CT-guided ¹²⁵I brachytherapy for hepatocellular carcinoma in high-risk locations after transarterial chemoembolization combined with microwave ablation: a propensity score-matched study

This retrospective study was approved by the institutional review board of Sun Yat-sen University Cancer Center that waived the need for written informed consent. The data of 1577 primary HCC patients who had received TACE plus MWA as first-line therapeutic options between February 2015 to March 2021 at our center were retrospectively identified. A total of 287 patients were identified by the following eligibility criteria: (a) Diagnosed with HCC according to the Guidelines of the European Association for the Study of the Liver or American Association for the Study of Liver Diseases^3,30; (b) BCLC stage B or C patients who were not eligible for surgical resection or liver transplantation⁴; (c) presenting with HCC in high-risk locations; (d) TACE combined with sequential MWA was performed as the first-line therapy; (e) Patients had not previously undergone liver resection or liver transplantation. Totally 106 patients were excluded based on the following exclusion criteria: (a) HCC complicated with other malignancies; (b) MWA or ¹²⁵I brachytherapy was not used to treat the tumors in high-risk locations; (c) Incomplete preoperative and postoperative clinical and radiographic data; (d) Child-Pugh class C or D disease and Eastern Cooperative Oncology Group (ECOG) performance status≥2 (Figure 1).

Figure 1

Referring to the previous studies^31,32, The high-risk locations were defined as: (1) Type 1: less than 5 mm from the large vessels (the first- or second-grade branches of the portal veins, hepatic veins, and bile ducts); (2) Type 2: less than 5mm from the hepatic capsule or extrahepatic organs (such as heart, thoracic/abdominal wall, diaphragm, gastric, intestinal, and gall bladder). If the tumor was closed to both structures, the nearest one was chosen to define a high-risk location.

Before TACE-MWA treatment, all patients received a standardized pretreatment evaluation including history, laboratory, and imaging. All TACE and MWA were performed by five interventional radiologists with experience of more than 5 years. For TACE, a selective 5-F catheter (Yashiro type; Terumo Corporation) was introduced, and hepatic arterial angiography was performed to identify the tumor-feeding arteries. Then the tumor-feeding arteries were super-selective catheterized with a 2.7-F microcatheter (Renegade Hi Flo; Boston Scientific Corporation). The embolization emulsion was a mixture of 50 mg/m² of lobaplatin (Hainan Changan International Pharmaceutical Co., Ltd.), 10–40 mg of pirarubicin (Shenzhen Main Luck Pharmaceuticals Inc.) diluted in iodized oil (Lipoid ultra-fluid, Guerbet). MWA was performed within two weeks after TACE. MWA was performed with a commercially available system (ECO-100; ECO Microwave Electronic Institute) under CT guidance. A suitable route for puncture and ablation was designed. According to the size, number and anatomic location of the tumors, physicians chose the number of needles, the power (40–80W), and corresponding time (5–20 min) of ablation as well as the adjustable position of needles to eliminate the residual tumor. All ablations were conducted under intravenous moderate sedation and local anesthesia.

After MWA, CT scanning was conducted immediately to assessed the ablation area and residual tumor adjacent to high-risk sites. Then, interstitial needles were inserted into the target zone under CT guidance. The number and distribution of particles were determined by the treatment planning system (TPS) (BT-RSI, Beijing Atom and High Technique Inc.) to achieve a satisfactory dose distribution. After finishing implantation, a repeated CT scan was performed to check for complications and transmitted to TPS for dose verification. A total of 493 ¹²⁵I seeds (Yunke Pharmaceutical Limited Liability Company) were implanted by three radiologists with at least 5 years’ experience in 49 patients with an average of 12.1 ± 15.1 seeds per patient.

In both groups, patients generally underwent contrast-enhanced CT or MRI 4–6 weeks postoperatively to evaluate initial tumor response. Patients were reviewed every 3 months during the first year and every 6 months thereafter. Repeated TACE, MWA, or ¹²⁵I seeds implantation was performed according to the location and proportion of residual tumor. Intrahepatic tumor response was graded according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) by two radiologists independently and discrepancies of assessment results was resolved by discussions.³³ Tumor response in the high-risk sites was assessed between baseline and best response according to a modified standard: the product of maximum perpendicular diameters of the tumors in the high-risk sites were calculated and compared to the initial value.³⁴ The primary study endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate [ORR], disease control rate (DCR) and safety. PFS was calculated from the date of the first session of MWA or MWA-¹²⁵I for the tumor in high-risk site to the date of tumor progression, death, or last follow-up; OS was calculated from the same treatment to the date of death due to any cause or last follow-up. The ORR was defined as the sum of complete and partial response, whereas DCR was defined as ORR plus stable disease rate. The best overall response was categorized as the final response during the treatment. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (Version 5.0).

To decrease the selection bias between the two groups, propensity scores were computed by logistic regression model for each patient using the following covariates: age (y), BCLC stage (B/C), maximum tumor diameter³⁵, tumor number (1-2/≥3), high-risk site (Type 1/2), portal vein tumor thrombosis (PVTT) (Y/N). A 1:2 propensity score matching was performed using the nearest-neighbor matching algorithm with an optimal caliper of 0.1 without replacement.

