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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., Competing Interests: Declarations. Conflicts of Interest/Competing interests: Marnix Lam, MD, PhD: Is a consultant for Boston Scientific, Terumo and Quirem Medical. He receives research support from Boston Scientific, Terumo and Quirem Medical. The UMC Utrecht receives royalties from Quirem Medical. Etienne Garin, MD, PhD: Serves as a consultant for Boston Scientific. Paul Haste, MD: Is a consultant for Boston Scientific. Alban Denys, MD, MSc: Is a consultant for Cook, Neuwave, and received grants from Johnson and Johnson. Brian Geller, MD: Nothing to disclose. S. Cheenu Kappadath, PhD: Is a consultant for Boston Scientific, Sirtex Medical, and Terumo Medical. He receives research support from Boston Scientific, Sirtex Medical and ABK Biomedical. Cuneyt Turkmen, MD: Is a consultant for Boston Scientific. Daniel Y Sze, MD, PhD: Was a consultant for Argon, Artio Medical, Astra-Zeneca, Bayer, BlackSwan Vascular, Boston Scientific, Bristol Meyers Squibb, Eisai, FludX, W.L. Gore, Guerbet, Koli, Sirtex, Terumo, TriSalus, and Varian; received institutional research support from Boston Scientific, W.L. Gore, Merit Medical, and Sirtex; held equity in BlackSwan Vascular, Confluent Medical, Koli, Proteus Digital Health, Radiaction, and TriSalus; and serves on data safety monitoring boards for W.L. Gore and Replimune. Hamad Saleh Alsuhaibani, MD: Nothing to disclose. Ken Herrmann, MD: Reports personal fees from Bayer, personal fees and other from Sofie Bioscienes, personal fees from SIRTEX, non-financial support from ABX, personal fees from Adacap, personal fees from Curium, personal fees from Endocyte, grants and personal fees from Boston Scientific, personal fees from IPSEN, personal fees from Siemens Healthineers, personal fees from GE Healthcare, personal fees from Amgen, personal fees from Novartis, personal fees from ymabs, personal fees from Aktis Oncology, personal fees from Theragnostics, personal fees from Pharma15, outside the submitted work. Marco Maccauro, MD: Nothing to disclose. Murat Cantasdemir, MD: Is a consultant for Boston Scientific. Matthew Dreher, PhD: Works for Boston Scientific. Kirk D. Fowers, PhD: Works for Boston Scientific. Vanessa Gates, PhD: Is a consultant for Boston Scientific. Riad Salem, MD: Is a consultant for Boston Scientific, AstraZeneca, Genentech, Sirtex, Cook, Eisai, Bard and QED Therapeutics. Ethics approval: Not Applicable. Consent to participate: Not Applicable., (© 2024. The Author(s).)

Purpose: To determine 6-month interim safety, effectiveness, and multimodal imageability of imageable glass microsphere yttrium-90 ( 90 Y) radioembolization for unresectable hepatocellular carcinoma (HCC) in a first-in-human trial., Materials and Methods: Imageable microspheres (Eye90 Microspheres; ABK Biomedical, Halifax, Nova Scotia, Canada), a U.S. Food and Drug Administration (FDA) Breakthrough-Designated Device consisting of glass radiopaque 90 Y microspheres visible on computed tomography (CT) and single photon emission CT (SPECT), were used to treat 6 subjects with unresectable HCC. Patients underwent selective (≤2 segments) treatment in a prospective open-label pilot trial. Key inclusion criteria included liver-only HCC, performance status ≤1, total lesion diameter ≤9 cm, and Child-Pugh A status. Prospective partition dosimetry was utilized. Safety (measured by Common Terminology Criteria for Adverse Events [CTCAE] v5), multimodal imageability on CT and SPECT, and 3- and 6-month imaging response by modified Response Evaluation Criteria in Solid Tumors on magnetic resonance (MR) imaging were evaluated., Results: Seven tumors in 6 subjects were treated and followed to 180 days. Administration success was 100%. Microsphere distribution measured by radiopacity on CT correlated with SPECT. Ninety-day target lesion complete response (CR) was observed in 3 of 6 subjects (50%) and partial response (PR) in 2 (33.3%). At 180 days, target lesion CR was maintained in 3 subjects (50%) and PR in 1 (16.7%). Two subjects could not be reassessed, having undergone intervening chemoembolization. All subjects reported adverse events (AEs), and 5 reported AEs related to treatment. There were no treatment-related Grade ≥3 AEs., Conclusions: Radioembolization using imageable microspheres was safe and effective in 6 subjects with unresectable HCC at 6-month interim analysis. Microsphere distribution by radiopacity on CT correlated with radioactivity distribution by SPECT, providing previously unavailable CT-based tumor targeting information., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Personalized dosimetry improves overall survival (OS) in patients with hepatocellular carcinoma (HCC) treated with glass 90 Y radioembolization. This study evaluated personalized tumor dose (TD) as a predictor of OS, progression-free survival (PFS), and local duration of response (DOR) in patients with surgically unresectable HCC treated with resin 90 Y radioembolization., Patients and Methods: This prospective, single-center, single-arm clinical trial (NCT04172714) evaluated the efficacy of scout activity of resin 90 Y versus 99m Tc-MAA for treatment planning. A secondary aim of this study was to evaluate personalized dosimetry as a predictor of OS, PFS, and DOR. Partition dosimetry model was utilized for nonsegmental therapies with targeted TD >200 Gy and nontumoral liver dose <70 Gy. Single compartment dose of 200 Gy was used for segmentectomies. OS, PFS, and local DOR from 90 Y was estimated using Kaplan-Meier estimation with log-rank analysis used to determine predictors of prolonged survival., Findings: Thirty patients with treatment-naive HCC and 33 tumors (19 segmental and 14 nonsegmental) were included. Overall, 18 patients underwent segmental Y90-RE and 12 underwent non-segmental/lobar therapies. The mean 90 Y TD was 493 Gy. The median follow-up since enrollment into the study was 37 months. The mean OS was 32.2 months for the entire cohort. A total of 5 patients underwent orthotopic liver transplantation post 90 Y and were excluded from further survival analysis. The mean OS for the remainder of the cohort was 30.1 months (median not reached). The mean TD >250 Gy resulted in prolonged mean OS and PFS. The median local DOR was 32.7 months with mean TD 330 Gy predicting prolonged DOR., Interpretation: For patients with surgically unresectable HCC treated with resin 90 Y, there is mean TD threshold predicting prolonged OS, PFS, and local DOR. Therefore, there should be further emphasis on personalized dosimetry for optimization of patient outcomes., Competing Interests: Conflicts of interest and sources of funding: This study was jointly funded by Radiological Society of North America and Sirtex Medical Ltd. The study sponsors had no role in the design, data interpretation, or decision to publish this study. N.K. discloses he works as a consultant for Sirtex Medical Ltd. No other potential conflicts of interest relevant to this article exist., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: There is an increasing body of evidence indicating Y90 dose thresholds for tumor response and treatment-related toxicity. These thresholds are poorly studied in resin Y90, particularly in hepatocellular carcinoma (HCC)., Purpose: To evaluate the efficacy of prospective voxel-based dosimetry for predicting treatment response and adverse events (AEs) in patients with HCC undergoing resin-based Y90 radioembolization., Materials and Methods: This correlative study was based on a prospective single-arm clinical trial (NCT04172714), which evaluated the efficacy of low/scout (555 MBq) activity of resin-based Y90 for treatment planning. Partition model was used with goal of tumor dose (TD) > 200 Gy and non-tumoral liver dose (NTLD) < 70 Gy for non-segmental therapies. Single compartment dose of 200 Gy was used for segmentectomies. Prescribed Y90 activity minus scout activity was administered for therapeutic Y90 followed by Y90-PET/CT. Sureplan® (MIM Software, Cleveland, OH) was used for dosimetry analysis. Treatment response was evaluated at 3 and 6 months. Receiver operating characteristic curve determined TD response threshold for objective response (OR) and complete response (CR) as well as non-tumor liver dose (NTLD) threshold that predicted AEs., Results: N = 30 patients were treated with 33 tumors (19 segmental and 14 non-segmental). One patient died before the first imaging, and clinical follow-up was excluded from this analysis. Overall, 26 (81%) of the tumors had an OR and 23 (72%) had a CR. A mean TD of 253 Gy predicted an OR with 92% sensitivity and 83% specificity (area under the curve (AUC = 0.929, p < 0.001). A mean TD of 337 Gy predicted a CR with 83% sensitivity and 89% specificity (AUC = 0.845, p < 0.001). A mean NTLD of 81 and 87 Gy predicted grade 3 AEs with 100% sensitivity and 100% specificity in the non-segmental cohort at 3- and 6-month post Y90, respectively., Conclusion: In patients with HCC undergoing resin-based Y90, there are dose response and dose toxicity thresholds directly affecting outcomes., Clinical Trial Number: NCT04172714., (© 2023. The Author(s).)

