Realistic tissue dosimetry models using Monte Carlo simulations. Applications for radionuclide therapies

Abstract: Radionuclide therapy (RNT) is a generic term for treatment modalities that use a radionuclide labeled to a target-specific molecule. This so-called radiopharmaceutical accumulates in the target, where the ionizing radiation damages the cells. At sufficient levels of radiation, the cells cannot repair themselves. The quantity of the energy deposited in a target region is referred to as the absorbed dose Gy. Absorbed dose calculations in RNTs are associated with large uncertainties, originating from determination of the activity as well as uncertainties in absorbed dose conversion factors (S factors). S factors are derived for mathematical described source-target combinations (so called phantoms) using Monte Carlo techniques to simulate the particle transport from various radionuclides. The accuracy of the S factor depends on how well the phantom reflects the patient anatomy. The phantoms most used in conventional dosimetry models rely on crude anatomic descriptions; therefore, calculated absorbed doses and radiation-induced biological effects are rarely well correlated. The aim of this thesis was to develop more realistic phantoms to create more accurate dosimetry models. Most preclinical evaluations of new radiopharmaceuticals or treatment strategies are performed on small animals, and the efficacy should be evaluated with the absorbed dose. In practice, dosimetry calculations are not a standard procedure; instead, activity levels below those reported to produce severe side effects are used. Papers I, II, and III present dosimetry models based on Monte Carlo simulations using realistic phantoms of mice and rats that produce reliable S factors, which could be useful in dosimetry studies. In Paper III, we used our rat dosimetry model with data from an activity-escalating study of 90Y- and 177Lu-BR96 monoclonal antibodies. Two novel parameters that can be used to quantify decreases in peripheral blood cells were derived. We showed that the data derived with these parameters correlated well with the absorbed dose in red bone marrow. In Papers IV and V, we propose two small-scale anatomic models for the small intestine and the testis, respectively. The large difference from conventional models is that different tissue structures are incorporated, allowing for the calculation of absorbed doses to the most radiosensitive cells in the tissue while considering heterogeneous uptake therein. Differences in order of magnitude are possible when calculating absorbed doses using these new dosimetry models. These dosimetry models will be important when making correlations with biological effects.