Radium Ra 223 Dichloride (Xofigo)

Number: 0874

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Note: Requires Precertification:

Precertification of radium Ra 223 dichloride (Xofigo) is required of all Aetna participating providers and members in applicable plan designs. For precertification of radium Ra 223 dichloride (Xofigo), call (866) 752-7021 (Commercial), or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

For Medicare Part B plans, call (866) 503-0857, or fax (844) 268-7263.

1. Criteria for Initial Approval

   Prostate Cancer

   Aetna considers one course (a total of 6 injections of radium Ra 223 dichloride (Xofigo) medically necessary for treatment of bone metastases for members with castration-resistant prostate cancer when both of the following criteria are met:

   1. The member has symptomatic bone metastases; and
   2. The member does not have visceral metastatic disease.
      
      Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   See Dosage and Administration information.

Related Policies

• CPB 0361 - Radiopharmaceuticals Strontium-89 (Metastron) and Samarium-153 (Quadramet) for Bone Pain
• CPB 0802 - Prostate Cancer Vaccine
• CPB 0806 - Cabazitaxel (Jevtana)

Dosage and Administration

Xofigo (radium Ra 223 dichloride) is available as a single-dose vial at a concentration of 1,100 kBq/mL (30 microcurie/mL) at the reference date with a total radioactivity of 6,600 kBq/vial (178 microcurie/vial) at the reference date.

The recommended dose regimen of Xofigo is 55 kBq (1.49 microcurie) per kg body weight, given at 4-week intervals for 6 injections. Xofigo is to be administered by slow intravenous injection over 1 minute.

Note: Safety and efficacy beyond 6 injections with Xofigo have not been studied.

See Full Prescribing Information for calculation of volume to be administered (mL). 

Source: Bayer Healthcare, 2019

Experimental and Investigational

Aetna considers more than one course (total of 6 injections) of radium Ra 223 dichloride (Xofigo) experimental and investigational because the safety and efficacy of more than one course has not been established. 

Aetna considers the use of radium Ra 223 dichloride (Xofigo) experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications have not been established:

• Bone metastasis from breast cancer, kidney cancer, lung cancer and paraganglioma
• Breast cancer
• For use in combination with bortezomib for the treatment of multiple myeloma
• For use in combination with docetaxel or any other chemotherapy
• For use in combination with irreversible electroporation for the treatment of prostate cancer bone metastasis
• Osteosarcoma
  

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Xofigo (radium (Ra-223) dichloride):
Other CPT codes related to the CPB:
0600T	Ablation, irreversible electroporation; 1 or more tumors per organ, including imaging guidance, when performed, percutaneous
0601T	Ablation, irreversible electroporation; 1 or more tumors, including fluoroscopic and ultrasound guidance, when performed, open
96413 - 96417	Chemotherapy administration; intravenous infusion technique
HCPCS codes covered if selection criteria are met:
A9606	Radium RA-223 dichloride, therapeutic, per microcurie
Other HCPCS codes related to the CPB:
J9041	Injection, bortezomib (Velcade), 0.1 mg
J9046	Injection, bortezomib, (dr. reddy's), not therapeutically equivalent to J9041, 0.1 mg
J9048	Injection, bortezomib (fresenius kabi), not therapeutically equivalent to J9041, 0.1 mg
J9049	Injection, bortezomib (hospira), not therapeutically equivalent to J9041, 0.1 mg
J9217	Injection, docetaxel, 1 mg
ICD-10 codes covered if selection criteria are met:
C61	Malignant neoplasm of prostate (dual diagnosis required - report C61 and C79.51)
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
C40.00 - C41.9	Malignant neoplasm of bone [osteosarcoma]
C50.011 - C50.929	Malignant neoplasm of breast
C64.1 - C64.9	Malignant neoplasm of kidney
C79.51	Secondary malignant neoplasm of bone [renal cell carcinoma]
C90.00 – C90.02	Multiple myeloma

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Xofigo is an alpha particle-emitting radioactive therapeutic agent indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.

Radium Ra 223 dichloride is available as Xofigo (Bayer HealthCare Pharmaceuticals Inc). Radium Ra 223 dichloride mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The high linear energy transfer of alpha particles (80 keV/micrometer) leads to a high frequency of double-strand DNA breaks in adjacent cells including tumor cells, osteoblasts and osteoclasts, resulting in an anti-tumor 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 the surrounding normal tissue (Bayer HealthCare Pharmaceuticals, 2019).

The label for Xofigo carries warning and precautions for bone marrow suppression, increased fractures and mortality in combination with abiraterone plus prednisone/prednisolone, and embryo-fetal toxicity. The most common adverse drug reactions (10% or more) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema. The most common hematologic laboratory abnormalities (10% or more) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia.

Prostate Cancer

Approximately 85 % to 90 % of patients with castration-resistant prostate cancer (CRPC) have radiological evidence of bone metastases, which are a major cause of decreased quality-of-life, disability, and death.  To-date, however, treatments for bone metastases have been primarily palliative (Cheetham and Petrylak, 2012).  Radiation-based treatments have been shown to provide palliative care in patients with advanced PC.  Radium Ra 223, a well-tolerated alpha-emitter with a half-life of 11.4 days, is a calcium mimetic that naturally self-targets to areas of increased bone turnover in bone metastases.  It emits high-energy alpha particles of short range (less than 100 um) that produce a potent and highly localized cytotoxic effect in the target areas.  Recent studies have reported that Ra-223 has a favorable safety profile with minimal myelotoxicity in patients with bone metastases; thus, it may serve as a new therapeutic modality in patients with bone metastatic CRPC. 

