Activity quantification and dosimetry in radiopharmaceutical therapy with reference to 177Lutetium.

Radiopharmaceutical therapy has been widely adopted owing primarily to the development of novel radiopharmaceuticals. To fully utilize the potential of these RPTs in the era of precision medicine, therapy must be optimized to the patient's tumor characteristics. The vastly disparate dosimetry methodologies need to be harmonized as the first step towards this. Multiple factors play a crucial role in the shift from empirical activity administration to patient-specific dosimetry-based administrations from RPT. Factors such as variable responses seen in patients with presumably similar clinical characteristics underscore the need to standardize and validate dosimetry calculations. These efforts combined with ongoing initiatives to streamline the dosimetry process facilitate the implementation of radiomolecular precision oncology. However, various challenges hinder the widespread adoption of personalized dosimetry-based activity administration, particularly when compared to the more convenient and resource-efficient approach of empiric activity administration. This review outlines the fundamental principles, procedures, and methodologies related to image activity quantification and dosimetry with a specific focus on 177Lutetium-based radiopharmaceuticals.

The prognostic utility of 18F-FDG PET parameters in lymphoma patients under CAR-T-cell therapy: a systematic review and meta-analysis.

Background: Chimeric antigen receptor (CAR) T-cell therapy has attracted considerable attention since its recent endorsement by the Food and Drug Administration, as it has emerged as a promising immunotherapeutic modality within the landscape of oncology. This study explores the prognostic utility of [18F]Fluorodeoxyglucose positron emission tomography ([18F]FDG PET) in lymphoma patients undergoing CAR T-cell therapy. Through meta-analysis, pooled hazard ratio (HR) values were calculated for specific PET metrics in this context. Methods: PubMed, Scopus, and Ovid databases were explored to search for relevant topics. Dataset retrieval from inception until March 12, 2024, was carried out. The primary endpoints were impact of specific PET metrics on overall survival (OS) and progression-free survival (PFS) before and after treatment. Data from the studies were extracted for a meta-analysis using Stata 17.0. Results: Out of 27 studies identified for systematic review, 15 met the criteria for meta-analysis. Baseline OS analysis showed that total metabolic tumor volume (TMTV) had the highest HR of 2.66 (95% CI: 1.52-4.66), followed by Total-body total lesion glycolysis (TTLG) at 2.45 (95% CI: 0.98-6.08), and maximum standardized uptake values (SUVmax) at 1.30 (95% CI: 0.77-2.19). TMTV and TTLG were statistically significant (p < 0.0001), whereas SUVmax was not (p = 0.33). For PFS, TMTV again showed the highest HR at 2.65 (95% CI: 1.63-4.30), with TTLG at 2.35 (95% CI: 1.40-3.93), and SUVmax at 1.48 (95% CI: 1.08-2.04), all statistically significant (p ≤ 0.01). The ΔSUVmax was a significant predictor for PFS with an HR of 2.05 (95% CI: 1.13-3.69, p = 0.015). Conclusion: [18F]FDG PET parameters are valuable prognostic tools for predicting outcome of lymphoma patients undergoing CAR T-cell therapy.

Design of 225Ac-PSMA for targeted alpha therapy in prostate cancer.

The first alpha emitting radiopharmaceutical, 223RaCl2, radium dichloride, was approved 10 years ago into the clinical armament of treating bone metastases in metastatic castration-resistant prostate cancer (mCRPC). In addition to this, the first beta-emitting radionuclide Lu-177 chelated with a prostate-specific membrane antigen (PSMA) compound, got last year its marketing approval for the third line treatment of mCRPC. Therefore, there is great excitement about combining alpha-emitters and prostate cancer targeting PSMA compounds. This review describes the clinical history of alpha-emitting PSMA in treating mCRPC. Here, we present the potential, current status, and opportunities for 225Ac-PSMA therapy. The work reviews the basic concepts, current treatment outcome, and toxicity, and areas requiring further investigations such as dosimetric aspects in clinical studies covering more than 400 patients. In general, approximately two-thirds of the patients benefit from this third-line therapy. There is also successful evidence of using 225Ac-PSMA in the second-line of prostate cancer management. The future potential of 225Ac-PSMA therapy and targeted alpha therapy (TAT) of cancer in general is enormous. According to our overview the clinical experience with 225Ac-PSMA therapy to date has shown great benefit and physicians dedicated to theragnostics are anxiously waiting for new applications. Hopefully, this review helps in deeper understanding of the strengths and limitations of TAT and may help in creating effective therapy protocols.

