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Page 10 of 19 Marasco et al. Hepatoma Res 2020;6:33 I http://dx.doi.org/10.20517/2394-5079.2020.01

More than a dozen staging systems have been described and some have been put into clinical practice for
either HCC prognostication or as treatment guidelines [193] . Amongst them, the Cancer of the Liver Italian
Program (CLIP) score (takes into account liver function reserves and tumor characteristics), and the ALBI-
CLIP grade (consisting of a formula based on albumin and bilirubin) were good predictors of survival up
to 2-years after TACE [145,146] . The CLIP system was superior to the Okuda system for predicting the survival
of patients with unresectable HCC treated with TACE [194] . MELD is inferior to the Child-Pugh system in
predicting patient survival in those with unresectable HCC after TACE [195] . Instead, the CLIP and MELD
systems are superior to the Okuda system in predicting the survival of patients with viral hepatitis and
unresectable HCC treated with TACE [196] . A nomogram based on AFP, IGC15, portal vein invasion, tumor
capsule, AST and the tumor number has been developed and validated in a precise prognostic model in
patients treated with TACE for unresectable HCC [197] . Finally, sarcopenia has also been correlated with
[76]
disease-free survival and poorer OS in patients with HCC . Recently, the rate of change (< -4.6%) in skeletal
muscle mass (ΔL3 SMI) over six months after TACE has been associated with a poor prognosis [164] . Venous
ketone bodies, which mirrors muscles status and hepatic reserve function, has been negatively correlated
with survival and is thus, a useful predictor of HCC treatment response and prognosis [198] .

Molecular and genetics biomarkers
It has been reported that some patients have developed resistance to chemotherapy drugs in which efficacy
becomes greatly reduced and toxicity to normal hepatocytes has grown. Therefore, molecular biomarkers
capable of predicting treatment response have been studied to improve chemotherapy efficacy.

Many single nucleotide polymorphism (SNP) have been evaluated as an independent prognosis biomarker
for HCC after TACE treatment. The main recently studied SNPs were: SNP rs1126497 in the epithelial
cell adhesion/activating molecule (EPCAM) gene [199] , multidrug resistance gene 1 (MDR1) C1236T and
C3435T [200] , isocitrate dehydrogenase (IDH) gene [201] , polypeptide N-Acetylgalactosaminyltransferase 14
(GALNT14) “TT” genotype [202] and pri-let-7a-1 [203] . Moreover, recently a TACE-specific 14-gene signature
has been independently related to early disease-free survival and OS in an Asian cohort of HCC patients and
further validated in a European cohort [204] .

MicroRNAs in circulating blood have also been studied as prognostic markers in HCC [149,150] .

Imaging predictive factors
There is a notion that imaging techniques (ultrasound, CT and MRI) might facilitate the visualisation
and characterization of HCC nodules clearly and accurately. Additionally, it may also aid in displaying
perfusion differences between residual carcinoma and necrotic tissue following TACE ablation. Ultrasound
techniques, mainly contrast-enhanced ultrasound, can act as a valuable tool to assess the results of TACE
and exhibit mostly optimal effects in the early and very early evaluation of TACE [153,205] . More recently,
Xuan et al. [138] showed that four contrast-enhanced ultrasound parameters prior to TACE, including time
to peak, maximum tumor intensity, washout time, and rise time, were associated with the recurrence and
prognosis of HCC after TACE. Time to peak tumor reflected the structure of the blood supply in tumor
lesions and was correlated with enhanced tumor metastasis and invasion that can lead to worse survival rates
and an unfavourable prognosis [138] .

Multi-detector CT is the most commonly used imaging technology for assessing therapeutic response to
TACE [154,156] . Patients with hypervascular HCC (defined by an enhancement pattern on the arterial-phase
of a CT scan) were more likely to respond to TACE with a reduction in tumor size and increased survival
than patients with a less vascular tumor [139] ; it is also notable that patients with hypervascular HCCs have a
[157]
survival benefit from TACE, even if they are classified as non-responders by size criteria . Other criteria
such as higher arterial enhancement and grey-level co-occurrence matrix moments (by dynamic CT texture