Abstract
Bone metastases markedly reduce the quality of life due to bone pain, pathologic fractures, loss of mobility, and hypercalcemia. A graded three-step approach, as recommended by the World Health Organization (WHO), is used to treat pain according to its severity. Nonsteroidal anti-inflammatory drugs are used in patients with mild to moderate pain. When pain persists or increases, a weak opioid such as codeine or hydrocodone is added. Higher doses or more potent opioids are used if the pain persists or becomes more severe. Bisphosphonates (BPs) are useful in the treatment of osteoporosis and metastatic disease by decreasing the resorption of the bone. BPs bind to bone mineral and directly interfere with the activation of osteoclasts. They are internalized by osteoclasts and inhibit specific biochemical and metabolic pathways in these cells; they also reduce skeletal complications and reduce the rate of development of new lesions and delay progression in bone metastases. External beam radiation therapy given as a single or multifractionated dose is an effective treatment and provides early relief, especially for localized bone pain due to bone metastasis. Therapy with bone-seeking radiopharmaceuticals is effective for reducing pain in patients with widespread, painful bone metastases from various malignancies particularly prostate cancer. A variety of radiopharmaceuticals have been used and tested, including many beta-emitting nuclides and alpha-emitting radium-223 (223Ra) dichloride. Each of these agents targets the bone by chemical bonding or adsorbing to the trabecular surface of the bone, the metal-chelated radiotracer to the trabecular surface, while 32P-sodium orthophosphate and 89Sr-chloride distribute more widely throughout the bone. 89Sr-chloride and 153Sm-EDTMP are two FDA-approved beta-emitting radiopharmaceuticals that have largely replaced 32P-sodium orthophosphate in the treatment of metastatic bone pain in the USA. More recently, alpha-emitting 223Ra-dichloride has been used in symptomatic castration-resistant prostate cancer (CRPC). The onset of pain relief commonly occurs within 7–21 days. Retreatment is possible after allowing for marrow recovery; however, multiple therapies require consideration of cumulative marrow toxicity.
89Sr-chloride and 153Sm-EDTMP have been used extensively, primarily for the treatment of bone pain from breast and prostate cancer due to the presence of osteoblastic disease that enables high uptake of the agents. Radionuclide therapy may be used alone or in combination with chemotherapy or radiation therapy to enhance pain relief and delay onset of new pain; consideration needs to be directed to overlapping or cumulative toxicities especially in the marrow that may require supportive treatment. Patients most suitable for bone pain therapy are those with multiple sites of bone metastases confirmed by a bone scan showing focal sites of increased radiopharmaceutical uptake and those who have symptoms related to osseous disease that requires increased doses of pain medication or is refractory to pain medication. 223Ra is an alpha-emitting radionuclide that accumulates in the bone as it is analogous to calcium. The high linear energy transfer of alpha radiation leads to double-strand DNA breaks within the cells. While effective for pain palliation, it has also shown survival benefit in those with metastatic osseous disease from prostate cancer. However, it is currently approved for use only in symptomatic CRPC patients who have no other visceral diseases.
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Abbreviations
- AEs:
-
Adverse events
- ALARA:
-
As low as reasonably achievable
- ALP:
-
Alkaline phosphatase
- ALSYMPCA:
-
Alpharadin in Symptomatic Prostate Cancer Patients
- ATP:
-
Adenosine triphosphate
- BPs:
-
Bisphosphonates
- CD:
-
Cluster of differentiation
- CPFS:
-
Clinical progression-free survival
- CRPC:
-
Castration-resistant prostate cancer
- DLT:
-
Dose-limiting toxicity
- DNA:
-
Deoxyribonucleic acid
- DOTMP:
-
1,4,7,10 - tetraazacyclododecane -1,4,7,10-tetramethylene phosphonic acid
- DTPMP:
-
Diethylenetriamine pentakis (methylphosphonic acid)
