Advances in the interventional therapy of hepatocellular carcinoma originating from the caudate lobe

Shanmiao Ke

The Second Affiliated Hospital of Nanchang University, Department of Gastroenterology, Nanchang, 330006, China

Keywords:Liver neoplasms Transcatheter arterial chemoembolization Radiofrequency ablation Microwave ablation Percutaneous ethanol injection Efficacy Safety analysis

ABSTRACT

1. Introduction

The independent portal venous supply and venous drainage of the caudate lobe allow hepatocellular carcinoma (HCC)in the caudate lobe to frequently invade vessels, such as the portal and inferior vena cava,and the frequent formation of cancer thrombi can result in early intra-or extra-hepatic metastases.For resectable hepatocellular carcinoma in the caudate lobe that meets Milan's criteria, surgical treatment has better recurrence-free survival and overall survival (OS) than radiofrequency ablation (RFA)1; however, in some cases, surgical resection carries the risk of heavy bleeding and high early recurrence rates. In contrast,minimally invasive interventions, including endovascular and extravascular interventions,have the advantages of being safe and effective with minimal impact on liver function and are increasingly becoming the choice of treatment for unresectable caudate lobe HCC. Among the interventions, the efficacy of percutaneous RFA for caudate lobe tumors meeting the Milan criteria is significantly better than that of superselective transcatheter arterial chemoembolization(TACE).2

2. Transcatheter arterial chemoembolization

The OS and progression-free survival (PFS) rates are significantly higher with superselective TACE for caudate lobe HCC than with nonsuperselective TACE.3Because of the variable and complex vascular supply of the caudate lobe and the fact that the caudate artery mostly originates proximal to the hepatic artery, non-superselective TACE is ineffective for the treatment of caudate lobe hepatocellular carcinoma.4,5Alterations in the proximal hepatic artery supply to the caudate lobe and the source of the supplying artery may make TACE difficult to treat HCC in the caudate lobe.6,7The technical success rate of superselective embolization is currently about 62–85% according to available studies.2,8–10Multiple caudate lobe supply arteries significantly affect the success rate of superselective embolization, local tumor recurrence and survival in TACE for HCC in the caudate lobe.8–10The highest 1,2,3-year survival rates for HCC in the caudate lobe treated with superselective TACE are currently 89.0–92%,79–80.8%,and 62.0–65%,respectively.2,8In theory, multiple repeat embolizations may reduce tumor recurrence,but the arteries supplying the HCC in the caudate lobe that recurs after endovascular intervention are frequently altered during subsequent chemoembolization therapy,11making repeat chemoembolization difficult. The caudate arteries can initially originate from the extrahepatic arteries,12and the right inferior phrenic artery (RIPA) is the most common extrahepatic artery.12–14Other less common vessels supplying recurrent tumors include the right gastric artery, the left gastric artery,the pancreatic artery and the adrenal artery.5,7,11The possibility of extrahepatic arterial supply, such as the RIPA, should therefore not be overlooked during hepatic arteriography. In addition, poor or thin collateral arteries have been shown on imaging to thicken and supply recurrent tumors after TACE is completed or even become the main tumor-supplying artery. The caudate artery can overlap with other hepatic arteries and be difficult to identify on digital subtraction angiography(DSA),so it has been suggested that full and adequate intraand postoperative angiography of the right and left hepatic arteries and multiple angiograms should be performed to avoid missing tumors.9C-arm computed tomography (CT) can identify more than 90% of the tumor-supplying arteries of HCC in the caudate lobe and clearly show their origin and anatomy and the vascular extent of embolized branches,preventing non-target embolization and detection of residual tumor.15Stereo magnification angiography has also been used in some studies.Selective hepatic artery embolization of the caudate lobe artery carries the risk of stenosis of the main bile duct in the porta hepatis, especially with repeated TACE treatment.16When C-arm CT or CT suggests bile duct enhancement,complete obstruction of the caudate artery should be avoided,or a finer catheter may be advanced distal to the caudate artery,as the bile duct arteries tend to originate proximally.16Collateral flow from other caudate arteries can reverse the flow in the embolized artery,causing the emboli to retreat, and it is therefore recommended that the microcatheter should be advanced distal to the anastomotic branch to avoid accidental extensive embolization. For the diagnosis of residual tumor after TACE, the diagnostic performance of contrast-enhanced ultrasonography (CEUS) for residual tumor after TACE was considered superior to that of contrast-enhanced CT (CE-CT) in the study by Liu et al.17DB-TACE can be used in caudate arteries which are impossible to treat with superselective TACE, avoiding damage to normal liver parenchyma and improving the aggregation of chemoembolization material.18

