Overview
Radium 223 was approved by the FDA in 2013 for treating males with metastatic castrate-resistant prostate cancer following a phase III randomized study demonstrating an increase in the overall survival rates. It is a therapeutic alpha-emitting radiopharmaceutical that preferentially binds to sites of enhanced bone turnover in bone metastases and gives high linear energy transfer with a short range (less than 100 µm or 2 to 10 cell diameters). This calcium-mimicking targets recently formed bone stroma in the milieu of osteoblastic or sclerotic metastases. High-energy alpha-particle radiation produces breakage of the double-stranded DNA, resulting in a powerful, highly localized cytotoxic impact in the target locations. Due to the short route of the alpha particles, harmful effects on nearby healthy tissue, notably bone marrow, may be reduced.
Uses of Radium-223 Dichloride:
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Radium-223 dichloride is used to treat individuals who have advanced castration-resistant prostate cancer that has progressed even after two prior cancer therapies, excluding treatments to maintain low male hormone levels (hormone therapy) or who cannot take any other cancer treatment.
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Castration-resistant prostate cancer is a kind of prostate cancer (a gland in the male reproductive system) that does not respond to hormone-reduction therapy.
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Radium-223 dichloride is only used when the illness has progressed to the bone but not other internal organs and is generating symptoms.
Dosage and Administration:
Recommended Dosage: Radium-233 dichloride is administered at four-week intervals at 50 kBq (kilo becquerel) per kg body weight for six injections.
Dosage Forms and Strengths: Radium-223 dichloride injection is available in single-use vials containing 6 mL of solution with a total radioactivity of 6,000 kBq/vial (162 microcurie/vial) at the reference date.
Dosage Calculations:
The volume to be given should be estimated using the:
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Body weight of the patient (kg).
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The dosage level is 50 kBq per kg body weight or 1.35 microcurie per kg.
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Radioactivity concentration of the injection (1,000 kBq/mL; 27 microcurie/mL) on the reference date.
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Radium-223 physical decay can be rectified using the decay correction factor.
The total volume to be administered to a patient is calculated as follows:
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Volume to be administered (mL) = Body weight in kg × 50 kBq per kg body weight / Decay factor × 1,000 kBq/mL.
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Volume to be administered (mL) = Body weight in kg × 1.35 microcurie per kg body weight / Decay factor × 27 microcurie/mL.
Administration: Radium-233 dichloride can be injected as a slow intravenous injection over one minute.
Contraindications: Radium-233 dichloride is not used in pregnancy because it can cause deleterious effects on the fetus according to the mechanism of action.
Warnings and Precautions:
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Bone Marrow Suppression: Assess blood counts before initiating treatment and before each dose of Radium-233 dichloride. If blood tests do not increase after six to eight weeks of therapy, discontinue Radium-233 dichloride. Patients with poor bone marrow reserve should be continuously monitored. In patients with life-threatening problems, discontinue the treatment even after supportive care.
Use in Specific Populations:
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Pediatric Use: The safety and effectiveness of Radium-233 dichloride in pediatric patients have yet to be completely assessed.
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Geriatric Use: There is no need to adjust the dose in elderly patients.
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Patients with Hepatic Impairment: Hepatic impairment is unlikely to alter the pharmacokinetics of Radium-223 dichloride since it is neither processed by the liver nor excreted by the bile. According to randomized clinical studies, dose modification is not required in individuals with hepatic impairment.
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Patients with Renal Impairment: No dosage modification is required in individuals with renal impairment. Considering urinary excretion is limited, and the primary route of elimination is through the feces, renal impairment is unlikely to alter the pharmacokinetics of radium-223 dichloride.
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Males of Reproductive Potential:
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Contraception: Due to the obvious effects of radiation on spermatogenesis, instruct sexually active males to use condoms and their female partners of reproductive potential to use a highly efficient contraceptive technique during and also for six months after completing the chemotherapy.
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Fertility: There is a chance that Radium-233 dichloride radiation will impair fertility. Please consult with the doctor, especially if the patient wants to have children in the future. Before beginning therapy, patients are advised to obtain guidance on preserving the sperm.
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For Patients:
What Is Prostate Cancer?
