1. Introduction

Globally, liver cancer ranks fourth in terms of cancer-related fatalities and is the fifth most frequent type of cancer. The most prevalent type of primary liver cancer is called hepatocellular carcinoma (HCC), which also happens to be the fourth leading cause of cancer-related deaths globally, especially in areas with high rates of persistent hepatitis B and C infections [1-3]. The prognosis for HCC remains dismal despite scientific advancements, particularly for patients diagnosed at advanced stages when conventional curative alternatives including liver transplantation, surgical resection, and systemic therapy are frequently impractical or ineffective [3]. Therefore, alternative therapeutic strategies that can effectively target tumors while preserving liver function are urgently needed.

A promising treatment option for HCC has been identified as yttrium-90 (Y-90) microsphere therapy, also known as radioembolization or selective internal radiation therapy (SIRT), especially for individuals who are not candidates for surgery or other targeted therapies [4]. When encapsulated in microspheres and administered through the hepatic artery, the beta-emitting radioisotope Y-90 enables targeted internal radiation therapy to the tumor [5]. With minimal exposure to the surrounding healthy liver tissue, this approach can deliver large doses of radiation to the tumor and lower the risk of side effects [5,6].

According to a systematic review by Salem et al., Y-90 radioembolization has been shown in current research to be effective in prolonging survival and enhancing quality of life in patients with incurable HCC. For example, Y-90 radioembolization provides similar survival outcomes to transarterial chemoembolization (TACE), with a favorable safety profile.

This paper aims to assess the clinical usefulness of Y-90 radioembolization for the management of HCC. A review of recent research, an examination of clinical results, and an appraisal of the treatment's place in relation to developing HCC treatment approaches will all be part of this assessment. By doing this, the study hopes to improve HCC management and offer suggestions for possible future developments on the application of Y-90 in clinical practice.

2. Therapeutic mechanism

Y-90 radioembolization, also known as selective internal radiation therapy, or SIRT, is a highly targeted treatment method that is crucial for controlling HCC, particularly for patients who are not candidates for surgical resection or other curative treatments. The reason Y-90 is such a successful treatment is that its two modes of action—targeted radiation injection and embolization—cooperate to kill tumor cells.

2.1. Localized radiation delivery

The core of Y-90 therapies lies in its ability to deliver high-energy beta particles directly to the tumor site. Y-90 microspheres are injected into the hepatic artery, which supplies blood primarily to HCC tumors. Due to the hypervascular nature of these tumors, the microspheres preferentially lodge within the tumor’s microvasculature. This selective deposition allows Y-90 to focus the radiation dose where it is most needed—within the tumor—while sparing surrounding healthy liver tissue [4].

Once the microspheres are strategically positioned, they emit beta particles with an energy level of approximately 0.94 MeV. The limited penetration depth of these particles, around 2.5 mm, ensures that the radiation remains concentrated within the tumor, maximizing damage to cancer cells while minimizing exposure to healthy tissues. This targeted delivery leads to double-strand DNA breaks in tumor cells, triggering mechanisms such as apoptosis and mitotic catastrophe. Apoptosis is a controlled cell death process that does not provoke inflammation, whereas mitotic catastrophe results from errors in cell division, ultimately leading to cell death [5, 6].

Because HCC is frequently hypervascular and dependent on arterial blood flow, the tumor is especially well-suited for targeted radiation therapy. Because of its ability to specifically target these tumor cells, Y-90 has demonstrated significant treatment efficacy, making it a viable alternative for patients whose tumors are incurable [4].

2.2. Embolization effect

Beyond its targeted radiation delivery, Y-90 radioembolization also exerts a powerful embolic effect, enhancing its therapeutic efficacy in treating HCC. The microspheres used in Y-90 therapy physically obstruct the tumor's microvasculature, leading to ischemia—a condition in which the blood supply is restricted or reduced. This blockage deprives the tumor cells of essential nutrients and oxygen, contributing to their death through a mechanism distinct from radiation alone [5].

The combination of radiation-induced cytotoxicity and ischemia amplifies the overall effectiveness of the treatment. By simultaneously delivering radiation and inducing vascular occlusion, Y-90 therapy targets the tumor from two fronts: the radiation damages the tumor DNA, while the ischemia starves the tumor cells, enhancing cell death. This dual action differentiates Y-90 from other locoregional therapies, such as transarterial chemoembolization (TACE), which primarily relies on chemotherapy-induced cytotoxicity combined with embolization but lacks the added benefit of radiation [5, 6].

