Abstract
Background/Aim: A porous glass membrane-pumping emulsification device (GMD) enables the formation of a high-percentage water-in-oil emulsion with homogeneous and stable droplets. Although GMD is expected to improve the locoregional therapeutic effects of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC), its effectiveness in the management of solitary HCC remains unclear. Patients and Methods: Patients treated for solitary HCCs (<5 cm) were retrospectively reviewed. A total of 46 patients who could not undergo liver resection and were unsuitable for radiofrequency ablation were included in this study. Among these, 22 patients underwent TACE using a GMD (GMD-TACE group) and 24 underwent stereotactic body radiotherapy (SBRT) using a robotic radiosurgery system (SBRT group). Local control rates were compared between the two groups. Results: The median HCC tumour size was 24 mm (range=12-50 mm) and 22 mm (range=8-39 mm) in the GMD-TACE and SBRT groups, respectively; however, the difference between the groups was not significant. Age, liver function test results, or Child-Pugh scores were not significantly different between the two groups. The rate of local control at 6 months after treatment was 100% in both groups. Although the 1-year local control rate was higher in the SBRT group (92.3%) than in the GMD-TACE group (81.8%), there was no significant difference in the log-rank test (p=0.654). No major treatment-related complications occurred in either group during the observation period. Conclusion: TACE with GMD could be considered an effective treatment option for the management of solitary HCC.
- Hepatocellular carcinoma
- transarterial chemoembolization
- porous glass membrane pumping emulsification device
Recent advances in the treatment of hepatocellular carcinoma (HCC) have made selecting an appropriate treatment for each case important to achieve better clinical outcomes (1, 2). Although surgical resection and radiofrequency ablation (RFA) are widely used curative treatments for early-stage HCC, they are not suitable in some cases owing to liver function, complications, and anatomical location. Transarterial chemoembolization (TACE) and stereotactic body radiotherapy (SBRT) are commonly performed in such cases. TACE is a locoregional therapeutic option for HCC and is recommended especially for patients with intermediate HCC (3). A novel porous glass membrane pumping emulsification device (GMD; MicroMagic, Piolax Medical Devices, Yokohama, Japan) enables the formation of a higher percentage of water-in-oil emulsions with homogeneous and stable droplets than the conventional 3-way stopcock pumping technique (4, 5). Therefore, TACE using GMD is expected to have a better local therapeutic effect than conventional TACE; however, its clinical effectiveness remains unclear (6). This study aimed to investigate the local therapeutic efficacy of TACE using GMD for solitary HCC compared with that of SBRT.
Patients and Methods
Study population. Patients treated for solitary HCC between 2020 and 2022 at Nagoya University Hospital (Nagoya, Japan) were retrospectively reviewed. A total of 46 patients who could not undergo liver resection and were unsuitable for RFA were included in this study. Patients with solitary HCCs >5 cm in size were excluded from the study. Among the included patients, 22 underwent TACE using a GMD (GMD-TACE group) and 24 underwent SBRT using a robotic radiosurgery system (SBRT group). Therapeutic efficacy and safety were retrospectively investigated. This study was approved by the ethics committee of Nagoya University Hospital (2021-0247).
TACE. In all patients undergoing GMD-TACE, TACE was performed according to the standard treatment protocol (7). Epirubicin hydrochloride (50 mg epirubicin; Nippon Kayaku, Tokyo, Japan) was dissolved in 2.5 ml of the contrast agent iopamidol (Iopamiron; Bayer, Osaka, Japan). Ethiodized oil was then mixed with epirubicin solution using GMD. The ratio of epirubicin to lipiodol was 1:2. The pumping of the mixture was performed 20 times before arterial injection. The emulsion was injected into the tumour-feeding artery, followed by embolization using 1-mm gelatine particles (Gelpart; Nippon Kayaku, Tokyo, Japan).
SBRT. SBRT was performed using a robotic radiosurgery system (CyberKnife M6; Accuray, Sunnyvale, CA, USA). Briefly, a fiducial marker (VISICOIL Twin-line; RadioMed Corporation, Bartlett, TN, USA) was inserted into the site adjacent to the tumour using ultrasonography, and the patients underwent contrast-enhanced computed tomography and contrast-enhanced magnetic resonance imaging for simulation and planning. The fractions and dosage of SBRT were determined using the Child-Pugh score and neighbouring organs. Patients were typically treated with five fractions delivered at a median dose of 40 Gy under active breathing control.
Assessment of treatment effect and adverse events. Treatment efficacy was evaluated using contrast-enhanced computed tomography 1-3 months after TACE using GMD or SBRT and every 2-3 months thereafter. Local control rates were compared between the two groups. Local control was defined as the continuous shrinkage of the tumour without the development of a new lesion inside or adjacent to the tumour. The safety of TACE with GMD and SBRT was evaluated using the Common Terminology Criteria for Adverse Events version 5.0. Blood tests were performed before and 1 month after each procedure.
Statistical analysis. Local control rates were analysed using the Kaplan–Meier method and log-rank test. A paired t-test was performed to evaluate changes in the Child-Pugh score. Statistical significance was defined as p<0.05. All statistical analyses were performed using GraphPad Prism, version 9 (GraphPad Software, San Diego, CA, USA).
