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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.)

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.)

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.)

Intravenous 177 Lu-high-affinity (HA)-DOTATATE has shown promising results for the treatment of surgery- and radiotherapy-refractory meningiomas. We aimed to investigate the added value of intraarterial administration. Methods: Patients underwent at least 1 intravenous 177 Lu-HA-DOTATATE treatment first and subsequent intraarterial cycles. Inpatient and intrapatient comparison was based on posttreatment 177 Lu-HA-DOTATATE imaging 24 h after injection. The technical success rate and adverse events were recorded. Results: Four patients provided informed consent. The technical success rate was 100%, and no angiography-related or unexpected adverse events occurred. Intrapatient comparison showed an increased target lesion accumulation on both planar imaging (mean, +220%) and SPECT/CT (mean, +398%) after intraarterial administration, compared with intravenous administration. No unexpected adverse events occurred during follow-up. Conclusion: Intraarterial peptide receptor radionuclide therapy significantly increases tracer accumulation and is a safe and promising improvement for salvage meningioma patients. Future prospective studies on intraarterial peptide receptor radionuclide therapy are needed to determine the gain in efficacy and survival., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

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.)

Peptide receptor radionuclide therapy (PRRT) with 177 Lu-labeled somatostatin analogs in patients with somatostatin receptor-expressing tumors is often performed using administration protocols prescribing a 30-min infusion time. The most often used method of infusion is the gravity method, by which the complete dose is effectively administered exponentially. However, there is no evidence to explicitly support an infusion time of 30 min. This study aims to investigate the safety of an infusion time of less than 5 min. Methods: A cohort study was performed, examining the biochemical and clinical toxicity after PRRT when using a fast-infusion protocol with a maximum infusion time of 5 min. Data on patient characteristics, laboratory tests, follow-up visits, and pre- and posttreatment imaging using 68 Ga-DOTATOC PET/CT from patients treated with PRRT at the University Medical Center Utrecht (UMC Utrecht) were collected. All patients receiving PRRT using the fast-infusion protocol were included. If no laboratory or clinical follow-up was available, patients were excluded. In addition, a laboratory experiment was performed, simulating the standard-infusion protocol using the gravity method. Results: Thirty-one patients, treated using the fast-infusion protocol, were included. Clinical toxicity mainly consisted of grade 1/2 fatigue (87.1%) and grade 1 nausea or vomiting (67.7%) during follow-up. No acute or long-term clinical toxicity possibly related to the fast-infusion protocol was reported. Grade 3/4 hematologic toxicity occurred after PRRT in 1 patient (3.2%). No grade 3/4 renal toxicity occurred. The laboratory experiment showed that when using the gravity method for infusion, half of the activity is infused after 3.5 min, and 95% is infused within 15 min. Conclusion: A faster infusion of PRRT using an infusion time of less than 5 min is safe and feasible in clinical practice., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Radioembolization is a treatment option for colorectal cancer (CRC) patients with inoperable, chemorefractory hepatic metastases. Personalized treatment requires established dose thresholds. Hence, the aim of this study was to explore the relationship between dose and effect (i.e., response and toxicity) in CRC patients treated with 166 Ho radioembolization. Methods: CRC patients treated in the HEPAR II and SIM studies were analyzed. Absorbed doses were estimated using the activity distribution on posttreatment 166 Ho SPECT/CT. Metabolic response was assessed using the change in total-lesion glycolysis on 18 F-FDG PET/CT between baseline and 3-mo follow-up. Toxicity between treatment and 3 mo was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5, and its relationship with parenchyma-absorbed dose was assessed using linear models. The relationship between tumor-absorbed dose and patient- and tumor-level response was analyzed using linear mixed models. Using a threshold of 100% sensitivity for response, the threshold for a minimal mean tumor-absorbed dose was determined and its impact on survival was assessed. Results: Forty patients were included. The median parenchyma-absorbed dose was 37 Gy (range, 12-55 Gy). New CTCAE grade 3 or higher clinical and laboratory toxicity was present in 8 and 7 patients, respectively. For any clinical toxicity (highest grade per patient), the mean difference in parenchymal dose (Gy) per step increase in CTCAE grade category was 5.75 (95% CI, 1.18-10.32). On a patient level, metabolic response was as follows: complete response, n = 1; partial response, n = 11; stable disease, n = 17; and progressive disease, n = 8. The mean tumor-absorbed dose was 84% higher in patients with complete or partial response than in patients with progressive disease (95% CI, 20%-180%). Survival for patients with a mean tumor-absorbed dose of more than 90 Gy was significantly better than for patients with a mean tumor-absorbed dose of less than 90 Gy (hazard ratio, 0.16; 95% CI, 0.06-0.511). Conclusion: A significant dose-response relationship in CRC patients treated with 166 Ho radioembolization was established, and a positive association between toxicity and parenchymal dose was found. For future patients, it is advocated to use a 166 Ho scout dose to select patients and yo personalize the administered activity, targeting a mean tumor-absorbed dose of more than 90 Gy and a parenchymal dose of less than 55 Gy., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

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.)