Background and Aims
United Network for Organ Sharing (UNOS) recently implemented a national policy granting priority listing for liver transplantation (LT) in patients who achieved down‐staging of ...hepatocellular carcinoma (HCC) to Milan criteria. We aimed to evaluate the national experience on down‐staging by comparing two down‐staging groups with (1) tumor burden meeting UNOS down‐staging (UNOS‐DS) inclusion criteria and (2) “all‐comers” (AC‐DS) with initial tumor burden beyond UNOS‐DS criteria versus patients always within Milan.
Approach and Results
This is a retrospective analysis of the UNOS database of 3,819 patients who underwent LT from 2012 to 2015, classified as always within Milan (n = 3,276), UNOS‐DS (n = 422), and AC‐DS (n = 121). Median time to LT was 12.8 months in long wait regions, 6.5 months in mid wait regions (MWR), and 2.6 months in short wait regions (SWR). On explant, vascular invasion was found in 23.7% of AC‐DS versus 16.9% of UNOS‐DS and 14.4% of Milan (P = 0.002). Kaplan‐Meier 3‐year post‐LT survival was 83.2% for Milan, 79.1% for UNOS‐DS (P = 0.17 vs. Milan), and 71.4% for AC‐DS (P = 0.04 vs. Milan). Within down‐staging groups, risk of post‐LT death in multivariable analysis was increased in SWR or MWR (hazard ratio HR, 3.1; P = 0.005) and with alpha‐fetoprotein (AFP) ≥ 100 ng/mL at LT (HR, 2.4; P = 0.009). The 3‐year HCC recurrence probability was 6.9% for Milan, 12.8% for UNOS‐DS, and 16.7% for AC‐DS (P < 0.001). In down‐staging groups, AFP ≥ 100 (HR, 2.6; P = 0.02) was the only independent predictor of HCC recurrence.
Conclusions
Our results validated UNOS‐DS criteria based on comparable 3‐year survival between UNOS‐DS and Milan groups. Additional refinements based on AFP and wait time may further improve post‐LT outcomes in down‐staging groups, especially given that reported 3‐year recurrence was higher than in those always within Milan criteria.
We report on the long‐term intention‐to‐treat (ITT) outcome of 118 patients with hepatocellular carcinoma (HCC) undergoing downstaging to within Milan/United Network for Organ Sharing T2 criteria ...before liver transplantation (LT) since 2002 and compare the results with 488 patients listed for LT with HCC meeting T2 criteria at listing in the same period. The downstaging subgroups include 1 lesion >5 and ≤8 cm (n = 43), 2 or 3 lesions at least one >3 and ≤5 cm with total tumor diameter ≤8 cm (n = 61), or 4‐5 lesions each ≤3 cm with total tumor diameter ≤8 cm (n = 14). In the downstaging group, 64 patients (54.2%) had received LT and 5 (7.5%) developed HCC recurrence. Two of the five patients with HCC recurrence had 4‐5 tumors at presentation. The 1‐ and 2‐year cumulative probabilities for dropout (competing risk) were 24.1% and 34.2% in the downstaging group versus 20.3% and 25.6% in the T2 group (P = 0.04). Kaplan‐Meier's 5‐year post‐transplant survival and recurrence‐free probabilities were 77.8% and 90.8%, respectively, in the downstaging group versus 81% and 88%, respectively, in the T2 group (P = 0.69 and P = 0.66, respectively). The 5‐year ITT survival was 56.1% in the downstaging group versus 63.3% in the T2 group (P = 0.29). Factors predicting dropout in the downstaging group included pretreatment alpha‐fetoprotein ≥1,000 ng/mL (multivariate hazard ratio HR: 2.42; P = 0.02) and Child's B versus Child's A cirrhosis (multivariate HR: 2.19; P = 0.04). Conclusion: Successful downstaging of HCC to within T2 criteria was associated with a low rate of HCC recurrence and excellent post‐transplant survival, comparable to those meeting T2 criteria without downstaging. Owing to the small number of patients with 4‐5 tumors, further investigations are needed to confirm the efficacy of downstaging in this subgroup. (Hepatology 2015;61:1968–1977)
Down‐staging of hepatocellular carcinoma prior to liver transplantation (LT) has generated a lot of interest in recent years and has been identified in two recent national conferences on ...hepatocellular carcinoma as one of the priorities for research. Down‐staging is defined as reduction in the tumor burden using local regional therapy specifically to meet acceptable criteria for LT. The rationale behind down‐staging of tumors initially exceeding conventional criteria for LT is to select a subgroup of tumors with favorable biology and prognosis for LT as assessed by their response to local regional therapy. The expectation is to achieve comparable posttransplant survival between patients who achieve successful tumor down‐staging before LT and those whose tumors meet LT criteria at the outset without needing down‐staging. The application of tumor down‐staging requires a highly structured approach using a treatment protocol that includes five essential components: eligibility criteria, down‐staging endpoints, selection of the type of local regional therapy, minimal observation period from successful tumor down‐staging to LT, and criteria for treatment failure and exclusion from LT. This review article summarizes published data on down‐staging and addresses key questions related to each of the components of the down‐staging protocol as well as treatment efficacy. Conclusion: Based on a review of published data and recommendations from recent national and international conferences on hepatocellular carcinoma and LT, a standardized down‐staging protocol is proposed to further evaluate the feasibility and efficacy of applying tumor down‐staging on a broader scale. (Hepatology 2016;63:1014–1025)
Liver transplantation (LT) offers excellent long-term outcome for certain patients with hepatocellular carcinoma (HCC), with a push to not simply rely on tumor size and number. Selection criteria ...should also consider tumor biology (including alpha-fetoprotein), probability of waitlist and post-LT survival (ie, transplant benefit), organ availability, and waitlist composition. These criteria may be expanded for live donor LT (LDLT) compared to deceased donor LT though this should not adversely affect the double equipoise in LDLT, namely ensuring both acceptable recipient outcomes and donor safety. HCC patients with compensated liver disease and minimal tumor burden have low urgency for LT, especially after local-regional therapy with complete response, and do not appear to derive the same benefit from LT as other waitlist candidates. These guidelines were developed to assist in selecting appropriate HCC patients for both deceased donor LT and LDLT.
