2-(2-nitro-1h-imidazol-1-yl)-n-(2-2-3-3-3-pentafluoropropyl)acetamide and Head-and-Neck-Neoplasms

Ten patients with newly diagnosed head and neck cancer (HNC) received three static PET/CT scans before chemoradiotherapy: two with [

Topics: Aged; Etanidazole; Female; Fluorine Radioisotopes; Head and Neck Neoplasms; Humans; Hydrocarbons, Fluorinated; Male; Middle Aged; Neoplasm Staging; Positron Emission Tomography Computed Tomography; Prospective Studies; Tumor Hypoxia

Localization and quantitation of 2-nitroimidazole drug binding in low pO2 tumors is a technique that can allow the assessment of hypoxia as a predictive assay. EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] is such a drug, and it has been shown to be predictive of radiation response in rodent tumors. Using fluorescence immunohistochemical techniques, we provide data on the presence, distribution, and levels of EF5 binding as a surrogate for hypoxia in human head and neck and uterine cervix squamous cell cancers (SCCs). Six patients with SCC were studied. Four patients had head and neck tumors, and two had uterine cervix cancers. The incubation of fresh tissue cubes in EF3 under hypoxic conditions ("reference binding") demonstrated that all tumors were capable of binding drug, and that this binding varied by a factor of 2.9-fold (174.5-516.1) on an absolute fluorescence scale. In the five patients treated at the lowest drug doses (9 mg/kg), in situ binding was quantitatable. For all six patients, the maximum rate of in situ binding varied by a factor of 6.7 between the lowest and highest binding tumor (24.8-160.3) on an absolute fluorescence scale. In tumors with high binding regions, intratumoral heterogeneity was large, extending from minimal fluorescence (<1%) up to 88.6% of reference binding. In tumors with minimal binding, there was little intratumoral heterogeneity. These studies demonstrate substantial heterogeneity of in situ binding between and within individual squamous cell tumors.

Topics: Adult; Aged; Antineoplastic Agents; Binding Sites; Carcinoma, Squamous Cell; Cell Hypoxia; Etanidazole; Female; Head and Neck Neoplasms; Humans; Hydrocarbons, Fluorinated; Male; Middle Aged; Uterine Cervical Neoplasms

In order to improve the treatment of squamous cell carcinoma of the head and neck, precise information on the treated tumour's biology is required and the prognostic importance of different biological parameters needs to be determined. The aim of our study was to determine the predictive value of pretreatment PET/CT imaging using [(18)F]FDG, a new hypoxia tracer [(18)F]EF5 and the perfusion tracer [(15)O]H₂O in patients with squamous cell cancer of the head and neck treated with radiochemotherapy.. The study group comprised 22 patients with confirmed squamous cell carcinoma of the head and neck who underwent a PET/CT scan using the above tracers before any treatment. Patients were later treated with a combination of radiochemotherapy and surgery. Parametric blood flow was calculated from dynamic [(15)O]H₂O PET images using a one-tissue compartment model. [(18)F]FDG images were analysed by calculating standardized uptake values (SUV) and metabolically active tumour volumes (MATV). [(18)F]EF5 images were analysed by calculating tumour-to-muscle uptake ratios (T/M ratio). A T/M ratio of 1.5 was considered a significant threshold and used to determine tumour hypoxic subvolumes (HS) and hypoxic fraction area. The findings were finally correlated with the pretreatment clinical findings (overall stage and TNM stage) as well as the outcome following radiochemotherapy in terms of local control and overall patient survival.. Tumour stage and T-classification did not show any significant differences in comparison to the patients' metabolic and functional characteristics measured on PET. Using the Cox proportional hazards model, a shorter overall survival was associated with MATV (p = 0.008, HR = 1.108), maximum [(18)F]EF5 T/M ratio (p = 0.0145, HR = 4.084) and tumour HS (p = 0.0047, HR = 1.112). None of the PET parameters showed a significant effect on patient survival in the log-rank test, although [(18)F]EF5 maximum T/M ratio was the closest (p = 0.109). By contrast, tumour blood flow was not correlated with any of the clinical endpoints. There were no statistically significant correlations among [(18)F]FDG SUVmax, [(18)F]EF5 T/M ratio and blood flow.. Our study in a limited number of patients confirmed the importance of MATV in the prognosis of locally advanced squamous cell carcinoma of the head and neck. It is of interest that high uptake of the hypoxia tracer [(18)F]EF5 showed a stronger correlation with a poor clinical outcome than [(18)F]FDG uptake. This confirms the importance of hypoxia in treatment outcome and suggests that [(18)F]EF5 may act as a surrogate marker of radioresistance.

