ORIGINAL ARTICLE Imaging response during therapy with radium-223 for castration-resistant prostate cancer with bone metastases—analysis of an international multicenter database D Keizman 1,11 , MO Fosboel 2,11 , H Reichegger 3,4 , A Peer 5 , E Rosenbaum 6 , M-C Desax 3,4 , V Neiman 6 , PM Petersen 7 , J Mueller 3,4 , R Cathomas 8 , M Gottfried 1 , H Dresler 1 , D Sarid 9 , W Mermershtain 10 , K Rouvinov 10 , J Mortensen 2 , S Gillessen 3,4 , G Daugaard 7,12 and A Omlin 3,4,12 BACKGROUND: The imaging response to radium-223 therapy is at present poorly described. We aimed to describe the imaging response to radium-223 treatment. METHODS: We retrospectively evaluated the computed tomography (CT) and bone scintigraphy response of metastatic castration-resistant prostate cancer (CRPC) patients treated with radium-223, in eight centers in three countries. RESULTS: A total of 130 patients were included, the majority (n = 84, 65%) received radium-223 post docetaxel. Thirty-four of 99 patients with available data (34%) received concomitant abiraterone or enzalutamide. A total of 54% (n = 70) patients completed the planned six injections of radium-223. In patients with available data, a transient increase in bone metastases-related pain was observed in 27% (n = 33/124) and an improvement of bone metastases-related pain on treatment with radium-223 was noted in 49% of patients (n = 61/124). At 3 and 6 months of treatment with radium-223, bone imaging showed stable disease in 74% (n = 84/113) and 94% of patients (n = 93/99) with available data, respectively. An increase in the number of bone lesions was documented at 3 months compared with baseline in 26% (n = 29/113) and at 6 months compared with 3 months in 6% of patients (n = 6/99), respectively. Radiological extraskeletal disease progression occurred in 46% of patients (n = 57/124) with available CT data at 3 and/or 6 months. CONCLUSIONS: Progression of bone metastases during radium-223 therapy is uncommon. A bone flare (pain and/or radiological) may be noted during the first 3 months, and should not be confused with progression. Imaging by CT scan should be considered after three and six doses of radium-223 to rule out extraskeletal disease progression. Prostate Cancer and Prostatic Diseases advance online publication, 28 February 2017; doi:10.1038/pcan.2017.6 INTRODUCTION Prostate cancer is the second leading cause of cancer-related death among men in the western world 1 and 90% of patients with metastatic castration-resistant prostate cancer (mCRPC) have bone metastases. 2 Bone metastases are associated with skeletal-related events such as pain, fractures and spinal cord compression. 3 Radium-223 is an alpha-emitting radioisotope with calcium- mimetic properties, which therefore accumulates in bone areas with an increased turnover. Radium-223 targets bone meta- stases, and improves overall survival in patients with bone metastases, 4 but is not indicated in mCRPC patients with visceral or bulky lymph node disease. Improved overall survival was observed in the pivotal phase 3 ALSYMPCA trial. 4,5 The ALSYMPCA study did not mandate baseline staging or regular monitoring of antitumor activity by imaging. 4 Thus, the use of radiological examinations, and how to interpret response to therapy, in patients receiving radium-223 is at present poorly defined. 6,7 Furthermore, in the ALSYMPCA trial, a ⩾ 30% decline of the tumor marker PSA was reported in only 16% of patients. 4 In daily practice, management of a patient receiving radium-223 can be challenging in the absence of a PSA decline and due to uncertain imaging response data. Extraskeletal imaging may be important in patients with CRPC, since up to 50% will develop visceral metastases, that are not targeted by radium-223. 8 The present study aimed to assess the radiological response in patients with mCRPC and bone metastases during radium-223 treatment. 1 Genitourinary Oncology Service, Institute of Oncology, Meir Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 2 Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 3 Department of Oncology and Haematology, Kantonsspital St Gallen, St Gallen, Switzerland; 4 Department of Radiology and Nuclear Medicine, Kantonsspital St Gallen, St Gallen, Switzerland; 5 Department of Oncology, Rambam Medical Center, Haifa, Israel; 6 Department of Oncology, Rabin Medical Center, Petah Tikva, Israel; 7 Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 8 Department of Oncology, Kantonsspital Chur, Chur, Switzerland; 9 Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel and 10 Department of Oncology, Soroka Medical Center, Beer-Sheva, Israel. Correspondence: Dr D Kejzman, Genitourinary Oncology Service, Institute of Oncology, Meir Medical Center, Sackler School of Medicine, Tel Aviv University, Tshernichovsky 59, Kfar Saba 44281, Israel. E-mail: danielkeizman@gmail.com 11 These two authors contributed equally to this work. 12 These two authors contributed equally to this work. Part of the data was presented (poster) at the annual meeting of the American Society of Clinical Oncology (ASCO), Chicago, June 2016, and published in abstract form (J Clin Oncol 34, 2016, suppl; abstr 5057). Received 21 September 2016; revised 12 December 2016; accepted 20 December 2016 Prostate Cancer and Prostatic Diseases (2017) 00, 1 – 5 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1365-7852/17 www.nature.com/pcan