Effectiveness and Patient Experiences of Rhenium Skin Cancer Therapy for Nonmelanoma Skin Cancer: Interim Results from the EPIC-Skin Study.

Nonmelanoma skin cancer and its treatment represent a significant global cancer burden for health care systems and patients. Rhenium skin cancer therapy (Rhenium SCT) is a novel noninvasive radionuclide nonmelanoma skin cancer treatment, which can be provided in a single outpatient session. The aim of this prospective, multicenter, single-arm, international, phase IV study (EPIC-Skin) is to assess clinic- and patient-reported outcomes of Rhenium SCT as a treatment for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Methods: Eligible patients had biopsy-proven stage I or stage II BCC or SCC lesions no more than 3 mm deep and no larger than 8 cm2 in area. Rhenium SCT resin was applied to an adhesive foil affixed to the target lesion in a single session. Interim efficacy and safety analysis were planned once 50% of target patients had recorded a 6-mo follow-up visit. Primary outcome is the proportion of lesions achieving complete response using modified RECIST. Secondary and other outcome measures include patient-reported quality of life (QoL), treatment comfort, and cosmesis. Results: A total of 182 patients was enrolled and administered Rhenium SCT (50 Gy dose to deepest point of target) to at least 1 BCC or SCC. Of 81 patients who reached the 6-mo posttreatment follow-up, it was found that 97.2% (103/106) of lesions showed complete responses and 2.8% (3/106) had partial responses. Improvements in QoL were also reported, whereas no patients reported any pain or discomfort during treatment. Adverse events were reported in 15.9% (29/182) of patients and were rated grade 1 (n = 19), grade 2 (n = 9), or grade 3 (n = 1). Conclusion: This preliminary analysis of the EPIC-Skin study indicates that Rhenium SCT is safe and effective for the treatment of BCC and SCC and is associated with significant QoL improvements. It will be particularly beneficial for lesions that are difficult to treat surgically because of size and location. It is also beneficial for patients with comorbidities or those unable to receive conventional fractionated radiotherapy.

Chemokine Receptor-4 Targeted PET/CT Imaging with 68Ga-Pentixafor in Head and Neck Cancer-A Comparison with 18F-FDG and CXCR4 Immunohistochemistry.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is common, and its incidence is increasing, particularly in HIV-infected individuals who present with more aggressive disease. Despite aggressive treatment, the prognosis remains poor because of resistance to chemoradiation therapy. So far, studies report very low [68Ga]Ga-Pentixafor avidity in HNSCC. This study investigated the diagnostic performance of CXCR4-directed imaging of carcinoma of the oral cavity, oropharynx, and nasopharynx with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine ligand [68Ga]Ga-Pentixafor and explored its ability to quantify CXCR4 expression in vivo. MATERIALS AND METHODS: In this prospective cross-sectional study, twenty-three (23) patients aged 52.9 ± 10.4 (19.6), 17 males and 6 females with primarily diagnosed (n = 17) or pre-treated (n = 6) SCC of the oral cavity (OCSCC, n = 11), oropharynx (OPSCC, n = 9), nasopharynx (NPSCC, n = 2) and unknown primary (n = 1) underwent imaging with [68Ga]Ga-Pentixafor-PET/CT. In 16/23 patients 2-[18F]fluoro-2-deoxy-D-glucose ([18F]F-FDG) served as a standard reference. All lesions were visually rated using a 5-point Likert scale. For both tracers, maximum standardized uptake values (SUVmax) and the total lesion uptake (TLU) were recorded and compared using the Wilcox-signed rank test. In addition, the tumor-to-background ratios were derived using the liver (TLR), spleen (TSR), and posterior cervical muscles (TMR) as background. The relationships between the SUVs of the two tracers were assessed using the Spearman correlation. CXCR4 immunohistochemistry (IHC) staining was correlated with 68Ga-Pentixafor-PET/CT in 21/23 patients. RESULTS: Ninety-one percent (21/23) of tumors were visually detected on [68Ga]Ga-Pentixafor; however, [68Ga]Ga-Pentixafor was less intense compared with [18F]F-FDG-PET. Quantitative analysis showed higher [18F]F-FDG SUVmax in comparison with [68Ga]Ga-Pentixafor (16 ± 6.7 vs. 5.8 ± 2.6 g/mL, p = 0.011) and SUVmean (9.3 ± 4.1 vs. 3± 1.6 g/mL, p < 0.001) and TBR 4.9 ± 2.3 vs. 2.36 ± 1.4 p = 0.014. Nasopharyngeal cancer demonstrated more intense tracer accumulation than oropharyngeal and oral cavity malignancies. CXCR4 IHC staining was positive in 15/21 patients, and there was a statistically significant correlation between IHC staining and [68Ga]Ga-Pentixafor SUVmean r = 0.5 p = 0.027, and performance status r = 0.83 p = 0.0104. CONCLUSIONS: In conclusion, although [68Ga]Ga-Pentixafor cannot replace [18F]F-FDG as a diagnostic tool because of its lower avidity, the correlation between CXCR4 targeted 68Ga-Pentixafor PET imaging and CXCR4 IHC staining indicates the potential of 68Ga-Pentixafor as an effective tool for selecting patients who may benefit from therapies targeting CXCR4. In addition, [68Ga]Ga-Pentixafor has no physiological brown fat uptake, which often obscures cervical lesions on [18F]F-FDG PET/CT imaging.

