Int J Gastrointest Interv 2021; 10(4): 152-160
Published online October 31, 2021 https://doi.org/10.18528/ijgii210042
Copyright © International Journal of Gastrointestinal Intervention.
Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, Osaka, Japan
Correspondence to:*Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
E-mail address: firstname.lastname@example.org (H. Higashihara).
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Conventional transarterial chemoembolization (TACE) using ethiodized oil and gelatin sponge (GS) particles is a standard treatment for unresectable BCLC-B stage hepatocellular carcinoma (HCC). Ethiodized oil can cause temporary embolic micro-interactions in tumor sinuses, portal veins, hepatic venous sinuses, and arteries as a temporary embolic material for the microvasculature. Using GS particles as an added embolic material, strong ischemic effects can be achieved not only in HCC, but also in the surrounding liver parenchyma. In recent years, various technical innovations in TACE using ethiodized oil have been made in Japan to improve the outcomes of TACE, such as a device for emulsifying ethiodized oil and water-soluble anticancer drugs, the use of intraoperative embolization guidance software to plan embolization during TACE, and the introduction of various microcatheters. This report examines some of the technical innovations that have been adopted to improve TACE outcomes.
Keywords: Carcinoma, hepatocellular, Conventional transarterial chemoembolization, Ethiodized oil, Radiology, interventional, Transarterial chemoembolization
Each year, primary liver cancer accounts for more than 38,000 deaths in Japan and more than 15,000 deaths in Korea, representing the fourth most common cause of death in Japan, and the third most common in Korea.1 Among primary liver cancers, about 95% in Japan and 85% in Korea are hepatocellular carcinoma (HCC), most of which are caused by chronic hepatitis or cirrhosis due to persistent viral infection. The main cause is chronic hepatitis or cirrhosis caused by persistent infection with hepatitis C or B virus.
Since Yamada et al2 first reported transarterial chemoembolization (TACE) in 1983, the Japanese development of TACE using ethiodized oil (Lipiodol 480; Guerbet Japan, Tokyo, Japan) has been widely adopted worldwide.3–6 In particular, Asian countries took up this method long before the confirmation of its survival benefit in randomized controlled trials.7–14 In this manuscript, TACE using ethiodized oil and gelatin sponge particles was considered to represent “conventional TACE.”
In a multicenter, prospective study conducted jointly by Japan and Korea and involving 99 patients with HCC in the early to intermediate stage according to BCLC classification who underwent conventional TACE, the median survival and 1- and 2-year survival rates were 3.1 years, 89.6% and 75.0%, respectively.15
For the past 30 years, conventional TACE has been referenced in many publications, with varying levels of detail regarding preparation and administration. In 2016, a global expert panel published consensus technical recommendations to encourage standardization and promote conventional TACE.16
In addition, multiple molecularly targeted drugs have been introduced for HCC, causing a paradigm shift in the treatment strategy for HCC in the BCLC-B stage. New applications, devices and microcatheters have emerged in Japan to enhance local control of individual HCC lesions. In this review, we mention and introduce the technically advanced progress of conventional TACE in Japan.
A HCC is usually a hypervascularized tumor with arterial dominance.17 The goal of conventional TACE is to achieve antitumor effects with anti-cancer drugs and cytotoxic effects by achieving ischemia in tumor tissue with arterial embolization. Ethiodized oil injected into the hepatic artery has been found to accumulate predominantly in HCCs and to show long-lasting retention in tumors.18–20 Ethiodized oil circulates beyond the feeding arteries of the tumor to the distal portal vein through the peribiliary capillary plexus and drainage channels from the tumor.21,22 Ethiodized oil infused from the hepatic artery exerts temporary embolic effects on both the hepatic artery and portal vein branches when it flows out to the portal vein side.23 When ethiodized oil is used as a means of delivering chemotherapeutic agents, an ethiodized oil-anticancer drug emulsion followed by embolization with particles shows better pharmacokinetics than either ethiodized oil-anticancer drug emulsion without embolization or water-soluble anticancer drugs alone without ethiodized oil24 and induces significant necrosis of the main tumor and satellite tumor nodules compared to either ethiodized oil or anticancer drug injected alone.
Uchida et al5 and Matsui et al6 established the so-called segmental TACE and subsegmental TACE techniques to embolize a segment or sub-segment of the liver parenchyma containing a tumor using ethiodized oil.
