This was a cohort study conducted as a retrospective analysis of a prospective database in a single center. In our group, there were 732 consecutive HCC patients who underwent ultrasound-guided percutaneous RFA in our center from January 2000 to January 2013. The inclusion criteria for this study were as follows: (1) a tumor size ≤ 5 cm and tumor number ≤ 3; (2) an absence of significant direct tumor invasion of adjacent organs or tumor thrombi in the main or lobar portal system; (3) a tumor not invading a main bile duct or being obviously exophytic; (4) a liver function of Child-Pugh A and B or Child-C (whose liver function was improved after liver protection therapy and tumor size <3 cm, no obvious ascites next to the puncture site of liver); (5) a tumor accessible via a percutaneous approach; (6) international standard ratio < 1.6 and platelet count > 50000/μL; (7) No extrahepatic metastasis before RFA; and (8) a follow-up of at least one year after the first RFA treatment.

Among our study subjects, 416 patients did not meet the inclusion criteria and were excluded from the study. The remaining 316 patients, who met the inclusion criteria and received percutaneous RFA as a first-line treatment were enrolled in this study (Figure 1). These patients underwent percutaneous RFA due to severe liver cirrhosis, advanced age, chronic respiratory/cardiac diseases or preferred minimally-invasive therapy. There were 250 men and 66 women. Patients age ranged from 24 to 87 years (mean, 60.1 ± 10.8 years). Two hundred and fifty patients had liver function of Child-Pugh class A, whereas 57 patients had class B, and 9 class C. A total of 278 (88.0%) patients were found with liver cirrhosis, which was caused by hepatitis B in 231 patients, hepatitis C in 37, alcohol abuse in 4 and other causes in 6. The remaining 38 patients had fatty liver (n =24) and normal liver (n = 14) (Table 1).

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Figure 1 Flow chart summarizing the patients selected for this study. HCC: Hepatocellular carcinoma; TACE: Transcatheter arterial chemoembolization; AFP: Alpha-fetoprotein.

The diagnosis of HCC was histologically proven (n = 204) or established according to noninvasive criteria (n = 112)[11]. Liver biopsies were performed when the noninvasive criteria were not satisfied.

All patients underwent a baseline evaluation, which included an enhanced CT or MRI scan of the abdomen and pelvis within one month before the treatment. Serum laboratory tests consisting of a complete blood count, coagulation profile, liver and kidney functional tests (such as ALT, AST) and serum tumor markers (such as AFP) were performed in the two weeks before the treatment. Contrast-enhanced ultrasound (CEUS) was regularly performed to confirm tumor coverage and tumor number prior to RFA. SonoVue (Bracco SpA, Italy) was used as the contrast agent in this study.

All RFA procedures were performed by two of four radiologists (YW, WW, CMH, and YK), all of them had more than 5 years of experience in ultrasound-guided interventional procedures. The tumor size, shape and border were obtained mainly using ultrasound scans, and enhanced CT/MRI was used as a reference. If liver cirrhosis was present, a full evaluation of the portal vein system was performed. We evaluated the related ultrasound parameters for the diagnosis of portal hypertension in the liver cirrhosis patients[12]. “Risky procedure location” was defined as a tumor located adjacent to (≤ 0.5 cm) the diaphragm, bowel, gallbladder, main bile duct or large vessels (i.e., potentially critical structures).

Currently, in clinical practice, most RFA devices are able to create an ablation sphere having a maximum diameter of up to 5 cm in the liver. When treating spherical tumors larger than 3 cm in diameter with 5-cm ablation spheres, we generally used multiple overlapping ablations based on a mathematical protocol[13]. Ablative margins covered 0.5-1.0 cm beyond the original tumor with the exception of tumors adjacent to major structures such as the diaphragm, gastrointestinal tract, or gallbladder. For these latter cases, the ablative margin was limited; thus, an individualized protocol was developed[14-16].

During RFA, intravenous moderate sedation provided by an anesthesiologist was induced using 2.5-5.0 mg of midazolam (Roche; Basel, Switzerland) and 50-100 μg fentanyl (Fentaini; Renfu, Yichang, China). The patient was conscious when the RFA electrode was placed, and vital signs and oxygen saturation were continuously monitored during the procedure. After RFA, the patient was observed for 2-4 h and discharged if no evidence of active bleeding was found.

