Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Radium-223: Difference between pages

{{Short description|Isotope of radium}}

{{Use dmy dates|date=August 2020}}

{{Infobox isotope

| alternate_names = actinium X, AcX

| symbol = Ra

| mass_number = 223

| mass = 223.0185007(22)

| num_neutrons = 135

| num_protons = 88

| abundance =

| halflife = {{val|11.43|0.05|u=days}}

| image =

| image_caption = image caption

| decay_product = radon-219

| decay_symbol = ²¹⁹Rn

| decay_mass =

| decay_mode1 = α

| decay_energy1 = 5.979{{AME2016 II|ref|name-list-style = vanc }}

| decay_mode2 =

| decay_energy2 =

| decay_mode3 =

| decay_energy3 =

| decay_mode4 =

| decay_energy4 =

| parent = thorium-227

| parent_symbol = ²²⁷Th

| parent_mass =

| parent_decay =

| parent2 = francium-223

| parent2_symbol = ²²³Fr

| parent2_mass =

| parent2_decay =

| spin =

| excess_energy =

| binding_energy =

}}

'''Radium-223 ''' (²²³Ra, Ra-223) is an [[Isotopes of radium#Radium-223|isotope]] of [[radium]] with an 11.4-day [[half-life]]. It was discovered in 1905 by T. Godlewski,<ref name="Godlewski_1905a">{{cite journal| vauthors = Godlewski T |title=A new radio-active product from actinium |journal=Nature |volume=71 |issue=1839 |year=1905 |pages=294–295 |issn=0028-0836 |doi=10.1038/071294b0|bibcode=1905Natur..71..294G|s2cid=4047285 |url=https://zenodo.org/record/2115992}}</ref><ref name="Godlewski_1905b">{{cite journal| vauthors = Godlewski T |title=V. Actinium and its successive products|journal=The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science|volume=10|issue=55|year=1905|pages=35–45|issn=1941-5982|doi=10.1080/14786440509463342|url=https://zenodo.org/record/2216022}}</ref><ref name="Hahn1906">{{cite journal| vauthors = Hahn O |title=A new product of actinium|journal=Nature|volume=73|issue=1902|year=1906|pages=559–560|issn=0028-0836|doi=10.1038/073559b0|bibcode=1906Natur..73..559H|s2cid=4052127 |url=https://zenodo.org/record/1705916}}</ref> a Polish chemist from [[Kraków]], and was historically known as [[Decay chain#Actinium series|actinium X]] (AcX).<ref name="Kirby_1971">{{cite journal | vauthors = Kirby HW |title=The discovery of actinium |year=1971 |journal=Isis |volume=62 |issue=3 |pages=290–308 |doi =10.1086/350760 |jstor=229943 |s2cid=144651011 }}</ref><ref name="FryThoennessen2013">{{cite journal| vauthors = Fry C, Thoennessen M |title=Discovery of actinium, thorium, protactinium, and uranium isotopes|journal=Atomic Data and Nuclear Data Tables|volume=99|issue=3|year=2013|pages=345–364|issn=0092-640X|doi=10.1016/j.adt.2012.03.002|bibcode=2013ADNDT..99..345F|arxiv=1203.1194|s2cid=97142872}}</ref> Radium-223 dichloride is an alpha particle-emitting radiotherapy drug that mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover.<ref>{{Cite book|title=Medical-Surgical Nursing: Assessment and Management of Clinical Problems | edition = 10th | vauthors = Lewis SL, Bucher L, Heitkemper M, Harding MM |publisher=Elsevier|year=2017|isbn=978-0-323-32852-4}}</ref> The principal use of radium-223, as a [[radiopharmaceutical]] to treat [[Metastasis|metastatic]] cancers in [[bone]], takes advantage of its chemical similarity to [[calcium]], and the short range of the [[alpha radiation]] it emits.<ref name="Marques_2018">{{cite journal | vauthors = Marques IA, Neves AR, Abrantes AM, Pires AS, Tavares-da-Silva E, Figueiredo A, Botelho MF | title = Targeted alpha therapy using Radium-223: From physics to biological effects | journal = Cancer Treatment Reviews | volume = 68 | pages = 47–54 | date = July 2018 | pmid = 29859504 | doi = 10.1016/j.ctrv.2018.05.011 | s2cid = 44144271 }}</ref>

