Abstract
BackgroundEsophageal cancer is an aggressive disease with poor survival rates. A more patient-tailored approach based on predictive biomarkers could improve outcome. We aimed to predict radiotherapy (RT) response by imaging tumor hypoxia with 18F-FAZA PET/CT in an esophageal adenocarcinoma (EAC) mouse model. Additionally, we investigated the radiosensitizing effect of the hypoxia modifier nimorazole in vitro and in vivo.MethodsIn vitro MTS cell proliferation assays (OACM5 1.C SC1, human EAC cell line) were performed under normoxic and hypoxic (< 1%) conditions: control (100 μL PBS), nimorazole, irradiation (5, 10 or 20 Gy) with or without nimorazole. In vivo, subcutaneous xenografts were induced in nude mice (OACM5 1.C SC1). Treatment was given daily for 5 consecutive days: (A) control (600 μl NaCl 0.9% intraperitoneally (IP)) (N = 5, n = 7), (B) RT (5 Gy/d) (N = 11, n = 20), (C) combination (nimorazole (200 mg/kg/d IP) 30 min before RT) (N = 13, n = 21). N = number of mice, n = number of tumors. 18F-FAZA PET/CT was performed before treatment and tumor to background (T/B) ratios were calculated. Relative tumor growth was calculated and tumor sections were examined histologically (hypoxia, proliferation).ResultsA T/B ≥ 3.59 on pre-treatment 18F-FAZA PET/CT was predictive for worse RT response (sensitivity 92.3%, specificity 71.4%). Radiation was less effective in hypoxic tumors (T/B ≥ 3.59) compared to normoxic tumors (T/B < 3.59) (P = 0.0025). In vitro, pre-treatment with nimorazole significantly decreased hypoxic radioresistance (P < 0.01) while in vivo, nimorazole enhanced the efficacy of RT to suppress cancer cell proliferation in hypoxic tumor areas (Ki67, P = 0.064), but did not affect macroscopic tumor growth.ConclusionsTumor tissue hypoxia as measured with 18F-FAZA PET/CT is predictive for RT response in an EAC xenograft model. The radiosensitizing effect of nimorazole was questionable and requires further investigation.
Highlights
Esophageal cancer is an aggressive disease with poor survival rates
18F-Fluoroazomycin arabinoside (FAZA) PET/CT as predictive biomarker Forty-eight tumors were included for 18F-FAZA PET/CT (Fig. 1a)
Pre-treatment 18F-FAZA uptake (T/B ratios) was significantly higher in radioresistant tumors than in radiosensitive tumors (P = 0.0046) (Fig. 1b), demonstrating that more hypoxic tumors are more resistant to RT than less hypoxic tumors
Summary
Esophageal cancer is an aggressive disease with poor survival rates. A more patient-tailored approach based on predictive biomarkers could improve outcome. We aimed to predict radiotherapy (RT) response by imaging tumor hypoxia with 18F-FAZA PET/CT in an esophageal adenocarcinoma (EAC) mouse model. Identification of predictive imaging biomarkers is an important challenge. Tumor hypoxia is an attractive predictive factor as it has been correlated with chemoresistance, radioresistance, invasiveness, propensity to metastasize, genomic instability and worse prognosis in different solid tumors [3]. Hypoxia has been correlated with worse outcomes. Histologic examination of carbonic anhydrase 9 (CAIX) and hypoxia-inducible factor 1-alpha (HIF-1α), two factors that are overexpressed in hypoxic conditions, were correlated with worse outcomes and hypoxia imaging with 18F-FETNIM (fluoroerythronitroimidazole) positron emission tomography
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