Consensus Practice Guidelines for Conventional Transarterial Chemoembolization (cTACE) in the Treatment of Hepatocellular Carcinoma

Abstract

This consensus guidelines document is a collaborative effort by a panel of interventional radiologists from India. It defines the criteria for selecting appropriate patients, outlines the standard techniques for performing conventional chemoembolization [cTACE], and establishes a consistent framework for the evaluation and follow-up of treated patients. By adopting these standardized practices, the authors seek to harmonize the cTACE procedure across various healthcare settings, ultimately contributing to improved patient care, optimized resource utilization, and enhanced clinical outcomes.

Keywords

cTACE - best practice - Indian guidelines

Introduction

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths in India. Though the prevalence is less compared with that of the world, the incidence is rising due to the high prevalence of viral hepatitis, alcoholic liver disease, and metabolic dysfunction-associated steatotic liver disease (MASLD) that predisposes to chronic liver disease and HCC.[1] Most patients are diagnosed late and are often triaged to conventional transarterial chemoembolization (cTACE). The basic principle of cTACE is the transarterial delivery of high local concentrations of chemotherapeutic drugs, followed by the embolization of tumor-feeding arteries. The surrounding liver parenchyma is spared due to its preferential blood supply by the portal venous circulation.[2]

Over the past three decades, numerous studies have evaluated the role of cTACE in the treatment of HCC and provided recommendations on patient selection, technical aspects, and treatment protocols. There is significant heterogeneity in the presentation of HCC in India, specifically the intermediate (BCLC B stage), which is traditionally triaged for cTACE. In addition, there is a significant disparity in the techniques and practices of cTACE among Indian interventional radiologists. These factors call for a practice guidelines document to standardize patient selection, procedure technique, and follow-up, to ensure parity in results and achieve high technical success rates.

With the above objectives in mind, a panel of experts from high-volume cTACE centers across India was set up in 2022. A conscious effort was made to have representation of interventional radiologists from all parts of the country. There were two invited members, one from the United States and one from South Korea, to provide insights and perspectives from the West and East, respectively. After intensive discussion and careful consideration by the first author and last author of this document, a set of 25 most relevant questions contributing to the heterogeneous practices of cTACE in India was circulated among the expert panel. These were discussed over multiple meetings, and after a thorough review of the literature and serial deliberations, a consensus document on best practices of cTACE was formulated. The expertise and perspective of the invited members have been instrumental in enriching our discussion and guiding the standardization of best practices of cTACE.

Generation of Recommendations

These consensus statements provide recommendations (strong or weak) based on the level of evidence (low, moderate, high) according to a simplified adaptation of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.

Level of Evidence and Grade of Recommendations (Adapted from GRADE System)

Level of evidence	Rationale	Confidence in evidence
High	Data derived from meta-analyses or systematic reviews or from (multiple) randomized trials with high quality	Further research is unlikely to change our confidence in the estimate of benefit and risk
Moderate	Data derived from a single RCT or multiple nonrandomized studies	Further research (if performed) is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate
Low	Small studies, retrospective observational studies, and registries	Any estimate of effect is uncertain
Recommendations grade		Wording associated with the grade of recommendation
Strong		“Must,” “should,” or “expert panel recommends”
Weak		“Can,” “may,” or “expert panel suggests”

• Q1. In patients with HCC for whom cTACE has been selected as the treatment modality, what clinical parameters define appropriate candidacy?

• A. Patients with Child–Pugh score ≤B7, ECOG PS 0–1, tumor burden up to INASL (Indian National Association for Study of the Liver) modified BCLC (Barcelona Clinic Liver Cancer) category B2, no vascular invasion, and no extrahepatic disease (EHD) are deemed appropriate for treatment by cTACE.

Level of Evidence: High; Grade of Recommendation: Strong

Patients with performance status ECOG PS > 2 or Child–Pugh score of > B7 are less likely to benefit from cTACE (also refer to Q1B).[3] [4] Although no absolute contraindications to cTACE exist, patients with more than 50% replacement of the liver by tumor, lactate dehydrogenase level greater than 425 IU/L, aspartate aminotransferase levels >5 times normal, and total bilirubin level > 3 mg/dL would have poor outcomes following cTACE. In such patients, the risk of acute liver failure outweighs any benefit from the procedure. In addition, the utility of cTACE is questionable in patients with severe comorbid disease, extrahepatic metastases, and/or hepatic encephalopathy.[3] [5]

• B. Patients with a Child–Pugh score of > B7 can still be treated with cTACE, especially those who are being triaged for liver transplantation, provided embolization is performed at least super-selectively, minimizing nontarget embolization to nontumor liver.

Level of Evidence: Low, Grade of Recommendation: Weak

The patient population with intermediate HCC (as per BCLC guidelines)[6] is heterogeneous with varying degrees of hepatic dysfunction. It is critical to identify patients who will benefit most from cTACE or for whom the risks of irreversible hepatic dysfunction outweigh the potential benefits of cTACE. cTACE is not recommended in the setting of Child's C liver disease, main portal vein thrombosis, or a serum bilirubin level > 3.0 mg/dL unless super selective treatment is possible and liver transplantation is considered.[5] [7] cTACE may increase mortality and may precipitate a need for urgent liver transplantation in these situations.[5]

The use of Albumin-Bilirubin (ALBI) score to stratify patient selection and for accurate prognostication, irrespective of tumor burden, has been emphasized in the 2022 BCLC model and proposed over Child–Pugh and model for end-stage liver disease (MELD) scores. The ALBI grade has shown a good prognostic predictive ability and has been used to categorize BCLC B patients receiving cTACE. The ALBI grade has demonstrated a greater level of homogeneity in outcomes compared with the Child–Pugh score and MELD score in patients who underwent cTACE.[6] [8]

• Q2. When should cTACE be considered in patients who are otherwise eligible for curative treatment (thermal ablation/resection/liver transplantation)? cTACE should be considered only when curative treatments (thermal ablation, resection, or liver transplantation) are not technically feasible or as a bridging therapy for liver transplantation.

Level of Evidence: Moderate, Grade of Recommendation: Strong

The concept of treatment stage migration has been well described in the BCLC 2022 update.[6] It emphasizes that while a given treatment option for a particular BCLC stage should be considered first, an expert evaluation of all the clinical and technical aspects may result in choosing an option that would be a preferred treatment for a more advanced stage or an earlier stage.

cTACE should be considered in patients if ablation or surgery is not feasible for technical reasons. These may include difficult anatomy, unfavorable location of the lesion making it unsafe for ablation, failed image guidance for ablation, high surgical risk, and the patient's refusal of surgery.[9] [10] [11]

cTACE has also been used as a bridging treatment strategy to reduce the dropout rate by 3 to 13% in patients with early-stage HCC and being considered for liver transplantation, especially in those patients whose waiting time for transplantation is expected to exceed 6 months.[12]

• Q3. In patients beyond curative options and with good hepatic functional reserve, what tumor size, number, and burden are best suited for cTACE?

cTACE is best suited for patients with a total liver tumor burden (LTB) (tumor volume / total liver volume by CT scan) of < 50% and for those in whom the tumor load according to the 6 to 12 tumor scoring criteria places the patient within the medium- and low-risk group.

Level of Evidence: Moderate, Grade of Recommendation: Strong

cTACE is one of the treatment options for patients with intermediate-stage HCC. However, there is substantial heterogeneity among patients with intermediate-stage HCC due to considerable differences in tumor burden, tumor distribution, and liver function. This heterogeneity hampers prognosis prediction, and consequently, making treatment decisions for these patients remains difficult. To support the decision-making process, several scoring systems ([Table 1]) have been proposed to define the tumor burden.[13] [14] [15] [16] [17]

Table 1 Risk stratification scoring system according to the tumor burden

Scoring system	Calculations	Risk group and OS (months)
		Low risk	Medium risk	High risk
Tumour burden score	Square root [(max tumor diameter)[2] + (number of tumor)[2]]	<3.36 33 mo	3.36–13.74 18.3 mo	>13.74 12.8 mo
Six-and-twelve score	Largest diameter (cm) + tumor number	<6 30 mo	>6 but <12 16.9 mo	>12 10.2 mo
Seven–eleven criteria	Largest diameter (cm) + tumor number	<7 27 mo	>7 but < 11 16.7 mo	>11 10.5 mo

Direct head-to-head comparison of three scoring systems for HCC prognosis found that the six-and-twelve score (SAT) is superior to the tumor burden score (TBS) and the seven–eleven criteria (SEC) in survival stratification and predictive ability. Thus, the SAT should be preferred when stratifying patients according to tumor burden.[15]

Treatment decisions should not be made based on tumor burden alone. Instead, a thorough interdisciplinary discussion that considers all types of risk factors (e.g., tumor distribution, functional hepatic reserve, performance status) is required to improve patient selection, treatment outcomes, and patient survival.[15]

The method of performing cTACE (ultra-selective, super-selective, selective, non-selective, single session or sequential) should be based on the percentage of liver involvement by the tumor, tumor burden, tumor distribution (unilobar or bilobar), and underlying hepatic functional reserve.

