Optimising Radium 223 Therapy for Metastatic Castration-Resistant Prostate Cancer -5-year Real-World Outcome: Focusing on Treatment Sequence and Quality of Life.

AIMS: Real-world evidence of radium 223 (Ra-223) for the treatment of men with metastatic castration-resistant prostate cancer is emerging. In this prospective single-centre service evaluation, we report for the first time in the UK, real-world quality of life (QoL) and survival outcomes, including the sequencing impact, in 228 treated patients. We aim to share our 5-year experience on how to optimise Ra-223 treatment. MATERIALS AND METHODS: Patients who received Ra-223 therapy between 2014 and 2018 at the Northern Centre for Cancer Care, Newcastle upon Tyne, UK were included in this evaluation. Demographics, clinical characteristics, blood parameters, treatment sequencing and QoL data using abbreviated Functional Assessment of Cancer Therapy-Prostate questionnaires were prospectively collected and analysed. RESULTS: In total, 228 patients were included; median age 72 years (51-87). The medium overall survival was 11.1 months. Overall survival in post-chemotherapy and chemotherapy-naïve patients was 8.1 and 12.3 months, respectively (P = 0.02, hazard ratio 1.52, 95% confidence interval 1.06-2.17); in pre-enzalutamide and post-enzalutamide patients was 11.3 and 10.4 months, respectively (P = 0.65, hazard ratio 0.92, 95% confidence interval 0.63-1.33); in pre-abiraterone and prednisolone and post-abiraterone and prednisolone patients was 11.8 and 10.5 months, respectively (P = 0.08, hazard ratio 0.74, 95% confidence interval 0.51-1.06); in this latter group, the fracture rate was 24% (15/63). QoL post Ra-223 (n = 101 evaluated) showed that pain scores improved in 54%, there was no change in 17% and pain scores worsened in 30% of treated patients. Overall QoL scores showed a similar trend. QoL was not significantly associated with overall survival. CONCLUSIONS: Ra-223 palliates pain and improves disease-related QoL in most patients in the real-world setting. Our survival outcome is comparable with other real-world studies. Chemotherapy-naïve patients seemed to have better survival than those who received prior chemotherapy. No significant survival differences were observed between pre- and post-abiraterone and prednisolone or enzalutamide patients. The fracture rate in the post-abiraterone and prednisolone group seemed to be high. Bone health evaluation and protection should be incorporated as standard of care.

[Therapy of bone metastases with radium-223. German guidelines]. / Radionuklidtherapie von Knochenmetastasen mittels Radium-223. DGN-Handlungsempfehlung.

This document describes the guideline for therapy of bone metastases with radium-223 ((223)Ra) published by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften in Germany (AWMF) under the auspices of the Deutsche Gesellschaft für Nuklearmedizin (DGN), Östereichische Gesellschaft für Nuklearmedizin (OGN), and Schweizerische Gesellschaft für Nuklearmedizin (SGNM). This guidance is based on an interdisciplinary consensus. These recommendations are a prerequisite for the quality management in the treatment of patients with bone metastases from prostate cancer using (223)Ra. They are aimed at guiding nuclear medicine specialists in selecting candidates to receive therapy and to deliver the treatment in a safe and effective manner. The document contains background information and definitions. It covers the rationale, indications and contraindications for therapy with (223)Ra. Essential topics are the requirements for institutions performing the therapy, which patient data have to be available prior to performance of therapy, and how treatment has to be carried out technically and organisationally. Moreover, essential elements of follow-up and aftercare are specified. As a matter of principle, the treatment inclusive aftercare has to be realised in close cooperation with the involved medical disciplines.

Determination of photon emission probabilities for the main gamma-rays of ²²³Ra in equilibrium with its progeny.

The currently published (223)Ra gamma-ray emission probabilities display a wide variation in the values depending on the source of the data. The National Institute of Standards and Technology performed activity measurements on a (223)Ra solution that was used to prepare several sources that were used to determine the photon emission probabilities for the main gamma-rays of (223)Ra in equilibrium with its progeny. Several high purity germanium (HPGe) detectors were used to perform the gamma-ray spectrometry measurements.

The radium legacy: Contaminated land and the committed effective dose from the ingestion of radium contaminated materials.

