Skip to main content

Advertisement

SpringerLink
Log in

Radium-223 dichloride in prostate cancer: proof of principle for the use of targeted alpha treatment in clinical practice

  • Review Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

To summarise data with radium-223 dichloride (223RaCl2), a mechanism-mediated targeted alpha therapy (TAT), in metastatic castration-resistant prostate cancer (mCRPC) and to chart the development of TAT in mCRPC and in other tumour types.

Methods

Literature for this systematic review was identified using a PubMed search: (“targeted alpha therapy” or “targeted alpha particle therapy”) or (213-bismuth or bismuth-213 or 213Bi) or (225-actinium or actinium-225 or 225Ac) or (211-astatine or astatine-211 or 211At) or (212-lead or lead-212 or 212Pb) or (227-thorium or thorium-227 or 227Th) or (223-radium or radium-223 or 223Ra or alpharadin) and (malignancy or cancer). Results were limited to English-language publications in humans, with the article type “clinical trial”.

Results

Forty-one publications were included (30 from the literature search and 11 from manual searches/reviews). In clinical trials in mCRPC, 223RaCl2 monotherapy is well tolerated, with significantly longer overall survival than placebo and improved quality of life. Clinical trial data have been reinforced by findings from real-world studies. 223RaCl2 has also shown promise in other tumour types with bone metastases, including advanced breast cancer and advanced renal cell carcinoma (in combination with anti-vascular endothelial growth factor). Several astatine-211- and bismuth-213-labelled molecules have demonstrated anti-tumour activity and acceptable toxicity in other tumour types.

Conclusions

223RaCl2 has demonstrated “proof of concept” for use of TAT in cancer in clinical practice. The efficacy and safety of 223RaCl2 monotherapy have been demonstrated in mCRPC, and 223RaCl2 combination therapies are under investigation in various tumours. TAT has broad applicability across tumour types.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

225Ac:

actinium-225

211At:

astatine-211

213Bi:

bismuth-213

212Pb:

lead-212

223RaCl2 :

radium-223 dichloride

227Th:

thorium-227

AE:

adverse event

AJCC/UICC:

American Joint Committee on Cancer /Union for International Cancer Control

ALP:

alkaline phosphatase

ALL:

acute lymphocytic leukaemia

ALSYMPCA:

Alpharadin in Symptomatic Prostate Cancer

ALT:

alanine transaminase

AML:

acute myeloid leukaemia

AST:

aspartate aminotransferase

CI:

confidence interval

CLAG-M:

cladribine, cytarabine, granulocyte-colony stimulating factor, mitoxantrone

DNA:

deoxyribonucleic acid

EAP:

Early Access Programme

ECOG:

Eastern Cooperative Oncology Group

EGFR:

epidermal growth factor receptor

EMA:

European Medicines Agency

EOBD:

extent of bone disease category

EQ-5D:

EuroQoL 5D

FACT-P:

Functional Assessment of Cancer Therapy-Prostate

FDA:

Food and Drug Administration

HAMA:

human-antimouse-antibody

HER2:

human epidermal growth factor 2

HR:

hazard ratio

LDH:

lactate dehydrogenase

LNRH:

luteinising hormone-releasing hormone

mCRPC:

metastatic castration-resistant prostate cancer

MHLW:

Ministry of Health, Labour and Welfare

MTD:

maximum tolerated dose

OS:

overall survival

PSA:

prostate-specific antigen

PSMA:

prostate-specific membrane antigen

QOL:

quality of life

RANKL:

receptor activator of nuclear factor-kappaB ligand

REASSURE:

Radium-223 Alpha Emitter Agent in Non-intervention Safety Study in mCRPC popUlation for Long-teRm Evaluation

SSRE:

symptomatic skeleton-related events

TAT:

targeted alpha therapy

TCMC:

S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane

TEAE:

treatment-emergent adverse event

ULN:

upper limit of normal

WHO:

World Health Organization

References

  1. Sofou S. Radionuclide carriers for targeting of cancer. Int J Nanomedicine. 2008;3:181–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Marcu L, Bezak E, Allen BJ. Global comparison of targeted alpha vs targeted beta therapy for cancer: in vitro, in vivo and clinical trials. Crit Rev Oncol Hematol. 2018;123:7–20.

    Article  PubMed  Google Scholar 

  3. Sartor O, Sharma D. Radium and other alpha emitters in prostate cancer. Transl Androl Urol. 2018;7:436–44.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bayer. Xofigo Summary of Product Characteristics. 2018. Available from: https://www.medicines.org.uk/emc/product/5204/smpc. Accessed 13 Dec 2018.

  5. Bayer. Xofigo Prescribing Information. 2018. Available from: http://labeling.bayerhealthcare.com/html/products/pi/Xofigo_PI.pdf. Accessed 13 Dec 2018.

