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Purpose: The purpose of this study was to evaluate the radiotherapy planning feasibility of dose escalation with intensity‐modulated proton therapy (IMPT) to hypoxic tumor regions identified on 18F‐Fluoromisonidazole (FMISO) positron emission tomography and computed tomography (PET‐CT) in NPC. Materials and methods: Nine patients with stages T3‐4N0‐3M0 NPC underwent 18F‐FMISO PET‐CT before and during week 3 of radiotherapy. The hypoxic volume (GTVhypo) is automatically generated by applying a subthresholding algorithm within the gross tumor volume (GTV) with a tumor to muscle standardized uptake value (SUV) ratio of 1.3 on the 18F‐FMISO PET‐CT scan. Two proton plans were generated for each patient, a standard plan to 70 Gy and dose escalation plan with upfront boost followed by standard 70GyE plan. The stereotactic boost was planned with single‐field uniform dose optimization using two fields to deliver 10 GyE in two fractions to GTVhypo. The standard plan was generated with IMPT with robust optimization to deliver 70GyE, 60GyE in 33 fractions using simultaneous integrated boost technique. A plan sum was generated for assessment. Results: Eight of nine patients showed tumor hypoxia on the baseline 18F‐FMISO PET‐CT scan. The mean hypoxic tumor volume was 3.9 cm3 (range.9–11.9cm3). The average SUVmax of the hypoxic volume was 2.2 (range 1.44–2.98). All the dose‐volume parameters met the planning objectives for target coverage. Dose escalation was not feasible in three of eight patients as the D0.03cc of temporal lobe was greater than 75GyE. Conclusions: The utility of boost to the hypoxic volume before standard course of radiotherapy with IMPT is dosimetrically feasible in selected patients. Clinical trials are warranted to determine the clinical outcomes of this approach. [ABSTRACT FROM AUTHOR]

Introduction: Tumor hypoxia is a centerpiece of disease progression mechanisms such as neoangiogenesis or aggressive hypoxia-resistant malignant cells selection that impacts on radiotherapy strategies. Early identification of regions at risk for recurrence and prognostic-based classification of patients is a necessity to devise tailored therapeutic strategies. We developed an image-based algorithm to spatially map areas of aerobic and anaerobic glycolysis (Glyoxia). Methods: 18F-FDG and 18F-FMISO PET studies were used in the algorithm to produce DICOM-co-registered representations and maximum intensity projections combined with quantitative analysis of hypoxic volume (HV), hypoxic glycolytic volume (HGV), and anaerobic glycolytic volume (AGV) with CT/MRI co-registration. This was applied to a prospective clinical trial of 10 glioblastoma patients with post-operative, pre-radiotherapy, and early post-radiotherapy 18F-FDG and 18F-FMISO PET and MRI studies. Results: In the 10 glioblastoma patients (5M:5F; age range 51–69 years), 14/18 18F-FMISO PET studies showed detectable hypoxia. Seven patients survived to complete post-radiotherapy studies. The patient with the longest overall survival showed non-detectable hypoxia in both pre-radiotherapy and post-radiotherapy 18F-FMISO PET. The three patients with increased HV, HGV, and AGV volumes after radiotherapy showed 2.8 months mean progression-free interval vs. 5.9 months for the other 4 patients. These parameters correlated at that time point with progression-free interval. Parameters combining hypoxia and glycolytic information (i.e., HGV and AGV) showed more prominent variation than hypoxia-based information alone (HV). Glyoxia-generated images were consistent with disease relapse topology; in particular, one patient had distant relapse anticipated by HV, HGV, and AGV maps. Conclusion: Spatial mapping of aerobic and anaerobic glycolysis allows unique information on tumor metabolism and hypoxia to be evaluated with PET, providing a greater understanding of tumor biology and potential response to therapy. [ABSTRACT FROM AUTHOR]

Purpose: To assess noninvasively the tumor microenvironment of neck nodal metastases in patients with head-and-neck cancer by investigating the relationship between tumor perfusion measured using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and hypoxia measured by 18F-fluoromisonidazole (18F-FMISO) positron emission tomography (PET). Methods and Materials: Thirteen newly diagnosed head-and-neck cancer patients with metastatic neck nodes underwent DCE-MRI and 18F-FMISO PET imaging before chemotherapy and radiotherapy. The matched regions of interests from both modalities were analyzed. To examine the correlations between DCE-MRI parameters and standard uptake value (SUV) measurements from 18F-FMISO PET, the nonparametric Spearman correlation coefficient was calculated. Furthermore, DCE-MRI parameters were compared between nodes with 18F-FMISO uptake and nodes with no 18F-FMISO uptake using Mann-Whitney U tests. Results: For the 13 patients, a total of 18 nodes were analyzed. The nodal size strongly correlated with the 18F-FMISO SUV (ρ = 0.74, p < 0.001). There was a strong negative correlation between the median kep (redistribution rate constant) value (ρ = −0.58, p = 0.042) and the 18F-FMISO SUV. Hypoxic nodes (moderate to severe 18F-FMISO uptake) had significantly lower median Ktrans (volume transfer constant) (p = 0.049) and median kep (p = 0.027) values than did nonhypoxic nodes (no 18F-FMISO uptake). Conclusion: This initial evaluation of the preliminary results support the hypothesis that in metastatic neck lymph nodes, hypoxic nodes are poorly perfused (i.e., have significantly lower Ktrans and kep values) compared with nonhypoxic nodes. [Copyright &y& Elsevier]