The definitions for selective, super-selective, and ultraselective treatment are based on the position of the micro-catheter tip up at the segmental or proximal subsegmental or distal subsegmental arterial tumor feeders, respectively, when performing cTACE. The treatment is considered nonselective when the catheter tip is up at the lobar branch.

If tumor burden is high (refer to [Table 1]) and distributed in most hepatic segments, performing a bilobar nonselective procedure may cause deterioration of liver function, especially in patients with marginal liver function. Hence, selective and sequential cTACE is preferred over single-session or nonselective cTACE. On the contrary, if the same tumor burden is distributed in one hepatic sector (anterior or posterior segments of the right lobe or medial or lateral segments of the left lobe), it is possible to perform a safe and effective nonselective cTACE without the risk of hepatic decompensation.

For patients with tumor burden in the low- and medium-risk group ([Table 1]) and good functional reserve and unilobar or bilobar disease, a single session, ultraselective or superselective, or selective cTACE should be considered over a nonselective cTACE.

For patients with high tumor burden (refer to [Table 1]) and good functional reserve, bilobar distribution of disease, sequential and selective cTACE is safer than single session and nonselective cTACE.

For all the patients with marginal functional reserve (Child B), irrespective of tumor burden and distribution, one should consider selective and sequential cTACE.

• Q4. Can cTACE be considered in patients with macrovascular invasion of (1) the portal vein or (2) the hepatic vein?

(1) Portal Vein Tumor Thrombus

In patients with ECOG PS 0–1, good liver function (Child–Pugh A), HCC limited to the liver, and subsegmental or segmental portal vein tumor thrombosis (PVTT), and some cases of lobar PVTT with/without main PVTT, a specially protocolized cTACE can be safe and effective, with acceptable survival rates.

Level of Evidence: High, Grade of Recommendation: Strong

(2) Hepatic vein tumor thrombus (HVTT): Though there is scant evidence with regard to the use of cTACE for HCC with HVTT, it may be considered in patients deemed unresectable.

Level of Evidence: Low, Grade of Recommendation: Weak

PVT has been described as a relative contraindication to cTACE due to the associated risk of hepatic infarction and worsening of liver function. EASL, AASLD, and BCLC staging systems do not recommend the use of cTACE for patients with macrovascular invasion. However, a survey of interventional oncologists revealed that cTACE is chosen by 52% of physicians when treating HCC with PVTT.[18]

PVTT Classification

Three methods of PVTT classification have been described ([Table 2]).

Table 2 Portal vein tumor thrombosis classifications

Xu et al[199]
Type A	Tumor thrombus in the main portal vein trunk or both the left and right portal vein branches
Type B	Tumor thrombus in one branch of the portal vein (PV) (right/left)
Shuqun et al[200]
Type I	Tumor thrombus in the PV segmental branches or distal
Type II	Tumor thrombus extending to the right or left PV
Type III	Tumor thrombus extending to the main trunk of the PV
Type IV	Tumor thrombus extending to the main trunk of PV and to SMV
Kudo et al[201]
Vp0	No tumor thrombus in the portal venous system
Vp1	Tumor thrombus in the third-order PV branch or distal
Vp2	Tumor thrombus in the second-order PV branch
Vp3	Tumor thrombus in the first-order PV branch
Vp4	Tumor thrombus in the main trunk of the PV

Patient Selection

The decision to utilize cTACE in the setting of PVTT should rely upon the patient's performance status, extent of PVTT, and baseline liver function. cTACE in patients with PVTT should be performed with a microcatheter advanced into the most distal tumor-feeding vessel while sparing the nontumor hepatic parenchyma. These “superselective” or “ultraselective” techniques have allowed HCC patients with PVTT to be considered for cTACE. Even with the main portal vein occlusion, superselective cTACE can preserve arterial perfusion to the nontumor liver and minimize the risk of ischemic necrosis and subsequent liver failure.[19]

In combination with cTACE, other treatment options such as ablation, external beam radiation therapy (EBRT), and systemic therapy can be considered with input from a multidisciplinary meeting.

HVTT Classification

HVTT is classified[20] as follows:

• Type I: tumor thrombosis involving the hepatic vein, including microvascular invasion.

• Type II: tumor thrombosis involving the intrahepatic segment of the inferior vena cava (IVC).

• Type III: tumor thrombosis involving the supradiaphragmatic segment of the IVC.[6]

Management of HCC with HVTT is evolving. The current decision to utilize cTACE for HVTT should depend on patients' performance status, extent of HVTT, and liver function. The treatment modalities include hepatectomy combined with thrombectomy, cTACE, RT, and systemic therapy. As long as the tumor is resectable and the tumor thrombus is limited to a major hepatic vein, liver resection may be considered, especially in patients with good liver function.[21] The decision to use cTACE alone or in combination with other modalities, such as radiotherapy (RT) and systemic therapy, must be made in a multidisciplinary setting.

For patients with HVTT, the prognostic value of cTACE is still unclear. The median overall survival (OS) is between 6.5 months and 1.61 years when treated with cTACE alone.[21] [22] [23]

• Q5. While performing cTACE for patients with PVTT, what other locoregional therapies can augment treatment outcomes?

Patients with PVTT who are undergoing cTACE can benefit from the addition of stereotactic body radiation therapy (SBRT), EBRT, or percutaneous thermal ablation.

Level of Evidence: Low, Grade of Recommendation: Weak

PVTT occurs in approximately 35 to 50% of patients with HCC and involves the main trunk at the time of diagnosis in 15 to 30% of cases.[24] Patients with HCC and PVTT remain a subgroup with poor survival, despite the efforts to expand treatment indications outside the BCLC algorithm. The involvement of a multidisciplinary tumor board is mandatory to provide the best therapeutic decision for complex, selected cases. Liver function remains a decisive factor in the selection of therapeutic options. OS in patients with PVTT has been estimated to range from 5 months to 5 years and is influenced by a multitude of factors, such as underlying liver function, tumor features (degree of portal system involvement and biological aggressiveness of the tumor), complications caused by portal hypertension, treatment applied, and tolerance to antineoplastic treatments.[25] [26] [27] [28] In the absence of therapy, the median survival has been reported to be 2.7 to 4 months.[27] [28]

cTACE

The efficacy of cTACE in treating PVTT is related to the degree of hepatic arterial supply to the thrombus. Patients demonstrating a good accumulation of Lipiodol in the PVTT after cTACE presented a better response to cTACE, with OS of 10 versus 2.7 months in patients with a mild or poor Lipiodol accumulation.[29]

cTACE with Radiotherapy

cTACE leads to necrosis of tumor thrombus by reducing the arterial supply and stimulates G0 phase cells (a form of the resting state, or quiescence, in which cells reside until they receive appropriate signals) to enter into the proliferating phase, allowing the increased sensitization of the tumor to RT-related antitumor effect.[25]

Radiotherapy has been shown to have objective response rates ranging from 39 to 62% in patients with HCC and macrovascular invasion. Despite high local control rates by RT alone, failure outside the radiation field provides the rationale for combining regional or systemic treatments with RT. cTACE is a proven treatment for locally advanced HCC, and cTACE and RT may complement each other. Focal field RT targeting macrovascular invasion may relieve intravascular tumor growth and maintain portal blood flow, allowing the maintenance of liver function, limiting intrahepatic tumor spread, and thereby, allowing additional cTACE sessions.[30]

In very selected patients, improved outcomes have been observed by applying percutaneous transhepatic portal vein stenting and cTACE, with or without three-dimensional conformal radiotherapy (3-DCRT): median OS was 16.5 months in the RT group versus 4.8 months in the non-RT group, emphasizing the role of RT as a combination strategy. The study did not show any severe symptomatic adverse events or any apparent late radiation-induced complications. Radiation-induced liver disease was not observed in any of the patients receiving 3-DCRT.[31]

Percutaneous Ablation Therapies

Percutaneous ablative treatments have been proposed for HCC complicated by PVTT, but particular caution must be paid because of the potential risk of damaging portal and biliary structures. Combined treatment with radiofrequency ablation (RFA) and cTACE for HCC complicated by PVTT (PVTT type I, II, or partial III) was reported to achieve a mean survival time of 29.5 months, with 1-, 3-, and 5-year survival rates of 63, 40, and 23%, respectively.[32]

A prospective study of microwave ablation (MWA) following cTACE for HCC with PVTT (PVTT type I, II, or partial III) demonstrated improved median OS when compared with a historical cohort of patients treated with cTACE alone (13.5 vs. 9.5 months). The 3-year survival rates were 24, 26, and 20% for types I, II, and III PVTT, respectively. This improvement was seen even with broad inclusion parameters that enrolled patients with EHD, Child–Pugh Class A and B, and segmental and main PVTT.[33]

• Q6. Which patients with EHD are best suited for cTACE?

c-TACE, in conjunction with systemic therapy, is considered safe for a select group of patients with limited EHD, provided there are no other contraindications.

