Role of SIRT in Patients With Hepatocellular Carcinoma: Current Clinical Indications and Future Perspectives

Abstract

Background/Aim

A retrospective, exploratory study was conducted on patients with hepatocellular carcinoma (HCC) who underwent Selective Internal Radiation Therapy (SIRT) between 2021 and 2024. The aim was to evaluate its efficacy in tumor downsizing prior to surgical resection, downstaging before liver transplantation, and achieving local tumor control.

Patients and Methods

This is a single-center study conducted at the University Hospital of Naples Federico II. We retrospectively reviewed the medical records of patients with an HCC diagnosis who were subjected to SIRT following discussion within a multidisciplinary tumor board specialized in hepato-biliary diseases. SIRT is a locoregional treatment option for HCC that involves trans-arterial delivery of a therapeutic radioisotope, most frequently the β-emitter yttrium-90 incorporated into glass or resin microspheres. All investigated patients were evaluated by dynamic contrast-enhanced computed tomography and/or magnetic resonance imaging before and after treatment. Radiological tumor response to treatment was evaluated according to modified Response Evaluation Criteria in Solid Tumors.

Results

Twenty patients with Child-Pugh A liver function were included. Overall, complete response (CR) was achieved in 6 patients (30%), partial response (PR) in 10 (50%), and progressive disease (PD) in 4 (20%). In the downstaging group (n=5), 1 patient achieved CR, 3 achieved PR, and 1 experienced PD. In the downsizing group (n=4), 3 patients achieved PR and 1 had PD. In the local control group (n=11), 5 patients achieved CR, 4 achieved PR, and 2 experienced PD. No significant post-procedural complications were observed.

Conclusion

These findings support the role of SIRT as a versatile locoregional therapy in selected patients with HCC, across different therapeutic intents.

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related mortality worldwide. The incidence of HCC is higher in men than women, with a reported ratio of 4 to 1 (1). In 2025, it was estimated that there will be 42,240 new cases of liver and intrahepatic bile duct cancer in the United States, with an age-adjusted incidence rate of approximately 9.4 per 100,000 population (2). In 2024, approximately 12,612 new cases of liver cancer were estimated, including 8,838 male and 3,774 female patients, with a male-to-female ratio of approximately 2:1. As for prevalence, approximately 30,200 people in Italy are alive after a diagnosis of liver cancer, comprising 22,300 men and 7,900 women (3). The major risk factors for HCC include viral infection such as HBV or HCV, chronic alcohol consumption, diabetes or obesity-related Nonalcoholic steatohepatitis (NASH). Chronic HCV infection is the leading underlying liver disease in patients with HCC in North America, Europe, and Japan (4). HCC is generally diagnosed at advanced stages when the tumor is unresectable, and the only viable option is systemic therapy (5). The treatment for HCC requires a multidisciplinary approach (6). When diagnosed at early stages, it is treatable with locoregional procedures including surgical resection, liver transplantation (LT), radio-frequency or microwave ablation (RFA/MWA) and trans-arterial chemoembolization (TACE) (5); another locoregional therapy is trans-arterial radioembolization (TARE) also known as selective internal radiation therapy (SIRT) (7). The Barcelona Clinic Liver Cancer (BCLC) staging system establishes the prognosis and proposes treatments for each stage (8). According to the BCLC classification, very-early and early stages are managed with curative-intent therapies, including surgical resection, liver transplantation, or ablation, depending on tumor burden and liver function (8). Intermediate-stage disease is treated with locoregional or systemic therapies, whereas advanced and end-stage disease are managed with systemic treatment or best supportive care (8). The role of SIRT in HCC has progressively expanded over the last two decades (9), and the 2022 BCLC update incorporated radioembolization for very-early and early stages, while its role in intermediate and advanced disease remains under investigation (10). The BCLC strategy has been updated in 2025 to incorporate recent advances in evidence and therapeutic options while maintaining its core structure linking stages to evidence-based modalities. According to recent BCLC recommendations, selective internal radiation therapy may be considered in early-stage disease for radiation lobectomy in patients with large tumors and limited future liver remnant, as well as to prevent tumor progression when liver transplantation waiting time exceeds six months (8). Based on LEGACY trial criteria, SIRT may also be applied in selected intermediate-stage patients with a solitary tumor ≤8 cm and preserved liver function (8, 11). Initially adopted mainly as a palliative option in advanced or TACE-refractory disease, SIRT has progressively evolved into a versatile treatment with curative or conversion intent in early and intermediate stages, including downsizing before resection, downstaging to liver transplantation, and local tumor control (12, 13). Accordingly, this retrospective study evaluated the role of SIRT across different clinical scenarios-downsizing, downstaging, and disease control- highlighting its potential impact on long-term outcomes in patients with hepatocellular carcinoma.

