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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
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