Radiopharmaceuticals Strontium-89 (Metastron) and Samarium-153 (Quadramet) for Malignant Bone Pain

Number: 0361


Strontium-89 (Metastron)

  1. Aetna considers strontium-89 chloride injection (Metastron) medically necessary for the relief of bone pain in members with painful skeletal metastases and whose bone metastases was confirmed prior to strontium-89 therapy. 

  2. Aetna considers continuation of the requested medication medically necessary in members with skeletal metastases when there is no evidence of unacceptable toxicity on the current regimen. 

Samarium-153 (Quadramet)

  1. Aetna considers samarium-153 (Qaudramet) medically necessary for either of the following when criteria met:

    1. Painful skeletal metastases: for relief of pain with confirmed osteoblastic metastatic bone lesions that enhance on radionuclide bone scan. 
    2. Osteosarcoma: for treatment of bone pain from unresectable, recurrent, or progressive osteosarcoma when the pain is not controlled by conventional treatment (including chemotherapy, hormonal therapy, external beam radiation, and/or analgesics, as appropriate)
  2. Aetna considers continuation of the requested medication medically necessary for members with painful skeletal metastases or osteosarcoma when there is no evidence of unacceptable toxicity on the current regimen.

Experimental and Investigational

Aetna considers radiopharmaceuticals such as strontium-89 and samarium-153 experimental and investigational for all other indications including the following (not an all-inclusive list):

  • Intra-articular injection of samarium-153 particulate hydroxyapatite for the treatment of knee synovitis in members with rheumatoid arthritis.
  • Use in members with cancer not involving the bone
  • Use of samarium-153 for the treatment of non-metastatic prostate cancer after radical prostatectomy
  • Use of samarium-153 labeled microspheres for trans-arterial radioembolization of hepatocellular carcinoma and liver metastasis
  • Use of strontium-89 for controlling intractable hypoglycemia in persons with malignant insulinoma.

Dosing Recommendations

Strontium-89 (Metastron)

Strontium Chloride Sr-89 (Metastron) is supplied in a 5 mL vial containing 148 MBq, 4mCi.

The recommended dose of Sr-89 is 148 MBq, 4 mCi, administered by slow intravenous injection (1-2 minutes). Alternatively, a dose of 1.5 - 2.2 MBq/kg, 40-60 µCi/kg body weight may be used. (MBq = megabecquerel (one mCi equals 37 MBq); mCi = milliCurie). Repeated administrations of Sr-89 should be based on an individual’s response to therapy, current symptoms, and hematologic status, and are generally not recommended at intervals of less than 90 days. The individual’s dose should be measured by a suitable radioactivity calibration system immediately prior to administration. 

Source: QBioMed, 2020

Samarium-153 (Quadramet)

Samarium-153 is available as Quadramet and is supplied frozen in single-dose glass vials containing 3 mL with 5550 MBq (150 mCi) of samarium-153 at calibration.

The recommended dose of Quadramet is 1.0 mCi/kg as a single dose, administered intravenously over a period of one minute through a secure in-dwelling catheter and followed with a saline flush. Dose adjustment in persons at the extremes of weight have not been studied. Caution should be exercised when determining the dose in very thin or very obese persons.

Source: Lantheus, 2017


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

  • Metastron (strontium-89 chloride injection) is indicated for the relief of bone pain in patients with painful skeletal metastases. The presence of bone metastases should be confirmed prior to therapy (QBioMed, 2020).
  • Quadramet (samarium-153) is indicated for relief of pain in patients with confirmed osteoblastic metastatic bone lesions that enhance on radionuclide bone scan (Lantheus, 2017).

Compendial Uses

  • Samarium-153 is indicated for pain palliation in locally recurrent, or progressive osteosarcoma or osteoblastic bone metastases (NCCN, 2020).