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., (© 2022. The Author(s).)

Purpose: To compare the accuracy and safety of 0.56 GBq resin yttrium-90 ( 90 Y) (scout 90 Y) microspheres with those of technetium-99m macroaggregated albumin (MAA) in predicting the therapeutic 90 Y (Rx 90 Y) dose for patients with hepatocellular carcinoma (HCC)., Materials and Methods: This prospective single-arm clinical trial (Clinicaltrials.gov: NCT04172714) recruited patients with HCC. Patients underwent same-day mapping with MAA and scout 90 Y. Rx 90 Y activity was administered 3 days after mapping. Using paired t test and Pearson correlation, the tumor-to-normal ratio (TNR), lung shunt fraction (LSF), predicted mean tumor dose (TD), and nontumoral liver dose (NTLD) by MAA and scout 90 Y were compared with those by Rx 90 Y. Bland-Altman plots compared the level of agreement between the TNR and LSF of scout 90 Y and MAA with that of Rx 90 Y. The safety of scout 90 Y was evaluated by examining the discrepancy in extrahepatic activity between MAA and scout 90 Y., Results: Thirty patients were treated using 19 segmental and 14 nonsegmental (ie, 2 contiguous segments or nonsegmental) therapies. MAA had weak LSF, moderate TNR, and moderate TD linear correlation with Rx 90 Y. Scout 90 Y had a moderate LSF, strong TNR, strong TD, and very strong NTLD in correlation with those of Rx 90 Y. Furthermore, the TNR and LSF of scout 90 Y had a stronger agreement with those of Rx 90 Y than with those of MAA. In the nonsegmental subgroup, MAA had no significant correlation with the TD and NTLD of Rx 90 Y, whereas scout 90 Y had a very strong correlation with both of these factors. In the segmental subgroup, both MAA and scout 90 Y had a strong linear correlation with the TD and NTLD of Rx 90 Y., Conclusions: Compared with MAA, scout 90 Y is a more accurate surrogate for Rx 90 Y biodistribution for nonsegmental therapies., (Copyright © 2022 SIR. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the accuracy and biases of predicted lung shunt fraction (LSF) and lung dose (LD) calculations via 99m Tc-macro-aggregated albumin ( 99m Tc-MAA) planar imaging for treatment planning of 90 Y-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 99m Tc-MAA planar and SPECT/CT imaging. For each procedure, multiple planar LSFs and LDs were calculated using different: (1) contours, (2) views, (3) liver 99m Tc-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., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Purpose: To develop a multidisciplinary consensus for high quality multidisciplinary implementation of brachytherapy using Yttrium-90 ( 90 Y) microspheres transarterial radioembolization ( 90 Y TARE) for primary and metastatic cancers in the liver., Methods and Materials: Members of the American Brachytherapy Society (ABS) and colleagues with multidisciplinary expertise in liver tumor therapy formulated guidelines for 90 Y TARE for unresectable primary liver malignancies and unresectable metastatic cancer to the liver. The consensus is provided on the most recent literature and clinical experience., Results: The ABS strongly recommends the use of 90 Y microsphere brachytherapy for the definitive/palliative treatment of unresectable liver cancer when recommended by the multidisciplinary team. A quality management program must be implemented at the start of 90 Y TARE program development and follow-up data should be tracked for efficacy and toxicity. Patient-specific dosimetry optimized for treatment intent is recommended when conducting 90 Y TARE. Implementation in patients on systemic therapy should account for factors that may enhance treatment related toxicity without delaying treatment inappropriately. Further management and salvage therapy options including retreatment with 90 Y TARE should be carefully considered., Conclusions: ABS consensus for implementing a safe 90 Y TARE program for liver cancer in the multidisciplinary setting is presented. It