Platinum Priority – Review – Prostate Cancer Editorial by Oliver Sartor on pp. 427–428 of this issue| Volume 70, ISSUE 3, P416-426, September 01, 2016

Radiopharmaceuticals for Palliation of Bone Pain in Patients with Castration-resistant Prostate Cancer Metastatic to Bone: A Systematic Review



      The majority of patients with castration-resistant prostate cancer develop bone metastatic disease. It is often challenging to optimally palliate malignant bone pain. In case of multifocal pain due to diffuse osteoblastic metastases, treatment with bone-seeking radiopharmaceuticals can be considered.


      This systematic review evaluates the efficacy of different bone-seeking radiopharmaceuticals for palliation of malignant bone pain from prostate cancer.

      Evidence acquisition

      The PubMed (Medline) and Embase databases were searched for publications on 89-strontium-chloride (89Sr), 153-samarium-EDTMP (153Sm), 186-rhenium-HEDP (186Re), 188-rhenium-HEDP (188Re), and 223-radium-chloride (223Ra). Randomised controlled trials and prospective cohort studies were included. Metastatic bone pain had to be registered as outcome measure for prostate cancer patients separately.

      Evidence synthesis

      This review included 36 articles of which 13 randomised trials and 23 prospective studies. Of all trials, 10 studies used 89Sr, 7 153Sm, 12 186Re, 2 188Re, and 2 223Ra; three reported on a combination of different radionuclides. Only a few trials contained a blinding procedure and several studies contained incomplete follow-up or lack of intention-to-treat analysis. It was not possible to calculate a pooled estimate of pain response to treatment with any of the radionuclides because different definitions of pain response were used.


      Overall, pain response percentages greater than 50–60% were seen with each radionuclide. Haematological toxicity was reported in 26 of the 36 studies and more than half of these trials stated no grade 3/4 leukopenia or thrombocytopenia occurred.

      Patient summary

      In this report we reviewed the efficacy of bone-seeking radionuclides for treating bone pain from metastatic prostate cancer. Overall, treatment with bone-seeking radionuclides resulted in pain responses greater than 50–60%.