Level of Evidence: Moderate, Grade of Recommendation: Strong

Patients with HCC die of intrahepatic disease more often than EHD. Hence, local control of disease is important for improved survival.[34] cTACE in a select group of patients with good performance status and limited EHD and without PVTT is considered safe and offers reasonable median survival.[35]

The use of systemic treatment following cTACE is independently associated with improved progression-free survival (PFS) in patients with or without limited EHD. Limited EHD is defined as solitary bone/adrenal/soft tissue metastasis, scattered small lung nodules, or regional nodal disease.[36] A heavier burden of EHD was independently associated with poor OS, and hence, such patients should not be considered for cTACE. A recent multicenter study reported that patients with HCC and EHD achieved better OS following transarterial chemoembolization (15.1 months) than those managed with systemic therapy alone (4.7 months).[37]

• Q7. What is the preferred modality for planning cTACE?

Triple-phase CT or dynamic contrast-enhanced MRI (CEMR) of the abdomen should be obtained within 30 days before cTACE. If triple-phase CT is planned, then it is preferable to include CT of the chest (noncontrast or contrast-enhanced) to rule out metastatic disease in the lungs.

Level of Evidence: Moderate, Grade of Recommendation: Strong

Though triple-phase CT and dynamic CEMR are considered complementary modalities for imaging of HCC, any one of them can be opted for planning cTACE, as long as at least three phases, including unenhanced, arterial, portal, and venous phases, are obtained. However, some studies have shown that MRI with liver-specific contrast materials, such as gadoxetic acid/gadobenate dimeglumine, provides higher sensitivity and overall accuracy in HCC detection when compared with conventional multiphasic CT and therefore may be considered in cases with atypical enhancement patterns on multiphasic CT.[38] [39] The pretreatment imaging should ideally be performed less than 1 month prior to cTACE, but should definitely not exceed 2 months, considering the chance of tumor progression in the interval period.[40]

The inclusion of CT of the chest and its findings would not change the planning of cTACE; however, it may impact the overall treatment plan and may help in predicting prognosis.

• Q8. What chemotherapeutic drugs can be used with Lipiodol for cTACE?

The most commonly used anticancer drugs for cTACE are doxorubicin, cisplatin, and epirubicin. No one drug has proven to be superior to the other.

Level of Evidence: High, Grade of Recommendation: Strong

Several drugs have been used as monotherapy or as a part of a multidrug regimen in cTACE. The most commonly used anticancer drugs for cTACE are doxorubicin/epirubicin (48%), cisplatin (31%), mitoxantrone (8%), and mitomycin C (8%) ([Tables 3] and [4]) and can be considered as the drugs of choice in cTACE.[41] Some other drugs that have also been used in cTACE are idarubicin, oxaliplatin, 5-fluorouracil, gemcitabine, and paclitaxel.[41]

Table 3 Single-drug regimens of commonly used drugs[202] [203]

	Dose range	Dose range per m2 of body surface area
Doxorubicin	10–100 mg	50–75 mg/m2 or 1 mg/kg
Epirubicin	5–120 mg	12.5–120 mg/m2
Cisplatin	10–100 mg	80–100 mg/m2
Miriplatin	20–140 mg	80–100 mg/m2
Mitomycin C	2–30 mg	8 mg/m2
Carboplatin	10–100 mg	80–100 mg/m2

Table 4 Commonly used multidrug regimens[202] [204]

Chemotherapeutic agent	Dose range
Doxorubicin + cisplatin or mitomycin	30 mg doxorubicin and 100 mg cisplatin or 30 mg mitomycin
Doxorubicin + cisplatin + mitomycin	30 mg doxorubicin, 100 mg cisplatin, and 30 mg mitomycin

Variable dosages of anticancer drugs have been reported ([Table 3]): some studies used a fixed dose, and some used doses based on the body surface area, patient weight, tumor size, or bilirubin level.[42] Most clinicians tend to limit the cumulative dose of conventional doxorubicin to 400 to 450 mg/m².[43]

A lower dose of doxorubicin (50 vs. 100 mg) was reported to be associated with a milder postembolization syndrome (PES) without compromising tumor response or OS.[44] Similar observations have been made with high-dose versus low-dose multidrug regimens.[45] Different doxorubicin formulations (plain and liposomal forms) are available for commercial use. The liposomal doxorubicin formulation was seen to reduce the incidence of adverse reactions and significantly improve the OS as compared with its plain formulation.[45]

The cancer therapy-related cardiac dysfunction (CTRCD) associated with the cumulative dose of doxorubicin is found in 9% of the patient population being treated with this drug. CTRCD is defined as a decline in left ventricular ejection fraction of more than 10% to a value smaller than 53%.[46] [47] [48] [49] Even though it is ideal to perform a baseline cardiac assessment in every patient scheduled to receive a potentially cardiotoxic agent, it is often not practically possible. Hence, it is recommended to perform a pre-cTACE cardiac assessment in those considered to be at high risk for CTRCD. These include patients with left ventricular dysfunction, more than 65 years of age, and those scheduled to receive high doses of anthracycline agents (>300 mg/m² of cumulative dose) or combination chemotherapy.[50]

Drug or dose modification is desirable in cases where the patient is at high risk of developing cardiac toxicity. Epirubicin, idarubicin, and mitoxantrone are anthracycline analogs that are less cardiotoxic than conventional anthracyclines.[51] There is a significantly increased risk of congestive heart failure in patients who receive a cumulative dose of epirubicin greater than 950 mg/m2 compared with doxorubicin,[52] which has a maximum permitted cumulative dose of 400 to 450 mg/m².[43]

Protocol for Monotherapy

The drug(s) selected for cTACE is/are mixed with Lipiodol to form an emulsion. Water-in-oil emulsion (droplets of the internal phase containing the drug in an aqueous solution and a continuous external phase of oily Lipiodol) was demonstrated to be more densely retained within the tumors than the alternative oil-in-water emulsion. To favor a water-in-oil emulsion, the volume of Lipiodol should be higher than the drug aqueous solution (ideally 2:1 or 3:1 or 4:1).[40] [53] [54] [55]

Contrast material (300 mg/mL or more) should be used for the preparation of doxorubicin aqueous solution to improve the stability of the emulsion[56]; the use of a non-ionic contrast material increases the density of the drug solution and thus may favor the stability of the drug/Lipiodol emulsion by lowering the sedimentation process induced by gravity.[56] In vitro studies of 4:1, 3:1, 2:1, and 1:1 lipid in aqueous emulsions have shown that 4:1 emulsion was the most stable.[57]

The emulsion is prepared by using the three-way stopcock method with glass or polycarbonate syringes and a metal/polyethylene stopcock that resists degradation by the emulsion. Mixing is initiated by pushing the contents of the drug-loaded syringe toward the syringe containing Lipiodol, to favor a water-in-oil emulsion. Vigorous mixing of the chemotherapy aqueous solution and Lipiodol via the three-way stopcock generates sufficient energy to decrease the size of the internal phase droplets. At least 20 pumping exchanges through the stopcock are needed to obtain an internal phase size of droplets in the range of 70 to 100 microns.[58] The emulsion must be prepared at the time of administration and must be used immediately after preparation. Re-homogenization of the emulsion is recommended during treatment sessions.

