Radiation segmentectomy with resin microspheres for hepatocellular carcinoma: a state-of-the-art review highlighting evidence gaps and future research needs

Abstract

Introduction

Radiation segmentectomy (RS) has emerged as a promising approach for hepatocellular carcinoma (HCC), particularly when high tumor doses are achieved. While the clinical utility of ablative doses with glass microspheres is well established, data on resin microspheres remain scarce and inconsistent. This state-of-the-art review aims to provide a descriptive, hypothesis-generating overview of the available evidence and to highlight key gaps in the literature.

Methods

A structured search of PubMed and Embase was conducted to identify clinical studies, technical reports, and reviews evaluating RS using resin microspheres in patients with HCC. Inclusion was limited to studies reporting dosimetric data or clinical outcomes following high-dose delivery. Both published and unpublished sources were considered to ensure a comprehensive overview.

Results

Six publications met the inclusion criteria: four studies with primary clinical data and two narrative reviews. Most were retrospective and single-center, with considerable heterogeneity in methodology and outcome reporting. Reported tumor doses varied widely, and no prospective study has validated safety or efficacy thresholds to date. Nevertheless, selected studies suggest that resin microspheres may achieve tumoricidal doses (> 300 Gy), with encouraging response rates and acceptable safety profiles in highly selective settings.

Conclusion

The use of resin microspheres in radiation segmentectomy represents a promising, yet underexplored, therapeutic strategy in HCC. However, the current evidence base is limited, heterogeneous, and not suitable for definitive clinical conclusions. This review is intended to frame the current evidence landscape and generate hypotheses, supporting the need for prospective, standardized investigations to define optimal dosimetry and guide future research.

Introduction

Hepatocellular carcinoma (HCC) is one of the most common and lethal forms of primary liver cancer, imposing a significant global health burden. With over 900,000 new cases and approximately 800,000 deaths in 2020, HCC ranks as the third leading cause of cancer-related mortality [1]. It is mostly based on chronic liver disease, typically liver cirrhosis, which affects not only the prognosis but also the treatment options. Despite advancements in early detection and new therapies, prognosis remains poor for many, especially those with advanced or unresectable disease [2].

Radiation segmentectomy (RS) has emerged as an innovative radioembolization approach for the treatment of hepatocellular carcinoma (HCC). This technique utilizes yttrium-90 (⁹⁰Y) labeled microspheres to deliver ablative absorbed doses to one or two hepatic segments harboring the tumor. By concentrating the activity within a limited volume, RS achieves a potent tumoricidal effect while mitigating radiation-induced damage to the underlying non-tumoral liver parenchyma [3]. Initially developed using glass microspheres, RS protocols, including dosimetric thresholds, have largely been based on studies with these spheres. These studies serve as the foundation for clinical practice and research in hepatic radioembolization [4, 5].

Resin microspheres, characterized by their density and high particle count per milliliter, offer uniform radiation distribution within tumors, making them effective for extensive treatments or large tumors requiring maximum coverage. However, in highly selective treatments like radiation segmentectomy, the increased number of spheres and their density can complicate high-dose delivery due to the tumor bed’s limited capacity to accommodate the volume of spheres [6].

Studies have demonstrated efficacy with absorbed doses exceeding 200 Gy in selective treatments with this type of microspheres, and it is widely accepted that higher absorbed doses lead to better tumor response [7]. On the other hand, while numerous studies have confirmed the safety and effectiveness of these ablative doses in RS, showing significant objective response rates (ORR) and disease control rates (DCR) with an adequate safety profile, a thorough review of the literature remains essential [8]. This is necessary to consolidate and refine the existing evidence, explore potential gaps, and fully assess the long-term benefits and broader applications of this approach. Ongoing advancements in dosimetry and treatment planning continue to optimize radiation delivery, further improving clinical outcomes and patient survival [3, 7].

Consequently, RS with resin microspheres presents a promising option, particularly for HCC patients ineligible for liver transplantation, surgical resection or percutaneous ablation [9]. Ongoing clinical studies and trials are essential to further refine this technique, providing robust data on optimal dosing, patient selection, and best practices for treatment [10].

