Search

Optimal patient management protocols for metastatic castration-resistant prostate cancer (mCRPC) are poorly defined and even further complexified with new therapy approvals, such as radiopharmaceuticals. The prostate-specific membrane antigen (PSMA)-targeted agent 177 Lu vipivotide tetraxetan ([ 177 Lu]Lu-PSMA-617), approved after the phase III VISION study, presents physicians with additional aspects of patient management, including specific adverse event (AE) monitoring and management, as well as radiation safety. Drawing on our experience as VISION study investigators, here we provide guidance on best practices for delivering PSMA-targeted radiopharmaceutical therapy (RPT) to patients with mCRPC. After a comprehensive review of published evidence and guidelines on RPT management in prostate cancer, we identified educational gaps in managing the radiation safety and AEs associated with [ 177 Lu]Lu-PSMA-617. Our results showed that providing sufficient education on AEs (e.g., fatigue and dry mouth) and radiation safety principles is key to effective delivery and management of patient expectations. Patient counseling by health care professionals, across disciplines, is a cornerstone of optimal patient management during PSMA-targeted RPT. Multidisciplinary collaboration is crucial, and physicians must adhere to radiation safety protocols and counsel patients on radiation safety considerations. Treatment with [ 177 Lu]Lu-PSMA-617 is generally well tolerated; however, additional interventions may be required, such as dosing modification, medications, or transfusions. Urinary incontinence can be challenging in the context of radiation safety. Multidisciplinary collaboration between medical oncologists and nuclear medicine teams ensures that patients are monitored and managed safely and efficiently. In clinical practice, the benefit-to-risk ratio should always be evaluated on a case-by-case basis., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

[ 177 Lu]Lu-PSMA-617 was approved by the U.S. Food and Drug Administration for patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC). Since the time of regulatory approval, however, real-world data have been lacking. This study investigated the efficacy, safety, and outcome predictors of [ 177 Lu]Lu-PSMA-617 at a major U.S. academic center. Methods: Patients with mCRPC who received [ 177 Lu]Lu-PSMA-617 at the Johns Hopkins Hospital outside clinical trials were screened for inclusion. Patients who underwent [ 177 Lu]Lu-PSMA-617 and had available outcome data were included in this study. Outcome data included prostate-specific antigen (PSA) response (≥50% decline), PSA progression-free survival (PFS), and overall survival (OS). Toxicity data were evaluated according to the Common Terminology Criteria for Adverse Events version 5.03. The study tested the association of baseline circulating tumor DNA mutational status in homologous recombination repair, PI3K alteration pathway, and aggressive-variant prostate cancer-associated genes with treatment outcome. Baseline PSMA PET/CT images were analyzed using SelectPSMA, an artificial intelligence algorithm, to predict treatment outcome. Associations with the observed treatment outcome were evaluated. Results: All 76 patients with PSMA-positive mCRPC who received [ 177 Lu]Lu-PSMA-617 met the inclusion criteria. A PSA response was achieved in 30 of 74 (41%) patients. The median PSA PFS was 4.1 mo (95% CI, 2.0-6.2 mo), and the median OS was 13.7 mo (95% CI, 11.3-16.1 mo). Anemia of grade 3 or greater, thrombocytopenia, and neutropenia were observed in 9 (12%), 3 (4%), and 1 (1%), respectively, of 76 patients. Transient xerostomia was observed in 23 (28%) patients. The presence of aggressive-variant prostate cancer-associated genes was associated with a shorter PSA PFS (median, 1.3 vs. 6.3 mo; P = 0.040). No other associations were observed between circulating tumor DNA mutational status and treatment outcomes. Eighteen of 71 (25%) patients classified by SelectPSMA as nonresponders had significantly lower rates of PSA response than patients classified as likely responders (6% vs. 51%; P < 0.001), a shorter PSA PFS (median, 1.3 vs. 6.3 mo; P < 0.001), and a shorter OS (median, 6.3 vs. 14.5 mo; P = 0.046). Conclusion: [ 177 Lu]Lu-PSMA-617 offered in a real-world setting after regulatory approval in the United States demonstrated antitumor activity and a favorable toxicity profile. Artificial-intelligence-based analysis of baseline PSMA PET/CT images may improve patient selection. Validation of these findings on larger cohorts is warranted., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Radiopharmaceutical therapies (RPTs) based on fibroblast activation protein (FAP) and FAP inhibitors (FAPIs) are a new option for progressive metastatic cancer in patients pretreated multiple times. To date, published in-human data refer to initial experiences with β-emitting 90 Y- and 177 Lu-based RPT. However, the short tumor retention time of FAPI ligands is considered a major limitation of FAPI RPT. Therefore, fractionated FAPI RPT with 213 Bi, an α-emitter with a half-life of 46 min, appears to be a promising FAPI RPT regimen. Here, we report on our initial experiences with regard to the feasibility, tolerability, and response of fractionated 213 Bi-FAPI-46 RPT. Methods: Six patients (4 women and 2 men) with progressive metastatic solid tumors (3 colon cancer, 1 anal cancer, 1 breast cancer, and 1 prostate cancer) aged 16-77 y were treated with a mean of 1,609 MBq of 213 Bi-FAPI-46, fractionated into 53 single applications (range, 5-12 RPT applications per patient; mean, 8.8 applications) over a period of up to 107 h per patient. Of the 6 patients, 4 patients received adjuvant treatment with pembrolizumab. 