Transarterial Radioembolization in the Treatment of Hepatocellular Carcinoma and Combination Strategies

Abstract

Objectives

This review provides a comprehensive overview of transarterial radioembolization (TARE) using Yttrium-90 (Y-90), a minimally invasive locoregional therapy for HCC patients who are ineligible for surgical resection.

Material and methods

A narrative review of the literature was conducted using PubMed/MEDLINE and Scopus databases. Studies focusing on patient selection, technical aspects, dosimetry, safety, oncologic outcomes and combination strategies were included. Clinical guidelines, prospective and retrospective studies, and comparative analyses were synthesized. A total of 43 key publications were synthesized, including landmark randomized controlled trials (SARAH, SIRveNIB, DOSISPHERE-01), recent meta-analyses and current clinical practice guidelines from EASL, AASLD and ESMO.

Results

Transarterial radioembolization demonstrates high objective response rates and favorable survival outcomes across Barcelona Clinic Liver Cancer (BCLC) stages, with a favorable safety profile compared to systemic therapies. Personalized dosimetry approaches significantly improve response rates as demonstrated in the DOSISPHERE-01 trial. Combination strategies with immune checkpoint inhibitors and tyrosine kinase inhibitors show promising synergistic potential, supported by ongoing phase II/III trials including IMMUWIN, ROWAN and EMERALD-Y90.

Conclusions

Transarterial radioembolization is a safe and effective locoregional therapy for HCC, with expanding indications including radiation segmentectomy with curative intent, downstaging for transplantation and combination with systemic therapies. Future research should focus on optimal sequencing, personalized dosimetry thresholds and identification of patients who are most likely to benefit from combination approaches.

INTRODUCTION

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the most common primary cancer of the liver (1-5). The incidence of HCC has risen markedly due to cirrhosis, chronic viral hepatitis (B/C), alcohol, aflatoxins and metabolic conditions including non-alcoholic steatohepatitis (NASH) and diabetes. With chronic liver disease projected to increase, the HCC burden is expected to rise further (6-13). Current international guidelines, including those from the European Association for the Study of the Liver (EASL), the American Association for the Study of Liver Diseases (AASLD) and the European Society for Medical Oncology (ESMO), emphasize the importance of multidisciplinary management and stage-based treatment strategies in patients with HCC (8, 14-17). Liver transplantation was initially avoided in patients with HCC due to early reports of frequent tumor relapse. However, a landmark study by Mazzaferro et al. (1996) demonstrate that, when patients with very early-stage disease are carefully selected according to the Milan criteria, transplantation can achieve recurrence rates below 10% and survival rates comparable to recipients without cancer (18). Although surgical resection and transplantation remain the most definitive curative treatments, approximately 70% of patients are ineligible due to tumor size and location, coexisting comorbidities, or impaired liver function (1, 4, 7, 8, 11, 16). Ablation can eradicate disease but is limited to small tumors in accessible locations. Consequently, alternative locoregional approaches have gained prominence. Yttrium-90 (Y-90) radioembolization (TARE) has emerged as a valuable treatment modality for unresectable HCC, serving both as a primary treatment and as a bridging or downstaging strategy to enable transplantation or resection (1, 4, 6-8, 11, 16, 17). With screening programs identifying more small tumors at earlier stages, regional therapies are expected to assume an increasingly central role in HCC management.

The Barcelona Clinic Liver Cancer (BCLC)

The Barcelona clinic liver cancer (BCLC) staging system integrates tumor burden, liver function and performance status for prognostic and therapeutic allocation in HCC (5, 19). The 2022 update emphasizes individualized decision-making, incorporating the albumin-bilirubin (ALBI) score alongside Child-Pugh classification (5). While early-stage disease (BCLC 0-A) continues to be managed with curative-intent strategies including resection, ablation, or transplantation, intermediate-stage disease (BCLC B) is recognized as a heterogeneous group requiring treatment tailoring rather than a uniform approach (5, 19). Although transarterial chemoembolization (TACE) remains the standard recommendation, alternative locoregional modalities, including radioembolization, may be appropriate in selected patients depending on tumor distribution, liver function, and technical feasibility (3, 17, 20-22). For advanced disease (BCLC C), systemic therapy constitutes the mainstay of treatment, with immune checkpoint inhibitor-based combinations now considered first-line options (15). The stage-specific treatment allocation and the potential integration of TARE are summarized in Table 1.

