Efficacy and Relevance of Endoarterial Therapy (TACE/TARE) in Unresectable Liver Cancer

Introduction

Liver cancer, or hepatocellular carcinoma (HCC), is a widespread and deadly form of cancer, ranking as the sixth most prevalent cancer and the third leading cause of cancer-related deaths worldwide.¹ The incidence of liver cancer is expected to continue growing, with over 1 million individuals estimated to be affected annually by 2025.²

HCC is the most common form of primary liver cancer, accounting for 75%-85% of cases.³ It is predominantly found in Asia and Sub-Saharan Africa due to the prevalence of chronic hepatitis B virus (HBV infection) in those regions.⁴ Men are more affected than women, with liver cancer being the leading cause of cancer-related deaths in over 20 countries. The global incidence of HCC has been increasing over the past two decades and is projected to continue rising until 2030 in certain countries, such as the United States.⁵

The development of HCC is frequently linked to liver cirrhosis caused by chronic liver conditions like chronic hepatitis, (HBV) or hepatitis C virus (HCV) infection, and autoimmune hepatitis. Additional risk factors include heavy alcohol intake, Non Alcoholic Steatohepatitis (NASH), Non-Alcoholic Fatty Liver Disease (NAFLD), exposure to aflatoxin, diabetes mellitus, tobacco use, and occasionally genetic disorders such as alpha-1 antitrypsin deficiency, haemochromatosis, tyrosinemia, porphyria, and Wilson’s disease.⁶

Purpose of the Review

To evaluate the efficacy and relevance of transarterial chemoembolization (TACE) and transarterial radioembolization (TARE).

The main therapeutic strategies for early and very early-stage HCC involve surgical procedures like liver transplantation or surgical resection (SR), ablation techniques such as radiofrequency ablation (RFA), microwave ablation (MWA), Case Studies The Images Students’ Corner accepted in Asian countries, reflecting its diverse applicability and success in different contexts.9 Its multifaceted nature, endorsed by its use across different clinical situations and geographic regions, highlights its role as a well-established and adaptable strategy in managing HCC. The treatment has evolved through two techniques: conventional TACE (cTACE) and TACE with drug-eluting beads (DEB-TACE). cTACE uses a lipiodol-based emulsion and embolizing agent to deliver chemotherapy through transcatheter means, producing robust cytotoxic and ischaemic effects. DEBs, on the other hand, gradually release chemotherapeutic agents, increasing the intensity and duration of ischaemic effects. This innovative approach emphasizes precision and controlled release for enhanced therapeutic impact.10 cryotherapy ablation (CRA), percutaneous ethanol injection (PEI), no-touch RFA, non-catheter-based treatments like stereotactic body radiotherapy (SBRT), and catheter-based embolic interventions like TACE. Hepatocellular carcinoma exhibits a highly diverse immune environment, which impacts the response to different embolization methods and subsequently affects the effectiveness of immunotherapy.⁷

Despite the ongoing use of locoregional treatments (LRTs) in HCC management, approximately half of patients eventually turn to lifelong systemic therapies. Procedures such as TACE, Selective Internal Radiation Therapy (SIRT), and thermal ablation significantly enhance the immunosuppressive state of HCC. Nevertheless, this situation can be alleviated by combining these treatments with immunotherapy, with the goal of restoring lymphocyte activity and cellular immune factor secretion. The integration of immune therapy with both locoregional and systemic approaches has led to a significant shift in HCC treatment. It is clear that combining locoregional treatments with immunotherapy may produce distinct therapeutic results compared to traditional methods.

Background of endoarterial therapies:

Endoarterial therapies, also known as intra-arterial therapies, are advanced treatments for liver cancer, particularly HCC and certain types of liver metastases. These therapies deliver therapeutic agents directly into the liver's arterial blood supply, making them more effective and targeted than systemic treatments. They are often used in conjunction with other treatments, such as systemic therapies, surgical resection, or liver transplantation, depending on the stage and characteristics of the cancer.⁸ Endoarterial therapies are part of a personalized treatment approach aimed at improving outcomes and quality of life for patients with liver cancer. Some of the therapies include Transarterial Chemotherapy (TAC), TACE, TARE, SIRT, and Intra-Arterial Radioimmunotherapy (IART).

