post-LT Hepatocellular Carcinoma Recurrence Research Articles

Outcomes of liver transplantation for hepatocellular carcinoma in donation after circulatory death compared with donation after brain death: A systematic review and meta-analysis

Introduction and ObjectivesDue to organ shortages, liver transplantation (LT) using donation-after-circulatory-death (DCD) grafts has become more common. There is limited and conflicting evidence on LT outcomes using DCD grafts compared to those using donation-after-brain death (DBD) grafts for patients with hepatocellular carcinoma (HCC). We aimed to summarize the current evidence on the outcomes of DCD-LT and DBD-LT in patients with HCC. Materials and MethodsOnline databases were searched for studies comparing DCD-LT and DBD-LT outcomes in patients with HCC and a meta-analysis was conducted using fixed- or random-effects models. ResultsFive studies involving 487 (33.4%) HCC DCD-LT patients and 973 (66.6%) DBD-LT patients were included. The meta-analysis showed comparable 1-year [relative risk (RR)=0.99, 95%CI:0.95 to 1.03, p=0.53] and 3-year [RR=0.99, 95%CI:0.89 to 1.09, p=0.79] recurrence-free survival. The corresponding 1-year [RR=0.98, 95%CI:0.93 to 1.03, p=0.35] and 3-year [RR=0.94, 95%CI:0.87 to 1.01, p=0.08] patient survival and 1-year [RR=0.91, 95%CI:0.71 to 1.16, p=0.43] and 3-year [RR=0.92, 95%CI:0.67 to 1.26, p=0.59] graft survival were also comparable. There were no significant differences between the two cohorts regarding the tumor characteristics, donor/recipient risk factors and the incidence of post-operative complications, including acute rejection, primary non-function, biliary complications and retransplantation. ConclusionsBased on the current evidence, it has been found that comparable outcomes can be achieved in HCC patients using DCD-LT compared to DBD-LT, particularly when employing good quality graft, strict donor and recipient selection, and effective surgical management. The decision to utilize DCD-LT for HCC patients should be personalized, taking into consideration the risk of post-LT HCC recurrence. (PROSPERO ID: CRD42023445812).

Significant Reduction in Posttransplant Hepatocellular Carcinoma Recurrence in the Post 6-Mo Waiting Policy Era.

In 2015, the United Network for Organ Sharing implemented a policy introducing a 6-mo waiting period before granting model for end-stage liver disease exception points to liver transplant (LT) candidates with hepatocellular carcinoma (HCC). This study analyzes the policy impact on post-LT HCC recurrence. This was a United Network for Organ Sharing retrospective cohort study of patients with HCC who underwent LT from January 1, 2010, to May 31, 2019. HCC-specific data included alpha-fetoprotein, tumor characteristics, locoregional therapy (LRT), and explant data used to calculate the Risk Estimation of Tumor Recurrence After Transplant score. The primary exposure was pre-/post-policy era, divided on October 8, 2015. Survival analysis techniques were used to evaluate the unadjusted and sequentially adjusted association between policy era and HCC recurrence, accounting for competing risks. A total of 7940 patients were included, 5879 (74.0%) pre-policy era and 2061 (26.0%) post-policy era. Post-policy patients were older, received more LRT, and had lower alpha-fetoprotein levels and smaller tumor sizes at transplant. Incidence rates of HCC recurrence were 19.8 and 13.7 events per 1000 person-years for pre- and post-policy eras, respectively. Post-policy era was associated with an unadjusted 35% reduction in the risk of HCC recurrence ( P < 0.001). After adjusting for recipient, donor, and tumor characteristics at listing this association remained (subhazard ratio 0.69; 95% confidence interval, 0.55-0.86; P = 0.001); however, after additionally adjusting for LRT episodes and Risk Estimation of Tumor Recurrence After Transplant score, there was no longer a statistically significant association (subhazard ratio 0.77; 95% confidence interval, 0.59-1.00; P = 0.054). We observed a significant reduction in post-LT HCC recurrence after policy implementation. This may be due to waitlist selection of healthier patients, increased LRT utilization, and potential selection of favorable tumor biology.

