Medical Policy: 06.01.36 

Original Effective Date: September 2017 

Reviewed: September 2019 

Revised: September 2018 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

An estimated 167,650 new cases of prostate cancer will be diagnosed in 2019, accounting for 20% of new cancer cases in men. Researchers have estimated prostate cancer to account for 9.8% of male cancer deaths in 2018. The use of prostate specific antigen (PSA) screening and monitoring has allowed prostate cancer to be diagnosed at a localized stage. Despite early detection and appropriate treatment, some individual’s progress to metastatic, hormone refractory prostate cancer after the failure of several lines of anti-hormonal therapies, and approximately 85% to 90% of patients will have radiologic evidence of bone metastases which are a major cause of death, disability and decreased quality of life. Weakened bones due to cancer metastases can lead to fractures and compression of the spinal cord. They necessitate procedures such as surgery and radiation, which are designed to prevent or manage bone complications. The primary goal of treatment for bone metastases is to prevent the occurrence of debilitating bone complications that can affect an individual’s quality of life. Radiation treatment has been shown to provide palliative care in patients with advanced prostate cancer.

 

Radium Ra 223 dichloride (Xofigo®), also known as radium-223, is an alpha particle-emitting radiotherapeutic agent. Radium-223 injection mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover. The high-energy alpha particle radiation causes breaks in the double stranded DNA of the targeted area resulting in an anti-tumor effect on the bone metastases. The short path of the alpha particles limits the damage to the surrounding normal tissue and bone marrow (the radium-223 binds to minerals in the bone to deliver radiation directly to the tumor that has spread to the bones while limiting damage to the surrounding body tissues). The U.S. Food and Drug Administration (FDA) in May 2013, approved radium-223 for the treatment of patients with castration-resistant prostate cancer (CRPC), with symptomatic bone metastases and no known visceral metastatic disease.

 

The FDA approval was based on clinical data from a multicenter, phase 3, randomized trial (ALSYMPCA) that included 921 men with symptomatic CRPC, 2 or more bone metastases, and no known visceral disease. Fifty-seven percent of the patients received prior docetaxel and all patients received best supportive care. Patients were randomized in a 2:1 ratio to 6 monthly radium-223 intravenous injections or placebo. Compared to placebo, radium-223 significantly improved overall survival (medial 14.9 months vs. 11.3 months; HR, 0.70; 95% CI, 0.058-0.83; P < 0001) and prolonged time to first SRE (medial 15.6 months vs. 9.8 months). Preplanned subset analyses showed that survival benefit of radium-223 was maintained regardless of prior docetaxel use. Intention-to-treat analyses from ALSYMPCA showed that radium-223 also may reduce the risk of symptomatic skeletal related events (SREs). Grade ¾ hematologic toxicity was low (3% neutropenia, 6% thrombocytopenia and 13% anemia), likely due to the short range of radioactivity. Fecal elimination of the agent led to generally mild non-hematologic side effects, which include nausea, diarrhea, and vomiting. Radium-223 was associated with improved or slower decline of quality of life in ALSYMPCA.

 

The dosing regimen of radium Ra 223 dichloride (Xofigo®) is given at 4 week intervals for a total of 6 injections. It is administered by a slow intravenous injection over 1 minute. Adverse reactions from this therapy include a risk of bone marrow suppression and gastrointestinal symptoms including nausea, vomiting and diarrhea. To monitor for bone marrow suppression a hematologic evaluation of patients must be performed at baseline and prior to every dose of radium-223 (Xofigo®). According to the FDA approved label, before the first administration the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥10 g/dL. Before subsequent administrations, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of radium-223 (Xofigo®), despite receiving supportive care, further treatment with radium-223 (Xofigo®) should be discontinued. Additional FDA labeling includes the following: the safety and efficacy beyond 6 injections with radium-223 (Xofigo®) has not been studied; and the safety and efficacy of concomitant chemotherapy with radium-223 (Xofigo®) have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, radium-223 (Xofigo®) should be discontinued. 

   

Other Indications

Currently, there are ongoing phase I/II clinical trials investigating the use of radium-223 for other indications to include breast cancer, osteosarcoma, lung cancer and in combination with docetaxel for the use in treatment of castration-resistant prostate cancer (CRPC) and bone metastases. Presently, there is insufficient published literature to demonstrate the safety and effectiveness of radium-223 when used for these indications.

