Radiofrequency ablation (RFA) is performed worldwide for patients with hepatocellular carcinoma (HCC) as a curative local therapy because of the low rates of morbidity and mortality, and the high level of efficacy (1–5). Developments in ultrasonography (US) and contrast-enhanced US (CEUS) agents for hepatic tumors have enabled the diagnosis of HCC in the early stage, as CEUS makes it easier to detect small HCC tumors that are invisible to B-mode US.

In January 2007, Sonazoid^® (Perflubutane, Daiichi Sankyo Co., Ltd., Japan) was approved as a new CEUS agent in Japan (6). Hatanaka et al found that this contrast agent has higher sensitivity and accuracy for the diagnosis of hepatic malignancy (7). We reported on the diagnostic efficacy of CEUS with Sonazoid in cases of HCC which were <2 cm (8). The primary characteristic of this agent is the ability to repeatedly obtain a continuous enhanced view in the Kupffer phase. Numata et al also noted that repeated and continuous scanning in the Kupffer phase using CEUS with Sonazoid allowed for the easy detection of target lesions during RFA procedures (9). Thus, this contrast enhancement agent is considered to have a positive effect on therapeutic strategy. However, there are no known reports of changes in therapies prior to and following the introduction of CEUS with Sonazoid.

In order to evaluate the usefulness of Sonazoid as a treatment of patients with HCC, we investigated the changes in therapies for the period before and after its introduction at our institution.

For the patients studied, there were no significant differences in the clinical backgrounds between the groups (Table I). HCC patient percentages, with the Milan criteria in the two groups, did not show a significant difference. However, the ratio of patients treated with RFA increased after CEUS was introduced [pre-CEUS vs. post-CEUS, 21 (95/451) vs. 32% (219/691); P<0.01]. Furthermore, of the patients treated with RFA in the post-CEUS group, 18.4% (41/219) received RFA with Sonazoid.

There were 130 naïve HCC patients in the pre-CEUS group and 171 in the post-CEUS group, with no significant differences in clinical background between the two groups (Table II). Naïve HCC patient percentages with the Milan criteria in the two groups were similar. However, the ratio of patients treated with RFA increased after CEUS was introduced [pre-CEUS vs. post-CEUS, 32 (41/130) vs. 52% (89/171); P<0.01]. During the RFA procedure, assistance with CEUS was used in 15.7% (14/89) of naïve patients treated with RFA in the post-CEUS group. The clinical backgrounds of naïve HCC patients treated with RFA in the two groups were not significantly different, except for the number of tumors (pre-CEUS vs. post-CEUS, 1.15±0.48 vs. 1.40±0.67; P<0.01; Table III). In addition, the percentage of tumors <1 cm in diameter in naïve patients increased after the introduction of CEUS with Sonazoid, though the difference was not significant (0 vs. 8%; P=0.097).

CEUS with Sonazoid, which is able to provide continuous imaging of target lesions in the Kupffer phase, has been reported to have a 94.7% rate of sensitivity and 81.8% rate of specificity for diagnosing small HCCs (<2 cm), while the positive and negative predictive values for those were 94.7 and 81.8%, respectively (8). Minami et al reported that CEUS with Levovist^® (Schering, Berlin, Germany) was useful as an indicator and guide for RFA (23). However, the combination of CEUS with another agent besides Sonazoid does not reveal the Kupffer phase continuously, because imaging during that phase is performed by bursting microbubbles that accumulate in Kupffer cells by sound waves (24). Continuous imaging in the Kupffer phase with Sonazoid occurs because the images are obtained with vibration rather than bursting microbubbles by sound waves, making it easy to observe abnormal areas continuously (9). Although RFA guided by CEUS with Sonazoid has been reported (9), there are no known reports of changes in therapies at any institution prior to and following the introduciton of this procedure.

No differences in clinical backgrounds, including the ratio of patients with Milan criteria, hepatic reserve function and TNM stage were noted between the groups in the present study. In contrast, the RFA ratio for 1142 subjects, as well as the naïve cases significantly increased after CEUS was introduced. We consider that these differences were attributable to continuous imaging in the Kupffer phase with Sonazoid, which enabled us to detect invisible HCCs by conventional B-mode US. Sonazoid allowed us to confirm that a greater number of target lesions were more visible by additional CEUS examination. As a result, we were able to perform the RFA procedure with confidence in the tumor location in those cases.

Livraghi et al reported that the same therapeutic effect was obtained after comparing patients, who had undergone surgical resection or RFA, with single HCC tumors ≤2.0 cm in diameter (25). We previously reported that RFA was safer and had a similar effect to surgical resection, though the number of patients with liver cirrhosis Child-Pugh B class treated with RFA was greater than that of patients treated with surgical resection (5). The results encouraged us to select RFA for liver cirrhosis patients with HCC. Sonazoid is a powerful agent for screening and performing RFA procedures for HCC nodules, which can be detected by other modalities such as dynamic CT but are difficult to detect by conventional B-mode US.

With the increasing number of small HCCs detectable by CEUS with Sonazoid, the number of patients that can potentially be treated with RFA will also increase, indicating that curative and low invasive RFA procedures will be performed in a larger number of HCC patients in the near future. We found that CEUS with Sonazoid allowed for the use of RFA for a considerable number of patients with HCCs, which would have otherwise been invisible by conventional B-mode US.