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Purpose: In 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). Methods: The 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. Results: Committee 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. Conclusion: Updated 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. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the accuracy and biases of predicted lung shunt fraction (LSF) and lung dose (LD) calculations via 99mTc‐macro‐aggregated albumin (99mTc‐MAA) planar imaging for treatment planning of 90Y‐microsphere radioembolization. Methods and materials: LSFs in 52 planning and LDs in 44 treatment procedures were retrospectively calculated, in consecutive radioembolization patients over a 2 year interval, using 99mTc‐MAA planar and SPECT/CT imaging. For each procedure, multiple planar LSFs and LDs were calculated using different: (1) contours, (2) views, (3) liver 99mTc‐MAA shine‐through compensations, and (4) lung mass estimations. The accuracy of each planar‐based LSF and LD methodology was determined by calculating the median (range) absolute difference from SPECT/CT‐based LSF and LD values, which have been demonstrated in phantom and patient studies to more accurately and reliably quantify the true LSF and LD values. Results: Standard‐of‐care LSF using geometric mean of lung and liver contours had median (range) absolute over‐estimation of 4.4 percentage points (pp) (0.9 to 11.9 pp) from SPECT/CT LSF. Using anterior views only decreased LSF errors (2.4 pp median, −1.1 to +5.7 pp range). Planar LD over‐estimations decreased when using single‐view versus geometric‐mean LSF (1.3 vs. 2.6 Gy median and 7.2 vs. 18.5 Gy maximum using 1000 g lung mass) but increased when using patient‐specific versus standard‐man lung mass (2.4 vs. 1.3 Gy median and 11.8 vs. 7.2 Gy maximum using single‐view LSF). Conclusions: Calculating planar LSF from lung and liver contours of a single view and planar LD using that same LSF and 1000 g lung mass was found to improve accuracy and minimize bias in planar lung dosimetry. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The purpose of this study is to perform post-administration dosimetry in yttrium-90 radioembolization through micro-CT imaging of radiopaque microsphere distributions in a porcine renal model and explore the impact of spatial resolution of an imaging system on the extraction of specific dose metrics. Following the administration of radiopaque microspheres to the kidney of a hybrid farm pig, the kidney was explanted and imaged with micro-CT. To produce an activity distribution, 400 MBq of yttrium-90 activity was distributed throughout segmented voxels of the embolized vasculature based on an established linear relationship between microsphere concentration and CT voxel value. This distribution was down-sampled to coarser isotropic grids ranging in voxel size from 2.5 to 15 mm to emulate nominal resolutions comparable to those found in yttrium-90 PET and Bremsstrahlung SPECT imaging. Dose distributions were calculated through the convolution of activity distributions with dose-voxel kernels generated using the GATE Monte Carlo toolkit. Contours were computed to represent normal tissue and target volumes. Dose-volume histograms, dose metrics, and dose profiles were compared to a ground truth dose distribution computed with GATE. The mean dose to the target for all studied voxel sizes was found to be within 5.7% of the ground truth mean dose. was shown to be strongly correlated with image voxel size of the dose distribution (r2 = 0.90). is cited in the literature as an important dose metric and its dependence on voxel size suggests higher resolution dose distributions may provide new perspectives on dose-response relationships in yttrium-90 radioembolization. This study demonstrates that dose distributions with large voxels incorrectly homogenize the dose by attributing escalated doses to normal tissues and reduced doses in high-dose target regions. High-resolution micro-CT imaging of radiopaque microsphere distributions can provide increased confidence in characterizing the absorbed dose heterogeneity in yttrium-90 radioembolization. [ABSTRACT FROM AUTHOR]

