In the past decade, clinical studies using the Eppendorf needle electrode system have demonstrated an association between poor treatment outcome and hypoxia in several tumor sites. The number of patients included in these trials has been small and there are various monetary, technical and tumor-site-related problems which limit the ability to extend these observations to the general patient population. Despite its potential importance, tumor hypoxia can be considered as only one of many prognostic factors which affect patient outcome. Our goal is to better understand the role of hypoxia as a predictive indicator of outcome in order to develop individualized therapies for each patient. We recognize that hypoxia measurements must not be limited by tumor site or technique, and they must be considered in conjunction with other known prognostic factors (e.g. proliferation, vascular density, necrosis). We have developed a technique for measuring tumor hypoxia based on metabolism of the 2-nitroimidazole EF5. This method has been validated in rodent tumor models and assessed in a Phase I clinical trial. In this trial we demonstrated the lack of toxicity of EF5 at doses suitable for quantitative assessment of hypoxia (21 mg/kg). We found profound differences in the degree and extent of hypoxia in several tumor sites including head and neck squamous cell carcinomas and soft tissue sarcomas. Data from these studies suggest that EF5 binding is correlated with other measurements of oxygenation and spatially associated with hypoxia-mediated pathophysiological processes. An association between high EF5 binding and metastasis in soft tissue sarcoma patients and nodal involvement in head/neck squamous cell carcinoma patients is suggested by our Phase I data. In our competing continuation grant, we will continue the study of patients with high grade soft tissue sarcomas and head and neck squamous cell cancers of the oral cavity. A correlative study design will be employed. EF5 binding will be assessed in each patient by flow cytometry of tissue-derived cells and in frozen tissue sections by fluorescence immunohistochemistry. Data will be analyzed by quantitative techniques which will allow an overall assessment of the level and distribution of tumor pO2. These data will be compared, wherever possible, with Eppendorf electrode measurements. Survival analysis will consider both hypoxia measurements and several other indices including clinical and pathologic descriptors, proliferation indices, vascular density, apoptosis, molecular markers and tumor necrosis. Primary endpoints of survival analyses will be metastasis in soft tissue sarcoma patients and local- regional recurrence in head and neck squamous cell carcinoma patients.
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