Joint Regional Uptake Quantification of Thorium-227 and Radium-223 Using a Multiple-Energy-Window Projection-Domain Quantitative SPECT Method

Thorium-227 (Th-227)-based alpha-particle radiopharmaceutical therapies (alpha-RPTs) are currently being investigated in several clinical and pre-clinical studies. After administration, Th-227 decays to Ra-223, another alpha-particle-emitting isotope, which redistributes within the patient. Reliable dose quantification of both Th-227 and Ra-223 is clinically important, and SPECT may perform this quantification as these isotopes also emit X- and gamma-ray photons. However, reliable quantification is challenging for several reasons: the orders-of-magnitude lower activity compared to conventional SPECT, resulting in a very low number of detected counts, the presence of multiple photopeaks, substantial overlap in the emission spectra of these isotopes, and the image-degrading effects in SPECT. To address these issues, we propose a multiple-energy-window projection-domain quantification (MEW-PDQ) method that jointly estimates the regional activity uptake of both Th-227 and Ra-223 directly using the SPECT projection data from multiple energy windows. We evaluated the method with realistic simulation studies conducted with anthropomorphic digital phantoms, including a virtual imaging trial, in the context of imaging patients with bone metastases of prostate cancer who were treated with Th-227-based alpha-RPTs. The proposed method yielded reliable (accurate and precise) regional uptake estimates of both isotopes and outperformed state-of-the-art methods across different lesion sizes and contrasts, as well as in the virtual imaging trial. This reliable performance was also observed with moderate levels of intra-regional heterogeneous uptake as well as when there were moderate inaccuracies in the definitions of the support of various regions. Additionally, we demonstrated the effectiveness of using multiple energy windows and the variance of the estimated uptake using the proposed method approached the Cram & eacute;r-Rao-lower-bound-defined theoretical limit. These results provide strong evidence in support of this method for reliable uptake quantification in Th-227-based alpha-RPTs.