Elsevier

Journal of Hepatology

Volume 74, Issue 4, April 2021, Pages 829-837
Journal of Hepatology

Research Article
A novel waitlist dropout score for hepatocellular carcinoma – identifying a threshold that predicts worse post-transplant survival

https://doi.org/10.1016/j.jhep.2020.10.033Get rights and content

Highlights

  • Increasing tumour burden, alpha-fetoprotein, Child-Pugh, and model for end-stage liver disease score predict HCC wait-list dropout.

  • Novel HCC dropout risk score stratifies 1-year dropout risk from 7% up to 40%.

  • Patients with HCC with the highest dropout risk score >30 have poor transplant survival.

  • In all others with HCC, calculated dropout risk can safely guide wait-list priority.

Background & Aims

It has been suggested that patients with hepatocellular carcinoma (HCC) at high risk of wait-list dropout would have done poorly after liver transplantation (LT) because of tumour aggressiveness. To test this hypothesis, we analysed risk of wait-list dropout among patients with HCC in long-wait regions (LWRs) to create a dropout risk score, and applied this score in short (SWRs) and mid-wait regions (MWRs) to evaluate post-LT outcomes. We sought to identify a threshold in dropout risk that predicts worse post-LT outcome.

Methods

Using the United Network for Organ Sharing database, including all patients with T2 HCC receiving priority listing from 2010 to 2014, a dropout risk score was created from a developmental cohort of 2,092 patients in LWRs, and tested in a validation cohort of 1,735 patients in SWRs and 2,894 patients in MWRs.

Results

On multivariable analysis, 1 tumour (3.1–5 cm) or 2–3 tumours, alpha-fetoprotein (AFP) >20 ng/ml, and increasing Child-Pugh and model for end-stage liver disease-sodium scores significantly predicted wait-list dropout. A dropout risk score using these 4 variables (C-statistic 0.74) was able to stratify 1-year cumulative incidence of dropout from 7.1% with a score ≤7 to 39.5% with a score >23. Patients with a dropout risk score >30 had 5-year post-LT survival of 60.1% vs. 71.8% for those with a score ≤30 (p = 0.004). There were no significant differences in post-LT survival below this threshold.

Conclusions

This study provided evidence that patients with HCC with the highest dropout risk have aggressive tumour biology that would also result in poor post-LT outcomes when transplanted quickly. Below this threshold risk score of ≤30, priority status for organ allocation could be stratified based on the predicted risks of wait-list dropout without significant differences in post-LT survival.

Lay summary

Prioritising patients with hepatocellular carcinoma for liver transplant based on risk of wait-list dropout has been considered but may lead to inferior post-transplant survival. In this study of nearly 7,000 patients, we created a threshold dropout risk score based on tumour and liver-related factors beyond which patients with hepatocellular carcinoma will likely have poor post-liver transplant outcomes (60% at 5 years). For patients below this risk score threshold, priority status could be stratified based on the predicted risk of wait-list dropout without compromising post-transplant survival.

Introduction

Following the implementation of the model for end-stage liver disease (MELD) system of organ allocation for hepatocellular carcinoma (HCC) in 2002, the proportion of liver transplants (LTs) performed in the USA for HCC has dramatically increased from <5% before 2002 to nearly 30%.[1], [2], [3] The rising incidence rates of HCC in the ageing hepatitis C population and in those with non-alcoholic fatty liver disease and metabolic syndrome are major contributing factors.[4], [5], [6], [7] Additionally, HCC screening in at-risk populations, recommended by all liver societies, increases the proportion diagnosed with early-stage HCC. As a result, HCC wait-list registrations in the USA rose by nearly 2000 within the 5 yr period from 2005–2009 to 2010–2014.8

As the transplant community is faced with the increasing demands of deceased donors for HCC, maximising LT survival benefit by improving patient selection (utility) must be carefully balanced against serving those with a higher risk for wait-list removal because of tumour progression (urgency).[9], [10], [11], [12] The lack of a reliable instrument built upon optimal LT timing for patients with HCC according to specific tumour characteristics represents 1 of the greatest challenges in organ allocation for HCC.11 Several systems have been proposed to give additional priority to patients with HCC with a greater risk for dropout, which typically include those with larger tumours and higher alpha-fetoprotein (AFP).[13], [14], [15], [16] This strategy, however, raises the concern of selecting those with less favourable tumour biology for LT, leading to a higher rate of post-LT HCC recurrence and worse survival.17,18

