Transcatheter Arterial Embolic Therapies for Hepatocellular Carcinoma: A Literature Review

Indications and Contraindications for TACE

The EASL guidelines recommend TACE for unresectable, Child-Pugh A or B multiple HCC with no vascular invasion while in Japan the therapy is recommended even for HCC with vascular invasion if it is Vp1 (tumor invasion to peripheral site than the second branch of portal vein) or Vp2 (tumor invasion to the second branch of portal vein) (11, 15). Liver function is a critical component for careful patient selection for TACE. While patients with absolute contraindication for TACE include those with decompensated liver cirrhosis, severely reduced portal vein flow due to non-tumoral portal vein occlusion or hepatofugal blood flow, extensive tumor with massive replacement of both lobes, technical contraindications to transcatheter arterial therapies (e.g. untreatable arterio-venous shunt) or severe comorbidities involving compromised organ function such as renal deficiency (16).

Choice of Chemotherapeutic Drug for TACE and Comparison Between Different Treatment Regimens in TACE for HCC

Worldwide, the most popular anticancer agent for TACE in patients with HCC is doxorubicin (4). In Japan, epirubicin, mitomycin, cisplatin and miriplatin, a cisplatin derivative (Miripla; Dainippon Sumitomo Co., Ltd., Tokyo, Japan), have also been used for TACE as chemotherapeutic agents (17, 18). However, there is no clear consensus regarding the optimal chemotherapeutic drug to use in cTACE. Sahara et al. conducted a randomized control trial (RCT) for comparing the safety and short-term efficacy of TACE using cisplatin-lipiodol suspension (n=12) with that using epirubicin-lipiodol emulsion (n=16) in patients with recurrent HCC and demonstrated that no significant difference was found with regard to adverse effects, the treatment effect on HCC nodules, or overall tumor response in the two groups (19). Yodono et al. retrospectively examined clinical outcome in 202 HCC patients treated with TACE using either epirubicin-lipiodol emulsion (n=106) or a fine-powder formulation of cisplatin-lipiodol suspension (n=96) and reported that TACE using a gelatin sponge and lipiodol with cisplatin led to better progression-free and overall survival (OS) rates than TACE with the epirubicin-lipiodol emulsion in patients with HCC (20). On the other hand, Oguro et al. retrospectively investigated the short-term therapeutic effects and adverse effects associated with the use of miriplatin-lipiodol suspension for TACE in patients with HCC (n=48), using TACE with cisplatin-lipiodol suspension as the historical control (n=50), and demonstrated that TACE using miriplatin-lipiodol suspension yielded worse short-term responses than did cisplatin-lipiodol suspension, although the rates of adverse events were significantly lower in the miriplatin-lipiodol-treated group (21). Handa et al. retrospectively compared the treatment efficacy of TACE using miriplatin in patients with HCC (n=124) and that using epirubicin (n=97). They concluded that although miriplatin-TACE was superior to epirubicin-TACE in the short term, it proved inferior to the latter in the long-term (22). In view of these results, as mentioned earlier, the optimal chemotherapeutic agent for HCC treatment with TACE remains unclear. Further studies are required to reach definitive conclusion. Previous reports regarding comparison between different chemotherapeutic regimens for TACE in HCC are listed in Table I.

Improving Treatment Efficacy of TACE (Superselective TACE and Warmed Miriplatin)

Superselective TACE is defined as TACE from the distal portion of the feeding subsegmental hepatic artery to evoke severe ischemic effects on a small, limited area of the liver, thus avoiding damage to liver functional reserve; common complications of this technique are mild fever, mild pain and temporary minimal changes of liver function (26). Several investigators reported that using this technique, approximately 40-70% of patients with HCC with tumors sized <4-5 cm can obtain complete tumor necrosis or remain local tumor progression free for more than three years after superselective TACE (27). However, there is a problem that this technique depends highly on the skill of the operator.

