Radio-ligand therapy (RLT) with¹⁷⁷Lu-PSMA-617 is a promising option for patients with metastatic castration-resistant prostate-cancer (mCRPC). A prospective phase-II study (EUDRACT/RSO,2016-002732-32) on mCRPC is ongoing at IRST (Meldola, Italy). A total of 9 patients (median age: 68 y, range: 53–85) were enrolled for dosimetry evaluation of parotid glands (PGs), kidneys, red marrow (RM) and whole body (WB). Folic polyglutamate tablets were orally administered as PGs protectors and 500 mL of a 10% mannitol solution was intravenously infused to reduce kidney uptake. The whole body planar image (WBI) and blood samples were acquired at different times post infusion (1 h, 16–24 h, 36–48 h and 120 h). Dose calculation was performed with MIRD formalism (OLINDA/EXM software). The median effective half-life was 33.0 h (range: 25.6–60.7) for PGs, 31.4 h (12.2–80.6) for kidneys, 8.2 h (2.5–14.7) for RM and 40.1 h (31.6–79.7) for WB. The median doses were 0.48 mGy/MBq (range: 0.33–2.63) for PGs, 0.70 mGy/MBq (0.26–1.07) for kidneys, 0.044 mGy/MBq (0.023–0.067) for RM and 0.04 mGy/MBq (0.02–0.11) for WB. A comparison with previously published dosimetric data was performed and a significant difference was found for PGs while no significant difference was observed for the kidneys. For PGs, the possibility of reducing uptake by administering glutamate tablets during RLT seems feasible while further research is warranted for a more focused evaluation of the reduction in kidney uptake.

Radioligand therapy is a type of internal radiotherapy combining a short-range radioisotope labeled to a carrier with a high affinity for a specific receptor expressed on tumor cells. Targeted alpha therapy (TAT) combines a high-linear energy transfer (LET) emitter (²²⁵Ac) with a prostate-specific membrane antigen (PSMA) carrier, specifically binding tumor cells in patients with metastatic castration-resistant prostate cancer. Although the antitumor activity of ²²⁵Ac-PSMA is well-documented, this treatment is nowadays only used as salvage therapy because the high incidence of xerostomia limits the therapeutic window. Thus, methods to reduce salivary toxicity and models able to describe xerostomia incidence are needed. We recently studied the efficacy of salivary gland protectors administered in combination with ¹⁷⁷Lu-PSMA therapy. Starting from these data, we performed a predictive dosimetric evaluation of ²²⁵Ac-PSMA to assess the impact of salivary gland protectors in TAT. ²²⁵Ac-PSMA predictive dosimetry was performed in 13 patients treated with ¹⁷⁷Lu-PSMA. Sequential whole-body planar images were acquired 0.5–1, 16–24, 36–48, and 120 h post-injection. ¹⁷⁷Lu time-activity curves were corrected for ²²⁵Ac physical decay and assumed in equilibrium for all daughters. The OLINDA/EXM spherical model was used for dose estimation of the parotid and submandibular glands. The dose for each daughter was calculated and summed for the total dose estimation. The biologically effective dose formalism was extended to high-LET emitters. For the total biologically effective dose formalism extended to high-LET emitters, including the contribution of all daughter isotopes, the brachytherapy formalism for a mixture of radionuclides was implemented. Equivalent doses in 2 Gy/fraction (EQD2) were then calculated and compared with the normal tissue complication probability model derived from external beam radiotherapy for grade ≥2 xerostomia induction. Median predictive doses were 0.86 Bd_RBE5/MBq for parotid glands and 1.05 Bd_RBE5/MBq for submandibular glands, with a 53% reduction compared with previously published data. The results show that the radiobiological model implemented is conservative, as it overestimates the complication rate with respect to the clinical data. Our data shows the possibility of reducing salivary gland uptake in TAT with the coadministration of organ protectors, but these results should be confirmed for TAT with ²²⁵Ac-PSMA by carrying out prospective trials with defined toxicity endpoints and dosimetry procedures.

Purpose: To validate and compare the deformable image registration and parotid contour propagation process for head and neck magnetic resonance imaging in patients treated with radiotherapy using 3 different approaches—the commercial MIM, the open-source Elastix software, and an optimized version of it. Materials and Methods: Twelve patients with head and neck cancer previously treated with radiotherapy were considered. Deformable image registration and parotid contour propagation were evaluated by considering the magnetic resonance images acquired before and after the end of the treatment. Deformable image registration, based on free-form deformation method, and contour propagation available on MIM were compared to Elastix. Two different contour propagation approaches were implemented for Elastix software, a conventional one (DIR_Trx) and an optimized homemade version, based on mesh deformation (DIR_Mesh). The accuracy of these 3 approaches was estimated by comparing propagated to manual contours in terms of average symmetric distance, maximum symmetric distance, Dice similarity coefficient, sensitivity, and inclusiveness. Results: A good agreement was generally found between the manual contours and the propagated ones, without differences among the 3 methods; in few critical cases with complex deformations, DIR_Mesh proved to be more accurate, having the lowest values of average symmetric distance and maximum symmetric distance and the highest value of Dice similarity coefficient, although nonsignificant. The average propagation errors with respect to the reference contours are lower than the voxel diagonal (2 mm), and Dice similarity coefficient is around 0.8 for all 3 methods. Conclusion: The 3 free-form deformation approaches were not significantly different in terms of deformable image registration accuracy and can be safely adopted for the registration and parotid contour propagation during radiotherapy on magnetic resonance imaging. More optimized approaches (as DIR_Mesh) could be preferable for critical deformations.