Expanding Role for Gallium-68 PET Imaging in Oncology.

Gallium-68 has gained substantial momentum since 2003 as a versatile radiometal that is extremely useful for application in the development of novel oncology targeting diagnostic radiopharmaceuticals. It is available through both generator produced radioactivity and via cyclotron production methods and can therefore be implemented in either small- or large-scale production facilities. It can also be implemented within different spectrum of infrastructure settings with relative ease. Whilst many of the radiopharmaceuticals are being development and investigated, which is summarized in this manuscript, [68Ga]Ga-SSTR2 and [68Ga]Ga-PSMA has prominence in current clinical guidelines. The novel tracer [68Ga]Ga-FAPi has also gained significant interest in the clinical context. A comparison of the labelling strategies followed to incorporate gallium-68 and fluorine-18 into the same molecular targeting constructs clearly demonstrate that gallium-68 complexation is the most convenient approach. Recently, cold kit based starting products are available to make the small-scale production of gallium-68 radiopharmaceuticals even more efficient when combined with generator produced gallium-68. The regulatory aspects is currently changing to support the implementation of gallium-68 and other diagnostic radiopharmaceuticals, simplifying the translation towards clinical use. Overall, the development of gallium-68 based radiopharmaceuticals is not only rapidly changing the landscape of diagnosis in oncology, but this growth also promotes innovation and progress in new applications of therapeutic radiometals such as lutetium-177 and actinium-225.

[18F]F-Poly(ADP-Ribose) Polymerase Inhibitor Radiotracers for Imaging PARP Expression and Their Potential Clinical Applications in Oncology.

Including poly(ADP-ribose) polymerase (PARP) inhibitors in managing patients with inoperable tumors has significantly improved outcomes. The PARP inhibitors hamper single-strand deoxyribonucleic acid (DNA) repair by trapping poly(ADP-ribose)polymerase (PARP) at sites of DNA damage, forming a non-functional "PARP enzyme-inhibitor complex" leading to cell cytotoxicity. The effect is more pronounced in the presence of PARP upregulation and homologous recombination (HR) deficiencies such as breast cancer-associated gene (BRCA1/2). Hence, identifying HR-deficiencies by genomic analysis-for instance, BRCA1/2 used in triple-negative breast cancer-should be a part of the selection process for PARP inhibitor therapy. Published data suggest BRCA1/2 germline mutations do not consistently predict favorable responses to PARP inhibitors, suggesting that other factors beyond tumor mutation status may be at play. A variety of factors, including tumor heterogeneity in PARP expression and intrinsic and/or acquired resistance to PARP inhibitors, may be contributing factors. This justifies the use of an additional tool for appropriate patient selection, which is noninvasive, and capable of assessing whole-body in vivo PARP expression and evaluating PARP inhibitor pharmacokinetics as complementary to the currently available BRCA1/2 analysis. In this review, we discuss [18F]Fluorine PARP inhibitor radiotracers and their potential in the imaging of PARP expression and PARP inhibitor pharmacokinetics. To provide context we also briefly discuss possible causes of PARP inhibitor resistance or ineffectiveness. The discussion focuses on TNBC, which is a tumor type where PARP inhibitors are used as part of the standard-of-care treatment strategy.

