FEATURED TECHNOLOGY THERASPHERE™ Y-90 GLASS MICROSPHERES Sponsored by Boston Scientific Corporation Making Critical Radioembolization Therapy Available for More Patients With Hepatocellular Carcinoma TheraSphere™ Y-90 Glass Microspheres are the only radioembolization therapy FDA-approved for HCC. By Riad Salem, MD, MBA epatocellular carcinoma (HCC) is the most arteries that supply blood to hepatic tumors, preferen- prevalent form of primary liver cancer, and tially depositing radiation directly into the tumor while more than half a million new global cases are sparing surrounding normal parenchyma. It is a simple diagnosed each year.1 The American Cancer but elegant technique to deliver targeted, high-dose HSociety estimates that approximately 32,000 new cases radiotherapy. of HCC will be diagnosed in the United States in 2021.2 Unlike conventional external radiotherapy, Concerningly, HCC is also the fastest-growing cause TheraSphere treatment does not pass through healthy of cancer-related death in the United States.3 There are a variety of treatment options for HCC, including surgical resection, liver transplantation, ablation, transarterial chemoembolization (TACE), transarterial radioembolization (TARE), or systemic therapy. Importantly, depending on the stage of the tumor(s) and the status of the patient, surgical resection or transplantation may not be possible. TARE—also commonly referred to as selective inter- nal radiation therapy (SIRT)—and TACE are often used for patients with unresectable HCC. There are different types of SIRT, each using radiotherapy to control HCC or other types of liver tumors that cannot be removed with surgery. Over the last 2 decades, radioembolization with TheraSphere™ Y-90 Glass Microspheres (Boston Scientific Corporation) has emerged as an effective SIRT for HCC. During the procedure, millions of yttrium-90 (Y-90) glass microspheres are injected into hepatic TheraSphere™ Y-90 Glass Microspheres. APRIL 2021 INSERT TO ENDOVASCULAR TODAY 1 FEATURED TECHNOLOGY THERASPHERE™ Y-90 GLASS MICROSPHERES Sponsored by Boston Scientific Corporation 1999 FDA HDE 2006 DOWNSTAGING AND 2011 RADIATION SEGMENTECTOMY: 2018 CURATIVE INTENT: EARLY 2021 PMA: 1ST AND ONLY Y-90 APPROVAL BRIDGING TO TRANSPLANT2 HIGH-DOSE RADIATION DELIVERED HCC AND LOW TUMOR BURDEN6 THERAPY APPROVED BY THE FDA TO ≤ 2 HEPATIC SEGMENTS4 FOR HCC 2004 ADVANCED HCC 2009 RADIATION LOBECTOMY: 2014 RADIATION 2020 LEGACY CONFIRMS 2021 TARGET: GLOBAL WITH OR WITHOUT PVT 1 LOCAL TUMOR SHRINKAGE AND SEGMENTECTOMY NEOADJUVANT OR STANDALONE REAL-WORLD STUDY CONFIRMS HYPERTROPHY OF NORMAL LIVER3 THRESHOLD DOSE TREATMENT IN HCC8 TUMOR ABSORBED DOSE IS >190 Gy5 CRITICAL FOR PREDICTABLE DOSISPHERE-01 TUMOR RESPONSE AND OS PERSONALIZED DOSIMETRY IN BROAD POPULATION9 APPROACH IMPROVES 1. Salem R, Lewandowski R, Roberts C et al. J Vasc Interv Radiol. 2004; 15(4) 335-45 OVERALL SURVIVAL7 2. Kulik LM, Atassi B, van Holsbeeck L et al. J Surg Oncol. 2006;94: 572-586 3. Gaba RC, Lewandowski RJ, Kulik LM et al. Ann Surg Oncol. 2009 Jun;16(6):1587-96 4. Riaz A, Gates VL, Atassi B et al. Int J Radiat Oncol Biol Phys. 2011 Jan 1;79(1):163-71 5. Vouche M, Habib A, Ward TJ et al. Hepatology. 2014;60(1):192-201 6. Lewandowski RJ, Gabr A, Abouchaleh N et al. Radiology. 2018;287(3) epub 7. Garin E, Tselikas L, Guiu B et al. Personalized versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial. Lancet Gastroenterol Hepatol. 2021, 6: 17-29 8. 3020.2: Yttrium-90 Glass Microspheres in the Treatment of Hepatocellular Carcinoma: The LEGACY Study,” CIRSE 2020 Virtual Summit, September 12-15, 2020; Salem R, Johnson GE, Kim E, Riaz A, Bishay V, Boucher E, Fowers K, Lewandowski R, Padia SA. Yttrium-90 Radioembolization for the Treatment of Solitary, Unresectable Hepatocellular Carcinoma:The LEGACY Study. Hepatology. 2021 Mar 19. doi: 10.1002/hep.31819 9. Lam, Marnix. A Global Study of Advanced Dosimetry in the Treatment of Hepatocellular Carcinoma with Yttrium-90 Glass Microspheres: Analyses from the TARGET Study. Presented at SIR. March 25, 2021 Figure 1. A 20-year legacy of clinical evidence and milestones. (Abbreviation note: PVT, portal vein thrombosis.) body tissues and organs to reach the tumor, which need IRB approval to administer TheraSphere therapy, and substantially minimizes normal tissue from the negative most importantly, this life-prolonging treatment option is effects of nontargeted radiation. TheraSphere treat- now accessible to a larger number of HCC patients. ment does not require hospitalization and is typically performed as an outpatient procedure in as little as A BRIEF HISTORY OF THERASPHERE5 1 hour. Over the years, hundreds of studies have been The idea to deliver HCC