Transarterial Chemoembolization Plus Radiofrequency Ablation and Iodine-125 Seed Implantation for Hepatocellular Carcinoma in High-Risk Locations: A Propensity Score-Matched Analysis

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide.¹ Radiofrequency ablation (RFA) has been accepted as an effective alternative to surgery in the management of small- to intermediate-sized (≤5 cm) HCCs.^2–4 However, for RFA of HCCs in high-risk locations (tumors close to the diaphragm, large vessels, liver capsule, gallbladder, gastrointestinal tract, or kidney), it is difficult to achieve an effective and safe ablation periphery with a 1 cm surgical margin beyond the tumor confinement for protecting these adjacent critical structures from heat damage, which thus often leads to a local tumor recurrence. Attempts have been made to address this issue, such as RFA combined with transarterial chemoembolization (TACE) or iodine-125 (¹²⁵I) seed implantation.^5,6 However, the local tumor recurrence rates and patients’ long-term survival are still not satisfactory.^7,8 Thus, there is a pressing clinical need to develop a more effective treatment strategy to improve the effect of RFA on HCCs in high-risk locations.

Due to its minimal invasiveness, safety, and effectiveness, ¹²⁵I seed implantation is a favourable therapy for some solid malignant tumors, including HCC.^9–11 Several previous studies^5,7,12 reported that ¹²⁵I seed implantation could further improve the effects of TACE or RFA on HCCs. To the best of our knowledge, there was no report of the triple-combination treatment (TACE + RFA + ¹²⁵I seed implantation) for HCC in high-risk locations.

Percutaneous RFA and ¹²⁵I seed implantation procedures were usually performed under ultrasound or computed tomography (CT) guidance.^13,14 However, for HCCs in high-risk locations, ultrasound-guided percutaneous RFA or ¹²⁵I seed implantation is challenging for poor tumor visualization or suboptimal electrode path due to the overlapped ribs, lung, gallbladder, or gastrointestinal tract, which may result in incomplete RFA, thermal injury to the surrounding organs, or uneven distribution of ¹²⁵I seed in tumors. Although CT imaging usually provides a clearer visualization for such HCCs compared with ultrasound imaging, a CT-guided puncture may result in injury to the diaphragm, blood vessels, gastrointestinal tract, or gallbladder for lack of real-time dynamic imaging. So a real-time and accurate imaging guidance strategy is needed for RFA and ¹²⁵I seed implantation in the treatment of HCCs in high-risk locations.

In the present study, patients with HCC in high-risk locations were first treated with TACE, followed by RFA and ¹²⁵I seed implantation treatments (TACE-RFA-¹²⁵I), which were performed under ultrasound plus CT guidance, and the clinical data of these patients were retrospectively analyzed. The purpose of this study was to evaluate whether this therapy could lead to better tumor control and patients’ survival compared with TACE plus RFA (TACE-RFA) for HCC in high-risk locations, and provide a more effective and safe treatment strategy in the management of this type of HCC.

Patients and Methods

Study Design and Patient Selection

This retrospective study was conducted in accordance with the principles of the Declaration of Helsinki. The study received approval from the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (Approval no.: UHCT241019). A written informed consent was waived by our ethics committee because of the retrospective nature of this study. From January 2010 to June 2023, the clinical data of 126 hCC patients who received the treatment of TACE-RFA-¹²⁵I or TACE-RFA in our center was retrospectively analyzed. The clinical outcomes between the two treatment groups were compared after propensity score matching (PSM) analysis. Meanwhile, a subgroup analysis according to tumor size (≤3 cm and 3–5 cm) was performed to compare the effects of these two different treatments in the two subgroups. The report of this study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies (Supplementary Table 1).

