What Are the Optimal Liver Transplantation Criteria for Hepatocellular Carcinoma?

Watch a video presentation of this article

Watch the interview with the author

Abbreviations

AFP

alpha‐fetoprotein

AUROC

area under the curve of the receiver operating characteristic

DCP

des‐γ carboxyprothrombin

ETC

extended Toronto criteria

¹⁸F‐FDG‐PET

¹⁸F‐labeled fluoro‐2‐deoxyglucose positron emission tomography

HALT‐HCC

hazard associated with LT for HCC

HCC

hepatocellular carcinoma

LDLT

live donor liver transplant

LT

liver transplantation

LRT

local‐regional therapy

MELD

Model for End‐Stage Liver Disease

MoRAL

model of recurrence after LT

mRECIST

modified Response Evaluation Criteria in Solid Tumors

NLR

neutrophil‐to‐lymphocyte ratio

TNR

tumor‐to‐nontumor ratio

TTV

total tumor volume

UNOS

United Network for Organ Sharing

As recently as 5 years ago, any discussion regarding the optimal liver transplantation (LT) criteria for hepatocellular carcinoma (HCC) would have revolved primarily around tumor size and number. However, the previous debate surrounding the Milan criteria versus expanded criteria has largely subsided for several reasons. Not only have worldwide organ shortages led to concern that expanded criteria may cause undue prejudice for those patients with even slightly better post‐LT prognosis, they have also led to longer LT wait times, which in turn has led to increased use of local‐regional therapy (LRT) as a bridge to LT. To this end, the optimal LT criteria for HCC must not only account for tumor size and number, but additional markers of tumor biology including alpha‐fetoprotein (AFP) and novel biomarkers, response to LRT, and ¹⁸F‐labeled fluoro‐2‐deoxyglucose positron emission tomography (¹⁸F‐FDG‐PET) imaging.

Transplant Survival Benefit and Identifying Patients with HCC with a Low Risk of Dropout

When outlining the optimal LT criteria for patients with HCC, it is imperative to account for transplant survival benefit, defined as a patient’s post‐LT life expectancy minus their wait‐list life expectancy. Although most HCC selection criteria have focused on the former (ensuring acceptable post‐LT life expectancy), the latter is just as important in that patients with a long wait‐list life expectancy will derive less benefit from LT. Berry and Ioannou1 found that patients with HCC derive a significantly lower 5‐year survival benefit from LT than patients without HCC. Importantly, however, the goal for LT for patients with (and without) HCC is survival well beyond 5 years, whereas wait‐list removal because of tumor progression is accompanied by poor long‐term survival. When approaching wait‐list survival to design the optimal LT criteria, both tumor and liver‐related factors should be considered. Using the European HCC and LT (EurHeCaLT) project, Lai et al.2 studied more than 2100 patients and found that Model for End‐Stage Liver Disease (MELD) score less than 13, tumor burden within Milan criteria, and complete response to LRT were all factors that decreased the survival benefit of LT. These results are similar to a previous analysis from our center3 that showed that patients with a single, small 2‐ to 3‐cm tumor and low AFP level less than 20 ng/mL who had a complete response to LRT (20% of cohort) have a very low risk of wait‐list dropout, and thus likely derive minimal short‐term benefit from LT. Finally, an analysis of the United Network of Organ Sharing (UNOS) database4 found that a combination of tumor (single lesion 2‐3 cm and AFP < 20 ng/mL) and liver‐related characteristics (Child A cirrhosis and MELD–sodium [MELD‐Na] < 15) identifies a subgroup with a low wait‐list dropout risk. Taken together, patients with compensated liver disease and relatively minimal tumor burden who have a low AFP level and complete response to LRT have a long wait‐list life expectancy, and thus optimal LT criteria should reduce (or eliminate) priority for these patients.