The manufacture and use of radium in the early to mid-20th century within industrial, medicinal and recreational products have resulted in a large number of contaminated sites across a number of countries with notable examples in the USA and Europe. These sites, represent a significant number of unregulated sources of potential radiological exposure that have collectively and hitherto not been well characterised. In 2007, the Radioactive Contaminated Land (RCL) Regulations came into force in the UK, providing the statutory guidance for regulators to classify and deal with RCL. Here we report on results derived from digestion experiments to estimate committed effective dose, a key aspect of the RCL Regulations, from the ingestion of radium contaminated sources that can be found in the environment. This case study includes particles, clinker and artefacts that arise from past military activities on a site that was once an airfield at Dalgety Bay on the Firth of Forth, UK. Since 2011 the number of radium contaminated finds has increased by one order of magnitude on the foreshore areas of Dalgety Bay. The increase in finds may in large part be attributed to a change in monitoring practice. A subsample of sixty sources was selected, on the basis of their activity and dimensions, and subjected to digestion in simulated stomach and lower intestine solutions. The study demonstrated that more radium-226 ((226)Ra) and lead-210 ((210)Pb; driven by Polonium solubility) are dissolved from sources in artificial 'stomach' solutions compared with 'lower intestine' solutions. The combined 'gut' solubility for (226)Ra and apparent (210)Pb varied from less than 1% to up to 35% ICRP 72 conversion factors were used to convert the activities measured in solution to committed effective dose. A little over 10% of the sources tested dissolved sufficient radioactivity to result in 100mSv committed effective dose to an infant. Using the solubility of 35% as a worst case, minimum source activities necessary to deliver 100mSv to the full age range of users of the foreshore were estimated. All the estimated activities have been detected and recovered through routine monitoring.

Activity standardisation of ²²6Ra by 4πα liquid scintillation counting method.

Activity of (226)Ra in radium daughter products free solution was determined by 4πα liquid scintillation counting (LSC) method, where the detection efficiency of radium decay is practically equal to 1. The sources were prepared from solution with known (226)Ra mass concentration, from which, immediately before LS counting, (222)Rn and its daughter nuclides were removed by solvent extraction. LS counting results were corrected practically only for a <0.6% loss of radium from measured sample and for the ingrowth of (222)Rn and (218)Po concentrations in the sample after the separation was completed. The combined relative standard uncertainty was estimated to be lower than 0.34%.

Radium equivalent activity in the light of UNSCEAR report.

Radium equivalent activity (Ra ( eq )) has been in practice for the last 40 years for the assessment of radiological hazard of radioactivity in environmental materials. The in-practice model for the calculation of the Ra ( eq ) has been critically reviewed in the light of the UNSCEAR 2000 report. Annual effective dose (E) values of (232)Th and (40)K were found to be not equal to that of (226)Ra derived from the activity concentrations of these radionuclides used in the expression for the Ra ( eq ). Therefore, a modified model has been proposed for the determination of the Ra ( eq ) for outdoor external exposure to gamma rays. The relation between the E and Ra ( eq ) has been explored. It is recommended that while describing the radiological hazard of the materials containing radioactivity, there should be no need to calculate the Ra ( eq ) if the E has already been determined or vice versa.

Standardization of radium-223 by liquid scintillation counting.

Liquid scintillation (LS) counting was undertaken as part of the primary standardization of (223)Ra. Radium-223 decays with a half life of 11.43 d through a chain of shorter-lived daughter radionuclides, resulting in five alpha decays and three beta decays. The CIEMAT/NIST method of tritium efficiency tracing was employed, with the beta efficiencies being calculated using the program CN2004, developed by the Physikalisch-Technische Bundesanstalt (PTB). The total calculated LS efficiency, considering all daughter radionuclides, was approximately 598%. Separate experiments were performed to rule out loss of the 3.96 s (219)Ra daughter from the cocktail and possible counting loss of the 1.78 ms (215)Po daughter due to LS counter dead-time. No loss was observed in either experiment. In the final experiment an expanded uncertainty (k=2) of 0.55% was achieved. Results were in excellent agreement with confirmatory measurements performed by 2pialpha proportional counting. However, results are not in agreement with methods based on gamma ray measurements.

Calibration of the direct LSC method for radon in drinking water: Interference from (210)Pb and its progenies accumulated in (226)Ra standard solution.

The standard ASTM method is the most commonly applied method for determining (222)Rn in drinking water. The method is calibrated with a (226)Ra standard solution that usually contains variable amounts of (210)Pb, (210)Bi and (210)Po if the standard has not recently been purified. Until now it has not been experimentally confirmed that these progenies do not interfere when the method is calibrated. In this study, interference was examined using three different organic cocktails and alpha/beta liquid scintillation spectrometry to separately assess the effect of three radionuclides. The interference from (210) Po was 4% for one of the cocktails if the (226)Ra standard had been purified 5 years earlier. The interferences from (210)Pb and (210)Bi were negligible compared to that of (210)Po.

Radiological aspects of the usability of red mud as building material additive.

