A retrospective study on the outcomes of yttrium-90 radiation segmentectomy with resin microspheres compared to microwave ablation for early primary hepatocellular carcinoma

Introduction

Patient management of hepatocellular carcinoma (HCC) has improved over the past decade due to advances in medical and surgical treatments. In 2024, 41,630 patients were diagnosed with liver cancers in the US, with estimated deaths of 29,840 (1). Advancements have focused predominantly on HCC because it is the most common primary liver cancer, and the incidence of HCC continues to increase while other types of tumors are decreasing (2). For patients with solitary HCC tumors, current treatment options include surgical resection, external beam radiation, transplantation, percutaneous ablation, chemoembolization, and radiation segmentectomy (RS) using yttrium-90 (Y-90) (3-5). The American Association for the Study of Liver Diseases (AASLD) Practice Guidance positions percutaneous thermal ablation, particularly radiofrequency ablation (RFA) and microwave ablation (MWA), as first-line therapies for HCC in early-stage disease (6,7). Complementary to AASLD guidance, the 2026 Barcelona Clinic Liver Cancer (BCLC) update by Reig et al. maintains thermal ablation as the first-line curative-intent treatment for early-stage HCC (BCLC 0/A), positioning Y-90 RS as an alternative when ablation is not feasible (8). The updated framework introduces the CUSE (complexity, uncertainty, subjectivity, emotion) methodology, enabling multidisciplinary teams to consider RS within treatment-stage migration pathways when clinical context warrants deviation from first-line recommendations (8). Further investigation in comparing these modalities is warranted to determine their role in the treatment paradigm for HCC.

Y-90 RS involves selective intra-arterial administration of microspheres loaded with a radioactive compound to 2 or fewer segments of the liver (9,10). There are two types of microspheres available in practice: resin microspheres [selective internal radiation (SIR)-Spheres; SIRTex Medical, Woburn, USA] and glass microspheres (Theraspheres; Boston Scientific, Watertown, USA) (11). In the landmark LEGACY trial established the evidence base for Y-90 glass microspheres, achieving an 88.3% objective response rate and 86.6% 3-year overall survival (OS) in solitary HCC ≤8 cm (12). A study conducted by Arndt et al. found no statistical difference in tumor response and OS between Y-90 RS using glass microspheres compared to percutaneous MWA in non-surgical early HCC candidates, defined as a solitary <4 cm tumor without vascular invasion (13). Furthermore, they found potentially improved progression-free survival (PFS) in favor of the Y-90 procedure (13). Notably, published RS outcome data have predominantly utilized glass microspheres; data specifically evaluating resin microsphere performance remain limited. The purpose of the current study is to investigate the efficacy of resin microspheres to further define Y-90 segmentectomy’s role in the treatment of HCC. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0208/rc).

Methods

Study design

This single-center, Health Insurance Portability and Accountability Act (HIPAA) compliant, retrospective cohort study was approved by the hospital’s institutional review board. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Vanderbilt University Medical Center (No. IORG0012411) and individual consent for this retrospective analysis was waived. The study population was defined as patients aged 18 years or older at the time of referral to the interventional radiology service at this institution between January 1^st, 2016 and June 1^st, 2024. The patients presented with a solitary early HCC lesion for the initial locoregional procedural treatment. For this study, early HCC is defined as American Joint Committee on Cancer (AJCC) stage TI (TIa and TIb) tumors (14,15) that are solitary with an index size of 4.0 cm or less. The patients underwent an MWA or a Y-90 RS using resin microspheres (SIR-Spheres; SIRTex Medical). Pre- and post-operative imaging was available in all patients. Patients who died within 1 month after the procedure were excluded from this study.

