Impact of Injection Technique on Microsphere Distribution During Transarterial Radioembolization in a Successively Bifurcating In Vitro Model

[Purpose] Transarterial radioembolization (TARE) is an established treatment modality for patients with unresectable liver cancer. However, a better understanding of treatment parameters that influence microsphere distribution could further improve the therapy. This systematic review examines and summarizes the available evidence on intraprocedural parameters that influence the microsphere distribution during TARE as investigated by in vivo, ex vivo, in vitro and in silico studies. [Methods] A standardized search was performed in Medline, Embase and Web of Science to identify all published articles investigating microsphere distribution or dynamics during TARE. Studies presenting original research on parameters influencing the microsphere distribution during TARE were included. [Results] A total of 42 studies reporting a total of 11 different parameters were included for narrative analysis. The investigated studies suggest that flow distribution is not a perfect predictor of microsphere distribution. Increasing the injection velocity may help increase the similarity between flow and microsphere distributions. Furthermore, the microsphere distributions are very sensitive to the radial and axial catheter position. [Conclusion] The most promising parameters for future research which can be controlled in the clinic appear to be microsphere injection velocity as well as the axial catheter position. Up to now, many of the included studies do not take clinical feasibility into account, limiting the translation of results to clinical settings. Future research should therefore focus on the applicability of in vivo, in vitro, or in silico research to patient specific scenarios to improve the efficacy of radioembolization as treatment for liver cancer.

To experimentally investigate the behavior of a clinically used microcatheter during transarterial radioembolization (TARE) microsphere injection in a successively bifurcating in vitro model. A symmetrical phantom was developed which bifurcated 3 times into 8 outlets. A blood-mimicking fluid was pumped through the phantom using a physiological representative waveform. Holmium-165 microspheres were injected in a pulsed manner at 3 different locations using a standard microcatheter and a rigid counterpart with same dimensions as a control. Motion of the catheter was studied with a top- and side-view camera on the phantom. Microspheres were collected at each outlet and their distribution over the 8 outlets was analyzed. Due to the pulsatile flow in the phantom, strengthened by the pulsatile microsphere injection, the clinical catheter showed maximum displacements of 0.87 mm within a vessel with a diameter of 3.6 mm. This motion resulted in a different microsphere distribution for the clinical catheter compared with the rigid counterpart (75.9% vs 49.4% of the microspheres went to outlet 1-4, respectively). In this in vitro model, the motion of the clinical catheter affected distribution of microspheres. Since the pulsatile administration of microspheres resulted in increased motion of the clinical catheter, standardizing microsphere administration could be beneficial to reduce interprocedural differences in TARE. Our study demonstrated that microsphere distribution during transarterial radioembolization (TARE) is affected by catheter motion. Furthermore, increased catheter motion was observed as a result of the injection profile. Predictive tools such as the contrast CBCT and scout dose use different injection profiles compared to therapeutic TARE injections, potentially altering catheter tip behaviour and microsphere distribution, which could compromise their predictive values. Additionally, current TARE microsphere injection guidelines provide limited details, which may lead to variability across institutes and interventional radiologists. Standardizing injection techniques could reduce catheter motion variability and may facilitate more consistent and predictable microsphere distribution patterns.

