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Page 4 of 13 Giovanis et al. Hepatoma Res 2018;4:10 I http://dx.doi.org/10.20517/2394-5079.2018.21

Table 3. Primarily International Guidelines and level of evidence associated to radioembolization
Guidelines Recommendation Level of recommendation
ESMO 2012 [65] Radioembolization may be competitive with sorafenib or TACE in subsets of patients, such Category III, C
as those with prior TACE failure, excellent liver function, macrovascular invasion and the
absence of extra-hepatic disease

Current phase 3 studies are evaluating the place of radioembolization versus TACE in
patients with intermediate stage HCC, and as single modality or combined with sorafenib in
patients with advanced HCC compared with sorafenib
AASLD 2010 [66] Radioembolization with Yttrium90-labeled glass beads has been shown to induce extensive Level II
tumour necrosis with acceptable safety profile. However, there no studies demonstrating an
impact on survival and hence, its value in the clinical setting has not been established and
cannot be recommended as standard therapy for advanced HCC outside clinical trials
TACE: transhepatic arterial chemoembolization; HCC: hepatocellular carcinoma

Table 4. Efficacious systemic therapies for HCC
Study Arms OS benefit HR Adverse events (Grade 3-4)
(months)
1st line setting SHARP [5] Sorafenib vs. 10.7 (vs. 7.9) 0.69 Hand-foot skin reaction (8%), diarrhoea (8%), fatigue (3),
placebo hypertension (3%)
ASIA PACIFIC [26] Sorafenib vs. 6.5 (vs. 4.2) 0.68 Hand-foot skin reaction (11%), diarrhoea (6%), fatigue (3%)
placebo
SELECT [55] Lenvatinib vs. 13.6 (vs. 12.3) 0.92 Hypertension (23%), increased blood bilirubin (7%), proteinuria
sorafenib (6%), elevate aspartate aminotransferase (5%)
2nd line setting RESORCE [50] Regorafenib 10.6 (vs. 7.8) 0.63 Hypertension (15%), hand-foot skin reaction (13%), fatigue (9%),
vs. placebo diarrhoea (3%)
CELESTIAL [58] Cabozantinib 10.2 (vs. 8.0) 0.76 Hand-foot skin reaction (17%), hypertension (16%), increased
vs. placebo aspartate aminotransferase (12%), fatigue (10%)
CheckMate Nivolumab 15.6 - Increased aspartate aminotransferase (18%), increased alanine
040 [59] single arm aminotransferase(11%), increased blood bilirubin (7%), immune-
(expansion mediated hepatitis (5%)
cohort)

were conducted in patients with intermediate or advanced HCC no longer susceptible to TACE [24,25] . Both
trials failed to demonstrate a survival benefit from transarterial radioembolization compared with sorafenib.
Moreover, the median overall survival of patients treated with TARE resulted lower than sorafenib. In
addition, in both studies a significant proportion of patients randomized to TARE never received the
planned therapy (26.5% and 28.6% of patients of TARE arm vs. 7% and 9.0% in the sorafenib arm respectively
in SARAH and SIRVENIB). This may suggest difficulties in selecting patients and implementing TARE
procedure in clinical practice.

Worth to be mentioned is that these studies demonstrated only the inferiority of TARE to systemic
treatment and not the non-inferiority. In fact, in study designs the hypothesis of non-inferiority had not been
prespecified in the protocol.

SYSTEMIC TREATMENTS FOR HCC
Table 4 reports the efficacious systemic therapies in intermediate and advanced stage of HCC, estimated as
therapies achieving successful in phase 3 trials or early approved by health authorities accounting for phase
2 data. A summary of the main studies currently available are described in this section.

Sorafenib
Sorafenib is an oral multikinase inhibitor that has antiangiogenic, anti-proliferative, anti-metastatic and
anti-immunosuppressive activities. Sorafenib inhibits the activity of targets present in the tumour cell
(CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2, VEGFR-3,
and PDGFR-ß). RAF kinases are serine/threonine kinases, whereas c-KIT, FLT-3, VEGFR-2, VEGFR-3, and