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Introduction

Radiofrequency ablation (RFA) has been accepted as a minimally invasive treatment for liver tumors (1) due to its tolerable side effects (2,3). Although RFA is a major technique for the treatment of liver tumors, there is an important limitation of image-guided RFA, including higher local recurrence rate compared with that of surgical resection. It has been reported that the main cause of the higher local recurrence rate associated with RFA is inadequate volumes of tumor ablation (4–8). In order to improve these results, significant efforts have been focused on enhancing the therapeutic effects of RFA by combining it with other modalities, such as transcatheter arterial chemoembolization (9,10), saline injection (11,12), and percutaneous ethanol injection (PEI) (13). However, the local recurrence rate remains high.

D-sorbitol has been used as an irrigating fluid during transurethral prostate resection (14) and considered to be a dielectric fluid (15). During transurethral resection of the prostate, D-sorbitol is used as lavage for removing blood and tissue fragments. If absorbed, D-sorbitol is metabolized to carbon dioxide and water via the fructose pathway, or excreted by the kidneys. To the best of our knowledge, thus far no experimental trial has demonstrated the efficacy of combination therapy using D-sorbitol and RFA.

In the present study, we attempted to demonstrate the efficacy of RFA with D-sorbitol in increasing the total volume of coagulation necrosis and analyzed the total delivered energy to elucidate the underlying mechanism.

Materials and methods

Animals and ethics

All animal experiments were performed in the Preclinical Animal Laboratory of Kagawa University (Kagawa, Japan). The protocol of this study was approved by the Institutional Animal Care and Use Committee of Kagawa University. Adult pig livers were purchased from Tokyo Shibaura Zoki K.K. (Tokyo, Japan). The 13-month-old dogs were purchased from Hokuzan Rabesu (Nagano, Japan) and maintained in a pathogen-free facility under controlled conditions with a 12-h light-dark cycle.

Anesthesia and procedure

RFA and D-sorbitol RFA were performed under general anesthesia with intramuscular injection of ketamine (10 mg/kg) and xylazine hydrochloride (4 mg/kg). Intubation was performed 10–15 min later and the administration of 5% sevoflurane mixed with oxygen was maintained at 1–2 l/min. RFA was initiated after stable anesthesia was attained.

Equipment and D-sorbitol RFA procedure

D-sorbitol was purchased from Baxter Ltd. (Tokyo, Japan). D-sorbitol RFA was performed under real-time ultrasonographic guidance with a 3.5 MHz sector probe (Power Vision 5000; Toshiba Medical, Tokyo, Japan) using the Cool-tip RF ablation system (Radionics, Burlington, MA, USA). For the D-sorbitol RFA treatment, a 16-gauge RFA needle was first inserted into the center of the tumor and a 18-gauge PEI needle was then introduced through the same hole of the attachment beside the echo probe. D-sorbitol 3% was slowly injected into the lesion through the side hole of the handpiece. The maximum total injected volume of D-sorbitol was 20 ml and RFA was terminated if the threshold of impedance was exceeded. RFA was performed for 20 W in 2 min, 30 W in 2 min and 50 W until the end. The maximum allowable output power was 50 W under the impedance control injecting D-sorbitol.

Calculation of energy requirement for ablation and assessment of coagulation necrosis

The energy required for ablation was calculated as follows: Energy (J) = Watt (W) × duration of ablation (sec). Animal livers containing RFA-induced coagulation were sliced in the transverse plane perpendicular to the electrode tracks. The approximation volume of the whole coagulated necrosis area in cm3 was calculated as follows:

Whole coagulation volume = 4/3π × r1 × r2 × r3,

where r1, longest diameter/2; r2, shortest diameter/2; and r3, height/2, all measured in cm. Two hepatologists with 10 years of clinical experience, who were blinded to the information regarding the RFA techniques used in the study, measured these parameters.

Stastistical analysis

All data are presented as means ± standard deviation. Statistical significance was set at P<0.05 for Student's unpaired t-tests.

Results

Comparison of coagulation between RFA and D-sorbitol-RFA in pig liver

RFA and D-sorbitol RFA were performed in 5 different parts of pig livers. All RFA techniques were performed using the Cool-tip RF system and 20 ml of D-sorbitol was injected into the lesion through a 18-gauge PEI needle during RFA (Fig. 1A and B, right). The results of the comparison of the volume of coagulation necrosis and the total delivered energy for inducing coagulation between the two groups are summarized in Table I. The volumes of coagulation necrosis in the D-sorbitol RFA group (Fig. 1A and B, right) were significantly higher compared with those in the RFA group (Fig. 1A and B, left). Of note, the total delivered energy in the D-sorbitol RFA group was also higher compared with that in the RFA group (Table I).