Johnson and Padia established the concept of "radiation segmentectomy," which is a particular use of this dual process. By confining Y-90 microspheres to a specific liver segment, a procedure known as radiation segmentectomy minimizes systemic exposure while enabling the direct delivery of a higher radiation dosage to the tumor. Patients with small, localized tumors or those with limited liver function who are not candidates for more thorough treatments will benefit most from this technique [5]. Radiation segmentectomy is a highly targeted and efficient treatment technique because it preserves as much healthy liver tissue as possible while optimizing the therapeutic advantages through the selective confinement of the Y-90 microspheres.

Clinical results further show that the embolic effect improves the accuracy of Y-90 therapy. Research has demonstrated that, when compared to alternative treatments like TACE or systemic chemotherapy, the combination of radiation therapy with embolization can lead to better local tumor control. The ischemia environment that the embolization creates makes the tumor more radiation-sensitive, which amplifies Y-90's lethal effects. Combining these two treatments not only increases response rates but also lowers the risk of tumor recurrence, improving the prognosis and quality of life for patients [6, 7].

2.3. Personalized dosimetry

A key component of Y-90 therapy is personalized dosimetry, which guarantees that each patient receives a radiation dose specific to their particular tumor features and liver function. Y-90 therapy, in contrast to conventional, one-size-fits-all methods of radiation therapy, uses advanced imaging and planning methods to customize treatment for each patient, maximizing therapeutic benefit and lowering side effect risk.

Advanced imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), and digital subtraction angiography, map the hepatic vasculature and accurately identify the location, size, and shape of the tumor to achieve the goal [4, 5]. This detailed anatomical information is crucial for determining the ideal distribution and quantity of Y-90 microspheres needed to achieve the desired therapeutic effect. According to Levillain et al., such individualized treatment planning allows clinicians to deliver a sufficient dose to the tumor while limiting radiation exposure to healthy tissues [4].

Radiation-induced liver disease (RILD) and other consequences can be avoided by customizing the dose to the patient's unique anatomy and liver function, especially in individuals with cirrhosis or reduced liver function. On the other hand, larger or more aggressive tumors may require higher doses, indicating a precision medicine strategy that improves treatment efficacy [4].

Studies, such as those by Johnson and Padia, demonstrate that patients receiving customized Y-90 dosing achieve better tumor control and fewer side effects compared to standard dosing approaches [5]. This demonstrates how crucial customized dosimetry is for maximizing therapeutic benefits and lowering dangers.

Overall, the transition to precision medicine is best illustrated by personalized dosimetry in Y-90 therapy, which guarantees a customized course of action that optimizes effectiveness while preserving patient safety.

3. Clinical outcomes

HCC has been shown to respond differently to Y-90 radioembolization in terms of safety and efficacy. This section assesses the clinical results of Y-90 therapy in patients with early, intermediate, and advanced-stage HCC, with an emphasis on side effects and efficacy.

3.1. Early-stage HCC patients

Y-90 radioembolization is often used for individuals with early-stage HCC who are not good candidates for surgical resection as a final therapy option or as a stopgap before liver transplantation. According to Gabr et al., Y-90 therapy led to a considerable downstaging of tumors, making 58% of patients who were previously ineligible for liver transplantation eligible. Because it increases the number of patients who may get potentially curative therapies, this outcome is especially significant as it raises the overall survival rates. The study highlights how Y-90 can make transplantation more feasible for patients who would otherwise be deemed inappropriate because of the size or spread of their tumors.

Furthermore, Salem et al. showed that, even in cases of single, incurable HCC, Y-90 radioembolization provides effective local tumor control. According to the LEGACY research, the median overall survival was similar to that of patients following surgical resection, indicating that Y-90 may be a useful, less intrusive treatment with comparable survival results [6]. This is especially important for individuals who have co-occurring conditions that make surgery riskier, making Y-90 an attractive substitute.

When used for early-stage HCC, Y-90 treatment is typically well tolerated and has a low rate of serious adverse effects. Typical moderate side effects include nausea, lethargy, and stomach aches. According to Salem et al, a small percentage of patients experienced mild radiation-induced liver disease (RILD), which is usually reversible with the right supportive care [7]. The targeted aspect of Y-90 therapy, which limits radiation exposure to the tumor while preserving healthy liver tissue, accounts for a substantial portion of its low rate of serious side effects. Y-90 therapy is especially beneficial for individuals who are not candidates for more harsh procedures, including systemic chemotherapy or surgery, because of its selective delivery.

3.2. Intermediate-stage HCC patients

Y-90 radioembolization is frequently taken into consideration as a TACE substitute in intermediate-stage HCC. When compared to traditional TACE, Y-90 therapy is linked to better clinical outcomes, such as increased local tumor control and overall survival [10]. The combination of localized radiation and the embolic effect, which lowers systemic exposure and related toxicities while simultaneously reducing tumor size, is partially responsible for this improved efficacy.

