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PURPOSE: Pre-treatment [(99m)Tc]TcMAA-based radioembolization treatment planning using multicompartment dosimetry involves the definition of the tumor and normal tissue compartments and calculation of the prescribed absorbed doses. The aim was to compare the real-world utility of anatomic and [(99m)Tc]TcMAA-based segmentation of tumor and normal tissue compartments. MATERIALS AND METHODS: Included patients had HCC treated by glass [(90)Y]yttrium microspheres, ≥ 1 tumor, ≥ 3 cm diameter and [(99m)Tc]TcMAA SPECT/CT imaging before treatment. Segmentation was performed retrospectively using dedicated dosimetry software: (1) anatomic (diagnostic CT/MRI-based), and (2) [(99m)Tc]TcMAA threshold-based (i.e., using an activity-isocontour threshold). CT/MRI was co-registered with [(99m)Tc]TcMAA SPECT/CT. Logistic regression and Cox regression, respectively, were used to evaluate relationships between total perfused tumor absorbed dose (TAD) and objective response rate (ORR) and overall survival (OS). In a subset-analysis pre- and post-treatment dosimetry were compared using Bland-Altman analysis and Pearson’s correlation coefficient. RESULTS: A total of 209 patients were enrolled. Total perfused tumor and normal tissue volumes were larger when using anatomic versus [(99m)Tc]TcMAA threshold segmentation, resulting in lower absorbed doses. mRECIST ORR was higher with increasing total perfused TAD (odds ratio per 100 Gy TAD increase was 1.22 (95% CI: 1.01-1.49; p = 0.044) for anatomic and 1.19 (95% CI: 1.04-1.37; p = 0.012) for [(99m)Tc]TcMAA threshold segmentation. Higher total perfused TAD was associated with improved OS (hazard ratio per 100 Gy TAD increase was 0.826 (95% CI: 0.714-0.954; p = 0.009) and 0.847 (95% CI: 0.765-0.936; p = 0.001) for anatomic and [(99m)Tc]TcMAA threshold segmentation, respectively). For pre- vs. post-treatment dosimetry comparison, the average bias for total perfused TAD was + 11.5 Gy (95% limits of agreement: -227.0 to 250.0) with a strong positive correlation (Pearson’s correlation coefficient = 0.80). CONCLUSION: Real-world data support [(99m)Tc]TcMAA imaging to estimate absorbed doses prior to treatment of HCC with glass [(90)Y]yttrium microspheres. Both anatomic and [(99m)Tc]TcMAA threshold methods were suitable for treatment planning. TRIAL REGISTRATION NUMBER: NCT03295006.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and third leading cause of cancer-related mortality worldwide. While surgical resection and transplantation are the standard first-line treatments for early-stage HCC, most patients do not fulfill criteria for surgery. Fortunately, catheter-directed and percutaneous locoregional approaches have evolved as major treatment modalities for unresectable HCC. Improved outcomes have been achieved with novel techniques which can be employed for diverse applications ranging from curative-intent for small localized tumors, to downstaging or bridging to resection and transplantation for early and intermediate disease, and locoregional control and palliation for advanced disease. This review explores recent advances in liver-directed techniques for HCC including bland transarterial embolization, chemoembolization, radioembolization, and ablative therapies, with a focus on patient selection, procedural technique, periprocedural management, and outcomes.

Abstract PurposeIn light of recently published clinical reports and trials, the TheraSphere Global Dosimetry Steering Committee (DSC) reconvened to review new data and to update previously published clinical and dosimetric recommendations for the treatment of hepatocellular carcinoma (HCC).MethodsThe TheraSphere Global DSC is comprised of health care providers across multiple disciplines involved in the treatment of HCC with yttrium-90 (Y-90) glass microsphere–based transarterial radioembolization (TARE). Literature published between January 2019 and September 2021 was reviewed, discussed, and adjudicated by the Delphi method. Recommendations included in this updated document incorporate both the results of the literature review and the expert opinion and experience of members of the committee.ResultsCommittee discussion and consensus led to the expansion of recommendations to apply to five common clinical scenarios in patients with HCC to support more individualized efficacious treatment with Y-90 glass microspheres. Existing clinical scenarios were updated to reflect recent developments in dosimetry approaches and broader treatment paradigms evolving for patients presenting with HCC.ConclusionUpdated consensus recommendations are provided to guide clinical and dosimetric approaches for the use of Y-90 glass microsphere TARE in HCC, accounting for disease presentation, tumor biology, and treatment intent.