Selection of the RFA device was based upon the tumor size, morphology and location. In the present study, three types of RFA systems were used: multi-tined (RITA Medical System, United States), multi-polar (Celon Lab Power, Germany) and internally-cooled (Tyco Healthcare, United States) electrodes. Real-time Aloka ultrasound systems (Alokaα-10, Tokyo, Japan) and GE systems (E9, GE, United States) were used for scanning with 3.5-5.0 MHz convex probes with needle guide devices for all ablation procedures. Track ablation was performed when withdrawing the RFA electrode in all patients.

To evaluate the technical success of the RFA therapy, contrast-enhanced CT/MRI was performed 1 mo after treatment. Primary technical success was defined as the absence of contrast enhancement in the target tumor[17]. Residual tumor was retreated if the patient was physically strong enough to tolerate another RFA session. Secondary technical success was defined as the absence of contrast enhancement after re-ablation. Complete ablation that was achieved after a maximum of three iterative procedures within 3 mo after initial RFA was regarded as a treatment success. Therefore, persistence of active tumor foci that were untreatable by RFA after a maximum of three iterative procedures was regarded as treatment failure.

Subsequently, patients were followed with repeat CT/MRI every 2-3 mo during the first year and then every 4-6 mo. Contrast enhancement that was detected in the ablation zone on follow-up CT/MRI scans was considered to represent local tumor progression[18]. New nodules in other sites of the liver were considered new tumor occurrence. When local tumor progression or new tumors were identified, additional RFA treatment was considered according to the same criteria used at the time of the initial RFA. When these criteria were not met, liver transplantation, resection, transarterial chemoembolization (TACE), or other treatments were considered if possible.

Fifteen potential prognostic factors were considered in this study, and their classification scores are listed in Table 2. Transplanted patients were censored from this study at the date of transplantation. The probability of local progression-free survival was defined as the interval between the treatment and the date of local tumor progression or death. Overall survival duration was counted in months from the date of RFA to death. Survival curves were plotted using a Kaplan-Meier model and compared using a log-rank test. A univariate Cox proportional hazards model was fitted to each variable. All significant variables were subject to multivariate analysis to assess their value as independent prognostic factors. SPSS 21.0 software (SPSS, Chicago, IL, United States) was used to perform the analysis, and P < 0.05 was considered to be statistically significant.

For the treatment of initial tumors, primary technical success was achieved in 301 patients (95.2%). Residual tumor was observed in 15 nodules in 15 patients, including 3 nodules close to the main branch of the portal vein, 2 close to the gallbladder, 2 close to the diaphragm, 2 close to the bowel, 4 larger than 4 cm, and 2 with poorly defined margins during ultrasound imaging. Among the 15 patients, four patients (26.7%) had secondary technical success after 2-3 RFA sessions. The other 11 patients did not receive repeated RFA or still had residual tumor after re-ablation due to difficulty with respect to the ablation location, poor liver function, or development of multiple new tumors (Figure 2).

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Figure 2 Outcomes of radiofrequency ablation as a first-line treatment for 316 patients with liver cirrhosis and hepatocellular carcinoma. RFA: Radiofrequency ablation; HCC: Hepatocellular carcinoma; TACE: Transcatheter arterial chemoembolization.

Local tumor progression and/or new tumor development was observed in 43.3% (132/305) of the patients during the follow-up period. Twenty-two patients had local tumor progression and new tumors, whereas 20 patients had local progression only, and 90 patients had new tumors only. A total of 53 patients underwent repeated RFA sessions (2-5 sessions); 43 received TACE, 12 received resection, 8 liver transplantion, and the other 16 patients received other treatments such as PEI, radiotherapy or supportive treatment (Figure 2).

