The Ethical Committee of the Fifth Medical Center of Chinese PLA General Hospital approved this study, and informed consent was obtained from each patient’s guardian. 683 HCC patients underwent RF ablation treatment at the Fifth Medical Center of the Chinese PLA General Hospital between July 2009 and December 2018. A retrospective analysis of 683 patients was conducted, 164 of whom met the inclusion criteria. The inclusion criteria were as follows: age of 18-75 years; patients who did not receive liver transplantation; HCC patients confirmed by pathology or imaging; HCC patients who did not receive previous treatment except for the RFA or liver resection; diameter of solitary tumor of 5.0 cm or lower; multiple tumors with each having a diameter of 3.0 cm or lower; three or fewer tumors; no invasion into the major portal and hepatic vein branches; no extrahepatic metastases; no severe liver dysfunction (Child-Pugh class C) or no significant coagulopathy (platelet count, <40 × 10⁹/mm³; prothrombin activity, <40%); and Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 1. Patients with incomplete clinical data, infection with HIV or other malignancies, or prior anti-cancer treatment for HCC, including sorafenib, were excluded from the study. As a conclusion, 87 patients who underwent RFA alone were compared with 77 patients who underwent RFA+Sor treatment.

Patients’ baseline clinical data were extracted from medical records; they included their age, their sex, their ECOG performance status, their RFA sessions, their laboratory and pathological examinations, their MR and CT images, and their treatment procedures.

Dexmedetomidine hydrochloride (Jiangsu Hengrui Medicine Co., Ltd., Aibeining: 2mL; 200μg) 0.5μg/kg/h was infused intravenously 30 min before RFA, and the infusion was continued for 15 minutes. In order to anesthetize the local area, lidocaine hydrochloride was administered (2%; Northeast Pharmaceutical Group Co., Ltd., Shenyang, China). Additionally, patients were given pethidine hydrochloride (100 mg, Northeast Pharmaceutical Group Co., Ltd., Shenyang, China) according to the actual situation, 25–100 mg at a time.

All patients underwent percutaneous radiofrequency ablation under dual-phase spiral CT guidance (GE Medical Systems, Milwaukee, WI). During the RFA procedure, we used bipolar radiofrequency ablation probes (Celon ProSurge 150-T30 or Celon ProSurge 150-T40, Celon AG Medical Instruments) with active tips of 30-40 mm measuring 1.8 mm in diameter, 1-250 W output power, 470 kHz frequency, and three bipolar channels. Prior to RFA, all patients underwent plain MR imaging and enhanced MR imaging in order to identify the number, location, and scope of lesions. A CT scan was used for localization during RFA treatment, and the tumor center was selected for puncture as a result of a preoperative MRI examination. Following probe insertion, a CT scan was performed, and RFA was performed once an accurate localization had been achieved. When a non-enhancing region was greater than the previous tumor area, we considered that the RFA treatment was complete. Multiple overlaps were abated using the technique of Chen et al. (22), if the largest tumor diameter exceeded 3 cm.

Sorafenib (Bayer Pharma, Germany) treatment was initiated at the time point of 3 days post-radiofrequency ablation, once liver function had returned to near-normal levels. All patients achieved a complete response at the imaging level following RFA, with the assessment conducted immediately post-RFA. Each patient received a standard dose of sorafenib (400 mg, once daily, orally). If drug-related adverse events occurred, therapy was interrupted or dose reduced (200 mg once daily, orally). Symptomatic treatment was provided to patients who experienced adverse reactions to the medication. Whenever a grade 3 adverse event occurred, treatment interruption was recommended. It is also recommended to discontinue sorafenib treatment when tumor recurrence is observed in the patient.

Each patient was examined at baseline and their medical histories were recorded. Child-Pugh class, ECOG performance status, alpha fetal protein (AFP) levels, and routine laboratory tests were conducted. CT and MR imaging were used to assess tumors. Patients in the RFA+Sor group were recorded as to their sorafenib medication status. One month after RFA, all patients underwent abdominal contrast-enhanced CT or MR imaging, as well as routine laboratory testing. Every three months, the treatment response was assessed. After two to five years after RFA, routine examinations were extended to every four months, and after five years to every six months. The MR and CT images were evaluated independently by two authors with more than ten years of experience in a blinded manner.

When CT was unable to confirm the presence of a residual tumor, MR imaging was performed. All CT examinations, including plain and contrast-enhanced exams, were conducted using a multi-detector row CT scanner (GE Medical Systems, Milwaukee, WI, USA) for the sequential acquisition of 8-mm thick sections at 120 kV and 300 mA. At a flow rate of 3.0-4.5 mL/s, patients were administered intravenous non-ionic contrast agents (iopromide injection; iodine concentration 1.5-2 mL/kg, 300-350 mg I/mL; Bayer Pharma, Berlin, Germany). Following the injection of contrast agents, arterial phase, venous phase, and delayed phase scans were obtained after 30, 60, and 120 seconds.

A 1.5-T MR unit (GE Medical Systems, Milwaukee, WI, USA) was used to perform MR imaging with a 16-channel phased-array body coil. Non-enhanced T1-weighted gradient-echo (TR/TE: 210/2.3 ms; 80°flip angle; 256 × 134 matrix; number of excitations = 1; 8-mm thick section with 1-mm spacing) and respiratory-triggered T2-weighted fast spin-echo (TR/TE: 1900/64 ms; 128 × 128 matrix; number of excitations = 1; 8-mm thick section with 1-mm spacing) pulse sequences were obtained. A pre-saturation band was applied above and below the scanning field to eliminate the influence of lung gas, heartbeats, intestinal gas, and gastrointestinal peristalsis on the imagey. Artifacts related to chemical shift were eliminated using fat-suppression techniques. The images were acquired during two breath-holds. The same technical parameters were used for the dynamic enhanced scans following plain scanning. The dynamic contrast-enhanced MRI examination was performed using gadobenate dimeglumine (0.15 mmol/kg, MultiHance; Bracco Sine, Shanghai, China) at a flow rate of 3 mL/s. Arterial phase, venous phase, equilibrium phase, and delayed phase scans were performed 20, 50, 90, and 600 seconds after injection of contrast agents.

