HEPATIC RESECTION AND percutaneous

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1 bs_bs_banner doi: /hepr Review Article Recent advances in medical management of hepatocellular carcinoma Kenji Ikeda Department of Hepatology, Toranomon Hospital, Tokyo, Japan Transcatheter arterial therapies for hepatocellular carcinoma (HCC) have developed during the last decade. A fine powder formulation of cisplatin and the new platinum agent miriplatin became standard medicines in addition to anthracyclines in transcatheter arterial chemoembolization (TACE) in Japan. Recent prospective and retrospective studies supported the usefulness of platinum agents as a chemotherapeutic at the time of varied TACE therapy. Although balloon-occluded TACE is an effective therapy for localized HCC and drug-eluting microspheres seemed to show a higher response rate in certain HCCs, the definite advantages of those procedures still remain uncertain. Intermediate stage HCC, or Barcelona Clinic Liver Cancer stage B, is regarded as a heterogeneous category with a wide spectrum of tumors and patients, and several subclassifications of the stage have been proposed to show different prognoses; there are also different recommended therapies in each subgroup. Authors have subclassified patients based on combinations of tumor size, tumor number, and liver function, with or without performance status. Because of differences of available medical resources and techniques in treatment procedures between countries, the most ideal and useful subgrouping remains inconclusive at present. Recently, a few systemic chemotherapies proved to be effective for advanced stage HCC in phase III studies: lenvatinib as the first line of therapy, and regorafenib, cabozantinib, and ramucirumab as second-line therapy. Other molecular-targeted and immune-oncological medicines are expected to follow in the near future. Some studies have suggested an advantage of early introduction of moleculartargeted therapy for TACE-resistant HCC in the intermediate stage. Key words: Anthracycline, B-TACE, cisplatin, hepatocellular carcinoma, immune oncology, intermediate stage INTRODUCTION THE PROGNOSIS OF hepatocellular carcinoma (HCC) is one of the poorest among common malignancies. 1 The number of deaths has increased so that HCC now ranks as the third most common cancer in the world; 2 several treatment guidelines have been produced to inform appropriate treatments and strategies according to various clinicopathological states. 3 7 Recent advances in the medical treatment of HCC include sophisticated locoregional therapy and its assisting technology, newly available medicines and procedures in transcatheter arterial therapy, new molecular-targeted drugs and immuno-oncology, Correspondence: Dr Kenji Ikeda, Department of Hepatology, Toranomon Hospital, Toranomon 2-2-2, Minato-ku, Tokyo, , Japan. ikedakenji@tora. .ne.jp Conflict of interest: The author reports personal fees from Dainippon- Sumitomo Pharmaceutical and Eisai. Financial support: None declared. Received 19 July 2018; revision 20 September 2018; accepted 2 October refined devices of external radiation, and direct-acting antiviral therapy for patients with hepatitis C virus (HCV)- related HCC. This review focuses on several topics regarding the medical treatment of HCC: varied transarterial treatment, strategies for intermediate stage HCC, and current chemotherapy including molecular-targeted medicines. TRANSCATHETER ARTERIAL THERAPY HEPATIC RESECTION AND percutaneous locoregional ablation are applicable in only 30 40% of patients, and transcatheter arterial chemoembolization (TACE) has been recommended as an effective palliative treatment option for patients with intermediately advanced HCC. 3 9 As transcatheter arterial infusion therapy without embolization was not recommended in any guidelines, except for those from Japan, this review does not include hepatic arterial infusion jchemotherapy for HCC. After 2000, cisplatin has been used for transcatheter treatment of HCC, and after 2010 miriplatin also became available as a next-generation 14

2 Recent advances in management of HCC 15 platinum agent in Japan. In the last decade, microspheres with or without drug-eluting activity have been developed to improve the direct antitumor effect of transcatheter therapy. This review discusses many prospective and retrospective studies, regarding the efficacy of chemotherapeutic drugs, significance of changing chemotherapeutic agents, power of new platinum agents, impact of balloonoccluded TACE (B-TACE), and comparisons between microspheres and conventional TACE (ctace). Conventional TACE and antitumor agents The term conventional transcatheter arterial embolization (ctace) has become popular in comparison with microsphere embolization since ,11 Although ctace has been used for various stages of HCC since the 1980s worldwide, there are some technical differences depending on area and era. Conventional TACE is usually defined as arterial embolization using chemotherapeutics and gelatin sponges, and usually with lipiodol. A catheter is inserted super-selectively as peripherally as possible, and emulsion of water-soluble antitumor agent is often used after mixing with ethiodized oil. 12 Although common chemotherapeutics used for TACE are doxorubicin, epirubicin, mitomycin C, and cisplatin, there is no unified protocol using single or multiple combined anticancer drugs as first-line treatment. Water-soluble doxorubicin or epirubicin were preferred in the initial procedures of ctace due to high solubility to small amount of water or contrast media. Embolic agents, gelatin sponges or microspheres, seem to be used arbitrarily for various features of HCC, and there is also no informative guideline for the choice of embolic substances globally. As resistance to treatment does occur several times in the majority of HCCs, additional TACE has been tried with more superselective techniques, exploration of parasitic tumor feeders, and changing of chemotherapeutic agents. A new cisplatin powder (DDPH, IA-Call; Nippon Kayaku, Tokyo, Japan), designed for hepatic arterial infusion, became available in 2004 in Japan. Several authors compared the usefulness between cisplatin including the fine powder formulation and conventional anthracyclines in TACE (Table 1) Ono et al. 13 first compared cisplatin and doxorubicin in TACE for unresectable HCC. This retrospective study showed no difference in response rate but the survival rate was higher in the cisplatin group (P < 0.05). Kamada et al. 14 also showed higher survival rates in patients in the cisplatin-tace group than in the doxorubicin-tace group (P < 0.05), but direct tumor response expressed by lipiodol accumulation was not different between the two groups. In a small study (n =28), Sahara et al. 15 also showed no difference in tumor response rates between liquid cisplatin and epirubicin groups. Based on large numbers of study patients, Kasai et al. (n =164) 16 and Yodono et al. (n =202) 17 reported the superiority of the fine powder formulation of cisplatin in response rates, progression-free survival, and overall survival (OS) rates. Yamanaka et al. 18 showed an advantage of DDPH in TACE therapy for patients with multiple tumors. Four authors described the efficacy of TACE with platinum agents as a second-line treatment for advanced HCC unresponsive to epirubicin lipiodol emulsion (Table 2). Kawamura et al. 19 first reported the advantageous effect of platinum agents in 152 consecutive patients with HCC refractory to TACE using epirubicin. Computed tomography evaluation at 3 months after therapy showed complete response (CR) in 6 patients (4.0%), partial response (PR) in 28 (18%), stable disease (SD) in 35 (23%), and progressive disease (PD) in 83 (55%). The cumulative survival rates for PR/CR patients who received platinum analogue with or without embolization (81.8% at first year, 53.9% at second year, and 33.1% at third year) were significantly higher than those of SD/PD patients (36.6%, 17.5%, and 7.4%, respectively) (P < 0.001). Median survival time was prolonged by 1.4 years in PR/CR patients. Maeda et al. 20 also reported a retrospective data regarding second-line use of cisplatin for 51 patients with epirubicin-tace unresponsive advanced HCC. Response rates were 11.8 and 27.5% by Response Evaluation Criteria in Solid Tumors and European Association for the Study of the Liver (EASL) criteria, respectively. Overall survival rates were 61.9, 48.2, and 28.9% at 1, 2, and 3 years, respectively, and the median survival time was 15.4 months. The progression-free survival (PFS) rate was 35.2% at 1 year, and median PFS time was 3.1 months. They concluded that switching from epirubicin to cisplatin might be A feasible option for advanced HCC, even when considered resistant to the initial form of TACE. Seki et al. 21 reported the efficacy of cisplatin-loaded microspheres to HCC refractory to epirubicin-loaded microspheres. Among 85 patients, CR was found in 3 (3.5%) and partial response in 31 (36.5%) patients after 6 months. They also concluded that switching the loaded agent from epirubicin to cisplatin was efficacious as salvage TACE treatment. Goda et al. 22 summarized the effect of miriplatin-based TACE in 18 patients with epirubicin TACE-resistant HCC. Four patients (22%) showed PR, but the other 4 patients (22%) showed deterioration of liver function. In spite of the rather small number of subjects, they suggested that platinum-based anticancer drugs should be considered as an option in retreatment chemoembolization.

