Key words : Hepatitis C virus, Model for End-Stage Liver Disease, Multivariate analysis

Introduction

Although measures for treatment are continuously evolving, liver transplant (LT) still remains the most effective curative treatment option for patients with cirrhosis and hepatocellular carcinoma (HCC) within Milan criteria.¹ Currently, deceased donor liver transplant (DDLT) is the predominant type of LT in the United States.² An analysis of 30-year Scientific Registry of Transplant Recipients (SRTR) data (1987-2017) among DDLT recipients showed hepatitis C virus (HCV) as the most common cause of liver disease leading to HCC.³ Recent observations have revealed a 50% increase in nonalcoholic fatty liver disease (NAFLD)-related HCC among LT cases.³ Although the number of LTs for HCC is increasing, there is still a growing mismatch between organ supply and demand, making living donor liver transplant (LDLT) a vital option to expand the donor pool.⁴

In contrast to the United States, in some Asian countries, and some other parts of the globe, where the deceased donor pool is limited, LDLT has been used as the only available transplant option for HCC.⁵ Despite promising results from these LDLT centers, there has been conflicting literature regarding the efficacy of LDLT over DDLT, and reports of a higher rate of HCC recurrence following LDLT may have hampered its progression in the Western world.^6-8 Notwithstanding, LDLT for HCC is continuously evolving, and newer center-specific criteria have been proposed.^9-11 However, none of these have been externally validated.¹² Therefore, there is variability in patient selection for LDLT in various transplant centers.

In the United States, the Model for End-Stage Liver Disease (MELD) exception criteria for HCC has been constantly updated.^2,13 These changes have resulted in a decreased rate of LT for HCC over time.³ In the SRTR’s most recent annual report (2019), there have been 12767 new registrations with HCC comprising 10.6% of the cases.^2,14 Therefore, LDLT as an option to increase the donor pool to meet organ shortages should be revisited. Although the overall rate of LDLT has increased in the United States over the last decade (Figure 1),¹⁵ its role in HCC has not been fully explored.

In this study, we aimed to explore the clinical characteristics and long-term outcomes of LDLT compared with DDLT in the United States, using United Network of Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) data.

Materials and Methods

Data source
The data reported here have been supplied by UNOS as the contractor for the OPTN. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy of or interpretation by the OPTN or the US Government.

Study design and patient population
The study design was a retrospective cohort of UNOS from January 2003 to December 2019. Study subjects included patients with LDLT or DDLT who were ≥18 years old with diagnostic codes for HCC. Pediatric cases, non-HCC cases, candidates with null information on tumor number/size, and status 1 patients were excluded from the study.

Information used
We obtained the following recipient data through the UNOS database: (1) demographics (age, male/female, race/ethnicity); (2) clinical features (including etiology of liver disease); (3) laboratory data (MELD score, alpha-fetoprotein [AFP] level); (4) tumor features (number, largest tumor size); and (5) outcomes (survival).

Study outcomes
The primary outcome of the study was survival after LT. In addition, to evaluate the time-to-mortality, we studied duration of follow-up for performing the survival analyses.

Statistical analyses
Information was acquired from the database and transferred to the STATA software package (version 16.1; Stata Corp), which was used for data cleaning, management, and analyses. The categorical variables are reported as numbers and percentages, and the continuous variables are reported as means and standard deviations. Relationships between variables were estimated with the chi-square test (for categorical variables) or the independent t test (for continuous variables). Data for survival analysis were plotted on the Kaplan-Meier curve. We also used a step-by-step multivariate Cox proportional hazard model to evaluate the predictors of mortality. A hazard ratio (HR) represented a 95% confidence interval (CI). Statistical significance was defined asP≤ .05.

Results

Trend of living donor liver transplant in the United States
Per the OPTN database, the number of LDLT cases has increased in the United States. This trend has become more prominent, especially during the past decade (Figure 1). Between 2003 and 2019, 17.4% of adult LDLT recipients had a diagnosis of HCC. Among DDLT recipients, HCC was an indication for transplant in 32.5% of patients.