Abbreviation HCC hepatocellular carcinoma RFA radiofrequency ablation TACE transcatheter arterial chemoembolization RIPA right inferior phrenic artery CE-US contrast-enhanced ultrasound CE-CT contrast-enhanced CT MWA microwave ablation LTP local tumor progression OS overall survival RFS recurrence-free survival DFS disease-free survival PFS progress free survival PTCLI percutaneous transhepatic chemotherapy-lipiodol injection TACE-RFA transcatheter arterial chemoembolization combined with radiofrequency ablation CT Computed Tomography MRI Magnetic Resonance Imaging SIRT selective internal radiation therapy NS-RFA normal saline-enhanced radiofrequency HRFA hydrochloric acid-enhanced radiofrequency ablation

3. Percutaneous ablation

3.1. Thermal ablation

3.1.1. Efficacy,complications and the influencing factors of thermal ablation

Microwave ablation (MWA) does not rely on heat conduction and is less affected by the dissipative effect than RFA,19so MWA may be more widely used than RFA. According to current studies,20–23the initial complete ablation rate of ultrasound-guided RFA or MWA for HCC in the caudate lobe was approximately 76.9–93.5%, with the tumor diameter significantly affecting the initial complete ablation rate. According to related reports,20–25the incidence of more serious complications such as obstructive jaundice, bleeding, infection, and bile leakage was approximately 13.3–15.4%, but no procedure-related deaths were observed. Studies by Chen et al.23and Kariyama et al.25showed better survival and prognosis in ultrasound-guided RFA for HCC in the caudate lobe within the Milan criteria. Studies by Cui et al.22and Li et al.24showed that the 1-, 3- and 5-year survival rates of HCC in the caudate lobe treated with ultrasound-guided thermal ablation could reach 84.6–91.6%, 76.9–83.3% and 46.1–66.7%, respectively, but some studies20–22,25suggested that recurrence was easy after thermal ablation,with recurrence rates as high as 38.5% within 1 year, and 41.7% at 3 years. According to the present researchers, the factors affecting the efficacy and prognosis of thermal ablation are summarized as follows:Thermal ablation,especially RFA,is affected by the heat deposition effect of large veins and the restricted access to the puncture electrode. (1)Adjacent large vessels: one study26found that partial ablation of the spigelian lobe, paraventricular,and caudate margins achieved adequate ablation in 25%,40%and 100%of cases,respectively,and that the difference in ablation outcome was clearly related to sites such as adjacent large veins or the hepatic pericardium.Dou et al.19have also found that the ablation effect is compromised by the increased thermal settling effect of thermal ablation when the tumor is located in the paraventricular portion of the vena cava. A research20indicated that a distance of <0.5 cm between the tumor and the inferior vena cava is a high-risk factor for residual tumor.(2)Tumor diameter:the incidence of distant metastases and survival can be significantly affected when the diameter of HCC in the caudate lobe is greater than 2 cm.27(3)Ablation margins:according to an existing study,19thermal ablation combined with alcohol ablation still only achieved margins of more than 5 mm in 55%of patients,while 22.2%of patients who underwent conformal ablation or had margins less than 5 mm,had local tumor progression(LTP)during a certain follow-up period, and only 9.1% of patients with at least 5 mm margins had LTP.This is particularly important for patient survival but remains difficult for patients with caudate lobe HCC.

3.1.2. Location and shape of hepatocellular carcinoma in the caudate lobe

The location and shape of the tumor are closely related to the outcome of radiofrequency ablation treatment.28,29The following methods are available to address the specific location and shape of HCC in the caudate lobe: (1) Artificial Pleural effusion can improve imaging under ultrasound of the tumor at the top of the liver but cannot reduce the possibility of diaphragmatic injury.30On the other hand, artificial ascites not only improves ultrasound imaging, but also minimizes damage to intra-abdominal vessels,bile ducts,and organs from the puncture needle.31(2) The positioning adjustment of RFA electrodes is difficult and the puncture route is restricted, which may lead to insufficient ablation margins, so it is particularly important to choose a suitable puncture route.In addition,a multidirectional approach can compensate for the limited puncture route, but a transthoracic route should be avoided because it is more prone to serious complications such as hemothorax and pneumothorax.32(3) Applying conformal ablation can ensure the maximum ablation area and reduce the number of perforations.31Bypass ablation can avoid puncturing large vessels and bile ducts.Parallel orientation can expand the contact surface between the ablation needle and the vessel and reduce the heat dissipation effect, but it may not be applied at complex vessels.