18 F-FDG (4 patients) and 68 Ga-FAPI-46 (5 patients) PET/CT scans were performed before and after RPT. PET images were assessed visually and by calculating total lesion glycolysis and total lesion FAPI. Results: RPT with 213 Bi-FAPI-46 was well tolerated without adverse side effects. In terms of visual response assessment, there was 1 partial response (16.7%), 1 patient with stable disease (16.7%), and 4 patients with progressive disease (66.7%). Concordantly, total lesion glycolysis and total lesion FAPI were decreased in the responding patient (not applicable and -24.3%, respectively), slightly decreased in the patient with stable disease (-10.6% and -5.9%, respectively), and increased in the 4 patients with progression (mean, +104.4% and +321.3%, respectively). Conclusion: Fractionated FAPI RPT with the short-half-life α-emitter 213 Bi-FAPI-46 is a promising approach that matches the pharmacokinetics of FAPI-46 better than the 177 Lu- or 90 Y-labeled compounds. In this pilot project, fractionated RPT with 213 Bi-FAPI-46 showed good clinical tolerability and even led to regressive or stable disease in the short term in 2 of 6 patients. Further studies with larger patient cohorts are required to evaluate the actual efficacy and long-term effects of this variant of FAPI RPT., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Radiopharmaceutical cocktails have been developed over the years to treat cancer. Cocktails of agents are attractive because 1 radiopharmaceutical is unlikely to have the desired therapeutic effect because of nonuniform uptake by the targeted cells. Therefore, multiple radiopharmaceuticals targeting different receptors on a cell is warranted. However, past implementations in vivo have not met with convincing results because of the absence of optimization strategies. Here we present artificial intelligence (AI) tools housed in a new version of our software platform, MIRDcell V4, that optimize a cocktail of radiopharmaceuticals by minimizing the total disintegrations needed to achieve a given surviving fraction (SF) of tumor cells. Methods: AI tools are developed within MIRDcell V4 using an optimizer based on the sequential least-squares programming algorithm. The algorithm determines the molar activities for each drug in the cocktail that minimize the total disintegrations required to achieve a specified SF. Tools are provided for populations of cells that do not cross-irradiate (e.g., circulating or disseminated tumor cells) and for multicellular clusters (e.g., micrometastases). The tools were tested using model data, flow cytometry data for suspensions of single cells labeled with fluorochrome-labeled antibodies, and 3-dimensional spatiotemporal kinetics in spheroids for fluorochrome-loaded liposomes. Results: Experimental binding distributions of 4 211 At-antibodies were considered for treating suspensions of MDA-MB-231 human breast cancer cells. A 2-drug combination reduced the number of 211 At decays required by a factor of 1.6 relative to the best single antibody. In another study, 2 radiopharmaceuticals radiolabeled with 195m Pt were each distributed lognormally in a hypothetical multicellular cluster. Here, the 2-drug combination required 1.7-fold fewer decays than did either drug alone. Finally, 2 225 Ac-labeled drugs that provide different radial distributions within a spheroid require about one half of the disintegrations required by the best single agent. Conclusion: The MIRDcell AI tools determine optimized drug combinations and corresponding molar activities needed to achieve a given SF. This approach could be used to analyze a sample of cells obtained from cell culture, animal, or patient to predict the best combination of drugs for maximum therapeutic effect with the least total disintegrations., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

177 Lu can be imaged after administration using SPECT/CT. Most work to date has focused on using posttreatment imaging to measure normal organ and tumor dose. We aimed to assess the impact of posttreatment SPECT/CT on the management of patients undergoing 177 Lu-prostate-specific membrane antigen (PSMA) radiopharmaceutical therapy (RPT). Methods: In this retrospective study, 122 patients underwent PSMA RPT with subsequent SPECT/CT 24 h after treatment. We determined a qualitative response at each cycle and reviewed patient charts to assess the impact that posttreatment SPECT/CT had on patient management. Changes in patient management were classified as changes on the basis of progression and response, and specific cycles when they occurred were noted. Miscellaneous changes in patient management were also evaluated. Results: Among the 122 consecutive patients examined, 42%-56% exhibited stable disease, whereas 19%-39% of patients exhibited response on visual assessment across treatment cycles. In total, 49% ( n = 60) of patients experienced changes in management, of which 57% ( n = 34) were due to progression, 40% ( n = 24) were due to response, and 3% ( n = 2) were due to miscellaneous changes. Changes due to disease progression were observed mostly after cycles 2 and 4. Changes due to response to RPT occurred mostly after cycles 3 and 4. Conclusion: At our center, 49% of patients experienced changes in management based on posttreatment SPECT/CT, and most of these changes occurred at cycles 2 and 4. Integrating posttreatment SPECT/CT into routine PSMA RPT protocols can aid in patient management., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Image-based dosimetry-guided radiopharmaceutical therapy has the potential to personalize treatment by limiting toxicity to organs at risk and maximizing the therapeutic effect. The 177 Lu dosimetry challenge of the Society of Nuclear Medicine and Molecular Imaging consisted of 5 tasks assessing the variability in the dosimetry workflow. The fifth task investigated the variability associated with the last step, dose conversion, of the dosimetry workflow on which this study is based. Methods: Reference variability was assessed by 2 medical physicists using different software, methods, and all possible combinations of input segmentation formats and time points as provided in the challenge. General descriptive statistics for absorbed dose values from the global submissions from participants were calculated, and variability was measured using the quartile coefficient of dispersion. Results: For the liver, which included lesions with high uptake, variabilities of up to 36% were found. The baseline analysis showed a variability of 29% in