Treatment protocol

Procedure selection depended on the feasibility of MWA. Per guidelines, MWA was offered primarily if feasible (6-8). MWA was preferentially selected for peripheral lesions measuring less than 4 cm where adequate margins could be achieved, while RS was reserved for centrally located lesions or challenging anatomical positions where sufficient margins could not be achieved. Specific anatomical challenges that influenced procedure selection included lesion proximity to critical vascular structures, the liver dome, cardiac structures, and adjacent organs including the gallbladder, stomach, and bowel. Lesions in these high-risk anatomical locations required careful assessment of achievable ablation zones to prevent thermal injury to surrounding structures. Ultimately, anatomic feasibility and margin adequacy were the deciding factors for procedure selection within the cohort. MWA procedures were performed under general anesthesia in an outpatient setting. A standardized protocol was followed, including preoperative imaging and assessment in a multidisciplinary tumor board including transplant surgery, medical oncology, radiation oncology and interventional radiology. MWA was guided using computed tomography (CT) with optional concurrent ultrasound to optimize probe placement. Ablation was achieved using a microwave generator system (Emprint; Medtronic) with power and duration parameters based on manufacturer recommendations and lesion characteristics. Probe placement and number were determined by tumor size and proximity to critical structures, such as the gallbladder, intrahepatic bile ducts, and portal veins. Post-ablation imaging with multiphasic contrast-enhanced CT was performed immediately to confirm complete tumor ablation. Any residual viable tumor detected during this imaging was treated with additional ablation in the same session. All ablations had margins of at least 5 mm (Figure 1). Patients received intravenous hydration, pain management, and antiemetics as needed.

Figure 1 A 65-year-old male with a history of primary biliary cholangitis and HCV cirrhosis was found to have a 2.3 cm lesion on surveillance imaging as indicated by the yellow arrow. Pre-operative MRI demonstrated a lesion with early homogenous arterial enhancement (with washout on delayed phase) consistent with LI-RADS 5 in segment V (A). Utilizing ultrasound (B) and intermittent CT, a 15-cm 13-gauge Covidien Emprint percutaneous antenna (Medtronic) was advanced into the lesion (C). The lesion was ablated for 4:30 minutes at 150 W to achieve a 3.5 cm diameter spherical zone. Spiral CT was performed to demonstrate an ablation zone with adequate margins (D). Two-month follow-up MRI showed no abnormal enhancement or washout within the treatment cavity (E). CT, computed tomography; HCV, hepatitis C virus; LI-RADS, Liver Imaging Reporting and Data System; MRI, magnetic resonance imaging.

RS was performed using Y-90 resin microspheres (SIR-Spheres; SIRTex Medical) in an outpatient setting. Treatment planning included a pre-procedure evaluation with angiography and technetium-99m macroaggregated albumin (Tc-99m MAA) administration for dosimetry and lung shunt fraction assessment. Treatment doses were calculated using the partition model. Microspheres were administered via superselective catheter placement to ensure maximal tumor coverage and minimal non-target liver exposure (Figure 2). Post-procedural care included pain management, antiemetics, and dietary modifications to support recovery. Proton pump inhibitor was started 1 week prior and continued 1 month after Y-90 dose administration

Figure 2 A 74-year-old female with a history of HCV cirrhosis was found to have a 2.2 cm segment VII LI-RADS 5 lesion on surveillance imaging as indicated by the yellow arrow (A). Mapping procedure revealed right hepatic artery arising directly from the abdominal aorta, supplying abnormal tumoral enhancement via segment 7 branch (B). Subsequent nuclear medicine scan demonstrated focal accumulation of activity in the target tumor and a lung shunt fraction of 5.2% (C). A dose of 270.4 Gy of Y-90 was delivered to the tumor via the segment 7 branch of the right hepatic artery using resin microspheres (D). Two-month follow-up CT shows a complete response to treatment, shown by the yellow arrow (E). CT, computed tomography; HCV, hepatitis C virus; LI-RADS, Liver Imaging Reporting and Data System; Y-90, Yttrium-90.

Data collection

Study data were collected and managed using REDCap (16,17), which is a secure, web-based software platform designed to support data capture for research studies. A review of the institution’s picture archiving and communication system (PACS) was conducted to collect all patients who have undergone MWA and Y-90 segmentectomy between January 1^st, 2016 and June 1^st, 2024. Using the population criteria described, this list was narrowed using information from the PACS system and the electronic medical record (EMR). Study variables were collected for qualified patients. These include patient demographics, pre-operative laboratory values, Model for End-Stage Liver Disease (MELD) 3.0 scores, MELD Na scores, Child-Pugh score, Eastern Cooperative Oncology Group (ECOG) status, tumor size, prior treatments, and underlying etiology of cirrhosis. The primary outcomes of interest of this study were tumor response and patient survival. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) 1.1 criteria (18,19). For this evaluation, the baseline imaging used was the pre-operative imaging, which was compared to the 3-month post-operative imaging. The tumor response was categorized into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). For survival analysis, the two outcomes calculated are PFS and OS. PFS was defined as the time from operation until disease progression is confirmed with imaging or patient mortality. OS was defined as the time from operation to patient mortality.

