Vox Voxel: Calculating Y90 Tumor Dose and Sphere Distribution with Voxel Dosimetry

Using Voxel-Based Dosimetry to Evaluate Sphere Concentration and Tumor Dose in Hepatocellular Carcinoma Treated with Yttrium-90 Radiation Segmentectomy with Glass Microspheres

Clinical question

How can we use voxel-based dosimetry to better understand sphere distribution and tumor dose in Y90 glass microsphere radiation segmentectomy; and does it validate the current literature on radiologic and pathologic outcomes following radiation segmentectomy?

Take away point

Voxel dosimetry is a crucial tool in better understanding of Y90 sphere activity/distribution and their effects on tumor treatment response and lasting oncologic outcomes. It is indispensable

Reference

Sandow, T., Gimenez, J., Nunez, K., Tramel, R., Gilbert, P., Oliver, B., Cline, M., Fowers, K., Cohen, A., & Thevenot, P. (2024). Using Voxel-Based Dosimetry to Evaluate Sphere Concentration and Tumor Dose in Hepatocellular Carcinoma Treated with Yttrium-90 Radiation Segmentectomy with Glass Microspheres. Journal of vascular and interventional radiology : JVIR, 35(11), 1602–1612.e1. https://doi.org/10.1016/j.jvir.2024.05.020

Click here for the full article

Study Design

Retrospective, observational, single institution

Funding Source

None

Setting

Academic setting, Oschner Health, New Orleans, LA.

Figure

Summary

This retrospective study looked at 56 patients with treatment-naive, solitary hepatocellular carcinoma (HCC) with Barcelona clinic Liver Cancer (BCLC) Stage 0-A tumor burden over a two-year period from January 2020 to October 2022. The included patients were treated with Y90 glass microspheres in a segmental or subsegmental delivery for ablation radiation segmentectomy. Treatment was done in two-step fashion starting with a mapping angiography session, which included calculation of a lung shunt fraction, followed by a treatment session. Initially, target radiation doses were > 200 Gy. This was increased to > 400 Gy after the publication of the LEGACY study in 2021. Immediately following treatment, patients were imaged using Bremsstrahlung SPECT/CT. For post-treatment dosimetry, pre-treatment diagnostic CT or MRI studies were incorporated with the post-treatment nuclear medicine SPECT/CT.

Using voxel dosimetry and the Mirada DBx Build 1.2.0 Simplicit90Y software, total liver volume, perfused volumes, and tumor volume were calculated. Tumor absorbed dose (TAD) and normal tissue absorbed dose were calculated using the multicompartment dosimetry model. Additional calculations included the sphere concentration per tumor volume, the number of spheres delivered to normal and tumoral tissue, minimum absorbed doses at 70% (D70), 90% (D90), and 99% (D99) of the total tumor volume, and minimum dose threshold to the entire tumor for 200 Gy (V200 100%) and 400 Gy (V400 100%). The primary endpoint for the study was progression of HCC based on mRECIST imaging criteria. In patients successfully bridged to transplant, pathologic information related to degree of necrosis was obtained. Statistical analysis included linear regression, Kaplan-Meier survival curves, Mann-Whitney test for continuous variables, and chi-square or Fisher exact test for categorical variables. Adverse events were monitored for 180 days and graded based on the Common Terminology Criteria for Adverse Events version 5.0.

Key findings:
· Smaller perfused volumes correlated with higher sphere concentrations in nontumoral liver and tumor.
· Larger tumors showed a nonlinear increase in total spheres deposited.
· Tumoral and nontumoral sphere concentrations had a direct linear relationship.

Clinical outcomes:
· Objective response rate: 96% (83% complete response [CR], 14% partial response).
· CR correlated with higher D70, D90, D99, and V400 100%.
· Histopathology (15 patients): 33% achieved complete pathologic necrosis (CPN); remaining tumors showed 80-99% necrosis.
· CPN was associated with smaller tumors and higher D99.
· All adverse events were treatment-related (≤Grade 3) and unrelated to nontumoral TAD.

Commentary

As the literature on Y90 radioembolization for grows in both quantity and nuance, sphere activity (SA) and sphere distribution has grown in importance. To understand why, it’s useful to review both the goal of radioembolization and the current techniques of treatment. The goal of Y90 treatment in HCC is to deliver a critical radiation dose to the tumor, with the ideal goal being complete pathologic necrosis (CPN). The LEGACY trial included a cohort of patients who received median doses of 400 Gy, 100% of which had CPN. Since the LEGACY trial, 400 Gy has become the benchmark dose for achieving CPN.

