Radium-223

Radium-223
General
Name, symbol Radium-223,223Ra
Neutrons 135
Protons 88
Nuclide data
Half-life 11.43 ± 0.05 d
Isotope mass 223.0185022(27) u

Radium-223 (Ra-223, 223Ra) 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 1601-year half-life. 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.

Origin and preparation

Although radium-223 is formed naturally in trace amounts by the decay of uranium-235, it is generally made artificially,[1] 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.[1]

Medical use

Radium-223 chloride
Clinical data
Trade names Xofigo
AHFS/Drugs.com xofigo
Pregnancy
category
  • US: X (Contraindicated)
Routes of
administration		 injection
ATC code V10XX03 (WHO)
Legal status
Legal status
  • US: ℞-only
  • (experimental in most countries)
Identifiers
CAS Number 444811-40-9 N
ChemSpider none
UNII RJ00KV3VTG YesY
ChEBI CHEBI:74895
Chemical and physical data
Formula 223RaCl2
Molar mass 296.91 g/mol
 NYesY (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 [2] 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 (1.3 uCi per kg), repeated at 4-week intervals.[3]

Mechanism of action

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.[4] 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.[5] Alpha radiation has very short range in tissues, around 2-10 cells, compared to beta or gamma radiation. 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.[6] 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 8 fold higher than other non-targeted tissues[3]

Clinical trials and FDA approval

The phase II study of radium-223 in CRPC patients with bone metastases showed minimum myelotoxicity and good tolerance for the treatment.[7]

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 castration-resistant prostate cancer (CRPC) in 922 patients.[8]

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).[8] Earlier phase II of the trial showed 4.5 months increased survival.(Mean or median ) The lower figure of 2.8 months increased survival in phase III, is a probable result of stopping the trail. Survival time for the patients still alive could not be calculated.

In May 2013, 223Ra received marketing approval by the U.S. Food and Drug Administration (FDA)[9] as a treatment for castration-resistant prostate cancer (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.[10]

This study also led to approval in the EU on Sep. 19, 2013[11]

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.[12]

Other radium-223-based compounds

Although radium does not easily form stable molecular complexes,[13] 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.[14]

See also

References

  1. 1 2 Bruland OS, Larsen RH. Radium revisited. In: Bruland OS, Flgstad T, editors. Targeted cancer therapies: an odyssey. University Library of Tromso, Ravnetrykk No. 29. ISBN 82-91378-32-0 (2003); p 195-202
  2. ↑ "Preparation and use of radium-223 to target calcified tissues for pain palliation, bone cancer therapy, and bone surface conditioning" US 6635234 http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=Radium-223.TI.&s2=%22skeletal+metastases%22&OS=TTL/Radium-223+AND+
  3. 1 2 FDA Access Data on Xofigo (Radium-223 dichloride)
  4. ↑ Nilsson, S.; Larsen, R. H.; Fosså, S. D.; Balteskard, L; Borch, K. W.; Westlin, J. E.; Salberg, G; Bruland, O. S. (2005). "First Clinical Experience with -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.
  5. ↑ Bruland, O. S.; Nilsson, S.; Fisher, D. R.; Larsen, R. H. (2006). "High-Linear Energy Transfer Irradiation Targeted to Skeletal Metastases by the α-Emitter 223Ra: Adjuvant or Alternative to Conventional Modalities?". Clinical Cancer Research. 12 (20): 6250s–6257s. doi:10.1158/1078-0432.CCR-06-0841. PMID 17062709.
  6. ↑ Henriksen, Gjermund; Fisher, Darrell R.; Roeske, John C.; Bruland, Øyvind S.; Larsen, Roy H. (2003). "Targeting of Osseous Sites with α-Emitting 223Ra: Comparison with the β-Emitter 89Sr in Mice". Journal of Nuclear Medicine. 44 (2): 252–9. PMID 12571218.
  7. ↑ Nilsson, Sten; Franzén, Lars; Parker, Christopher; Tyrrell, Christopher; Blom, René; Tennvall, Jan; Lennernäs, Bo; Petersson, Ulf; Johannessen, Dag C; Sokal, Michael; Pigott, Katharine; Yachnin, Jeffrey; Garkavij, Michael; Strang, Peter; Harmenberg, Johan; Bolstad, Bjørg; Bruland, Øyvind S (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.
  8. 1 2 Full data report from the ALSYMPCA trial of radium-223 presented
  9. ↑ "FDA OKs pinpoint prostate cancer radiation drug Xofigo from Bayer, Algeta". Archived from the original on 2013-05-15.
  10. ↑ http://www.cancer.org/cancer/news/news/fda-approves-xofigo-for-advanced-prostate-cancer[]
  11. ↑ http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002653/human_med_001692.jsp&mid=WC0b01ac058001d124
  12. ↑ "FDA approves new drug for advanced prostate cancer". US FDA. Archived from the original on 2013-05-15.
  13. ↑ Henriksen, G; Hoff, P; Larsen, R. H. (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.
  14. ↑ Henriksen, Gjermund; Schoultz, B.W.; Michaelsen, T.E.; Bruland, Ø.S.; Larsen, R.H. (2004). "Sterically stabilized liposomes as a carrier for α-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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