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Prostate carcinoma is the third most common disease diagnosed in Europe and the fifth major cause of cancer deaths globally among men.
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Treatment targeted at eliminating the primary tumor mostly with surgery or radiation is ineffective in around one-third of men who develop recurrent cancer that eventually spreads to distant areas.
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Around 10 percent to 20 percent of males with prostate cancer will have an untreatable advanced or metastatic condition.
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Patients with metastatic cancers are often treated with androgen suppression treatment using bilateral orchiectomy or, more frequently, luteinizing hormone-releasing hormone agonist or antagonist treatment, which often results in total tumor regression.
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Unfortunately, these regressions are usually temporary, with eventual tumor reappearance as castration-resistant cancer, which is always deadly. Nowadays, the average survival time for individuals with metastatic castration-resistant prostate cancer (mCRPC) is two years.
What Is Radium-233 Dichloride?
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Radium-233 dichloride is a radioactive substance resembling calcium in the bones. When radium-223 is administered to a patient, it travels to the bone where the disease has metastasized and releases short-range radiation (alpha particles), which destroys the surrounding tumor cells.
What Are the Things to Know Before Injecting Radium -233 Dichloride?
Radium-233 dichloride should not be given in combination with Abiraterone and Prednisolone due to the increased risk of bone fractures and death.
Warnings and Precautions:
If the patient needs to take Radium-233 dichloride after treatment with Abiraterone and Prednisolone, then the patient must wait five days before initiating the treatment. If the patient needs to take other chemotherapy after Radium-233 dichloride, then the patient has to wait for a minimum of 30 days before initiating the therapy. If the patient takes calcium, phosphate, or vitamin D supplements, the doctor will temporarily stop taking this medication before starting the treatment.
What Are the Possible Side Effects?
Just like most other medications, this medication also causes some adverse effects. The most severe side effects include:
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A reduction in the total blood platelets (thrombocytopenia).
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A decrease in the number of neutrophils, which are white blood cells (neutropenia, which may result in a greater risk of infection). Contact the doctor as early as possible if the patient develops any following symptoms, which might indicate thrombocytopenia or neutropenia.
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Any abnormal bruises.
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Excessive bleeding than following normal injury.
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Fever.
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If the patient notices getting affected by a lot of infections.
The following are the most prevalent adverse effects extremely common (one in ten people gets affected):
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Diarrhea, nausea (feeling unwell), vomiting, thrombocytopenia (low blood platelet count), and fracture of bones.
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Dehydration Risk: Dizziness, excessive thirst, reduced urine, or dry skin since these are all signs of dehydration. It is necessary to stay hydrated by consuming enough fluids. Inform the doctor immediately if the patient experiences any signs of dehydration.
Other Potential Adverse Effects Are
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Common (One in Ten People Are Affected):
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A reduction in red and white blood cells and blood platelets (pancytopenia).
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Reactions at the injection location (for example, redness of the skin (erythema), pain, and swelling).
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Uncommon (One in Hundred People Are Affected):
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A reduction in the number of lymphocytes, which are white blood cells (lymphopenia).
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Bone weakness (osteoporosis).
Please consult the doctor if the patient experiences pain, swelling, tingling, or loss of sensation in the jaw, a "heavy jaw sensation," or tooth loosening. People on Radium-233 dichloride have developed osteonecrosis of the jaw (dead tissue in the jaw bone, which is commonly observed in patients taking bisphosphonates). All these occurrences occurred exclusively in patients with bisphosphonates before or simultaneously with Radium-233 dichloride and chemotherapy before starting treatment.
For Doctors:
What Is Radium-233 Dichloride?
Radium Ra 223 dichloride is a radiotherapeutic medication that emits alpha particles. It is provided as a clear, colorless, isotonic, and sterile intravenous solution with a pH between six and eight. Each milliliter of solution contains 1,000 kBq Radium-223 dichlorides (27 microcuries), equating to 0.53 ng Radium-223. Radium exists in solution as a free divalent cation.
Each vial contains 6 mL of solution contains 6,000 kBq Radium-223 dichloride(162 microcuries), 6.3 mg/mL sodium chloride (tonicity agent), 7.2 mg/mL sodium citrate (for pH adjustment), 0.2 mg/mL hydrochloric acid (for pH adjustment), and water for injection are the inactive components.