Patients and Methods

Patients.This is a study conducted at the University Hospital of Naples Federico II. We retrospectively reviewed the medical records of patients with a diagnosis of HCC discussed within a multidisciplinary tumor board specialized in hepato-biliary (HB) diseases with final indication to SIRT between 2021 and 2024. All these cases were patients provided written informed consent for every diagnostic and therapeutic procedure. All investigated patients were evaluated using dynamic contrast-enhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) before and after treatment. Radiological tumor response to treatment was divided into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) and was conducted according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) as shown in Table I (14).

Table I. Assessment of target lesion response.

Computed tomography. CT examinations were performed using a 64-detector row CT scanner (Aquilion 64; Toshiba Medical Systems, Otawara, Japan). The protocol included an unenhanced baseline liver scan followed by multiphasic contrast-enhanced acquisitions with arterial, portal venous, and equilibrium phases. A nonionic iodinated contrast agent was administered intravenously at a rate of 3 ml/s.

Magnetic resonance imaging acquisition. MR studies were performed with a 3-Tesla scanner (Magnetom Trio, Siemens Medical System, Germany). The protocol included T2-weighted HASTE sequences (with and without fat saturation), T1-weighted sequences, and breath-hold in-phase and out-of-phase gradient-echo imaging. Dynamic contrast-enhanced imaging was performed using a 3D VIBE technique with fat saturation after intravenous administration of Gd-EOB-DTPA (Primovist, Bayer Schering, Pharma A, Berlin, Germany) (0.025 mmol/kg) at 2 ml/s followed by a saline flush. Arterial (25-35 s), portal venous (70-80 s), delayed (180 s), and hepatobiliary phases (15 min) were acquired.

SIRT. Selective angiography with visceral catheterization and pre-treatment 99mTc-MAA imaging were performed to assess vascular anatomy and lung shunt fraction (LSF). Treatment was delivered via a transfemoral approach with selective hepatic artery catheterization and prophylactic embolization of extrahepatic branches, followed by slow manual administration of resin microspheres (SIR-Spheres; Sirtex Medical Limited, Sydney, Australia) under fluoroscopic guidance. Bilobar disease was treated sequentially with an interval of 6-8 weeks to reduce the risk of radioembolization-induced liver disease. LSF was evaluated using planar imaging and Single Photon Emission Computed Tomography + Computed Tomography (SPECT/CT) (15), with semi-automated segmentation performed using MIM software (v6.9) (16). Tumor-to-normal ratio and therapeutic activity were derived from SPECT/CT data. Dosimetry was planned using the partition model, targeting >200 Gy to the tumor and <40 Gy to non-tumoral liver in non-segmental treatments, and 200 Gy in segmental approaches (17-19). Treatment strategy was based on angiographic tumor supply. The prescribed activity was administered three days after mapping, and no patients were excluded due to dosimetric constraints.

Results

Between 2021 and 2024, 20 patients with HCC underwent SIRT. The cohort included 16 male patients (80%) and four female patients (20%), with a median age of 71.2 years (range=51-88 years). All patients had well-compensated liver disease (Child-Pugh A) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Thirteen patients (65%) were treatment-naïve, whereas seven (35%) had recurrent HCC. The median body mass index (BMI) was 26.84 kg/m² (range=16.94-42.6 kg/m²). Underlying liver disease was related to hepatitis C virus (HCV) infection in 10 patients (50%), hepatitis B/D virus (HBV/HDV) in four (20%), and alcoholic or metabolic liver disease in six (30%). Alpha-fetoprotein (AFP) levels showed marked variability, ranging from 1.1 to 11,946 ng/ml, with a median value of 923.57 ng/ml. Fifteen patients (75%) had AFP <200 ng/ml, while five (25%) had AFP ≥200 ng/ml.