Transarterial chemoembolization (TACE)

The Barcelona Clinic Liver Cancer (BCLC) system recommends using TACE when other treatments become ineffective in the early stages of HCC. TACE is adaptive and versatile, making it a valuable intervention in HCC management. It is widely accepted in Asian countries, reflecting its diverse applicability and success in different contexts.⁹ Its multifaceted nature, endorsed by its use across different clinical situations and geographic regions, highlights its role as a well-established and adaptable strategy in managing HCC. The treatment has evolved through two techniques: conventional TACE (cTACE) and TACE with drug-eluting beads (DEB-TACE). cTACE uses a lipiodol-based emulsion and embolizing agent to deliver chemotherapy through transcatheter means, producing robust cytotoxic and ischaemic effects. DEBs, on the other hand, gradually release chemotherapeutic agents, increasing the intensity and duration of ischaemic effects. This innovative approach emphasizes precision and controlled release for enhanced therapeutic impact.¹⁰

Indications

The BCLC and European Association for the Study of the Liver (EASL) guidelines recommend TACE as the first-line treatment for patients with HCC in Stage B with preserved liver function and Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of zero. HCC does not fall within resection or transplantation criteria, if the patient has multinodular disease, with more than 3 nodules or if any tumour size is greater than 3cm. The National Comprehensive Cancer Network (NCCN) guidelines recommend TACE as first-line treatment if the patient's HCC tumour burden is non-resectable, their liver function is no worse than Child-Pugh B, and their overall function is no worse than performance score (PS) 2.¹¹

Contraindications

TACE is a treatment option for primary cholangiocarcinoma, but it has several contraindications. These include poor expected survival, chemotherapy-related restrictions, inability or unwillingness to adhere to follow-up guidelines, extra-hepatic metastases, malignant ascites, tumours larger than 5cm, poor baseline liver function, end-stage cirrhosis, encephalopathy, jaundice, active alcohol consumption, hypervascular tumours, main portal vein thrombosis, biliary obstruction or bilirubin levels greater than 3 mg/dL, and patients eligible for potentially more effective therapy.¹¹

TACE should not be performed in patients with decompensated cirrhosis, ascites, encephalopathy, jaundice, or variceal bleeding. TACE usually does not cause significant damage to the adjacent liver parenchyma uninvolved with the tumour, as HCC primarily receives its blood supply via the hepatic artery while the normal liver parenchyma predominantly receives blood from the portal vein. Portal vein thrombosis is not a contraindication to palliative TACE provided there is adequate collateral hepatopetal flow to supply the liver parenchyma being embolized.

The mortality associated with TACE is reported to be below 1%, with most deaths attributed to liver failure. Therefore, selecting the right patient for this procedure is crucial.¹² Many physicians address bile duct obstruction before offering TACE, as the procedure may exacerbate the bile duct obstruction. The NCCN guidelines do not include TACE in its treatment algorithm for primary cholangiocarcinoma.

Overview of Procedure

Cross-sectional imaging with contrast-enhanced computed tomography (CECT) or magentic resonance imaging (/MRI) is crucial for diagnostic and treatment planning in TACE, as it can identify potential anatomical or pathological issues that may affect its safety or effectiveness. Radiologists often use platinum coils to embolize arteries near the planned artery for chemotherapy, but this is not mandatory. Patients may also undergo a "planning" arteriogram before the coils are placed. TACE typically uses conscious sedation, and periprocedural anaesthesia risk is site-dependent. Hospitals often require physicians to assess patients using the American Society of Anesthesiology (ASA) physical classification system and a Mallampati score. For patients classified as ASA class 4 or higher, or those with other anaesthetic risk factors, consultation with an anaesthesiologist and/or medical specialist may be recommended to address these risk factors.

The procedure involves obtaining arterial catheter access and performing arteriography to document the arterial supply to single or multiple tumours. High-risk arteries are occluded with coils. A microcatheter, with an outer diameter of about 1mm, is used to reach the artery or arteries feeding the tumour. Embolization particles, contrast, and chemotherapy are administered near the target area until arterial flow stasis is seen during fluoroscopy, ensuring successful embolization. Follow-up arteriography is performed to document persistence or absence of flow to the region of interest. The maximum chemotherapy administered is precalculated based on the tumour's location in one or two liver lobes.¹³

Complications of TACE Procedure

Major complications in TACE occur in 5-10 out of 100 patients, with the most common being liver failure, death, and abscess. Other major complications include tumour rupture, cholecystitis, biloma, permanent biliary stricture, arterial dissection, pulmonary emboli, and tissue injury from non- target embolization, leading to gastrointestinal hemorrhage.^14,15