absorbed dose results for the liver from datasets where lesions included and excluded were grouped, indicating that variation in how lesions in normal liver were treated was a significant source of variability. For other organs and lesions, variability was within 7%, independently of software used except for the local deposition method. Conclusion: The choice of dosimetry method or software had a small contribution to the overall variability of dose estimates., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Understanding the relationship between lesion-absorbed dose and tumor response in 177 Lu-PSMA-617 radiopharmaceutical therapies (RPTs) remains complex. We aimed to investigate whether baseline lesion-absorbed dose can predict lesion-based responses and to explore the connection between lesion-absorbed dose and prostate-specific antigen (PSA) response. Methods: In this retrospective study, we evaluated 50 patients with 335 index lesions undergoing 177 Lu-PSMA-617 RPT, who had dosimetry analysis performed on SPECT/CT at 24 h after cycles 1 and 2. First, we identified the index lesions for each patient and measured the lesion-based absorbed doses. Lesion-based response was calculated after cycle 2. Additionally, PSA50 response (a decline of 50% from baseline PSA) after cycle 2 was also calculated. The respective responses for mean and maximum absorbed doses and prostate-specific membrane antigen (PSMA) volumetric intensity product (VIP-PSMA) at cycles 1 and 2 were termed SPECT mean , SPECT maximum , and SPECT VIP-PSMA , respectively. Results: Of the 50 patients reviewed, 46% achieved a PSA50 response after cycle 2. Of the 335 index lesions, 58% were osseous, 32% were lymph nodes, and 10% were soft-tissue metastatic lesions. The SPECT lesion-based responses were higher in PSA responders than in nonresponders (SPECT mean response of 46.8% ± 26.1% vs. 26.2% ± 24.5%, P = 0.007; SPECT maximum response of 45% ± 25.1% vs. 19% ± 27.0%, P = 0.001; SPECT VIP-PSMA response of 49.2% ± 30.3% vs. 14% ± 34.7%, P = 0.0005). An association was observed between PSA response and SPECT VIP-PSMA response ( R 2 = 0.40 and P < 0.0001). A limited relationship was found between baseline absorbed dose measured with a 24-h single time point and SPECT lesion-based response ( R 2 = 0.05, P = 0.001, and R 2 = 0.03, P = 0.007, for mean and maximum absorbed doses, respectively). Conclusion: In this retrospective study, quantitative lesion-based response correlated with patient-level PSA response. We observed a limited relationship between baseline absorbed dose and lesion-based responses. Most of the variance in response remains unexplained solely by baseline absorbed dose. Establishment of a dose-response relationship in RPT with a single time point at 24 h presented some limitations., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Response Evaluation Criteria in Prostate-Specific Membrane Antigen Imaging (RECIP) 1.0 is an evidence-based framework to evaluate therapeutic efficacy in metastatic prostate cancer using prostate-specific membrane antigen (PSMA) PET/CT. This study aimed to evaluate the associations of interim PSMA PET/CT by RECIP 1.0 with short-term outcome after radiopharmaceutical treatment. Methods: This multicenter retrospective study included patients with metastatic castration-resistant prostate cancer who underwent [ 177 Lu]Lu-PSMA radiopharmaceutical therapy at 3 academic centers and received PSMA PET/CT at baseline and at 12 wk. Pairs of PSMA PET/CT images were assessed by 5 readers for visual RECIP 1.0. The primary outcome was the association of RECIP with prostate-specific antigen progression-free survival (PSA-PFS) by Kaplan-Meier analysis. Results: In total, 124 of 287 screened patients met the inclusion criteria, with 0 (0%), 29 (23%), 54 (44%), and 41 (33%) of those 124 patients having complete response, partial response, stable disease, or progressive disease (PD) by visual RECIP 1.0, respectively. Patients with visual RECIP PD had a significantly shorter PSA-PFS than those with RECIP stable disease or with RECIP partial response (2.6 vs. 6.4 vs. 8.4 mo; P < 0.001). The median PSA-PFS among patients with RECIP PD versus those with non-RECIP PD was 2.6 versus 7.2 mo (hazard ratio, 13.0; 95% CI, 7.0-24.1; P < 0.001). Conclusion: PSMA PET/CT by RECIP 1.0 after 2 cycles of [ 177 Lu]Lu-PSMA is prognostic for PSA-PFS. PSMA PET/CT by RECIP 1.0 may be used in earlier stages of prostate cancer to evaluate drug efficacy and to predict progression-free survival., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Hematologic toxicity, although often transient, is the most common limiting adverse effect during somatostatin peptide receptor radionuclide therapy. This study investigated the association between Monte Carlo-derived absorbed dose to the red marrow (RM) and hematologic toxicity in patients being treated for their neuroendocrine tumors. Methods: Twenty patients each receiving 4 treatment cycles of [ 177 Lu]Lu-DOTATATE were included. Multiple-time-point 177 Lu SPECT/CT imaging-based RM dosimetry was performed using an artificial intelligence-driven workflow to segment vertebral spongiosa within the field of view (FOV). This workflow was coupled with an in-house macroscale/microscale Monte Carlo code that incorporates a spongiosa microstructure model. Absorbed dose estimates to RM in lumbar and thoracic vertebrae within the FOV, considered as representations of the whole-body RM absorbed dose, were correlated with hematologic toxicity markers at about 8 wk after each cycle and at 3- and 6-mo follow-up after completion of all cycles. Results: The median of absorbed dose to RM in lumbar and thoracic vertebrae within the FOV ( D median,vertebrae ) ranged from 0.019 to 0.11 Gy/GBq. The median of cumulative absorbed dose across all 4 cycles was 1.3 Gy (range, 0.6-2.5 Gy). Hematologic toxicity was generally mild, with no grade 2 or higher toxicity for platelets, neutrophils, or hemoglobin. However, there was a decline in blood counts over time, with a fractional value relative to baseline at 6 mo of 74%, 97%, 57%, and 97%, for platelets, neutrophils, lymphocytes, and