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Page 2 of 15 Hall et al. Hepatoma Res. 2026;12:20

research priorities to optimize outcomes.

INTRODUCTION
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third leading cause
of cancer-related death worldwide . Treatment options depend on tumor stage and liver function, with
[1]
curative therapies such as ablation, resection, and transplantation typically limited to early-stage disease.
Despite improvements in surveillance, many patients present with intermediate or advanced disease and are
therefore excluded from traditionally curative options . For these patients, locoregional therapies, including
[2,3]
transarterial chemoembolization (TACE) and selective internal radiation therapy (SIRT) with yttrium-90
(Y-90) microspheres, are often used to control tumor burden [4,5,6] . In parallel, systemic therapies, including
multi-kinase inhibitors such as sorafenib and lenvatinib, and immune checkpoint inhibitors (ICIs) combined
with anti-angiogenic monoclonal antibodies, such as atezolizumab plus bevacizumab, have reshaped the
therapeutic landscape [7,8,9] .

The Barcelona Clinic Liver Cancer (BCLC) prognosis and treatment strategy has long been at the forefront of
guiding decision-making in HCC management . The five stages within the BCLC strategy are determined
[10]
by considering tumor burden, performance status, and liver function. In the 2020 BCLC update, clinicians
are provided with greater management flexibility, reflecting advances in HCC treatment strategies.

In addition to transplantation, surgical resection and ablation remain the primary curative treatments for
very early- to early-stage HCC; however, the latest BCLC guidelines include Y-90 radioembolization as an
appropriate treatment modality for patients with very early- to early-stage disease. In intermediate-stage
disease, locoregional treatments including Y-90 therapy can downstage tumors and make patients eligible for
transplantation. Beyond its antitumor effects, lobar Y-90 administration can promote contralateral hepatic
lobe hypertrophy, thereby facilitating surgical resection in cases where primary resection is not safe or
feasible. While portal vein ligation or embolization has traditionally been used to induce preoperative future
liver remnant hypertrophy, studies show that lobar Y-90 can achieve comparable results, providing both
direct therapeutic benefit and optimization of surgical candidacy .
[11]

Y-90 radioembolization delivers targeted internal radiation to tumors while minimizing harm to
non-tumorous tissue. When paired with systemic therapies, it offers the potential to combine precise local
tumor destruction with broader systemic disease control. This review aims to provide a comprehensive
overview of Y-90 combination therapies in HCC, focusing on mechanistic rationale, clinical outcomes, safety
considerations, and future directions to optimize patient outcomes.

MECHANISTIC RATIONALE FOR Y-90 COMBINATION THERAPIES
Y-90 radioembolization: principles and effects
Y-90 is a high-energy beta-emitting radionuclide with beta particles that penetrate tissue to an average depth
of about 2.5 mm, allowing for targeted radiation delivery within the tumor while sparing adjacent
tissues [6,12,13] . The microspheres, available as either glass or resin formulations with distinct physical and
dosimetric properties (see Table 1), are selectively delivered into hepatic artery branches feeding the tumor,
exploiting preferential arterial blood supply to HCC compared to the portal venous supply of normal liver
parenchyma .
[14]

There are currently two commercially available Y-90 microsphere products in clinical use worldwide:
TheraSphere™ (glass microspheres) manufactured by Boston Scientific (Marlborough, MA) and SIR-Spheres®
(resin microspheres) manufactured by Sirtex Medical Inc. (Wilmington, MA) . These products differ
[15]