Transarterial radioembolisation (TARE) is a treatment for liver malignancies, involving the injection of radioactive microspheres in the hepatic artery (HA). Tumour-to-nontumour uptake varies among patients, possibly influenced by patient-specific blood flow profiles. To examine the impact of HA blood flow rate and high microsphere dosages on microsphere distribution in normal liver parenchyma, ex vivo magnetic resonance imaging (MRI)-guided machine perfusion experiments were conducted in porcine livers. Porcine livers were subjected to oxygenated normothermic machine perfusion at three HA flow rates (0.02, 0.15, and 0.22 mL/min/g liver tissue; n = 3 per condition). Five fractions of 250 mg nonradioactive 165Ho-loaded microspheres were administered to n = 9 livers, and four additional fractions of 1,000 mg to n = 6 livers. Dynamic contrast-enhanced and Ho-sensitive T2*-weighed MR scans were acquired to extract perfusion rates, fictive dose maps, and homogeneity indices (HI). Microsphere distribution correlated moderately with perfusion rate at low HA flow rate (r = 0.611), and very strongly at higher HA flow rates (r = 0.977 and 0.951 for 0.15 and 0.22 mL/min/g, respectively). Homogeneity increased with increasing flow rates, with HIs ranging from 3.68-4.72 at low, to 2.01-2.66 at medium, and 1.60-2.36 at high HA flow rate. HI decreased with higher microsphere concentrations, though distribution patterns remained unchanged. In our ex vivo model, higher HA flow rates resulted in more homogeneous microsphere distributions. The impact on tumourous tissue needs further investigation to determine whether pre-TARE HA blood flow measurements could improve microsphere distribution predictions. Mapping of the hepatic arterial blood flow rate before transarterial radioembolisation and adjusting the treatment accordingly may help to improve outcomes for patients with liver cancer. Parameters influencing microsphere distribution were studied in MRI-perfused healthy porcine livers. Higher hepatic arterial blood flow rates led to more homogeneous microsphere distributions. Administering large numbers of microspheres did not alter microsphere distribution patterns. Impact on tumour tissue should be further investigated.

Transarterial radioembolization (TARE) is an established treatment method for non-resectable liver tumors. One of the challenges of the approach is the accurate prediction of the microsphere biodistribution in the liver. We propose to use ultrasound contrast microbubbles as holmium microsphere precursors, which allows real-time prediction of the microsphere trajectories and biodistribution using dynamic contrast-enhanced ultrasound (DCE-US). The immediate goal in this in vitro study was to investigate the predictive capabilities of microbubbles as microsphere precursors. The study was conducted in an experimental in vitro model which represents the bifurcating right branch of the hepatic artery. A controlled injection of experimental BR-14 ultrasound contrast microbubbles and non-radioactive holmium-165 microspheres was performed in separate consecutive experiments in an arterial flow phantom. The microbubbles and microspheres were collected separately at the outlets of the phantom and counted using a Coulter counter to determine their distribution over the different outlets. The flow profile, the injection velocity, and the catheter position were monitored during the measurements to ensure stability. The results showed a good correlation between the microbubble and the microsphere distributions (p = 0.0038, r = 0.88) measured at the outlets. Differences in the distributions could be attributed to the characteristics of microbubbles and microspheres alone (e.g. particle size and concentration), since critical parameters were kept stable between the two experiments. The current in vitro study provides confidence that the microsphere biodistribution can be predicted using contrast microbubbles. The comparison provided by this study forms a foundation for the development of a DCE-US guided TARE treatment.

