Yttrium-90 microsphere therapy for hepatocellular carcinoma: Clinical efficacy, mechanistic insights, and comparative therapeutic perspectives

Abstract

Yttrium-90 (Y-90) microsphere therapy, known as radioembolization, has emerged as a pivotal treatment modality for hepatocellular carcinoma (HCC), delivering targeted radiation with minimal collateral damage to healthy liver tissues. This review meticulously synthesizes current evidence regarding the clinical efficacy, underlying therapeutic mechanisms, patient selection criteria, and comparative advantages of Y-90 therapy. Clinical studies consistently demonstrate significant improvements in overall survival and progression-free survival, coupled with robust tumor response rates and manageable adverse events. The therapy’s efficacy is substantially enhanced by advanced dosimetric techniques, enabling precise radiation delivery tailored to individual tumor profiles. Comparative analyses reveal that Y-90 therapy provides superior local tumor control and a preferable safety profile compared to conventional treatments such as transarterial chemoembolization and external beam radiation therapy. Additionally, its clinical outcomes are comparable to those achieved with contemporary systemic therapies. Ongoing research into combination treatments incorporating Y-90 with systemic therapies, including targeted agents and immune checkpoint inhibitors, suggests promising advancements in comprehensive HCC management. Future directions highlight the necessity for continued refinement of dosimetry and patient stratification approaches, aiming to further optimize therapeutic outcomes.

Key Words: Hepatocellular carcinoma; Yttrium-90 microsphere therapy; Radioembolization; Dosimetry; Clinical outcomes; Comparative efficacy

Core Tip: Yttrium-90 (Y-90) microsphere therapy effectively prolongs overall survival and progression-free survival in hepatocellular carcinoma patients, demonstrating excellent tumor response rates and minimal severe adverse events. Advanced dosimetry and integration with systemic therapies further enhance its efficacy. Compared to conventional treatments, Y-90 offers improved local tumor control and better safety, marking it a pivotal component in contemporary multimodal cancer management.

INTRODUCTION

Hepatocellular carcinoma (HCC) remains a significant global health burden, ranking as one of the leading causes of cancer-related deaths worldwide. Traditional management strategies include surgical resection, liver transplantation, and various locoregional therapies. Among these, Yttrium-90 (Y-90) microsphere therapy, also known as radioembolization, has emerged as an effective, minimally invasive approach, targeting liver tumors directly with radioactive particles delivered through hepatic arterial infusion. This review evaluates the clinical outcomes, mechanism of action, patient demographics, and performs a comparative analysis of Y-90 therapy with conventional and emerging treatment modalities (Table 1).

Table 1 Key insights from yttrium-90 microsphere therapy studies.

Outcome/parameter	Key findings	Ref.
Overall survival	Median OS: 15-32.2 months	Van Thai et al[1]; Chen et al[2]
Tumor response rate	ORR: 58%-73.3%; CR: 7%-21.9%	Huang et al[3]; Baloji et al[9]
Progression-free survival	Median PFS: 4-8 months	Chen et al[2]; Huang et al[3]
Tumor absorbed dose	Higher TAD (> 150-200 Gy) correlates with better outcomes	Lam et al[6]; Kokabi et al[7]
Adverse events	Grade 3 + toxicity: < 5%; common side effects include abdominal pain and fatigue	Huang et al[3]; Sarwar et al[5]

OS: Overall survival; ORR: Overall response rate; CR: Complete response; PFS: Progression-free survival; TAD: Tumor absorbed dose.

CLINICAL OUTCOMES

The clinical outcomes of Y-90 microsphere therapy in patients with unresectable HCC have demonstrated promising results. Numerous studies have shown significant improvements in overall survival (OS), with median OS reported between 15 and 32.2 months. Tumor response rates (complete response, partial response, and stable disease) range widely, with successful response rates reported between 65.6% and 90%[1,2]. These outcomes emphasize the significant potential of Y-90 therapy to improve prognosis in advanced HCC patients.

Progression-free survival (PFS) represents another critical indicator of treatment effectiveness. Studies indicate median PFS ranging from 4 to 8 months, especially in cohorts utilizing advanced, personalized dosimetry techniques[3]. These results highlight the value of individualized treatment planning to optimize therapeutic effectiveness.

Additionally, Y-90 therapy effectively facilitates downstaging in patients initially ineligible for surgical intervention or liver transplantation. Evidence suggests that 34.4% to 40% of treated patients can be successfully down staged, subsequently becoming eligible for curative interventions such as liver transplantation, greatly improving their long-term prognosis[4].