Strontium-89 is a beta-emitting radionuclide that preferably localizes in areas of active bone formation (areas of high osteoblast activity such as metastatic lesions).  It functions as a calcium analog that releases high-energy beta particles as the compound decays to yttruim-89.  This local radiation results in at least partial pain relief without extensive hematologic toxicity or myelosuppression.  The mechanism by which strontium-89 relieves bone pain is not known.  Some believe that local irradiation stops the tumor from producing pain-producing enzymes, while others believe it may act through suppression of tumor growth.

Strontium-89 was approved by the FDA for the treatment of bone pain in cancer patients with painful skeletal metastases.  It is not indicated for use in patients with cancer not involving the bone.  Strontium-89 was marketed under the brand name Metastron through a joint venture of Amersham Healthcare and Zeneca Pharmaceuticals, and then subsequently GE Healthcare. However, in 2019, Metastron was acquired by QBioMed, Inc. and now Metstron is primarily referred to as strontium-89 (SR89).

Strontium-89 is indicated for patients with definite signs of discomfort from skeletal metastases and with inadequate relief with other forms of therapy (e.g., chemotherapy, hormone therapy, and analgesics).  Other causes of bone pain (e.g., osteoarthritis, nerve root compression) should be ruled out.  Strontium-89 is contraindicated in patients with elevated calcium levels.  According to established guidelines, white blood counts should be greater than 2,400 to 3,000 and platelets greater than 40 to 100 10(9)/L prior to therapy.  Product information indicates that caution should be used in patients with platelet counts below 60 x 10(9)/L and white blood cell counts below 2,400.

Strontium-89 is an effective alternative for the treatment of bone pain in patients with painful skeletal metastases.  The drug is only a palliative measure and not a cure for bone pain or cancer.  Moreover, it is ineffective in relieving pain originating from soft tissue tumors, unless bone metastases are involved.

Evidence of pain relief is generally seen within 7 to 21 days and sustained for 3 to 6 months.  The literature indicates that a repeat dose can be administered at 3-month intervals if necessary.

Amato et al (2008) noted that bone-targeted therapy that combines strontium-89 (Sr-89) with alternating weekly chemohormonal therapy may improve clinical outcomes in patients with metastatic hormone-refractory prostate cancer.  This phase II study examined the addition of Sr-89 to an alternating weekly regimen of doxorubicin and ketoconazole with paclitaxel and estramustine in patients with progressive prostate cancer and bone involvement.  A total of 29 patients with progressive adenocarcinoma of the prostate and osteoblastic bone metastases who failed conventional hormonal therapy were registered for the study.  Of those, 27 were treated with Sr-89 on day 1 of week 1.  On weeks 1, 3, and 5, patients received doxorubicin (20 mg/m on day 1) and oral ketoconazole (400 mg 3 times a day for 7 days).  On weeks 2, 4, and 6, patients received paclitaxel (100 mg/m(2)) and oral estramustine (280 mg 3 times a day for 7 days).  No treatment was given during weeks 7 and 8.  Cycles were repeated every 8 weeks.  A greater than or equal to 50 % reduction in prostate-specific antigen level was maintained for at least 8 weeks in 77.7 % of the patients (n = 21) at 16 weeks and in 66.6 % (n = 18) at 32 weeks.  The median progression-free survival was 11.27 months (range of 1.83 to 29.53), and the median overall survival was 22.67 months (range of 1.83 to 57.73+).  Two patients died during study because of disease progression.  Overall, the chemotherapy combined with Sr-89 was well-tolerated.  The authors concluded that these findings demonstrated that the combination of alternating weekly chemohormonal therapies with Sr-89 resulted in a prolonged progression-free and overall survival with acceptable toxicity.  They stated that further investigation of combination therapies with Sr-89 is warranted.

Tu and Lin (2008) stated that the propensity of prostate cancer to metastasize to bone and the prognostic significance of bone metastasis suggest that effective treatment of bone metastasis may provide clinical benefits.  Both osteoblasts and osteoclasts have been shown to play a central role in the interactions between the metastatic prostate cancer cells and bone.  Although most prostate cancer bone metastasis is osteoblastic, it remains unclear which cell type is initially involved in the process.  Other components in the bone, such as the endothelium and stroma, may also play an important role in this process.  The osteoblastic feature of prostate cancer bone metastasis has led to therapies focused on targeting osteoblast activity.  Clinical trials targeting osteoblasts use radiopharmaceuticals (e.g., Sr-89 and samarium-153), the endothelin A receptor inhibitor atrasentan, or the vitamin D analog calcitriol.

