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Purpose To evaluate the safety and feasibility of a novel hybrid nuclear and fluoroscopy C-arm scanner to be used during the work-up procedure of hepatic radioembolization. Materials and Methods In this prospective first-in-human clinical study, 12 participants (median age, 67 years [range: 37-78 years]; nine [75%] male, three [25%] female) with liver tumors undergoing work-up for yttrium 90 radioembolization were included (ClinicalTrials.gov NCT06013774). Work-up angiography and technetium 99m-macroaggregated albumin injection were performed in an angiography suite equipped with a hybrid C-arm that could simultaneously perform fluoroscopy and planar nuclear imaging. Technetium 99m-macroaggregated albumin was injected under real-time hybrid imaging, followed by in-room SPECT imaging. Safety and feasibility were studied by assessing adverse events, technical performance, additional x-ray radiation dose, and questionnaires completed by radiologists and technologists. Results No adverse events were attributed to the hybrid C-arm scanner. The additional x-ray radiation dose was low (median, 19 Gy · cm 2 ; minimum: 12 Gy · cm 2 ; maximum: 21 Gy · cm 2 for participants who completed all imaging steps). The interventional personnel considered use of the hybrid C-arm scanner safe and feasible, although the additional time spent in the intervention room was considered long (median, 64 minutes; minimum: 55 minutes; maximum: 77 minutes for participants who completed all imaging steps). Conclusion Use of the hybrid C-arm scanner during the work-up procedure of hepatic radioembolization was found to be safe and feasible in this first-in-human clinical study. Keywords: Angiography, Fluoroscopy, Interventional-Vascular, Radionuclide Studies, Radiosurgery, Gamma Knife, Cyberknife, SPECT, Instrumentation, Physics, Technical Aspects, Technology Assessment Supplemental material is available for this article. Published under a CC BY 4.0 license. Clinical trial registration no. NCT06013774.

To date, the imaging and diagnosis of hepatocellular carcinoma (HCC) rely on CT/MRI, which have well-known limitations. Glypican-3 (GPC3) is a cell surface receptor highly expressed by HCC but not by normal or cirrhotic liver tissue. Here we report initial clinical results of GPC3-targeted PET imaging with [ 68 Ga]Ga-DOTA-RYZ-GPC3 (RAYZ-8009), a peptide-based GPC3 ligand in patients with known or suspected HCC. Methods: [ 68 Ga]Ga-RAYZ-8009 was obtained after labeling the peptide precursor with 68 Ga from a 68 Ge/ 68 Ga generator and heating at 90°C for 10 min followed by sterile filtration. After administration of [ 68 Ga]Ga-RAYZ-8009, a dynamic or static PET/CT scan was acquired between 45 min and 4 h after administration. Radiotracer uptake was measured by SUVs for the following tissues: suspected or actual HCC or hepatoblastoma lesions, non-tumor-bearing liver, renal cortex, blood pool in the left ventricle, and gastric fundus. Additionally, tumor-to-healthy-liver ratios (TLRs) were calculated. Results: Twenty-four patients (5 patients in the dynamic protocol; 19 patients in the static protocol) were scanned. No adverse events occurred. Two patients had no lesion detected and did not have HCC during follow-up. In total, 50 lesions were detected and analyzed. The mean SUV max of these lesions was 19.6 (range, 2.7-95.3), and the mean SUV mean was 10.1 (range, 1.0-49.2) at approximately 60 min after administration. Uptake in non-tumor-bearing liver and blood pool rapidly decreased over time and became negligible 45 min after administration (mean SUV mean , <1.6), with a continuous decline to 4 h after administration (mean SUV mean , 1.0). The opposite was observed for HCC lesions, for which SUVs and TLRs continuously increased for up to 4 h after administration. In individual lesion analysis, TLR was the highest between 60 and 120 min after administration. Uptake in the gastric fundus gradually increased for up to 45 min (to an SUV max of 31.3) and decreased gradually afterward. Conclusion: [ 68 Ga]Ga-RAYZ-8009 is safe and allows for high-contrast imaging of GPC3-positive HCC, with rapid clearance from most normal organs. Thereby, [ 68 Ga]Ga-RAYZ-8009 is promising for HCC diagnosis and staging. Further research is warranted., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

This article provides a thorough overview of the practice and multistep approach of hepatic radioembolization. The current literature on hepatic radioembolization in primary or metastatic liver tumors as well as future perspectives are discussed., Competing Interests: Disclosure A.J.A.T. Braat is a consultant for Boston Scientific and Terumo and receives research support from Ariceum Therapeutics. M.L.J. Smits is a consultant for Terumo and has received speaking fees for Medtronic and Philips. G. El-Haddad is a consultant for Boston Scientific, Terumo, Novartis, Bayer, and NorthStar Medical Radioisotopes. M.G.E.H. Lam is a consultant for Boston Scientific and Terumo and receives research support from Novartis, Boston Scientific and Terumo. The UMC Utrecht receives research support and royalties from Terumo., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Radiation pneumonitis