Radium-223 dichloride has a molecular weight of 293.9 g/mol. The half-life of radium-223 is 11.4 days. Radium-223 has a specific activity of 1.9 MBq (51.4 microcuries)/ng.
Radium-223 decays in six stages to stable lead-207 through short-lived daughters, followed mostly by alpha emissions. There are also beta and gamma emissions with varying energy and probability of emission. Radium-223 and its offspring emit 95.3 percent of their energy as alpha-particles (energy range of 5 - 7.5 MeV). The percentage emitted as beta particles is 3.6 percent (average energies of 0.445 and 0.492 MeV), whereas the fraction emitted as gamma radiation is 1.1 percent (energy range of 0.01 - 1.27 MeV).
Clinical Pharmacology:
Mechanism of Action: The alpha particle-emitting radium-223 isotope (as radium Ra 223 dichloride) is the active moiety that resembles calcium and creates complexes with the bone mineral hydroxyapatite in sites of accelerated bone turnover, such as bone metastases. Alpha emitters having high linear energy (80 keV per micrometer) cause a high frequency of double-strand DNA breakage in neighboring cells, leading to an anti-tumor effect on bone metastases. Radium-223 dichloride's alpha particle range is less than 100 micrometers (less than ten cell diameters), limiting harm to nearby normal tissue.
Pharmacodynamics: All five serum biomarkers for bone turnover were studied during the second phase randomized study (bone formation markers: bone alkaline phosphatase [ALP], total ALP, and procollagen I N propeptide [PINP], bone resorption markers: C-terminal crosslinking telopeptide of type I collagen [S-CTX-I] and type I collagen crosslinked C-telopeptide) showed a significant difference in favor of Radium-233 dichloride.
Pharmacokinetics: The pharmacokinetics of radium-223 dichloride in blood were linear in terms of dose ratio and time independence in dosage range evaluation.
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Distribution: Radium-223 is quickly eliminated from the blood after intravenous administration and is transported largely to bone or excreted. About twenty percent of the administered radioactivity remained in the blood fifteen minutes after injection. Four percent remained in the blood after four hours, decreasing to less than one percent after one day. Radioactivity was detected in the bone and gut ten minutes after injection.
The percentage of radioactive dosage that remained in bone and gut after hours post-injection was around 61 percent and 49 percent, respectively. Other organs, such as the heart, liver, kidneys, urinary bladder, and spleen, showed no significant absorption after four hours of injection.
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Metabolism: Radium-223 is an isotope that decays and does not get metabolized.
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Elimination: According to whole-body measures, roughly 63 percent of the injected radioactivity was eliminated from the body after seven days following injection. The primary method of elimination from the body is through fecal excretion. The overall fecal excretion was 13 percent (range 0 to 34 percent), while the total urine excretion was 2 percent (range 1 to 5 percent) 48 hours after injection. Based on imaging data, there was no evidence of hepatobiliary excretion.
The substantial variation in intestinal transit rates throughout the population influences the rate of clearance of Radium-223 dichloride from the gastrointestinal system. Patients having a slower intestinal transit rate may be exposed to more intestinal radiation. It is unclear if this may enhance gastrointestinal toxicity.
Nonclinical Toxicology:
Carcinogenesis, Mutagenesis, Impairment of Fertility
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There are no animal studies done to assess the carcinogenic effects of Radium-223 dichloride. Moreover, osteosarcomas, an established consequence of bone-seeking radionuclides, were detected at clinically relevant doses 7 to 12 months after the initiation of therapy in rat repeat-dose toxicity tests. Other neoplastic alterations, such as lymphoma and mammary gland cancer, were also seen in rats' 12 to 15-month repeat-dose toxicity tests.
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There are no genetic toxicity investigations using Radium-223 dichloride. The mode of action of Radium-223 dichloride, on the other hand, includes the initiation of double-strand DNA breakage, which is a recognized effect of radiation.
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According to its method of action, Radium-223 dichloride may affect fertility and reproductive function in humans. But there are no animal studies to assess the effects of Radium-223 dichloride on male or female fertility or reproductive potential.
