The medical records of consecutive 297 patients with HCC who received the treatment of RFA or iodine -125 at our hospital between January 1, 2014 and May 31, 2018 were retrospectively reviewed. The inclusion criteria in this study were: (1) patients who were diagnosed with 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) patients received the treatment of TACE combined with iodine 125 or TACE combined with RFA; (3) patients with good liver function; (4) patients with the Eastern Cooperative Oncology Group (ECOG) score of 0; (5) patients with the platelet count higher than 40×109/L. The exclusion criteria in this study were: (1) the tumors of patients invaded blood vessel or metastasis distant organs; (2) patients have received the treatments of TACE or RFA or iodine 125 or liver resection before been included into the study; (3) the tumors of patients were diffuse; (4) patients had a history of liver cancer rupture. According to the inclusion and exclusion criteria, a total of 112 patients were included in this study (Additional FileFigure 1). Approval for this investigation was obtained from the Ethics Committee of our college Institutional Review Board, and the requirement for informed consent was waived.
The decision to perform the TACE-RFA or TACE-Iodine 125 was based on the multidisciplinary liver conference and patients’ preference prior to the operation. Patients with early stage HCC were recommended to receive surgical resection, liver transplantation, or RFA. Among them, some patients were not candidates for 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 stage HCC were recommended to receive the TACE treatment because of the available evidence that the efficacy of TACE-RFA or TACE-Iodine 125 therapies is better than a single treatment. Patients with intermediate stage HCC were recommended to receive TACE treatment. For these cases, RFA or iodine 125 seeds implantation acted as a adjuvant therapy because of the low tumor necrosis rate following the TACE treatment.
The extent of hepatic tumor burden was assessed before the surgery by triphasic dynamic enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of liver. The liver function and patients’ medical condition were determined by laboratory tests and physical examinations, respectively.
The TACE was performed by two operators who respectively had 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, 5-10ml of the emulsion was injected through the catheter into the tumor-feeding arteries. Lastly, the 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 guidance of ultrasound and CT imaging. The iodine 125 seeds were enclosed in the NiTinol capsule (China Institute of Atomic Energy, Beijing, China). The seeds with 0.8 mm in diameter and 4.5 mm in length were implanted into the tumors at 2-3 weeks after TACE. One week before the implantation, the patients underwent a CT scan of liver, and the CT images were transmitted to the Treatment Planning System (TPS). The number and positions of the iodine 125 seeds were determined by the TPS according to the minimum peripheral dose (mPD, 90 to 165Gy) 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 the RFA procedures utilized the guidance of ultrasound and were conducted 1-2 weeks after the TACE procedure. 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 patients’ pain from puncture needles. Two grounding pads were attached to the patients’ legs. Subsequently, the electrode needles were inserted into the tumor under the guidance of the real-time ultrasound imaging. After the tips of the electrode needles were placed in the tumor, the 8 hook-shaped expandable probes of the electrode needle (Rita Medical System, Mountain View, CA, USA) were released to cover the entire 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, the patients received the enhanced CT scans to ensure no residual tumors. 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 the patients underwent the follow-ups with laboratory and imaging examinations, and the end of the follow-up time was May 31, 2019. The median follow-up time was 29 months (range: 5-63 months). The 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 patients should receive a repeated treatment (TACE, RFA, or iodine 125 seeds implantation). The number of treatments for each patient was recorded.
The preoperative characteristics of patients in the two groups were recorded and compared. Continuous variables were compared by a Student’s t-test or a Mann-Whitney U test, and categorical variables were analyzed by a Chi-square test or a Fisher’s exact test. The OS and PFS in the two groups and subgroups were calculated by the Kaplan-Meier method. A cox proportional risk model was used to analyze the predictors for death and recurrence, and adjuste the age, gender, Child-Pugh, BCLC stage and AFP. All the tests were two-tailed, and the P-value of less than 0.05 was considered statistically significant. SPSS 24.0 software (IBM, Chicago, IL, USA) and SAS software, version 9.4 (SAS Institute, Cary, NC) were used to perform the statistical analyses.
Propensity score matching and inverse probability of treatment weighting
A propensity score matching (PSM) analysis was applied to reduce the selection bias and the potential confounding effects of this study. The following baseline characteristics of patients were included in the PSM assessment: age, gender, alanine aminotransferase (ALT), hemoglobin, platelet, lymphocyte, neutrophil, leukocyte, 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 35 pairs of patients. After the PSM, there was no significantly statistical difference of the baseline characteristics (Table 1).
Inverse probability weighting (IPTW) was used to estimate the average TACE-Iodine 125 treatment effect on the TACE-RFA treatment (TACE-Iodine 125 weight: [1 – propensity score]/propensity score; TACE-RFA weight: 1). After IPTW, there were 54.4 samples in the TACE-Iodine 125 group and 74 samples in the TACE-RFA group. The baseline characteristics of patients were presented in Additional File Table 1.