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Chan et al. Hepatoma Res 2018;4:5  I  http://dx.doi.org/10.20517/2394-5079.2017.49                                                 Page 7 of 17


               Table 8. Recent studies on the efficacy of transarterial chemoembolization in the management of high-burden hepatocellular
               carcinoma with portal vein invasion
                                                             1-year   3-year   5-year   Median
                                         Vascular   Number of
                Year  Place   Authors                       survival   survival   survival   survival   Recruitment year
                                         invasion  patients (n)
                                                              (%)     (%)     (%)   (months)
                2012  China  Niu et al. [78]  All types  115  27.8     -       -      8.67     2007-2010
                2012  China  Peng et al. [43]  All types  402  37.8    7.3     0.5    13.1     2002-2007
                2014  India  Ajit et al. [74]  All types  17  47.0     -       -      10       2011-2013
                2014  Taiwan  Chern et al. [75]  Vp3 and Vp4  50.0  54.0  10.0  -     6.2      2006-2012
                2014  Taiwan  Liu et al. [48]  Vp1 to Vp3  181  60     42      33     32       2002-2012
                2016  China   Zheng et al. [49]  All types  134  77.6  47.6    20.9   -        2000-2008
                2017  Korea  Choi et al. [76]  Vp1 and Vp2  50  -      -       -      9.4      2003-2012
                2017  USA  Gorodetski et al. [77]  All types  133  -   -       -      4.53     2006-2013

               In view of this, much effort has been made to devise new intra-arterial therapies with less systemic toxicities.
               In recent years, TARE has become an alternative to TACE in treating high-burden HCC. TARE is an intra-
               arterial therapy that involves the delivery of microspheres containing yttrium-90 into the hepatic arteries.
               TARE asserts the main effect through the internal radiotherapy delivered by Y-90, a radioactive substance,
               which causes necrosis of the tumor.

               As data is lacking for TARE, much of the evidences came from retrospective studies of experimental
               intent [86-94] . These studies either looked into the efficacy of TARE by itself, or made a comparison with
               TACE, the gold standard for unresectable high-burden HCC. The median survival rate for high-burden
               HCC treated with TARE was 15.0 (range: 11.5-20.0) months, with a response rate of 41.5% by the mRECIST
               criteria [Table 9]. In those studies comparing TARE and TACE retrospectively, they were not able to show
               any difference between survival [88,93,94] . However, TARE was found to be associated with longer time-to-
               progression, less toxicity and shorter hospital stay comparing with TACE, suggesting that it may be a more
               favorable treatment modality for unresectable high-burden HCC. As for large solitary tumor or multifocal
               tumors, where TACE is known to be ineffective due to the severe adverse effects , TARE could also be a
                                                                                    [95]
               preferred alternative.

               Despite its better safety profile, TARE is not yet considered standard treatment by a number of clinicians.
               Apart from the lack of high quality evidence to support its efficacy on high-burden HCC, TARE is an
                                                                               [96]
               expensive procedure and it requires specialized training for implementation . Given the promising results
               from retrospective studies, more clinical trials are needed in the coming years to formally evaluate its
               effectiveness and safety profile, and its potential to replace TACE’s role in the treatment of unresectable high-
               burden HCC.


               Radiotherapy
               External radiation historically had limited role in the management of HCC. This is mainly due to the
               radiotoxicity on the non-tumorous surrounding tissue. Radiation induced liver disease (RILD) is a common
               side effect of radiotherapy for liver cancer. In the RTOG 84-05 dose escalation study, among the patients
               receiving whole liver RT of 33 Gy in 1.5 Gy, around 10% of patients experienced RILD .
                                                                                       [97]
               However, with the recent advancements in irradiation technique, treatment modalities such as 3D-conformal
               RT (3D-CRT) and stereotactic body radiation (SBRT) have emerged as feasible options to treat high-burden
               HCC. With these technologies, high dose radiation can be effectively delivered to a precise area, sparing the
               surrounding normal liver tissue. This is particularly important for those patients with high-burden HCC
               who are not eligible for surgery or local therapies due to suboptimal liver reserve, anatomical locations of the
               tumors or poor performance status. Therefore, radiotherapy has become an attractive alternative in those
               cases.
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