Radium-223

Radium-223 Full table
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, 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.

Medical use

Radium-223 chloride

Systematic (IUPAC) name
Radium-223 chloride
Clinical data
Trade names	Xofigo
AHFS/Drugs.com	entry
Pregnancy category	US: X (Contraindicated)
Legal status	US: ℞-only (experimental in most countries)
Routes of administration	injection
Identifiers
CAS Number	444811-40-9 N
ATC code	V10XX03 (WHO)
UNII	RJ00KV3VTG Y
ChEBI	CHEBI:74895
Chemical data
Formula	223RaCl2
Molecular mass	296.91 g/mol
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The pharmaceutical product and medical use of radium-223 against skeletal metastases was invented by Roy H. Larsen, Gjermund Henriksen and Øyvind S. Bruland 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 (1000 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 50 kBq/kg (1.3 uCi per kg), repeated at 4-week intervals.

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. 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. 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. 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

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.

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.

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). 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) 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.

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

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.

Other radium-223-based compounds

Although radium does not easily form stable molecular complexes, 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.

See also

• Radium chloride

External links

• US National Institute of Health information an Alpharadin
• Algeta's information about Xofigo
• Alpharadin phase III study participation
• Alpharadin information from researcher Professor Oyvind S. Bruland