3 16 K. Ikeda Table 1 Comparison of cisplatin and anthracyclines in transcatheter arterial chemoembolization (TACE) Primary author (ref.) Study design number Case (cisplatin) Control (anthracyclines) Efficacy Ono Retro 84 CDDP (ctace) ADM (ctace) ORR, 44.7 vs (NS) 2-yr survival, 49 vs. 31% 5-yr survival, 19 vs. 6% (P < 0.05) Mean no. of treatments, 3.3 vs. 1.9 (P < 0.01) Kamada Retro 134 CDDP (ctace) ADM (ctace) 3-yr survival, 41 vs. 18% (P < 0.05) Lipiodol accumulation 50%, 67.6 vs. 73.1% (NS) Sahara Pro 28 CDDP (ctace) EpADM (ctace) ORR per nodule, 72.6 vs. 66.7% (P =0.894) ORR per patient, 50.0 vs. 37.5% (P =0.615) TACE-free control curve, P =0.513 Kasai Retro 164 DDPH (ctace) ADM (ctace) ORR, 53.9 vs. 23.9% (P < 0.001) Median PFS, 8.6 vs. 3.0 mo (P < 0.001) 12-mo survival, 81 vs. 68% 24-mo survival, 67 vs. 37% (P =0.002) Yodono Retro 202 DDPH EpADM (ctace) 3-yr PFS, 15.7 vs. 1.5% (P = ) 3-yr survival, 62.4 vs. 36.5% (P = ) Yamanaka Retro 85 DDPH (ctace) EpADM (ctace) ORR (overall), 62.5 vs. 51.5% (NS) ORR (multiple tumors), 66.7 vs. 39.6% (Adjusted HR, 4.11, 95% CI, ) ADM, adriamycin or doxorubicin; CDDP, liquid cisplatin; CI, confidence interval; ctace, conventional TACE; DDPH, fine powder formulation of cisplatin; EpADM, epi-adriamycin or epirubicin; HR, hazard ratio; mo, month; NS, not significant; ORR, objective response rate; PFS, progression-free survival; Pro, prospective; Retro, retrospective; yr, year. Anthracyclines and platinum agents have different anticancer spectra in the transcatheter treatment of HCC, and platinum derivatives seem worth switching to for patients with anthracycline TACE-resistant HCC. Miriplatin as an intra-arterial anticancer drug Miriplatin ([SP-4-2]-[(1R, 2R)-cyclohexane-1,2-diamine- N,N 0 ]-bis (tetradecanoato-o) platinum monohydrate (Dainippon Sumitomo Pharmaceutical, Osaka, Japan) is a lipophilic cisplatin derivative that can be suspended in lipiodol. 23,24 Miriplatin is retained in local tumors with lipiodol and slowly releases an active platinum drug for a persistent antitumor effect; little transfer occurs to the systemic circulation, and systemic adverse events are reduced. Until recently, a total of 12 retrospective and prospective reports have been published regarding miriplatin compared with other anticancer drugs in the treatment of TACE (Table 3). Although miriplatin seemed to have an ideal chemical and pharmacological structure in lipiodolusing TACE, Miyayama et al. 26 reported that the anticancer activity was not higher than conventional TACE using ordinary epirubicin. Iwazawa et al. 31 also reported that the effect of miriplatin-tace was lower, but vascular toxicity was also lower than that of TACE using epirubicin. Among all studies, the effect of miriplatin was inferior to anthracycline- or cisplatin-based ctace in three articles, slightly inferior but not significant in one, and the other eight papers described an almost equivalent effect between miriplatin and conventional medicines. As the viscosity of miriplatin lipiodol suspension is higher than lipiodol alone, 37 it hardly flows into the peripheral hepatic artery compared with other emulsified anticancer drugs. We should realize the efficiency of the use of warmed miriplatin suspension at transcatheter

4 Recent advances in management of HCC 17 Table 2 Retrospective studies of significance of switching of anticancer agent for hepatocellular carcinoma refractory to epirubicinbased transcatheter arterial chemoembolization (TACE) Primary author (ref.) number Previous TACE Switched TACE Efficacy (one arm of switched medicine) Kawamura EpADM (ctace) Platinum (ctace) CR, 6 (4.0%); PR, 28 (18.4%) 1-yr survival, 81.8% (CR/PR) vs. 36.6% (SD/PD) (P < 0.001) 2-yr survival, 53.9% (CR/PR) vs. 17.5% (SD/PD) 1-yr survival, 81.8% (CR/PR) vs. 36.6% (SD/PD) (P < 0.001) Maeda EpADM (ctace) Cisplatin (ctace) RR, 11.8% (RECIST criteria); 27.5% (EASL criteria) 1-, 2-, and 3-yr survival: 61.9%, 48.2%, and 28.9% Thrombocytopenia (Gr. 3/4), 5.8% AST elevation (Gr. 3/4), 35.3% Seki EpADM (SAP) Cisplatin (SAP) CR, 3.5%; PR, 36.5% TTTF, 7.2 mo; MST, 13.3 mo Gr. 3/4 AE, 9.4% Goda EpADM (ctace) Miriplatin (ctace) RR, 22.2% Deterioration of liver function, 22.2% Cisplatin or carboplatin. AE, adverse event; AST, aspartate aminotransferase; CR, complete response; ctace, conventional TACE; EASL, European Association for the Study of the Liver; EpADM, epirubicin or epiadriamycin; Gr., grade; mo, month; MST, median survival time; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; RR, response rate; SAP, superabsorbent polymer microsphere (HepaSphere, Nippon Kayaku, Tokyo, Japan); SD, stable disease; TTTF, time to treatment failure; yr, year. arterial injection: two retrospective comparisons showed the objective response rates of warmed miriplatin were higher 29,33 and one prospective study showed a longer time to tumor progression. 