Clinical Policy Bulletin: Radiopharmaceuticals Metastron® (Strontium-89) and Samarium-153 (Quadramet) for Metastatic Bone Pain
Aetna considers the radiopharmaceuticals strontium-89 (Metastron®) and samarium-153 (Quadramet) medically necessary for treatment of bone pain in cancer members with painful skeletal metastases (e.g., bone metastases from breast cancer, liver cancer, prostate cancer, or any other cancer that metastasizes to the bone) and bone pain from unresectable osteosarcoma, where pain is not adequately controlled with conventional treatment (including chemotherapy, hormonal therapy, external beam radiation, and/or opioid analgesics, as appropriate).
Aetna considers radiopharmaceuticals such as strontium-89 (Metastron®) and samarium-153 (Quadramet) experimental and investigational for all other indications including use in members with cancer not involving the bone, use of strontium-89 for controlling intractable hypoglycemia in persons with malignant insulinoma, and intra-articular injection of samarium-153 particulate hydroxyapatite for the treatment of knee synovitis in members with rheumatoid arthritis.
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.
Strontium-89 was approved by the Food and Drug Administration (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 is marketed under the brand name Metastron through a joint venture of Amersham Healthcare and Zeneca Pharmaceuticals.
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 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.
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 greaterthan 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.
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.
CPT Codes / HCPCS Codes / ICD-9 Codes
Other CPT codes related to the CPB:
HCPCS codes covered if selection criteria are met:
Strontium Sr-89 chloride, therapeutic, per millicurie
Samarium Sm-153 lexidronam, therapeutic, per treatment dose, up to 150 millicuries
ICD-9 codes covered if selection criteria are met:
170.0 - 170.9
Malignant neoplasm of bone and articular cartilage [osteosarcoma]
Secondary malignant neoplasm of bone and bone marrow
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
140.0 - 165.9, 198.4, 198.6 - 209.36, 209.75
Malignant neoplasms [other than metastatic to bone] [other than osteosarcoma]
Benign neoplasm of islets of Langerhans Islet cell tumor
230.0 - 234.9
Carcinoma in situ
251.0 - 251.2
714.0 - 714.33
Rheumatoid arthritis [with knee synovitis]
Villonodular synovitis of the lower leg [related to the rheumatoid arthritis]
Other ICD-9 codes related to the CPB:
Disorder of bone and cartilage, unspecified
The above policy is based on the following references:
Medi-Physics, Inc. Metastron (strontium-89 chloride injection). Prescribing Information. Arlington Heights, IL: Amersham Healthcare; January 1998. Available at: http://www.cancerpaintherapy.com/METATECHPAGE.htm. Accessed June 8, 2005.
Hansen DV, Holmes ER, Catton G, et al. Strontium-89 therapy for painful osseous metastatic prostate and breast cancer. Am Fam Physician. 1993;47(8):1795-1800.
Robinson RG, Preston DF, Baxter KG, et al. Clinical experience with strontium-89 in prostatic and breast cancer patients. Semin Oncol. 1993;20(3 Suppl 2):44-48.
Porter AT, McEwan AJB. Strontium-899 as an adjuvant to external beam radiation improves pain relief and delays disease progression in advanced prostate cancer. Results of a randomized controlled trial. Semin Oncol. 1993;20 (3 Suppl 2):38-43.
Baziotis N, Yakoumakis E, Zissimopoulos A, et al. Strontium-89 chloride in the treatment of bone metastases from breast cancer. Oncology. 1998;55(5):377-381.
Pons F, Herranz R, Garcia A, et al. Strontium-89 for palliation of pain from bone metastases in patients with prostate and breast cancer. Eur J Nucl Med. 1997;24(10):1210-1214.
Lee CK, Aeppli DM, Unger J, et al. Strontium-89 chloride (Metastron) for palliative treatment of bony metastases. The University of Minnesota experience. Am J Clin Oncol. 1996;19(2):102-107.
Nightengale B, Brune M, Blizzard SP, et al. Strontium chloride Sr 89 for treating pain from metastatic bone disease. Am J Health Syst Pharm. 1995;52(20):2189-2195.
Robinson RG, Preston DF, Schiefelbein M, et al. Strontium 89 therapy for the palliation of pain due to osseous metastases. JAMA. 1995;274(5):420-424.
Medical Services Advisory Committee (MSAC). Samarium-153-lexidronam for bone pain due to skeletal metastases. Final Assessment Report. MSAC application 1016. Canberra, ACT: MSAC; 1999.
McEwan AJ. Use of radionuclides for the palliation of bone metastases. Semin Radiat Oncol. 2000;10(2):103-114.
Silberstein EB, Eugene L, Saenger SR. Painful osteoblastic metastases: The role of nuclear medicine. Oncology (Huntingt). 2001;15(2):157-163; discussion 167-170, 174.
Giammarile F, Mognetti T, Resche I. Bone pain palliation with strontium-89 in cancer patients with bone metastases. Q J Nucl Med. 2001;45(1):78-83.
Ashayeri E, Omogbehin A, Sridhar R, Shankar RA. Strontium 89 in the treatment of pain due to diffuse osseous metastases: A university hospital experience. J Natl Med Assoc. 2002;94(8):706-711.