Preparation of the Dual-Drug Emulsion

Various methods of multidrug emulsion preparation are reported in the literature. Multidrug regimens are shown to increase OS when used in patients with invasive disease.[59] [60] The powder form of drugs should be dissolved in contrast material, then mixed with Lipiodol using a three-way stopcock similar to doxorubicin–Lipiodol emulsion preparation. A 2:1 or 3:1 water-in-oil emulsion is desirable.[61]

Modified Transarterial Chemoembolization (Sandwich Technique)

The modified transarterial chemoembolization protocol consists of cTACE followed by an additional intra-arterial cisplatin infusion.[59] [62] Cisplatin is prepared as a solution at a concentration of 0.5 mg/mL and is infused into the tumor-feeding vessels at a rate of 4 to 10 mL/min after cTACE. Additional cisplatin infusion is started after obtaining near-complete stasis of vascular flow of target arteries (i.e., assessed by nonclearing of contrast material column within five heartbeats). The endpoint of cTACE is set as the very slow antegrade flow of target arteries so that cisplatin at a 4- to 10-mL/min flow rate runs into the target arteries, even though part of the infused cisplatin may reflux into nontarget arteries. When it is necessary to treat multiple segmental or lobar arteries, cisplatin is infused via each treated artery with a divided dose of cisplatin according to the tumor volume supplied by the target artery. The dosage of cisplatin is estimated considering the tumor volume, patient body weight, and liver function. For example, the dose of cisplatin is 100 mg for patients with large tumor volume, average body weight, and Child–Pugh class A5, and is 50 mg for patients with small tumor volume, slim body, and Child–Pugh class A6.[59] The practice of modified cTACE has been reported in literature from select centers in the Asia-Pacific region for patients with HVTT and hence can be considered in this select group of patients.

Preparation of Triple-Drug Regimen Emulsion

This mixture comprises 100 mg of cisplatin, 50 mg of doxorubicin, and 10 mg of mitomycin C, mixed in 5 mL of water-soluble contrast material. The chemotherapy solution is then emulsified in 10 mL of Lipiodol. If the powder form of any one of the drugs is not available, then modified cTACE (sandwich technique) can be used.

• Q9. What is the maximum dose of Lipiodol that can be given per session?

The standard Lipiodol dose used for cTACE is 10 mL and should not exceed 15 mL per session in adults.

Level of Evidence: Moderate, Grade of Recommendation: Strong

A dose of up to 10 mL has been reported in clinical studies. It is recommended to use a volume of Lipiodol up to 15 mL per session in adults in multicenter cohort studies and expert consensus reviews.[63] [64] The use of Lipiodol over 20 mL poses a high risk of potentially life-threatening adverse events, including liver failure and pulmonary toxicity from hepatovenous shunting to the lungs.[40] The volume of Lipiodol required depends on the volume of the tumor, the vascularity of the tumor, and the catheter position. For example, for superselective cTACE of small-sized masses, Lipiodol dose would be approximately two to three times the tumor diameter (2–3 mL/cm) for hypervascular lesions and equal to the diameter (1 mL/cm) for lesions with poor arterial supply.[65] For larger lesions, tumor volume exponentially increases with an increase in diameter. Hence, Lipiodol requirement increases accordingly.[66]

• Q10. What is the role of cone-beam CT (CBCT) in planning and performing cTACE?

The use of CBCT reduces nontarget embolization and improves tumor response, PFS, and OS following cTACE.

Level of Evidence: High, Grade of Recommendation: Strong

Whenever available, CBCT or hybrid CT/angio-CT/4D-CT should be used during cTACE. CBCT during cTACE improves the detection of tumors, especially those measuring <3 cm and recurrent tumors. It further aids in the identification of tumor-feeding arteries for superselective and ultraselective therapy.[67] [68] [69] [70] [71] Immediately following cTACE, CBCT allows “on-table” detection of Lipiodol deposition within the tumors (thus obviating the need for a post-cTACE CT), early identification of any untreated areas, and can help identify any additional arterial supply.[72] [73] [74]

CBCT may identify additional subcentimeter arterially enhancing lesions that were not identified on the prior CT/MR imaging. These lesions can be further characterized with “dual-phase” CBCT.[75] Corona enhancement seen on “dual-phase” CBCT is characteristic of hypervascular HCC and differentiates them from pseudo-lesions such as arterioportal shunts.[76] Lesions not characterized as HCC usually remain stable, and a close follow-up on subsequent imaging is recommended.

• Q11. What is the optimal catheter position for hepatic angiography and embolization?

Tumor characteristics and liver reserve influence selective, superselective, and ultraselective catheter position (using appropriate microcatheters) during cTACE in an effort to minimize nontarget embolization.

Level of Evidence: Moderate, Grade of Recommendation: Strong

In descending order of preference, ultraselective, superselective, and selective catheterization of tumor feeders should be considered as the optimum catheter tip position for cTACE. Such practices are associated with superior Lipiodol deposition in the tumor, improved tumor response rates, decreased local recurrence, decreased need for repeated treatments, and improved OS.[77] [78] [79] [80] [81] [82] [83] [84]

Practitioners should evaluate the potential risks of ultraselective catheterization (dissection, vascular spasm, and thrombosis) and take appropriate measures, such as the use of smaller profile microcatheters (1.7–2 Fr microcatheters) and adjunctive techniques such as pharmaco-angiography using intra-arterial vasodilators (nitroglycerin, verapamil, papaverine) and anticoagulation with IV heparin to support ultraselective catheterization by alleviating vascular spasm and reducing thrombotic risks. However, due to the lack of any standardized consensus, indications, dosage ranges (e.g., nitroglycerin 100–200 mcg intra-arterially), and timing vary across operators and institutions.

• Q12. What is the management for arterioportal and arteriovenous shunts during cTACE?

Arterioportal and arteriovenous shunts, with or without PVTT, can often be safely treated with embolization during cTACE. This approach improves the quality of life and OS.

Level of Evidence: Moderate, Grade of Recommendation: Strong

The incidence, location, size, and multiplicity of arterioportal and arteriovenous shunts vary widely. Some of the shunts may be evident only on DSA or CBCT. These shunts pose the risk of nontarget embolization of cTACE embolic materials. These can be treated or minimized with ultraselective, superselective, or selective catheterization of the shunts based on the timing of visualization of venous structures on angiography and subsequent embolization with appropriate materials (such as particles, gel foam, coils/plugs, alcohol, and n-BCA). SBRT as a standalone modality targeted to reduce the shunt and control the disease is a viable alternative option. cTACE should be considered after successful occlusion or reduction of these shunts. Different strategies for different locations, sizes, and multiplicity of shunts have been described.[85] [86] [87] [88] [89] [90] [91] [92] [93] [94]

• Q13. What is the strategy to prevent nontarget deposition of Lipiodol during cTACE?

The arteries at risk of nontarget embolization should be identified meticulously during angiography. Techniques to prevent nontarget embolization include the use of CBCT, selective catheterization of tumor feeder artery, use of dedicated non-refluxing catheters, side-hole catheters, and prophylactic embolization of nontarget vessels.

Level of Evidence: Low, Grade of Recommendation: Weak

Prophylactic embolization of nontarget vessels that cannot be excluded from the treatment territory may be considered to protect adjoining nontumor liver parenchyma from ischemic damage due to cTACE.

Antireflux double-balloon catheter is indicated in the treatment of tumors supplied by tortuous atretic vessels (especially following multiple sessions of prior cTACE) or in severely cirrhotic livers. The microcatheter is placed in the parent artery, and the chemoemulsion is infused laterally into the perpendicular branch. This approach prevents reflux and nontarget embolization to adjacent hepatic parenchyma and extrahepatic arteries such as the cystic, the gastroduodenal, and the gastric arteries.[95]

Balloon TACE is a modified cTACE procedure utilizing a temporary balloon occlusion microcatheter. This catheter allows restoration of flow distal to the temporarily occluded vascular segment via collateral arteries (interlobar, intersegmental arteries), resulting in pressure-driven embolization through the balloon catheter while preventing reflux into the nontarget vessels proximal to the point of injection.[96] [97] [98] The micro-balloon catheter is positioned proximal to all lesion feeders to maximize efficacy.

The side-hole catheter technique, where tumor feeder vessels can be cannulated with a microcatheter through a side hole in the guiding catheter, is useful where selective catheterization by conventional microcatheter technique has failed. This technique is useful when there is poor stability of the angiographic catheters or when the target artery arises from the very proximal portion of the parent artery.[99]

• Q14. What is the “on-table” endpoint of injection of Lipiodol emulsion?

