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Chan et al. Hepatoma Res 2018;4:5 I http://dx.doi.org/10.20517/2394-5079.2017.49 Page 11 of 17

than the classically defined intermediate-stage HCC, if the optimal treatment can be chosen for this group of
patients, the impact on their survival rates can be significant. Results from various retrospective and cohort
studies in the past decade have been encouraging, providing strong support for multimodality treatment in
the management of high-burden HCC.

In this review, we showed that surgical approach to high-burden HCC, if feasible, provides the highest
median survival across all treatment modalities. Nonetheless, there has not been a large-scale RCT that
quantified its positive effect in managing high-burden HCC in direct comparison with other treatment
modalities.

In cases where surgical resection is not feasible, intra-arterial embolization is commonly adopted as an
alternative treatment modality. Thus far, studies have not been able to demonstrate a significant difference
in survival between the two available intra-arterial embolization options, TACE and TARE. Overall, TARE
appears to be superior in terms of providing a better safety profile and associating with fewer adverse
outcomes. Nonetheless, it is a novel method for HCC and expertise might only be available in selective
tertiary centers.

Advancements in irradiation technique have enabled radiotherapy to emerge as another unconventional
treatment option for high-burden HCC. Early results in 3D-CRT and SBRT have been promising but further
evidences are needed to delineate their role in managing high-burden HCC.

Targeted therapy has been in a bottleneck for treating high-burden HCC since the introduction of sorafenib.
Regorfanib, now being the second-line agent to sorafenib, is the only newer targeted agent thus far that has
been proved effective in managing high-burden HCC. On the other side, breakthroughs have been made in
immunotherapy in the past decade with promising results with nivorumab and other immunostimulating
agents. Many RCTs are underway to further establish the role of immunotherapy in managing HCC and we
expect more results to emerge in the next few years.

As majority of the HCCs are attributed from HBV or HCV infection, the use of antivirals as adjunctive
treatment is also of paramount importance. It can effectively reduce HCC recurrence and prolong survival.
Despite early studies regarding use of DAAs in the treatment of HCV-related HCC suggest higher tumor
recurrence rate, those studies have been heavily criticized of poor design. Further studies are needed to
elucidate the role of DAAs as an adjunctive treatment for HCV-related HCC.

In summary, high-burden HCC remains a difficult cancer entity to manage. Yet, multiple treatment options
are available of which optimal selection can effectively prolong survival for this group of patients. Treatment
modalities are evolving in the management of high-burden HCC and promising results from retrospective
and cohort studies are plentiful. But high-quality studies are lacking. Larger scale controlled studies with
more specific patient selection criteria are needed for various treatment modalities, to further assess and
compare the benefits of these different options.

DECLARATIONS
Authors’ contributions
Conceptualization: Chan LL, Chan SL
Literature search: Chan LL
First draft: Chan LL
Revision and final proofread: Chan LL, Chan SL

Financial support and sponsorship
None.