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Page 2 of 13 Giovanis et al. Hepatoma Res 2018;4:10 I http://dx.doi.org/10.20517/2394-5079.2018.21

evident in areas of oncology such as breast, colon or kidney cancer where the prognosis associated with
these pathologies was only of some months few years ago, conversely therapeutic strategies allow to reach
[1]
survivals quantifiable in order of years at present time . Unfortunately, such therapeutic successes are still
challenging for patients currently receiving diagnosis of intermediate or advanced stage of hepatocellular
carcinoma (HCC), because of the restricted efficacy for systemic therapies. Such difficulty in finding an
active systemic therapy is strictly related to the biology of HCC: differently than other oncological diseases,
the primary malignancy of the liver occurs predominantly in patients with two diseases: the tumor and the
[3]
underlying cirrhosis . Therefore, if the single drug can slow down the oncological progression, the same
[3,4]
drug may worsen the cirrhotic component of HCC leading the patient towards to exitus .

Systemic therapies in liver cancer achieved the first important goal in 2007 when the introduction of the
target agent sorafenib provided a therapeutic option for patients with HCC in progression or evaluated
[5,6]
not suitable for locoregional treatments . After this initial success, a sense of nihilism persisted in the
oncology community in the subsequent decades due to failure of the new studies with molecular targeted
agents to demonstrate a benefit in OS or time to tumor progression (TTP) or progression-free survival
(PFS). Phase 3 trials failed to show superiority of sunitinib, erlotinib plus sorafenib, FOLFOX, doxorubicin,
[6]
or non-inferiority of brivanib, linifanib to sorafenib in the first-line setting . Similarly, the drugs brivanib,
everolimus, linifanib, ramucirumab and tivantinib failed pivotal studies designed in second-line settings in
[6]
patients progressing or intolerant to sorafenib .
In this depressing scenario a turning point was reached very recently, after the announcement of positive
results of the phase 3 studies conducted with new biological therapies. The first drug showing to prolong
[7,8]
the overall survival sequentially to sorafenib was regorafenib . After short time, lenvatinib resulted non-
[7]
inferior to sorafenib in the first line of treatment , cabozantinib showed efficacy after sorafenib progression
[9]
or in patients with intolerance to this drug , and nivolumab received conditioned FDA approval for
[10]
patients pretreated with sorafenib . At the same time, the experience with sorafenib in HCC after many
years increased outcomes in survival due to better patient selection and better adverse events management,
encouraging the medical community to pursue excellence in disease management with this mature
drug [11,12] .

The goal of this paper is to take stock the situation regarding systemic drugs evaluated in the intermediate
and advanced HCC setting. We focused only on therapies which achieved positive results in phase 3 trials
or an early approval by health authorities after phase 1/2 conducted, and we tried to position every therapy
according to data nowadays available.

RADICAL THERAPIES VERSUS SYSTEMIC TREATMENTS
Radical therapies are the most frequently used treatment in HCC and are represented by surgical resection,
liver transplantation and the local destruction methods known as loco-regional therapies. These are able
to turn out to the radical destruction of the tumor but they have never demonstrated to prolong OS in
prospective phase 3 studies conducted on HCC populations with intermediate or advanced stage [13-15] .
Therefore, current evidence indicates that potentially curative treatments result only for very early- and
early-stage HCC.

The surgical treatments transplantation and resection are evaluated as potentially curative in early stages of
the disease for carefully selected HCC patients, but are usually discouraged in advanced phases due to the
[15]
high risk of hepatic decompensation and neoplastic progression in the frame time awaiting surgery .
The BCLC algorithm reported transarterial chemoembolization (TACE) as the first-line treatment for the
intermediate stage in HCC patients, however TACE may have high recurrence rates and should therefore not