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        • Saad F.
        • Clarke N.
        • Colombel M.
        Natural history and treatment of bone complications in prostate cancer.
        Eur Urol. 2006; 49: 429-440
        • Van Dodewaard-de Jong J.M.
        • Verheul H.M.W.
        • Bloemendal H.J.
        • de Klerk J.M.
        • Carducci M.A.
        • van den Eertwegh A.J.
        New treatment options for patients with metastatic prostate cancer: what is the optimal sequence?.
        Clin Genitourin Cancer. 2015; 13: 271-279
        • Mercadente S.
        Malignant bone pain: pathophysiology and treatment.
        Pain. 1997; 69: 1-18
        • Ripamonti C.
        • Fulfaro F.
        Malignant bone pain: pathophysiology and treatments.
        Curr Rev Pain. 2000; 4: 187-196
        • Lam M.G.E.H.
        • de Klerk J.M.H.
        • van Rijk P.P.
        • Zonnenberg B.A.
        Bone seeking radiopharmaceuticals for palliation of pain in cancer patients with osseous metastases.
        Anticancer Agents Med Chem. 2007; 7: 381-397
        • Roqué I.
        • Figuls M.
        • Martinez-Zapata M.J.
        • Scott-Brown M.
        • Alonso-Coello P.
        Radioisotopes for metastatic bone pain.
        Cochrane Database Syst Rev. 2011; 6: CD003347
        • Oosterhof G.O.N.
        • Roberts J.T.
        • de Reijke ThM
        • et al.
        Strontium89 chloride versus palliative local field radiotherapy in patients with hormonal escaped prostate cancer: a phase III study of the European Organisation for Research and Treatment of Cancer Genitourinary Group.
        Eur Urol. 2003; 44: 519-526
        • Windsor P.M.
        Predictors of response to Strontium-89 (Metastron) in skeletal metastases from prostate cancer: report of a single centre's 10-year experience.
        Clin Oncol. 2001; 13: 219-227
        • Turner S.L.
        • Gruenewald S.
        • Spry N.
        • Gebski V.
        Less pain does equal better quality of life following strontium-89 therapy for metastatic prostate cancer.
        Br J Cancer. 2001; 84: 297-302
        • Quilty P.M.
        • Kirk D.
        • Bolger J.J.
        • et al.
        A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer.
        Radiother Oncol. 1994; 31: 33-40
        • Fosså S.D.
        • Paus E.
        • Lochoff M.
        • Backe S.M.
        • Aas M.
        89Strontium in bone metastases from hormone resistant prostate cancer: palliation effect and biochemical changes.
        Br J Cancer. 1992; 66: 177-180
        • Lewington V.J.
        • McEwan A.J.
        • Ackery D.M.
        • 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: 954-958
        • Laing A.H.
        • Ackery D.M.
        • Bayly R.J.
        • et al.
        Strontium-89 chloride for pain palliation in prostatic skeletal malignancy.
        Br J Radiol. 1991; 64: 816-822
        • Buchali K.
        • Correns H.J.
        • Schuerer M.
        • Schnorr D.
        • Lips H.
        • Sydow K.
        Results of a double blind study of 89-strontium therapy of skeletal metastases of prostatic carcinoma.
        Eur J Nucl Med. 1988; 14: 349-351
        • Robinson R.G.
        • Spicer J.A.
        • Preston D.F.
        • et al.
        Treatment of metastatic bone pain with strontium-89.
        Nucl Med Biol. 1987; 14: 219-222
        • Correns H.J.
        • Mebel M.
        • Buchali K.
        • Schnorr D.
        • Seidel C.
        • Mitterlechner E.
        89Strontium therapy of bone metastases of carcinoma of the prostatic gland.
        Eur J Nucl Med. 1979; 4: 33-35
        • Ripamonti C.
        • Fagnoni E.
        • Campa T.
        • Seregni E.
        • Maccauro M.
        • Bombardieri E.
        Incident pain and analgesic consumption decrease after samarium infusion: a pilot study.
        Support Care Cancer. 2007; 15: 339-342
        • 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: 86-92
        • Baczyk M.
        • Milecki P.
        • Pisarek M.
        • Gut P.
        • Antczak A.
        • Hrab M.
        A prospective randomised trial: A comparison of the analgesic effect and toxicity of 153Sm radioisotope treatment in monotherapy and combined therapy including local external beam radiotherapy (EBRT) among metastatic castrate resistance prostate cancer (mCRPC) patients with painful bone metastases.
        Neoplasma. 2013; 60: 328-333
        • Sartor O.
        • Reid R.H.
        • Hoskin P.J.
        • et al.
        Samarium-153-lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer.
        Urology. 2004; 63: 940-945
        • Serafini A.N.
        • Houston S.J.
        • Resche I.
        • 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: 1574-1581
        • Resche I.
        • Chatal J.F.
        • Pecking A.
        • et al.
        A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases.
        Eur J Cancer. 1997; 33: 1583-1591
        • Collins C.
        • Eary J.F.
        • Donaldson G.
        • et al.
        Samarium-153-EDTMP in bone metastases of hormone refractory prostate carcinoma: a phase I/II trial.
        J Nucl Med. 1993; 34: 1839-1844
        • Zafeirakis A.
        • Papatheodorou G.
        • Arhontakis A.
        • Gouliamos A.
        • Vlahos L.
        • Limouris G.S.
        Predictive implications of bone turnover markers after palliative treatment with 186Re-HEDP in hormone-refractory prostate cancer patients with painful osseous metastases.
        Eur J Nucl Med Mol Imaging. 2010; 37: 103-113
        • O'Sullivan J.M.
        • Norman A.R.
        • McCready V.R.
        • et al.
        A phase 2 study of high-activity 186Re-HEDP with autologous peripheral blood stem cell transplant in progressive hormone-refractory prostate cancer metastatic to bone.
        Eur J Nucl Med Mol Imaging. 2006; 33: 1055-1061
        • Han S.H.
        • de Klerk J.M.H.
        • Tan S.
        • et al.