Therefore, the objective of this review is to present the current state-of-the-art on the use of resin microspheres in RS for HCC, covering advances in dosimetry, available clinical evidence, and future directions. By synthesizing existing data and identifying research gaps, this work aims to improve the understanding of this approach in clinical oncology. Importantly, this review is conceived as a descriptive, hypothesis-generating overview intended to map the current evidence landscape rather than to provide a formal systematic synthesis or clinical recommendations.

Search and selection of studies

To provide a descriptive overview of the available evidence on the use of resin microspheres in RS for the treatment of HCC, an exhaustive literature search was performed using the PubMed database. The search focused on studies evaluating the efficacy and safety of ablative doses of yttrium-90 (Y90) labeled resin microspheres in the elimination of liver tumors.

This review was not designed as a formal systematic review, and no quantitative synthesis or meta-analysis was planned. The aim was to identify and contextualize relevant evidence rather than to perform exhaustive or comparative evaluation.

Inclusion criteria

Studies including patients with HCC treated with RS using resin microspheres. Studies reporting radiation doses exceeding 200 Gy or an average dose above this value. Peer-reviewed articles published in English. Clinical studies, systematic reviews, meta-analyses, and randomized controlled trials.

Exclusion criteria

Studies not specifying the type of microsphere used. Studies not reporting specific results on radiation doses. Case reports or case series with fewer than 10 patients. Non-peer-reviewed articles, commentaries, editorials, and letters to the editor.

Search strategy

Specific search terms were used to ensure the identification of relevant studies. The search terms included combinations of the following keywords: “Yttrium-90,” “radioembolization,” “radiation segmentectomy,” “resin microspheres,” “hepatocellular carcinoma,” “ablative dose,” and “dosimetry.”

The search was conducted in PubMed, selecting articles published up to June 2024. Filters were applied to include only human studies and articles written in English. Additionally, the references of selected articles were reviewed to identify further relevant studies.

Quality assessment of studies

Each selected study was critically evaluated to determine its methodological quality and the validity of its findings. The aspects evaluated included: Study design (prospective vs. retrospective), sample size and demographic characteristics of patients, dosimetry methods used to calculate radiation dose, inclusion and exclusion criteria for patients, statistical analysis methods and bias control.

Data analysis

Key data were extracted from each selected study, including clinical outcomes such as ORR, DCR, overall survival (OS), progression-free survival (PFS), and the incidence of treatment-related adverse events (AEs).

The extracted data were tabulated and summarized to identify common patterns and significant differences among the studies.

Results

Selection process

The initial search yielded a total of 235 articles. These articles were initially screened by title and abstract to identify those that potentially met the inclusion criteria. After this initial review, duplicates were removed, and exclusion criteria were applied, resulting in the selection of 15 articles for full-text review.

Following a detailed full-text evaluation, five published articles were selected that met all inclusion criteria and provided relevant data on RS with resin microspheres at ablative doses for the treatment of HCC [11–15]. Of these five selected articles, two were review studies [14, 15] and three contained primary data [11–13]. Additionally, our work, which still contains unpublished data (results not formally published), has also been added to this body of evidence [16] (Fig. 1).

Fig. 1.

Search process and inclusion of studies

Description of selected studies with primary data

All selected studies had retrospective designs. The studies covered a wide range of subjects included, varying from 30 to 148. The average age of the subjects was > 65 years, with a higher prevalence of males in most studies.

The mean tumor size reported varied between 3.1 and 4.7 cm, as well as the mean tumor to normal ratio (TNR). The radiation dose administered to tumors using resin microspheres varied considerably among the studies. This variability in dosimetry reflects differences in treatment protocols, dosimetric thresholds, and patient selection. Main design characteristics in Table 1.

Table 1.

Summary of the characteristics of the reviewed studies on segmental radioembolization in the treatment of hepatocellular carcinoma

Study	Study design	N. of patients	Intervention	AEs	Follow-up
Sarwar et al	Retrospective single-center study	67	Radiation segmentectomy with yttrium-90. Resin microspheres	1.5% Grade 3 (abdominal pain)	Two years survival rates analyzed
Villalobos et al	Retrospective, single-center cohort study	81	Radiation segmentectomy using glass or resin microspheres for 90Y-TARE	0% grade 3. Common events abdominal pain and serum albumin changes	3 months post-procedure for tumor response and adverse events monitoring
Young et al	Retrospective, single-center study	148	TARE using both glass and resin microspheres, assessing TNRs and dosimetry models	No significant adverse events reported	Data collected from 2015 to 2020
Orcajo et al	Retrospective single-center study	30	High-dose RS using resin microspheres	One patient developed a liver abscess, resolved with antibiotics	Radiological response assessed at 1 and 3 months

