Oxygen Guided Hypofractionated Radiotherapy for Gliomas

描述(由申请人提供)：尽管在手术、化疗和放射治疗方面取得了许多进展，但恶性胶质瘤患者的预后仍然令人沮丧。治疗选择主要是根据经验确定的，因此需要基于肿瘤生理学或遗传学的新方法来改善这种高度恶性肿瘤患者的预后。脑肿瘤的治疗基于肿瘤的临床和解剖特征，但很少基于单个肿瘤的分子或生理特征。低氧是辐射抵抗的一个已知因素。放射治疗预计会改变肿瘤的氧合作用，这种影响可能会随着每部分的剂量和剂量之间的间隔而变化，因此可能会显著改变治疗的效果。证实脑胶质瘤中存在低氧，特别是利用放射后复氧的可能性，这为开发个性化的RT方案提供了希望，该方案可能会提高放射抵抗胶质瘤细胞对治疗的反应。我们假设，如果在最佳的肿瘤氧合时间使用放射治疗，则低分割放射治疗的治疗结果可以显著提高，而高氧治疗与低分割放射治疗的联合使用不能通过使用肿瘤内氧水平的信息来优化。由于神经胶质瘤放射治疗预后较差，这将是一个非常重要的进展。我们将使用多点EPR(电子顺磁共振)血氧仪测量接受低分割放射治疗的实验性颅内9L肿瘤的氧分压(PO2)，并将低氧和低氧变化与肿瘤生长延迟的预后联系起来。这在以前是不可能的，因为缺乏合适的体内技术，在整个治疗过程中重复非侵入性地测量同一肿瘤的氧分压。核磁共振成像和组织学将被用来确定肿瘤组织特征，这些特征可能与治疗过程中的时间点的氧气变化机制有关，并与测量的肿瘤氧分压有关。我们还将确定高压氧(高压氧2-4ATA时100%氧气)和碳氧(95%O2/5%CO2)高氧治疗期间，放射诱导的肿瘤氧合变化与肿瘤PO2增加程度之间的关系。本研究将为低分割立体定向放射治疗的应用提供理论依据，使其发挥最佳的治疗效果，并建立可用于提高胶质瘤尤其是一般肿瘤的治疗效果的方法学。

DESCRIPTION (provided by applicant): 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.