Follow-up ranged from 12 to 158 mo (median: 72.5 mo; mean: 71.8 mo), (Table 3). In all, 105 patients died, 10 received transplants, and 172 were alive without transplants. The remaining 29 patients (9.2%) were lost to follow-up (mean 20.4 mo), largely due to logistic and geographic challenges in making follow-up visits (Figure 2). Overall, 100 deaths were related to HCC progression or cirrhosis complications, and 5 were unrelated to liver disease. The overall estimated 1, 3, 5, 7 and 10 year survival rates were 90.0%, 70.8%, 49.7%, 41.1%, and 28.4%, respectively. Median overall survival was 61.0 mo (Figure 3). When comparing the different periods of enrollment, the overall survival in the second enrollment from 2007 to 2013 was significantly better than survival in the first enrollment from 2000 to 2007 (median 65 mo vs 44 mo, P < 0.001).

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Figure 3 Kaplan-Meier curve showing an overall 10-year survival. Overall estimated 1-, 3-, 5-, 7-, and 10-year survival rates are 90.0%, 70.8%, 49.7%, 41.1%, and 28.4%, respectively (n = 234, 181, 136, and 71 for 3, 5, 7, and 10 years, respectively).

The factors associated with overall survival are reported in Table 4 and Table 5. Univariate analysis identified 8 factors that were related to the post-RFA overall survival rate. Patient-related factors included Child-Pugh classification (HR = 3.210, P < 0.001) and portal vein hypertension (HR = 2.686, P < 0.001). The tumor-related factors included the number of tumors (HR = 2.293, P < 0.001), Serum AFP (HR = 1.501, P = 0.039) and pathological grade of tumor (HR = 2.509, P < 0.001). Procedure-related factors included CEUS pre-RFA (HR = 0.438, P < 0.001), choice of RFA electrodes (HR = 0.191, P < 0.001), and primary technical success (HR = 2.592, P = 0.009). The factors that showed statistical significance from the univariate analysis were included in the multivariate analysis. Among them, Child-Pugh classification, portal vein hypertension, and number of tumors were independent prognostic factors for overall survival (Table 5 and Figure 4).

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Figure 4 Post-radiofrequency ablation overall survival curves in hepatocellular carcinoma patients with different independent prognostic factors. A: The 1-, 3-, 5-, 7-, and 10-year overall survival for patients with Child-Pugh class A liver function of were 94.1%, 78.9%, 60.1%, 50.5%, and 33.6%, whereas the overall survival rates were 82.5%, 46.8%, 25.9%, 17.2%, and 17.2%, respectively, for Child-Pugh class B, and 28.6%, 14.3%, 0%, 0%, and 0% for Child-Pugh class C, respectively (P < 0.001); B: The 1-, 3-, 5-, 7-, and 10-year overall survival rates were 94.2%, 78.5%, 63.0%, 51.8%, and 36.2%, respectively, for patients without portal vein hypertension and 79.8%, 53.2%, 30.2%, 20.4%, and 10.2%, respectively, for patients with portal vein hypertension (P = 0.002); C: The 1-, 3-, 5-, 7-, and 10-year survival rates were 90.6%, 75.3%, 59.3%, 46.8%, and 34.5%, respectively, for patients with a single tumor and 87.6%, 54.6%, 27.0%, 21.6%, and 10.8%, respectively, for patients with more than one tumor (P = 0.003).

The 1, 3, 5, 7 and 10 year local progression-free survival rates were 83.2%, 59.3%, 42.7%, 35.1%, and 19.5%, respectively (Figure 5). Median local progression-free survival was 45.0 mo. The factors associated with the local progression-free survival are shown in Table 6. Univariate analysis showed 11 factors that were related to the local progression-free survival rate. Of them, 7 factors were the same as above including pathological grade, portal vein hypertension, Child-Pugh classification, number of tumors, serum AFP, CEUS pre-RFA, type of RFA electrodes. The 4 additional factors were the etiology of cirrhosis (HR = 0.851, P = 0.048), number of RFA sessions (HR = 1.574, P = 0.001), tumor size (HR = 1.587, P = 0.013), and risky location (HR = 1.442, P = 0.042). Multivariate analysis showed that Child-Pugh liver function classification (HR = 2.416, P < 0.001), number of tumors (HR = 1.588, P = 0.036) and number of RFA sessions (HR = 1.550, P = 0.002) were strongly related to the local progression-free survival (Table 6, Figure 6).

