Subscribe to RSS
DOI: 10.1055/s-0045-1809342
Targeted Alpha Radiopharmaceutical Therapy and Key Considerations for Nuclear Medicine Technologists
Abstract
The use of radionuclides for targeted radiopharmaceutical therapy (RPT) is a rapidly evolving field in nuclear medicine and oncology. With the integration of imaging and therapy, therapeutic nuclear medicine has made remarkable progress in recent years. One particularly promising area of research is the use of α-emitting radionuclides, which possess unique physical properties that provide notable advantages, including the ability to target single tumor cells with high precision. Although the only targeted α therapy (TAT) currently approved by the United States Food and Drug Administration is 223Ra-dichloride for the treatment of castration-resistant prostate cancer with skeletal metastases, a search on clinicaltrials.gov yields a significant number of early- and late-stage clinical trials utilizing 223-Ra, 225-Ac, 211-At, 212-Pb, and 227-Th are in progress, indicating that more TATs are on the horizon. As the prevalence of use for TAT increases, it is important to consider the logistics of TAT administration and the requirements for radiation safety and patient discharge. This review aims to provide a comprehensive overview of the advancements, relevant clinical trials, and logistical considerations associated with targeted α RPT in oncology.
#
Keywords
alpha-particle - beta-particle - molecular target - radiopharmaceutical therapy - targeted α therapyIntroduction
Radiopharmaceutical therapies (RPT) designed for curative treatment, disease control, or palliation are poised to play a significant role in the future of nuclear medicine. RPT involves administering radionuclides that are either linked to tumor-targeting carrier molecules—such as antibodies, peptides, or small molecules—or that naturally accumulate in tumors through cancer cell-specific physiological processes.[1] [2] The primary subject of this paper is targeted alpha (α)-therapy (TAT), but there is a discussion of beta (β)-particle RPT highlighting differences in clinical practice. It is important to consider the differences between α- and β-RPT and how these differences impact not only disease management strategies but also the administration requirements, radiation safety protocols, and patient precautions.
#
Methods
The authors conducted a comprehensive search of the clinicaltrials.gov database to identify both early- and late-phase clinical trials involving TAT. Among the existing α-emitting radionuclides, only a select few have demonstrated potential for therapeutic applications, particularly in TAT. From this group, the most suitable candidates—namely, 225-actinium (225Ac), 211-astatine (211At), 212-bismuth (212Bi), 213-bismuth (213Bi), 212-lead (212Pb), 223-radium (223Ra), 149-terbium (149Tb), and 227-thorium (227Th)—were used as key terms in the search for relevant clinical trials. Additional search terms included “targeted alpha therapy,” “alpha,” “RPT,” and “radionuclide therapy.” Trials that had been withdrawn, terminated, suspended, or completed, as well as those with unknown status, were excluded from the results. The search parameters were not further refined by adding other qualifiers such as eligibility criteria, study phase, study type, study results, funding source, or date range. Given the significant number of clinical trials, the authors also performed a literature search to compile radiation safety recommendations relevant to the administration of α-particle RPT. These recommendations are reviewed in the discussion of this article.
#
Results
A total of 42 single-center and multicenter clinical trials were identified on clinicaltrials.gov, utilizing the following radionuclides: 225Ac, 211At, 212Bi, 213Bi, 212Pb, 223Ra, and 227Th. Among these, 225Ac and 223Ra were the most frequently employed, featured in 13 and 27 trials, respectively. A summary of ongoing clinical trials involving α-particle therapies, as identified from clinicaltrials.gov,[3] is presented in [Table 1].[3]
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BCR, biochemically recurrent; CD33, center of differentiation 33; CD38, center of differentiation 38; CD45, center of differentiation 45; CEA, carcinoembryonic antigen; CRCP, castration-resistant prostate cancer; ES-SCLC, extensive stage small cell lung cancer; GEP-NETs, gastroenteropancreatic neuroendocrine tumors; GI-NET, gastrointestinal neuroendocrine tumors; GRPR, gastrin-releasing peptide receptor; HR +/HER2-, hormone receptor-positive, human epidermal growth factor receptor 2 negative; MC1R-melanocortin sub-type 1 receptor; mCRCP, metastatic castration-resistant prostate cancer; MDS, myelodysplastic syndrome; mRCC, metastatic renal cell cancer; NSCLC, non-small-cell lung cancer; NTSR1-neurotensin receptor; PPGL, pheochromocytoma/paraganglioma; PRRT, peptide receptor radionuclide therapy; PSMA. prostate specific membrane antigen; RLT, radioligand therapy; SABR, stereotactic ablative radiation; SCLC, small cell lung cancer; SSAs, somatostatin analogues; SSTR2, somatostatin Receptor subtype 2; SSTR, somatostatin receptor.
