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Hall et al. Hepatoma Res. 2026;12:20 Page 9 of 15

Table 3. Ongoing Y-90 combination therapy trials
Study
Trial ID Population Design Intervention Primary endpoint(s) Status
phase

Within MC: RRT defined by
Age ≥ 18 years and CT/MRI and decrease in AFP by ≥
NCT07059494 IV HCC within MC OR Parallel Y-90 + Atezolizumab + 50%ORBeyond MC: Rate of Recruiting
HCC beyond MC assignment Bevacizumab radiographic downstaging to within
MC
Y-90 + HAIC +
Age 18-74 years and Not yet
NCT06867432 II Single-arm Atezolizumab + ORR by mRECIST
unresectable HCC recruiting
Bevacizumab
Best objective
Age ≥18 years and Y-90 + Tremelimumab
NCT05809869 II Single-arm responseandobjective response Recruiting
HCC + Durvalumab
rate
HCC: Hepatocellular carcinoma; MC: Milan Criteria; Y-90: yttrium-90 radioembolization; RRT: response rate to treatment; AFP: alpha-fetoprotein;
HAIC: hepatic arterial infusion chemotherapy (specifically: oxaliplatin + fluorouracil + leucovorin); ORR: objective response rate; mRECIST: modified
Response Evaluation Criteria in Solid Tumors [8,40,41] .

Hepatic toxicity
Transient elevations in liver enzymes such as alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) are common following Y-90 treatment due to localized radiation-induced
hepatocyte injury and inflammation . These enzyme elevations are typically self-resolving and peak within
[43]
weeks of Y-90 treatment. Severe hepatic toxicity, including radiation-induced liver disease (RILD) or liver
failure, is rare when patients with preserved hepatic function, generally Child-Pugh class A or early B7, are
selected [43,44] . Therefore, combining Y-90 with systemic therapies, some of which have hepatotoxic potential,
necessitates close monitoring of hepatic function to detect early signs of hepatic decompensation and
manage accordingly.

Systemic toxicity of targeted agents
Targeted therapies such as sorafenib and lenvatinib present predictable systemic toxicities. Fatigue is among
the most common adverse effects reported, alongside hypertension and dermatologic toxicities, including
palmar-plantar erythrodysesthesia . These side effects are typically dose-dependent and manageable
[45]
through supportive care, dose adjustments, and patient education. Current evidence indicates that the
addition of Y-90 radioembolization does not exacerbate these systemic toxicities, supporting the safety of
combined regimens with appropriate monitoring .
[46]

Immune-related adverse events (irAEs) from ICIs
ICIs can induce immune-related adverse events (irAEs) due to nonspecific immune activation, with
manifestations such as immune-mediated hepatitis, colitis, pneumonitis, endocrinopathies, and dermatologic
reactions . While these events can be severe, timely recognition and immunosuppressive treatment are
[47]
often effective. Data suggest that combining ICIs with Y-90 radioembolization does not significantly increase
the frequency or severity of irAEs . The localized nature of radiation and judicious patient selection may
[48]
mitigate additive toxicity risks.

Patient selection and monitoring
Ensuring patient safety requires stringent selection criteria, favoring those with preserved liver function
(Child-Pugh A or selected B7) and good performance status (Eastern Cooperative Oncology Group, ECOG
0-1) [44,45] . Baseline evaluation of liver reserve, portal hypertension, and bilirubin levels informs candidacy and
risk stratification. Serial monitoring of liver enzymes, hematologic parameters, blood pressure, and
symptoms after treatment facilitates early detection of toxicities and guides timely interventions such as dose