hemoglobin, respectively. Statistically significant correlations were found between a subset of hematologic toxicity markers and RM absorbed doses, both during treatment and at 3- and 6-mo follow-up. This included a correlation between the platelet count relative to baseline at 6-mo follow up: D median,vertebrae ( r = -0.64, P = 0.015), D median,lumbar ( r = -0.72, P = 0.0038), D median,thoracic ( r = -0.58, P = 0.029), and D average,vertebrae ( r = -0.66, P = 0.010), where D median,lumbar and D median,thoracic are median absorbed dose to the RM in the lumbar and thoracic vertebrae, respectively, within the FOV and D average,vertebrae is the mass-weighted average absorbed dose of all vertebrae. Conclusion: This study found a significant correlation between image-derived absorbed dose to the RM and hematologic toxicity, including a relative reduction of platelets at 6-mo follow up. These findings indicate that absorbed dose to the RM can potentially be used to understand and manage hematologic toxicity in peptide receptor radionuclide therapy., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

In radiopharmaceutical therapy, intratumoral uptake of radioactivity usually leads to heterogeneous absorbed dose distribution. The likelihood of treatment success can be estimated with the tumor control probability (TCP), which requires accurate dosimetry, estimating the absorbed dose rate per unit activity to individual tumor cells. Methods: Xenograft cryosections of the prostate cancer cell line LNCaP treated with [ 177 Lu]Lu-PSMA-617 were evaluated with digital autoradiography and stained with hematoxylin and eosin. The digital autoradiography images were used to define the source in a Monte Carlo simulation of the absorbed dose, and the stained sections were used to detect the position of cell nuclei to relate the intratumoral absorbed dose heterogeneity to the cell density. Simulations were performed for 225 Ac, 177 Lu, and 90 Y. TCP was calculated to estimate the mean necessary injected activity for a high TCP. A hypothetical case of activity mainly taken up on the tumor borders was generated and used to simulate the absorbed dose. Results: The absorbed dose per decay to tumor cells was calculated from the staining and simulation results to avoid underestimating the tumor response from low absorbed doses in tumor regions with low cell density. The mean of necessary injected activity to reach a 90% TCP for 225 Ac, 177 Lu, and 90 Y was found to be 18.3 kBq (range, 18-22 kBq), 24.3 MBq (range, 20-29 MBq), and 5.6 MBq (range, 5-6 MBq), respectively. Conclusion: To account for the heterogeneous absorbed dose generated from nonuniform intratumoral activity uptake, dosimetry models can estimate the mean necessary activity to reach a sufficient TCP for treatment response. This approach is necessary to accurately evaluate the efficacy of suggested radiopharmaceuticals for therapy., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Auger electron (AE) radiopharmaceutical therapy (RPT) may have the same therapeutic efficacy as α-particles for oncologic small disease, with lower risks of normal-tissue toxicity. The seeds of using AE emitters for RPT were planted several decades ago. Much knowledge has been gathered about the potency of the biologic effects caused by the intense shower of these low-energy AEs. Given their short range, AEs deposit much of their energy in the immediate vicinity of their site of decay. However, the promise of AE RPT has not yet been realized, with few agents evaluated in clinical trials and none becoming part of routine treatment so far. Instigated by the 2022 "Technical Meeting on Auger Electron Emitters for Radiopharmaceutical Developments" at the International Atomic Energy Agency, this review presents the current status of AE RPT based on the discussions by experts in the field. A scoring system was applied to illustrate hurdles in the development of AE RPT, and we present a selected list of well-studied and emerging AE-emitting radionuclides. Based on the number of AEs and other emissions, physical half-life, radionuclide production, radiochemical approaches, dosimetry, and vector availability, recommendations are put forward to enhance and impact future efforts in AE RPT research., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Dosimetry for personalized radiopharmaceutical therapy has gained considerable attention. Many methods, tools, and workflows have been developed to estimate absorbed dose (AD). However, standardization is still required to reduce variability of AD estimates across centers. One effort for standardization is the Society of Nuclear Medicine and Molecular Imaging 177 Lu Dosimetry Challenge, which comprised 5 tasks (T1-T5) designed to assess dose estimate variability associated with the imaging protocol (T1 vs. T2 vs. T3), segmentation (T1 vs. T4), time integration (T4 vs. T5), and dose calculation (T5) steps of the dosimetry workflow. The aim of this work was to assess the overall variability in AD calculations for the different tasks. Methods: Anonymized datasets consisting of serial planar and quantitative SPECT/CT scans, organ and lesion contours, and time-integrated activity maps of 2 patients treated with 177 Lu-DOTATATE were made available globally for participants to perform dosimetry calculations and submit their results in standardized submission spreadsheets. The data were carefully curated for formal mistakes and methodologic errors. General descriptive statistics for ADs were calculated, and statistical analysis was performed to compare the results of different tasks. Variability in ADs was measured using the quartile coefficient of dispersion. Results: ADs to organs estimated from planar imaging protocols (T2) were lower by about 60% than those from pure SPECT/CT (T1), and the differences were statistically significant. Importantly, the average differences in dose estimates when at least 1 SPECT/CT acquisition was available (T1, T3, T4, T5) were within ±10%, and the differences with respect to T1 were not statistically significant for most organs and lesions. When serial SPECT/CT images were used, the quartile coefficients