Safety of Repeated Trans-arterial Radioembolization with Multicompartment Dosimetry

doi:10.21203/rs.3.rs-6764926/v1

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Research Article

Safety of Repeated Trans-arterial Radioembolization with Multicompartment Dosimetry

https://doi.org/10.21203/rs.3.rs-6764926/v1

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published 20 Aug, 2025

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Purpose

Transarterial radioembolization (TARE) is one of the local treatment options for primary and metastatic liver tumors. However, our knowledge regarding the safety of repeated TARE remains limited. In this study, we aimed to evaluate the safety of repeated transarterial radioembolization with multicompartment dosimetry.

Methods

In this retrospective single-center study we analyzed the data of the patients who were treated with at least two separate sessions of radioembolization with Y-90 microspheres. Multi-compartment and voxel-wise dosimetry was performed for every treatment session and cumulative whole liver normal tissue absorbed radiation dose (D_norm), V20-V100 values for whole liver normal tissue were calculated. Toxicity was assessed with CTCAE grading system for ALT/AST/bilirubin levels and INR before and after each treatment. In addition, ALBI scores, grades and changes in ALBI score (ΔALBI) were recorded. Difference between the ALBI scores before and after the treatment was compared with Wilcoxon tests and relationships between ΔALBI and dosimetric variables were compared linear regression analyses.

Results

A total of 24 patients (6 males, 18 females; median age: 57 years) were included in the analysis. The most common diagnosis was colorectal carcinoma liver metastases (46%). Seventeen patients (71%) underwent two TARE treatments, five (21%) underwent three, and two (8%) underwent four. The median interval between the first and second treatments was 138 days (range: 34–782), and between the second and third treatments was 210 days (range: 72–435). No CTCAE grade 3 or 4 toxicities were observed. ALBI score analysis revealed no significant changes after the first two treatments, but a significant difference was noted after the third treatment (p = 0.043), with one patient progressing to ALBI Grade 3 with significant hypoalbuminemia. No significant relationship was found between ΔALBI and treatment intervals. ALT/AST elevations were mostly transient and mild, with only one case of grade 2 hepatotoxicity in each of the first two treatments. In patients treated with glass microspheres in their first two treatments (n = 12), a significant linear correlation was found between cumulative D_norm and ΔALBI (R²=0.512, p = 0.007). Cumulative dose-volume histogram parameters, particularly V30, V40, and V50, showed significant correlations with ΔALBI. However, in patients treated with resin microspheres (n = 6), no statistically significant relationship was observed between cumulative D_norm and ΔALBI (p = 0.718).

Conclusion

Repeated TARE with a multicompartment personalized dosimetric approach appears to be safe for the first two cycles, with limited low-grade toxicity. However significant increase in ALBI scores after the third treatment was observed. ALBI score changes after second TARE were associated with cumulative liver radiation exposure in patients treated with glass microspheres. Larger studies are needed to further explore predictors of hepatotoxicity in repeated TARE.

Radioembolization

Liver

Multicompartment Dosimetry

Yttrium-90

Safety

Transarterial radioembolization (TARE) is one of the local treatment options for primary and metastatic liver tumors. It has been proven to be safe across a wide spectrum of indications, ranging from ablative/curative to palliative intent. Several studies have demonstrated the benefits of TARE in advanced-stage hepatocellular carcinoma (HCC), intrahepatic cholangiocellular carcinoma (ICC), and colorectal cancer liver metastasis (CRCLM) [1, 2]. Although it is generally considered safe, TARE can potentially result in severe adverse effects, including gastrointestinal ulcers, cytopenia, post-radioembolization syndrome, and radioembolization-induced liver disease (REILD) [2–6]. However, our knowledge regarding the safety of repeated TARE remains limited. The available literature includes only a few retrospective analyses of patients treated with BSA-based or single-compartment dosimetry [7–10].

