Radioembolization is a transcatheter intra-arterial therapy using radioisotope yttrium 90 (⁹⁰Y), and is also called as transarterial radioembolization (TARE), selective internal radiation therapy (SIRT), and ⁹⁰Y therapy. Microspheres impregnated with ⁹⁰Y are delivered through the hepatic artery to the tumors with preferential blood flow. Whereas transarterial chemoembolization (TACE) is the standard treatment option for patients with intermediate stage of hepatocellular carcinoma (HCC), TARE is not included in the Barcelona Clinic Liver Cancer (BCLC) staging system guidelines. However, TARE is acquiring popularity in Western countries and expanding its indication. Current ongoing randomized clinical trials are expected to establish the role of TARE in the management of HCC in the near future. Until now, overall survival appears comparable between TACE and TARE, but TARE has longer time-to-progression, higher quality of life, and shorter hospitalization compared with TACE [1-4]. This review discusses the essential features of TARE, with emphasis on the interventional radiology perspective for the treatment of HCC.

Currently, two ⁹⁰Y products are commercially available: TheraSphere^® glass microspheres (BTG, London, United Kingdom) and SIR-Spheres resin microspheres (Sirtex Medical, North Sydney, Australia). Although both microspheres are approved by the US Food and Drug Administration (FDA) for the intra-arterial delivery of ⁹⁰Y, they are different with regard to microsphere composition, size, degree of embolic effect, and specific activity per sphere (Table 1). There are no randomized studies comparing the two microspheres, but current literature has shown similar clinical outcomes [5-9]. One recent article showed lower toxicity and improved overall survival with glass microspheres in the treatment of HCC with portal vein invasion [10].

TheraSphere^® has minimal embolic effect and can be infused without concern for blood flow stasis [11]. Glass microspheres have specific activity of 2500 Bq at calibration and variable specific activity (150-1000 Bq) at administration, depending on the treatment schedule. Specific activity of TheraSphere^® would be about 250 Bq at week 2 (Tuesday treatment), which is preferred by the author. Custom doses between 3 GBq and 20 GBq with increments of 0.5 GBq are available, but usage of custom doses may sometimes delay the treatment schedule by 1 week. Six regular doses (3, 5, 7, 10, 15, and 20 GBq) may not be enough for fine dose adjustment, although this adjustment would not be critical in most cases. Several vials can be ordered for 1 treatment; thus, the maximal activity at administration is not limited, which can be an advantage over SIR-Spheres for large tumors. For large tumors, the week 2 treatment schedule is preferred for a more uniform tumor absorbed dose. Due to high activity of the microspheres, tumor absorbed dose is greater with TheraSphere^® than with SIR-Spheres.

SIR-Spheres are a moderately embolic device consisting of slightly larger particles with a specific activity of 50 Bq at administration. One vial of 3 GBq is delivered to the hospital and should be dispensed by the nuclear medicine technician. Fine dose adjustment of each aliquot is possible. A higher number of microspheres are required to deliver an effective dose and angiographic stasis can be reached during the procedure [12]. Due to a higher number of microspheres, SIR-Spheres show more uniform tumor absorbed dose, particularly in large tumors. However, maximal activity of SIR-Sphere is 3 GBq, which may not be enough for a large tumor. Because SIR-Spheres are usually delivered to the hospital one day before the treatment, if SIR-Sphere is administered just after delivery, maximal activity could be as high as 3.7 GBq.

Patient selection for TARE is similar with that of TACE and includes an assessment of disease burden, biochemical profile, and performance status. In Korea, since radioactive microspheres are not currently reimbursed by the national health insurance system, economic status and private health insurance are important factors. Patients with an ECOG score >2 are excluded. Patients should have a serum bilirubin <2 mg/dL. Patients with excessive tumor burden (more than 70% of liver volume) are also excluded. Ideal candidates have HCC confined to the liver, although combination therapy of TARE and sorafenib can be used for patients with metastases.

TARE requires pretreatment simulation test including hepatic angiography and ^99mTc-MAA nuclear scan. Angiographic evaluation should examine celiac trunk and hepatic artery anatomy, non-hepatic artery from the hepatic artery, possible extrahepatic collateral arteries, portal vein patency, and the presence of arterioportal shunting. HCC may parasitize blood flow from extrahepatic collateral arteries, and failure to recognize a vessel feeding the tumor may lead to incomplete treatment. If radioactive microspheres are injected into non-hepatic arteries such as the cystic artery and gastric artery, serious complications can occur. Although coil embolization of the gastroduodenal artery is no longer routinely recommended, accessory left gastric arteries, right gastric arteries, hepatic falciform arteries and esophageal branches from the replaced left hepatic artery are commonly embolized before treatment if present. Cone-beam computed tomography has become an indispensable tool for angiographic evaluation and is particularly useful to visualize small non-hepatic arteries.

