Updates in liver transplantation policy for patients with hepatocellular carcinoma (HCC)

INTRODUCTION Liver transplantation (LT) is an excellent treatment option for early-stage (and select intermediate stage) patients with HCC not eligible for resection, resulting in approximately 80% 5-year post-LT survival with relatively low rates of recurrence. While HCC accounts for up to 25% of liver transplants nationally, organ shortages have led to challenges in determining which patients with HCC are ideal candidates for LT and how best to allocate organs accordingly. In this article, we focus on the assessment of transplant candidacy in patients with HCC with attention to both deceased donors and living donor liver transplantation (LDLT), including incorporating markers of tumor biology and downstaging. The current state of organ allocation in the United States for patients with HCC will also be described, including efforts to improve waitlist outcomes and maximize LT survival benefit. ASSESSMENT OF TRANSPLANT SELECTION CRITERIA IN PATIENTS WITH HCC In the United States, the Milan criteria (1 lesion≤5 cm or 2–3 lesions≤3 cm) remain the standard for selecting candidates of LT, whereas most other countries have successfully adopted expanded selection criteria while still maintaining acceptable post-LT survival (Table 1). The key to such expanded criteria is assessing surrogates of tumor biology in order to offer LT to a larger group who are more likely to benefit from this curative therapy. With respect to biomarkers, high alpha-fetoprotein (AFP) levels have been consistently identified with increased post-LT recurrence1–4 starting at a cutoff of ~20 ng/mL, with approximately half of those with AFP >1000 ng/mL experiencing post-LT recurrence. Therefore, patients with AFP >1000 are not eligible for LT in the United States until their AFP decreases to <500 ng/mL with local-regional therapy (LRT) or systemic therapy. In combining tumor size and number with AFP, many selection criteria, including the Metroticket 2.0 calculator,1 French AFP model,2 and the New York/California score3 (Table 1) incorporate radiographic and biochemical response to LRT to predict post-LT outcome more accurately than relying on tumor burden alone. AFP is not the only notable HCC biomarker, with both des-γ carboxyprothrombin (DCP) and lectin-reactive alpha-fetoprotein % gaining renewed attention recently. In the first western prospective experience with these 3 biomarkers tested prior to LT,5 DCP and lectin-reactive alpha-fetoprotein % outperformed AFP in terms of recurrence prediction with C-statistics of 0.81 and 0.86, respectively, compared with 0.74 for AFP. Most notably, those exceeding a dual-biomarker threshold of lectin-reactive alpha-fetoprotein %≥15% and DCP≥7.5 had<50% 3-year post-LT recurrence-free survival compared to>90% in the remainder. TABLE 1 - Summary of proposed pretransplant selection criteria Pre-LT selection model Tumor burden Biomarker(s) Additional criteria 5-y post-LT overall survival AUROC US National Policy Milan or downstaged to Milan AFP>1000 ng/mL reduced to <500 — 80% — French AFP Model Size and number (lowest risk: largest tumor ≤3 cm and ≤3 tumors) AFP (lowest risk:≤100 ng/mL) — 68% if AFP model≤2 vs.47% if AFP model>2 0.70 Metro-Ticket 2.0 Tumor number + size of largest tumor AFP — — 0.72 TTV-AFP Model Total tumor volume ≤115 cm3 AFP ≤400 ng/mL — 75% (at 4 y) for those>Milan but within TTV-AFP 0.80 NYCA Score Size and number (lowest risk: single tumor ≤3) AFP response (based on max and last AFP) — 5-y RFS: 90% low risk 80% acceptable risk60% high-risk 0.73 Extended Toronto Criteria No limit — (1) Bx of largest tumor w/ poorly diff excluded(2) No cancer-related sx 68% for those >Milan but within ETC — Hangzhou Criteria Total tumor diameter <8 cm AFP ≤400 ng/mL >8 cm TTD allowed if not poor tumor diff 75% for those within Hangzhou Criteria — Pre-MORAL Largest tumor size (lowest risk:≤3 cm) AFP (lowest risk:<200 ng/mL) NLR (lower risk<5) 5-y RFS: 99% low risk 70% medium-risk56% high risk 0.82 HALT-HCC Hypotenuse between tumor number and largest tumor size lnAFP MELD-Na — 0.61 Medanta India (LDLT) UCSF expanded criteria AFP <100 ng/mL Negative 18F-FDG-PET scan 5-y RFS: 89% low risk 71% medium-risk41% high-risk 0.72 MoRAL (LDLT) No limit AFP , DCP — 83% for those >Milan but low MoRAL score 0.84 National Cancer Center Korea (LDLT) Total tumor diameter <10 cm — Negative 18F-FDG-PET scan 84% (vs. 60% in those exceeding criteria) 0.80 Kyoto/Japanese Criteria (LDLT) ≤10 tumors, largest tumor ≤5 cm DCP≤7.5 ng/mL — 82% (vs. 42% in those exceeding criteria) tumor #: 0.68 size: 0.64DCP: 0.71 Abbreviations: AFP, alpha-fetoprotein; DCP, des-γ carboxyprothrombin; ETC, Extended Toronto Criteria; FDG, fluorodeoxyglucose; HALT-HCC, hazard