The Impact of Dosimetry Extrapolation Methods for Theranostic Applications of Fibrosing Mediastinitis

Fibrosing mediastinitis (FM) is a benign but potentially fatal condition characterized by excessive fibrous tissue proliferation in the mediastinum, leading to compression of vital structures. A radioisotope-based therapeutic approach using 177Lu-FAPI-46 has demonstrated promising results in preclinical models; however, the lack of animal-to-human dosimetry data has hindered clinical translation. In this study, we aimed to evaluate various animal-to-human dosimetry extrapolation methods to support the potential clinical use of 177Lu-FAPI-46 in FM treatment. Five extrapolation methods were investigated, including direct application of rat time-integrated activity coefficients (TIACs) to human organs (M1), relative mass scaling (M2), metabolic rate scaling (M3), combined mass and metabolic rate scaling (M4), and organ-specific allometric scaling (M5). The correlation between these methods and uterine uptake, as well as clinical imaging data, was further analyzed. Notable variability was observed in the estimated absorbed dose distribution across organs using the different methods, with higher uptake consistently noted in the intestines, kidneys, ovaries, and uterus. Physiological uptake in the uterus, ovaries, and small intestine was confirmed, and the uterus was identified as the dose-limiting organ, with the maximum permissible administered activity estimated to be below 2.78 GBq. Extrapolated absorbed dose estimates suggest that a uterine dose of 16 Gy could be reached with an administered activity of less than 2.78 GBq, depending on the dosimetry model used. These findings highlight the necessity of careful dose planning and special consideration for protecting reproductive organs, particularly in younger female patients, during future clinical trials of 177Lu-FAPI-46 for FM.