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Chan et al. Hepatoma Res 2018;4:5 I http://dx.doi.org/10.20517/2394-5079.2017.49 Page 3 of 17

therapy depends on the extent of the disease, the liver function and the patient’s performance status. Each
treatment option will be discussed individually here.

Surgery
Previously thought only to have a role in early HCC, advancement in surgical techniques have enabled
hepatic resection to become a therapeutic option for high-burden HCC. Although high quality evidence is
still lacking, many retrospective studies have provided support for hepatic resection to be a safe and effective
method in managing high-burden HCC. In fact, many Asian liver centers prefer hepatic resection, as long
as it is feasible, to other local treatment options. We will now review the recent studies published between
2007 and 2017 to give the most updated picture of the efficacy of hepatic resection in the management of
high-burden HCC [5-39] [Table 1]. Of note, few studies have examined the effect of tumor size and number of
tumors independently on survival, so we would group them together in the following discussion, with large (≥
5 cm) and multifocal tumor as one single population (large/multifocal HCC).

For patients with large/multifocal high-burden HCC treated with surgery, the median survival rate was
27.6 months, and the median 1-, 3-, and 5-year overall survival rates were 74.3%, 51.2%, and 39.2%
respectively. Among patients treated with surgery, survival was particularly favorable among those with
solitary large tumor (≥ 5 cm), with median 1-, 3-, and 5-year survival rates of 87.2%, 63.2%, and 56.1%
respectively. Large tumor size has been repeatedly reported as a poor prognostic factor for HCC. This is
consistent with the results we found in high-burden HCC treated with surgery [Table 2]: the median 1-, 3-,
and 5-year overall survival rates for huge/multifocal tumor (≥ 10 cm) were 70.0%, 45.0%, and 36.0%, whereas
those for moderately-large/multifocal tumors (≥ 5 and < 10 cm) were 73.0%, 55.1%, and 50.8% respectively.
However, it is worth noting that larger tumors do not appear to be associated with higher post-operative
mortality. The median postoperative mortality for huge/multifocal (≥ 10 cm) tumors was 2.6%, compared
with 4.3% for large/multifocal tumors.

Portal vein invasion remains to be another poor prognostic factor for HCC patients despite advancements
[40]
in treatment modalities, especially for tumors invading into the main or contralateral portal vein . Surgery
[41]
has been considered contraindicated by many institutions, including the BCLC system . However, many
studies, particularly those from the Asian centers, have reported hepatic resection to be safe and effective
for patients with portal vein invasion [28,42-58] [Table 3]. The median 1-, 3- and 5-year overall survival rates for
patients with all forms of portal vein invasion treated with surgery were 61.0%, 32.9% and 27.0% respectively.
The prognosis worsens with the degree of portal vein involvement [Table 4]. For Vp1 and Vp2 involvement,
the median 1-, 3- and 5-year overall survival rates after surgery were 69.1%, 42.2% and 38.7%, whereas for
those with main portals or the 1st branch involvement (Vp3 and Vp4), the median 1-, 3- and 5-year overall
survival rates after surgery were 52.8%, 23.4% and 14.6% respectively [Table 5].

Transarterial chemoembolization
Before the advent of intra-arterial therapy, surgery has been the mainstay of treatment for HCC. However,
less than 30% of patients were eligible for liver resection due to advanced staging of the disease [59,60] . TACE
revolutionized the treatment for high-burden HCC when it was first introduced in the early 90’s [61-65] . It
takes advantage of the differential portal and arterial contributions to the blood supply of the tumor and the
normal liver parenchyma. Normal liver parenchyma receives majority of the blood supply from the portal
vein while the tumor feeds itself mainly from the hepatic arteries. The effects of TACE are two-fold. First, it
delivers cytotoxic drugs to kill tumor cells. At the same time, by embolization of the arterial supply to the
tumor, it creates an ischemic environment while keeping the cytotoxic agents within the tumor. The overall
effect is to induce tumor necrosis via both direct poisoning and starvation.

Nowadays, TACE is the treatment of choice for unresectable high-burden HCC. The positive efficacy of
TACE has been reported in numerous case reports and retrospective studies since its introduction in