- EBRT:
-
External beam radiation therapy
- ECM:
-
Extracellular matrix
- ER:
-
Estrogen receptor
- [18F]FDG:
-
2-deoxy-2-[18F]fluoro-d-glucose
- FDA:
-
United States Food and Drug Administration
- FPPS:
-
Farnesyl pyrophosphate synthase
- GFAP:
-
Glial fibrillary acidic protein
- GFR:
-
Glomerular filteration rate
- GI:
-
Gastrointestinal
- GMP:
-
Good manufacturing practices
- GTP:
-
Guanosine Triphosphate
- Gy:
-
Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)
- ICER:
-
Incremental cost-effectiveness ratio
- IMRT:
-
Intensity-modulated radiotherapy
- IV:
-
Intravenous
- LDH:
-
Lactate dehydrogenase
- LET:
-
Linear energy transfer
- MTD:
-
Maximum tolerated dose
- NCCN:
-
National Comprehensive Cancer Network
- NRC:
-
Nuclear Regulatory Commission
- NSAIDs:
-
Nonsteroidal anti-inflammatory drugs
- OPGL:
-
Osteoprotegerin ligand
- OS:
-
Overall survival
- PFS:
-
Progression-free survival
- PGA:
-
Physician’s global assessment
- PSA:
-
Prostate-specific antigen
- PTHrP:
-
Parathyroid hormone-related protein
- QALY:
-
Quality-adjusted life-year
- QOL:
-
Quality of life
- 186Re-HEDP:
-
186Re Hydroxyethylidene diphosphonate
- RANK:
-
Receptor activator of nuclear factor kappa-B
- RANKL:
-
Receptor activator of nuclear factor kappa-B ligand
- RP:
-
Radiopharmaceutical
- RT:
-
Radiotherapy
- 153Sm-EDTMP:
-
153Sm- Ethylenediamine Tetramethylene Phosphoric Acid
- 117mSn-DTPA:
-
117mSn-Diethylenetriaminepentaacetic acid
- SAE:
-
Serious adverse event
- SBRT:
-
Stereotactic body radiation therapy
- SEP:
-
Sum of effect product
- SRE:
-
Skeletal relevant events
- 99mTc-MDP:
-
99mTc-Methylene Diphosphonate
- TGF-β:
-
Transforming growth factor-beta
- TNF:
-
Tumor necrosis factor
- TTHMP:
-
Triethylenetetraminehexamethylene phosphonic acid
- ULN:
-
Upper limit of normal
- uNTX-1:
-
Urinary N-telopeptide of type 1
- VAS-AUPC:
-
Visual analog scale-area under the pain curve
- WBC:
-
White blood cell
- WHO:
-
World Health Organization
- XRT:
-
External radiation therapy
- ZA:
-
Zoledronic acid
References
Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27(3):165–76.
Frassica FJ, Gitelis S, Sim FH. Metastatic bone disease: general principles, pathophysiology, evaluation, and biopsy. Instr Course Lect. 1992;41:293–300.
Hage WD, Aboulafia AJ, Aboulafia DM. Incidence, location, and diagnostic evaluation of metastatic bone disease. Orthop Clin North Am. 2000;31(4):515–28.vii.
WHO. World Health Organization. Cancer pain relief. Geneva: World Health Organization; 1986. http://www.WHO.int/cancer/palliative/painladder/en/
NCCN practice guidelines: adult cancer pain. 2016. https://www.nccn.org/professionals/ physician_gls/f_guidelines.asp
Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med. 2006;12(8):895–904.
Steeg PS. Targeting metastasis. Nat Rev Cancer. 2016;16(4):201–18.
Choong PF. The molecular basis of skeletal metastases. Clin Orthop Relat Res. 2003;415(Suppl):S19–31.
Zhao Y, Wang Y, Liu J. P-selectin and tumor metastasis. Zhonghua Jie He He Hu Xi Za Zhi. 2001;24(9):568–70.
Yeatman TJ, Nicolson GL. Molecular basis of tumor progression: mechanisms of organ-specific tumor metastasis. Semin Surg Oncol. 1993;9(3):256–63.
Tang DG, Honn KV. Adhesion molecules and tumor metastasis: an update. Invasion Metastasis. 1994;14(1–6):109–22.
Laubli H, Borsig L. Selectins promote tumor metastasis. Semin Cancer Biol. 2010;20(3):169–77.
Kim YJ, et al. P-selectin deficiency attenuates tumor growth and metastasis. Proc Natl Acad Sci U S A. 1998;95(16):9325–30.
Coupland LA, Chong BH, Parish CR. Platelets and P-selectin control tumor cell metastasis in an organ-specific manner and independently of NK cells. Cancer Res. 2012;72(18):4662–71.
Koukoulis GK, Patriarca C, Gould VE. Adhesion molecules and tumor metastasis. Hum Pathol. 1998;29(9):889–92.
Blair JM, et al. Mechanisms of disease: roles of OPG, RANKL and RANK in the pathophysiology of skeletal metastasis. Nat Clin Pract Oncol. 2006;3(1):41–9.
Rabbani SA, et al. Over-production of parathyroid hormone-related peptide results in increased osteolytic skeletal metastasis by prostate cancer cells in vivo. Int J Cancer. 1999;80(2):257–64.