builds on previous guidelines to include recommendations for appropriate implementation based on current literature and practices in experienced centers. Practitioners and cooperative groups are encouraged to use this document as a guide to formulate their clinical practices and to adopt the most recent dose reporting policies that are critical for a unified outcome analysis of future effectiveness studies., Competing Interests: Conflicts of Interest Dr. Sharma received honoraria, research grant, and is a consultant for SIRTEX Medical Inc. Dr. Kappadath received honoraria and research funding from Boston Scientific, SIRTEX Medical, and ABK Biomedical. Dr. Choung received honoraria from SIRTEX Medical Inc. Dr Jabbour is a consultant for Merck & Co Inc; Syntactx, IMX Medical; and has grant funding from the NIH and Merck & Co, Inc. Dr Jeyarajah is a consultant for Angiodynamics, SIRTEX Medical Inc., Ethicon. Dr. Liu is a consultant for SIRTEX Medical Inc, Eisai Pharmaceuticals, and a speaker for Astra Zeneca and Eisa Pharmaceuticals. Dr. Meyer has a research grant and honorarium from Varian Medical Systems. Dr. Mikell has a research grant funding from Varian. Dr. Patel is a consultant to SIRTEX Medical and Medtronic Inc. and a speaker for Boston Scientific. Drs. Folkert, Kennedey, Gibbs, Yang, and Mourtada report no conflict of interest., (Copyright © 2022 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: There are no published data on organ doses following intra-hepatic-arterial administration of 99m Tc-macroaggregated-albumin (IHA 99m Tc-MAA) routinely used in 90 Y-radioembolization treatment planning to assess intra- and extra-hepatic depositions and calculate lung-shunt-fraction (LSF). We propose a method to model the organ doses following IHA 99m Tc-MAA that incorporates three in vivo constituent biodistributions, the 99m Tc-MAA that escape the liver due to LSF, and the 99m Tc-MAA dissociation fraction (DF)., Methods: The potential in vivo biodistributions for IHA 99m Tc-MAA are: Liver-Only MAA with all activity sequestered in the liver (LSF = 0&DF = 0), Intravenous MAA with all activity transferred intravenously as 99m Tc-MAA (LSF = 1&DF = 0), and Intravenous Pertechnetate with all activity is transferred intravenously as 99m Tc-pertechnetate (LSF = 0&DF = 1). Organ doses for Liver-Only MAA were determined using OLINDA/EXM 2.2, where liver was modeled as the source organ containing 99m Tc-MAA, while those for Intravenous MAA and Intravenous Pertechnetate were from ICRP 128. Organ doses for the general case can be determined as a weighted-linear-combination of the three constituent biodistributions depending on the LSF and DF. The maximum-dose scenario was modeled by selecting the highest dose rate for each organ amongst the three constituent cases., Results: For Liver-Only MAA, the liver as source organ received the highest dose at 98.6 and 126 mGy/GBq for the adult male and adult female phantoms, respectively; all remaining organs received <27 and <32 mGy/GBq. For Intravenous MAA, the lung as source organ received the highest dose at 66 and 97 mGy/GBq; all remaining organs received <16 and <21 mGy/GBq. The organ with the highest dose for Intravenous Pertechnetate was the upper-large-intestinal wall at 56 and 73 mGy/GBq; all remaining organs received <26 and <34 mGy/GBq. The liver and lung doses for the maximum-dose scenario with 5 mCi (185 MBq) 99m Tc-MAA were estimated at 18.2 and 12.2 mGy, and 23.3 and 17.9 mGy, for the adult male and adult female phantoms, respectively., Conclusion: Organ dose estimates following IHA 99m Tc-MAA based on constituent biodistribution models and patient-specific LSF and DF values have been derived. Liver and lung were the organs with highest dose, receiving at most 15-25 mGy in the maximum-dose scenario, following 5 mCi IHA 99m Tc-MAA., (© 2022 American Association of Physicists in Medicine.)

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., (© 2022. The Author(s).)

