard ratios for recurrence and death. Currently used predictive models including the Milan and UCSF criteria, GALAD score, and AFP model were compared with the BALAD models using c-statistics. A new multivariate model incorporating the three tumor markers and largest tumor diameter was created from these statistically significant variables. The long follow-up period allows assessment of the long term outcomes of the liver transplant patients.

Research results

113 patients were included in the study. The diameter of the largest tumor at the time of transplant, neutrophil-lymphocyte ratio of more than 4, elevated AFP, AFP-L3, and DCP by BALAD score cut-off were associated with both recurrence and death. The HRs per each unit increase in BALAD score for recurrence and death were 1.48 (1.15-1.91) and 1.59 (1.28-1.97). The HRs per each unit increase in BALAD class for recurrence and death were 1.45 (1.06-1.98) and 1.38 (1.09-1.76), respectively. By c-statistics, a model based on the combination of AFP, AFP-L3, and DCP using the BALAD score cut-off had a higher predictive performance than any of the prior models (0.66 for both recurrence and death). Further, a multivariate model incorporating the three biomarkers and the largest diameter of the tumor, designated the S-LAD model, showed a higher c-statistic than all other models (0.71 for recurrence and 0.69 for death). The main limitation of this study is the need for validation of the S-LAD model.

Research conclusions

BALAD and BALAD-2 are valid in transplant HCC patients, but less predictive than the three biomarkers in combination or the three biomarkers in combination with largest tumor diameter (S-LAD).

Research perspectives

Due to the limited number of patients included, further cohort studies to assess the performance of the BALAD and S-LAD models in hepatocellular carcinoma patients receiving liver transplant are warranted.