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223 Ra-dichloride ( 223 Ra) and 177 Lu-prostate-specific membrane antigen (PSMA) are approved treatments for metastatic castration-resistant prostate cancer (mCRPC). The safety and effectiveness of sequential use of 223 Ra and 177 Lu-PSMA in patients with mCRPC are not well described. This study aimed to evaluate 177 Lu-PSMA safety and efficacy in patients with mCRPC previously treated with 223 Ra. Methods: The radium→lutetium (RALU) study was a multicenter, retrospective, medical chart review. Participants had received at least 1 223 Ra dose and, in any subsequent therapy line, at least 1 177 Lu-PSMA dose. Primary endpoints included the incidence of adverse events (AEs), serious AEs, grade 3-4 hematologic AEs, and abnormal laboratory values. Secondary endpoints included overall survival, time to next treatment/death, and change from baseline in serum prostate-specific antigen and alkaline phosphatase levels. Results: Data were from 133 patients. Before 177 Lu-PSMA therapy, 56% (75/133) of patients received at least 4 life-prolonging therapies; all patients received 223 Ra (73% received 5-6 injections). Overall, 27% (36/133) of patients received at least 5 177 Lu-PSMA infusions. Any-grade treatment-emergent AEs were reported in 79% (105/133) of patients and serious AEs in 30% (40/133). The most frequent grade 3-4 laboratory abnormalities were anemia (30%, 40/133) and thrombocytopenia (13%, 17/133). Median overall survival was 13.2 mo (95% CI, 10.5-15.6 mo) from the start of 177 Lu-PSMA. Conclusion: In this real-world setting, 223 Ra followed by 177 Lu-PSMA therapy in heavily pretreated patients with mCRPC was clinically feasible, with no indication of impairment of 177 Lu-PSMA safety or effectiveness., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

The radium lutetium (RALU) study evaluated the feasibility of sequential α- and β-emitter use in patients with bone-predominant metastatic castration-resistant prostate cancer. Methods: This preplanned interim retrospective analysis investigated safety and survival outcomes with 177 Lu-PSMA in patients treated with prior 223 Ra. Results: Forty-nine patients were evaluated. Patients received a median of 6 223 Ra injections; 59% of patients received at least 4 177 Lu-PSMA cycles. Most (69%) patients received at least 4 life-prolonging therapies before 177 Lu-PSMA. Common Terminology Criteria for Adverse Events grade 3-4 treatment-emergent adverse events during 177 Lu-PSMA therapy and a 30-d follow-up period included anemia (18%) and thrombocytopenia (2%). Median overall survival was 12.6 mo (95% CI, 8.8-16.1 mo) and 31.4 mo (95% CI, 25.7-37.6 mo) from starting 177 Lu-PSMA or 223 Ra, respectively. Conclusion: 177 Lu-PSMA treatment was well tolerated in patients who had received prior 223 Ra. 223 Ra use before 177 Lu-PSMA is feasible and can be considered for future assessment of the optimal treatment sequence., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

We analyzed real-world clinical outcomes of sequential α-/β-emitter therapy for metastatic castration-resistant prostate cancer (mCRPC). Methods: We assessed safety and overall survival in 26 patients who received 177 Lu-prostate-specific membrane antigen ligand ( 177 Lu-PSMA) after 223 Ra in the ongoing noninterventional REASSURE study ( 223 Ra α-Emitter Agent in Nonintervention Safety Study in mCRPC Population for Long-Term Evaluation; NCT02141438). Results: Patients received 223 Ra for a median of 6 injections and subsequent 177 Lu-PSMA for a median of 3.5 mo (≥ the fourth therapy in 69%). The median time between 223 Ra and 177 Lu-PSMA treatment was 8 mo (range, 1-31 mo). Grade 3 hematologic events occurred in 9 of 26 patients (during or after 177 Lu-PSMA treatment in 5/9 patients; 8/9 patients had also received docetaxel). Median overall survival was 28.0 mo from the 223 Ra start and 13.2 mo from the 177 Lu-PSMA start. Conclusion: Although the small sample size precludes definitive conclusions, these preliminary data, especially the 177 Lu-PSMA treatment duration, suggest that the use of 177 Lu-PSMA after 223 Ra is feasible in this real-world setting., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Immune checkpoint blockade represents a promising approach in oncology, showing antitumor activities in various cancers. However, although being generally far better tolerated than classic cytotoxic chemotherapy, this treatment, too, may be accompanied by considerable side effects and not all patients benefit equally. Therefore, careful patient selection and monitoring of the treatment response is mandatory. At present, checkpoint-specific molecular imaging is being increasingly investigated as a tool for patient selection and response evaluation. Here, an overview of the current developments in immune checkpoint imaging is provided., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Pretargeted radioimmunotherapy (PRIT) with the β-emitting radionuclide 177 Lu is an attractive approach to