18f-faza and Carcinoma--Squamous-Cell

Radiotherapy based on functional imaging consists to deliver a heterogeneity dose based on biological proprieties. This approach is termed biologically conformal radiotherapy or dose painting with biological target volume inside the gross tumor volume. Diffusion-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced MRI can also be used to define a specific biological target volume. Three main tracers are used: ((18)F)-fluorodeoxyglucose to target the hypermetabolism, ((18)F)-fluoromizonidazole and ((18)F)- fluoroazomycin arabinoside to target areas of hypoxia. In this review, we give a practical approach to achieving a treatment-guided radiotherapy molecular and the main issues raised by this imaging technique. Despite the provision of all the technological tools to the radiotherapist, this new therapeutic approach is still evaluated in clinical studies to demonstrate a real clinical benefit compared to radiotherapy based on anatomic imaging.

Topics: Carcinoma, Squamous Cell; Cell Hypoxia; Clinical Trials as Topic; Diffusion Magnetic Resonance Imaging; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Head and Neck Neoplasms; Humans; Image Interpretation, Computer-Assisted; Magnetic Resonance Imaging; Misonidazole; Multimodal Imaging; Nitroimidazoles; Positron-Emission Tomography; Radiopharmaceuticals; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Image-Guided; Tumor Burden

Positron emission tomography (PET) has become a standard in staging Head and Neck cancer. While (18)F-fluoro-2-deoxy-D-glucose (FDG) is the most frequently used radiopharmaceutical, glycolysis is not the only metabolic process that can be visualized. Different PET tracers can also be used to visualize other metabolic processes and in this manner, the disadvantages of FDG PET can be avoided. In this review, we describe a comprehensive overview of alternatives to FDG that can be used in identifying head and neck cancer. The potential advantages and disadvantages of these radiopharmaceuticals are discussed.

Topics: Amino Acids; Antibodies, Monoclonal; Carbon Radioisotopes; Carcinoma, Squamous Cell; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Head and Neck Neoplasms; Humans; Misonidazole; Nitroimidazoles; Nucleosides; Positron-Emission Tomography; Radiopharmaceuticals

Despite the large variety of treatment methods available for the management of advanced head and neck carcinomas, these tumours remain highly challenging due to their aggressiveness and complex anatomical location. Among the treatment challenges associated with head and neck cancers, hypoxia and tumour repopulation during treatment are, most likely, the main reason for locoregional treatment failure. Whilst the number of techniques and predictive assays designed to assess the oxygenation status or the proliferative ability of tumours is rather large, they all come with drawbacks which limit their implementation as routine clinical procedures. Latest developments in the field of nuclear medicine have opened the road to new possibilities in functional imaging, thus overcoming some of the confines imposed by the more conventional techniques.. The current paper presents the role of PET imaging as a quantitative evaluation tool for hypoxia status and proliferative ability of advanced head and neck tumours. Traditional as well as novel radioisotopes with high affinity towards hypoxia and proliferative tumour activity are presented and their pre-clinical/clinical results analysed.. While the number of clinical studies which aimed to validate novel radiotracers for head and neck cancer is limited, a number of results show promising correlation between uptake/marker activity and treatment outcome.. There is need for further studies and well designed clinical trials to obtain more conclusive results.

Topics: Carcinoma, Squamous Cell; Cell Hypoxia; Cell Proliferation; Fluorine Radioisotopes; Head and Neck Neoplasms; Humans; Nitroimidazoles; Positron-Emission Tomography; Radioisotopes; Radiotherapy, Image-Guided; Squamous Cell Carcinoma of Head and Neck

