This study describes our 10-year clinical experience with RFA at a high-volume center. We performed the 2,982 RFA treatments on a total of the 1,170 primary HCC patients, showing that RFA has a high antitumor effect. Tumors were judged to have been completely ablated by final CT imaging in 99.4% of the treatments. Complete response was achieved not only in the first RFA but also in iterative RFA for recurrence. Although complete response rate differed with tumor size, there was not a sharp drop-off in effectiveness. The complete response rate may be higher in this study than others probably because we generally repeated the procedure until CT imaging demonstrated complete tumor necrosis, whereas many other studies limited the procedure number of RFA to 2–3 (11
). Complete ablation of tumors has been reported to be related to improved survival (25
). There were the 18 treatments in which we did not perform additional RFA for residual cancer tissue. In those treatments, usefulness of RFA had been unclear at the initial session because of liver dysfunction or tumor burden.
This study shows that RFA could achieve long-term survival for as long as 10 years. Sixteen patients treated by RFA survived for >10 years. The variables relevant to survival were similar to those found in previous studies on ethanol injection (26
), RFA, hepatic resection (28
), and transarterial chemoembolization (29
). Both liver function and tumor-related factors were associated with survival. In addition, age and anti-HCV were relevant to survival in this study. Age was among the prognostic factors, probably because 23.0% of the patients were >75 years old, which resulted in a higher percentage (18.5%) of liver-unrelated deaths in this study compared with others. Anti-HCV was among the prognostic factors, probably because anti-HCV-positive patients developed distant recurrence more frequently.
HCC frequently recurred after RFA; most recurrences were, however, not local tumor progression but distant recurrence. Frequent recurrence is not specific to RFA. After hepatic resection, the tumor recurrence rate exceeds 70% at 5 years (30
). In this study, periodic follow-up detected most recurrences at limited stage. RFA was performed again for first recurrence in almost 90% of cases, although multimodal treatments were used in a long-term follow-up. On the other hand, repeat resection rate for first recurrence has been reported to range from 10.4 to 30.6% (31
). Because RFA is less invasive than hepatic resection, iterative RFA can be performed for recurrence more easily.
Local tumor progression was found less frequently in this study than in other studies, having been reported to be around 10% at 3 years following RFA (13
). Furthermore, different from the findings in previous reports (33
), tumor size was not related to local tumor progression in this study. These differences are probably because we repeated RFA until we considered we had ablated not only the tumor itself but also some of the liver tissue surrounding it. Furthermore, to avoid local tumor progression, we were more cautious in the treatment of larger tumors when deciding whether sufficient ablation had been performed. Only serum DCP level was significantly related to local tumor progression in this study. Elevated serum DCP level may be related to the malignant potential of HCC such as the development of portal venous invasion (35
The frequency of distant recurrence in this study was similar to that reported in other studies (13
). Among the variables significantly related to distant recurrence, tumor size, tumor number, serum AFP level, and serum DCP level were probably related to micrometastasis, which had not been detected by imaging modalities before the treatment, while anti-HCV, Child-Pugh class, and platelet count were related to metachronous multicentric carcinogenesis, which developed based on underlying chronic liver disease.
From the viewpoint of survival and distant recurrence, patients with 2.1–5.0
cm tumors had significantly worse outcomes than those with ≤2.0
cm tumors while those with tumors >5.0
cm did not have worse rates than those with tumors ≤2
cm. This is probably because the number of patients with tumors >5.0
=35) were not large enough for the difference to be statistically significant. Another possibility is selection bias. It is possible that patient with tumors >5.0
cm who underwent RFA had more favorable conditions for survival and distant recurrence except tumor size than those with 2.1–5.0
In this study, 324 of the 1,170 patients were treated with combination of TACE and RFA at the initial treatment. Thus, we evaluated the combination as a possible variable that influences survival or recurrence. Univariate analysis demonstrated that the combined therapy was significantly correlated to overall survival, whereas multivariate analysis did not show the relationship. TACE was generally combined with RFA in patients with either ≥4 tumors or those with even one tumor >3.0
cm in diameter. This is why the correlation was significant in univariate analysis, while it was not in multivariable model in which the effect of other risk factors, such as tumor number and tumor size were adjusted. The combination of TACE and RFA was not significantly related to either local tumor progression or distant recurrence.