AFP-L3 and DCP strongly predict early hepatocellular carcinoma recurrence after liver transplantation

Alpha-fetoprotein (AFP) predicts hepatocellular carcinoma (HCC) recurrence after liver transplant (LT) but remains an imperfect biomarker. The role of DCP (des-gamma-carboxyprothrombin) and AFP-L3 (AFP bound to Lens culinaris agglutinin) in predicting HCC recurrence remains incompletely characterized. AFP-L3 and DCP could identify patients at high risk of post-transplant HCC recurrence and serve as liver transplant exclusion criteria to defer transplant until patients receive additional risk-reducing pre-transplant locoregional therapy. This prospective cohort study included consecutive patients with HCC who underwent LT (within or down-staged to Milan criteria) between 2017 and 2022. Pre-transplant AFP, AFP-L3, and DCP measurements were obtained. The primary endpoint was the ability of biomarkers to predict HCC recurrence-free survival. This cohort included 285 patients with a median age of 67 (IQR 63-71). At LT, median biomarker values were AFP 5.0ng/ml (IQR 3.0-12.1), AFP-L3 6.7% (0.5-13.2), and DCP 1.0ng/ml (0.3-2.8). Most (94.7%) patients received pre-LT locoregional therapy. After a median post-LT follow-up of 3.1 years, HCC recurrence was observed in 18 (6.3%) patients. AFP-L3 and DCP outperformed AFP with C-statistics of 0.81 and 0.86 respectively, compared with 0.74 for AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted 61.1% of HCC recurrences, whereas HCC only recurred in 7 of 265 (2.6%) patients not meeting this threshold. The Kaplan-Meier recurrence-free survival rate at 3 years post-LT was 43.7% for patients with dual-positive biomarkers compared to 97.0% for all others (p <0.001). Dual-positivity for AFP-L3 ≥15% and DCP ≥7.5 strongly predicted post-LT HCC recurrence. This model could refine LT selection criteria and identify high-risk patients who require additional locoregional therapy prior to LT. Alpha-fetoprotein (AFP) is used to predict hepatocellular carcinoma (HCC) recurrence after liver transplant, but it remains an imperfect biomarker. In this prospective study, the biomarkers DCP (des-gamma-carboxyprothrombin) and AFP-L3 (AFP bound to Lens culinaris agglutinin) strongly predicted early HCC recurrence and outperformed AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted the majority of recurrences and could be used to further refine liver transplant eligibility criteria.

Tracking the evolving ecosystem of recurrent hepatocellular carcinoma after liver transplantation.

4114 Background: Liver transplant (LT) contributes to the cure of hepatocellular carcinoma (HCC) by extending the conventional surgical margin, while removing the concurrent tumor-favoring conditions of the diseased liver. Over the past two decades, HCC has emerged as a preferable indication for LT, accounting for 22-45% of the cases globally. However, despite the stringent selection criteria, recurrence still occurs in a substantial proportion of patients, leaving 10-13 months of median survival after tumor relapse. To address this challenge, a thorough exploration of molecular mechanism behind HCC recurrence after LT is required. Here, for the first time, we performed a comprehensive analysis to depict the evolving and unique ecosystem of HCC in the context of LT and immunosuppressant (IS) administration. Methods: We retrospectively reviewed our biobank and collected 91 paired (primary tumors (PT) from the explant after LT and relapsed tumors (RT) from hepatectomy) FFPE tumor samples from 15 patients for whole exome sequencing (WES). Also, from Jan 2021, we prospectively collected surgical tumor specimens and their adjacent non-tumor tissues from 15 primary and 6 post-LT intrahepatic recurrence patients for single-cell RNA sequencing. Moreover, 6 paired samples from 3 patients were used for spatial transcriptomic analysis. Results: By analysing WES data, we confirmed that RT samples represent recurrent, instead of de novo tumors. Also, the phylogenetic analysis demonstrated strong clonal relationship between PT and RT based on shared SNVs. As to mutation landscape differences of PT and RT, we identified a significantly enriched mutation panel from RT, including MUC16, FAT3, APOB, COL6A3 and POTEC. And the accuracy of this panel for post-LT HCC recurrence surveillance using plasma derived cfDNA sequencing has been preliminarily validated in a prospective cohort of 17 patients. From the single-cell profiling, distinct immune microenvironment between PT and RT is identified. As predicted, proliferating T cells are decreased in RT due to IS. Pseudotime analysis of T cells revealed that T cells from PT mainly distribute at the terminal end of cytotoxic stage whereas T cells from RT mostly represent a naïve state, further confirming the T cell blocking effect of IS. In terms of myeloid cells, we surprisingly found that FOLR2+ tumor associated macrophages, which is conventionally considered as a favorable prognosis factor, is increased in RT. Spatial transcriptomics and IHC also confirmed their active interplay with tumor cells at invasive margin. We postulate that such increase might be a result of the healthy nature of liver graft. Conclusions: Our comprehensive dissection of the HCC ecosystem provides deeper insights into the tumor relapse after LT. Targeting novel mutations and strengthen the antigen presenting process between increased TAM and disabled T cells can be the future direction in this field. Clinical trial information: NCT04506398 .

Immunotherapy for hepatocellular carcinoma recurrence after liver transplantation, can we harness the power of immune checkpoint inhibitors?

