TheraSphere Shows Efficacy, Limited Toxicity, and Potential Synergy With Immunotherapy in HCC


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Yttrium-90 glass microspheres, a personalized radiotherapeutic cancer treatment, induced an overall response rate of 72.2% per blinded independent central review as neoadjuvant or stand-alone treatment in 143 evaluable patients with unresectable hepatocellular carcinoma.

Beau Toskich, MD

Beau Toskich, MD

Yttrium-90 (Y-90) glass microspheres (TheraSphere), a personalized radiotherapeutic cancer treatment, induced an overall response rate of 72.2% per blinded independent central review (BICR) as neoadjuvant or stand-alone treatment in 143 evaluable patients with unresectable hepatocellular carcinoma (HCC), according to findings from the retrospective LEGACY trial.1

Additionally, at median follow-up of 29.9 months (95% CI, 24.7-34.6), 76.1% of patients derived a duration of response of longer than 6 months with TheraSphere per modified RECIST (mRECIST) criteria, meeting both primary end points of the study. 

“These results were in line with what we would expect with thermal ablation, only we are treating tumors up to 8 cm, which are challenging to treat with thermal ablation,” said Beau Toskich, MD, an interventional radiologist at Mayo Clinic.

Neoadjuvant therapy with locoregional approaches is a key treatment modality in HCC to bridge patients to transplant or resection.2 TheraSphere, given as neoadjuvant or stand-alone therapy, is a highly personalized form of radiation therapy that consists of Y-90–infused, formulated glass microspheres.

“Y-90 is a beta-emitter, so when it is delivered on a vehicle [such as microspheres], the radiation penetrates very limited distance within the tissue,” said Guy E. Johnson, MD, PharmD, a radiologist at the University of Washington (UW) Medical Center, and an assistant professor of radiology at UW Medicine. “That is useful because it allows us to tailor the dosimetry to the patient’s needs. Then we can bring high doses [of Y-90] to the target lesions and limit radiation to nontarget regions of the liver. That is the cutting-edge [element] of Y-90 today.”

The multicenter, single-arm LEGACY study included patients with unresectable solitary liver lesions that were 8 cm or smaller in size. Eligible patients had to have Child-Pugh A and Barcelona Clinic Liver Cancer (BCLC) A or BCLC C disease (ECOG 1 performance status). Patients could not have had prior liver transplantation, resection, locoregional treatment, or systemic therapy. Additionally, patients with portal vein thrombosis or extrahepatic disease were excluded.

The median age of eligible patients (n = 162) was 66; 17.9% of patients were 75 or older. More than half of patients (60.5%) had BCLC A disease, and 39.5% had BCLC C disease. The median tumor size was 2.6 cm (range, 0.9-8.1). Of the eligible patients, 45 were unevaluable because of transplant or resection (n = 20), lack of confirmatory imaging (n = 20), among other reasons (n = 5). 

Patients received selective, lobar, or mixed administration of TheraSphere at a median dose to perfused liver volume of 410 Gy. TheraSphere was given as neoadjuvant therapy with the intent to bridge patients to transplant or resection or as stand-alone treatment. The majority of patients (80.2%) received 1 TheraSphere infusion, and the remainder of patients received 2 or more treatments. 

Additional data from the LEGACY trial showed that 100% of evaluable patients derived a partial or complete response with TheraSphere per localized mRECIST criteria. Responses were defined as a response within the Y-90 microsphere treatment area.

The results revealed a 3-year overall survival (OS) rate of 93% in patients who had undergone transplant or resection following treatment with TheraSphere. Additionally, the rate of best response with TheraSphere was 88% per localized mRECIST criteria.

Almost all (93.9%) patients who received TheraSphere were alive and progression free by localized mRECIST criteria at 24 months. Per mRECIST and RECIST v1.1 criteria, these percentages were 78.8% and 76.7%, respectively.

Regarding safety, the results indicated that the majority of adverse effects (AEs) were mild and resolved without medical intervention. Maintained albumin and bilirubin liver function was observed in 92.9% and 85.3% of patients, respectively. 

“Patients were treated with an average of 410 Gy, which is more than triple what our initial, [historic] doses [of Y-90] were,” said Toskich. “However, no major AEs were reported that required anything more than medical treatment for abdominal pain, nausea, and other toxicities that we would expect to see after local therapy.”

Notably, hints of a synergistic effect between TheraSphere and checkpoint inhibitors have also been observed, said Toskich and Johnson. 

Findings from a single-institution retrospective study of 22 patients with unresectable HCC who received Y-90 radioembolization around the time of checkpoint inhibitors reported no grade 4 toxicities within 6 months of radioembolization.3 Though, 13.6% of patients experienced grade 3 hepatobiliary toxicities within 6 months. Two of these events occurred because of rapid disease progression and 1 occurred from a biliary stricture. One patient each experienced grade 4 colitis at 6 months and hepatic abscess at 3 months following radioembolization. 

Within this study, the median OS from first radioembolization with Y-90 was 20 months (95% CI, 12.5-27.5). The median OS from first immunotherapy was 23 months (95% CI, 15.9-30.1).

Notably, the patients included in the study had diseases other than HCC, including uveal melanoma (n = 12; 54.5%), soft tissue sarcoma (n = 3; 13.6%), cutaneous melanoma (n = 3; 14%), and others (n = 4; 18.2%).

Patients with uveal melanoma had a median OS of 17 months (95% CI, 14.2-19.8). 

The median time to progression was 7.8 months (95% CI, 3.3-12.2), and the median progression-free survival was 7.8 months (95% CI, 3.1-12.4). 

Despite the encouraging retrospective activity observed with TheraSphere, prospective, randomized trials are needed, said Toskich. However, challenges will likely need to be addressed before such a trial can be effectively designed. 

“Randomizing patients to [TheraSphere versus] thermal ablation or resection is going to be challenging. That is a problem with personalized oncology: we now have subcategories of patients who want what treatment is best based on what we know. It is a lot easier to do that for systemic therapy. I’d like to see a tailored study where patients are prospectively enrolled because they have a particular phenotype,” concluded Toskich. 


  1. TheraSphere Y-90 glass microspheres LEGACY study. Boston Scientific. 2021. Accessed January 21, 2021.
  2. Salem R. Johnson GE, Riaz A, et al. 992P Yttrium-90 glass microspheres in the treatment of early and advanced hepatocellular carcinoma: the LEGACY study. Ann Oncol. 2020;31(suppl 4):S692-S693. doi:10.1016/j.annonc.2020.08.1108
  3. Ruohoniemi DM, Zhan C, Wei J, et al. Safety and effectiveness of yttrium-90 radioembolization around the time of immune checkpoint inhibitors for unresectable hepatic metastases. J Vasc Interv Radiol. 2020;31(8);1233-1241. doi:10.1016/j.jvir.2020.04.029
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