In an ideal treatment scenario, each part of the tumor would see at least 400 Gy and become completely necrotic. However, HCC’s intrinsic heterogeneity—driven by “solid stress” from tumor growth compressing vessels—creates cold areas with limited sphere deposition. Enough activity needs to be deposited into all parts of the tumor, even the cold areas, so the surrounding tumor cells get adequate absorbed dose to achieve complete pathologic necrosis. Balancing sufficient SA to penetrate these regions while avoiding uneven distribution remains a challenge.

Utilizing voxel dosimetry, the article by Sandow et al. reproduced and further delineated many of the findings from the Y90 literature. Voxel dosimetry metrics of D70, D90, D99, and V400 100% correlated strongly with radiologic and pathologic response. Smaller tumors, likely due to homogeneous hypervascularity, achieved higher sphere concentrations and CPN rates. Sphere concentration linearly predicted dose coverage (D70/ D99), emphasizing the need for both activity and distribution optimization.

The study validates voxel dosimetry as a robust analytic tool for future research in personalized Y90 radioembolization for the treatment of HCC and other types of malignancies, offering granular insights into radioembolization dose thresholds and tumor biology.

Post Author
Sean Roger, MD
Interventional Radiology Fellow, PGY-6
University of Massachusetts

GLASS Classification Correlates with Primary Patency in Chronic Limb-Threatening Ischemia Patients Treated Endovascularly

Primary Limb-Based Patency for Chronic Limb-Threatening Ischemia Treated with Endovascular Therapy Based on the Global Limb Anatomic Staging System

Clinical question

In a large population and with long follow-ups, does the GLASS classification correlate with primary patency in patients with chronic limb-threatening ischemia who underwent endovascular therapy? And what were the risk factors for primary patency loss?

Take away point

GLASS classification may be an indicator of prognosis after intervention in patients with chronic limb-threatening ischemia.

Reference

Peng M, Li C, Nie C, Chen J, Tan J. Primary Limb-Based Patency for Chronic Limb-Threatening Ischemia Treated with Endovascular Therapy Based on the Global Limb Anatomic Staging System. J Vasc Interv Radiol. 2024 Jul 24:S1051-0443(24)00472-X. doi: 10.1016/j.jvir.2024.07.015. Epub ahead of print. PMID: 39059464.

Click here for abstract

Study design

Retrospective, observational, descriptive study

Funding Source

N/A

Setting

Chongqing University Three Gorges Hospital, Wanzhou, Chongqing, China (academic institution)

Figure

Kaplan-Meier curves for primary limb-based patency stratified by Global Limb Anatomic Staging System (GLASS) stage for limbs with chronic limb-threatening ischemia undergoing endovascular therapy. (a) At 1 year after intervention: GLASS Stage I versus II, 78.8% versus 69.5%; P = .232; GLASS Stage I versus III, 78.8% versus 41.6%; P < .001; GLASS Stage II versus III, 69.5% versus 41.6%; P = .001. (b) At the end of follow-up: GLASS Stage I versus II, 54.2% versus 38.6%; P = .042; GLASS Stage I versus III, 54.2% versus 10.5%; P < .001; GLASS Stage II versus III, 38.6% versus 10.5%; P < .001. G = grade; HR = hazard ratio.

Summary

The Global Limb Anatomic Staging System (GLASS) classification system, proposed in 2019, aims to standardize the assessment of limb anatomy in patients with critical limb threatening ischemia (CLTI) in order to guide treatment decisions. It consists of three stages, with Stage III representing the highest severity of disease. Prior studies were inconclusive regarding the ability of GLASS to predict limb-based patency. This study was conducted in order to assess the potential of the GLASS classification system to predict prognostic outcomes of patients with CLTI who underwent endovascular therapy with a larger patient population and longer follow-up.

