Radium-223 was discovered in 1905 by T. Godlewski, a Polish chemist from Kraków, and is historically known as actinium X, or AcX. 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. 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 naturally formed 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 in turn decays via thorium-227 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. 223Ra itself decays to 219Rn, a short-lived gaseous radon isotope, by emitting an alpha particle of 5.979 MeV.
Medical use
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 nameXofigo, and is distributed as a solution containing radium-223 chloride, 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, 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 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. 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.
Clinical trials and FDA and EMA approval
The phase II study of radium-223 in castration-resistant prostate cancer 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 study for bone metastases resulting from 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. 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 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. This study also led to approval in the European Union on September 19, 2013 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. 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 and urine N-telopeptide, key markers of bone turnover associated with bone metastases in breast cancer.
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.
