Modeling the impact of two forms of hypoxia on novel radiotherapy approaches

Theoretical modeling of the biological response is considered for inclusion into treatment planning algorithms. However, the results are model sensitive and therefore the choice of the model is very important. In this thesis we aimed to compare the predictions in the clinical dose range for the linear quadratic (LQ) model and the linear quadratic model with inducible repair (LQ/IR) and to determine the possible therapeutic gain of different treatment strategies, taking into consideration the microenvironmental conditions known to exist in tumors. The main focus was on the availability of oxygen and other nutrients to tumor cells, knowing that tumor vasculature is very poor compared to that in normal tissues. The brief interruption of oxygen supply to the acutely hypoxic cells determines an increased radioresistance, while the lack of oxygen and other nutrients in starved hypoxic cells results in a radiosensitization due to the reduction of cellular energy charge. It is the first time this latter aspect of tumor sensitivity was considered for a theoretical model. The modeling showed that there are some important differences in the clinical dose range between the predicted responses with the two models. Some of these differences provide an alternative explanation to the success of hyperfractionation and also explain some unusual results reported in the literature with respect to hypoxic protection. The analysis of the complex relationship between the induction of repair and the intrinsic radioresistance indicates the possible therapeutic gain that can be expected from more extreme fractionation. The existence of starved chronically hypoxic cells in tumors, with their incapacity to activate repair provides a better understanding of the tumor response to radiation treatments