Repeated TARE refers to the administration of Y-90 microspheres to the same or overlapping perfused volume of the liver. Since the healthy liver parenchyma is treated again, an increase in liver toxicity is naturally expected due to the cumulative effects of the treatments. To mitigate rising hepatotoxicity rates, multicompartment dosimetry models are recommended to limit the absorbed radiation dose to healthy liver tissue. Given the widespread adoption of personalized multicompartment dosimetry over the past decade, it is assumed that the incidence of liver toxicity from repeated TARE should have decreased. However, data on this topic remain limited; the safety of second — or even third — treatments, the impact of the cumulative absorbed radiation dose on hepatotoxicity, and the effect of the time interval between treatments are still unclear. Therefore, in this single-center study, we aim to analyze the safety data of patients who received repeated TARE with personalized multicompartment dosimetry.

Patients and Study Design

This study was designed as a retrospective, single-center observational trial in a tertiary hospital. The protocol was approved by the local ethics committee (No. İ01-100-25), and the trial was conducted in accordance with the Declaration of Helsinki. All patients who received TARE with a multicompartment dosimetric approach between January 2021 and December 2024 were identified. Imaging data from a total of 42 patients who underwent TARE at least twice were re-evaluated. Patients who received TARE at least twice to the same perfused volume or to overlapping areas covering at least one segment were included in the analysis (n = 24). Eligibility for each TARE treatment session was determined based on adequate liver function (AST and ALT ≤ 5× upper limit of normal; total bilirubin ≤ 2 mg/dL; albumin ≥ 30 g/L), renal function, and INR levels. To assess toxicity, pre- and post-treatment serum AST, ALT, total bilirubin, albumin, and INR levels were recorded. ALBI scores and grades were calculated at baseline and after each treatment session. Additionally, the CTCAE scoring system was used to evaluate toxicity related to ALT/AST, total bilirubin, and INR levels.

Radioembolization Procedure, Y-90 PET Protocol and Post-Therapy Dosimetry

The patients, who were referred for radioembolization, underwent evaluation with hepatic artery perfusion scintigraphy and SPECT/CT with ^99mTc-macroaggregated albumin (MAA) prior to treatment. All invasive angiographic procedures (digital subtraction angiography [DSA] and cone-beam CT) were performed by an experienced interventional radiologist. Following hepatic artery perfusion scintigraphy, treatments planned with multi-compartmental dosimetry model in accordance with current guidelines [11–13]. Lung shunt fraction was calculated using the geometric means of lung and liver regions-of-interests (ROI) on anterior and posterior planar images. For patients treated with glass microspheres, the target minimum tumor dose was 250 Gy for primary liver tumors and 200 Gy for metastatic disease, with the dose adjusted to preserve liver function. The predicted maximum whole liver normal tissue absorbed dose was limited to 90–100 Gy for patients with normal liver function, and 50–60 Gy for those with chronic liver parenchymal disease or mild to moderate liver dysfunction. For resin microspheres, the minimum target tumor dose was 100–120 Gy, and the dose to perfused normal liver parenchyma was limited to 30–40 Gy. Within two weeks radioembolization procedures were performed following hepatic artery perfusion scintigraphy.

Patients were then monitored overnight in the in-patient clinic, followed by Y-90 PET imaging conducted within the day after procedure. Integrated GE Healthcare SIGNA™ PET/MRI (GE Healthcare, Milwaukee, Wisconsin, USA) or GE Healthcare Discovery™ IQ PET/CT (GE Healthcare, Milwaukee, Wisconsin, USA) system was used for Y-90 PET imaging. For both systems one bed position with 30 minutes of acquisition time centered on the liver were used for PET imaging. For PET/MRI, reconstruction with Q.Clear™ algorithm – a bayesian penalized likelihood reconstruction algorithm - with β value of 1500, 256x256 matrix size with 2.34x2.34x2.78mm voxel size, attenuation correction from the maps generated with MRAC sequences and time-of-flight enabled with VPFX algorithm and 5mm post-processing gauss filter were employed [17]. For PET/CT imaging, reconstruction with Q.Clear™ algorithm with β value of 1500, 192x192 matrix size with 3.65x3.65x3.26mm voxel size, attenuation correction from the maps generated with low dose CT sequences, VPHD algorithm and 5mm post-processing gauss filter were employed.