HCC: Hepatocellular carcinoma; TARE: Transarterial radioembolization; AEs: Adverse events; RS: Radiation segmentectomy; TNR: Tumor-to-Normal Ratio

Sarwar et al. (2024)

This study, conducted by Ammar Sarwar and his team, was published in the journal Radiology in May 2024 [11]. The objective was to evaluate the efficacy and safety of RS with yttrium-90 (90Y) resin microspheres in patients with HCC using a single compartment Medical Internal Radiation Dose (MIRD) model.

This retrospective, single-center study included 67 adult patients with HCC treated between July 2014 and December 2022. The median age was 69 years (IQR: 63–78 years), and 81% were male. Most patients (82%) had liver cirrhosis, and 73% were classified as Child–Pugh class A5. The median Model for End-Stage Liver Disease (MELD) score was 8 (IQR: 7–11). The majority (84%) had a unifocal HCC with a median tumor size of 3.1 cm (IQR: 2–4.5 cm), and 57% were treatment-naive. In terms of staging, 85% of patients were classified as BCLC stage A, while 15% were in stage C due to vascular invasion. PET/CT evaluations and post-treatment dosimetry were performed, and adverse events were assessed according to the Common Terminology Criteria for Adverse Events, version 5.0. Response rates were measured using the Modified Response Evaluation Criteria in Solid Tumors (mRECIST), and overall survival (OS) was assessed using Kaplan–Meier analysis.

The results showed that the mean absorbed dose by the tumor was 232 Gy, with an interquartile range (IQR) of 163 to 405 Gy. At 3 months, 70% of patients achieved complete response (CR) per lesion. Additionally, 88% of patients maintained the response for one year or more. The median post-treatment OS was 26 months, and the 2-year disease progression was significantly lower in the group receiving 300 Gy or more (17%) compared to the group receiving less than 300 Gy (61%), p = 0.047. Full details in Table 2 and Fig. 2.

Table 2.

Sarwar et al.: Detailed patient characteristics and treatment outcomes

Variable	Value
Age (Median, IQR)	69	63–78
Sex (Male, n,%)	54	81%
Cirrhosis (n,%)	55	82%
MELD score (Median, IQR)	8	7–11
Child–Pugh Class A (n,%)	61	91%
BCLC Grade A (n, %)	57	85%
HCC Size in cm (Median, IQR)	3.1	2–4.5
Previous Therapy (n, %)	28	42%
Median tumor absorbed dose in Gy (median, IQR)	232	163–405
Per-lesion complete response at 3 months (n,%)	47	70%
Per-lesion objective response at 6 moths (n,%)	50	94%
Per-patient objective response at 6 months (n,%)	36	78%
Disease progression at 2 years (≥ 300 Gy) (n,%)	3	17%
Disease progression at 2 years (< 300 Gy) (n,%)	11	61%
Local progression (≥ 300 Gy) (n,%)	0	–

IQR: Interquartile range; n,%: number and percentage of patients; MELD: Model for End-stage liver disease; BCLC: Barcelona clinic liver cancer stating system; HCC: Hepatocellular carcinoma: Gy: Gray

Fig. 2.

Sarwar et al. Results based on adsorbed dose. Data in Gray

Thus, RS with 90Y demonstrated high efficacy in the treatment of HCC, with significant response rates and disease control. Only one patient experienced a grade 3 adverse event (abdominal pain), highlighting the safety of the procedure. Moreover, patients who received a tumor-absorbed dose of 300 Gy or more had a significantly lower rate of disease progression.

Villalobos et al. (2023)

This study by Alexander Villalobos [12] and his team aimed to evaluate the differences in safety, efficacy, and dosimetry between ablative TR with yttrium-90 (90Y-TARE) using glass and resin microspheres in the treatment of HCC.

This retrospective study included 81 patients with HCC, of whom 20 were treated with resin microspheres and 61 with glass microspheres, during the period from 2019 to 2020. Tumor response evaluations and AEs were assessed using the mRECIST and the common terminology criteria for adverse events (CTCAEs) at 3 months post-procedure. Voxel-based dosimetry was used to create tumor dose (TD) and normal tissue dose (NTD) histograms.

