Medical Policy: 06.01.36
Original Effective Date: September 2017
Reviewed: September 2020
Revised: September 2018
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.
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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.
In 2020 an estimated 191,930 new cases of prostate cancer will be diagnosed with an estimated 33,330 deaths from prostate cancer. 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.
Currently, there are ongoing studies investigating the use of radium-223 for other indications to include breast cancer, osteosarcoma, bone metastases in breast cancer, kidney cancer, lung cancer and paraganglioma and is also being studied 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.
In 2019, Kairemo et. al. developed novel criteria in a clinical trial of radium-223 dichloride for response assessment in osteosarcoma, NAFCIST (Na18F PET Response Criteria for Solid Tumors). Patients received one to six cycles of 223RaCl2, and cumulative doses varied from 6.84 MBq to 57.81 MBq. Molecular imaging with technetium-99m phosphonate scintigraphy, fluorine-18-fluorodeoxyglucose (18FDG) positron emission tomography (PET) or sodium fluoride-18 (Na18F) PET was used to characterize the disease. Correlation of biomarkers and survival was analyzed with NAFCIST measure from Na18F PET. Of the 18 patients, 17 had bone lesions visible in at least one of the imaging studies. In four of seven patients with multiple skeletal lesions (>5), FDG PET and NaF PET studies could be compared. The skeletal tumor locations varied in our patient population: cranium=2, extremities=7, pelvis=10, spine=12 and thorax=9. The 18F-FDG PET and Na18F PET studies could be compared in all four patients who had multiple lung lesions (>5). Overall the Response Evaluation Criteria in Solid Tumors response was seen in one patient, but four patients experienced mixed responses better defined by Na18F PET. Changes in NAFCIST were correlated with changes in bone alkaline phosphatase levels (r=0.54) and negatively with cumulative dose of 223RaCl2 (r=− 0.53). NAFCIST correlated with overall survival (p value of 0.037) while the PERCIST (PET Response Criteria in Solid Tumors) did not (p value of 0.19). The authors concluded our results indicate that Na18F PET should be further studied in osteosarcoma staging. NAFCIST may be a promising criteria for high-risk osteosarcoma response evaluation and correlates with survival. Further validation studies are needed.
Subbiah et. al. in 2019 in this study NCT01833520 which is an an investigator-initiated trial of alpha particle–emitting radium 223 in high-risk osteosarcoma. The study was approved by the MD Anderson Cancer Center institutional review board and the US FDA in accordance with the Declaration of Helsinki. The radioactive isotopes were provided by Bayer HealthCare Pharmaceuticals. Eligible patients were registered in a secure central database, and the study was monitored by the institutional IND office. Eligible patients included those with progressive, locally recurrent, or metastatic osteosarcoma (i.e., high-risk osteosarcoma only) with no standard curative options available and at least one indicator lesion avid on a technetium medronic acid (99mTc-MDP) scan or on a sodium fluoride (NaF) positron emission tomography (PETscan and/ or a fluorodeoxyglucose (FDG) PET scan that could be subjected to further quantitative assessment by these scans. In addition, patients with extremely rare bone-forming osteosarcoma-like tumors that behave like osteosarcoma phenotypically and are clinically treated like osteosarcoma (e.g., malignant fibrous histiocytoma of bone or malignant transformation of giant cell tumor of the bone) were included if the patients satisfied all the other inclusion criteria. Additional key eligibility criteria included an age of ≥15 years, a weight of ≥40 kg, and an Eastern Cooperative Oncology Group performance status of at least 2. Patients or the parents or guardians of patients who were minors provided written informed consent. The required hematology and serum biochemistry screening values were as follows: white blood cell count, ≥1,500/mm3; absolute neutrophil count ≥1,000/mm3; platelet count, ≥75 × 103/mm3; hemoglobin level, ≥8 g/dL; total bilirubin level, ≤1.5 × institutional upper limit of normal (ULN); aspartate aminotransferase and alanine aminotransferase levels, ≤2.5 × ULN for each; creatinine level, ≤1.5 × ULN; and albumin level, >25 g/L. A 3+3 phase I, dose-escalation trial of 223RaCl2 (50, 75, and 100 kBq/kg) was designed in recurrent or metastatic osteosarcoma patients. Objective measurements including serum alkaline phosphatase and bone turnover markers at baseline, mid-study, and the end of the study were compared with changes in standardized uptake values on PET–computed tomography (CT) (with FDG and/or NaF) and single-photon emission CT (SPECT)-CT (with 99mTc-MDP). The following labs were obtained at baseline and at every cycle: hemoglobin (g/dL), albumin (g/dL), absolute lymphocyte count (k/uL), serum lactate dehydrogenase (IU/L), serum alkaline phosphatase(IU/L), bone alkaline phosphastase (mcg/L), serum carboxy-terminal collagen crosslinks or serum crossLaps (CTX)(pg/mL) and osteocalcin (ng/mL) as exploratory markers of response, or adverse events. 223RaCl2 was administered as a slow bolus IV injection at intervals of every 4 weeks (±6 days) for a total of up to six doses, i.e., six cycles. Patients were assigned to dose levels according to a 3+3 phase I dose escalation schedule. Doses of 50, 75, or 100 kBq/kg were assigned in cohorts of three patients after study registration. Dose 1 was given within 30 days of study registration. At least three patients were required to successfully complete 6 weeks of therapy before the study advanced to the next cohort. Individual patients received the same dose of 223RaCl2 as they did at dose 1 for all subsequent doses. Among 18 patients enrolled (including 15 males) aged 15-71 years, tumor locations included spine (n=12, 67%), pelvis (n=10, 56%), ribs (n=9, 50%), extremity (n=7, 39%), and skull (n=2, 11%). Patients received 1-6 cycles of 223RaCl2; cumulative doses were 6.84-57.81 MBq. NaF PET revealed more sites of metastases than did FDG PET. One patient showed a metabolic response on FDG PET and NaF PET. Four patients had mixed responses, and one patient had a response in a brain metastasis. Bronchopulmonary hemorrhage from Grade 3 thrombocytopenia (N=1) was a DLT. The median overall survival time was 25 weeks. The authors concluded future studies of 223RaCl2 to treat osteosarcoma in an earlier setting and in combination with standard therapies and local control are warranted.
Radium-223 and Other Radiopharmaceuticals
In May 2013, the U.S. Food and Drug Administration (FDA) approved radium-223 dichloride, an alpha particle-emitting radioactive agent. This first-in-class radiopharmaceutical was approved for treatment of metastatic CRPC in patients with symptomatic bone metastases and no known visceral metastatic disease. 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 OS (median 14.9 months vs 11.3 months); HR, 0.70; 95% CI, 0.058-0.83; P < .001) and prolonged time to first skeletal -related event (SRE) (median 15.6 months vs 9.8 months). Preplanned subset analyses showed that all 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 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 included nausea, diarrhea, and vomiting. Radium-223 was associated with improved or slower decline of QOL in ALSYMPCA.
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).
All patients with metastatic CRPC should maintain castrate levels of serum testosterone (< 50 ng/dL; <1.7 nmol/L) and receive best supportive care.
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.
Patients with disease progression or relapse after second-line therapy could be managed with resection, palliative RT (that may include Ra 223 and Sm 153-EDTMP), or best supportive care. Participation in a clinical trial should be strongly encouraged.
This guideline does not include or indicate the use or Radium Ra-223 Dichloride (Xofigo) in the treatment management of breast cancer.
In May 2013 (amended 2018), the America Urological Association issued a guideline for castration resistant prostate cancer, which included the following guideline statements:
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.
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:
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:
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.
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