3.1.3. Reduction of the thermal dissipation effect of vessels

3.1.4. Reduction of serious complications such as bile duct injury and tumor implantation

Ethanol ablation is less capable of complete ablation than thermal ablation, has a low effective margin reach rate, a high recurrence rate,and is only used for tumors less than 3 cm in diameter or lesions in highrisk locations such as near vessels. In theory, alcohol can destroy the vessels around the tumor,as well as tumors that may metastasize through microvessels after thermal ablation; or make the tissues around the electrode less susceptible to carbonization,promote heat conduction,and reduce the heat sink effect, which can be used as a complementary treatment to reduce the residual tumor after thermal ablation. But whether ethanol ablation can improve the prognosis of patients undergoing thermal ablation for caudate lobe carcinoma,remains to be proven.In contrast, other stronger chemical ablation agents, such as acetic acid and hydrochloric acid, demonstrate good efficacy in the ablation of tumors at other sites and may be a better choice for caudate lobe hepatocellular carcinoma.

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3.1.5. Guidance modalities for thermal ablation

(1) Influenced by the deeper location of the caudate lobe, real-time ultrasound often displays poorly, which may easily cause damage to important structures along the puncture path.After guiding to complete ablation,it is still recommended to enhance CT to clarify residual lesions.(2)The 1-,3-,and 5-year survival rates,and 1-,3-,and 5-year disease-free survival (DFS) rates of stereo ultrasound guiding multi-needle RFA,38were roughly comparable with ultrasound-guided RFA1; and the value and safety of its application needs to be further investigated. (3) Some scholars39found that the LTP rate of ultrasonography-guided ablation was significantly lower than that of ultrasound, and the application of ultrasonography also has great potential. (4) Other scholars used CT-guided thermal ablation of HCC in the caudate lobe to achieve a complete ablation rate of 100% without serious complications.40(5) At present, combined guidance of ultrasound and CT has been applied in some studies,and Bao et al.41treated 33 cases of HCC in the caudate lobe with CT combined with ultrasound-guided MWA.The complete ablation rate was 100%,and the recurrence rate was only 9.3%in 8–16 months,but the incidence of surgery-related grade IV complications was still 2/33,which shows that the combined guidance is more effective,but still cannot completely guarantee the safety of ablation. In contrast, fusion imaging guidance techniques combining the advantages of real-time imaging with ultrasound or ultrasonography and high resolution CT or magnetic resonance imaging (MRI) have also been applied,42,43suggesting better safety and good prospects for application.(6)Laparoscopic or open ablation can significantly shorten the distance of needle puncture and has the significant advantage of allowing direct visualization of the lesion.In Jiang et al.’s study,laparoscopy-guided RFA was used to treat 27 cases of HCC in the caudate lobe with a mean diameter of 2.8 cm.The survival rates at 1, 2, 3, 4, and 5 years reached 96.3%, 88.9%, 74.1%,74.1%,and 62.9%,respectively, while the DFS rates at 1, 2,3, 4,and 5 years reached 92.6%,52.9%,44.4%,33.3%,and 33.3%,with only minor adverse effects.44A similar study by Jiang et al.45treated 10 cases of tumors with an average diameter of 2.6 cm, and displayed a complete ablation rate of 100%, survival rates of more than 2 years in all cases,confirming safety and effectiveness.

3.2. Cryoablation

In recent years, the application of cryoablation has gradually increased, and several studies have found that cryoablation is significantly safer for HCC near the base of the diaphragm,the heart,or other vital organs.46–49Both studies50,51found that cryoablation significantly reduced major vascular complications such as peritumoral vascular thrombosis and liver infarction,and it was found to be more effective in controlling local tumor progression, comparable to radiofrequency ablation.In another study,52cryoablation for HCC in high-risk sites also significantly reduced the rate of local tumor progression compared with microwave ablation but did not improve the overall survival, or recurrence-free survival.However,it was less effective for tumors larger than 4 cm in diameter than for smaller tumors in terms of technical effectiveness, local tumor progression, and occurrence of adverse effects.53Minimum ablation margins <5 mm are also an important prognostic factor for cryoablation of LTP.54The use of multi-slice spiral CT guidance to improve efficacy and reduce complications has been suggested in a study.55The use of MRI-CT fusion imaging to evaluate cryoablation margins in hepatocellular carcinoma has also been suggested.56Despite the lack of clinical studies on cryoablation of caudate lobe HCC, cryoablation has shown very good potential application for the treatment thereof.