While a range of cancer types were evaluated, the three most prominent were metastatic castration-resistant prostate cancer (mCRPC), neuroendocrine tumors (NET), and acute myeloid leukemia (AML).[3] The common therapeutic targets across these trials included hydroxyapatite for mCRPC, somatostatin receptors (SSTR) for NET, and myeloid cell antigens—specifically clusters of differentiation (CD) 33, 38, and 45—for AML or other myelodysplastic diseases.[3]
As a result of the established clinical use of 223Ra-dichloride in treating skeletal metastases in mCRPC, several clinical trials with 223Ra are exploring the efficacy of combination therapies with hormone therapy, chemotherapy, immunotherapy, targeted therapy, and stereotactic body radiation.[3] Further, observational and surveillance trials are evaluating the long-term effects of 223Ra-dichloride treatment in mCRPC.[3] For the 223Ra-treatment of skeletal metastases associated with mCRPC, skeletal scintigraphy has been an established pretreatment evaluation; however, clinical trials identified in the search are now investigating the role of PSMA-PET scans for the diagnostic positivity in the progression of 68Ga-PSMA PET versus skeletal scintigraphy.[3] Outside of the evaluation of mCRPC, clinical trials are also investigating 223Ra to treat skeletal metastases in patients with renal cell carcinoma (RCC) and breast cancer.[3] Although 223Ra has long been used for the treatment of mCRPC, its clinical utility has been restricted to skeletal metastases. Clinical trials with 225Ac-PSMA are investigating the treatment of mCRPC with soft tissue or visceral disease progression as well as skeletal lesions.
In the case of AML, the well-characterized nature of cell surface antigens, combined with the radiosensitivity and accessibility of leukemia cells, has driven long-standing interest in radioimmunotherapy (RIT) to complement or replace conventional therapies and improve patient outcomes. While β-particle RIT with radionuclides such as 131I and 90Y has been used to intensify conditioning regimens before allogeneic hematopoietic cell transplantation (HCT), α-particle RIT, using radionuclides like 225Ac or 211At, is being investigated for its precise, potent, and efficient destruction of target cells, with reduced toxicity to surrounding healthy cells.[3] This precision may expand the therapeutic use of α-particle RIT beyond HCT, offering a promising avenue for treatment.
#
Discussion
Targeted RPT capitalizes on the distinct differential targeting abilities of molecular vectors to deliver a potent radiation dose directly to cells with higher concentrations of the target. This approach is intended to treat both primary and metastatic cancers in patients identified through molecular imaging, which confirms the presence of biological targets on cancer cells' surfaces or within the vascular or stromal components of metastatic disease.[1] [2] The radioisotopes used for RPT emit β- or α-particles, or auger electrons (AE).[2] [Table 2] provides a comparison of α and β-particle therapeutic radiation emission characteristics, cytotoxicity, and use.[2] [4] [5] [6]
Historically, targeted RPT primarily relied on β-emitting radionuclides like 131-iodine and 90-yttrium. In recent years, the β-emitting radionuclide 177-lutetium has gained significant clinical relevance, as evidenced by the U.S. Food and Drug Administration (FDA) approvals of 177Lu-PSMA-617 (Novartis, Indiana, approved in 2022) for treating metastatic mCRPC expressing prostate-specific membrane antigen (PSMA), and 177Lu-DOTATATE (Lutathera, Advanced Accelerated Applications, Inc., New Jersey, approved in 2018) for the treatment of somatostatin receptor-positive NET.[1] β-particles are particularly effective in treating medium to large tumors due to their extended particle pathlength and low linear energy transfer (LET). As β-emitters traverse biological tissue, they primarily cause cytotoxicity with single-stranded DNA breaks and the production of reactive oxygen species, exhibiting approximately 500 times lower cytotoxic potency than α-particles.[2] [4] While the extended range of β-particles and the resulting cross-fire effect is advantageous for distributing the radiation dose across heterogeneous tumors it can also result in the unintended irradiation of healthy tissue surrounding the tumor site.[2]
