Dosimetry and pharmacokinetics of [<sup>223</sup>Ra]Ra-dichloride alpha therapy in prostate cancer patients with bone metastases.

Abstract

Objective. Currently, [223Ra]RaCl2alpha-radiation radiopharmaceutical therapy (αRPT) has been clinically approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC) by employing short-range alpha-emitters for targeting bone metastasis (BM). The aim of this prospective study was to estimate the absorbed dose (AD) delivered to the target tissues post [223Ra]RaCl2αRPT in patients with mCRPC and symptomatic BMs by means of quantitative single-photon emission computed tomography/computed tomography (SPECT/CT) imaging.Approach. Four patients with mCRPC were administered [223Ra]RaCl2by injection in an activity of about 55 kBq kg-1intravenously on a four-week schedule for up to six cycles. The dosimetry study was performed after the first treatment cycle. Pre-treatment assessment was done using [68Ga]Ga-prostate-specific membrane antigen PET/CT, [99mTc]Tc-MDP bone scan, and laboratory measurements. The SPECT/CT images were obtained after 3-6 h, 18-30 h, and 163-242 h of post-administration. The calibration phantom method was used to quantify the images, and volumes of interests delineation was performed for trabecular bone, cortical bone, bone marrow, intestines, liver, and kidneys. A tri-exponential model was applied to calculate time-integrated activity coefficients. The ADs were computed by Organ Level INternal Dose Assessment/EXponential Modeling software.Main results. There were rapid excretions from the liver and kidneys, while the bone compartments had high accumulation of [223Ra]RaCl2because of its bone-seeking effect. Large interpatient variability was noticed, especially in the intestine. High values of AD coefficients (ADCs) were found in osteogenic cells (184 mGy MBq-1), followed by red marrow (38.10 mGy MBq-1), kidneys (58 mGy MBq-1), and the liver (26.2 mGy MBq-1). The total body ADC was 7.68 mGy MBq-1, showing selective bone targeting and low radiation ADs to soft tissue. Quantitative analysis showed the bone uptake, gastrointestinal transit, rectosigmoid accumulation, and fecal clearance.Significance. In this paper, we performed the first quantitative Ra-223 SPECT/CT imaging in mCRPC patients with BMs, providing the possibility of carrying out patient-specific dosimetry at multiple time points. The high AD for endosteal bones shows good targeting of bone and low radiation off-target in this patient group. Individualized treatment can increase the efficacy of the therapy while decreasing toxicity. Further research needs to be done on larger populations to perform more AD escalation studies.