Advances in PSMA Alpha Theragnostics.

Alpha theranostics offer an attractive alternative form of therapy, which has best been investigated and documented with 225Ac-PSMA in patients with prostate cancer. Advantages offered by targeted alpha therapy include overcoming radiation resistance, oxygen independence, effecting double-stranded DNA breakages within the tumors with anticipated improved clinical outcomes and an acceptable side effect profile. The previous Seminars article on this topic, published in 2020, had to rely mostly on published case reports and small observational studies. In the last few years, however, several meta-analyses have emerged that evaluate the safety and efficacy of 225Ac-PSMA in prostate cancer patients, followed most recently by a multi-center retrospective study initiated by WARMTH. The findings of these publications, together with the exploration of TAT offered in clinical conditions other than as a last resort, is the focus of this updated overview. Unresolved clinical issues that remain, include the appropriate selection of patients that would benefit most from treatment with 225Ac-PSMA, treatment timing within the disease landscape, optimal dosing schedule, dosimetry, when and how to best use combination therapies and minimization and treatment of side effects, particularly that of xerostomia.

Can current preclinical strategies for radiopharmaceutical development meet the needs of targeted alpha therapy?

Preclinical studies are essential for effectively evaluating TAT radiopharmaceuticals. Given the current suboptimal supply chain of these radionuclides, animal studies must be refined to produce the most translatable TAT agents with the greatest clinical potential. Vector design is pivotal, emphasizing harmonious physical and biological characteristics among the vector, target, and radionuclide. The scarcity of alpha-emitting radionuclides remains a significant consideration. Actinium-225 and lead-212 appear as the most readily available radionuclides at this stage. Available animal models for researchers encompass xenografts, allografts, and PDX (patient-derived xenograft) models. Emerging strategies for imaging alpha-emitters are also briefly explored. Ultimately, preclinical research must address two critical aspects: (1) offering valuable insights into balancing safety and efficacy, and (2) providing guidance on the optimal dosing of the TAT agent.

Prostate-specific Membrane Antigen: Alpha-labeled Radiopharmaceuticals.

Novel prostate-specific membrane antigen (PSMA) ligands labeled with α-emitting radionuclides are sparking a growing interest in prostate cancer treatment. These targeted alpha therapies (TATs) have attractive physical properties that deem them effective in progressive metastatic castrate-resistant prostate cancer (mCRPC). Among the PSMA TAT radiopharmaceuticals, [225Ac]Ac-PSMA has been used extensively on a compassionate basis and is currently undergoing phase I trials. Notably, TAT has the potential to improve quality of life and has favorable antitumor activity and outcomes in multiple scenarios other than in mCRPC. In addition, resistance mechanisms to TAT may be amenable to combination therapies.

Advances in Radioligand Theranostics in Oncology.

Theranostics with radioligands (radiotheranostics) has played a pivotal role in oncology. Radiotheranostics explores the molecular targets expressed on tumor cells to target them for imaging and therapy. In this way, radiotheranostics entails non-invasive demonstration of the in vivo expression of a molecular target of interest through imaging followed by the administration of therapeutic radioligand targeting the tumor-expressed molecular target. Therefore, radiotheranostics ensures that only patients with a high likelihood of response are treated with a particular radiotheranostic agent, ensuring the delivery of personalized care to cancer patients. Within the last decades, a couple of radiotheranostics agents, including Lutetium-177 DOTATATE (177Lu-DOTATATE) and Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA), were shown to prolong the survival of cancer patients compared to the current standard of care leading to the regulatory approval of these agents for routine use in oncology care. This recent string of successful approvals has broadened the interest in the development of different radiotheranostic agents and their investigation for clinical translation. In this work, we present an updated appraisal of the literature, reviewing the recent advances in the use of established radiotheranostic agents such as radioiodine for differentiated thyroid carcinoma and Iodine-131-labeled meta-iodobenzylguanidine therapy of tumors of the sympathoadrenal axis as well as the recently approved 177Lu-DOTATATE and 177Lu-PSMA for differentiated neuroendocrine tumors and advanced prostate cancer, respectively. We also discuss the radiotheranostic agents that have been comprehensively characterized in preclinical studies and have shown some clinical evidence supporting their safety and efficacy, especially those targeting fibroblast activation protein (FAP) and chemokine receptor 4 (CXCR4) and those still being investigated in preclinical studies such as those targeting poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor 2.