Categorical data are reported as counts and percentages, and continuous data are reported as medians or interquartile ranges. The Chi-square test or Fisher’s exact test were used to analyze the differences in categorical variables, and the Mann-Whitney test was applied to the continuous variables. PFS and OS curves were constructed by the Kaplan-Meier (KM) method and estimated by the log-rank test. Univariate was used to analyze prognostic factors for PFS and OS using a Cox proportional hazards model. Significant univariate factors were included in the multivariate models. All tests were two-tailed and P values less than 0.05 were considered to indicate a statistically significant difference. All statistical analyses were performed by R statistical package version 3.4.1 (R Foundation for Statistical Computing, Vienna, Austria).

Between February 2015 to March 2021, a total of 181 HCC patients with tumors in high-risk locations were enrolled in this study. Before PSM, there were significant differences between the two groups in the BCLC stage, maximum tumor diameter, and high-risk location. In the TACE-MWA group (group B), 59 (44.7%) and 73 (55.3%) patients were classified as BCLC stage B and C, respectively. The maximum tumor diameter was significantly smaller than that in the TACE +MWA+¹²⁵I group (group A) (26.5 vs. 36.0 mm, P = 0.039). And there were more tumors in type 2 high-risk sites (50.8%) in group B. After PSM, all characteristics were balanced between the two groups. The baseline characteristics of the unweighted and weighted cohorts are outlined in Table 1. During the follow-up, patients in group A required significantly fewer sessions of TACE and MWA than that in group B (0.73 vs. 1.27, P = 0.048; 0.88 vs. 1.74, P = 0.013, respectively).

In the PSM cohort, Tumor responses of the intra-hepatic tumor and high-risk locations tumor are shown in Table 2. For the tumor in high-risk locations, the ORR and DCR were significantly higher in the group A (67.3% vs. 38.8%, P < 0.001; 93.9% vs. 79.6%, P = 0.025, respectively). Likewise, the ORR of intrahepatic tumors in the group A was higher than that in the TACE-MWA group (51.0% vs. 29.6%, P = 0.011). The DCR in the group A was slightly higher than that in the group B without a statistical difference (85.7% vs. 71.4%, P = 0.055)

In the unweighted cohort, the median PFS time was 7.9 months (95CI%: 10.9–18.5 months) for patients in the group A, and 3.7 months in the group B (95CI%: 7.1–11.4 months) (P = 0.021) (Figure 2A). In the weighted cohort, the median follow-up for the study population was 16.2 months (range, 1.0–80.4 months). At the time of censoring, median PFS was 3.3 months (95%CI: 6.1–10.5 months) for patients in the group B, and 7.9 months (95%CI: 10.9–18.5 months) in the group A with significant difference (P = 0.007) (Figure 2B). Univariable analyses revealed that treatment method, maximum tumor diameter, high-risk location, PVTT, and AFP level were significantly correlated with PFS (P < 0.1). Based on these results, the multivariate analysis including all factors of univariate analysis was performed and it identified treatment method and PVTT as independent prognostic factors for PFS (Table 3) (P < 0.05) (Figure 3A).

Figure 2

There was no significant difference in OS between the two groups in both unweighted and weighted cohorts (Figure 2C, 2D). As shown in Supplementary Table 1, univariate analysis results showed that sex, BCLC stage, high-risk location, PVTT, total bilirubin, and Child-pugh class were significant (P < 0.1). Because of assumed collinearity between PVTT and BCLC stage, as well as the total bilirubin and Child-pugh class, PVTT and total bilirubin were deleted from the multivariate model. Results of the multivariate analysis demonstrated that sex and BCLC stage were prognostic factors for OS (P < 0.05). However, no significant difference was detected between male and female groups (P = 0.057). KM analysis showed significant difference between the BCLC B/C groups (P = 0.012) (Figure 3B, 3C).

Figure 3

The patients without PVTT tended to get a better PFS in group B (P < 0.05) (Figure 4A). No significant difference was detected in group A between PVTT and non-PVTT patients (Figure 4B). Moreover, we observed significant differences between the two groups concerning PFS in both PVTT and non-PVTT patients (Figure 4C, 4D). For the 95 patients with tumors located in the high-risk site 1 (less than 5 mm from the large vessels or bile ducts), the mean PFS time was 11.4 months (95%CI: 7.9–14.9 months) in group A and 7.1 months (95%CI: 4.6–9.5 months) in group B (P < 0.01) (Figure 4e). Similarly, for the 52 patients with tumors located in the high-risk site 2 (less than 5 mm from the hepatic capsule or extrahepatic organs), the PFS time in group A was longer than that in group B (20.3 vs. 10.1 months, P = 0.02) (Figure 4F).

Figure 4

Adverse events for both treatment groups were listed in Table 4. During follow-up, there were no treatment-related deaths in either group and all of these patients were relieved after symptomatic treatment. The most common complication after treatment was abdominal pain in both groups and it was more frequent in the group B (P = 0.007). A slightly higher puncture hemorrhage rate was found in the group B (8.2%), without a significant difference (P = 0.274). One patient developed liver abscess after MWA in the group B. No displacement of ¹²⁵I seeds or radiation-induced liver disease was noted. All of these patients recovered with conservative treatment during the hospital stay.