Key words : Graft survival, Liver allograft, Scientific Registry of Transplant Recipients, Transplant oncology, Wait list

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common cancer and fourth leading cause of cancer-related deaths worldwide.¹ The incidence of HCC, currently 5.5 to 14.9 per 100?000 population, has steadily increased annually since 1980, growing by approximately 2% since 2007.^2-4 The average 5-year survival rate for HCC varies widely depending on stage at diagnosis and treatment modality, with up to 70% survival in patients undergoing liver transplant (LT).³ Orthotopic whole liver transplant (WLT) was first introduced by Starzl in the 1960s and was later shown to be a viable treatment strategy in select patients with HCC by Mazzaferro and colleagues in 1996.^5,6 Since then, WLT has been shown to offer optimal curative treatment in patients meeting the Milan criteria, where patients have survival rates comparable to individuals transplanted for non­malignant liver disease. Several groups have sought to broaden these criteria for transplantation to offer improved survival for a larger number of patients with HCC.^7-9

The current supply of organs has not increased to meet this increased demand, leaving a growing number of these patients on wait lists while their disease continues to progress. Up to 42% of patients with HCC develop contraindications to transplant while waiting for LT, ultimately leading to removal from the wait list.^10,11 In an effort to address the organ shortage, several other strategies to increase the pool of transplantable livers have been developed, notably living donor liver transplant (LDLT) and split liver transplant (SLT).

In many countries globally, LDLT now supplies the majority of the current organ donor pool, with LDLT constituting more than 80% of annual LT in many countries throughout Asia.¹² Although LDLT was initially introduced to offer appropriately sized grafts for the pediatric transplant population, its use has since grown and has more recently offered a potential source of transplants for patients with HCC. However, data are currently conflicted regarding the possibility of increased HCC recurrence compared with use of deceased WLT for a multitude of reasons, including possible contribution of growth factors and cytokines released during rapid regeneration of a partial graft.^13-20

Similarly, SLT has also been proposed as a solution to increase liver donor availability and reduce wait list time and mortality. Skeptics of the use of SLT for HCC have cautioned against the possibly elevated risk of HCC recurrence compared with WLT, drawing comparisons to the theoretical risk associated with LDLT in HCC. In this study, we aimed to examine graft survival following deceased donor SLT compared with both a propensity score-matched WLT cohort and a random WLT cohort of HCC patients using national registry data.

Materials and Methods

Data source, inclusion criteria, comparison cohort formation, and data encoding
This study used data from the Scientific Registry of Transplant Recipients (SRTR). The SRTR data system includes data on all donors, wait listed candidates, and transplant recipients in the United States, submitted by the members of the Organ Procurement and Transplantation Network (OPTN). The Health Resources and Services Administration (HRSA), US Department of Health and Human Services, provides oversight to the activities of the OPTN and SRTR contractors. This study was approved by the Vanderbilt Institutional Review Board.

We identified the records in the June 2017 release of the SRTR Standard Analysis Files of adults (age ?18 years) with HCC who underwent a primary SLT or WLT between 2002 and June 2017. Patients with HCC were identified based on receiving a Model for End-Stage Liver Disease (MELD) score exception for HCC. The MELD score exception points are awarded to patients within the Milan criteria. Six binary variables represented the presence or absence of co-diagnoses, including hepatitis C virus, hepatitis B virus (HBV), alcoholic liver disease, primary biliary cirrhosis or primary sclerosing cholangitis, nonal­coholic steatohepatitis, and other co-diagnoses. Backward stepwise logistic regression-based propensity score matching, with stratification based on calendar year of transplant (to permit balanced opportunity for follow-up), was used to form a 1:1 comparison cohort of WLT recipients that was comparable in age, laboratory MELD score, history of diabetes (whether present or not), and donor-to-recipient weight ratio (whether ?1.00). An additional, large cohort (>12 WLT to 1 SLT) of randomly selected WLT recipients was constructed to provide a second comparison cohort that would be more broadly representative of the WLT recipients in general.

Statistical analyses
Data were summarized and between-group com­parisons were performed using parametric and nonparametric methods, as appropriate. Kaplan-Meier survival analysis with log-rank tests and multivariable Cox proportional hazards regression were used to evaluate unadjusted and covariable-adjusted effects of SLT compared with propensity score-matched and random WLT cohorts of HCC liver transplant recipients. Cox model covariables included the following: (1) recipient age (years), sex (reference = female), laboratory MELD at transplant, and presence of co-diagnoses (reference for each = no); (2) donor-to-recipient weight ratio (reference of <1.00); (3) donor and recipient history of diabetes (reference = no) and body mass index (BMI, measured as weight in kg divided by height in m2) class of <18.5 (underweight), 18.5 to <25.0 (normal weight), 25.0 to <30.0 (overweight), 30.0 to <35.0 (obese class 1), 35.0 to <40.0 (obese class 2), and ?40.0 (obese class 3) (reference = normal weight); and (4) liver donor risk index (LDRI).