Importantly, the updated BCLC strategy introduces the concepts of "treatment stage migration" and multidisciplinary clinical decision-making, acknowledging that therapeutic allocation should not be strictly stage-restricted but rather adapted to individual patient characteristics and response patterns. This flexible approach supports the integration of TARE across different stages, particularly for patients unsuitable for resection or chemoembolization, those with portal vein tumor thrombosis, or in downstaging and bridging settings prior to transplantation (5, 19). Consequently, the BCLC 2022 framework provides a practical basis for incorporating personalized locoregional therapies such as TARE within contemporary HCC management algorithms.

Transarterial radioembolization (TARE) procedure

Transarterial radioembolization is a catheter-based therapy used to treat primary and metastatic liver tumors. During this procedure, an interventional radiologist delivers Y-90–loaded microspheres directly into the arteries feeding the cancer. Because HCC draws most of its blood supply from the hepatic artery, this targeted approach allows very high radiation exposure to the tumor while largely sparing healthy liver tissue. Although TACE is traditionally the standard treatment for intermediate-stage (BCLC B) HCC, TARE has become increasingly important. Despite being used in patients with more advanced disease, TARE provides longer time to progression, fewer side effects and better quality of life. It is also effective in patients with portal vein thrombosis, where TACE is often contraindicated and can serve as an alternative to ablation or as a bridge to surgery in early-stage tumors (8, 15, 19, 23).

Patient selection

Appropriate candidates undergo clinical evaluation, laboratory tests, cross-sectional imaging and angiography with a macroaggregated albumin (MAA) lung shunt study. Imaging includes chest computed tomography (CT), either a CT or magnetic resonance (MR) scan of the abdomen, and bone scan. Ideal candidates have HCC confined to the liver with tumor comprising less than 70% of the liver volume. Patients with prior intervention in the biliary tract may require prophylactic antibiotics. Inclusion and exclusion criteria are listed in Table 2 (24).

Suitable patients generally have an ECOG performance status of 0–2; bilirubin ≤ 2 mg/dL (segmental therapy may be used selectively if higher); and liver-limited disease involving <70% of the liver volume (3, 10, 17). The following algorithm summarizes a practical stepwise approach derived from the reviewed evidence (Figure 1).

TABLE 1.

Barcelona Clinic Liver Cancer staging system (2022 update) and stage-oriented treatment strategies with potential integration of transarterial radioembolization

TABLE 2.

Patient inclusion and exclusion criteria (27)

FIGURE 1.

Proposed clinical decision-making algorithm for patient selection and treatment planning with transarterial radioembolization (TARE) in hepatocellular carcinoma, integrating Barcelona Clinic Liver Cancer (BCLC) staging, liver function and tumor burden

Pre-treatment evaluation

Transarterial radioembolization requires two angiographic sessions. The first one maps the hepatic arterial anatomy, identifies vessels supplying other organs and evaluates lung shunting. Significant uptake in the gastrointestinal tract must be eliminated, often with selective coiling. A lung shunt fraction >20% or anticipated lung dose >30 Gy contraindicates treatment. After MAA imaging determines dosimetry, typically targeting >120 Gy to the tumor and <20 Gy to the lungs, the second session delivers the calculated Y-90 dose. Because Y-90 emits only beta radiation over a very short range, the procedure does not require radiation shielding and post-embolization symptoms are minimal (3, 8, 10, 17, 19, 24, 25).

Dosimetry and personalized treatment planning

Accurate dosimetry is essential for maximizing treatment efficacy while minimizing toxicity. Three principal dosimetric approaches are currently utilized in clinical practice, as detailed below.

Body surface area (BSA) method – An empirical approach calculating activity based on patient BSA and tumor involvement. Simple but not accounting for individual variations in vascularity or liver volume, partly explaining the negative results of early trials (6, 7, 26).

