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

risk factors were shown to have no benefit from LT, and that accounted for 19.2% of the study population. This
study has introduced the concept of ITT benefit for transplantation that can stratify patients towards a more
effective allocation system.

In a separate study that included patients registered at the SRTR database (n = 6478), a total tumour volume
[19]
3
(TTV) ≥ 115 cm and AFP > 400 were independent predictors of survival . After combining the two variables,
3
with patients being beyond criteria if they had either TTV ≥ 115 cm or an AFP > 400, the composite score ef-
ficiently predicted overall survival (HR 2, 95% CI: 1.7-2.4, P < 0.001).
A prospective validation of the proposed criteria was subsequently performed on 233 patients transplanted in
3
3 different centres. Patients with an AFP > 400 ng/mL and TTV > 115 cm were excluded from LT. Although
the risk of drop out was higher in patients within TTV/AFP but beyond Milan criteria, a similar recurrence
(9.4 vs. 4.4, P > 0.05) and survival rate (74.6% vs. 78.7%, P > 0.05) was demonstrated between the two groups. To
account for the higher drop out and worse ITT survival in the TTV/AFP groups, the proposed listing criteria
[9]
are recommended to centres with waiting time of 8 months or more .
A retrospective single centre study that included 137 recipients with more than 50% of the total patient number
being beyond Milan or University of California San Francisco criteria at pre-transplant imaging, showed that
tumour number > 3 based on explant findings, AFP level ≥ 400 ng/mL, microvascular invasion and rejection
[20]
needing anti-lymphocytic antibodies were independent predictors of recurrence .

Another study from China has also confirmed that AFP ≥ 400 ng/mL is independently associated with
adverse outcomes. Based on prognostic stratification, the Hangzhou criteria were proposed, based on which,
patients with total tumour diameter less than or equal to 8 cm, or total tumour diameter more than 8 cm, with
histopathologic grade I or II and preoperative AFP level less than or equal to 400 ng/mL simultaneously, were
[21]
shown to have favourable post-transplant outcomes .

Several other studies have reported on different AFP values as predictors of recurrence in the recent literature.
This includes a study that included 101 patients from a single centre in the U.S. showed that AFP > 100 ng/mL
(OR = 5.0, 95% CI : 1.23-29.71, P = 0.006) and tumour size on explant (OR = 4.1, 95% CI : 1.2-13.5, P = 0.013)
[22]
were associated with microvascular invasion and post-LT recurrence . Another single centre study including
140 HCC patients confirmed the validity of AFP > 100 ng/mL as cut-off value in predicting the risk of post-
LT recurrence, in patients meeting the San Francisco or up-to-seven criteria (Warsaw criteria) . The authors
[23]
have shown that the expanded proposed criteria increased the transplant eligibility rate by 20.3% without
compromising post-transplant outcomes.

A multi-centre Korean study that included 688 patients with advanced HCC (beyond Milan criteria on explant)
or far advanced HCC (defined as maximum tumour diameter ≥ 10 cm, 10 or more nodules, or accompanying
macro-vascular invasion) has shown that both AFP and the biomarker prothrombin induced by vitamin K
absence or antagonist-II (PIVKA-II) were significant risk factors for recurrence . In particular, a sum of AFP
[24]
plus PIVKA-II < 300 was a better predictor than either marker alone and can provide valuable information on
tumour biology and behaviour in advanced HCCs.

Finally, a single centre study of 250 Korean patients has shown that patients with AFP > 400 ng/mL had
[25]
significantly worse disease-free and overall survival . On discriminative analysis; a cut off value of 54 ng/mL was
significantly associated with disease recurrence, whereas cut-off value of 105 ng/mL was a better discriminator
[25]
of overall survival .
Table 1 summarises the studies that have evaluated different cut-off values of AFP as significant predictors of
recurrence and survival following LT.