  6. Pharmaceuticals and Medical Devices Agency Japan. Annual Report FY 2015. Available from: https://ss.pmda.go.jp/en_all/muv_ajax.x?u=http%3A%2F%2Fwww.pmda.go.jp%2Ffiles%2F000214925.pdf%23page%3D195&p=195&t=&q=xofigo&s=qV0C6RpV7dquA8XpExigITDmeas4Getv3NRnOl7tdNESUBPUMP1Od-2SPxc1wnSjSIZf5FhtuhkxQjzWifiv4-7EB0KxSmNdQOYk8A4MmU-SaochybEWcUKDVQvXVmnB. Accessed 20 Feb 2019.

  7. Nilsson S, Larsen RH, Fosså SD, Balteskard L, Borch KW, Westlin J-E, et al. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res. 2005;11:4451–9.

    Article  PubMed  CAS  Google Scholar 

  8. Chittenden SJ, Hindorf C, Parker CC, Lewington VJ, Pratt BE, Johnson B, et al. A phase 1, open-label study of the biodistribution, pharmacokinetics, and dosimetry of 223Ra-dichloride in patients with hormone-refractory prostate cancer and skeletal metastases. J Nucl Med. 2015;56:1304–9.

    Article  PubMed  CAS  Google Scholar 

  9. Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8:587–94.

    Article  PubMed  CAS  Google Scholar 

  10. Nilsson S, Strang P, Aksnes AK, Franzèn L, Olivier P, Pecking A, et al. A randomized, dose-response, multicenter 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;48:678–86.

    Article  PubMed  CAS  Google Scholar 

  11. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213–23.

    Article  PubMed  CAS  Google Scholar 

  12. Parker C, Coleman R, Sartor O, Vogelzang N, Bottomley D, Heinrich D, 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.

    Article  Google Scholar 

  13. Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014;15:738–46.

    Article  PubMed  CAS  Google Scholar 

  14. Sartor O, Coleman RE, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, et al. An exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific antigen dynamics in the phase 3 ALSYMPCA trial with radium-223. Ann Oncol. 2017;28:1090–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Parker C, Zhan L, Cislo P, Reuning-Scherer J, Vogelzang NJ, Nilsson S, 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.

    Article  PubMed  CAS  Google Scholar 

  16. Parker C, Finkelstein SE, Michalski JM, O’Sullivan JM, Bruland Ø, Vogelzang NJ, et al. Efficacy and safety of radium-223 dichloride in symptomatic castration-resistant prostate cancer patients with or without baseline opioid use from the phase 3 ALSYMPCA trial. Eur Urol. 2016;70:875–83.

    Article  PubMed  CAS  Google Scholar 

  17. Hoskin P, Sartor O, O’Sullivan JM, Johannessen DC, Helle SI, Logue J, et al. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPC. Lancet Oncol. 2014;15:1397–406.

    Article  PubMed  CAS  Google Scholar 

  18. Sartor O, Hoskin P, Coleman RE, Nilsson S, Vogelzang NJ, Petrenciuc O, et al. Chemotherapy following radium-223 dichloride treatment in ALSYMPCA. Prostate. 2016;76:905–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Vogelzang NJ, Coleman RE, Michalski JM, Nilsson S, O’Sullivan JM, Parker C, et al. Hematologic safety of radium-223 dichloride: baseline prognostic factors associated with myelosuppression in the ALSYMPCA Trial. Clin Genitourin Cancer. 2017;15:42–52.e8.

    Article  PubMed  Google Scholar 

  20. Nilsson S, Cislo P, Sartor O, Vogelzang NJ, Coleman RE, O’Sullivan JM, et al. Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol Off J Eur Soc Med Oncol. 2016;27:868–74.

    Article  CAS  Google Scholar 

  21. Uemura H, Uemura H, Matsubara N, Kinuya S, Hosono M, Yajima Y, et al. Safety and efficacy of radium-223 dichloride in Japanese patients with castration-resistant prostate cancer and bone metastases. Int J Clin Oncol. 2017;22:954–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Matsubara N, Nagamori S, Wakumoto Y, Uemura H, Kimura G, Yokomizo A, et al. Phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer. Int J Clin Oncol. 2018;23:173–80.

    Article  PubMed  CAS  Google Scholar 

  23. Saad F, Carles J, Gillessen S, Heidenreich A, Heinrich D, Gratt J, 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;17:1306–16.

    Article  PubMed  CAS  Google Scholar 

  24. Carles J, Méndez MJ, Pinto Á, Sáez MI, Arranz JA, Maroto P, et al. Radium-223 international early access program: results from the Spanish subset. Future Oncol. 2018;14:41–50.

