Offer Acceptance Patterns for Liver Donors Aged 70 and Older
Despite a documented survival benefit, older liver donor (OLD, age â‰¥70) graft offers are frequently declined, with utilization worsening over the last decade. To understand how offer acceptance varies by center, we studied 1113 eventually transplanted OLD grafts from 2009 to 2017 using Scientific Registry of Transplant Recipients (SRTR) data and random-intercept multilevel logistic regression. To understand how center-level acceptance of OLD graft offers might be associated with waitlist and posttransplant outcomes, we studied all adult, actively listed, liver-only candidates and recipients during the study period using Poisson regression (transplant rate), competing risks regression (waitlist mortality), and Cox regression (posttransplant mortality). Among 117 centers, OLD offer acceptance ranged from 0 (23 centers) to 95 acceptances, with a median odds ratio of 2.88. Thus, a candidate may be three times as likely to receive an OLD graft simply by listing at a different center. Centers in the highest quartile (Q4) of OLD acceptance (accepted 39% of OLD offers) accepted more nationally shared organs (Q4 versus Q1: 14.1% versus 0.0%, PÂ <Â 0.001) and had higher annual liver transplant volume (Q4 versus Q1: 80 versus 21, PÂ <Â 0.001). After adjustment, nationally shared OLD offers (adjusted odds ratio [aOR]: 0.16, 95% confidence interval [CI]: 0.13-0.20) and offers to centers with higher median Model for End-Stage Liver Disease (MELD) at transplant (aOR: 0.74, 95% CI: 0.62-0.87) were less likely to be accepted. OLD offers to centers with higher annual transplant volume were more likely to be accepted (aOR: 1.21, 95% CI: 1.14-1.30). Additionally, candidates listed at centers within the highest quartile of OLD graft offer acceptance had higher deceased donor liver transplantation (DDLT) rates (adjusted incidence rate ratio: 1.45, 95% CI: 1.41-1.50), lower waitlist mortality (adjusted subhazard ratio: 0.76, 95% CI: 0.72-0.76), and similar posttransplant survival (adjusted hazard ratio: 0.93, 95% CI: 0.86-1.01) when compared with those listed at centers in the lowest quartile of OLD graft offer acceptance. The wide variation in OLD offer acceptance supports the need for optimizing the organ offer process and efficiently directing OLD offers to centers more likely to use them.
Liver transplantation for non-resectable colorectal liver metastases: the International Hepato-Pancreato-Biliary Association consensus guidelines
Colorectal cancer is a prevalent disease worldwide, with more than 50% of patients developing metastases to the liver. Despite advances in improving resectability, most patients present with non-resectable colorectal liver metastases requiring palliative systemic therapy and locoregional disease control strategies. There is a growing interest in the use of liver transplantation to treat non-resectable colorectal liver metastases in well selected patients, leading to a surge in the number of studies and prospective trials worldwide, thereby fuelling the emerging field of transplant oncology. The interdisciplinary nature of this field requires domain-specific evidence and expertise to be drawn from multiple clinical specialities and the basic sciences. Importantly, the wider societal implication of liver transplantation for non-resectable colorectal liver metastases, such as the effect on the allocation of resources and national transplant waitlists, should be considered. To address the urgent need for a consensus approach, the International Hepato-Pancreato-Biliary Association commissioned the Liver Transplantation for Colorectal liver Metastases 2021 working group, consisting of international leaders in the areas of hepatobiliary surgery, colorectal oncology, liver transplantation, hepatology, and bioethics. The aim of this study was to standardise nomenclature and define management principles in five key domains: patient selection, evaluation of biological behaviour, graft selection, recipient considerations, and outcomes. An extensive literature review was done within the five domains identified. Between November, 2020, and January, 2021, a three-step modified Delphi consensus process was undertaken by the workgroup, who were further subgrouped into the Scientific Committee, Expert Panel, and Transplant Centre Representatives. A final consensus of 44 statements, standardised nomenclature, and a practical management algorithm is presented. Specific criteria for clinico-patho-radiological assessments with molecular profiling is crucial in this setting. After this, the careful evaluation of biological behaviour with bridging therapy to transplantation with an appropriate assessment of the response is required. The sequencing of treatment in synchronous metastatic disease requires special consideration and is highlighted here. Some ethical dilemmas within organ allocation for malignant indications are discussed and the role for extended criteria grafts, living donor transplantation, and machine perfusion technologies for non-resectable colorectal liver metastases are reviewed. Appropriate immunosuppressive regimens and strategies for the follow-up and treatment of recurrent disease are proposed. This consensus guideline provides a framework by which liver transplantation for non-resectable colorectal liver metastases might be safely instituted and is a meaningful step towards future evidenced-based practice for better patient selection and organ allocation to improve the survival for patients with this disease.