Partition model – A more refined approach estimating absorbed doses to the tumor, normal liver and lungs based on the distribution of technetium-99m MAA on pre-treatment imaging. The partition model considers the tumor-to-normal liver ratio and provides a more individualized dose estimation compared to BSA-based methods. However, it relies on the assumption that MAA distribution accurately reflects Y-90 microsphere distribution, which may not always hold true (6, 7, 26).

Voxel-based dosimetry – The most advanced approach utilizing three-dimensional imaging data to calculate dose distributions on a voxel-by-voxel basis using post-treatment positron emission tomography (PET)/CT or bremsstrahlung single-photon emission CT (SPECT). It enables precise calculation of tumor-absorbed doses and normal tissue exposure, facilitating truly personalized treatment planning. This approach has been associated with superior tumor response rates and reduced toxicity compared to conventional methods (6, 7, 26).

The clinical importance of personalized dosimetry was definitively demonstrated in the DOSISPHERE-01 trial, a randomized open-label multicentre phase 2 study that compared personalized versus standard dosimetry in patients with locally advanced HCC (2). The study showed that personalized dosimetry with a tumor-absorbed dose threshold of ≥205 Gy significantly improved objective response rates (71% vs. 35%, p<0.001) and overall survival (median 26.6 vs. 10.7 months, p=0.009) compared with standard methods (6). These findings have fundamentally altered clinical practice, establishing personalized dosimetry as the standard of care in TARE treatment planning.

Current European Association of Nuclear Medicine (EANM) guidelines recommend personalized dosimetry approaches, particularly the partition model and voxel-based methods, for all patients undergoing TARE (15). The optimal tumor-absorbed dose target is generally considered to be >200 Gy for HCC, with normal liver doses maintained below 70 Gy for whole-liver treatment and lung doses below 30 Gy per treatment session (6, 7, 26).

Techniques and applications

Radiation lobectomy (RL) – It is a technique that promotes an atrophy–hypertrophy complex in which the treated hepatic lobe progressively atrophies while the untreated lobe undergoes compensatory hypertrophy; as a result, this can convert patients with initially insufficient future liver remnant (FLR) to surgical candidates, with FLR thresholds typically exceeding 20% in individuals without underlying parenchymal disease and 40% in those with cirrhosis. Radiation lobectomy is performed with glass microspheres at doses of approximately 120–150 Gy. It promotes FLR hypertrophy and treating the tumor at the same time, induces gradual lobar atrophy through slow scarring, resulting in a more delayed shift in portal flow in contrast to portal vein embolization which may stimulate tumor progression. Radiation lobectomy compared with the abrupt diversion seen in embolization, FLR hypertrophy after RL is time dependent and typically slower. Importantly, the period of hypertrophy also serves as a biologic "test-of-time", as patients who demonstrate radiologic response or absence of progression during this interval exhibit more favorable tumor biology and are better candidates for resection (3, 5, 11, 17, 28).

Radiation segmentectomy (RS) – This technique aims to achieve ablative tumor therapy with adequate margin to target potential adjacent satellite lesions, reducing the risk of marginal recurrence, with the optimal results being seen in patients with Child-Pugh class A disease with solitary peripheral tumors that measure >8 cm. In contrast to other ablative therapies, needle-track seeding, hepatic injury and arterioportal fistula are avoided, while treating areas that are difficult or unsafe to access by percutaneous ablation, such as the hepatic dome, caudate lobe, hilum and locations adjacent to vessels and bile ducts (3, 5, 11, 17, 29).

Safety and complications

Recent years have seen a decline in TARE-related complications, largely due to improved patient selection, better familiarity with the devices and advances in angiographic techniques such as cone-beam CT. Transarterial radioembolization is often completed on an outpatient basis, and fatigue remains the most frequent post-procedure symptom. Severe adverse events caused by unintended radiation exposure – including gastrointestinal ulceration, radiation pneumonitis, cholecystitis due to irradiation, or skin injury – are now uncommon. Liver dysfunction related to radioembolization as well as perihepatic fluid collections or pleural effusions is mainly observed in patients with poor hepatic reserve who undergo lobar or sequential-lobar approaches and is less typical after segmental therapy. Additional issues, such as biliary necrosis, bilomas, or hepatic abscesses, tend to occur more often in metastatic liver disease than in primary HCC (3, 17, 30, 31).