Second generation Al18F-labeled D-amino acid peptide for CXCR4 targeted molecular imaging.

BACKGROUND: The C-X-C chemokine receptor type 4 (CXCR4) is overexpressed in many cancers, e.g. multiple myeloma and acute leukemia, yet solely [68Ga]PentixaFor is used for clinical PET imaging. The aim of this study was to develop and assess a second generation Al18F-labeled D-amino acid peptide based on the viral macrophage inflammatory protein II for CXCR4 targeted molecular imaging. METHODS: We designed a library of monomer and multimer constructs and evaluated their binding affinity for human and mouse CXCR4. Based on these results, we selected the best vector molecule for development of an Al18F-labeled ligand, [18F]AlF-NOTA-2xDV1(c11sc12s), which was further evaluated in a cell-based binding assay to assess its binding properties and specificity for CXCR4. Next, pharmacokinetics and tumor uptake of [18F]AlF-NOTA-2xDV1(c11sc12s) were evaluated in naïve mice and mice with xenografts derived from U87.CXCR4 cells. Finally, we performed an imaging study in a non-human primate to assess the in vivo distribution of this novel radioligand in a species closely related to humans. RESULTS: The lead ligand AlF-NOTA-2xDV1(c11sc12s) showed six-fold higher affinity for human CXCR4 compared to Ga-Pentixafor. The corresponding radiotracer was obtained in a good radiochemical yield of 40.1 ± 13.5 % (n = 4) and apparent molar activity of 20.4 ± 3.3 MBq/nmol (n = 4) after optimization. In U87.CD4.CXCR4 cell binding assays, the total bound fraction of [18F]AlF-NOTA-(2×)DV1(c11sc12s) was 32.4 ± 1.8 %. This fraction could be reduced by 82.5 % in the presence of 75 µM AMD3100. In naïve mice, [18F]AlF-NOTA-2xDV1(c11sc12s) accumulated in organs expressing mouse CXCR4, e.g. the liver (SUVmean (mean standardized uptake value) 75 min p.i. 11.7 ± 0.6), which was blockable by co-injecting AMD3100 (5 mg/kg). In U87.CXCR4 xenografted tumor mice, the tumor uptake of [18F]AlF-NOTA-2xDV1(c11sc12s) remained low (SUVmean 0.5 ± 0.1), but was reduced by co-administration of AMD3100. Surprisingly, [18F]AlF-NOTA-2xDV1(c11sc12s) exhibited a similar biodistribution in a non-human primate as in mice indicating off-target binding of [18F]AlF-NOTA-2xDV1(c11sc12s) in liver tissue. We confirmed that [18F]AlF-NOTA-2xDV1(c11sc12s) is taken up by hepatocytes using in vitro studies and that the uptake can be blocked with AMD3100 and rifampicin, a potent organic anion-transporting-polypeptide (OATP)1B1 and OATP1B3 inhibitor. CONCLUSION: The second generation D-peptide AlF-NOTA-2xDV1(c11sc12s) showed high affinity for human CXCR4 and the corresponding radiotracer was produced in good radiochemical yields. However, [18F]AlF-NOTA-2xDV1(c11sc12s) is not specific for CXCR4 and is also a substrate for OATP1B1 and/or OATP1B3, known to mediate hepatic uptake. Therefore, D-amino acid peptides, based on the viral macrophage inflammatory protein II, are not the prefered vector molecule for the development of CXCR4 targeting molecular imaging tools.

Six country vignettes: Strengthening radiotherapy and theranostics.