Additionally, because Y-90 therapy usually requires fewer repeat treatments than TACE, it is better for the quality of life of patients. This is especially important for patients in the intermediate stage, since they frequently need several rounds of locoregional therapy to slow the progression of their illness [8]. Y-90 plays a crucial role in improving overall patient management because fewer treatments mean fewer hospital visits, lower healthcare expenditures, and less interruption to patients' everyday lives.

When Y-90 radioembolization is performed on intermediate-stage patients, side effects are typically milder than with TACE. Post-embolization syndrome is a common side effect that manifests as fever, exhaustion, and stomachache. On the other hand, compared to TACE, where chemotherapeutic drugs are administered and may result in considerable systemic toxicities, these effects are usually less common and milder [9,10]. Salem et al. also observed that patients treated with Y-90 experienced less serious adverse events, such as gastrointestinal hemorrhage or liver failure, than patients receiving TACE [7]. For patients with intermediate-stage HCC, Y-90 appears to be a safer and more bearable choice due to its positive safety profile.

3.3. Advanced-stage HCC patients

In advanced-stage HCC, Y-90 radioembolization is still one of the few effective locoregional therapy, especially in patients with extrahepatic spread or portal vein thrombosis (PVT). Drug-eluting embolic transarterial chemoembolization (DEB-TACE) and Y-90 radioembolization were evaluated by McDevitt et al., who discovered that Y-90 had comparable overall survival benefits with less toxicity [11]. This finding is especially important for individuals with advanced cancer, as their options for treatment are frequently restricted because of their substantial tumor load and poor liver function.

Sangro et al. have provided support for the use of Y-90 in cases of advanced HCC by emphasizing its capacity to increase survival and enhance quality of life, even in patients who have already had various liver-directed therapies [12]. Taken together, these studies show that Y-90 therapy has significant palliative benefits, such as improved quality of life and symptom reduction, making it an essential choice for patients in advanced stages who do not respond well to systemic medicines such as lenvatinib or sorafenib.

Patients with advanced-stage HCC are more likely to have adverse reactions from Y-90 therapy because of their worsened liver function and more advanced disease. In this patient cohort, conditions like ascites, severe RILD, and liver decompensation are more frequent [12]. These results emphasize the necessity of cautious patient selection and comprehensive pre-treatment evaluation in order to reduce the hazards related to Y-90 therapy in advanced-stage HCC.

Nevertheless, by using individualized dosimetry and careful observation both before and after treatment, these hazards can be reduced and radiation exposure to healthy liver tissue is kept to a minimum [4]. Y-90 is a feasible alternative even in difficult advanced-stage cases because of its tailored strategy, which increases treatment efficacy and improves patient safety.

4. Conclusion

This paper evaluated the therapeutic processes, clinical uses, and outcomes of Y-90 radioembolization in the treatment of HCC in a comprehensive manner across various disease stages. The dual action of targeted radiation administration and embolization provided by Y-90 has been emphasized by the analysis as a unique strategy to controlling HCC, particularly in situations when surgical resection or other curative treatments are not practical. The results show that Y-90 is useful for patients with different stages of HCC in terms of local tumor management, increased survival rates, and improved quality of life.

The article's findings highlight the significance of Y-90 therapy in the management of HCC today, demonstrating its ability to close therapeutic gaps and offer a customized method of patient care. Y-90 therapy is in line with the movement toward precision medicine by placing an emphasis on customized dosimetry and cautious patient selection, which maximizes therapeutic efficacy while lowering hazards. This information is important for future studies because it implies that Y-90's use in conjunction with other cutting-edge treatments like immunotherapy and targeted medicines may enhance results even more.

The article's findings highlight the significance of Y-90 therapy in the management of HCC today, demonstrating its ability to close therapeutic gaps and offer a customized method of patient care. Y-90 therapy is in line with the movement toward precision medicine by placing an emphasis on customized dosimetry and cautious patient selection, which maximizes therapeutic efficacy while lowering hazards. This information is important for future studies because it implies that Y-90's use in conjunction with other cutting-edge treatments like immunotherapy and targeted medicines may enhance results even more.

Subsequent investigations ought to concentrate on surmounting these constraints by carrying out more thorough clinical studies and investigating inventive amalgamations of Y-90 with novel therapeutic agents. Improvements in imaging and dosimetry may allow for more precise patient selection and dosage calculations, improving the safety and effectiveness of Y-90 therapy and securing its place in the changing HCC treatment environment.