The Spanish Society of Clinical Oncology’s clinical guidelines for the treatment of PC (Arranz Arija et al, 2012) noted that many patients with PC have prolonged survival and die of other diseases, so therapeutic decisions are often influenced by age and co-morbidities.  The main procedure to diagnose PC is an ultrasound-guided core needle biopsy, which is indicated when a digital rectal examination finds nodularity or when prostate-specific antigen (PSA) is greater than 10 ng/ml, but is also recommended with PSA between 4.0 and 10 ng/ml.  Depending on age, PSA, Gleason score and characteristics of the tumor, therapeutic options for localized PC are active surveillance, radical prostatectomy, and radiotherapy.  Androgen deprivation treatment should be added to radiotherapy for men with intermediate- or high-risk PC.  Androgen deprivation treatment is the current standard first-line treatment for metastatic PC.  Several treatments such as Ra-223, sipuleucel-T, docetaxel-based chemotherapy, cabazitaxel or abiraterone plus prednisone, zoledronic and denosumab, are useful for CRPC.

Harrison et al (2013) discussed the clinical data currently available regarding the safety and effectiveness of Ra-223.  Data from clinical trials including abstracts were collected and reviewed using the PubMed database, as well as the American Society of Clinical Oncology abstract database.  Current bone-targeted therapies can be categorized into 2 main groups:

1. anti-resorptive agents (e.g., denosumab, zoledronic acid), which have been shown to delay skeletal-related events (SREs), and
2. radiopharmaceuticals (e.g., samarium-153, strontium-89), which may have a role in pain palliation.

Historically, neither anti-resorptive agents nor radiopharmaceuticals have shown definitive evidence of improved overall survival (OS) or other anti-tumor effects in metastatic CRPC.  Radiopharmaceuticals are limited by myelosuppression, renal excretion, and thrombocytopenia.  In a recently reported randomized phase III trial in men with symptomatic bone-metastatic CRPC who had received or were ineligible for docetaxel chemotherapy, Ra-223 treatment resulted in improved OS and delayed SRE.  Toxicity consisted of minor gastro-intestinal side effects and mild neutropenia and thrombocytopenia that were rarely severe.

Nilsson and associates (2012) examined the dose-response relationship and pain-relieving effect of Ra-223.  A total of 100 patients with CRPC and painful bone metastases were randomized to a single intravenous dose of 5, 25, 50 or 100 k Bq/kg of body weight Ra-223.  The primary end-point was pain index (visual analog scale [VAS] and analgesic use); pain index was also used to classify patients as “responders” or “non-responders”.  A significant dose response for pain index was seen at week 2 (p = 0.035).  At week 8 there were 40 %, 63 %, 56 % and 71 % pain responders (reduced pain and stable analgesic consumption) in the 5, 25, 50 and 100 k Bq/kg groups, respectively.  On the daily VAS, at week 8, pain decreased by a mean of -30, -31, -27 and -28 mm, respectively (p = 0.008, p = 0.0005, p = 0.002, and p < 0.0001) in these responders (post-hoc analysis).  There was also a significant improvement in the brief pain inventory functional index for all dose-groups (p = 0.04, 0.01, 0.002 and 0.02, Wilcoxon signed rank test).  Furthermore, a decrease in bone alkaline phosphatase (a disease-related biomarker) in the highest dose-group was demonstrated (p = 0.0067).  All doses were safe and well-tolerated.  The authors concluded that pain response was seen in up to 71 % of the patients with a dose response observed 2 weeks after administration; and the highly tolerable side effect profile of Ra-223 previously reported was confirmed.

In a phase II, randomized, placebo-controlled study, Nilsson and colleagues (2013) evaluated the safety and effectiveness of Ra-223 in patients with CRPC and painful bone metastases.  In this study, these researchers reported the 24-month OS and safety data from the period 12 to 24 months after the first injection of study medication.  Patients with CRPC and bone pain were randomized 1:1 to receive 4 injections of Ra-223 (50 kBq/kg [n = 33]) or placebo [n = 31]) after external-beam radiotherapy; each injection was given every 4 weeks.  End-points for this report were 24-month OS, long-term safety, and treatment-related adverse events (AEs) occurring in the 12- to 24-month period.  After 24 months, 10 (30 %) patients were alive in the Ra-223 group compared with 4 patients (13 %) in the placebo group.  Patients who received at least 1 dose of study medication had a median OS of 65 weeks in the Ra-223 group versus 46 weeks in the placebo group (log-rank p = 0.056).  The hazard ratio (HR) for OS, adjusted for baseline co-variates, was 0.476 (95 % confidence interval [CI]: 0.258 to 0.877; Cox regression p = 0.017).  The most frequent cause of death for both arms was disease progression.  There were no reports of treatment-related AEs or long-term hematologic toxicity during the 12- to 24-month follow-up.  The authors concluded that Ra-223 had a highly favorable safety profile, with no evidence of second malignancies at 24-month follow-up.  The significant improvement in OS observed in patients receiving Ra-223 versus placebo suggested that treatment of bone disease with Ra-223 has survival benefits.

In a phase II, double-blind, multi-center clinical trial, Parker et al (2013a) prospectively evaluated the safety and effectiveness of 3 different doses of Ra-223 in patients with CRPC and bone metastases.  A total of 122 patients were randomized to receive 3 injections of Ra-223 at 6-week intervals, at doses of 25 kBq/kg (n = 41), 50 kBq/kg (n = 39), or 80 kBq/kg (n = 42).  The study compared the proportion of patients in each dose group who had a confirmed decrease of greater than or equal to 50 % in baseline PSA levels.  Effectiveness was evaluated using blood samples to measure PSA and other tumor markers, recorded SREs, and pain assessments.  Safety was evaluated using AEs, physical examination, and clinical laboratory tests.  The Jonckheere-Terpstra test assessed trends between groups.  The study met its primary end-point with a statistically significant dose-response relationship in confirmed greater than or equal to 50 % PSA declines for no patients (0 %) in the 25 kBq/kg dose group, 2 patients (6 %) in the 50 kBq/kg dose group, and 5 patients (13 %) in the 80 kBq/kg dose group (p = 0.0297).  A greater than or equal to 50 % decrease in bone alkaline phosphatase levels was identified in 6 patients (16 %), 24 patients (67 %), and 25 patients (66 %) in the 25, 50, and 80 kBq/kg dose groups, respectively (p < 0.0001).  The most common treatment-related AEs (greater than or equal to 10 %) occurring up to week 24 across all dose groups were diarrhea (21 %), nausea (16 %), and anemia (14 %).  No difference in incidence of hematologic events was seen among dose groups.  The authors concluded that Ra-223 had a dose-dependent effect on serum markers of CRPC activity, suggesting that control of bone disease with Ra-223 may affect cancer-related outcomes.  They noted that Ra-223 was well-tolerated at all doses.