Hepatic chemoembolization, performed by an interventional radiologist in consultation with an oncologist, has been shown to improve survival rates compared to the best supportive care. Median-survival with TACE ranges from 26 to 40 months.¹⁶ Combining TACE with systemic drugs like sorafenib or brivanib has not shown improved survival. No randomised phase 3 trial has compared survival rates between TACE and Yttrium-90 (Y90) radioembolization, but many retrospective and cohort studies have shown similar safety and objective response rates for both treatments.¹⁷ Y90 radioembolization, either alone or in combination with sorafenib, has not shown improved survival compared to sorafenib monotherapy in patients with locally advanced or inoperable HCC.¹⁸

Transarterial radioembolization (TARE)

Transarterial radioembolization therapy takes advantage of the liver's dual blood supply to achieve its therapeutic effect. Tumours are mainly nourished by the arterial blood supply, while the liver itself receives most of its blood from the portal system. Unlike embolization or chemoembolization, the goal of TARE is not to block the arterial supply. Instead, radioactive microspheres are used to target arterioles within or around the tumour, delivering Y90 to induce DNA damage.¹⁹

Indications

Indications for TARE encompass downsizing intrahepatic tumours, enlarging the future liver remnant (FLR) size pre surgery, bridging to transplantation for HCC, managing tumour size and inducing FLR hypertrophy before resection (radiation lobectomy), providing palliation or delaying progression for advanced HCC, and treating isolated liver lesions as the primary therapy (radiation segmentectomy [RS]).^20,21

There are established criteria for the delivery of TARE, including patient eligibility requirements such as ECOG-PS of 0-2, normal liver function, normal creatinine levels, Child-Turcotte-Pugh score A-B7, minimal comorbidities, non-infiltrative tumour type, and <70% bulk disease or tumour nodules that are not too numerous to count.²²

Procedure overview

TARE involves using microspheres containing the radioisotope Yttrium 90 (90Y) to deliver localized internal radiation therapy to liver tumours with preferential blood flow through the hepatic artery.²³

TARE is a radiation-induced treatment for HCC that involves the administration of 20- to 60-μm particles labelled with 90Y into the hepatic artery branches supplying the tumour. The radiation-induced production of free radicals results in double strand DNA breaks, leading to irreversible tumour cell damage. Two 90Y microsphere agents are available: glass and resin microspheres. Glass microspheres have been approved by the Food and Drug Administration (FDA) for HCC treatment under a Humanitarian Device Exemption, while resin microspheres have been approved for colorectal metastases to the liver. Their use for other malignancies, including HCC, is considered off-label.

Treatment dosimetry differs between glass and resin microspheres. Standard dosing results in an absorbed liver radiation dose of 120-150 Gy for glass microspheres, while the absorbed dose for resin microspheres is approximately 40-60 Gy.24 The safety and efficacy of these two agents have not been compared prospectively. A recent meta-analysis indicated a modest efficacy advantage for resin microspheres, but a more recent large single-arm series reported similar efficacy results for unresectable HCC patients using both types of microspheres.²⁵

The use of 90Y in TARE involves a high-energy beta emitter with beta particles having a maximum energy of 2.28 MeV, an average energy of 0.93 MeV, a half-life of 64.1 hours, a maximum tissue range of 11mm, and an average tissue range of 2.5mm.26 A recently introduced device in Europe contains Holmium-166, which emits a beta with slightly lower penetration (max 1.85 MeV) and a gamma (81 keV) suitable for single photon emission CT (SPECT)/CT imaging, and is compatible with MRI.

Complications of TARE

The most frequent adverse effect of TARE is postradioembolisation syndrome, which includes fatigue, nausea/vomiting, abdominal pain, and loss of appetite/weight loss.²⁷ Its occurrence varies from 20% to 70%, peaking within the first 2 weeks after TARE administration. A less common side effect is radioembolization/radiation-induced liver disease (REILD), with a risk ranging from 0% to 11% for patients with HCC and 0% to 20% for patients with metastases. Randomised trials for both HCC and metastatic colorectal cancer (mCRC) showed a much lower incidence of REILD, with only a 0%−1% incidence of "radiation hepatitis" reported.²⁸ Gastroduodenal ulcer/bleeding, biliary toxicity, and radiation pneumonitis are all relatively uncommon with TARE.²⁹