is a serious complication of radioembolization. In holmium-166 ([ 166 Ho]) radioembolization, the lung mean dose (LMD) can be estimated (eLMD) using a scout dose with either technetium-99 m-macroaggregated albumin ([ 99m Tc]MAA) or [ 166 Ho]-microspheres. The accuracy of eLMD based on [ 99m Tc]MAA (eLMD MAA ) was compared to eLMD based on [ 166 Ho]-scout dose (eLMD Ho-scout ) in two prospective clinical studies., Materials and Methods: Patients were included if they received both scout doses ([ 99m Tc]MAA and [ 166 Ho]-scout), had a posttreatment [ 166 Ho]-SPECT/CT (gold standard) and were scanned on the same hybrid SPECT/CT system. The correlation between eLMD MAA /eLMD Ho-scout and LMD Ho-treatment was assessed by Spearman's rank correlation coefficient (r). Wilcoxon signed rank test was used to analyze paired data., Results: Thirty-seven patients with unresectable liver metastases were included. During follow-up, none developed symptoms of radiation pneumonitis. Median eLMD MAA (1.53 Gy, range 0.09-21.33 Gy) was significantly higher than median LMD Ho-treatment (0.00 Gy, range 0.00-1.20 Gy; p < 0.01). Median eLMD Ho-scout (median 0.00 Gy, range 0.00-1.21 Gy) was not significantly different compared to LMD Ho-treatment (p > 0.05). In all cases, eLMD MAA was higher than LMD Ho-treatment (p < 0.01). While a significant correlation was found between eLMD Ho-scout and LMD Ho-treatment (r = 0.43, p < 0.01), there was no correlation between eLMD MAA and LMD Ho-treatment (r = 0.02, p = 0.90)., Conclusion: [ 166 Ho]-scout dose is superior in predicting LMD over [ 99m Tc]MAA, in [ 166 Ho]-radioembolization. Consequently, [ 166 Ho]-scout may limit unnecessary patient exclusions and avoid unnecessary therapeutic activity reductions in patients eligible for radioembolization., Trail Registration: NCT01031784, registered December 2009. NCT01612325, registered June 2012., (© 2024. The Author(s).)

Our objective was to compare 3 different therapeutic particles used for radioembolization in locally advanced intrahepatic cholangiocarcinoma. Methods: 90 Y-glass, 90 Y-resin, and 166 Ho-labeled poly(l-lactic acid) microsphere prescribed activity was calculated as per manufacturer recommendations. Posttreatment quantitative 90 Y PET/CT and quantitative 166 Ho SPECT/CT were used to determine tumor-absorbed dose, whole-normal-liver-absorbed dose, treated-normal-liver-absorbed dose, tumor-to-nontumor ratio, lung-absorbed dose, and lung shunt fraction. Response was assessed using RECIST 1.1 and the [ 18 F]FDG PET-based change in total lesion glycolysis. Hepatotoxicity was assessed using the radioembolization-induced liver disease classification. Results: Six 90 Y-glass, 8 90 Y-resin, and 7 166 Ho microsphere patients were included for analysis. The mean administered activity was 2.6 GBq for 90 Y-glass, 1.5 GBq for 90 Y-resin, and 7.0 GBq for 166 Ho microspheres. Tumor-absorbed dose and treated-normal-liver-absorbed dose were significantly higher for 90 Y-glass than for 90 Y-resin and 166 Ho microspheres (mean tumor-absorbed dose, 197 Gy for 90 Y-glass vs. 73 Gy for 90 Y-resin and 50 Gy for 166 Ho; mean treated-normal-liver-absorbed dose, 79 Gy for 90 Y-glass vs. 37 Gy for 90 Ho). The whole-normal-liver-absorbed dose and tumor-to-nontumor ratio did not significantly differ between the particles. All patients had a lung-absorbed dose under 30 Gy and a lung shunt fraction under 20%. The 3 groups showed similar toxicity and response according to RECIST 1.1 and [ 166 Ho). The whole-normal-liver-absorbed dose and tumor-to-nontumor ratio did not significantly differ between the particles. All patients had a lung-absorbed dose under 30 Gy and a lung shunt fraction under 20%. The 3 groups showed similar toxicity and response according to RECIST 1.1 and [ 18 F]FDG PET-based total lesion glycolysis changes. Conclusion: The therapeutic particles used for radioembolization differed from each other and showed significant differences in absorbed dose, whereas toxicity and response were similar for all groups. This finding emphasizes the need for separate dose constraints and dose targets for each particle., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: High dose unilobar radioembolization (also termed 'radiation lobectomy')-the transarterial unilobar infusion of radioactive microspheres as a means of controlling tumour growth while concomitantly inducing future liver remnant hypertrophy-has recently gained interest as induction strategy for surgical resection. Prospective studies on the safety and efficacy of the unilobar radioembolization-surgery treatment algorithm are lacking. The RALLY study aims to assess the safety and toxicity profile of holmium-166 unilobar radioembolization in patients with hepatocellular carcinoma ineligible for surgery due to insufficiency of the future liver remnant., Methods: The RALLY study is a multicenter, interventional, non-randomized, open-label, non-comparative safety study. Patients with hepatocellular carcinoma who are considered ineligible for surgery due to insufficiency of the future liver remnant (< 2.7%/min/m 2 on hepatobiliary iminodiacetic acid scan will be included. A classical 3 + 3 dose escalation model will be used, enrolling three to six patients