In a phase III clinical trial, Parker et al (2013b) assessed the safety and effectiveness of Ra-223 as compared with placebo, in addition to the best standard of care, in men with CRPC and bone metastases.  These investigators randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive 6 injections of Ra-223 (at a dose of 50 kBq/kg intravenously) or matching placebo; 1 injection was administered every 4 weeks.  In addition, all patients received the best standard of care.  The primary end-point was OS.  The main secondary efficacy end-points included time to the first symptomatic SREs and various biochemical end-points.  A pre-specified interim analysis, conducted when 314 deaths had occurred, assessed the effect of Ra-223 versus placebo on survival.  An updated analysis, when 528 deaths had occurred, was performed before cross-over from placebo to Ra-223.  At the interim analysis, which involved 809 patients, Ra-223, as compared with placebo, significantly improved OS (median of 14.0 months versus 11.2 months; HR, 0.70; 95 % CI: 0.55 to 0.88; 2-sided p = 0.002).  The updated analysis involving 921 patients confirmed the Ra-223 survival benefit (median of 14.9 months versus 11.3 months; HR, 0.70; 95 % CI: 0.58 to 0.83; p < 0.001).  Assessments of all main secondary efficacy end-points also showed a benefit of Ra-233 as compared with placebo.  Radium-223 was associated with low myelosuppression rates and fewer AEs.  The authors concluded that in this study, which was terminated for efficacy at the pre-specified interim analysis, Ra-223 improved OS.

In an editorial that accompanied the afore-mentioned study, Vapiwala and Glatstein (2013) stated that Ra-223 is the first alpha emitter to undergo phase III testing and received Food and Drug Administration (FDA) approval for clinical use in metastatic CRPC.  They also noted that there is an active but not recruiting phase II clinical trial in the use of Ra-223 for breast cancer, and 2 open phase I-IIA studies in the use of Ra-223 in combination with docetaxel for metastatic CRPC.

In a review on “Emerging therapies in metastatic castration-sensitive and castration-resistant prostate cancer”, MacVicar and Hussain (2013) stated that for chemotherapy-naive, metastatic CRPC, abiraterone is effective.  Trials with additional agents targeting androgen receptor (AR) signaling, such as TAK-700 and enzalutamide, are ongoing.  Other agents in development target the endothelin pathway, angiogenesis, AR chaperones, and immune mechanisms.  Docetaxel with prednisone remains the standard first-line chemotherapeutic regimen as trials incorporating novel agents with docetaxel have been negative.  Post-docetaxel, enzalutamide improves survival.  Early results with cabozantinib are encouraging, and phase III studies are ongoing.  Denosumab and Ra-223 reduce the risk of SREs, but only Ra-223 improves survival.

On May 15, 2013, the FDA approved Xofigo (Ra-223 dichloride) for the treatment of men with symptomatic metastatic CRPC that has spread to bones but not to other organs.  It is intended for men whose cancer has spread after receiving medical or surgical therapy to lower testosterone.  The clinical trial supporting FDA's approval of Xofigo used 6 doses of Ra-223 every 4 weeks.  The most common side effects reported during clinical trials in men receiving Xofigo were diarrhea, nausea, vomiting, as well as swelling of the leg, ankle or foot.  The most common abnormalities detected during blood testing included anemia, leukopenia, lymphocytopenia, and neutropenia, and thrombocytopenia.

The clinical trial supporting Food and Drug Administration's approval of Xofigo used 6 doses of Ra-223 (1 dose every 4 weeks).  Third and subsequent doses of Xofigo should be discontinued if absolute neutrophil count does not return to greater than or equal to 1.0 x 10(9)/L, and platelet count does not return to greater than or equal to 50 x 10(9)/L 6 to 8 weeks after the administration of the second or last dose.

Takalkar et al (2014) stated that hormone-refractory breast cancer metastatic to bone is a clinically challenging disease associated with high morbidity, poor prognosis, and impaired quality of life owing to pain and skeletal-related events.  In a pre-clinical study using a mouse model of breast cancer and bone metastases, Ra-223 dichloride was incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all p values < 0.001) in-vitro.  Ra-223 dichloride also induced double-strand DNA breaks in cancer cells in-vivo.  The FDA recently approved Xofigo injection (Ra-223) for the treatment of symptomatic bone metastases in patients with CRPC.  On the basis of a strong pre-clinical rationale, these researchers used Ra-223 dichloride to treat bone metastases in a patient with breast cancer.  These investigators presented the case of a 44-year old white woman with metastatic breast cancer who was estrogen receptor-positive, BRCA1-negative, BRCA2-negative, PIK3CA mutation (p.His1047Arg) positive presented with diffuse bony metastases and bone pain.  She had hormone refractory and chemotherapy refractory breast cancer.  After Ra-223 therapy initiation her bone pain improved, with corresponding decrease in tumor markers and mixed response in (18)F-fluorodeoxyglucose positron emission tomography and computed tomography (FDG PET/CT) and (18)F-NaF bone PET/CT.  The patient derived clinical benefit from therapy.  The authors concluded that they have shown that Ra-223 dichloride can be safely administered in a patient with hormone-refractory bone metastasis from breast cancer at the FDA-approved dose for prostate cancer.  Furthermore, because the treatment did not cause any drop in hematologic parameters, it has the potential to be combined with other radio-sensitizing therapies, which may include chemotherapy or targeted therapies.  Given that Ra-223 dichloride is already commercially available, this case report may help future patients and provide a rationale for initiating clinical research in the use of Ra-223 dichloride to treat bone metastasis from breast cancer.  They stated that a randomized clinical trial (RCT) is needed to provide evidence of efficacy, safety, and good outcomes.