The purpose of this study is to evaluate the correlation between pretreatment planning technetium-99m ((99m)Tc) macroaggregated albumin (MAA) SPECT images and posttreatment transarterial radioembolization (TARE) yttirum-90 ((90)Y) PET/CT images by comparing the ratios of tumor-to-normal liver counts. Fifty-two patients with advanced hepatic malignancy who underwent (90)Y microsphere radioembolization from January 2010 to December 2012 were retrospectively reviewed. Patients had undergone (99m)Tc MAA intraarterial injection SPECT for a pretreatment evaluation of microsphere distribution and therapy planning. After the administration of (90)Y microspheres, the patients underwent posttreatment (90)Y PET/CT within 24h. For semiquantitative analysis, the tumor-to-normal uptake ratios in (90)Y PET/CT (TNR-yp) and (99m)Tc MAA SPECT (TNR-ms) as well as the tumor volumes measured in angiographic CT were obtained and analyzed. The relationship of TNR-yp and TNR-ms was evaluated by Spearman's rank correlation and Wilcoxon's matched pairs test. In a total of 79 lesions of 52 patients, the distribution of microspheres was well demonstrated in both the SPECT and PET/CT images. A good correlation was observed of between TNR-ms and TNR-yp (rho value = 0.648, p < 0.001). The TNR-yp (median 2.78, interquartile range 2.43) tend to show significantly higher values than TNR-ms (median 2.49, interquartile range of 1.55) (p = 0.012). The TNR-yp showed weak correlation with tumor volume (rho = 0.230, p = 0.041). The (99m)Tc MAA SPECT showed a good correlation with (90)Y PET/CT in TNR values, suggesting that (99m)Tc MAA can be used as an adequate pretreatment evaluation method. However, the (99m)Tc MAA SPECT image consistently shows lower TNR values compared to (90)Y PET/CT, which means the possibility of underestimation of tumorous uptake in the partition dosimetry model using (99m)Tc MAA SPECT. Considering that (99m)Tc MAA is the only clinically available surrogate marker for distribution of microsphere, we recommend measurement of tumorous uptake using (90)Y PET/CT should be included routinely in the posttherapeutic evaluation.

Transarterial radioembolization using Y microspheres is a novel therapeutic option for inoperable hepatic malignancies. As these spheres are radiolucent, real-time assessment of their distribution during the infusion process under fluoroscopic guidance is not possible. Bremsstrahlung radiations arising from 90Y have conventionally been used for imaging its biodistribution. Recent studies have proved that sources of 90Y also emit positrons, which can further be used for PET/computed tomography (CT) imaging. This study aimed to assess the feasibility of 90Y PET/CT imaging in evaluating microsphere distributions and to compare its findings with those of Bremsstrahlung imaging. Thirty-five sessions of 90Y microsphere transarterial radioembolization were performed on 30 patients with hepatic malignancies. 90Y PET/CT imaging was performed within 3 h of therapy. Bremsstrahlung imaging was also performed for each patient. The imaging findings were compared for concordance in the distribution of microspheres. Exact one-to-one correspondence between 90Y PET/CT imaging and 90Y Bremsstrahlung imaging was observed in 97.14% of cases (i.e. in 34/35 cases). Discordance was observed only in one case in which 90Y PET/CT imaging resolved the microsphere uptake in the inferior vena cava tumor thrombus, which was, however, not visualized on Bremsstrahlung imaging. There is good concordance in the imaging findings of 90Y PET/CT and 90Y Bremsstrahlung imaging. 90Y PET/CT imaging scores over the conventionally used Bremsstrahlung imaging in terms of better resolution, ease of technique, and comparable image acquisition time. This makes it a preferred imaging modality for assessment of the distribution of 90Y microspheres.

Dosimetric assessment of Gadolinium-159 for hepatic radioembolization: Tomographic images and Monte Carlo simulation

No. 439 Histological outcomes in resected tumor specimens after Yttrium-90 transarterial radioembolization using resin microspheres

