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Marasco et al. Hepatoma Res 2020;6:33 I http://dx.doi.org/10.20517/2394-5079.2020.01 Page 9 of 19

TRANS-ARTERIAL CHEMOEMBOLIZATION
TACE, a direct therapy with a minimally invasive catheter, is the most commonly used interventional
radiology technique for the first-line treatment of intermediate stage (BCLC-B) and unresectable HCC [178,179] .
The TACE procedure works on the pathophysiological principle that malignant hepatic lesions receive blood
supply from the hepatic artery. Thus, the intra-arterial infusion of a cytotoxic agent followed by embolisation
of the blood vessels that feed the tumor leads to a direct cytotoxic and ischemic effect on the tumor mass.
HCC, indeed, tends to be fed entirely through the arterial supply, unlike the surrounding parenchyma
which receives most of its inflow through the portal system. During TACE procedures, a catheter super-
selectively places an emulsion of the water-soluble antitumor agent mixed usually with ethiodized oil [180] .
The effectiveness of TACE is through providing highly concentrated doses of chemotherapy to the tumor
bed, while sparing the surrounding liver parenchyma. Conventional TACE, also known as Lipiodol TACE,
consists of catheter delivery of the chemotherapeutic emulsified with Lipiodol, followed by vascular
stagnation obtained with embolisation of the particles [181] . During these procedures, the most commonly
used chemotherapy drugs are epirubicin, doxorubicin, miriplatin or cisplatin [181] . Besides conventional
TACE, other image-guided transcatheter techniques have been developed recently (chemo-lipiodolisation,
bland transcatheter embolisation and intra-arterial chemotherapy) but not recommended clinically yet [179] .
Recently, drug-eluting beads transcatheter arterial chemoembolization (DEB-TACE) has become a routinely
used locoregional treatment for unresectable HCC. DEB-TACE have the same clinical outcomes and reduced
procedure-related side effects compared to conventional transcatheter arterial chemoembolization [182,183] .
Many potential factors affecting HCC recurrence after TACE treatment have been investigated in the last
decades [Table 2].

Tumor-related factors
HCC is a hypervascular tumour such that tumour angiogenesis may be essential to its growth, invasion,
or metastasis [184,185] . The changes induced by TACE in the expression of angiogenic and invasiveness
factors [basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), urokinase-
type plasminogen activator (uPA) and mammalian chitinase-like proteins without chitinase activity (YKL-
40 -CHI3L1)] have been investigated. These markers work synergically and seem to be overexpressed
after TACE as a result of the related ischemic damage, which renders them useful for predicting treatment
response to TACE. In fact, when TACE is not adequate, a significant neoangiogenesis reaction happens,
as suggested by an increase in VEGF, uPA, b-FGF and YKL-40 following treatment, and affects patient
survival [135-138,186] . Moreover, the systemic inflammatory response [187] reflects the state of angiogenesis,
DNA damage and tumor invasion [188] . Among these, systemic immune-inflammation index [143] , aspartate
aminotransferase-lymphocyte ratio index and CRP/Alb ratio [144] are useful non-invasive biological markers
with high negative predictive values for HCC OS after TACE. As a matter of fact, tumor size and portal
invasion represent the most well-validated HCC prognostic factors after TACE treatment [132] . In 87% of
patients, the low-grade tumors (grade 0, 1, or 2) have shown encouraging long-term treatment response
(49%; stable disease or local disease progression, 13%; partial response, 38%; complete response) vs. 33% of
high-grade tumors (grade 3 or 4) (stable disease or disease progression, 67%; partial response, 33%; complete
response, 0%) after TACE [133] .

Circulating biomarkers and patients’ characteristics
Several laboratory markers have been associated with prognostic outcomes in HCC patients undergoing
TACE. AFP levels and changes [140-142] , low pretreatment platelets [189] , low baseline serum 25-hydroxyvitamin
(D25-OHD) levels [190] , high values of CRP [138] , high levels of serum gamma-glutamyl transferase [191] and high
levels of bilirubin [132] are all potentially useful biomarkers to predict the poor prognosis in patients with HCC
treated with TACE. Moreover, procalcitonin is a precursor of the hormone calcitonin and usually rises in
bacterial infections; it was recently proposed as an important prognostic factor for foretelling the prognosis
of patients treated with TACE with unresectable HCC [192] .