Coleman et al (2014) noted that Ra-223 mimics calcium and emits high-energy, short-range alpha-particles resulting in an anti-tumor effect on bone metastases.  In an open-label, phase IIa non-randomized study, these researchers investigated the safety and short-term effectiveness of Ra-223 in breast cancer patients with bone-dominant disease.  A total of 23 advanced breast cancer patients with progressive bone-dominant disease, and no longer candidates for further endocrine therapy, received Ra-223 (50 kBq/kg IV) every 4 weeks for 4 cycles.  The co-primary end points were change in urinary N-telopeptide of type 1 (uNTX-1) and serum bone alkaline phosphatase (bALP) after 16 weeks of treatment.  Exploratory end-points included sequential FDG PET/CT to assess metabolic changes in osteoblastic bone metastases.  Safety data were collected for all patients.  Radium-223 significantly reduced uNTX-1 and bALP from baseline to end of treatment.  Median uNTX-1 change was -10.1 nmol bone collagen equivalents/mmol creatinine (-32.8 %; p = 0.0124); median bALP change was -16.7 ng/ml (-42.0 %; p = 0.0045).  Twenty of 23 patients had FDG PET/CT identifying 155 hypermetabolic osteoblastic bone lesions at baseline: 50 lesions showed metabolic decrease (greater than or equal to 25 % reduction of maximum standardized uptake value from baseline) after 2 Ra-223 injections [32.3 % metabolic response rate (mRR) at week 9], persisting after the treatment period (41.5 % mRR at week 17).  Radium-223 was safe and well-tolerated.  The authors concluded that Ra-223 targeted areas of increased bone metabolism and showed biological activity in advanced breast cancer patients with bone-dominant disease.

Anderson et al (2014) stated that osteosarcoma is a cancer characterized by formation of bone by malignant cells.  Routine bone scan imaging with Tc-99m-MDP is done at diagnosis to evaluate primary tumor uptake and check for bone metastases.  At time of relapse the Tc-99m-MDP bone scan also provides a specific means to assess formation of bone by malignant osteosarcoma cells and the potential for bone-seeking radiopharmaceuticals to deliver radioactivity directly into osteoblastic osteosarcoma lesions.  These investigators reviewed and compared a bone-seeking radiopharmaceutical that emits beta-particles, samarium-153-EDTMP, with an alpha-particle emitter Ra-223.  The charged alpha particles from Ra-223 have far more mass and energy than beta particles (electrons) from Sm-153-EDTMP.  Because Ra-223 has less marrow toxicity and more radiobiological effectiveness, especially if inside the bone forming cancer cell than samarium-153-EDTMP, Ra-223 may have greater potential to become widely used against osteosarcoma as a targeted therapy.  Radium-223 also has more potential to be used with chemotherapy against osteosarcoma and bone metastases.  Because osteosarcoma makes bone and Ra-223 acts like calcium, this radiopharmaceutical could possibly become a new targeted means to achieve safe and effective reduction of tumor burden as well as facilitate better surgery and/or radiotherapy for difficult to resect large, or metastatic tumors.

Nilsson (2014) noted that bone metastases, which are commonly seen in patients with advanced cancers, are a major cause of skeletal events, disability, and death.  Radium-223 dichloride (Xofigo, formerly Alpharadin), a first-in-class, alpha-emitting radiopharmaceutical that selectively targets bone metastases with high-energy short-range alpha-particles, has been approved for the treatment of patients with CRPC with symptomatic bone metastases and no known visceral metastases.  Approval is based on results of the randomized phase III trial Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA), in which Ra-223 prolonged OS and time to first symptomatic SRE versus placebo among patients with CRPC with symptomatic bone metastases and was generally well-tolerated, with low myelosuppression rates and manageable gastro-intestinal adverse events.  Long-term follow-up of the ALSYMPCA safety population showed that the incidence of myelosuppression remained low among patients treated with Ra-223, with no additional safety issues of acute myelogenous leukemia, myelodysplastic syndrome, aplastic anemia, or primary bone cancer within approximately 1.5 years after treatment.  The Ra-223 OS benefit and low toxicity make it an effective, well-tolerated, and novel treatment option for CRPC and symptomatic bone metastases and opens the possibility of exploring Ra-223 in the treatment of bone metastases from other cancers.  A phase I clinical trial of patients with breast and prostate cancer with skeletal metastases demonstrated that Ra-223 was safe and well-tolerated at all therapeutically relevant dosages.  Moreover, a phase IIa trial of patients with advanced breast cancer and progressive bone-dominant disease demonstrated that Ra-223 targeted areas of increased bone metabolism and showed biologic activity.

