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Page 2 of 17 Chan et al. Hepatoma Res 2018;4:5 I http://dx.doi.org/10.20517/2394-5079.2017.49

and treatment, prognosis of liver cancer remains poor. In 2012, World Health Organization estimated the
[1]
incidence-to-mortality ratio of liver cancer to be as high as 95% .

One of the major challenges in treating HCC is its heterogeneity and complexity. In contrast to other
cancers, the prognosis of HCC not only depends on the tumor load, but also on the underlying etiology
as well as the remaining liver reserve. Multiple staging systems have been proposed in the management of
HCC. Many of them classify the patients into three groups. The first group of patients are those with the best
prognosis, with little tumor burden and good liver reserve. They are often offered treatment with curative
intent. The second group represents those patients with advanced disease of which tumor load is high
and liver reserve is poor. These patients have very few treatment options and are offered systemic therapy,
enrollment into clinical trials or supportive treatment.

The third group is the intermediate group which includes patients who do not fulfill the criteria of the first
and second group. They have high tumor burden yet with relatively good liver reserve, and are potential
candidates for multiple or combination of therapies, some of which can be with curative intent. This is the
group which is made up of the most heterogeneous patient population, and hence it remains a challenge to
devise the best therapeutic strategy for them.

In this review, the latest therapeutic options for this heterogeneous, high-tumor burden group of HCC
patients will be discussed. Firstly, we will define our target population of high-burden HCC based on the
size, the number of tumors, and the presence of portal vein invasion. Secondly, we will outline the various
therapeutic options available and evaluate their impact on survival. Thirdly, we will briefly discuss the
etiological adjunctive treatment for high-burden HCC. Finally, we will summarize the future directions in
the management of high-burden HCC.

DEFINITION
Multiple factors have been identified to affect the survival rates of patients with HCC. While many of
them are surrogate markers of liver reserve, a few anatomical factors have also been found to persistently
[2-4]
affect prognosis , including the size, the number of tumors and the presence of portal vein invasion.
The application of these anatomical factors is important because it affects the choice of optimal treatment
modalities.

Historically, large HCC is defined as tumors of size ≥ 5 cm, owing to the poor efficacy of radiofrequency
ablation in managing HCC beyond that size. This is also the cutoff used in the Barcelona Clinic Liver
Cancer (BCLC) staging system to classify tumors which are not amenable to curative treatment. Multiplicity
of tumor is usually defined as number of tumors ≥ 3, and the higher number of tumors means curative
treatment would unlikely be successful. Portal vein invasion is another important poor prognostic indicator,
not only because it indicates an advanced disease, it would also limit the number of feasible treatment
options. According to BCLC, portal vein invasion is a contraindication for transarterial chemoembolization
(TACE). As a result, only systemic therapy and best supportive care are feasible options for this group of
patients.

The focus of our discussion will be on treatment options available to high-burden HCC, which we define
as HCC satisfying the following criteria: (1) presence of any tumor of size ≥ 5 cm; (2) number of tumors
≥ 3; (3) presence of portal vein invasion; and (4) without extrahepatic metastasis. This group of patients were
traditionally considered to carry a grim outlook but recent treatment advancements have improved their
prognosis.

TREATMENT OPTIONS FOR HIGH-BURDEN HCC
In the literature, a plethora of therapeutic options are available for high-burden HCC. These include surgery,
TACE, transarterial radioembolization (TARE), radiotherapy (RT) and systemic therapy. The choice of