3.3. Chemical ablation

The thermal dissipation effect of vessels can reduce thrombosis and vascular injury,which can also lead to residual tumors.For the heat sink effect, in addition to conformal, bypass, and parallel ablation methods,the following methods are available:(1)Masashi et al.’s study33showed that multi-electrode RFA significantly increased the rate of complete tumor necrosis, improved relapse-free survival (RFS) of patients and reduced the rate of LTP without increasing serious complications. In contrast, Serror et al.34reported that complete necrosis of tumors adjacent to large vessels could only be achieved using a multi-electrode technique. However, another research31has also concluded that the increased number of multipolar perforations and repositioning of electrodes can increase the risk of tumor implantation and needle tract dissemination. It was also concluded that reinsertion of electrodes significantly increases the risk of penetrating blood vessels, bile ducts,etc.Whether multipolar ablation can improve prognosis still needs to be confirmed by numerous clinical studies.(2)Physiological saline-infused radiofrequency ablation (NSRFA) and hydrochloric acid-enhanced radiofrequency ablation (HRFA) increases the conductivity around the radiofrequency electrode.The electrode can be placed in the center of the lesion,allowing the formation of an ablation zone larger than 5 cm with a single electrode, thus increasing the volume of ablation without serious complications. Thus, they are expected to be used for the treatment of large caudate lobe HCC.35

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4. Combination of various interventions

4.1. Transcatheter arterial chemoembolization combined with thermal ablation

Ablative therapy can induce peripheral immune responses.One study showed that combined immunotherapy can still be safe for the treatment of advanced HCC with complications such as hepatic insufficiency,rash,pruritus, autoimmune pneumonia, colitis, and thyroid dysfunction.71A prospective study found that sequential nonspecific immunotherapy after RFA was effective in extending the overall survival time of patients with early-stage HCC compared with RFA alone.72A retrospective study by Yang et al.73found 86.6%,77.4%,and 66.0%disease control rates at 1,3,and 6 months,respectively,in TACE combined with immunotherapy for intermediate-stage hepatocellular carcinoma.Although one case of fatal lung injury,abnormal thyroid function and reactive cutaneous capillary hyperplasia occurred in most patients, the efficacy was still greater. A randomized controlled trial74and a retrospective study75confirmed that TACE combined with sorafenib significantly improved the efficiency of treatment relative to TACE alone. Another retrospective study76found that TACE combined with sorafenib for inoperable patients was well tolerated and safe, although toxic side effects associated with sorafenib were observed.

To prevent the occurrence of bile duct injury,the electrode needs to be kept more than 5 mm from the bile duct36;and endoscopic nasobiliary drainage tube cooling37is a preventive measure against bile duct injury.To prevent tumor implantation,the use of larger electrodes and multiple perforations should be avoided,and the normal liver parenchyma should be crossed as far as possible before entering the tumor.There are special ablation techniques for tumors in special locations to avoid tumor implantation in the abdominal cavity. For example, ablation of exophytic HCC in the caudate lobe should be performed by ablating the intrahepatic portion first,blocking the blood supply to the exophytic portion,and gradually increasing the radiofrequency ablation energy, thus improving the safety of ablation.

4.2. Transcatheter arterial chemoembolization combined with chemical ablation

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4.3. Cryoablation combined with other interventional methods

Cryoablation has also been used in combination with other interventional methods. Combining cryoablation with radiofrequency ablation to take advantage of their respective strengths can ensure the efficacy and safety of the treatment.It has also been found that the total clinical efficacy of TACE combined with cryoablation for unresectable large hepatocellular carcinoma can reach 93.5%with an overall adverse effect rate of only 12.9%, thus effectively improving the cellular immunity of patients.69

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5. Ultrasound endoscopy

Ultrasound endoscopy-guided laser ablation for HCC in the caudate lobe has been reported.70The study showed that it significantly reduced complications, but further studies are required to establish the efficacy thereof. Ultrasound endoscopy-guided thermal ablation and chemical ablation have been used for the treatment of liver carcinoma in other areas and have great potential for the treatment of caudate lobe liver carcinoma.

Percutaneous transhepatic chemotherapy-lipiodol injection (PTCLI)has good tracer properties and conformability, and reduces damage to the normal liver, so it has great value for application. Dai et al.66compared TACE combined with PTCLI or RFA for the treatment of HCC and found that PTCLI treatment had fewer complications and good results. Liu et al.67found that the complete inactivation rate of TACE combined with PTCLI for giant HCC was 58.3% (42/72), which was higher than the 31.8%(14/44)in the combined MWA treatment group.One study68used TACE and CT-guided PTCLI to treat exophytic HCC in the caudate lobe without serious complications such as liver failure,tumor necrosis, and hemorrhage from tumor rupture, showing that it is safe and reliable.

