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INTRODUCTION
Hepatocellular carcinoma (HCC) is associated with a high recurrence rate even after curative treatment.1-3 The 5-year recurrence rate after hepatic resection is reportedly as high as 70%.1,3 Unlike other malignancies, both the tumor and underlying liver function play a pivotal role in the management of recurrent HCC (rHCCs). Therefore, the diverse clinical situations of rHCCs make it difficult to establish a universal treatment strategy, underscoring the need for innovative approaches that balance efficacy with minimal invasiveness.4
Repeated resection or radiofrequency ablation (RFA) is generally a preferred option.4,5 Previous studies have reported superior survival rates with repeat resection or RFA over transcatheter arterial chemoembolization (TACE) for rHCC after curative treatment.6,7 Nevertheless, the feasibility of repeat resection is frequently limited because of impaired liver function or anatomical location of the tumor. RFA has been found to produce unfavorable outcomes in tumors larger than 3 cm or in perivascular lesions.8,9
The recent Barcelona Clinic Liver Cancer (BCLC) guidelines justify the role of TACE for rHCCs.2 However, TACE has limitations such as washout of chemoemulsion or limited penetration to the tumor periphery due to the contribution of tumor blood flow by adjacent portal venules.10,11 Therefore, superselective ablative chemoembolization (SACE) has emerged as a promising transarterial therapy that addresses the inherent limitations of TACE.10-17 SACE offers a unique approach that exploits the cytotoxic effects of ethanol directly on tumor cells and the embolization effect by targeting both tumor-feeding arterioles and periportal venules, thereby circumventing the limitations observed with conventional TACE.14
While the effectiveness of SACE in primary HCC has been documented, its application in recurrent cases necessitates a thorough investigation to delineate its feasibility, safety, and potential role in a broader HCC treatment algorithm. Therefore, this study aimed to evaluate the safety and effectiveness of SACE for the treatment of patients with recurrent single HCCs.
METHODS
Patients
This retrospective study included consecutive patients treated at a single tertiary medical center (Seoul National University Bundang Hospital, Seongnam, Korea) between January 2022 and June 2023. The inclusion criteria were as follows: 1) single rHCCs without vascular invasion or metastasis and 2) ultrasound-guided RFA-infeasible lesions, such as invisible lesions on ultrasonography or lesions obscured by the main portal vein or hepatic vein.18 rHCCs were diagnosed according to European and Korean guidelines and arterial phase enhancement and washout in the venous/late phase on contrast-enhanced dynamic cross-sectional imaging, such as multiphasic computed tomography (CT) or magnetic resonance imaging (MRI).19,20
The exclusion criteria included a maximal tumor diameter >5 cm, major vessel invasion or extrahepatic metastasis on CT/MRI, contrast media allergy, myocardial infarction within 6 months, chronic renal failure, active infection, and other coexisting malignancies. This study was approved by the institutional review board, which waived the need for informed consent.
SACE procedure
SACE was performed by a single radiologist (JHL) with 8 years of experience in interventional radiology. For the SACE emulsion, the protocol reported in previous reports12-14,21 was modified to enhance its cytotoxic effect. In brief, 50 mg of doxorubicin hydrochloride (Adriamycin; Ildong Pharmaceutical, Seoul, Korea) in a 2.5 mL of contrast agent (Xenetix 350 [Iobitridol]; Guerbet, Villepinte, France) was emulsified with 10 mL of ethiodized oil (Lipiodol; Guerbet).22 Ethanol (dehydrated alcohol 99.5%; Taiwan Biotech, Taoyuan, Taiwan) was mixed with the emulsion at a volume ratio of 1:2.12-14,21 After confirming the tumor feeders by rotational cone-beam CT hepatic arteriography as previously reported,22,23 SACE was performed as selectively as possible through the tumor-feeding arteries using a microcatheter with a 1.5-F tip (Velute Ultra; Asahi, Tokyo, Japan).22,24,25 Completion of SACE was determined when tumor arterial staining disappeared and the tumor-feeding arteries were completely embolized.22 Post-treatment, non-contrast CT was performed to check for ethiodized oil uptake by the tumors. If ethiodized oil uptake at the tumor was incomplete, repeat angiography was performed to detect missing feeders followed by additional embolization.
Outcome assessment
The technical success of SACE was defined as successful completion of the treatment process according to the previously mentioned procedural targets.13 Per-tumor and per-patient outcomes at 1 and 6 months were evaluated according to the modified response evaluation criteria in solid tumors.1,23,26 Complete response (CR) was defined as the absence of any tumor tissue that exhibited enhancement during the arterial phase of dynamic CT or MRI.14 One- and 6-month follow-up dynamic CT scans were performed in all patients, and the images were read by consensus by two radiologists with more than 6 years of experience in abdominal imaging.
