Oliver Sartor1, Robert Coleman2, Sten Nilsson3, Daniel Heinrich4, Svein I Helle5, Joe M O'Sullivan6, Sophie D Fosså7, Aleš Chodacki8, Paweł Wiechno9, John Logue10, Anders Widmark11, Dag Clement Johannessen12, Peter Hoskin13, Nicholas D James14, Arne Solberg15, Isabel Syndikus16, Nicholas J Vogelzang17, C Gillies O'Bryan-Tear18, Minghua Shan19, Øyvind S Bruland20, Christopher Parker21. 1. Tulane Cancer Center, New Orleans, LA, USA. Electronic address: osartor@tulane.edu. 2. Weston Park Hospital, Sheffield Cancer Research Centre, Sheffield, UK. 3. Karolinska University Hospital, Radiumhemmet, Stockholm, Sweden. 4. Akershus University Hospital, Department of Oncology, Lørenskog, Norway. 5. Haukeland University Hospital, Bergen, Norway. 6. Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK. 7. Oslo University Hospital, Radiumhospital, Oslo, Norway. 8. Hospital Chomutov, Nuclear Medicine Department, Chomutov, Czech Republic. 9. Centrum Onkologii-Instytut im Marii Skodowskiej-Curie, Warsaw, Poland. 10. Christie Hospital, Manchester, UK. 11. Umeå University, Department of Radiation Sciences, Oncology, Sweden. 12. Ullevål University Hospital, Oslo, Norway. 13. Mount Vernon Hospital Cancer Centre, Northwood, Middlesex, UK. 14. Cancer Research Unit, University of Warwick, Coventry, UK; University Hospital, Birmingham NHS Trust, Birmingham, UK. 15. St Olavs Hospital, Trondheim, Norway. 16. Clatterbridge Cancer Centre, Clatterbridge Health Park, Bebington, Wirral, UK. 17. Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA. 18. Algeta ASA, Kjelsaas, Oslo, Norway. 19. Bayer Healthcare, Whippany, NJ, USA. 20. Norwegian Radium Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway. 21. The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, Surrey, UK.
Abstract
BACKGROUND: Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. METHODS: In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable fordocetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751. FINDINGS:Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5-18·0] vs 9·8 months [7·3-23·7]; hazard ratio [HR]=0·66, 95% CI 0·52-0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53-0·85) and spinal cord compression (HR=0·52, 95% CI 0·29-0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35-1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28-1·82). INTERPRETATION:Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. FUNDING: Algeta and Bayer HealthCare Pharmaceuticals.
RCT Entities:
BACKGROUND:Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. METHODS: In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751. FINDINGS: Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5-18·0] vs 9·8 months [7·3-23·7]; hazard ratio [HR]=0·66, 95% CI 0·52-0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53-0·85) and spinal cord compression (HR=0·52, 95% CI 0·29-0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35-1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28-1·82). INTERPRETATION:Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. FUNDING: Algeta and Bayer HealthCare Pharmaceuticals.
Authors: Sunil Parimi; Suraya Bondy; Erica Tsang; Michael Ross McKenzie; Francois Bachand; Maria Aparicio; Graeme Duncan; Katherine Sunderland; Robert Anton Olson; Howard Huaihan Pai; Abraham Skaria Alexander; Vincent LaPointe; Kim N Chi; Scott Tyldesley Journal: Can Urol Assoc J Date: 2019-10 Impact factor: 1.862
Authors: Oliver Sartor; Nicholas J Vogelzang; Christopher Sweeney; Daniel C Fernandez; Fabio Almeida; Andrei Iagaru; Alan Brown; Matthew R Smith; Manish Agrawal; Adam P Dicker; Jorge A Garcia; Jose Lutzky; Yu-Ning Wong; Oana Petrenciuc; Jeremy Gratt; Neal D Shore; Michael J Morris Journal: Oncologist Date: 2017-11-28