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Page 10 of 14 Cullen et al. Hepatoma Res 2020;6:76 I http://dx.doi.org/10.20517/2394-5079.2020.69

treatment with sorafenib in LT recipients with high-risk features does not improved HCC recurrence-free
[56]
or overall survival . When used, it is crucial to be aware of reported early and severe toxicities such as
[57]
hepatotoxicity, thrombocytopenia, anorexia, fatigue, hand-foot syndrome, and diarrhea .
An ongoing phase 3 study [IMbrave150 study (NCT03434379)] is being done to compare atezolizumab
with bevacizumab combination therapy with the standard of care (Sorafenib) among a large cohort of
patients with systemic treatment-naïve unresectable HCC. Preliminary phase Ib results showed that
the proposed combination resulted in improved progression-free survival compared with atezolizumab
[58]
monotherapy and had a tolerable safety profile . Other clinical trials evaluating treatment combinations
[59]
with acceptable safety profile are currently being developed .
While promising, additional studies will be necessary to further elucidate the potential benefits of specific
immunosuppressive regimens as an adjuvant therapy after LDLT for advanced HCC.

Recurrence risk surveillance and useful prognosis tools
Tumor recurrence after LT is seen in approximately 15%-20% of HCC patients despite being within the
[54]
Milan criteria . These data are even more worrisome in patients with advanced HCC, which supports the
notion that identification of risk factors for recurrence and a proper evaluation for LT plays a pivotal role in
the management of these patients.

Risk factors related to recurrence of HCC after LT include tumor factors such as staging, vascular invasion,
differentiation, and AFP level, among others. Relevant patient factors such as obesity, viral etiology,
HCV treatment, and NAFLD are also important, as well as factors related to the transplant, including
percutaneous tumor biopsy, waiting time, bridging therapy, donor’s age, ischemia time, surgical technique,
and post-transplant immunosuppression regimen and adjuvant therapy.

There is no consensus regarding the protocol for monitoring recurrence after LT. However, important
scores have been proposed and should be taken into account when performing follow-up for these
[60]
patients .
MORAL score
[61]
The Model of Recurrence After Liver (MORAL) transplant for HCC is a score developed by Halazun et al.
at Columbia University Medical Center to predict recurrence and risk-stratification pre- and post-
operatively. Variables included in the MORAL scoring system include pre-operative NLR ≥ 5, maximum
AFP > 200 ng/mL, largest tumor size > 3 cm, grade 4 tumors, vascular invasion, largest size on path > 3 cm,
and tumor number on path > 3. The recurrence risk stratification according to Pre-MORAL score divide
the risk of recurrence in low risk (0-2), medium risk (3-6), high risk (7-10) and very high risk (> 10).

Other authors, including a group from South Korea, have published variations of this model. Their
variation was derived using PIVKA II levels and AFP to stratify risk and predict HCC recurrence and was
developed including 205 patients with HCC beyond Milan criteria undergoing LDLT. The authors found
that a low MORAL score (≤ 314.8) was associated with significantly longer recurrence-free and overall
survivals in the beyond Milan criteria group. The 5-year recurrence-free and OS rates among these patients
were 66.3% and 82.6%, respectively. They conclude that their model provides advanced prognostication and
support the idea that HCC patients beyond Milan criteria without extrahepatic metastasis and low MORAL
[62]
score might be potential candidates for LDLT .

Metroticket 2.0 model
The model for Analysis of Competing Risks of Death After Liver Transplantation (Metroticket 2.0) for
HCC is a web-based calculator recognized by the European Liver and Intestine Transplant Association