The ideal endpoint of Lipiodol emulsion injection is the visualization of portal vein radicles immediately adjacent to the tumor (for small tumors), or when the maximum administrable dose of the emulsion has been reached (for larger tumors).

Level of Evidence: Moderate, Recommendation: Strong

Further secondary endpoints include a dense Lipiodol uptake and CBCT confirmation of a complete uptake conforming to the preoperative imaging.

Level of Evidence: Low, Recommendation: Weak

During cTACE, injection of Lipiodol emulsion into small HCC can temporarily block tumor sinusoids, portal venules through the peribiliary plexus, hepatic sinusoids, and arterial micro-communications.[80] [100] Therefore, the endpoint of Lipiodol chemoemulsion injection for cTACE in small HCC should be the visualization of the adjacent portal vein radicles or till stasis is achieved.[100] [101] [102] [103] In large HCC, achieving stasis of Lipiodol chemoemulsion or complete injection of the dose is the endpoint.[40] [101] [102] [103] [104] [105] In both scenarios, care is to be taken to avoid any dense lipiodolization of the nontarget adjoining liver parenchyma.

• Q15. What are the technical considerations in hypovascular HCC?

Hypovascular HCC or nodular hypovascularity within a typical hypervascular HCC predicts a poorer prognosis. Thermal ablation (TA) or SIRT should be preferred over cTACE for the treatment of hypovascular HCC. If cTACE is considered, it should be performed in an ultraselective fashion and with CBCT guidance.

Level of Evidence: Low, Grade of Recommendation: Weak

Hypovascular nodules are defined as low- or medium-enhancement nodules in the arterial and portal phases of CT or MRI with faint or no blush on hepatic artery catheter angiography. When isolated, they may represent smaller tumors earlier in the course of carcinogenesis and can be biologically less aggressive[106] but can also be larger, poorly marginated lesions, alone or coexistent with typical hypervascular nodules, multicentric in origin, and chart a poorer prognosis.[107] [108] They can also represent a collision tumor (HCC—intrahepatic cholangiocarcinoma [iCCA] spectrum or sarcomatoid HCC).[109] [110]

Hypovascular (on multiphasic CT/MR imaging) nodules may also be characterized as per LI-RADS and treated appropriately. These nodules can be labeled at best as LR4 lesions under this classification if the diagnostic findings fulfill the criteria.[111] However, if selected for transarterial treatment and found to be hypervascular on angiography/CBCT/angio-CT, then they need to be placed in the LI-RADS lexicon for nodules with arterial phase hyperenhancement, and if found appropriate, the angiographic treatment is taken to completion.

Compared with hypervascular tumors, the hypovascular HCCs have been shown to have worse recurrence-free survival (RFS) and OS,[108] shorter time to TACE refractoriness, and a poorer prognosis.[112] In addition, intrahepatic cholangiocarcinoma or collision cholangiocellular HCC imparts a poorer objective response, PFS, and OS when compared with HCC.[110] [113]

Thermal ablation or SIRT may be a superior treatment modality when triaging hypovascular HCC.[106]

• Q16A. What criteria influence the choice of particles during embolization following Lipiodol chemoemulsion deposition?

• Q16B. What is the technique and end point of particulate embolization following injection of Lipiodol chemoemulsion?

• 16A: Choice of embolic material should be made based on the selectivity of catheter placement and the need for repeat procedure.

• 16B: Gelfoam or permanent embolic particles should be injected very slowly till there is near stasis (subjective angiographic chemoembolization endpoint [SACE] level 2 or 3) in the artery directly feeding the tumor. In the case of ultraselective or balloon-assisted cTACE, embolization can continue until complete stasis (SACE level 4) to the tip of the microcatheter.

Level of Evidence: Moderate, Grade of Recommendation: Strong

• 16A: Embolization following injection of Lipiodol chemoemulsion is a standard practice for optimizing the results of the index treatment session by achieving adequate ischemia and preventing washout of the drug. However, in situations where optimal Lipiodol chemoemulsion deposition has not been achieved (due to flow characteristics of the tumor or dose limits prohibiting further injection of Lipiodol chemoemulsion), retreatment is mandatory, and hence, maintaining patency of the feeding artery is key to subsequent therapy. Gelfoam is a temporary embolic material and is usually reabsorbed within 1 to 2 weeks,[114] proving it to be advantageous in situations where a repeat session of cTACE through the same artery is anticipated.[40]

Gelfoam, ideally cut into 1.0- to 1.5-mm particles and suspended evenly in iodinated contrast material, is the most commonly used embolizing material for cTACE. This method provides a more homogeneous mixture compared with a gel foam slurry created by mixing small gelfoam particles or shavings across two syringes.

Use of nonabsorbable, spherical, or nonspherical permanent embolizing particles (of size 100–300 μm) such as tris-acryl gelatin microspheres or polyvinyl alcohol (PVA) particles instead of gelfoam is also practiced, though more commonly in the West.[115] [116] [117] [118] [119] The use of PVA particles is hence more justified when repeat treatment through the index artery is not anticipated. In settings of an ultraselective or superselective cTACE and after the achievement of optimal Lipiodol emulsion deposition in the tumor bed, subsequent embolization can be performed with either gelfoam or PVA particles (choice of which is mostly governed by geographical and institutional practices).

• 16B: The rationale for cTACE is that the local intra-arterial delivery of an emulsion, made by a chemotherapeutic drug such as doxorubicin or cisplatin mixed with Lipiodol, followed by embolization of the blood vessel with gelatin sponge particles or other particulate embolic materials, will result in a strong cytotoxic effect augmented by ischemia.

By adding particle embolization, both the hepatic artery and the portal vein can be embolized, resulting in strong ischemic effects not only on the tumor but also on the peritumoral liver, resulting in more complete necrosis.[101] This aggressive technique is usually recommended for ultraselective cTACE, where the catheter allows a more forced embolization with the Lipiodol chemoemulsion being pushed further into the adjoining portal vein or neighboring arterial branches through the peribiliary plexus. The micrometastases or satellite nodules in the corona of the tumor in the same vascular territory can be treated to deliver a more effective cTACE. Ideally, a safety margin of 5 and 10 mm should be included in the embolized corona for tumors <25 mm and >25 mm, respectively.[104]

The angiographic endpoint for embolization after Lipiodol emulsion injection is subjective but can be reasonably quantified by adopting the Subjective Angiographic Chemoembolization Endpoint (SACE) scale,[103] with moderate interobserver agreement. Four such levels are described based on the presence of antegrade arterial flow in the direct branch to the tumor and the residual tumor blush ([Table 5]).

Table 5 Subjective angiographic chemoembolization endpoint (SACE) scale

SACE Level 1	Arterial flow and tumor blush are near preembolization level
SACE Level 2	Arterial flow and tumor blush are reduced
SACE Level 3	Arterial flow is reduced, but there is no tumor blush
SACE Level 4	Arterial flow is completely absent, and there is no tumor blush

There is some evidence to suggest that embolization to SACE level 2 or 3 improves survival and prognosis compared with a complete stasis endpoint as in SACE level 4.[116] In addition, there is a lesser severity of the PES, which is particularly important to practice when lobar and segmental cTACE is being performed for large tumors.[105] This principle also allows repeat sessions of chemoembolization. An objective way to confirm whether SACE 2/3 has been achieved is to see the clearance of contrast material from the feeding artery in two to three heartbeats (after stoppage of contrast material injection during angiography). SACE 2/3 in selective or nonselective cTACE should show stasis only up to the tumor feeder branches while preserving the flow in the segmental and lobar arteries. The appearance has been described as a “tree in winter” appearance in nonselective cTACE.[40]

Once an endpoint is achieved, it is recommended that there is a 5-minute wait before another angiogram is performed since particulate redistribution may occur, requiring further particulate embolization.[120]

• Q17. What is the protocol for further management if complete tumor lipiodolization is not achieved after injection of the scheduled volume of Lipiodol chemoemulsion?

If complete lipiodolization of the tumor has not been achieved despite injecting the calculated volume of chemoemulsion, further treatment strategy should be determined based on the tumor size/burden, vascularity, and the patient's clinical status.

• - Child–Pugh B patients:

The procedure should be performed more selectively, and the endpoint of cTACE should be more conservative to minimize normal parenchymal damage, and another session of cTACE should be scheduled.

• - Child A patients:

For 5–8 cm HCCs: Additional embolization with gelfoam/PVA particles may be performed.

For >8 cm HCCs: For tumors with single arterial feeders, additional partial embolization using gelfoam/PVA may be considered. For HCCs with multiple feeders, some feeders may be considered for embolization, and the remaining may be treated in the next session of cTACE.

