Radium-223

Radium-223 (223Ra, Ra-223) was discovered in 1905 by T. Godlewski,[2][3][4] a Polish chemist from Kraków, and is historically known as actinium X, or AcX.[5][6] It is an isotope of radium with an 11.4-day half-life, in contrast to the more common isotope radium-226, discovered by the Curies, which has a 1600-year half-life. Radium-223 dichloride is an alpha particle-emitting radiotherapy drug that mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover.[7] The principal use of radium-223, as a radiopharmaceutical to treat metastatic cancers in bone, takes advantage of its chemical similarity to calcium, and the short range of the alpha radiation it emits.[8]

Radium-223, 223Ra
General
Symbol223Ra
Namesradium-223, Ra-223, actinium X, AcX
Protons88
Neutrons135
Nuclide data
Half-life11.43 ± 0.05 d
Parent isotopes227Th
223Fr
Decay products219Rn
Isotope mass223.0185007(22) u
Decay modes
Decay modeDecay energy (MeV)
α5.979[1]
Isotopes of radium
Complete table of nuclides

Origin and preparation

Although radium-223 is naturally formed in trace amounts by the decay of uranium-235, it is generally made artificially,[9] by exposing natural radium-226 to neutrons to produce radium-227, which decays with a 42-minute half-life to actinium-227. Actinium-227 (half-life 21.8 years) in turn decays via thorium-227 (half-life 18.7 days) to radium-223. This decay path makes it convenient to prepare radium-223 by "milking" it from an actinium-227 containing generator or "cow", similar to the moly cows widely used to prepare the medically important isotope technetium-99m.[9]

223Ra itself decays to 219Rn (half-life 3.96 s), a short-lived gaseous radon isotope, by emitting an alpha particle of 5.979 MeV.[1]

Medical use
Radium-223 chloride
Clinical data
Trade namesXofigo
AHFS/Drugs.comMicromedex Detailed Consumer Information
License data
Pregnancy
category
  • US: X (Contraindicated)
    Routes of
    administration    		injection
    ATC code
    Legal status
    Legal status
    • US: ℞-only
    • Experimental in most countries
    Identifiers
    CAS Number
    PubChem CID
    ChemSpider
    • none
    UNII
    KEGG
    ChEBI
    Chemical and physical data
    Formula223RaCl2
    Molar mass296.91 g/mol
     NY (what is this?)  (verify)

    The pharmaceutical product and medical use of radium-223 against skeletal metastases was invented by Roy H. Larsen, Gjermund Henriksen and Øyvind S. Bruland[10] and has been developed by the former Norwegian company Algeta ASA, in a partnership with Bayer, under the trade name Xofigo (formerly Alpharadin), and is distributed as a solution containing radium-223 chloride (1100 kBq/ml), sodium chloride, and other ingredients for intravenous injection. Algeta ASA was later acquired by Bayer who is now the sole owner of Xofigo. The recommended regimen is six treatments of 55 kBq/kg (1.5 μCi/kg), repeated at 4-week intervals.[11]

    Mechanism of action
    See also: Targeted alpha-particle therapy

    The use of radium-223 to treat metastatic bone cancer relies on the ability of alpha radiation from radium-223 and its short-lived decay products to kill cancer cells. Radium is preferentially absorbed by bone by virtue of its chemical similarity to calcium, with most radium-223 that is not taken up by the bone being cleared, primarily via the gut, and excreted.[12] Although radium-223 and its decay products also emit beta and gamma radiation, over 95% of the decay energy is in the form of alpha radiation.[13] Alpha radiation has a very short range in tissues compared to beta or gamma radiation: around 2-10 cells. This reduces damage to surrounding healthy tissues, producing an even more localized effect than the beta-emitter strontium-89, also used to treat bone cancer.[14] Taking account of its preferential uptake by bone and the alpha particles' short range, radium-223 is estimated to give targeted osteogenic cells a radiation dose at least eight times higher than other non-targeted tissues.[15]

    Clinical trials and FDA and EMA approval

    The phase II study of radium-223 in castration-resistant prostate cancer (CRPC) patients with bone metastases showed minimum myelotoxicity and good tolerance for the treatment.[16]

    223Ra successfully met the primary endpoint of overall survival in the phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer patients) study for bone metastases resulting from CRPC in 922 patients.[17]

    The ALSYMPCA study was stopped early after a pre-planned efficacy interim analysis, following a recommendation from an Independent Data Monitoring Committee, on the basis of achieving a statistically significant improvement in overall survival (two-sided p-value = 0.0022, HR = 0.699, the median overall survival was 14.0 months for 223Ra and 11.2 months for placebo).[17] Earlier phase II of the trial showed 4.5 months increased survival. The lower figure of 2.8 months increased survival in phase III, is a probable result of stopping the trial. Survival time for the patients still alive could not be calculated.

    In May 2013, 223Ra received marketing approval from the U.S. Food and Drug Administration (FDA)[18] as a treatment for CRPC with bone metastases in patients with symptomatic bone metastases and without known visceral disease. 223Ra received priority review as a treatment for an unmet medical need, based on its ability to extend overall survival as shown its Phase III trial.[19]

    This study also led to approval in the European Union on September 19, 2013[20] The European Medicines Agency subsequently recommended restricting its use to patients who have had two previous treatments for metastatic prostate cancer or who cannot receive other treatments. The medicine must also not be used with abiraterone acetate, prednisone or prednisolone and its use is not recommended in patients with a low number of osteoblastic bone metastases.[21]

    223Ra also showed promising preliminary results in a phase IIa trial with bone metastases resulting from breast cancer that no longer responds to endocrine therapy. The data showed that 223Ra reduced the levels of bone alkaline phosphatase (bALP) and urine N-telopeptide (uNTX), key markers of bone turnover associated with bone metastases in breast cancer.

