Radium-223 (
223Ra, Ra-223) is an
isotope
Isotopes are two or more types of atoms that have the same atomic number (number of protons in their nuclei) and position in the periodic table (and hence belong to the same chemical element), and that differ in nucleon numbers (mass numbers) ...
of
radium
Radium is a chemical element with the symbol Ra and atomic number 88. It is the sixth element in group 2 of the periodic table, also known as the alkaline earth metals. Pure radium is silvery-white, but it readily reacts with nitrogen (rather t ...
with an 11.4-day
half-life
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...
. It was discovered in 1905 by T. Godlewski,
a Polish chemist from
Kraków
Kraków (), or Cracow, is the second-largest and one of the oldest cities in Poland. Situated on the Vistula River in Lesser Poland Voivodeship, the city dates back to the seventh century. Kraków was the official capital of Poland until 1596 ...
, and was historically known as
actinium X (AcX).
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
Radiopharmaceuticals, or medicinal radiocompounds, are a group of pharmaceutical drugs containing radioactive isotopes. Radiopharmaceuticals can be used as diagnostic and therapeutic agents. Radiopharmaceuticals emit radiation themselves, which is ...
to treat
metastatic
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
cancers in
bone
A bone is a Stiffness, rigid Organ (biology), organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red blood cell, red and white blood cells, store minerals, provid ...
, takes advantage of its chemical similarity to
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
, and the short range of the
alpha radiation
Alpha decay or α-decay is a type of radioactive decay in which an atomic nucleus emits an alpha particle (helium nucleus) and thereby transforms or 'decays' into a different atomic nucleus, with a mass number that is reduced by four and an atom ...
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,
[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. , pp. 195–202]
by exposing natural radium-226 to
neutron
The neutron is a subatomic particle, symbol or , which has a neutral (not positive or negative) charge, and a mass slightly greater than that of a proton. Protons and neutrons constitute the nuclei of atoms. Since protons and neutrons beh ...
s to produce radium-227, which decays with a 42-minute half-life to
actinium-227
Actinium (89Ac) has no stable isotopes and no characteristic terrestrial isotopic composition, thus a standard atomic weight cannot be given. There are 33 known isotopes, from 204Ac to 236Ac, and 7 isomers. Three isotopes are found in nature, 225 ...
. Actinium-227 (half-life 21.8 years) in turn decays via
thorium-227
Thorium (90Th) has seven naturally occurring isotopes but none are stable. One isotope, 232Th, is ''relatively'' stable, with a half-life of 1.405×1010 years, considerably longer than the age of the Earth, and even slightly longer than the gene ...
(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
Technetium-99m (99mTc) is a metastable nuclear isomer of technetium-99 (itself an isotope of technetium), symbolized as 99mTc, that is used in tens of millions of medical diagnostic procedures annually, making it the most commonly used medical ra ...
.
223Ra itself
decays to
219Rn (half-life 3.96 s), a short-lived gaseous
radon
Radon is a chemical element with the symbol Rn and atomic number 86. It is a radioactive, colourless, odourless, tasteless noble gas. It occurs naturally in minute quantities as an intermediate step in the normal radioactive decay chains through ...
isotope, by emitting an
alpha particle
Alpha particles, also called alpha rays or alpha radiation, consist of two protons and two neutrons bound together into a particle identical to a helium-4 nucleus. They are generally produced in the process of alpha decay, but may also be produce ...
of 5.979
MeV
In physics, an electronvolt (symbol eV, also written electron-volt and electron volt) is the measure of an amount of kinetic energy gained by a single electron accelerating from rest through an Voltage, electric potential difference of one volt i ...
.
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
Algeta ASAALGETA:NO was founded in 1997 by Roy H. Larsen and Øyvind S. Bruland in Oslo, Norway as a private biotechnology and pharmaceutical company. The company’s research and development focus lies in the field of alpha-particle emitting ra ...
ASA, in a partnership with
Bayer
Bayer AG (, commonly pronounced ; ) is a German multinational corporation, multinational pharmaceutical and biotechnology company and one of the largest pharmaceutical companies in the world. Headquartered in Leverkusen, Bayer's areas of busi ...
, 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.
Mechanism of action
The use of radium-223 to treat metastatic bone cancer relies on the ability of
alpha radiation
Alpha decay or α-decay is a type of radioactive decay in which an atomic nucleus emits an alpha particle (helium nucleus) and thereby transforms or 'decays' into a different atomic nucleus, with a mass number that is reduced by four and an atom ...