Purpose To investigate the relationships between tumor absorbed dose (TAD) or normal tissue absorbed dose (NTAD) and clinical outcomes in hepatocellular carcinoma (HCC) treated with yttrium-90 glass microspheres. Methods TARGET was a retrospective investigation in 13 centers across eight countries. Key inclusion criteria: liver-dominant HCC with or without portal vein thrombosis, < 10 tumors per lobe (at least one ≥ 3 cm), Child–Pugh stage A/B7, BCLC stages A–C, and no prior intra-arterial treatment. Multi-compartment pre-treatment dosimetry was performed retrospectively. Primary endpoint was the relationship between ≥ grade 3 hyperbilirubinemia (such that > 15% of patients experienced an event) without disease progression and NTAD. Secondary endpoints included relationships between (1) objective response (OR) and TAD, (2) overall survival (OS) and TAD, and (3) alpha fetoprotein (AFP) and TAD. Results No relationship was found between NTAD and ≥ grade 3 hyperbilirubinemia, which occurred in 4.8% of the 209 patients. The mRECIST OR rate over all lesions was 61.7%; for the target (largest) lesion, 70.8%. Responders and non-responders had geometric mean total perfused TADs of 225.5 Gy and 188.3 Gy ( p  = 0.048). Probability of OR was higher with increasing TAD ( p  = 0.044). Higher TAD was associated with longer OS (HR per 100 Gy increase = 0.83, 95% CI: 0.71–0.95; p  = 0.009). Increased TAD was associated with higher probability of AFP response ( p  = 0.046 for baseline AFP ≥ 200 ng/mL). Conclusion Real-world data confirmed a significant association between TAD and OR, TAD and OS, and TAD and AFP response. No association was found between ≥ grade 3 hyperbilirubinemia and NTAD. Trial registration number NCT03295006.

Radioembolization with 90Y-labeled microspheres is an established locoregional therapy for primary and metastatic liver tumors, yet the molecular mechanisms underlying tumor response and resistance, particularly within hypoxic tumor microenvironments, remain poorly understood. Here, we developed an in vitro model of 90Y-microsphere irradiation to investigate the effects of beta radiation under normoxic and hypoxic conditions in human colon cancer (HCT 116), hepatocellular carcinoma (HepG2), and non-malignant liver (THLE2) cell lines. Cells were exposed to two microsphere dilutions, and absorbed doses were estimated using FLUKA-based Monte Carlo simulations. Cellular viability, proliferation, apoptosis-related gene expression, and secretion of angiogenic and inflammatory mediators were assessed. 90Y-microspheres exerted both cytotoxic and cytostatic effects in a cell type- and oxygen-dependent manner. In HCT 116 cells, radiation reduced metabolic activity and proliferation and induced Bax expression in normoxia, whereas hypoxia conferred radioresistance associated with Bcl-2 upregulation. HepG2 cells displayed pronounced resistance, with preserved viability but marked inhibition of proliferation, indicating a predominantly cytostatic response that was further attenuated by hypoxia. In contrast, THLE-2 cells were radiosensitive, showing reduced proliferation and increased Bax expression, while hypoxia partially protected against radiation-induced damage. Both hypoxia and microsphere exposure promoted a pro-angiogenic phenotype, characterized by increased VEGF secretion in radiosensitive tumor and healthy cells, whereas resistant HepG2 cells exhibited angiogenic signaling linked to TIMP2 suppression and IL-8 induction. Collectively, our findings demonstrate that hypoxia diminishes cellular sensitivity to 90Y beta radiation while fostering a microenvironment conducive to tumor progression. This in vitro model provides mechanistic insight into radioembolization responses and may support the development of more personalized therapeutic strategies.

To evaluate the feasibility of streamlined radioembolization using yttrium-90 resin microspheres without lung shunt fraction (LSF) assessment in patients with intrahepatic cholangiocarcinoma (ICC). This single-center retrospective study included 23 patients with ICC who underwent radioembolization using resin microspheres (SIR-Spheres; SIRTEX, Woburn, MA, USA) without LSF measurement between April 2022 and April 2025. Eligibility criteria, based on prior institutional data, included a target tumor size less than 10 cm, absence of hepatic vein invasion and intratumoral dysmorphic vessels, and an institutional waiting time exceeding one week for macroaggregated albumin scintigraphy. All patients had at least one follow-up imaging study. Radiation activity was prescribed according to tumor location, liver function, and clinical setting, using both single-compartment and multi-compartment dosimetry under the assumptions of a 5% LSF and a tumor-to-normal (TN) ratio of 3. Post-treatment yttrium-90 PET/CT dosimetry was performed in 12 patients. Treatment-related toxicity, tumor response, and local tumor progression-free survival were analyzed. The median administered activity was 1.43 GBq (interquartile range, 0.89-2.15). The median mean absorbed dose to the perfused tissue was 147 Gy, and the median tumor absorbed dose (TAD) was 339 Gy, assuming a TN ratio of 3. Post-treatment PET/CT analysis demonstrated a median TAD of 371 Gy and a median TN ratio of 4.7. No patient developed symptomatic radiation pneumonitis. Best tumor response was partial response in 52% of patients and stable disease in 48%. Local tumor progression-free survival rates at six months, one year, and two years were 95.2%, 81.1%, and 81.1%, respectively. Streamlined radioembolization without LSF assessment appears feasible and may represent a practical alternative to conventional multi-step workflows in patients with ICC measuring less than 10 cm.