The overall survival (OS) was defined as the period of time from the start of RFA treatment to the date of death or loss of follow-up. The recurrence-free survival (RFS) was defined as the period between the start of RFA treatment and the occurrence of a recurrence of the liver tumor, the progression of lymph node metastases, or the development of distant metastases. During hospitalization, all adverse events were evaluated and documented by telephone follow-up after discharge. CTCAE v5.0 was used to record and assess their performance.

Tumor progression in the treatment area after ablation was defined as tumor enhancement. A distant recurrence refers to the appearance of a new tumor in an untreated area of the liver or in an extrahepatic region (23). For local tumor progression or recurrence, treatment options included RFA, transcatheter arterial chemoembolization (TACE), chemotherapy, or conservative treatment, based on tumor status, routine laboratory tests, results of the multidisciplinary team’s discussion, and patient preference.

The statistical analyses were conducted using SPSS version 24.0 (International Business Machines Corp., USA) and GraphPad Prism version 8.0 (GraphPad, USA). The data are presented as counts (%) and means with standard deviations. Based on independent assessment, a subgroup analysis of OS was performed using Cox regression. Survival curves were generated using the Kaplan-Meier method, and the data were compared using the log-rank test with two-sided P-values. The baseline characteristics and safety profiles of the two treatment groups were compared using the Chi-squared test and the t-test. P < 0.05 was considered statistically significant.

A total of 683 patients were reviewed, but only 164 were included in the study. One group received RFA treatment (n=87) and the other received sorafenib adjuvant treatment after RFA (RFA+Sor, n=77). As shown in Figure 1 , the study process is summarized.

The baseline characteristics of the two groups were balanced, and none of the compared characteristics showed significant differences between the two groups (P>0.05). As shown in Table 1 , the baseline characteristics of the population are described. The mean ages of the RFA group and the RFA+Sor group were 56.6 ± 8.6 and 56.1 ± 9.6 years, respectively. In the RFA group, 68 patients (77.3%) were males, while in the RFA+Sor group, 59 patients (76.6%) were males. In both RFA and RFA+Sor groups, hepatitis B virus infection was the main cause of HCC. Most of the patients had a good physical condition, an ECOG performance status of zero, and a preserved liver function. After tumor recurrence, there was no statistically significant difference in the number of RFA sessions between the RFA and RFA+Sor groups.

The median OS in the RFA group was 35.0 months (95% CI: 29.99, 40.01) and 41.0 months (95% CI: 34.28, 47.72) in the RFA+Sor group (HR, 1.199; 95% CI: 0.866, 1.659, P=0.265) ( Figure 2A ).

The median RFS for the RFA group was 17.0 months (95% CI: 15.17, 18.83) and 16.0 months (95% CI: 14.44, 17.56) for the RFA+Sor group (hazard ratio [HR], 0.845; 95% CI: 0.618, 1.156, P=0.267; Figure 2B ). In Table 2 , treatment methods for recurrent HCC following RFA are shown, and there was no statistically significant difference between the two groups.

For the RFA group, the 1-, 2-, and 3-year RFS rates were 74.7%, 29.9%, and 11.5%, respectively. The 1-, 2-, and 3-year OS for the RFA+Sor group were 72.7%, 19.5%, and 11.7%, respectively. There was no statistically significant difference between 1-, 2- and 3-year RFS ( Figure 3 ). Representative images of tumor after RFA treatment are shown in Figures 4A, B .

Cox regression analysis was used to analyze the information of 164 patients with HCC ( Figure 5 ). A statistically significant difference was not observed among the subgroups defined by baseline stratification factors, including gender, age, family history of HCC, history of alcohol abuse, Eastern Cooperative Oncology Group performance status, number of tumors, and tumor marker. The difference in RFS between the RFA group and the RFA+Sor group was not statistically significant (P>0.05) for all subgroups.

The median duration of sorafenib treatment in the RFA+SOR group was 10.0 months (95% CI: 9.22-10.78). In total, 77.92% (60/77) of patients receiving sorafenib required a dose reduction, and 85.71% (66/70) required its discontinuation ( Table 3 ).

In terms of reasons for discontinuation, disease recurrence was the most common reason (81.82% [54/66] patients); 15.15% (10/66) of patients discontinued sorafenib due to adverse events; and 3.03% (2/66) of patients died ( Table 4 ).

We analyzed the safety data of 164 patients ( Table 5 ). There were no treatment-related deaths in our study, and all complications were grade III. A majority of the adverse events related to RFA were diarrhea (RFA group, 16/87 [18.4%] vs. RFA+Sor group, 23/77 [29.9%], P=0.078), vomiting (RFA group, 19/87 [21.8%] vs. RFA+Sor group, 18/77 [23.4%], P=0.930), abdominal pain (RFA group, 23/87 [26.4%] vs. RFA+Sor group, 20/77 [18.2%]), fatigue (RFA group, 18/87 [20.7%] vs. RFA+Sor group, 14/77 [18.2%], P=0.863), and hypertension (RFA group, 22/87 [25.3%] vs. RFA+Sor group, 17/77 [22.1%], P=0.797). In the RFA+Sor group, 15/77 (19.5%) patients developed skin rashes, while in the RFA alone group, none of the patients developed skin rashes.