EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Dropout rates, Exception points, Hepatocellular carcinoma, Living donor liver transplant, Model for End-stage Liver Disease, Transplant outcomes, 6-Month wait

Liver transplant (LT) surgery remains the best treatment for patients with end-stage liver disease (ESLD) or hepatocellular carcinoma (HCC).¹ Regrettably, organ demand exceeds the number of available organs for transplant. The scarcity of suitable organs for transplant is a worldwide problem; however, suitable organs from deceased donors are almost 10 times scarcer in Saudi Arabia compared with Western nations. Organ donation rates from the deceased donor pool are estimated to be 2 to 4 per million population among the Saudi population, compared with up to 20 to 40 per million population in European countries.^2,3 For patients with ESLD, the Model for End-Stage Liver Disease (MELD/MELD-Na) scoring system (and previously the Child-Pugh scoring system) was established as a tool to appropriately prioritize candidates on transplant wait lists.⁴ The MELD scoring system has gained global adoption since 2002 as it reflects the 3-month patient mortality risk in the absence of LT.⁵ Nonetheless, the MELD score has limitations. The MELD score is not in itself suitable to prioritize patients who would benefit from receiving a LT yet do not have significant metabolic deran-gements related to progressive liver failure. An excellent example of this situation exists for patients with HCC but without significant liver dysfunction. Hence, transplant urgency with regard to this population is not always accurately assessed with the MELD score without factoring in the underlying diagnosis. Therefore, some conditions and diagnoses, including HCC, have been assigned exception points to promote fairness in distribution of scarce organs to those with the greatest need.⁶ The primary rationale behind the exception point system was to improve equity in organ allocation; however, subsequent review of wait list mortality in Western nations has suggested that the present system of exemption points creates an overcorrection in favor of patients with HCC.⁷ Before adoption of the HCC-MELD exception point system in the United States, prior to 2002, only 5% of liver allografts were allocated to recipients with HCC diagnosis. After adoption of the HCC-MELD exception point system, the number of allocated liver allografts to recipients with HCC increased to 26%, which is a 5-fold to 6-fold increase.⁸ This disparity has since been addressed in the United States, and multiple modifications have been implemented to resolve it, including a 6-month mandatory wait before exception points may be awarded to patients with HCC diagnosis.⁹ During this wait time, the use of bridging locoregional therapy has been seen to reduce the wait list dropout rate while managing the disease, resulting in more favorable outcomes.^10,11 In Saudi Arabia, the organ distribution system remains center-based rather than nationally governed. All transplant centers use the MELD/MELD-Na scoring system to prioritize patients and manage their respective wait list and patient selection. Hence, the adoption of a wait time requirement for patients with HCC before granting HCC-MELD exception points has not gained widespread traction. Furthermore, the landscape of LT activity in Saudi Arabia differs from Western nations. In addition to differences in the prevalence of liver-related diseases, a significant proportion of living donor liver transplant (LDLT) activity occurs for which waiting may not be favored.¹² Subsequently, it is unclear whether the currently adopted allocation system in Saudi Arabia contains a flaw in organ distribution, similar to the problem in the United Sates after 2002, caused by use of HCC-MELD exception points with no further modifiers. In our present study, we compared the outcomes of potential liver recipients with HCC and non-HCC diagnoses and investigated their respective wait list dropout rates at our transplant center.