Naganuma et al (2012) reported the case of a 57-year old woman with liver and bone metastases from malignant insulinoma, who was afflicted with severe hypoglycemia.  Treatment of the liver metastases using octreotide, diazoxide and trans-arterial embolization failed to raise her blood glucose level and she required constant glucose infusion (about 1,000 kcal/day) and oral feeding (about 2,200 kcal/day) to avoid a hypoglycemic attack.  Subsequently, 110 MBq (2.0 MBq/kg) of strontium-89 were administered by intravenous injection.  Three weeks after the strontium-89 injection, the dose of constant glucose infusion could be reduced while maintaining a euglycemic status.  Six weeks after the injection, the constant glucose infusion was discontinued.  Although strontium-89 therapy is indicated for patients with multiple painful bone metastases, it was also useful as a means of inhibiting tumor activity and controlling hypoglycemia in this case.  The authors concluded that this is the first report to provide evidence that strontium-89 can be useful in controlling intractable hypoglycemia in patients with malignant insulinoma with bone metastases.  The findings of this single-case study need to be validated by well-designed studies.

Quadramet (samarium-153 lexidronam injection) has been approved to treat patients with severe pain associated with cancers that have spread to bone.  It is indicated for relief of pain in patients with confirmed osteoblastic metastatic bone lesions that enhance on radionuclide bone scan.  In a review on the role of radiopharmaceuticals in the palliation of metastatic bone pain in adults with uncomplicated, multi-focal painful bone metastases whose pain is not controlled with conventional analgesic regimens, Bauman et al (2005) concluded that use of single-agent radiopharmaceuticals (e.g., strontium-89 and samarium-153) should be considered as a possible option for the palliation of multiple sites of bone pain from metastatic cancer where pain control with conventional analgesic regimens is unsatisfactory and where activity on a bone scan of the painful lesions is demonstrated.  This is in agreement with the observation of Silberstein (2005) as well as that of Finlay et al (2005).

In a randomized, controlled, double-blind study, dos Santos et al (2009) examined the effectiveness of radiation synovectomy with samarium-153 particulate hydroxyapatite in rheumatoid arthritis patients with knee synovitis.  A total of 58 patients (60 knees) with chronic knee synovitis were randomized to receive either an intra-articular injection with 40 mg triamcinolone hexacetonide alone (TH group) or 40 mg triamcinolone hexacetonide combined with 15 mCi samarium-153 particulate hydroxyapatite (Sm/TH group).  Blinded examination at baseline (T0) and at 1 (T1), 4 (T4), 12 (T12), 32 (T32), and 48 (T48) weeks post-intervention were performed on all patients and included a visual analog scale for joint pain and swelling as well as data on morning stiffness, flexion, extension, knee circumference, Likert scale of improvement, percentage of improvement, SF-36 generic quality of life questionnaire, Stanford Health Assessment Questionnaire (HAQ), Lequesne index, use of non-steroidal anti-inflammatory drugs or oral corticosteroids, events and adverse effects, calls to the physician, and hospital visits.  The sample was homogeneous at baseline, and there were no withdrawals.  Improvement was observed in both groups in relation to T0, but no statistically significant differences between groups were observed regarding all variables at the time points studied.  The Sm/TH group exhibited more adverse effects at T1 (p < 0.05), but these were mild and transitory.  No severe adverse effects were reported during follow-up.  The authors concluded that intra-articular injection of samarium-153 particulate hydroxyapatite (15 mCi) with 40 mg of triamcinolone hexacetonide is not superior to triamcinolone hexacetonide alone for the treatment of knee synovitis in patients with rheumatoid arthritis at 1 year of follow-up.