Recent advancements in targeted radionuclide delivery and the availability of clinically relevant α-emitters have significantly expanded therapeutic possibilities. Although research on α-emitters spans several decades, their current application in targeted RPT represents a pivotal advancement in cancer treatment. Alpha particles are large in size, highly energetic, and have a moderate path length in tissue.[2] Alpha-emitting radionuclides possess the unique ability to selectively destroy targeted tumor cells while sparing adjacent normal tissues due to their high-LET and concentrated radiation deposition, thus making them suitable for small neoplasms, micrometastases, and tumors that are resistant to conventional therapies and β-particle RPT.[2] [5] Unlike β-particles, α-particles maintain an almost linear path with destruction occurring all along the path. Efficient cell destruction is accomplished through complex multiple clusters and irreparable double-strand DNA damage.[2] [5] Additionally, the interaction of α-particles with water generates reactive oxygen species, which can further react with biomolecules such as proteins, phospholipids, RNA, and DNA, leading to irreversible cellular damage.[5] Due to their particle range, β-emitters are typically believed to produce a stronger cross-fire effect; however, recent studies demonstrating that α-particles can have a significant therapeutic impact on large tumors challenge this assumption.[2] This heightened biological effectiveness, while beneficial for targeting and destroying cancerous cells, also necessitates meticulous handling to prevent unintended exposure. Proper containment, accurate dosimetry, patient monitoring, and adherence to safety protocols are crucial to maximizing therapeutic efficacy and minimizing risks to both patients and healthcare providers.
As TAT clinical trials continue to expand and yield approved therapeutic applications, it is important to consider how this will impact the clinical work for technologists and influence patient interactions and discharge instructions. Alpha particles have a high LET, depositing a significant amount of energy over a short distance, which results in dense ionization and severe biological damage to cells. Due to this characteristic, meticulous handling is essential to prevent unintended exposure.[7] Proper handling of α-emitters is radionuclide-dependent. It is important to consider the decay of progeny for each individual radionuclide when determining shielding requirements, as attenuation of both β and photon radiation may be required with these radionuclides. Using long-handled tools, such as tongs, and shielded syringes or vials helps reduce extremity radiation exposure.[7] Occupational exposure can be further minimized by selecting proper storage methods and shielding. When working with α-emitting radionuclides, depending on the specific radionuclide, lead or plexiglass may be used for shielding. Some α-emitting radiopharmaceuticals, such as 223RaCl2, are supplied as unit dosages and are shipped and stored in specialized containers like the Xofigo Plastic Pig. Other α-emitting radiopharmaceuticals may require dose manipulation and are often shipped and stored in lead containers.[7]
Alpha particles, despite their significant ionizing power due to their double-positive charge, have limited penetration because of their large mass. Alpha particles have a very limited range in the air—only a few centimeters—and can be effectively stopped by a thin barrier, such as paper or clothing. Since α-particles require at least 7.5 MeV to penetrate a protective skin layer that is 0.07 mm thick, they do not pose an external radiation risk.[2] However, the primary concern arises from the potential internalization of these particles through inhalation, ingestion, or entry via wounds, which can lead to significant internal damage due to energy deposition in living tissues. To minimize the risk of internal exposure, it is crucial to use appropriate personal protective equipment (PPE), such as gloves (double gloves preferred) and laboratory coats when handling radiopharmaceuticals.[7] Facilities may also require the use of face shields and masks when working with RPT.