Background: Selective internal radiation therapy (SIRT) with yttrium-90 ( 90 Y) resin microspheres is an established locoregional treatment option for unresectable hepatocellular carcinoma (HCC), which delivers a lethal dose of radiation to hepatic tumors, while sparing surrounding healthy tissue. DOORwaY90 is a prospective, multicenter, open-label, single arm study, designed to evaluate the safety and effectiveness of 90 Y resin microspheres as first-line treatment in patients with unresectable/unablatable HCC. It is unique in that it is the first study with resin microspheres to utilize a personalized 90 Y dosimetry approach, and independent review for treatment planning and response assessment., Methods: Eligibility criteria include unresectable/unablatable HCC, Barcelona Clinic Liver Cancer stage A, B1, B2, or C with a maximal single tumor diameter of ≤ 8 cm, and a sum of maximal tumor diameters of ≤ 12 cm, and at least one tumor ≥ 2 cm (long axis) per localized, modified Response Evaluation Criteria in Solid Tumors. Partition model dosimetry is used to determine the optimal dose; the target mean dose to tumor is ≥ 150 Gy. Patients are assessed at baseline and at regular intervals up until 12 months of treatment for response rates, safety, and quality of life (QoL). Post-treatment dosimetry is used to assess dose delivered to tumor and consider if retreatment is necessary. The co-primary endpoints are best objective response rate and duration of response. Secondary endpoints include grade ≥ 3 toxicity, QoL, and incidence of liver resection and transplantation post SIRT. Target recruitment is 100 patients., Discussion: The results of this trial should provide further information on the potential use of SIRT with 90 Y resin microspheres as first-line therapy for unresectable HCC., Trial Registration: Clinicaltrials.gov; NCT04736121; date of 1st registration, January 27, 2021, https://clinicaltrials.gov/ct2/show/NCT04736121 ., (© 2022. The Author(s).)

Radioembolization, also known as selective internal radiation therapy (SIRT), is an established treatment for the management of patients with unresectable liver tumors. Advances in liver dosimetry and new knowledge about tumor dose-response relationships have helped promote the well-tolerated use of higher prescribed doses, consequently transitioning radioembolization from palliative to curative therapy. Lung dosimetry, unfortunately, has not seen the same advances in dose calculation methodology and renewed consensus in dose limits as normal liver and tumor dosimetry. Therefore, the efficacy of curative radioembolization may be compromised in patients where the current lung dose calculations unnecessarily limit the administered activity. The field is thus at a stage where a systematic review and update of lung dose limits is necessary to advance the clinical practice of radioembolization. This work summarizes the historical context and literature for origins of the current lung dose limits following radioembolization, that is, the 25-year-old, single institution, small patient cohort series that helped establish the lung shunt fraction and dose limits. Newer clinical evidence based on larger patient cohorts that challenges the historical data on lung dose limits are then discussed. We conclude by revisiting the rationale for current lung dose limits and by proposing a staged approach to advance the field of lung dosimetry and thus the practice of radioembolization as a whole., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: A multidisciplinary expert panel convened to formulate state-of-the-art recommendations for optimisation of selective internal radiation therapy (SIRT) with yttrium-90 ( 90 Y)-resin microspheres., Methods: A steering committee of 23 international experts representing all participating specialties formulated recommendations for SIRT with 90 Y-resin microspheres activity prescription and post-treatment dosimetry, based on literature searches and the responses to a 61-question survey that was completed by 43 leading experts (including the steering committee members). The survey was validated by the steering committee and completed anonymously. In a face-to-face meeting, the results of the survey were presented and discussed. Recommendations were derived and level of agreement defined (strong agreement ≥ 80%, moderate agreement 50%-79%, no agreement ≤ 49%)., Results: Forty-seven recommendations were established, including guidance such as a multidisciplinary team should define treatment strategy and therapeutic intent (strong agreement); 3D imaging with CT and an angiography with cone-beam-CT, if available, and 99m Tc-MAA SPECT/CT are recommended for extrahepatic/intrahepatic deposition assessment, treatment field definition and calculation of the 90 Y-resin microspheres activity needed (moderate/strong agreement). A personalised approach, using dosimetry (partition model and/or voxel-based) is recommended for activity prescription, when either whole liver or selective, non-ablative or ablative SIRT is planned (strong agreement). A mean absorbed dose to non-tumoural liver of 40 Gy or less is considered safe (strong agreement). A minimum mean target-absorbed dose to tumour of 100-120 Gy is recommended for hepatocellular carcinoma, liver metastatic colorectal cancer and cholangiocarcinoma (moderate/strong agreement). Post-SIRT imaging for treatment verification with 90 Y-PET/CT is recommended (strong agreement). Post-SIRT dosimetry is also recommended (strong agreement)., Conclusion: Practitioners are encouraged to work towards adoption of these recommendations.