BACKGROUND: For cancer patient populations worldwide, the synchronous scale-up of diagnostics and treatments yields meaningful gains in survival and quality of life. Among advanced cancer therapies, radiotherapy (RT) and theranostics are key to achieving practical, high-quality, and personalized precision medicine - targeting disease manifestations of individual patients and broad populations, alike. Aiming to learn from one another across different world regions, the six country vignettes presented here depict both challenges and victories in de novo establishment or improvement of RT and theranostics infrastructure. METHODS: The International Atomic Energy Agency (IAEA) convened global RT and theranostics experts from diverse world regions and contexts to identify relevant challenges and report progress in their own six countries: Belgium, Brazil, Costa Rica, Jordan, Mongolia, and South Africa. These accounts are collated, compared, and contrasted herein. RESULTS: Common challenges persist which could be more strategically assessed and addressed. A quantifiable discrepancy entails personnel. The estimated radiation oncologists (ROs), nuclear medicine physicians (NMPs), and medical physicists (MPs for RT and nuclear medicine) per million inhabitants in the six collective countries respectively range between 2.69-38.00 ROs, 1.00-26.00 NMPs, and 0.30-3.45 MPs (Table 1), reflecting country-to-country inequities which largely match World Bank country-income stratifications. CONCLUSION: Established goals for RT and nuclear medicine advancement worldwide have proven elusive. The pace of progress could be hastened by enhanced approaches such as more sustainably phased implementation; better multinational networking to share lessons learned; routine quality and safety audits; as well as capacity building employing innovative, resource-sparing, cutting-edge technologic approaches. Bodies such as ministries of health, professional societies, and the IAEA shall serve critical roles in convening and coordinating more innovative RT and theranostics translational research, including expanding nuanced global database metrics to inform, reach, and potentiate milestones most meaningfully. POLICY SUMMARY: Aligned with WHO 25×25 NCDs target; WHA70.12 and WHA76.5 resolutions.

Imaging Molecular Targets and Metabolic Pathways in Breast Cancer for Improved Clinical Management: Current Practice and Future Perspectives.

Breast cancer is the most frequently diagnosed cancer and leading cause of cancer-related deaths worldwide. Timely decision-making that enables implementation of the most appropriate therapy or therapies is essential for achieving the best clinical outcomes in breast cancer. While clinicopathologic characteristics and immunohistochemistry have traditionally been used in decision-making, these clinical and laboratory parameters may be difficult to ascertain or be equivocal due to tumor heterogeneity. Tumor heterogeneity is described as a phenomenon characterized by spatial or temporal phenotypic variations in tumor characteristics. Spatial variations occur within tumor lesions or between lesions at a single time point while temporal variations are seen as tumor lesions evolve with time. Due to limitations associated with immunohistochemistry (which requires invasive biopsies), whole-body molecular imaging tools such as standard-of-care [18F]FDG and [18F]FES PET/CT are indispensable in addressing this conundrum. Despite their proven utility, these standard-of-care imaging methods are often unable to image a myriad of other molecular pathways associated with breast cancer. This has stimulated interest in the development of novel radiopharmaceuticals targeting other molecular pathways and processes. In this review, we discuss validated and potential roles of these standard-of-care and novel molecular approaches. These approaches' relationships with patient clinicopathologic and immunohistochemical characteristics as well as their influence on patient management will be discussed in greater detail. This paper will also introduce and discuss the potential utility of novel PARP inhibitor-based radiopharmaceuticals as non-invasive biomarkers of PARP expression/upregulation.

Global Research Output of Lutetium-177 PSMA in Prostate Cancer: Bibliometric and Altmetric Analyses.

AIM: The integration of innovative radio-pharmaceutical agents targeting prostate-specific membrane antigen (PSMA) within nuclear medicine has transformed prostate cancer detection and management. This study aims to investigate the present landscape of [177Lu]Lu-PSMA in prostate cancer, elucidating trends, global contributions, scholarly outlets, institutions, and thematic concentrations with an aim to inform forthcoming research endeavors. METHODS: We systematically probed the Scopus repository for relevant [177Lu]Lu-PSMA literature. An assessment of bibliometric and altmetric data was carried out. Finally, we assessed the correlation between the altmetric attention scores and the number of citations for the retrieved data. RESULTS: Spanning January 2015 to July 2023, the study encompassed 466 articles concerning [177Lu]Lu-PSMA therapy for prostate cancer. Predominant citation accolades gravitated towards metastatic castration-resistant prostate cancer investigations and assessments of [177Lu]Lu-PSMA therapy's safety and efficacy. Further research encompassed adverse effects linked to [177Lu]Lu-PSMA intervention, including xerostomia, thrombocytopenia, anemia, and fatigue. Germany emerged as the primary academic contributor, with The Journal of Nuclear Medicine dominating publications (n = 55). A moderate significant correlation was detected between the number of citations and altmetric attention scores . CONCLUSION: The findings highlight the growing interest and advancements in the utilization of [177Lu]Lu-PSMA therapy in prostate cancer and offer a comprehensive global perspective on future research directions.

Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicentre, retrospective study.

BACKGROUND: Actinium-225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC). We aimed to report the safety and antitumour activity of 225Ac-PSMA RLT of mCRPC in a large cohort of patients treated at multiple centres across the world. METHODS: This retrospective study included patients treated at seven centres in Australia, India, Germany, and South Africa. We pooled data of consecutive patients of any age and Eastern Cooperative Oncology Group performance status with histopathologically confirmed adenocarcinoma of the prostate who were treated with one or more cycles of 8 MBq 225Ac-PSMA RLT administered intravenously for mCRPC. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium-177 (177Lu) PSMA RLT, and radium-223 dichloride. The primary outcomes were overall survival and progression-free survival. FINDINGS: Between Jan 1, 2016, and May 31, 2023, 488 men with mCRPC received 1174 cycles of 225Ac-PSMA RLT (median two cycles, IQR 2-4). The mean age of the patients was 68·1 years (SD 8·8), and the median baseline prostate-specific antigen was 169·5 ng/mL (IQR 34·6-519·8). Previous lines of treatment were docetaxel in 324 (66%) patients, cabazitaxel in 103 (21%) patients, abiraterone in 191 (39%) patients, enzalutamide in 188 (39%) patients, 177Lu-PSMA RLT in 154 (32%) patients, and radium-223 dichloride in 18 (4%) patients. The median follow-up duration was 9·0 months (IQR 5·0-17·5). The median overall survival was 15·5 months (95% CI 13·4-18·3) and median progression-free survival was 7·9 months (6·8-8·9). In 347 (71%) of 488 patients, information regarding treatment-induced xerostomia was available, and 236 (68%) of the 347 patients reported xerostomia after the first cycle of 225Ac-PSMA RLT. All patients who received more than seven cycles of 225Ac-PSMA RLT reported xerostomia. Grade 3 or higher anaemia occurred in 64 (13%) of 488 patients, leukopenia in 19 (4%), thrombocytopenia in 32 (7%), and renal toxicity in 22 (5%). No serious adverse events or treatment-related deaths were recorded. INTERPRETATION: 225Ac-PSMA RLT shows a substantial antitumour effect in mCRPC and represents a viable therapy option in patients treated with previous lines of approved agents. Xerostomia is a common side-effect. Severe bone marrow and renal toxicity are less common adverse events. FUNDING: None.

European Association of Nuclear Medicine Focus 5: Consensus on Molecular Imaging and Theranostics in Prostate Cancer.

