The medical records of consecutive 297 patients diagnosed with HCC who received RFA or iodine − 25 seeds implantation treatment at our hospital between January 1, 2014, and May 31, 2018, were retrospectively reviewed. According to the inclusion and exclusion criteria, a total of 134 patients were included in this study (Appendix Fig. 1). Approval for this investigation was obtained from the Ethics Committee of our college Institutional Review Board. The requirement to obtain informed consent was waived by the Institutional Review Board.
The decision to perform the TACE-RFA or TACE-Iodine 125 seeds implantation was based on the multidisciplinary liver conference and patients’ preference prior to the operation. Patients with early HCC were recommended to receive surgical resection, liver transplantation, or RFA. Among them, some patients were not candidates for the RFA treatment due to a suboptimal location of the tumor, and some declined the surgery because they had been treated surgically before inclusion in this study. For these patients, iodine 125 seeds were recommended as the first-line treatment. All patients with early HCC were recommended to receive the TACE treatment because of the available evidence that the efficacy of combined TACE-RFA or TACE-Iodine 125 seeds implantation therapies is better than a single treatment. Patients with intermediate HCC were recommended to undergo TACE treatment. In these cases, RFA or iodine 125 seeds implantation acted as the adjuvant therapy because of the low tumor necrosis rate following the TACE treatment.
The inclusion criteria in this study were: (1) diagnosis of primary early-intermediate HCC by biopsy or imaging, based on European Association for the Study of the Liver (EASL) guideline and Barcelona Clinic Liver Cancer (BCLC) stage; (2) no previous TACE or RFA or iodine 125 seeds implantation treatment; (3) good liver function (Child-Pugh class A or B); (4) the Eastern Cooperative Oncology Group (ECOG) score of 0; (4) the platelet count higher than 40 × 109/L; (5) absence of diffuse liver cancer; (6) no history of liver cancer rupture.
The extent of hepatic tumor burden was assessed before the surgery by triple-phase computed tomography (CT) or magnetic resonance imaging (MRI). The liver function and patients’ medical condition were determined by laboratory tests and physical examination, respectively.
The TACE was performed by two operators who had, respectively, at least eight years and twenty years of experience in performing this type of procedures. Initially, the tip of a 5-French catheter (Cook, Bloomington, IN, USA) or 3-French microcatheter (Progreat, Terumo, Tokyo, Japan) was advanced into the tumor-feeding arteries. Then, an emulsion was prepared by mixing 1 part of lipiodol (Lipiodol Ultrafluido, Guerbet, Villepinte, France) and 2 parts of doxorubicin hydrochloride (Hisun Pharmaceutical Co. Ltd, Zhejiang, China). Depending on the liver function and the tumor size, 5–10 ml of the emulsion was injected through the catheter into the tumor-feeding arteries. Lastly, embolization with gelatin sponge seeds (300–700 µm, Cook) was performed until the stasis of arteries flow was achieved.
Iodine 125 Seeds Implantation
Iodine 125 seeds implantation was performed by three operators with seven, ten, and fifteen years of experience in interventional radiology therapy, respectively. The iodine 125 seeds were implanted into the tumors under the guide of ultrasound and CT. The iodine 125 seeds were enclosed in the NiTinol capsule (China Institute of Atomic Energy, Beijing, China). The seeds, 0.8 mm in diameter and 4.5 mm in length, were implanted at 2–3 weeks after TACE. One week before the implantation, the patients underwent a CT scan, and the obtained images were transmitted to the Treatment Planning System (TPS). The number and positions of the iodine 125 seeds were determined by TPS according to the minimum peripheral dose (mPD, 90 to 165 Gy) prescribed for each tumor. Thus, X- and γ-rays could cover the planned target volume, including the tumor and 0.5-1 cm of adjacent non-tumorous tissue. The placement of the needles (18-gauge, XinKe Pharmaceutical Ltd, Shanghai, China) was performed under CT guidance, and the seeds were implanted into tumors at the interval of 1 to 1.5 cm through the needles. In the current study, a median of 20 seeds (range: 1–48 seeds) were implanted in each patient.
All RFA procedures utilized the guide of ultrasound and were conducted 1–2 weeks after TACE. The protocol was performed by two operators with twenty-three and thirty-two years of experience in interventional radiology, respectively. The tumor location was determined by ultrasound. Local lidocaine anesthesia was applied to relieve a patient’s pain from puncture needles. Two grounding pads were attached to the patient’s legs. Subsequently, the probe needles were inserted into the tumor under the guide of real-time ultrasound. After the tips of probe needles were placed in the tumor, the RFA needle with 5 hook-shaped expandable electrodes with a diameter of 3.5 cm at expansion (Rita Medical System, Mountain View, CA, USA) was extended to cover the tumor and 1 cm adjacent non-tumorous tissue. The ablation temperature was kept at 90–100 °C for 10–15 minutes. To ascertain that the ablation was complete, patients received enhanced CT scan to ensure that no residual tumor remained. Otherwise, the RFA was repeated to achieve a complete ablation.
Assessment Of Clinical Outcomes And Follow-up
The primary endpoint was overall survival (OS). The secondary endpoints were progress-free survival (PFS) and objective response rate (ORR). OS was defined as the time from the initial TACE procedure until the last follow-up or patient death. PFS was defined as the time from the first implantation of iodine 125 seeds or RFA treatment to the time of the diagnosis of tumor progression or patient death; this definition was based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). The ORR was defined as the percentage of patients with a response rated as a complete response (CR) and partial response (PR). CR was defined as no enhancement in the arterial stage, and PR was defined as 30% off of the treated tumor with a residual arterial enhancement. Tumor progression was defined as an increase in the size of the treated tumor by 20%, interval development of new intrahepatic tumors, or metastasis based on the mRECIST assessment.
All patients underwent follow-up laboratory and imaging examination, and the end of the follow-up period was May 31, 2019. The median follow-up time was 29 months (range: 5–63 months). Patients were evaluated one month after initial treatment and then every two months by laboratory tests, contrast-enhanced CT, or contrast-enhanced MRI. The imaging results were evaluated by two radiologists and an interventional radiologist to decide whether the patient should receive a repeated treatment (TACE, RFA, or iodine 125 seeds implantation). The number of treatments for every patient was recorded.
The preoperative characteristics of patients in the two groups were recorded and compared. Continuous variables were compared by Student’s t-test and Mann-Whitney U test, and categorical variables were analyzed by the Chi-square test and Fisher’s exact test. OS and PFS in the two groups and subgroups were calculated by the Kaplan-Meier method. Cox proportional risk method was used to analyze the predictors for death and recurrence and adjusted for age, gender, liver resection, Child-Pugh, BCLC stage and AFP. All tests were two-tailed, and the P-value of less than 0.05 was considered statistically significant. SPSS v24.0 (IBM, Chicago, IL, USA) was used to perform all statistical analyses.
Propensity Score Matching
Propensity score matching (PSM) was applied to reduce the effect of selection bias and potential confounding effects. The following baseline characteristics of patients were included in the PSM assessment: age, gender, alanine aminotransferase (ALT), hemoglobin, platelet, lymphocyte, neutrophil, leukocyte, surgery, hepatitis B virus (HBV), alpha-fetoprotein (AFP) level, TACE number, number of tumors, tumor size level, Child-Pugh class, BCLC stage. A 1:1 ratio matching with an optimal caliper of 0.2 without replacement generated 47 pairs of patients. After the PSM, there was no significantly statistical difference of baseline characteristics (Table 1).