Overview of Yttrium-90 radioembolization for advanced hepatocellular carcinoma: Current status and future perspectives

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with a majority of patients presenting at intermediate or advanced stages, precluding curative interventions. Radioembolization, also known as selective internal radiation therapy, has emerged as a promising locoregional therapy that delivers high-dose yttrium-90 microspheres directly to hepatic tumors while sparing healthy parenchyma. This technique is especially beneficial for patients with portal vein tumor thrombosis or impaired liver function. This editorial provides a comprehensive overview of the mechanism, technical considerations, and clinical efficacy of radioembolization in advanced HCC. Landmark trials such as SARAH, SIRveNIB, and DOSISPHERE-01 demonstrate comparable or superior outcomes to systemic therapies like sorafenib, particularly when personalized dosimetry is applied. Radioembolization contributes to tumor downstaging, transplant bridging, and improved disease control rates. The integration of radioembolization with systemic therapies, including immune checkpoint inhibitors and tyrosine kinase inhibitors, represents a key area of ongoing research. Despite current challenges such as microsphere heterogeneity, dosimetry standardization, and limited accessibility, emerging innovations in imaging, isotopes, and personalized treatment strategies are expected to refine its application. Overall, radioembolization is poised to play an increasingly central role in the multidisciplinary management of advanced HCC.

Key Words: Hepatocellular carcinoma; Radioembolization; Yttrium-90; Portal vein tumor thrombosis; Selective internal radiation therapy

Core Tip: Radioembolization with yttrium-90 microspheres represents a pivotal locoregional treatment option for patients with advanced hepatocellular carcinoma (HCC), especially those with portal vein tumor thrombosis or limited tolerance to systemic therapies. Landmark trials confirm its favorable safety profile and potential for tumor downstaging. Emerging strategies such as personalized dosimetry and combination with immunotherapy are poised to enhance efficacy. Radioembolization continues to evolve as a core component of multimodal therapy in advanced HCC management.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related deaths globally[1]. Approximately 70% of patients present with intermediate or advanced-stage disease at the time of diagnosis, limiting their eligibility for potentially curative therapies such as surgical resection or liver transplantation[2]. In such scenarios, locoregional and systemic treatments become the mainstay of therapy[3]. Radioembolization, also referred to as selective internal radiation therapy, has gained increasing attention over the past two decades for its capacity to deliver high-dose internal radiation directly to liver tumors while sparing surrounding healthy tissue[4,5]. It is especially relevant in patients with advanced HCC and portal vein tumor thrombosis (PVTT), where other modalities may be contraindicated or ineffective[6].

MECHANISM OF ACTION AND TECHNICAL ASPECTS

Radioembolization involves the transarterial administration of yttrium-90-loaded microspheres into the hepatic artery[7]. Owing to the hypervascular nature of HCC, these microspheres preferentially accumulate in the tumor vasculature, emitting β-radiation (average range: 2.5 mm) and inducing tumor necrosis[8]. The selective uptake minimizes damage to non-tumorous parenchyma, making it particularly suitable for patients with compromised liver function. Two types of yttrium-90 microspheres are currently available: Glass microspheres (TheraSphere) with high specific activity and lower particle number per dose; Resin microspheres (SIR-Spheres) with lower specific activity and higher particle number per dose[9]. Before treatment, patients undergo hepatic angiography and technetium-99m macroaggregated albumin scanning to map hepatic arterial anatomy, assess lung shunt fraction, and evaluate risk of gastrointestinal reflux or extrahepatic embolization[10].

CLINICAL EVIDENCE AND OUTCOMES

Numerous retrospective and prospective studies have demonstrated the clinical benefit of radioembolization in advanced HCC. Median overall survival (OS) in well-selected patients typically ranges from 10 to 15 months. Studies have shown that radioembolization can achieve objective response rates of 30%-40% or higher (mRECIST criteria), disease control in 60%-80% of cases, and comparable or improved OS relative to systemic therapy such as sorafenib in patients with preserved liver function. Radioembolization plays an important role in downstaging patients beyond liver transplant criteria (e.g., outside Milan/UCSF) to within acceptable limits, and bridging therapy during transplant waitlist period to control disease progression. Clinical studies suggest that up to 30% of patients initially deemed unresectable may become eligible for transplantation or resection after radioembolization. Landmark trials are listed in Table 1.

