Radium-223 Chloride: Extending Life in Prostate Cancer Patients by Treating Bone Metastases

Abstract

The treatment scope for patients with metastatic castrate-resistant prostate cancer (mCRPC) is rapidly expanding. On May 15, 2013, the U.S. Food and Drug Administration (FDA) approved radium-223 chloride ( 223 RaCl 2 ) for the treatment of mCRPC patients whose metastases are limited to the bones. Radium-223is an a-emitting alkaline earth metal ion, which, similar to calcium ions, accumulates in the bone. In a phase III study (ALSYMPCA), mCRPC patients with bone metastases received best standard-of-care treatment with placebo or 223 RaCl 2 . At a prespecified interim analysis, the primary endpoint of median overall survival was significantly extended by 3.6 months in patients treated with radium-223 compared with placebo (P < 0.001). The radioisotope was well tolerated and gave limited bone marrow suppression. 223 RaCl 2 is the first bone-targeting antitumor therapy that received FDA approval based on a significant extended median overall survival. Further studies are required to optimize its dosing and to confirm its efficacy and safety in cancer patients.

One-Year Postapproval Clinical Experience with Radium-223 Dichloride in Patients with Metastatic Castrate-Resistant Prostate Cancer

“…[16][17][18][19][20][21] The overall survival benefit, manageable adverse events, safety, buy-in from the medical community, and the ease of administration have contributed to the early adoption of this therapy. We introduced the Radium-223 dichloride therapy in our clinic soon after its approval through the attentive combined efforts among leaders in oncology, nuclear medicine, radiology business administration, and the Cancer Center.…”

Molecular Targeted α-Particle Therapy for Oncologic Applications

“…In the phase 3 ALSYMPCA (Alpharadin in the Treatment of Patients With Symptomatic Bone Metastases in Castration-Resistant Prostate Cancer) trial, patients with prostate cancer with osseous metastatic disease treated with 223 Ra had increased survival and decreased bone pain [41]. The mechanism of action for 223 Ra is similar to that of other nuclear bone-seeking agents in that it mimics calcium and forms complexes with hydroxyapatite in remodeling bone [1]. In contrast to 90 Sr, the traditional β-particle-emitter used to alleviate malignancy-induced bone pain, 223 Ra showed increased survival in patients with osseous metastasis [41].…”

“…Radium-223 is effective in its unconjugated state because of its affinity to areas of bone turnover, which surround osseous metastasis in prostate cancer [1]. However, because of its chemical properties, radium is difficult to conjugate to molecular delivery systems that target tumor-restricted biomarkers.…”

“…Fortunately, other α-particle-emitting isotopes are available that have similar therapeutic potential as 223 Ra but can also be conjugated to antibodies, proteins, and other delivery systems. The most commonly used α-particle emitters that have been shown to be efficacious in clinical molecular targeting applications are 213 Bi, 225 Ac, and 211 At [1, 42–65] (Table 1). Although there is compelling evidence for using the targeted α-particle approach, the principal drawbacks of these radioisotopes are their availability and expense.…”

“…Although achieving this goal remains elusive, recent separate developments in molecular biology and nuclear medicine have shown the feasibility of this approach in clinical trials. These advances include the recent U.S. Food and Drug Administration (FDA) approvals of an α-particle therapy against prostate cancer [1] and a separate drug antibody conjugate against breast cancer that targets the HER2/ERRB2 (formerly HER2/neu ) biomarker [2]. New methods that combine these two innovations into a single targeted therapeutic strategy promise to approach the elusive goal of creating a “magic-bullet” therapy that will specifically target and eradicate cancer cells without harming normal tissue.…”