The prognostic value of positron emission tomography/computed tomography (PET/CT) with (18)F-fluoroazomycin arabinoside (FAZA) was evaluated in patients with head and neck squamous cell carcinoma (HNSCC) who underwent chemoradiotherapy (CRT).. Twenty-nine patients with head and neck cancer underwent FAZA PET/CT before treatment. Data acquisition started 2 h after FAZA administration. In 26 patients with squamous cell carcinoma, FAZA uptakes by the primary lesions (tumor-muscle ratio in primary lesion: Pr T/M) and by the lymph node metastases (tumor-muscle ratio in lymph node metastasis) were compared with various clinical parameters. For the HNSCC patients who completed CRT protocol (n = 23), those who experienced disease progression were compared with those who did not experience disease progression with respect to the clinical and PET parameters. The prognostic values of the clinical and PET parameters were then evaluated with regard to progression-free survival (PFS).. Pr T/M positively correlated with the lesion's maximum diameter, and it was significantly higher in stage IV lesions compared with stage I-III lesions. No significant differences were observed between the patients who experienced disease progression and those who did not, with respect to the clinical parameters. The average Pr T/M tended to be higher in patients with disease progression, although the differences were not statistically significant (p = 0.086). Kaplan-Meier analysis with log-rank tests indicated that Pr T/M was an only significant predictor of PFS among PET and clinical parameters evaluated (p = 0.010).. FAZA uptake by the primary lesion was a significant prognostic indicator in HNSCC patients undergoing CRT. Hence, FAZA PET/CT may provide useful information in the management of HNSCC patients treated with CRT. Registration number of clinical trial's registry: UMIN000003440.

Topics: Carcinoma, Squamous Cell; Chemoradiotherapy; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Nitroimidazoles; Positron Emission Tomography Computed Tomography; Prognosis; Squamous Cell Carcinoma of Head and Neck

To evaluate from a planning point of view the dose distribution of adaptive radiation dose escalation in head and neck squamous cell carcinoma (HNSCC) using (18)F-Fluoroazomycin arabinoside (FAZA) positron emission tomography/computed tomography (PET-CT).. Twelve patients with locally advanced HNSCC underwent three FAZA PET-CT before treatment, after 7 fractions and after 17 fractions of a carboplatin-5FU chemo-radiotherapy regimen (70 Gy in 2 Gy per fraction over 7 weeks). The dose constraints were that every hypoxic voxel delineated before and during treatment (newborn hypoxic voxels) should receive a total dose of 86 Gy. A median dose of 2.47 Gy per fraction was prescribed on the hypoxic PTV defined on the pre-treatment FAZA PET-CT; a median dose of 2.57 Gy per fraction was prescribed on the newborn voxels identified on the first per-treatment FAZA PET-CT; a median dose of 2.89 Gy per fraction was prescribed on the newborn voxels identified on the second per-treatment FAZA PET-CT.. Ten of 12 patients had hypoxic volumes. Six of 10 patients completed all the FAZA PET-CT during radiotherapy. For the hypoxic PTVs, the average D50% matched the prescribed dose within 2% and the homogeneity indices reached 0.10 and 0.12 for the nodal PTV 86 Gy and the primary PTV 86 Gy, respectively. Compared to a homogeneous 70 Gy mean dose to the PTVs, the dose escalation up to 86 Gy to the hypoxic volumes did not typically modify the dose metrics on the surrounding normal tissues.. From a planning point of view, FAZA-PET-guided dose adaptive escalation is feasible without substantial dose increase to normal tissues above tolerance limits. Clinical prospective studies, however, need to be performed to validate hypoxia-guided adaptive radiation dose escalation in head and neck carcinoma.

Topics: Aged; Carcinoma, Squamous Cell; Dose Fractionation, Radiation; Female; Head and Neck Neoplasms; Humans; Image Interpretation, Computer-Assisted; Male; Middle Aged; Multimodal Imaging; Nitroimidazoles; Positron-Emission Tomography; Radiopharmaceuticals; Radiotherapy Planning, Computer-Assisted; Squamous Cell Carcinoma of Head and Neck; Tomography, X-Ray Computed

