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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075285-06
Application #
6651572
Study Section
Radiation Study Section (RAD)
Program Officer
Stone, Helen B
Project Start
1997-09-30
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
6
Fiscal Year
2003
Total Cost
$377,611
Indirect Cost
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Evans, Sydney M; Du, Kevin L; Chalian, Ara A et al. (2007) Patterns and levels of hypoxia in head and neck squamous cell carcinomas and their relationship to patient outcome. Int J Radiat Oncol Biol Phys 69:1024-31
Evans, Sydney M; Schrlau, Amy E; Chalian, Ara A et al. (2006) Oxygen levels in normal and previously irradiated human skin as assessed by EF5 binding. J Invest Dermatol 126:2596-606
Evans, Sydney M; Fraker, Douglas; Hahn, Stephen M et al. (2006) EF5 binding and clinical outcome in human soft tissue sarcomas. Int J Radiat Oncol Biol Phys 64:922-7
Busch, Theresa M; Hahn, Stephen M; Wileyto, E Paul et al. (2004) Hypoxia and Photofrin uptake in the intraperitoneal carcinomatosis and sarcomatosis of photodynamic therapy patients. Clin Cancer Res 10:4630-8
Evans, Sydney M; Judy, Kevin D; Dunphy, Isolde et al. (2004) Hypoxia is important in the biology and aggression of human glial brain tumors. Clin Cancer Res 10:8177-84
Evans, Sydney M; Judy, Kevin D; Dunphy, Isolde et al. (2004) Comparative measurements of hypoxia in human brain tumors using needle electrodes and EF5 binding. Cancer Res 64:1886-92
Busch, Theresa M; Wileyto, E Paul; Evans, Sydney M et al. (2003) Quantitative spatial analysis of hypoxia and vascular perfusion in tumor sections. Adv Exp Med Biol 510:37-43
Koch, C J; Hahn, S M; Rockwell Jr, K et al. (2001) Pharmacokinetics of EF5 [2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] in human patients: implications for hypoxia measurements in vivo by 2-nitroimidazoles. Cancer Chemother Pharmacol 48:177-87
Evans, S M; Hahn, S M; Magarelli, D P et al. (2001) Hypoxic heterogeneity in human tumors: EF5 binding, vasculature, necrosis, and proliferation. Am J Clin Oncol 24:467-72
Ziemer, L S; Koch, C J; Maity, A et al. (2001) Hypoxia and VEGF mRNA expression in human tumors. Neoplasia 3:500-8

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