Orr FW, et al. Tumor-bone interactions in skeletal metastasis. Clin Orthop Relat Res. 1995;312:19–33.
Parfitt AM. Targeted and nontargeted bone remodeling: relationship to basic multicellular unit origination and progression. Bone. 2002;30(1):5–7.
Parfitt AM. Bone remodeling, normal and abnormal: a biological basis for the understanding of cancer-related bone disease and its treatment. Can J Oncol. 1995;5(Suppl 1):1–10.
Raisz LG. Physiology and pathophysiology of bone remodeling. Clin Chem. 1999;45(8 Pt 2):1353–8.
Powell GJ, et al. Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res. 1991;51(11):3059–61.
Mantyh PW, et al. Molecular mechanisms of cancer pain. Nat Rev Cancer. 2002;2(3):201–9.
Pareek TK, et al. Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1. Proc Natl Acad Sci U S A. 2007;104(2):660–5.
Sabino MA, et al. Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2. Cancer Res. 2002;62(24):7343–9.
Heidenreich A, Ohlmann CH. Ibandronate: its pharmacology and clinical efficacy in the management of tumor-induced hypercalcemia and metastatic bone disease. Expert Rev Anticancer Ther. 2004;4(6):991–1005.
Heidenreich A, Hofmann R, Engelmann UH. The use of bisphosphonate for the palliative treatment of painful bone metastasis due to hormone refractory prostate cancer. J Urol. 2001;165(1):136–40.
Honore P, et al. Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat Med. 2000;6(5):521–8.
Russell RG. Bisphosphonates: from bench to bedside. Ann N Y Acad Sci. 2006;1068:367–401.
Vitte C, Fleisch H, Guenther HL. Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption. Endocrinology. 1996;137(6):2324–33.
Finley RS. Bisphosphonates in the treatment of bone metastases. Semin Oncol. 2002;29(1 Suppl 4):132–8.
Liu J, et al. Bisphosphonates in the treatment of patients with metastatic breast, lung, and prostate cancer: a meta-analysis. Medicine (Baltimore). 2015;94(46):e2014.
Van Acker HH, et al. Bisphosphonates for cancer treatment: mechanisms of action and lessons from clinical trials. Pharmacol Ther. 2016;158:24–40.
Berenson JR, et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer. 2001;91(7):1191–200.
Strobl S, et al. Adjuvant bisphosphonates and breast cancer survival. Annu Rev Med. 2016;67:1–10.
Rennert G, et al. Oral bisphosphonates and improved survival of breast cancer. Clin Cancer Res. 2017;23(7):1684–9.
Lebret T, et al. The use of bisphosphonates in the management of bone involvement from solid tumours and haematological malignancies – a European survey. Eur J Cancer Care (Engl). 2017;26(4):e12490.
Hendriks LE, et al. Effect of bisphosphonates, denosumab, and radioisotopes on bone pain and quality of life in patients with non-small cell lung cancer and bone metastases: a systematic review. J Thorac Oncol. 2016;11(2):155–73.
Saad F. The role of bisphosphonates in the management of prostate cancer. Curr Oncol Rep. 2006;8(3):221–7.
Berry S, et al. The use of bisphosphonates in men with hormone-refractory prostate cancer: a systematic review of randomized trials. Can J Urol. 2006;13(4):3180–8.
Smith MR, et al. Denosumab for the prevention of skeletal complications in metastatic castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events. Ann Oncol. 2015;26(2):368–74.
Smith MR, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361(8):745–55.
Fizazi K, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813–22.
Gartrell BA, et al. Toxicities following treatment with bisphosphonates and receptor activator of nuclear factor-kappaB ligand inhibitors in patients with advanced prostate cancer. Eur Urol. 2014;65(2):278–86.
Cookson MS, et al. Castration-resistant prostate cancer: AUA guideline amendment. J Urol. 2015;193(2):491–9.
Sze WM, et al. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy – a systematic review of randomised trials. Clin Oncol (R Coll Radiol). 2003;15(6):345–52.
Chow E, et al. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol. 2007;25(11):1423–36.
Jeremic B, et al. A randomized trial of three single-dose radiation therapy regimens in the treatment of metastatic bone pain. Int J Radiat Oncol Biol Phys. 1998;42(1):161–7.
Lo SS, et al. Expert panel on Radiation Oncology Bone metastases et al. ACR appropriateness criteria. (R) spinal bone metastases. J Palliat Med. 2013;16(1):9–19.
