Radium-223: Sequence or Overlay in Advanced Prostate Cancer (mCRPC)?

Steven Eric Finkelstein, MD
Published: Friday, May 23, 2014
Dr. Steven Eric Finkelstein

Steven Eric Finkelstein, MD

According to the National Cancer Institute, 238,598 new cases of prostate cancer will have been diagnosed in 2013. More than 90% of men with symptomatic metastatic castration-resistant prostate cancer (mCRPC) have radiologic evidence of metastasis to bone either on technetium SPECT or sodium fluoride PET/CT bone scan.

Unlike with other cancers, it appears that death from mCRPC is often due to bone disease and its subsequent complications. Bone metastasis can cause intense pain, weakness, and bone fractures, greatly impairing patent quality of life, and is associated with disability, increased cost of treatment, and death. In a recent study with mCRPC, the 5-year overall survival (OS) of men with bone metastases was approximately 3%. Treatment options for patients with advanced stage prostate cancer have traditionally been limited. Indeed, the main focus of treatment at this clinical juncture is to improve the quality of life; however, new agents are aiming to improve OS.

On May 15, 2013, the US Food and Drug Administration approved radium-223 dichloride (radium-223; Xofigo; Bayer HealthCare Pharmaceuticals and Algeta ASA) for the treatment of patients with mCRPC with symptomatic bone metastases and no known visceral metastatic disease. This is the sixth novel agent for advanced prostate cancer approved in the past 5 years. Radium-223, the first of its class of alpha-particle emitting radiotherapeutics, mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover, such as bone metastases, and kills the prostate cancer cells by causing double-stranded DNA breaks.

As a first-of-its-kind therapy to have significant focused impact on multiple systemic bone metastases, the ability of radium-223 to target lesions with such precision as opposed to beta/gamma-emitting radiotherapeutics or chemotherapy may be revolutionary. The approval of radium-223 was based on ALSYMPCA—a double-blind, randomized, placebo-controlled trial in patients with mCRPC with symptomatic bone metastases and no known visceral metastatic disease.1 In his article, “Radium-223 Dichloride: A Novel Treatment for CRPC and Symptomatic Bone Metastases,” on page 6 of this issue, Nicholas J. Vogelzang, MD, details early clinical experience with radium-223, as well as the results of ALSYMPCA and the practical implications of the use of radium-223 for clinical oncologists. In brief, patients were allocated 2:1 to radium-223, 50 kBq/kg (1.35 microcurie/kg), intravenously, every 4 weeks for 6 cycles plus best standard of care (n = 541) or to matching placebo plus best standard of care (n = 268). With respect to key findings, at the prespecified interim analysis a statistically significant improvement in OS was demonstrated (hazard ratio [HR] 0.70; 95% confidence interval [CI] 0.55-0.88; P = .002). The median OS was 14.0 and 11.2 months in the radium-223 and placebo arms, respectively. The OS benefit in ALSYMPCA was supported by a delay in time to first symptomatic skeletal event favoring the radium-223 arm. Thus, this is considered by many to be an agent given to improve OS rather than just for palliative intent.

This agent may also be quite favorable with respect to side effect profile. Alpha particle range from radium-223 is <100 μm (<10 cell diameters), which limits damage to surrounding normal tissue. The most common (≥10%) adverse events in patients receiving radium-223 were nausea, diarrhea, vomiting, and peripheral edema.2 The most common (≥10%) hematologic laboratory abnormalities were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia.2 Thus, based on ALSYMPCA, the recommended dose and schedule for radium-223 is 50 kBq/kg (1.35 microcuries/kg) administered by slow intravenous injection over 1 minute every 4 weeks for 6 doses.

Yet even as radium-223 is coming into use in clinical practice, numerous key questions remain as to how to best utilize this novel agent. Future clinical trials will need to address the vital issues regarding whether 6 doses are optimal, gather data in specific patient subgroups, and test combinations with other agents such as stereotactic body radiation therapy.

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35th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® Clinical Vignette SeriesJan 31, 20192.0
Oncology Briefings™: Current Perspectives on Preventing and Managing Tumor Lysis SyndromeJun 30, 20191.0
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