Miriplatin is a novel chemotherapeutic drug designed for use in transarterial infusion chemotherapy with or without embolization for HCC (28). Miriplatin: (i) inhibits cell proliferation in a similar fashion to cisplatin and has superior solubility in ethyl esters of iodized fatty acids derived from poppy seed oil; (ii) releases its platinum constituent continuously, together with the ethyl esters (sustained release), by remaining at the site of the tumor; and (iii) has fewer side-effects, because of its sustained release and its minimal presence in the general circulation (29, 30). In Japan, miriplatin was approved for use in October 2009. Seko et al. investigated the difference in antitumor efficacy between patients who underwent TACE for HCC using warmed (40°C) miriplatin (n=45) and those treated using room-temperature miriplatin (n=158) (31). In their results, 17 patients (44.3%) treated with room temperature miriplatin and 32 patients (71.1%) with warmed miriplatin experienced complete or partial responses. Thus, they concluded that warmed miriplatin can be considered as one of the standard treatments for unresectable HCC in patients who are eligible for TACE (31). Their favorable results of warmed miriplatin for TACE may be associated with reduced viscosity and injection pressure through microcatheters of miriplatin-lipiodol suspension (31, 32).

Assessment of Treatment Response, Treatment Schedule and Definition of TACE Failure

Assessment of tumor response is important in patients undergoing TACE for HCC as it is associated with clinical outcome (4, 18, 20). However, unfortunately, conventional methods for tumor response evaluation, such as Response Evaluation Criteria in Solid Tumors (RECIST), have no predictive value in HCC patients who underwent TACE because these criteria only rely on tumor shrinkage as a measure of anticancer activity (3, 11, 33). As mentioned above, TACE for HCC is a procedure whereby an embolic agent is injected into the tumor feeding artery to deprive it of its major nutrient source by means of embolization and this results in direct ischemic necrosis of the targeted HCC tumor. Its antitumor effect is not paralleled by a reduction in overall tumor load but rather by a reduction in viable tumor, as identified by imaging modalities such as contrast-enhanced computed tomography (CT). Modified RECIST (mRECIST) for HCC therapy is based on the fact that diameter of the targeted HCC tumors with viable tumor should guide all measurements (34). Tumor response assessed by mRECIST after TACE therapy for HCC has been demonstrated to correlate well with survival (35). The recent Clinical Practice Guidelines jointly issued by the EASL and the European Organization for Research and Treatment of Cancer recommend that assessment of treatment response in HCC therapy should be based on mRECIST criteria by performing contrast-enhanced CT or magnetic resonance imaging (MRI) 4 weeks after initial therapy for HCC (11). On the other hand, TACE has been performed both at regular pre-defined time intervals (every 2 to 8 months in general) and on demand, according to treatment response as assessed by imaging modalities (on-demand TACE) (5). However, no RCTs have been conducted to investigate the optimal frequency of TACE therapy. In Japan, on-demand TACE is common and further TACE treatment is usually considered in patients with residual viable HCC tumor at 8 to 12 weeks after the initial treatment (6).

Patients with HCC treated with TACE often have unfavorable clinical outcomes with repeated TACE and there is considerable uncertainty surrounding the criteria for repeating or discontinuing TACE therapy. It is important to provide a clearer indication of when TACE should be repeated and more importantly, when TACE should be stopped. An Expert Panel Opinion on Interventions in Hepatocellular Carcinoma recommended the following: (i) TACE should be performed on demand and the decision to repeat TACE should be based not only on treatment response or tumor progression but also on the patient's clinical conditions and tolerance, which should be evaluated before each new cycle of TACE; (ii) HCC stage progression such as the development of vascular invasion or extrahepatic spread during follow-up may provide a useful surrogate measure of refractoriness to TACE; (iii) In clinical practice, three sessions of TACE (within 6 months) should be adequate for effective tumor control and patients without effective tumor control after these procedures should be regarded as having TACE-refractory disease (36). On the other hand, several investigators proposed that Assessment for Retreatment with TACE score (ART score) as assessed by the increase of aspartate aminotransferase by >25% from baseline, an increase of Child-Pugh score of 1 or more than 1 point from baseline, and the absence of radiological tumor response is useful for predicting refractoriness to TACE and a score of 2.5 or more prior to the second TACE identifies patients with a dismal prognosis who may not benefit from further TACE sessions (37, 38).