To investigate dosimetry-derived tumor-to-perfused normal tissue ratio (T/N) and corresponding clinical outcomes of patients receiving yttrium-90 radioembolization with glass microspheres for tumors identified as hypovascular on arterial-phase cross-sectional imaging. Patients with hypovascular lesions undergoing 90 Y-RE at a single institution were included. Inclusion criteria were hypodense or hypoattenuating tumors relative to normal liver on arterial phase CT or MRI, excluding necrotic tumors. Pre-treatment planning mapping angiography 99mTc-MAA SPECT/CT was used for multi-compartment dosimetry for T/N estimation. The final cohort comprised 27 patients (median age 68, range 52–85 years), including 13 with Child-Pugh A cirrhosis, and ECOG status of 0 ( n  = 15), 1 ( n  = 11), and 2 ( n  = 1). Tumor types were hepatocellular carcinoma ( n  = 11), intrahepatic cholangiocarcinoma ( n  = 8), and liver metastases ( n  = 8). Treatment strategies included lobar (19%), lobar plus segmentectomy (22%), single segmentectomy (33%) and multiple segmentectomies (30%). The mean index tumor size was 5.7 ± 3.2 cm. Mean tumor and perfused normal tissue doses were 480 ± 314 Gy and 270 ± 138 Gy, respectively. Median T/N ratio on planning SPECT/CT was 1.56 (range 0.28–4.79). Response assessments using mRECIST criteria for index lesions were complete response (41%), partial response (33%), stable disease (22%), and progressive disease (4%). Nine patients experienced Grade 1 adverse events (ALP, ALT, or AST serum markers) with no other adverse events. Calculated T/N ratios were greater than 1.00 for most patients with hypovascular tumors, indicating that tumor uptake of 90 Y may be greater than perceived from arterial-phase cross-sectional imaging. Post-treatment follow-up demonstrated favorable outcomes for this patient population.

Abstract Background Combination checkpoint inhibition therapy with yttrium-90 (Y90) radioembolization represents an emerging area of interest in the treatment of advanced hepatocellular carcinoma (HCC). HCRN GI15-225 is an open-label, single-arm multicenter, pilot study (NCT03099564). Methods Eligible patients had poor prognosis, localized HCC defined as having portal vein thrombus, multifocal disease, and/or diffuse disease that were not eligible for liver transplant or surgical resection. Patients received pembrolizumab 200 mg intravenously every 3 weeks in conjunction with glass yttrium-90 (Y90) radioembolization TheraSphere. Primary endpoint was 6-month progression-free survival (PFS6) per RECIST 1.1. Secondary endpoints included time to progression (TTP), objective response rate (ORR), overall survival (OS), and safety/tolerability. Results Between October 23, 2017 and November 24, 2020, 29 patients were enrolled: 2 were excluded per protocol. Fifteen of the remaining 27 patients were free of progression at 6 months (55.6%; 95% CI, 35.3-74.5) with median PFS 9.95 months (95% CI, 4.14-15.24) and OS 27.30 months (95% CI, 10.15-39.52). One patient was not evaluable for response due to death; among the remaining 26 patients, ORR was 30.8% (95% CI, 14.3-51.8) and DCR was 84.6% (95% CI, 65.1-95.6). Conclusion In patients with localized, poor prognosis HCC, pembrolizumab in addition to glass Y90 radioembolization demonstrated promising efficacy and safety consistent with prior observations (ClinicalTrials.gov Identifier: NCT03099564; IRB Approved: 16-3255 approved July 12, 2016). This pilot study explored whether using immunotherapy drugs in combination with locoregional therapies for patients with non-metastatic hepatocellular carcinoma is safe and beneficial, using pembrolizumab every 3 weeks starting 1 week before initial Y90 radioembolization.

The TheraSphere Global Dosimetry Steering Committee was formed in 2017 by BTG International to review existing data and address gaps in knowledge related to dosimetry. This committee is comprised of health care providers with diverse areas of expertise and perspectives on radiation dosimetry. The goal of these recommendations is to optimize glass microspheres radiation therapy for hepatocellular carcinoma while accounting for variables including disease presentation, tumour vascularity, liver function, and curative/palliative intent. The recommendations aim to unify glass microsphere users behind standardized dosimetry methodology that is simple, reproducible and supported by clinical data, with the overarching goal of improving clinical outcomes and advancing the knowledge of dosimetry.