Administration of lower doses of radium-224 to ankylosing spondylitis patients results in no evidence of significant overall detriment

Priest, Nicholas; Dauer, Lawrence T.; Hoel, David G.

doi:10.1371/journal.pone.0232597

Cited by 8 publications

(12 citation statements)

References 16 publications

(24 reference statements)

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“…Concerning long-term side effects, Priest et al ( 36 ) compared, in a reanalysis of the AS patient data of the Wick study, the higher incidence of radiation-induced cancer with the fact that the patient treatment resulted decreased pain and increased mobility. Both of which are associated with decreased mortality by non-cancer diseases and from all causes of death.…”

Section: Discussionmentioning

confidence: 99%

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Comparing absorbed doses and radiation risk of the α-emitting bone-seekers [223Ra]RaCl2 and [224Ra]RaCl2

Laßmann

Eberlein²

2023

Front. Med.

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[223Ra]RaCl2 and [224Ra]RaCl2 are bone seekers, emitting high LET, and short range (< 100 μm) alpha-particles. Both radionuclides show similar decay properties; the total alpha energies are comparable (223Ra: ≈28 MeV, 224Ra: ≈26 MeV). [224Ra]RaCl2 has been used from the mid-1940s until 1990 for treating different bone and joint diseases with activities of up to approximately 50 MBq [224Ra]RaCl2. In 2013 [223Ra]RaCl2 obtained marketing authorization by the FDA and by the European Union for the treatment of metastatic prostate cancer with an activity to administer of 0.055 MBq per kg body weight for six cycles. For intravenous injections in humans a model calculation using the biokinetic model of ICRP67 shows a ratio of organ absorbed dose coefficients (224Ra:223Ra) between 0.37 (liver) and 0.97 except for the kidneys (2.27) and blood (1.57). For the red marrow as primary organ-at-risk, the ratio is 0.57. The differences are mainly caused be the differing half-lives of the decay products of both radium isotopes. Both radionuclides show comparable DNA damage patterns in peripheral blood mononuclear cells after internal ex-vivo irradiation. Data on the long-term radiation-associated side effects are only available for treatment with [224Ra]RaCl2. Two epidemiological studies followed two patient groups treated with [224Ra]RaCl2 for more than 25 years. One of them was the “Spiess study”, a cohort of 899 juvenile patients who received several injections of [224Ra]RaCl2 with a mean specific activity of 0.66 MBq/kg. Another patient group of ankylosing spondylitis patients was treated with 10 repeated intravenous injections of [224Ra]RaCl2, 1 MBq each, 1 week apart. In total 1,471 of these patients were followed-up in the “Wick study”. In both studies, an increased cancer mortality by leukemia and solid cancers was observed. Similar considerations on long-term effects likely apply to [223Ra]RaCl2 as well since the biokinetics are similar and the absorbed doses in the same range. However, this increased risk will most likely not be observed due to the much shorter life expectancy of prostate cancer patients treated with [223Ra]RaCl2.

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Section: Discussionmentioning

confidence: 99%

“…In their analysis they found no excess mortality in the group of AS patients. According to the authors, “the study demonstrates the need to consider all causes of death and longevity when assessing health impacts following irradiation” ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Comparing absorbed doses and radiation risk of the α-emitting bone-seekers [223Ra]RaCl2 and [224Ra]RaCl2

Laßmann

Eberlein²

2023

Front. Med.

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“…Administration of total activities of 5.6-11.1 MBq 224 Ra (1 MBq of 224 Ra chloride solution per weekly injection) to these patients between 1945 and 1975 had neither negative impact on the survival, nor increased significantly the overall rate of second malignancies, as compared to the control population after a mean follow-up time of 24 years ( 46). The incidence rates of leukemias were 0.014 and 0.009 [hazard ratio 2.56 (95% confidence interval (CI) 0.89-7.54)] in in patients treated and non-treated with 224 Ra, respectively (46,48,50). Such long-term follow up of a large non-cancer patient population seems very relevant from a radiation safety perspective.…”

Section: Pb In One Solutionmentioning

confidence: 99%

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Juzeniene

Stenberg²,

Bruland³

et al. 2023

Front. Med.