^99mTc-MAA is injected into the hepatic artery to assess pulmonary shunting and distribution of microspheres. For TheraSphere^®, a lung dose >30 Gy per treatment or cumulative lung dose of 50 Gy is the recommended limit. For SIR-Spheres, 20% of lung shunting is a suggested limit, and reduced activity is recommended for patients with 10-20% of lung shunting. Although single photon emission computed tomography (SPECT)/CT is not essential in dosimetry, SPECT/CT can show exact distribution of ^99mTc-MAA on axial image, which may be useful to predict tumor response and elaborate dosimetry of partition model.

Many published articles regarding TARE in HCC has shown consistent outcomes in overall survival, ranging from 15.4 months to 17.2 months in BCLC B stage [5-9]. These results are similar to previously reported overall survival after TACE in BCLC B disease. Recent prospective randomized control trials also showed no statistical difference in overall survival between the two therapies [18]. Although many studies have not shown differences in overall survival, several studies have demonstrated that TARE had a longer time to progression (TTP) than TACE, thus TARE may have better role in a bridge to transplantation at centers with a long wait time. In addition, TARE was more effective in downstaging patients from United Network for Organ Sharing (UNOS) T3 to T2 than TACE [19].

TARE can be performed on an outpatient base because of minimal incidence of post-embolization syndrome, while TACE typically needs brief hospitalization for symptom management. Many studies demonstrated that TARE results in shorter hospitalization times, fewer necessitated treatment sessions, and fewer visits to hospital than TACE. Thus, in terms of quality of life, TARE is superior to TACE [20,21].

Oral sorafenib is considered the standard of care for BCLC C disease such as portal vein invasion. But, in Korea, sorafenib is not commonly chosen by hepatologists as a primary treatment option in HCC with portal vein invasion due to its low response rate. TACE followed by external radiation therapy showed better outcome than TACE alone or sorafenib [22,23]. Some studies have suggested that TARE is more advantageous than sorafenib in portal vein thrombosis [24]. Thus, further comparative study between TARE vs sorafenib vs TACE followed by external radiation vs other combination therapy is needed.

The mild postembolization syndrome and outpatient-based treatment are attractive advantages for TARE over conventional TACE. However, non-target radiation may cause serious complications, which should be managed by surgical treatment. Most of these complications are preventable by comprehensive angiographic evaluation.

The origin of the cystic artery is quite variable, including the segmental hepatic artery, even though the cystic arteries commonly from main trunk of the right hepatic artery. Although the incidence of radiation cholecystitis requiring surgical cholecystectomy is quite low, imaging findings of gallbladder injury are relatively common, including enhancing gallbladder wall, gallbladder edema, and mural disruption.

Nontarget administration of microspheres into the accessory left gastric artery, the right gastric artery, and the gastroduodenal artery may cause gastrointestinal ulcer by radiation. Radiation ulcer is commonly refractory to medical treatment and needs surgical resection. For angiographic technique to prevent gastrointestinal ulcer refer to the current literature.

Radiation pneumonitis is quite uncommon, provided proper lung shunting studies and dosimetry are obtained. When the right inferior phrenic artery, the most common extrahepatic collateral artery, supplies the tumor, special caution is needed to prevent radiation pneumonitis, because the right inferior phrenic artery commonly accompanies pulmonary shunting.

The classical manifestation of radiation-induced liver disease includes anicteric ascites, increased alkaline phosphatase levels, and thrombocytopenia. The exact tolerable dose to the liver by TARE is not known, and true absorbed dose to the normal liver tissue can be hardly assessed. Thus, the easiest and definite way to prevent radiation-induced liver disease is to avoid whole liver irradiation in single treatment or sequential treatment.

TARE is an attractive intra-arterial treatment modality with powerful anti-tumor effect and minimal post-embolization syndrome. Although patients who can afford TARE are limited due to its high cost in Korea, doctors should inform all HCC patients of TARE as a possible treatment option. In BCLC A, radiation segmentectomy may eliminate the pain after surgical resection. In the early stages of BCLC B, TARE may have better tumor control and higher chance to liver transplantation than TACE. In late stage of BCLC B or BCLC C, TARE may offer better quality of life and fewer visits to the hospital than TACE. TARE has specific roles in inducing contralateral lobe hypertrophy and in downstaging to liver transplantation and can be used as an alternative to TACE, ablation, surgical resection, and sorafenib. The utility of TARE continues to expand with new insights in interventional oncology.