The inclusion criteria of this study were as follows: (1) patients were diagnosed with HCC according to the European Association for the Study of the Liver or American Association for the Study of Liver Disease guidelines;^15,16 (2) patients with HCC in high-risk locations, which were defined as these located < 5 mm of vital structures, such as the diaphragm, large vessels, liver capsule, gallbladder, gastrointestinal tract, and kidneys;¹⁷ (3) a solitary HCC (≤ 5.0 cm) or multiple (up to three) HCC lesions (each ≤ 3.0 cm); (4) patients were not eligible for surgical resection or liver transplantation; (5) the procedures of RFA and ¹²⁵I seed implantation were performed under combined ultrasound/CT guidance; (6) no vascular invasion or no extrahepatic metastasis; (7) Eastern Cooperative OncologyGroup (ECOG) performance status 0; (8) Child-Pugh class A or B; (9) blood platelet count > 40×10⁹ /L. The exclusion criteria of this study were as follows: (1) before TACE-RFA-¹²⁵I or TACE-RFA treatment, patients received other treatments for HCC, such as stereotactic body radiotherapy, chemotherapy, and liver transplantation, et al; (2) patients were accompanied by other malignancies; (3) patients were accompanied by severe cardiac and renal dysfunction; (4) the clinical data of patients were incomplete or lost to follow-up.

TACE Procedure and Ultrasound Plus CT-Guided RFA and ¹²⁵I Seed Implantation

All the patients received TACE treatment before RFA and ¹²⁵I seed implantation procedures, and the TACE procedures were performed as described in our previous study.¹⁸ After TACE, symptomatic treatments and protective liver function treatments were administered to address TACE-related fever, nausea, vomiting, abdominal pain, and liver dysfunction. RFA was performed 5–10 days after TACE. Before RFA treatment, laboratory examinations, such as complete blood count, liver and renal function, and prothrombin time, were performed to assess whether the patients fulfilled the RFA treatment criteria. The RFA procedures were performed with a RITA 1500 generator (RITA Medical Systems Inc., Mountain View, USA) and a 14-gauge multiple electrode (Rita Medical Systems, Mountain View, California, USA) under combined ultrasound/CT guidance, as described in our previous study.¹⁸ The analgesia was conducted by local injection of 5 mL of 2% lidocaine and intravenous administration of 50–100 mg of a flurbiprofen axetil injection (Tide Pharmaceutical Co., Ltd., Beijing, China).

The procedures of ¹²⁵I seed implantation were performed within 7 days after RFA treatment. The ¹²⁵I seeds were implanted in the insufficient ablation tumor margin or the highly suspected zone of residual viable tumors. The number and distribution of ¹²⁵I seed were determined by the Treatment Planning System (TPS) (HGGR300, Hokai Medical Instruments Co., Ltd., Zhuhai, China). An interstitial needle (17-gauge, hollow needles, 15 cm long) was inserted into the site close to the tumor under ultrasound guidance, and then CT images were used to precisely guide the placement of the interstitial needle. A Mick applicator (Mick Radionuclear Instruments, Bronx, NY) was then sequentially attached to the distal end of each needle to place the ¹²⁵I seed (0.7 millicuries per seed) into the tumor, spaced approximately 1 cm apart along the needle track. After ¹²⁵I seed implantation, a CT scan was performed again to assess the ¹²⁵I seed position and the presence of major complications, and the images were transmitted to TPS for dose verification. Adverse events were reported using the Common Terminology Criteria for Adverse Events version 5.0.¹⁹

Follow-Up

Contrast-enhanced CT or contrast-enhanced magnetic resonance imaging (MRI) of the chest and liver, blood tests such as liver and kidney function, blood routine, and tumor markers were performed at each follow-up. The first follow-up was conducted 4–6 weeks after the initial treatment, and then the patients were reviewed every 3 months during the first year and every 6 months thereafter. Repeated TACE, RFA, or ¹²⁵I seed implantation was used to treat the recurrent or residual tumors. The follow-up of this study ended on November 30, 2023.

In the present study, local tumor progression was defined as the appearance of any viable tumor within 1 cm from the ablated margin of tumors on CT/MRI images during follow-up, and intrahepatic tumor progression was defined as the occurrence of a new tumor within the liver, except for local tumor progression. Local progression-free survival (LPFS) was defined as the time from the initial TACE to local tumor progression or death from any cause. Progression-free survival (PFS) was defined as the time from the initial TACE to local, intrahepatic, distant tumor progression, or death from any cause. Overall survival (OS) was defined as the time from the initial TACE to any cause of the patients’ death. Tumor assessments were conducted by two radiologists with more than 10 years of experience (X.L. and B.L)., and reviewed by an independent radiologist (X.K).