Results showed that the resin cohort had a higher percentage of males (89% vs. 65%, p = 0.03), a lower TNR (1.81 ± 0.39 vs. 2.22 ± 0.94, p = 0.03), a higher tumor particle load (40,172 particles/mL ± 28,039 vs. 17,081 particles/mL ± 12,555, p = 0.0001), a lower specific activity (158 Bq/particle ± 3 vs. 1,058 Bq/particle ± 331, p = 0.001), and a lower mean TD (308 Gy ± 210 vs. 794 Gy ± 523, p = 0.0002) than the glass cohort. The overall objective and complete response rates were 85% (95% resin vs. 82% glass; p = 0.1) and 65% (95% resin vs. 56% glass; p = 0.003), respectively. Full details in Table 3 and Fig. 3.

Table 3.

Villalobos et al.: Detailed patient characteristics and dose threshold for response

Variable	Value
	Resin	Glass
Age (Mean, SD)	68 (± 7)	66 (± 8)
Sex (Male, n,%)	17 (89)	40 (65)
Lung Shunt fraction %	7.6 (± 3.0)	6.3 (± 2.7)
Tumor particle load (particles/mL, mean ± SD)	40,172 (± 28,039)	17,081 (± 12,555)
Specific activity (Bq/particle, mean ± SD)	158 (± 3)	1,058 (± 331)
Tumor-to-normal ratio (Mean ± SD)	1.81 (± 0.39)	2.22 (± 0.94)
Tumor volume (mL, mean ± SD)	59 (± 82)	39 (± 56)
Tumor size (cm, mean ± SD)	4.1 (± 1.8)	3.7 (± 1.4)
BCLC stage grade A (n, %)	14 (70)	46 (75)
Mean tumor dose (Gy, mean, ± SD)	308 (± 210)	794 (± 523)
Mean tumor dose threshold for objective response (Gy, AUC)	176 Gy (AUC 0.91)	290 Gy (AUC 0.95)
Mean tumor dose threshold for complete response (Gy, AUC)	247 Gy (AUC 0.98)	481 Gy (AUC 0.91)

Sd: Standard deviation; n,%: Number and percentage of patients; Bq: Becquerel; BCLC: Barcelona clinic liver cancer staging system; Gy: Gray; AUC: Area under the curve

Fig. 3.

Villalobos et al. Tumor response, assessed using the modified response evaluation criteria in solid tumors (mRECIST)

The mean dose thresholds predictive of objective and CR were 176 Gy and 247 Gy for resin radioembolization, and 290 Gy and 481 Gy for glass radioembolization, respectively. No significant differences were found in baseline AEs between cohorts, with an AE incidence of any grade at 74% and no grade ≥ 3 events.

Young et al. (2022)

This study by Shamar Young [13] and his team aimed to determine TNR in patients undergoing RS and to establish the relationship between TNR and particle load in transarterial radioembolization (TARE).

The retrospective study included 148 patients with HCC who underwent 184 TARE procedures between January 1, 2015, and March 15, 2020. Evaluations were conducted using post-treatment SPECT CT imaging to analyze TNRs, employing voxel-based dosimetry software. Additionally, a model normalized activity to achieve 400 Gy using single compartment dosimetry to determine the effect of TNR on the absorbed TD. Simple and multiple linear regression models were used to evaluate the relationship between TNR and various factors.

Results showed that the mean TNR in radiation segmentectomies was 2.88 ± 1.60, significantly higher for glass microspheres compared to resin microspheres (3.07 ± 1.68 vs. 2.24 ± 1.21, p = 0.01). Furthermore, TNR was higher in RS compared to lobar deliveries (2.88 ± 1.60 vs. 2.16 ± 1.12, p < 0.01). When normalizing activity to achieve 400 Gy using MIRD dosimetry, significant differences were found in the absorbed tumor dose when divided by mean tumor dose (601.2 ± 133.3 vs. 1146.9 ± 297.5, p < 0.01) or mean TNR (1119.2 ± 341 Gy vs. 635.7 ± 160.2 Gy, p < 0.01). Particle load was significantly associated with TNR in both univariate (p < 0.01) and multivariate (p < 0.01) analyses. Full details in Table 4.

