Clinical UM Guideline


Subject: Radium Ra 223 Dichloride (Xofigo®)
Guideline #: CG-DRUG-77 Publish Date:    12/12/2018
Status: Revised Last Review Date:    11/08/2018


This document addresses the use of radium Ra 223 dichloride (Xofigo, Bayer HealthCare Pharmaceuticals, Wayne, NJ) injection, an alpha particle-emitting radioactive therapeutic agent which mimics calcium to bind with bone minerals in areas of bone metastases. The agent has an anti-tumor effect which occurs due to energy transfer from the radioactive material to nearby cancer cells.

Clinical Indications

Medically Necessary:

Radium Ra 223 dichloride is considered medically necessary for individuals who meet all the following criteria:

  1. Age 18 years or older with symptomatic bone metastasis from castrate-resistant prostate cancer (CRPC); and
  2. Planned course of six monthly injections; and
  3. Serum testosterone level is less than or equal to 50 ng per deciliter ([1.7 nmol per liter] after bilateral orchiectomy or during maintenance treatment consisting of androgen-ablation therapy with a luteinizing hormone-releasing hormone agonist or polyestradiol phosphate); and
  4. Prostate-specific antigen (PSA) level is 5 ng per milliliter or higher with evidence of progressively increasing PSA values (two consecutive increases over the previous reference value) or objective evidence of progression of osseous metastases on imaging studies at time of initiation of Radium Ra 223 dichloride; and
  5. No known history or presence of visceral metastatic disease; and
  6. Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 to 2; and
  7. No evidence of imminent or established spinal cord compression; and
  8. Has not received systemic radiotherapy with radioisotopes within the previous 24 weeks; and
  9. Has not been treated with chemotherapy or biologic therapy within the previous 4 weeks; and
  10. Will not be used concurrently with other chemotherapy or biologic therapy (Note: this does not include androgen-ablation therapy or other hormonal therapy) for prostate cancer.

Not Medically Necessary:

Radium Ra 223 dichloride is considered not medically necessary when the above criteria are not met, including but not limited to any of the following:

  1. Has imminent or established spinal cord compression;
  2. Used in combination with abiraterone acetate plus prednisone/prednisolone;
  3. Has received systemic radiotherapy with radioisotopes within the previous 24 weeks;
  4. Was treated with chemotherapy or biologic therapy within the previous 4 weeks;
  5. Has received a previous course of Radium Ra 223 dichloride;
  6. Reason for treatment other than diagnoses of CRPC.

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.




Radiopharmaceutical therapy, by intravenous administration [when specified as injection of Xofigo]






Radium Ra-223 dichloride, therapeutic, per microcurie [Xofigo]



ICD-10 Diagnosis




Malignant neoplasm of prostate



Secondary malignant neoplasm of bone



Rising PSA following treatment for malignant neoplasm of prostate



Hormone resistant malignancy status


Discussion/General Information

In the evaluation of individuals with prostate cancer the National Cancer Institute (2013) reported that:

In the United States, most prostate cancers are diagnosed as a result of screening; therefore, symptoms of cancer are infrequent at the time of diagnosis. Nevertheless, local growth of the tumor may produce symptoms of urinary obstruction such as decreased urinary stream, urgency, hesitancy, nocturia, or incomplete bladder emptying. These symptoms are nonspecific and more indicative of benign prostatic hyperplasia than cancer. Although rare in the current era of widespread screening, prostate cancer may also present with symptoms of metastases, such as bone pain, pathologic fractures, or symptoms caused by bone marrow involvement.

According to the National Cancer Institute (NCI), prostate cancer is the most common cancer, other than skin cancers, in American men and is the second leading cause of cancer death in men, behind only lung cancer. The NCI estimates that in 2018 there will be about 164,690 new cases of prostate cancer diagnosed in the United States and nearly 29,430 men will die from the disease. Deaths as a result of prostate cancer are typically the result of metastatic CRPC and the mean survival for men has historically been 2 years or less (NCI, 2018).

