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Page 8 of 17                                                  Chan et al. Hepatoma Res 2018;4:5  I  http://dx.doi.org/10.20517/2394-5079.2017.49


               Table 9. Recent studies on the efficacy of transarterial chemoembolization in the management of high-burden hepatocellular
               carcinoma
                                                                      Time to   Median
                                             Number of                                   Response  Recruitment
                Year   Place     Authors              Evaluation criteria  progression   survival
                                            patients (n)                                 rate (%)  year
                                                                     (months)  (months)
                2010  European  Hilgard et al. [86]  108  EASL         10      16.4        40     -
                2010  USA     Salem et al. [89]  291  WHO              7.9     BCLC-B: 13.3   42  -
                                                                               BCLC-C: 6.0
                2010  USA     Carr et al. [90]  99    WHO              7.9     11.5        41     -
                2011  European  Sangro et al. [87]  325  -             -       12.8        -      -
                2011  USA     Salem et al. [88]  123  WHO              13.3    20.5        49     1999-2008
                2013  Italy   Mazzaferro et al. [92]  52  RECIST/WHO/EASL  11  15          40.4   2007-2009
                2013  USA     Moreno-Luna et al. [93]  61  mRECIST     -       15          51     2005-2008
                2015  Korea   Kim et al. [91]  40     mRECIST          18      -           63.8   2008-2010
                2015  Germany  El Fouly et al. [94]  44  mRECIST       13.3    16.4        37%    2009-2011

               Multiple retrospective studies, albeit small scale, have demonstrated the efficacy and safety of 3D-CRT and
               SBRT in treating high-burden HCC [54,98-109]  [Table 10]. The response rates of these two techniques ranged
               from 22% to 76.2%, and the 1-year survival rates ranged from 16.7% to 55%. Given that this group of patients
               are expected to be in much poorer conditions than those amenable to surgery or intra-arterial embolization,
               the results achieved are encouraging. However, there has been no direct comparison between 3D-CRT and
               SBRT, and variability of results was wide. Therefore, larger scale studies are needed to establish the role of RT
               in managing high-burden HCC.


               Systemic therapy
               Our definition of high-burden HCC excludes patients with extrahepatic metastasis, for whom systemic
               therapy would be the preferred option. However, even for patients without extrahepatic metastasis, when all
               the other treatment modalities fail, systemic therapy would be the last resort. In this section, we will discuss
               the systemic therapies which are applicable to high-burden HCC [Table 11].


               Targeted therapy
               Traditional systemic therapy has never been favored for a long time in treating advanced HCC due to its
               poor efficacy and the general cytotoxicity which preclude its application in this group of frail patients. It
               was only since 2008, we celebrated the introduction of sorafenib, a multikinase inhibitor, which has been
               demonstrated to prolong survival in two large randomized controlled trials [110,111] . In the SHARP trial, the
               median survival of patients with advanced disease treated with sorafenib was 10.7 months, vs. 7.9 months in
               those who received placebo (harzard ratio 0.69, 95%CI: 0.55-0.87; P < 0.001). The Asia-Pacific trial was able
               to replicate similar findings, suggesting sorafenib to be an effective drug across patients with advanced HCC
               regardless of etiology and ethnicity.


               Since then, much effort has been spent on exploring newer targeted therapies. Unfortunately, none of the
               trials in the past decade was able to identify a better targeted agent in treating advanced HCC [112-116] . Only
                                       [117]
               recently in 2017, Bruix et al.  in the RESORCE trial has found regorafenib, an oral multikinase inhibitor
               that blocks angiogenesis, oncogenesis, metastasis and tumor immunity, to be an effective second line
               treatment for patients who have failed sorafenib. The median survival rate for patients on regorafenib after
               sorafenib use was 10.6 months compared to 7.8 months in the placebo group. The side effects associated with
               regorafenib use are typical of multi-kinase inhibitors, including hypertension, hand-foot skin reaction and
               gastrointestinal disturbances. Rate of drug-related adverse events leading to discontinuation of regorafenib
               is similar to that of sorafenib (10% vs. 11%) [110,117] . Regorafenib thus has become the only clinically proven
               second line systemic drug available in sorafenib-resistant cases thus far.

               Immunotherapy
               Although targeted therapy seems to have hit a roadblock, other routes of development have been ongoing.
               Immunotherapy is the most notable one. Ever since the introduction of immune checkpoint inhibitors
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