Researchers in a recent multicenter study developed and validated a novel prognostic index, Risk Estimation of Tumor Recurrence After Transplant (RETREAT), which incorporates α‐fetoprotein (AFP) at ...liver transplantation (LT), microvascular invasion, and the sum of the largest viable tumor and number of tumors on explant. We now aim to evaluate RETREAT in the United Network for Organ Sharing (UNOS) database in patients with hepatocellular carcinoma (HCC) who meet Milan criteria by imaging and underwent LT between 2012 and ‐2014. On explantation (n = 3276), 13% had microvascular invasion, 30% had no viable tumor, and 15% exceeded Milan criteria. Post‐LT survival at 3 years decreased with increasing RETREAT score: 91% for a score of 0, 80% for a score of 3, and 58% for a score ≥5 (P < .001). Post‐LT HCC recurrence probability within 3 years increased from 1.6% with RETREAT score of 0% to 29% for a score ≥5 (P < .001). Increasing RETREAT score was also associated with a shorter time to HCC recurrence. RETREAT was superior to Milan criteria (explant) in predicting HCC recurrence by the net reclassification index (P < .001). This study validates the prognostic power of RETREAT, which may help standardize post‐LT surveillance, provide a framework for tumor staging and risk stratification, and select candidates for adjuvant therapies.
This study of hepatocellular carcinoma patients using the United Network for Organ Sharing database validates the Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score as a prognostic scoring system, which may help standardize posttransplant surveillance strategies and select appropriate candidates for adjuvant therapies after liver transplant.
Abstract
The success of liver transplant (LT) for hepatocellular carcinoma (HCC) is dependent on accurate tumor staging using validated imaging criteria, and adherence to acceptable criteria based on ...tumor size and number. Other factors including α-fetoprotein (AFP) and response to local regional therapy (LRT) have now played a larger role in candidate selection. Tumor downstaging is defined as reduction in the size of viable tumors using LRT to meet acceptable criteria for LT, and serves as a selection tool for a subgroup of HCC with more favorable biology. The application of tumor downstaging requires a structured approach involving three key components in tumor staging—initial tumor stage and eligibility criteria, tumor viability assessment following LRT, and target tumor stage prior to LT—and incorporation of AFP into staging and treatment response assessments. In this review, we provide in-depth discussions of the key role of these staging definitions in ensuring successful outcome.
High alpha‐fetoprotein (AFP) > 1,000 ng/mL is associated with poor outcomes after liver transplantation (LT) for hepatocellular carcinoma (HCC). A new national policy has been implemented for AFP > ...1,000 ng/mL requiring a decrease to < 500 ng/mL before LT, but there is a paucity of data on the optimal AFP threshold before LT. We aimed to evaluate the effects of a reduction in AFP from > 1,000 ng/mL to different AFP thresholds before LT on survival and HCC recurrence after LT using the United Network for Organ Sharing database. We identified 407 patients who underwent transplant between January 2005 and September 2015 and who had AFP > 1,000 ng/mL at least once before LT. The last AFP measurement before LT was > 1,000 ng/mL in 72.0%, decreased from > 1,000 to 101‐499 ng/mL in 9.6%, and decreased to ≤ 100 ng/mL in 14.3%. Local‐regional therapy was not performed in 45.4% of patients with AFP > 1,000 ng/mL at LT versus 12.8% of those with AFP of 101‐499 ng/mL and 10.3% of those with AFP ≤ 100 ng/mL at LT (P < 0.001). Kaplan‐Meier 5‐year post‐LT survival for those with AFP > 1,000 ng/mL at LT was 48.8% versus 67.0% for those with a decrease in AFP to 101‐499 ng/mL (P < 0.001) and 88.4% for those with AFP ≤ 100 ng/mL at LT (P < 0.001). HCC recurrence probability at 5 years was 35.0% for patients with AFP > 1,000 ng/mL versus 13.3% for patients with AFP of 101‐499 ng/mL and 7.2% for patients with AFP ≤ 100 ng/mL at LT (P < 0.001). In multivariable analysis, a decrease in the AFP to 101‐499 ng/mL was associated with a > 2‐fold reduction in posttransplant mortality (P = 0.01) and a nearly 3‐fold reduction in HCC recurrence (P = 0.02) compared with AFP > 1,000 ng/mL at LT. Conclusion: Our results demonstrated significantly improved post‐LT outcomes when restricting LT to patients with a reduction in AFP from > 1,000 to < 500 ng/mL, validating the recently implemented national policy.
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