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death globally and liver transplantation (LT) can serve as the best curative treatment option. However, HCC recurrence after LT remains the major obstacle to the long-term survival of recipients. Recently, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many cancers and provided a new treatment strategy for post-LT HCC recurrence. Evidence has been accumulated with the real-world application of ICIs in patients with post-LT HCC recurrence. Notably, the use of these agents as immunity boosters in recipients treated with immunosuppressors is still controversial. In this review, we summarized the immunotherapy for post-LT HCC recurrence and conducted an efficacy and safety evaluation based on the current experience of ICIs for post-LT HCC recurrence. In addition, we further discussed the potential mechanism of ICIs and immunosuppressive agents in regulating the balance between immune immunosuppression and lasting anti-tumor immunity.

Induction Immunosuppression Does Not Worsen Tumor Recurrence After Liver Transplantation for Hepatocellular Carcinoma.

Prior studies are inconsistent regarding the impact of antibody induction therapy on outcomes after liver transplantation (LT) for hepatocellular carcinoma (HCC). Adults transplanted with HCC exception priority were identified from February 27, 2002, to March 31, 2019, using the United Network for Organ Sharing database. Time-to-event analyses evaluated the association of antibody induction therapy (none, nondepleting induction [NDI], depleting induction [DI]) with overall post-LT patient survival and HCC recurrence. Separate multivariable models adjusted for tumor characteristics on either last exception or on explant. The interaction of induction and maintenance regimen at LT discharge was investigated. Among 22 535 LTs for HCC, 17 688 (78.48%) received no antibody induction, 2984 (13.24%) NDI, and 1863 (8.27%) DI. Minimal differences in patient and tumor characteristics were noted between induction groups, and there was significant center variability in practices. NDI was associated with improved survival, particularly when combined with a calcineurin inhibitor (CNI) and antimetabolite (hazard ratio [HR] 0.73 versus no induction plus 3-drug therapy in the last exception model [ P < 0.001]; HR 0.64 in the explant model [ P = 0.011]). The combination of DI with CNI alone was also protective (HR 0.43; P = 0.003). Neither NDI nor DI was associated with tumor recurrence (all P > 0.1). However, increased HCC recurrence was observed with no induction plus CNI monotherapy (HR 1.47, P = 0.019; versus no induction plus 3-drug therapy). In conclusion, induction immunosuppression was not associated with worse post-LT outcomes in patients transplanted with HCC exception priority. An improvement in survival was possibly observed with NDI.

AFP score and metroticket 2.0 perform similarly and could be used in a “within-ALL” clinical decision tool

Two recently developed composite models, the alpha-fetoprotein (AFP) score and Metroticket 2.0, could be used to select patients with hepatocellular carcinoma (HCC) who are candidates for liver transplantation (LT). The aim of this study was to compare the predictive performance of both models and to evaluate the net risk reclassification of post-LT recurrence between them using each model's original thresholds. This multicenter cohort study included 2,444 adult patients who underwent LT for HCC in 47 centers from Europe and Latin America. A competing risk regression analysis estimating sub-distribution hazard ratios (SHRs) and 95% CIs for recurrence was used (Fine and Gray method). Harrell's adapted c-statistics were estimated. The net reclassification index for recurrence was compared based on each model's original thresholds. During a median follow-up of 3.8 years, there were 310 recurrences and 496 competing events (20.3%). Both models predicted recurrence, HCC survival and survival better than Milan criteria (p <0.0001). At last tumor reassessment before LT, c-statistics did not significantly differ between the two composite models, either as original or threshold versions, for recurrence (0.72 vs. 0.68; p= 0.06), HCC survival, and overall survival after LT. We observed predictive gaps and overlaps between the model's thresholds, and no significant gain on reclassification. Patients meeting both models ("within-ALL") at last tumor reassessment presented the lowest 5-year cumulative incidence of HCC recurrence (7.7%; 95% CI 5.1-11.5) and higher 5-year post-LT survival (70.0%; 95% CI 64.9-74.6). In this multicenter cohort, Metroticket 2.0 and the AFP score demonstrated a similar ability to predict HCC recurrence post-LT. The combination of these composite models might be a promising clinical approach. Composite models were recently proposed for the selection of liver transplant (LT) candidates among individuals with hepatocellular carcinoma (HCC). We found that both the AFP score and Metroticket 2.0 predicted post-LT HCC recurrence and survival better than Milan criteria; the Metroticket 2.0 did not result in better reclassification for transplant selection compared to the AFP score, with predictive gaps and overlaps between the two models; patients who met low-risk thresholds for both models had the lowest 5-year recurrence rate. We propose prospectively testing the combination of both models, to further optimize the LT selection process for candidates with HCC.

National experience with living donor liver transplantation for hepatocellular carcinoma.