Purpose: 99mTc‐MAA‐SPECT/CT may be used in 90Y‐glass microsphere radioembolization treatment planning to assess perfused liver volumes and absorbed dose distributions. The partition model (PM) offers a more detailed planning dosimetry option beyond the single‐compartment model more traditionally used in 90Y radioembolization. As 90Y radioembolization treatments shift toward activities and doses that aim to achieve tumor control, accurate and reliable treatment planning dosimetry for both tumors and normal liver (NL) becomes more critical. In this work, we explore the accuracy and precision of 90Y dosimetry predictions from pretherapy 99mTc‐MAA and PM. Methods: Both PM and voxel dosimetry models were used to calculate tumor and NL mean doses using both planning 99mTc‐MAA and verification 90Y‐SPECT/CT in this retrospective analysis of hepatocellular carcinoma cases treated with glass microspheres (NCT01900002, n = 32). Linear regression models were developed at first access, and then later correct, the estimates by (a) 99mTc‐MAA for 90Y voxel dosimetry and (b) 99mTc‐MAA PM for voxel dosimetry, separately for both tumors and NL. Bland‐Altman analysis was then used to evaluate the accuracy and precision of the regression model predictions with the mean bias and 95% prediction intervals (PI, ±1.96σ). Two categories of cases were stratified (catheter matched vs catheter unmatched) by establishing the level of 99mTc‐MAA and 90Y catheter position alignment. Only catheter‐matched cases were included in the 99mTc‐MAA vs 90Y voxel dosimetry comparison, while all cases were used to compare dosimetry models (PM vs voxel). Results: Half (16/32) of cases were deemed catheter matched. 99mTc‐MAA could reliably predict NL doses in catheter‐matched cases after application of the linear model, with mean bias (PI) of −1% (±31%). PM was equivalent to voxel dosimetry for NL doses with mean bias (PI) of 0% (±1%). Even among catheter‐matched cases, 99mTc‐MAA planning for 90Y tumor voxel doses was poor, overestimating dose by an average of nearly 40%. Upon application of the linear model, 99mTc‐MAA predictions for 90Y tumor voxel dose were only minimally biased (−4%) but possessed very large PI (±104%). PM predictions for tumor voxel dose using the linear model also showed small bias (−6%) but maintained similarly high PI of ±90%. Cases with tumors representing a large majority (>80%) of the total tumor volume demonstrated the best scenarios for 99mTc‐MAA and PM tumor dose predictions, with mean biases (PI) of −3% (±53%) and −4% (±21%), respectively. Conclusion: The unconditional use of 99mTc‐MAA to predict 90Y dosimetry across all cases is not recommended due to: (a) demonstrated the risk of unmatched catheter positions between procedures, and (b) large bias and uncertainty in 99mTc‐MAA predictions in cases with matched catheter locations. However, NL voxel dose predictions with 99mTc‐MAA are clinically viable and either PM or voxel dosimetry can be used to produce equivalent predictions. Both 99mTc‐MAA and PM can provide tumor dose predictions with potential clinical utility, but only in catheter‐matched cases and with tumors comprising a clear majority (>80%) of the total tumor volume. These findings stratify the predictive fidelity of 99mTc‐MAA‐ and PM‐based treatment planning for 90Y dosimetry in improving treatment outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: 90Y‐microsphere selective internal radiation therapy (90Y‐SIRT or 90Y‐radioembolization) is used in the management of unresectable liver tumors. 90Y‐SIRT presents a unique situation where the total 90Y activity inside the liver can be determined with high accuracy (> 95%). 90Y bremsstrahlung single‐photon emission computed tomography (SPECT)/computed tomography (CT) can be self‐calibrated to provide quantitative images that facilitate voxel‐level absorbed dose calculations. We investigated the effects of different approaches for 90Y‐SPECT self‐calibration on the quantification of absorbed doses following 90Y‐SIRT. Methods: 90Y bremsstrahlung SPECT/CT images of 31 patients with hepatocellular carcinoma, collected following 90Y‐SIRT, were analyzed, yielding 48 tumor and 31 normal liver contours. We validated the accuracy of absorbed doses calculated by a commercial software against those calculated using Monte Carlo‐based radiation transport. The software package was used to analyze the following definitions of SPECT volume of interest used for 90Y‐SPECT self‐calibration: (a) SPECT field‐of‐view (FOV), (b) chest‐abdomen contour, (c) total liver contour, (d) total liver contour expanded by 5 mm, and (e) total liver contour contracted by 5 mm. Linear correlation and Bland–Altman analysis were performed for tumor and normal liver tissue absorbed dose volume histogram metrics between the five different approaches for 90Y‐SPECT self‐calibration. Results: The mean dose calculated using the commercial software was within 3% of Monte Carlo for tumors and normal liver tissues. The tumor mean dose calculated using the chest‐abdomen calibration was within 2% of that calculated using the SPECT FOV, whereas the doses calculated using the total