Results
Patient characteristics. There were 16 men and 6 women in the GMD-TACE group and 18 men and 6 women in the SBRT group. Table I shows the characteristics of the patients in the two groups. There were no significant differences in age, sex, tumour size, liver function test results, or Child-Pugh scores between the two groups. In the GMD-TACE group, epirubicin was used in all cases and the median dosage of GMD-made emulsion was 2.5 ml (range=1.0-7.5 ml). A representative case from the GMD-TACE group is shown in Figure 1A. In the SBRT group, the median dose of radiotherapy was 40 Gy (range=35-50 Gy) and the median fraction was 5 times (range=5-14). A representative case from the SBRT group is shown in Figure 1B.
Patient characteristics.
Representative cases of transarterial chemoembolization using a glass membrane pumping emulsification device and stereotactic body radiotherapy. (A) A 50-mm hepatocellular carcinoma was treated with transarterial chemoembolization using a glass membrane pumping emulsification device. A total of 7.5 ml of the emulsion was injected into the tumour-feeding artery, followed by embolization using 1-mm gelatine particles. The treatment course with images is shown left to right, computed tomography (CT) during arterial portography before the treatment, plain CT at the end of the treatment, and contrast-enhanced CT at 2 and 5 months after the treatment. (B) A 30-mm hepatocellular carcinoma was treated with stereotactic body radiotherapy using a robotic radiosurgery system. A total dose of 40 Gy was delivered in five fractions. The treatment course with images is shown left to right, contrast-enhanced magnetic resonance imaging before the treatment and contrast-enhanced CT at 2, 5, and 8 months after the treatment. GMD-TACE: Transarterial chemoembolization using a glass membrane-pumping emulsification device; SBRT: stereotactic body radiotherapy.
Treatment effects. The local control rates of the target tumours were 100% at 6 months and 81.8% at 1 year in the GMD-TACE group and 100% at 6 months and 92.3% at 1 year in the SBRT group (Figure 2). Although the 1-year local control rate was higher in the SBRT group than in the GMD-TACE group, there was no significant difference in the log-rank test (p=0.6541).
Local control rates in target nodules after transarterial chemoembolization using a glass membrane pumping emulsification device and stereotactic body radiotherapy. The graph shows the local control rates calculated using the Kaplan–Meier method. p-Value was calculated using the log-rank test. GMD-TACE: Transarterial chemoembolization using a glass membrane-pumping emulsification device; SBRT: stereotactic body radiotherapy.
Adverse events and changes in liver function. In the post-treatment follow-up, no serious complications were observed in either group. In the GMD-TACE group, mild elevations in liver enzyme levels, fever, and anorexia were observed. However, none of the patients required additional intervention or prolonged hospitalization. By contrast, no adverse events were observed in the SBRT group. Paired t-tests revealed no significant differences in Child-Pugh scores before and 1 month after treatment in both groups.
Discussion
The results of this study showed that local tumour control with TACE using GMD for solitary HCC was 81.8% at 1 year, which was not significantly different from the result of SBRT in solitary HCC. These results indicate that the use of GMD in TACE can be considered an acceptable alternative locoregional treatment option for patients with solitary HCC who are not surgical candidates or are unsuitable for ablative techniques. GMD is a simple device that enables the preparation of a high percentage (97.9%) and stable water-in-oil emulsion and has been shown to have a better effect on anticancer drug retention in tumours in the VX2 liver cancer rabbit model (4, 5). Although better TACE treatment outcomes are expected using GMD, its efficacy in solitary HCC remains unclear (6). This study showed a local control rate of 81.8% at 1 year in the GMD-TACE group, which was not significantly different from the local control rate of 92.3% in the SBRT group. Although no serious adverse events were observed in this study, most cases in the GMD-TACE group experienced mild elevations in liver enzymes, fever, and anorexia, which are comparable to previous reports of “conventional” TACE treatment (8). Although surgical resection and RFA are the standard treatment for solitary HCC, there are not a negligible number of patients with HCC who are not eligible to undergo these treatments. TACE and SBRT are commonly considered for such cases. SBRT has been reported to noninvasively achieve excellent local control in patients with HCC (9, 10). However, owing to its high cost and low treatment accessibility, patients who can select SBRT are relatively limited (11). The results of this study suggest that GMD-TACE may be an alternative treatment option for such patients. This study had limitations. First, the number of patients in each group was limited. Second, only patients who underwent TACE with GMD or SBRT were enrolled in this study. Third, because of its retrospective design, the presence of bias related to the selection of patients for HCC treatment cannot be ruled out. Although a further comparative study is needed to determine better patient selection for each procedure, a local control rate of 81.8% in the GMD-TACE group at 1 year seems a promising option for locoregional treatment for patients with solitary HCC who are not candidates for surgical resection or ablative therapies.
Conclusion
TACE with GMD could be considered an effective treatment option for the management of solitary HCC.
Footnotes
Authors’ Contributions
Concept and study design: N. Imai; Acquisition of data: N. Imai, M. Ishigami, Y. Oie, M. Kumagai, Y Inukai, S. Yokoyama, K. Yamamoto, T. Ito, Y. Ishizu, T. Honda, and H. Kawashima; Writing the article: N. Imai. Statistical analysis: N. Imai.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received June 18, 2022.
- Revision received July 5, 2022.
- Accepted July 6, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
