Published online Mar 28, 2018. doi: 10.3748/wjg.v24.i12.1321
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
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.
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.
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.
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.
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.
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).
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.