in each cohort. The primary objective is to determine the maximum tolerated treated non-tumourous liver-absorbed dose (cohorts of 50, 60, 70 and 80 Gy). Secondary objectives are to evaluate dose-response relationships, to establish the safety and feasibility of surgical resection following unilobar radioembolization, to assess quality of life, and to generate a biobank., Discussion: This will be the first clinical study to assess the unilobar radioembolization-surgery treatment algorithm and may serve as a stepping stone towards its implementation in routine clinical practice., Trial Registration: Netherlands Trial Register NL8902 , registered on 2020-09-15., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Immunotherapy in the form of checkpoint inhibitors has changed the treatment paradigm in oncology. Combining selective internal radiation therapy (SIRT) with immunotherapy has been suggested to potentially improve outcomes in hepatocellular carcinoma (HCC) and metastatic colorectal carcinoma (mCRC). In this systematic review, the authors discuss the current developments and available clinical data regarding the combination of immunotherapy and SIRT in treating hepatic malignancies. Methods: PubMed, Embase, and Cochrane library were systematically searched for eligible studies (adhering to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines). Original patient studies written in English language with patients with HCC or mCRC who were treated with SIRT and immunotherapy were included. Endpoints evaluated included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Results: 1038 publications were screened, from which 1034 publications were excluded. Four studies with a total of 87 patients were included in this systematic review, of which two consisted of mCRC and the other two HCC. All four studies showed no increased toxicities of the combination therapy over known data on monotherapy. One mCRC study reported a median OS of 8 months, while the other mCRC study ended due to futility. Both reported an ORR of 0%. The two HCC studies reported a median OS of 16.5 and 16.2 months. Median PFS was 5.6 and 5.7 months. ORR ranged from 31% to 80%. Conclusion: The combination of SIRT and immunotherapy has been studied in four early-phase studies showing a favorable safety profile. Further studies are necessary to understand the possible synergy and possible benefit of combination therapy.

The safety and efficacy of 166 Ho radioembolization was first determined in the HEPAR and HEPAR II studies, which, however, excluded patients with hepatocellular carcinoma (HCC). The aim of this prospective clinical early phase II study was to establish the toxicity profile of 166 Ho radioembolization in patients with measurable, liver-dominant HCC; Barcelona clinic liver cancer stage B or C; a Child-Pugh score of no more than B7; and an Eastern Cooperative Oncology Group performance status of 0-1 without curative treatment options. Methods: The primary endpoint was a rate of unacceptable toxicity defined as grade 3 hyperbilirubinemia (Common Terminology Cancer Adverse Events, version 4.03) in combination with a low albumin or ascites level in the absence of disease progression or treatment-related serious adverse events. Secondary endpoints included overall toxicity, response, survival, change in α-fetoprotein, and quality of life. Thirty-one patients with Barcelona clinic liver cancer stage B (71%) or C (29%) HCC were included, mostly multifocal (87%) or bilobar (55%) disease. Results: Common grade 1 or 2 clinical toxicity included fatigue (71%), back pain (55%), ascites (32%), dyspnea (23%), nausea (23%), and abdominal pain (23%), with no more than 10% grade 3-5 toxicity. Grade 3 laboratory toxicity (>10%) included an aspartate transaminase and γ-glutamyltransferase increase (16%), hyperglycemia (19%), and lymphopenia (29%). Treatment-related unacceptable toxicity occurred in 3 of 31 patients. At 3 mo, 54% of target lesions showed a complete or partial response according to modified RECIST. Median overall survival was 14.9 mo (95% CI, 10.4-24.9 mo). No significant changes in quality of life or pain were observed. Conclusion: The safety of 166 Ho radioembolization was confirmed in HCC, with less than 10% unacceptable toxicity. Efficacy data support further evaluation., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Since its first suggestion as possible option for liver radioembolization treatment, the therapeutic isotope holmium-166 ( 166 Ho) caught the experts' attention due to its imaging possibilities. Being not only a beta, but also a gamma emitter and a lanthanide, 166 Ho can be imaged using single-photon emission computed tomography and magnetic resonance imaging, respectively. Another advantage of 166 Ho is the possibility to perform the scout and treatment procedure with the same particle. This prospect paves the way to an individualized treatment procedure, gaining more control over dosimetry-based patient selection and treatment planning. In this review, an overview on 166 Ho liver radioembolization will be presented. The current clinical workflow, together with the most relevant clinical findings and the future prospective will be provided., (© 2022. The Author(s).)