Level of Evidence: Moderate, Grade of Recommendation: Strong

Patient compliance and acceptance for a multisession cTACE should be evaluated during preprocedure counseling. For tumors less than 5 cm in diameter, the maximum dose limit, as per the criteria for optimizing dosage, very seldom becomes the limiting factor in achieving complete lipiodolization.

Patients with Child–Pugh class A status and ECOG-0 with HCC measuring 5 to 8 cm and not consenting to multisession treatment should have a detailed angiogram demonstrating all the tumor feeders after finalizing the microcatheter position. Possible scenarios that could present are as follows:

• A. Tumors with a single feeder and achieving suboptimal lipiodolization can be embolized to SACE levels 2/3 in a single treatment session by using gel foam/PVA particles.[105] [116] [121] [122]

• B. Tumors with multiple feeders and identifiable dominant feeder vessel can be treated by sequentially cannulating all the feeders, starting with a dominant feeder, injecting Lipiodol emulsion till achieving the endpoint for each feeder, as per criteria defined in this document earlier, followed by embolization of all feeders (lipiodolized and non-lipiodolized) with gel foam/PVA particles to SACE level 2/3.

• C. Tumors with multiple feeders and with no dominant feeders can be treated by injecting the Lipiodol emulsion in equally divided doses through all the feeders and then taken to completion with embolization with gelfoam/PVA.

Patients with Child A cirrhosis and good performance status (ECOG-0), an HCC measuring 5 to 8 cm, and consenting for multisession treatment, should have a detailed angiogram demonstrating all the tumor feeders after finalizing the microcatheter position.

Possible scenarios that could present are as follows:

• D. Tumors with a single feeder and after suboptimal lipiodolization can be further embolized with gel foam or PVA particles to SACE levels 2/3 in a single treatment session. The patient may be scheduled for repeat treatment based on posttreatment imaging.

• E. Tumors with multiple feeders and with or without a dominant feeder are treated by sequentially catheterizing each feeder artery for injection of the chemoemulsion. When the entire dose of the emulsion has been delivered, all the lipiodolized feeders are sequentially embolized with gel foam. Arteries through which Lipiodol emulsion has not been administered should be addressed in the next treatment session, along with re-interrogating the previously lipiodolized feeders.

Tumors > 8 cm may often need large volumes of Lipiodol chemoemulsion and embolization particles for complete coverage. There may be circumstances when, despite injecting the maximum dose limit of Lipiodol chemoemulsion, large parts of the tumor may not receive any drug.[105] [116] These patients would require multiple sessions of cTACE.[121] [123] [124] Young patients with well-preserved liver function and excellent performance status, and not consenting for multiple session treatment, may be considered for embolization as per scenarios described earlier for tumors of 5 to 8 cm with an option for multiple sessions (after careful consideration of risk vs. benefits).[105] [116]

• Q18. When should the follow-up imaging be obtained? What imaging modality and protocols should be used?

• i. Posttreatment follow-up imaging should be performed at 1, 3, 6, 9, and 12 months and every 6 months in the subsequent years.

Level of Evidence: High, Grade of Recommendation: Strong

• ii. “High-risk” patients need closer follow-up.

Level of Evidence: High, Grade of Recommendation: Strong

• iii. Dynamic CEMRI with DWI is the investigation of choice following cTACE.

Level of Evidence: High, Grade of Recommendation: Strong

Apart from the preoperative criteria suggesting high risk of recurrence (high AFP/PIVKA II [protein induced by vitamin K absence] levels, FGD avid, and infiltrative lesion),[125] incomplete treatment, equivocal imaging findings, new clinical symptoms, and rising α-fetoprotein/PIVKA II suggest a closer follow-up, the timings of which need to be individualized.

MRI is advantageous in assessing treatment-related changes in HCC (mainly postcontrast T1W MRI and DWI)[126] [127] and is superior to CECT in evaluating patients who have undergone Lipiodol-based cTACE therapies. Lipiodol does not adversely affect MR signal intensity, while beam-hardening artifacts on CT may obscure small enhancing tumors.[128] [129] Patients not suitable to undergo an MR scan should be followed up with spectral CECT.

The protocol for imaging can be followed as per recommendations by the American College of Radiology (ACR) or equivalent international societies.[130] [131]

• Q19. What localized response evaluation method should be used to assess response following cTACE?

Post-cTACE treatment response should be evaluated using enhancement-based criteria, with modified Response Evaluation Criteria In Solid Tumors (mRECIST) and LI-RADS LR-TR both recognized as valid and institution-dependent frameworks.

Level of Evidence: High, Grade of Recommendation: Strong

Conventional methods of tumor response assessment, such as the WHO criteria, RECIST, and RECIST 1.1, rely on a simple size-based approach to indicate tumor response. cTACE and other locoregional therapies for HCC demonstrate antitumoral activity by tumor necrosis rather than immediate tumor shrinkage.[132] Tumor response with such treatment strategies is not adequately assessed with the traditional assessment criteria.[133] Localized response assessment following cTACE should be based on enhancement-based criteria that reflect residual tumor viability. The European Association for the Study of the Liver (EASL) criteria[134] and mRECIST guidelines proposed by the AASLD-JNCI (American Association for the Study of Liver Diseases - Journal of the National Cancer Institute)[135] [136] take into account the tumor necrosis induced by treatment to determine the viable tumor.[133] [136] This is based on enhancement characteristics of the residual tumor on the arterial phase of CT/MRI.[133] [134] [135] [136] These criteria also correlate better with OS and time to progression.[137] [138] [139] [140] [141] [142] While both EASL and mRECIST can reliably predict the survival of HCC patients undergoing cTACE, currently, the mRECIST represents the gold standard for radiologically evaluating tumor response during HCC treatment.[143] [144] Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and European Association for the Study of the Liver (EASL) guidelines remain widely utilized, particularly in clinical trials and interventional radiology practice. Additionally, the Liver Imaging Reporting and Data System (LI-RADS) Treatment Response algorithm (LR-TR), developed by the American College of Radiology and endorsed by the AASLD, offers a structured lesion-level framework for categorizing treated observations as viable, nonviable, equivocal, or nonevaluable. LR-TR is especially relevant in MRI-based follow-up and is increasingly adopted across institutions for its standardized reporting and diagnostic clarity.[145] While mRECIST and LR-TR differ in granularity and application, both are valid tools for post-cTACE response evaluation, and the choice may depend on institutional protocols and radiologist preference.

• Q20. What is the best time to repeat treatment (for the index lesion with residual component or the remaining lesions)?

• “On-demand” repetition of treatment is recommended for patients who have achieved the endpoint of cTACE in a single treatment session.

• The interval between treatments in a multisession cTACE protocol is tailored according to the underlying liver reserve and performance status.

Level of Evidence: Moderate, Grade of Recommendation: Strong

Shorter intervals of cTACE do not adversely affect survival outcomes of Child–Pugh class A patients. However, it may adversely affect survival for patients with Child–Pugh class B due to severe adverse effects.[146]

There is no consensus on the frequency of cTACE and the interval between two sessions of cTACE. However, “on-demand” cTACE (repeat cTACE based on residual disease on follow-up imaging) has been preferred over “on-schedule” cTACE (predefined number of sessions regardless of “at-interim” response or safety evaluations) due to fewer adverse effects and no difference in the effectiveness of the former method.[147] [148]

While many lesions treated with cTACE are large and unlikely to be completely managed in a single session, a staged treatment approach is often warranted. In such cases, repeat sessions should ideally be completed within a 2-month interval to ensure cumulative therapeutic efficacy. This staged cTACE strategy is distinct from on-demand TACE, which refers to retreatment performed in response to radiologic or clinical evidence of recurrence or progression, beyond the scope of the initial treatment plan.

Most HCC patients who are candidates for cTACE already have a poor hepatic reserve and may experience serious hepatic dysfunction after repeated cTACE. Thus, a sufficient amount of time is necessary for recovery to normal hepatic function in between successive cTACE sessions. Since repeated treatment sessions may cause progressive liver damage, repetition of cTACE should be planned based on tumor response and patient tolerance (which should be assessed before each additional treatment).[149] However, intervals of ≥ 2 months between cTACE sessions may also be suboptimal in controlling tumor progression.[147]

• Q21. When should cTACE be discontinued for nonresponsive lesions or progressive disease?

cTACE should be discontinued in case there is no objective tumor response on imaging after three technically successful treatment sessions, or there is “unTACEable” tumor progression.