Evaluation of the Intention-to-Treat Benefit of Living Donation in Patients With Hepatocellular Carcinoma Awaiting a Liver Transplant
Importance:Living-donor liver transplant (LDLT) offers advantages over deceased-donor liver transplant (DDLT) of improved intention-to-treat outcomes and management of the shortage of deceased-donor allografts. However, conflicting data still exist on the outcomes of LDLT in patients with hepatocellular carcinoma (HCC). Objective:To investigate the potential survival benefit of an LDLT in patients with HCC from the time of waiting list inscription. Design, Setting, and Participants:This multicenter cohort study with an intention-to-treat design analyzed the data of patients aged 18 years or older who had an HCC diagnosis and were on a waiting list for a first transplant. Patients from 12 collaborative centers in Europe, Asia, and the US who were on a transplant waiting list between January 1, 2000, and December 31, 2017, composed the international cohort. The Toronto cohort comprised patients from 1 transplant center in Toronto, Ontario, Canada who were on a waiting list between January 1, 2000, and December 31, 2015. The international cohort centers performed either an LDLT or a DDLT, whereas the Toronto cohort center was selected for its capability to perform both LDLT and DDLT. The benefit of LDLT was tested in the 2 cohorts before and after undergoing an inverse probability of treatment weighting (IPTW) analysis. Data were analyzed from February 1 to May 31, 2020. Main Outcomes and Measures:Intention-to-treat death was defined as a patient death that occurred for any reason and was calculated from the time of waiting list inscription for liver transplant to the last follow-up date (December 31, 2019). Four multivariable Cox proportional hazards regression models for intention-to-treat death were created. Results:A total of 3052 patients were analyzed in the international cohort, of whom 2447 were men (80.2%) and the median (IQR) age at first referral was 58 (53-63) years. The Toronto cohort comprised 906 patients, of whom 743 were men (82.0%) and the median (IQR) age at first referral was 59 (53-63) years. In all the settings, LDLT was an independent protective factor, reducing the risk of overall death by 49% in the pre-IPTW analysis for the international cohort (HR, 0.51; 95% CI, 0.36-0.71; Pâ€‰<â€‰.001), 33% in the post-IPTW analysis for the international cohort (HR, 0.67; 95% CI, 0.53-0.85; Pâ€‰=â€‰.001), 43% in the pre-IPTW analysis for the Toronto cohort (HR, 0.57; 95% CI, 0.45-0.73; Pâ€‰<â€‰.001), and 48% in the post-IPTW analysis for the Toronto cohort (HR, 0.52; 95% CI, 0.42 to 0.65; Pâ€‰<â€‰.001). The discriminatory ability of the mathematical models further improved in all of the cases in which LDLT was incorporated. Conclusions and Relevance:This study suggests that having a potential live donor could decrease the intention-to-treat risk of death in patients with HCC who are on a waiting list for a liver transplant. This benefit is associated with the elimination of the dropout risk and has been reported in centers in which both LDLT and DDLT options are equally available.
Black Patients Have Unequal Access to Listing for Liver Transplantation in the United States
BACKGROUND AND AIMS:The Model for End-Stage Liver Disease score may have eliminated racial disparities on the waitlist for liver transplantation (LT), but disparities prior to waitlist placement have not been adequately quantified. We aimed to analyze differences in patients who are listed for LT, undergo transplantation, and die from end-stage liver disease (ESLD), stratified by state and race/ethnicity. APPROACH AND RESULTS:We analyzed two databases retrospectively, the Center for Disease Control Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) and the United Network for Organ Sharing (UNOS) databases, from 2014 to 2018. We included patients aged 25-64Â years who had a primary cause of death of ESLD and were listed for transplant in the CDC WONDER or UNOS database. Our primary outcome was the ratio of listing for LT to death from ESLD-listing to death ratio (LDR). Our secondary outcome was the transplant to listing and transplant to death ratios. Chi-squared and multivariable linear regression evaluated for differences between races/ethnicities. There were 135,367 patients who died of ESLD, 54,734 patients who were listed for transplant, and 26,571 who underwent transplant. Patients were mostly male and White. The national LDR was 0.40, significantly lowest in Black patients (0.30), PÂ <Â 0.001. The national transplant to listing ratio was 0.48, highest in Black patients (0.53), PÂ <Â 0.01. The national transplant to death ratio was 0.20, lowest in Black patients (0.16), PÂ <Â 0.001. States that had an above-mean LDR had a lower transplant to listing ratio but a higher transplant to death ratio. Multivariable analysis confirmed that Black race is significantly associated with a lower LDR and transplant to death ratio. CONCLUSIONS:Black patients face a disparity in access to LT due to low listing rates for transplant relative to deaths from ESLD.