Serum Markers

Nearly all of the proposed pre‐LT selection criteria models have incorporated one or more serum makers in addition to various tumor size and number cutoffs. AFP has received the most attention, with a plethora of data suggesting that an elevated AFP level significantly worsens post‐LT outcome. A recent multicenter study5 and analysis of the UNOS database6 have shown that post‐LT outcome worsens beginning at an AFP cutoff of 16 to 20 ng/mL. On the other end of the spectrum, various cutoffs have been used for exclusion from LT including a more than 400 ng/mL cutoff7 and a 1000 ng/mL cutoff in the United States.8 However, the optimal LT criteria would go one step further to take into account AFP response to LRT (Table 1). In the UNOS database, for patients with an AFP ever greater than 1000 ng/mL, reduction of AFP at LT to less than 100 ng/mL after LRT results in a 5‐year survival rate of 88% compared with 67% in those whose AFP level at LT reduced to 101 to 499 ng/mL and only 49% if AFP remained greater than 1000 ng/mL at the time of LT.9 Similarly, Halazun et al.10 showed that AFP responders to LRT (e.g., AFP 200‐1000 ng/mL that decreased to <200 ng/mL with LRT) had significantly better post‐LT outcome than AFP nonresponders. Rising AFP slope of more than 7.5 to 15 ng/mL/month despite LRT also predicts poor post‐LT outcome.11, 12 Additional serum marker cutoffs associated with inferior post‐LT outcome include AFP‐L3 greater than 35%, des‐γ carboxyprothrombin (DCP) greater than 400 mAU/mL (or 7.5 ng/mL), and neutrophil‐to‐lymphocyte ratio (NLR) greater than 513, 14, 15 (Table 1), although these findings require confirmation.

Table 1.

Optimal (and Acceptable) Criteria Prior to Liver Transplant (Beyond Tumor Size and Number)

Pre‐LT Predictor	Optimal Criteria for LT	Minimal Acceptable Criteria for LT	LT Not Recommended (if Limited Organ Supply)
Biomarkers
AFP at LT (ng/mL)	<16‐20*	<400‐1000	>1000
Response to LRT if AFP ever >1000 ng/mL while awaiting LT	AFP at LT: <100	AFP at LT: 101‐499	AFP at LT: >1000
AFP slope (ng/mL/month)	<0 (i.e., decreasing AFP)	<7.5‐15	>15
AFP‐L3 (%)	<10‐15	<35	>35
DCP	<100 mAU/mL	100‐400 mAU/mL	>400 mAU/mL
	<1.2‐7.5 ng/mL
NLR	<4‐5
18F‐FDG‐PET scan	FDG‐negative	FDG‐positive but TNR < 2	FDG‐positive and TNR > 2
Radiographic response to LRT (mRECIST)	Complete response*/partial response	Stable disease	Progressive disease
Wait time from HCC diagnosis to LT	6‐18 months

^*Excluding those patients with a single, small (<3 cm), well‐treated tumor after LRT.

Response to LRT and ¹⁸F‐FDG‐PET

Although post‐LT outcome for the majority of patients within Milan criteria (excluding those with a very high AFP) are quite good, one relatively recent advance has been to better identify those patients beyond Milan criteria who will have acceptable post‐LT survival. One common strategy in such patients is tumor down‐staging, especially in the United States, where currently patients must be within Milan criteria to receive MELD exception. Although tumor progression after LRT typically portends a poor post‐LT prognosis,2, 12 complete or partial response to down‐staging treatments functions as a criterion to select those with good tumor biology, and thus likely acceptable post‐LT outcome. Single‐center and multicenter studies from UNOS Region 516, 17 have shown excellent post‐LT outcome after successful down‐staging in carefully selected patients exceeding the Milan criteria with post‐LT outcomes comparable with those always within Milan. This down‐staging protocol (Table 2) has recently become national policy in the United States. However, in patients with HCC exceeding these criteria (“all‐comers”) who undergo attempted down‐staging (Table 2), both wait‐list outcome and intention‐to‐treat survival are poor. Sinha et al.18 found an 80% probability of dropout within 3 years of HCC diagnosis for those presenting within “all‐comers” criteria, along with a 5‐year intention‐to‐treat survival rate of only 20%, suggesting that an upper limit in tumor burden probably exists beyond which successful LT after tumor down‐staging becomes an unrealistic goal.