Level of Evidence: Moderate, Grade of Recommendation: Strong

There is no clear-cut recommendation for discontinuing cTACE. To have guidelines for discontinuing treatment, we need to understand certain terminologies, such as TACE failure, unTACEable progression, and cTACE refractoriness. These terminologies should not be used interchangeably.

TACE failure is a term that should be reserved to describe the inability to deliver the chemoemulsion and achieve ideal end points of embolization, as per the criteria discussed earlier in this document.

TACE refractoriness indicates the failure to achieve significant tumor necrosis (tumor with >50% viable volume on posttreatment imaging)[150] of the index tumor even after three sessions of cTACE within a period of 6 months. The option of changing chemotherapeutics is up to the discretion of the operator. Each treatment session requires a reanalysis of the tumor-feeding arteries. This is especially important as 50% of patients may not be initial responders to the first session of cTACE.[151] In a study of 200 patients who underwent cTACE, the authors concluded that patients who show no objective response to two sessions of cTACE will have a poor objective response to subsequent cTACE sessions.[152] In a study of 4,154 subjects, patients with stable disease (labeled as nonresponders) after the first cTACE, the response rate after the second cTACE was 46.1%. For patients with stable disease (labeled as nonresponders) after the second cTACE session, the response rate after the third cTACE session was 58.3%.[153] Therefore, it is recommended that three sessions of cTACE should be performed before abandoning cTACE for intermediate-stage HCC. TACE refractoriness, therefore, indicates a lack of efficacy of the TACE treatment,[154] which, by extrapolation from the above strategy, is a label that can be used if the index tumor shows stable disease despite three sessions of TACE.

Untreatable or unTACEable tumor progression refers to a point where the tumor has progressed to a stage where further TACE treatments are deemed ineffective or no longer beneficial often due to massive liver involvement by the tumor, significant extrahepatic spread of HCC, vascular invasion of the main portal vein or the first-order branches, and impaired liver function (stage B8 and above), or worsening performance status (ECOG > 2).[155]

Some scoring systems have objectively evaluated the efficacy and toxicity of retreatment with cTACE. The Assessment for Retreatment with Transarterial Chemoembolization (ART) score looks at three factors: an increase in aspartate transaminase (AST) level by more than 25%, an increase in Child–Pugh score from baseline, and the absence of tumor response as predictors of prognosis after a second TACE.[156] Patients with an ART score of 0 to 1.5 points benefit from a second TACE, while those with a score of > 2.5 do not benefit from a second TACE and may be switched to another treatment. ART score has also been used to predict the response to the third or fourth TACE.[157] However, in two series, the ART score was not found to be an effective objective tool to guide retreatment with TACE.[158] [159] Another scoring system, the ABCR (α-fetoprotein, Barcelona Clinic Liver Cancer, Child–Pugh, and Response) score, evaluated four prognostic factors, including AFP levels and BCLC stage at baseline, increase in Child–Pugh score, and absence of radiological response. An ABCR score of ≥ 4 before the second session of TACE was found to identify patients with a dismal prognosis.[160] These objective scores are useful only when TACE is used for palliative treatment. However, they are not a part of any practice guideline.

A recent study concluded that the reason for discontinuation of TACE could influence survival in patients with HCC.[161] In a study of 166 patients who underwent a median of two TACE procedures, the authors found that hepatic decompensation and worsening of performance status after TACE were independent predictors of OS and post-progression survival.

• Q22. When should other locoregional treatments with cTACE be used to improve treatment outcomes?

Combination therapy of cTACE + ablation (RFA/MWA) is safe, well-tolerated, and more effective than cTACE alone for the treatment of HCC >3 cm to <5 cm.

Level of Evidence: High; Grade of Recommendation: Strong

A meta-analysis from 2017 reported that TACE plus RFA attained higher tumor response rates (OR = 6.08, 95% CI: 4.00–9.26, p < 0.00001) and achieved longer RFS rates (ORRFS = 3.78, 95% CI: 2.38–6.02, p < 0.00001) and OS rates (OR 1 year = 3.92, 95% CI: 2.41–6.39, p < 0.00001; OR 3 years = 2.56; 95% CI: 1.81–3.60; p < 0.00001; OR 5 years = 2.78; 95% CI: 1.77–4.38; p < 0.0001) when compared with TACE alone in patients with intermediate HCC. However, there were a larger number of complications in the TACE plus RFA group than in the TACE alone group (OR = 2.74, 95% CI: 1.07–7.07, p = 0.04).[162] [163]

Another meta-analysis,[163] [164] comparing TACE with TACE + MWA in single and up to three HCC nodules exceeding 5 cm, included over 1,700 patients, and showed a significantly higher OS for the latter (1-year OS rate: RR = 1.36, 95% CI: 1.28–1.44; 2-year OS rate: RR = 1.56, 95% CI: 1.40–1.74, and 3-year OS rate: RR = 2.07, 95% CI: 1.67–2.57, p < 0.001). There are synergistic effects between RFA and TACE in combined treatment, providing better results than RFA and TACE alone for the treatment of large HCC, defined as those exceeding 3 cm in size.[165] [166]

TACE prior to RFA decreases blood flow to the tumor and reduces the heat-sink effect, with a resultant increase in the extent of an RFA-induced coagulation zone. The presence of micro-metastases in the periphery and the heat-sink effect from the presence of a large blood vessel adjacent to the lesion can adversely affect the outcomes of RFA in HCCs larger than 3 cm. TACE decreases the chance of incomplete ablation (RFA/MWA), a known negative prognostic factor of OS after RFA, by eliminating any existing micro-metastases or microvascular invasion through embolization and chemotherapy.[167]

TACE followed by RT is therapeutically more beneficial than TACE alone for treating HCC, and should be recommended for suitable patients with unresectable HCC.[168] A meta-analysis of 25 trials (11 RCTs, 18 included patients with advanced HCC with macrovascular invasion) showed significantly improved pool OS in the TACE + radiation therapy patient group (22.7 months) compared with the TACE-alone group (13.5 months). There were, however, significantly higher rates of gastric ulcerations and abnormal transaminases/bilirubin with combination treatment.[169]

• Q23. In patients with HCC undergoing cTACE, what is the current role of systemic therapies—including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs)—in augmenting treatment outcomes?

Combination therapy with sorafenib may benefit BCLC B patients with a Child–Pugh score <8 and an ECOG PS <2, especially when initiated 2 to 3 weeks before cTACE and continued thereafter. In cases with PVTT, lenvatinib may offer improved outcomes over sorafenib. Recent trials, including EMERALD-1 and TALENTACE, suggest immunotherapy-based combinations—such as atezolizumab plus bevacizumab with cTACE—can enhance treatment response and PFS.

Level of Evidence: High, Grade of Recommendation: Strong

There is upregulation of vascular endothelial growth factor (VEGF) due to local hypoxia caused by TACE. This may cause tumor revascularization and increase the chances of local recurrence. Several trials have examined the outcomes of combining TACE with antiangiogenic agents to inhibit tumor revascularization.

The SPACE,[170] TACE 2,[171] and TACTICS[172] trials compared TACE plus sorafenib versus TACE alone. The BRISK-TA study[173] compared TACE with TACE + brivanib, and the ORIENTAL study[174] compared TACE with TACE + orantinib. Except for TACTICS, none of the trials showed clinical benefit from combining TACE with systemic therapy.

TACTICS[172] was a randomized phase II trial that compared TACE plus sorafenib with TACE alone. TACE plus sorafenib resulted in a major improvement in PFS: 25.2 months in the TACE plus sorafenib group versus 13.5 months in the TACE alone group (p = 0.006).

The improved outcomes observed in the TACTICS trial can be explained by the differences in the study protocol compared with previous trials. New intrahepatic lesions were regarded as natural tumor biology of HCC and not considered to be treatment failure. Progression was defined as untreatable (unTACEable) progression (e.g., > 25% of intrahepatic tumor progression, deterioration of liver function to Child–Pugh class C after TACE, macrovascular invasion, or extrahepatic spread). Treatment was continued until unTACEable progression, TACE refractoriness, or unacceptable toxicity. Sorafenib was started 2 to 3 weeks prior to the first TACE in this trial. As a result, patients in the TACTICS trial received sorafenib treatment for a much longer period than in previous trials, with a median of 38.7 weeks and 17.0 to 21.0 weeks, respectively. Even in the negative SPACE trial (though this used DEB and not cTACE), the subgroup analysis showed Asian patients had better outcomes with combination therapy. These patients also had a longer duration of sorafenib (30 months) when compared with non-Asian patients who had it for 17.4 weeks.

