Moving Radium-223 Forward in the Treatment Timeline for Prostate Cancer With Bone Metastases

Ariela Katz
Published: Sunday, Jun 10, 2018
Richard G. Stock, MD

Richard G. Stock, MD

Radium-223 (Xofigo) has efficacy in treating patients with prostate cancer and bone metastases, but is usually introduced into the patient's traetment plan after they have symptomatic disease. These symptoms are often painful, and the metastases can be difficult to treat at this stage. Moving radium-223 up in the treatment paradigm for these patients could provide better outcomes and longer survival, according to Richard G. Stock, MD, professor and director of genitourinary oncology at the Icahn School of Medicine at Mount Sinai in New York.

“Clearly, what we know is, when bone metastases are present, patients have a decrease in overall survival. This is a problem that needs to be addressed, and skeletal tumor burden is an independent predictor of death in patients with advanced prostate cancer,” Stock said during a presentation at New York GU™: 11th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies.

Bone metastases are quite common in prostate cancer, Stock said. About 14% of the patients who undergo surgical or chemical castration will develop castration-resistant prostate cancer (CRPC), and about 90% of those patients will develop metastases in the bone. The 5-year survival rate for patients with bone metastases is about 30%.1

Typically, prostate cancer progresses from nonmetastatic local disease (M0), with a possible rise in prostate-specific antigen levels and biochemical relapse, to CRPC when patients fail androgen-deprivation therapy. Patients with newly diagnosed metastatic CRPC (M1) are often chemotherapy naïve, and 4% of patients with prostate cancer present initially with M1, hormone-sensitive disease.

The treatment challenge is that prostate tumor cells may colonize the bone during this disease progression. In vitro data show that the colonization of bone tissue may be driven by chemoattraction and preferential attachment.2,3 Prostate cancer metastases are also associated with osteoblastic activity, so the balance shifts from bone destruction to bone deposition, where the osteoblasts secrete more proteins to form excess bone beyond the body’s bone resorption capabilities. This leads to osteoblastic lesions in the mineralized bone tissue where tumor cells have gathered, and it correlates with higher levels of alkaline phosphatase and osteocalcin, which would signify liver or gallbladder toxicity.4,5

When bone metastases are present, overall survival (OS) is lower. Results from a population-based cohort study of patients with prostate cancer showed that fewer patients with bone metastases were alive at 5 years (3%; 95% CI, 2.2%-3.4%) than patients with no bone metastases (56%; 95% CI, 54.9%-56.7%). In the study, 23,087 patients had an initial diagnosis of prostate cancer; 22,404 of those patients had no bone metastases, and 569 presented with bone metastases at diagnosis.6

Investigators in the field of prostate cancer therapeutics have seen different isotopes being used to treat bone metastases in patients with prostate cancer, but most have fallen by the wayside due to bone marrow toxicities. Radium-223 has remained a standard radiotherapy since its approval by the FDA in 2013, due in part to its more favorable toxicity profile and its mechanism of action.

Radium-223 is an alpha-pharmaceutical that targets bone metastases by mimicking calcium, forming complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The short range of the alpha particles emitted (<10 cell diameters) limits damage to the surrounding normal tissue, leading to less bone marrow toxicity. The alpha particles predominantly cause double-strand DNA breaks in adjacent cells, resulting in the antitumor effect on bone metastases.7

Because radium-223 is absorbed primarily by the bone marrow, there is a small risk for bone marrow–related toxicities, such as myelosuppression. However, radium-223 can also lead to adverse events (AEs) outside of the bone. The agent can be absorbed by other organs, including the gastrointestinal system, leading to AEs that can include nausea, diarrhea, and vomiting.7

Stock recommended watching out for these and other AEs. “For those of us who do this in a clinical practice, we check the blood count, and it is very rare that patients have to discontinue treatment due to myelosuppression,” he said. It is important, he continued, to monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Radium-223 should be discontinued in patients who experience life-threatening complications despite supportive care for bone marrow failure.

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