Table 2.

UNOS Down‐Staging Protocols in Patients With HCC Presenting Beyond Milan Criteria

UNOS National Down‐Staging Protocol	UNOS Region 5 All‐Comers Protocol
Inclusion Criteria
HCC exceeding UNOS T2 criteria but meeting one of the following: Single lesion <8 cm 2 or 3 lesions each <5 cm with the sum of the maximal tumor diameters <8 cm 4 or 5 lesions each <3 cm with the sum of the maximal tumor diameters <8 cm Absence of vascular invasion or extrahepatic disease based on cross‐sectional imaging	HCC exceeding UNOS national down‐staging protocol by any of the following: HCC tumor number HCC tumor size Total HCC tumor diameter Absence of vascular invasion or extrahepatic disease based on cross‐sectional imaging
Criteria for Successful Down‐Staging
Residual tumor(s) within Milan criteria (for both deceased donor liver transplant and LDLT)
Criteria for Down‐Staging Failure and Exclusion From Liver Transplant
Progression of tumor(s) beyond inclusion criteria for down‐staging based on tumor size and number Any evidence of extrahepatic, lymphatic, or vascular tumor spread	Progression of tumor burden beyond Milan criteria after initial successful down‐staging Development of any new HCC lesion(s) (does not include residual/recurrent disease at previous LRT site) Any evidence of extrahepatic, lymphatic, or vascular tumor spread
Additional Guidelines
Minimal observation period of 3 months between down‐staging and liver transplant	Minimal observation period of 6 months between down‐staging and liver transplant
AND A patient with acute hepatic decompensation after LRT is not eligible for LT unless criteria for successful down‐staging and minimal observation period are met.

Another potential selection criterion for patients beyond Milan criteria, especially in LT centers with either short LT wait times or prior to live donor liver transplant (LDLT), is to use ¹⁸F‐FDG‐PET scans, an excellent predictor of worse tumor differentiation and microvascular invasion. FDG‐negative patients beyond Milan criteria have satisfactory post‐LT outcome,19, 20 whereas those with a tumor‐to‐nontumor ratio (TNR) greater than 2 tend to do poorly19 (Table 1).

Transplant Wait Times

Worldwide, time from HCC diagnosis to LT varies quite significantly by center and primarily depends on deceased donor organ supply versus demand, as well as how commonly LDLT is performed. In the United States, a mandatory delay of 6 months before granting MELD exception was introduced in 2015 primarily to balance access to LT for patients with and without HCC, but it may improve candidate selection as well. A minimal observation period is required to assess tumor behavior (e.g., radiographic and AFP response to LRT) to avoid transplanting aggressive tumors21 (Fig. 1). Analyses of the UNOS database have found that a short waiting time of less than 4 to 6 months is associated with worse post‐LT outcome.22 Long wait times, in contrast, could lead to more aggressive tumor biology and unnecessary wait‐list dropout. A recent multicenter study found that the optimal time from HCC diagnosis to deceased donor LT to minimize wait‐list dropout and post‐LT recurrence was 6 to 18 months (Table 1), because those who received LT outside this “sweet spot” had a 60% increased risk for recurrence within 5 years of LT (16% versus 10%).23

Figure 1.

Approach to the selection of patients with HCC for LT.

