Doxorubicin (Adriacin; Kyowa Hakko Kogyo, Tokyo, Japan) is an anthracycline-based anticancer drug that had been conventionally used as a first-line therapy for HCC. In 1982, Hirose et al. reported that one shot of high-dose doxorubicin intra-arterial infusion therapy showed useful chemotherapeutic effects against HCC [18]. In 1994, Yasui et al. reported that of 86 patients with unresectable or recurrent HCC who underwent doxorubicin containing HAIC, 21 (34.4%) showed an objective response, and responders to doxorubicin containing HAIC achieved longer survival than non-responders [19]. In 1999, Tzoracoleftherakis et al. reported a randomized comparative study between HAIC with doxorubicin and systemic chemotherapy with doxorubicin involving 72 patients with unresectable (Stage IVA) HCC; patients who received HAIC with doxorubicin had a higher rate of objective and subjective remission and greater Karnofsky performance status improvement than did those in the systemic chemotherapy with doxorubicin group [20]. However, previous studies of systemic chemotherapy with doxorubicin had confirmed the minimal efficacy of this anticancer drug in HCC [9,10,11]. In Japan, doxorubicin is used for both HAIC and TACE in the treatment of advanced HCC [21].

Epirubicin (Farmorubicin; Nihon Kayaku, Tokyo, Japan) is the 4-epimer of doxorubicin. It has a more favorable toxicity profile with less myelosuppression and cardiotoxicity than doxorubicin, and is routinely used for HCC. Because epirubicin easily undergoes glucuronidation, it is less toxic than doxorubicin. In 1986, the Japan Epirubicin Study Group for Hepatocellular Carcinoma reported that of 53 HCC patients who received HAIC with epirubicin, eight patients (15.1%) showed an objective response (complete response [CR] or partial response [PR]) [22]. Furthermore, a retrospective comparison with intra-arterial administration of doxorubicin showed that epirubicin was more effective than doxorubicin in terms of survival rate. Since then, epirubicin has been routinely used in HAIC for HCC in Japan [22]. Additional clinical trials have been performed in several faculties. Epirubicin alone or in combination with other chemotherapeutic agents such as mitomycin C or 5-FU has been used in HAIC for HCC in various Asian countries including Japan, with objective response rates ranging from 5% to 78% [22,23,24,25,26,27,28,29]. Reports of HAIC with anthracycline-based chemotherapeutic agents are listed in Table 1.

Mitomycin C is an antineoplastic antibiotic isolated from the culture fluid of Streptomyces caespitosus. The objective response rate of intra-arterial chemotherapy with mitomycin C alone has been reported as 25% (9/36) [31]. However, this agent has recently been used in HAIC as a combination therapeutic agent. In Japan, mitomycin C alone has never been used in HAIC [21,24,32].

The pyrimidine antimetabolite 5-FU was the first reported chemotherapeutic agent used in the treatment of HCC. Monotherapy with intra-arterial 5-FU has a relatively low objective response rate, ranging from 13% to 22%, with a median survival of only 3.5 to 14 months [33,34]; therefore, 5-FU is often used in combination in HAIC for HCC.

Combined therapy comprising intra-arterial infusion of 5-FU and systemic interferon-α (IFN-α) (FAIT) has been reported to be useful as a palliative treatment for HCC patients with major vascular invasion, although monotherapy with IFN-α had minimal objective response rate against HCC [35,36,37]. In 2002, Sakon et al. reported that of 11 advanced HCC patients with portal vein tumor thrombus (PVTT), eight patients (73%) showed an objective response to FAIT [38]. In 2006, Obi et al. reported that in 116 advanced HCC patients with PVTT who received FAIT, 19 (16%) showed a CR and another 42 (36%) showed a PR; adverse events were limited to nausea and appetite loss, and the overall survival rates at 1 and 2 years were 34% and 18%, respectively [39]. In 2011, Nagano et al. reported that of 102 HCC patients with PVTT, 40 (39.2%) showed an objective response to FAIT, and no major treatment-related complications were noted [40]. In 2006, Kondo et al. reported that a combination of 5-FU and IFN-α strongly inhibited the growth of human HCC cells, and suggested that the effects of this combination therapy may be attributable to changes in the induction of apoptosis through IFN-α/β receptors [41]. In 2009, Kasai et al. reported that intra-arterial 5-FU and systemic pegylated (PEG)-IFN-α2b combination therapy for advanced HCC had an objective response rate of 71.4% [42]. In 1999, Yano et al. compared the in vivo antitumor effects of PEG-IFN-α2b and IFN-α in nude mice injected with cultured HCC cells, and found that PEG-IFN-α2b induced apoptosis more strongly than IFN-α [43]. Intra-arterial 5-FU infusion and systemic PEG-IFN-α2b combination therapy appears to be highly promising, although further prospective studies are required [42,44]. Reports of the use of HAIC with 5-FU combined with systemic IFN in advanced HCC are listed in Table 2.

