Evaluation of Hypoxia by EF5 Binding in Cervix Cancer

描述（由申请人提供）：多年来已知贫血性宫颈癌患者的预后和对放射治疗的反应比血液血红蛋白水平正常的类似患者差。妇科肿瘤组（GOG）正在进行第一个III期试验（GOG 191），以确定是否修改患者血红蛋白水平与重组人促红细胞生成素将改善放疗和顺铂后的结果。宫颈贫血患者预后差的一个可能机制是肿瘤缺氧。这将使肿瘤具有辐射抗性和/或由于缺氧介导的分子/细胞因子变化而更具生物学侵袭性。由于后勤原因，GOG 191试验中未纳入评价预处理肿瘤缺氧重要性的方法，但GOG已将其确定为关键的生物学问题。GOG通过为我们提供患者组织来支持这项分析;该试验被称为GOG 8002。我们建议评估进入GOG 191的患者的肿瘤缺氧，并确定这一发现的临床意义。我们的总体假设是，由EF 5结合确定的缺氧是宫颈癌生物学和治疗反应的关键决定因素。EF 5已被详细研究，使用定量荧光免疫组织化学，并可用于测量缺氧面积和绝对组织pO 2。这种技术与大型多机构试验兼容，因为药物安全且易于管理，组织可以被送到中央设施进行处理。我们的具体目标是：一曰：确定EF 5结合水平与治疗前血红蛋白水平、肿瘤大小、分期的关系; 2.探讨治疗前肿瘤是否缺氧（通过EF 5结合测量）与总生存期、无进展间期和局部控制相关，并且3：探索EF 5结合和CD-31标记（肿瘤血管）以及EF 5结合和Ki-67标记（细胞增殖）之间的关系。EF 5结合将以几种方式定量。将在体外测定最大结合率，并将以最大值的百分比评估原位结合。这将允许结合转化为肿瘤pO 2。进一步的分析将包括各种结合水平下涉及的组织区域。GOG将提供患者随访和统计评价。

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.