Radiation pneumonitis is a rare but possibly fatal side effect of 90 Y radioembolization. It may occur 1-6 mo after therapy, if a significant part of the 90 Y microspheres shunts to the lungs. In current clinical practice, a predicted lung dose greater than 30 Gy is considered a criterion to exclude patients from treatment. However, contrasting findings regarding the occurrence of radiation pneumonitis and lung dose were previously reported in the literature. In this study, the relationship between the lung dose and the eventual occurrence of radiation pneumonitis after 90 Y radioembolization was investigated. Methods: We retrospectively analyzed 317 90 Y liver radioembolization procedures performed during an 8-y period (February 2012 to September 2020). We calculated the predicted lung mean dose (LMD) using 99m Tc-MAA planar scintigraphy (LMD MAA ) acquired during the planning phase and left LMD (LMD Y-90 ) using the 90 Y PET/CT acquired after the treatment. For the lung dose computation, we used the left lung as the representative lung volume, to compensate for scatter from the liver moving in the craniocaudal direction because of breathing and mainly affecting the right lung. Results: In total, 272 patients underwent 90 Y procedures, of which 63% were performed with glass microspheres and 37% with resin microspheres. The median injected activity was 1,974 MBq (range, 242-9,538 MBq). The median LMD MAA was 3.5 Gy (range, 0.2-89.0 Gy). For 14 procedures, LMD MAA was more than 30 Gy. Median LMD Y-90 was 1 Gy (range, 0.0-22.1 Gy). No patients had an LMD Y-90 of more than 30 Gy. Of the 3 patients with an LMD Y-90 of more than 12 Gy, 2 patients (one with an LMD Y-90 of 22.1 Gy and an LMD MAA of 89 Gy; the other with an LMD Y-90 of 17.7 Gy and an LMD MAA of 34.1 Gy) developed radiation pneumonitis and consequently died. The third patient, with an LMD Y-90 of 18.4 Gy (LMD MAA , 29.1 Gy), died 2 mo after treatment, before the imaging evaluation, because of progressive disease. Conclusion: The occurrence of radiation pneumonitis as a consequence of a lung shunt after 90 Y radioembolization is rare (<1%). No radiation pneumonitis developed in patients with a measured LMD Y-90 lower than 12 Gy., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

In neuroendocrine neoplasms (NENs), the presence of distant metastases has a severe impact on survival leading to a relevant decrease in the 5-y survival rate. Here, 90 Y radioembolization ( 90 Y RE) might be an important treatment option; however, data to support clinical benefits for 90 Y RE are scarce. Therefore, the purpose of this study was to analyze the use of 90 Y RE in NEN patients with hepatic metastases in an international, multicenter retrospective analysis and assess the potential role of 90 Y RE in a multimodal treatment concept. Methods: In total, 297 angiographic evaluations in NEN patients before 90 Y RE were analyzed. Baseline characteristics and parameters derived from imaging evaluation and 90 Y RE were analyzed. Tumor response was assessed using RECIST 1.1, and survival data were collected. Mean overall survival (OS) between different groups was compared using Kaplan-Meier curves and the log rank test. A P value of less than 0.05 indicated statistical significance. Results: After 90 Y RE, the disease control rate according to RECIST 1.1 was 83.5% after 3 mo and 50.9% after 12 mo. OS in the entire population was 38.9 ± 33.0 mo. High tumor grade ( P < 0.006) and high tumor burden ( P  = 0.001) were both associated with a significant decrease in OS. The presence of extrahepatic metastases ( P = 0.335) and the type of metastatic vascularization pattern ( P = 0.460) had no influence on OS. Patients who received 90 Y RE as second-line therapy had a slightly longer but not statistically significant OS than patients who had 90 Y RE in a salvage setting (44.8 vs. 30.6 mo, P  = 0.078). Hepatic and global progression-free survival after 90 Y RE was significantly decreased in heavily pretreated patients, compared with patients with second-line therapy ( P = 0.011 and P  = 0.010, respectively). Conclusion: 90 Y RE could be an important alternative to peptide receptor radionuclide therapy as second-line treatment in patients with progressive liver-dominant disease pretreated with somatostatin analogs., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: In radioembolization, response is achieved through the irradiation and damaging of tumor DNA. For hepatic metastases of neuroendocrine tumors, a dose-response relationship has not been established yet. This study assesses whether increasing tumor-absorbed doses lead to increased response rates., Methods: We included all patients who underwent yttrium-90 ( 90 Y) glass microspheres radioembolization in our center if both pre- and post-treatment contrast-enhanced CT and post-injection PET/CT were available. Up to five hepatic tumors and the healthy hepatic tissue were delineated, and absorbed dose was quantified using post-injection PET/CT. Response was measured according to RECIST 1.1 on patient and tumor level. Linear mixed models were used to study the relationship between absorbed dose and response on tumor level. Logistic regression analysis was used on patient level to study dose-response and hepatic dose-toxicity relationships., Results: A total of 128 tumors in 26 patients (31 procedures) were included in the response analysis. While correcting for confounding by tumor volume, a significant effect of response on dose was found (p = 0.0465). Geometric mean of absorbed dose for responding tumors was 170 Gy, for stable disease 101 Gy, and for progressive disease 67 Gy. No significant dose-toxicity relationship could be identified., Conclusion: In patients with neuroendocrine tumor liver metastases, treated with 90 Y-radioembolization, a clear dose-response relationship was found. We propose to perform 90 