ISIT-QA: In Silico Imaging Trial to Evaluate a Low-Count Quantitative SPECT Method Across Multiple Scanner-Collimator Configurations for 223Ra-Based Radiopharmaceutical Therapies

Personalized dose-based treatment planning requires accurate and reproducible noninvasive measurements to ensure safety and effectiveness. Dose estimation using SPECT is possible but challenging for alpha (α)-particle-emitting radiopharmaceutical therapy (α-RPT) because of complex γ-emission spectra, extremely low counts, and various image-degrading artifacts across a plethora of scanner- collimator configurations. Through the incorporation of physics-based considerations and skipping of the potentially lossy voxel-based reconstruction step, a recently developed projection-domain low-count quantitative SPECT (LC-QSPECT) method has the potential to provide reproducible, accurate, and precise activity concentration and dose measures across multiple scanners, as is typically the case in multicenter settings. To assess this potential, we conducted an in silico imaging trial to evaluate the LC-QSPECT method for a 223Ra-based α-RPT, with the trial recapitulating patient and imaging system variabilities. Methods: A virtual imaging trial titled In Silico Imaging Trial for Quantitation Accuracy (ISIT-QA) was designed with the objectives of evaluating the performance of the LC-QSPECT method across multiple scanner-collimator configurations and comparing performance with a conventional reconstruction-based quantification method. In this trial, we simulated 280 realistic virtual patients with bone-metastatic castration-resistant prostate cancer treated with 223Ra-based α-RPT. The trial was conducted with 9 simulated SPECT scanner-collimator configurations. The primary objective of this trial was to evaluate the reproducibility of dose estimates across multiple scanner-collimator configurations using LC-QSPECT by calculating the intraclass correlation coefficient. Additionally, we compared the reproducibility and evaluated the accuracy of both considered quantification methods across multiple scanner-collimator configurations. Finally, the repeatability of the methods was evaluated in a test-retest study. Results: In this trial, data from 268 223RaCl2 treated virtual prostate cancer patients, with a total of 2,903 lesions, were used to evaluate LC-QSPECT. LC-QSPECT provided dose estimates with good reproducibility across the 9 scanner- collimator configurations (intraclass correlation coefficient . 0.75) and high accuracy (ensemble average values of recovery coefficients ranged from 1.00 to 1.02). Compared with conventional reconstructionbased quantification, LC-QSPECT yielded significantly improved reproducibility across scanner-collimator configurations, accuracy, and test-retest repeatability (P<0:01). Conclusion: LC-QSPECT provides reproducible, accurate, and repeatable dose estimations in 223Ra-based α-RPT as evaluated in ISIT-QA. These findings provide a strong impetus for multicenter clinical evaluations of LC-QSPECT in dose quantification for α-RPTs.