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Brachytherapy 2023α-particle targeted radionuclide therapy has shown promise for optimal cancer management, an exciting new era for brachytherapy. Alpha-emitting nuclides can have... (Review)
Review
α-particle targeted radionuclide therapy has shown promise for optimal cancer management, an exciting new era for brachytherapy. Alpha-emitting nuclides can have significant advantages over gamma- and beta-emitters due to their high linear energy transfer (LET). While their limited path length results in more specific tumor 0kill with less damage to surrounding normal tissues, their high LET can produce substantially more lethal double strand DNA breaks per radiation track than beta particles. Over the last decade, the physical and chemical attributes of Actinium-225 (Ac) including its half-life, decay schemes, path length, and straightforward chelation ability has peaked interest for brachytherapy agent development. However, this has been met with challenges including source availability, accurate modeling for standardized dosimetry for brachytherapy treatment planning, and laboratory space allocation in the hospital setting for on-demand radiopharmaceuticals production. Current evidence suggests that a simple empirical approach based on Ac administered radioactivity may lead to inconsistent outcomes and toxicity. In this review article, we highlight the recent advances in Ac source production, dosimetry modeling, and current clinical studies.
Topics: Humans; Brachytherapy; Neoplasms; Radiopharmaceuticals; Actinium
PubMed: 37690972
DOI: 10.1016/j.brachy.2023.06.228 -
Current Radiopharmaceuticals 2018Recent reports of the remarkable therapeutic efficacy of 225Ac-labeled PSMA- 617 for therapy of metastatic castration-resistant prostate cancer have underlined the... (Review)
Review
BACKGROUND
Recent reports of the remarkable therapeutic efficacy of 225Ac-labeled PSMA- 617 for therapy of metastatic castration-resistant prostate cancer have underlined the clinical potential of targeted alpha therapy.
OBJECTIVE AND CONCLUSION
This review describes methods for the production of 225Ac and its daughter nuclide 213Bi and summarizes the current clinical experience with both alpha emitters with particular focus on recent studies of targeted alpha therapy of bladder cancer, brain tumors, neuroendocrine tumors and prostate cancer.
Topics: Actinium; Alpha Particles; Bismuth; Clinical Trials as Topic; Humans; Neoplasms; Radiochemistry; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals
PubMed: 29732998
DOI: 10.2174/1874471011666180502104524 -
Nuclear Medicine Communications Sep 2022Actinium-225 (225Ac) has emerged as a promising therapeutic radioisotope for targeted alpha therapy. It emits net four alpha particles during its decay to stable... (Review)
Review
Actinium-225 (225Ac) has emerged as a promising therapeutic radioisotope for targeted alpha therapy. It emits net four alpha particles during its decay to stable daughter bismuth-209, rightly called an in-vivo nano-generator. Compared to the worldwide demand of 225Ac, the amount produced via depleted thorium-229 sources is minimal, making it an expensive radionuclide. However, many research groups are working on optimizing the parameters for the production of 225Ac via different routes, including cyclotrons, reactors and high-energy linear accelerators. The present review article focuses on the various aspects associated with the development of 225Ac radiopharmaceuticals. It includes the challenges and opportunities associated with the production methods, labeling chemistry, in-vivo kinetics and dosimetry of 225Ac radiopharmaceuticals. A brief description is also given about the 225Ac radiopharmaceuticals at preclinical stages, clinical trials and used routinely.
Topics: Actinium; Alpha Particles; Radioisotopes; Radiopharmaceuticals
PubMed: 35950353
DOI: 10.1097/MNM.0000000000001594 -
The Lancet. Oncology Feb 2024Actinium-225 (Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC). We...
BACKGROUND
Actinium-225 (Ac) 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 Ac-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 Ac-PSMA RLT administered intravenously for mCRPC. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium-177 (Lu) 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 Ac-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, Lu-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 Ac-PSMA RLT. All patients who received more than seven cycles of Ac-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
Ac-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.
Topics: Aged; Humans; Male; Actinium; Dipeptides; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radiopharmaceuticals; Radium; Retrospective Studies; Treatment Outcome; Xerostomia; Middle Aged
PubMed: 38218192
DOI: 10.1016/S1470-2045(23)00638-1 -
European Urology Mar 2021Beta-emitting Lu-177-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a new option for metastatic castration-resistant prostate cancer...