Hypoxia is a cause of resistance to radiotherapy, especially in patients with head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to evaluate (18)F-fluoroazomycin arabinoside (FAZA) positron emission tomography (PET)/computed tomography (CT) hypoxia imaging as a prognostic factor in HNSCC patients receiving radiotherapy.. Forty patients with HNSCC treated with radiotherapy (66-76 Gy) were included. Static FAZA PET/CT imaging 2h post injection was conducted prior to irradiation. The hypoxic volume (HV) was delineated using a tumor-to-muscle value ≥ 1.4. In 13 patients, a repetitive FAZA PET/CT scan was conducted during the radiotherapy treatment.. A hypoxic volume could be identified in 25 (63%) of the 40 tumors. FAZA PET HV varied considerably with a range from 0.0 to 30.9 (median: 0.3) cm(3). The T(max)/M(med) ranged from 1.1 to 2.9 (median: 1.5). The distribution of hypoxia among the Human Papillomavirus (HPV) positive (12/16) and negative (13/24) tumors was not significant different. In the FAZA PET/CT scans performed during radiotherapy, hypoxia could be detected in six of the 13 patients. For these six patients the location of HV remained stable in location during radiotherapy treatment, though the size of the HV decreased. In 30 patients a positive correlation was detected between maximum FAZA uptake in the primary tumor and the lymph node. During a median follow up of 19 months a significant difference in disease free survival rate with 93% for patients with non hypoxic tumors and 60% for patients with hypoxic tumors could be detected.. This study emphasizes the role of FAZA PET/CT imaging as a suitable assay with prognostic potential for detection of hypoxia in HNSCC.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Cell Hypoxia; Female; Head and Neck Neoplasms; Humans; Lymph Nodes; Male; Middle Aged; Multimodal Imaging; Nitroimidazoles; Positron-Emission Tomography; Prognosis; Tomography, X-Ray Computed

The aim of this pilot study was to assess tumour hypoxia in patients with cervical cancer before, during and after combined radio-chemotherapy and Magnetic Resonance Imaging (MRI) guided brachytherapy (BT) by use of the hypoxia Positron Emission Tomography (PET) tracer (18)F-fluoroazomycin-arabinoside ((18)FAZA ).. Fifteen consecutive patients with locally advanced cervical cancer referred for definitive radiotherapy (RT) were included in an approved clinical protocol. Stage distribution was 3 IB1, 1 IB2, 10 IIB, 1 IIIB, tumour volume was 55 cm(3) (+/- 67, SD). Dynamic and static (18)FAZA -PET scans were performed before, during and after external beam therapy (EBRT) and image guided BT +/- concomitant cisplatin. Dose was prescribed to the individual High Risk Clinical Target Volume (HR CTV) taking into account the dose volume constraints for adjacent organs at risk.. Five patients had visually identifiable tumours on (18)FAZA -PET scans performed prior to radio-chemotherapy and four patients before brachytherapy. One of five (18)FAZA PET positive patients had incomplete remission three months after RT, one had regional recurrence. Four of ten (18)FAZA-PET negative patients developed distant metastases. The one patient with incomplete remission received 69 Gy (D90) in the HR CTV, whereas all other patients received mean 99 Gy (+/-12, SD).. PET imaging with (18)FAZA is feasible in patients with cancer of the uterine cervix. However, its predictive and prognostic value remains to be clarified. This applies in particular for the additional value of (18)FAZA-PET compared to morphologic repetitive MRI within the setting of image guided high dose radiotherapy which may contribute to overcome hypoxia related radioresistance.

Topics: Adaptation, Biological; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Female; Humans; Magnetic Resonance Imaging; Middle Aged; Nitroimidazoles; Periodicity; Pilot Projects; Positron-Emission Tomography; Radiography; Radiotherapy Dosage; Radiotherapy, Computer-Assisted; Uterine Cervical Neoplasms