Intermediate-stage HCC: Comparison of TACE and Other Therapies Regarding survival

The BCLC intermediate stage, or BCLC-B, includes patients with Child-Pugh A and B with large, single-focus HCC (>5 cm) and patients with multifocal HCC, defined as more than three tumors of any size, or 2-3 tumors with a maximal diameter greater than 3 cm. To be categorized as having BCLC-B HCC, patients should be asymptomatic and have no vascular invasion or extrahepatic spread. The BCLC classification indicates that these patients are optimal candidates for TACE (3). However, the BCLC-B stage includes patients varying widely in tumor stage, liver function (Child-Pugh A or B), performance status 0-2 and etiology of underlying liver disease. TACE may thus not be the optimal therapy for all of them. Some patients with intermediate-stage HCC may benefit from other treatment options, which are currently approved or being explored.

Zhong et al. reported that out of a total of 257 and 135 BCLC-B patients with HCC undergoing SR and TACE, the SR group had significantly higher OS rates than the TACE group (1 year, 87% vs. 77%; 3 years, 62% vs. 44%; 5 years, 35% vs. 20%; p=0.025) after propensity score matching adjusting for possible variables associated with survival (39). Similarly, Hsu, et al. demonstrated that in a total of 268 and 455 patients with, the 1-, 3- and 5- year survival rates of HCC patients undergoing SR and TACE were 82% vs. 65%, 68% vs. 29% and 46% vs. 22%, respectively, in the propensity score matching model (146 pairs, p<0.001) (40). In view of these results, SR for intermediate-stage HCC can be a treatment option for some selected patients. On the other hand, Zhao et al. compared clinical outcomes between patients treated with TACE and those treated with TACE-plus-radiofrequency ablation (RFA) in intermediate or advanced HCC (n=167) (41). They concluded that the treatment regimen of TACE-plus-RFA has the advantages of tumor control, liver function protection and survival extending in the treatment of HCC compared with TACE alone in intermediate or advanced stage HCC (41).

The introduction of sorafenib in the therapeutic armamentarium for HCC has provided a new treatment option for the treatment of patients with intermediate-stage HCC for whom TACE is unsuitable due to anatomical reasons or in whom TACE resulted in unacceptable toxicity. Based on available evidence, sorafenib has a role in patients with HCC who fail or are not eligible for TACE (16). Bruix et al. performed a subgroup analysis of the landmark SHARP study to examine the efficacy of sorafenib in patients with intermediate-stage HCC (sorafenib group, n=54; placebo group, n=51) (42). They demonstrated that patients treated with sorafenib had a longer median OS [14.5 vs. 11.4 months, hazard ratio (HR)=0.72], time-to-progression (TTP) (6.9 vs. 4.4 months, HR=0.47) and a higher disease control rate (50.0% vs. 43.1%) than those who received placebo (42).

Conventional TACE and DEB-TACE

Transcatheter arterial embolization was initially used to treat HCC by Doyon et al. in 1974 and was applied to most unresectable HCC using gelatin sponge particles and anticancer agents by Yamada et al. in Japan (43, 44). In the 1980s, TACE was the only non-surgical therapy for unresectable HCC until the introduction of percutaneous ethanol injection therapy for HCC. In the mid-1990s, lipiodol was newly introduced to enhance mainly the therapeutic effect. It is a substance which is selectively retained within tumor and increases chemotherapeutic exposure as a drug carrier (45, 46). Lipiodol permits the anticancer drug to concentrate in the targeted tumor and is retained for weeks, while in normal hepatocytes excretion is around seven days. The antitumor efficacy of TACE using lipiodol emulsion is higher than that of anticancer drugs and iodized oil when administered alone (44-49). TACE using lipiodol emulsion for unresectable HCC (i.e. conventional TACE) has thus been gaining popularity.

