Radium-223 Dichloride (Ra-223)

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REVIEW ARTICLE

Radium-223 Dichloride (Ra-223) for the Treatment of Metastatic Castration-resistant Prostate Cancer: Optimizing Clinical Practice in Nuclear Medicine Centers Wim Oyen, M.D., Ph.D., Francis Sundram, MBBCh, BAO, BMedSc, MRCPI, MRCPS, M.Sc, Alexander R. Haug, M.D., Kalevi Kairemo, M.D., Ph.D., M.Sc (Tech), Valerie Lewington, MBBS, Hanna Mäenpää, M.D., Jann Mortensen, M.D., DMSc, Felix Mottaghy, M.D., Ph.D., Irene Virgolini, M.D., Joe M. O’Sullivan, M.D., FRCPI, FFRRSCI, FRCR, and Dirk Wyndaele, M.D.

Abstract

Radboud University Medical Center, Nijmegen, the Netherlands (W.O.); University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom (F.S.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Germany (A.R.H.); Docrates Cancer Center, Helsinki, Finland (K.K.); Kings College London, London, United Kingdom (V.L.); Helsinki University Central Hospital, Helsinki, Finland (H.M.); Rigshospitalet, Copenhagen, Denmark (J.M.); Maastricht University Medical Center, Maastricht, the Netherlands (F.M.); Universita¨tsklinikum der RWTH Aachen, Aachen, Germany (F.M.); Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria (I.V.); Queen’s University Belfast and the Northern Ireland Cancer Centre, Belfast, Northern Ireland (J.M.O.); Catharina Hospital, Eindhoven, the Netherlands (D.W.). Correspondence: Joe O’Sullivan, M.D., FRCPI, FFRRSCI, FRCR, The Northern Ireland Cancer Centre, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland ([email protected]).

Options for the treatment of metastatic castration-resistant prostate cancer (mCRPC) have expanded significantly during the last decade, with six new agents receiving regulatory approval in Europe and the United States. One of these treatments is radium-223 dichloride (Ra-223), the first radiopharmaceutical to offer significant clinical benefits in patients with mCRPC, including prolonging overall survival. The availability of Ra-223 for treating mCRPC marks a paradigm shift in the role of therapeutic nuclear medicine from one of bone pain palliation into one of frontline treatment. As experience in the use of Ra-223 expands, it has become clear that it is vital for nuclear medicine specialists to understand the clinical profile of Ra-223 and where it fits in the treatment algorithm in order to optimize use of the treatment in clinical practice. Participation in the multidisciplinary team responsible for the management of mCRPC patients is essential to ensure appropriate selection of patients and the delivery of safe and effective care. Effective interaction with radiation safety authorities is also required to ensure that local policies reflect the low-risk profile of this life-prolonging treatment. This paper aims to encourage an exchange of best practice between nuclear medicine centers around the world, assisting centers as they initiate or expand their therapeutic services. Keywords: castration-resistant prostate cancer; mCRPC; radium-223; Ra-223; nuclear medicine; clinical practice

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INTRODUCTION Submitted December 12, 2014; accepted December 17, 2014 TJOP 2015;3:1–25 DOI: 10.13032/tjop.2052-5931.100121. Copyright # 2015 Optimal Clinical (Doctors.MD).

Prostate cancer is the third most diagnosed cancer in Europe1 and the fifth leading cause of cancer-related death in men worldwide.2 Treatment aimed at eradicating the primary tumor – typically with surgery or radiation – is unsuccessful in around one-third of men, who subsequently develop recurrent disease that eventually the journal of oncopathology 3:1

april 2015

The Journal of Oncopathology Copyright # 2015 Optimal Clinical (Doctors.MD). All rights reserved.

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metastasizes to distant sites. Approximately 10– 20% of men with prostate cancer will present with incurable advanced or metastatic disease.3 Patients who develop metastatic disease are usually treated with androgen deprivation therapy by bilateral orchiectomy or, more commonly, luteinizing hormone-releasing hormone agonist/ antagonist therapy, which frequently leads to tumor regression. Unfortunately, these regressions are typically transient (median duration of approx‐ imately 11 months)4, with an eventual tumor regrowth as castration-resistant disease that is invariably fatal.5,6 Median survival in patients who develop metastatic castration-resistant prostate cancer (mCRPC) in the modern era is 22 months.4 Bone is the most frequent metastatic site in prostate cancer, with approximately 90% of patients with mCRPC having radiological evidence of bone metastases.3,7 Bone metastases profoundly affect an individual’s quality of life, increase the risk of bone marrow failure8 and skeletal-related events (SREs) such as pathological fractures and spinal cord compression,9,10 and significantly reduce life expectancy.11,12 Unlike deaths from many other types of cancer, deaths from prostate cancer are usually due to bone disease and its complications.13 During the last decade, treatment options for patients with mCRPC have expanded significantly and now include: (1) The chemotherapies, docetaxel and cabazitaxel; (2) The androgen biosynthesis inhibitor, abiraterone acetate; (3) The androgen signaling inhibitor, enzalutamide; and (4) Immunotherapy with sipuleucel-T. All of these agents have demonstrated improved overall survival in randomized controlled studies.

In 2013, the bone-seeking radiopharmaceutical, radium-223 dichloride (Ra-223), was introduced into clinical practice. Radium-223 is indicated for the treatment of patients with mCRPC and symptomatic bone metastases, offering overall survival benefits comparable to the other new treatment options available.14 The availability of Ra-223 has generated considerable interest amongst the nuclear medicine community and, in many centers around the world, nuclear medicine physicians have joined the multidisciplinary treatment team (MDT) involved in the management of patients with mCRPC. In this paper, the clinical profile of Ra-223 is reviewed and some of the practical issues involved in delivering patient-centered care in nuclear medicine centers discussed. Experiences in the development of Ra-223 treatment services are shared with the aim of stimulating an exchange of best practice and helping to equip nuclear medicine centers with the knowledge and skills required to engage effectively with other members of the MDT as well as with local and external radiation protection authorities.

Ra-223 FOR THE TREATMENT OF mCRPC Radium-223 is an alpha-emitting therapeutic radiopharmaceutical that selectively binds to areas of increased bone turnover in bone metastases and delivers high linear energy transfer with a short range (