of dispersion of ADs for organs and lesions were on average less than 20% and 26%, respectively, for T1; 20% and 18%, respectively, for T4 (segmentations provided); and 10% and 5%, respectively, for T5 (segmentation and time-integrated activity images provided). Conclusion: Variability in ADs was reduced as segmentation and time-integration data were provided to participants. Our results suggest that SPECT/CT-based imaging protocols generate more consistent and less variable results than planar imaging methods. Effort at standardizing segmentation and fitting should be made, as this may substantially reduce variability in ADs., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Suborgan absorbed dose estimates in mouse kidneys are crucial to support preclinical nephrotoxicity analyses of α- and β-particle-emitting radioligands exhibiting a heterogeneous activity distribution in the kidneys. This is, however, limited by the scarcity of reference dose factors (S values) available in the literature for specific mouse kidney tissues. Methods: A computational multiregion model of a mouse kidney based on high-resolution MRI data from a healthy mouse kidney was developed. The model was used to calculate S values for 5 kidney tissues (cortex, outer and inner stripes of outer medulla, inner medulla, and papilla and pelvis) for a wide range of β- or α-emitting radionuclides (45 in total) of interest for radiopharmaceutical therapy, using Monte Carlo calculations. Additionally, regional S values were applied for a 131 I-labeled single-domain antibody fragment with predominant retention in the outer stripe of the renal outer medulla. Results: The heterogeneous activity distribution in kidneys of considered α- and low- to medium-energy β-emitters considerably affected the absorbed dose estimation in specific suborgan regions. The suborgan tissue doses resulting from the nonuniform distribution of the 131 I-labeled antibody fragment largely deviated (from -40% to 57%) from the mean kidney dose resulting from an assumed uniform activity distribution throughout the whole kidney. The absorbed dose in the renal outer stripe was about 2.0 times higher than in the cortex and in the inner stripe and about 2.6 times higher than in inner tissues. Conclusion: The use of kidney regional S values allows a more realistic estimation of the absorbed dose in different renal tissues from therapeutic radioligands with a heterogeneous uptake in the kidneys. This constitutes an improvement from the simplistic (less accurate) renal dose estimates assuming a uniform distribution of activity throughout kidney tissues. Such improvement in dosimetry is expected to support preclinical studies essential for a better understanding of nephrotoxicity in humans. The dosimetric database has added value in the development of new molecular vectors for radiopharmaceutical therapy., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Single-domain antibody fragments (sdAbs) are attractive for targeted α-particle therapy, particularly with 211 At, because of their rapid accumulation in tumor and clearance from normal tissues. Here, we evaluate the therapeutic potential of this strategy with 5F7 and VHH&#95;1028-2 sdAbs that bind with high affinity to domain IV of human epidermal growth factor receptor type 2 (HER2). Methods: The HER2-specific sdAbs and HER2-irrelevant VHH&#95;2001 were labeled using N -succinimidyl-3- 211 At-astato-5-guanidinomethyl benzoate ( iso - 211 At-SAGMB). The cytotoxicity of iso- 211 At-SAGMB-5F7 and iso- 211 At-SAGMB-VHH&#95;2001 were compared on HER2-expressing BT474 breast carcinoma cells. Three experiments in mice with subcutaneous BT474 xenografts were performed to evaluate the therapeutic effectiveness of single doses of iso- 211 At-SAGMB-5F7 (0.7-3.0 MBq), iso- 211 At-SAGMB-VHH&#95;1028 (1.0-3.0 MBq), and iso- 211 At-SAGMB-VHH&#95;1028 and iso- 211 At-SAGMB-VHH&#95;2001 (∼1.0 MBq). Results: Clonogenic survival of BT474 cells was reduced after exposure to iso- 211 At-SAGMB-5F7 (D 0  = 1.313 kBq/mL) whereas iso- 211 At-SAGMB-VHH&#95;2001 was ineffective. Dose-dependent tumor growth inhibition was observed with 211 At-labeled HER2-specific 5F7 and VHH&#95;1028 but not with HER2-irrelevant VHH&#95;2001. At the 3.0-MBq dose, complete tumor regression was seen in 3 of 4 mice treated with iso- 211 At-SAGMB-5F7 and 8 of 11 mice treated with iso- 211 At-SAGMB-VHH&#95;1028; prolongation in median survival was 495% and 414%, respectively. Conclusion: Combining rapidly internalizing, high-affinity HER2-targeted sdAbs with the iso- 211 At-SAGMB residualizing prosthetic agent is a promising strategy for targeted α-particle therapy of HER2-expressing cancers., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

The purpose of this work was to perform an independent and National Institute of Standards and Technology-traceable activity measurement of 90 Y SIR-Spheres (Sirtex). γ-spectroscopic measurements of the 90 Y internal pair production decay mode were made using a high-purity germanium detector. Methods: Measured annihilation radiation detection rates were corrected for radioactive decay during acquisition, dead time, source attenuation, and source geometry effects. Detection efficiency was determined by 2 independent and National Institute of Standards and Technology-traceable methods. Results: Measured SIR-Spheres vials ( n = 5) contained more activity than specified by the manufacturer calibration; on average, the ratio of measured activity to calibrated was 1.233 ± 0.030. Activity measurements made using 2 distinct efficiency calibration methods agreed within 1%. Conclusion: The primary SIR-Spheres activity calibration appears to be a significant underestimate of true activity., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