Because α-emitting radiopharmaceuticals generate minimal external dose rates, the need for lead shielding or other exposure minimizing shielding in the treatment rooms is minimized. The low external dose rates also facilitate improved patient care, as healthcare staff are not subjected to the same occupational radiation exposure constraints.[7] Administering RPT carries a risk of contamination, particularly since most RPTs are delivered intravenously. To minimize the risk in the event of a spill, absorbent pads should be used to line the injection table and placed around the injection site.[6] Due to the potential hazards associated with α-particles, it is crucial for technologists to implement stringent contamination control measures and decontamination policies, including regular monitoring of workspaces and personal exposure. While a standard Geiger–Muller (GM) detector can be used for monitoring, an α-probe such as ZnS(Ag) scintillator is generally more effective for detecting minimal detectable activity due to its ability to filter out β-particles and photons, thereby achieving lower background levels.[2] [7] The counting efficiency of a GM detector depends on various factors, including the type and energy of the radiation being detected. It is essential to review the manufacturer's specifications to ensure accurate energy sensitivity.
A few key administration considerations are crucial, particularly due to the increased risks associated with needle sticks and skin contamination during IV administrations. These include always ensuring IV patency, utilizing ultrasound guidance for insertion when available, and regularly checking patency to prevent IV infiltrations. The use of needleless connectors is encouraged when possible, along with the placement of absorbent pads or gauze at connection sites to prevent leaks or spills on the patient's skin during connection.
The Nuclear Regulatory Commission (NRC) requirements related to needlestick injuries and skin contamination are specific to the United States. It is important to note that regulatory frameworks vary by country, and each nation may have its own standards and reporting protocols for managing radiation-related occupational exposures. Accidental needle sticks and skin contamination during treatments are classified as special events by the NRC and require an immediate and appropriate response due to the potential risk of radioactive material intake.[7] Prompt decontamination of the affected area, along with continuous monitoring, is critical.[7] NRC Regulatory Guide 8.9 outlines detailed procedures for assessing radioactive material intake through bioassay and determining if further investigation is necessary.[7] In situations requiring specialized monitoring, any suspected intake of radioactive material should be thoroughly evaluated to ensure the proper response is taken to mitigate potential risks.
A study published by Serencsits et al evaluated external exposure rates in patients treated with 223Ra, 225Ac, and 227Th.[7] As expected, the external exposure rates for patients treated with α-emitting radionuclides were found to be minimal, with median dose rates of less than 0.5 μSv/hour measured at a 1-m distance. Considering the low external dose rates, it is highly unlikely that any patient would expose a member of the public to more than 1 mSv of radiation—the threshold outlined in the U.S. NRC regulatory guide 8.39 for the release of patients treated with radioactive materials.[7] This aspect of α-emitting radionuclide therapy offers a distinct advantage, eliminating many of the restrictions commonly associated with other forms of radiopharmaceutical treatment.
In most jurisdictions, patients can resume their normal activities immediately after treatment without the need for radiation safety precautions; however, caution is still advised when handling specimens containing bodily fluids to prevent accidental ingestion of radioactive material.[7] To minimize any potential risk to the public or household members, specific guidelines regarding the management of bodily fluids are provided to patients upon discharge (see [Table 3]). These recommendations include sitting while using the restroom, thoroughly washing hands after any contact with bodily fluids, and promptly cleaning up any spills of vomit or bodily fluids. These precautions are advised for 1 week following therapy, although most radioactive excretion occurs within the first 72 hours. Beyond this period, the remaining levels of radioactivity are negligible and pose no significant risk of exposure to others.[7]
Taking into account the distinct differences between α- and β-RPTs, medical institutions must develop specific competencies and clear guidelines as part of a comprehensive RPT management program. Institutions offering both α- and β-RPT will require well-designed and streamlined standard operating procedures (SOPs) to address the unique demands of these therapies. Key considerations for such a program include scheduling, staff utilization, room requirements, and radiation safety practices, all of which are significantly impacted by the characteristics of α- and β-particle therapies. [Table 4] outlines practical considerations for implementing a radiopharmaceutical management program, while [Table 5] provides a comparative analysis of practical considerations specific to α- and β-RPTs.[7] These tools aim to guide institutions in creating efficient, safe, and effective RPT programs that meet the operational and regulatory requirements for both therapy types.