The National Comrehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN, Version 1.2023) include the following for use of radium-223 for prostate cancer:

• Radium-223 has been shown to extend survival in men who have CRPC with symptomatic bone metastases, but not visceral metastases.
• Radium-223 alone has not been shown to extend survival in men with visceral metastases or bulky nodal disease (greater than 3-4 cm).
• Radium-223, an alpha-emitting radiopharmaceutical, differs from beta-emitting agents (e.g., samarium 153 and strontium-89), which are palliative and have no survival advantage.
• 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 (ANC) greater than or equal to 1.5 x 10⁹/L, platelet count greater than or equal to 100 x 10⁹/L, and hemoglobin greater than or equal to 10 g/dL.
• Prior to subsequent doses, patients must have ANC greater than or equal to 1 x 10⁹/L and platelet count greater than or equal to 50 x 10⁹/L (per label).
• Radium-223 is not intended to be used in combination with chemotherapy due to the potential for additive myelosuppression, except in clinical trial. 
• Radium-223 is not recommended for use in combination with docetaxel or any other systemic therapy except ADT and should not be used in patients with visceral metastases.
• Concomitant use of denosumab or zoledronic acid is recommended; it does not interfere with the beneficial effects of radium-223 on survival.

Combination Treatments

Combined Radium-223 and Bortezomib for the Treatment of Multiple Myeloma

Suominen and colleagues (2021) stated that osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function.  The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients.  Radium-223, the 1st targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis.  These researchers hypothesized that Ra-223 and bortezomib combination treatment would have additive effects on MM.  In-vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy.  In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and Ra-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone.  Bortezomib decreased the number of osteoclasts at the tumor-bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts.  Furthermore, the combination therapy improved the incorporation of Ra-223 into MM-bearing bone.  More importantly, the combination therapy decreased tumor burden and restored body weights in MM mice.  The authors concluded that the findings of this study suggested that the combination of Ra-223 and bortezomib is a promising novel therapy in MM and provide a rationale for further studies in the clinical setting.

Combined Radium-223 and Irreversible Electroporation for the Treatment of Prostate Cancer Bone Metastasis

Rojo and colleagues (2021) stated that metastatic prostate cancer in bone is difficult to treat as the tumor cells are relatively resistant to hormonal or chemotherapies when compared to primary prostate cancer.  Irreversible electroporation (IRE) is a minimally invasive ablation procedure that has potential applications in the management of prostate cancer in bone.  However, a common limitation of IRE is tumor recurrence, which arises from incomplete ablation that allows remaining cancer cells to proliferate.  In this study, thee researchers combined IRE with Ra-223 (Ra-223), a bone-seeking radionuclide that emits short track length alpha particles and thus is associated with reduced damage to the bone marrow and examined the impact of the combination treatment on bone-forming prostate cancer tumors.  The anti-tumor activity of IRE and Ra-223 as single agents and in combination was tested in-vitro against 3 bone morphogenetic protein 4 (BMP4)-expressing prostate cancer cell lines (C4-2B-BMP4, Myc-CaP-BMP4, and TRAMP-C2-BMP4).  Similar evaluation was carried out in-vivo using a bone-forming C4-2B-BMP4 tumor model in nude mice.  IRE and Ra-223 as monotherapy inhibited prostate cancer cell proliferation in-vitro, and their combination resulted in significant reduction in cell viability compared to monotherapy.  In-vivo evaluation revealed that IRE with single-dose administration of Ra-233, compared to IRE alone, reduced the rate of tumor recurrence by 40 % following initial apparent complete ablation and decreased the rate of proliferation of incompletely ablated tumor as quantified in Ki-67 staining (53.58 ± 16.0 % for IRE versus 20.12 ± 1.63 %; for IRE plus Ra-223; p = 0.004).  Histological analysis qualitatively showed the enhanced killing of tumor cells adjacent to bone by Ra-223 compared to those treated with IRE alone.  The authors concluded that IRE in combination with Ra-223, which enhanced the destruction of cancer cells that were adjacent to bone, resulted in reduction of tumor recurrence via improved clearance of proliferative cells in the tumor region.  Moreover, these researchers stated that further pre-clinical studies using orthotopic models that recapitulate the tumor microenvironment in the bone are needed to examine if the combination of IRE with Ra-223 and possibly a 3rd agent is effective for prostate cancer bone metastasis.

Combined Radium-223, Androgen Deprivation Therapy, and Pelvic Radiotherapy for the Treatment of Metastatic Hormone-Sensitive Prostate Cancer

Turner and colleagues (2021) stated that Ra-223 is an alpha-emitting radionuclide associated with OS improvement in metastatic castration-resistant prostate cancer (mCRPC).  External beam radiotherapy (EBRT) to prostate extends OS in men with metastatic hormone-sensitive prostate cancer (mHSPC) limited to less than 4 metastases.  These researchers hypothesized that combination Ra-223 + pelvic EBRT could safely deliver maximal radiotherapy (RT) doses to primary and metastatic prostate cancer and may improve disease control.  A total of 30 patients with de-novo bone mHSPC who had commenced androgen deprivation therapy (ADT) and docetaxel were recruited to a prospective, open-label, single-arm clinical trial: Neo-adjuvant ADT, pelvic RT and Ra-223 (ADRRAD; for new presentation T1-4 N0-1 M1B adenocarcinoma of prostate).  Study treatments included ADT, 6 cycles of Ra-223 q28 days, conventionally fractionated prostate RT (74 Gy) and simultaneous integrated boost to pelvic lymph nodes (60 Gy).  No grade-4 or grade-5 toxicity was observed; 3 patients experienced grade-3 leukopenia, and 1 each experienced grade-3 neutropenia and thrombocytopenia; all were asymptomatic; 1 patient each experienced grade-3 dysuria and grade-3 urinary infection.  No grade-3 gastro-intestinal (GI) toxicity was observed.  On treatment completion, there was a signal of efficacy; 24 (80 %) patients had whole-body MRI evidence of tumor response or stability; 27 (90 %) patients showed a reduction in alkaline phosphatase (ALP) compared with pre-treatment levels.  Median PFS was 20.5 months.  The authors concluded that this was the 1st trial of combination Ra-223, ADT and EBRT to pelvis, post-docetaxel; the combination was safe, with an efficacy signal.  Moreover, these researchers stated that multi-center RCTs are needed.

