GRAPHICAL ABSTRACT

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 reports^12-14,21 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.

Article information

Conflicts of Interest

Jae Hwan Lee is an editorial board member of Journal of Liver Cancer, and was not involved in the review process of this article. Otherwise, the authors have no conflicts of interest to disclose.

Ethics Statement

This retrospective study was approved by SNUBH institutional review board (No. B-2108-705-305), and the requirement for informed consent was waived.

Funding Statement

This work was supported by the SNUBH research fund (14-2020-005, 02-2022-0008), and the Korean Liver Cancer Association Research Award 2022. The funders had no role in the study design, data analysis, or manuscript preparation.

Data Availability

The data presented in this study are available upon reasonable request from the corresponding author.

Author Contributions

Conceptualization: JHL, MK, CJY

Data curation: JHL, KYK, CL

Formal analysis: JHL, KYK

Funding acquisition: JHL

Investigation: JHL, CL, CJY

Methodology: JHL, KYK, CL, CJY

Software: KYK

Supervision: CJY

Validation: MK

Writing - original draft: JHL, KYK, CL, MK, CJY

Writing - review & editing: JHL, KYK, CL, MK, CJY

References

• 1. Korean Liver Cancer Association (KLCA), National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. J Liver Cancer 2023;23:1−120.ArticlePubMedPMCPDF
• 2. Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol 2022;76:681−693.ArticlePubMedPMC
• 3. Xia Y, Li J, Liu G, Wang K, Qian G, Lu Z, et al. Long-term effects of repeat hepatectomy vs percutaneous radiofrequency ablation among patients with recurrent hepatocellular carcinoma: a randomized clinical trial. JAMA Oncol 2020;6:255−263.ArticlePubMedPMC
• 4. Papaconstantinou D, Tsilimigras DI, Pawlik TM. Recurrent hepatocellular carcinoma: patterns, detection, staging and treatment. J Hepatocell Carcinoma 2022;9:947−957.ArticlePubMedPMCPDF
• 5. Yoon JH, Choi SK. Management of early-stage hepatocellular carcinoma: challenges and strategies for optimal outcomes. J Liver Cancer 2023;23:300−315.ArticlePubMedPMCPDF
• 6. Famularo S, Donadon M, Cipriani F, Bernasconi DP, LaBarba G, Dominioni T, et al. Curative versus palliative treatments for recurrent hepatocellular carcinoma: a multicentric weighted comparison. HPB (Oxford) 2021;23:889−898.ArticlePubMed
• 7. Gou H, Liu S, Zhu G, Peng Y, Li X, Yang X, et al. Effectiveness of radiofrequency ablation versus transarterial chemoembolization for recurrent hepatocellular carcinoma: a meta-analysis. Acta Radiol Open 2022;11:20584601221085514. ArticlePubMedPMCPDF
• 8. Lee S, Kang TW, Cha DI, Song KD, Lee MW, Rhim H, et al. Radiofrequency ablation vs. surgery for perivascular hepatocellular carcinoma: propensity score analyses of long-term outcomes. J Hepatol 2018;69:70−78.ArticlePubMed
• 9. Chen J, Peng K, Hu D, Shen J, Zhou Z, Xu L, et al. Tumor location influences oncologic outcomes of hepatocellular carcinoma patients undergoing radiofrequency ablation. Cancers (Basel) 2018;10:378. ArticlePubMedPMC
• 10. Yu SC, Hui JW, Hui EP, Mo F, Lee PS, Wong J, et al. Embolization efficacy and treatment effectiveness of transarterial therapy for unresectable hepatocellular carcinoma: a case-controlled comparison of transarterial ethanol ablation with lipiodol-ethanol mixture versus transcatheter arterial chemoembolization. J Vasc Interv Radiol 2009;20:352−359.ArticlePubMed
• 11. Yu SC, Hui EP, Wong J, Wong H, Mo F, Ho SS, et al. Transarterial ethanol ablation of hepatocellular carcinoma with lipiodol ethanol mixture: phase II study. J Vasc Interv Radiol 2008;19:95−103.ArticlePubMed
• 12. Yu SCH, Hui JW, Li L, Cho CC, Hui EP, Chan SL, et al. Comparison of chemoembolization, radioembolization, and transarterial ethanol ablation for huge hepatocellular carcinoma (≥10 cm) in tumour response and long-term survival outcome. Cardiovasc Intervent Radiol 2022;45:172−181.ArticlePubMedPDF
• 13. Yu SCH, Hui JWY, Chong CCN, Chu CM, Cheung S, Wong J, et al. Transarterial ethanol ablation for small hepatocellular carcinoma (≤3 cm): a comparative study versus radiofrequency ablation. Cardiovasc Intervent Radiol 2020;43:732−739.ArticlePubMedPDF
• 14. Yu SCH, Chan SL, Lee KF, Hui JWY, Hui EP, Chu CM, et al. Ablative chemoembolization for hepatocellular carcinoma: a prospective phase I case-control comparison with conventional chemoembolization. Radiology 2018;287:340−348.ArticlePubMed
• 15. Yu SC, Hui EP, Tang P, Chan SK, Chu CC, Hui JW, et al. Transarterial ethanol ablation for unresectable hepatocellular carcinoma: analysis of clinical and tumor outcomes. J Vasc Interv Radiol 2016;27:639−649.ArticlePubMed