Survival benefits obtained by TACE were demonstrated in two RCTs. In 2002, Llovet et al. demonstrated in their RCT that TACE had survival benefits compared with conservative treatment [HR=0.47, 95% confidence interval (CI)=0.25-0.91, p=0.025] (50). Similarly, in 2002, Lo et al. demonstrated in their RCT that TACE resulted in a marked tumor response, and the 1-, 2- and 3- year survival rates were significantly better in the TACE group (57%, 31% and 26%, respectively) than in the control group (32%, 11% and 3%, respectively, p=0.002) (51). On the other hand, the survival benefit of TACE has been examined in other RCTs, and two of these did not show a prolonged survival time as compared with control group of patients (52, 53). However, in 2003, Llovet et al. conducted a meta analysis of transcatheter arterial embolization or TACE for HCC (seven trials, 545 patients) and reported that both transcatheter arterial embolization and TACE improved 2-year survival compared with the control group with best supportive care (HR=0.53, 95% CI=0.32-0.89, p=0.017) (54). Currently, the EASL guidelines recommend TACE for intermediate-stage HCC while in Japan the therapy is recommended even for HCC with vascular invasion if it is Vp1 or Vp2 (11, 15).

TACE-related adverse events are transient and manageable in general, however, they can occur in a significant proportion of individuals (30-100%) (5, 6, 16). They include ascites, deterioration of liver function, infection such as liver abscess, gastrointestinal bleeding and post-embolization syndrome comprising of fever and abdominal pain (5, 6, 16). In summary, conventional TACE may be associated with some survival benefits. However, since the level of survival benefits from conventional TACE varies, a careful selection of patients with HCC may be crucial.

DEB-TACE uses doxorubicin-loaded beads rather than the conventional doxorubicin-lipiodol emulsion (4, 5). DEB-TACE ensures sustained and slow release of the chemotherapeutic drug locally in addition to causing ischemic injury to the tumor and it has been shown that this treatment modality can result in an overall favorable toxicity profile and anticancer efficacy (4, 5). In 2010, Lammer et al. in their RCT (PRECISION V trial) compared DEB-TACE with cTACE for the treatment of 212 cirrhotic patients with HCC and found that the DEB-TACE group had higher rates of complete response, objective response and disease control as compared with the cTACE group. In subgroup analyses of patients with Child-Pugh B, PS 1, bilobar disease and recurrent disease, the DEB-TACE group exhibited significantly higher response rates and DEB-TACE was associated with a reduction in serious liver toxicity and a lower rate of doxorubicin-related side-effects as compared with cTACE (8). In 2010, in their RCT which compared DEB-TACE with doxorubicin (n=41) and bland transcatheter arterial embolization (transcatheter arterial embolic therapy without chemolization) with BeadBlock (n=43), Malagari et al. reported that at six months, objective response rates were 73.2% (30/41) in the DEB-TACE group and 55.8% (24/43) in the bland transcatheter arterial embolization group, HCC recurrence rate was higher for the bland transcatheter arterial embolization group (78.3% vs. 45.7%) at 12 months, but TTP was longer for the DEB-TACE group (42.4 weeks vs. 36.2 weeks, p=0.008) (9). Thus, they concluded that DEB-TACE leads to a better local response, fewer recurrences, and a longer TTP than bland transcatheter arterial embolization with BeadBlock (9). On the other hand, in 2012, Song et al. showed in their retrospective study that the treatment response in the DEB-TACE group (n=60) was significantly higher than that of the cTACE group (n=69) (p<0.001) and TTP was significantly longer (11.7 and 7.6 months, respectively, p=0.018), although there was no statistically significant difference in liver toxicity between the groups (p>0.05) (55). Furthermore, Martin et al. (56) and Huang et al. (57) in their meta-analyses demonstrated that DEB-TACE is an effective therapy with a favorable pharmacokinetic profile with significantly less systemic doxorubicin exposure when compared to cTACE. In view of these results, DEB-TACE may be associated with an increased response rate and reduced treatment-related toxicity compared to cTACE. DEB-TACE has been increasingly used as a first-line transcatheter arterial embolic therapy for HCC, although phase III trials comparing DEB-TACE and conventional regimens are lacking and the clinical data for DEB-TACE using chemothereapeutic agents other than doxorubicin such as epirubicin, cisplatin and miriplatin frequently used in Japan are also lacking. However, if favorable results are obtained in studies using these regimens, DEB-TACE will likely replace cTACE in the near future. Previous studies regarding comparison between DEB-TACE and cTACE or bland transcatheter arterial embolization in HCC are listed in Table II.