Statistical analysis
To evaluate the tumor response at 1 and 6 months, analyses stratified by demographic variables were conducted. Per-lesion analysis involved stratification according to the tumor size. Continuous variables are presented as mean±standard deviation, whereas categorical variables are reported as frequencies and percentages. The proportion of CR in each subgroup were compared using Pearson’s chi-square test or Fisher’s exact test. All statistical analyses were performed using SPSS version 18 (IBM, Armonk, NY, USA). A P-value of less than 0.05 was considered statistically significant.
RESULTS
Of the 168 patients referred for TACE for rHCC during the study period, 23 were finally enrolled. However, access to tumor-feeding vessels was precluded in one patient due to vessel dissection, leaving 22 patients for the analysis of tumor responses (Table 1). Fifty percent of the patients had BCLC stage 0 disease, and 59.1% patients exhibited a tumor diameter of less than 2 cm.
Tumor response
A summary of the tumor responses is presented in Table 2. All patients underwent 1-month and 6-month follow-up CT or MRI to evaluate the treatment response after SACE. CR was achieved in all patients (22/22, 100.0%). Follow-up was censored in four patients. Two patients underwent external radiotherapy for the target lesion without radiological evidence of local tumor recurrence, and the other two patients were lost to follow-up. At the 6-month follow-up, 15 patients (83.3%) achieved CR. Among the tumors <2 cm in size, CR was achieved in all cases. Three patients with tumors ranging from 2 to 5 cm in size (n=1 with local tumor recurrence; n=2 with intrahepatic distant metastasis) showed disease progression.
Safety
The incidence of adverse events after the procedure is shown in Table 3. Postembolization syndrome was observed in eight patients (36.4%). The majority of symptoms were mild and categorized as either grade 1 or 2. No cases of grade 3 symptoms were reported.
Regarding liver function according to the Child-Pugh classification, no decline in liver function was reported to a class worse than Child-Pugh B7 at the 6-month follow-up period. Additionally, two patients initially categorized as Child-Pugh class C demonstrated improvement, reaching Child-Pugh class A and B, respectively.
DISCUSSION
In the current study, CR was observed in 83.3% of patients overall and in 100.0% of patients with recurrent tumors <2 cm at the 6-month follow-up, which is consistent with prior findings of SACE or RFA for small HCCs.11,13,14,27
However, the optimal treatment strategy for intrahepatic rHCC remains controversial.4 Although the BCLC guideline suggests TACE or radioembolization for localized rHCC without vascular invasion, repeat hepatectomy or RFA is often the preferred choice for patients with preserved liver function.2,4,7,27-30 Previous studies have favored ablation for small tumors up to 3 cm in size and repeat hepatectomy for tumors >3 cm or those exceeding the Milan criteria as long as they are operable.4
Thus, SACE is a novel transarterial therapy for HCC.10-17 This formulation consists of an ethiodized oil-ethanol mixture and water-soluble cytotoxic drugs, and is designed to leverage the dual embolization capability of both arteriolar and portal venular feeders, which enables it to penetrate and obliterate the tumor’s blood supply more effectively than conventional TACE.10,11,15-17 Upon contact with the tumor cells, ethanol causes direct chemical ablation of the cell wall. Moreover, it is a potent sclerosing agent that enables the prompt embolization of tumor feeders. These two synergistic actions appear to be important factors for enhanced local tumor control.13
In a previous prospective study comparing SACE and conventional TACE in HCC patients with BCLC A or B, the CR rates at 6 months were 100.0% for SACE and 43.3% for conventional TACE. The median progression-free survival was 28 months and 10 months for conventional TACE.14 A comparative study showed no significant difference in CR rates between SACE and RFA for treating small HCC lesions up to 3 cm (95.5% vs. 96.4%; P=0.700) or in the time to progression (11.9 vs. 9.5 months; P=0.773).13
In the present study, the 6-month tumor response to SACE was comparable to previous results with surgical resection, RFA.13,27,31 or combined TACE with ablation,28 and appeared to be superior to conventional TACE28 or drug eluting bead TACE.23 Considering that anatomical factors can be crucial limitations for local ablation or surgery,8,9 these findings highlight SACE’s broader applicability of SACE, especially for lesions near major vessels or areas at risk of RFA-induced thermal damage.
Overall, adverse events after SACE were similar to previous studies.23,32-34 and no serious events (grade 3 or higher) were reported. Additionally, no biliary complications or abscesses were noted. As previously reported, the administration of intra-arterial ethanol combined with ethiodized oil in a 1:2 volume ratio at an ethanol concentration of 33% did not result in biliary problems, such as biliary necrosis or stenosis.14
This study has several limitations. First, owing to its retrospective, single-arm evaluation, further comparisons with different treatment modalities, such as RFA or surgical resection, are required. Second, given the small number of included patients, a prospective study with a larger sample size and long-term results is needed to confirm the value of SACE in rHCC treatment.
In conclusion, SACE for a single rHCC was highly effective in achieving a favorable 6-month tumor response and showed acceptable adverse events. However, further prospective studies are required to verify these findings.
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