treat carcinoembryonic antigen (CEA)-expressing tumors. The therapeutic efficacy of PRIT might be improved using α-emitting radionuclides such as 213 Bi. Herein, we report and compare the tumor-targeting properties and therapeutic efficacy of 213 Bi and 177 Lu for PRIT of CEA-expressing xenografts, using the bispecific monoclonal antibody TF2 (anti-CEA × anti-histamine-succinyl-glycine [HSG]) and the di-HSG-DOTA peptide IMP288. Methods: The in vitro binding characteristics of 213 Bi-IMP288 were compared with those of 177 Lu-IMP288. Tumor targeting of 213 Bi-IMP288 and 177 Lu-IMP288 was studied in mice bearing subcutaneous LS174T tumors that were pretargeted with TF2. Finally, the effect of 213 Bi-IMP288 (6, 12, or 17 MBq) and 177 Lu-IMP288 (60 MBq) on tumor growth and survival was assessed. Toxicity was determined by monitoring body weight, analyzing blood samples for hematologic and renal toxicity (hemoglobin, leukocytes, platelets, creatinine), and immunohistochemical analysis of the kidneys. Results: The in vitro binding characteristics of 213 Bi-IMP288 (dissociation constant, 0.45 ± 0.20 nM) to TF2-pretargeted LS174T cells were similar to those of 177 Lu-IMP288 (dissociation constant, 0.53 ± 0.12 nM). In vivo accumulation of 213 Bi-IMP288 in LS174T tumors was observed as early as 15 min after injection (9.2 ± 2.0 percentage injected dose [%ID]/g). 213 Bi-IMP288 cleared rapidly from the circulation; at 30 min after injection, the blood levels were 0.44 ± 0.28 %ID/g. Uptake in normal tissues was low, except for the kidneys, where uptake was 1.8 ± 1.1 %ID/g at 30 min after injection. The biodistribution of 213 Bi-IMP288 was comparable to that of 177 Lu-IMP288. Mice treated with a single dose of 213 Bi-IMP288 or 177 Lu-IMP288 showed significant inhibition of tumor growth. Median survival for the groups treated with phosphate-buffered saline, 6 MBq 213 Bi-IMP288, 12 MBq 213 Bi-IMP288, and 60 MBq 177 Lu-IMP288 was 22, 31, 45, and 42 d, respectively. Mice receiving 17 MBq 213 Bi-IMP288 showed significant weight loss, resulting in a median survival of only 24 d. No changes in hemoglobin, platelets, or leukocytes were observed in the treatment groups. However, immunohistochemical analysis of the kidneys of mice treated with 17 or 12 MBq 213 Bi-IMP288 showed signs of tubular damage, indicating nephrotoxicity. Conclusion: To our knowledge, this study shows for the first time that PRIT with TF2 and 213 Bi-IMP288 is feasible and at least as effective as 177 Lu-IMP288. However, at higher doses, kidney toxicity was observed. Future studies are warranted to determine the optimal dosing schedule to improve therapeutic efficacy while reducing renal toxicity., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

We retrospectively evaluated the utility of 68 Ga-PSMA-11 PET for planning 223 RaCl 2 therapy of patients with metastatic prostate cancer and its impact on the therapeutic response as determined by prostate-specific antigen (PSA) and alkaline phosphatase (ALP), as well as the correlation of PSA changes with the results of prostate-specific membrane antigen (PSMA) PET follow-up scans. Methods: Sixty-three patients with a median age of 73 y who underwent 307 cycles of therapy with 223 RaCl 2 were analyzed. In 31 patients, bone scanning and radiologic imaging were performed for pretherapeutic imaging (group 1). In 32 patients, bone scanning and PSMA PET were performed before therapy (group 2). Patients with small lymph node metastases and local recurrence were not excluded from treatment, consistent with current guidelines. PSA and ALP were measured before each treatment cycle and 4 wk after the final cycle. Thirteen patients from group 2, who underwent a second PSMA PET scan as a follow-up, were evaluated to determine the significance of PSA changes as a follow-up marker. Results: In group 1, 4 patients (12.9%) showed a PSA decline, of whom 2 patients and 1 patient showed a PSA decline of more than 30% and more than 50%, respectively. In contrast, in group 2, 14 patients (43.8%) showed a PSA decline, of whom 10 and 8 patients showed a decline of more than 30% and more than 50%, respectively ( P = 0.007). Thirty-seven patients had a high ALP level (19 from group 1 and 18 from group 2). Twelve (63.2%) and 16 (88.9%) patients in groups 1 and 2, respectively, showed an ALP decline. This difference was not significant; however, 7 (36%) and 13 (72.2%) patients in groups 1 and 2, respectively, showed an ALP decline of more than 30% ( P = 0.04). Considering any ALP decline as a response, no patient with increasing ALP showed a PSA response ( P = 0.036). There was a significant correlation between the PSA changes and the therapeutic response according to follow-up PSMA PET. Conclusion: When PSMA PET is used as the gatekeeper in addition to bone scanning, radionuclide therapy with 223 Ra may be more effective and have more success regarding changes in the PSA. An increase in PSA during therapy cycles occurs because of disease progression., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Radiolabeling