Evaluation of the LI-RADS treatment response algorithm in hepatocellular carcinoma after trans-arterial chemoembolization
PURPOSE/OBJECTIVE:To evaluate the diagnostic performance of LI-RADS treatment response algorithm (LR-TRA) and modified RECIST (mRECIST) for the detection of viable hepatocellular carcinoma (HCC) on MRI after trans-arterial chemoembolization (TACE). MATERIALS AND METHODS/METHODS:This retrospective study includes cirrhotic patients that underwent trans-arterial chemoembolization prior to liver transplantation from 2013 to 2017 with a pre- and post-treatment MRI available. Three blinded readers assigned a LR-TRA and mRECIST category to each lesion. Lesions on MRI and explant pathology were matched and characterized as complete (100% necrosis) or incomplete necrosis (â‰¤99% necrosis). Diagnostic performance of LR-TRA and mRECIST were calculated with a generalized estimating equation. RESULTS:A total of 52 patients with 71 lesions were included, 47 with incomplete and 24 with complete necrosis. In consensus, 45 lesions were categorized as LR-TR Nonviable, of which 62.2% (28/45) had incomplete and 37.8% (17/45) had complete necrosis. Six lesions were categorized as LR-TR Equivocal, of which 33.3% (2/6) had incomplete and 66.7% (4/6) had complete necrosis. Twenty lesions were categorized as LR-TR Viable of which 85.0% (17/20) had incomplete and 15.0% (3/20) had complete necrosis. The sensitivity of LR-TR Viable for detecting incompletely necrotic tumor when LR-TR Equivocal was considered as viable, in consensus was 40.4%; specificity 70.8%; accuracy 50.7%. The sensitivity of mRECIST for detecting incompletely necrotic tumor was 37.0%; specificity 79.2%; accuracy 51.4%. There was no significant difference in diagnostic performance between mRECIST and LR-TRA (pÂ =Â 0.14-0.33). Agreement for LR-TRA category was moderate (kÂ =Â 0.53 [95% CI: 0.45, 0.67]). CONCLUSION/CONCLUSIONS:LI-RADS treatment response algorithm demonstrates high specificity and low to moderate sensitivity for the detection of viable HCC after TACE in a North American cirrhotic cohort, without significant difference in diagnostic performance between LR-TRA and mRECIST.
Dynamic Î±-Fetoprotein Response and Outcomes After Liver Transplant for Hepatocellular Carcinoma
Importance:Accurate preoperative prediction of hepatocellular carcinoma (HCC) recurrence after liver transplant is the mainstay of selection tools used by transplant-governing bodies to discern candidacy for patients with HCC. Although progress has been made, few tools incorporate objective measures of tumor biological characteristics, resulting in inclusion of patients with high recurrence rates and exclusion of others who could otherwise be cured. Objective:To externally validate the New York/California (NYCA) score, a recently published multi-institutional US HCC selection tool that was the first model incorporating a dynamic Î±-fetoprotein response (AFP-R) and compare the validated score with currently accepted HCC selection tools, namely, the Milan Criteria (MC), the French-AFP (F-AFP), and Metroticket 2.0 models. Design, Setting, and Participants:A retrospective, multicenter prognostic analysis of prospectively collected databases of 2236 adults undergoing liver transplant for HCC was conducted at 3 US, 1 Canadian, and 4 European centers from January 1, 2001, to December 31, 2013. The AFP-R was measured as the difference between maximum and final pre-liver transplant AFP level. Cox proportional hazards regression and competing risk regression analyses examined recurrence-free and overall survival. Receiver operating characteristic analyses and net reclassification index were used to compare NYCA with MC, F-AFP, and Metroticket 2.0. Data analysis was performed from June 2019 to April 2020. Main Outcomes and Measures:The primary study outcome was 5-year recurrence-free survival; overall survival was the secondary outcome. Results:Of 2236 patients, 1808 (80.9%) were men; mean (SD) age was 58.3 (7.96) years. A total of 545 patients (24.4%) did not meet the MC. The NYCA score proved valid on competing risk regression analysis, accurately predicting recurrence-free and overall survival (5-year cumulative incidence of recurrence risk in NYCA risk categories was 9.5% for low-, 20.5%, for acceptable-, and 40.5% for high-risk categories; Pâ€‰<â€‰.001 for all). The NYCA also predicted recurrence-free survival on a center-specific level: 453 of 545 patients (83.1%) who did not meet MC, 213 of 308 (69.2%) who did not meet the French-AFP, 292 of 384 (76.1%) who did not meet Metroticket 2.0 would be recategorized into NYCA low- and acceptable-risk groups (>75% 5-year recurrence-free survival). The Harrell C statistic for the validated NYCA score was 0.66 compared with 0.59 for the MC and 0.57 for the F-AFP models (Pâ€‰<â€‰.001). The net reclassification index for NYCA was 8.1 vs MC, 12.9 vs F-AFP, and 10.1 vs Metroticket 2.0. Conclusions and Relevance:This study appears to externally validate the importance of AFP-R in the selection of patients with HCC for liver transplant. The AFP-R represents one of the truly objective measures of biological characteristics available before transplantation. Incorporation of AFP-R into selection criteria allows safe expansion of MC and other models, offering liver transplant to patients with acceptable tumor biological characteristics who would otherwise be denied potential cure.
