Oxygen Guided Hypofractionated Radiotherapy for Gliomas

描述（由申请人提供）：尽管手术、化疗和放射治疗方式取得了许多进展，但恶性胶质瘤患者的预后仍然令人沮丧。治疗方案大多是根据经验确定的，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。脑肿瘤的治疗是基于肿瘤的临床和解剖特征的一系列分离方案，但很少基于单个肿瘤的分子或生理特征。缺氧是辐射抵抗的一个已知因素。放疗有望改变肿瘤中的氧合作用，这种作用可能随每部分剂量和剂量间隔而变化，因此可能显著改变治疗的有效性。在胶质瘤中建立缺氧的存在，特别是利用辐照后再氧化的可能性，为开发个性化的放射治疗方案提供了希望，这可能会改善放射耐药胶质瘤细胞对治疗的反应。我们假设，如果在最佳肿瘤氧合时间使用放射治疗，可以显著提高胶质瘤低分割放疗的治疗效果，而使用高氧治疗结合低分割放疗不能通过使用肿瘤中的氧水平信息来优化。由于胶质瘤放射治疗预后不良，这将是一个非常重要的进展。我们将使用多位点电子顺磁共振（EPR）血氧仪测量实验性颅内9L肿瘤接受低分割放疗的氧分压（pO2），并将缺氧和缺氧变化与肿瘤生长延迟的结果联系起来。这在以前是不可能的，因为在整个治疗过程中缺乏合适的体内技术来重复测量同一肿瘤的非侵入性pO2。MRI和组织学将用于确定肿瘤组织特征，这些特征可能与治疗期间各时间点氧气变化的机制有关，并与测量的肿瘤pO2有关。我们还将通过高压氧治疗（2-4 ATA 100%氧气）和碳（95%O2/5%CO2）进行高氧治疗，确定辐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疗的应用提供理论基础，使其能够获得最佳效果，并建立可用于提高胶质瘤特别是肿瘤的治疗效果的方法，也可用于一般肿瘤。

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.