Combined Radium-223 Plus Abiraterone or Atezolizumab or Enzalutamide for the Treatment of Metastatic Castration-Refractory Prostate Cancer

Maughan and colleagues (2021) stated that they previously showed the combination of Ra-223 and enzalutamide to be safe and associated with improved efficacy based on a concomitant decline in serum bone metabolism markers compared with enzalutamide alone in a phase-II clinical trial of men with mCRPC.  Secondary endpoints were not included in the initial report, and these researchers included them herein, after a median follow-up of 22 months.  These objectives included long-term safety, PSA progression-free survival (PFS), and radiographic PFS ; PSA-PFS2 (time from start of protocol therapy to PSA progression on subsequent therapy); time to next subsequent therapy (TTNT); and OS.  Survival analysis and log-rank tests were carried out using the R statistical package v.4.0.2 (https://www.r-project.org). Statistical significance was defined as p < 0.05.  Of 47 patients (median age of 68 years) in this study, 35 received the combination and 12 enzalutamide alone.  After a median follow-up of 22 months, final safety results did not show any increase in fractures or other AEs in the combination arm.  PSA-PFS2 was significantly improved, and other efficacy parameters were numerically improved in the combination over the enzalutamide arm.  The authors concluded that the findings of this study were hypothesis-generating; however, routine use of combined Ra-223 and enzalutamide may not be recommended based on these results.  The ongoing phase-III clinical trial (the PEACE-3 Trial) randomizing patients to Ra-223 plus enzalutamide versus enzalutamide alone in men with mCRPC will conclusively determine the therapeutic role of this combination. 

Kim and associates (2021) noted that Ra-223, abiraterone, and enzalutamide have each been shown to significantly improve survival as monotherapy in patients with mCRPC; however, effects of combination Ra-223 plus abiraterone or enzalutamide on survival and safety remain unclear.  In a retrospective, single-center, cohort study, these researchers used electronic health record data of patients with mCRPC and bone metastases who were treated with Ra-223 between April 1, 2014 and February 19, 2019.  Patients who received Ra-223 monotherapy were compared to patients who received a combination of Ra-223 plus either abiraterone or enzalutamide.  The primary endpoint was OS; secondary endpoints included PFS, time to symptomatic skeletal event, symptomatic skeletal event (SSE)-free survival, and incidence of drug-related AEs.  Time-to-event analyses were estimated by log rank tests using Kaplan-Meier curves; HR and 95 % CIs were derived from Cox proportional hazards models.  Chi-square tests evaluated difference in serious AEs between the 2 arms.  A total of 60 patients met inclusion criteria (n = 41 in the monotherapy arm, n = 19 in the combination arm).  Differences in median OS were not observed (12.7 versus 12.8 months; HR 1.15, 95 % CI: 0.59 to 2.23; p = 0.68), but median PFS was significantly longer in the combination arm (7.6 versus 4.9 months; HR 1.94, 95 % CI: 1.11 to 3.40; p = 0.02).  Significant differences were not observed in time to 1st SSE (p = 0.97), SSE-free survival (p = 0.16), or in the overall incidence of serious AEs (p = 0.45).  The authors concluded that combination Ra-223 plus abiraterone or enzalutamide did not improve OS, but prolonged PFS without increasing the incidence of serious AEs in mCRPC patients with bone metastases.  Moreover, these researchers stated that these findings were limited by small numbers and patient selection inherent in retrospective analysis. 

The authors stated that while these findings identified a possible association between Ra-223 combination therapy and PFS in a real-world medical oncology practice setting, which provided potential rationale to support future prospective lines of clinical and translational research, this study had several drawbacks.  For example, while abiraterone and enzalutamide are both inhibitors of the androgen receptor (AR) signaling axis, they have distinct mechanisms of action.  With only 19 patients eligible for the combination arm of this real-world retrospective study (13 prescribed abiraterone and 6 prescribed enzalutamide), combining them into 1 arm could have the potential to confound results.  Overall, one of the main drawbacks of this study was power to detect an OS benefit in patients treated with Ra-223 combination therapy.  These researchers stated that future prospective studies with power to detect OS, especially to examine the effects of Ra-223 plus enzalutamide, could help discern if combination therapy is beneficial.  This includes the randomized phase-III clinical trial -- EORTC-1333-GUCG/PEACE III trial, which seeks to evaluate radiographic PFS, OS, first SSE, and time and incidence of 1st skeletal progression-free endpoints with Ra-223 plus enzalutamide compared to enzalutamide alone in asymptomatic or mildly symptomatic patients with chemotherapy naive mCRPC. 

Fong and co-workers (2021) stated that men with mCRPC have limited therapeutic options after progressing on hormonal therapy and chemotherapy.  In a phase-Ib clinical trial, these researchers examined the safety and efficacy of atezolizumab (anti-PD-L1) plus Ra-223 dichloride in men with mCRPC.  They evaluated atezolizumab plus Ra-223 in men with mCRPC and bone and lymph node and/or visceral metastases that progressed after androgen pathway inhibitor treatment.  Following safety assessment of concurrent dosing, 45 men were randomized 1:1:1 to concurrent or 1 of 2 staggered dosing schedules with either agent introduced 1 cycle before the other.  This was followed by a safety-efficacy expansion cohort (randomized 1:1:1).  The primary endpoints were safety and ORR by RECIST 1.1.  Secondary endpoints included radiographic PFS (rPFS), PSA responses, and OS.  As of October 4, 2019, 44 of 45 men were evaluable.  All 44 had greater than or equal to 1 all-cause AE; 23 (52.3 %) had a grade-3/4 AE; 15 (34.1 %) grade-3/4 and 3 (6.8 %) grade-5 AEs were related to atezolizumab; none was related to Ra-223.  Confirmed ORR was 6.8 % [95 % CI: 1.4 to 18.7], median rPFS was 3.0 months (95 % CI: 2.8 to 4.6), median PSA progression was 3.0 months (95 % CI: 2.8 to 3.3), and median OS was 16.3 months (95 % CI: 10.9 to 22.3).  The authors concluded that the findings of this study demonstrated that atezolizumab plus Ra-223, regardless of administration schedule, had greater toxicity than either drug alone, with no clear evidence of additional clinical benefit for patients with mCRPC and bone and lymph node and/or visceral metastases; and no further studies are ongoing for this combination. 