Statistical analysis

Patient demographic and clinical characteristics were summarized with medians and interquartile ranges (IQRs) for continuous variables and counts and percentages for categorical variables as shown in Table 1. Further, any possible differences in the characteristics between the treatments were tested with Wilcoxon-rank sum tests for numerical variables and Pearson’s χ² test or Fisher’s exact test for all categorical variables. To assess whether mRECIST tumor response differed at all between MWA and RS treatments, CR proportion was compared between two procedure groups using Pearson’s χ² test. Differences in overall and PFS were also assessed between the two treatment groups. Given the retrospective nature of this study, the cutoffs were set for duration of follow-up to avoid biasing survival outcomes. Subjects who expired without a precise date of passing were censored at the date of their last follow-up study. Kaplan-Meier curves stratified by treatment and differences in survival curves were tested with log-rank tests; median survival times were also calculated stratified by treatment and bootstrap confidence intervals (CIs) for the difference in median survival time between RS and MWA treatments were constructed. Next, Cox regression models were fit for OS and PFS, with procedure as the predictor of interest, while adjusting for a limited, most important set of covariates due to sample size: age, sex, tumor location, and tumor size. Hazard ratios (HRs) and 95% CIs are presented to illustrate the magnitude of effects, and model-estimated survival curves by procedure were also calculated.

All analyses were run in R 4.5.0, with all survival analyses being done using the rms package (20,21).

Results

The patient characteristics are summarized in Table 1. After applying the inclusion and exclusion criteria to the original cohort (Figure 3), a total of 60 patients were included in this study (MWA: n=40, RS: n=20). The median age of the patients was 69 years. The majority of the patients were male (63%). The median MELD-Na score was 9, and the most common etiology of cirrhosis was non-alcoholic steatohepatitis (40%, n=24). Most of the patients were treated as destination therapy (70%, n=42). The remaining patients were treated as a bridge to transplant. The median radiation dose delivered to the tumor for the Y-90 cohort was 169.69 Gy with a range of 50.55 to 2,023.3 Gy.

Figure 3 Flow diagram outlining patient selection for the retrospective cohort study. Patients were identified based on treatment with either MWA or yttrium-90 RS using resin microspheres for hepatocellular carcinoma. Exclusion criteria included multifocal disease, prior locoregional therapy, or insufficient imaging follow-up. MWA, microwave ablation; RS, radiation segmentectomy.

Most demographic and clinical characteristics did not appear to be significantly different between the two procedures. Tumor sizes were significantly larger in the RS treatment group with a median size of 3.05 (IQR, 2.20–3.65) cm compared to the median of 1.90 (IQR, 1.55–2.30) cm in the MWA group (P<0.001; Table 1). As illustrated in Figure 4, tumor response was similar (P>0.999; Table 1) between the two treatments, with 82.5% of subjects achieving a CR in the MWA group and a similar 85% of subjects achieving a CR in the RS group.

Figure 4 This bar graph is a comparison of tumor response using RECIST 1.1 outcomes of MWA represented in blue vs. yttrium-90 RS with resin (SIR-spheres) microspheres represented in blue. The graph illustrates the portion of patients in each cohort response to treatment fitted into one of 4 categories: CR, PR, SD, and PD. CR, complete response; MWA, microwave ablation; PD, progression disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; RS, radiation segmentectomy; SD, stable disease; SIR, selective internal radiation.