Increasingly, lenvatinib is being used as first-line systemic chemotherapy and has replaced sorafenib for HCC. The REFLECT study[175] concluded that compared with sorafenib, lenvatinib exhibits a better overall response rate (ORR) (29.6 vs. 6.9%; p < 0.001), PFS (7.2 vs. 4.6 months, p < 0.001), and noninferior OS (13.6 vs. 12.3 months).

Yang et all[176] in a prospective cohort study compared the efficacy of TACE plus lenvatinib (TACE-L) versus TACE plus sorafenib (TACE-S) for unresectable HCC with PVTT. The study compared 59 and 57 consecutive patients who were treated with TACE-L and TACE-S, respectively. The median OS time was 16.4 and 12.7 months in the TACE-L and TACE-S groups, respectively. TACE-L was also significantly superior to TACE-S with respect to median PFS (10.6 vs. 5.4 months) and ORR (66.8 vs. 33.3%).

Published results from two phase-III randomized controlled trials—EMERALD 1 and LEAP 012 trials—have shown significant improvement in objective response rate and PFS by using immunotherapy with TACE for the treatment of HCC compared with TACE alone. There are a few ongoing trials evaluating combination therapies with immune checkpoint inhibitors for which results are expected to be announced soon. These include evaluation of the combination of pembrolizumab with TACE for the treatment of advanced HCC (PETAL trial; NCT03397654), nivolumab combined with TACE for intermediate-stage HCC (IMMUTACE; NCT03572582), nivolumab with drug-eluting beads (DEBs)-TACE (NCT03143270), and tremelimumab and durvalumab combined with TACE/ablation strategies for advanced HCC (NCT02821754). Besides these, there are a few other studies,[177] [178] [179] [180] mostly retrospective, which have evaluated the safety and efficacy of combination therapies of TACE with immune checkpoint inhibitors for HCC, such as camrelizumab,[181] and have shown favorable results.

• Q24. When should cTACE be used in downsizing or bridging treatment for liver transplants?

For patients requiring downsizing or bridging to liver transplant beyond 6 months, cTACE is a favored option when Y90 radioembolization is not considered.

Level of Evidence: High, Grade of Recommendation: Strong

The term “bridging” refers to strategies that are implemented in patients who already qualify for transplantation according to the accepted selection criteria so that they can wait until a graft is available. A bridging strategy can be effective because it allows candidates to wait for a longer time while remaining a transplant candidate[182] or it improves the results of transplantation by improving patient selection as it filters out biologically aggressive cancers that could manifest in the form of progression of a tumor or extrahepatic spread, thus rendering them unsuitable for transplantation.[183]

Although the word “down-staging” refers to the reduction of the clinical stage of a disease from any initial stage (e.g., from UNOS T2 to T1), downstaging in the context of transplantation for HCC is used for strategies allowing the transplantation of patients who at first do not qualify for liver transplantation because the tumors are outside the accepted criteria (UNOS T3 or higher). Downstaging strategies may use the same neoadjuvant and locoregional treatments that are used in bridging strategies.

The main purpose of TACE as a bridge to transplantation is to achieve local tumor control until a donor organ becomes available. TACE is one of the preferred single-treatment modalities in downstaging protocols, especially for multifocal tumors.[183] TACE has been reported in the past to be the most commonly used form of neoadjuvant therapy, alone or in combination with ablation (RFA/MWA)/resection, in patients who are listed for liver transplant, for bridging treatment, or downstaging.[184] [185]

Some patients with advanced HCC beyond the Milan criteria were reported to achieve long-term survival after liver transplantation, and these reports have led to the development of expanded criteria worldwide.[186] University of California, San Francisco (UCSF) criteria (a single tumor of < 6.5 cm, a maximum of three total tumors <4.5 cm in size, and cumulative tumor size <8 cm) and Asian criteria (tumor diameter not >5 cm, number of lesions <7, and no gross vascular invasion) are well known as the extended criteria.[187] [188] The Milan group also created a new up-to-seven criteria (7 is the sum of the size of the largest tumor [in cm] and the number of tumors), and the authors reported that patients who met these criteria achieved a 5-year OS of 71.2% (64.2–77.0).[9] Moreover, the BCLC 2022[6] and INASL 2023[189] guidelines propose tailoring the “extended liver transplant criteria” as per the institutional practices, thereby leaving some room for institute-based discretion in patient selection.

The timing and adequacy of HCC treatment before liver transplantation to control the disease are unclear. The recommendation of bridging therapy is more important in UNOS T2 HCC patients to decrease dropout rates and achieve good posttransplant outcomes.[190] [191]

The appropriate neoadjuvant therapies prior to liver transplantation are resection, ablation, transarterial chemoembolization (TACE), Y-90 radioembolization, systemic therapies, or their combinations. In the pre-Y90 era, it was recommended to treat patients waiting for transplant with ablation (RFA/MWA) and/or chemoembolization when the waiting time was estimated to exceed 6 months.[190] [191] However, many studies have now shown the advantages of Y90 radioembolization over TACE to keep patients eligible for transplant due to the prolonged time to tumor progression with Y90.[192] [193]

• Q25. What are the prognostic outcome indicators of cTACE in the treatment of HCC?

• A. Increasing tumor size, multiplicity, micro/macrovascular invasion, and poorly marginated tumors have poor prognostic value and should be considered in the pre-TACE planning and patient counseling.

Level of Evidence: Moderate, Grade of Recommendation: Strong

• B. FDG PET relevance in diagnosing HCC is questionable; however, it has significant prognostic relevance in terms of SUV-derived tumor to the normal liver ratio (TLR) in pre- and post-TACE imaging.

Level of Evidence: Moderate, Grade of Recommendation: Strong

• C. Increased levels of tumor markers are associated with poor prognosis in HCC treatment with TACE. Serum AFP level can be used as a reliable prognostic tool pre- and post-TACE treatment. Specifically, AFP > 1,000 indicates a poor long-term prognosis.

Level of Evidence: High, Grade of Recommendation: Strong

Tumor size, number of nodules, micro- and macrovascular invasion features seen on the radiological imaging have been well established as important prognostic indicators in the treatment of HCC, and equally for cTACE, and these have been discussed in detail in the early part of this document. An ill-defined tumor capsule has also been linked to poor prognosis compared with a well-encapsulated HCC.[194]

Patients with advanced liver disease, including the presence of ascites and lower serum albumin, as well as those with greater tumor burden, have poorer outcomes following cTACE treatment. Such findings provide a better understanding of the variation in survival after cTACE and help facilitate the selection and timely stage migration of patients undergoing this therapy.

There are multiple scoring systems that are used as adjuncts to prognosis, including ALBI, Child–Pugh score, and MELD score, and have been detailed in this article earlier.

The five most common independent predictors of poor prognosis with cTACE in HCC are portal vein thrombosis, tumor size, AFP, Child–Pugh class, and serum bilirubin levels.[195]

FDG PET has become an important part of the oncological imaging and staging system. Though MRI scores over PET-CT in terms of local tumor anatomy delineation within the liver, PET indices such as SUV-derived TLR, and metabolic tumor volume representing the extent of abnormal FDG uptake within the tumor have potential prognostic relevance. A decrease in the tumor to normal liver SUV ratio post-cTACE functions as a reliable prognostic predictor. A tumor-to-liver ratio of more than or equal to 2 indicates high malignant potential and poor prognosis post-cTACE.[196]

There are multiple biochemical markers aiding in the prognostication of HCC, such as the serum AFP, des-gamma-carboxy prothrombin (DCP), also known as PIVKA-II, and AFP-L3. Elevated levels of these markers indicate a poor prognosis, irrespective of the treatment chosen. An AFP level of more than 1,000 ng/dL has a high predictive value of poor prognosis in both liver transplantation and locoregional therapies such as cTACE.

The CLIP scoring system (Cancer of the Liver Italian Program) includes all four of these predictors (portal vein thrombosis, tumor size, Child–Pugh class, and AFP), and the CLIP staging system itself was identified as an important predictor of mortality.[197]

Multivariate analysis showed that HBV infection, AFP value, TNM stage, Child–Pugh class, PVTT, and tumor number were independent prognostic factors in the younger cohort; the elderly had similar independent prognostic factors except for HBV infection.[198]

Conflict of Interest

None declared.

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Publication History

Article published online:
17 February 2026