 

Morris et. al. (2019) investigated whether combining radium-223 with docetaxel in patients with castration-resistant prostate cancer and bone metastases: a phase I dose escalation/randomized phase 2a trial.  The phase I trial was a dose escalation study to define a recommended phase 2 dose (RP2D) of docetaxel and radium-223. In the phase 2a trial, patients were randomized 2:1 to the recommended combination regimen of docetaxel at a dose of 75 mg/m2 every 3 weeks (q3w). Patients with bone-predominate metastatic castration-resistant prostate cancer (mCRPC) were eligible. End-points were safety, efficacy and treatment related changes in serum and imaging biomarkers. Twenty patients were enrolled in phase 1; 53 patients were randomized in phase 2a: 36 to combination treatment and 17 to docetaxel alone. The RP2D for the combination was radium-223 55 kBq/kg every six weeks × 5 doses, plus docetaxel 60 mg/m2 q3w × 10 doses. Febrile neutropenia was dose limiting. A higher rate of febrile neutropenia was seen in the docetaxel monotherapy arm (15% versus 0%); the safety profile of the treatment groups was otherwise similar. The combination arm had more durable suppression of prostate-specific antigen (median time to progression, 6.6 versus 4.8 months, respectively), alkaline phosphatase (9 versus 7 months) and osteoblastic bone deposition markers. The authors concluded, radium-223 in combination with docetaxel at the RP2D was well tolerated. Exploratory efficacy data suggested enhanced anti-tumor activity for the combination relative to docetaxel alone. Comparative studies with end-points of clinical benefit are warranted.

 

Practice Guideline and Position Statements 

National Comprehensive Cancer Network (NCCN) 

Prostate Cancer Version 4.2019
Principles of Radiation Therapy – Radiopharmaceutical Therapy 
  • Radium-223 is an alpha-emitting radiopharmaceutical that has been shown to extend survival in men who have castration recurrent prostate cancer (CRPC) with symptomatic bone metastases, but no visceral metastases. Radium-223 alone has not been shown to extend survival in men with visceral metastases or bulky nodal disease (> 3 to 4 cm). 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.
  • Radium-223 is administered intravenously once a month for 6 months by an appropriately licensed facility, usually in nuclear medicine or RT departments.
  • Prior to the initial dose, patients must have absolute neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, and hemoglobin ≥ 10g/dL
  • Prior to subsequent doses, patients must have absolute neutrophil count ≥ 1 x 109/L and a platelet count ≥ 50 x 109/L (per label, although this may be too low in practice). Radium-223 should be discontinued if a delay of 6-8 weeks does not result in the return of blood counts to these levels.
  • Non-hematologic side effects are generally mild, and include nausea, diarrhea, and vomiting. These symptoms may occur because radium-223 is eliminated by fecal excretion.
  • Radium-223 is not intended to be used in combination with chemotherapy due to the potential for additive myelosuppression, except on a clinical trial.
  • Concomitant use of denosumab or zoledroic acid does not interfere with the beneficial effects of radium-223 on survival

 

Progress to CRPC 

Patients who disease progresses to CRPC during primary ADT should receive a laboratory assessment to assure a castrate level of testosterone (< 50 ng/dL; <1.7 nmol/L).

 

Metastatic CRPC 

All patients with metastatic CRPC should maintain castrate levels of serum testosterone (< 50 ng/dL; <1.7 nmol/L) and receive best supportive care.

 

Bone Cancer Version 1.2020 
Osteosarcoma – Relapsed or Refractory Disease 

Radium-223 dichloride (Ra 223) is a bone seeking, alpha particle-emitting radiopharmaceutical that is under early stage investigation for treatment metastatic or recurrent osteosarcoma. This agent is approved in the United States for treating bone metastases associated with castration-resistant prostate cancer. Preliminary studies suggest that this agent is active in osteosarcoma and may have less marrow toxicity and greater efficacy than beta particle-emitting radiopharmaceuticals such as Sm 153-EDTMP.

 

American Urological Association 

In May 2013 (amended 2018), the America Urological Association issued a guideline for castration resistant prostate cancer, which included the following guideline statements:

  • Symptomatic, mCRPC with good performance status and no prior docetaxel chemotherapy: Clinicians should offer radium-223 to patients with symptoms from bony metastases from mCRPC with good performance status and no prior docetaxel chemotherapy and without known visceral disease. (Standard; Evidence Level Grade B)
  • Symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy: Clinicians may offer radium-223 to patients with symptoms from bony metastases from mCRPC with poor performance status and no prior docetaxel chemotherapy and without known visceral disease in select cases, specifically when the performance status is directly related to symptoms related to bone metastases. (Expert Opinion)
  • Symptomatic, mCRPC with good performance status and prior docetaxel chemotherapy: Clinicians should offer radium-223 to patients with symptoms from bony metastases from mCRPC with good performance status who received prior docetaxel chemotherapy and without known visceral disease. (Standard; Evidence Level Grade B)

 

Regulatory Status 

Radium Ra 223 dichloride (Xofigo®) injection was approved by the FDA on May 15, 2013 for the treatment of individuals with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease.