α-Particle emitters targeting the prostate-specific membrane antigen (PSMA) proved effective in treating patients with prostate cancer who were unresponsive to the corresponding β-particle therapy. 211 At is an α-emitter that may engender less toxicity than other α-emitting agents. We synthesized a new 211 At-labeled radiotracer targeting PSMA that resulted from the search for a pharmacokinetically optimized agent. Methods: A small series of 125 I-labeled compounds was synthesized from tin precursors to evaluate the effect of the location of the radiohalogen within the molecule and the presence of lutetium in the chelate on biodistribution. On that basis, 211 At- 3 -Lu was selected and evaluated in cell uptake and internalization studies, and biodistribution and PSMA-expressing (PSMA+) PC3 PIP tumor growth control were evaluated in experimental flank and metastatic (PC3-ML-Luc) models. A long-term (13-mo) toxicity study was performed for 211 At- 3 -Lu, including tissue chemistries and histopathology. Results: The radiochemical yield of 211 At- 3 -Lu was 17.8% ± 8.2%. Lead compound 211 At- 3 -Lu demonstrated total uptake within PSMA+ PC3 PIP cells of 13.4 ± 0.5% of the input dose after 4 h of incubation, with little uptake in control cells. In SCID mice, 211 At- 3 -Lu provided uptake that was 30.6 ± 4.8 percentage injected dose per gram (%ID/g) in PSMA+ PC3 PIP tumor at 1 h after injection, and this uptake decreased to 9.46 ± 0.96 %ID/g by 24 h. Tumor-to-salivary gland and tumor-to-kidney ratios were 129 ± 99 at 4 h and 130 ± 113 at 24 h, respectively. Deastatination was not significant (stomach, 0.34 ± 0.20 %ID/g at 4 h). Dose-dependent survival was demonstrated at higher doses (>1.48 MBq) in both flank and metastatic models. There was little off-target toxicity, as demonstrated by hematopoietic stability, unchanged tissue chemistries, weight gain rather than loss throughout treatment, and favorable histopathologic findings. Conclusion: Compound 211 At- 3 -Lu or close analogs may provide limited and acceptable toxicity while retaining efficacy in management of prostate cancer., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

With the ongoing dramatic growth of radiopharmaceutical therapy, research and development in internal radiation dosimetry continue to advance both at academic medical centers and in industry. The basic paradigm for patient-specific dosimetry includes administration of a pretreatment tracer activity of the therapeutic radiopharmaceutical; measurement of its time-dependent biodistribution; definition of the pertinent anatomy; integration of the measured time-activity data to derive source-region time-integrated activities; calculation of the tumor, organ-at-risk, and/or whole-body absorbed doses; and prescription of the therapeutic administered activity. This paper provides an overview of the state of the art of patient-specific dosimetry for radiopharmaceutical therapy, including current methods and commercially available software and other resources., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Radiopharmaceutical therapy (RPT) is defined as the delivery of radioactive atoms to tumor-associated targets. In RPT, imaging is built into the mode of treatment since the radionuclides used in RPT often emit photons or can be imaged using a surrogate. Such imaging may be used to estimate tumor-absorbed dose. We examine and try to elucidate those factors that impact the absorbed dose-versus-response relationship for RPT agents. These include the role of inflammation- or immune-mediated effects, the significance of theranostic imaging, radiobiology, differences in dosimetry methods, pharmacokinetic differences across patients, and the impact of tumor hypoxia on response to RPT., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

The use of radiopharmaceutical therapies (RPTs) in the treatment of cancers is growing rapidly, with more agents becoming available for clinical use in last few years and many new RPTs being in development. Dosimetry assessment is critical for personalized RPT, insofar as administered activity should be assessed and optimized in order to maximize tumor-absorbed dose while keeping normal organs within defined safe dosages. However, many current clinical RPTs do not require patient-specific dosimetry based on current Food and Drug Administration-labeled approvals, and overall, dosimetry for RPT in clinical practice and trials is highly varied and underutilized. Several factors impede rigorous use of dosimetry, as compared with the more convenient and less resource-intensive practice of empiric dosing. We review various approaches to applying dosimetry for the assessment of activity in RPT and key clinical trials, the extent of dosimetry use, the relative pros and cons of dosimetry-based versus fixed activity, and practical limiting factors pertaining to current clinical practice., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Because of challenges in performing routine personalized dosimetry in radiopharmaceutical therapies, interest in single-time-point (STP) dosimetry, particularly using only a single SPECT scan, is on the rise. Meanwhile, there are questions about the reliability of STP dosimetry, with limited independent validations. In the present work, we analyzed 2 STP dosimetry methods and evaluated dose errors for several radiopharmaceuticals based on effective half-life distributions. Methods: We first challenged the common assumption that radiopharmaceutical effective half-lives across the population are gaussian-distributed (i.e., follow a normal distribution). Then, dose accuracy was estimated using 2 STP dosimetry methods for a wide range of potential post injection (p.i.) scan time points for different radiopharmaceuticals applied to neuroendocrine tumors and prostate cancer. The accuracy and limitations of each of the STP methods were discussed. Results: A lognormal distribution was more appropriate for capturing effective half-life distributions. The STP framework was promising for dosimetry of 177 Lu-DOTATATE and for kidney dosimetry of different radiopharmaceuticals (errors < 30%). Meanwhile, for some radiopharmaceuticals, STP accuracy was compromised (e.g., in bone marrow and tumors for 177 -labeled prostate-specific membrane antigen [PSMA])). The optimal SPECT scanning time for 177 Lu-DOTATATE was approximately 72 h p.i., whereas 48 h p.i. was better for 177 Lu-PSMA. Conclusion: Simplified STP dosimetry methods may compromise the accuracy of dose estimates, with some exceptions, such as for 177 Lu-DOTATATE and for kidney dosimetry in different radiopharmaceuticals. Simplified personalized dosimetry in the clinic continues to be challenging. On the basis of our results, we make suggestions and recommendations for improved personalized dosimetry using simplified imaging schemes., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

