Citations

Background : Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality. Optimal treatment decisions are challenging, and existing treatment allocation frameworks may not fully reflect the evolving therapeutic landscape or contemporary clinical practices in North America. Methods : Using a modified Delphi process, a multidisciplinary panel of 20 North American experts in hepatology, medical oncology, surgery, radiology, and radiation oncology developed a consensus-based treatment framework for HCC, termed the BEACON-HCC system. The framework was informed by current evidence and expert opinion through iterative discussion and voting. In a pilot study using 29 real-world patient cases, we assessed concordance between external expert recommendations and BEACON-HCC recommendations and Barcelona Clinic Liver Cancer (BCLC) 2025 treatment recommendations. Results : The BEACON-HCC treatment allocation framework diverges from prior frameworks by incorporating nuanced clinical features such as degree of intrahepatic tumor burden and vascular invasion, and adverse tumor prognostic markers, to align treatment allocation with tumor biology and therapeutic potential. Key innovations include the incorporation of emerging modalities such as external beam radiation therapy (EBRT), transarterial radioembolization (TARE), and systemic-locoregional combination therapies. In the pilot exercise, expert treatment decisions showed 96.6% concordance with BEACON-HCC recommendations and 72.4% concordance with BCLC recommendations. Conclusions : BEACON-HCC is a consensus-based framework for treatment allocation that incorporates the expanding range of therapeutic options available to patients in the North American HCC population. Expert treatment decisions showed a high concordance with the BEACON-HCC system; further validation using empiric clinical data is planned through the HCC-Live Consortium.

Objective: To evaluate long-term oncologic outcomes of patients post–living donor liver transplantation (LDLT) within and outside standard transplantation selection criteria and the added value of the incorporation of the New York-California (NYCA) score. Background: LDLT offers an opportunity to decrease the liver transplantation waitlist, reduce waitlist mortality, and expand selection criteria for patients with hepatocellular carcinoma (HCC). Methods: Primary adult LDLT recipients between October 1999 and August 2019 were identified from a multicenter cohort of 12 North American centers. Posttransplantation and recurrence-free survival were evaluated using the Kaplan-Meier method. Results: Three hundred sixty LDLTs were identified. Patients within Milan criteria (MC) at transplantation had a 1, 5, and 10-year posttransplantation survival of 90.9%, 78.5%, and 64.1% versus outside MC 90.4%, 68.6%, and 57.7% (P = 0.20), respectively. For patients within the University of California San Francisco (UCSF) criteria, respective posttransplantation survival was 90.6%, 77.8%, and 65.0%, versus outside UCSF 92.1%, 63.8%, and 45.8% (P = 0.08). Fifty-three (83%) patients classified as outside MC at transplantation would have been classified as either low or acceptable risk with the NYCA score. These patients had a 5-year overall survival of 72.2%. Similarly, 28(80%) patients classified as outside UCSF at transplantation would have been classified as a low or acceptable risk with a 5-year overall survival of 65.3%. Conclusions: Long-term survival is excellent for patients with HCC undergoing LDLT within and outside selection criteria, exceeding the minimum recommended 5-year rate of 60% proposed by consensus guidelines. The NYCA categorization offers insight into identifying a substantial proportion of patients with HCC outside the MC and the UCSF criteria who still achieve similar post-LDLT outcomes as patients within the criteria.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22–1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04–1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35–1.73, p < 0.001), microvascular (HR = 2.37, 95%–CI, 1.87–2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41–4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29–2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54–3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