    Side effects

    The most common side effects reported during clinical trials in men receiving 223Ra were nausea, diarrhea, vomiting and swelling of the leg, ankle or foot. The most common abnormalities detected during blood testing were anemia, lymphocytopenia, leukopenia, thrombocytopenia and neutropenia.[22]

    Other radium-223-based compounds

    Although radium does not easily form stable molecular complexes,[23] there has been presented data on methods to increase and customize its specificity for particular cancers by linking it to monoclonal antibodies, by enclosing the 223Ra in liposomes bearing the antibodies on their surface.[24]

    See also

    References
    1. Wang M, Audi G, Kondev FG, Huang WJ, Naimi S, Xu X (2017). "The AME2016 atomic mass evaluation (II). Tables, graphs, and references" (PDF). Chinese Physics C. 41 (3): 030003-1–030003-442. doi:10.1088/1674-1137/41/3/030003.
    2. Godlewski T (1905). "A new radio-active product from actinium". Nature. 71 (1839): 294–295. Bibcode:1905Natur..71..294G. doi:10.1038/071294b0. ISSN 0028-0836.
    3. Godlewski T (1905). "V. Actinium and its successive products". The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science. 10 (55): 35–45. doi:10.1080/14786440509463342. ISSN 1941-5982.
    4. Hahn O (1906). "A new product of actinium". Nature. 73 (1902): 559–560. Bibcode:1906Natur..73..559H. doi:10.1038/073559b0. ISSN 0028-0836.
    5. Kirby HW (1971). "The discovery of actinium". Isis. 62 (3): 290–308. doi:10.1086/350760. JSTOR 229943.
    6. Fry C, Thoennessen M (2013). "Discovery of actinium, thorium, protactinium, and uranium isotopes". Atomic Data and Nuclear Data Tables. 99 (3): 345–364. arXiv:1203.1194. Bibcode:2013ADNDT..99..345F. doi:10.1016/j.adt.2012.03.002. ISSN 0092-640X.
    7. Lewis SL, Bucher L, Heitkemper M, Harding MM (2017). Medical-Surgical Nursing: Assessment and Management of Clinical Problems (10th ed.). Elsevier. ISBN 978-0-323-32852-4.
    8. Marques IA, Neves AR, Abrantes AM, Pires AS, Tavares-da-Silva E, Figueiredo A, Botelho MF (July 2018). "Targeted alpha therapy using Radium-223: From physics to biological effects". Cancer Treatment Reviews. 68: 47–54. doi:10.1016/j.ctrv.2018.05.011. PMID 29859504.
    9. Bruland O.S., Larsen R.H. (2003). Radium revisited. In: Bruland O.S., Flgstad T., editors. Targeted cancer therapies: An odyssey. University Library of Tromso, Ravnetrykk No. 29. ISBN 82-91378-32-0, p. 195–202.
    10. "Preparation and use of radium-223 to target calcified tissues for pain palliation, bone cancer therapy, and bone surface conditioning" US 6635234
    11. "Xofigo Summary of Product Characteristics" (PDF). European Medicines Authority. Bayer. 11 October 2018. Retrieved 9 October 2019.
    12. Nilsson S, Larsen RH, Fosså SD, Balteskard L, Borch KW, Westlin JE, et al. (June 2005). "First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases". Clinical Cancer Research. 11 (12): 4451–9. doi:10.1158/1078-0432.CCR-04-2244. PMID 15958630.
    13. Bruland ØS, Nilsson S, Fisher DR, Larsen RH (October 2006). "High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities?". Clinical Cancer Research. 12 (20 Pt 2): 6250s–6257s. doi:10.1158/1078-0432.CCR-06-0841. PMID 17062709.
    14. Henriksen G, Fisher DR, Roeske JC, Bruland ØS, Larsen RH (February 2003). "Targeting of osseous sites with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice". Journal of Nuclear Medicine. 44 (2): 252–9. PMID 12571218.
    15. FDA Access Data on Xofigo (Radium-223 dichloride)
    16. Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, et al. (July 2007). "Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study". The Lancet. Oncology. 8 (7): 587–94. doi:10.1016/S1470-2045(07)70147-X. PMID 17544845.
    17. Full data report from the ALSYMPCA trial of radium-223 presented
    18. "FDA OKs pinpoint prostate cancer radiation drug Xofigo from Bayer, Algeta". Archived from the original on 15 May 2013.
    19. http://www.cancer.org/cancer/news/news/fda-approves-xofigo-for-advanced-prostate-cancer%5B%5D
    20. "Xofigo". 17 September 2018.
    21. "EMA restricts use of prostate cancer medicine Xofigo". European Medicines Agency. 28 September 2018.
    22. "FDA approves new drug for advanced prostate cancer". US FDA. Archived from the original on 15 May 2013.
    23. Henriksen G, Hoff P, Larsen RH (May 2002). "Evaluation of potential chelating agents for radium". Applied Radiation and Isotopes. 56 (5): 667–71. doi:10.1016/s0969-8043(01)00282-2. PMID 11993940.
    24. Henriksen G, Schoultz BW, Michaelsen TE, Bruland ØS, Larsen RH (May 2004). "Sterically stabilized liposomes as a carrier for alpha-emitting radium and actinium radionuclides". Nuclear Medicine and Biology. 31 (4): 441–9. doi:10.1016/j.nucmedbio.2003.11.004. PMID 15093814.

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