Propensity Score Matching Analysis

A PSM analysis was conducted to reduce the potential biases that may have originated from differences in the baseline characteristics of patients in the present study. A propensity score was generated for each patient from a logistic regression model using 9 variables, including age, gender, Child-Pugh class, Barcelona Clinic Liver Cancer (BCLC) stage, tumor size, tumor number, ascites, hepatitis B virus infection, and serum α-fetoprotein level. Two pairs of matched patients (TACE-RFA-¹²⁵I or TACE-RFA) were obtained using a 1:1 nearest-neighbor matching algorithm with a caliper of 0.05 and without replacement. Usually a maximum standardized mean difference of 0.1 is considered acceptable.²⁰

Statistical Analyses

The x² test and Mann–Whitney U-test were used for comparison of the baseline characteristics between the two groups. The LPFS, PFS, and OS between the two groups were estimated by the Kaplan-Meier method and compared by the Log rank test. The uni- and multi-variate Cox proportional hazards regression analyses were used to identify the prognostic factors associated with the LPFS, PFS, and OS. The variables with a p value ≤0.1 in the univariate analysis were entered into a multi-variate analysis. All the statistical analyses were performed using SPSS (Version 26, Chicago, Illinois, USA) or R Foundation for Statistical Computing software (Version 4.3.1, Vienna, Austria). The statistical significance was two-tailed, and a p value less than 0.05 was considered statistically significant.

Results

Study Population, Technical Success Rate, and Safety

As described in Figure 1, 126 patients with HCC in high-risk locations were enrolled in this study, including 70 patients in the TACE-RFA group and 56 patients in the TACE-RFA-¹²⁵I group, and 46 pairs of patients were matched after the PSM analysis. The baseline characteristics of patients between the two groups were balanced after the PSM analysis, which were shown in Table 1. All of the TACE, RFA, or ¹²⁵I seed implantation procedures of the 46 pairs of patients were successfully performed, and there was no occurrence of major complications or procedure-related deaths (Table 2). The median follow-up period was 43.5 months (range, 31–68 months). One representative case of TACE-RFA-125I therapy for HCC in high-risk locations is shown in Figure 2.

Table 1 The Patients’ Baseline Characteristics Between the TACE-RFA and TACE-RFA-125I Groups Before and After PSM Analysis

Table 2 Adverse Events Related to TACE, RFA and 125I Seeds Implantation After PSM Analysis

Figure 1 The flow diagram of patient selection. Abbreviations: HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization; RFA, radiofrequency ablation; 125I, iodine-125; SBRT, stereotactic body radiation therapy; PEI, percutaneous ethanol injection; MWA, microwave ablation.

Figure 2 A 58-year-old male patient with an unresectable HCC in high-risk locations received the TACE-RFA-125I treatment. (A) A contrast-enhanced CT scan showed a 3 cm HCC (white arrow) near the right branch of the portal vein and the right kidney. (B) The RFA treatment for HCC (white arrow) was performed after the TACE. (C) The 125I seed implantation for HCC (white arrow) was performed after the RFA treatment. (D-E) The follow-up at seven years after TACE-RFA-125I treatment with contrast-enhanced CT and MRI showed a significant shrinkage of tumor size (white arrow), and there was no enhancement of the tumor. Meanwhile, the AFP value decreased from the initial 2800 μg/L to 2.7 μg/L in the last follow-up. The treatment effect of HCC in this patient was a complete response according to the modified Response Evaluation Criteria in Solid Tumors. Abbreviations: HCC, hepatocellular carcinoma; TACE-RFA-125I, transarterial chemoembolization (TACE) plus radiofrequency ablation (RFA) and iodine-125 seed implantation.

The Tumor Recurrence Rates Between the Two Groups After PSM

The 1-, 2-, 3-, 4-, and 5-years of local recurrence rates in the TACE-RFA-¹²⁵I group and TACE-RFA group were 0%, 11.1%, 16.9%, 16.9%, 20.1%, and 6.5%, 15.8%, 33.2%, 46.1%, 46.1%, respectively. The overall recurrence rates (including local, intrahepatic distant, and extrahepatic recurrences) at 1-, 2-, 3-, 4-, and 5-years were 2.1%, 24.4%, 38.5%, 53.8%, and 61.5% in the TACE-RFA-¹²⁵I group and 17.5%, 40%, 66.1%, 81.1%, and 90.9% in the TACE-RFA group, respectively. Both the local and overall recurrence rates in the TACE-RFA-¹²⁵I group were significantly lower than those in the TACE-RFA group (p = 0.037, p = 0.004).