Purpose: 99m Tc-MAA-SPECT/CT may be used in 90 Y-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 90 Y radioembolization. As 90 Y 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 90 Y dosimetry predictions from pretherapy 99m Tc-MAA and PM., Methods: Both PM and voxel dosimetry models were used to calculate tumor and NL mean doses using both planning 99m Tc-MAA and verification 90 Y-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) 99m Tc-MAA for 90 Y voxel dosimetry and (b) 99m Tc-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 99m Tc-MAA and 90 Y catheter position alignment. Only catheter-matched cases were included in the 99m Tc-MAA vs 90 Y 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. 99m Tc-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, 99m Tc-MAA planning for 90 Y tumor voxel doses was poor, overestimating dose by an average of nearly 40%. Upon application of the linear model, 99m Tc-MAA predictions for 90 Y 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 99m Tc-MAA and PM tumor dose predictions, with mean biases (PI) of -3% (±53%) and -4% (±21%), respectively., Conclusion: The unconditional use of 99m Tc-MAA to predict 90 Y 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 99m Tc-MAA predictions in cases with matched catheter locations. However, NL voxel dose predictions with 99m Tc-MAA are clinically viable and either PM or voxel dosimetry can be used to produce equivalent predictions. Both 99m Tc-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 99m Tc-MAA- and PM-based treatment planning for 90 Y dosimetry in improving treatment outcomes., (© 2020 American Association of Physicists in Medicine.)

Purpose: Peptide receptor radionuclide therapy (PRRT) and radioembolization are increasingly used in neuroendocrine neoplasms patients. However, concerns have been raised on cumulative hepatotoxicity. The aim of this sub-analysis was to investigate hepatotoxicity of yttrium-90 resin microspheres radioembolization in patients who were previously treated with PRRT., Methods: Patients treated with radioembolization after systemic radionuclide treatment were retrospectively analysed. Imaging response according to response evaluation criteria in solid tumours (RECIST) v1.1 and clinical response after 3 months were collected. Clinical, biochemical and haematological toxicities according to common terminology criteria for adverse events (CTCAE) v4.03 were also collected. Specifics on prior PRRT, subsequent radioembolization treatments, treatments after radioembolization and overall survival (OS) were collected., Results: Forty-four patients were included, who underwent a total of 58 radioembolization procedures, of which 55% whole liver treatments, at a median of 353 days after prior PRRT. According to RECIST 1.1, an objective response rate of 16% and disease control rate of 91% were found after 3 months. Clinical response was seen in 65% (15/23) of symptomatic patients after 3 months. Within 3 months, clinical toxicities occurred in 26%. Biochemical and haematological toxicities CTCAE grade 3-4 occurred in ≤ 10%, apart from lymphocytopenia (42%). Radioembolization-related complications occurred in 5% and fatal radioembolization-induced liver disease in 2% (one patient). A median OS of 3.5 years [95% confidence interval 1.8-5.1 years] after radioembolization for the entire study population was found., Conclusion: Radioembolization after systemic radionuclide treatments is safe, and the occurrence of radioembolization-induced liver disease is rare., Level of Evidence: 4, case series.