Tumour hypoxia is thought to play a significant role in the outcome of solid tumour therapy. Positron emission tomography (PET) is the best-validated noninvasive technique able to demonstrate the presence of hypoxia in vivo. The locally developed PET tracer for imaging hypoxia, 1-alpha-D: -(5-deoxy-5-[(18)F]-fluoroarabinofuranosyl)-2-nitroimidazole ((18)F-FAZA), has been shown to accumulate in experimental models of tumour hypoxia and to clear rapidly from the circulation and nonhypoxic tissues. The safety and general biodistribution patterns of this radiopharmaceutical in patients with squamous cell carcinoma of the head and neck (HNSCC), small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC), malignant lymphoma, and high-grade gliomas, were demonstrated in this study.. Patients with known primary or suspected metastatic HNSCC, SCLC or NSCLC, malignant lymphoma or high-grade gliomas were dosed with 5.2 MBq/kg of (18)F-FAZA, then scanned 2-3 h after injection using a PET or PET/CT scanner. Images were interpreted by three experienced nuclear medicine physicians. The location and relative uptake scores (graded 0 to 4) of normal and abnormal (18)F-FAZA biodistribution patterns, the calculated tumour-to-background (T/B) ratio, and the maximum standardized uptake value were recorded.. Included in the study were 50 patients (32 men, 18 women). All seven patients with high-grade gliomas showed very high uptake of (18)F-FAZA in the primary tumour. In six out of nine patients with HNSCC, clear uptake of (18)F-FAZA was observed in the primary tumour and/or the lymph nodes in the neck. Of the 21 lymphoma patients (15 with non-Hodgkin's lymphoma and 6 with Hodgkin's disease), 3 demonstrated moderate lymphoma-related uptake. Of the 13 lung cancer patients (12 NSCLC, 1 SCLC), 7 had increased (18)F-FAZA uptake in the primary lung tumour. No side effects of the administration of (18)F-FAZA were observed.. This study suggests that (18)F-FAZA may be a very useful radiopharmaceutical to image hypoxia in the tumour types selected. Especially the high uptake by gliomas was encouraging. Given the good imaging properties, including acceptable T/B ratios in the tumour categories studied, (18)F-FAZA could be considered as a very promising agent for assessing the hypoxic fraction of these tumour types.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Fluorine Radioisotopes; Glioma; Head and Neck Neoplasms; Humans; Hypoxia; Lung Neoplasms; Lymphoma; Male; Middle Aged; Neoplasms; Nitroimidazoles; Positron-Emission Tomography; Radiopharmaceuticals; Young Adult

PET-guided dose painting (DP) aims to target radioresistant tumour regions in order to improve radiotherapy (RT) outcome. Besides the well-known [. Fourteen patients with unresectable lung cancer underwent FDG and FAZA 4D-PET/CT on consecutive days at three time-points: prior to RT (pre), and during the second (w2), and the third (w3) weeks of RT. All PET/CT were reconstructed in their time-averaged midposition (MidP). The metabolic tumour volume (MTV: FDG standardised uptake value (SUV) > 50% SUV. Volume-based analysis showed large overlap between MTV and HV: median overlapping fraction was 0.90, 0.94 and 0.94, at the pre, w2 and w3 time-points, respectively. Voxel-wise analysis between FDG and FAZA intratumoral PET uptake distributions showed high correlation: median Spearman's rank correlation coefficient was 0.76, 0.77 and 0.76, at the pre, w2 and w3 time-points, respectively. Interestingly, tumours with high FAZA uptake tended to show more similarity between FDG and FAZA intratumoral uptake distributions than those with low FAZA uptake.. In unresectable lung carcinomas, FDG and FAZA PET uptake distributions displayed unexpectedly strong similarity, despite the distinct pathways targeted by these tracers. Hypoxia PET with FAZA brought very little added value over FDG from the perspective of DP in this population.

