Page 12 - Read Online
P. 12

Page 4 of 13                                            Giovanis et al. Hepatoma Res 2018;4:10  I  http://dx.doi.org/10.20517/2394-5079.2018.21


               Table 3. Primarily International Guidelines and level of evidence associated to radioembolization
                Guidelines                                                                    Recommendation  Level of recommendation
                ESMO 2012 [65]  Radioembolization may be competitive with sorafenib or TACE in subsets of patients, such   Category III, C
                             as those with prior TACE failure, excellent liver function, macrovascular invasion and the
                             absence of extra-hepatic disease

                             Current phase 3 studies are evaluating the place of radioembolization versus TACE in
                             patients with intermediate stage HCC, and as single modality or combined with sorafenib in
                             patients with advanced HCC compared with sorafenib
                AASLD 2010 [66]  Radioembolization with Yttrium90-labeled glass beads has been shown to induce extensive   Level II
                             tumour necrosis with acceptable safety profile. However, there no studies demonstrating an
                             impact on survival and hence, its value in the clinical setting has not been established and
                             cannot be recommended as standard therapy for advanced HCC outside clinical trials
               TACE: transhepatic arterial chemoembolization; HCC: hepatocellular carcinoma


               Table 4. Efficacious systemic therapies for HCC
                               Study      Arms    OS benefit   HR          Adverse events (Grade 3-4)
                                                  (months)
                 1st line setting  SHARP [5]  Sorafenib vs.   10.7 (vs. 7.9)  0.69  Hand-foot skin reaction (8%), diarrhoea (8%), fatigue (3),
                                        placebo                  hypertension (3%)
                            ASIA PACIFIC [26]  Sorafenib vs.   6.5 (vs. 4.2)  0.68  Hand-foot skin reaction (11%), diarrhoea (6%), fatigue (3%)
                                        placebo
                            SELECT [55]  Lenvatinib vs.  13.6 (vs. 12.3) 0.92  Hypertension (23%), increased blood bilirubin (7%), proteinuria
                                        sorafenib                (6%), elevate aspartate aminotransferase (5%)
                2nd line setting  RESORCE [50]  Regorafenib   10.6 (vs. 7.8)  0.63  Hypertension (15%), hand-foot skin reaction (13%), fatigue (9%),
                                        vs. placebo              diarrhoea (3%)
                            CELESTIAL [58]  Cabozantinib  10.2 (vs. 8.0)  0.76  Hand-foot skin reaction (17%), hypertension (16%), increased
                                        vs. placebo              aspartate aminotransferase (12%), fatigue (10%)
                            CheckMate   Nivolumab   15.6     -   Increased aspartate aminotransferase (18%), increased alanine
                            040 [59]    single arm               aminotransferase(11%), increased blood bilirubin (7%), immune-
                            (expansion                           mediated hepatitis (5%)
                            cohort)


               were conducted in patients with intermediate or advanced HCC no longer susceptible to TACE [24,25] . Both
               trials failed to demonstrate a survival benefit from transarterial radioembolization compared with sorafenib.
               Moreover, the median overall survival of patients treated with TARE resulted lower than sorafenib. In
               addition, in both studies a significant proportion of patients randomized to TARE never received the
               planned therapy (26.5% and 28.6% of patients of TARE arm vs. 7% and 9.0% in the sorafenib arm respectively
               in SARAH and SIRVENIB). This may suggest difficulties in selecting patients and implementing TARE
               procedure in clinical practice.

               Worth to be mentioned is that these studies demonstrated only the inferiority of TARE to systemic
               treatment and not the non-inferiority. In fact, in study designs the hypothesis of non-inferiority had not been
               prespecified in the protocol.


               SYSTEMIC TREATMENTS FOR HCC
               Table 4 reports the efficacious systemic therapies in intermediate and advanced stage of HCC, estimated as
               therapies achieving successful in phase 3 trials or early approved by health authorities accounting for phase
               2 data. A summary of the main studies currently available are described in this section.


               Sorafenib
               Sorafenib is an oral multikinase inhibitor that has antiangiogenic, anti-proliferative, anti-metastatic and
               anti-immunosuppressive activities. Sorafenib inhibits the activity of targets present in the tumour cell
               (CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2, VEGFR-3,
               and PDGFR-ß). RAF kinases are serine/threonine kinases, whereas c-KIT, FLT-3, VEGFR-2, VEGFR-3, and
   7   8   9   10   11   12   13   14   15   16   17