#
Conclusion
Targeted α-therapy (TAT) is emerging as one of the most promising innovations in cancer treatment. By delivering highly cytotoxic doses directly to cancer cells while sparing surrounding healthy tissue, TAT offers a distinct advantage over other forms of radiation therapy. Utilizing the high LET and short path length of α-particles, this approach enhances therapeutic efficacy and reduces potential side effects. With appropriate PPE, training, and radiation detection protocols in place, α-emitting radionuclides can be safely handled and administered in clinical settings, minimizing contamination risks and ensuring the safety of healthcare professionals and the public. Additionally, patient release guidelines for TAT often require only basic hygiene precautions to prevent accidental ingestion or inhalation of radioactive material by others, allowing patients to resume normal activities without the strict radiation restrictions seen in other therapies. The field of TAT is widely regarded as one of the most exciting areas of innovation in cancer therapy today. Early- and late-stage clinical trials for NET and metastatic prostate cancer are already progressing and industry support is advancing new TAT concepts. As research and development continue, TAT, along with β-particle RPT, is expected to significantly broaden the range of options available for cancer treatment, including effective combination therapies to maximize outcomes.
#
#
Conflict of Interest
None declared.
Authors' Contributions
J.B. was the primary author of the manuscript. She was also responsible for resource gathering and review, clinical trials review, authorship of four-fifths tables, manuscript review, and manuscript revisions. D.G. was responsible for secondary authorship of the manuscript, manuscript review, and authorship of the radiation safety/discharge instructions table and other clinical recommendations. J.B. and D.G. have read and approved the manuscript. Both authors believe the manuscript represents honest work.
-
References
- 1 Bruland ØS, Larsen RH, Baum RP, Juzeniene A. Editorial: targeted alpha particle therapy in oncology. Front Med (Lausanne) 2023; 10: 1165747
- 2 Poty S, Francesconi LC, McDevitt MR, Morris MJ, Lewis JS. α-Emitters for radiotherapy: from basic radiochemistry to clinical studies-part 1. J Nucl Med 2018; 59 (06) 878-884
- 3 Clinical Trials.[online]. Accessed September 13, 2024 at: clinicaltrials.gov
- 4 Hatcher-Lamarre JL, Sanders VA, Rahman M, Cutler CS, Francesconi LC. Alpha emitting nuclides for targeted therapy. Nucl Med Biol 2021; 92: 228-240
- 5 Pallares RM, Abergel RJ. Development of radiopharmaceuticals for targeted alpha therapy: where do we stand?. Front Med (Lausanne) 2022; 9: 1020188
- 6 Heskamp S, Hernandez R, Molkenboer-Kuenen JDM. et al. α- Versus β-emitting radionuclides for pretargeted radioimmunotherapy of carcinoembryonic antigen-expressing human colon cancer xenografts. J Nucl Med 2017; 58 (06) 926-933
- 7 Serencsits B, Chu BP, Pandit-Taskar N, McDevitt MR, Dauer LT. Radiation safety considerations and clinical advantages of α-emitting therapy radionuclides. J Nucl Med Technol 2022; 50 (01) 10-16
Address for correspondence
Publication History
Article published online:
03 June 2025
© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
-
References
- 1 Bruland ØS, Larsen RH, Baum RP, Juzeniene A. Editorial: targeted alpha particle therapy in oncology. Front Med (Lausanne) 2023; 10: 1165747
- 2 Poty S, Francesconi LC, McDevitt MR, Morris MJ, Lewis JS. α-Emitters for radiotherapy: from basic radiochemistry to clinical studies-part 1. J Nucl Med 2018; 59 (06) 878-884
- 3 Clinical Trials.[online]. Accessed September 13, 2024 at: clinicaltrials.gov
- 4 Hatcher-Lamarre JL, Sanders VA, Rahman M, Cutler CS, Francesconi LC. Alpha emitting nuclides for targeted therapy. Nucl Med Biol 2021; 92: 228-240
- 5 Pallares RM, Abergel RJ. Development of radiopharmaceuticals for targeted alpha therapy: where do we stand?. Front Med (Lausanne) 2022; 9: 1020188
- 6 Heskamp S, Hernandez R, Molkenboer-Kuenen JDM. et al. α- Versus β-emitting radionuclides for pretargeted radioimmunotherapy of carcinoembryonic antigen-expressing human colon cancer xenografts. J Nucl Med 2017; 58 (06) 926-933
- 7 Serencsits B, Chu BP, Pandit-Taskar N, McDevitt MR, Dauer LT. Radiation safety considerations and clinical advantages of α-emitting therapy radionuclides. J Nucl Med Technol 2022; 50 (01) 10-16