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
Abstract
AIM

To assess the performance of BALAD, BALAD-2 and their component biomarkers in predicting outcome of hepatocellular carcinoma (HCC) patients after liver transplant.

METHODS

BALAD score and BALAD-2 class are derived from bilirubin, albumin, alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxyprothrombin (DCP). Pre-transplant AFP, AFP-L3 and DCP were measured in 113 patients transplanted for HCC from 2000 to 2008. Hazard ratios (HR) for recurrence and death were calculated. Univariate and multivariate regression analyses were conducted. C-statistics were used to compare biomarker-based to predictive models.

RESULTS

During a median follow-up of 12.2 years, 38 patients recurred and 87 died. The HRs for recurrence in patients with elevated AFP, AFP-L3, and DCP defined by BALAD cut-off values were 2.42 (1.18-5.00), 1.86 (0.98-3.52), and 2.83 (1.42-5.61), respectively. For BALAD, the HRs for recurrence and death per unit increased score were 1.48 (1.15-1.91) and 1.59 (1.28-1.97). For BALAD-2, the HRs for recurrence and death per unit increased class were 1.45 (1.06-1.98) and 1.38 (1.09-1.76). For recurrence prediction, the combination of three biomarkers had the highest c-statistic of 0.66 vs. 0.64, 0.61, 0.53, and 0.53 for BALAD, BALAD-2, Milan, and UCSF, respectively. Similarly, for death prediction, the combination of three biomarkers had the highest c-statistic of 0.66 vs 0.65, 0.61, 0.52, and 0.50 for BALAD, BALAD-2, Milan, and UCSF. A new model combining biomarkers with tumor size at the time of transplant (S-LAD) demonstrated the highest predictive capability with c-statistics of 0.71 and 0.69 for recurrence and death.

CONCLUSION

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 maximal tumor diameter (S-LAD).

Keywords: Alpha-fetoprotein, AFP-L3, Des-gamma-carboxyprothrombin, BALAD, BALAD-2, Hepatocellular carcinoma, Liver transplant, Recurrence, Outcome

Core tip: BALAD score and BALAD-2 class incorporating alpha-fetoprotein (AFP), AFP-L3, and des-gamma-carboxyprothrombin are used to predict survival of patients with hepatocellular carcinoma. However, there were limited numbers of patients who received liver transplant in previous cohorts in which performance of the BALAD was studied. Our study showed that pre-transplant BALAD score and BALAD-2 class are useful for predicting outcome of hepatocellular carcinoma patients receiving liver transplant. However, a more predictive model uses the combination of all three biomarkers using the cut-offs from the BALAD score along with maximum tumor size at the time of transplant.