NAFLD will soon be the most common indication for liver transplantation (LT). In NAFLD, HCC may occur at earlier stages of fibrosis and present with more advanced tumor stage, raising concern for aggressive disease. Thus, adult LT recipients with HCC from 20 US centers transplanted between 2002 and 2013 were analyzed to determine whether NAFLD impacts recurrence-free post-LT survival. Five hundred and thirty-eight (10.8%) of 4981 total patients had NAFLD. Patients with NAFLD were significantly older (63 vs. 58, p<0.001), had higher body mass index (30.5 vs. 27.4, p<0.001), and were more likely to have diabetes (57.3% vs. 28.8%, p<0.001). Patients with NAFLD were less likely to receive pre-LT locoregional therapy (63.6% vs. 72.9%, p<0.001), had higher median lab MELD (15 vs. 13, p<0.001) and neutrophil-lymphocyte ratio (3.8 vs. 2.9, p<0.001), and were more likely to have their maximum pre-LT alpha fetoprotein at time of LT (44.1% vs. 36.1%, p<0.001). NAFLD patients were more likely to have an incidental HCC on explant (19.4% vs. 10.4%, p<0.001); however, explant characteristics including tumor differentiation and vascular invasion were not different between groups. Comparing NAFLD and non-NAFLD patients, the 1, 3, and 5-year cumulative incidence of recurrence (3.1%, 9.1%, 11.5% vs. 4.9%, 10.1%, 12.6%, p=0.36) and recurrence-free survival rates (87%, 76%, and 67% vs. 87%, 75%, and 67%, p=0.97) were not different. In competing risks analysis, NAFLD did not significantly impact recurrence in univariable (HR: 0.88, p=0.36) nor in adjusted analysis (HR: 0.91, p=0.49). With NAFLD among the most common causes of HCC and poised to become the leading indication for LT, a better understanding of disease-specific models to predict recurrence is needed. In this NAFLD cohort, incidental HCCs were common, raising concerns about early detection. However, despite less locoregional therapy and high neutrophil-lymphocyte ratio, explant tumor characteristics and post-transplant recurrence-free survival were not different compared to non-NAFLD patients.

BACKGROUND: Liver transplantation (LT) is an effective strategy for patients with unresectable hepatocellular carcinoma (HCC). To qualify for standardized LT model for end-stage liver disease exception points, the United Network for Organ Sharing National Liver Review Board (NLRB) requires that the presenting and final HCC tumor burden be within the University of California San Francisco criteria, which were recently expanded (within expanded UCSF [W-eUCSF]). Current NLRB criteria may be too restrictive because it has been shown previously that the initial burden does not predict LT failure when tumors downstage to UCSF. This study aims to assess LT outcomes for HCC initially presenting beyond expanded UCSF (B-eUCSF) criteria in a large multicenter collaboration. STUDY DESIGN: Comparisons of B-eUCSF and W-eUCSF candidates undergoing LT at seven academic institutions between 2001 and 2017 were made from a multi-institutional database. Survival outcomes were compared by Kaplan-Meier and Cox regression analyses. RESULTS: Of 1,846 LT recipients with HCC, 86 (5%) met B-eUCSF criteria at initial presentation, with the remainder meeting W-eUCSF criteria. Despite differences in tumor burden, B-eUCSF candidates achieved comparable 1-, 5- and 10-year overall (89%, 70%, and 55% vs 91%, 74%, and 60%, respectively; p = 0.2) and disease-free (82%, 60%, and 53% vs 89%, 71%, and 59%, respectively; p = 0.07) survival to patients meeting W-eUCSF criteria after LT. Despite increased tumor recurrence in B-eUCSF vs W-eUCSF patients (24% vs 10%, p = 0.0002), post-recurrence survival was similar in both groups (p = 0.69). CONCLUSION: Transplantation for patients initially presenting with HCC B-eUSCF criteria offers a survival advantage similar to those with tumors meeting W-eUCSF criteria at presentation. The current NLRB policy is too stringent, and considerations to expand criteria should be discussed.

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 (n = 4001), 65 to 69 years (n = 683), 70 to 74 years (n = 252), and ≥75 years (n = 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 50 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 (P = 0.004), and not HCC‐related death (P = 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 (n = 302). Patients older than 65 years had a higher incidence of de novo cancer (18.1% versus 7.6%; P = 0.006) after transplantation and higher overall cancer‐related mortality (14.3% versus 6.6%; P = 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.