36 Miriplatin is currently used for nonselective infusion for bilobar multiple HCCs, 37 epirubicinrefractory HCC, and for targeted balloon-occluded TACE (B-TACE) against localized HCCs, but ideal use of warming and ways of injection are not fully elucidated. Balloon-occluded TACE Balloon-occluded TACE a using microballoon catheter was proposed by Irie et al. 38,39 to improve the therapeutic efficacy of ordinary TACE. Lipiodol uptake and retention significantly increased at TACE under microballoonocclusion. Four articles showed response rates and adverse events of B-TACE compared with conventional TACE (Table 4). Arai et al. 40 and Ogawa et al. 41 reported B-TACE was significantly superior to ctace in response rates when the procedure was carried out with miriplatin as the chemotherapeutic agent. Maruyama et al. 42 showed adverse events were more often found in patients with B-TACE, when TACE was carried out using epirubicin. Irie et al. 43 attained a very high CR rate with B-TACE (89.9%) together with ctace (65.3%) and significantly high tumor control rate with B-TACE. Although Maruyama et al. described a high rate of side-effects in the treatment with B-TACE using epirubicin, Irie et al. showed the same TACE-induced adverse events in the TACE using doxorubicin plus mitomycin C. Currently, to avoid biliary and vascular injury caused by B-TACE, miriplatin is usually chosen as the anticancer drug because of its less hazardous damage against peripheral small vessels. Kawamura et al. 44 described details of the effect of B-TACE and tumor characteristics during treatment. Visualization of peripheral portal veins was significantly associated with high necrosis rates of tumors after B-TACE, which was also a well-known phenomenon in ctace. 45 Microspheres without loading of anticancer drug Bland TAE, transcatheter arterial embolization without loading of anticancer drug, was compared with arterial chemoembolization in three studies (Table 5). Nicolini et al. 46 studied 16 patients with HCC before orthotopic liver transplantation: eight were treated with bland

5 18 K. Ikeda Table 3 Miriplatin versus other anticancer drugs in transcatheter arterial chemoembolization (TACE) therapy Primary author (ref.) Study design number Case (ctace) Control (ctace) Efficacy (case vs. control) Okabe Retro 246 MPT CDDP CR, 47.0 vs. 43.3% (NS) Miyayama Retro 129 MPT EpADM/MMC Recurrence at 10 mo, 67.3% vs. 47.6% (P < ) Oguro Retro 98 MPT CDDP ORR, 56.3 vs. 86.0% (P =0.005) Aramaki Retro 69 MPT EpADM ORR, 81.5 vs. 85.7% (NS) Seko Retro 203 wmpt MPT ORR, 71.1 vs. 44.3% (P =0.002) Ueda Retro 46 MPT CDDP ORR, 50.0% vs. 81.1% (P =0.011) DCR, 79.4 vs. 97.3% (P =0.017) Iwazawa Retro 118 MPT EpADM Time to re-tace, 182 vs. 234 days Arterial damage, 1.6 vs (P < 0.001) Handa Retro 192 MPT EpADM CR, 46.8 vs. 33.0% (NS) 18-mo recurrence, 71.2 vs. 43.1% (P =0.19) Yasui Retro 100 wmpt EpADM CR, 34.1vs. 12.5% ORR, 40.0 vs. 12.5% (P = ) Otsuji Pro 49 MPT CDDP ORR, 45.0 vs. 42.3% (P =0.855) 2-yr survival, 60.0 vs. 51.8% (P =0.905) Ikeda Pro 247 MPT EpADM CR, 44.4 vs. 37.4% (P =0.184) TTTF vs mo (P =0.250) MST, 1111 vs days (P =0.946) Kubota Pro 198 wmpt EpADM ORR, 79.8vs. 77.8% (P =0.862) TTP, 7.6 vs. 5.9 mo (P =0.021) CDDP, cisplatin; CR, complete response; ctace, conventional TACE; DCR, disease control rate; EpADM, epi-adriamycin; MMC, mitomycin C; mo, month; MPT, miriplatin; NS, not significant; ORR, objective response rate (complete response + partial response); Pro, prospective; Retro, retrospective; TTP, time to progression; TTTF, time to treatment failure; wmpt, warmed miriplatin. Table 4 Comparison of balloon-occluded transcatheter arterial chemoembolization (B-TACE) versus conventional TACE Primary author (ref.) Study design number B-TACE Anticancer agents Control (ctace) Efficacy (B-TACE vs. ctace) Arai Retro 97 MPT MPT CR, 55.1 vs. 39.6% (P < 0.05) AE, ALT elevation (grade 3), 14.3 vs. 8.3% (P < 0.05) Ogawa Retro 61 MPT MPT CR, 49.2 vs. 27.0% (P =0.035) AE, no difference Maruyama Retro 100 EpADM EpADM Local control rate/lipiodol retention, NS AE, abscess 6%, infarction 2% in B-TACE Irie Retro 77 ADM + MMC ADM + MMC CR, 89.3 vs. 65.3% (P =0.016) 3-yr tumor control rate, 69.9 vs. 31.6% (P = ) OS, NS (P =0.20) ADM, adriamycin (doxorubicin); AE, adverse event; ALT, alanine aminotransferase; CR, complete response; ctace, conventional TACE; EpADM, epi-adriamycin; MMC, mitomycin C; MPT, miriplatin; NS, not significant; Retro, retrospective; yr, year. embolization and the other eight with epirubicinloaded DC Bead (Biocompatibles, Farnham, UK) particles. Chemoembolization with drug-eluting beads achieved complete necrosis in 77% of lesions whereas bland embolization achieved the same result in only 27.2% of lesions (P =0.043).

