Tumour vasculature, oxygenation and radiosensitivity - a numerical modelling study

Abstract

This thesis aims to investigate theoretically how parameters such as vessel density, blood oxygenation, blood velocity, spatial oxygen variation along vessels, tissue oxygen consumption and their distributions in uence the radiosensitivity of tumours. Numerical calculations are made in Matlab using voxel-based models. Direct and indirect Monte Carlo based methods are used, e.g. kernels for dose calculations and randombased models for simulation of in oxygen and activity distributions in tumours. Oxygen di usion is calculated using a Green's function based method and oxygen consumption follows the Michaelis-Menten kinetic model. Cryosectioning and immunostaining of insulinoma from mouse is done for model development. The linear quadratic cell survival model , including the oxygen e ect, is used to calculate tumour control probability (TCP) and absorbed doses. Convolutions, with di usion and dose kernels, are preferably made in frequency space for computational reasons. By raising the oxygen pressure (pO2), through antiangiogenic treatment, in tumours and retaining TCP, radiation damage to normal tissues can be strongly reduced. Variation of blood pO2 a ects the position of the pO2 distribution while altered vessel density a ects the distribution shape. The greatest increase in radiosensitivity by increased pO2 is achieved for 50% relative vessel density. In tumour oxygenation modelling, pO2 of the blood must vary along the vessel and a random distribution of pO2 in incoming blood is used to get realistic results. Combining improved oxygenation and radionuclide uptake shows great potential of improving radionuclide treatment. There is an optimum region of vessel density where the highest increase in radiosensitivity is achieved by increasing blood pO2. It appears to be possible to determine the cause of hypoxia from the shape of the pO2 distribution. To make a good estimate of treatment result, it is crucial to know the full pO2 distribution and not only the mean or the hypoxic fraction. Improving oxygenation of partly necrotic tumours is not always bene cial for radiation treatment. Small spherical tumours are more sensitive than larger ones to the shape of the pO2 distribution. This is likely because a hypoxic region of a small tumour is more a ected by its location relative to the tumour centre, given constant thickness, due to the relatively greater di erence in radius and therefore volume.