Post-TARE assessment

After TARE treatment, the appearance of the treated lesion on imaging can be misleading, especially during the first weeks. Hemorrhage, necrosis, inflammation, or edema within the tumor can cause it to remain the same size or even appear larger than before treatment. This early swelling contributes to what is known as pseudoprogression, a temporary increase in tumor size that typically emerges about four to five weeks after therapy and may persist for several months. Because of these changes, imaging performed too soon after TARE often does not reflect the true treatment effect. Instead, the absence of contrast enhancement – suggesting tumor necrosis – offers a more dependable early indicator of response. Tumor size alone is therefore insufficient for evaluation and must be interpreted alongside other radiologic features. Over time, most lesions gradually decrease in diameter, but this reduction should always be assessed in combination with the broader imaging pattern rather than taken as an isolated sign of success (3, 8, 17, 31).

Outcomes

Several clinical studies have demonstrated favorable tumor response and survival outcomes following TARE. High objective response rates, prolonged time-to-progression and comparable overall survival to TACE have been reported, with improved tolerability and quality of life.

SARAH trial – TARE vs sorafenib in advanced HCC; no overall survival (OS) difference (8.0 vs. 9.9 months, p=0.18); and TARE showing better safety (grade ≥3: 43% vs. 67%, p<0.001) and quality of life (19, 32).

SIRveNIB trial – This Asia-Pacific phase III trial (n=230) compared TARE with sorafenib in patients with advanced HCC (14). Overall survival was comparable between groups (median OS 8.8 vs. 10.0 months, p=0.36). TARE demonstrated a favorable safety profile with fewer treatment-related adverse events and better quality of life scores (4).

DOSISPHERE-01 – As described above, this randomized phase II trial demonstrated the critical importance of personalized dosimetry, showing significantly improved objective response rates (71% vs. 35%, p<0.001) and OS (26.6 vs. 10.7 months, p=0.009) with a personalized approach targeting ≥205 Gy to the tumor (6).

LEGACY study – This multicenter retrospective study evaluated radiation segmentectomy in 162 patients with solitary unresectable HCC (11). The objective response rate was 88%, with a complete response rate of 54%. Median OS was 17-20 months, supporting the potential curative role of RS in appropriately selected patients (2).

TARE vs. TACE comparative studies – Multiple comparative analyses have demonstrated that TARE provides longer time-to-progression compared to TACE, with fewer side effects and better quality of life (1, 3, 17, 30, 33). In a meta-analysis of comparative studies, TARE was associated with superior objective response rates (OR 1.57, 95% CI 1.08-2.28, p=0.02) and similar OS compared to TACE (1). Transarterial radioembolization has also demonstrated efficacy in patients with portal vein thrombosis, where TACE is often contraindicated (1, 3, 17, 34).

Subgroup analyses – Response rates vary by BCLC stage. In BCLC B disease, objective response rates range from 40-75% depending on tumor burden and dosimetry approach. In BCLC C disease with portal vein thrombosis, response rates are lower but still clinically meaningful at 30-50%, with median survival ranging from 12-18 months in selected patients (4, 6, 9).

Combination therapies

Transarterial radioembolization and immune checkpoint inhibitors (ICIs) – TARE-ICI synergy relies on radiation-induced immunogenic cell death, releasing tumor antigens and damage-associated molecular patterns (DAMPs) that stimulate systemic anti-tumor immunity. Activated T cells show increased PD-1/LAG-3 expression and ICIs may sustain this response (20, 21, 30, 35-38). Notably, the largest rise in checkpoint-expressing T cells occurs approximately one month after radioembolization, which may represent the ideal time to initiate ICI therapy to enhance both immune and clinical outcomes (30). A case report by Ceren et al. described the successful use of TARE alongside immunotherapy in managing HCC, suggesting that the two modalities can complement one another (39).

Transarterial radioembolization and tyrosine kinase inhibitors (TKIs) – Combining TARE with TKIs such as sorafenib or lenvatinib represents another promising strategy, with anti-angiogenic synergy as the underlying rationale. Several retrospective and single-arm studies have reported encouraging outcomes, though prospective data remain limited. The potential for increased hepatotoxicity requires careful patient selection and monitoring (21, 36, 22, 40).