Purpose: To evaluate how changes in tumor hypoxia, according to serial fluorine-18-labeled fluoro-misonidazole (18F-FMISO) positron emission tomography (PET) imaging, affect the efficacy of intensity-modulated radiotherapy (IMRT) dose painting. Methods and Materials: Seven patients with head and neck cancers were imaged twice with FMISO PET, separated by 3 days, before radiotherapy. Intensity-modulated radiotherapy plans were designed, on the basis of the first FMISO scan, to deliver a boost dose of 14 Gy to the hypoxic volume, in addition to the 70-Gy prescription dose. The same plans were then applied to hypoxic volumes from the second FMISO scan, and the efficacy of dose painting evaluated by assessing coverage of the hypoxic volumes using Dmax, Dmin, Dmean, D95, and equivalent uniform dose (EUD). Results: Similar hypoxic volumes were observed in the serial scans for 3 patients but dissimilar ones for the other 4. There was reduced coverage of hypoxic volumes of the second FMISO scan relative to that of the first scan (e.g., the average EUD decreased from 87 Gy to 80 Gy). The decrease was dependent on the similarity of the hypoxic volumes of the two scans (e.g., the average EUD decrease was approximately 4 Gy for patients with similar hypoxic volumes and approximately 12 Gy for patients with dissimilar ones). Conclusions: The changes in spatial distribution of tumor hypoxia, as detected in serial FMISO PET imaging, compromised the coverage of hypoxic tumor volumes achievable by dose-painting IMRT. However, dose painting always increased the EUD of the hypoxic volumes. [Copyright &y& Elsevier]

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Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. This aggressiveness is in part attributed to the closely interrelated phenomena tumor hypoxia and angiogenesis, although few in vivo data exist in human brain tumors. This work aimed to study hypoxia and angiogenesis, in vivo and in situ, in patients admitted with GBM using multimodal imaging. Methods: Twenty-three GBM patients were assessed by 18 F-fluoromisonidazole ( 18 F-FMISO) PET and conventional and perfusion MRI before surgery. The level and location of hypoxia ( 18 F-FMISO uptake, evaluated by tumor-to-blood [T/B] ratio), vascularization (cerebral blood volume [CBV]), and vascular permeability (contrast enhancement after gadolinium injection) were analyzed. The spatial relationship between tumor hypoxia and angiogenesis was assessed by an overlap analysis of the volume of 18 F-FMISO uptake and the volumes of the high CBV regions and the contrast-enhancement regions. Results: A significant correlation was found between hypoxia and hypervascularization, especially for their maximum values (volume of maximal tumor hypoxia vs. relative CBV: r = 0.61, P = 0.002) and their volumes (hypoxia vs. hypervascularization: r = 0.91, P < 0.001). A large proportion of the high CBVs collocated with hypoxia (81.3%) and with contrast enhancement (46.5%). Conclusion: These results support the hypothesis of a tight association between hypoxia and angiogenesis. Our results suggest that there is insufficient tumor oxygenation in human GBM, despite increased tumor vascularization., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

High-grade gliomas are often characterized by hypoxia, which is associated with both poor long-term prognosis and therapy resistance. The adverse role hypoxia plays in treatment resistance and disease progression has led to the development of hypoxia imaging methods and hypoxia-targeted treatments. Here, we determined the tumor hypoxia and vascular perfusion characteristics of 2 rat orthotopic glioma models using 18-fluoromisonidozole positron emission tomography. In addition, we determined tumor response to the hypoxia-activated prodrug evofosfamide (TH-302) in these rat glioma models. C6 tumors exhibited more hypoxia and were less perfused than 9L tumors. On the basis of these differences in their tumor hypoxic burden, treatment with evofosfamide resulted in 4- and 2-fold decreases in tumor growth rates of C6 and 9L tumors, respectively. This work shows that imaging methods sensitive to tumor hypoxia and perfusion are able to predict response to hypoxia-targeted agents. This has implications for improved patient selection, particularly in clinical trials, for treatment with hypoxia-activated cytotoxic prodrugs, such as evofosfamide., Competing Interests: None to report.