==Origin and preparation==

Although radium-223 is naturally formed in trace amounts by the [[Decay chain#Actinium series|decay of uranium-235]], it is generally made artificially,<ref name="Revisited">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}}, pp. 195–202. [http://www.bruland.info/PDF/195-202.pdf] {{Webarchive|url=https://web.archive.org/web/20160421060024/http://www.bruland.info/PDF/195-202.pdf |date=21 April 2016 }}</ref> by exposing natural radium-226 to [[neutron]]s to produce radium-227, which decays with a 42-minute half-life to [[actinium-227]]. Actinium-227 (half-life 21.8&nbsp;years) in turn decays via [[thorium-227]] (half-life 18.7&nbsp;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 [[Technetium-99m generator|moly cows]] widely used to prepare the medically important isotope [[technetium-99m]].<ref name="Revisited" />

²²³Ra itself [[alpha decay|decays]] to [[radon-219|²¹⁹Rn]] (half-life 3.96&nbsp;s), a short-lived gaseous [[radon]] isotope, by emitting an [[alpha particle]] of 5.979 [[electronvolt|MeV]].{{AME2016 II|ref|name-list-style = vanc}}

==Medical use==

| drug_name = Radium-223 chloride

| Watchedfields = changed

| verifiedrevid = 477348686

| image =

| alt =

| caption =

<!-- Clinical data -->

| tradename = Xofigo

| Drugs.com = {{Drugs.com|cons|xofigo}}

| MedlinePlus =

| licence_EU = yes

| DailyMedID = Xofigo

| pregnancy_category=

| routes_of_administration = [[Intravenous]]

| ATCvet =

| ATC_prefix = V10

| ATC_suffix = XX03

| legal_AU = S4

| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2014 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 | access-date=10 April 2023}}</ref>

| legal_US = Rx-only

| legal_status =

<!-- Pharmacokinetic data -->

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

| excretion =

<!-- Identifiers -->

| CAS_number = 444811-40-9

| PubChem = 6335825

| ChEBI = 74895

| DrugBank =

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = none

| KEGG = D10398

<!-- Chemical data -->

| molecular_weight = 296.91

| molecular_weight_comment = g/mol

The pharmaceutical product and medical use of radium-223 against skeletal metastases was invented by Roy H. Larsen, Gjermund Henriksen and Øyvind S. Bruland<ref>"Preparation and use of radium-223 to target calcified tissues for pain palliation, bone cancer therapy, and bone surface conditioning" US 6635234</ref> 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 [[Becquerel|kBq]]/kg (1.5 [[Curie (unit)|μCi]]/kg), repeated at 4-week intervals.<ref name="XofigoSPC">{{cite web |title=Xofigo Summary of Product Characteristics |url=https://www.ema.europa.eu/en/documents/product-information/xofigo-epar-product-information_en.pdf |website=European Medicines Authority |publisher=Bayer |access-date=9 October 2019 |date=11 October 2018}}</ref>

=== 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.<ref>{{cite journal | vauthors = Nilsson S, Larsen RH, Fosså SD, Balteskard L, Borch KW, Westlin JE, Salberg G, Bruland OS | display-authors = 6 | title = First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases | journal = Clinical Cancer Research | volume = 11 | issue = 12 | pages = 4451–9 | date = June 2005 | pmid = 15958630 | doi = 10.1158/1078-0432.CCR-04-2244 | s2cid = 72948306 | doi-access = }}</ref> Although radium-223 and its decay products also emit [[beta particle|beta]] and [[gamma radiation]], over 95% of the decay energy is in the form of alpha radiation.<ref>{{cite journal | vauthors = Bruland ØS, Nilsson S, Fisher DR, Larsen RH | title = High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? | journal = Clinical Cancer Research | volume = 12 | issue = 20 Pt 2 | pages = 6250s–6257s | date = October 2006 | pmid = 17062709 | doi = 10.1158/1078-0432.CCR-06-0841 | doi-access = | s2cid = 21171264 }}</ref> 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.<ref>{{cite journal | vauthors = Henriksen G, Fisher DR, Roeske JC, Bruland ØS, Larsen RH | title = Targeting of osseous sites with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice | journal = Journal of Nuclear Medicine | volume = 44 | issue = 2 | pages = 252–9 | date = February 2003 | pmid = 12571218 | url = http://jnm.snmjournals.org/cgi/pmidlookup?view=long&pmid=12571218 }}</ref> Taking account of its preferential uptake by bone and the alpha particles' short range, radium-223 is estimated to give targeted [[Ossification|osteogenic cells]] a radiation dose at least eight times higher than other non-targeted tissues.<ref name="FDA">[http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203971lbl.pdf FDA Access Data on Xofigo (Radium-223 dichloride)]</ref>