Another confounding factor is the wide regional variation in waiting time for LT across the USA.8,19 Regions with short-wait time offer the inherent advantage of rapid LT and a very low probability of wait-list dropout.8 Studies using the United Network for Organ Sharing (UNOS) database have also suggested worse post-LT survival and a greater risk of HCC recurrence with short-wait time,2,20 possibly because of inclusion of more aggressive tumours for LT without sufficient time to observe tumour behaviour.

In the present study, we analysed the risk of wait-list dropout among patients with HCC in long-wait regions (LWRs) to create a dropout risk score and to apply this score in mid-wait regions (MWRs) and short-wait regions (SWRs) to evaluate post-LT outcomes. Using this novel approach, we aimed to test the hypothesis that those with the highest dropout risk (determined in long-wait-time regions) have aggressive tumour biology that would also result in poor post-LT outcomes when transplanted in shorter-wait-time regions. Based on the same assumption, we also sought to identify a threshold in this dropout risk score beyond which LT should no longer be considered an acceptable immediate treatment option.

Section snippets

Study design and patient population

This was a retrospective cohort study of patients aged 18 yr and older listed for primary LT in the UNOS database (Standard Transplant Analysis and Research files released in March 2018) who received initial MELD exception for stage T2 HCC between January 2010 and December 2014. Patients were excluded from the study if they were listed for multi-organ transplant or received a living-donor LT. We also excluded patients who ever exceeded the Milan criteria before listing given that there was no

Patient characteristics

Baseline demographic and clinical characteristics of the 2092 patients with HCC comprising the LWR development cohort are summarised in Table 1 and compared with the 2 validation cohorts, which included 1735 patients listed in SWR and 2894 patients listed in MWR. Overall, the median age was 59 yr (IQR 55–63) and 76.6% were men. A significantly higher percentage of non-Caucasians were listed in LWR. Hepatitis C was the most common aetiology of liver disease. Hepatitis B and alcoholic liver

Discussion

HCC is a heterogeneous disease with highly variable patterns of progression after the initial diagnosis.25 This tumour heterogeneity is not accounted for under the traditional dogma of restricting LT for HCC solely on the basis of tumour size and number. Observing tumour behaviour following LRT while on the waiting list for LT has recently emerged as the main driver for improving candidate selection beyond the ‘1 size (and number) fits all’ approach.11,26 A crucial element in patient selection

Financial support

This work was supported by the Clinical & Translational Core of the University of California, San Francisco Liver Center (P30 DK026473).

Authors’ contributions

Concept and design: N.M., F.Y.Y.

Data acquisition, analysis, or interpretation: all authors

Drafting of paper: N.M., J.L.D., F.Y.Y.

Critical revision of paper for important intellectual content: all authors

Statistical analysis: N.M., J.L.D., F.Y.Y.

Supervision: J.P.R., F.Y.Y.

Data availability statement

The data that support the findings of this study are openly available in the UNOS database (Standard Transplant Analysis and Research files released March 2018).

Conflicts of interest

The authors declare no conflicts of interest that pertain to this work.

Please refer to the accompanying ICMJE disclosure forms for further details.

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      Citation Excerpt :

      We found 3 factors associated with increased risk of dropout, including a higher listing MELD score, initial total tumor diameter, and initial AFP level >20 ng/mL. Previous studies similarly have found that HCC patients with more severe cirrhosis, based on MELD score or Child–Pugh class, have a high risk of waitlist dropout.16 Many patients with liver dysfunction have fewer LRT options and may receive less-aggressive treatments owing to the risk of hepatic decompensation after LRT and also are more likely to have liver-related death without LT. In addition, compared with AFP level ≤20 ng/mL, increasing AFP levels were found to be increasingly associated with a higher risk of dropout.

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