6 Recent advances in management of HCC 19 Table 5 Efficacy and adverse events of bland embolization using microspheres without loading of anticancer drug Primary author (ref.) Study design number Case (embolization) Control arm Efficacy (case vs. control) Nicolini Retro 16 Bland TAE (Embosphere) Malagari Pro 84 Bland TAE (BeadBlock) Brown Pro 101 Bland TAE (BeadBlock) DC bead EpADM CR, 27.2 vs. 77% (P =0.043) No complications in either group DC bead CR, 14.0 vs. 26.8% (P =0.006) (ADM) 12-mo recurrence, 78.3 vs. 45.7% (P < ) TTP, 36.2 vs wk (P =0.008) DC bead (ADM) ORR (RECIST), 5.9% vs. 6.0% (P =0.11) PFS, 6.2 vs. 2.8 mo (P =0.11) MST, 19.6 vs mo (P =0.64) ADM, adriamycin (doxorubicin); CR, complete response; DC-Bead, low-compressible bead; EpADM, epi-adriamycin or epirubicin; mo, month; MST, median survival time; ORR, objective response rate; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; TAE, transcatheter arterial embolization; TTP, time to progression; wk, week. Two prospective studies 47,48 reached slightly different conclusions. Malagari et al. showed a few advantages of doxorubicin-eluting bead TACE over bland embolization with BeadBlock (Infiniti Medical, Redwood, CA, USA). At 6 months, CR (EASL criteria) was seen in 11 of 41 patients (26.8%) in the drug-eluting bead (DEB) TACE group and in 6 of 43 patients (14%) in the bland embolization group; PR was achieved in 19 patients (46.3%) and 18 (41.9%) patients, respectively. Recurrence at 12 months was higher for bland embolization (78.3% vs. 45.7%). Time to progression (TTP) was significantly longer for the DEB-TACE group (42.4 ± 9.5 vs ± 9.0 weeks, P = 0.008). Although survival benefit was not proven, DEB-TACE presented a better local response, fewer recurrences, and a longer TTP than bland embolization. Brown et al. 48 also introduced a randomized controlled trial of arterial embolization using doxorubicin-eluting microspheres compared with bland embolization. Fifty-one patients received BeadBlock without anticancer drug and the other 50 patients were treated with LC Beads (Biocompatibles) with doxorubicin. Median PFS was 6.2 versus 2.8 months (hazard ratio [HR], 1.36; 95% confidence interval [CI], ; P = 0.11), and OS, 19.6 versus 20.8 months (HR, 1.11; 95% CI, ; P =0.64) for the BeadBlock and LC Bead groups, respectively. There was no apparent difference between the treatment arms in the latter study. Drug-eluting bead TACE (Table 6) DC Bead has been designed to deliver a higher and more sustained release of drug directly into HCC and a low release of drug into the systemic circulation, with the intention to maximize the drug s effectiveness in terms of response, while significantly reducing its systemic toxicity. The microspheres contain anionic groups in their chemical structures that might interact with positively charged parts of anthracyclines by an ion-exchange mechanism, leading to controlled and sustained intratumoral drug retention. After Varela et al. 11 reported the effectiveness of DEB- TACE, many authors published retrospective and prospective comparisons between DEB-TACE and ctace using lipiodol plus absorbable gelatin particles. Del Poggio et al., 10 in a letter responding to Varela et al. s article, compared the two therapies and reported an overall response rate (CR + PR) in five patients (71%) treated with DEB-TACE and in three (43%) patients with ctace (Fisher s exact test, not significant). They observed three major complications in the DEB-TACE group: liver abscess in one, splenic infarction in one, and alanine aminotransferase flare with hepatitis B virus reactivation in one. Only one major complication was observed in the ctace group: an asymptomatic hepatic artery thrombosis, occurring immediately after treatment. Among 16 articles that retrospectively analyzed DEB- TACE versus ctace, 10,50 64 five described the superiority of DEB-TACE, three showed an advantage of ctace, and the remaining eight showed equivalent effect or adverse events. Individual evaluation of objective response rate, TTP, OS, and adverse events, did not show definite advantages of DEB-TACE over ctace in these retrospective studies. Lammer et al. 65 first reported results of a prospective randomized control trial of DEB-TACE (DC Bead) and ctace in 212 patients with HCC (Table 7). The objective of the study was to evaluate the safety and 6-month tumor response of chemoembolization in both arms, but the

7 20 K. Ikeda Table 6 Non-randomized retrospective studies for comparisons between embolization with drug-eluting bead (DEB) and conventional transcatheter arterial chemoembolization (ctace) Primary author (ref.) number Case (DEB) Control (ctace) Efficacy (case vs. control) Del Poggio 10 (letter) DC Bead ADM ctace EpADM ORR, 71.4 (5/7) vs. 42.9% (3/7) (NS) Major complication, 3 vs. 1 case Forrer DC Bead ADM PEI/RFA ORR (EASL criteria), 75.0 vs. 87.1% (P =0.009) Scartozzi Microsphere ctace TTP, 16 vs. 30 mo (P =0.003) OS, 19 vs. 46 mo (P < ) Dhanasekaran DC Bead ADM ctace ADM + MMC ctace OS, 610 vs. 284 days (P =0.03) MST from TACE, 403 vs. 114 days (P =0.01) Sacco DC Bead ctace CR (1 mo), 51.5 vs. 70.6% PR (1 mo), 48.5 vs. 29.4% Wiggermann ADM ctace CDDP ORR, 22.7 vs. 22.7% SD, 68.2 vs. 31.8% (P = 0.066) OS, 651 vs. 414 days (P =0.01) Recchia DC Bead ADM ctace RFS, 13.1 vs. 8.4 mo (NS) OS, 18.4 vs mo (NS) Song DC Bead ADM ctace ADM or EpADM + CDDP ORR, 81.6 vs. 49.4% (P < 0.001) TTP, 11.7 vs. 7.6 mo (P =0.018) 18-mo survival, 88 vs. 61% (P =0.005) Nicolini DC Bead ADM ctace EpADM Necrosis rate 90%, 44.7 vs. 32.0% (P =0.28) Cumulative necrosis area, 58.8 vs. 50.2% (P =0.49) Petruzzi DC Bead ADM ADM + Lp ADM + MMC + CDDP ORR, 82% (DEB) vs. 51%(ADM + Lp) vs. TTT, 153 vs. 218 vs. 275 days (P =0.07) 84% (ADM + MMC + CDDP + Lp) Kloeckner DC Bead ADM ctace MMC OS, 369 vs. 409 days (P =0.76) OS (Child A), 627 vs. 602 days (P =0.39) Arabi DC Bead ADM ctace CDDP ORR, 35 vs. 36% (P =0.74) 2-yr survival, 58 vs. 60% (P =0.4) ALT increase, 7.2 vs units (P = 0.001) Hospital stay, 7.8 vs days (P = 0.038) Liu DC Bead ADM ctace ADM + Embo CR, DCB 32.1%, ctace 6.3%, Embo 2.4% (P < 0.001), minor AE, 5.7%, 54.7%, 34.1% Facciorusso DC Bead ADM ctace ADM ORR, 74.8 vs. 85.3% (P =0.039) TTP, 11 vs. 17 mo (P < 0.001) MST, 32 vs. 39 mo (P =0.10) Duan DC Bead + SAP ADM ctace ADM ORR, DEB 63.8%, SAP 53.8%, ctace 65.4% (P =0.085) Gorodetski DC Bead ADM ctace OS (advanced stage), 3.33 vs. 5.0 mo (P =0.157) MMC + ADM Post-embolization syn, 61.3 vs. 30.0% (Continues)