The Local Progression-Free Survival Between the Two Groups After PSM Analysis

The 1-, 2-, 3-, 4-, and 5-years LPFS rates in the TACE-RFA-¹²⁵I group were 100%, 82.4%, 74.8%, 63.5%, and 54%, respectively, which were significantly higher than those of 91.3%, 69.4%, 50.7%, 29.4%, and 26.7% in the TACE-RFA group, respectively (p = 0.004; Figure 3A). The uni- and multi-variate analyses demonstrated that the TACE-RFA-¹²⁵I treatment, tumor size ≤ 3 cm, a solitary HCC, and BCLC stage A were the protective factors for patients’ LPFS (Table 3).

Table 3 The Uni- and Multi-Variate Analyses of LPFS Between the TACE-RFA and TACE-RFA-125I Groups After PSM Analysis

Figure 3 The Kaplan-Meier curves of LPFS, PFS, and OS for patients with HCC in high-risk locations who received TACE-RFA or TACE-RFA-125I treatment after PSM. (A) The LPFS rates at 1-, 2-, 3-, 4-, and 5-years in the TACE-RFA-125I group were significantly higher than those in the TACE-RFA group (p = 0.004). (B) The PFS rates at 1-, 2-, 3-, 4-, and 5-years in the TACE-RFA-125I group were significantly higher than those in the TACE-RFA group, and the median PFS in the TACE-RFA-125I group was also significantly longer than that of the TACE-RFA group (42.0 months vs 29.0 months, p = 0.002). (C) The OS rates at 1-, 2-, 3-, 4-, and 5-years were significantly higher than those in the TACE-RFA group (p = 0.011). Abbreviations: LPFS, local progression-free survival; PFS, progression-free survival; OS, overall survival; HCC, hepatocellular carcinoma; TACE-RFA, transarterial chemoembolization combined with radiofrequency ablation; TACE-RFA-125I, transarterial chemoembolization plus radiofrequency ablation and iodine-125 seed implantation; PSM, propensity score matching.

The Progression-Free Survival Between the Two Groups After PSM Analysis

The 1-, 2-, 3-, 4-, and 5-years PFS rates in the TACE-RFA-¹²⁵I group were 97.8%, 69.3%, 53.7%, 38.2%, and 31.8%, respectively, which were significantly higher than those of 84.8%, 54.3%, 29.3%, 16.3%, and 7.2% in the TACE-RFA group, respectively.The median PFS was 42.0 months in the TACE-RFA-¹²⁵I group, and 29.0 months in the TACE-RFA-¹²⁵I group (p = 0.002; Figure 3B). The uni- and multi-variate analyses indicated that the TACE-RFA-¹²⁵I treatment, tumor size ≤3 cm, a solitary HCC, BCLC stage A, and absence of ascites were the protective factors for patients’ PFS (Table 4).

Table 4 The Uni- and Multi-Variate Analyses of PFS Between the TACE-RFA and TACE-RFA-125I Groups After PSM Analysis

The Overall Survival Between the Two Groups After PSM Analysis

At the end of follow-up, 28.3% (13/46) patients in the TACE-RFA-¹²⁵I group and 56.5% (26/46) patients in the TACE-RFA group died. The 1-, 2-, 3-, 4-, and 5-years OS rates were 100%, 93.4%, 80.7%, 74.9%, and 64.7% in the TACE-RFA-¹²⁵I group, respectively, which were significantly higher than those of 97.8%, 78%, 68.6%, 51.1%, and 45.3% in the TACE-RFA group, respectively (p = 0.011; Figure 3C). The uni- and multi-variate analyses showed that the TACE-RFA-¹²⁵I treatment, tumor size ≤3 cm, a solitary HCC, BCLC stage A, and Child-Pugh class A were the protective factors for patients’ OS (Table 5).