In a phase I clinical trial, Valicenti and colleagues (2011) determined the maximum tolerated dose of samarium-153 EDTMP (153Sm) with hormonal therapy (HT) and radiation therapy (RT) in high-risk clinically non-metastatic prostate cancer.  High-risk M0 prostate cancer patients (prostate-specific antigen [PSA] greater than 20 ng/ml, Gleason score greater than 7, or greater than T3) were eligible for this prospective trial of dose-escalated radioactive 153Sm-EDTMP (0.25 to 2.0 mCi/kg body weight) as primary or post-operative therapy.  After 1 month of HT, 153Sm-EDTMP was administered followed by 4 more months of HT, 46.8 Gy to the pelvic region and 23.4 Gy to the prostate target (TD = 70.2 Gy).  The primary end point was grade III toxicity or higher by the National Cancer Institute Common Toxicity Criteria.  A total of 29 patients were enrolled in this study (median PSA = 8.2 ng/ml, 27/29 (93 %) T stage greater than or equal to T2b, 24/29 (83 %) had Gleason greater than 7) and received 153Sm-EDTMP (0.25 mCi/kg, 4 patients; 0.5 mCi/kg, 4 patients; 0.75 mCi/kg, 6 patients; 1.0 mCi/kg, 6 patients; 1.5 mCi/kg, 5 patients; 2.0 mCi/kg, 4 patients).  Twenty-eight patients underwent all planned therapy without delays (1 patient required surgery before the start of RT).  With a median follow-up time of 23 months, there were 2 patients (7 %) experiencing grade III hematologic toxicity.  There were no other grade III or IV side effects.  The authors concluded that these findings demonstrated that 2 mCi/kg 153Sm -EDTMP with HT and RT was safe and feasible in men with high-risk M0 prostate cancer.  They noted that a phase II study to test this treatment is currently underway by the Radiation Therapy Oncology Group.

Berger and colleagues (2012) noted that bone metastatic patients with osteosarcoma have a very poor prognosis.  Targeted radiation therapy has been pursued as a valid alternative.  The primary end point of this study was progression-free survival (PFS) at 4 months.  A total of 22 osteosarcoma patients were treated with samarium-153 EDTMP ((153)Sm-EDTMP) at various dosages.  Administered activities ranged from 150 (3 mCi/kg) to 1,140 MBq/kg (30 mCi/kg).  Autologous hematopoietic stem cell infusion was carried out on day 14 after the (153)Sm-EDTMP infusion.  The median PFS was 61 days (18 to 436 days) and the median overall survival (OS) was 189 days (31 to 1175 days).  PFS and OS for the entire patient population were 32 % [95 % confidence interval (CI): 16 to 50] and 76 % (95 % CI: 52 to 89) at 4 months, respectively.  No statistical differences emerged according to (153)Sm-EDTMP administered or 24-hr retained activity.  One-month pain palliation was only observed in a minority of subjects and in none at 4 months.  The authors concluded that based on their findings, the PFS is dramatically short even when higher activity of (153)Sm-EDTMP is administered.  They stated that this would mean that, even at high level, (153)Sm-EDTMP is itself ineffective against relapsed osteosarcoma or the residual activity is too low to be active on these particular subsets of patients.

The National Institute for Health and Care Excellence’s clinical guideline on “Prostate cancer: diagnosis and treatment” (2014) stated that “Strontium-89 should be considered for men with hormone-relapsed prostate cancer and painful bone metastases, especially those men who are unlikely to receive myelosuppressive chemotherapy”.