8 Recent advances in management of HCC 21 Table 6. (Continued) Primary author (ref.) number Case (DEB) Control (ctace) Efficacy (case vs. control) Embosphere Encephalopathy, 3.2 vs. 5.8% Monier DC Bead ctace TTP, 100 vs. 261 days (P =0.025) ADM ADM Biliary injury, 32.5 vs. 9.6% (P < 0.001) ADM, adriamycin (doxorubicin); AE, adverse event; ALT, alanine aminotransferase; CDDP, cisplatin; CR, complete response; DCB, DC Bead; EASL, European Association for the Study of the Liver; Embo, embolization; EpADM, epi-adriamycin or epirubicin; Lp, lipiodol; MMC, mitomycin C; mo, month; MST, median survival time; NS, not significant; ORR, objective response rate; OS, overall survival; PEI, percutaneous ethanol injection; PR, partial response; RFA, radiofrequency ablation; RFS, recurrence-free survival; SAP, superabsorbent polymer; SD, stable disease; TTP, time to progression; TTT, time to transplantation. Table 7 Prospective randomized control studies regarding transcatheter arterial chemoembolization (TACE) using drug-eluting beads (DEB) Primary author (ref.) number Case (DEB-TACE) Control arm Efficacy (case vs. control) Lammer 65 (PRECISION V) DC Bead (ADM) ctace (ADM) CR, 26.9 vs. 22.2% (NS) ORR, 51.6 vs. 43.5% (NS) Malagari DC Bead ADM Bland TAE (BeadBlock) CR, 26.8 vs. 14.0% (P =0.006) 12-mo recurrence, 45.7 vs. 78.3% (P < ) TTP, 42.4 vs wk (P =0.008) Golfieri 66 (PRECISION ITALIA) DC Bead (ADM) ctace (EpADM) ORR (3 mo), 74.7 vs. 74.1% (NS) TTP, 9 vs. 9 mo (P =0.766) 2-yr survival, 56.8 vs. 55.4% (P =0.949) Pitton DC Bead (ADM) SIRT ( 90 Yt-SirShere) PFS, 216 vs. 180 days (NS) MST, 788 vs. 592 days (NS) Brown DC Bead (ADM) Bland TAE (BeadBlock) ORR (RECIST), 6.0% vs. 5.9% (P =0.11) PFS, 2.8 vs. 6.2 mo (P =0.11) MST, 20.8 vs mo (P =0.64) ADM, adriamycin (doxorubicin); CR, complete response; ctace, conventional TACE; EpADM, Epi-adriamycin; mo, month; MST, median survival time; NS, not significant; ORR, objective response rate; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; SIRT, selective internal radiotherapy; TAE, transcatheter arterial embolization; TTP, time to progression; wk, week; yr, year. hypothesis of superiority in tumor response was not met (one-sided P = 0.11). However, patients with Child Pugh B, Eastern Cooperative Oncology Group performance status (ECOG PS) of 1, bilobar disease, and recurrent disease showed a significant increase in objective response (P =0.038)comparedtocTACE.DCBeadwasassociated with improved tolerability, with a significant reduction in serious liver toxicity (P = 0.001) and a significantly lower rate of doxorubicin-related side-effects (P = ). The authors concluded that TACE with DC Bead and doxorubicin was safe and effective in the treatment of HCC and offered a benefit to patients with more advanced disease. Malagari et al. 47 compared DEB-TACE using DC Bead with bland embolization with BeadBlock in a randomized control trial. The DEB-TACE method showed a better local response, fewer recurrences, and a longer TTP than bland embolization with BeadBlock, but survival benefit with DEB-TACE was not obtained. Golfieri et al. 66 introduced a randomized trial of DEB-TACE and ctace for 177

9 22 K. Ikeda patients with HCC. Drug-eluting bead TACE and ctace were equally effective and safe, with the only advantage of DEB-TACE being less post-procedural abdominal pain. Facciorusso et al. 68 reviewed and summarized four randomized controlled trials and eight observational studies with 1449 patients in a meta-analysis. They showed no significant differences between DEB-TACE and ctace in terms of objective response rates, survival rates, and adverse events. Chemoembolization with superabsorbent polymer Superabsorbent polymer microspheres (HepaSphere; Nippon Kayaku, Tokyo, Japan) became available for TACE in management of HCC, as non-biodegradable, spherical, dry particles made of sodium acrylate and vinyl alcohol copolymer. The product is available in a few standard particle sizes that can be calibrated in increments of approximately 50 μm between 50 and 200 μm. Superabsorbent polymer microspheres swell within several minutes after absorbing fluid, and the swollen particles are elastic and compressible but hold their spherical or oval shape. The microspheres contain anionic groups in their chemical structures that could interact with positively charged parts of doxorubicin or irinotecan by an ionexchange mechanism, leading to controlled and sustained intratumoral drug retention. Grosso et al. 69 and Seki et al. 70 reported a promising effect and high safety for the treatment of HCC in their early experiences. Until recently, one prospective and three retrospective studies have been published regarding the efficacy of SAP-TACE compared with ctace or bland embolization (Table 8). Van Malenstein 71 showed TACE with SAP microspheres led to low plasma levels of doxorubicin and therefore minimized toxicity compared to ctace in their prospective study. However, all authors 62,71 73 reported equivalent efficacy to ctace, and could not show an advantage in response rates or survival rates. Although Kucukay et al. 72 described lower TTR in the SAP group compared with Embosphere (Nippon Kayaku, Tokyo, Japan) embolization using adriamycin plus mitomycin C, median survival time was not different between the treatment arms. Subgrouping of intermediate stage HCC All guidelines intend to describe recommended treatments for each progression stage of HCC, including those published by the American Association for the Study of Liver Diseases, 7 European Association for the Study of the Liver, 6 and Asian Pacific Association for the Study of the Liver, 5 Japanese clinical practice guidelines, 4 and consensus-based guidelines by the Japanese Society of Hepatology. 3 Intermediate stage HCC is also known as Barcelona Clinic Liver Cancer (BCLC) stage B in the BCLC staging system, 8,9 which is a composite model including tumor factor, liver function factors, and general health status. As this stage is placed between early and advanced stage HCC, and just between candidates for curative treatment and patients with difficult-to-treat local disease, it includes a broad range of diseases and consists of varied clinicopathological entities. Table 8 Efficacy of superabsorbent polymer (SAP) in the treatment of hepatocellular carcinoma Primary author (ref.) number Study design Trial medicine Control arm Efficacy (trial medicine vs. control) van Malenstein Pro SAP (ADM) ctace (ADM) Cmax, 495 vs ng/ml (P < 0.001) AUC, 69.7 vs. 165 ng/ml/min (P < 0.001) Gr. 3 AE, 5/16 vs. 15/14 Gr. 4 AE, 0/15 vs. 8/14 SD, 77 vs. 92% (P =0.54) Kucukay Retro SAP (ADM + MMC) Embosphere (ADM + MMC) MST, 37.4 vs mo (P =0.88) TTR, 5.0 vs mo (P =0.006) Duan Retro SAP (ADM) ctace ORR, 53.8 vs. 63.8% (NS) (ADM ± CDDP) Morimoto Retro SAP ctace ORR, 62 vs. 50% (P =0.358) 1-yr survival, 76 vs. 74% (P =0.810) ADM, adriamycin (doxorubicin); AE, adverse event; AUC, area under the receiver operating characteristic curve; CDDP, cisplatin; ctace, conventional transcatheter arterial chemoembolization; Gr., grade; MMC, mitomycin C; mo, month; MST, median survival time; NS, not significant; ORR, objective response rate; Pro, prospective; Retro, retrospective; SD, stable disease; TTR, time to recurrence; yr, year.

