Quantitative imaging of 223Ra-chloride (Alpharadin) for targeted alpha-emitting radionuclide therapy of bone metastases.

OBJECTIVE: Ra is an alpha particle emitter that targets areas of increased bone turnover in bone metastases. Alpha particles account for 95% of the 27.8 MeV emitted per decay. Less than 2% of the emissions are from photons. This means that a high absorbed dose will be delivered locally, although the number of photons for imaging will be low. The purpose of this study was to investigate the possibility of quantitative imaging of Ra to enable biodistribution studies. METHODS: A Philips Forte gamma camera, equipped with a medium-energy collimator, was used. Basic imaging parameters were determined from phantom studies, and the accuracy of activity quantification was tested in a phantom study and within a patient study. RESULTS: Imaging parameters were determined for the three most suitable photon peaks from the acquired energy spectrum (82, 154 and 270 keV). Camera sensitivity is constant for circular sources with areas greater than 10 cm. The spatial resolution (full-width at half-maximum) was 1.1 cm for each of the three energy windows. The possibility for quantitative imaging was further investigated for the 82 keV energy window, which showed the highest sensitivity and spatial resolution. A phantom study showed that activity could be quantified to within 10% for a 200 ml volume placed within water containing background activity and to within 50% for a 0.5 ml phantom. Quantification of activity in bone after administrations of 100 kBq/kg of Ra-chloride proved the feasibility of quantitative imaging of patients who have received radionuclide therapy. CONCLUSION: Because of the high-energy deposition of Ra, only a low injected activity is required for therapy, which results in a low count rate for the gamma camera. Nevertheless, this study has demonstrated that it is possible to quantify uptake with a sufficient degree of accuracy to obtain clinically relevant information

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 ALSYMPCA trial

Background Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted alpha-emitter, improved overall survival compared with placebo and was well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223. Methods In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Findings Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio [HR] 0 . 70, 95% CI 0 . 56-0 . 88; p=0 . 002; no previous docetaxel use, HR 0 . 69, 0 . 52-0 . 92; p=0 . 01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3-4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3-4 thrombocytopenia with radium-223 than with placebo (31 [9%] of 347 patients vs five [3%] of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven [3%] of 253 patients vs one [1%] of 130 patients). The incidences of grade 3-4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups. Interpretation Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use