According to the Barcelona Clinic Liver Cancer (BCLC) staging system, 12 patients (60%) were classified as BCLC B and eight (40%) as BCLC C. All BCLC C patients presented with portal vein thrombosis without evidence of extrahepatic spread.

Tumor burden was heterogeneous: nine patients (45%) had a single nodule, eight (40%) had 2-5 nodules, and three (15%) had more than five lesions. Morphologically, tumors were classified as solitary (45%), multinodular (40%), or massive (15%). Disease distribution was predominantly unilobar (90%, n=18), with bilobar involvement in two patients (10%). The maximum tumor diameter ranged from 0.9 to 22 cm, with a median size of 5.5 cm; seven patients (35%) had lesions >7 cm.

Among the seven recurrent cases, previous treatments included surgical resection (n=3), percutaneous ablation (n=3), and transarterial chemoembolization (TACE) (n=1).

All patients underwent multiphase contrast-enhanced CT at baseline and at 3-month follow-up; a subset also underwent MRI. Patients were stratified according to treatment intent: five patients (25%) underwent downstaging prior to liver transplantation (Group 1), four (20%) received downsizing before surgical resection (Group 2), and 11 (55%) were treated for local tumor control (Group 3). No procedure-related complications were observed. Demographic and clinical characteristics according to treatment intent are summarized in Table II. Treatment outcomes are reported in Table III. Representative cases are illustrated in Figure 1 and Figure 2 (Group 1), Figure 3 (Group 2), and Figure 4, Figure 5 and Figure 6 (Group 3).

Table II. Distribution of patient characteristics and imaging features.

^aPatients can have multiple prior locoregional procedures.

Table III. Response to treatment in assessed.

Figure 1.

Computed tomography (CT) scans. A) CT scans performed on 16.09.2022 before treatment showed a hypervascular lesion (57×37 mm) in hepatic segment VII, located peripherally to the treated area. The lesion exhibited arterial phase enhancement with portal venous and delayed phase washout, consistent with hepatocellular carcinoma (HCC). B) Follow-up CT scans performed on 09.02.2023 after treatment demonstrated a reduction in tumor size (45×29 mm).

Figure 2.

Computed tomography (CT) scans. A) CT scans performed on 19.09.2022 before treatment showed in the hepatic segment VII a nodule of approximately 20 mm characterized by wash-in in the arterial phase and wash-out in the venous phase. B) Follow-up CT scans performed on 15.05.2023 after treatment showed in segment VII a small area (6 mm) characterized by wash-in in the arterial phase and wash-out in the delayed phase, compatible with residual disease. C) Follow-up CT scans performed on 15.05.2023 after treatment showed also other two nodules characterized by wash-in in the arterial phase (9 mm and 8.3 mm) and wash-out in the delayed phase.

Figure 3.

Computed tomography (CT) scans. A) CT scans performed on 28.06.2021 before treatment showed in hepatic segments V-VIII a lesion consisting of multiple confluent nodules of overall dimension of 100´70 mm, hypervascular in the arterial phase and hypodense in the delayed phase. B) Follow-up CT scans performed on 05.10.2021 after treatment showed HCC with confluent nodules in segments V-VIII, decreased in size (70×50 mm).

Figure 4.

Computed tomography (CT) scans. A) CT scans performed on 20.05.2021 before treatment showed in hepatic segments VIII-V an encapsulated nodule (59×55 mm) characterized by a contextual necrotic component and an intense enhancement area in the arterial phase that shows modest wash-out in the following phases. B) Follow-up CT scans performed on 16.09.2021 after treatment showed a colliquative necrosis area after treatment.

Figure 5.