 

Prior Approval:

 

Not applicable

 

Policy:

Radium Ra 223 dichloride (Xofigo®), also known as radium-223 is considered medically necessary and, therefore, covered for a maximum of six injections for the treatment of prostate cancer when ALL of the following criteria are met:

  • The individual has been diagnosed with castration-resistant prostate cancer (CRPC); and
  • The individual has symptomatic skeletal (bone) metastases; and
  • The individual has no evidence of bulky nodal disease >3 to 4 cm or visceral metastases on imaging; and
  • Will not be used concurrently with other chemotherapy or biologic therapy
    • Note: the individual may be kept on ablative hormonal treatment to maintain a castrate level in accordance to the National Comprehensive Cancer Network (NCCN) guidelines which is defined as serum testosterone level <50 ng/dL

 

Radium Ra 223 dichloride (Xofigo®), also known as radium-223 is considered investigational when the above criteria is not met, including but not limited to the any of the following:

  • Reason for treatment is other than the diagnosis of castration-resistant prostate cancer (CRPC)
  • When used in combination with chemotherapy or biologic therapy
  • Has received a previous course of Radium Ra 223 dichloride (Xofigo®)
  • Beyond 6 injections (exceeding the FDA approved dosing)

 

Based on the peer reviewed medical literature the safety and effectiveness for indications other than the medically necessary indication listed above has not been established. Additional studies are needed to further investigate the safety and efficacy of radium-223 (Xofigo®) for the patient populations other than castration-resistant prostate cancer (CRPC). Also, the FDA approved label indication state the safety and efficacy beyond 6 injections with radium-223 (Xofigo®) has not been studied; and the safety and efficacy of concomitant chemotherapy with radium-223 (Xofigo®) have not been established. The evidence is insufficient to demonstrate the effects on net health outcomes for the indications listed above. 

 

Policy Guidelines

  • Prior to the initial dose of radium-223, patients must have an absolute neutrophil count ≥ 1.5 X 109/L, platelet count ≥ 100 X 109, and hemoglobin ≥ 10g/dL. 
  • Prior to subsequent doses of radium-223, patients must have absolute neutrophil count ≥ 1 X 109/L and platelet count ≥ 50 X 109 per label. 
  • Radium-223 should be discontinued if a delay of 6-8 weeks does not result in return of blood counts to these levels.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • A9606 Radium RA-223 dichloride, therapeutic per microcurie

 

Selected References:

  • Cookson M, Roth B, Dahm P, et. al. Castration-Resistant Prostate Cancer: American Urological Association Guideline. May 2013 (Amended April 2015). J Urol 2015 Feb;193(2):491-9. PMID 25444753
  • National Comprehensive Cancer Network (NCCN) Prostate Cancer Version 4.2019.
  • National Comprehensive Cancer Network (NCCN) Bone Cancer Version 1.2020.
  • UpToDate. Radium-223 Drug Information Lexicomp.
  • UpToDate. Bone Metastases in Advanced Prostate Cancer: Management. A Oliver Sartor M.D., Steven J. DiBiase M.D., Topic last updated July 16, 2019.
  • UpToDate. Overview of the Treatment of Castration-Resistant Prostate Cancer (CRPC). Nancy A. Dawson M.D., Topic last updated September 10, 2018.
  • UpToDate. Radiation Therapy for the Management of Painful Bone Metastases. Lisa A. Kachinic M.D., Steven J. DiBiase M.D., Topic last updated May 30, 2019.
  • UpToDate. Cancer Pain Management: Adjuvant Analgesics (Coanalgesics). Russell K. Portenoy M.D., Ebtesam Ahmed, PharmD, MS, Yair Y. Keilson M.D., Topic last updated September 4, 2018. 
  • UpToDate. Overview of Therapeutic Approaches for Adult Patients with Bone Metastasis from Solid Tumors. H. Michael Yu, M.D.,ScM, Sarah E. Hoffe M.D., Topic last updated May 10, 2019. 
  • UpToDate. Radiation Therapy Techniques in Cancer Treatment. Topic last updated August 1, 2017.
  • Anderson PM, Subbiah V, Rohren E. Bone seeking radiopharmaceuticals as targeted agents of osteosarcoma: samarium-153-EDTMP and radium-223. Adv Exp Med Biol 2014;804:291-304. PMID 24924191
  • Cheetam PJ, Petrylak DP. Alpha particles as radiopharmaceuticals in the treatment of bone metastases: mechanism of action of radium-223 chlroide (Alpharadin) and radiation protection. Oncology (Williston Park) 2012 Apr;26(4):330-7. PMID 22655525
  • Harrison MR, Wong TZ, Armstrong AJ, et. al. Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease. Cancer Manag Res 2013;5:1-14. PMID 23326203
  • Nilsson S, Strang P, Aksnes AK, et. al. A randomized, dose response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. Eur J Cancer 2012 Mar;48(5):578-86. PMID 22341993
  • Nilsson S, Franzen L, Parker C, et. al. Two-year survival follow-up of the randomized, double-blind placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases. Clin Genitourin Cancer 2013 Mar;11(1):20-6. PMID 23021204
  • Parker CC, Pascoe S, Chodacki A, et. al. A randomized double-blind, dose-finding, multicenter, phase 2 study of radium chloride (RA 223) in patients with bone metastases and castration-resistant prostate cancer. Eur Urol 2013 Feb;63(2):189-97. PMID 23000088
  • Parker C, Nilsson S, Heinrich D, et. al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. The New England Journal of Medicine July 18, 2013 Vol. 369 No. 3     
  • Vapiwala N, Glatstein E. Fighting prostate cancer with radium-223 not your Madame’s isotope. N Engl J Med 2013 Jul 18;369(3):276-8. PMID 23863055
  • MacVicar GR, Hussain MH. Emerging therapies in metastatic castration-sensitive and castration-resistant prostate cancer. Curr Opin Oncol 2013 May;25(3):252-60. PMID 23511665
  • Takalkar A, Adams S, Subbiah V. Radium-223 dichloride bone-targeted alpha particle therapy for hormone refractory breast cancer metastatic to bone. Exp Hematol Oncol 2014 Sep 8;3:23. PMID 25243101
  • Colman R, Aksnes AK, Naume B, et. al. A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease. Breast Cancer Res Treat 2014 Jun;145(2):411-8. PMID 2472861
  • Subbiah V, Anderson P, Rohren E. Alpha-emitter radium 223 in high risk osteosarcoma: first clinical evidence of response and blood-brain barrier penetration. JAMA Oncol 2015 May;1(2):253-5. PMID 26181034
  • Nilsson S. Alpha-emitter radium-223 in the management of solid tumors: current status and future directions. Am Soc Clin Oncol Educ Book 2014:e132-9. PMID 24857093
  • Silva SC, Wilson C, Woll PJ. Bone Targeted agents in the treatment of lung cancer. Ther Adv Med Oncol 2015 Vol. 7(4) 219-228
  • Saad F, Carles J, Gillessen S, et. al. Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open label, single arm phase 3b trial. Lancet Oncol 2016 Sep;17(9):1306-16. PMID 27473888
  • Joung JY, Ha YS, Kim IY, Radium Ra 223 dichloride in castration-resistant prostate cancer. Drugs Today (Barc) 2013 Aug;49(8):483-90. PMID 23977665
  • Xofigo-Radium Ra 223 Dichloride.
  • Doyle CM, Mills M, Damgaci S, et. al. Integration of Radium-223 Dichloride (Xofigo) into Clinical Practice for the Treatment of Castration-Resistant Prostate Cancer. Journal of Clinical Oncology 2019 37;7 suppl 312-312
  • American Cancer Society. What’s New in Osteosarcoma Research? 
  • Deshayes E, Roumiguie M, Thibault C, et. al. Radium 223 dichloride for prostate treatment. Drug Des Devel Ther 2017;11:2643-2651. PMID 28919714
  • Morris MJ, Loriot Y, Sweeney CJ, et. al. Radium-223 in combination with docetaxel in patients with castration-resistant prostate cancer and bone metastases: a phase 1 dose escalation/randomized phase 2a trial. Eur J Cancer 2019 Jun;114:107-116. PMID 31082669
  • Subbiah V, Anderson PM, Keriemo K, et. al. Alpha particle radium 223 dichloride in high risk osteosarcoma: a phase I dose escalation trial. Clin Cancer Res 2019 Jul 1;25(13):3802-3810. PMID 30733229
  • Taber AM, Riley D, Adam J, et. al. Radium-223 following front line chemotherapy for patients with non-small cell lung cancer and bone metastases. Journal of Clinical Oncology 2018 36:15 suppl  e21211-e21211
  • Geva R, Lopez J, Danson S, Joensuu H, et. al. Radium-223 in combination with pacilataxel in cancer patients with bone metastases: safety results from an open label, multicenter phase Ib study. Eur J Nucl Med Mol Imaging 2019 May;46(5):1092-1101. PMID 30547207
  • Sullivan J, Carles J, Cathomas R, et. al. Radium-223 within the evolving treatment options for metastatic castration-resistant prostate cancer: recommendations from a European Expert Working Group.
  • Silva S, Wilson C, Woll P. Bone-targeted agents in the treatment of lung cancer. Ther Adv Med Oncol 2015 Jul;7(4):219-228. PMID 26136853

 

Policy History:

  • September 2019 - Annual Review, Policy Renewed
  • September 2018 - Annual Review, Policy Revised
  • September 2017 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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