Table 4.

Young et al. TNR in radiation segmentectomy patients and comparison of lobar and segmental deliveries and spheres

Variable	Value
Radiation segmentectomy patients	Resin	Glass
Realized TNR	2.24 (± 1.21)	3.07 (± 1.68)
Perfused volume (mL)	437.6 (± 225.1)	439.4 (± 379.8)
Tc 99 m MAA TNR	3.22 (± 3.04)	3.47 (± 3.33)
Tumor size (cm)	4.5 (± 3.2)	4.7 (± 1.5)

Lobar and segmental deliveries	Lobar	Segmental
Realized TNR	2.16 (± 1.12)	2.88 (± 1.60)
TNR for Glass	2.29 (± 1.23)	3.07 (± 1.68)
TNR for Resin	1.99 (± 0.92)	2.24 (± 1.21)
Perfused volume (mL)	1008.7 (± 487.3)	439 (± 346.1)

TNR: Tumor-to-normal ratio; Tc 99m MAA: Technetium-99m macroaggregated albumin; mL: Milliliters; cm: Centimeters

These findings indicate that significant TNRs observed in RS suggest the need for multicompartimental dosimetry techniques in this context. Particle load can affect TNR, and differences in TNR between glass and resin microspheres highlight the importance of advanced dosimetry techniques to achieve precise tumor dosing. This study underscores the relevance of advanced dosimetry to optimize clinical outcomes in patients with HCC treated with TARE.

Orcajo Javier et al. (unpublished data)

Our study [16] aims to demonstrate the feasibility of performing supraselective procedures with resin microspheres using ablative doses and to describe therapeutic outcomes in terms of radiological response and AEs.

This retrospective design included lesions treated with RS using ablative doses from April 2021 to September 2023. Response monitoring was conducted via CT scans at one and three months post-procedure using mRECIST criteria, classifying responses as complete, partial, or progressive. AEs and relevant dosimetric data, including theoretical tumor absorbed dose and final absorbed dose (calculated using voxel-based dosimetry software, D50, and D70 values), were collected from clinical histories. Additional data included angiosome tumor volume and the number of liver segments involved.

As of September 2023, the study has included 30 HCC lesions with a mean tumor size of 34.33 mm and a mean angiosome volume of 34.004 cc. Procedures involved a single liver segment in 83.33% of cases and two segments in 16.67%. The calculated mean target dose was 377.78 Gy (median 400 Gy), while the mean final absorbed dose on ^90Y-PET/CT was 429.53 Gy, with D50 and D70 values of 401.9 and 303.3 Gy, respectively. Radiological CR was observed in 73.33% of lesions at three months, partial response in 20%, and progression in 6.66%. Only one patient experienced liver abscesses as an AE, which was resolved with antibiotic therapy. Full details in Table 5 (Fig. 4).

Table 5.

Orcajo et al. Detailed patient characteristics and treatment outcomes

Variable	Value
Number of lesions treated	30
Mean tumor size (mm, mean ± SD)	34.33	± 22.06
Mean angiosome volume (cc, mean ± SD)	340.04	± 211.90
Single segment treatment (n, %)	25	83.33%
Two-segment treatments (n, %)	5	16.67%
Mean target dose (Gy, mean ± SD)	377.78	± 41.88
Mean adsorbed dose (Gy, mean ± SD)	429.53	± 189.15
Complete response (n, %)	22	73.33%
Partial response (n, %)	6	20%
Progression (n, %)	2	6.67%

Mm: Millimeters; SD: Standard deviation; cc: Cubic centimeters; n,%: number and percentage of patients; GY: Gray

Fig. 4.