Results

The sample comprised 330 HCC SLT recipients, 330 propensity score-matched HCC WLT recipients,
and 4143 randomly selected HCC WLT recipients (Table 1). The mean patient age was 58.7 ± 7.6 years overall, and the recipient between-cohort average age differed by no more than 1 year. Recipients of SLT were more likely to be female compared with the 2 WLT recipient cohorts (SLT: 43.3% vs WLT matched: 26.1% vs WLT random: 23.5%). The last laboratory MELD scores averaged 13.3 overall, and recipient between-cohort average scores differed by no more than 1 point. In all 3 cohorts, around one-third of the patients had HCC and cirrhosis only (without other co-diagnosis), while another third had a co-diagnosis of hepatitis C virus infection. Except for primary sclerosing cholangitis or primary biliary cirrhosis, which was more commonly reported in the SLT and matched WLT cohorts compared with the random WLT cohort, no other significant between-cohort differences were identified regarding co-diagnosis. The proportion of recipients of normal weight was significantly higher in the SLT cohort compared with either WLT cohort (SLT: 40.9% vs WLT matched: 24.5% vs WLT random: 25.5%); similarly the proportion of donors of normal weight in the SLT cohort was significantly higher compared with that of either WLT cohort (SLT: 58.2% vs WLT matched: 34.8% vs WLT random: 34.6%). No between-group differences were detected regarding the donor-to-recipient weight ratio. The proportion of donors with a history of diabetes in the SLT cohort was significantly lower compared with the 2 WLT cohorts, and LDRI was significantly higher in the SLT cohort than in either WLT cohort.

Unadjusted analysis demonstrated no statistically significant difference in graft survival between the SLT cohort and either the matched or the random WLT cohort (P = .78) (Figure 1). The multivariable Cox model (Table 2) demonstrated that neither the matched (adjusted hazard ratio [HR] = 1.19; 95% CI, 0.90-1.59; P = .23) nor the random WLT cohort (adjusted HR = 1.11; 95% CI, 0.89-1.38; P = .36) exhibited a statistically significant difference in the likelihood of graft failure compared with the SLT cohort. As expected, increasing recipient age (P = .04) and increasing last laboratory MELD score (P = .007) were associated with an increased likelihood of graft failure. Notably, having a co-diagnosis of HBV infection was associated with a decreased risk of graft failure compared with having no HBV infection (P < .001), whereas having any other co-diagnosis was not found to be associated with the likelihood of graft failure. Regarding donor characteristics, donor history of diabetes (P = .006), donor BMI category (P = .02), and increasing LDRI (P < .001) were identified as factors associated with inferior graft survival.

Discussion

Both SLT and LDLT were initially developed to provide size-appropriate liver grafts for pediatric patients. With the pervasive organ shortage, these methods also serve as potential ways to increase liver grafts for the adult population. There were initial concerns regarding LDLT for patients with HCC, which involved increased recurrence rates secondary to tumor stimulation by liver regeneration, earlier transplant, and increased tumor burden.^16,18 Several recent studies, however, have reported acceptable outcomes of LDLT versus deceased donor LT for patients with HCC.^15,19,21,22 The multicenter A2ALL study published in 2012 examined outcomes of 229 patients with HCC.¹⁵ The LDLT patients had an increased HCC recurrence rate, which could be accounted for by increased tumor burden in these patients in the MELD era. The 5-year graft survival between HCC LDLT versus deceased donor LT patients was equivalent. A recent study compared LDLT for HCC in 133 patients in Japan with 362 patients from the United States who underwent deceased donor LT (94% WLT) for HCC.¹⁹ These groups were similar in terms of Milan criteria tumor burden and microvascular invasion. The 2 groups had similar HCC recurrence rates, and the LDLT cohort had statistically improved graft survival.

There has been little increase in the use of SLT for adult patients, and studies have not been robust. In addition to the above oncologic concerns with the regeneration of grafts, SLTs were initially classified as “marginal” grafts. A 2013 study that examined United Network for Organ Sharing (UNOS) data for SLT for all indications reported nonsignificant differences in outcomes in the MELD-era SLT compared with WLT.²³ However, the study reported an increased risk for graft failure in patients with an HCC exception who received SLT compared with WLT. Recent studies have reported equivalent graft and patient outcomes or an increased risk of graft failure with SLT, which can be mitigated with decreasing cold ischemic times or utilizing younger donors.^24-26 A multicenter Italian study examined 81 matched pairs of SLT and WLT and found equivalent 5- and 10-year graft and patient survival in patients who survived past the first posttransplant year.²⁷ This Italian study also advocated for the use of SLT from younger donors. These studies included patients with HCC but did not report outcomes specific to this patient population. Our study focused on SLT in patients with HCC and utilized both a matched and random cohort for comparison. We found equivalent graft survival between SLT and both cohorts of WLT. Significant differences among the populations included a higher percentage of female recipients and normal weight recipients in the SLT group. One could speculate this was due to the selection of smaller recipients to ensure the split graft provided adequate liver volume.

A recent study by Perito and associates utilized the UNOS database to determine “split-able” livers.²⁸ By their conservative standards, 6.3% of livers were potentially split-able and only 3.8% were split. They further determined that the number of split-able livers was greater than the number of deaths on the pediatric wait list in every region (acknowledging the lack of data on nuanced decision making and patient specifics). Additionally, a large transplant center in the United Kingdom reported the success of their implementation of an “intention to split” policy, which led to an increase in SLT, a 0% mortality on the pediatric wait list, and acceptable graft outcomes in pediatric and adult LT.²⁹ Italy similarly implemented a mandatory split policy in 2015 and recently reported an increase since that time in the rate of SLT with a corresponding decrease in wait list mortality for both pediatric and adult patients, with acceptable post­transplant outcomes.³⁰ These studies, in addition to our present study, encourage continued investigation into how to best utilize and incentivize SLT.

Limitations of our study are those inherent to every large database study, which are the retrospective nature of the study and the reliance on the accuracy of the dataset. Additionally, although the large number of patients in a national database is an advantage, there is correspondingly a lack of granularity, especially with regard to HCC recurrence. The HCC recurrence data are poorly populated and therefore could not be analyzed in this study. Mandating and standardizing HCC recurrence reporting would enable the analysis of this important outcome.

Conclusions

Split liver transplant for patients with HCC results in equivalent graft outcomes compared with WLT. More investigations are needed and should be supported to continue to optimize outcomes and develop ways to encourage SLT.

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