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Metastases are the primary cause of death among cancer patients and efficacious new treatments are sorely needed. Targeted alpha-emitting radiopharmaceuticals that are highly cytotoxic may fulfill this critical need. The focus of this paper is to describe and explore a novel technology that may improve the therapeutic effect of targeted alpha therapy by combining two radionuclides from the same decay chain in the same solution. We hypothesize that the dual targeting solution containing bone-seeking 224Ra and cell-directed complexes of progeny 212Pb is a promising approach to treat metastatic cancers with bone and soft tissue lesions as well as skeletal metastases of mixed lytic/osteoblastic nature. A novel liquid 224Ra/212Pb-generator for rapid preparation of a dual targeting solution is described. Cancer cell targeting monoclonal antibodies, their fragments, synthetic proteins or peptides can all be radiolabeled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, 224Ra targets stromal elements in sclerotic bone metastases and 212Pb-chelated-conjugate targets tumor cells of metastatic prostate cancer or osteosarcoma. The dual targeting solution may also be explored to treat metastatic breast cancer or multiple myeloma after manipulation of bone metastases to a more osteoblastic phenotype by the use of bisphosphonates, denosumab, bortezomib or hormone therapy prior to treatment. This may improve targeting of bone-seeking 224Ra and render an augmented radiation dose deposited within metastases. Our preliminary preclinical studies provide conceptual evidence that the dual 224Ra-solution with bone or tumor-targeted delivery of 212Pb has potential to inhibit cancer metastases without significant toxicity. In some settings, the use of a booster dose of purified 212Pb-conjugate alone could be required to elevate the effect of this tumor cell directed component, if needed, e.g., in a fractionated treatment regimen, where the dual targeting solution will act as maintenance treatment.

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“…Animals experiments with 224 Ra showed that a significant fraction of 220 Rn diffused away from bone site, when redistribution was only estimated below 1% of the total activity in bone for 223 Ra [ 245 , 246 ]. Nevertheless, 224 Ra shows interesting therapeutic properties and was one of the first α-emitters to be used in clinical application for treatment of ankylosing spondylitis for a while, but questions about the dose administered as well as doubts about the development of others malignancies in treated patients resulted to the market withdrawal of 224 Ra dichloride [ 247 , 248 ]. Unlike 223 Ra, 224 Ra appears no longer in use under its dichloride form, however, it has been described as generator of 212 Pb/ 212 Bi [ 202 ], or in others strategies to prevent redistribution phenomenon described above by use of 224 Ra in solution with a chelating agent EDTMP for retention of 212 Pb [ 249 ] or by encapsulation in microparticles [ 250 ] or liposomes [ 251 ].…”

Section: Radium-223mentioning

confidence: 99%

Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”

et al. 2021

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Among all existing radionuclides, only a few are of interest for therapeutic applications and more specifically for targeted alpha therapy (TAT). From this selection, actinium-225, astatine-211, bismuth-212, bismuth-213, lead-212, radium-223, terbium-149 and thorium-227 are considered as the most suitable. Despite common general features, they all have their own physical characteristics that make them singular and so promising for TAT. These radionuclides were largely studied over the last two decades, leading to a better knowledge of their production process and chemical behavior, allowing for an increasing number of biological evaluations. The aim of this review is to summarize the main properties of these eight chosen radionuclides. An overview from their availability to the resulting clinical studies, by way of chemical design and preclinical studies is discussed.

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Administration of lower doses of radium-224 to ankylosing spondylitis patients results in no evidence of significant overall detriment

Cited by 8 publications

References 16 publications

Comparing absorbed doses and radiation risk of the α-emitting bone-seekers [223Ra]RaCl2 and [224Ra]RaCl2

Comparing absorbed doses and radiation risk of the α-emitting bone-seekers [223Ra]RaCl2 and [224Ra]RaCl2

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”

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