Characteristics of patients with hepatocellular carcinoma
There were a total of 25659 recipients with a diagnosis of HCC in our study. Among LT recipients for HCC within this cohort, 385 (1.5%) received LDLT and 25274 (98.5%) received DDLT. The mean age (SD) of patients in the LDLT and DDLT groups was 58.5 (8.9) and 59.1 (7.4) years, respectively. Male distribution was 69.4% in the LDLT group and 77.2% in the DDLT group. There were no differences in etiology of liver disease between the groups, with HCV being the most common cause. There were fewer Black/African Americans in the LDLT group (4.2% vs 9.3%; P = .01). The proportion of patients waiting ≥6 months on the LT wait list was higher in the DDLT group than in the LDLT group (55.9% vs 45.2%; P < .001). There was no statistical difference between the 2 groups in terms of the number of tumors, largest tumor size, being outside of Milan criteria, and AFP level at the time of transplant. There was a trend toward higher biological MELD (13 vs 12; P = .07) in the DDLT versus the LDLT group, but it did not reach statistical significance. On the other hand, the mean allocation MELD was higher in the DDLT group than in the LDLT group (27 vs 21; P < .001). Figure 1 shows the demographic and clinical characteristics of the LT recipients with HCC and the donor variables.

Survival analysis
Overall, 1-, 5-, and 10-year overall survival among the DDLT and LDLT groups were similar (91.2%, 74%, and 58.9% vs 92%, 76.4%, and 56.5%, respectively; P = .69) (Figure 2).

Table 2 shows the results of the multivariate analysis of donor and recipient variables for survival after LT for all HCC patients in the DDLT and LDLT groups. Older donor or recipient age was associated with a higher hazard of death. Black/African American race/ethnicity was associated with worse outcomes than White race/ethnicity as reference (HR = 1.186; 95% CI, 1.102-1.277; P < .001), whereas Hispanics and Asians were more protected. Alcohol liver disease, hepatitis B virus, NAFLD, and autoimmune liver disease were associated with lower hazard of death compared with HCV. Tumor characteristics, ≥3 lesions, largest tumor size, and higher AFP levels were associated with worse outcomes. Wait time on the LT list of ≥6 months was associated with better outcomes compared with <6 months (HR = 0.883; 95% CI, 0.843-0.925; P < .001). Type of organ transplant (that is, deceased vs living donor) did not reach statistical significance on multivariate analysis.

However, when we analyzed the same variables in the multivariate analysis of survival after LT among LDLT recipients only, the single variable that reached statistical significance was largest tumor size (HR = 1.259; 95% CI, 1.072-1.479; P = .005).

Discussion

Living donor liver transplant is an alternative option to increase the available donor pool in HCC. However, in the United States, LDLT still constitutes a minority of HCC-related transplants (1.5%) (Table 1). Nevertheless, among patients waiting for transplant, HCC is the indication for transplant among 32.5% of DDLT recipients, while it is the indication in 17.4% of LDLT cases. Furthermore, the wait list time was significantly different between those with HCC who received LDLT versus those with HCC who received DDLT. Within the LDLT group, 45.2% of recipients waited more than 6 months versus 55.9% of DDLT recipients (P = .001; Table 2). This difference was found despite the similarity in tumor characteristics (that is, number of tumors, AFP level, largest size, and being outside Milan criteria; Table 2). This prolonged wait time within the DDLT group may have potentially resulted in dropout in DDLT for HCC.

The utilization of LDLT in patients with HCC is variable across the globe. Unlike the United States, in some countries, particularly in Asia, LDLT is the main source of transplants for HCC. Thus, comparatively, most reports of LDLT for HCC are reported from these regions. A large multicenter observational study from China comparing LDLT versus DDLT for HCC showed encouraging results for LDLT, with 1-, 3-, and 5-year overall survival of 86.7%, 70.1%, and 66.3% versus 74.2%, 54.2%, and 46.9% (P < .001), respectively, and disease-free survival of 78.4%, 63.6%, and 61.6% versus 65.6%, 48.6%, and 41.8% (P < .001).¹⁶ The results suggested worse outcomes with DDLT, with the caveat that this was an observational study prone to selection bias. It is important to note that the DDLT group had a higher pretransplant rate of macrovascular invasion and total tumor diameter. In contrast, there have been concerns regarding higher 5-year recurrence with LDLT (38%) compared with DDLT (11%) (P = .0004), as reported by the US A2ALL cohort.¹⁷ However, 5-year unadjusted survival probability was similar between the LDLT (59%) and DDLT (66%) groups (HR = 1.32; P = .27).¹⁷ Likewise, in another study, Vakili and colleagues reported 5-year survival of 81% with a recurrence rate of 28.6% in recipients with LDLT for HCC, which was strongly correlated with tumor grade.¹⁸