Living donor liver transplantation (LDLT) is an attractive option to decrease waitlist dropout, particularly for patients with hepatocellular carcinoma (HCC) who face lengthening waiting times. Using the United Network for Organ Sharing (UNOS) national database, trends in LDLT utilization for patients with HCC were evaluated, and post-LT outcomes for LDLT versus deceased donor liver transplantation (DDLT) were compared. From 1998 to 2018, LT was performed in 20,161 patients with HCC including 726 (3.6%) who received LDLT. The highest LDLT utilization was prior to the 2002 HCC Model for End-Stage Liver Disease (MELD) exception policy (17.5%) and dropped thereafter (3.1%) with a slight increase following the 6-month wait policy in 2015 (3.8%). LDLT was more common in patients from long-wait UNOS regions with blood type O, in those with larger total tumor diameter (2.3 vs. 2.1cm, p=0.02), and higher alpha-fetoprotein at LT (11.5 vs. 9.0ng/ml, p=0.04). The 5-year post-LT survival (LDLT 77% vs. DDLT 75%), graft survival (72% vs. 72%), and HCC recurrence (11% vs. 13%) were similar between groups (all p>0.20). In conclusion, LDLT utilization for HCC has remained low since 2002 with only a slight increase after the 6-month wait policy introduction in 2015. Given the excellent post-LT survival, LDLT appears to be an underutilized but valuable option for patients with HCC, especially those at high risk for waitlist dropout.

Lower Alpha-Fetoprotein Threshold of 500 ng/mL for Liver Transplantation May Improve Posttransplant Outcomes in Patients With Hepatocellular Carcinoma.

Under current United Network for Organ Sharing (UNOS) policy, patients with hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP) levels ≥1000 ng/mL are required to show a reduction in AFP level to <500ng/mL before liver transplantation (LT). However, effects of AFP reduction on post-LT HCC outcomes among patients with HCC with moderately elevated AFP levels between 100 and <1000ng/mL are unclear. Adults in the UNOS registry who underwent LTs from January 2005 to September 2015 with initial AFP levels of 100 to 999ng/mL at listing for Model for End-Stage Liver Disease exceptions were included. Primary predictor was AFP level at LT, categorized as <100, 100 to 499, or ≥500ng/mL, and patients with only 1 recorded pre-LT AFP value (AFP 1-value). Survival was compared using the Kaplan-Meier curve method. Factors associated with post-LT survival and HCC recurrence were assessed in a multivariable Cox regression model. Among 1766 included patients, 50.2% had AFP 1-value, followed by 24.7%, 18.9%, and 6.2% with AFP levels <100, 100 to 499, and ≥500ng/mL, respectively. The 5-year post-LT survival rate was lowest in the AFP ≥500 category, at 56.1%, compared with 72.7%, 70.4%, and 65.6% in the AFP <100, 100 to 499ng/mL, and AFP 1-value categories, respectively. In multivariable analysis, AFP ≥500 ng/mL at LT was associated with a greater risk of post-LT death (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.1-2.1) and HCC recurrence (HR, 1.9; 95% CI, 1.1-3.1) when compared with the AFP <100ng/mL category; other significant variables included donor risk index, age, race/ethnicity, Child-Turcotte-Pugh class, and tumor diameter. Among AFP levels ≥500 ng/mL at LT, 40.4% had AFP levels ≥1000, but no difference in post-LT survival or recurrence was seen between those patients with AFP levels < or ≥1000ng/mL. Mandating AFP <500 ng/mL at LT for all patients, not only for those with initial AFP levels ≥1000ng/mL, may improve post-LT outcomes and can be considered in future UNOS policy.

The RETREAT score provides valid predictions regarding hepatocellular carcinoma recurrence after liver transplantation.

Prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) with knowledge of explant data is important for guiding post-LT surveillance and treatment. The RETREAT score was recently introduced for this purpose, but has not been validated outside the USA. In a retrospective single-center study of 169 consecutive patients undergoing LT in Gothenburg, through 2000-2017 (mean age 57 years, 80% men), there were 34 HCC recurrences during a median 4.6-year follow-up. The 5-year cumulative incidence of HCC recurrence was 0% with RETREAT scores of 0-1 (18%), 11-22% with scores of 2-4 (58%), and 65% with scores of 5-8 (24%). The C-statistic, as a measure of discrimination for prediction of HCC recurrence was 0.762, 0.664, 0.616, and 0.717, for the RETREAT score, Milan criteria, UCSF criteria, and post-MORAL criteria. The RETREAT score had no significant impact on patient survival after HCC recurrence (HR 1.00, P = 0.97). In conclusion, the RETREAT score provided valid predictions of post-LT HCC recurrence in a European setting, with the ability to discriminate between high, intermediate, and low risk for HCC recurrence in a clinically important way. Prognosis after recurrence did not differ according to the RETREAT score in our study.

