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Page 10 of 15 Hall et al. Hepatoma Res. 2026;12:20

modifications or supportive care. This degree of monitoring is facilitated by a multidisciplinary approach.

TREATMENT SEQUENCING AND OPTIMIZATION
Determining the optimal sequencing and timing of Y-90 radioembolization in combination with systemic
therapies remains a critical and actively investigated area in HCC management. The complexity of tumor
biology, patient heterogeneity, and treatment-related toxicities necessitates a strategic approach to maximize
therapeutic benefit while minimizing adverse effects.

Sequential therapy
One approach is to use Y-90 radioembolization as the initial locoregional intervention, followed by systemic
therapy. This sequence allows for significant tumor debulking through localized radiation, potentially
reducing tumor burden and vascularity, which may subsequently enhance the efficacy of systemic agents.
Clinical studies frequently initiate systemic therapy approximately 2 to 4 weeks after Y-90 treatment, a
window that balances sufficient recovery from procedure-related toxicities and early intervention against
micro-metastatic or residual disease [49,50] . This approach aims to exploit the distinct mechanisms of action
sequentially: radiation to induce direct tumor cytotoxicity and vascular disruption, followed by systemic
inhibition of tumor proliferation and metastasis.

Concurrent therapy
Synchronous administration of Y-90 and systemic agents represents an appealing strategy to maximize
potential synergy. The rationale centers on the ability of concurrent systemic agents to augment
radiation-induced effects, such as preventing angiogenic rebound and enhancing immune-mediated tumor
cell killing. However, the concomitant use of these treatments may increase the risk and severity of toxicities,
including liver dysfunction, fatigue, and irAEs. Existing data on concurrent administration are limited,
largely derived from small cohorts and early-phase trials, underscoring the need for well-designed
prospective studies to evaluate safety profiles, optimal dosing, and clinical efficacy in this setting.

Personalized strategies
Personalized therapeutic approaches are becoming increasingly integrated into treatment sequencing
decisions. Biomarkers such as alpha-fetoprotein (AFP) levels, which correlate with tumor burden and
biological aggressiveness, can inform prognosis and response to therapy [31,51] . Radiological response
assessments using modified Response Evaluation Criteria in Solid Tumors (mRECIST) provide early
indicators of treatment efficacy and may guide subsequent therapy initiation or modification . Moreover,
[52]
advances in immune profiling - including tumor-infiltrating lymphocyte (TIL) characterization and
circulating immune markers - hold promise for predicting responsiveness to immunotherapy and tailoring
combination regimens . Leveraging these biomarkers may enable clinicians to individualize timing and
[53]
agent selection, potentially improving outcomes and reducing unnecessary toxicity.

REAL-WORLD EXPERIENCES AND FUTURE DIRECTIONS
Data derived from registries and retrospective analyses have provided invaluable insights into the practical
application of Y-90 radioembolization combined with systemic therapies in diverse, heterogeneous patient
populations. These data generally corroborate findings from controlled clinical trials, affirming the
feasibility, safety, and efficacy of combination approaches outside the confines of tightly regulated study
settings. These data highlight critical factors influencing outcomes, particularly patient selection criteria.
Patients with well-preserved liver function (Child-Pugh class A) and limited intrahepatic tumor burden
consistently demonstrate the most favorable responses, underscoring the need for careful assessment of
hepatic reserve and disease extent before treatment initiation. Moreover, these datasets reveal manageable
toxicity profiles even among patients with greater comorbidity and advanced disease, lending support to