Low-dose cisplatin (CDDP) combined with 5-FU (low-dose FP therapy) has synergistic effects. This combination is often used in the treatment of gastrointestinal tract malignancies. In combination with 5-FU, cisplatin is a modulator rather than an effector, and increases the antitumor efficacy of 5-FU by increasing the intracellular concentration of reduced folate [37,50]. In 2002, Ando et al. reported that of 48 HCC patients with PVTT, 23 (48.0%) showed an objective response to low-dose FP therapy and concluded that HAIC using low-dose FP might be a useful therapeutic option for patients with advanced HCC with PVTT [51]. In 2010, Ueshima et al. reported that of 52 advanced HCC patients, 20 (38.5%) showed an objective response to low-dose FP therapy [52]. However, there are few reports of favorable objective response rates with the use of high-dose CDDP combined with 5-FU therapy for the treatment of advanced HCC [53,54,55]. Reports of intra-arterial 5-FU and CDDP combination therapy in HAIC are listed in Table 3.

Clinical investigation of cisplatin (cis-diamminedichloroplatinum; CDDP) had been started in 1972. The usefulness of CDDP as an anticancer agent was first confirmed in the treatment of urinary tract cancers. Currently, CDDP is a key chemotherapeutic agent for the treatment of various cancers, including tumors of the respiratory, genitourinary, and digestive systems [60]. The anticancer effect of CDDP is characterized by both time-dependent and concentration-dependent features.

The response rate of CDDP monotherapy administered by HAIC for advanced HCC ranges from 14% to 42% [61,62,63,64]. Reported objective response rates to arterial infusion regimens containing CDDP, such as low-dose FP therapy, range from 0% to 56%, although high efficacy of systemic chemotherapy with CDDP has not been reported in HCC [17,51,52,53,65,66,67,68,69,70,71].

Microfine powder CDDP preparations (DDP-H) (IA-call; Nippon Kayaku Co., Ltd., Japan) for arterial infusion were approved for its use in Japan in 2004. Recently in Japan, favorable results have been obtained using DDP-H in the treatment of advanced HCC patients. In 2008, Yoshikawa et al. conducted a phase II study in advanced HCC patients, reporting that in 80 patients who received HAIC with DDP-H, the overall response rate was 33.8%, the 1-year and the 2-year survival rates were 67.5% and 50.8%; respectively, they concluded that DDP-H has higher antitumor effect than other anticancer drugs when administered by HAIC [62]. The usefulness of DDP-H as a second-line treatment for advanced HCC refractory to TACE using an epirubicin-lipiodol emulsion has also been reported [72,73].

Systemic combination therapy with S-1 and CDDP is a promising treatment for advanced HCC. In 2010, Katamura et al. reported that of 16 HCC patients with extrahepatic metastases who received S-1 and CDDP combination therapy, two (13%), none (0%), five (31%), and nine (56%) showed CR, PR, stable disease, and progressive disease, respectively, with an overall objective response rate of 13% (2/16) and an overall survival rate at 1 year of 77% [74].

There is one report that RFA with sequential HAIC using cisplatin contributed to a longer disease-free interval [16]. HAIC using cisplatin before RFA might prevent an increase in the size of pre-existing microscopic tumor foci.

SMANCS is a lipophilic intra-arterial chemotherapeutic agent for HCC. In 1983, Konno et al. reported a reduction in tumor size and tumor markers in 13 of 14 patients with HCC following arterial infusion of SMANCS-lipiodol emulsion [75]. A subsequent study of 124 patients with HCC or metastatic liver tumors showed significantly higher survival rate following infusion of a SMANCS-lipiodol emulsion [76].