Gaultney J, et al. Results of a Dutch cost-effectiveness model of radium-223 in comparison to cabazitaxel, abiraterone, and enzalutamide in patients with metastatic castration resistant prostate cancer previously treated with docetaxel. Value Health. 2015;18(7):A459.
Macedo A, et al. Cost-effectiveness of samarium-153-EDTMP for the treatment of pain due to multiple bone metastases in hormone-refractory prostate cancer versus conventional pain therapy, in Portugal. Acta Medica Port. 2006;19(5):421–6.
McEwan AJ, et al. A retrospective analysis of the cost effectiveness of treatment with Metastron (89Sr-chloride) in patients with prostate cancer metastatic to bone. Nucl Med Commun. 1994;15(7):499–504.
Silberstein EB. Dosage and response in radiopharmaceutical therapy of painful osseous metastases. J Nucl Med. 1996;37(2):249–52.
Silberstein EB, Elgazzar AH, Kapilivsky A. Phosphorus-32 radiopharmaceuticals for the treatment of painful osseous metastases. Semin Nucl Med. 1992;22(1):17–27.
Lawrence JH, Low-Beer BV, Carpender JW. Chronic lymphatic leukemia; a study of 100 patients treated with radioactive phosphorus. J Am Med Assoc. 1949;140(7):585–8.
Lawrence JH, Dobson RL, et al. Chronic myelogenous leukemia; a study of 129 cases in which treatment was with radioactive phosphorus. J Am Med Assoc. 1948;136(10):672–7.
Maxfield Jr JR, et al. The use of radioactive phosphorus and testosterone in metastatic bone lesions from breast and prostate. South Med J. 1958;51(3):320–7.
Cheung A, et al. Evaluation of radioactive phosphorus in the palliation of metastatic bone lesions from carcinoma of the breast and prostate. Radiology. 1980;134(1):209–12.
Silberstein EB. The treatment of painful osseous metastases with phosphorus-32-labeled phosphates. Semin Oncol. 1993;20(3 Suppl 2):10–21.
Blake GM, et al. Sr-89 therapy: strontium kinetics in disseminated carcinoma of the prostate. Eur J Nucl Med. 1986;12(9):447–54.
Laing AH, et al. Strontium-89 chloride for pain palliation in prostatic skeletal malignancy. Br J Radiol. 1991;64(765):816–22.
Silberstein EB, et al. Strontium-89 therapy for the pain of osseous metastases. J Nucl Med. 1985;26(4):345–8.
McEwan AJ. Unsealed source therapy of painful bone metastases: an update. Semin Nucl Med. 1997;27(2):165–82.
Baumrucker S. Palliation of painful bone metastases: Strontium-89. Am J Hosp Palliat Care. 1998;15(2):113–5.
Mertens WC, Stitt L, Porter AT. Strontium 89 therapy and relief of pain in patients with prostatic carcinoma metastatic to bone: a dose response relationship? Am J Clin Oncol. 1993;16(3):238–42.
Blake GM, et al. Strontium-89 therapy: measurement of absorbed dose to skeletal metastases. J Nucl Med. 1988;29(4):549–57.
McEwan AJ. Use of radionuclides for the palliation of bone metastases. Semin Radiat Oncol. 2000;10(2):103–14.
Lewington VJ, et al. A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer. 1991;27(8):954–8.
Sciuto R, et al. Radiosensitization with low-dose carboplatin enhances pain palliation in radioisotope therapy with strontium-89. Nucl Med Commun. 1996;17(9):799–804.
Tu SM, et al. Strontium-89 combined with doxorubicin in the treatment of patients with androgen-independent prostate cancer. Urol Oncol. 1996;2(6):191–7.
Giammarile F, et al. Bone pain palliation with 85Sr therapy. J Nucl Med. 1999;40(4):585–90.
Fuster D, et al. Usefulness of strontium-89 for bone pain palliation in metastatic breast cancer patients. Nucl Med Commun. 2000;21(7):623–6.
Jager PL, et al. Treatment with radioactive 89strontium for patients with bone metastases from prostate cancer. BJU Int. 2000;86(8):929–34.
Kraeber-Bodere F, et al. Treatment of bone metastases of prostate cancer with strontium-89 chloride: efficacy in relation to the degree of bone involvement. Eur J Nucl Med. 2000;27(10):1487–93.
Giammarile F, et al. Bone pain palliation with strontium-89 in cancer patients with bone metastases. Q J Nucl Med. 2001;45(1):78–83.
Windsor PM. Predictors of response to strontium-89 (Metastron) in skeletal metastases from prostate cancer: report of a single centre’s 10-year experience. Clin Oncol (R Coll Radiol). 2001;13(3):219–27.