Computed tomography (CT) scans. A) CT scans performed on 29.08.2023 before treatment showed in hepatic segments V-VI an encapsulated nodule (100×80 mm) characterized by a large central colliquative necrotic area and some peripheral solid components which showed intense enhancement in the arterial phase and rapid washout in the portal phase. B) Follow-up CT scans performed on 10.01.2024 after treatment showed a predominantly necrotic nodule (80×60 mm) with some smaller residual peripheral solid component.

Figure 6.

Computed tomography (CT) scans. A) CT scans performed on 06.09.2022 before treatment showed on the left lobe a nodule characterized by wash-in in arterial phase and wash-out in delayed phase (91×78 mm). B) Follow-up CT scans performed on 24.02.2023 after treatment showed a big liver lesion characterized by inhomogeneous enhancement, increased in size (100×73 mm).

Discussion

Treatment of HCC depends on tumor burden, liver function, performance status, and therapeutic goals (20). SIRT, initially used with palliative intent in advanced or treatment-refractory disease, has progressively evolved into a therapeutic option across different disease stages, including earlier settings (20, 21). Increasing evidence supports its curative potential and its role as a bridge to surgical therapies, with outcomes comparable to resection in selected patients and favorable survival, local control, and safety profiles, as confirmed by the LEGACY study (22, 23). In more advanced disease, the DOSISPHERE trial demonstrated that personalized dosimetry with higher tumor-absorbed doses significantly improves survival, highlighting the importance of selective delivery and individualized planning to optimize SIRT outcomes (23). According to recent BCLC updates, SIRT may be used with curative intent in very-early and early-stage disease as an alternative to ablation or resection, particularly in elderly patients, those with contraindications to surgery, difficult-to-treat nodules, or as a bridge to surgery (24). In intermediate-stage disease, SIRT is commonly applied after transarterial chemoembolization failure but is increasingly adopted as a first-line option in selected patients (25). Owing to the small size of microspheres and its limited ischemic effect, SIRT represents a suitable treatment option for patients with portal vein thrombosis, in whom other embolic therapies may be contraindicated (26). Although SIRT-related adverse events have been reported, including liver failure, biliary complications, post-embolization syndrome, gastrointestinal injury, and radiation-induced pneumonitis, appropriate patient selection and procedural planning substantially reduce these risks (6). Voxel-based and personalized dosimetry are key to optimizing tumor control while limiting liver toxicity, with established tumor dose-response relationships and non-tumoral liver dose thresholds, although variability across post-hoc and prospective studies highlights the need for further refinement and prospective validation (19, 27, 28). Survival outcomes are consistent across BCLC stages, with median overall survival ranging from approximately 24-27 months in early-stage disease, 16-18 months in intermediate-stage disease, and 7-13 months in advanced-stage disease (29). Beyond disease control, SIRT is effective for tumor downstaging and as a bridge to liver transplantation, providing additional benefits such as rapid tumor shrinkage, prolonged time to progression, limited post-embolization syndrome, and contralateral liver hypertrophy, while also contributing to biological selection of transplant candidates during waiting periods (30-32).

Conclusion

In conclusion, despite the limitations of a small, single-center retrospective cohort, our findings support the effectiveness of SIRT across diverse clinical scenarios in HCC, with a high rate of clinical benefit and a favorable safety profile. The exploratory, purpose-driven analysis provides real-world insight into the multifaceted role of SIRT in clinical practice. While larger prospective studies are needed to refine patient selection and dosimetric thresholds, these results suggest that, when guided by meticulous personalized dosimetric planning, SIRT is a versatile and effective therapeutic option.

Conflicts of Interest

The Authors declare no conflicts of interest related to this study.

Authors’ Contributions

Conceptualization: G.F.; Methodology: G.F., R.F.; Investigation: G.F., R.F., M.S.; Data curation: G.F., M.S.; Formal analysis: G.F.; Resources: R.F.; Supervision: R.F.; Writing – original draft: G.F.; Writing – review and editing: all authors. All Authors read and approved the final manuscript.

Artificial Intelligence (AI) Disclosure

No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.