The authors concluded that this study had several drawbacks, including its small size (n = 45) and lack of power due to being a phase-I pilot study.  This small size was also potentially limiting for the exploratory biomarker analyses as the ability to associate changes with activity was likely reduced.  Furthermore, a dose de-escalation or escalation phase was not carried out to find the maximal tolerated dose for this combination due to the lack of overlapping toxicities.  This potentially limited the effectiveness of this combination versus if lower doses had been evaluated as part of the study design.

Other Indications

Lung Cancer Bone Metastasis

Silva and colleagues (2015) stated that over 1/3 of patients with lung cancer will develop bone metastases during the course of their disease, resulting in symptoms of pain and immobility, and SREs such as fracture, hypercalcemia, surgery or radiotherapy to bones, and malignant spinal cord compression.  These reduce quality of life and increase mortality.  Pre-clinical research has identified the interactions between tumor cells and bone that are key to tumor cell survival and associated osteolysis.  These data have led to the development of drugs to prevent osteoclast-mediated bone breakdown, such as zoledronic acid and denosumab, which are now approved for use in patients with bone metastases from solid tumors.  Both zoledronic acid and denosumab reduce the risk of SREs and increase time to first SRE, with minimal side effects.  In addition, denosumab improved survival in patients with lung cancer compared with zoledronic acid.  Ongoing trials are examining if these drugs can prevent the development of bone metastases from lung cancer.  New bone-targeted agents showing promise in breast and prostate cancer include Ra-223, cabozantinib and Src inhibitors.  These agents require further evaluation in patients with lung cancer.

Paraganglioma Bone Metastasis

Makis et al (2016) reported the case of a 26-year old woman with a 5-year history of metastatic paraganglioma due to hereditary paraganglioma-pheochromocytoma syndrome with SDHB mutation, who had failed multiple treatment regimens and had transfusion-dependent pancytopenia, presented with progressive liver and bone metastases.  She was unable to sleep due to painful skull metastases and had severe weakness in her extremities that limited her mobility and daily activities.  She was treated with 2 doses of Ra-223 (Xofigo) and had a dramatic improvement in pain control, mobility, and overall quality of life for 8 weeks, before passing away from pulmonary hemorrhage.

Renal Cell Carcinoma with Bone Metastases

Mckay and colleagues (2018) examined the biologic activity of radium-223 with vascular endothelial growth factor (VEGF)-targeted therapy in patients with advanced renal cell carcinoma (aRCC) and bone metastases.  A total of 15 treatment-naïve patients received pazopanib 800-mg orally once-daily, and 15 previously treated patients received sorafenib 400 mg orally twice-daily.  Radium-223 55 kilo-becquerel/kg was administered concurrently every 4 weeks for up to 6 infusions in both cohorts.  The primary end-point was decline in bone turnover markers (Procollagen I Intact N-Terminal, N-telopeptide, C-telopeptide, osteocalcin, and bone-specific alkaline phosphatase) compared with baseline.  Secondary end-points included safety, rate of symptomatic skeletal event (SSE) and time to first SSE, objective response rate (ORR), change in analgesic use, and quality of life (QOL).  Exploratory analysis of tumor genomic alterations was performed.  Of the 30 patients enrolled, 83 % had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate- or poor-risk disease, 33 % had liver metastases, and 83 % had a history of SSE prior to enrollment.  No dose-limiting toxicity (DLT) was observed.  All bone turnover markers significantly declined from baseline at week 8 and 16; 40 % of patients experienced treatment-related grade greater than or equal to 3 AEs.  Response rates were 15 % and 18 % per RECIST v1.1 and bone response was 50 % and 30 % per MD Anderson criteria, in the pazopanib and sorafenib cohort, respectively.  Median SSE-free interval was 5.8 months and not reached, respectively.  Analgesic use remained stable over the study time.  The authors concluded that radium-223 combined with VEGF-targeted therapy was biologically active and safe.  Moreover, they stated that RCTs are needed to define the role of radium-223 in aRCC with skeletal metastases.