Materials and Methods

Our retrospective review included all adult patients who were listed for LT at King Abdulaziz Medical City in Riyadh, Saudi Arabia, between January 2016 and July 2020. The chart review was carried out until September 2021 through the electronic medical records and the departmental transplant database system to ensure sufficient follow-up. The included variables were demographic details, primary etiology of liver disease, MELD-Na score and its components (bilirubin, international norma-lized ratio, creatinine, serum sodium, and frequency of dialysis), and the presence of HCC, as well as HCC size, number, and stage. The MELD-Na scores were assessed at the time of listing and at the time of LT. The outcomes of interest regarding patients on the wait list were categorized as (1) received a transplant, (2) dropped out, or (3) remained on the wait list. The date of listing and the date of the outcome were also included. We defined dropout as removal from the wait list before transplant, due to death or other medical and nonmedical reasons. All transplants were categorized according to donor type: living or deceased. Almost all LDLT procedures were among first-degree or second-degree relatives except for 4 couples: 2 couples were fourth-degree relatives and 2 were emotionally but not biologically related. The Saudi law and ethical code directs that emotionally related donations are permissible, but these require a stringent case-by-case vetting process to ensure absence of donor coercion or financial gain and to preserve the altruistic nature of living donation. For patients who received a transplant, the type of graft was noted: a whole graft in the setting of a deceased donor liver transplant (DDLT) or a partial graft in the LDLT setting. Complications after LT were also recorded. For patients who dropped out from the wait list, the cause of that event was further investigated, to discover whether it was due to death or other reasons. Patient outcomes after transplant were also recorded, particularly with regard to survival and recurrence of HCC. Furthermore, in addition to the charted MELD/MELD-Na scores, biologic MELD-Na scores were manually recalcu-lated for all patients using its primary components according to the following formula: MELD-Na = MELD + 1.32 × (137 - Na) – (0.033 × MELD × [137 - Na]), where MELD = 10 × (0.957 × ln[creatinine]) + (0.378 × ln[bilirubin]) + (1.12 × ln[INR]) + 6.43; INR is the international normalized ratio.¹³ For patients diagnosed with HCC, their cases are evaluated by 2 separate committees: the hepato-biliary tumor board and the LT selection committee. Patients with good liver function and small or resec-table lesions were evaluated by the hepatobiliary tumor board, and treatment plans were implemented without plans for transplant listing. Additionally, patients who were judged to need liver transplant planning were referred to the LT selection committee. Records from both committees were reviewed. Data pertaining to treatment plans for patients with HCC were recorded, which included interventional actions and surgical procedures suggested by the hepato-biliary tumor board. Patients who were subsequently approved by the LT selection committee for LT listing received 20 to 22 MELD exception points, with discretion. On few occasions, the MELD exception points were further increased 2 points upon reeva-luation of the case. While on the wait list, bridging liver-directed therapy (B-LDT) was considered for tumor control. Timing and response data were recor-ded. Eventual outcomes were reported for all patients. Data analyses were performed with SPSS software (version 27). Categorical data were described as frequencies (with percentage), whereas numerical data were described as median values (with IQR) as these violate the test of normality. The chi-square test was used to compare proportional values, and the Mann-Whitney U test was used to compare median values. Kaplan-Meier curves with 1 minus survival and hazard ratio functions, as well as log rank and Cox regression, were used to compare time-related events between groups. Statistical significance was considered at P < .05. This study was approved by the institutional review board (No. RC20.554.R) of King Abdullah International Medical Research Center.

Our review included the data for 214 patients aged 17 to 76 years at the time of transplant listing, with an average age of 55.2 ± 11.6 years. Hepatocellular carcinoma was present in 31.8% (n = 68/214) of the sample. (Table 1) lists the demographic details after grouping the patients according to the presence or absence of HCC in the primary diagnosis at the time of LT listing. Nonalcoholic steatohepatitis was the most common diagnosis in the non-HCC group (n = 42/146; 28.8%), followed by hepatitis B virus infection (n = 20/146; 13.7%) and cryptogenic cirrhosis (n = 19/146; 13%). On the other hand, in the HCC group, hepatitis B virus was the most common diagnosis (n = 27/69; 39.7%), followed by nonalcoholic steatohepatitis (n = 14/69; 20.6%) and hepatitis C virus infection (n = 13/69; 19.1%). Listed patient outcomes were either (1) received liver transplant (n = 165/214; 77.1%), (2) dropped out (n = 38/214; 17.8%), or (3) remained on the wait list (n = 11/214; 5.1%). Each group outcome is shown in (Table 2). Of the HCC group, 83.8% (n = 57/58) received LT compared with 74% (n = 108/146) of non-HCC patients (P = .11). The distribution of DDLT and LDLT between the 2 groups was proportionally different and tended toward statistical significance (P = .066). Patients with HCC diagnosis tended to receive a higher proportion of deceased organ offers. Nearly three-fourths (n = 42/57; 73.7%) of those who received LT in the HCC group received DDLT, compared with a little over half (n = 64/108; 59.2%) in the non-HCC group. Moreover, although patients with HCC constituted 31.7% of the wait list, they received about 40% of deceased organ offers (P = .015). Patients in the HCC group had lower calculated/biologic MELD-Na scores on listing (10.7 [8.9-18.7] vs 19.5 [14.8-25.2]; P < .001) and on transplant (11.5 [9.1-17.6] vs 20.1 [16.1-26.3]; P < .001) (Table 1). However, when the HCC-MELD exception points were factored, the scores were similar for both groups on listing and transplant. A total of 60 patients received B-LDT shortly before listing or while on the transplant wait list. Of the 60 patients, 59 were in the HCC group and 1 was in the non-HCC group. The patient from the non-HCC group was initially listed with no evidence of HCC; however, while on the wait list, the patient developed a single small HCC lesion. The lesion was treated and completely resolved with B-LDT; the patient remained on the wait list. A total of 109 procedures were used to manage those patients (Table 3). Transarterial chemoembolization was the most common procedure (n = 66/109; 60.6%). After B-LDT, the condition of most patients stabilized or regressed (n = 51/60; 85%). There were 48 patients (80%) who were treated with B-LDT and subsequently received a transplant (Table 4). The median time of B-LDT prior to LT was 166 days (101-329.5 days). After transplant, 2 patients had recurrence of tumor. One patient received a transplant despite progression of disease after B-LDT and was found to have HCC-cholangiocarcinoma variant on explant. The other patient had 2 small slowly growing HCC lesions, with the largest measuring 2.5 cm in diameter, in the background of cirrhotic liver. Hence, he was offered LT within 7 months from listing with no attempts of B-LDT. Excluding those who remained on the transplant wait list, 86.7% of patients either received a transplant or dropped out by the end of the first year and 95.6% by the end of the second year from the date of listing. The likelihood of receiving a transplant or dropping out during the first 2 years after listing was examined and compared between the HCC and non-HCC groups. There were no statistically significant differences between the likelihood of receiving LT or dropping out ((Figure 1A) and (Figure 1B)). Patients who received LT were further stratified into subgroups: LDLT versus DDLT ((Figure 1C) and (Figure 1D)). A higher likelihood of receiving LDLT was noted for patients in the non-HCC group, with a hazard ratio of 2.7 (1.5-4.9) (P < .001). The median follow-up after transplant was 39.4 months (22.7-50.6 months). During the follow-up period, 29 patients were confirmed dead or had ceased follow-up for >6 months with no record of medication refill. Twelve patients died from infectious complications, 4 from early postoperative complications, 3 from oncologic complications, 1 from cardiorespiratory failure, and 10 from unknown causes. The median 1-year, 3-year, and 5-year posttransplant survival rates were 93%, 85%, and 65%, respectively. Although the non-HCC group had higher median survival, there was no statistical difference between the survival curves between both groups (P = .07) (Figure 2).