6. Multidisciplinary treatment

6.1. Combination of interventional therapy with immunotherapy or molecular targeted therapy

Transcatheter arterial chemoembolization can reduce the heat dissipation effect of other arteries or portal vein57,and reduce the probability of tumor metastasis or tumor size to improve the safety of thermal ablation.In addition,segmental TACE can improve the visibility of small HCCs that are not easily detected by conventional examination through enhanced contrast or iodinated oil injection, making CT-guided percutaneous radiofrequency ablation possible.58,59Tissue necrosis after TACE can enhance the thermal ablation effect of RFA;moreover,tissue necrosis after thermal ablation makes it easier for chemotherapeutic agents to spread,so the two interventions can be mutually reinforcing.Studies on the treatment of HCC in the caudate lobe32,60,61have shown that although combined interventions are still subject to the inherent limitations of each intervention, the combination of the two significantly increased the rate of complete tumor destruction, which could reach 90–100%, with survival rates of 100%, 80.8% and 80.8% at 1, 3 and 5 years for HCC in the caudate lobe with a diameter<2 cm.60For HCC in the caudate lobe within Milan Criteria,1-,3-and 5-year survival rates of 94.4%, 86.6%, and 67.5%, respectively, were achieved,32which are significantly higher than those of studies with superselective TACE alone.2,8In addition,the reproducibility of the combination therapy may also significantly improve OS. This therapy has shown good efficacy in large HCC in the caudate lobe in one study,62which has achieved a mean survival of more than 2 years by treating 5.0–8.1 cm diameter tumors with TACE combined with hydrochloric acid-enhanced RFA. However,some scholars63concluded that there are no differences in LTP,OS,and RFS between TACE-RFA and RFA for patients with small (≤3 cm) HCC.Therefore, TACE-RFA was not recommended for the first-line treatment of small HCC.However,Kim et al.63have shown that TACE-RFA is better than TACE alone for small HCC and is therefore recommended for situations where RFA is not appropriate. In contrast, Fujimori et al.32recommended combination therapy for patients with intrahepatic tumors smaller than 5 cm in diameter and liver function Child-Pugh scores equal to or less than 7. In their study64treating HCC at other sites, Liu et al.found that combination therapy induces more thrombosis or segmental liver infarction than RFA monotherapy. In the study of Hyun et al.,60combination intervention for HCC in the caudate lobe also identified one case of portal vein thrombosis resulting in asymptomatic liver infarction.This is possibly because the reduced heat dissipation effect of TACE increased the likelihood of large vein thrombosis.Previous studies have reported complications after TACE-RFA, including liver infarction, liver failure, bile duct stricture with cholestasis, liver abscess, and arterial hemorrhage.65It has also been shown that the combination of TACE and RFA can increase the incidence of complications.63However, it is clear from the available studies32,60,61that all complications, with the exception of the increased likelihood of liver infarction due to portal vein thrombosis, may occur with a single intervention. Therefore, clinical decisions should be made by assessing the risk of venous thrombosis and reducing the possible complications of a single intervention by various measures to prevent a superposition of the respective complications.

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6.2. Combination of interventional therapy with radiation therapy

Radiation therapy alone has been used in the treatment of caudate lobe HCC and has shown positive outcomes.77–79Other radiation therapy methods, such as stereotactic radiation therapy and selective internal radiation therapy(SIRT), have been used as additional options for local treatment. Brachytherapy can be used for the treatment of residual caudate lobe tumors that cannot be completely ablated. In an existing study,80transarterial chemoembolization and I125seed implantation for caudate lobe HCC had an objective response rate of 60.0%and a median OS of 35 months,while biliary tract injury only occurred in about 5%of cases,suggesting that it could become a new treatment option.

6.3. Combination of interventional therapy with surgery etc.

Interventional therapy has been used in combination with surgery,radiotherapy,and targeted therapy.One study81has used hepatic artery embolization prior to surgery and concluded that it improves the prognosis of patients without significantly increasing the difficulty or reducing the safety of the procedure. On the other hand, it is now also recommended that small resectable tumors should be avoided for local treatment.82

7. Summary

In the interventional treatment of hepatocellular carcinoma in the caudate lobe, the efficacy of super-selective TACE is still influenced by the multiple origins of the caudate lobe arteries, pending the development of hepatic arteriography techniques. Combining multiple imageguided methods can improve the efficacy and safety of ablative interventions. The sequential combination of multiple intervention methods is the trend of interventional treatment for HCC in the caudate lobe. Multidisciplinary treatment is also essential to improve the prognosis of patients with HCC in the caudate lobe.

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Declaration of competing interest

The authors declare no conflict of int erest.