Radium-223 dichloride, trade name Xofigo, is a radiopharmaceutical approved for the treatment of patients with symptomatic bone metastases and no visceral disease from prostate cancer resistant to anti androgen therapy. The molecule mimics calcium and forms a complex with hydroxyapatite at sites of increased bone turnover. High energy alpha particles induce cell death by causing double stranded DNA breaks. The destruction of osteoblasts and osteoclasts at the tumor site potentially disrupts signaling pathways that promote tumor growth, and the release of cellular contents also possibly promotes native immune response.
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Characteristics
Ra-223 has a half-life of 11.4 days
alpha decay with 95.3% of energy emitted as alpha particles, smaller amounts as beta particles and gamma rays (energy range of 0.01 - 1.27 MeV)
alpha particle maximum penetration of 100 micrometers (10 cell diameters) allows for targeted cytotoxic activity with limited effect on surrounding normal tissue
Use
Before treatment, diagnostic imaging is performed using CT and nuclear medicine bone scans to correlate tumor with sites of pain.
Patients undergoing this therapy undergo laboratory testing before each treatment. Required baseline lab values before undergoing the first treatment are an absolute neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Between Xofigo treatments, the absolute neutrophil count should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. Supportive care (tranfusions) may be given between treatments. However, if serum lab values do not recover, it is recommended that treatment be discontinued.
Xofigo is administered intravenously at a dose of 55 kBq (1.49 microcurie) per kilogram of patient body weight for 6 doses at 4-week intervals.
Xofigo is primarily distributed into bone, where it is incorporated into the bone matrix, with a smaller amount excreted through the gastrointestinal system.
Potential side effects
myelosuppression – anemia, thrombocytopenia, leukopenia
increased fractures when concurrently administered with abiraterone and steroids (not recommended for patients on this regimen)
nausea, vomiting, diarrhea
possible adverse effects on the reproductive system and embryonic toxicity
Of note, this therapy has not been tested in female patients.
History
The phase III ALSYMPCA (ALpharadin in SYMPtomatic Prostate CAncer) randomized controlled trial demonstrated improved overall survival (median of 11.2 months with standard of care versus 14.0 months with radium-223 dichloride in addition) and improved time to first symptomatic skeletal event.
The REASSURE ((Radium-223 alpha Emitter Agent in Safety Study in mCRPC popUlation for long-teRm Evaluation) trial is a long-term multinational observational study that focuses on the side effects of Radium-223 treatment including secondary primary malignancies as well as overall survival, pain, and fracture incidence. Results thus far (as of August 2023) show that 35% of patients had drug-related adverse events, 1% of which resulted in death. Adverse events included sequela of myelosuppression, most commonly anemia. Disease progression remained the main cause of death in these patients, highlighting the role of Radium-223 as a symptomatic and not curative therapy. 50% of patients reported a numerical improvement in pain after treatment. Final outcomes are expected in 2024.
The ERA 223 trial investigated the effects of concurrent use of Radium-223 and prednisone plus abiraterone acetate and found an increased fracture rate (29% versus 11% in the placebo group) and no statistically significant improvement in survival. The results of this trial led to a warning from the FDA and European Medicines Agency against this combined treatment regimen.
Radium-223 dichloride was FDA-approved in May 2013 for the treatment of patients with symptomatic bone metastases secondary to castration resistant metastatic prostate cancer. In addition, patients must not have visceral metastases.
Xofigo, previously known as Alpharadin, was developed by Algeta ASA. Algeta was acquired by Bayer in 2013. It is manufactured by Bayer HealthCare Pharmaceuticals Incorporated (Bayer Aktiengesellschaft).
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