Currently, investigators are utilizing post-therapy 90Y PET/CT to compute absorbed doses to tumour and normal tissue (NT). Strong relationships between absorbed doses and outcomes have been demonstrated for lesions; however, there is significant variability in reported threshold absorbed doses, potentially due to differences in methodology, including imaging techniques. Additionally, there is a distinction between absorbed dose thresholds for resin and glass microspheres, and radiobiological dosimetry has been suggested to reconcile the variances.³⁰ For NT, the dose-toxicity relationship has been more challenging to establish, and the potential need for microdosimetry to account for nonuniform dose deposition at the microscale level using models of the liver lobules, arterial tree, and microsphere clustering is under investigation.³¹ Once robust thresholds for response and toxicity are identified and validated in trials, TARE will shift away from body surface area (BSA)-style planning to the more personalized precision medicine (PM) and voxel based dosimetry.

Clinical efficacy of TACE and TARE and future prospects

TACE has been proven to have a survival benefit over best supportive care for patients with unresectable HCC who have good PS and preserved liver function. TARE has been evaluated in prospective single-arm studies, revealing a median overall survival (OS) of 13- 16 months after radioembolization.³² The median OS is longer for patients with Child-Pugh A cirrhosis and those without portal vein tumour thrombus. Several multicenter RCTs are currently underway to determine the survival benefit for radioembolization compared to sorafenib for unresectable HCC patients. Most available data on the safety and efficacy of TACE and TARE for unresectable HCC is from retrospective studies.

The largest retrospective study to date, by Salem et al.³³, involved 245 patients with unresectable HCC without portal vein thrombosis. TACE was performed with doxorubicin, mitomycin C, cisplatin, ethiodized oil, and permanent particles, while TARE used glass microspheres. The study showed a significantly longer time to disease progression after TARE compared to TACE (8.4 months) and a nonsignificant trend toward improvement in median OS. Postembolization syndrome symptoms were more common after TACE, but the rates of severe adverse events for TACE and TARE were similar.

A pilot multicenter RCT by Kolligs et al. involved 28 patients with unresectable HCC and a Child-Pugh-Turcotte score of up to 7.³⁴ The patients were randomised to receive TACE with epirubicin, ethiodized oil, and tris-acryl gelatin microspheres at 6-week intervals or a single TARE treatment with resin microspheres. The primary endpoint was health- related quality of life (HRQOL), assessed using the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire. Secondary endpoints included adverse events, radiographic response, progression-free survival (PFS), and OS calculated from the day of the first procedure. The HRQOL outcomes could only be evaluated for 18 patients (64%), and patients randomised to TARE had significantly lower baseline FACT Hep scores. After 12 weeks, the FACT-Hep scores for the two groups became similar. Radiologic responses for TACE and TARE were not significantly different, and median PFS values were similar. The frequency of adverse events was 92.3% for the TARE group and 66.7% for the TACE group, but there were more gastrointestinal adverse events in the TARE group than in the TACE group.

A study by Salem et al.³⁵ compared the quality-of-life of 29 patients who underwent TARE and 27 who underwent TACE for unresectable HCC. The study found that patients in the TACE group had lower hepatic tumour burden, allowing for segmental artery injection. Despite advanced disease, patients who received radioembolization had better social wellbeing, functional well-being, and embolotherapy-specific scores. The TARE group had a trend towards better overall quality of life.

Conclusion

The American Association for the Study of Liver Diseases (AASLD) practice guideline recommends TACE for intermediate stage HCC patients with good PS and preserved liver function. TARE is not included in the treatment algorithm, but both are used for most sub-populations of HCC patients. Their clinical uses extend beyond intermediate-stage HCC, including downsizing to surgical resection or thermal ablation, bridging or downstaging to transplant, treating patients with portal vein tumour thrombus (PVTT), and infiltrative HCC. The relative advantages of TACE and TARE are likely equivalent in most clinical scenarios. However, TARE appears to have an advantage in facilitating surgical resection and possibly treating patients with PVTT. TACE is the transarterial treatment of choice for patients with marginal hepatic reserve who may be candidates for a transplant. In the coming years, the results of ongoing multicenter RCTs comparing TACE with TARE and TARE with standard-of-care sorafenib will be published, helping guide clinical decision making.

Flowchart: Flow chart showing overview of utilization of transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) with 90Y microspheres in current clinical practice for treatment of patients with hepatocellular carcinoma (HCC)