of the prostate-specific membrane antigen (PSMA) inhibitor Glu-NH-CO-NH-Lys(Ahx) using the 68 Ga chelator HBED-CC (PSMA HBED ) allows imaging of prostate cancer lesions because of high expression of PSMA in prostate carcinoma cells and in bone metastases and lymph nodes related to the disease. The aim of this work was to optimize labeling of 68 Ga-PSMA HBED using the efficient cation-exchange postprocessing of 68 Ga as well as the development of a thin-layer chromatography (TLC)-based quality control system. Methods: Labeling was optimized for online ethanol-postprocessed 68 Ga eluate investigating various parameters, such as buffer molarity (0.1-1 M), temperature (25°C-90°C), tracer amount (0.11-0.74 nmol), and labeling time. In addition, purification of the crude product was tested. For radio-TLC quality control, various mobile phases were analyzed using silica gel 60 plates and the results were validated using high-performance liquid chromatography. The most superior mobile phases were also applied on instant thin-layer chromatography (ITLC) silica gel plates. Results: Using optimized conditions, labeling yields of more than 95% were obtained within 10 min when ethanol-based postprocessing was applied using PSMA HBED amounts as low as 0.1 nmol. A higher precursor concentration (0.7 nmol) further increased labeling and quantitative yields to more than 98% within 5 min. In clinical routine, patient batches (>200 applications) with radiochemical purity greater than 98% and specific activities of 326 ± 20 MBq/nmol are obtained reproducibly. When TLC quality control was performed on silica gel 60 plates, 4 mobile phases with suitable separation properties and complementary R f values were identified. Two systems showed equivalent separation on ITLC silica gel plates, with ITLC analysis finished within 5 min, in contrast to 20 min for the TLC system. Labeling of PSMA HBED was optimized for cation-exchange postprocessing methods, ensuring almost quantitative labeling and high nuclide purity of final 68 Ga-PSMA HBED , making subsequent purification steps unnecessary. Conclusion: The new radio-TLC method allows quality control in a short time using a fast, reliable, low-cost method with little equipment complexity. Using this approach, the synthesis is easily adopted by automated synthesis modules., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Radioligand therapy (RLT) with 177 Lu-PSMA-617 (PSMA is prostate-specific membrane antigen) is a novel targeted therapy for metastatic prostate cancer. In this study, we evaluated the effect of different pretherapeutic parameters on the therapeutic response measured by prostate-specific antigen (PSA) 2 mo after RLT., Methods: RLT was performed in 40 hormone-refractory patients with distant metastases and progressive disease (mean age, 71.4 y). 68 Ga-PSMA-11 PET/CT was performed in all patients 1-2 wk before RLT. All patients were treated with a mean of 6 GBq. The SUV max of tumor lesions was determined using region-of-interest analysis. Complete blood counts, renal and liver function assessments, previous therapies, pain medication, and SUVs were included in the analysis. PSA was assessed 2 mo after RLT., Results: In the univariate analysis, younger age, higher levels of γ-glutamyl transferase, lower pretherapeutic hemoglobin, a higher Gleason score, a higher number of platelets, higher C-reactive protein, regular need for pain medication, and higher lactate dehydrogenase had a negative impact on the therapeutic response; however, the multivariate analysis revealed that the most significant independent factors were the number of platelets and regular need for pain medication. The response was independent of the amount of PSMA uptake as well as previous therapies and other measured factors., Conclusion: A PSA decline of more than 50% was observed significantly more in patients without a regular need for analgesics., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

177 Lu-labeled PSMA-617 is a promising new therapeutic agent for radioligand therapy (RLT) of patients with metastatic castration-resistant prostate cancer (mCRPC). Initiated by the German Society of Nuclear Medicine, a retrospective multicenter data analysis was started in 2015 to evaluate efficacy and safety of 177 Lu-PSMA-617 in a large cohort of patients., Methods: One hundred forty-five patients (median age, 73 y; range, 43-88 y) with mCRPC were treated with 177 Lu-PSMA-617 in 12 therapy centers between February 2014 and July 2015 with 1-4 therapy cycles and an activity range of 2-8 GBq per cycle. Toxicity was categorized by the common toxicity criteria for adverse events (version 4.0) on the basis of serial blood tests and the attending physician's report. The primary endpoint for efficacy was biochemical response as defined by a prostate-specific antigen decline ≥ 50% from baseline to at least 2 wk after the start of RLT., Results: A total of 248 therapy cycles were performed in 145 patients. Data for biochemical