Several researchers have examined and achieved favourable results in connection with the building industry's use of red mud extracted in large quantities from the processing of bauxite. These days more and more precedence is being given to limiting the radiological dose to the population. In this study carried out in Hungary, the use of red mud, bauxite, and clay additives recommended for the production of special cements, were examined from a radiological aspect. (226)Ra and (232)Th activity concentrations measured in Hungarian bauxite, red mud and clay samples were significantly similar with the levels for such raw materials mentioned in international literature. Taking radiation protection aspects into consideration, none of these products can be directly used for building construction. Taking Hungarian and international values into consideration, a small amount of red mud, not exceeding 15% could be used for brick production, for example as a colouring material. However, beyond this amount the standards for building materials would not be met. For the production of cements an even stricter limit needs to be determined when both bauxite and red mud are used.

Performance assessment model development and parameter acquisition for analysis of the transport of natural radionuclides in a Mediterranean watershed.

This paper describes the methodology developed to construct a model for predicting the behaviour of the natural radioisotopes of U, Th and Ra in a Mediterranean watershed. The methodology includes the development of the performance assessment model, obtaining water flow and radiological parameters based on experimental data and analysis of results. The model, which accounts for both water flows and mass balances of the radionuclides in a semi-natural environment, provides assessments of radionuclide behaviour in grassland and agricultural soils, rivers and reservoirs, including the processes of radionuclide migration through land and water and interactions between both. From field and laboratory data, it has been possible to obtain parameters for the driving processes considered in the model, water fluxes, source term definition, soil to plant transfer factors and distribution coefficient values. Ranges of parameter values obtained have shown good agreement with published literature data. This general methodological approach was developed to be extended to other radionuclides for the modelling of a biosphere watershed in the context of performance assessment of a High Level Waste (HLW) repository under Mediterranean climate conditions, as well as for forecasting radionuclide transport under similar Mediterranean conditions that will occur in the future in other areas. The application of sensitivity and uncertainty analysis was intended to identify key uncertainties with the aim of setting priorities for future research. The model results for the activity concentration in the reservoir indicate that for (238)U and (230)Th the most relevant parameter is the initial concentrations of the radionuclides in the reservoir sediments. However, for (226)Ra the most important parameter is the precipitation rate over the whole watershed.

Beverages: bottled water. Direct final rule.

The Food and Drug Administration (FDA) is amending its bottled water quality standard regulations by establishing an allowable level for the contaminant uranium. As a consequence, bottled water manufacturers are required to monitor their finished bottled water products for uranium at least once each year under the current good manufacturing practice (CGMP) regulations for bottled water. Bottled water manufacturers are also required to monitor their source water for uranium as often as necessary, but at least once every 4 years unless they meet the criteria for the source water monitoring exemptions under the CGMP regulations. FDA will retain the existing allowable levels for combined radium-226/-228, gross alpha particle radioactivity, and beta particle and photon radioactivity. This direct final rule will ensure that the minimum quality of bottled water, as affected by uranium, combined radium-226/-228, gross alpha particle radioactivity, and beta particle and photon radioactivity, remains comparable with the quality of public drinking water that meets the Environmental Protection Agency's (EPA's) standards. FDA is issuing a direct final rule for this action because the agency expects that there will be no significant adverse comment on this rule. Elsewhere in this issue of the Federal Register, FDA is publishing a companion proposed, rule under the agency's usual procedure for notice-and-comment rulemaking, to provide a procedural framework to finalize the rule in the event the agency receives any significant adverse comments and withdraws this direct final rule. The companion proposed rule and direct final rule are substantively identical.

The 1999 Lauriston S. Taylor lecture--back to background: natural radiation and radioactivity exposed.

I am profoundly grateful for being chosen as the twenty-third presenter of the Lauriston S. Taylor Lecture, and I share this honor with a list of distinguished scientists, including my husband, who pay tribute to the premier leader in radiation protection. In 1938, Laurie was working for the National Bureau of Standards and chaired the Advisory Committee on X-ray and Radium Protection, a group of 8 persons, who set the pace for all forthcoming radiation standards. NBS had, since 1913, been standardizing essentially all of the radium offered for sale in the U.S., and the problem arose to revise the handbook on proper conditions for handling radium based on the then current knowledge. This resulted in Handbook 23 (1938) superseding the 1934 work. At the time Laurie was a scientist working in the measurements side of radiation and though he contributed much to that field, his name is inseparably linked with guidance in radiation protection. Today we pay tribute for his leadership that he carried out with intelligence, grace, and personal warmth. My talk today deals mostly with measured data for naturally occurring internal radiation emitters and how these data can be used for predictive purposes in estimating the dose and risk from internal body contamination. This stresses the "and Measurements" part of the Council's title. The topic of this year's NCRP Annual Meeting is "Radiation Protection in Medicine: Contemporary Issues." I believe that physicians and State and Federal agencies will have to cope with complaints following various exposure situations resulting from the cleanup of background radionuclides during closure at nuclear facilities, military use of radioactivity, and occurrences of high natural background in some locations. They will find comfort in the knowledge that existing background radiation data can be the basis for predictions of realistic dose and risk in most situations.