A 72-year-old male with a diagnosis of hepatocellular carcinoma (HCC) in hepatic segment VIII and elevated alpha-fetoprotein (AFP) levels. The multidisciplinary team decided on radiation segmentectomy followed by surgery. a and b Pre-TARE CT images with contrast in the arterial phase (a) and delayed phase (b). A 5 cm focal hepatic lesion in segment VIII is identified, showing peripheral enhancement (a) and washout (b), consistent with hepatocellular carcinoma (HCC). c and d Volumetric CT images. HCC (nodular lesion in red) in segment VIII (dark green). e 90Y-PET/CT dosimetry image post-radiation segmentectomy with resin microspheres from the segment VIII artery. The deposition of microspheres over the tumor lesion (olive green line) and in the angiosome (violet line) is confirmed. f Histogram showing percentage coverage/dose (Gy). The post-treatment dosimetric study demonstrates the tumor curve with a mean absorbed dose of 984 Gy, achieving a D70 of 577 Gy and a 238 Gy. Follow-up CT images (g and h): g CT at 3 months post-TARE and h CT post-segmentectomy. g A predominantly hypodense lesion without enhancement is observed, suggestive of necrosis and compatible with a treatment response. h Surgical resection of segment VIII is noted, with a collection without signs of superinfection and post-resection pathology report showing a necrotic lesion without viable residual tomor (complete regression) with a foreign body granulomatous reaction (microspheres)

Mourad et al. (2024)

The article by Mourad et al. [14] reviews the technique, indications, and outcomes of transarterial RS with yttrium-90 (Y90) for the treatment of HCC. This modality is highlighted as a versatile, safe, and effective ablative therapy for early-stage HCC. Advances in patient selection, technique, and dosimetry have positioned this modality as a curative treatment supported by clinical guidelines.

Regarding microspheres, the article notes that glass microspheres, marketed as TheraSphere, are FDA-approved for the treatment of solitary, uHCC in patients with preserved liver function. These microspheres are characterized by high specific activity per microsphere. Due to their efficacy and safety, they have been included in multiple international guidelines for the treatment of HCC.

On the other hand, resin microspheres, known as SIR-Spheres, are FDA-approved in USA for the treatment of hepatic metastases from colorectal cancer in combination with intra-arterial floxuridine. These microspheres have lower specific activity and different specific gravity compared to glass microspheres. These differences can influence radiobiology as well as intravascular transport and intratumoral dissemination.

Resin microspheres, with their lower specific activity and different specific gravity, present variations in distribution and dosage of the treatment compared to glass microspheres. The total number and distribution of microspheres per treatment volume, along with specific activity, dictate the total dose administered to the patient.

However, there are few direct comparative studies between glass and resin microspheres. Most of the literature is based on the use of glass microspheres due to their broader approval and clinical use. Glass microspheres have demonstrated safety and efficacy, leading to their widespread adoption in clinical practice.

The article emphasizes that, although there are technical and dosimetric differences between resin and glass microspheres, most of the literature and clinical practice has focused on the use of glass microspheres. This is due to their approval for a wider range of indications and their implementation in various international clinical guidelines. The article concludes that more studies are needed concerning resin microspheres.

Serhal et al. (2024)

The article by Serhal et al. [15] focuses on the use of RS as a treatment technique for HCC. This review examines the evolution of TARE with Yttrium-90 (Y90), which has historically been used as a palliative treatment for advanced HCC, towards its application in earlier stages of the cancer through RS. This technique is characterized by the segmental administration of an ablative radiation dose, offering a locoregional treatment option for patients with early-stage HCC. The article explores technical considerations, advances in dosimetry, and patient selection, comparing the outcomes of RS with other conventional treatments such as transarterial chemoembolization (TACE), percutaneous thermal ablation, and surgical resection.

Yttrium-90 (Y90) microspheres are fundamental in the RS technique. These microspheres are used to deliver precise radiation doses directly to liver tumors. The article describes two main dosimetry models used with these microspheres. The first is the MIRD model, frequently used for glass microspheres in RS, which assumes uniform distribution within the target tissue. However, this model can result in partial treatment of large tumors or significant deviation in diseased liver and lung tissues from the ideal density. The second model is the Partition Model (PM), created by Ho et al. in 1996, which considers tumor, non-tumor, and lung compartments in the MIRD equation. This more complex and precise model is usable for both glass and resin microspheres and helps prevent hepatic toxicity by separating the total activity into tumor tissue and non-tumor tissue.

Y90 microspheres release high-energy β particles that penetrate surrounding tissues and exert their ablative effect. The distribution and activity of these microspheres are crucial for achieving complete pathological necrosis of the tumor. Studies have shown that doses exceeding 400 Gy are effective in achieving necrosis in most cases, with the MIRD model being the predominant choice for smaller treatment areas. The precise application of these microspheres allows for effective tumor treatment while minimizing damage to surrounding healthy liver tissue.