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
Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Modern Greek, it represents the voiced labiod ...
and
gamma radiation
A gamma ray, also known as gamma radiation (symbol γ or \gamma), is a penetrating form of electromagnetic radiation arising from the radioactive decay of atomic nuclei. It consists of the shortest wavelength electromagnetic waves, typically s ...
, 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
Strontium-89 () is a radioactive isotope of strontium produced by nuclear fission, with a half-life of 50.57 days. It undergoes β− decay into yttrium-89. Strontium-89 has an application in medicine.
History
It was used for the first time b ...
, 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.
[FDA Access Data on Xofigo (Radium-223 dichloride)](_blank)
/ref>
Clinical trials and FDA and EMA approval
The phase II study of radium-223 in castration-resistant prostate cancer
Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that surr ...
(CRPC) patients with bone metastases
Bone metastasis, or osseous metastatic disease, is a category of cancer metastases that results from primary tumor invasion to bone. Bone-originating primary tumors such as osteosarcoma, chondrosarcoma, and Ewing's sarcoma are rare; the most common ...
showed minimum myelotoxicity
Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (t ...
and good tolerance for the treatment.
223Ra successfully met the primary endpoint of overall survival
Survival rate is a part of survival analysis. It is the proportion of people in a study or treatment group still alive at a given period of time after diagnosis. It is a method of describing prognosis in certain disease conditions, and can be use ...
in the phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer patients) 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 (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).][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). 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.
In May 2013, 223Ra received marketing approval from the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) 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
The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been des ...
on 19 September 2013 The European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
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
Abiraterone acetate, sold under the brand name Zytiga among others, is a medication used to treat prostate cancer. Specifically it is used together with a corticosteroid for metastatic castration-resistant prostate cancer (mCRPC) and metastatic ...
, 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 enrolling 23 women with bone metastases resulting from breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
that no longer responds to endocrine therapy. 223Ra treatment reduced the levels of bone alkaline phosphatase
The enzyme alkaline phosphatase (EC 3.1.3.1, alkaline phosphomonoesterase; phosphomonoesterase; glycerophosphatase; alkaline phosphohydrolase; alkaline phenyl phosphatase; orthophosphoric-monoester phosphohydrolase (alkaline optimum), systematic ...
(bALP) and urine 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 endocrine therapy in hormone-receptor-positive, bone-dominant breast cancer metastasis.
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
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
, lymphocytopenia
Lymphocytopenia is the condition of having an abnormally low level of lymphocytes in the blood. Lymphocytes are a white blood cell with important functions in the immune system. It is also called lymphopenia. The opposite is lymphocytosis, which ...
, leukopenia
Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...
, thrombocytopenia
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
and neutropenia
Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
.
Other radium-223-based compounds
Although radium does not easily form stable molecular complexes, data has been presented on methods to increase and customize its specificity for particular cancers by linking it to monoclonal antibodies
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ca ...
, by enclosing the 223Ra in liposome
A liposome is a small artificial vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, liposomes can be used as drug deliver ...
s bearing the antibodies on their surface.
See also
* Actinium-225
Actinium-225 (225Ac, Ac-225) is an isotope of actinium. It undergoes alpha decay to francium-221 with a half-life of 10 days, and is an intermediate decay product in the neptunium series (the decay chain starting at 237Np). Except for minuscu ...
* Actinium series
In nuclear science, the decay chain refers to a series of radioactive decays of different radioactive decay products as a sequential series of transformations. It is also known as a "radioactive cascade". Most radioisotopes do not decay directly ...
* Bismuth-213
Bismuth (83Bi) has 41 known isotopes, ranging from 184Bi to 224Bi. Bismuth has no stable isotopes, but does have one very long-lived isotope; thus, the standard atomic weight can be given as . Although bismuth-209 is now known to be unstable, it ...
* Isotopes of radium
Radium (88Ra) has no stable or nearly stable isotopes, and thus a standard atomic weight cannot be given. The longest lived, and most common, isotope of radium is 226Ra with a half-life of . 226Ra occurs in the decay chain of 238U (often referre ...
* Radium chloride
Radium chloride (RaCl2) is a salt of radium and chlorine, and the first radium compound isolated in a pure state. Marie Curie and André-Louis Debierne used it in their original separation of radium from barium. The first preparation of radium met ...
References
External links
*
*
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