Kasalicky J, Krajska V. The effect of repeated strontium-89 chloride therapy on bone pain palliation in patients with skeletal cancer metastases. Eur J Nucl Med. 1998;25(10):1362–7.
Quilty PM, et al. A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol. 1994;31(1):33–40.
Porter AT, McEwan AJ. Strontium-89 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.
Sciuto R, et al. Effects of low-dose cisplatin on 89Sr therapy for painful bone metastases from prostate cancer: a randomized clinical trial. J Nucl Med. 2002;43(1):79–86.
Akerley W, et al. A multiinstitutional, concurrent chemoradiation trial of strontium-89, estramustine, and vinblastine for hormone refractory prostate carcinoma involving bone. Cancer. 2002;94(6):1654–60.
Tu SM, et al. Therapy tolerance in selected patients with androgen-independent prostate cancer following strontium-89 combined with chemotherapy. J Clin Oncol. 2005;23(31):7904–10.
Tu SM, et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial. Lancet. 2001;357(9253):336–41.
Kuroda I, et al. Strontium-89 for prostate cancer with bone metastases: the potential of cancer control and improvement of overall survival. Ann Nucl Med. 2014;28(1):11–6.
Zyskowski A, et al. Strontium-89 treatment for prostate cancer bone metastases: does a prostate-specific antigen response predict for improved survival? Australas Radiol. 2001;45(1):39–42.
Amato RJ, et al. 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):532–8.
James ND, et al. Clinical outcomes and survival following treatment of metastatic castrate-refractory prostate cancer with docetaxel alone or with strontium-89, zoledronic acid, or both: the TRAPEZE randomized clinical trial. JAMA Oncol. 2016;2(4):493–9.
Heianna J, et al. Concurrent use of strontium-89 with external beam radiotherapy for multiple bone metastases: early experience. Ann Nucl Med. 2015;29(10):848–53.
Bilen MA, et al. Randomized phase 2 study of bone-targeted therapy containing strontium-89 in advanced castrate-sensitive prostate cancer. Cancer. 2015;121(1):69–76.
Sciuto R, et al. Metastatic bone pain palliation with 89-Sr and 186-Re-HEDP in breast cancer patients. Breast Cancer Res Treat. 2001;66(2):101–9.
Pons F, 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):1210–4.
Baziotis N, et al. Strontium-89 chloride in the treatment of bone metastases from breast cancer. Oncology. 1998;55(5):377–81.
Heianna J, et al. Tumor regression of multiple bone metastases from breast cancer after administration of strontium-89 chloride (Metastron). Acta Radiol Short Rep. 2014;3(4):2047981613493412.
Zenda S, et al. Strontium-89 (Sr-89) chloride in the treatment of various cancer patients with multiple bone metastases. Int J Clin Oncol. 2014;19(4):739–43.
Maeda O, et al. A patient with esophageal cancer with bone metastasis who achieved pain relief with repetitive administration of strontium-89 chloride. Clin J Gastroenterol. 2014;7(5):387–91.
McEwan AJ, et al. A retrospective analysis of the cost effectiveness of treatment with Metastron in patients with prostate cancer metastatic to bone. Eur Urol. 1994;26(Suppl 1):26–31.
James N, et al. TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer. Health Technol Assess. 2016;20(53):1–288.
Andronis L, et al. Cost-effectiveness of zoledronic acid and strontium-89 as bone protecting treatments in addition to chemotherapy in patients with metastatic castrate-refractory prostate cancer: results from the TRAPEZE trial (ISRCTN 12808747). BJU Int. 2017;119(4):522–9.
Singh A, et al. Human pharmacokinetics of samarium-153 EDTMP in metastatic cancer. J Nucl Med. 1989;30(11):1814–8.
Eary JF, et al. Samarium-153-EDTMP biodistribution and dosimetry estimation. J Nucl Med. 1993;34(7):1031–6.
Farhanghi M, et al. Samarium-153-EDTMP: pharmacokinetic, toxicity and pain response using an escalating dose schedule in treatment of metastatic bone cancer. J Nucl Med. 1992;33(8):1451–8.
Collins C, et al. Samarium-153-EDTMP in bone metastases of hormone refractory prostate carcinoma: a phase I/II trial. J Nucl Med. 1993;34(11):1839–44.
Sartor O. Overview of samarium Sm 153 lexidronam in the treatment of painful metastatic bone disease. Rev Urol. 2004;6(Suppl 10):S3–S12.
Serafini AN, et al. Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. J Clin Oncol. 1998;16(4):1574–81.