BACKGROUND
Beta-emitting Lu-177-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a new option for metastatic castration-resistant prostate cancer (mCRPC), but its antitumor effect can decrease over time.
OBJECTIVE
To report the safety and activity of alpha-emitting Ac-225-PSMA-617 RLT in mCRPC that has progressed after Lu-177-PSMA.
DESIGN, SETTING, AND PARTICIPANTS
Twenty-six patients were treated under a compassionate use protocol. The eligibility criteria included previous treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy, progression after Lu-177-PSMA, and positive PSMA-ligand uptake. The median number of previous mCRPC regimens was 6. Ac-225-PSMA-617 was given every 8 wk until progression/intolerable side effects.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Prostate-specific antigen (PSA) decline, PSA progression-free survival (PSA-PFS), clinical progression-free survival (cPFS), overall survival (OS), and toxicity were measured.
RESULTS AND LIMITATIONS
Sixty-one cycles of Ac-225-PSMA-617 (median number of cycles 2; median activity 9 MBq) were administered. A PSA decline of ≥50% was achieved in 17/26 patients. The median PSA-PFS, cPFS, and OS periods were 3.5 (95% confidence interval [CI] 1.8-11.2), 4.1 (95% CI 3-14.8), and 7.7 (95% CI 4.5-12.1) mo, respectively. Liver metastases were associated with shorter PSA-PFS (median 1.9 vs 4.0 mo; p = 0.02), cPFS (median 1.8 vs 5.2 mo; p = 0.001), and OS (median 4.3 vs 10.4 mo; p = 0.01). Hematological grade 3/4 toxicities were anemia (35%), leucopenia (27%), and thrombocytopenia (19%). All patients experienced grade 1/2 xerostomia. Two and six patients stopped due to hematological toxicity and xerostomia, respectively. A limitation is the retrospective design.
CONCLUSIONS
Ac-225-PSMA-617 showed measurable antitumor effect after Lu-177-PSMA failure in late-stage mCRPC. Grade 3/4 hematological side effects were observed in up to one-third of patients, and xerostomia led to treatment halt in a relevant number of patients.
PATIENT SUMMARY
Ac-225-labeled prostate-specific membrane antigen (PSMA)-617 therapy showed substantial antitumor effect in late metastatic castration-resistant prostate cancer after Lu-177-PSMA failure. However, dry mouth is a common side effect that caused about a quarter of patients to stop therapy.
Topics: Actinium; Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radiopharmaceuticals; Retrospective Studies; Treatment Outcome; Xerostomia
PubMed: 33293081
DOI: 10.1016/j.eururo.2020.11.013 -
Theranostics 2024Targeted alpha particle therapy (TAT) has emerged as a promising strategy for the treatment of prostate cancer (PCa). Actinium-225 (Ac), a potent alpha-emitting... (Review)
Review
Targeted alpha particle therapy (TAT) has emerged as a promising strategy for the treatment of prostate cancer (PCa). Actinium-225 (Ac), a potent alpha-emitting radionuclide, may be incorporated into targeting vectors, causing robust and in some cases sustained antitumor responses. The development of radiolabeling techniques involving EDTA, DOTA, DOTPA, and Macropa chelators has laid the groundwork for advancements in this field. At the forefront of clinical trials with Ac in PCa are PSMA-targeted TAT agents, notably [Ac]Ac-PSMA-617, [Ac]Ac-PSMA-I&T and [Ac]Ac-J591. Ongoing investigations spotlight [Ac]Ac-hu11B6, [Ac]Ac-YS5, and [Ac]Ac-SibuDAB, targeting hK2, CD46, and PSMA, respectively. Despite these efforts, hurdles in Ac production, daughter redistribution, and a lack of suitable imaging techniques hinder the development of TAT. To address these challenges and additional advantages, researchers are exploring alpha-emitting isotopes including Th, Ra, At, Bi, Pb or Tb, providing viable alternatives for TAT.