Radium Ra 223 dichloride (Xofigo) (also known as radium-223) was granted approval in May 2013 by the U.S. Food and Drug Administration (FDA) for treatment of men with symptomatic late-stage (metastatic) CRPC that has spread to bones but not to other organs (Product Information Label, 2018).

The FDA approval was based in part on the interim analysis of the results of the ALSYMPCA trial, a multicenter, phase III, double blind study that randomized 809 participants with CRPC and bone metastases to receive either radium-223 (n=541) or placebo (n=268) (Parker, 2013). Castrate-resistant prostate cancer was defined as a serum testosterone level of 50 ng per deciliter or lower (less than or equal to 1.7 nmol per liter) after bilateral orchiectomy or after maintenance treatment consisting of androgen-ablation therapy with a luteinizing hormone-releasing hormone agonist or polyestradiol phosphate. Additionally, all participants had symptomatic bone disease requiring the regular use of analgesic medicine or treatment with external-beam radiation therapy. Other eligibility criteria included PSA level of 5 ng per milliliter or higher with evidence of progressively increasing PSA values, ECOG performance-status score of 0 to 2, adequate hematologic, renal and liver function, and life expectancy of 6 months or longer. Participants were excluded from the study if they had visceral disease or received chemotherapy within the prior 4 weeks or had not recovered from adverse events due to chemotherapy, previous hemibody external radiotherapy, systemic radiotherapy with radioisotopes within the prior 24 weeks, a blood transfusion or use of erythropoietin-stimulating agents within the prior 4 weeks, a malignant lymphadenopathy 3 cm or more in the short-axis diameter, a history of or the presence of visceral metastases, and imminent or established spinal cord compression. The radium-223 group showed significant improvement in overall survival compared to placebo (median 14.0 months versus 11.2 months; hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.58 to 0.83; p<0.001).

It should be noted that the study was specifically designed to measure overall survival and not palliation of bone pain. For example, Parker (2013) points out the following:

More than 90% of patients with metastatic CRPC have radiologic evidence of bone metastases, which are a major cause of death, disability, decreased quality of life, and increased treatment cost among these patients. Unlike deaths from many other types of cancer, deaths from prostate cancer are often due to bone disease and its complications. Current bone-targeted therapies have not been shown to improve survival, and the benefits derived from bisphosphonates, denosumab, and existing radioisotope treatments are primarily limited to pain relief and delay of skeletal events.

The National Comprehensive Cancer Network (NCCN®), Clinical Practice Guideline in Oncology for Prostate Cancer (2018) states:

Radium-223 is an alpha-emitting radiopharmaceutical that has been shown to extend survival in men who have CRPC with symptomatic bone metastases, but no visceral metastases. Radium-223 differs from beta-emitting agents, such as samarium 153 and strontium 89, which are palliative and have no survival advantage. Radium-223 causes double-strand DNA breaks and has a short radius of activity. Grade 3-4 hematologic toxicity (2% neutropenia, 3% thrombocytopenia, 6% anemia) occurs at low frequency.

In 2018, the American Urological Association (AUA) released amended guideline, addressing the treatment of castration-resistant prostate cancer. In this guideline the AUA recommendations for radium-223 are unchanged:

The updated NCCN clinical practice guideline for bone cancer (2018) (V.1.2019) offers a category 2A recommendation for use of Radium dichloride (Ra 223) in the treatment of osteosarcoma with relapse or progression after failure of chemotherapy and/or resection if possible. The second recommendation is for the treatment of metastatic disease, stating may “consider use of Sm-EDTMP and Radium 223”. The NCCN panel recommendations are based on limited evidence currently available, in the form of a case report and a review article.

Currently, there is an ongoing phase I/II clinical trial evaluating the use of radium-223 for breast cancer, breast cancer bone metastasis, and osteosarcoma, and for use in combination with docetaxel for use in treatment of CRPC and bone metastases. Presently, there is insufficient published literature to support the safety and effectiveness of radium-223when used for these indications.

Radium Ra 223 Dichloride (Xofigo)

The following are contraindications, warnings and precautions from the Product Information Label (2018):



Warnings and Precautions:

Bone Marrow Suppression: Measure blood counts prior to treatment initiation and before every dose of Xofigo. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after treatment. Monitor patients with compromised bone marrow reserve closely. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care measures.

