In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
Indication
On May 15, 2013, radium Ra 223 dichloride (Xofigo) was approved for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease.1,2
Approval was based on a double-blind, randomized, placebo-controlled trial in which 809 patients with metastatic castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease received intravenous radium-223 dichloride 50 kBq/kg (1.35 microcurie/kg) every 4 weeks for six cycles plus best standard of care (n = 541) or placebo plus best standard of care (n = 268). Standard of care included local radiotherapy, corticosteroids, antiandrogens, estrogens, estramustine, or ketoconazole. All patients were to continue androgen-deprivation therapy. Among all patients, median age was 71 years, 94% were Caucasian, 86% had ECOG performance status of 0 or 1, 58% had received prior docetaxel, 85% had six or more bone scan lesions, 41% had received prior bisphosphonates, and 54% used opiate and 44% non-opiate pain medications.
Treatment was continued until unacceptable toxicity or initiation of cytotoxic chemotherapy, other systemic radioisotope treatment, hemibody external beam radiation therapy, or other investigational drug therapy. Patients with Crohn’s disease, ulcerative colitis, prior hemibody radiation, or untreated imminent spinal cord compression were excluded from the study. In patients with bone fractures, orthopedic stabilization was performed before starting or resuming treatment with radium-223 dichloride.
During treatment, 83% of patients in the radium-223 dichloride group and 82% of patients in the placebo group received gonadotropin-releasing hormone agonists, and 21% and 34% of patients, respectively, received concomitant antiandrogens. Use of systemic steroids (41%) and bisphosphonates (40%) was balanced between groups.
At a prespecified interim analysis, median overall survival, the primary endpoint of the trial, was significantly prolonged in the radium-223 dichloride group (14.0 vs 11.2 months, hazard ratio [HR] = 0.70, P = .00185). The improvement in overall survival was supported by a delay in time to first symptomatic skeletal event in the radium-223 dichloride group (defined as external beam radiation therapy to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention).
How It Works
The active component of radium-223 dichloride is the alpha particle–emitting isotope radium-223 (as radium Ra 223 dichloride), which mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, including bone metastases. The high linear energy transfer of alpha emitters (80 keV/micrometer) leads to a high frequency of double-strand DNA breaks in adjacent cells, resulting in an antitumor effect on bone metastases. The alpha particle range from radium-223 dichloride is less than 100 micrometers (less than 10 cell diameters), which limits damage to surrounding normal tissue.
How It Is Given
The recommended dose of radium-223 dichloride is 50 kBq/kg (1.35 microcurie/kg) given at 4-week intervals for six injections. Safety and efficacy beyond six injections have not been studied. Determination of the volume of drug to be given involves a calculation incorporating the radioactivity concentration of the product as of a reference date and a decay correction factor to correct for physical decay of radium-223 based on number of days from the reference date. Calculated absorbed radiation doses to different organs are provided in the drug labeling.
Administration of the drug is associated with potential risks to other persons (including medical staff, caregivers, and the patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Thus, radiation protection precautions must be used.
Safety Profile
The most common adverse events of any grade (≥ 10%) in patients receiving radium-223 dichloride were nausea (36% vs 35% in placebo group), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Overall, grade 3 or 4 adverse events occurred in 57% of patients receiving radium-223 dichloride and 63% of patients receiving placebo. The most common hematologic laboratory abnormalities in patients receiving radium-223 dichloride were anemia (93% vs 88%, grade 3 or 4 in 6% vs 6%), lymphocytopenia (72% vs 53%, grade 3 or 4 in 20% vs 7%), leukopenia (35% vs 10%, grade 3 or 4 in 3% vs <1%), thrombocytopenia (31% vs 22%, grade 3 or 4 in 3% vs < 1%), and neutropenia (18% vs 5%, grade 3 or 4 in 2% vs < 1%). Bone marrow failure or ongoing pancytopenia occurred in 2% of radium-223 dichloride patients and no placebo patients.
Treatment discontinuations due to adverse events occurred in 17% of radium-223 dichloride and 21% of placebo patients. The most common hematologic laboratory abnormalities leading to discontinuation in radium-223 dichloride patients were anemia (2%) and thrombocytopenia (2%). Injection site reactions were reported in 1% of radium-223 dichloride patients.
Radium-223 dichloride carries warnings/precautions for bone marrow suppression. Blood counts should be measured prior to treatment initiation and before every dose of radium-223 dichloride. Treatment should be discontinued if hematologic values do not recover within 6 to 8 weeks after administration. Patients with compromised bone marrow reserve must be closely monitored. Treatment should be discontinued in patients who experience life-threatening complications despite supportive care measures. ■
References
1. U.S. Food & Drug Administration: Radium Ra 223 dichloride. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm352393.htm. Accessed June 20, 2013.
2. Xofigo™ (radium Ra 223 dichloride) injection prescribing information, Bayer HealthCare Pharmaceuticals Inc, May 2013. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203971lbl.pdf. Accessed June 20, 2013.