BACKGROUND: In prostate cancer (PCa), questions remain on indications for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging and PSMA radioligand therapy, integration of advanced imaging in nomogram-based decision-making, dosimetry, and development of new theranostic applications. OBJECTIVE: We aimed to critically review developments in molecular hybrid imaging and systemic radioligand therapy, to reach a multidisciplinary consensus on the current state of the art in PCa. DESIGN, SETTING, AND PARTICIPANTS: The results of a systematic literature search informed a two-round Delphi process with a panel of 28 PCa experts in medical or radiation oncology, urology, radiology, medical physics, and nuclear medicine. The results were discussed and ratified in a consensus meeting. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Forty-eight statements were scored on a Likert agreement scale and six as ranking options. Agreement statements were analysed using the RAND appropriateness method. Ranking statements were analysed using weighted summed scores. RESULTS AND LIMITATIONS: After two Delphi rounds, there was consensus on 42/48 (87.5%) of the statements. The expert panel recommends PSMA PET to be used for staging the majority of patients with unfavourable intermediate and high risk, and for restaging of suspected recurrent PCa. There was consensus that oligometastatic disease should be defined as up to five metastases, even using advanced imaging modalities. The group agreed that [177Lu]Lu-PSMA should not be administered only after progression to cabazitaxel and that [223Ra]RaCl2 remains a valid therapeutic option in bone-only metastatic castration-resistant PCa. Uncertainty remains on various topics, including the need for concordant findings on both [18F]FDG and PSMA PET prior to [177Lu]Lu-PSMA therapy. CONCLUSIONS: There was a high proportion of agreement among a panel of experts on the use of molecular imaging and theranostics in PCa. Although consensus statements cannot replace high-certainty evidence, these can aid in the interpretation and dissemination of best practice from centres of excellence to the wider clinical community. PATIENT SUMMARY: There are situations when dealing with prostate cancer (PCa) where both the doctors who diagnose and track the disease development and response to treatment, and those who give treatments are unsure about what the best course of action is. Examples include what methods they should use to obtain images of the cancer and what to do when the cancer has returned or spread. We reviewed published research studies and provided a summary to a panel of experts in imaging and treating PCa. We also used the research summary to develop a questionnaire whereby we asked the experts to state whether or not they agreed with a list of statements. We used these results to provide guidance to other health care professionals on how best to image men with PCa and what treatments to give, when, and in what order, based on the information the images provide.

The Theranostic Optimization of PSMA-GCK01 Does Not Compromise the Imaging Characteristics of [99mTc]Tc-PSMA-GCK01 Compared to Dedicated Diagnostic [99mTc]Tc-EDDA/HYNIC-iPSMA in Prostate Cancer.

PURPOSE: Radiolabeled PSMA-ligands play a major role in today's nuclear medicine. Since approval of [177Lu]Lu-PSMA-617 for therapy of metastatic prostate cancer, availability of 177Lu became bottleneck of supply due to the high demand. Recently, a theranostic PSMA-ligand, PSMA-GCK01, was developed which can be labeled either diagnostically with 99mTc or therapeutically with 188Re with both nuclides available from well-known generator systems. This novel tracer might aid to overcome aforementioned supply limitations. In this investigation, the biodistribution and general imaging characteristics of [99mTc]Tc-PSMA-GCK01 were compared with the diagnostic reference compound [99mTc]Tc-EDDA/HYNIC-iPSMA in patients with advanced stage prostate cancer. In addition, the binding of both ligands to PSMA was analyzed at the molecular level using molecular docking. PROCEDURES: Two cohorts (n = 19 vs. n = 21) of patients with metastatic castration-resistant prostate cancer matched for age, tumor stage, and Gleason score underwent a planar gamma camera imaging with [99mTc]Tc-EDDA/HYNIC-iPSMA or [99mTc]Tc-PSMA-GCK01 prior to PSMA-ligand therapy for PSMA-phenotyping. The imaging data were retrospective analyzed for salivary gland, kidney, liver, soft tissue, and tumor uptake on a semi-automated ROI-analysis using HERMES Medical Solutions AB (HMS, Sweden). RESULTS: The data sets were semi-automated quantified on a ROI-based analysis. The tumor-to-background presented equal results of [99mTc]Tc-PSMA-GCK01 compared to [99mTc]Tc-EDDA/HYNIC-iPSMA. The physiological PSMA-positive organs like salivary gland presented also equal uptake in counts/MBq (salivary gland median 9.48 [99mTc]Tc-PSMA-GCK01 vs. median 9.11 [99mTc]Tc-EDDA/HYNIC-iPSMA), while liver-to-kidney ratio presented a slight shift to the liver parenchyma using [99mTc]Tc-PSMA-GCK01 (0.83) compared to [99mTc]Tc-EDDA/HYNIC-iPSMA (0.55) with no statistical significance. This is in agreement with the results from the docking study revealing only a minor difference in the docking scores for both ligands. CONCLUSIONS: The novel theranostic tracer [99mTc]Tc/[188Re]Re-PSMA-GCK01 demonstrates comparable general imaging characteristic with the reference compound [99mTc]Tc-EDDA/HYNIC-iPSMA. These results pave the way for the PSMA-targeting imaging and theranostic agents for a broader, rather low-cost, generator applied radio-ligand therapy utilization.