Resche I, et al. A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer. 1997;33(10):1583–91.
Sartor O, et al. Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology. 2004;63(5):940–5.
Wang RF, et al. A comparative study of samarium-153-ethylenediaminetetramethylene phosphonic acid with pamidronate disodium in the treatment of patients with painful metastatic bone cancer. Med Princ Pract. 2003;12(2):97–101.
Marcus CS, et al. Lack of effect of a bisphosphonate (pamidronate disodium) infusion on subsequent skeletal uptake of Sm-153 EDTMP. Clin Nucl Med. 2002;27(6):427–30.
Turner JH, et al. A phase II study of treatment of painful multifocal skeletal metastases with single and repeated dose samarium-153 ethylenediaminetetramethylene phosphonate. Eur J Cancer. 1991;27(9):1084–6.
Turner JH, et al. A phase I study of samarium-153 ethylenediaminetetramethylene phosphonate therapy for disseminated skeletal metastases. J Clin Oncol. 1989;7(12):1926–31.
Sartor O, et al. Safety and efficacy of repeat administration of samarium Sm-153 lexidronam to patients with metastatic bone pain. Cancer. 2007;109(3):637–43.
Suttmann H, et al. Combining Sm-153-lexidronam and docetaxel for the treatment of patients with hormone-refractory prostate cancer: first experience. Cancer Biother Radiopharm. 2008;23(5):609–18.
Morris MJ, et al. Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer. J Clin Oncol. 2009;27(15):2436–42.
Autio KA, et al. Repetitively dosed docetaxel and 153samarium-EDTMP as an antitumor strategy for metastatic castration-resistant prostate cancer. Cancer. 2013;119(17):3186–94.
Tu SM, et al. Phase I study of concurrent weekly docetaxel and repeated samarium-153 lexidronam in patients with castration-resistant metastatic prostate cancer. J Clin Oncol. 2009;27(20):3319–24.
Fizazi K, et al. Phase II trial of consolidation docetaxel and samarium-153 in patients with bone metastases from castration-resistant prostate cancer. J Clin Oncol. 2009;27(15):2429–35.
Lin J, et al. Phase I trial with a combination of docetaxel and 153Sm-lexidronam in patients with castration-resistant metastatic prostate cancer. Urol Oncol. 2011;29(6):670–5.
Barai S, et al. Effects of low-dose capecitabine on Samarium-153-EDTMP therapy for painful bone metastases. Indian J Nucl Med. 2015;30(2):111–5.
Winderen M, et al. Pronounced therapeutic effect of samarium 153-ethylenediaminetetramethylene phosphonate in an orthotopic human osteosarcoma tibial tumor model. J Natl Cancer Inst. 1995;87(3):221–2.
Franzius C, et al. High-activity samarium-153-EDTMP therapy followed by autologous peripheral blood stem cell support in unresectable osteosarcoma. Nuklearmedizin. 2001;40(6):215–20.
Franzius C, et al. High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol. 2002;20(7):1953–4.
Anderson PM, et al. High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol. 2002;20(1):189–96.
Anderson PM, et al. Gemcitabine radiosensitization after high-dose samarium for osteoblastic osteosarcoma. Clin Cancer Res. 2005;11(19 Pt 1):6895–900.
Henriksen G, et al. Ra-223 for endoradiotherapeutic applications prepared from an immobilized Ac-227/Th-227 source. Radiochim Acta. 2001;89(10):661–6.
Biersack HJ, et al. Radium-223 in prostate cancer. N Engl J Med. 2013;369(17):1659.
Henriksen G, et al. Significant antitumor effect from bone-seeking, alpha-particle-emitting 223Ra demonstrated in an experimental skeletal metastases model. Cancer Res. 2002;62(11):3120–5.
Nilsson S, et al. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res. 2005;11(12):4451–9.
Carrasquillo JA, et al. Phase I pharmacokinetic and biodistribution study with escalating doses of 223Ra-dichloride in men with castration-resistant metastatic prostate cancer. Eur J Nucl Med Mol Imaging. 2013;40(9):1384–93.
Kairemo K, et al. Evaluation of alpha-therapy with radium-223-dichloride in castration resistant metastatic prostate cancer-the role of gamma scintigraphy in dosimetry and pharmacokinetics. Diagnostics (Basel). 2015;5(3):358–68.
Nilsson S, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8(7):587–94.
Nilsson S, et al. Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases. Clin Genitourin Cancer. 2013;11(1):20–6.
Parker C, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213–23.