Topics: Adenocarcinoma; Aged; Carcinoma, Squamous Cell; Female; Fluorodeoxyglucose F18; Humans; Lung Neoplasms; Male; Middle Aged; Nitroimidazoles; Positron Emission Tomography Computed Tomography; Prognosis; Radiopharmaceuticals; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Small Cell Lung Carcinoma

(18)F-fluoroazomycinarabinoside ((18)F-FAZA) is a promising hypoxia radiopharmaceutical agent with outstanding biokinetic parameters. We aimed to determine the accuracy of (18)F-FAZA-PET/CT scan in detecting hypoxic regions within the tumor using immunohistochemical markers in a pilot study.. Eleven patients with primary or recurrent laryngeal squamous cell carcinoma were indicated for total laryngectomy (TLE). Patients underwent (18)F-FAZA-PET/CT scan before TLE. Hypoxic regions inside the laryngeal tumor were determined. After TLE, regions with high uptake on (18)F-FAZA-PET scan were selected for immunohistochemical examination for exogenous (pimonidazole) and endogenous (HIF1α, CA-IX and GLUT-1) hypoxia markers. To assess the accuracy of (18)F-FAZA-PET scanning, radiopharmacon accumulation was related with immunohistochemical expression of hypoxia markers.. Inter- and intratumoral heterogeneity of tumor hypoxia was observed on (18)F-FAZA-PET scan. Nine of the eleven tumors were hypoxic with (18)F-FAZA-PET. Hypoxia could also be detected with pimonidazole, HIF1α, CA-IX and GLUT-1 expression in some tumors. No clear association was observed between (18)F-FAZA uptake and hypoxia markers.. This pilot study could not prove the accuracy of (18)F-FAZA-PET in determining hypoxic subvolumes in laryngeal cancer. Further study is required to investigate the benefit of (18)F-FAZA-PET imaging in radiotherapy planning.

Topics: Aged; Aged, 80 and over; Biomarkers; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Hypoxia; Laryngeal Neoplasms; Laryngectomy; Male; Middle Aged; Multimodal Imaging; Neoplasm Recurrence, Local; Nitroimidazoles; Pilot Projects; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Squamous Cell Carcinoma of Head and Neck; Tomography, X-Ray Computed

Hypoxia in head and neck squamous cell carcinoma (HNSCC) is associated with poor prognosis and outcome. (18) F-Fluoroazomycin arabinoside (FAZA) is a positron emission tomography (PET) tracer developed to enable identification of hypoxic regions within tumor. The aim of this study was to evaluate the use of (18) F-FAZA-PET for assessment of hypoxia before and during radiation therapy.. Twelve patients with locally advanced HNSCC underwent (18) F-FAZA-PET scans before and at fraction 7 and 17 of concomitant chemo-radiotherapy. A hypoxic voxel was defined as a voxel expressing a standardized uptake value (SUV) equal or above the SUVmean of the posterior contralateral neck muscles plus three standard deviations. The fractional hypoxic volume fraction (FHV) and the spatial move of hypoxic volumes during treatment were analyzed.. A hypoxic volume could be identified in ten patients before treatment. FAZA-PET FHV varied from 0 to 54.3% and from 0 to 41.4% in the primary tumor and in the involved node, respectively. Six out of these ten patients completed all the FAZA-PET-computed tomography (CT) during the radiotherapy. In all patients, FHV and SUVmax values decreased. All patient presented a spatial move of hypoxic volume, but only three patients had newborn hypoxic voxels after 17 fractions.. This study indicated that (18) F-FAZA-PET could be used to identify and quantify tumor hypoxia before and during concomitant radio-chemotherapy in patients with locally advanced HNSCC. In addition to the information on prognostic value, the use of (18) F-FAZA-PET allowed the delineation of hypoxic volumes for dose escalation protocols. However, due to fluctuation of hypoxia during treatment, repeated scan will have to be performed (i.e. adaptive radiotherapy).