Y-radioembolization with an absolute minimum planned tumor-absorbed dose of 150 Gy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Radioembolization based on personalized treatment planning requires established dose-response and dose-toxicity relationships. The aim of this study was to investigate dose-response and dose-toxicity relationships in patients with colorectal liver metastases (CRLMs) treated with glass 90 Y-microspheres. Methods: All CRLM patients treated with glass 90 Y-microspheres in our institution were retrospectively analyzed. The tumor-absorbed dose was calculated for each measurable metastasis (i.e., 18 F-FDG-positive and more than a 5-cm 3 tumor volume) on posttreatment 90 Y PET. Metabolic tumor response was determined on 18 F-FDG PET/CT by measuring the total lesion glycolysis at baseline and at 3 mo after treatment. The relationship between tumor-absorbed dose and metabolic response was determined on a per-lesion and per-patient basis using a linear mixed-effects regression model. Clinical toxicity and laboratory toxicity were correlated with healthy liver-absorbed dose. Results: Thirty-one patients were included. The median tumor-absorbed dose of 85 measurable metastases was 133 Gy (range, 20-1001 Gy). Per response category, this was 196 Gy for complete response (CR), 177 Gy for partial response (PR), 72 Gy for stable disease, and 95 Gy for progressive disease (PD). A significant dose-response relationship was found on a tumor level, with a significantly higher tumor-absorbed dose in metastases with CR (+94%) and PR (+74%) than in metastases with PD ( P < 0.001). A similar relationship was found on a patient level, with PR having a higher tumor-absorbed dose than did PD (+58%, P = 0.044). A tumor-absorbed dose of more than 139 Gy predicted a 3-mo metabolic response with the greatest accuracy (89% specificity and 77% sensitivity), whereas a tumor-absorbed dose of more than 189 Gy predicted response with 97% specificity and 45% sensitivity. The median healthy liver-absorbed dose was 63 Gy (range, 24-113 Gy). Toxicity was limited mostly to grades 1 and 2, with 1 case of radioembolization-induced liver disease in a patient who received the highest healthy liver-absorbed dose. A positive trend was seen for most laboratory parameters in our dose-toxicity analysis. Conclusion: A significant relationship was observed between dose and response in CRLM patients treated with glass 90 Y radioembolization., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: The objective of this study was to investigate whether the use of an anti-reflux catheter improves tumor targeting for colorectal cancer patients with unresectable, chemorefractory liver metastases (mCRC) treated with holmium-166 ( 166 Ho)-radioembolization., Materials and Methods: In this perspective, within-patient randomized study, left and right hepatic perfusion territories were randomized between infusion with a Surefire® anti-reflux catheter or a standard microcatheter. The primary outcome was the difference in tumor to non-tumor (T/N) activity distribution. Secondary outcomes included the difference in infusion efficiency, absorbed doses, predictive value of 166 Ho-scout, dose-response relation, and survival., Results: Twenty-one patients were treated in this study (the intended number of patients was 25). The median T/N activity concentration ratio with the use of the anti-reflux catheter was 3.2 (range 0.9-8.7) versus 3.6 (range 0.8-13.3) with a standard microcatheter. There was no difference in infusion efficiency (0.04% vs. 0.03% residual activity for the standard microcatheter and anti-reflux catheter, respectively) (95%CI - 0.05-0.03). No influence of the anti-reflux catheter on the dose-response rate was found. Median overall survival was 7.8 months (95%CI 6-13)., Conclusion: Using a Surefire® anti-reflux catheter did not result in a higher T/N activity concentration ratio in mCRC patients treated with 166 Ho-radioembolization, nor did it result in improved secondary outcomes measures., Trial Registration: clinicaltrials.gov identifier: NCT02208804.

Purpose: To evaluate the safety and feasibility of same-day treatment, including the simulation procedure for assessment of intrahepatic and extrahepatic distribution of the microspheres, with holmium-166 ( 166 Ho)-radioembolization., Materials and Methods: This was a secondary analysis of patients included in the 4 prospective studies (HEPAR I, HEPAR II, HEPAR PLuS, and SIM) on 166 Ho-radioembolization. The technical success rate of the same-day treatment protocol, defined as the number of patients who completed the same-day treatment, was measured. Total in-room time, duration of the scout procedure, time to imaging, and duration of the treatment procedure were recorded. Reasons for discontinuation or adjustment of treatment were identified. Adverse events that occurred during the treatment day were recorded., Results: One hundred five of 120 scheduled patients completed the same-day treatment with 166 Ho-radioembolization (success rate, 88%). After the simulation procedure, treatment was cancelled in 15 patients because of extrahepatic deposition (n = 8), suboptimal tumor targeting (n = 1), unanticipated vascular anatomy (n = 5), and dissection (n = 1). In another 14 patients, the treatment plan was adjusted. The median total procedure time (ie, simulation, imaging, and treatment) was 6:39 hours:minutes (range, 3:58-9:17 hours:minutes). Back pain was a major same-day treatment-related complaint (n = 28)., Conclusion: 166 Ho-radioembolization as a same-day treatment procedure is feasible in most selected patients, although treatment was adjusted in 12% of patients and cancelled in 12% of patients. This approach might be beneficial for a select patient population, such as patients needing a radiation segmentectomy., (Copyright © 2020 SIR. Published by Elsevier Inc. All rights reserved.)