10 Recent advances in management of HCC 23 Intermediate stage HCC includes tumors of varied size and number, varied liver damage ranging from Child Pugh score 5 to 9, and ECOG PS of 0 or 1; therefore, an ideal single manner of therapy cannot be recommended in a simple way. In order to elucidate more accurate prognosis and to identify the most appropriate therapy, Bolondi et al. 74 first proposed a new subclassification system for intermediate stage HCC (Table 9). Intermediate stage was subclassified into B1 B4, based on tumor burden (up-to-seven criteria), liver function (Child Pugh score 5 9), and performance status (ECOG PS 0 or 1). The best status, B1, was defined as within up-to-seven, Child Pugh of 5 to 7, and PS 0. The worst status, B4, was defined as any tumor burden without portal vein invasion, Child Pugh of 8 to 9,and PS of 0 or 1.Recommended treatment in B1 class was TACE as first-line therapy and TACE plus ablation as alternative option. Recommended treatments for B3 or B4 classes were best supportive care, research trial, and liver transplantation. Ha et al. 75 verified the validity of the subgrouping system by Bolondi et al. using their 466 Korean patients with BCLC stage B HCC. They accepted the significance of the subgrouping of intermediate stage, but proposed modifying the subclassification into three groups, by merging B3 and B4 subgroups. Yamakado et al. 76 proposed a novel subclassification based on 329 Japanese patients with BCLC stage B. They divided the patient group into three subclasses based on tumor burden (four tumors of 7 cm criterion, 4-of-7-cm criterion) and Child Pugh score. Survival rates of B1, B2, and B3 stages were clearly different (B1 vs. B2, P < ; B2 vs. B3, P = ). Kudo et al. 77 also published a subclassification of the stage, based on tumor status (beyond Milan and within up-to-seven criteria) and liver function (Child Pugh score 5 7 or 8 9). The Kinki criteria classified BCLC B stage into B1 (Child Pugh score 5 7 and within up-to-7), B2 (Child Pugh score 5 7 and beyond up-to-7), and B3 (Child Pugh score 8,9 and any tumor status). This subclassification seems simple and easy to assess HCC treatment. Lee et al. 78 also subclassified BCLC stage B together with BCLC stage C with portal vein invasion or extrahepatic Table 9 Subclassification of intermediate stage hepatocellular carcinoma (retrospective studies) Primary author (ref.) Subclass Class of tumor Class of background Features Bolondi B1, B2, B3, B4 Up-to-7 C-P score B1, best candidates for TACE, transplantation or ECOG-PS TACE +ablation;b3 4, BSC or palliative Ha BI, BII, BIII Up-to-7 C-P score Verification of Bolondi s subclassification Modification: BI (=B1), BII (=B2), and BIII (B3 + 4) Yamakado B1, B2, B3 4 tumors 7 cm C-P score MST after TACE: B1, 40.5 mo; B2, 28.1 mo; B3, 13.0 mo Kudo B1, B2, B3a, B3b Up-to-7 C-P score B1, curative intention; B2, TACE/HAIC/ sorafenib B3a, curative intent when within up-to 7 B3b, palliative Lee B1, B2, B3 5 cm C-P score MST: B1 (<5 cm),b2( 5 cm, C-P A), B3 ( 5 cm,c-pb) vs vs mo (P < 0.001) Hiraoka B1, B2, B3, B4 Up-to-7 ALBI score MST of B1, B2, B3, B4: 65.1, 48,1, 29.6, 14.6 mo (P < 0.01, each) Treatment with hepatectomy/rfa: 67.0, 51.4, 28.3, 12.1% ALBI, albumin grade; BSC, best supportive care; C-P, Child Pugh; ECOG PS, Eastern Cooperative Oncology Group performance status; HAIC, hepatic arterial infusion chemotherapy; mo, month; MST, median survival time; RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization.

11 24 K. Ikeda spread. Hiraoka et al. 79 devised another subclassification system using the ALBI score 80 instead of Child Pugh classification 82 for liver function estimation. The Modified Intermediate Stage of Liver Cancer criteria are also useful for prediction of prognosis and establishment of treatment strategy. All the authors equally emphasized the wide variety of BCLC stage B and attempted its subclassification. Subsequent to Bolondi et al., Kudo et al. also suggested three concise subgroups, in which more specific therapies were individually recommended, such as DEB-TACE, ctace, and hepatic arterial infusion chemotherapy. Unlike Bolondi et al., Kudo et al., Ha et al., and Hiraoka et al., only Yamakado et al. established a subclassification of BCLC stage B based on the tumor factor of four nodules and 7 cm, instead of the up-to-seven criteria. Multiple tumors with large nodules of 6 cm or more are suggested as the best candidate for DEB-TACE, 77 there has been insufficient evidence regarding the ideal utilization of ctace and DEB- TACE until recently. There prognosis and recommended therapy of each subgroup might change with current development of novel molecular-targeted therapy and immune-oncology. Although the most recommended treatment was TACE in intermediate stage HCC in all the algorithms of the guidelines, a few retrospective studies disclosed that early switching of treatment from TACE to sorafenib might have significant survival benefit when HCC was unresponsive to repeated TACE (Table 10). The OPTIMIS study 85 also suggested that switching from intra-arterial treatment to sorafenib could bring about a longer survival period when the patient s background was appropriately matched in the observed cohorts. SYSTEMIC CHEMOTHERAPY Cytotoxic agents IN THE PRESORAFENIB era, no standard systemic therapy for advanced HCC had been established, because randomized controlled trials and meta-analyses failed to confirm any survival benefit of cytotoxic regimens, hormonal therapies, or interferon therapies in patients with advanced HCC. Doxorubicin, epirubicin, 5-fluorouracil, and cisplatin were principally used intra-arterially or in systemic administration, for a long period without evidence from prospective randomized trials. Molecular-targeted agents for advanced HCC Sorafenib is a multikinase inhibitor of Raf kinase, which is involved in cancer cell proliferation, and also of vascular endothelial growth factor receptor (VEGFR)2/3 and platelet-derived growth factor receptor-β (PDGFR-β), which are involved in peritumor neovascularization. Sorafenib became the standard of care for advanced HCC following confirmation of its effect by significantly improving OS over placebo in two large-scale trials, the SHARP trial 86 and the Asia-Pacific trial. 87 However, the efficacy is modest: the median survival is <1 yearand the tumor response rate is less than 5%. Thus, there remains a critical and unmet need for aggressive development of new and more effective agents for advanced HCC. After the introduction of sorafenib, a number of phase III trials of various molecular-targeted agents versus sorafenib as first-line treatment have been undertaken to determine whether any could offer a longer OS than sorafenib However, many agents examined had not been Table 10 Significance of early switching from repeated embolization therapy to sorafenib in patients with transcatheter arterial chemoembolization (TACE)-refractory hepatocellular carcinoma Primary author (ref.) number Study design Trial medicine Control arm Efficacy (trial medicine vs. control) Ogasawara Retro Sorafenib ctace TTDP, 22.3 vs. 7.7 mo (P =0.001) OS, 25.4 vs mo (P =0.003) Arizumi Retro Sorafenib ctace OS, 24.7 vs mo (P =0.002) Ohki Retro Sorafenib ctace 5-yr survival of msor vs. mcon groups (adjusted by frequency of treatment), 57.6 vs. 28.8% (P =0.005) Multivariate, switching HR = 0.42 (P =0.008) Radosavljevic Pro Sorafenib ctace Crude MST, 16.2 vs mo Adjusted MST, 16.2 vs mo ctace, conventional TACE; HR, hazard ratio; mcon, matched control group; mo, month; msor, matched sorafenib group; MST, median survival time; OS, overall survival; Pro, prospective; Retro, retrospective; TTDP, time to disease progression; yr, year.