Preoperative TACE Prior to SR or LT

TACE has also been performed as preoperative adjuvant chemotherapy in patients with resectable HCC with the aim of improving survival (61-66). Four RCTs assessed the efficacy of preoperative TACE in terms of survival (61-64). Wu et al. conducted an RCT in 52 patients with large HCC (n=24 in the pretreatment TACE group and n=28 in the control group), concluding that preoperative TACE for resectable large HCC should be avoided since it does not provide complete necrosis of large HCC tumors and results in delayed surgery and difficulty in the treatment of recurrent lesions without any survival benefit (64). Yamasaki et al. conducted an RCT on 97 patients (solitary HCC, 2-5 cm in size; n=50 in the pretreatment transcatheter arterial embolization group and n=47 in the control group) and demonstrated that preoperative transcatheter arterial embolization did not improve postoperative survival (63). Similarly, Zhou et al. (61) and Kaibori et al. (62) reported in their RCTs that preoperative TACE did not improve clinical outcomes. In summary, preoperative TACE for HCC may not be associated with improved clinical outcomes.

In patients with HCC on the waiting list for LT, cTACE is the most frequently used therapy before LT for HCC (so-called bridging therapy) since such patients can experience HCC progression beyond the accepted criteria for LT (67, 68). However, due to the small number of prospective studies of cTACE before LT with well-defined entry criteria and the variability of results, the role of cTACE in tumor down-staging is still to be defined. On the other hand, there are several studies comparing outcome of cTACE and DEB-TACE before LT for HCC. Nicolini et al. compared recurrence-free survival (RFS) after LT for HCC and effects of HCC necrosis on tumor histology between patients treated with cTACE before LT (n=16) and those treated with DEB-TACE (n=22) (10). They reported that the 3-year RFS was significantly higher in DEB-TACE-treated patients than in cTACE-treated patients (87.4% vs. 61.5%, p=0.0493) and fibrotic and inflammatory reactions surrounding the tumor nodule were markedly more common in the DEB-TACE group (p<0.0001 for both), concluding that DEB-TACE can effectively promote HCC necrosis and improves RFS after LT for HCC (10). Frenette et al. investigated rates of necrosis and HCC recurrence in 111 consecutive patients with HCC who underwent cTACE (n=76) or DEB-TACE (n=35) before LT and reported that rates of necrosis and HCC recurrence did not differ between groups and dropout from the transplant list was equal for both groups (69). In view of these results, whether DEB-TACE before LT can obtain better tumor necrosis rate and survival merit than cTACE before LT remains unclear. Further studies are required to confirm these results.

Radioembolization

Radioembolization or selective internal radiation therapy has recently emerged as a treatment option for intermediate-stage HCC and its role for the treatment of unresectable HCC is still being refined (12-14). For patients with HCC treated with radioembolization, implantable radioactive microspheres are delivered into the feeding arteries of the tumor so that tumor nodules are treated irrespective of their location, number or size (12-14). Radioembolization is distinctly different from external-beam radiation therapy. Currently, the most popular radioembolization technique uses microspheres coated with Y90 β-emitting isotope (TheraSphere or SIR Sphere) (12-14). Unlike cTACE or DEB-TACE, arterial occlusion is not the intent with radioembolization.

