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Page 2 of 10 Carr. Hepatoma Res 2019;5:3 I http://dx.doi.org/10.20517/2394-5079.2018.113

INTRODUCTION
The prognosis of hepatocellular carcinoma (HCC) depends on multiple factors, hence the large number
of staging systems. In particular, it depends on the size and location within the liver of the HCC and the
number of HCC nodules, the presence and degree of portal venous invasion, the presence or absence of
[1]
distant metastases, as well as the degree of liver damage (Child-Pugh class) . Patients with a single tumor
[2]
nodule of < 2 cm have the best prognosis and larger size and number of nodules have worse prognosis . T1
lesions are single < 2 cm lesions without portal vein thrombosis (PVT). T2 lesions are > 2 cm to 5 cm, single
or multiple, as well as single lesions > 2 cm with vascular invasion. T3 lesions are multiple, with at least one
being > 5 cm. The best survival outcomes occur after treatment with ablation, resection or transplantation,
[3]
in patients having Barcelona Clinic Liver Cancer staging system (BCLC) 0 stage (single < 2 cm) or early
stage A (1-3 nodules, any < 3 cm with good liver function Child-Pugh class A or early class B cirrhosis). All
other patients, who have BCLC stages B (multinodular of any size) or stage C (presence of PVT, lymph nodes
or metastases), cannot be offered therapies with curative intent, and constitute the majority of HCC patients
who are diagnosed in the absence of a surveillance program and whose treatment is the subject of this
[4]
review. This constituted at least 65% of newly diagnosed HCC patients in our large series [Table 1].
The main treatment modality for these BCLC intermediate stage B patients has been for many years
chemoembolization [transarterial chemoembolization (TACE)]. More recently, selective internal radiation
therapy (SIRT) or transarterial radioembolization (TARE) has been increasingly seen as a promising
treatment approach in this setting, in many institutions. For stage C patients having either or both PVT or
metastases, systemic therapy is widely used, involving multikinase inhibitors such as sorafenib, although
immune checkpoint inhibitors and newly-approved multikinase inhibitors are changing that landscape.
Furthermore, in addition to sorafenib, radioembolization is increasingly considered as both useful and safe
(unlike much TACE) in the presence of branch PVT. This review summarizes each of the major treatment
modalities for patients who are not suitable for treatments with curative intent and then summarizes current
clinical practice and finally evaluates some likely future directions in this rapidly moving field.

NON-SURGICAL TREATMENT MODALITIES
Current first line therapies
Chemoembolization or TACE
Several reviews have been published on the chemotherapy drugs and types of embolization particles that
[4,5]
have been used for chemoembolization or TACE . Objective partial responses have been reported in
[4]
30%-60% of patients , and an increase in survival was initially reported in 2 randomized placebo-controlled
trials, using doxorubicin or cisplatin, respectively [6-8] . Due to its relative safety, especially in patients
with Child-Pugh A and many with Child-Pugh B cirrhosis and tumors of almost any size and number,
it has been a standard of therapy for non surgical and non metastatic HCC for several decades. A wide
range of chemotherapeutic agents have been used, but there has not been an analysis of which agents, or
combination of agents, nor of which of multiple embolization particle types might be optimal, although
[9]
doxorubicin, cisplatin or mitomycin C, often mixed with lipiodol, are most commonly used , or with
defined size embolization particles. Recently, drug-eluting beads have become popular, but their superiority
[10]
for survival to plain and cheaper particles has been disputed , although they may be safer. TACE has
[11]
been combined with radiofrequency invasion for enhanced results and has also been used as bridging
[12]
therapy to transplant . Current trials are in progress to assess improved efficacy of TACE when combined
with multikinase inhibitors [13,14] or immune checkpoint inhibitors. TACE has been considered the standard
[15]
therapy for non surgically treatable HCC , with SIRT being also widely adopted as an alternative standard.
SIRT
TARE with SIR-Spheres or Transarterial radiotherapy with Therasphere [Table 1].