Post-therapy dosimetry performed with 3D Slicer version 5.2.1 [14, 15]. An in-house module was written specifically to convert PET images to radiation dose maps (in Gy) in 3D Slicer for this study. For dose calculations, absolute calibration and local deposition method was utilized. The density of the liver tissue was used as 1.05 g/mL. Voxel-wise conversion of PET images (Bq/mL) to Gy dose maps were performed with the following formula after application of decay correction:

$$\:Activity\:\left[GBq\right]=\:\frac{D\left[Gy\right]\times\:Mass\left[kg\right]}{49.67\:J/GBq}$$

Whole liver normal tissue mean absorbed dose (D_norm) and tumor mean absorbed dose (D_tumor) were calculated. Additionally, dose-volume histograms (DVHs) were calculated by quantifying the absorbed radiation dose of each voxel in the tumor compartments and sorting these voxels according to their dose values. For dose-volume histogram calculations SlicerRT toolkit was utilized [16, 17]. D values are defined as the dose absorbed by the voxel at a specific percentile (e.g., D20 refers to the dose at the 20th percentile, meaning 20% of voxels received a higher dose). V values represent the percentage of the volume (or voxels) that absorbed a dose greater than a specified dose value (e.g., V20 refers to the volume percentage that received more than 20 Gy). V20, V30, V40, V50, V60, V70, V80, V90 and V100 values (in %) were calculated from the DVHs for whole and perfused liver normal tissue compartments. Lastly, as dynamic changes in liver shape and volume did not allow cumulative voxel-wise addition of radiation dose maps, cumulative Dnorm and V values were simply calculated with the summation of the first and second treatment variables for the patients treated with the same microspheres in the first and second treatments. Lastly, response to treatment was assessed visually at the 3rd month after the treatment with dynamic contrast-enhanced multiparametric liver MRI.

Statistical Analysis

Descriptive statistics are summarized as counts and percentages for categorical variables; mean and standard deviations and median (minimum-maximum) for others. Change in the ALBI scores before after each treatment session was analyzed by Wilcoxon Test. Linear regression analyses was utilized to analyze the relationship between D_norm and V values and ALBI scores. For statistical analysis, p values smaller than 0.05 were considered to be statistically significant. Statistical analysis was performed using IBM SPSS Version 27.0.

Patient Population and Descriptive Data

Total 24 (6M, 18F, median age: 57 years) patients were included to the analysis. The most common diagnosis was colorectal carcinoma liver metastases with 11 (46%) patients. Details of patient demographics and treatments were presented in Table 1.

Procedural Characteristics

Seventeen patients (71%) underwent two radioembolization treatments, five patients (21%) underwent three treatments, and two patients (8%) underwent four treatments. Among the first treatments, 18 were performed using glass microspheres and 6 with resin microspheres. For the second treatments, 12 were performed with glass microspheres and 12 with resin microspheres. Among the third treatments, 4 were performed with glass microspheres and 3 with resin microspheres, while the fourth treatments included one case with glass microspheres and one with resin microspheres. In the first two sessions, in which all patients received at least two treatments, twelve patients were treated with glass microspheres in both sessions, six patients received resin microspheres in both sessions, and six patients were initially treated with glass microspheres and later with resin microspheres (Fig. 1). The median time interval between the first and second treatments was 138 days (range: 34–782) and the median time interval between the second and third treatments was 210 days (range: 72–435).