Background and Aims The Organ Procurement and Transplantation Network recently approved liver transplant (LT) prioritization for patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are down‐staged (DS) with locoregional therapy (LRT). We evaluated post‐LT outcomes, predictors of down‐staging, and the impact of LRT in patients with beyond‐MC HCC from the U.S. Multicenter HCC Transplant Consortium (20 centers, 2002‐2013). Approach and Results Clinicopathologic characteristics, overall survival (OS), recurrence‐free survival (RFS), and HCC recurrence (HCC‐R) were compared between patients within MC (n = 3,570) and beyond MC (n = 789) who were down‐staged (DS, n = 465), treated with LRT and not down‐staged (LRT‐NoDS, n = 242), or untreated (NoLRT‐NoDS, n = 82). Five‐year post‐LT OS and RFS was higher in MC (71.3% and 68.2%) compared with DS (64.3% and 59.5%) and was lowest in NoDS (n = 324; 60.2% and 53.8%; overall P < 0.001). DS patients had superior RFS (60% vs. 54%, P = 0.043) and lower 5‐year HCC‐R (18% vs. 32%, P < 0.001) compared with NoDS, with further stratification by maximum radiologic tumor diameter (5‐year HCC‐R of 15.5% in DS/<5 cm and 39.1% in NoDS/>5 cm, P < 0.001). Multivariate predictors of down‐staging included alpha‐fetoprotein response to LRT, pathologic tumor number and size, and wait time >12 months. LRT‐NoDS had greater HCC‐R compared with NoLRT‐NoDS (34.1% vs. 26.1%, P < 0.001), even after controlling for clinicopathologic variables (hazard ratio [HR] = 2.33, P < 0.001) and inverse probability of treatment‐weighted propensity matching (HR = 1.82, P < 0.001). Conclusions In LT recipients with HCC presenting beyond MC, successful down‐staging is predicted by wait time, alpha‐fetoprotein response to LRT, and tumor burden and results in excellent post‐LT outcomes, justifying expansion of LT criteria. In LRT‐NoDS patients, higher HCC‐R compared with NoLRT‐NoDS cannot be explained by clinicopathologic differences, suggesting a potentially aggravating role of LRT in patients with poor tumor biology that warrants further investigation.

Objective: The aim of the study was to determine the rate, predictors, and impact of complete pathologic response (cPR) to pretransplant locoregional therapy (LRT) in a large, multicenter cohort of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT). Background: LRT is used to mitigate waitlist dropout for patients with HCC awaiting LT. Degree of tumor necrosis found on explant has been associated with recurrence and overall survival, but has not been evaluated in a large, multicenter study. Methods: Comparisons were made among patients receiving pre-LT LRT with (n = 802) and without (n = 2637) cPR from the United States Multicenter HCC Transplant Consortium (UMHTC), and multivariable predictors of cPR were identified using logistic regression. Results: Of 3439 patients, 802 (23%) had cPR on explant. Compared with patients without cPR, cPR patients were younger; had lower Model for End-stage Liver Disease (MELD) scores, AFP levels, and neutrophil–lymphocyte ratios (NLR); were more likely to have tumors within Milan criteria and fewer LRT treatments; and had significantly lower 1-, 3-, and 5-year incidence of post-LT recurrence (1.3%, 3.5%, and 5.2% vs 6.2%, 13.5%, and 16.4%; P < 0.001) and superior overall survival (92%, 84%, and 75% vs 90%, 78%, and 68%; P < 0.001). Multivariable predictors of cPR included age, sex, liver disease diagnosis, MELD, AFP, NLR, radiographic Milan status, and number of LRT treatments (C-statistic 0.67). Conclusions: For LT recipients with HCC receiving pretransplant LRT, achieving cPR portends significantly lower posttransplant recurrence and superior survival. Factors predicting cPR are identified, which may help prioritize patients and guide LRT strategies to optimize posttransplant cancer outcomes.