=== Clinical trials and FDA and EMA approval ===

The phase II study of radium-223 in [[castration-resistant prostate cancer]] (CRPC) patients with [[Bone metastasis|bone metastases]] showed minimum [[myelotoxicity]] and good tolerance for the treatment.<ref name="Nilsson 2007">{{cite journal | vauthors = Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, Yachnin J, Garkavij M, Strang P, Harmenberg J, Bolstad B, Bruland OS | display-authors = 6 | title = Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study | journal = The Lancet. Oncology | volume = 8 | issue = 7 | pages = 587–94 | date = July 2007 | pmid = 17544845 | doi = 10.1016/S1470-2045(07)70147-X }}</ref>

²²³Ra successfully met the primary endpoint of [[overall survival]] in the [[Phases of clinical research|phase III]] ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer patients) study for bone metastases resulting from CRPC in 922 patients.<ref name=FR2011/>

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&nbsp;months for ²²³Ra and 11.2&nbsp;months for placebo).<ref name=FR2011>[http://prostatecancerinfolink.net/2011/09/26/full-data-report-from-the-alsympca-trial-of-radium-223-presented/ Full data report from the ALSYMPCA trial of radium-223 presented]</ref> Earlier phase II of the trial showed a median increased survival of 18.9 weeks (around 4.4 months).<ref name="Nilsson 2007" /> The lower figure of 2.8 months increased survival in interim phase III results is a probable result of stopping the trial; median survival time for patients still alive could not be calculated. A 2014 update indicates a median increased survival of 3.6 months.<ref name="Parker et al 2013">{{cite journal | vauthors = Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wichno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzén L, Coleman R, Volgelzang NJ, O'Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland ØS, Sartor O | display-authors = 6 | title = Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer | journal = New England Journal of Medicine | volume = 369 | issue = 3 | pages = 213–223 | date = 18 July 2013 | pmid = 23863050 | doi = 10.1056/NEJMoa1213755| doi-access = free }}</ref>

In May 2013, ²²³Ra received marketing approval from the U.S. [[Food and Drug Administration]] (FDA)<ref name=FBT-FDA2013>{{Cite web |title=FDA OKs pinpoint prostate cancer radiation drug Xofigo from Bayer, Algeta |url=http://www.fiercebiotech.com/story/breaking-fda-oks-pinpoint-prostate-cancer-radiation-drug-xofigo-bayer-alget/2013-05-15 |archive-url=https://web.archive.org/web/20140122022947/http://www.fiercebiotech.com/story/breaking-fda-oks-pinpoint-prostate-cancer-radiation-drug-xofigo-bayer-alget/2013-05-15 |archive-date=22 January 2014 |url-status=dead |access-date=15 May 2013 }}</ref> 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.<ref>{{Cite web | url=https://www.thepharmaletter.com/article/fast-fda-approval-for-bayer-s-new-drug-for-advanced-prostate-cancer-xofigo|title=Fast FDA approval for Bayer's new drug for advanced prostate cancer, Xofigo |date=16 May 2013 | website=The Pharma Letter}}</ref>

This study also led to approval in the [[European Union]] on 19 September 2013<ref>{{Cite web| url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002653/human_med_001692.jsp&mid=WC0b01ac058001d124| title=Xofigo| date=2018-09-17| access-date=3 September 2015| archive-date=19 August 2018| archive-url=https://web.archive.org/web/20180819182318/http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002653/human_med_001692.jsp&mid=WC0b01ac058001d124| url-status=dead}}</ref> 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.<ref>{{Cite web|url=https://www.ema.europa.eu/en/medicines/human/referrals/xofigo|title=EMA restricts use of prostate cancer medicine Xofigo |date=28 September 2018|website=European Medicines Agency}}</ref>