Breast Cancer

Winter et al (2022) noted that about 70 % of patients with metastatic breast cancer (MBC) develop bone metastases.  Despite advances in systemic therapeutic options and the use of bone targeted agents in the management of bone metastases to reduce skeletal morbidity, there remains an unmet need for further therapeutic options.  Ra223 is an alpha-emitting radiopharmaceutical that is preferentially taken up into bone at sites of increased osteoblastic activity where it emits high-energy, short-range alpha-particles that could provide a targeted anti-tumor effect on bone metastases.  In a phase-IB and randomized phase-IIA clinical trial, these researchers examined the safety, feasibility and effectiveness of the combination of Ra223 with capecitabine chemotherapy in patients with MBC with bone involvement.  CARBON is an open-label, multi-center, phase-IB/IIA clinical trial examining the combination of Ra223 (55 kBq/kg day 1 given on 6 weekly schedule) and capecitabine (1,000 mg/m2 bd days 4 to 17 every 21 days) in patients with bone metastases from MBC (± other disease sites).  Other eligibility criteria included ECOG performance status of 0 to 2, 2 or less lines of chemotherapy for MBC and current bisphosphonate or denosumab use for 6 or more weeks.  The phase-IB part of the trial (6 patients) was carried out to provide preliminary feasibility and safety of capecitabine + Ra223; thus, 28 patients were randomized (2:1) to capecitabine + Ra223 or capecitabine alone to further characterize the safety profile and examine effectiveness, the primary effectiveness endpoint was the bone turnover marker (urinary n-telopeptide of type I collagen) change from baseline to end of cycle 5 and secondary endpoints of time to 1st symptomatic skeletal event, and disease progression at extra-skeletal and bone disease.  In addition to bone metastases, 10/23 [44 %] and 13/23 [57 %] capecitabine + Ra223 and 2/11 [18 %] and 9/11 [82 %] capecitabine alone patients had soft tissue and visceral disease sites, respectively.  More capecitabine + Ra223 patients had received prior chemotherapy for MBC: 11/23 [48 %] versus 2/11 [18 %].  The analysis populations comprised 34 patients (23 capecitabine + Ra223, 11 capecitabine); 2 patients randomized to capecitabine + Ra223 received capecitabine alone and were included in the capecitabine arm.  Median number of cycles received was 8.5 in capecitabine + Ra223 (range of 3 to 12) and 12 in the capecitabine arm (range of 1 to 12); 94/95 prescribed Ra223 cycles were administered.  No DLTs were observed in phase-IB and no patients developed grade III or higher diarrhea.  GI, hematological and palmer-planter erthyrodysesthesia AEs were similar in both arms.  Although formal statistical comparisons were not performed, changes in bone turnover markers, the times to extra-skeletal progression and bone disease progression, and the frequency of symptomatic skeletal events were similar across the 2 treatment arms.  The authors concluded that capecitabine + Ra223 at the planned dose was safe and feasible in MBC patients with bone metastases; however, no effectiveness signals were observed that might suggest greater effectiveness of the combination over capecitabine alone clinically or biochemically.

Osteosarcoma

Kairemo et al (2021) noted that patients with osteoblastic metastases from high-risk osteosarcoma continue to have a poor prognosis after progression from standard-of-care (SOC) multi-agent chemotherapy.  In a first-in-human dose escalation study of bone targeted Ra223 dichloride alpha-particle therapy in 18 patients with advanced osteosarcoma, only 1 patient responded based on conventional Response Evaluation Criteria in Solid Tumors (RECIST).  Na18F PET response Criteria in Solid Tumors (NAFCIST), based on sodium fluoride-18 (Na18F) positron emission tomography (PET)-CT was developed to better examine bone specific response.  To further appreciate the spatial and temporal heterogeneity of the partial or mixed responses, a radiomics method was developed.  Analyses were carried out with Na18F PET imaging studies before and after alpha-particle therapy.  Radioactive 18F- atom concentrations were measured in soft-tissues, in approximately 1,000 concentration data points for 18F- per 1 cm3 metastatic tumor.  Data were analyzed from the SUV intensity values, the histogram of intensities and entropy values.  Radiomics may inform intra-tumoral and inter-tumoral heterogeneity in response of bone forming osteosarcoma to alpha particle therapy.  Each patient (and each tumor) represents an "n of 1" case and warrants in depth analysis individually.

Souza et al (2022) stated that alpha and beta particulate radiation are used for non-treated neoplasia, due to their ability to reach and remain in tumor sites.  Radium-223 (223Ra) promotes localized cytotoxic effects, while radio-active gold (198Au), beta-type energy, reduces radiation in the surrounding tissues.  Nanotechnology, including several radio-active nanoparticles, can be safely and effectively used in cancer treatment.  These researchers examined the anti-tumoral effects of [223Ra]Ra nano-micelles co-loaded with radio-active gold nanoparticles ([198Au]AuNPs).  They synthesized and characterized nano-micelles, as well as analyzed several parameters (e.g., particle size, radio-activity emission, dynamic light scattering, and microscopic atomic force).  [223Ra]Ra nano-micelles co-loaded with [198Au]AuNPs, with simultaneous alpha and beta emission, showed no instability, a mean particle size of 296 nm, and a poly-dispersity index (PDI) of 0.201 (± 0.096).  Furthermore, nano-micelles were tested in an in-vitro cytotoxicity assay.  The authors observed a significant increase in tumor cell death using combined alpha and beta therapy in the same formulation, compared with these components used alone.  These investigators stated that their in-vitro findings were the 1st to show the remarkable ability of alpha–beta nanoprobes to kill cancer cells using a low radio-active dose.  They stated that future investigations should examine the in-vivo therapeutic effect and safe use of their nano-micelles of [223Ra]RaCl2 co-loaded with [198Au]AuNPs in bone cancer-bearing mice.  Conversely, this work may lead to further studies involving the functionalization of these alpha–beta nano-probes for targeted radionuclide therapy beyond bone cancer.

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Appendix

Table: Decay Correction Factor Table for Radium Ra 223 Dichloride (Xofigo)

Days from Reference Date	Decay Factor	Days from Reference Date	Decay Factor
-14	2.296	0	0.982
-13	2.161	1	0.925
-12	2.034	2	0.870
-11	1.914	3	0.819
-10	1.802	4	0.771
-9	1.696	5	0.725
-8	1.596	6	0.683
-7	1.502	7	0.643
-6	1.414	8	0.605
-5	1.330	9	0.569
-4	1.252	10	0.536
-3	1.178	11	0.504
-2	1.109	12	0.475
-1	1.044	13	0.447
		14	0.420

The Decay Correction Factor Table is corrected to 12 noon Central Standard Time (CST). To determine the decay correction factor, count the number of days before or after the reference date. The Decay Correction Factor Table includes a correction to account for the 7 hour time difference between 12 noon Central European Time (CET) at the site of manufacture and 12 noon US CST, which is 7 hours earlier than CET.

Source: Bayer Healthcare, 2019

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References