    Article  PubMed  CAS  Google Scholar 

  25. Dizdarevic S, Meidahl Petersen P, Essler M, Versari A, Bourre J-C, la Fougere C, et al. Interim analysis of the REASSURE (Radium-223 alpha Emitter Agent in non-intervention Safety Study in mCRPC popUlation for long-teRm Evaluation) study: patient characteristics and safety according to prior use of chemotherapy in routine clinical practice. 2019;46:1102–10.

  26. Miederer M, Thomas C, Beck J, Hampel C, Krieger C, Baqué PE, et al. Haematopoietic toxicity of radium-223 in patients with high skeletal tumour burden. Nuklearmedizin. 2015;54:197–203.

    Article  PubMed  CAS  Google Scholar 

  27. Sartor O, Heinrich D, Mariados N, Méndez Vidal MJ, Keizman D, Thellenberg Karlsson C, 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 Off J Eur Soc Med Oncol. 2017;28:2464–71.

    Article  CAS  Google Scholar 

  28. Dizdarevic S, Jessop M, Begley P, Main S, Robinson A. 223Ra-dichloride in castration-resistant metastatic prostate cancer: improving outcomes and identifying predictors of survival in clinical practice. Eur J Nucl Med Mol Imaging. 2018;45:2264–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Dan TD, Eldredge-Hindy HB, Hoffman-Censits J, Lin J, Kelly WK, Gomella LG, et al. Hematologic toxicity of concurrent administration of radium-223 and next-generation antiandrogen therapies. Am J Clin Oncol. 2017;40:342–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. European Medicines Agency. Prostate cancer medicine Xofigo must not be used with Zytiga and prednisone/prednisolone. 2018. Available from: https://www.ema.europa.eu/en/news/prostate-cancer-medicine-xofigo-must-not-be-used-zytiga-prednisoneprednisolone. Accessed 18 Dec 2018.

  31. Shore ND, Tutrone RF, Mariados NF, Nordquist LT, Mehlhaff BA, Steere KJ, 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.

    Article  PubMed  Google Scholar 

  32. Kratochwil C, Bruchertseifer F, Rathke H, Hohenfellner M, Giesel FL, Haberkorn U, et al. Targeted α-therapy of metastatic castration-resistant prostate cancer with 225Ac-PSMA-617: swimmer-plot analysis suggests efficacy regarding duration of tumor control. J Nucl Med. 2018;59:795–802.

    Article  PubMed  CAS  Google Scholar 

  33. Sathekge M, Bruchertseifer F, Knoesen O, Reyneke F, Lawal I, Lengana T, et al. 225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study. Eur J Nucl Med Mol Imaging. 2019;46:129–38.

    Article  PubMed  CAS  Google Scholar 

  34. Coleman R, Aksnes A-K, Naume B, Garcia C, Jerusalem G, Piccart M, 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;145:411–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. McKay R, Bosse D, Gray K, Michaelson M, Krajewski K, Jacene H, 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. https://doi.org/10.1158/1078-0432.CCR-17-3577.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Zalutsky MR, Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman HS, et al. Clinical experience with -particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6. J Nucl Med. 2007;49:30–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Andersson H, Cederkrantz E, Bäck T, Divgi C, Elgqvist J, Himmelman J, et al. Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211)At-MX35 F(ab’)2--a phase I study. J Nucl Med. 2009;50:1153–60.

    Article  PubMed  CAS  Google Scholar 

  38. Allen BJ, Raja C, Rizvi S, Li Y, Tsui W, Graham P, et al. Intralesional targeted alpha therapy for metastatic melanoma. Cancer Biol Ther. 2005;4:1318–24.

    Article  PubMed  CAS  Google Scholar 

  39. Allen BJ, Singla AA, Rizvi SMA, Graham P, Bruchertseifer F, Apostolidis C, et al. Analysis of patient survival in a phase I trial of systemic targeted α-therapy for metastatic melanoma. Immunotherapy. 2011;3:1041–50.

    Article  PubMed  CAS  Google Scholar 

  40. Raja C, Graham P, Abbas Rizvi SM, Song E, Goldsmith H, Thompson J, et al. Interim analysis of toxicity and response in phase 1 trial of systemic targeted alpha therapy for metastatic melanoma. Cancer Biol Ther. 2007;6:846–52.

    Article  PubMed  CAS  Google Scholar 

  41. Rosenblat TL, McDevitt MR, Mulford DA, Pandit-Taskar N, Divgi CR, Panageas KS, et al. Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin Cancer Res. 2010;16:5303–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Jurcic JG, Caron PC, Nikula TK, Papadopoulos EB, Finn RD, Gansow OA, et al. Radiolabeled anti-CD33 monoclonal antibody M195 for myeloid leukemias. Cancer Res. 1995;55:5908s–10s.

