The medical records of patients with small HCC who received NTDP-RFA at our center between January 2017 and March 2018 were retrieved and retrospectively analyzed (Fig. 1). A total of 56 consecutive patients were included in this retrospective study.
The inclusion criteria for this study were as follows: (1) 18-70 years old; (2) primary HCC with a background of cirrhosis; (3) single nodules with a diameter ≤ 3 cm; (4) no invasion of the portal vein, the hepatic vein trunk or secondary branches; (5) no intrahepatic and extrahepatic metastases; (6) Child-Pugh grade A/B; (7) the indocyanine green retention rate at 15 min (ICGR-15) ≤ 30%; (8) follow-up period of up to 2 years; and (9) no other antitumor therapy received before treatment. The exclusion criteria for this study were as follows: (1) lost-to-follow-up or follow-up period of less than 2 years; (2) multiple HCC nodules or a single HCC nodule > 3 cm; (3) patients with severe portal hypertension, a history of esophageal variceal hemorrhage, severe hypersplenism syndrome, or refractory ascites; (4) lesions adjacent to the gallbladder, important blood vessels and bile ducts of the hepatic hilum and surrounding organs; (5) patients who were willing to receive hepatectomy or liver transplantation; and (6) severe bleeding tendency, platelet count < 50 ×10^9/L, or prolonged prothrombin time > 3 seconds.
Diagnosis of HCC and cirrhosis
Before NTDP-RFA treatment, all patients underwent imaging studies, including contrast-enhanced computed tomography (CT) and/or magnetic resonance imaging (MRI). To plan the NTDP-RFA procedure, all patients underwent contrast-enhanced ultrasound (US) before NTDP-RFA. he diagnosis of HCC and cirrhosis was confirmed by biopsy during the NTDP-RFA procedure.
Equipment: RF electrodes and RF systems
All NTDP-RFA procedures involved the use of internally cooled wet electrodes with a directional injection function (LDDJS1-0200200, Mianyang Lide Electronics Co., Ltd., Mianyang, China), which can perform both intraelectrode cooling and extraelectrode saline perfusion. The electrode has an outer diameter of 14 G, and there is a pipe inside to circulate the cooled hypertonic saline in the electrode, and the perfusion rate is set to 40 ml/min. The tip of the electrode has an exposed hot end with a length of 2 cm. At distance of 0.5 cm and 1.5 cm from the tip, there are only two injection holes on one side of the hot end, each of which is 0.5 cm long and 0.2 cm wide. A solution of 5% NaCl was used as the infusion solution, and the flow rate was adjusted to 1 ml/min. The RF energy is provided by a 400 kHz RF generator (LDRF-120S, Mianyang Lide Electronics Co., Ltd., Mianyang, China), which can activate multiple electrodes simultaneously.
All RFA procedures were performed by a hepatobiliary surgeon with more than 15 years of experience in RFA. All operations were performed under monitoring anesthesia, and puncture was performed percutaneously under the guidance of real-time US. An injection of fentanyl citrate (0.1-0.2 mg, Humanwell Pharmaceutical Co., Ltd., Yichang, China) was used for analgesia, an injection of dexmedetomidine hydrochloride (50-100 mg, Hengrui Medicine Co., Ltd., Jiangsu, China) was administered for sedation, and an injection of lidocaine hydrochloride (Zhaohui Pharmaceutical Co., Ltd., Shanghai, China) was used for topical anesthesia. The number of RF electrodes used depended on the diameter of the tumor. For tumors with a diameter of ≤ 20 mm, two electrodes were used; for tumors with a diameter between 20-30 mm, three electrodes were used. Preoperative contrast-enhanced US was performed to identify the tumor site. The optimal treatment position and needle insertion route (selected to avoid large blood vessels, bile ducts and adjacent organs) were selected, and the puncture point was marked on the skin.
The specific implementation steps of NTDP-RFA were as follows: two or three electrodes were inserted in parallel into the liver parenchyma around the target tumor, and the side hole at the hot end of the electrodes was pointed in the direction of the tumor. The precise placement of the electrodes is shown in Fig. 2. The initial power was set to 60 W, and then the power was increased at a rate of 10 W/min until the maximum power of 120 W was reached. During ablation, hypertonic saline solution was continuously injected into the tissue through the side hole of the electrode, and the RFA system continuously measured tissue resistance. The power output was stopped automatically if resistance exceeded a specific limit (300 Ω). Therefore, the time of the procedure changed according to the situation. At the same time, the electrode interior was cooled by the circulating perfusion of saline during ablation. The ablation procedures were monitored by real-time US, and the ablation was not terminated until the transient hyperechoic cloud caused by the gas covered all units of the tumor. After ablation was completed, the electrode needle was removed in "needle tract ablation mode (35 W) " to prevent bleeding.
Follow-up and definitions of terminology
At 15 min after NTDP-RFA completion, contrast-enhanced US was immediately reexamined to evaluate the therapeutic effect. Complete ablation was defined as no enhancement area during the arterial and portal phases. If there were discontinuous, focal or nodular enhancement areas at the tumor site, indicating incomplete treatment, NTDP-RFA was performed again. In the first and second months after NTDP-RFA and every two months thereafter, patients were followed up by contrast-enhanced US, CT or MRI. LTP was defined as the appearance of new tumor foci within 2 cm of the edge of the ablation area by at least one follow-up imaging examination. Otherwise, new tumors were defined as distant tumor progression (classified as intrahepatic distant recurrence and extrahepatic metastasis). Intrahepatic distant recurrence was defined as the detection of a tumor lesion 2 cm away from the ablation position within the liver. A visual analog scale (VAS) was used to assess postoperative pain on a scale of 0 to 10 (0, no pain; 10, worst imaginable pain). Postoperative complications were also assessed according to the Society of Interventional Radiology (SIR) classification. Technical success was defined as completion of the NTDP-RFA procedure as planned. Fifteen minutes after completion of the NTDP-RFA procedure, contrast-enhanced US indicated that complete ablation was defined as clinical effectiveness.
The primary endpoint of the study was the rate of LTP. The secondary endpoints were the comparison of (i) intrahepatic distant recurrence rates; (ii) tumor progression-free survival rates; and (iii) overall survival rates. Tumor progression-free survival and overall survival were calculated from the date of initial NTDP-RFA treatment to the date of tumor recurrence or death.
Continuous data are expressed as medians and interquartile ranges. Categoric variables are expressed as frequencies and proportions. Repeated measures ANOVA was used to compare biochemical indicators of liver function. Survival curves were estimated by using the Kaplan-Meier method. Cox proportional hazards regression analyses were performed to determine significant baseline clinical-biologic and nodule parameters for the prediction of local and overall tumor progression-free survival rates. All variables with P < 0.200 were included in the multivariate analysis; a stepwise Cox proportional hazards regression model was used to evaluate their value as independent predictors. In stepwise regression, P < 0.05 was considered to indicate a significant difference. SPSS for version 25.0 (IBM, Armonk, New York, USA) was used for statistical analysis.