liver contour, expanded total liver contour, and contracted total liver contour were within 68%, 47%, and 107%, respectively, of doses calculated using the SPECT FOV. The normal liver tissue mean dose calculated using the chest‐abdomen contour was within 1.3% of that calculated using the SPECT FOV, whereas the doses calculated using the total liver contour, expanded total liver contour, and contracted total liver contour were within 73%, 50%, and 114%, respectively, of doses calculated using the SPECT FOV. Conclusions: The mean error of < 3% for commercial software can be considered clinically acceptable for 90Y‐SIRT dosimetry. Absorbed dose quantification using 90Y‐SPECT self‐calibration with the chest‐abdomen contour was equivalent to that calculated using the SPECT FOV, but self‐calibration with the total liver contour yielded substantially higher (~70%) dose values. The large biases revealed by our study suggest that consistent absorbed dose calculation approaches are essential when comparing 90Y‐SIRT dosimetry between different clinical studies. [ABSTRACT FROM AUTHOR]

Radioembolization is an established treatment for chemoresistant and unresectable liver cancers. Currently, treatment planning is often based on semi-empirical methods, which yield acceptable toxicity profiles and have enabled the large-scale application in a palliative setting. However, recently, five large randomized controlled trials using resin microspheres failed to demonstrate a significant improvement in either progression-free survival or overall survival in both hepatocellular carcinoma and metastatic colorectal cancer. One reason for this might be that the activity prescription methods used in these studies are suboptimal for many patients.In this review, the current dosimetric methods and their caveats are evaluated. Furthermore, the current state-of-the-art of image-guided dosimetry and advanced radiobiological modeling is reviewed from a physics’ perspective. The current literature is explored for the observation of robust dose-response relationships followed by an overview of recent advancements in quantitative image reconstruction in relation to image-guided dosimetry.This review is concluded with a discussion on areas where further research is necessary in order to arrive at a personalized treatment method that provides optimal tumor control and is clinically feasible. [ABSTRACT FROM AUTHOR]

Purpose: To quantify differences that exist between dosimetry models used for 90Y selective internal radiation therapy (SIRT).Methods and Materials: Retrospectively, 37 tumors were delineated on 19 post-therapy quantitative 90Y single photon emission computed tomography/computed tomography scans. Using matched volumes of interest (VOIs), absorbed doses were reported using 3 dosimetry models: glass microsphere package insert standard model (SM), partition model (PM), and Monte Carlo (MC). Univariate linear regressions were performed to predict mean MC from SM and PM. Analysis was performed for 2 subsets: cases with a single tumor delineated (best case for PM), and cases with multiple tumors delineated (typical clinical scenario). Variability in PM from the ad hoc placement of a single spherical VOI to estimate the entire normal liver activity concentration for tumor (T) to nontumoral liver (NL) ratios (TNR) was investigated. We interpreted the slope of the resulting regression as bias and the 95% prediction interval (95%PI) as uncertainty. MCNLsingle represents MC absorbed doses to the NL for the single tumor patient subset; other combinations of calculations follow a similar naming convention.Results: SM was unable to predict MCTsingle or MCTmultiple (p>.12, 95%PI >±177 Gy). However, SMsingle was able to predict (p<.012) MCNLsingle, albeit with large uncertainties; SMsingle and SMmultiple yielded biases of 0.62 and 0.71, and 95%PI of ±40 and ± 32 Gy, respectively. PMTsingle and PMTmultiple predicted (p<2E-6) MCTsingle and MCTmultiple with biases of 0.52 and 0.54, and 95%PI of ±38 and ± 111 Gy, respectively. The TNR variability in PMTsingle increased the 95%PI for predicting MCTsingle (bias = 0.46 and 95%PI = ±103 Gy). The TNR variability in PMTmultiple modified the bias when predicting MCTmultiple (bias = 0.32 and 95%PI = ±110 Gy).Conclusions: The SM is unable to predict mean MC tumor absorbed dose. The PM is statistically correlated with mean MC, but the resulting uncertainties in predicted MC are large. Large differences observed between dosimetry models for 90Y SIRT warrant caution when interpreting published SIRT absorbed doses. To reduce uncertainty, we suggest the entire NL VOI be used for TNR estimates when using PM. [ABSTRACT FROM AUTHOR]