        The Placorhen study: A double-blind, placebo-controlled, randomised radionuclide study with 186Re-Etidronate in hormone-resistant prostate cancer patients with painful bone metastases.
        J Nucl Med. 2002; 43: 1150-1156
        • Kolesnikov-Gauthier H.
        • Carpentier P.
        • Depreux P.
        • Vennin P.
        • Caty A.
        • Sulman C.
        Evaluation of toxicity and efficacy of 186Re-hydroxyethylidene diphosphonate in patients with painful bone metastases of prostate or breast cancer.
        J Nucl Med. 2000; 41: 1689-1694
        • Tennvall J.
        • Abrahamsson P.A.
        • Ahlgren G.
        • et al.
        Palliative radiation with a radiolabeled diphosphonate (Rhenium-186 Etidronate) in patients with hormone-refractory disseminated prostate carcinoma.
        Scand J Urol Nephrol. 2000; 34: 188-193
        • Sciuto R.
        • Tofani A.
        • Festa A.
        • Giannarelli D.
        • Pasqualoni R.
        • Maini C.L.
        Short- and long-term effects of 186Re-1,1-hydroxyehtylidene diphosphonate in the treatment of painful bone metastases.
        J Nucl Med. 2000; 41: 647-654
        • Giannakenas C.
        • Kalofonos H.P.
        • Apostolopoulos D.J.
        • Zarakovitis J.
        • Kosmas C.
        • Vassilakos P.J.
        Preliminary results of the use of Re-186-HEDP for palliation of pain in patients with metastatic bone disease.
        Am J Clin Oncol. 2000; 23: 83-88
        • Israel O.
        • Keidar Z.
        • Rubinov R.
        • et al.
        Quantitative bone single-photon emission computed tomography for prediction of pain relief in metastatic bone disease treated with rhenium-186 etidronate.
        J Clin Oncol. 2000; 18: 2747-2754
        • Limouris G.S.
        • Shukla S.K.
        • Manetou A.
        • et al.
        Rhenium-186-HEDP palliative treatment in disseminated bone metastases due to prostate cancer.
        Anticancer Res. 1997; 17: 1699-1704
        • Schoeneich G.
        • Palmedo H.
        • Heimbach D.
        • Biersack H.J.
        • Müller S.C.
        Advanced prostate cancer: systemic radiopharmaceutical therapy of metastatic prostate cancer with rhenium-186 hydroxyethylidene diphosphonate.
        Onkologie. 1997; 20: 316-319
        • Quirijnen J.M.S.P.
        • Han S.H.
        • Zonnenberg B.A.
        • et al.
        Efficacy of rhenium-186-etidronate in prostate cancer patients with metastatic bone pain.
        J Nucl Med. 1996; 37: 1511-1515
        • Maxon III, H.R.
        • Schroder L.E.
        • Thomas S.R.
        • et al.
        Re-186(Sn) HEDP for treatment of painful osseous metastases: Initial clinical experience in 20 patients with hormone-resistant prostate cancer.
        Radiology. 1990; 176: 155-159
        • Liepe K.
        • Kropp J.
        • Runge R.
        • Kotzerke J.
        Therapeutic efficiency of rhenium-188-HEDP in human prostate cancer skeletal metastases.
        Br J Cancer. 2003; 89: 625-629
        • Palmedo H.
        • Manka-Waluch A.
        • Albers P.
        • et al.
        Repeated bone-targeted therapy for hormone-refractory prostate carcinoma: Randomised phase II trial with the new, high-energy radiopharmaceutical rhenium-188-hydroxyethylidenediphosphonate.
        J Clin Oncol. 2003; 21: 2869-2875
        • Parker C.C.
        • Pascoe S.
        • Chodacki A.
        • et al.
        A randomised, double-blind, dose-finding, multicenter, phase 2 study of radium chloride (Ra 223) in patients with bone metastases and castration-resistant prostate cancer.
        Eur Urol. 2013; 63: 189-197
        • Nilsson S.
        • Strang P.
        • Aksnes A.K.
        • et al.
        A randomised, dose-response, multicentre phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer.
        Eur J Cancer. 2012; 48: 678-686
        • Bączyk M.
        • Czepczyński
        • Milecki P.
        • Pisarek M.
        • Oleksa R.
        • Sowiński J.
        89Sr versus 153Sm-EDTMP: Comparison of treatment efficacy of painful bone metastases in prostate and breast carcinoma.
        Nucl Med Commun. 2007; 28: 245-250
        • Dafermou A.
        • Colamussi P.
        • Giganti M.
        • Cittanti C.
        • Bestagno M.
        • Piffanelli A.
        A multicentre observational study of radionuclide therapy in patients with painful bone metastases or prostate cancer.
        Eur J Nucl Med. 2001; 28: 788-798
        • Liepe K.
        • Runge R.
        • Kotzerke J.
        The benefit of bone-seeking radiopharmaceuticals in the treatment of metastatic bone pain.
        J Cancer Res Clin Oncol. 2005; 131: 60-66
        • Parker C.
        • Nilsson S.
        • Heinrich D.
        • et al.
        Alpha emitter radium-223 and survival in metastatic prostate cancer.
        N Engl J Med. 2013; 369: 213-223
        • Morris M.J.
        • Pandit-Taskar N.
        • Carrasquillo J.
        • et al.
        Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer.
        J Clin Oncol. 2009; 27: 2436-2442
        • Fizazi K.
        • Beuzeboc P.
        • Lumbroso J.
        • 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: 2429-2435
        • Tu S.M.
        • Mathew P.
        • Wong F.C.
        • Jones D.
        • Johnson M.M.
        • Logothetis C.J.
        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: 3319-3324
        • Van Dodewaard-de Jong J.M.
        • de Klerk J.M.H.
        • Bloemendal H.J.
        • et al.
        A phase I study of combined docetaxel and repeated high activity 186Re-HEDP in castration-resistant prostate cancer (CRPC) to bone (the TAXIUM trial).
        Eur J Nucl Med Mol Imaging. 2011; 38: 1990-1998
        • Dworkin R.H.
        • Turk D.C.
        • Peirce-Sandner S.
        • et al.
        Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations.
        Pain. 2012; 153: 1148-1158
        • Dworkin R.H.
        • Turk D.C.
        • Wyrwich K.W.
        • et al.
        Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations.
        J Pain. 2008; 9: 105-121