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Chan et al. Hepatoma Res 2018;4:5  I  http://dx.doi.org/10.20517/2394-5079.2017.49                                                  Page 9 of 17


               Table 10. Recent studies on the efficacy of radiotherapy in the management of high-burden hepatocellular carcinoma
                                               Number                  1-year   3-year  Median
                                                  of   Dose/  Evaluation                  Response   Recruit-
                Year  Place  Authors      Method                      survival  survival  survival
                                               patients  fraction  criteria  (%)  (%)  (mos)  rate (%)  ment year
                                                 (n)
                2007 Japan  Toya et al. [103]  3DCRT  38  17.5-50.4   mRECIST  39.4  -  9.6  44.7  1999-2005
                                                      Gy; 1.8-4
                                                      Gy/Fr
                2009 China  Huang et al. [83]  3DCRT  326  60 Gy; 2-3   -  16.7  -    3.8   25.2  1997-2005
                                                      Gy/Fr
                2010 Korea  Oh et al. [104]  TACE + 3DCRT  40  30-54 Gy;   -  72  -   19    62.8  2006-2007
                                                      2.5-5 Gy/
                                                      Fr
                2012 Korea  Yoon et al. [108]  TACE + 3DCRT  412  21-60 Gy;   mRECIST  42.5  -  10.6  28.1  2002-2008
                                                      2-5 Gy/Fr
                2013 Canada Bujold et al. [101]  SBRT  102  30-54 Gy;   mRECIST  55  -  17  44    2004-2010
                                                      6 Gy/Fr
                2013 Korea  Bae et al. [99]  SBRT  35  30-60 Gy;   mRECIST  52  21    14    41    2003-2011
                                                      3-5 Gy/Fr
                2013 China  Tang et al. [54]  TACE + 3DCRT  185  30-52 Gy;   -  42.2  17.3  12.3  -  2006-2008
                                                      3-4 Gy/Fr
                2014 Canada Culleton et al. [100]  SBRT  29  19.7-46.8   mRECIST  32.3  -  7.9  -  2004-2012
                                                      Gy; 6 Gy/
                                                      Fr
                2014 Korea  Cho et al. [105]  TACE + 3DCRT  67  30-45 Gy;   -  -  -   14.1  -     2007-2011
                                                      2-4.5 Gy/
                                                      Fr
                2016 Japan  Matsuo et al. [98]  SBRT  43  45-55 Gy;   -  49.3  -      11    67    2008-2013
                                                      10-15 Gy/
                                                      Fr
                2016 Japan  Matsuo et al. [98]  3DCRT  54  45-50 Gy;   -  29.3  -     6     46    2008-2013
                                                      15-25 Gy/
                                                      Fr
                2016 Japan  Okazaki et al. [109]  3DCRT  56  22-50 Gy;   mRECIST  -  -  6.4  22   2007-2013
                                                      2 Gy/Fr
                2017 Taiwan  Lo et al. [102]  SBRT  89  25-60 Gy;   -   45.9   24.3   10.9  76.2  2007-2015
                                                      4-6 Gy/Fr
               TACE: transarterial chemoembolization

               to cancer treatment, results of clinical studies have far exceeded expectation. In 2013, the journal Science
                                                                          [118]
               has selected cancer immunotherapy as the Breakthrough of the Year . Cancer immunotherapy has been
               shown to be effective in treating cancers in multiple tissue organs, most notably lung cancer, melanoma and
               renal-cell carcinoma [119-121] .


               Latest studies have demonstrated promising results in the application of immunotherapy in treating
               advanced HCC [122,123] . Nivolumab, a PD-1 inhibitor, has been shown to prolong survival in patients with
               advanced HCC unsuitable for surgery or other local therapies [123] . In an international phase 1/2 trial
               (CheckMate040), nivolumab was demonstrated to have an objective response rate of 15%-20% in patients
                                                           [123]
               with advanced HCC, irrespective of line of therapy . This was a significant improvement to the first-line
                                                       [110]
               sorafenib therapy, with a response rate of 2%-3% , and the second-line regorafenib therapy, with a response
                        [117]
               rate of 7% . The overall 9-month survival rate was 74%, which showed a marked improvement compared
               to the median survival of 6 months for untreated advanced HCC.

               Despite the relatively promising results shown in immunotherapy on HCC, studies so far conducted were
               relatively small scale. Larger scales are needed to evaluate the efficacy of immunotherapy on HCC.



               ETIOLOGICAL ADJUNCTIVE TREATMENT FOR HIGH-BURDEN HCC
               While we have discussed above the different treatment modalities available for high-burden HCC, it is
               also of paramount importance to control the underlying risk factors during treatment. By far, HBV and
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