Overall, 16 patients died, and 33 patients experienced disease progression. The median follow-up time was 17.51 (IQR, 5.54–32.74) months. We observed no significant difference in survival curves between the two procedures for both PFS (P=0.28; Figure 5A) and OS (P=0.16; Figure 5B). The median PFS times for MWA [11.97 (IQR, 11.01–30.18) months] were shorter than those who received RS [30.51 (IQR, 9.27–not reached) months], although this result was not statistically significant, with the bootstrap CI for the difference in median PFS time between RS and MWA containing 0 (IQR, −6.02 to 19.50) months. Median OS time was longer in the MWA group [53.56 (IQR, 42.74–not reached) months] compared to the RS group [30.51 (IQR, 16.67–not reached) months] months in the RS group; the bootstrap CI for the difference in median OS time between the treatment groups showed that median survival was longer in the MWA group (−39.85 vs. −9.54 months). After controlling for covariates in the Cox regression models, RS was estimated to reduce risk of progression/mortality with 44% reduced risk compared to MWA (HR =0.56, 95% CI: 0.20–1.51, P=0.25; Table 2), but increase the risk of mortality by 38% (HR =1.38, 95% CI: 0.30–6.34, P=0.68; Table 2), though again these effects were not significant. Cox model-estimated survival curves for PFS and OS were presented in Figure S1.

Figure 5 Kaplan Meier curves demonstrating progression-free survival (A) and overall survival (B). P values showed no significant difference in survival outcomes between MWA in black and yttrium-90 RS with resin (SIR-spheres) microspheres in yellow. MWA, microwave ablation; RS, radiation segmentectomy; SIR, selective internal radiation.

The adverse events noted across both cohorts were overall self-limiting and can be categorized as grade 1 based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 (22). Twelve patients demonstrated adverse events after treatment with MWA. Two patients experienced small volume hemorrhage, necessitating an overnight stay for monitoring and both were discharged the following day without further intervention or need for blood transfusion. A single MWA patient reported transient confusion and altered mental status (AMS) due to exacerbation of hepatic encephalopathy, but was able to be discharged the following day after mental status returned to baseline. An additional 9 MWA patients were admitted overnight for post-ablation pain control. One patient in the Y-90 cohort experienced mild access-site bruising without associated pain or evidence of hematoma, and remained hemodynamically stable, allowing for same-day discharge.

Discussion

This study compared oncologic outcomes including tumor response, survival, and toxicity between Y-90 radioembolization with resin microspheres (SIR-spheres) and MWA in patients with solitary HCC ≤4 cm (AJCC stage 1). Both cohorts had statistically similar tumor responses to the treatments, as assessed by the mRESICT 1.1 criteria. Through Cox regression and Kaplan-Meier analyses, survival measures were comparable between the two groups for both PFS and OS. These findings align with the hypothesis that Y-90 RS with resin microspheres produces similar outcomes to MWA in the treatment of solitary ≤4 cm HCC AJCC stage T1 tumors. Another interesting result from our study is the relative lack of adverse events from the Y-90 cohort compared to MWA. While the adverse events were minimal across all treated patients, there was a need for fewer overnight admissions in the Y-90 cohort (30% vs. 0%) due to post-operative pain requiring IV pain medication after MWA, suggesting a potential benefit of using Y-90 over MWA. This study suggests that ablation should continue to be performed, especially in smaller lesions where a 5–10 mm margin can be adequately achieved, but RS should certainly be considered in any lesions where a margin cannot be obtained or if there is concern for significant heat sink or damage to surrounding critical structures, such as the biliary system, gallbladder, or adjacent vasculature.

The treatment of HCC with MWA has been compared to different procedures in many studies. Randomized controlled trials (RCTs) have shown no difference in survival outcomes when comparing surgical resection to percutaneous ablation of solitary HCC (23-25). Sheta et al. conducted a randomized controlled study demonstrating that combined transarterial chemoembolization (TACE) with MWA achieved an 80% success rate at 6 months compared to 70% for TACE combined with RFA and 50% for TACE alone in patients with unresectable single-lesion HCC greater than 4 cm, findings further supported by meta-analyses showing superior OS, CR rates, and PFS with TACE + MWA over TACE + RFA, particularly for tumors ≥3 cm (26,27). A prospective analysis demonstrated that MWA achieved higher complete ablation rates, lower recurrence, and superior survival, while Patel et al. confirmed in a systematic review and meta-analysis that non-embolization therapies including MWA outperformed embolization-based treatments such as TACE across both PFS and OS endpoints (28,29). Multiple studies have demonstrated that combining TACE with MWA yields superior tumor response, lower recurrence, and improved survival compared to MWA alone for HCC, particularly for tumors ≥3 cm (30-32). According to current evidence from AASLD and BCLC guidelines (6-8), MWA remains the preferred first-line treatment when feasible. However, emerging research, including this study, is increasingly exploring RS with Y-90 as an alternative therapeutic approach.