Posttransplant Outcomes in Older Patients With Hepatocellular Carcinoma Are Driven by Non-Hepatocellular Carcinoma Factors
The incidence of hepatocellular carcinoma (HCC) is growing in the United States, especially among the elderly. Older patients are increasingly receiving transplants as a result of HCC, but the impact of advancing age on long-term posttransplant outcomes is not clear. To study this, we used data from the US Multicenter HCC Transplant Consortium of 4980 patients. We divided the patients into 4 groups by age at transplantation: 18 to 64 years (nÂ =Â 4001), 65 to 69 years (nÂ =Â 683), 70 to 74 years (nÂ =Â 252), and â‰¥75Â years (nÂ =Â 44). There were no differences in HCC tumor stage, type of bridging locoregional therapy, or explant residual tumor between the groups. Older age was confirmed to be an independent and significant predictor of overall survival even after adjusting for demographic, etiologic, and cancer-related factors on multivariable analysis. A dose-response effect of age on survival was observed, with every 5-year increase in age older than 50Â years resulting in an absolute increase of 8.3% in the mortality rate. Competing risk analysis revealed that older patients experienced higher rates of non-HCC-related mortality (PÂ =Â 0.004), and not HCC-related death (PÂ =Â 0.24). To delineate the precise cause of death, we further analyzed a single-center cohort of patients who received a transplant as a result of HCC (nÂ =Â 302). Patients older than 65Â years had a higher incidence of de novo cancer (18.1% versus 7.6%; PÂ =Â 0.006) after transplantation and higher overall cancer-related mortality (14.3% versus 6.6%; PÂ =Â 0.03). Even carefully selected elderly patients with HCC have significantly worse posttransplant survival rates, which are mostly driven by non-HCC-related causes. Minimizing immunosuppression and closer surveillance for de novo cancers can potentially improve the outcomes in elderly patients who received a transplant as a result of HCC.
Multi-Center Analysis of Liver Transplantation for Combined Hepatocellular Carcinoma-Cholangiocarcinoma Liver Tumors
BACKGROUND:Combined hepatocellular-cholangiocarcinoma liver tumors (cHCC-CCA) with pathologic differentiation of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma within the same tumor are not traditionally considered for liver transplantation due to perceived poor outcomes. Published results are from small cohorts and single centers. Through a multicenter collaboration, we performed the largest analysis to date of the utility of liver transplantation for cHCC-CCA. STUDY DESIGN:Liver transplant and resection outcomes for HCC (nÂ = 2,998) and cHCC-CCA (nÂ = 208) were compared in a 12-center retrospective review (2009 to 2017). Pathology defined tumor type. Tumor burden was based on radiologic Milan criteria at time of diagnosis and applied to cHCC-CCA for uniform analysis. Kaplan-Meier survival curves and log-rank test were used to determine overall survival and disease-free survival. Cox regression was used for multivariate survival analysis. RESULTS:Liver transplantation for cHCC-CCA (nÂ = 67) and HCC (nÂ = 1,814) within Milan had no significant difference in overall survival (5-year cHCC-CCA 70.1%, HCC 73.4%, pÂ =Â 0.806), despite higher cHCC-CCA recurrence rates (23.1% vs 11.5% 5 years, pÂ <Â 0.001). Irrespective of tumor burden, cHCC-CCA tumor patient undergoing liver transplant had significantly superior overall survival (pÂ = 0.047) and disease-free survival (p < 0.001) than those having resection. For cHCC-CCA within Milan, liver transplant was associated with improved disease-free survival over resection (70.3% vs 33.6% 5 years, p < 0.001). CONCLUSIONS:Regardless of tumor burden, outcomes after liver transplantation are superior to resection for patients with cHCC-CCA. Within Milan criteria, liver transplant for cHCC-CCA and HCC result in similar overall survival, justifying consideration of transplantation due to the higher chance of cure with liver transplantation in this traditionally excluded population.
RAPID-ly Increasing the Availability of Livers? [Comment]
SARS-CoV-2 infection increases tacrolimus concentrations in solid-organ transplant recipients [Letter]