Theoretical modeling of tumor oxygenation and influences on treatment outcome

Abstract

One of the main problems in curing cancer resides in the different microenvironments existing in tumors compared to normal tissues. The mechanisms of failure are different for radiotherapy and chemotherapy, but they all relate to the poor blood supply known to exist in tumors. It is therefore very important to know the tumor microenvironmental conditions in order to devise techniques that will overcome the problems and will therefore improve the result of the treatment. The aim of this thesis was the modeling of tumor oxygenation and the simulation of polarographic oxygen measurements in order to assess and possibly to improve the accuracy of the electrode in measuring tumor oxygenation. It also aimed to evaluate the implications of tumor microenvironment for the radiotherapy outcome. The project used theoretical modeling as the main tool. The physical processes of oxygen diffusion and consumption for different conditions were described mathematically, the result being a very accurate distribution of oxygen in tissues. A first simple model of tissue oxygenation was based on the oxygen diffusion around a single blood vessel. A more complex model built from the basic physical processes and measurable parameters allowed the simulation of realistic tissues with heterogeneous vasculature. This model also allowed the modeling of the two types of hypoxia known to appear in tumors and their influence on the tumor microenvironment. The computer simulation of tissues was also used for assessing the accuracy of the polarographic technique for measuring tumor oxygenation. The results of this study have shown that it is possible to model theoretically the tissue oxygenation starting from the basic physical processes. The particular application of our theoretical simulation to the polarographic oxygen electrode has shown that this experimental method does not give the oxygen values in individual cells. Because the electrode measures the average oxygenation in a relatively large tissue volume, the resulting oxygen distributions are different from the real ones, and the extreme high and low values are not detected. It has further been found that the polarographic electrode cannot make distinction between various types of hypoxia existing in tumors, the geometrical distribution of the hypoxic cells influencing mostly the accuracy of the measurement. It was also shown that, because of the averaging implied by the measurement process, electrode results should not be used directly to predict the response to radiation. Thus, the differences between the predictions in clinical tumor control obtained from the real or the measured oxygenations are of the order of tens of percent in absolute value. A method to improve the accuracy of the electrode in the attempt to improve the correlation between the results of the measurements and the actual tissue oxygenation was proposed. In conclusion, theoretical modeling has been shown to be a very powerful tool for predicting the outcome of radiotherapy and it has the advantage of describing the tumor oxygenation in the least invasive manner. Furthermore, it allows the investigation of the invasiveness and the accuracy of various experimental methods. © 2005, American Association of Physicists in Medicine. All rights reserved.