Topics: Adult; Aged; Chemoradiotherapy; Etanidazole; Female; Fluorodeoxyglucose F18; Head and Neck Neoplasms; Humans; Hydrocarbons, Fluorinated; Male; Middle Aged; Multimodal Imaging; Positron-Emission Tomography; Prognosis; Survival Analysis; Tomography, X-Ray Computed; Young Adult

The aim of this study was to evaluate 2-(2-nitro-(1)H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5) labeled with (18)F-fluorine to image hypoxia in patients with squamous cell carcinoma of the head and neck (HNSCC).. Fifteen patients with HNSCC were studied. Measurement of tumor blood flow was followed by an (18)F-EF5 PET/CT scan. On a separate day, (18)F-FDG PET/CT was performed to determine the metabolically active tumor volume. In 6 patients, dynamic (18)F-EF5 images of the head and neck area were acquired, followed by static images acquired at 1, 2, and 3 h after injection. In the remaining 9 patients, only static images were obtained. (18)F-EF5 uptake in tumors was compared with that in neck muscle, and the (18)F-EF5 findings were correlated with the (18)F-FDG PET/CT studies.. A total of 13 primary tumors and 5 lymph node metastases were evaluated for their uptake of (18)F-EF5. The median tumor-to-muscle (18)F-EF5 uptake ratio (T/M) increased over time and was 1.38 (range, 1.1-3.2) 3 h after tracer injection. The median blood flow in tumors was 36.7 mL/100 g/min (range, 23.3-78.6 mL/100 g/min). Voxel-by-voxel analysis of coregistered blood flow and (18)F-EF5 images revealed a distinct pattern, resulting in a T/M of 1.5 at 3 h to be chosen as a cutoff for clinically significant hypoxia. Fourteen of 18 tumors (78%) had subvolumes within the metabolically active tumor volumes with T/M greater than or equal to 1.5.. On the basis of these data, the potential of (18)F-EF5 to detect hypoxia in HNSCC is encouraging. Further development of (18)F-EF5 for eventual targeting of antihypoxia therapies is warranted.

Topics: Adult; Aged; Carcinoma, Small Cell; Cell Hypoxia; Etanidazole; Female; Fluorine Radioisotopes; Head and Neck Neoplasms; Humans; Hydrocarbons, Fluorinated; Male; Middle Aged; Oxygen; Positron-Emission Tomography; Radiopharmaceuticals; Sensitivity and Specificity; Young Adult

Topics: Antigens, Neoplasm; Biomarkers; Carbonic Anhydrase IX; Carbonic Anhydrases; Carcinoma, Squamous Cell; Cell Hypoxia; Electrodes; Etanidazole; Head and Neck Neoplasms; Humans; Hydrocarbons, Fluorinated; Intracellular Signaling Peptides and Proteins; Mitochondrial Proteins; Neoplasm Proteins; Nitroimidazoles; Osteopontin; Oxygen; Partial Pressure; Radiation-Sensitizing Agents; Tirapazamine; Triazines

EF5, a 2-nitroimidazole hypoxia marker, was used to study the presence, levels, and prognostic significance of hypoxia in primary head and neck squamous cell tumors.. Twenty-two patients with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, or larynx with at least 2 years of clinical follow-up were included in this study. Quantitative analyses of EF5 immunofluorescence was carried out, and these data were compared with patient outcome.. EF5 immunostaining showed substantial intra- and intertumoral hypoxic heterogeneity. The majority of cells in all tumors were well oxygenated. Three patterns of EF5 binding in cells were identified using criteria based on the cellular region that was stained (peripheral or central) and the relationship of binding to necrosis. We tested the association between EF5-binding levels with event-free and overall survival irrespective of the pattern of cellular binding or treatment regimen. Patients with tumors containing EF5-binding regions corresponding to severe hypoxia (< or =0.1% oxygen) had a shorter event-free survival time than patients with pO(2) values greater than 0.1% (p = 0.032). Nodal status was also predictive for outcome.. These data illustrate the potential utility of EF5 binding based on quantitative immunohistochemistry of tissue pO(2) and provide support for the development of noninvasive hypoxia positron emission tomographic studies with fluorine 18-labeled EF5.

Topics: Aged; Carcinoma, Squamous Cell; Cell Hypoxia; Etanidazole; Female; Fluorescent Antibody Technique; Head and Neck Neoplasms; Humans; Hydrocarbons, Fluorinated; Indicators and Reagents; Laryngeal Neoplasms; Male; Middle Aged; Mouth Neoplasms; Oropharyngeal Neoplasms; Prospective Studies