Purpose: Radioembolization of liver metastases of neuroendocrine neoplasms (NEN) has shown promising results; however, the current literature is of limited quality. A large international, multicentre retrospective study was designed to address several shortcomings of the current literature., Materials: 244 NEN patients with different NEN grades were included., Methods: Primary outcome parameters were radiologic response 3 and 6 months after treatment according to RECIST 1.1 and mRECIST. Secondary outcome parameters included clinical response, clinical and biochemical toxicities., Results: Radioembolization resulted in CR in 2%, PR in 14%, SD in 75% and PD 9% according to RECIST 1.1 and in CR in 8%, PR in 35%, SD in 48% and PD in 9% according to mRECIST. Objective response rates improved over time in 20% and 26% according to RECIST 1.1. and mRECIST, respectively. Most common new grade 3-4 biochemical toxicity was lymphocytopenia (6.7%). No unexpected clinical toxicities occurred. Radioembolization-specific complications occurred in < 4%. In symptomatic patients, improvement and resolution of symptoms occurred in 44% and 34%, respectively. Median overall survival from first radioembolization was 3.7, 2.7 and 0.7 years for G1, G2 and G3, respectively. Objective response is independent of NEN grade or primary tumour origin. Significant prognostic factors for survival were NEN grade/Ki67 index, ≥ 75% intrahepatic tumour load, the presence of extrahepatic disease and disease control rate according to RECIST 1.1., Conclusion: Safety and efficacy of radioembolization in NEN patients was confirmed with a high disease control rate of 91% in progressive patients and alleviation of NEN-related symptoms in 79% of symptomatic patients., Level of Evidence: 4.

Purpose: To investigate hepatocellular carcinoma tumor dose-response characteristics based on voxel-level absorbed doses (D) and biological effective doses (BED) using quantitative 90 Y-single-photon emission computed tomography (SPECT)/computed tomography (CT) after 90 Y-radioembilization with glass microspheres. We also investigated the relationship between normal liver D and toxicities., Methods and Materials: 90 Y-radioembolization activity distributions for 34 patients were based on quantitative 90 Y-bremsstrahlung SPECT/CT. D maps were generated using a local-deposition algorithm. Contrast-enhanced CT or magnetic resonance imaging scans of the liver were registered to 90 Y-SPECT/CT, and all tumors larger than 2.5 cm diameter (53 tumors) were segmented. Tumor mean D and BED (Dmean and BEDmean) and dose volume coverage from 0% to 100% in 10% steps (D0-D100 and BED0-BED100) were extracted. Tumor response was evaluated on follow-up using World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), and modified RECIST (mRECIST) criteria. Differences in dose metrics for responders and nonresponders were assessed using the Mann-Whitney U test. A univariate logistic regression model was used to determine tumor dose metrics that correlated with tumor response. Correlations among tumor size, tumor Dmean, and tumor dose heterogeneity (defined as the coefficient of variation) were assessed., Results: The objective response rates were 14 of 53, 15 of 53, and 30 of 53 for WHO, RECIST, and mRECIST criteria, respectively. WHO and RECIST response statuses did not correlate with D or BED. For mRECIST responders and nonresponders, D and BED were significantly different for Dmean, D20 to D80, BEDmean, and BED0 to BED80. Threshold doses (and the 95% confidence interval) for 50% probability of mRECIST response (D 50% ) were 160 Gy (123-196 Gy) for Dmean and 214 Gy (146-280 Gy) for BEDmean. Tumor dose heterogeneity significantly correlated with tumor volume. No statistically significant association between Dmean to normal liver and complications related to bilirubin, albumin, or ascites was observed., Conclusions: Hepatocellular carcinoma tumor dose-response curves after 90 Y-radioembolization with glass microspheres showed Dmean of 160 Gy and BEDmean of 214 Gy for D 50% with a positive predictive value of ∼70% and a negative predictive value of ∼62%. No complications were observed in our patient cohort for normal liver Dmean less than 44 Gy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To quantify differences that exist between dosimetry models used for 90 Y selective internal radiation therapy (SIRT)., Methods and Materials: Retrospectively, 37 tumors were delineated on 19 post-therapy quantitative 90 Y 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. MC NL single 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 MC T single or MC T multiple (p>.12, 95%PI >±177 Gy). However, SM single was able to predict (p<.012) MC NL single , albeit with large uncertainties; SM single and SM multiple yielded biases of 0.62 and 0.71, and 95%PI of ±40 and ± 32 Gy, respectively. PM T single and PM T multiple predicted (p<2E-6) MC T single and MC T multiple with biases of 0.52 and 0.54, and 95%PI of ±38 and ± 111 Gy, respectively. The TNR variability in PM T single increased the 95%PI for predicting MC T single (bias = 0.46 and 95%PI = ±103 Gy). The TNR variability in PM T multiple modified the bias when predicting MC T multiple (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 90 Y 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., Competing Interests: Notification: AM receives research support from BTG and Sirtex., (Copyright © 2016 Elsevier Inc. All rights reserved.)