In 2002, Okusaka et al. reported a phase II study of TACE using SMANCS in which the overall response rate was 32% (16/50); they concluded that TACE using SMANCS, which was well tolerated, might be a useful treatment for advanced HCC [77]. However, hepatic arterial infusion with SMANCS caused severe vascular endothelial damage and loss of the hepatic artery for infusion [77,78]. SMANCS is thus unsuitable for repeated TACE/HAIC in HCC and is not widely used for this purpose in Japan.

Miriplatin (Miripla; Dainippon Sumitomo Co., Ltd., Tokyo, Japan), a cisplatin derivative, is a novel chemotherapeutic agent designed for use in transarterial infusion chemotherapy for HCC [79]. Miriplatin: (1) inhibits cell proliferation in a similar manner to cisplatin and has superior solubility in ethyl esters of iodized fatty acids derived from poppy seed oil; (2) releases its platinum constituent continuously, together with the ethyl esters (sustained release), by remaining at the site of the tumor; and (3) has fewer adverse effects, because of its sustained release and its minimal presence in the general circulation [80,81,82,83]. In Japan, miriplatin was approved for use in October 2009.

In 2004, Okusaka et al. conducted a phase II study of miriplatin to assess its antitumor effect and toxicity in treatment-naive patients with HCC. They reported that the CR rate was 56% (9/16) and that none of the patients exhibited grade 4 toxicity or episodes of renal dysfunction, and concluded that miriplatin was well tolerated and showed promising antitumor effect in patients with HCC [84]. In 2011, Okusaka et al. reported their phase II comparative study of miriplatin and SMANCS, in which HAIC with miriplatin had a similar efficacy to HAIC with SMANCS, and repeated dosing with miriplatin was possible without hepatic vascular injury in cases of relapse, whereas HAIC with SMANCS caused hepatic vascular injury [78]. In 2011, Imai et al. reported that in 162 unresectable HCC patients who underwent transcatheter arterial chemotherapy using miriplatin with or without embolization, the objective response rates to HAIC with miriplatin and TACE with miriplatin were 33% (13/40) and 57% (70/120), respectively; they concluded that an objective response was achieved in a significantly higher number of patients treated with TACE with miriplatin than with HAIC with miriplatin [85].

It is well known that HAIC with CDDP causes renal dysfunction [86]. However, in 2011, Imai et al. reported that HAIC with miriplatin could be used safely in HCC patients with chronic renal failure, probably owing to its minimal presence in the general circulation [87]. In terms of renal toxicity, HAIC with miriplatin is considered safer than HAIC with CDDP.

In an animal experiment comparing the antitumor effects of two platinum agents (miriplatin and DDP-H), Watanabe et al. reported no significant difference between miriplatin-lipiodol emulsion and DDP-H-lipiodol emulsion after 7 days post-administration [88]. To date, however, there is no convincing clinical evidence regarding the antitumor effects of these drugs. In Japan, several clinical studies comparing the antitumor effects of miriplatin and other chemotherapeutic agents such as CDDP and epirubicin for advanced HCC are ongoing. If the results for miriplatin are positive in these studies, it will become a key chemotherapeutic drug in the treatment of unresectable HCC.

The platinum-based chemotherapeutic agent oxaliplatin (L-OHP) displays a wide range of antitumor activities [89]. Oxaliplatin has often been used for the treatment of advanced colorectal cancer, in which its effectiveness has been confirmed in many clinical studies [90]. To date, however, few detailed clinical data are available concerning the effects of HAIC with oxaliplatin in advanced HCC. In Japan, oxaliplatin has not been used for the treatment of advanced HCC. In 2010, Rathore et al. reported that in their phase I trial, HAIC with oxaliplatin was feasible, well tolerated, and had demonstrated activity in patients with advanced HCC [91]. A phase II prospective randomized study of the effectiveness of HAIC with oxaliplatin in unresectable HCC is underway. If positive results are obtained, oxaliplatin could become a key chemotherapeutic agent in the treatment of advanced HCC.