This study concludes that RS with Y90 microspheres offers a promising and potentially curative alternative for treating early-stage HCC. The precision in dosimetry and the delivery of high radiation doses directly to the tumor, while preserving healthy liver tissue, are key advantages of this technique. However, additional studies are needed to optimize dosimetry and directly compare RS with surgical resection and other curative therapies.

Discussion

This literature review highlights that RS with yttrium-90 (Y90) resin microspheres emerges as a promising technique for treating HCC, based on its ability to deliver high radiation doses to one or two hepatic segments harboring the tumor while minimizing damage to healthy liver tissue. However, these findings should be interpreted within the descriptive and hypothesis-generating nature of this work. Given the limited number of available studies, their retrospective design, and the heterogeneity in methodologies, any interpretation of efficacy and safety remains exploratory. In this context, the discussion addresses the main technical and safety considerations derived from the available evidence.

All included studies demonstrated that resin microspheres can deliver ablative doses exceeding 200 Gy, necessary to induce complete tumor necrosis. The study by Sarwar et al. [11] showed that resin microspheres, when administered in adequate doses, can be highly effective in eliminating liver tumors, achieving a CR in a significant majority of patients and markedly improving post-treatment survival. Similarly, the study by Villalobos et al. [12] which compared the efficacy of resin and glass microspheres, found that the former have a higher tumor particle load due to lower specific activity, which helps facilitate a uniform and effective distribution of radiation within the tumor. This study highlighted differences in TNR tissue, tumor particle load, specific activity, and CR rate between both types of microspheres.

However, the use of lower doses with resin microspheres, compared to the thresholds established for glass microspheres, challenges the hypothesis that higher tumor-adsorbed doses result in better responses and greater necrosis [17]. This exposes a significant knowledge gap regarding the maximum safe ablative doses for resin microspheres [3]. While extensive literature on glass microspheres provides clear treatment protocols, high-quality studies are needed to establish similar guidelines for resin microspheres [18]. Understanding these limits is crucial, as shown by our findings of a median of 400 Gy achieving radiological CR > 70% with minimal AEs [16].

A uniform distribution over the vascularized periphery of tumors is crucial to achieving the ablative doses necessary for necrosis, ensuring that a larger proportion of the tumor volume receives a high therapeutic dose while minimizing damage to normal liver tissue [19]. Microdosimetric analyses show how the density of microspheres affects the homogeneity of the absorbed dose. The high number of particles per milliliter in resin microspheres allows for especially uniform radiation delivery and, consequently, an adequate distribution within the tumor [6]. This fact indicates that resin microspheres are excellent candidates for large tumors due to their lower specific activity per particle [20]. In addition, to use resin microspheres in small tumors or angiosomes, it is beneficial to use vials with higher activity, which ensures the complete administration of the dose and helps to prevent reflux [21].

Although resin microspheres have lower activity per unit of tumor volume compared to glass microspheres, some studies have shown their efficacy to be comparable [12]. In clinical practice, treatments often exceed doses of 200 Gy, further supporting their potential. However, despite these promising results, it remains necessary to delve deeper into aspects such as increased dosage with this type of microsphere to determine the optimal balance between local response and safety. These goals are the focus of ongoing studies, such as the current trial investigating resin microspheres with doses up to 400 Gy [22].

The safety of RS with resin microspheres evaluated in the selected studies suggests a relatively low incidence of severe AEs. In the study by Sarwar et al., only one patient experienced a grade 3 AE, highlighting the safety of the procedure even at high doses. Similarly, the study by Villalobos et al., observed no significant differences in severe AEs between the two cohorts. The incidence of any grade AEs was 74% with no grade ≥ 3 events. Previous studies also indicate the safety of this technique when using resin microspheres [9]. Even potential hepatic toxicity in cirrhotic patients can be prevented through modification of selection criteria and activity calculation methods [23]. Additionally, patients with HCC and portal vein thrombosis show minimal toxicity along with favorable median survival of 10 months [24]. A comparable safety profile is observed with other interventions, such as kinase inhibitors, which present higher fatigue and hematologic abnormalities [8].