associated with liver transplantation for HCC; LDLT, living donor liver transplant; LT, liver transplantation; MELD, Model for End Stage Liver Disease; MoRAL, model of recurrence after liver transplant; NLR, neutrophil-to-lymphocyte ratio; NYCA, New York/California; RFS, recurrence free survival; sx, symptoms; TTD, total tumor diameter; TTV, total tumor volume; UCSF, University of California, San Francisco. Selection criteria for patients with HCC may be different in LDLT than DDLT in selected cases provided there is no extrahepatic disease and/or macrovascular invasion with prior HCC consensus conferences proposing a minimum 5-year post-LDLT survival threshold of at least 50%–60%. Multiple Asian centers that primarily perform LDLT have successfully liberalized tumor burden criteria beyond Milan criteria in large part by relying heavily on tumor biomarkers and/or 18F-FDG-PET (18F-labeled fluoro-2-deoxyglucose positron emission tomography) scan (Table 1). Examples include the Kyoto/Japanese criteria where patients with <10 tumors, largest tumor size<5 cm, and DCP<7.5 ng/mL have 5-year post-LDLT survival exceeding 80% compared to 40% in those exceeding these criteria.6 More recently, Bhangui et al7 showed that patients with HCC with no or just one poor prognostic factor (AFP>100 ng/mL, intrahepatic 18F-FDG-PET positive, beyond University of California, San Francisco criteria) had<10% expected post-LDLT recurrence compared to nearly 50% recurrence in patients beyond University of California, San Francisco expanded criteria with AFP>100 ng/mL or in those with all 3 poor prognostic factors. UPDATES IN TUMOR DOWNSTAGING While the utilization of LDLT for HCC in certain parts of the world has allowed for expanded selection criteria, organ shortages in the US with longer wait times have led to the widespread use of neoadjuvant treatments (including LRT and systemic therapy) as a bridge to control tumor growth. In patients with HCC initially exceeding Milan criteria, downstaging is defined as a reduction in tumor burden using LRT to meet conventional LT criteria. It has been proposed that only patients with adequate hepatic function (eg, Child’s class A/B, bilirubin<3–4 mg/dL) should undergo attempted downstaging since declining liver function after LRT can limit future treatment options and shorten survival. Tumor response to downstaging treatment(s) should be based on the size of only viable tumors, with those with complete or partial response presumably having more favorable tumor biology. Accordingly, post-LT outcomes after successful downstaging have not been significantly different from those always within Milan when prespecified upper limits of tumor burden are employed.4 In a systematic review of nearly 1000 patients across 13 eligible studies not limited to tumor size or number, downstaging had a pooled success rate of 0.48 and a pooled post-LT HCC recurrence rate of ~15%.8 In 2017, United Network for Organ Sharing implemented standardized downstaging tumor criteria (UNOS-DS; Table 2) with successfully downstaged patients eligible for automatic priority LT listing. TABLE 2 - Down-staging (DS) protocols in patients with HCC presenting beyond Milan criteria “UNOS-DS” CRITERIA “BEYOND UNOS-DS” CRITERIA Inclusion Criteria 1. HCC exceeding UNOS T2 criteria but meeting one of the following: a. Single lesion ≤8 cm b. 2 or 3 lesions each ≤5 cm with the sum of the maximal tumor diameters ≤8 cm c. 4 or 5 lesions each ≤3 cm with the sum of the maximal tumor diameters ≤8 cm2. Absence of vascular invasion or extra-hepatic disease based on cross-sectional imaging3. Child’s A/B cirrhosis with total bilirubin<3–4 mg/dL 1. HCC exceeding UNOS-DS by any of the following: a. HCC tumor number b. HCC tumor size c. Total HCC tumor diameter2. Absence of vascular invasion or extrahepatic disease based on cross-sectional imaging3. Child’s A/B cirrhosis with total bilirubin<3–4 mg/dL Criteria for successful downstaging Residual tumor(s) within Milan criteria; complete tumor necrosis recommended 1. Only viable tumor(s) are considered; tumor diameter measurements should not include the area of necrosis from local-regional therapy. 