Radium-223 Treated Primary Patient Bone Biopsy Analysis: Macro to Microscale Analyses and Dosimetry

Objectives: In nuclear medicine and radiation oncology, dosimetry has an important role in guiding clinical trial design in order to maximize the likelihood of a successful, minimally toxic intervention. For alpha particle-emitting radiopharmaceuticals, personalized dosimetry is challenging because of local activity distribution heterogeneity, the short range of alpha particles and challenges in noninvasive imaging. Existing small-scale dosimetry methods predominately rely on standardized anatomical models of healthy tissues. Moreover, the fundamental assumption in their approach is of a uniform distribution of emitters in the source volume and a calculation that gives the average absorbed dose to the target volume. To overcome these problems, we investigated the microscopic distribution of ²²³Ra in bone biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC). Materials & Methods: Bone biopsies were obtained from four mCRPC patients under fluoroscopic guidance following a bone scan, 24h after injection of ²²³Ra. Blood samples were also collected at the same time. The ²²³Ra activity in each biopsy and blood sample was measured with a gamma-counter and evaluated with a high purity Germanium detector (Figure, a and c). Microsctructure images of the tissue was performed for each biopsy by µCT (20 µm resolution) (Figure, b). The samples were then cryosectioned and autoradiography was performed on the sections using a Cyclone PhosphorImager. The same sections were stained with hematoxylin and eosin (H&E). Histological images were finally segmented using machine learning and registered with autoradiographic images with an automated procedure. The autoradiographies were calibrated using a range of known activity of ²²³Ra on each phosphor sheet. The biokinetic of the radiopharmaceutical was considered to be fixed thus the cumulated activity was calculated considering only the physical decay. 2D dosimetry was done based on the MIRD formalism. A 3D phantom of each biopsy was created from the µCT acquisition and 3D dosimetry was done using MCNP6 Monte Carlo code. Results & Discussion: Microdistribution analysis revealed localization predominantly to the surface of the bone, with little activity in the marrow cavity surface (Figure, d). Figure-d) shows the automatic analysis workflow for one section and the final result with the absorbed dose distribution. In this section, the mean absorbed doses were found to be 6.3 Gy in the bone and 4.2 Gy in the cellular component. The microdistibution results on the 2D images were implemented in a 3D phantom created with the µCT acquisition to perform a dosimetric evaluation using Monte Carlo simulations. The results were compared to the dosimetric evaluation from existing models using only the activity in the whole biopsy and in the blood samples. Conclusion: Here we have performed fundamental studies to determine the activity concentrations in patients derived samples, and evaluated microstructural characteristics and their role in activity and dose distribution. These results provide the first patient sample microdosimetry values from a primary source. This work will help to improve the current small-scale dosimetry methods and demonstrate that autoradiographic and pathological samples can be used to provide direct and personalized dosimetric data. These results will have important implications for the design and interpretation of clinical studies evaluating treatment with ²²³Ra; with other investigational alpha particle emitting therapies; to guide clinical application with adapted dosing; and ultimately for more effective application.

• Download figure
• Open in new tab
• Download powerpoint