In recent years, in Japan, with improvements to microcatheters and the development of thinner microcatheter tips, active injection of ethiodized oil to more distal sub-segment levels has become possible in line with the concept of superselective TACE proposed by Miyayama et al25 The development of microballoon has also led to balloon occlusion TACE, in which the pressure gradient between the artery and portal vein is reduced before the ethiodized oil is injected.26 Both of these methods will be described later.
The standard method of conventional TACE involves pumping emulsified ethiodized oil and a cytotoxic drug back and forth using two syringes and a three-way stopcock to create an ethiodized oil-anticancer drug emulsion.19 The physicochemical properties of the emulsion influence the therapeutic effect.
Water-in-oil (W/O) emulsion can achieve high embolization efficacy by slowly releasing the drug, while offering enhanced tumor retention due to the high viscosity of the emulsion.19,27–31 However, emulsions produced by the current pump method using three-way cocks have an important limitation, in that they can only achieve a W/O ratio of about 70%.32
Emulsification devices were developed to improve the properties of ethiodized oil emulsions formed by the pumping method. In 1995, Higashi et al33 first reported a membrane emulsification technique to form W/O emulsion for use in intra-arterial injection therapy. This technology requires a dedicated metal module with a nitrogen gas inlet and a stirring rotor. Tanaka et al34 developed and reported a simple pump emulsifier equipped with a membrane to form W/O emulsions.
This pumped emulsifier comprises a microporous glass membrane made from volcanic ash from southern Kyushu, formed of a porous glass material consisting of Al2O3-SiO2. The disk-shaped glass-glass membrane had numerous micron-sized pores with a diameter of 50 μm as of the first report, but they later changed to micron-sized pores with a diameter of 100 μm. The membrane is coated with silicon to make it hydrophobic and to facilitate formation of the W/O emulsion. This membrane is placed between two syringe adapters made of rigid polyvinyl chloride resin (Fig. 1A).
The emulsion was prepared and emulsified by mixing ethiodized oil with an epirubicin solution comprising 50 mg of epirubicin hydrochloride powder (Epirubicin; Nippon Kayaku, Tokyo, Japan) dissolved in 6 mL of contrast medium (250 mg/mL). Emulsions were prepared at different concentrations using either a three-way cock or the pump emulsifier with glass membrane to evaluate the physicochemical properties of the results. The percentage of each W/O emulsion at 30 minutes showed that the pump emulsifier with glass membrane was significantly higher than the three-way cock at any W/O concentration ratio.35
Tanaka et al35 also reported the drug elution ability of an emulsion of epirubicin-ethiodized oil using either a pump emulsifier with glass membrane or a three-way cock. Immediately after preparing the emulsion (0 min), 1.73% ± 1.05% of epirubicin was released from the emulsion prepared by the pump emulsifier with glass membrane, while 41.02% ± 7.27% of epirubicin was already eluted by the 3-way cock, representing a significant difference (
This pump emulsifier with glass membrane can be used to create W/O emulsions with almost-uniform droplet size and slower drug elution capacity than the conventional method with three-way cocks. Currently, the MicroMagic emulsifier (Piolax Co., Yokohama, Japan) is being marketed and is actively used in Japan, and the design has been changed to a V-shape with a glass membrane containing numerous 100-μm holes (Fig. 1). The results of conventional TACE using this device are expected to be reported in the near future, and are expected to contribute to the improvement of therapeutic outcomes for conventional TACE.