Toxicity Analysis

Before the first treatment, the patients' median ALBI score values were − 3.05 (range: [-3.86] – [-2.08]), while after the treatment, the values were observed as -2.96 (range: [-3.87] – [-2.36]). Before the first treatment, 20 patients were ALBI Grade 1, and 4 patients were Grade 2; after the treatment, the ALBI grade of one patient downgraded from Grade 2 to Grade 1. There was no change in the ALBI grades of the other patients. In the analysis using Wilcoxon tests, no significant difference was found between ALBI scores before and after the first treatment (p = 0.876). In the evaluation of ALT and AST values, CTCAE Grade 2 ALT/AST hepatotoxicity in one patient (5%) and Grade 1 transient elevation of ALT/AST levels in five patients (21%) were observed after the first treatment. Three patients (12%) had Grade 1 hyperbilirubinemia and two of these patients (8%) also had Grade 1 prolonged INR. After the first treatment, complete response (CR) in one patient (5%), partial response (PR) in 18 patients (%78), stable disease (SD) in one patient (5%) and progressive disease (PR) in 4 patients (%17) was observed.

Before the second treatment, the patients' median ALBI score values were − 2.90 (range: [-3.87] – [-1.91]), while after the treatment, the values were observed as -2.78 (range: [-3.77] – [-2.08]). Before the first treatment, 19 patients were ALBI Grade 1, and 5 patients were Grade 2; after the treatment, the ALBI grade of 4 patients increased from Grade 1 to Grade 2. There was no change in the ALBI grades of the other patients. In the analysis using Wilcoxon tests, no significant difference was found between ALBI scores before and after the second treatment (p = 0.372). In the regression analysis of the change in ALBI score (ΔALBI) and time interval between the first and second treatments, no statistically significant relationship was observed (p = 0.266). In the evaluation of ALT and AST values, CTCAE Grade 2 ALT/AST hepatotoxicity in one patient (5%) and Grade 1 transient elevated ALT/AST levels in three patients (12%) were observed after the second treatment. One patient (5%) had Grade 2, and two patients had Grade 1 hyperbilirubinemia. After the second treatment, complete response (CR) in two patients (8%), partial response (PR) in 16 patients (%67), stable disease (SD) in three patients (13%) and progressive disease (PR) in three patients (%13) was observed.

Before the third treatment, the patients' median ALBI score values were − 2.86 (range: [-3.36] – [-2.37]), while after the treatment, the values were observed as -2.61 (range: [-3.13] – [-1.18]). Before the first treatment, 6 patients were ALBI Grade 1, and one patient was Grade 2; after the treatment, the ALBI grade of two patients increased from Grade 1 to Grade 2, and one patient's grade increased from Grade 2 to Grade 3 who had developed significant hypoalbuminemia (21 g/L) after the treatment. There was no change in the ALBI grades of the other patients. In the analysis using Wilcoxon tests, a statistically significant difference was observed between ALBI scores before and after the third treatment (p = 0.043). In the regression analysis of the ΔALBI and time interval between the second and third treatments, no statistically significant relationship was observed (p = 0.563). In the evaluation of ALT and AST values, only one patient experienced Grade 1 elevated AST/ALT levels according to the CTCAE grading after third treatment. After the third treatment, complete response (CR) in two patients (29%) and partial response (PR) in 5 patients (%71) was observed.

In patients who underwent a fourth treatment, the ALBI grades were observed as Grade 1 both before and after treatment (Fig. 2).

Dosimetric Analysis and Relationship with Toxicity

As the largest group in our study regarding the microspheres used in treatment, we performed multicompartment and voxel-based dosimetry in patients who have been treated with glass microspheres in their first and second treatments (n = 12). In the analysis of dosimetric data, the median whole liver normal tissue mean absorbed radiation dose (D_norm) in patients who experienced ALBI upgrade after the second treatment was 73.44 Gy (range: 50.65–96.23) in the first treatment and 43.81 Gy (range: 31.76–55.86) in the second treatment. In contrast, in patients who did not experience an ALBI upgrade, D_norm was 26.37 Gy (range: 7.59–102.50) in the first treatment (p = 0.218) and 22.87 Gy (range: 5.80–45.76) in the second treatment (p = 0.145).