P-112 ALPHA-FETOPROTEIN AS A PROGNOSTIC FACTOR IN PATIENTS WITH HEPATOCELLULAR CARCINOMA SUBMITTED TO LIVER TRANSPLANTATION – BRAZILIAN MULTICENTER STUDY

Liver transplantation (LT) is the treatment of choice for unresectable early hepatocellular carcinoma (HCC). Previous studies demonstrated that Alpha-fetoprotein (AFP) is an important biomarker of prognosis and tumor recurrence. The aim of our study was to analyze the role of AFP in the post-transplant outcomes of HCC patients undergoing LT. We conducted a multicenter, retrospective cohort study, analyzing medical records of 1,119 liver transplant recipients with HCC in Brazil. Survival curves were presented using the Kaplan-Meier and compared using the log-rank test. Univariate cox regression analysis was fitted. We performed an evaluation of the effect of the continuous variable on the risk ratio, to define the best "cutoff point" of AFP level at HCC diagnosis and pre-transplantation capable of differentiating patients from risk of recurrence and survival. Among 1,119 cases, 81% of patients were male, with a mean age at transplantation of 58 years. At HCC diagnosis, 85% were within Milan Criteria (MC). Median pre-LT AFP was 9.7 ng/ml (0-40,800 ng/ml) and 51% of patients had pre-LT AFP ≤ 10 ng/ml. The overall survival was 63% in 5 years and post-LT HCC recurrence was observed in 8% of patients. We found AFP > 400ng/ml at HCC diagnosis and AFP pre-LT > 200ng/ml as the better “cutoff points” for both overall survival and recurrence risk. Patients with AFP pre-LT ≤ 200 ng/ml had a better overall survival and recurrence-free survival compared with patients with AFP > 200 ng/ml, respectively, 76% and 92% versus 67% and 66% in 5-years (p <0.001). Pre-LT AFP >200ng/ml and being outside MC at diagnosis were also independent risk factors for post-LT HCC recurrence and poor survival in multivariate analysis. Our study demonstrated role of AFP as a main pre-transplant prognostic factor, both to predict post-LT tumor recurrence and survival.

P-110 POST-TRANSPLANT OUTCOMES IN PATIENTS WITH HEPATOCELLULAR CARCINOMA SUBMITTED TO DOWN-STAGING – BRAZILIAN MULTICENTER STUDY

Down-staging (DS) is used to convert hepatocellular carcinoma (HCC) patients outside the criteria for liver transplantation (LT) into patients within the criteria. However, LT after DS remains controversial in the literature. Compare the post-LT survival and recurrence risk of HCC patients transplanted after DS with patients transplanted within the Brazilian selection criteria. We conducted a multicenter, retrospective cohort study, analyzing medical records of 1,119 liver transplant recipients with HCC in Brazil. HCC treatment prior to LT and whether or not the patient was enrolled after down-staging was analyzed. Survival curves were presented using the Kaplan-Meier and compared using the log-rank test. Univariate and multiple cox regression analysis was fitted. 1,119 patients were included. 81% were males and mean age in the time of LT was 58 ± 8.2 years. In the majority of patients (91%) HCC was the reason for inclusion in transplant list and 8% of patients were listed after successful DS. At HCC diagnosis, 85% of patients were within Milan Criteria. TACE was the most frequent treatment performed. The overall survival (OS) of the entire series was 63% in 5 years, with an average follow-up time of 28 months and post-LT HCC recurrence was 8%. Relapse-free survival and OS, respectively, over 5 years, were 78% and 83% in DS patients and 75% and 89% in patients transplanted within criteria, with no statistical difference in the two analyzes. Evaluation of prognostic factors using simple and multiple Cox Regression did not show that DS was a risk factor for a worse survival or post-LT tumor recurrence. In our study, patients underwent DS show good post-transplant evolution, similar to those transplanted within criteria, suggesting that response to treatment is a good selection parameter for tumors with favorable tumor biology.

Neutrophil-to-Lymphocyte Ratio Predicts High-Risk Explant Features and Waitlist Survival But Is Not Independently Associated With Recurrence or Survival Following Liver Transplantation for Hepatocellular Carcinoma.