    PubMed  CAS  Google Scholar 

  43. Autenrieth ME, Seidl C, Bruchertseifer F, Horn T, Kurtz F, Feuerecker B, et al. Treatment of carcinoma in situ of the urinary bladder with an alpha-emitter immunoconjugate targeting the epidermal growth factor receptor: a pilot study. Eur J Nucl Med Mol Imaging. 2018;45:1364–71.

    Article  PubMed  CAS  Google Scholar 

  44. Kratochwil C, Giesel FL, Bruchertseifer F, Mier W, Apostolidis C, Boll R, et al. 213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience. Eur J Nucl Med Mol Imaging. 2014;41:2106–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Krolicki L, Bruchertseifer F, Kunikowska J, Koziara H, Królicki B, Jakuciński M, et al. Prolonged survival in secondary glioblastoma following local injection of targeted alpha therapy with 213Bi-substance P analogue. Eur J Nucl Med Mol Imaging. 2018;45:1636–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Krolicki L, Bruchertseifer F, Kunikowska J, Koziara H, Krolici B, Al E. Safety and efficacy of targeted alpha therapy with 213Bi-DOTA-substance P in recurrent glioblastoma. Eur J Nucl Med Mol Imaging. 2019;46:614–22.

    Article  PubMed  CAS  Google Scholar 

  47. Cordier D, Forrer F, Bruchertseifer F, Morgenstern A, Apostolidis C, Good S, et al. Targeted alpha-radionuclide therapy of functionally critically located gliomas with 213Bi-DOTA-[Thi8,Met(O2)11]-substance P: a pilot trial. Eur J Nucl Med Mol Imaging. 2010;37:1335–44.

    Article  PubMed  CAS  Google Scholar 

  48. Meredith RF, Torgue J, Azure MT, Shen S, Saddekni S, Banaga E, et al. Pharmacokinetics and imaging of 212 Pb-TCMC-trastuzumab after intraperitoneal administration in ovarian cancer patients. Cancer Biother Radiopharm. 2014;29:12–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Meredith R, Torgue J, Shen S, Fisher DR, Banaga E, Bunch P, et al. Dose escalation and dosimetry of first-in-human α radioimmunotherapy with 212Pb-TCMC-trastuzumab. J Nucl Med. 2014;55:1636–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Poeppel TD, Handkiewicz-Junak D, Andreeff M, Becherer A, Bockisch A, Fricke E, et al. EANM guideline for radionuclide therapy with radium-223 of metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2018;45:824–45.

    Article  PubMed  CAS  Google Scholar 

  51. Du Y, Carrio I, De Vincentis G, Fanti S, Ilhan H, Mommsen C, et al. Practical recommendations for radium-223 treatment of metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2017;44:1671–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. National Institute for Health and Care Excellence. Radium-223 dichloride for treating hormone-relapsed prostate cancer with bone metastases (TA412). 2016. p. 1–41. Available from: https://www.nice.org.uk/guidance/ta412. Accessed 20 Dec 2016.

  53. FierceBiotech. J&J leads $25M Series A in targeted radiotherapy startup. 2017. Available from: https://www.fiercebiotech.com/venture-capital/j-j-leads-25m-series-a-targeted-radiotherapy-startup. Accessed 20 Feb 2019.

Download references

Acknowledgements

Medical writing support was provided by AS&K Communications and funded by Bayer.

Availability of data and material

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Funding

Preparation of this manuscript was funded by Bayer.

Author information

Authors and Affiliations

  1. Brighton and Sussex Medical School, Brighton, UK

    Sabina Dizdarevic & Ralph McCready

  2. Brighton and Sussex University Hospitals NHS Trust, Department of Nuclear Medicine, Royal Sussex County Hospital, Brighton, BN2 5BE, UK

    Sabina Dizdarevic

  3. Royal Liverpool University Hospital, Liverpool, UK

    Sobhan Vinjamuri

Authors
  1. Sabina Dizdarevic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ralph McCready
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sobhan Vinjamuri
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors were involved in the analysis and interpretation of the review results. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Sabina Dizdarevic.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

Sabina Dizdarevic has served as a consultant to Bayer and has received travel support, and educational grants from Bayer, and has received honoraria from GE Healthcare.

Ralph McCready declares no conflict of interest in relation to this article.

Sobhan Vinjamuri was a member of an Advisory Board for Bayer and has received honoraria from Ipsen and Advanced Accelerator Applications.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Oncology – Genitourinary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dizdarevic, S., McCready, R. & Vinjamuri, S. Radium-223 dichloride in prostate cancer: proof of principle for the use of targeted alpha treatment in clinical practice. Eur J Nucl Med Mol Imaging 47, 192–217 (2020). https://doi.org/10.1007/s00259-019-04475-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-019-04475-5

Keywords

Search

Navigation