RFA was a safe procedure. Although many patients treated by RFA in this study were at high risk for surgical treatment because of advanced cirrhosis or other comorbidities, complications occurred in only 2.2% of the treatments. Other investigators have also reported low complication rates of 0–6.1% (11
). For hepatic resection, morbidity rates of 38–47% have been reported even in recent studies (36
To date, percutaneous ethanol injection has been considered the standard in ablation (5
). However, randomized controlled trials have demonstrated the superiority of RFA (6
), with RFA now largely replacing ethanol injection. We have also shifted from ethanol injection to RFA (10
). At our department, RFA is currently the first option and ethanol injection is performed only on patients on whom RFA cannot be performed safely because of either enterobiliary reflux, adhesion between the tumor and the gastrointestinal tract, or other reasons.
Surgical resection has been considered the treatment of choice for HCC. Our first option for resectable HCC was also surgery. However, most patients who came to our department visited us because they did not want surgical resection. Thus, many patients in this study underwent RFA not because of unresectable tumor but because of refusal of surgery. Those who preferred surgery would have directly gone to the surgical department that has extensive experience in hepatic resection (38
It is not easy to compare outcomes between RFA and surgical resection; the indications are different between the two treatments. Furthermore, indications for each treatment are different from institution to institution. Thus, a case adjudged to be treatable by RFA or surgical resection at an institution may not be given the same treatment at another. The best known indication criteria for surgical resection may be those proposed in the Barcelona Clinic Liver Cancer (BCLC) protocol (5
), which states that surgical resection should be restricted to patients with performance status 0, Child-Pugh class A, single HCC, normal portal pressure, and normal serum bilirubin level. In patients satisfying those criteria, the 5-year survival rate is expected to be >70% (30
). In this study, 237 (20.3%) of 1,170 patients satisfied those criteria and were thus considered good candidates for surgical resection; their 5-year survival rate was 75.9%, which appears satisfactory when compared with outcomes following surgical resection. Furthermore, in all 1,170 primary HCC patients treated by RFA, 5- and 10-year survival rates were 60.2% and 27.3%, respectively. In patients treated by surgical resection, 5- and 10-year survival rates were 34.4–70.0% and 10.5–52.0%, respectively (32
). Although this is an observational study with no control, survivals following RFA appear comparable to those reported following surgical resection.
Two recent randomized controlled trials showed no significant difference in survival between RFA and surgical resection (46
). Several nonrandomized controlled trials reported that RFA had similar overall survival rates to resection (48
), while others found resection to be associated with higher survival rates (51
). Further studies are necessary to resolve comparison of RFA with resection.
We have made strenuous efforts to standardize the RFA procedure. Although many physicians have participated in RFA at our institution, the procedure was invariably performed according to the institutional protocol and in the presence of experienced physicians. Video recording was also used to monitor the procedure. Additionally, preoperative planning and postoperative evaluation of technique effectiveness were also carried out by at least three physicians. We also believe that not only proficient practice of RFA but also detailed preoperative planning, cautious postoperative evaluation of therapeutic effect, and careful follow-up are vital to achieve satisfactory outcomes.
Source population in this study may represent selection bias, as we performed RFA on most patients who were hospitalized at our department; however, many patients with unfavorable tumor conditions for RFA might not have been referred to us. Therefore, caution is required when extrapolating our findings to the general population of HCC patients.
A second limitation is that study population cannot be clearly defined. This study was based on daily clinical practice over a 10-year period. Indication criteria of RFA have changed over time, mainly because another percutaneous ablation, that is, ethanol injection has also been performed. Furthermore, various treatments besides percutaneous ablation were available for HCC, such as surgical resection and transarterial chemoembolization, with frequently overlapping indications.
One further limitation is the fact that this was a single-center study; these results might not be reproducible consistently in other settings. To extrapolate the findings in this study to patients at other institutions, careful consideration should be given to differences in the indications, methods, expertise, performance of available ultrasound and CT equipment, and others. Treatment outcome may be influenced by the physicians' expertise and the institution's volume of care. We started ethanol injection in 1985 and microwave ablation in 1995, that is, before the introduction of RFA. Recently, we have performed over 900 RFA treatments per year, which may represent a far greater number of treatments than those in most other institutions. We would not recommend any change in daily clinical practice solely on the strength of our study findings.
In conclusion, our 10-year clinical experience shows that RFA could be locally curative, resulting in survival for as long as 10 years, and was a safe procedure. RFA might be a first-line treatment for selected patients with early-stage HCC.