therapy via the hepatic published that detail the impact of this therapy on artery originated in the 1950s with the discovery that HCC tumors. liver tumors get most of their blood supply from the hepatic artery, whereas parenchymal cells get theirs IMPROVED ACCESS FOR MORE PATIENTS mainly from the portal vein. The first reports of success- WITH HCC ful radioembolization of liver cancer with Y-90 micro- The United States Food and Drug Administration (FDA) spheres appeared in the 1960s and 1970s.6-8 first approved the TheraSphere microspheres in December Findings from several early phase trials with 1999 by granting it a humanitarian device exemp- TheraSphere therapy were first published in the 1980s tion (HDE) for use in patients with unresectable HCC and 1990s.9,10 Several dose-escalation studies showed the (Figure 1).4 An HDE is a regulatory pathway for products safety and early efficacy of TheraSphere therapy in HCC intended for diseases or conditions affecting small (rare) patients, confirming it selectively delivered high doses of populations. Under an HDE, there is a requirement that radiation to tumors and had acceptable toxicity. a local Institutional Review Board (IRB) approves its use. Additionally, HDEs limit the number of patients who can NOTEWORTHY CLINICAL OUTCOMES WITH be treated with the therapy to 8,000 each year.5 THERASPHERE Treatment with TheraSphere has amassed a 21-year As shown in Figure 1, a variety of large clinical studies track record of clinical trial and real-world success. The that focused on the safety, efficacy, and long-term out- treatment is the subject of > 500 publications in peer- comes of TheraSphere treatment were initiated after the reviewed journals, > 100 global investigator-initiated trials, 1999 HDE approval. Since then, studies have evaluated and has been used to treat > 70,000 HCC patients globally. personalized dosimetry with TheraSphere and whether it During this period, the LEGACY clinical trial, designed to could be used as a stand-alone therapy, as a neoadjuvant evaluate the safety and efficacy of TheraSphere for the treatment to downstage prior to resection, or as a neoad- treatment of early and advanced HCC, was completed. juvant treatment to bridge to transplantation. All studies These efforts culminated in the premarket approval of demonstrated noteworthy clinical outcomes. TheraSphere by the FDA in March of 2021, making it the The DOSISPHERE-01 design compared standard, only SIRT treatment approved for the treatment of unre- single-compartment dosimetry (uniform distribution sectable HCC in the United States. Clinicians no longer of absorbed dose within the perfused volume [both 2 INSERT TO ENDOVASCULAR TODAY APRIL 2021 FEATURED TECHNOLOGY THERASPHERE™ Y-90 GLASS MICROSPHERES Sponsored by Boston Scientific Corporation tumor and normal liver]) to personalized dosimetry (multicompartment Y-90 distribution of absorbed dose within the perfused volume that incorporates blood flow to the tumor).11 DOSISPHERE-01 was a prospec- tive, randomized, multicenter, investigator-sponsored phase 2 trial of 60 advanced HCC patients (intention- to-treat population) treated with TheraSphere therapy. The trial showed that median overall survival was significantly greater in the personalized dosimetry group (26.6 months) compared to the standard dosim- etry group (10.7 months). This study set the stage for personalized treatment in unresectable HCC— TheraSphere dosimetry can be tailored to each patient’s TheraSphere microspheres have an approximate mean unique tumor location, volume, and mass as well as diameter of 25 µm. vascular supply. This offers the clinician more control to optimize treatment. had high response rates, clinically meaningful duration Furthermore, in a 2020 retrospective analysis, a of response, and comparable overall survival to existing multidisciplinary team of specialists reviewed data curative therapy. The LEGACY study was the basis for from 207 patients with unresectable HCC who the recent FDA approval of TheraSphere. underwent liver transplantation after being treated with TheraSphere as part of a bridging or downstaging CONCLUSION care pathway. Results showed that 18% of patients were TheraSphere, the only approved therapy for HCC, downstaged to within Milan transplant criteria and 82% represents a major advancement in the treatment bridged to transplantation. The median overall survival of HCC, providing clinically meaningful therapeutic after liver transplantation was 12.5 years.12 options for a wide range of patients. Its versatility allows To further improve the treatment approach, it was for stand-alone use, neoadjuvant therapy for bridging important to understand the circumstances