In recent years, cone-beam computed tomography (CBCT) has become available by rotating the angiography unit. In addition, CT images can be obtained during interventional radiological procedures using an interventional radiology CT (IVR-CT)-equipped angiographic unit. These images during hepatic arteriography are now often widely taken in TACE for tumor delineation and decisions on embolization, and can be referred to as support images during TACE to improve local tumor control.36,37
In addition, TACE guidance software, including 3-dimensional automatic tumor feeding artery detection (AFD) software using either CBCT or IVR-CT data, has been developed. Such software can identify 85% to 93% of feeding arteries and improve the rates of technical success of TACE and early tumor response.38–42
Miyayama et al43 performed conventional TACE using AFD software and reported the evaluation of technical success for TACE and local tumor control rates and overall survival (OS) rates using unenhanced CT 1-week after TACE to determine the degree of ethiodized oil retention in HCC nodules. They reported that complete embolization with a safety margin (grade A) was achieved in 82.1% of HCCs treated with TACE, and 13.7% of HCCs were embolized without a safety margin (grade B). The rate of incomplete embolization was only 4.2% (grade C). Regarding OS and intrahepatic tumor recurrence (local tumor progression [LTP] or intrahepatic distant recurrence [IDR]) rates according to the degree of technical success, LTP and IDR rates at 1, 3, and 5 years were 31.7%, 49.4%, and 59.4%; and 33.9%, 58.2%, and 73.3%; respectively. LTP occurred more frequently in HCCs classified as grade B than in those classified as Grade A (
In Japan, all superselective conventional TACE is performed using a 1.7–2.4-Fr tip microcatheter with IVR-CT or CBCT guidance42,44 and digital subtraction angiography (DSA) (Fig. 3). After advancing the microcatheter tip into the feeding artery near the HCC at the sub-segmental level, the emulsion of ethiodized oil and anticancer drugs is slowly injected, followed by gelatin sponge particles. The dose (in milliliters) of ethiodized oil per dose of conventional TACE is approximately equal to the total diameter (in centimeters) of the target HCC.5 The maximum reported dosage per dose is 10 mL5,45 or 15 mL.46 The endpoint of conventional TACE is cessation of blood flow in the arteries feeding the tumor and disappearance of staining for the target HCC on DSA, although confirmation of the embolized area using CT or CBCT is also useful in determining the endpoint.44,36 A safety margin (at least 5 mm wide for tumors greater than 25-mm and 10-mm wide for tumors greater than 25 mm, corresponding to the coronal enhancement area) should be secured around the HCC.36,47 If the HCC is fed by multiple feeding arteries or if there are multiple HCCs, superselective conventional TACE should be performed for each feeding artery whenever possible.
As for technical innovations during the injection of the ethiodized oil emulsion, injecting the ethiodized oil emulsion slowly is important to avoid formation of an “oil cast” in the feeding artery. Also, if possible, the microcatheter should be advanced more distally to achieve a “semi-wedged condition”,25 so that the ethiodized oil emulsion can reach the portal vein circulation from the feeding arteries of the HCC across the peribiliary arteries, and enough ethiodized oil emulsion can be stored in the embolic region, as ethiodized oil may act as a temporary embolic material (Fig. 3). If multiple feeding branches are present, embolization of the main feeding branch should be performed at the very end. This is because immediately after ethiodized oil TACE, the surrounding hepatic parenchyma may be densely accumulated with ethiodized oil and contrast media, making residual tumor staining and the involvement of small feeding branches difficult to identify.25
In cases of conventional TACE for large HCCs, the use of a large amount of ethiodized oil in a single procedure may expose a certain risk of serious complications such as systemic embolism and tumor lysis syndrome.48–50 For localized tumors larger than 6 cm in diameter, repeated conventional TACE at regular intervals may be effective. Two to three sessions should be scheduled depending on the vascular structure of the feeding arteries, and each session should be performed superselectively at intervals of 3 to 10 weeks, considering the symptoms and laboratory data of the patient.45
An important concept of superselective conventional TACE is to increase the local control rate for individual HCCs targeted for embolization. The local recurrence rate of HCCs with significant visualization of portal veins by ethiodized oil has been reported to be significantly lower than that of tumors with little or no portal vein visualization (
However, several difficult situations can provide obstacles to super-selective TACE, such as sharp-angled bifurcation of the vessels, tortuosity of the hepatic artery, or a small diameter of the feeding artery from the proximal hepatic artery.
When dealing with sharp-angled bifurcations from tortuous vessels, selective catheter insertion can be very difficult. Even if the shape of the guidewire and catheter is selected to fit the desired bifurcations of vessels, selective catheter insertion is sometimes difficult and could be disrupted. In such situations, selective catheterization may be difficult and end up being abandoned.
In such cases, the use of a microcatheter with a steerable-tip (SwiftNINJA; Sumitomo Bakelite, Tokyo, Japan) may be one option (Fig. 5).51 Steerable microcatheters were developed in Japan in 2014. The SwiftNINJA has a remotely operated flexible tip with a steering dial at the proximal part of the grip, allowing the operator to optimally control the direction of the 2.4-Fr steerable tip, up to 180° in the opposite direction (Fig. 5A, 5B). The steering dial and tip are connected by two wires inserted from each lumen in the wall of the catheter shaft. If we want the tip of this catheter to tilt to a specific angle, turning the dial applies tension to either of the wires, causing the steerable tip to bend by a certain angle. Once the direction of the steerable tip is determined, the steering dial can be locked with the dial stopper to maintain the intended direction and orientation. This steerable microcatheter may facilitate more selective catheter insertion than a conventional microcatheter because of the controllable mechanism for the tip shape (Fig. 5).52
In addition, when an occlusion point is present in the route from the aorta to the hepatic artery, the catheter needs to be inserted through a collateral pathway such as the pancreatic arcade. The collateral pathway is often tortuous with sharp angles, and the stability of the parent catheter is sometimes impaired due to the kickback with counter-tension during microcatheter insertion, causing the parent catheter to become dislodged. The tip of the microcatheter thus may not reach the intended peripheral location of the hepatic artery.