Parlak et al (2015) determined the excretion of samarium-153-ethylenediaminetetramethylphosphonic acid ((153)Sm-EDTMP) in urine and calculated the dose rate of its retention in the body as a function of time and the dose received by the skin of laboratory staff's finger.  Urine samples were collected from 11 patients after intravenous injection of (153)Sm-EDTMP.  The measurements of dose rate were performed.  Thermoluminescent dosimeters were used for absorbed dose measurements.  Effective half-lives that were calculated from urine sample measurements were found as 7.1 ± 3 hours within the first 24 hours.  Whole body dose rates before collecting urine of patients were 60.0 ± 15.7 µSv h(-1) for within 1 hour following (153)Sm-EDTMP administration.  The highest finger radiation dose is to the right-hand thumb (3.8 ± 2 mGy).  The authors concluded that the results of the study imply that patients who received (153)Sm-EDTMP therapy should be kept a minimum of 8 hours in an isolated room at hospital and that 1 staff should give therapy at most 2 patients per week.

Note: Individuals with disseminated intravascular coagulation must be excluded from therapy with strontium-89 and samarium-153 therapy.  The American College of Radiology (ACR) and the American Society for Radiation Oncology (ASTRO)'s practice guideline for the performance of therapy with unsealed radiopharmaceutical sources (2010) listed disseminated intravascular coagulation (DIC) as a contraindication of strontium-89 and samarium-153.  Thus, patients with DIC must be excluded from therapy with strontium-89 and samarium-153 Lexidronam.

Ye and colleagues (2018) comparatively evaluated the efficacy of Sr-89 chloride (89 SrCl2) in treating bone metastasis-associated pain in patients with lung, breast, or prostate cancer.  The 126 patients with lung cancer included 88, 16, 15, 4, and 3 patients with adenocarcinoma, squamous cell carcinoma, non-small cell carcinoma, mixed carcinoma, and small cell carcinoma, respectively, and the control group consisted of patients with breast (71 patients) or prostate cancer (49 patients) who underwent 89 SrCl2 treatment during the same period.  The treatment dose of 89 SrCl2 was 2.22 MBq/kg.  The efficacy rate of treatment in the lung cancer group was 75.4 %, compared to 95.0 % in the control group.  Approximately 67 % of patients with lung cancer and bone metastases and 47 % of control patients exhibited mild-to-moderate reductions of leukocyte and platelet counts 4 weeks after 89 SrCl2 treatment.  The authors concluded that 89 SrCl2 could safely and effectively relieve bone pain caused by bone metastasis from lung cancer.  However, its efficacy was lower in patients with lung cancer with bone metastasis than in those with breast or prostate cancer with bone metastasis, and its effects on the peripheral hemogram were also significantly stronger in the lung cancer group.

Samarium-153 Followed by Salvage Prostatic Fossa Irradiation in High-Risk Clinically Non-Metastatic Prostate Cancer After Radical Prostatectomy

Valicenti and colleagues (2018) examined the utility of samarium-153 in the setting of men with prostate cancer (PCa) status post-radical prostatectomy who develop biochemical failure with no clinical evidence of osseous metastases.  Trial NRG Oncology RTOG 0622 was a single-arm, phase-II clinical trial that enrolled men with pT2-T4, N0-1, M0 PCa status post-radical prostatectomy, who met at least 1 of these biochemical failure criteria: PSA greater than 1.0 ng/ml; PSA greater than  0.2 ng/ml if Gleason score 9 to 10; or PSA greater than 0.2 ng/ml if N1.  Patients received samarium-153 (2.0 mCi/kg intravenously × 1) followed by salvage external beam radiation therapy (EBRT) to the prostatic fossa (64.8 to 70.2 Gy in 1.8-Gy daily fractions).  No androgen deprivation therapy was allowed. The primary objective was PSA response within 12 weeks of receiving samarium-153.  The secondary objectives were to evaluate the completion rate for the regimen of samarium-153 and EBRT; assess the hematologic toxicity and other adverse events (AEs) at 12 and 24 weeks; and determine the freedom from progression rate at 2 years.  A total of 60 enrolled eligible patients were included in this analysis.  Median follow-up was 3.97 years.  A PSA response was achieved in 7 of 52 evaluable patients (13.5 %), compared with the 25 % hypothesized.  The 2-year freedom from progression rate was 25.5 % (95 % CI: 14.4 % to 36.7 %), and the biochemical failure rate was 64.4 % (95 % CI: 50.5 % to 75.2 %).  Samarium-153 was well-tolerated, with 16 (of 60) grade 3 to 4 hematologic AEs; and no grade 5 hematologic AEs.  Radiation therapy was also well-tolerated, with no grade 3 to 5 acute radiation therapy-related AEs and 1 grade 3 to 4; and no grade 5 late radiation therapy-related AEs.  The authors concluded that Trial NRG Oncology RTOG 0622 did not meet its primary end-point of PSA response, although the regimen of samarium-153 and salvage EBRT was well-tolerated.  Moreover, they stated that although the toxicity profile supported study of samarium-153 in high-risk disease, it may not be beneficial in men receiving EBRT.

