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Fatourou et al. Hepatoma Res 2018;4:63 I http://dx.doi.org/10.20517/2394-5079.2018.62 Page 3 of 11

[6]
similar prognostic outcomes was addressed in a study by Merani et al. . This retrospective analysis included
6817 patients that were listed with a diagnosis of HCC in the Scientific Registry of Transplant Recipients
(SRTR) in the United States and showed that downstaging to an AFP level ≤ 400 ng/mL was associated with
good survival rates and prognosis, regardless of the initial AFP level. More specifically, patients who were
successfully downstaged to AFP ≤ 400 ng/mL had a similar dropout rate (10% in both groups) and post-
transplant survival rates (89% vs. 78% at 3 years, P = 0.11) to patients with AFP levels persistently ≤ 400 ng/mL.

A strong dose-response relationship between AFP level and post-transplant outcomes was demonstrated in
a study that utilised data from the UNOS registry, that included patients (n = 45,267) who were transplanted
[15]
in the US between 2002 and 2011 . Although patients with an AFP < 15 ng/mL prior to transplantation had
similar survival rates to patients without HCC, there was a significant decrease in survival as AFP increased;
16-65 ng/mL [adjusted hazard ratio (AHR) = 1.38, 95% CI : 1.23-1.54], 66-320 ng/mL (AHR = 1.65, 95% CI : 1.45-
1.88), and greater than 320 ng/mL (AHR = 2.37, 95% CI : 2.06-2.73). In addition, patients with tumours beyond
the Milan criteria at listing had excellent post-transplant survival if serum AFP level was ≤ 15 ng/mL (AHR =
0.97, 95% CI : 0.66-1.43). This study also showed that downstaging of AFP following locoregional treatment was
[15]
associated with improved post-transplant survival and prognosis .
[12]
In a prospective study by Lai et al. , mRESIST (modified Response Evaluation criteria in Solid Tumours)
progression following locoregional treatment and AFP slope > 15 ng/mL/month, as defined by the difference
between the initial and the last pre-LT AFP value divided by the time span between the two values, were
independent risk factors of recurrence and survival. Patients within and beyond radiological Milan criteria had
similar recurrence-free and overall survival rates if they had stable disease post locoregional treatment and/
or an AFP slope < 15 ng/mL/month. Similarly, patients within the Milan criteria but with either progressive
disease or AFP slope > 15 ng/mL/month were shown to have increased recurrence rates compared to patients
[12]
within or beyond Milan criteria with no risk factors . Another retrospective study from the same group, has
shown that AFP > 400 ng/mL can result in an 8-fold increase in the risk of recurrence and a combination with
a total tumour diameter < 8 cm can result comparable 5 year survival and recurrence rates .
[16]
The predictive value of AFP slope, rather than an AFP single value alone, was also examined in a study by
[17]
Vibert et al. , which included 252 patients transplanted between 1985 and 2005, in a single centre. AFP
progression, as defined by an increase greater than 15 ng/mL monthly, was significantly associated with
reduced 5 year recurrence-free (47% vs. 74%, P = 0.01) and overall survival (54% vs. 77%, P = 0.02). In the
multivariate analysis, progression of AFP was independently associated with recurrence-free and overall
survival. Interestingly, all examined static values of AFP prior to transplantation were not correlated with
overall or recurrence-free survival. AFP progression was also significantly associated with the presence of
vascular invasion and poor histological differentiation, which suggests that it can be a valuable surrogate pre-
operative marker of unfavourable histological findings .
[17]
[11]
Another study by Hameed et al. has shown that setting a cut-off value of 1000 ng/mL as an exclusion
criteria for transplantation, would have resulted in a 20% reduction in the rate of HCC recurrence at the cost
of excluding only 4.7% of patients listed. Following this observation, our own national (United Kingdom)
Transplant guidelines have applied this cut-off level as an exclusion criterion for LT. This study has also
demonstrated a strong correlation between AFP and micro-vascular invasion, especially in patients with AFP
[11]
values varying between 300-1000 ng/mL .
A large retrospective European multicentre study intended to identify variables for selecting patients that
would have the best benefit from transplantation . AFP ≥ 1000 ng/mL, MELD ≤ 13, mRESIST progressive
[18]
or complete response and within Milan criteria were associated with a poor intention to treat (ITT) benefit
from LT. Based on these risk factors, four benefit groups were identified. Patients that met three out of four