In the regression analysis of the ΔALBI after the second treatment with dosimetric data, a linear proportional relationship was observed with D_norm values in the patients treated with glass microspheres in both treatments. In the analysis between ΔALBI and the first treatment D_norm values, the R² value was 0.4, indicating a significant relationship (p = 0.008). In the analysis with the second treatment D_norm values, the R² value was 0.22, however the model did not reach statistical significance (p = 0.146). In the analysis with cumulative D_norm values (D_norm value in the first treatment + D_norm value in the second treatment), the R² value was 0.512 (p = 0.007) (Fig. 3). Similarly, a significant relationship was found between ΔALBI and cumulative V20-100 values obtained from dose-volume histograms. Among these, V30 (R²: 0.533, p = 0.008), V40 (R²: 0.545, p = 0.009), and V50 (R²: 0.536, p = 0.009) had the largest R² values (Figs. 4 and 5).

In the patients treated with resin microspheres in first and second treatments (n = 6), one patient had progressed from ALBI Grade 1 to Grade 2 after second treatment and no other ALBI upgrade was observed in other patients. In the patient with ALBI upgrade cumulative D_norm value was 87.68 Gy and the median cumulative D_norm in the other patients was 82.10 Gy (range: 56.84–100.84). In the regression analysis of the ΔALBI after the second treatment and cumulative D_norm values no statistically significant relationship was observed (p = 0.718).

In today's modern personalized nuclear medicine, dosimetric methods have significantly improved the safety of radionuclide treatments. Multicompartment personalized dosimetry has become the standard approach for planning radioembolization, aiming to enhance treatment response while minimizing treatment-related hepatotoxicity. While well-established healthy liver dose thresholds exist for single-treatment planning to mitigate hepatotoxicity, cumulative dose limits for repeated treatments remain unclear. Furthermore, the interval between repeated treatments may influence hepatotoxicity incidence, particularly in patients with limited liver reserve. Hepatotoxicity rates may also differ between patients receiving TARE as a "true repeated treatment" to the same or overlapping perfused volumes versus those receiving it in a sequential treatment design. Sensitivity to radiation toxicity within the same liver volume may change with each treatment session. For these reasons, implementing multicompartment dosimetry in planning repeated TARE sessions remains challenging for nuclear medicine professionals. In this single-center study, we aimed to share our experience with multicompartment dosimetry in patients who have undergone at least two repeated TARE sessions.

In earlier studies on repeated TARE, hepatotoxicity rates were higher compared to more recent studies. Lam M. et al. reported data from eight patients who underwent repeated TARE using the BSA-based dose estimation method, noting two deaths with signs of REILD [10]. Both of these patients had received whole-liver treatments planned using BSA-based estimations, a practice that is no longer routinely considered today due to the risk of over- or undertreatment. Since BSA is not the sole determinant of liver volume and functional reserve, its use can lead to suboptimal dosing, potentially increasing toxicity rates especially in bilobar treatments. In another study, Zarva et al. reported data from 21 patients who underwent repeated TARE with resin microspheres using the BSA method. The authors observed grade 3 or 4 toxicity in three patients [18]. In general, REILD rates after repeated TARE have been reported to be around 2–3%, with toxicity rates appearing to increase in heavily pre-treated patients undergoing treatment in salvage settings [10, 18, 19]. Recently Reed et al. reported their data of hepatotoxicity profile in specific patient group with HCC and underlying cirrhosis. Despite the presence of underlying cirrhosis, they observed grade 3 toxicity in only one patient, who required paracentesis after the first and second treatment cycles [8].