Background: In patients with metastatic neuroendocrine neoplasms, the liver is the most commonly affected organ and a crucial factor for prognosis and survival. Peptide receptor radionuclide therapy can prolong progression-free survival in these patients. Additional treatment of liver disease might further improve outcomes. We aimed to investigate the safety and efficacy of additional holmium-166 ( 166 Ho) radioembolisation after peptide receptor radionuclide therapy in patients with metastatic liver neuroendocrine neoplasms., Methods: The Holmium Embolization Particles for Arterial Radiotherapy Plus 177 Lu-Dotatate in Salvage Neuroendocrine Tumour Patients (HEPAR PLuS) study was a single-centre, phase 2 study done at the University Medical Center Utrecht (Utrecht, Netherlands). Patients, aged at least 18 years, with histologically proven grade 1 or 2 neuroendocrine neoplasms of all origins, an Eastern Cooperative Oncology Group performance status of 0-2, and three or more measurable liver metastases according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria received 166 Ho-radioembolisation within 20 weeks after four cycles of peptide receptor radionuclide therapy (lutetium-177-dotatate [ 177 Lu-dotatate]). The primary endpoint was objective liver tumour response in the treated liver volume, defined as complete response (disappearance of all lesions) or partial response (≥30% decrease in the sum of the longest diameters of the target lesions, compared with baseline measurements), according to RECIST 1.1, analysed per protocol at 3 months. Safety was assessed in all patients who received treatment. This study is registered with ClinicalTrials.gov, NCT02067988. Recruitment is completed and long-term follow-up is ongoing., Findings: From Oct 15, 2014, to Sept 12, 2018, 34 patients were assessed for eligibility. 31 patients received treatment and 30 (97%) patients were available for primary endpoint assessment and completed 6 months of follow-up. Three (9%) patients were excluded at screening and one (3%) patient was treated and died before the primary endpoint and was replaced. According to the per-protocol analysis 13 (43%; 95% CI 26-63) of 30 patients achieved an objective response in the treated volume. The most frequently reported Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 clinical and laboratory toxicities within 6 months included abdominal pain (three [10%] of 31 patients), increased γ-glutamyl transpeptidase (16 [54%]), and lymphocytopenia (seven [23%]). One (3%) fatal treatment-related serious adverse event occurred (radioembolisation-induced liver disease). Two (6%) patients had serious adverse events deemed to be unrelated to treatment (gastric ulcer and perforated cholecystitis)., Interpretation: 166 Ho-radioembolisation, as an adjunct to peptide receptor radionuclide therapy in patients with neuroendocrine neoplasm liver metastases, is safe and efficacious. Radioembolisation can be considered in patients with bulky liver disease, including after peptide receptor radionuclide therapy. A future randomised, controlled study should investigate the added benefit of this treatment on progression-free survival., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: As an alternative to technetium-99m-macroaggregated albumin ( 99m Tc-MAA), a scout dose of holmium-166 ( 166 Ho) microspheres can be used prior to 166 Ho-radioembolization. The use of identical particles for pre-treatment and treatment procedures may improve the predictive value of pre-treatment analysis of distribution. The aim of this study was to analyze the agreement between 166 Ho-scout and 166 Ho-therapeutic dose in comparison with the agreement between 99m Tc-MAA and 166 Ho-therapeutic dose., Methods: Two separate scout dose procedures were performed ( 99m Tc-MAA and 166 Ho-scout) before treatment in 53 patients. First, qualitative assessment was performed by two blinded nuclear medicine physicians who visually rated the agreement between the 99m Tc-MAA, 166 Ho-scout, and 166 Ho-therapeutic dose SPECT-scans (i.e., all performed in the same patient) on a 5-point scale. Second, agreement was measured quantitatively by delineating lesions and normal liver on FDG-PET/CT. These volumes of interest (VOIs) were co-registered to the SPECT/CT images. The predicted absorbed doses (based on 99m Tc-MAA and 166 Ho-scout) were compared with the actual absorbed dose on post-treatment SPECT., Results: A total of 23 procedures (71 lesions, 22 patients) were included for analysis. In the qualitative analysis, 166 Ho-scout was superior with a median score of 4 vs. 2.5 for 99m Tc-MAA (p < 0.001). The quantitative analysis showed significantly narrower 95%-limits of agreement for 166 Ho-scout in comparison with 99m Tc-MAA when evaluating lesion absorbed dose (- 90.3 and 105.3 Gy vs. - 164.1 and 197.0 Gy, respectively). Evaluation of normal liver absorbed dose did not show difference in agreement between both scout doses and 166 Ho-therapeutic dose (- 2.9 and 5.5 Gy vs - 3.6 and 4.1 Gy for 99m Tc-MAA and 166 Ho-scout, respectively)., Conclusions: In this study, 166 Ho-scout was shown to have a superior predictive value for intrahepatic distribution in comparison with 99m Tc-MAA.

Purpose: To evaluate the efficacy of coil embolization to obtain intrahepatic redistribution in patients undergoing radioembolization., Materials and Method: All patients treated with radioembolization at our institute were retrospectively analyzed, and all cases in which a tumor-feeding vessel was coil-embolized were selected. Two nuclear medicine physicians visually assessed the effect of redistribution. Furthermore, the redistribution of microspheres was measured by quantifying the activity distributed to the coil-embolized (dependent) segment relative to the other (non-dependent) segments and to the tumor(s) in that segment. Quantitative analysis was performed on post-treatment 90 Y-PET and 166 Ho-SPECT using Simplicit 90 Y software. Lesion response was measured according to RECIST 1.1 criteria at 3 months post-treatment., Results: Out of 37 cases, 32 were suitable for quantitative analysis and 37 for qualitative analysis. In the qualitative analysis, redistribution was deemed successful in 69% of cases. The quantitative analysis showed that the median ratio of the activity to the dependent embolized segments and the non-dependent segments was 0.88 (range 0.26-2.05) and 0.80 (range 0.19-1.62) for tumors in dependent segments compared with tumors in non-dependent segments. Using a cutoff ratio of 0.7 (30% lower activity concentration in comparison with the rest of the liver), 57% of cases were successful. At 3 months post-treatment, 6% of dependent tumors had partial response, 20% progressive disease, and 74% stable disease. In non-dependent tumors, this was, respectively, 16%, 20%, and 64%., Conclusion: Coil embolization of hepatic arteries to induce redistribution of microspheres has a limited success rate. Qualitative assessment tends to overrate redistribution.

