Brain tumors and synchrotron radiation: Methodological developments in quantitative brain perfusion imaging and radiation therapy

Abstract

High‐grade gliomas are the most frequent type of primary brain tumors in adults. Unfortunately, the management of glioblastomas is still mainly palliative and remains a difficult challenge, despite advances in brain tumor molecular biology and in some emerging therapies. Synchrotron radiation opens fields for medical imaging and radiation therapy by using monochromatic intense x‐ray beams. It is now well known that angiogenesis plays a critical role in the tumor growth process and that brain perfusion is representative of the tumor mitotic activity. Synchrotron radiation quantitative computed tomography (SRCT) is one of the most accurate techniques for measuring in vivo contrast agent concentration and thus computing precise and accurate absolute values of the brain perfusion key parameters. The methodological developments of SRCT absolute brain perfusion measurements as well as their preclinical validation are detailed in this thesis. In particular, absolute cerebral volume and blood brain barrier permeability high‐resolution (pixel size ) parametric maps were reported. In conventional radiotherapy, the treatment of these tumors remains a delicate challenge, because the damages to the surrounding normal brain tissue limit the amount of radiation that can be delivered. One strategy to overcome this limitation is to infuse an iodinated contrast agent to the patient during the irradiation. The contrast agent accumulates in the tumor, through the broken blood brain barrier, and the irradiation is performed with kilovoltage x rays, in tomography mode, the tumor being located at the center of rotation and the beam size adjusted to the tumor dimensions. The dose enhancement results from the photoelectric effect on the heavy element and from the irradiation geometry. Synchrotron beams, providing high intensity, tunable monochromatic x rays, are ideal for this treatment. The beam properties allow the selection of monochromatic irradiation, at the optimal energy, for a maximal dose deposit in the tumor, while sparing healthy tissues. The methodology, the associated dosimetry as well as the preclinical validation of iodine enhanced strereotactic synchrotron radiation therapy is developed in the thesis. Significant survival increases were obtained, especially when the delivery of iodine is coupled with a transient blood–brain–barrier opener. The two complementary methods developed in this thesis offer perspectives in the understanding of the glioma growth process and in their treatment by radiation therapy. They show the potential of synchrotron radiation for absolute high‐resolution morphological and functional CT imaging, and for new therapeutic modalities using intense monochromatic x rays.