Using a retrospective analysis, the investigators reviewed data from a total of 1,029 patients who underwent revascularization therapy for CLTI between January 1, 2018 and May 31, 2022 at the Chongqing University Three Gorges Hospital. After excluding patients with confounding variables, 231 patients (236 limbs) were included in the final analysis. The GLASS classification of the ischemic limbs was assessed using CTA or digital subtraction angiography prior to intervention. Of these patients, 52 (22%) were classified as GLASS Stage I, 59 (25%) were classified as GLASS Stage II, and 125 (53%) were classified as GLASS Stage III. Patients were followed up at 1-, 3-, 6-, and 12-months post-intervention and annually thereafter. Patient interviews, physical examinations, and vascular ultrasonography were used to assess patency at follow up.

The mean patient age was 74.45 years, with a predominance of male patients (76.7%). Notably, 36.9% of limbs were classified as clinical Stage IV according to the WIfI system, and common comorbidities included hypertension (64.8%) and diabetes (41.1%). For procedural details, 23.3% of limbs received no stents, while 58.1% were treated with bare nitinol stents. There were significant differences in the number of stents used across GLASS stages (P < .001) and in postoperative antithrombotic regimens (P = .004), but not in the type of stents used (P = 0.101). The median follow-up time was 1,279 days, with primary limb-based patency rates declining significantly with higher GLASS stages; for example, 1-year limb-based patency rates were 78.8% for Stage I and 41.6% for Stage III (P < .001). Univariate analysis identified GLASS stage III, diabetes, and smoking as independent risk factors for long-term patency loss, while male sex was associated with a lower risk. Multivariate analysis confirmed all these to be independent factors associated with limb-based patency.

The authors cited multiple prior studies that found evidence that the use of GLASS staging can predict limb-based patency rates in CLTI patients undergoing endovascular treatment. This study, which had a larger sample size and longer follow-up times than those cited, supports these findings and provides additional insight.

Commentary

The results from this study, along with those referenced within it, provide a strong argument for using the GLASS staging criteria as a prognostic tool for patients with CLTI undergoing endovascular treatment. Systems like GLASS are important for personalized procedural strategy, post-procedural medical management, and follow-up schedule, and the questions addressed in this study contribute to holistic approaches around patients with CLTI.

While the study's methodology was robust with a large patient population and long follow-up, further evaluation of endovascular strategies (specific types of stents and balloons, as well as potential changes of certain strategies during the study period, i.e. paclitaxel-coated devices), antiplatelet/antithrombotic strategies (especially given statistically significant differences in antithrombotic medications post-procedural), and patient-relevant quality-of-life outcome measures will provide further insights to the endovascular community. Additionally, some patient groups were excluded from the analysis; one in particular was the group with hepatocyte growth factor therapy involved. Offering clear explanations for each exclusion would strengthen the validity of the findings by demonstrating how these decisions improved the overall rigor of the study.

The discussion of confounding variables raises an important consideration: should GLASS staging criteria incorporate some of these factors? Perhaps a scoring system, rather than a purely staging-based approach, would offer physicians a more comprehensive tool for making informed treatment decisions. At the minimal, the study can benefit from a discussion on the impact of the study’s results in daily clinical practice. Should patients with higher GLASS staging criteria receive more aggressive antithrombotic regimen or more frequent clinical follow-up for potential repeat revascularization? Or was there a cost-effective time point at which procedural intervention should be discouraged? Ultimately, this paper addresses a scientific question methodically but leaves room for future research regarding the practical aspects.

Post Author
Isabel Okinedo, BA
UMass Chan Medical School
@isabelokinedo

Eye90 Beads Provide Safe and Effective Direct Visualization in Radioembolization

Imageable Radioembolization Microspheres for Treatment of Unresectable Hepatocellular Carcinoma: Interim Results from a First-in-Human Trial

Clinical question 

Can radiopaque yttrium-90 microspheres safely and effectively treat unresectable hepatocellular carcinoma while providing real-time visibility of treatment?

Take away point 

Eye90, a radiopaque Y90 microsphere, enables real-time evaluation and treatment adjustment during radioembolization, potentially improving tumor targeting and serving as a tumor response biomarker. Initial study showed 50% complete response at 3 months with no severe adverse events.

Reference 

Abraham, R.J., Arepally, A., Liu, D., Lewandowski, R., Kappadath, S.C., Verma, A., Dobrowski, D. and Holden, A., 2024. Imageable Radioembolization Microspheres for Treatment of Unresectable Hepatocellular Carcinoma: Interim Results from a First-in-Human Trial. Journal of Vascular and Interventional Radiology, 35(10), pp.1464-1473.

