Adv Ther DOI 10.1007/s12325-016-0324-7 REVIEW Transarterial Radioembolization with Yttrium-90 for the Treatment of Hepatocellular Carcinoma Joseph Ralph Kallini . Ahmed Gabr . Riad Salem . Robert J. Lewandowski Received: February 18, 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com ABSTRACT products, clinical considerations of treatment, salient clinical trial data establishing its utility, Background: Hepatocellular carcinoma (HCC) and the current and future roles of TARE in the is a common cause of worldwide mortality. management of HCC. Transarterial radioembolization (TARE) with Results: TARE is indicated for patients with yttrium-90 (Y90), a transcatheter intra-arterial unresectable, intermediate stage HCC. The two procedure performed by interventional available products are glass and resin radiology, has become widely utilized in microspheres. All patients undergoing TARE managing HCC. must be assessed with a history, physical Methods: The following is a focused review of examination, clinical laboratory tests, imaging, TARE covering its commercially available and arteriography with macroaggregated albumin. TARE is safe and effective in the treatment of unresectable HCC, as it has a Enhanced content To view enhanced content for this article go to http://www.medengine.com/Redeem/9B84 safer toxicity profile than chemoembolization, F06014B881BF. longer time-to-progression, greater ability to downsize and/or bridge patients to liver J. R. Kallini Á A. Gabr Á R. Salem Á R. J. Lewandowski (&) transplant, and utility in tumor complicated Department of Radiology, Section of Interventional by portal vein thrombosis. TARE can also serve Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago, as an alternative to ablation and chemotherapy. IL, USA Conclusion: TARE assumes an integral role in e-mail: [email protected] the management of unresectable HCC and has R. Salem been validated by numerous studies. Division of Transplantation, Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA Keywords: Hepatocellular carcinoma (HCC); R. Salem Oncology; Radioembolization; Transarterial Division of Hematology and Oncology, Department radioembolization (TARE); Yttrium-90 (Y90) of Medicine, Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA Adv Ther INTRODUCTION OVERVIEW OF HEPATOCELLULAR CARCINOMA Transarterial radioembolization (TARE) is a transcatheter intra-arterial procedure Synopsis performed by the interventional radiologist for the treatment of primary and secondary hepatic Hepatic cancer is the fifth most frequently cancers. Microspheres impregnated with the diagnosed cancer in men and seventh in radioisotope yttrium-90 (Y90, 90Y) are women worldwide, HCC being the most selectively delivered through the hepatic common. Incidence rates of HCC are vasculature to the target tumor(s). Selective increasing across the globe as a result of intra-arterial injection of these microspheres intravenous drug abuse, hepatitis C virus allows for the safe administration of high (HCV) infection, and nonalcoholic radiation doses to the tumor. While steatohepatitis (NASH) [1]. The incidence of transarterial chemoembolization (TACE) is the HCC in the USA is approximately 3 per 100,000 standard treatment paradigm for patients with persons, with significant gender, ethnic, and unresectable intermediate stage—Barcelona geographic variations. Approximately 22,000 Clinic Liver Cancer (BCLC) stage B— new cases and 18,000 deaths occur in the USA hepatocellular carcinoma (HCC), evidence yearly [2]. supports an increasing role for TARE. While From 75% to 85% of HCC is associated with imaging response rates and median overall underlying cirrhosis. Several underlying risk survival from day of treatment appear factors are associated with HCC: hepatitis B comparable between TACE and TARE, most virus (HBV) infection, HCV infection, alcohol patients treated with TARE have more ingestion, autoimmune hepatitis, and NASH. advanced disease than those with TACE and Less commonly associated are primary biliary the treatment is less selective. Despite this, cirrhosis and metabolic syndromes TARE exceeds TACE in terms of (hemochromatosis, Wilson’s disease, time-to-progression (TTP) of disease, toxicity a1-antitrypsin deficiency) [2]. profile, and post-treatment quality of life. TARE The clinical presentation of HCC includes also has demonstrated utility in patients with nausea, abdominal pain, weight loss, abdominal portal vein thrombosis (PVT), a relative fullness, and jaundice. Hematemesis results contraindication to TACE. TARE is also useful from esophageal variceal bleeding secondary as an alternative to ablation and in facilitating to underlying portal hypertension. On