Putting it All Together: PRE‐LT Selection Models

Given the desire to increase access to LT for as many patients with HCC as possible, along with the multitude of data suggesting that many patients beyond Milan criteria have acceptable post‐LT outcome, a number of pre‐LT selection models have been proposed (Table 3). One interesting aspect regarding these criteria is that centers with longer wait times use down‐staging/response to LRT by necessity, whereas centers that primarily perform LDLT and have short wait times tend to have fairly liberal tumor burden criteria but rely heavily on biomarkers and/or negative ¹⁸F‐FDG‐PET scan. For example, the National Cancer Center Korea criteria include total tumor diameter less than 10 cm and negative PET scan, and in LDLT recipients meeting these criteria, overall survival rate at 5 years post‐LT was 84% compared with only 60% in those exceeding these criteria.20 In addition, the Kyoto criteria include those with fewer than 10 tumors, largest tumor size less than 5 cm, and DCP level less than 400 mAU/mL with 5‐year post‐LDLT survival rate of 82% compared with 42% in those not meeting these criteria.15

Table 3.

Summary of Proposed Pretransplant Selection Models That Include Criteria Beyond Tumor Size and Number

Pre‐LT Selection Model	Tumor Burden	Biomarker(s)	Additional Criteria	5‐Year Post‐LT Overall Survival	AUROC
US National Policy8	Milan or down‐staged to Milan	AFP > 1000 ng/mL reduced to <500 ng/mL		80%
French AFP model24	Size and number (lowest risk: largest tumor ≤ 3 cm and ≤3 tumors)	AFP (lowest risk: ≤100 ng/mL)		68% if AFP model ≤ 2 versus 47% if AFP model > 2	0.7
Metro‐Ticket 225	Tumor number + size of largest tumor	AFP			0.72
TTV‐AFP model7	TTV ≤ 115 cm3	AFP ≤ 400 ng/mL		75% (at 4 years) for those beyond Milan criteria but within TTV‐AFP	TTV: 0.8
ETC26	No limit		Biopsy of largest tumor with poorly differentiated excluded No cancer‐related symptoms	68% for those beyond Milan criteria but within ETC
Pre‐MoRAL14	Largest tumor size (lowest risk: ≤3 cm)	AFP (lowest risk: <200 ng/mL)	NLR (lower risk <5)	5‐Year recurrence‐free survival: 99% low risk 70% medium risk 56% high risk	0.82
HALT‐HCC27	Hypotenuse between tumor number and largest tumor size*	Natural log (ln) AFP	MELD‐Na		0.61
MoRAL28 (LDLT)	No limit	$\sqrt{\mathrm{AFP}},\sqrt{\mathrm{DCP}}$		83% for those beyond Milan criteria but low MoRAL score	0.84
National Cancer Center Korea20 (LDLT)	Total tumor diameter < 10 cm		Negative 18F‐FDG‐PET scan	84% (versus 60% in those exceeding criteria)	0.80
Kyoto criteria15 (LDLT)	≤10 tumors, largest tumor ≤ 5 cm	DCP ≤ 400 mAU/mL		82% (versus 42% in those exceeding criteria)	Tumor #: 0.68 Size: 0.64 DCP: 0.71

^*By Pythagorean theorem (A ² + B ² = C ²); for example, a patient with three lesions with the largest 4 cm would receive a tumor burden score of 5.

Summary

To maximize survival benefit, the LT community should consider reducing (or eliminating) priority for the 10% to 20% of patients with HCC with very long wait‐list life expectancy (e.g., Child‐Pugh A, low MELD and AFP, and single tumor up to 3 cm with complete response to LRT). On the other end of the tumor burden spectrum, some determination of tumor biology should be obtained in patients presenting beyond Milan criteria (in addition to AFP). Reasonable approaches include LRT for tumor down‐staging, measuring novel biomarkers such as AFP‐L3 and DCP, and PET scan. Results from the various proposed pre‐LT models (Table 3) that include such criteria have suggested that acceptable post‐LT outcome can be achieved in selected patients with HCC beyond Milan criteria. Although it is impossible to compare all of these selection models, the optimal LT criteria should be center specific, taking into account the availability of donor organs and what post‐LT outcome is considered acceptable. Centers performing primarily LDLT may be willing to accept lower 5‐year post‐LT survival rates by using less restrictive criteria than centers with significant organ shortages, where post‐LT outcome for patients with or without HCC should be similar.