Evaluation of Hypoxia by EF5 Binding in Cervix Cancer

描述(申请人提供)：多年来，人们已经知道，宫颈癌贫血患者的预后和对放射治疗的反应比血液中血红蛋白水平正常的类似患者更差。妇科肿瘤组(GOG)正在进行第一阶段的第三阶段试验(GOG191)，以确定用重组人促红细胞生成素改变患者的血红蛋白水平是否会改善放射治疗和顺铂的结果。宫颈贫血患者预后不良的一个可能机制是他们的肿瘤缺氧。这将使肿瘤耐受辐射和/或由于低氧介导的分子/细胞因子变化而更具生物学侵袭性。由于后勤原因，GOG191试验没有纳入评估肿瘤缺氧预处理重要性的方法学，但GOG已经确定这是一个关键的生物学问题。GOG通过为我们提供接触患者组织的途径来支持这一分析；该试验被称为GOG8002。我们建议评估进入GOG191的患者的肿瘤缺氧情况，并确定这一发现的临床意义。我们的总体假设是，由EF5结合决定的缺氧是宫颈癌生物学和治疗反应的关键决定因素。EF5已经用定量荧光免疫组织化学方法进行了详细的研究，可以用来测量缺氧区和绝对组织的PO2。这项技术与大型多机构试验兼容，因为药物是安全和容易管理的，组织可以被送到中央设施进行处理。我们的具体目标是：1：确定EF5结合水平与治疗前血红蛋白水平、肿瘤大小和分期的关系；2：探讨治疗前肿瘤缺氧(以EF5结合衡量)是否与总生存期、无进展间期和局部控制有关；3：探讨EF5结合与CD-31标记(肿瘤血管)、EF5结合与Ki-67标记(细胞增殖)的关系。EF5结合将以几种方式量化。最大结合率将在体外确定，原位结合将以最大结合率的百分比进行评估。这将允许将结合转化为肿瘤pO2。进一步的分析将包括不同结合水平所涉及的组织区域。患者的随访和统计评估将由GOG提供。

DESCRIPTION (provided by applicant): It has been known for many years that anemic cervix cancer patients have a poorer prognosis and response to radiation therapy than similar patients with normal blood hemoglobin levels. The Gynecologic Oncology Group (GOG) is performing the first Phase III trial (GOG191) to determine whether modifying patient hemoglobin levels with recombinant human erythropoietin will improve outcome following radiation therapy and cisplatin. One possible mechanism underlying the poor prognosis of anemic cervix patients is that their tumors are hypoxic. This would make the tumors radiation resistant and/or more biologically aggressive due to hypoxia-mediated molecular/cytokine changes. The methodology to evaluate the importance of pretreatment tumor hypoxia was not incorporated into the GOG191 trial for logistical reasons but the GOG has identified this to be a critical biologic question. The GOG is supporting this analysis by providing us with access to patient tissues; the trial is referred to as GOG8002. We have proposed to assess tumor hypoxia in patients entered onto GOG191 and to determine the clinical significance of this finding. Our overall hypothesis is that hypoxia, as determined by EF5 binding, is a critical determinant of cervix cancer biology and treatment response. EF5 has been studied in detail using quantitative fluorescence immunohistochemistry and can be used to measure both hypoxic area and absolute tissue pO2. This technique is compatible with large multi-institutional trials because the drug is safely and easily administered and tissue can be sent to a central facility for processing. Our specific aims are to: 1: Determine the relationship between the level of EF5 binding and pre-treatment hemoglobin level, tumor size, and stage; 2: Explore whether pre-treatment tumor hypoxia (as measured by EF5 binding) is associated with overall survival, progression-free interval and local control and 3: Explore the relationships between EF5 binding and CD-31 labeling (tumor vasculature), and EF5 binding and Ki-67 labeling (cellular proliferation). EF5 binding will be quantified in several ways. The maximum binding rate will be determined in vitro and the in situ binding will be assessed as a percent of maximum. This will allow conversion of binding to tumor pO2. Further analyses will incorporate the area of tissue involved at various binding levels. Patient follow-up and statistical evaluations will be provided by the GOG.