Table 5 The Uni- and Multi-Variate Analyses of OS Between the TACE-RFA and TACE-RFA-125I Groups After PSM Analysis

The Subgroup Analyses by Tumor Size After PSM

In the subgroup analysis of patients with tumor size ≤3 cm, the 1-, 2-, 3-, 4-, and 5-years LPFS, PFS, and OS rates in the TACE-RFA-¹²⁵I group (LPFS rates: 100%, 92.9%, 89.1%, 85.3%, and 72.5%; PFS rates: 100%, 85.7%, 74.7%, 53.1%, and 44.2%; OS rates: 100%, 100%, 96.3%, 92.4%, and 79.8%, respectively) were all significantly better than those in the TACE-RFA group (LPFS rates: 100%, 80%, 69.4%, 44.9%, and 44.9%; PFS rates: 93.3%, 70%, 45.2%, 25.1%, and 11.2%; OS rates: 96.7%, 93.3%, 89.9%, 75%, and 66.5%, respectively) (p = 0.005, p = 0.005, p = 0.040, Figure 4A-C). Meanwhile, the median PFS in the TACE-RFA-¹²⁵I group was significantly longer than that in the TACE-RFA group (50.0 months vs 34.0 months, p = 0.005, Figure 4B).

Figure 4 The Kaplan-Meier curves of subgroup analyses for patients with tumor size ≤3 cm and 3–5 cm after PSM. For HCCs sized ≤3 cm, the 1-, 2-, 3-, 4-, and 5-years LPFS, PFS, and OS rates in the TACE-RFA-125I group were significantly higher than those in the TACE-RFA group (p = 0.005, p = 0.005, p = 0.040, respectively) (A-C), and the median PFS in the TACE-RFA-125I group was also significantly longer than that of the TACE-RFA group (B). For HCCs sized >3 and ≤5 cm, the 1-, 2-, and 3-years LPFS and OS rates in the TACE-RFA-125I group were significantly higher than those of in the TACE-RFA group (p = 0.034, p = 0.011, respectively) (D, F), the 1-, 2-years PFS rates in the TACE-RFA-125I group were significantly higher than those of in the TACE-RFA group (p = 0.011) (E), and the median LPFS, PFS, and OS in the TACE-RFA-125I group were also significantly longer than those of in the TACE-RFA group (D-F). Abbreviations: PSM, propensity score matching; HCC, hepatocellular carcinoma; LPFS, local progression-free survival; PFS, progression-free survival; OS, overall survival; TACE-RFA, transarterial chemoembolization combined with radiofrequency ablation; TACE-RFA-125I, transarterial chemoembolization plus radiofrequency ablation and iodine-125 seed implantation.

As described in Figure 4D-F, in the subgroup analysis of patients with tumor size >3 cm and ≤5 cm, the 1-, 2-, and 3-years LPFS and OS rates in the TACE-RFA-¹²⁵I group (LPFS rates: 100%, 82.6%, and 49.1%; OS rates: 100%, 82.6%, and 48.7%, respectively) were significantly higher than those in the TACE-RFA group (LPFS rates: 75%, 48.6%, and 13.9%; OS rates: 93.8%, 48.1%, and 24.8%, respectively) (p = 0.034, p = 0.011, respectively). The 1-, 2-years PFS rates in the TACE-RFA-¹²⁵I group (PFS rates: 94.4%, 42.4%, respectively) were also significantly higher than those in the TACE-RFA group (PFS rates: 56.3%, 25%, respectively) (p = 0.011). In addition, the median LPFS, PFS, and OS in the TACE-RFA-¹²⁵I group were significantly longer than that of in the TACE-RFA group (median LPFS: 36.0 months vs 23.0 months, p = 0.034; median PFS: 23.0 months vs 17.0 months, p = 0.011; median OS: 36.0 months vs 23.0 months, p = 0.011).

