Bone metastases are a major cause of death, disability, and decreased quality of life in patients with castration-resistant prostate cancer (CRPC). Radium 223 dichloride (radium-223) is a novel alpha-emitting radiopharmaceutical that selectively targets bone metastases with high-energy, short-range (<100 μm; 2-10 cell diameters) alpha particles and represents a unique treatment option for men with CRPC and symptomatic bone metastases. In early clinical studies, radium-223 had a positive impact on cancer-related as well as bone-related outcomes, and this was confirmed in the phase III Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) study. This randomized, double-blind, placebo-controlled study, which was prematurely stopped because of the positive effect of radium-223 on survival, showed that radium-223 significantly prolonged overall survival and time to first symptomatic skeletal event, along with reducing levels of alkaline phosphatase (ALP), a marker of bone turnover. Radium-223 was safe and well tolerated. Myelosuppression rates were low, and the most common nonhematologic adverse events were bone pain, nausea, diarrhea, fatigue, vomiting, and constipation. On the basis of these data, radium-223 has been approved by 34 countries so far for the treatment of patients with CRPC with symptomatic bone metastases and no known visceral metastatic disease. In conclusion, radium-223 is a highly effective and well-tolerated treatment for patients with CRPC and symptomatic bone metastases.
Nicholas J. Vogelzang, MD
The recent approval of several new agents for the treatment of prostate cancer has heralded a new era for managing this condition. “We’re right in the middle of a complete paradigm shift,” said Matthew Cooperberg, MD, MPH, in an interview published online on OncLive in December 2013.1
One of the most intriguing of these new agents is radium-223 dichloride (radium-223; Xofigo; Bayer HealthCare Pharmaceuticals and Algeta ASA), the first alpha emitter shown to confer a survival advantage and to be approved for the treatment of patients with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease.2
Advantages of Alpha-Emitting Radium-223
Radium-223 is a calcium mimetic that forms complexes with hydroxyapatite at areas of increased bone turnover, such as osteoblastic lesions.3,4
In preclinical studies, radium-223 showed marked accumulation in areas of high osteoblastic activity.5
Radium-223 begins to decay almost instantaneously, reaching a final product of stable lead over a 6-stage decay process. For each atom of radium-223, 4 alpha particles (each composed of 2 protons and 2 neutrons) are released, representing 94% of the total radiation energy emitted.5
Nanomolar quantities of radium are needed to achieve high localized radiation doses, given the high linear energy transfer (LET) of alpha radiation.
Unlike beta-emitting radiopharmaceuticals (such as strontium-89 and samarium-153), which are associated with significant myelotoxicity (particularly thrombocytopenia), the extremely short range of alpha particles allows for highly targeted tumor cell killing and may spare hematopoietic bone marrow cells from damage.3-5
Moreover, the high-LET radiation produced by alpha particles induces double-stranded DNA breaks in adjacent tumor cells and is more effective at killing cancer cells than the low-LET radiation produced by beta particles.3-5
Early Clinical Experience With Radium-223
Early studies with radium-223 showed a promising clinical profile in patients with bone metastases, including no dose-limiting hematologic toxicity6
; the most common adverse events (AEs) were transient diarrhea, bone pain, fatigue, nausea, and vomiting.6
In a phase I study in men and women with bone metastases, all patients showed a reduction in alkaline phosphatase (ALP) levels, but the effect was more marked in men than in women,6
suggesting that radium-223 may target osteoblastic lesions more effectively than osteolytic lesions.7