The majority of the data on RS has been conducted with glass microspheres. A retrospective study comparing Y-90 RS with glass microspheres and surgical resection for solitary HCC ≤8 cm suggested that the groups achieved comparable outcomes with fewer adverse events (33). Many studies have compared TACE to Y-90 RS with glass microspheres for unresectable solitary HCC, showing superior tumor control and survival outcomes (34-36). Biederman et al. conducted a study describing Y-90 RS with glass microspheres to be non-inferior to a combination of MWA and TACE for HCC lesions 3 cm or less (37). The glass equivalent of this study reported that Y-90 RS with glass microspheres had comparable outcomes to MWA for patients with solitary HCC tumors <4 cm (13). However, they observed longer PFS in the Y-90 RS group, which could signify more complete coverage compared to percutaneous ablation (13). Although this phenomenon was not observed in the current study, patients treated with Y-90 RS using resin microspheres had a significantly larger mean tumor size than the MWA group (2.93 vs. 1.92 cm) but showed no differences in tumor response or survival. This lack of difference in outcomes despite Y-90 RS with resin treating larger tumors could signify a role for treating larger tumors with Y-90 RS compared to MWA. Based on these results, next to those of Arndt et al., Y-90 RS has the potential to produce tumor responses and survival outcomes similar to MWA. These results support strong consideration of Y-90 RS as a potential first-line treatment option for HCC alongside MWA. However, additional high-quality evidence with the use of resin microspheres is needed before guideline reconsideration.

There is less available data comparing resin Y-90 RS to other procedures as opposed to glass for HCC treatment (38). There are single-arm studies evaluating Y-90 RS with resin for HCC treatment, such as the study by Sarwar et al., which reported an 88% per-lesion response duration of 1 year or greater and a median OS of 26 months, with low rates of severe adverse events (10). Another study was able to show histopathologic necrosis as evidence of Y-90 resin microsphere efficacy, demonstrating favorable pathologic outcomes in HCC lesions treated with transarterial radioembolization, further supporting the tumoricidal potential of resin-based Y-90 at the tissue level (39). However, the absence of comparative data hinders the comprehensive understanding of the outcomes with resin microspheres in patients with early HCC. The current outcomes support the performance of an RCT.

This study has its limitations due to it being a retrospective cohort study. Selection bias may have been introduced into the study as treatment modality choice was determined mainly by provider preference. This issue could not be fully accounted for due to the study’s retrospective design. Another limitation is that a retrospective cohort study cannot use randomization to control for a potentially uneven distribution of covariates between the two populations. To address this limitation, the use of Cox regression was utilized if a difference between the cohorts was found. Furthermore, the relatively small population size in the MWA and Y-90 RS with resin groups increases the likelihood of a type 2 error, potentially leading to false-negative results. Selection bias related to individual operator practice patterns is an inherent limitation of this retrospective study. Treatment selection may have been influenced by practitioner experience (e.g., confidence with CT-guided ablation or achievement of adequate margins), as well as baseline hepatic function or laboratory parameters that limited eligibility for Y-90 radioembolization. These factors could not be controlled for in a retrospective cohort design. Another limitation in the study results is the difference between the location of Tc-99m MAA administration and resin microsphere administration, which resulted in the omission of one Y-90 dose due to inaccurate dose calculation utilizing the partition model. Finally, the MWA cohort tumor response may be suboptimal compared to existing literature. However, this finding likely reflects the higher acuity and complexity of patients treated at an isolated tertiary referral center.

Conclusions

In conclusion, this study demonstrates similar outcomes between MWA and Y-90 RS with resin microspheres in the treatment of solitary AJCC stage I HCC ≤4 cm patients, despite the resin cohort having larger-sized tumors. These findings suggest that resin-based Y-90 radioembolization warrants further investigation before reconsideration as a first-line therapeutic option for early-stage HCC. Future investigations should focus on use of resin in Y-90 RS when compared to other standard procedures used in this patient population.

Acknowledgments

Preliminary results of this study were presented at the GEST (Global Embolization Symposium & Technologies) Annual Conference (May 15-18, 2025; New York, NY, USA).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0208/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0208/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0208/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0208/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Vanderbilt University Medical Center (No. IORG0012411) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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