Transarterial radioembolization in NASH-related HCC – Patients with non-alcoholic steatohepatitis (NASH)-related HCC represent an increasingly important subgroup with distinct clinical characteristics, including older age, higher prevalence of metabolic comorbidities and preserved liver function despite advanced fibrosis. Transarterial radioembolization has been safely used in this population, though specific data on outcomes in NASH-related HCC are limited. The presence of significant cardiovascular risk factors in these patients requires careful pre-treatment cardiovascular assessment (17, 41).

Transarterial radioembolization as downstaging strategy – TARE has been successfully used as a downstaging strategy to convert patients with HCC beyond Milan criteria to transplant eligibility. Response rates of 40-60% have been reported, with successful downstaging achieved in approximately 30-50% of patients. The median time to downstaging is typically 3-6 months and the post-transplant outcomes in successfully downstaged patients are comparable to those of patients initially meeting Milan criteria (3, 8, 17, 42).

Transarterial radioembolization TARE post-ICI progression – In patients who progress on first-line ICI-based systemic therapy, TARE may serve as a consolidation or salvage strategy for liver-dominant disease. This approach leverages the potential for radiation-induced immune priming to restore or enhance anti-tumor immunity. Early retrospective data suggest that TARE can be safely administered after ICI therapy, though careful attention to liver function is required as these patients may have compromised hepatic reserve (21, 39).

Transarterial radioembolization TARE in the post-transplant setting – The role of TARE in post-transplant patients is limited, but it may be considered for recurrent HCC in the liver allograft when surgical options are not feasible. Due to immunosuppression and the risk of hepatic artery complications in transplanted livers, this approach requires multidisciplinary evaluation and should be considered experimental (8, 9).

The proposed combination strategies and their clinical rationale are summarized in Table 3. Ongoing clinical trials are listed in Table 4.

TABLE 3.

Combination strategies

TABLE 4.

Ongoing clinical trials of TARE combination strategies

DISCUSSION

TARE vs TACE vs ablation: comparative effectiveness across BCLC stages

Transarterial radioembolization offers several advantages over TACE: minimal ischemic injury, enabling treatment of patients with portal vein thrombosis; longer time-to-progression; fewer side effects; and better quality of life (3, 17, 30). In BCLC B, TARE and TACE provide comparable OS, though TARE shows superior response rates and tolerability (1, 30, 33). In BCLC A, segmentectomy achieves >80% response rates, expanding options for non-surgical candidates (2, 3, 17).

Personalized dosimetry and trial interpretation

Negative results of SARAH and SIRveNIB may reflect conventional non-personalized dosimetry (4, 32). DOSISPHERE-01 demonstrated that personalized dosimetry (≥205 Gy) significantly improved response (71% vs 35%) and OS (26.6 vs 10.7 months), establishing it as standard of care (6, 7, 26).

Combination strategies and future directions

TARE-ICI combinations are promising, supported by robust rationale and ongoing trials (IMMUWIN, ROWAN, EMERALD-Y90) (20, 21, 30, 37, 43). TARE-TKI combinations require further study due to hepatotoxicity concerns (21, 39). Key unresolved questions include optimal sequencing, ideal tumor dose, patient selection, and integration with first-line ICI therapy (5, 15, 21, 37).

CONCLUSION

Transarterial radioembolization with Yttrium-90 has demonstrated safety and efficacy as locoregional therapy for hepatocellular carcinoma in patients who are not candidates for surgical resection. Evidence supports its use across all BCLC stages, offering meaningful tumor control while minimizing systemic toxicity. Advances in patient selection, imaging and dosimetry have further improved outcomes and reduced complications.

Combining Y-90 TARE with systemic therapies, including immunotherapy, shows promise for enhancing anti-tumor efficacy and personalizing treatment. Continued research and prospective studies are essential to optimize these approaches, refine patient selection and expand therapeutic options, ultimately improving survival and quality of life for HCC patients.

Conflicts of interest

none declared.

Financial support

none declared.