The Society of Nuclear Medicine and Molecular Imaging created the Value Initiative in 2017 as a major component of its strategic plan to further demonstrate the value of molecular imaging and molecularly targeted radiopharmaceutical therapy to patients, physicians, payers, and funding agencies. The research and discovery domain, 1 of 5 under the Value Initiative, has a goal of advancing the research and development of diagnostic and therapeutic nuclear medicine. Research and discovery efforts and achievements are essential to ensure a bright future for NM and to translate science to practice. Given the remarkable progress in the field, leaders from the research and discovery domain and society councils identified 5 broad areas of opportunity with potential for substantive growth and clinical impact. This article discusses these 5 growth areas, identifying specific areas of particularly high importance for future study and development. As there was an understanding that goals should be both visionary yet achievable, this effort was called the Mars shot for nuclear medicine., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

The currently available therapeutic radiopharmaceutical for high-risk neuroblastoma, 131 I-metaiodobenzylguanidine, is ineffective at targeting micrometastases because of the low-linear-energy-transfer (LET) properties of high-energy β-particles. In contrast, Auger radiation has high-LET properties with nanometer ranges in tissue, efficiently causing DNA damage when emitted near DNA. The aim of this study was to evaluate the cytotoxicity of targeted Auger therapy in preclinical models of high-risk neuroblastoma. Methods: We used a radiolabled poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor called 125 I-KX1 to deliver Auger radiation to PARP-1, a chromatin-binding enzyme overexpressed in neuroblastoma. The in vitro cytotoxicity of 125 I-KX1 was assessed in 19 neuroblastoma cell lines, followed by in-depth pharmacologic analysis in a sensitive and resistant pair of cell lines. Immunofluorescence microscopy was used to characterize 125 I-KX1-induced DNA damage. Finally, in vitro and in vivo microdosimetry was modeled from experimentally derived pharmacologic variables. Results: 125 I-KX1 was highly cytotoxic in vitro across a panel of neuroblastoma cell lines, directly causing double-strand DNA breaks. On the basis of subcellular dosimetry, 125 I-KX1 was approximately twice as effective as 131 I-KX1, whereas cytoplasmic 125 I-metaiodobenzylguanidine demonstrated low biological effectiveness. Despite the ability to deliver a focused radiation dose to the cell nuclei, 125 I-KX1 remained less effective than its α-emitting analog 211 At-MM4 and required significantly higher activity for equivalent in vivo efficacy based on tumor microdosimetry. Conclusion: Chromatin-targeted Auger therapy is lethal to high-risk neuroblastoma cells and has the potential to be used in micrometastatic disease. This study provides the first evidence for cellular lethality from a PARP-1-targeted Auger emitter, calling for further investigation into targeted Auger therapy., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Unlabelled: Radiopharmaceutical therapy, traditionally limited to refractory metastatic cancer, is being increasingly used at earlier stages, such as for treating minimal residual disease. The aim of this study was to compare the effectiveness of (90)Y, (177)Lu, (111)In, and (161)Tb at irradiating micrometastases. (90)Y and (177)Lu are widely used β(-)-emitting radionuclides. (161)Tb is a medium-energy β(-) radionuclide that is similar to (177)Lu but emits a higher percentage of conversion and Auger electrons. (111)In emits γ-photons and conversion and Auger electrons., Methods: We used the Monte Carlo code CELLDOSE to assess electron doses from a uniform distribution of (90)Y, (177)Lu, (111)In, or (161)Tb in spheres with diameters ranging from 10 mm to 10 μm. Because these isotopes differ in electron energy per decay, the doses were compared assuming that 1 MeV was released per μm(3), which would result in 160 Gy if totally absorbed., Results: In a 10-mm sphere, the doses delivered by (90)Y, (177)Lu, (111)In, and (161)Tb were 96.5, 152, 153, and 152 Gy, respectively. The doses decreased along with the decrease in sphere size, and more abruptly so for (90)Y. In a 100-μm metastasis, the dose delivered by (90)Y was only 1.36 Gy, compared with 24.5 Gy for (177)Lu, 38.9 Gy for (111)In, and 44.5 Gy for (161)Tb. In cell-sized spheres, the dose delivered by (111)In and (161)Tb was higher than that of (177)Lu. For instance, in a 10-μm cell, (177)Lu delivered 3.92 Gy, compared with 22.8 Gy for (111)In and 14.1 Gy for (161)Tb., Conclusion: (177)Lu, (111)In, and (161)Tb might be more appropriate than (90)Y for treating minimal residual disease. (161)Tb is a promising radionuclide because it combines the advantages of a medium-energy β(-) emission with those of Auger electrons and emits fewer photons than (111)In., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: Auger electron emitters such as (125)I have a high linear energy transfer and short range of emission (<10 μm), making them suitable for treating micrometastases while sparing normal tissues. We used a highly specific small molecule targeting the prostate-specific membrane antigen (PSMA) to deliver (125)I to prostate cancer cells., Methods: The PSMA-targeting Auger emitter 2-[3-[1-carboxy-5-(4-(125)I-iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid ((125)I-DCIBzL) was synthesized. DNA damage (via phosphorylated H2A histone family member X staining) and clonogenic survival were tested in PSMA-positive (PSMA+) PC3 PIP and PSMA-negative (PSMA-) PC3 flu human prostate cancer cells after treatment with (125)I-DCIBzL. Subcellular