Evaluation of Hypoxia by EF5 Binding in Cervix Cancer

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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.