We assessed the prognostic significance and the clinical stability of the neutrophil-to-lymphocyte ratio (NLR) before liver transplantation (LT) in a large cohort of patients with hepatocellular carcinoma (HCC) from a region with a long waitlist time. A high preoperative NLR ≥5 has been reported to predict poor outcomes following LT for HCC, and the NLR has been incorporated into several prognostic models. We evaluated 758 patients with HCC with Model for End-Stage Liver Disease exceptions and listed for LT from 2002 to 2015 at a single LT center, of which 505 underwent LT and 253 dropped out before LT. The NLR was collected in all patients at LT and, if available, between 15 and 90days before LT (NLR2) or at dropout. An NLR≥5 was associated with microvascular invasion (MVI), poorer tumor differentiation, and more advanced pathology on explant. Patients with an NLR≥5 exhibited no differences in alpha-fetoprotein, tumor burden at listing, or number of locoregional therapies compared with patients with an NLR<5. After a median post-LT follow-up of 4.7years, overall survival and recurrence rates were similar for patients with an NLR≥5 versus patients with an NLR<5. The NLR changed frequently, and 47% of patients whose NLR2 was≥5 had an NLR<5 by LT. The NLR was≥5 in 47.6% of patients at dropout compared with 14.9% of patients undergoing LT. Although the NLR at LT correlated with MVI and tumor stage at explant, the NLR did not predict post-LT survival or HCC recurrence. The NLR appeared to be a relatively unstable inflammatory marker during the immediate 3 months before LT for HCC.

Therapeutic Efficacy of Sorafenib in Patients with Hepatocellular Carcinoma Recurrence After Liver Transplantation: A Systematic Review and Meta-Analysis.

Hepatocellular carcinoma (HCC) recurrence is still threatening patient survival after liver transplantation (LT). The efficacy and safety of sorafenib in the setting of post-LT recurrence are still equivocal. This study aims to disclose the efficacy and safety profile of sorafenib in treating post-LT HCC recurrence. Electronic databases were searched to retrieve relevant publications suitable for inclusion. Data from 23 studies containing 411 patients were analyzed. The primary outcome of interest was 1-year survival rate after sorafenib treatment, and the secondary endpoints included median overall survival (OS), time to progression (TTP), treatment response, and adverse events. Patients with HCC recurrence after LT treated with sorafenib achieved a 1-year survival rate of 56.8%, with a median OS of 12.8 months and a median TTP of 6.0 months. Univariate logistic regression analysis showed that male gender (P = .048), TTP (P = .021), median duration of sorafenib (P = .021), diarrhea (P = .027), fatigue (P = .044), and partial response (P = .026) were associated with a better 1-year survival rate. In addition, sorafenib exerted a significant superior effect on OS compared with best supportive care in the setting of untreatable post-LT HCC recurrence. Based on the results of this meta-analysis, sorafenib therapy seems to be safe and feasible and exhibits survival benefit in patients with post-LT HCC recurrence. However, prospective randomized controlled trials with larger sample sizes and more rigorous study design are required to confirm the efficacy of sorafenib.

Early Detection of Hepatocellular Carcinoma Recurrence in the Posttransplant Population: A Comparison of RETREAT and Cleveland Clinic Florida Scoring System

BackgroundLiver transplantation (LT) for hepatocellular carcinoma (HCC) is curative in most cases; however, recurrence is observed in some patients. The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score is an externally validated scoring system for prediction of post-LT HCC recurrence. The Cleveland Clinic Florida Scoring System (CCFSS) is a potential new scoring system for prediction of HCC recurrence. Our study aimed to compare the RETREAT and CCFSS. MethodsWe conducted a retrospective cohort study of 52 adult patients with HCC who underwent LT at a tertiary care center. Mantel-Haenszel chi-square analyses were conducted to compare the RETREAT and CCFSS classifications for detecting HCC recurrence. ResultsA total of 52 patients underwent LT. The median follow-up period was 37 months. Four patients had post-LT HCC recurrence, with all recurrences occurring within 2 years of LT. The RETREAT score was better able to detect low, moderate, and high levels of risk (P < .001), compared to the CCFSS score (P = 0.480). Both risk scores had a sensitivity of 75%; the specificity of the RETREAT score was 95.8%, whereas the specificity of the CCFSS was 60.4%. Alpha-fetoprotein level at the time of LT was associated with HCC recurrence (P = .014). ConclusionsThis is the first study to evaluate the CCFSS as a potential new scoring system to predict HCC recurrence after LT. The RETREAT score is more specific than the CCFSS. The incorporation of alpha-fetoprotein level at the time of LT improves the estimation of HCC recurrence in the post-LT period.