PurposeTransarterial radioembolization (TARE) is a treatment for liver tumours based on injection of radioactive microspheres in the hepatic arterial system. It is crucial to achieve a maximum tumour dose for an optimal treatment response, while minimizing healthy liver dose to prevent toxicity. There is, however, no intraprocedural feedback on the dose distribution, as nuclear imaging can only be performed after treatment. As holmium-166 (166Ho) microspheres can be quantified with MRI, we investigate the feasibility and safety of performing 166Ho TARE within an MRI scanner and explore the potential of intraprocedural MRI-based dosimetry.MethodsSix patients were treated with 166Ho TARE in a hybrid operating room. Per injection position, a microcatheter was placed under angiography guidance, after which patients were transported to an adjacent 3-T MRI system. After MRI confirmation of unchanged catheter location, 166Ho microspheres were injected in four fractions, consisting of 10%, 30%, 30% and 30% of the planned activity, alternated with holmium-sensitive MRI acquisition to assess the microsphere distribution. After the procedures, MRI-based dose maps were calculated from each intraprocedural image series using a dedicated dosimetry software package for 166Ho TARE.ResultsAdministration of 166Ho microspheres within the MRI scanner was feasible in 9/11 (82%) injection positions. Intraprocedural holmium-sensitive MRI allowed for tumour dosimetry in 18/19 (95%) of treated tumours. Two CTCAE grade 3–4 toxicities were observed, and no adverse events were attributed to treatment in the MRI. Towards the last fraction, 4/18 tumours exhibited signs of saturation, while in 14/18 tumours, the microsphere uptake patterns did not deviate from the linear trend.ConclusionThis study demonstrated feasibility and preliminary safety of a first in-human application of TARE within a clinical MRI system. Intraprocedural MRI-based dosimetry enabled dynamic insight in the microsphere distribution during TARE. This proof of concept yields unique possibilities to better understand microsphere distribution in vivo and to potentially optimize treatment efficacy through treatment personalization.RegistrationClinicaltrials.gov, identifier NCT04269499, registered on February 13, 2020 (retrospectively registered).

In-depth clinical and dosimetric analysis of 166Ho-radioembolization in patients with liver cancer: An observational study.

PurposeAn international survey was conducted by the Cardiovascular Interventional Radiological Society of Europe (CIRSE) to evaluate radioembolization practice and capture opinions on real-world clinical and technical aspects of this therapy.Materials and MethodsA survey with 32 multiple choice questions was sent as an email to CIRSE members between November and December 2022. CIRSE group member and sister societies promoted the survey to their local members. The dataset was cleaned of duplicates and entries with missing data, and the resulting anonymized dataset was analysed. Data were presented using descriptive statistics.ResultsThe survey was completed by 133 sites, from 30 countries, spanning 6 continents. Most responses were from European centres (87/133, 65%), followed by centres from the Americas (22/133, 17%). Responding sites had been performing radioembolization for 10 years on average and had completed a total of 20,140 procedures over the last 5 years. Hepatocellular carcinoma treatments constituted 56% of this total, colorectal liver metastasis 17% and cholangiocarcinoma 14%. New sites had opened every year for the past 20 years, indicating the high demand for this therapy. Results showed a trend towards individualized treatment, with 79% of responders reporting use of personalized dosimetry for treatment planning and 97% reporting routine assessment of microsphere distribution post-treatment. Interventional radiologists played an important role in referrals, being present in the referring multi-disciplinary team in 91% of responding centres.ConclusionThis survey provides insight into the current state of radioembolization practice globally. The results reveal the increasing significance placed on dosimetry, evolving interventional techniques and increased technology integration.Graphical

Yttrium-90 (Y-90) transarterial radioembolization uses radioactive microspheres injected into the hepatic artery to irradiate liver tumors internally. One of the major challenges is the lack of reliable dosimetry methods for dose prediction and dose verification. We present a patient-specific dosimetry approach for personalized treatment planning based on computational fluid dynamics (CFD) simulations of the microsphere transport combined with Y-90 physics modeling called CFDose. The ultimate goal is the development of a software to optimize the amount of activity and injection point for optimal tumor targeting. We present the proof-of-concept of a CFD dosimetry tool based on a patient's angiogram performed in standard-of-care planning. The hepatic arterial tree of the patient was segmented from the cone-beam CT (CBCT) to predict the microsphere transport using multiscale CFD modeling. To calculate the dose distribution, the predicted microsphere distribution was convolved with a Y-90 dose point kernel. Vessels as small as 0.45mm were segmented, themicrosphere distribution between the liver segments using flow analysis was predicted,the volumetric microsphere and resulting dose distribution in the liver volume were computed. The patient was imaged with positron emission tomography (PET) 2h after radioembolization to evaluate the Y-90 distribution. The dose distribution was found to be consistent with the Y-90 PET images. These results demonstrate the feasibility of developing a complete framework for personalized Y-90 microsphere simulation and dosimetry using patient-specific input parameters.

Quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is emerging as a valuable tool for assessing tumor and parenchymal perfusion in the liver, playing a developing role in locoregional therapies (LRTs) for hepatocellular carcinoma (HCC). This review explores the conceptual underpinnings and early investigational stages of DCE-MRI for LRTs, including thermal ablation, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE). Preclinical and early-phase studies suggest that DCE-MRI may offer valuable insights into HCC tumor microvasculature, treatment response, and therapy planning. In thermal ablation therapies, DCE-MRI provides a quantitative measurement of tumor microvasculature and perfusion, which can guide more effective energy delivery and estimation of ablation margins. For TACE, DCE-MRI parameters are proving their potential to describe treatment efficacy and predict recurrence, especially when combined with adjuvant therapies. In 90Y TARE, DCE-MRI shows promise for refining dosimetry planning by mapping tumor blood flow to improve microsphere distribution. However, despite these promising applications, there remains a profound gap between early investigational studies and clinical translation. Current quantitative DCE-MRI research is largely confined to phantom models and initial feasibility assessments, with robust retrospective data notably lacking and prospective clinical trials yet to be initiated. With continued development, DCE-MRI has the potential to personalize LRT treatment approaches and serve as an important tool to enhance patient outcomes for HCC.

Introduction:Transarterial radioembolization is a treatment for nonresectable, hypervascular liver tumours where yttrium-90-infused microspheres are administered through the arterial vasculature of the liver to selectively target liver tumours. Compared to conventional PET and SPECT imaging, post-procedural CT imaging has the potential to provide superior spatial resolution imaging of microsphere distributions and improve dosimetry estimates. In this paper, we describe a methodology to quantify the inherent radiopacity of glass microspheres using CT. This methodology produces a calibration curve that relates microsphere concentration within a CT voxel to the corresponding change of Hounsfield unit for that voxel. Methods: The radiopaque microspheres under investigation are composed of proprietery blends of yttrium-strontium-gallium-silicate oxide glass similar in size and density to TheraSphere® microspheres. Tissue-equivalent phantoms were designed to determine CT voxel enhancement from uniformly distributed microspheres. Phantoms were imaged with a 128-slice CT scanner to determine the average Hounsfield unit value and with brightfield microscopy to determine the corresponding microsphere concentrations. Results: Hounsfield units (HU) and microsphere concentration (MS/mL) are positively correlated (r2 ≥ 0.930) over a range of CT acquisition parameters. Calibration curve slopes (sensitivities) range from 2.22 × 10−4 to 3.12 × 10−4 HU/MS/ml. Minimum detectable limits are between 1.83 × 105 and 2.54 × 105 MS mL−1. The application of this proposed methodology to recently developed microsphere formulations shows an improvement in correlation (r2 ≥ 0.995), sensitivity (7.53 × 10−4 HU/MS/ml), and minimum detectability (5.39 × 104 MS ml−1). Conclusion: CT has the potential to quantify the radiation dose from the infusion of microspheres for more accurate dosimetry in radioembolization. This finding may improve our understanding of the relationship between absorbed dose and tumour response, which could ultimately translate into improved patient outcomes. Optimization of the prototype microsphere composition to maximize its inherent radiopacity will be an important step in realizing this goal.

This study evaluates, for the first time by direct visualization, the microvascular distribution of microspheres in normal hamster cheek pouch and in hamster cheek pouch bearing tumor induced by 7, 12 Dimethylbenz (A) Anthracene solution (DMBA). In contrast to the results of the previously used open-chest technique, this carotid injection technique does not lead to irregular distribution of 15-mu carbonized microspheres, chain, or impaction phenomena. It is concluded that methodology differences may account for different results.