The prognosis for patients with malignant gliomas remains dismal in spite of many advances in surgical, chemotherapeutic and radiotherapeutic modalities. Treatment options are determined mostly empirically, and therefore new approaches based on tumor physiology or genetics are needed to improve outcome for patients with this highly malignant tumor. Brain tumors are treated with a spectrum of fractionation regimens based on the clinical and anatomical characteristics of the tumor but are rarely based on the molecular or physiological characteristics of the individual tumor. Hypoxia is a known factor in radioresistance. Radiotherapy is expected to change oxygenation in tumors, this effect is likely to vary with the dose per fraction and interval between doses, and therefore may significantly alter the effectiveness of the treatment. Establishing the presence of hypoxia and particularly the possibility of exploiting post-irradiation reoxygenation in gliomas offers the promise of developing individualized RT regimens that might improve the response of radioresistant glioma cells to therapy. We hypothesize that the therapeutic outcome of hypofractionated radiotherapy of gliomas can be significantly enhanced if radiotherapy is used at times of optimal tumor oxygenation and the use of hyperoxic therapies in conjunction with hypofractionated radiotherapy can 'be optimized by the use of information on oxygen levels in the tumors. This would be a highly significant development for gliomas due to their poor radiotherapy prognosis. We will measure partial pressure of oxygen (pO2) using multi-site EPR (Electron Paramagnetic Resonance) oximetry in experimental intracranial 9L tumors undergoing hypofractionated radiotherapy and relate hypoxia and changes in hypoxia to outcome in terms of tumor growth delay. This has not been possible previously due to a lack of suitable in vivo techniques for repeated non-invasive pO2 measurements in the same tumor during the entire course of therapy. MRI and histology will be used to determine tumor tissue characteristics that may be related to the mechanism of the changes in oxygen, at time points during therapy and in relation to measured tumor pO2. We also will determine the relationship between radiation-induced changes in tumor oxygenation and the extent of tumor pO2 increases during hyperoxygenation with hyperbaric oxygen therapy (100% oxygen at 2-4 ATA) and carbogen (95%O2/5%CO2). This study will provide a rationale basis for the application of hypofractionated stereotactic radiotherapy so that it can be used with optimal effectiveness, and establish methodology that can be used to enhanced therapeutic outcome of gliomas in particular but also for tumors in general.
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