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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.
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