One possible explanation of higher tumor recurrence in the LDLT group may be due to the shorter wait time.¹⁹ Thus, patients with more aggressive tumors may receive LDLT, whereas aggressive tumor biology on the longer DDLT wait list may lead to HCC dropout and preclude transplant.⁵ Similarly, some authors have argued that the surgical technique in LDLT, which requires meticulous dissection of the recipient’s liver with preservation of the native vena cava, and more hepatic artery and bile duct length increase the chances of residual tumor and violation of tumor capsule.²⁰

One difference in LDLT is that recipients are not restricted to being within Milan criteria as required by UNOS.¹² A recent meta-analysis showed no significant difference in overall survival rate at 1, 3, and 5 years among patients undergoing LT for HCC based on Milan or University of California, San Francisco (UCSF) criteria.²¹ Another study comparing LDLT and DDLT showed that AFP >600 ng/mL (HR = 2.83; 95% CI, 1.07-7.48; P = .036), tumor beyond UCSF criteria (HR = 2.36; 95% CI, 1.11-5.04; P = .026), and microvascular invasion (HR = 3.79; 95% CI, 1.81-7.94; P < .001) were independent poor prognostic factors for overall survival.²²

The UNOS criterion for HCC listing has been continuously revised. As per the recent policy updated in 2019 and 2020, a candidate would be receiving a MELD score that is 3 points below the median MELD at transplant of all recipients who were transplanted at hospitals within 250 nautical miles of the candidate’s listing hospital.²³ Furthermore, the exception points are denied if there is macrovascular invasion of the main portal vein or hepatic vein or AFP remains ≥500 ng/mL despite the previous treatment.²⁴ This recent policy for organ allocation for HCC with the static median MELD at transplant minus 3 may further result in longer wait times and potentially increase the dropout rates for HCC recipients.

In our analysis, 93.5% (n = 360) of the LDLT group and 92% (n = 23254) of the DDLT group had AFP <200 ng/mL (Table 1). Only a small percentage of LT recipients were outside Milan criteria (8.6% [n = 33] in the LDLT and 7.6% [n = 1907] in the DDLT group; Table 1). Furthermore, compared with White recipients, Black/African American recipients had worse outcomes (HR = 1.186; 95% CI, 1.102-1.277; P < .001). However, Hispanic (HR = 0.870; 95% CI, 0.814-0.931; P < .001) and Asian recipients (HR = 0.734; 95% CI, 0.660-0.816; P < .001) showed better outcomes than White recipients as reference. Our study also reported comparable 10-year survival rates between the LDLT and DDLT groups without any significant difference in AFP levels, tumor size, or tumor number (Figure 2). On multivariate analysis, the type of organ transplant in LT recipients with HCC (deceased vs living donor) was not associated with higher death. Therefore, favorable outcomes seem to be possible with LDLT if strict selection criteria are used, which is consistent with available literature.^25,26 Thus, exploring and expanding LDLT for HCC may play an instrumental role in expanding the donor pool in the United States in patients with HCC.

Limitations of our study included (1) the retrospective nature of the study, (2) the small sample size of LDLT, as it is not the predominant form of LT in the United States; (3) more than 90% of recipients having AFP <200 ng/mL, tumor number ≤2, and within Milan criteria; and (4) no data on tumor recurrence. This restricted our conclusion about the long-term outcomes of patients outside the Milan criteria. In addition, we did not evaluate differences between DDLT and LDLT for HCC in various MELD exception time eras.

Conclusions

Living donor liver transplant constitutes a small percentage (1.5%) of all adult LT procedures performed for diagnosis of HCC in the United States. In our study, patient and tumor characteristics, such as tumor number and size, AFP level, Milan criteria prior to downstaging, and survival, were comparable between the LDLT and DDLT groups. On multivariate analysis, overall old age, Black/African American race/ethnicity, tumor number ≥3, and higher AFP levels were associated with worse outcomes, with Hispanic or Asian race/ethnicity and wait time ≥6 months associated with better outcomes. The type of organ transplant in LT recipients for HCC, that is, living versus deceased donor, was not associated with higher death. In the LDLT group, a small proportion of transplants for HCC were outside of Milan criteria, which was comparable with DDLT, suggesting that transplant programs may be vigilant, in donor and recipient selection, for improved donor safety and posttransplant outcomes. Of note, the allocation MELD score was statistically lower in the LDLT group. With the recent HCC MELD exception changes to static median MELD at transplant minus 3, LDLT can be a vital option among transplant candidates with HCC to potentially reduce the wait time and decrease dropout rates.

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