Precise dosimetry is essential to maximize efficacy and minimize AEs in RS. The use of the MIRD model and the PM has enabled better treatment planning and more precise radiation delivery, allowing for more accurate and effective dosing [25]. Although both methods are currently accepted, the MIRD model is more commonly used due to its simplicity and convenience for achieving a minimum angiosome absorbed dose. Additionally, there is ongoing work on personalized organ-level dosimetry using deep learning algorithms, extending the voxelized MIRD approach to construct patient-specific three-dimensional dose maps [26]. Rapid predictive dosimetry schemes from the MIRD method, applicable to any beta-emitting microsphere, can be completed in minutes [27]. In the same way, in extensive treatments where damage to the non-tumor parenchyma must be avoided, there is an emphasis on the importance of using multicompartment dosimetry techniques to adjust the absorbed TD and minimize damage to healthy liver tissue. Particle load and TNR are key factors in advanced dosimetry, highlighting the need to personalize treatment planning for each patient [13].

On the other hand, several limitations exist in the reviewed studies. Most were retrospective and single center, which can introduce biases and limit the generalization of findings. Additionally, the heterogeneity of patient populations and differences in treatment protocols complicate direct comparison between studies. Prospective studies and randomized clinical trials are essential to validate these data and establish clear standards for dosimetry and patient selection [28]. Future research should also include designs to determine necrosis thresholds related to resin microspheres and long-term survival outcomes, providing a more comprehensive understanding of treatment effects. Aspects that are covered in our study, which still contains unpublished data, with the intention of providing evidence for the use of high doses with resin microspheres [16].

Future perspectives should also include developing new techniques and devices to improve microsphere administration and dosimetry precision. Integrating advanced imaging technologies and treatment planning software will likely provide greater personalization and efficacy in RS [15].

In summary, ablative RS using resin microspheres represents a promising yet insufficiently explored therapeutic option for patients with hepatocellular carcinoma. Preliminary data from selected studies suggest that this approach can achieve high tumor doses and favorable clinical outcomes, particularly in well-selected patients and when segmental targeting is feasible. However, these findings should be interpreted within the descriptive and hypothesis-generating nature of this review. The current body of evidence is limited in both quantity and quality, with most studies being retrospective, single-center, and lacking standardized dosimetric reporting, which makes any conclusions on efficacy and safety necessarily exploratory. In the absence of prospective studies, this review provides a conceptual and dosimetric framework for future clinical trials.

Importantly, no prospective studies have yet defined validated dose–response thresholds or confirmed the long-term safety of high-dose RS with resin microspheres. The heterogeneity in patient selection, microsphere characteristics, and treatment planning further complicates the interpretation of available results and reinforces the need for standardized, prospective investigations.

Author contributions

All authors contributed equally to the selection and evaluation of the literature, as well as the writing and critical review of the manuscript. All authors approved the final version of the manuscript.

Funding

None.

Data availability

No new data was generated or analyzed in this study. Data sharing is not applicable to this article.

Declarations

Ethics approval and consent to participate

Not applicable, as this work is a review of previously published studies and does not involve human or animal subjects.

Competing interests

J.O.R. has given training courses and participated in workshops on the use of microspheres, sponsored by Bayer, Sirtex, and Boston Scientific, and has received honoraria for these activities. L.R.B. has been involved in the practical aspects of courses related to interventional procedures sponsored by Bayer and Sirtex and has received honoraria for these activities. A.M.M.P. has provided training courses and participated in sponsored workshops by Bayer and Sirtex, receiving honoraria for these services. J.A.M. declares no conflicts of interest to disclose. M.G.L. has given training courses and participated in workshops on microsphere use, sponsored by Bayer and Boston Scientific, and has received honoraria for these activities. M.E.B. has given training courses and participated in workshops on the use of microspheres, sponsored by Bayer and Sirtex, and has received honoraria for these activities. L.M.P. has received honoraria for presentations from Bayer, EISAI, and Gilead. L.C.M. receives personal fees from Bayer and EISAI-MSD. A.A.L. declares no conflicts of interest to disclose. A.C.R. has provided training courses and participated in workshops on microsphere use, sponsored by Bayer, Sirtex, and Boston Scientific, and has received honoraria for these activities. J.C.A.F. has given training courses and participated in workshops on microsphere use, sponsored by Bayer, Sirtex, and Boston Scientific, and has received honoraria for these activities.