• 16. Yu SC, Lau TW, Tang P, Chan SK, Chu CC, Hui JW, et al. Mechanism and natural course of tumor involution in hepatocellular carcinoma following transarterial ethanol ablation. Cardiovasc Intervent Radiol 2016;39:1136−1143.ArticlePubMedPDF
• 17. Yu SC, Hui JW, Hui EP, Chan SL, Lee KF, Mo F, et al. Unresectable hepatocellular carcinoma: randomized controlled trial of transarterial ethanol ablation versus transcatheter arterial chemoembolization. Radiology 2014;270:607−620.ArticlePubMed
• 18. Hyun D, Cho SK, Shin SW, Park KB, Lee SY, Park HS, et al. Combined transarterial chemoembolization and radiofrequency ablation for small treatment-naïve hepatocellular carcinoma infeasible for ultrasound-guided radiofrequency ablation: long-term outcomes. Acta Radiol 2018;59:773−781.ArticlePubMedPDF
• 19. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2018;69:182−236.ArticlePubMed
• 20. 20Korean Liver Cancer Association (KLCA), National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. Clin Mol Hepatol 2022;28:583−705.ArticlePubMedPMCPDF
• 21. Yu SCH, Hui JWY, Chong CCN, Cho CCM, Cheung S, Wong J, et al. Comparison of survival outcomes in transarterial ethanol ablation and liver resection for solitary hepatocellular carcinoma≤5 cm in patients stratified by liver function. Cardiovasc Intervent Radiol 2022;45:315−327.ArticlePubMedPDF
• 22. Lee JH, Lee IJ, Kim HB, Park B, Kim BH, Park JW, et al. Efficacy and safety of transarterial chemoembolisation with cone-beam CT in patients with hepatocellular carcinoma within the Milan criteria: a retrospective cohort study. Clin Radiol 2019;74:407.e19−407.e28.ArticlePubMed
• 23. Lee M, Chung JW, Lee KH, Won JY, Chun HJ, Lee HC, et al. Korean multicenter registry of transcatheter arterial chemoembolization with drug-eluting embolic agents for nodular hepatocellular carcinomas: sixmonth outcome analysis. J Vasc Interv Radiol 2017;28:502−512.ArticlePubMed
• 24. Cho Y, Choi JW, Kwon H, Kim KY, Lee BC, Chu HH, et al. Transarterial chemoembolization for hepatocellular carcinoma: 2023 expert consensus-based practical recommendations of the Korean Liver Cancer Association. J Liver Cancer 2023;23:241−261.ArticlePubMedPMCPDF
• 25. Lee IJ, Lee JH, Lee YB, Kim YJ, Yoon JH, Yin YH, et al. Effectiveness of drug-eluting bead transarterial chemoembolization versus conventional transarterial chemoembolization for small hepatocellular carcinoma in Child-Pugh class A patients. Ther Adv Med Oncol 2019;11:1758835919866072. ArticlePubMedPMCPDF
• 26. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010;30:52−60.ArticlePubMed
• 27. Wang X, Liang H, Lu Z. Efficacy of transarterial chemoembolization compared with radiofrequency ablation for the treatment of recurrent hepatocellular carcinoma after radiofrequency ablation. Minim Invasive Ther Allied Technol 2020;29:344−352.ArticlePubMed
• 28. Ji J, Yang W, Shi HB, Liu S, Zhou WZ. Transcatheter arterial chemoembolization alone versus combined with microwave ablation for recurrent small hepatocellular carcinoma after resection: a retrospective comparative study. BMC Gastroenterol 2022;22:321. ArticlePubMedPMCPDF
• 29. Guo Y, Ren Y, Chen L, Sun T, Zhang W, Sun B, et al. Transarterial chemoembolization combined with camrelizumab for recurrent hepatocellular carcinoma. BMC Cancer 2022;22:270. ArticlePubMedPMCPDF
• 30. Wang C, Liao Y, Qiu J, Yuan Y, Zhang Y, Li K, et al. Transcatheter arterial chemoembolization alone or combined with ablation for recurrent intermediate-stage hepatocellular carcinoma: a propensity score matching study. J Cancer Res Clin Oncol 2020;146:2669−2680.ArticlePubMedPDF
• 31. Yang HJ, Lee JH, Lee DH, Yu SJ, Kim YJ, Yoon JH, et al. Small single-nodule hepatocellular carcinoma: comparison of transarterial chemoembolization, radiofrequency ablation, and hepatic resection by using inverse probability weighting. Radiology 2014;271:909−918.ArticlePubMed
• 32. Kim TH, Kim NH, Kim JD, Kim YN, Kim YJ, Kim EJ, et al. Transarterial chemoembolization using drug-eluting bead compared with radiofrequency ablation for treatment of single small hepatocellular carcinoma: a pilot non-randomized trial. J Liver Cancer 2021;21:146−154.ArticlePubMedPMCPDF
• 33. Lee KH, Joo SM, Yum TJ, Jung SH. Conventional versus drug-eluting beads trans-arterial chemoembolization for treatment of hepatocellular carcinoma at very early and early stages. J Liver Cancer 2017;17:144−152.Article
• 34. Yang B, You X, Yuan ML, Qin TQ, Duan LJ, He J, et al. Transarterial ethanol ablation combined with transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus. Hepat Mon 2016;16:e37584.PubMedPMC

Figure & Data

References

Citations

Citations to this article as recorded by