Topics: Aged; Carcinoma, Squamous Cell; Cell Hypoxia; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Nitroimidazoles; Oxygen; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals

To define the optimal time point for the integration of hypoxia (18)F-FAZA-PET/CT information into radiotherapy treatment planning to benefit from hypoxia modification or dose escalation treatment. Therefore, we performed a prospective cohort study, using serial hypoxic imaging ((18)F-FAZA-PET/CT) prior to and at several time-points during (chemo)radiotherapy (CHRT) in six head and neck squamous cell (HNSCC) and six non-small cell lung cancer (NSCLC) patients.. The spatio-temporal dynamics of tumor hypoxia and fractional hypoxic volumes (FHV) were evaluated using a voxel-by-voxel analysis based on a (18)F-FAZA-T/B ratio of 1.4 at four time points in HNSCC patients, at baseline (FAZA-BL), at week one (FAZA-W1), two (FAZA-W2), and four (FAZA-W4) during CHRT and at three time points in NSCLC patients (baseline; W2, W4).. Ten out of twelve patients showed a substantial pre-treatment tumor hypoxia representing a FHV⩾1.4 assessed by (18)F-FAZA-PET/CT. The median FHV was 38% (FAZA-BL), 15% (FAZA-W1), 17% (FAZA-W2) and 1.5% (FAZA-W4) in HNSCC patients, and 34% (FAZA-BL), 26% (FAZA-W2) and 26% (FAZA-W4) in NSCLC patients, respectively. Stable tumor hypoxia was observed in three HNSCC patients and two NSCLC patients at FAZA-W2. In three HNSCC patients and two NSCLC patients FHVs declined to non-detectable hypoxia levels at FAZA-W4 during CHRT, while two NSCLC patients, showed increasing FHVs.. Our results indicate that, instead of using the FAZA-BL scan as the basis for the dose escalation, FAZA-W2 of CHRT is most suitable and might provide a more reliable basis for the integration of (18)F-FAZA-PET/CT information into radiotherapy treatment planning for hypoxia-directed dose escalation strategies.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Hypoxia; Chemoradiotherapy; Cohort Studies; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Middle Aged; Multimodal Imaging; Nitroimidazoles; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Radiotherapy Planning, Computer-Assisted; Squamous Cell Carcinoma of Head and Neck; Tomography, X-Ray Computed

Positron emission tomography (PET) allows non-invasive detection and mapping of tumor hypoxia. However, slow tracer kinetics and low resolution, results in limited tumor-to-normal tissue contrast and the risk of missing areas where hypoxic cells are intermixed with necrosis. The shape of tumor time activity curves (TACs), as deduced from dynamic scans, may allow further separation of tumors/tumor sub-volumes that are inseparable based on static scans. This study was designed to define the added value of dynamic scans.. Three squamous cell carcinoma tumor models were grown in mice. Mice were injected with the (18)F-labeled PET hypoxia-tracer fluoroazomycin arabinoside (FAZA) and the immunologically-detectable hypoxia-marker pimonidazole, and PET scanned dynamically for three to six hours. Subsequently, microregional tracer retention (autoradiography) and the distribution of pimonidazole-retaining cells (immunohistology) and necrosis were analyzed in tumor tissue sections. Dynamic PET data were analysed based on a two-compartment model with irreversible tracer binding generating estimates of the putative hypoxia surrogate markers k(3) (tracer trapping rate constant) and K(i) (influx rate constant from plasma into irreversible bound tracer).. High tumor-to-reference tissue ratios and a strong linear correlation (R∼0.7 to 0.95) between density of hypoxic cells and FAZA concentration was observed three hours after tracer administration, suggesting that late time PET images provides an accurate measure of hypoxia against which kinetic model estimates can be validated. Tumor TACs varied widely (ranging from distinctly wash-out to accumulative type) among tumor types although pimonidazole-stainings revealed extensive hypoxia in all models. Kinetic analysis of tumor sub-volumes showed that k(3) correlated poorly with late time FAZA retention regionally in two of the three tumor models. The influx rate constant K(i) displayed far less variability and correlated strongly with late time FAZA retention (hypoxia) in two of three tumor models, whereas a non-consistent relationship was observed in the last tumor model. Our study demonstrates the potential usefulness of dynamic PET, but also that a simple two-compartment model may be inappropriate in some tumor models.