physical resection of BCLC stage A tumors. This review examination, 50–90% of patients have discusses the salient features of TARE, landmark hepatomegaly due to associated liver disease. clinical studies establishing its role in directed Ascites presents in 30–60% of patients. cancer therapy, and future directions. This Abdominal bruits are noted in 6–25%. article does not contain any studies with Splenomegaly is a common finding, mainly human participants or animals performed by due to portal hypertension. Other signs of any of the authors. chronic liver disease presenting with HCC Adv Ther include jaundice, abdominal vein dilatation, randomized clinical trials versus best palmar erythema, hepatomegaly, gynecomastia, supportive care [4, 5]. TARE has been typically testicular atrophy, and peripheral edema. employed in patients with unresectable HCC Budd–Chiari syndrome results from HCC deemed not to be good candidates for TACE or invasion of the hepatic veins, suspected by those who have failed prior TACE procedures. tense ascites and pain on palpation of the liver While TACE is most often delivered in a [2]. segmental or selective fashion, TARE has been historically delivered in a lobar or whole liver Current Management manner. Thus, much of the existing evidence for TARE for patients with HCC was produced in The BCLC system is currently the most patients with more advanced disease than that commonly used staging system to guide the for TACE [6, 7]. management of HCC (Fig. 1)[3]. TACE was According to the National Cancer Center established as the standard of care therapy for Network (NCCN), locoregional therapies (TACE unresectable intermediate stage HCC (BCLC B) and TARE) have an established role in in 2002 on the basis of two prospective neoadjuvant treatment of HCC if the waiting HCC Stage 0i Stage A-C Stage D Very early Early stage Intermediate Advanced Terminal stage (A)ii Stage (B)iii stage (C)iv stage (D) 3 nodules Single ≤3 cm Portal pressure/ Increased Prognostic bilirubin factors?v Normal Yes No Liver Best supportive Resection Ablation TACEvi Sorafenib Transplant care Fig. 1 BCLC staging system and treatment strategy mostly related to HCC that are defined as the ‘‘Milan (adapted from [3]). i Very early stage 0: single lesion criteria’’: (single tumors less than 5 cm or 3 nodules less \2 cm, carcinoma in situ. ii Early stage A: single or 3 than 3 cm). Whether patients at stage 0 can be offered local nodules B3 cm. iii Intermediate stage B: multinodular. iv ablation as a first-line treatment option is a topic of Advanced stage C: portal invasion, C1 involved lymph controversy since transplantation is potentially curative [3]. node, or metastasis. v Prognostic factors include variables vi TACE transarterial chemoembolization Adv Ther list times for transplant exceed 6 months excessive tumor burden and limited hepatic (evidence 2D; recommendation 2B) [3]. The function are ineligible [12]. Adverse events NCCN guidelines recognize the role of reported with TARE include fatigue, nausea, intra-arterial liver-directed therapy for the abdominal pain, gastrointestinal ulcers, and management of HCC. All such therapies, transaminitis [13–20]. Unlike TACE, its including TARE, are contraindicated with transarterial counterpart TARE is a serum bilirubin greater than 3 mg/dL unless predominantly outpatient procedure [21]. segmental injection can be performed. Such Currently, two Y90 products are therapies are relatively contraindicated in main commercially available: TheraSphereÒ glass PVT and Child–Pugh C disease, although TARE microspheres (BTG, Canada) and SIR-SpheresÒ has proven benefit in main and branch PVT [8]. resin microspheres (Sirtex Medical, Woburn, Treatment allocation should be decided by a MA, USA). multidisciplinary team of hepatologists, pathologists, radiologists, liver surgeons, and Glass Microspheres oncologists guided by personalized-based medicine [9]. The insoluble, Y90-impregnated glass microspheres have a diameter of 20–30 lm TRANSARTERIAL and an activity of 2500 Bq per sphere at the RADIOEMBOLIZATION time of calibration. Glass microspheres are indicated for inoperable HCC and HCC HCC receives approximately 90% of its blood complicated by PVT, with approval by the US supply from the hepatic artery, while the Food and Drug Administration (FDA) under a normal liver parenchyma obtains 70% of its Humanitarian Device Exemption (based on supply from the portal venous system. TARE proven safety and potential clinical benefit) capitalizes on this concept by delivering [22]. A total of 1.2 million microspheres targeted therapy to HCC with minimal produce 3 GBq of activity (2500 Bq per sphere). parenchymal compromise [10]. Y90