Table 1 Landmark trials.

Trial	Design	Intervention	Primary endpoint	Key findings	Clinical implications
SARAH	Phase III, open-label, randomized controlled trial	Yttrium-90 resin microspheres (radioembolization) vs sorafenib	OS	Median OS: Radioembolization 8.0 months vs sorafenib 99 months; no significant difference. Radioembolization group experienced fewer adverse events and better quality of life	Radioembolization offers comparable survival to sorafenib with improved tolerability, suggesting it as an alternative for certain patients[11]
SIRveNIB	Phase III, open-label, randomized controlled trial	Yttrium-90 resin microspheres (radioembolization) vs sorafenib	OS	Median OS: Radioembolization 8.8 months vs sorafenib 100 months; no significant difference. Radioembolization group had significantly fewer grade ≥ 3 adverse events (27.7% vs 50.6%)	Confirms radioembolization's comparable efficacy and better safety profile, supporting its use in selected patient populations[12]
DOSISPHERE-01	Phase II, open-label, randomized controlled trial	Personalized dosimetry radioembolization vs standard dosimetry radioembolization	OS	Median OS: Personalized dosimetry 26.6 months vs standard dosimetry 10.7 months (P = 0.0096). Higher tumor response rates and potential for downstaging to surgery in the personalized group	Personalized dosimetry significantly improves outcomes, advocating for individualized treatment planning in radioembolization[13]

OS: Overall survival.

INTEGRATION WITH SYSTEMIC THERAPIES

Radiation may enhance tumor immunogenicity via immunogenic cell death, a process in which dying tumor cells release danger signals and tumor antigens that activate the immune system, thereby creating synergy with immune checkpoint inhibitors[11]. Trials are ongoing to evaluate the combination of radioembolization with agents such as atezolizumab and nivolumab. TKIs such as lenvatinib and sorafenib may potentiate the anti-tumor effects of radioembolization by inhibiting angiogenesis and vascular remodeling[12]. However, careful timing and monitoring are required to avoid additive hepatic toxicity. Sequential or combination regimens of radioembolization with TACE (transarterial chemoembolization), systemic therapies, or other modalities are under exploration. Early-phase studies suggest improved disease control but require validation in randomized trials.

CURRENT CHALLENGES AND FUTURE DIRECTIONS

Despite its benefits, several challenges remain, such as non-uniform microsphere distribution especially in large or hypovascular tumors, difficulty in standardizing dosimetry particularly in bilobar disease, limited access and operator-dependent expertise, and cost and logistical barriers in low-resource settings[13]. Besides, patient selection plays a critical role in the success of radioembolization, with factors such as preserved liver function, Eastern Cooperative Oncology Group performance status, and tumor burden significantly impacting response and survival outcomes. Voxel-based and partition models are being developed to enable more accurate radiation planning and improved tumor coverage. Research is ongoing to identify genomic and radiomic biomarkers predictive of response and toxicity. New isotopes (e.g., holmium-166) and targeted radio-nanoparticles may allow improved selectivity, imaging compatibility, and safety[14]. Determining the optimal sequence of radioembolization with systemic agents and other locoregional therapies is an ongoing area of research[15].

CONCLUSION

Radioembolization has transformed the therapeutic landscape for patients with advanced HCC, especially those with PVTT or limited systemic options. It offers a well-tolerated, effective, and targeted approach with growing evidence for integration into multimodal strategies. Future advances in dosimetry, biomarkers, and combination therapy will further enhance its role in personalized cancer care. As part of a multidisciplinary treatment framework, radioembolization continues to evolve as a cornerstone in the management of advanced HCC.