Topics: Animals; Carcinoma, Squamous Cell; Female; Gingival Neoplasms; Humans; Hypoxia; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Neoplasms; Nitroimidazoles; Positron-Emission Tomography; Transplantation, Heterologous; Tumor Cells, Cultured; Uterine Cervical Neoplasms

PET allows non-invasive mapping of tumor hypoxia, but the combination of low resolution, slow tracer adduct-formation and slow clearance of unbound tracer remains problematic. Using a murine tumor with a hypoxic fraction within the clinical range and a tracer post-injection sampling time that results in clinically obtainable tumor-to-reference tissue activity ratios, we have analyzed to what extent inherent limitations actually compromise the validity of PET-generated hypoxia maps.. Mice bearing SCCVII tumors were injected with the PET hypoxia-marker fluoroazomycin arabinoside (FAZA), and the immunologically detectable hypoxia marker, pimonidazole. Tumors and reference tissue (muscle, blood) were harvested 0.5, 2 and 4h after FAZA administration. Tumors were analyzed for global (well counter) and regional (autoradiography) tracer distribution and compared to pimonidazole as visualized using immunofluorescence microscopy.. Hypoxic fraction as measured by pimonidazole staining ranged from 0.09 to 0.32. FAZA tumor to reference tissue ratios were close to unity 0.5h post-injection but reached values of 2 and 6 when tracer distribution time was prolonged to 2 and 4h, respectively. A fine-scale pixel-by-pixel comparison of autoradiograms and immunofluorescence images revealed a clear spatial link between FAZA and pimonidazole-adduct signal intensities at 2h and later. Furthermore, when using a pixel size that mimics the resolution in PET, an excellent correlation between pixel FAZA mean intensity and density of hypoxic cells was observed already at 2h post-injection.. Despite inherent weaknesses, PET-hypoxia imaging is able to generate quantitative tumor maps that accurately reflect the underlying microscopic reality (i.e., hypoxic cell density) in an animal model with a clinical realistic image contrast.

Topics: Animals; Carcinoma, Squamous Cell; Cell Count; Cell Hypoxia; Disease Models, Animal; Female; Hypoxia; Mice; Mice, Inbred C3H; Nitroimidazoles; Oxygen; Positron-Emission Tomography; Radiopharmaceuticals; Random Allocation; Sensitivity and Specificity; Tissue Distribution

Tumor hypoxia adversely affects treatment outcome, especially in squamous cell carcinomas (SCCs). Image guided radiotherapy (IGRT) based on PET-generated tumor hypoxia maps allows dose boosting to hypoxic sub-volumes and has received considerable interest. However, the combination of slow oxygenation-dependent tracer retention, slow clearance of unbound tracer from non-hypoxic tissue and the necessity to average signal over large non-homogenous tissue areas due to the low PET resolution remains problematic.. To assess pitfalls inherent to low-resolution imaging we have analyzed the fine-scale distribution of a PET hypoxia tracer (autoradiograms) and tissue architecture (immunofluorescence microscopy) in sectioned experimental SCCs, and compared the results to those obtained when applying macroscopic averaging mimicking the resolution in clinical PET scanners.. We show that tumor areas that would be classified as non-hypoxic based on simple PET threshold identification, often contains foci of hypoxic cells, in particular in tumors where necrosis and severely hypoxic cells are intermixed. In contrast, in a non-necrotic tumor model we found that the risk of missing hypoxic cells was greatly reduced, however, its patchy hypoxic pattern made a clear delineation of a target to boost unfeasible. We discuss the implications of these and other complicating factors in PET hypoxia-imaging and outline future strategies to overcome or circumvent them.