A multitude of factors, such as the heterogeneity of patient populations, the interval between repeated TARE sessions, the type of administered microspheres, and the treated perfused volumes, make it difficult to generalize the results of previous studies. Moreover, a major limitation of the existing data is the lack of a personalized dosimetric approach. In our analysis we only included the patients whose TARE sessions have been performed with personized multicompartment dosimetry. Since there are currently no clear recommended thresholds for cumulative dose to the healthy liver in repeated TARE sessions, multicompartment dosimetry is performed independently for each session. However, in routine clinical practice, to minimize hepatotoxicity, there is a tendency to limit the absorbed dose to healthy liver tissue to lower values when treating the same liver volume repeatedly in our institution. In our patient group, we did not observe any CTCAE grade 3 or 4 toxicity related to AST, ALT, INR, or bilirubin, and only one case of significant hypoalbuminemia, even among patients who received four treatment cycles. However, due to the notable number of patients with CTCAE grade 2 toxicity, we conducted an additional analysis using the ALBI scoring system. The first and second TARE sessions appeared to be safe and well-tolerated, with only a limited number of ALBI score upgrades after treatment. However, following the third TARE session, we observed a significant difference in ALBI scores before and after treatment, with one patient progressing to ALBI grade 3.

In our patient group, due to the presence of patients treated with a combination of glass and resin microspheres, we separately analyzed those who received the same type of microspheres to better assess the dose-toxicity relationships. In patients who received two doses of glass microspheres, Dnorm values in the first and second treatments were higher in those who experienced an ALBI score upgrade compared to those who did not. Moreover, we found that D_norm values in the first treatment and cumulative D_norm values were linearly correlated with ΔALBI levels. A similar relationship was also observed with voxel-based parameters. In the analysis of six patients who underwent two TARE sessions with resin microspheres, we did not find a significant relationship between D_norm and ΔALBI values. Additionally, D_norm values were similar between patients with and without ALBI score upgrades in this group. However, the lack of statistical significance may be due to the limited number of patients in this cohort.

In summary, across the entire patient group, we did not observe any CTCAE grade 3 or 4 toxicities. Only one patient experienced an increase of ALBI grade to 3 with significant hypoalbuminemia after the third TARE session. Based on our analyses, repeated TARE appears to be safe when using a multicompartment dosimetric approach. However, beyond the dosimetric method employed, several other factors may play a crucial role in predicting the safety of repeated TARE. Given the challenges in designing prospective studies with standardized patient selection criteria on this topic, larger multicenter analyses may help identify additional predictors of safety for repeated TARE.

The major limitation of our study is its retrospective design. However, the data of all included patients were thoroughly reviewed and re-evaluated, with toxicity rates carefully recorded. Additionally, patients without follow-up between TARE sessions were excluded to ensure data accuracy and consistency.

Repeated TARE using a multicompartment personalized dosimetric approach appears to be safe, with limited low-grade toxicity. The linear relationship between D_norm and ΔALBI highlights the importance of performing angiographic procedures as selectively as possible, considering the potential need for repeated TARE sessions.

Clinical Trial Number: Not applicable.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

All authors contributed to the study conception and design. Invasive radiological interventions were performed by Emre Can Celebioglu. Image interpretation, data collection and analysis were performed by Burak Demir, Cigdem Soydal, Mine Araz and Irem Mesci. Statistical analysis was done by Burak Demir and Cigdem Soydal. The first draft of the manuscript was written by Cigdem Soydal, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Ankara University (No. İ01-100-25).

Consent to Participate

Since this is a retrospective study, individual consent to participate could not be obtained. However, the study was approved by the Ethics Committee of Ankara University, and informed consent was obtained from all patients prior to treatment and all other procedures.

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Table 1 is available in the Supplementary Files section.

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Safety of Repeated Trans-arterial Radioembolization with Multicompartment Dosimetry

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Abstract

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Introduction

Materials and Methods

Patients and Study Design

Radioembolization Procedure, Y-90 PET Protocol and Post-Therapy Dosimetry

Statistical Analysis

Results

Patient Population and Descriptive Data

Procedural Characteristics

Toxicity Analysis

Dosimetric Analysis and Relationship with Toxicity

Discussion

Conclusion

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Table 1

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