Discussion

In recent years, the application of ¹²⁵I seed implantation in the treatment of some malignant solid tumors extended the indication of brachytherapy, and the therapeutic effectiveness was proven to be preferable, such as in HCC.^7,21 The results of our study showed that, for patients with HCC ≤ 5 cm in high-risk locations, the tumor control and patients’ survival in the TACE-RFA-¹²⁵I group were significantly better than those in the TACE-RFA group. Meanwhile, the results of our study showed that the treatment method of TACE-RFA-¹²⁵I was an independent protective factor for tumor control and patients’ survival outcomes. These outcomes supported the hypothesis that adding ¹²⁵I seed implantation therapy on the basis of TACE-RFA can further improve the effect of TACE-RFA on unresectable HCC (≤ 5 cm) in high-risk locations.

For unresectable HCC ≤ 5 cm, TACE-RFA or TACE in combination with microwave ablation (TACE-MWA) was a favourable treatment. A previous study²² reported the OS rates at 1-, 2-, 3-, and 4-years after TACE-RFA for patients with HCCs < 3 cm were 100%, 100%, 84.8%, and 72.7%, respectively, and the recurrence-free survival rates at 1-, 2-, 3-, and 4-years were 71.3%, 59.9%, 48.8%, and 36.6%, respectively. Meanwhile, a randomized controlled trial²³ reported that 93 patients with HCC ranging from 3 to 5cm received TACE-MWA treatment, the recurrence rate at 1 year was 22.47%, and the median OS was 24 months. Compared with these studies, our study focused on HCCs in high-risk locations, the treatment effects of which are usually inferior to those of HCCs in non-high-risk locations under the same treatment. However, in the present study, the results of our study were comparable or superior to those of studies, which indicated TACE-RFA-¹²⁵I was an excellent treatment strategy for patients with unresectable HCC (≤ 5 cm) in high-risk locations.

The possible potential mechanisms of TACE-RFA-¹²⁵I for HCC are as follows: (1) the tumor-killing effect of hyperthermia and radiotherapy complement each other. The tumor cells in the S phase of the cell cycle are less sensitive to radiotherapy, but respond relatively better to hyperthermia. Meanwhile, the sensitivity of anoxic tumor cells to radiotherapy is lower, but that to hyperthermia is relatively stable;^24,25 (2) radiofrequency hyperthermia could increase the vasodilation and vascular permeability in the treated peritumoral area, which could increase the oxygen supply of this area, and subsequently improve the treatment effect of radiotherapy on HCC;^26,27 (3) the RFA treatment could trigger the systemic anti-tumor immune response, and subsequently enhance the anti-tumor effect of radiotherapy;²⁸ (4) TACE treatment could embolize the tumor blood vessels and reduce the influence of heat-sink effect;^29,30 (5) the deposition of lipiodol in the tumor after TACE treatment can be used as a marker, which helps to achieve a precise RFA and iodine-125 seed implantation treatment. Based on these potential mechanisms, the triple combination treatment (TACE-RFA-¹²⁵I) strategy was used for unresectable HCC in high-risk locations in the present study.

MWA of HCC is becoming increasingly popular as MWA allows for a larger ablation zone in a relatively short time. However, for MWA of HCC in high-risk locations, this feature may cause thermal injury to the adjacent important structures of HCC, such as the biliary and gastrointestinal tracts. Compared to MWA, RFA has the characteristic of a slower heating rate, and thus it may reduce the risk of thermal damage to the surrounding tissues of ablated tumors. Therefore, in the present study, we used RFA instead of MWA for HCC. In addition, in this study, RFA and ¹²⁵I seed implantation were performed under ultrasound plus CT guidance. The advantages of co-guidance with ultrasound and CT are real-time, fast, and precise. Meanwhile, compared with CT guidance alone, it can reduce X-ray radiation to patients. We believed these were the main reasons for the absence of major complications and procedure-related deaths in our study.

Our study had limitations. This is a single center and retrospective study. Although a PSM analysis was performed to reduce the potential selection bias, it could not be completely avoided. So a prospective multi-center randomized controlled trial is necessary to confirmed the results of this study.

Conclusions

Compared with TACE-RFA treatment, TACE-RFA-¹²⁵I should be a more effective therapy for patients with unresectable HCC (≤5 cm) in high-risk locations. TACE-RFA-¹²⁵I under ultrasound plus CT guidance is an excellent and safe treatment strategy for this type of unresectable HCC, and is worth of clinical promotion and application.