Vogelzang NJ, et al. Hematologic safety of radium-223 dichloride: baseline prognostic factors associated with myelosuppression in the ALSYMPCA trial. Clin Genitourin Cancer. 2017;15(1):42–52.
Saad F, et al. Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial. Lancet Oncol. 2016;17(9):1306–16.
Sartor O, et al. Chemotherapy following radium-223 dichloride treatment in ALSYMPCA. Prostate. 2016;76(10):905–16.
Parker C, et al. Effect of radium-223 dichloride (Ra-223) on hospitalisation: an analysis from the phase 3 randomised Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial. Eur J Cancer. 2017;71:1–6.
Parker C, et al. Three-year safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases from phase 3 randomized alpharadin in symptomatic prostate cancer trial. Eur Urol. 2018;73:427–35.
Sartor O, et al. Radium-223 safety, efficacy, and concurrent use with abiraterone or enzalutamide: first U.S. experience from an expanded access program. Oncologist. 2018;23:193–202.
Morris MJ, et al. Radium-223 in combination with docetaxel in patients with castration-resistant prostate cancer and bone metastases: a phase 1 dose escalation/randomised phase 2a trial. Eur J Cancer. 2019;114:107–16.
Shore ND, et al. eRADicAte: a prospective evaluation combining radium-223 dichloride and abiraterone acetate plus prednisone in patients with castration-resistant prostate cancer. Clin Genitourin Cancer. 2018;16:149–54.
Ahmed ME, et al. Radium-223 in the third-line setting in metastatic castration-resistant prostate cancer: impact of concomitant use of enzalutamide on overall survival (OS) and predictors of improved OS. Clin Genitourin Cancer. 2021;19:223.
Shore ND, et al. Open label phase II study of enzalutamide with concurrent administration of radium 223 dichloride in patients with castration-resistant prostate cancer. Clin Genitourin Cancer. 2020;18:416–22.
Agarwal N, et al. Prospective evaluation of bone metabolic markers as surrogate markers of response to radium-223 therapy in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2020;26:2104–10.
Marshall CH, et al. Randomized phase II trial of Sipuleucel-T with or without radium-223 in men with bone-metastatic castration-resistant prostate cancer. Clin Cancer Res. 2021;27:1623–30.
Jarvis P, et al. Radium-223 therapy for metastatic castration-resistant prostate cancer: survival benefit when used earlier in the treatment pathway. Nucl Med Commun. 2021;42:332–6.
Frantellizzi V, et al. Overall survival in mCPRC patients treated with Radium-223 in association with bone health agents: a national multicenter study. Int J Radiat Biol. 2020;96:1608–13.
Yap KK, et al. Impact of timing of administration of bone supportive therapy on pain palliation from radium-223. Cancer Treat Res Commun. 2019;18:100114.
Smith M, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:408–19.
Wenter V, et al. Radium-223 for primary bone metastases in patients with hormone-sensitive prostate cancer after radical prostatectomy. Oncotarget. 2017;8:44131–40.
Sartor O, et al. Re-treatment with radium-223: first experience from an international, open-label, phase I/II study in patients with castration-resistant prostate cancer and bone metastases. Ann Oncol. 2017;28:2464–71.
Sartor O, et al. Re-treatment with radium-223: 2-year follow-up from an international, open-label, phase 1/2 study in patients with castration-resistant prostate cancer and bone metastases. Prostate. 2019;79:1683–91.
Keizman D, et al. Imaging response during therapy with radium-223 for castration-resistant prostate cancer with bone metastases-analysis of an international multicenter database. Prostate Cancer Prostatic Dis. 2017;20:289–93.
Kairemo K, et al. Final outcome of 223Ra-therapy and the role of 18F-fluoride-PET in response evaluation in metastatic castration-resistant prostate cancer – a single institution experience. Curr Radiopharm. 2018;11:147–52.
Castello A, et al. Prostate-specific antigen flare induced by 223RaCl2 in patients with metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2018;45:2256–63.
van der Doelen MJ, et al. Early alkaline phosphatase dynamics as biomarker of survival in metastatic castration-resistant prostate cancer patients treated with radium-223. Eur J Nucl Med Mol Imaging. 2021;48:3325.
Suominen MI, et al. Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis. J Natl Cancer Inst. 2013;105(12):908–16.
Coleman R, et al. A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease. Breast Cancer Res Treat. 2014;145(2):411–8.
Ueno NT, et al. Phase II study of Radium-223 dichloride combined with hormonal therapy for hormone receptor-positive, bone-dominant metastatic breast cancer. Cancer Med. 2020;9:1025–32.