Purpose: Prior to 90 Y hepatic radioembolization, a dosage of 99m Tc-macroaggregated albumin ( 99m Tc-MAA) is administered to simulate the distribution of the 90 Y-loaded microspheres. This pretreatment procedure enables lung shunt estimation, detection of potential extrahepatic depositions, and estimation of the intrahepatic dose distribution. However, the predictive accuracy of the MAA particle distribution is often limited. Ideally, 90 Y microspheres would also be used for the pretreatment procedure. Based on previous research, the pretreatment activity should be limited to the estimated safety threshold of 100 MBq, making imaging challenging. The purpose of this study was to evaluate the quality of intra- and extrahepatic imaging of 90 Y-based pretreatment positron emission tomography/computed tomography (PET/CT) and quantitative single photon emission computed tomography (SPECT)/CT scans, by means of phantom experiments and a patient study., Methods: An anthropomorphic phantom with three extrahepatic depositions was filled with 90 Y chloride to simulate a lung shunt fraction (LSF) of 5.3% and a tumor to nontumor ratio (T/N) of 7.9. PET /CT (Siemens Biograph mCT) and Bremsstrahlung SPECT/CT (Siemens Symbia T16) images were acquired at activities ranging from 1999 MBq down to 24 MBq, representing post- and pretreatment activities. PET/CT images were reconstructed with the clinical protocol and SPECT/CT images were reconstructed with a quantitative Monte Carlo-based reconstruction protocol. Estimated LSF, T/N, contrast to noise ratio of all extrahepatic depositions, and liver parenchymal and tumor dose were compared with the phantom ground truth. A clinically reconstructed SPECT/CT of 150 MBq 99m Tc represented the current clinical standard. In addition, a 90 Y pretreatment scan was simulated for a patient by acquiring posttreatment PET/CT and SPECT/CT data with shortened acquisition times., Results: At an activity of 100 MBq 90 Y, PET/CT overestimated LSF [+10 percentage point (pp)], underestimated liver parenchymal dose (-3 Gy/GBq), and could not detect the extrahepatic depositions. SPECT/CT more accurately estimated LSF (-0.7 pp), parenchymal dose (-0.3 Gy/GBq) and could detect all three extrahepatic depositions. 99m Tc SPECT/CT showed similar accuracy as 90 Y SPECT/CT (LSF: +0.2 pp, parenchymal dose: +0.4 Gy/GBq, all extrahepatic depositions visible), although the noise level in the liver compartment was considerably lower for 99m Tc SPECT/CT compared to 90 Y SPECT/CT. The patient's SPECT/CT simulating a pretreatment 90 Y procedure accurately represented the posttreatment 90 Y microsphere distribution., Conclusions: Quantitative SPECT/CT of 100 MBq 90 Y could accurately estimate LSF, T/N, parenchymal and tumor dose, and visualize extrahepatic depositions., (© 2019 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Background: Lutetium-177-DOTA-octreotate ( 177 Lu-DOTATATE) significantly increases survival and response rates in patients with grade I and grade II neuroendocrine tumors (NETs). However, survival and response rates are significantly lower in patients with bulky liver metastases. Increasing the tumor-absorbed dose in liver metastases may improve response to 177 Lu-DOTATATE. The LUTIA (Lutetium Intra-Arterial) study aims to increase the tumor-absorbed dose in liver metastases by intra-arterial (IA) administration of 177 Lu-DOTATATE, compared to conventional intravenous (IV) administration., Methods: A multicenter, within-patient randomized controlled trial (RCT) in 26 patients with progressive, liver-dominant, unresectable grade I or grade II NET will be conducted. Patients with bilobar bulky disease will be randomly allocated to receive IA treatment into either the left or the right hepatic artery. Using this approach, one liver lobe will be treated intra-arterially (first-pass effect), while the contralateral lobe will receive an intravenous treatment as a second-pass effect. The primary endpoint of this study is the difference in tumor-to-non-tumor ratio of 177 Lu-DOTATATE uptake between the two liver lobes on post-treatment SPECT/CT (IA versus IV). Secondary endpoints include absorbed dose in both liver lobes, tumor response, dose-response relationship, toxicity, uptake in extrahepatic lesions, and renal uptake., Discussion: This multicenter, within-patient RCT will investigate whether IA administration of 177 Lu-DOTATATE results in a higher activity concentration in liver metastases compared to IV administration., Trial Registration: ClinicalTrials.gov, NCT03590119. Registered on 17 July 2018.