Topics: Humans; Male; Actinium; Prostatic Neoplasms; Alpha Particles; Radiopharmaceuticals; Animals
PubMed: 38773983
DOI: 10.7150/thno.96403 -
Seminars in Nuclear Medicine Mar 2020The recent development of Ac-PSMA617 for therapy of prostate cancer has strikingly demonstrated the clinical potential of targeted alpha therapy. Further promising... (Review)
Review
The recent development of Ac-PSMA617 for therapy of prostate cancer has strikingly demonstrated the clinical potential of targeted alpha therapy. Further promising applications of the alpha emitters Actinium and its daughter nuclide Bismuth include the therapy of brain tumors, bladder cancer, neuroendocrine tumors, and leukemia. This paper will provide a brief overview on the current status of the clinical development of compounds labelled with Ac or Bi and describe the various production routes that are in place or are under development to meet the increasing demand for these radionuclides.
Topics: Actinium; Bismuth; Humans; Isotope Labeling; Male; Prostatic Neoplasms; Radioisotopes
PubMed: 32172796
DOI: 10.1053/j.semnuclmed.2020.02.003 -
PET Clinics Apr 2023The role of lutetium-177-DOTATATE in advanced well-differentiated gastro-entero-pancreatic neuroendocrine tumors is well established. However, there is a scope for... (Review)
Review
The role of lutetium-177-DOTATATE in advanced well-differentiated gastro-entero-pancreatic neuroendocrine tumors is well established. However, there is a scope for improving treatment outcomes. Actinium-225-DOTATATE is a form of targeted alpha therapy (TAT) that results in more efficient tumor cell killing owing to the substantially higher linear energy transfer of alpha particles. Systemic TAT is also safe given that the shorter path length of the alpha particles spares the surrounding healthy tissue and results in relatively fewer adverse events. Combination therapies with radiosensitizing and other chemotherapeutic agents have also gained popularity, especially in the setting of higher grade and fluorodeoxyglucose-avid tumors.
Topics: Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Actinium
PubMed: 36858746
DOI: 10.1016/j.cpet.2022.11.004 -
European Urology Mar 2021Optimisation of prostate-specific membrane antigen (PSMA) based radioligand therapy (RLT) requires a focus on prospective trials.
Optimisation of prostate-specific membrane antigen (PSMA) based radioligand therapy (RLT) requires a focus on prospective trials.
Topics: Actinium; Humans; Male; Precision Medicine; Prospective Studies; Prostate
PubMed: 33436167
DOI: 10.1016/j.eururo.2020.12.011 -
Frontiers in Medicine 2022Peptide receptor radionuclide therapy (PRRT) has over the last two decades emerged as a very promising approach to treat neuroendocrine tumors (NETs) with rapidly... (Review)
Review
Peptide receptor radionuclide therapy (PRRT) has over the last two decades emerged as a very promising approach to treat neuroendocrine tumors (NETs) with rapidly expanding clinical applications. By chelating a radiometal to a somatostatin receptor (SSTR) ligand, radiation can be delivered to cancer cells with high precision. Unlike conventional external beam radiotherapy, PRRT utilizes primarily β or α radiation derived from nuclear decay, which causes damage to cancer cells in the immediate proximity by irreversible direct or indirect ionization of the cells' DNA, which induces apoptosis. In addition, to avoid damage to surrounding normal cells, PRRT privileges the use of radionuclides that have little penetrating and more energetic (and thus more ionizing) radiations. To date, the most frequently radioisotopes are β emitters, particularly Yttrium-90 (Y) and Lutetium-177 (Lu), labeled SSTR agonists. Current development of SSTR-targeting is triggering the shift from using SSTR agonists to antagonists for PRRT. Furthermore, targeted α-particle therapy (TAT), has attracted special attention for the treatment of tumors and offers an improved therapeutic option for patients resistant to conventional treatments or even beta-irradiation treatment. Due to its short range and high linear energy transfer (LET), α-particles significantly damage the targeted cancer cells while causing minimal cytotoxicity toward surrounding normal tissue. Actinium-225 (Ac) has been developed into potent targeting drug constructs including somatostatin-receptor-based radiopharmaceuticals and is in early clinical use against multiple neuroendocrine tumor types. In this article, we give a review of preclinical and clinical applications of Ac-PRRT in NETs, discuss the strengths and challenges of Ac complexes being used in PRRT; and envision the prospect of Ac-PRRT as a future alternative in the treatment of NETs.
PubMed: 36569154
DOI: 10.3389/fmed.2022.1034315