Click here for article 

Study design 

Prospective, observational, descriptive study

Funding Source 

ABK Biomedical

Setting 

Auckland City Hospital, Auckland, New Zealand

Figure

A 53-year-old man with chronic hepatitis B. Axial contrast-enhanced computed tomography (CT) (arterial phase) demonstrated a 4.3-cm Segment 8 hepatocellular carcinoma (white arrow) adjacent to previous transarterial chemo- embolization scar (white arrowhead). CT image demonstrating radiopaque Eye90 microsphere distribution in hepatocellular carcinoma (arrow) and surrounding treated liver volume.

Summary

Current 90Y microspheres have limitations. Glass microspheres lack flexibility in quantity and activity customization, often necessitating multiple vials and kits for larger volumes. Resin 90Y provides quantity and activity customization, but at the cost of increased burden on nuclear medicine labs and operator risk. Both microspheres also have limitations in visibility, requiring post-treatment SPECT/ PET for assessing 90Y distribution, tumor targeting, and dosimetry.

Addressing these challenges, Eye90 Microspheres introduces radiopaque properties for direct CT visualization with a customizable dose with radioactivity between 0.4-9.6 GBq at 3 preset mass ranges: (a) small (100–200 mg), (b)medium (201–400 mg), and (c) large (401–600 mg). Personalized dose vial quantity and activity is determined using a 3-compartment partition model that considers various patient-specific factors based on the technetium-99m macro- aggregated albumin SPECT/CT. This personalized approach reportedly eliminates the need for dose-draw or multiple vials.

Accompanying the Eye90 Microspheres is the Eye90 delivery device, which utilizes a dual-syringe system to achieve a controlled uniform delivery concentration of 60 mg/mL. The delivery device also allows the users to pause, assess microcatheter location with contrast media, examine microsphere distribution using CT modalities, and resume administration as needed.

This study reports 6-month safety, effectiveness, and imageability results for Eye90 in 6 subjects with unresectable HCC (median size of 3.1 cm, range: 1.2 – 4.3 cm). Subjects underwent planning procedure (90Y mapping) followed by selective treatment (≤2 segments) using partition dosimetry by SurePlan LiverY90 aiming to deliver at least 205 Gy and preferably > 250 Gy to the tumor. Post-therapy SPECT/CT, unenhanced lung CT, and 4-phase liver CT within 24 hours of treatment were obtained to correlate microsphere radiopacity with radioactivity. Follow-up were scheduled on days 21, 42, 90, and 180 after treatment.

Post-treatment SPECT/CT demonstrated mean and median dose of 283 Gy and 132 Gy to the tumor, respectively. Microsphere density within the tumor was calculated at 26,988 per mL. All subjects reported adverse events, but no treatment-related Grade ≥3 AEs occurred. At 90 days, 50% achieved complete response (CR) and 33.3% partial response (PR). At 180 days, 50% maintained CR and 16.7% PR. The other patient with PR, and the patient with stable disease at 90 days, underwent TACE and could not be evaluated. Qualitative analysis showed agreement between microsphere radiopacity on CT and radioactivity on SPECT/CT, with CT revealing heterogeneous dose distribution, and absence of radiopacity in the region of a particular tumor despite SPECT/CT activity noted throughout this region. This particular tumor did not respond to treatment.

Commentary 

Eye90 Microspheres represent another advancement in transarterial radioembolization, offering direct visualization of microsphere and tumor targeting on CT modalities. This capability could lead to more precise treatment execution, real-time therapy adjustments, and potentially serve as a biomarker for predicting tumor response and a foundation for more accurate dose-response relationships. The dual-syringe administration system allows for customized quantity and activity of microspheres, enhancing treatment personalization.

While the initial results are promising, the small sample size, short follow-up period, lower-than-planned tumor doses, and mediocre treatment response necessitate further research. The ongoing U.S. Pivotal IDE Route90 trial will provide more comprehensive data on a larger cohort. If these results hold up in larger studies, Eye90 Microspheres could redefine the standard of care in HCC treatment. The potential for improved precision, personalization, and real-time assessment makes this a technology to watch closely in the coming years.

Post author
Leila Haghani, MD 

Research Fellow 

University of Massachusetts Chan Medical School
@dr_Leila_IRad