response in 99 patients as well as data for physician-reported and laboratory-based toxicity in 145 and 121 patients, respectively, were available. The median follow-up was 16 wk (range, 2-30 wk). Nineteen patients died during the observation period. Grade 3-4 hematotoxicity occurred in 18 patients: 10%, 4%, and 3% of the patients experienced anemia, thrombocytopenia, and leukopenia, respectively. Xerostomia occurred in 8%. The overall biochemical response rate was 45% after all therapy cycles, whereas 40% of patients already responded after a single cycle. Elevated alkaline phosphatase and the presence of visceral metastases were negative predictors and the total number of therapy cycles positive predictors of biochemical response., Conclusion: The present retrospective multicenter study of 177 Lu-PSMA-617 RLT demonstrates favorable safety and high efficacy exceeding those of other third-line systemic therapies in mCRPC patients. Future phase II/III studies are warranted to elucidate the survival benefit of this new therapy in patients with mCRPC., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Unlabelled: (18)F-FDG PET/CT is effective in the assessment of therapy response. Changes in glucose uptake or tumor size are used as a measure. Tumor heterogeneity was found to be a promising predictive and prognostic factor. We investigated textural parameters for their predictive and prognostic capability in patients with rectal cancer using histopathology as the gold standard. In addition, a comparison to clinical outcome was performed., Methods: Twenty-seven patients with rectal cancer underwent (18)F-FDG PET/CT before, 2 wk after the start, and 4 wk after the completion of neoadjuvant chemoradiotherapy. In all PET/CT scans, conventional parameters (tumor volume, diameter, maximum and mean standardized uptake values, and total lesion glycolysis [TLG]) and textural parameters (coefficient of variation [COV], skewness, and kurtosis) were determined to assess tumor heterogeneity. Values on pretherapeutic PET/CT as well as changes early in the course of therapy and after therapy were compared with histopathologic response. In addition, the prognostic value was assessed by correlation with time to progression and survival time., Results: The COV showed a statistically significant capability to assess histopathologic response early in therapy (sensitivity, 68%; specificity, 88%) and after therapy (79% and 88%, respectively). Thereby, the COV had a higher area under the curve in receiver-operating-characteristic analysis than did any analyzed conventional parameter for early and late response assessment. The COV showed a statistically significant capability to evaluate disease progression and to predict survival, although the latter was not statistically significant., Conclusion: Tumor heterogeneity assessed by the COV, being superior to the investigated conventional parameters, is an important predictive factor in patients with rectal cancer. Furthermore, it can provide prognostic information. Therefore, its application is an important step for personalized treatment of rectal cancer., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: By conventional imaging modalities, the discrimination between acute and chronic aortic dissection (AD) for surgical risk evaluation is not possible. However, acute and chronic stable AD potentially may be distinguished by detection of reparatory hypermetabolism in the lacerated aortic wall of acute AD using (18)F-FDG PET/CT. In this study, we analyzed the (18)F-FDG uptake in the aortic wall of acute and chronic stable AD., Methods: Eighteen patients with acute (n = 9), symptomatic progressive (n = 2), or known chronic stable (n = 7) type B AD underwent (18)F-FDG PET/CT. Images were analyzed qualitatively and quantitatively considering (18)F-FDG uptake patterns and the standardized uptake values (SUVs) of the aortic wall, dissection membrane, and luminal (18)F-FDG activity. The SUV ratio (maximum SUV in the aorta divided by mean SUV in the blood pool) was calculated to relativize individual luminal (18)F-FDG spillover effects., Results: In contrast to chronic stable AD, all acute or acute progressive AD showed accentuated (18)F-FDG uptake at the injured aortic wall or dissection membrane. The maximum SUV of the dissection membrane or aortic wall was significantly higher (P = 0.02) in acute AD than in chronic stable AD. Thereby, SUV varied from 3.03 to 4.64 (average maximum SUV, 3.84 +/- 0.51) for the dissection membrane and from 2.22 to 4.60 (average maximum SUV, 2.94 +/- 0.81) for the aortic wall, with false-negative and false-positive outliers. The discrimination between acute and stable AD was improved significantly (P < 0.001), and false-positive or -negative outliers were eliminated, using the SUV ratio method., Conclusion: Our results indicate that (18)F-FDG PET/CT might be useful in differentiation of acute from chronic AD in clinically unclear cases. However, larger studies are needed to confirm our preliminary results.