Background: Neuroendocrine liver metastases are clinically challenging due to their frequent disseminated distribution. This study aims to present a British experience with an emerging modality, radioembolisation with yttrium-90 labelled microspheres, and embed this within a meta-analysis of response and survival outcomes., Methods: A retrospective case series of patients treated with SIR-Spheres (radiolabelled resin microspheres) was performed. Results were included in a systematic review and meta-analysis of published results with glass or resin microspheres. Objective response rate (ORR) was defined as complete or partial response. Disease control rate (DCR) was defined as complete/partial response or stable disease., Results: Twenty-four patients were identified. ORR and DCR in the institutional series was 14/24 and 21/24 at 3 months. Overall survival and progression-free survival at 3-years was 77.6% and 50.4%, respectively. There were no grade 3/4 toxicities post-procedure. A fixed-effects pooled estimate of ORR of 51% (95% CI: 47%-54%) was identified from meta-analysis of 27 studies. The fixed-effects weighted average DCR was 88% (95% CI: 85%-90%, 27 studies)., Conclusion: Current data demonstrate evidence of the clinical effectiveness and safety of radioembolisation for neuroendocrine liver metastases. Prospective randomised studies to compare radioembolisation with other liver directed treatment modalities are needed., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Holmium microspheres have recently become available in the European market as the third type of microspheres for radioembolization of unresectable liver malignancies. Holmium microspheres come with a dedicated administration system, and since these microspheres contain holmium-166 ( 166 Ho) instead of yttrium-90, unique dosing and imaging possibilities have become available as well. In addition, a scout dose of 166 Ho microspheres (Conformité Européenne mark is now granted and not pending anymore) can be used instead of 99m Tc-macroaggragated albumin during the preparatory angiography procedure. So far, two prospective phase I and phase II clinical studies have been performed on 166 Ho radioembolization in a population of liver metastases from mixed origins. These studies showed that a mean whole-liver dose of 60 Gy is safe and induces tumor response. Ongoing trials investigate the effect of 166 Ho radioembolization in patients with neuroendocrine tumor metastases, hepatocellular carcinoma, and colorectal cancer metastases. Data derived from these studies will be used to refine the dosing schedule of 60 Gy to the whole liver and determine the optimal level of activity for each patient. This paper discusses several basics and provides an overview of relevant dosing aspects, technical aspects of performing holmium radioembolization, as well as a summary of completed and ongoing clinical studies and the upcoming developments regarding these microspheres., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Neuroendocrine tumours (NET) consist of a heterogeneous group of neoplasms with various organs of origin. At diagnosis 21% of the patients with a Grade 1 NET and 30% with a Grade 2 NET have distant metastases. Treatment with peptide receptor radionuclide therapy (PRRT) shows a high objective response rate and long median survival after treatment. However, complete remission is almost never achieved. The liver is the most commonly affected organ in metastatic disease and is the most incriminating factor for patient survival. Additional treatment of liver disease after PRRT may improve outcome in NET patients. Radioembolization is an established therapy for liver metastasis. To investigate this hypothesis, a phase 2 study was initiated to assess effectiveness and toxicity of holmium-166 radioembolization ( 166 Ho-RE) after PRRT with lutetium-177 ( 177 Lu)-DOTATATE., Methods: The HEPAR PLUS trial ("Holmium Embolization Particles for Arterial Radiotherapy Plus 177 Lu-DOTATATE in Salvage NET patients") is a single centre, interventional, non-randomized, non-comparative, open label study. In this phase 2 study 30-48 patients with > 3 measurable liver metastases according to RECIST 1.1 will receive additional 166 Ho-RE within 20 weeks after the 4th and last cycle of PRRT with 7.4 GBq 177 Lu-DOTATATE. Primary objectives are to assess tumour response, complete and partial response according to RECIST 1.1, and toxicity, based on CTCAE v4.03, 3 months after 166 Ho-RE. Secondary endpoints include biochemical response, quality of life, biodistribution and dosimetry., Discussion: This is the first prospective study to combine PRRT with 177 Lu-DOTATATE and additional 166 Ho-RE in metastatic NET. A radiation boost on intrahepatic disease using 166 Ho-RE may lead to an improved response rate without significant additional side-effects., Trial Registration: Clinicaltrials.gov NCT02067988 , 13 February 2014. Protocol version: 6, 30 november 2016.

Objective: Radioembolisation is generally preceded by a scout dose of technetium-99m-macroaggregated albumin to estimate extrahepatic shunting of activity. Holmium-166 microspheres can be used as a scout dose (±250 MBq) and as a therapeutic dose. The general toxicity of a holmium-166 scout dose ( 166 Ho-SD) and safety concerns of an accidental extrahepatic deposition of 166 Ho-SD were investigated., Methods: All patients who received a 166 Ho-SD in our institute were reviewed for general toxicity and extrahepatic depositions. The absorbed dose in extrahepatic tissue was calculated on SPECT/CT and correlated to clinical toxicities., Results: In total, 82 patients were included. No relevant clinical toxicity occurred. Six patients had an extrahepatic deposition of 166 Ho-SD (median administered activity 270 MBq). The extrahepatic depositions (median activity 3.7 MBq) were located in the duodenum (3x), gastric fundus, falciform ligament and the lesser curvature of the stomach, and were deposited in a median volume of 15.3 ml, which resulted in an estimated median absorbed dose of 3.6 Gy (range 0.3-13.8 Gy). No adverse events related to the extrahepatic deposition of the 166 Ho-SD occurred after a median follow-up of 4 months (range 1-12 months)., Conclusion: These results support the safety of 250 MBq 166 Ho-SD in a clinical setting., Key Points: • A holmium-166 scout dose is safe in a clinical setting. • Holmium-166 scout dose is a safe alternative for 99m Tc-MAA for radioembolisation work-up. • Holmium-166 scout dose potentially has several benefits over 99m Tc-MAA for radioembolisation work-up.

Radioembolization is an established treatment modality that has been subjected to many improvements over the last decade. Developments are occurring at a high pace, affecting patient selection and treatment. The aim of this review is therefore to provide an overview of current practice, with a focus on recent developments in the field of radioembolization. Several practical issues and recommendations in the application of radioembolization will be discussed, ranging from patient selection to treatment response and future applications., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)