Topics: Animals; Carcinoma, Squamous Cell; Cell Hypoxia; Mice; Mice, Nude; Microscopy, Fluorescence; Necrosis; Neoplasms, Experimental; Nitroimidazoles; Positron-Emission Tomography

Positron emission tomography (PET) allows noninvasive assessment of tumor hypoxia; however the combination of low resolution and slow tracer clearance from nonhypoxic tissue is problematic. The aim of this study was to examine the in vivo hypoxia selectivity of fluoroazomycin arabinoside ([18F]-FAZA), a promising tracer with improved washout kinetics from oxygenated tissue.. Three squamous cell carcinomas and one fibrosarcoma with widely differing spatial patterns of vascularization, hypoxia, and necrosis were grown in mice and evaluated with PET and complementary methods.. Eppendorf electrode measurements consistently demonstrated median PO2 values<1 mm Hg. In accordance with that, PET revealed that all tumors accumulated [18F]-FAZA in excess of reference tissue. Next the two-dimensional spatial distribution of [18F]-FAZA (from autoradiography) was compared with fluorescence images of the same tumor sections showing localization of the hypoxia marker pimonidazole and the perfusion marker Hoechst 33342. Pixel-by-pixel analysis of co-registered images showed a highly significant co-localization between the two hypoxia markers and an inverse correlation (except for the fibrosarcoma) between the distribution of [18F]-FAZA and Hoechst dye. Moreover intratumoral heterogeneity in tracer distribution was clearly visible on autoradiograms, with a [18F]-FAZA concentration approximately six times higher in poorly oxygenated areas than in vascular hot spots.. The distribution of [18F]-FAZA is consistent with hypoxia as the key driving force for tracer tissue retention in a selection of tumors with widely differing physiology.

Topics: Animals; Autoradiography; Carcinoma, Squamous Cell; Cell Hypoxia; Female; Fibrosarcoma; Fluorine Radioisotopes; Immunocompromised Host; Immunohistochemistry; Mice; Mice, Inbred C3H; Mice, Nude; Microscopy, Fluorescence; Nitroimidazoles; Oxygen; Polarography; Positron-Emission Tomography; Radiation-Sensitizing Agents; Transplantation, Heterologous

To evaluate the role of hypoxia positron emission tomography (PET) using [18F]fluoroazomycin-arabinoside (FAZA) in head and neck cancer for radiation treatment planning using intensity-modulated radiotherapy and dose painting.. Eighteen patients with advanced squamous cell head and neck cancer were included. Both FAZA-PET and axial CT were performed using mask fixation. The data were coregistered using software based on mutual information. Contours of tumor (primary gross tumor volume, GTV/CT-P) and lymph node metastases (GTV/CT-N) were outlined manually, and FAZA standardized uptake values (SUVs) were calculated automatically. The hypoxic subvolume (GTV/PET-FAZA) having at least 50% more FAZA uptake than background (mean SUV) neck muscle tissue was contoured automatically within GTV/CT-P (GTV/PET-FAZA-P) and GTV/CT-N (GTV/PET-FAZA-N).. The median GTV/PET-FAZA-P was 4.6 mL, representing 10.8% (range, 0.7-52%) of the GTV/CT-P. The GTV/PET-FAZA-P failed to correlate significantly with the GTV/CT-P (p = 0.06). The median GTV/PET-FAZA-N was 4.1 mL, representing 8.3% (range, 2.2-51.3%) of the GTV/CT-N. It was significantly correlated with the GTV/PET-N (p = 0.006). The GTV/PET-FAZA-P was located in a single confluent area in 11 of 18 patients (61%) and was diffusely dispersed in the whole GTV/CT-P in 4 of 18 patients (22%), whereas no hypoxic areas were identified in 3 of 18 patients (17%). The GTV/PET-FAZA-N was outlined as a single confluent region in 7 of 18 patients (39%), in multiple diffuse hypoxic regions in 4 of 18 patients (22%), and was not delineated in 7 of 18 patients (39%).. This study demonstrates that FAZA-PET imaging could be used for a hypoxia-directed intensity-modulated radiotherapy approach in head and neck cancer.

Topics: Aged; Carcinoma, Squamous Cell; Cell Hypoxia; Feasibility Studies; Female; Fluorine Radioisotopes; Head and Neck Neoplasms; Humans; Male; Middle Aged; Nitroimidazoles; Positron-Emission Tomography; Radiotherapy, Intensity-Modulated; Tomography, X-Ray Computed