By Nicholas Vogelzang, MD // Comprehensive Cancer Centers of Nevada

 

Overview

Radium-223 Dichloride, otherwise known as Xofigo, is the first alpha-emitting radiopharmaceutical used to treat prostate-cancer-related bone metastasis. The FDA approved Xofigo in May of 2013. The clinical trial that led to the FDA approval was called the ALSYMPCA trial. Eligible patients were randomized in a 2:1 fashion to either receive six monthly intravenous injections of radium-223 or best standard of care, such as antiandrogen hormonal therapy, local external beam radiation, corticosteroids, estramustine, or ketoconazole. The men who received radium-223 had improvement in bone pain and also experienced an increased survival. The patients who were not initially treated with Xofigo were allowed to cross over into the radium-223 arm because of this early noted increased survival. Radium-223 dichloride was also shown to increase the time to symptomatic skeletal events, such as the need for palliative external beam radiation or surgery to treat bone pain and bone fractures. These results led to the FDA fast track approval of this unique radioisotope treatment.

The mechanism of action of radium-223 dichloride should be given special consideration. Radium-223 is an alpha particle emitting radioactive isotope. Traditionally, the radioactive isotopes used to treat bone metastasis from prostate cancer have been primarily beta emitting radioisotopes. Strontium-89 and Samarium-153 were the two approved radioisotopes used most commonly in treatment of metastatic prostate carcinoma to bone, prior to the approval of radium-223 dichloride. Strontium-89 and Samarium-153 improved symptoms from bone metastasis, but did not improve overall survival. The side effects of treatment, most notably depression of blood counts and anemia, were greater with Samarium-153 and Strontium-89, as beta emitting radioisotopes result in more radiation to the bone marrow compartment of bone- as they deposit energy along a greater pathway than alpha emitters. Radium-223, because it is an alpha emitting radioisotope, deposits energy along a shorter pathway and results in lower amounts of radiation to the central bone marrow component of the bone. Thus, patients experience less bone marrow suppression and can receive other treatments with radium-223, making it a more attractive treatment option. Furthermore, radium-223 dichloride mimics calcium and primary concentrates in areas of higher bone turnover, or where areas of bone metastasis reside. The activity of radium-223 administered are in microcurie doses, whereas the activity administered for most therapeutic radioactive isotopes are in millicuries. The physical properties of alpha emitting radioisotopes, as well as the lower amount of activity needed to obtain clinical benefit, make the shielding requirements more convenient, and typically clothing is adequate. After intravenous injection, radium-223 is distributed primarily in the bone and intestine. The major route of elimination is fecal excretion. Because of the distribution and route of elimination, the side effects of radium-223 are primarily bone marrow depression and lower GI side effects. Nausea, vomiting, diarrhea, and depression of blood counts are most common and some patients may occasionally require hydration in cases when the diarrhea is severe. Prior to each injection, a complete blood count is necessary to make sure the patient has adequate bone marrow function. Some patients may need blood transfusions prior to or after administration if anemia occurs.

In Use

Radium-223 dichloride is the first FDA approved agent that extends overall survival in castrate-resistant prostate carcinoma by exerting an antitumor effect on bone metastasis. Because of its mechanism of action and favorable side effect profile, radium-223 is an attractive agent to use in combination with other agents in the treatment of castrate resistant metastatic prostate carcinoma. Physicians will use radium-223 with other FDA approved agents such as abiraterone (Zytiga) and enzalutamide (Xtandi). These agents act on the androgen pathway. While it is not currently routinely recommended to administer chemotherapy with radium-223 dichloride because of the potential added effects on the bone marrow, it has been shown in a small number of patients to be possible. In our clinic we routinely use radium-223 dichloride in combination with agents such as abiraterone and enzalutamide. The side effect profile of these agents in combination is favorable, with no real added bone marrow or GI toxicity. Whether these agents will have a synergistic or additive effect on overall survival is currently an area of investigation. We have also administered radium-223 in combination with chemotherapy in select patients. We observed greater hematologic toxicity in these patients with no increased GI toxicity. These patients need more intensive hematologic support, and may require more frequent blood transfusions. We often use radium-223 in our clinic earlier on in the disease course of metastatic prostate carcinoma with bone metastasis, and have found that men with lower burden of skeletal metastasis, fewer areas of uptake on bone scan, will often have better responses with improvement of disease on post treatment scans.

The Future

Future and current research with radium-223 are looking at combining radium-223 with other novel agents such as atezoluzimab (the PDL-1 antibody) looking at novel treatment schedules in combination with chemotherapy and repeat treatment with radium-223 six months or greater after completing the first course of treatment. This may answer an important question about using radium-223 dichloride early on in this disease, as many physicians are reluctant to use radium-223 early because of its finite dosing schedule. Other agents such as abiraterone and enzalutamide can be given until the patient’s disease progresses, as these agents can stop working.

Radium-223 should be administered by a committed team of healthcare professionals that should include a medical oncologist and radiation oncologist, or nuclear medicine physician who is licensed to handle radioactive materials. This team needs to understand the disease state of castrate resistant metastatic prostate carcinoma in order to deliver this unique agent to the appropriate patient at the appropriate time.


References

  1. Parker C, Nilsson S, et al. Alpha Emitter Radium 223 Dichloride and Survival in Metastatic Prostate Cancer. N Engl J Med 2013; 369: 213-223.
  2. Bayer Xofigo Radium 223 Dichloride Prescribing Information
  3. Sartor O, Coleman R, et al. Effect of Radium 223 Dichloride on Symptomatic Skeletal events in Patients with Castrate Resistant Prostate Cancer and Bone Metastasis: Results From a Phase 3 Double-Blind, Randomized Trial. Lancet Oncology S1470-2045(14)70183-4 70217-7 Published online.
  4. Sartor O, Heinrich D, et al. Radium 223 (Ra-223) re-treatment (Re-Tx): First Experience from an international, multicenter, prospective study in patients with castrate-resistant prostate cancer and bone metastasis (MCRPC). Journal Clinical Oncology 34, 2016 (suppl 2S; abstract 197)
  5. Shore ND et al. Interim Results from Eradicate: An Open-Label Phase 2 Study of Radium 223 Dichloride With Concurrent Administration of Abiraterone Acetate Plus Prednisone in Castrate-Resistant Prostate Cancer Subjects with Symptomatic Bone Metastasis. ASCO GU abstract 177. J Clinical Oncology. 2016; 34 (suppl 2S).

About Dr. Vogelzang:

Dr. Vogelzang is a renowned medical oncologist and cancer researcher with 35 years of internal medicine and medical oncology experience, with special areas of expertise in genitourinary cancer. His CV on Pubmed list four publications (26 in 2013) in addition to numerous book chapters and abstracts. He has given hundreds of lectures and presentations to his peers. 

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