2. If there is more than one area of residual tumor enhancement, then the diameter of the entire lesion should be counted toward the overall tumor burden Criteria for downstaging failure and exclusion from liver transplant 1. Progression of tumor(s) beyond inclusion criteria for downstaging based on tumor size and number 2. Any evidence of extrahepatic, lymphatic or vascular tumor spread 3. AFP≥1000 ng/mL; unless the AFP level decreases to<100–500 after local-regional therapy 1. Progression of tumor burden beyond Milan criteria after initial successful downstaging2. Development of any new HCC lesion(s) (not including residual/recurrent disease at previous LRT site) on case-by-case basis3. Any evidence of extrahepatic, lymphatic, or vascular tumor spread4. AFP≥1000 ng/mL; unless the AFP level decreases to<100–500 after local regional therapy Abbreviations: AFP, alpha-fetoprotein; LRT, local-regional therapy; UCSF, University of California, San Francisco; UNOS-DS, United Network for Organ Sharing Downstaging. The most common downstaging modalities are transarterial, most notably Y-90 radioembolization and chemoembolization. A recent multicenter prospective study9 showed >80% probability of successful downstaging from UNOS-DS criteria into Milan criteria with no differences in radiographic response or waitlist outcome between transarterial chemoembolization and transarterial radioembolization as the first downstaging treatment. While patients who undergo TARE had a higher proportion with completely necrotic tumor(s) (31% vs. 21%) and a lower proportion with explant tumor beyond Milan criteria (23% vs. 43%) and microvascular invasion (8% vs. 21%) compared to transarterial chemoembolization, these findings were not significantly different. Another recent multicenter downstaging prospective trial10 confirmed the substantial survival benefit of LT after downstaging with 4-year post-LT survival of 80% compared to only 40% for those randomized to non-LT therapy after successful downstaging. Unfortunately, liberalizing downstaging criteria beyond UNOS-DS criteria results in a lower rate of successful downstaging with higher waitlist dropout and worse post-LT survival.4,11 Given the tremendous advancement in HCC systemic therapies, centers have begun introducing systemic therapy after initial successful downstaging (or if LRT alone does not achieve downstaging) (Figure 1) to potentially allow for curative therapy (ie, LT) in this relatively small subset of patients with HCC who otherwise has poor expected survival. It will be critical to ensure acceptable post-LT graft and patient survival, especially given concerns surrounding the use of pre-LT immunotherapy coupled with inferior post-LT survival to date in this higher-risk population.4FIGURE 1: Proposed incorporation of systemic therapy into LT down-staging after local-regional therapy in high-risk patients. Reprinted with permission from Mehta et al.12 Abbreviations: CP, Child-Pugh; LT, liver transplantation; LRT, local-regional therapy; UNOS-DS, United Network for Organ Sharing Downstaging.HCC ORGAN ALLOCATION AND FUTURE DIRECTIONS In the face of organ shortages, ranking patients with and without HCC on the same waitlist has been challenging, especially since the sickest-first principle (ie, Model for End Stage Liver Disease score) is used for patients without HCC while patients with HCC often have compensated liver disease but can experience waitlist dropout due to tumor progression. Multiple policy changes since 2013 have standardized uniform HCC diagnostic criteria and attempted to equalize waitlist and post-LT outcomes for patients with and without HCC (Figure 2). Organ Procurement and Transplant Network and Liver Imaging Reporting and Data System classification are now largely aligned with Organ Procurement and Transplantation Network/Liver Imaging Reporting and Data System 5 lesions (ie, definite HCC) eligible for automatic MELD exception after a 6-month wait period for T2 HCC (single LR5 lesion 2–5 cm or 2 or 3 LR5 lesions 1–3 cm) or after successful downstaging from UNOS-DS to within Milan criteria. In response to significant geographic disparities in LT access, patients with HCC now receive a fixed score of 3 points lower than the median MELD at transplant based on a concentric circle around the donor hospital.FIGURE 2: United Network for Organ Sharing (UNOS) HCC policy timeline, including proposed future changes. Boxes shaded in gray denote historical policies; boxes in white reflect current policy. Reprinted with permission from Singal et al.13 Abbreviations: AFP, alpha-fetoprotein; MELD, Model for End Stage Liver Disease.While these policies have largely been successful, all listed patients with HCC continue to receive the same priority for LT despite significant heterogeneity. For example, those with favorable tumor characteristics (eg, single lesion 2–3 cm with complete response to LRT and AFP<20 ng/mL) and compensated liver disease have extremely low LT urgency but receive the same priority as a decompensated patient with multifocal HCC within Milan who has a much higher risk of waitlist dropout.14 For this reason, continuous distribution policy is being considered at a national level to vary priority based on multiple factors that influence waitlist and post-LT survival to prioritize those with the largest transplant survival benefit.

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