12 Recent advances in management of HCC 25 reported to offer survival benefit over sorafenib until 2017 (Table 11). Lenvatinib, an inhibitor of VEGFR1 3, fibroblast growth factor receptor (FGFR)1 4, PDGFR-α, Ret, and kit, was reported as non-inferior to sorafenib in terms of OS in untreated advanced HCC. 92 It was the second moleculartargeted agent showing usefulness as a first-line treatment for unresectable HCC. This was an open-label, phase III, multicenter, non-inferiority trial that recruited patients with unresectable HCC, who had not received treatment for advanced disease, from 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) to receive oral lenvatinib (12 mg/day for bodyweight 60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice daily in 28-day cycles. A total of 954 eligible patients were randomly assigned to lenvatinib (n =478)or sorafenib (n = 476). Median survival time for lenvatinib of 13.6 months (95% CI ) was non-inferior to sorafenib (12.3 months, ; HR, 0.92; 95% CI, ), meeting criteria for non-inferiority (noninferiority margin set at 1.08). The most common anygrade adverse events were hypertension (201 [42%]), diarrhea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysesthesia (249 [52%]), diarrhea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib. Several phase III trials of various molecular-targeted agents versus placebo have been carried out in HCC patients who were refractory or intolerant to sorafenib, to determine whether any could offer a longer OS than placebo, however, most of the agents examined have not been proven to offer survival benefit over placebo (Table 12). Recently, regorafenib, 99 cabozantinib, 100 and ramucirumab 101 for the second-line setting, showed clinical significance through phase III studies for the treatment of advanced HCC patients. Regorafenib is a multikinase inhibitor that targets kinases involved in angiogenesis, such as VEGFR1 3 or Tie2, oncogenesis, such as c-kit or Ret, and the tumor microenvironment, such as PDGFR or FGFR. In the randomized, double-blind, parallel-group, phase III trial undertaken at 152 sites in 21 countries, adults with HCC who tolerated sorafenib ( 400 mg/day for 20 of the last 28 days of treatment), progressed on sorafenib, and had Child Pugh A liver function were enrolled. Participants were randomly assigned (2:1) to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1 3 of each 4-week cycle. Among 573 patients, a total of 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Table 11 Results of prospective phase III trials of molecular-targeted medicine and immune-oncology as first-line therapy for advanced hepatocellular carcinoma Primary author (ref.) Trial name number Trial medicine Control arm Efficacy (trial medicine vs. control) Llovet 86 SHARP Sorafenib Placebo MST, 10.7 vs. 7.9 mo (P < 0.001) TTRP, 5.5 vs. 2.8 mo (P < 0.001) Cheng 87 Asia-Pacific Sorafenib Placebo MST, 6.5 vs. 4.2 mo (P =0.014) TTP, 2.8 vs. 1.4 mo (P = ) Cheng 88 SUN Sunitinib Sorafenib MST, 7.9 vs mo (P = ) PFS, 3.6 vs. 3.0 mo (P = ) Johnson 89 BRISK-FL Brivanib Sorafenib MST, 9.5 vs. 9.9 mo (P =0.373) TTP, 4.2 vs. 4.1 mo (P = ) Cainap 90 LiGHT Linifanib Sorafenib MST, 9.1 vs. 9.8 mo (NS) TTP, 5.4 vs. 4.0 mo (P =0.001) Zhu 91 SEARCH Erlotinib + sorafenib Sorafenib + placebo MST, 9.5 vs. 8.5 mo (P =0.408) TTP, 3.2 vs. 4.0 mo (P =0.102) DCR, 43.9 vs. 52.5% (P =0.021) Kudo 92 REFLECT Lenvatinib Sorafenib MST, 13.6 vs mo (non-inferiority) PFS, 7.4 vs. 3.7 mo (P < 0.001) DCR, disease control rate; mo, month; MST, median survival time; NS, not significant; PFS, progression-free survival; TTP, time to progression; TTRP, time to radiological progression.