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Figure 5 Kaplan-Meier curve shows a local progression-free 10-year survival. The 1-, 3-, 5-, 7- and 10-year local progression-free survival rates were 83.2%, 59.3%, 42.7%, 35.1%, and 19.5%, respectively.

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Figure 6 Post-radiofrequency ablation local progression-free survival curves in hepatocellular carcinoma patients with different independent prognostic factors. A: Patients with Child-Pugh class A had significantly greater local progression-free survival rate than patients with Child-Pugh class B and C (P < 0.001); B: Patients with a single tumor had a significantly higher local progression-free survival rate than patients with more tumors (P = 0.036); C: Patients who had one radiofrequency ablation session had a significantly greater local progression-free survival rate than patients who had multiple sessions (P = 0.002).

Ten major complications (1.8%) occurred after ablation in this group as summarized in Table 7. One death (0.2%) related to RFA occurred. This patient had a tumor located close to the colon and had a bowel perforation the day after RFA. After surgical repair, he ultimately died of septic shock within one month. Minor complications included mild skin burns (n = 1), moderate pleural effusion (n = 4), slight bowel adhesion without obstruction (n = 8), mild dilation of the biliary duct (n = 4), and inflammation or thickening of the gallbladder wall (n = 3).

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, causing more than 500000 deaths each year. Clinical evidence has confirmed the efficacy of radiofrequency ablation (RFA) for the treatment of localized HCC. The promising and optimistic short- and mid-term outcomes for RFA in HCC have been widely reported; however, the studies on the long-term outcomes of a 10-year follow-up are limited. RFA was not the sole first-line treatment in some of the 10-year studies. Additionally, this study showed the long-term outcomes of RFA as a first-line treatment in HCC patients in China in a more heterogeneous population with expanded inclusion criteria that included a larger number of treated tumors > 3 cm and tumors with poorer Child-Pugh class scores.

In this study, the overall 5- and 10-year survival rates for HCC patients with tumors of 3-5 cm were 47.3% and 25.2%, which appears to be fairly good despite tumor size being a prognostic factor for local progression-free survival through univariate analysis. Tumor size did not significantly affect the overall survival in a multivariate analysis. In addition to tumor factors and patient factors, procedural factors were prognostically analyzed in this study. Contrast-enhanced ultrasound application was found to be helpful in improving the overall survival after RFA, and the type of RFA electrodes had an effect on local progression-free survival.

Thus far, only a few studies have covered 10-year outcomes with a sufficient number of HCC patients to draw firm conclusions. This study showed the long-term outcome of RFA in 316 HCC patients, including a more heterogeneous population with expanded inclusion criteria that included a larger number of treated tumors > 3 cm and tumors with a poorer Child-Pugh class scores as a first-line treatment. Follow-up ranged from 12 to 158 mo (median: 72.5 mo) with 5-, 7-, and 10-year overall survival and local progression-free survival rates of 49.7%, 41.1%, and 28.4% and 42.7%, 35.1%, and 19.5%, respectively.

These 10-year survival outcomes after percutaneous RFA of HCC appear to be comparable to survival outcomes after surgical resection. Understanding the prognostic factors, which include tumor characteristics, liver function Child-Pugh classification, and application of contrast ultrasound before RFA, is critical for patient care, and this study is helpful in establishing a treatment protocol for HCC with ultrasound-guided RFA.

RFA - a medical procedure in which part of the electrical conduction system of the heart, tumor or other dysfunctional tissue is ablated using the heat generated from high-frequency alternating current. The radiofrequency waves passing through the electrode increase the temperature within the tumor tissue, which results in tumor destruction. First-line treatment: the initial, preferred, or best treatment for a disease. It is often the therapy that combines the best efficacy with the best safety profile and/or the lowest cost.

This is an interesting paper. This monocentric, large experience shows us that RFA is a good first-line treatment option in HCC patients. The analysis of the prognostic factors is also important. The authors have described their retrospective experience with the use of RFA in a large group of patients with HCC, and with a significant long-term follow-up. This is an important experience in the field of HCC therapy.