Samarium-153 Labeled Microspheres for Trans-Arterial Radioembolization of Hepatocellular Carcinoma and Liver Metastasis

Wong and colleagues (2019) stated that trans-arterial radio-embolization (TARE) has been proven as an effective treatment for unresectable liver tumor.  In this study, neutron-activated, 153Sm-labeled microspheres were developed as an alternative to 90Y-labeled microspheres for hepatic radio-embolization.  153Sm has a theranostic advantage as it emits both therapeutic beta and diagnostic gamma radiations simultaneously, in comparison to the pure beta emitter, 90Y.  Negatively charged acrylic microspheres were labeled with 152Sm ions through electrostatic interactions . In another formulation, the Sm-labeled microsphere was treated with sodium carbonate solution to form the insoluble 152Sm carbonate (152SmC) salt within the porous structures of the microspheres.  Both formulations were neutron-activated in a research reactor.  Physicochemical characterization, gamma spectrometry, and radiolabel stability tests were carried out to study the performance and stability of the microspheres.  The Sm- and SmC-labeled microspheres remained spherical and smooth, with a mean size of 35 µm before and after neutron activation.  Fourier transform infrared (FTIR) spectroscopy indicated that the functional groups of the microspheres remained unaffected after neutron activation.  The 153Sm- and 153SmC-labeled microspheres achieved activity of 2.53 ± 0.08 and 2.40 ± 0.13 GBq·g-1, respectively, immediate after 6-hour neutron activation in the neutron flux of 2.0 × 1012 n·cm-2·s-1.  Energy-dispersive X-ray (EDX) and gamma spectrometry showed that no elemental and radioactive impurities were present in the microspheres after neutron activation.  The retention efficiency of 153Sm in the 153SmC-labeled microspheres was excellent (approximately 99 % in distilled water and saline; approximately 97 % in human blood plasma), which was higher than the 153Sm-labeled microspheres (approximately 95 % and approximately 85 %, respectively).  The authors concluded that 153SmC-labeled microspheres had demonstrated excellent properties for potential application as theranostic agents for hepatic radioembolization.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Other CPT codes related to the CPB:

77261 - 77525 Radiation oncology
79101 Radiopharmaceutical therapy, by intravenous administration
96401 - 96450 Chemotherapy administration

HCPCS codes covered if selection criteria are met:

A9600 Strontium Sr-89 chloride, therapeutic, per millicurie
A9604 Samarium Sm-153 lexidronam, therapeutic, per treatment dose, up to 150 millicuries

ICD-10 codes covered if selection criteria are met:

C40.00 – C41.92 Malignant neoplasm of bone and articular cartilage [osteosarcoma]
C79.51 - C79.52 Secondary malignant neoplasm of bone and bone marrow

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C00.0 – C39.9, C61, C79.49
C79.60 - C96.9
Malignant neoplasms [other than metastatic to bone] [other than osteosarcoma]
C78.7 Secondary malignant neoplasm of liver and intrahepatic bile duct
D00.00 - D09.9 Carcinoma in situ
D13.7 Benign neoplasm of endocrine pancreas
E15 - E16.2 Hypoglycemia
M05.00 - M08.99 Rheumatoid arthritis [with knee synovitis]
M12.261 - M12.269 Villonodular synovitis (pigmented), knee [related to the rheumatoid arthritis]

The above policy is based on the following references:

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