Figure 1. Effects of D-sorbitol RFA in pig livers. (A) RFA was performed without (left) and with D-sorbitol (right). (B) Macroscopic appearance following RFA (left) and D-sorbitol RFA (right). RFA, radiofrequency ablation.

Table I. Comparison of mean parameter values between the two groups in pig liver.

Table I.

Comparison of mean parameter values between the two groups in pig liver.

Coagulation necrosis	RFA	D-sorbitol RFA	P-value
Dmax (mm)	14.4±1.14	28.2±7.79	0.0044
Dmin (mm)	11.4±0.89	16±2.92	0.0097
Dv (mm)	10.8±0.84	16.4±2.51	0.0015
Volume (mm3)	2,351.5±520.1	10,821.1±6,580.3	0.0209
Dmax/Dmin	1.33±0.05	1.70±0.23	0.0084
Total delivered energy (J)	6,340±313.0	14,800±3,898.7	0.0013

[i] Values are presented as mean ± standard deviation. RFA, radiofrequency ablation; Dmax, maximum diameter of ablation zone; Dmin, minimum diameter of ablation zone; Dv, vertical diameter of ablation zone. All P-values were statistically significant (<0.05).

Comparison of coagulation between RFA and D-sorbitol RFA in a dog model in vivo

The effect of D-sorbitol RFA was also examined in vivo using a dog model. The volumes of coagulation necrosis in the D-sorbitol RFA group were clearly higher compared with those in the RFA group in the dog model in vivo (Table II). In addition, the total delivered energy in the D-sorbitol RFA group was also higher compared with that in the RFA group (Table II). No significant complications, such as bleeding or damage, were observed during the procedures and 3 days after D-sorbitol RFA.

Table II. Comparison of mean parameter values between the two groups in dog liver.

Table II.

Comparison of mean parameter values between the two groups in dog liver.

Coagulation necrosis	RFA	D-sorbitol RFA	P-value
Dmax (mm)	18.2±0.31	32.1±2.97	0.0013
Dmin (mm)	14.9±1.37	24.1±0.36	0.0004
Dv (mm)	14.7±1.3	24.7±0.76	0.0003
Volume (mm3)	5,318.5±917.3	25,418.2±1,545.6	<0.0001
Dmax/Dmin	1.23±0.12	1.33±0.13	0.3213
Total delivered energy (J)	7,083.3±381.9	17,333±3,214.6	0.0054

[i] Values are presented as mean ± standard deviation. RFA, radiofrequency ablation; Dmax, maximum diameter of ablation zone; Dmin, minimum diameter of ablation zone; Dv, vertical diameter of ablation zone.

Discussion

RFA remains a promising technique for the local therapy of liver cancers, such as hepatocellular carcinoma and metastatic liver cancer (6,16,17). However, the efficacy of this technique is limited by the size of coagulation necrosis, and only tumors sized <3 cm are recommended for complete ablation, due to increased impedance. In order to control impedance during the ablation, D-sorbitol was used in combination with RFA therapy. During the D-sorbitol RFA procedure, impedance was regulated by the injection of D-sorbitol and the total operative time was longer compared with that of RFA alone. Therefore, the size of the areas of induced coagulation necrosis was increased using D-sorbitol in animal livers. This suggests that the total volume of coagulation necrosis may be controlled by the injected volume of D-sorbitol suppressing impedance elevation in the ablated livers. It has also been reported that combination of RFA with other modalities enhances the therapeutic effects of RFA (10,11,18). Kurokohchi et al demonstrated that ethanol-combined RFA increased the coagulated volumes 4-fold compared with those treated with RFA alone. In addition, the amount of injected ethanol and total energy were both required to increase coagulation necrosis (19). These studies support our finding that impedance control is key to the regulation of total energy, and D-sorbitol may increase the effectiveness of RFA treatment.

In conclusion, RFA combined with D-sorbitol increases the total volume of coagulation necrosis through controlling impedance in the ablated liver and, therefore, D-sorbitol may be useful for the treatment of liver cancers.

Glossary

Abbreviations

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References