The Importance of Dosimetry and Radiobiology in Nuclear Medicine : Quantitative methods and modelling

Abstract: Nuclear medicine uses radioactive pharmaceuticals for diagnostic or therapeutic purposes. The ionizing radiation emitted from the radiopharmaceutical is partially absorbed within the patient's body and internal dosimetry is the method to estimate the absorbed dose to a tumour or risk organ. This is of special importance in radiopharmaceutical therapy (RPT), where particle-emitting radionuclides are utilized for their therapeutic effect. A better understanding of where and to what extent the radiation energy is deposited, i.e. dosimetry, in combination with a better understanding of the irradiation-induced biological processes in tissues and tumours, i.e., radiobiology, is the foundation to establish an absorbed dose-effect relationship. This thesis comprises quantitative methods and modelling within dosimetry and radiobiology, with a special focus on quantitative methods for activity concentration, absorbed dose calculation and quantification of biological effects after nuclear medicine exposures. Nonuniformity of activity distribution and the biological effect of internal irradiation is considered in Paper I and Paper II. When a radiopharmaceutical primarily localizes within specific tissue substructures of an organ, the average absorbed dose to the whole organ may become insufficient for dosimetric analysis. Hence, the nonuniformities of the distribution of activity need to be considered and absorbed dose calculations to part of an organ, cellular, or a sub-cellular structure may be a better predictor of the therapy outcome or normal tissue toxicity. In Paper I, a small-scale anatomical dosimetry model of the liver tissue structure addressed the issue of activity nonuniformity. Monte Carlo simulations were performed to simulate the particle transport from various substructure sources within the organ model for some clinically available radionuclides. The model enabled comparison between the average absorbed dose to the entire organ and the local absorbed dose close to the source region, which for particle emitting radionuclides differed significantly. To address the resulting biological effect after internal irradiation, an ex vivo method using the γH2AX surrogate marker to visualize and quantify DNA double-strand breaks in in vivo-irradiated tissues was developed. The method was demonstrated to be useful for γH2AX-foci quantification in both the fast proliferating, radiosensitive testis tissue and the slow proliferating and more radioresistant liver tissue. Image-based activity quantification and absorbed dose estimation are considered in Paper III and Paper IV, using somatostatin receptor targeting agents for both diagnostic and therapeutic applications for neuroendocrine tumours. In Paper III, the quantitative accuracy of pre-therapeutic 111In-Octreoscan® SPECT/CT and [68Ga]Ga-DOTA-TATE PET/CT images was investigated due to the change in clinical method to use PET- instead of SPECT-imaging. Further, the quantitative relationship between the theragnostic pair of DOTA-TATE was investigated in Paper IV. The relationship between activity uptakes observed at [68Ga]Ga-DOTA-TATE PET imaging and absorbed doses at subsequent [177Lu]Lu-DOTA-TATE therapy was studied. The study demonstrated that on a group level, a higher tumour uptake measured from pretherapeutic PET images is associated with higher absorbed doses in subsequent therapy with [177Lu]Lu-DOTA-TATE. However, on the individual level, there are limitations of using the 68Ga PET as a predictor for therapy absorbed dose.