²²³Ra also showed promising preliminary results in a phase IIa trial enrolling 23 women with bone metastases resulting from [[breast cancer]] that no longer responds to [[Hormonal therapy (oncology)|endocrine therapy]].<ref name="Coleman et al 2014">{{cite journal | vauthors = Coleman R, Aksnes AK, Naume B, Garcia C, Jerusalem G, Piccart M, Vobecky N, Thuresson M, Flamen P | display-authors = 6 | title = A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease | journal = Breast Cancer Research and Treatment | volume = 145 | issue = 2 | pages = 411–418 | date = June 2014 | pmid = 24728613 | pmc = 4025174 | doi = 10.1007/s10549-014-2939-1 | doi-access = free }}</ref> ²²³Ra treatment reduced the levels of bone [[alkaline phosphatase]] (bALP) and urine [[N-terminal telopeptide|N-telopeptide]] (uNTX), key markers of bone turnover associated with bone metastases in breast cancer, diminished bone pain slightly though consistently, and was well tolerated. Another single-arm, open-label Phase II trial reported possible efficacy of ²²³Ra combined with [[Hormonal therapy (oncology)|endocrine therapy]] in hormone-receptor-positive, bone-dominant breast cancer metastasis.<ref name="Ueno et al 2020">{{cite journal | vauthors = Ueno NT, Tahara RK, Fujii T, Reuben JM, Gao H, Saigal B, Lucci A, Iwase T, Ibrahim NK, Damodaran S, Shen Y, Liu DD, Hortobagyi GN, Tripathy D, Lim B, Chasen BA | display-authors = 6 | title = Phase II study of Radium-223 dichloride combined with hormonal therapy for hormone receptor-positive, bone-dominant metastatic breast cancer | journal = Cancer Medicine | volume = 9 | issue = 3 | pages = 1025–1032 | date = February 2020 | pmid = 31849202 | pmc = 6997080 | doi = 10.1002/cam4.2780 | doi-access = free }}</ref>

===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]].<ref name=FDA2013-05>{{Cite web|title=FDA approves new drug for advanced prostate cancer |publisher=US FDA |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm352363.htm |archive-url=https://web.archive.org/web/20130607062951/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm352363.htm |archive-date=2013-06-07 |url-status=live }}</ref>

===Other radium-223-based compounds===

Although radium does not easily form stable molecular complexes,<ref>{{cite journal | vauthors = Henriksen G, Hoff P, Larsen RH | title = Evaluation of potential chelating agents for radium | journal = Applied Radiation and Isotopes | volume = 56 | issue = 5 | pages = 667–71 | date = May 2002 | pmid = 11993940 | doi = 10.1016/s0969-8043(01)00282-2 | bibcode = 2002AppRI..56..667H }}</ref> data has been presented on methods to increase and customize its specificity for particular cancers by linking it to [[monoclonal antibodies]], by enclosing the ²²³Ra in [[liposome]]s bearing the antibodies on their surface.<ref>{{cite journal | vauthors = Henriksen G, Schoultz BW, Michaelsen TE, Bruland ØS, Larsen RH | title = Sterically stabilized liposomes as a carrier for alpha-emitting radium and actinium radionuclides | journal = Nuclear Medicine and Biology | volume = 31 | issue = 4 | pages = 441–9 | date = May 2004 | pmid = 15093814 | doi = 10.1016/j.nucmedbio.2003.11.004 }}</ref>

== See also ==

* [[Actinium-225]]

* [[Decay chain#Actinium series|Actinium series]]

* [[Bismuth-213]]

* [[Isotopes of radium]]

* [[Radium chloride]]

== References ==

{{reflist}}

== External links ==

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/radium-223 | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Radium-223 }}

* {{Cite press release |title=FDA approves new drug for advanced prostate cancer |publisher=US FDA |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm352363.htm |archive-url=https://web.archive.org/web/20130604012752/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm352363.htm |archive-date=4 June 2013 |url-status=dead |access-date=16 December 2019 }}

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