Safety and tolerability remain major considerations in evaluating novel therapies. Y-90 therapy is generally well-tolerated, with serious adverse events (grade 3 or higher) occurring in fewer than 5% of patients. Common side effects reported include abdominal pain, nausea, and fatigue, which are typically manageable and transient[5].

MECHANISM OF ACTION

The therapeutic action of Y-90 microsphere therapy relies on its capacity to deliver localized radiation directly into liver tumors. Y-90 microspheres are small radioactive particles that are selectively infused into the hepatic artery, exploiting the predominant arterial blood supply to tumors. These microspheres lodge in the microvasculature of the tumors, where they emit beta radiation over short distances, leading to tumor cell death while sparing healthy liver parenchyma.

Dosimetry precision plays a pivotal role in optimizing the effectiveness of Y-90 therapy. Tumor absorbed dose levels of greater than 150-200 Gy have been shown to correlate positively with better clinical outcomes, including enhanced OS, improved tumor response rates, and prolonged PFS[6]. Furthermore, advanced dosimetry techniques, such as voxel-based microdosimetry, have been developed to improve precision. These methods allow for detailed mapping of radiation distribution within the tumor, significantly improving the therapeutic ratio by maximizing radiation delivery to malignant cells while minimizing collateral damage to normal liver tissue[7].

PATIENT DEMOGRAPHICS AND SELECTION CRITERIA

Identifying appropriate patient populations for Y-90 microsphere therapy is critical for optimizing outcomes. Ideal candidates typically include patients with unresectable, unilobar HCC, tumors smaller than 5 cm, limited tumor burden, and good liver function, categorized as Child-Pugh class A or B7. Additionally, patients with an Eastern Cooperative Oncology Group performance status of 0-1 represent the best potential responders[2,8].

Clinical predictors of a favorable response to Y-90 therapy include smaller tumor size, absence of portal vein invasion, and lower serum alpha-fetoprotein levels. Recognizing these predictive factors enables clinicians to effectively stratify patients and predict potential outcomes, facilitating tailored therapeutic strategies and improved patient management.

COMPARATIVE ANALYSIS

Comparative studies highlight several advantages of Y-90 therapy over conventional treatments. When compared to transarterial chemoembolization (TACE), Y-90 demonstrates superior tumor control, particularly beneficial in patients with complex scenarios such as portal vein thrombosis. Notably, Y-90 therapy provides better overall response rates and improved PFS, with fewer complications compared to TACE[9].

Recent phase III trials, such as IMbrave150 and HIMALAYA, have positioned immunotherapy-based combinations (e.g., atezolizumab-bevacizumab, durvalumab-tremelimumab) as first-line systemic treatments for advanced HCC. These regimens demonstrate median OS ranging from 16.4 to 16.8 months, which is comparable to or slightly superior to outcomes reported in retrospective Y-90 series. However, Y-90 therapy offers better local control with fewer systemic side effects, making it a valuable alternative or adjunct in selected patients.

In comparison with systemic therapies such as the combination of atezolizumab and bevacizumab, Y-90 therapy exhibits comparable efficacy in terms of OS and PFS, while presenting significantly fewer systemic side effects. This reduced side-effect profile makes Y-90 a particularly attractive option for patients with compromised systemic health or those intolerant to systemic chemotherapy[10].

Additionally, compared to external beam radiation therapy (EBRT), Y-90 therapy significantly reduces the risk of radiation-induced liver disease, a serious concern associated with EBRT. The selective radiation delivery inherent in Y-90 microspheres allows for higher localized doses without adversely impacting the non-target liver tissue[11].

Emerging data on combination therapies involving Y-90 microspheres and systemic agents, including targeted therapies such as lenvatinib and immune checkpoint inhibitors (programmed cell death protein 1 inhibitors), show promising potential. These combined approaches achieve substantially improved response rates and survival outcomes, highlighting an exciting future for multimodal therapeutic strategies in managing advanced HCC[3].

CONCLUSION

Y-90 microsphere therapy represents a major advancement in the management of HCC, significantly enhancing survival outcomes and providing robust tumor control with minimal adverse effects. Continued innovations in dosimetric techniques and integrated systemic therapy combinations will likely further solidify the role of Y-90 as an essential component of comprehensive cancer treatment protocols. Despite its clinical advantages, Y-90 therapy may be limited by high procedural costs and uneven access across regions. The infrastructure and expertise required for radioembolization are not universally available, potentially limiting its use in lower-resource settings. Future studies evaluating cost-effectiveness and health-economic outcomes are warranted to support broader adoption.