Agency for Healthcare Research and Quality (AHRQ). Management of cancer pain. Summary, Evidence Report/Technology Assessment No. 35. AHRQ Pub. No. 01-E033. Rockville, MD: AHRQ; January 2001. Available at: http://www.ahrq.gov/clinic/epcsums/canpainsum.htm. Accessed June 23, 2004.
Cancer Care Ontario Practice Guideline Initiative (CCOPGI). Use of strontium89 in patients with endocrine-refractory carcinoma of the prostate metastaic to bone. Practice Guideline Report No. 3-6. Toronto, ON: Cancer Care Ontario (CCO); October 2001.
Siegel HJ, Luck JV Jr, Siegel ME. Advances in radionuclide therapeutics in orthopaedics. J Am Acad Orthop Surg. 2004;12(1):55-64.
Roqué M, Martinez MJ, Alonso-Coello P, et al. Radioisotopes for metastatic bone pain. Cochrane Database Syst Rev. 2003;(4):CD003347.
Silberstein EB. Teletherapy and radiopharmaceutical therapy of painful bone metastases. Semin Nucl Med. 2005;35(2):152-158.
Bauman G, Charette M, Reid R, Sathya J. Radiopharmaceuticals for the palliation of painful bone metastasis-a systemic review. Radiother Oncol. 2005;75(3):258-270.
Finlay IG, Mason MD, Shelley M. Radioisotopes for the palliation of metastatic bone cancer: A systematic review. Lancet Oncol. 2005;6(6):392-400.
Tripathi M, Singhal T, Chandrasekhar N, et al. Samarium-153 ethylenediamine tetramethylene phosphonate therapy for bone pain palliation in skeletal metastases. Indian J Cancer. 2006;43(2):86-92.
Lin A, Ray ME. Targeted and systemic radiotherapy in the treatment of bone metastasis. Cancer Metastasis Rev. 2006;25(4):669-675.
Sartor O, Reid RH, Bushnell DL, et al. Safety and efficacy of repeat administration of samarium Sm-153 lexidronam to patients with metastatic bone pain. Cancer. 2007;109(3):637-643.
Lam MG, de Klerk JM, van Rijk PP, Zonnenberg BA. Bone seeking radiopharmaceuticals for palliation of pain in cancer patients with osseous metastases. Anticancer Agents Med Chem. 2007;7(4):381-397.
Anderson P, Nuñez R. Samarium lexidronam (153Sm-EDTMP): skeletal radiation for osteoblastic bone metastases and osteosarcoma. Expert Rev Anticancer Ther. 2007;7(11):1517-1527.
Amato RJ, Hernandez-McClain J, Henary H. Bone-targeted therapy: Phase II study of strontium-89 in combination with alternating weekly chemohormonal therapies for patients with advanced androgen-independent prostate cancer. Am J Clin Oncol. 2008;31(6):532-538.
Tu SM, Lin SH. Current trials using bone-targeting agents in prostate cancer. Cancer J. 2008;14(1):35-39.
Abruzzese E, Iuliano F, Trawinska MM, Di Maio M. 153Sm: Its use in multiple myeloma and report of a clinical experience. Expert Opin Investig Drugs. 2008;17(9):1379-1387.
dos Santos MF, Furtado RN, Konai MS, et al. Effectiveness of radiation synovectomy with samarium-153 particulate hydroxyapatite in rheumatoid arthritis patients with knee synovitis: A controlled randomized double-blind trial. Clinics (Sao Paulo). 2009;64(12):1187-1193.
Paes FM, Serafini AN. Systemic metabolic radiopharmaceutical therapy in the treatment of metastatic bone pain. Semin Nucl Med. 2010;40(2):89-104.
Suzawa N, Yamakado K, Takaki H, et al. Complete regression of multiple painful bone metastases from hepatocellular carcinoma after administration of strontium-89 chloride. Ann Nucl Med. 2010;24(8):617-620.
Valicenti RK, Trabulsi E, Intenzo C, et al. A Phase I trial of samarium-153-lexidronam complex for treatment of clinically nonmetastatic high-risk prostate cancer: First report of a completed study. Int J Radiat Oncol Biol Phys. 2011;79(3):732-737.
American College of Radiology (ACR), American Society for Radiation Oncology (ASTRO). ACR-ASTRO practice guideline for the performance of therapy with unsealed radiopharmaceutical sources. [online publication]. Reston (VA): American College of Radiology (ACR); 2010. Available at: http://www.guideline.gov/content.aspx?id=32528&search=strontium-89+. Accessed March 27, 2012.
Roque I Figuls M, Martinez-Zapata MJ, Scott-Brown M, Alonso-Coello P. Radioisotopes for metastatic bone pain. Cochrane Database Syst Rev. 2011;(7):CD003347.
Berger M, Grignani G, Giostra A, et al. 153Samarium-EDTMP administration followed by hematopoietic stem cell support for bone metastases in osteosarcoma patients. Ann Oncol. 2012;23(7):1899-1905.
Naganuma A, Mayahara H, Morizane C, et al. Successful control of intractable hypoglycemia using radiopharmaceutical therapy with strontium-89 in a case with malignant insulinoma and bone metastases. Jpn J Clin Oncol. 2012;42(7):640-645.
Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.