In such cases, a triple co-axial catheter system may be able to stably advance the tip of microcatheter more distally (Fig. 6). This catheter system consists of a small microcatheter with a 1.6 or 1.9-Fr non-tapered tip inserted into a large microcatheter with a large inner diameter of 2.7 Fr (high-flow type) into a 4- or 5-Fr parent catheter, as the so-called “tri-axial catheter technique.” The insertion of the microcatheter with the tri-axial catheter system enables stable catheter insertion into vessels with strong bending and tortuosity. Shimohira et al53 reported the initial results of using this catheter system for conventional TACE in HCCs. They reported that 30 patients with HCCs underwent TACE using this catheter system, and the level of embolization was sub-segmental TACE in 26.7% (8/30), more sub-sub-segmental TACE in 43.3% (13/30), and more distal TACE in 23.3% (7/30). Shimohira et al53 reported that they were able to insert the catheter more distally than the embolization site, where TACE was performed using a conventional microcatheter. When arteries are tortuous, or when a microcatheter has to be advanced via collateral pathways, sagging of the microcatheter may occur, and consideration of using this tri-axial catheter system may be an option (Fig. 6).
Furthermore, even with such catheters as the small-diameter microcatheter and the triaxial catheter system, we have empirically encountered cases in which selective catheter insertion into the feeding artery was difficult when the very thin feeding artery branched abruptly from the proximal hepatic artery. Conventional TACE is often difficult to perform in other cases where the HCC appears with the region of an arterial-portal (AP) shunt in the liver, due to changes associated with the deterioration and fibrosis of normal intrahepatic tissues associated with cirrhosis or repeated conventional TACE or radiofrequency ablation. This is the cause of the AP shunt, which is characterized by a high volume of blood flowing through the AP shunt to the portal vein region and a high blood flow velocity. Therefore, when ethiodized oil emulsion is injected from the proximal position to the AP shunt, most of the emulsion escapes into the portal vein without accumulating in the liver parenchyma around the HCC. To improve the efficiency of ethiodized oil emulsion retention in a HCC in this situation, conventional TACE under microballoon perfusion control may be one option. In this situation, a temporary reduction in blood flow through the hepatic artery using a microballoon catheter is necessary to block the distal portion from the orifice of the feeding artery for the HCC. The injection of ethiodized oil emulsion through a proximal side hole opened in the microballoon catheter is an effective method (Fig. 7).54 In standard microballoon catheters, the injected materials come out of the catheter tip, but in proximal side-hole microballoon catheters (Logosswitch; Piolax Co.), these materials flow from both the catheter tip and the side hole. The recently introduced proximal side-hole microballoon catheter is injected from both the catheter tip and side hole. This catheter can be inserted through a 4-Fr catheter. The tip of the microcatheter is 2 Fr, the diameter of the lumen is 0.019 inches, and the lateral hole is 17 mm from the tip of the microballoon catheter, with a diameter of 0.48 mm. The length of the microballoon is 8 to 13 mm and the diameter is 3 to 6 mm. These dimensions of the balloon can be controlled depending on the amount of fluid injected through the lumen of the microballoon, with 0.31 mL being the maximum amount of fluid. After the microballoon is inflated, the lumen of the microcatheter is occluded by exogenous pressure from the balloon. Material injected from the tip of the catheter therefore comes out of the lumen through the side hole (Fig. 7A, 7B). When the balloon is deflated, the injected material comes out of the end hole at the tip of the catheter. This new microballoon catheter may be useful for efficient and precise injection of ethiodized oil emulsions into the HCC when the microcatheter encounters difficulty with insertion into the feeding artery of the HCC (Fig. 7C–7G).
Superselective conventional TACE provides excellent anticancer efficacy for localized HCCs. Stabilization of ethiodized oil emulsions may be the key to conventional TACE. The position of the catheter is important for safe and effective TACE. Preparation of various types of characteristic microcatheter is also important in cases where advancing the catheter tip to the appropriate position is not possible.
No potential conflict of interest relevant to this article was reported.
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