13 26 K. Ikeda Table 12 Results of prospective phase III trials of molecular-targeted medicine and immune-oncology as second-line therapy for advanced stage hepatocellular carcinoma Primary author (ref.) Trial name number Trial medicine Control arm Efficacy (trial medicine vs. control) Llovet 93 BRISK-PS Brivanib Placebo MST, 9.4 vs. 8.2 mo (P = ) TTP, 4.2 vs. 2.7 mo (P < 0.001) ORR, 10 vs. 2% (P = ) Zhu 94 EVOLVE Everolimus Placebo MST, 7.6 vs. 7.3 mo (P =0.68) TTP, 3.0 vs. 2.6 mo (N.S.) DCR, 56.1 vs. 45.1% (P =0.01) Zhu 95 REACH Ramucirumab Placebo MST, 9.2 vs. 7.6 mo (P =0.14) Rimassa 96 METIV-HCC Tivantinib Placebo OS, 8.4 vs. 9.1 mo (P = 0.81) TEAE, 56 vs. 55% Kobayashi 97 JET-HCC Tivantinib Placebo PFS, 2.8 vs. 2.3 mo (HR = 0.72, P =0.065) OS, 9.9 vs. 8.5 mo (HR = 0.85, CI = ) Bruix 99 RESORCE Regorafenib Placebo MST, 10.6 vs. 7.8 mo Any AE, 100 vs. 93% Hypertension, 15 vs. 5% Hand foot skin 13 vs. 1% Abou-Alfa ADI-PEG 20 Placebo MST, 7.8 vs. 7.4mo (P =0.88) PFS, 2.6 vs. 2.6 mo (P = 0.07, HR 1.17) Abou-Alfa 100 CELESTIAL Cabozantinib Placebo OS, 10.2 vs. 8.0 mo (P = ) (HR 0.76; 95% CI, ) PFS 5.2 vs. 1.9 mo (P < ) (HR 0.44; 95% CI, ) Zhu 101 REACH Ramucirumab Placebo OS, 8.5 vs. 7.3 mo (P = ) PFS, 2.8 vs. 1.6 mo (P < ) (patients with AFP 400 ng/ml), not applicable; ADI-PEG, arginine deiminase conjugated with polyethylene glycol; AE, adverse event; AFP, α-fetoprotein; CI, confidence interval; DCR, disease control rate; HR, hazard ratio; mo, month; MST, median survival time; ORR, objective response rate, OS, overall survival; PFS, progression-free survival; TEAE, treatment-emergent adverse event; TTP, time to progression. Regorafenib improved OS with an HR of 0.63 (95% CI, ; one-sided P < ); median survival was 10.6 months (95% CI, ) for regorafenib versus 7.8 months ( ) for placebo. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs. 9 patients [5%] in the placebo group), hand foot skin reaction (47 patients [13%] vs. 1 [1%]), fatigue (34 patients [9%] vs. 9 patients [5%]), and diarrhea (12 patients [3%] vs. 0 patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), 7 (2%) were considered by the investigator to be related to the study drug in the regorafenib group and 2 (1%) in the placebo group, including 2 patients (1%) with hepatic failure in the placebo group. Regorafenib became the first systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. 99 Cabozantinib is an orally available small-molecule tyrosine kinase inhibitor that blocks phosphorylation of MET and VEGFR2. The global, randomized, double-blind, phase III CELESTIAL trial evaluated the benefit of cabozantinib in patients with HCC whose disease progressed on prior sorafenib or other systemic therapies. Patients were randomly assigned 2:1 ratio to receive 60 mg cabozantinib orally once daily or placebo. Cabozantinib improved survival, compared with placebo, with median survival reaching 10.2 months versus 8.0 months (HR, 0.76; P = ). Median PFS was 5.2 months with cabozantinib versus 1.9 months with placebo (HR, 0.44; P < ). The most common grade 3/4 adverse events seen more frequently in the cabozantinib group included hand foot syndrome (17% vs. 0%),

14 Recent advances in management of HCC 27 hypertension (16% vs. 2%), increased aspartate aminotransferase levels (12% vs. 7%), fatigue (10% vs. 4%), diarrhea (10% vs. 2%), asthenia (7% vs. 2%), and decreased appetite (6% vs. < 1%). 100 The REACH-2 study evaluated the benefit of ramucirumab treatment in patients with HCC who were intolerant to, or had disease progression while on or following treatment with, sorafenib and had a high α-fetoprotein (AFP) level ( 400 ng/ml). Approximately half of all advanced HCC patients have high AFP levels, and these patients are among those with the poorest prognosis relative to the general HCC patient population. Ramucirumab was first reported to show better efficacy in the biomarker-enriched population compared to the whole population. 101 Individualized cancer treatment using moleculartargeted agents based on the results of genome sequencing has begun to attract much interest in clinical practice. Also, some favorable outcomes have been reported of treatment with immune-oncology agents, such as anti-cytotoxic T-lymphocyte-associated protein 4(anti-CTLA-4) antibody and programmed cell death-1/programmed cell death ligand-1(pd-1/pdl1) antibody. Molecular-targeted agents as adjuvant therapy (Table 13) Peretinoin ([2E,4E,6E,10E]-3,7,11,15-tetramethylhexadeca-2,4,6,10,14- pentaenoic acid), a synthetic retinoid with a retinoic acid receptor and retinoid X receptor agonist activity, is known to suppress tumor growth in the human liver by inducing apoptosis and differentiation of liver cancer cells; it also acts by increasing p21 protein levels and reducing cyclin D1 levels to inhibit proliferation of these cells. Okita et al. 102 reported results of a multicenter, randomized, double-blind, placebo-controlled study of the prophylactic effect of HCC recurrence by peretinoin. A total of 377 patients were analyzed for efficacy. The recurrence-free survival rates in the 600-mg group, the 300-mg group, and the placebo group were 71.9, 63.6, and 66.0% at 1 year, and 43.7, 24.9, and 29.3% at 3 years, respectively. The primary comparison of peretinoin (300 and 600 mg) with placebo was not significant (P = 0.434). Although the superiority of peretinoin to placebo could not be validated, the authors described that 600 mg/day was shown to be the optimal dose, and that treatment might possibly reduce the recurrence of HCV-HCC, particularly after 2 years. Table 13 Results of prospective phase III trials of molecular-targeted medicine and immune-oncology as adjuvant therapy for early stage hepatocellular carcinoma (HCC) and as improvement of embolization for intermediate stage HCC Primary author (ref.) Trial name number Trial medicine Control arm Efficacy (trial medicine vs. control) Adjuvant therapy (prevention of recurrence) Okita 102 NIK Peretinoin Placebo RFS for 600 mg, 300 mg, and placebo: 71.9, 63.6, and 66.0% at 1 yr; 43.7, 24.9, 29.3% at 2 yr. ( vs. placebo, P =0.434) (600 vs placebo, P =0.048) Bruix 103 STORM Sorafenib Placebo RFS, 8.5 vs. 8.4 mo (P =0.26) Hand foot skin, 28 vs. <1% Diarrhea, 6 vs. <1% Improvement of TACE (intermediate stage) Kudo 104 Post-TACE Sorafenib Placebo TTP, 5.4 vs. 3.7 mo (P =0.252) HR for OS, 1.06 (P =0.790) Kudo 105 BRISK-TA Brivanib Placebo MST, 26.4 vs mo (P =0.528) TTP, 8.4 vs. 4.9 mo (P < ) Lencioni 106 SPACE Sorafenib Placebo TTP, 5.6 vs. 5.5 mo (P =0.076) (phase II) DEB-TACE DEB-TACE Kudo 107 ORIENTAL Oranitinib Placebo MST, vs mo (P =0.435) Serious AE, 45 vs. 30% Meyer 108 TACE Sorafenib DEB-TACE Placebo DEB-TACE PFS, 7.9 vs. 7.8 mo (P =0.94) Serious AE, 41.4 vs. 32.1% (P =0.100) AE, adverse event; DEB, drug-eluting bead; HR, hazard ratio; MST, median survival time; OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival; TACE, transcatheter arterial chemoembolization; TTP, time to progression; yr, year.