Salem et al. performed a comparative efficacy analysis of cTACE (n=122) and radioembolization (n=123) in patients with HCC (70). They reported that patients with HCC treated with cTACE or radioembolization had similar survival and radioembolization resulted in longer TTP and less toxicity than cTACE (70). There is one interesting report assessing quality of life (QoL) in patients with HCC treated with radioembolization. Salem et al. in their prospective study compared health-related QoL in patients treated by cTACE (n=27) or Y90 radioembolization (n=29) for HCC and reported that although Y90 radioembolization was used to treat patients with more advanced disease, those who received radioembolization had significant increased scores in several features of QoL, whereas patients who received cTACE had decreases in QoL scores (71).

Combination Strategies

One limitation of TACE has been the high incidence of HCC recurrence. An increase in plasma vascular endothelial growth factor levels after TACE has been well documented and may be a potential cause of HCC recurrence (72). After TACE, the microenvironment of HCC becomes deranged with increased hypoxia. This leads to an up-regulation in hypoxia-inducible factor-1α, which in turn up-regulates vascular endothelial growth factor and increases tumor angiogenesis (72, 73). Based on these observations, there has been interest in combining antiangiogenic molecular targeted-agents such as sorafenib with TACE to reduce post-TACE tumor angiogenesis and improve the treatment efficacy of TACE.

Kudo et al. conducted an RCT of sorafenib after TACE to evaluate the efficacy and safety of sorafenib in Japanese and Korean patients with unresectable HCC who responded to TACE (n=458; n=229 in the sorafenib group and n=229 in the placebo group). They reported that sorafenib did not significantly prolong TTP (HR=0.87, 95% CI=0.70-1.09, p=0.252) or OS (HR=1.06, 95% CI=0.69-1.64, p=0.790) in patients who responded to TACE (74). The dosing schedule of sorafenib in relation to TACE is an important factor in this combination therapy. The authors concluded that their study results may have been, in part, due to delays in starting sorafenib after TACE (74). On the other hand, Sansonno et al. demonstrated in their RCT that in 80 HCV-infected patients with BCLC-B HCC who underwent TACE, the median TTP was 9.2 months in the sorafenib-treated group and 4.9 months in the placebo-treated group (HR=2.5, 95% CI=1.66-7.56, p<0.001). (75) Pawlik et al. conducted phase II trial of sorafenib combined with concurrent DEB-TACE to evaluate safety and efficacy in patients with advanced HCC (single arm, n=35). They demonstrated that the objective response rate was 58% by EASL criteria and treatment-related toxicity was manageable with dose adjustment of sorafenib (76). In their meta analysis to assess the safety and efficacy of combination therapy of sorafenib and TACE in patients with unresectable HCC, Liu et al. reported that although the HR for TTP was 0.76 (95% CI=0.66-0.89, p<0.001), and the HR for OS was 0.81 (95% CI=0.65-1.01, p=0.061), concluding that combination therapy of sorafenib and TACE may bring benefits for patients with unresectable HCC in terms of TTP but not OS (77).

To date, more than 20 clinical trials of combined TACE and sorafenib have been reported. One major drawback is that the most noteworthy feature among these studies was the heterogeneous disease statuses of the target populations in terms of baseline liver function, HCC stage and background liver disease, and assessment method of treatment efficacy and TACE procedure may be different between these studies. Furthermore, there are three study designs to combine TACE and sorafenib: (i) an interrupted design where sorafenib is stopped around the time of TACE; (ii) a sequential design where several cycles of TACE are performed first and then sorafenib is initiated; and (iii) a continuous design where both are applied together (36). The results of clinical outcomes of these combination studies are eagerly awaited.