S1106 Early Detection of Hepatocellular Carcinoma Recurrence in the Post-Transplant Population: A Comparison of RETREAT and Cleveland Clinic Florida Scoring System

INTRODUCTION: Liver transplantation (LT) for hepatocellular carcinoma (HCC) is curative in most cases, however, recurrence is observed in some patients. The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score is an externally-validated scoring system for prediction of post-LT HCC recurrence. The Cleveland Clinic Florida Scoring System (CCFSS) is a potential new scoring system for prediction of HCC recurrence. Our study aimed to compare the RETREAT and CCFSS. METHODS: We conducted a retrospective cohort study of adult patients with HCC who underwent LT. The RETREAT score was classified as follows: low risk (scores 0-3), moderate risk (score 4), and high risk (score 5 or higher). The CCFSS is based on explant pathology and categorized as: low (score 1), moderate (score 2), and high risk (score 3). Mantel- Haenzsel chi-square analyses were conducted to compare the RETREAT and CCFSS classifications for detecting HCC recurrence. RESULTS: A total of 52 patients with HCC underwent LT. The median follow-up period was 37 months. The median age of the patient population was 65.5 years (range 30-74 years) and 75% were male. The most common underlying liver disease was hepatitis C (n = 29, 55.8%), followed by fatty liver disease (n = 13, 25%). On explant pathology, 41 patients (78.8%) had viable tumor size <5 cm, two patients (3.8%) had ≥5 cm tumor size and the rest had a complete pathological response. Sixteen patients (31%) showed microvascular invasion. In 14 patients (31%), the tumors were poorly differentiated. Thirty-four patients (65.4%) had only one or no HCC lesions on explant pathology. Four patients had post-LT HCC recurrence, all within 2 years of LT (Table 1). Both risk scores had a sensitivity of 75%; the specificity of RETREAT score was 95.8% while the specificity of CCFSS was 60.4%. The RETREAT score was better able to detect low, moderate and high levels of risk (P < 0.001), compared to the CCFSS score (P = 0.480). AFP levels at the time of LT were associated with HCC recurrences (P = 0.014). Patient age, gender, ethnicity, liver disease etiology, MELD scores, HCC lesions at the time of diagnosis, and number/type of locoregional therapy (LRT), were not predictive of HCC recurrence. CONCLUSION: This is the first study to evaluate the CCFSS as a potential new scoring system to predict HCC recurrence after LT. The RETREAT score is more specific than CCFSS. The incorporation of AFP levels at the time of LT improves the estimation of HCC recurrence in the post-LT period.Table 1

Clinical efficacy of direct-acting antiviral therapy for recurrent hepatitis C virus infection after liver transplantation in patients with hepatocellular carcinoma.

BACKGROUNDRecurrent hepatitis C virus (HCV) infection of transplanted liver allografts is universal in patients with detectable HCV viremia at the time of transplantation. Direct-acting antiviral (DAA) therapy has been adopted as the standard of care for recurrent HCV infection in the post-transplant setting. However, there are insufficient data regarding its efficacy in liver transplant (LT) recipients with a history of hepatocellular carcinoma (HCC), and the risk of HCC recurrence after DAA therapy is unknown.AIMTo demonstrate predictors of DAA treatment failure and HCC recurrence in LT recipients.METHODSA total of 106 LT recipients given DAAs for recurrent HCV infection from 2015 to 2019 were identified (68 with and 38 without HCC). Descriptive statistics and logistic regression models were used to estimate the multivariate odds ratios and respective 95% confidence intervals for predictors of treatment failure and HCC recurrence.RESULTSSix patients (6%) experienced DAA therapy failure post-LT and 100 (94%) had a sustained virologic response at follow-up week 12. A high alanine transaminase level > 35 U/L at treatment week 4 was a significant predictor of treatment failure. Relapse to pre-LT DAA therapy is a predictor of post-LT HCC recurrence, P = 0.04. DAA relapse post-LT was also associated with post-transplantation HCC recurrence, P = 0.05.CONCLUSIONDAAs are effective and safe in the treatment of recurrent HCV infection in LT recipients with history of HCC. Relapse to pre- and post-LT DAA therapy is associated with post-transplantation HCC recurrence.

Risk Factors and Center-Level Variation in Hepatocellular Carcinoma Under-Staging for Liver Transplantation.

Liver transplantation (LT) is curative for most patients with hepatocellular carcinoma (HCC). However, 10%-15% of patients experience HCC recurrence. Patients who are reported as within Milan criteria by imaging are frequently found to be outside the criteria on explant. This under-staging of HCC worsens post-LT outcomes. However, risk factors for under-staging have not been elucidated. Furthermore, it is not known if there is regional or center-level variation in under-staging. We conducted a retrospective analysis of adult patients transplanted for HCC in the United Network for Organ Sharing (UNOS) database between 2012 and 2016. Under-staging was determined on the basis of comparing pre-LT imaging to explant findings. Kaplan-Meier methods and Cox regression were used to evaluate the impact of under-staging on HCC recurrence and post-LT survival. Mixed effects logistic regression was used to identify risk factors for under-staging and to study regional and center-level variation in adjusted analyses. A total of 5424 patients were included in the cohort, of whom 24.9% (n=1353) were under-staged. Post-LT HCC recurrence and death were significantly associated with under-staging (each P<0.001). In adjusted analyses, independent predictors of under-staging included age (odds ratio [OR], 1.13 per 10 years; 95% confidence interval [CI], 1.03-1.25), male sex (OR, 1.61; 95% CI, 1.36-1.89), down-staging (OR, 4.03; 95% CI, 2.65-6.11), and pre-LT alpha-fetoprotein (P<0.001). There was also significant variation in under-staging between UNOS regions and among transplant centers, ranging from 14.8% to 38.1%. We report novel risk factors for HCC under-staging, which worsens post-LT outcomes. Significant center-level and regional variation in under-staging highlights the need for standards that achieve greater uniformity in staging.

