Imaging-guided bone marrow dosimetry in radiopharmaceutical therapy: An investigation of the influence of the bone marrow composition on the red marrow absorbed dose

• Applicant: Dr. Johannes Tran-Gia
• Subject Area: Medical Physics, Biomedical Technology ; Radiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521044818

Radiopharmaceutical therapies (RPTs) have evolved as a promising therapeutic approach for cancer treatment. Most radiopharmaceuticals (RPs) use carrier molecules labelled with beta-emitters designed to target binding sites overexpressed by tumor cells. Since RPs are injected systemically, the aim of RPT dosimetry is to optimize tumor absorbed doses while keeping absorbed doses to organs-at-risk as low as reasonably achievable, which is essential for patient safety. Due to its high radiosensitivity, the red bone marrow (RM) represents one of the most important organs-at-risk. Due to its highly complicated and patient-specific localization and tissue morphology, the implementation of RPT dosimetry procedures has proved highly complex and no standardized approach exists to date. This in turn results in a lack of knowledge about the maximum absorbed dose that can be tolerated by organs-at-risk such as the RM. The missing dose-response relationship constrains nuclear physicians to activity-based RPT planning that does not exceed, but also does not necessarily reach, the maximum tolerable absorbed dose to organs-at-risk. This may result in underdosage and inefficient tumor control or overdosage-related toxicities such as hematotoxicity, and leaves the major advantage of RPTs over chemotherapy or biologic therapy unexploited: the possibility to monitor the systemic application of RPs by imaging, and thus potentially optimize treatment for well-defined patient populations or even individual patients. To take a decisive step towards dose-based RPT planning, this research project aims to develop a methodology for patient-specific RM dosimetry. Going beyond the current state-of-the-art, which is based on the morphology of generic phantoms, we will take a radical step and incorporate the individual patient spongiosa morphology directly into dosimetry calculations. The proposed methodology will thus have to consider: a) comprehensive quantification of spongiosa composition based on cutting-edge MRI and dual-energy CT technology, b) determination of the RP’s RM pharmacokinetics based on quantitative SPECT/CT validated based on 3D printed lumbar vertebra phantoms, and c) calculation of RM absorbed doses based on microstructural radiation transport models. To demonstrate clinical applicability, the new methodology will be retrospectively applied in patients treated with 177Lu-PSMA-I&T in our standard of care setting. In summary, this research project will provide a pioneering methodology for implementing personalized RPTs. Our accurate method for patient-specific RM dosimetry will enable future clinical studies to establish reliable dose-response relationships between RM absorbed doses and hematotoxicity. Only by adjusting the administered activity to the point where the individual patient’s RM dose estimate is just below the dose threshold for hematotoxicity can we take the efficacy of RPTs to a new level and provide truly personalized medicine.

• DFG Programme: Research Grants