Increase Fractures and Mortality in Combination with Abiraterone plus Prednisone/Prednisolone: Xofigo is not recommended in combination with abiraterone acetate plus prednisone/prednisolone.


ECOG Performance Status: A scale used to assess how an individual's disease is progressing, determine how the disease affects the daily living abilities of the individual, and determine appropriate treatment and prognosis (Oken, 1982):

0 = Fully active, able to carry on all pre-disease performance without restriction
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3 = Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4 = Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5 = Dead

Metastatic: Spread of a disease from the organ or tissue of origin to another part of the body.

Prostate: A gland in the male reproductive system; the small walnut sized structure which wraps around the urethra.


Peer Reviewed Publications:

  1. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5(6):649-655.
  2. Parker C, Finkelstein SE, Michalski JM, et al. Efficacy and safety of Radium-223 in symptomatic castration-resistant prostate cancer patients with or without baseline opioid use from the phase 3 ALSYMPCA trial. Eur Urol. 2016; 70(5):875-883.
  3. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013; 369(3):213-223.
  4. Parker C, Zhan L, Cislo P, et al. Effect of radium-223 dichloride (Ra-223) on hospitalization: An analysis from the phase 3 randomised Alpharadin in symptomatic prostate cancer patients (ALSYMPCA) trial. Eur J Cancer. 2017; 71:1-6.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Urological Association (AUA). Castration-resistant prostate cancer: AUA guideline. Published 2013; Amended 2018. Available at: Accessed on September 25, 2018.
  2. Loblaw BE, Oliver TK, Carducci M, et al. Systemic therapy in men with metastatic castration-resistant prostate cancer (CRPC): American Society of Clinical Oncology and Cancer Care Ontario clinical Practice Guideline. September 8, 2014. Available at: Accessed on September 25, 2018.
  3. NCCN Clinical Practice Guidelines in Oncology (NCCN). © 2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: Accessed on September 21, 2018.
  4. Bone Cancer (V.1.2019) Revised August 3, 2018.
    • Prostate Cancer (V.4.2018). Revised August 15, 2018.
    • Radium Ra 223 dichloride (systemic). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. September 13, 2018. Available at: Accessed on September 21, 2018.
  5. Radium Ra 223 dichloride Monograph. Lexicomp® Online, American Hospital Formulary Services ® (AHFS ®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised August 19, 2017. Accessed on September 21, 2018.
  6. Xofigo® (radium Ra 223 dichloride) [Product Information]. Wayne, NJ. Bayer HealthCare Pharmaceuticals. August 31, 2018. Available at: Accessed September 25, 2018.
Websites for Additional Information
  1. American Cancer Society. Prostate cancer. How is prostate cancer staged? May 30, 2017. Available at: Accessed on September 25, 2018.
  2. American Cancer Society. Overview: prostate cancer. Revised March 3, 2010. Available at: Accessed on September 25, 2018.
  3. National Cancer Institute. Prostate Cancer (PDQ®). August 9, 2018. Available at: Accessed on September 25, 2018.
  4. Centers for Disease Control and Prevention. Prostate cancer. Last updated September 17, 2017. Available at: Accessed on September 25, 2018.
  5. National Cancer Institute. Radium-223 improves survival in patients with advanced prostate cancer. August 2, 2013. Available at: Accessed on September 25, 2018.

Castration- resistant prostate cancer (CRPC)
Radium Ra 223 Dichloride

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.







Medical Policy & Technology Assessment Committee (MPTAC) review.



Hematology/Oncology Subcommittee review. Revised NMN statement to address use of Radium Ra 223 dichloride in combination with abiraterone acetate plus prednisone/prednisolone. Updated Discussion, References and Websites sections.



MPTAC review.



Hematology/Oncology Subcommittee review. Initial document development. Moved content from DRUG.00061 Radium Ra 223 Dichloride (Xofigo®) to new clinical utilization management guideline document CG-DRUG-77 with same title.