drug distribution was assessed with confocal microscopy using a related fluorescent PSMA-targeting compound YC-36. In vivo antitumor efficacy was tested in nude mice bearing PSMA+ PC3 PIP or PSMA- PC3 flu flank xenografts. Animals were administered (intravenously) 111 MBq (3 mCi) of (125)I-DCIBzL, 111 MBq (3 mCi) of (125)I-NaI, an equivalent amount of nonradiolabeled DCIBzL, or saline., Results: After treatment with (125)I-DCIBzL, PSMA+ PC3 PIP cells exhibited increased DNA damage and decreased clonogenic survival when compared with PSMA- PC3 flu cells. Confocal microscopy of YC-36 showed drug distribution in the perinuclear area and plasma membrane. Animals bearing PSMA+ PC3 PIP tumors had significant tumor growth delay after treatment with (125)I-DCIBzL, with only 1 mouse reaching 5 times the initial tumor volume by 60 d after treatment, compared with a median time to 5 times volume of less than 15 d for PSMA- PC3 flu tumors and all other treatment groups (P = 0.002 by log-rank test)., Conclusion: PSMA-targeted radiopharmaceutical therapy with the Auger emitter (125)I-DCIBzL yielded highly specific antitumor efficacy in vivo, suggesting promise for treatment of prostate cancer micrometastases., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: (86)Y (half-life = 14.74 h, 33% β(+)) is within an emerging class of positron-emitting isotopes with relatively long physical half-lives that enables extended imaging of biologic processes. We report the synthesis and evaluation of 3 low-molecular-weight compounds labeled with (86)Y for imaging the prostate-specific membrane antigen (PSMA) using PET. Impetus for the study derives from the need to perform dosimetry estimates for the corresponding (90)Y-labeled radiotherapeutics., Methods: Multistep syntheses were used in preparing (86)Y- 4: - 6: PSMA inhibition constants were evaluated by competitive binding assay. In vivo characterization using tumor-bearing male mice was performed by PET/CT for (86)Y- 4: - 6: and by biodistribution studies of (86)Y- 4: and (86)Y- 6: out to 24 h after injection. Quantitative whole-body PET scans were recorded to measure the kinetics for 14 organs in a male baboon using (86)Y- 6 RESULTS: Compounds (86)Y- 4: - 6: were obtained in high radiochemical yield and purity, with specific radioactivities of more than 83.92 GBq/μmol. PET imaging and biodistribution studies using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu tumor-bearing mice revealed that (86)Y- 4-6: had high site-specific uptake in PSMA-positive PC-3 PIP tumor starting at 20 min after injection and remained high at 24 h. Compound (86)Y- 6: demonstrated the highest tumor uptake and retention, with 32.17 ± 7.99 and 15.79 ± 6.44 percentage injected dose per gram (%ID/g) at 5 and 24 h, respectively. Low activity concentrations were associated with blood and normal organs, except for the kidneys, a PSMA-expressing tissue. PET imaging in baboons reveals that all organs have a 2-phase (rapid and slow) clearance, with the highest uptake (8 %ID/g) in the kidneys at 25 min. The individual absolute uptake kinetics were used to calculate radiation doses using the OLINDA/EXM software. The highest mean absorbed dose was received by the renal cortex, with 1.9 mGy per MBq of (86)Y- 6:, Conclusion: Compound (86)Y- 6: is a promising candidate for quantitative PET imaging of PSMA-expressing tumors. Dosimetry calculations indicate promise for future (90)Y or other radiometals that could use a similar chelator/scaffold combination for radiopharmaceutical therapy based on the structure of 6., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: Combination treatment is a hallmark of cancer therapy. Although the rationale for combination radiopharmaceutical therapy was described in the mid-1990s, such treatment strategies have only been implemented clinically recently and without a rigorous methodology for treatment optimization. Radiobiologic and quantitative imaging-based dosimetry tools are now available that enable rational implementation of combined targeted radiopharmaceutical therapy. Optimal implementation should simultaneously account for radiobiologic normal-organ tolerance while optimizing the ratio of 2 different radiopharmaceuticals required to maximize tumor control. We have developed such a methodology and applied it to hypothetical myeloablative treatment of non-Hodgkin lymphoma (NHL) patients using (131)I-tositumomab and (90)Y-ibritumomab tiuxetan., Methods: The range of potential administered activities (AAs) is limited by the normal-organ maximum-tolerated biologic effective doses (MTBEDs) arising from the combined radiopharmaceuticals. Dose-limiting normal organs are expected to be the lungs for (131)I-tositumomab and the liver for (90)Y-ibritumomab tiuxetan in myeloablative NHL treatment regimens. By plotting the limiting normal-organ constraints as a function of the AAs and calculating tumor biologic effective dose (BED) along the normal-organ MTBED limits, we obtained the optimal combination of activities. The model was tested using previously acquired patient normal-organ and tumor kinetic data and MTBED values taken from the literature., Results: The average AA value based solely on normal-organ constraints was 19.0 ± 8.2 GBq (range, 3.9-36.9 GBq) for (131)I-tositumomab and 2.77 ± 1.64 GBq (range, 0.42-7.54 GBq) for (90)Y-ibritumomab tiuxetan. Tumor BED optimization results were calculated and plotted as a function of AA for 5 different cases, established using patient normal-organ kinetics for the 2 radiopharmaceuticals. Results included AA ranges that would deliver 95% of the maximum tumor BED, allowing for informed inclusion of clinical considerations, such as a maximum-allowable (131)I administration., Conclusion: A rational approach for combination radiopharmaceutical treatment has been developed within the framework of a proven 3-dimensional (3D) personalized dosimetry software, 3D-RD, and applied to the myeloablative treatment of NHL. We anticipate that combined radioisotope therapy will ultimately supplant single radioisotope therapy, much as combination chemotherapy has substantially replaced single-agent chemotherapy.