Deandreis D, et al. RADTHYR: an open-label, single-arm, prospective multicenter phase II trial of Radium-223 for the treatment of bone metastases from radioactive iodine refractory differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. 2021;48:3238.
McKay RR, et al. Radium-223 dichloride in combination with vascular endothelial growth factor-targeting therapy in advanced renal cell carcinoma with bone metastases. Clin Cancer Res. 2018;24:4081–8.
Subbiah V, et al. Alpha particle radium 223 dichloride in high-risk osteosarcoma: a phase I dose escalation trial. Clin Cancer Res. 2019;25:3802–10.
de Klerk JM, et al. Phase 1 study of rhenium-186-HEDP in patients with bone metastases originating from breast cancer. J Nucl Med. 1996;37(2):244–9.
Zafeirakis A, et al. Management of metastatic bone pain with repeated doses of rhenium 186-HEDP in patients under therapy with zoledronic acid: a safe and additively effective practice. Cancer Biother Radiopharm. 2009;24(5):543–50.
van der Poel HG, et al. Serum hemoglobin levels predict response to strontium-89 and rhenium-186-HEDP radionuclide treatment for painful osseous metastases in prostate cancer. Urol Int. 2006;77(1):50–6.
O’Sullivan JM, et al. High activity rhenium-186 HEDP with autologous peripheral blood stem cell rescue: a phase I study in progressive hormone refractory prostate cancer metastatic to bone. Br J Cancer. 2002;86(11):1715–20.
Lange R, et al. Applying quality by design principles to the small-scale preparation of the bone-targeting therapeutic radiopharmaceutical rhenium-188-HEDP. Eur J Pharm Sci. 2016;90:96–101.
ter Heine R, et al. Bench to bedside development of GMP grade rhenium-188-HEDP, a radiopharmaceutical for targeted treatment of painful bone metastases. Int J Pharm. 2014;465(1–2):317–24.
Liepe K, et al. Dosimetry of 188Re-hydroxyethylidene diphosphonate in human prostate cancer skeletal metastases. J Nucl Med. 2003;44(6):953–60.
Palmedo H, et al. Dose escalation study with rhenium-188 hydroxyethylidene diphosphonate in prostate cancer patients with osseous metastases. Eur J Nucl Med. 2000;27(2):123–30.
Liepe K, Runge R, Kotzerke J. Systemic radionuclide therapy in pain palliation. Am J Hosp Palliat Care. 2005;22(6):457–64.
Lange R, et al. Treatment of painful bone metastases in prostate and breast cancer patients with the therapeutic radiopharmaceutical rhenium-188-HEDP. Clinical benefit in a real-world study. Nuklearmedizin. 2016;55(5):188–95.
Krishnamurthy GT, et al. Tin-117m(4+)DTPA: pharmacokinetics and imaging characteristics in patients with metastatic bone pain. J Nucl Med. 1997;38(2):230–7.
Srivastava SC, et al. Treatment of metastatic bone pain with tin-117m Stannic diethylenetriaminepentaacetic acid: a phase I/II clinical study. Clin Cancer Res. 1998;4(1):61–8.
Ando A, et al. 177Lu-EDTMP: a potential therapeutic bone agent. Nucl Med Commun. 1998;19(6):587–91.
Chakraborty S, et al. 177Lu labelled polyaminophosphonates as potential agents for bone pain palliation. Nucl Med Commun. 2002;23(1):67–74.
Das T, et al. 177Lu-labeled cyclic polyaminophosphonates as potential agents for bone pain palliation. Appl Radiat Isot. 2002;57(2):177–84.
Chakraborty S, et al. 177Lu-EDTMP: a viable bone pain palliative in skeletal metastasis. Cancer Biother Radiopharm. 2008;23(2):202–13.
Yuan J, et al. Efficacy and safety of 177Lu-EDTMP in bone metastatic pain palliation in breast cancer and hormone refractory prostate cancer: a phase II study. Clin Nucl Med. 2013;38(2):88–92.
Thapa P, et al. Clinical efficacy and safety comparison of 177Lu-EDTMP with 153Sm-EDTMP on an equidose basis in patients with painful skeletal metastases. J Nucl Med. 2015;56(10):1513–9.
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Pandit-Taskar, N., Mahajan, S. (2022). Targeted Radionuclide Therapy for Bone Metastasis. In: Volterrani, D., Erba, P.A., Strauss, H.W., Mariani, G., Larson, S.M. (eds) Nuclear Oncology. Springer, Cham. https://doi.org/10.1007/978-3-031-05494-5_27
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