Donation After Circulatory Death Is Associated With Similar Posttransplant Survival in All but the Highest-Risk Hepatocellular Carcinoma Patients.

Liver transplantation (LT) recipients with hepatocellular carcinoma (HCC) receive a higher proportion of livers from donation after circulatory death (DCD) donors compared with non-HCC etiologies. Nevertheless, data on outcomes in patients with HCC receiving DCD grafts are limited. We evaluated the influence of DCD livers on post-LT outcome among HCC patients. We identified 7563 patients in the United Network for Organ Sharing (UNOS) database who underwent LT with Model for End-Stage Liver Disease score exceptions from 2012 to 2016, including 567 (7.5%) who received a DCD donor organ and 6996 (92.5%) who received a donation after brain death (DBD) donor organ. Kaplan-Meier probabilities of post-LT HCC recurrence at 3years were 7.6% for DCD and 6.4% for DBD recipients (P=0.67) and post-LT survival at 3 years was 81.1% versus 85.5%, respectively (P=0.008). On multivariate analysis, DCD donor (hazard ratio, 1.38; P=0.005) was an independent predictor of post-LT mortality. However, a survival difference after LT was only observed in subgroups at higher risk for HCC recurrence including Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score ≥4 (DCD 57.0% versus DBD 72.6%; P=0.02), alpha-fetoprotein (AFP) ≥100 (60.1% versus 76.9%; P=0.049), and multiple viable tumors on last imaging before LT (69.9% versus 83.1%; P=0.002). In this analysis of HCC patients receiving DCD versus DBD livers in the UNOS database, we found that patients with a low-to-moderate risk of HCC recurrence (80%-90% of the DCD cohort) had equivalent survival regardless of donor type. It appears that DCD donation can best be used to increase the donor pool for HCC patients with decompensated cirrhosis or partial response/stable disease after locoregional therapy with AFP at LT <100ng/mL.

Direct-Acting Antivirals and Hepatocellular Carcinoma: No Evidence of Higher Wait-List Progression or Posttransplant Recurrence.

The association between direct-acting antivirals (DAAs) and hepatocellular carcinoma (HCC) wait-list progression or its recurrence following liver transplantation (LT) remains uncertain. We evaluated the impact of DAAs on HCC wait-list progression and post-LT recurrence. This Latin American multicenter retrospective cohort study included HCC patients listed for LT between 2012 and 2018. Patients were grouped according to etiology of liver disease: hepatitis C virus (HCV) negative, HCV+ never treated with DAAs, and HCV+ treated with DAAs either before or after transplantation. Multivariate competing risks models were conducted for both HCC wait-list progression adjusted by a propensity score matching (pre-LT DAA effect) and for post-LT HCC recurrence (pre- or post-LT DAA effect). From 994 included patients, 50.6% were HCV-, 32.9% were HCV+ never treated with DAAs, and 16.5% were HCV+ treated with DAAs either before (n=66) or after LT (n=98). Patients treated with DAAs before LT presented similar cumulative incidence of wait-list tumor progression when compared with those patients who were HCV+ without DAAs (26.2% versus 26.9%; P=0.47) and a similar HCC-related dropout rate (12.1% [95% CI, 0.4%-8.1%] versus 12.9% [95% CI, 3.8%-27.2%]), adjusted for baseline tumor burden, alpha-fetoprotein values, HCC diagnosis after listing, bridging therapies, and by the probability of having received or not received DAAs through propensity score matching (subhazard ratio [SHR], 0.9; 95% CI, 0.6-1.6; P=0.95). A lower incidence of posttransplant HCC recurrence among HCV+ patients who were treated with pre- or post-LT DAAs was observed (SHR, 0.7%; 95% CI, 0.2%-4.0%). However, this effect was confounded by the time to DAA initiation after LT. In conclusion, in this multicenter cohort, HCV treatment with DAAs did not appear to be associated with an increased wait-list tumor progression and HCC recurrence after LT.