King Abdullah Medical City is 1 of 3 major transplant centers that do both LDLT and DDLT in Saudi Arabia and generate data that are relevant at a national level. Although organ distribution remains center-based, efforts are mounting toward establishment of a national listing system, making the topic of this study relevant at this period. The main objective of this study was to survey the organ distribution and equity between patients with liver diseases according to the presently adopted allocation system. Subsequently, there was an opportunity to objectively consider solutions and modifications to the allocation system to improve equity. The result of our study is also interesting as it tests the allocation system while equally informing on transplants from living relatives and deceased donors.¹⁴ Furthermore, given the judicious use of B-LDT for patients, this study incidentally examines the potential results of wait time before LT is offered for patients diagnosed with HCC. In this study, patients who were diagnosed with HCC and were eligible for LT were granted 20 to 22 HCC-MELD exception points with no enforced wait period. Given that the average MELD on our cohort was not high, there was rarely a need to grant further increments. Despite this, the data suggest that the dropout rates and transplant rates while awaiting transplant were largely equal between patients who had HCC and those who did not. Furthermore, the likelihood of dropout was 16.2% to 18.5%, which is in line with published literature.⁷ Nonetheless, there was a noted discrepancy in the analysis of the likelihood of receiving LT from the deceased donor pool versus a living related donor. For instance, for the distribution of LDLT, most (74.6%; n = 44/59) were in the non-HCC group, although they comprised 67% of the sample. The higher likelihood to receive LDLT (vs DDLT) among patients in the non-HCC group may reflect a greater severity of liver dysfunction and subsequently a greater perception of urgency for LT. Therefore, in the absence of available deceased donor livers, patients in the non-HCC group could be more likely to seek a living donor. On the other hand, patients with HCC had low biologic MELD-Na scores and their HCC was being managed with B-LDR. Hence, the patients with HCC were, arguably, less inclined to seek living donors early in the process, resulting in the noted discrepancy. The reliance on B-LDT to manage patients with HCC demonstrated good outcomes in terms of low recurrence rates (<5%) and provided time to assess tumor biology ((Table 3) and (Table 4). The dropout rates were also acceptable and comparable to the non-HCC group, suggesting that this is a sound strategy. Our data do suggest some disparity in deceased donor organ distribution that favors patients with HCC diagnosis. Fortunately, this did not seem to cause significant outcome discrepancies between groups, possibly due to the compensatory effect of the living donor program. Nonetheless, there could be a more significant effect if national listing were to be adopted. At present, there is no urgent need to modify the allocation system. Regardless, it seems wise to follow suit to implement delayed time and insist on a 6-month wait with bridging therapy, particularly for those patients who receive offers of deceased organs. Another benefit of the wait time is its potential advantage to discover HCC with aggressive tumor biology, which progresses despite B-LDT.¹⁵ This study, like several previous studies, has shown that the 6-month wait does not affect the ultimate outcomes after transplant but rather facilitates the appropriate selection of those patients who will do better with a transplant versus those who would gain a lesser benefit. This is supported by the “sweet spot” concept that associates HCC recurrence with short (<6 months) or long (>18 months) wait time.¹⁶ Although it was not planned in our cohort, most patients with HCC received approximately 6 months of B-LDT before they received LT. The posttransplant outcomes in terms of disease recurrence and long-term survival was satisfactory (Figure 2).

This study suggests that implementation of the 6-month wait time for patients with HCC before granting MELD exception points may not be necessary in programs with active living-related LT. However, such a plan remains a sound strategy to follow.

Volume: 21 Issue: 2 February 2023

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