[18F]FMISO and [18F]FDG PET imaging in soft tissue sarcomas: correlation of hypoxia, metabolism and VEGF expression

Abstract

Hypoxia imparts resistance to radiotherapy and chemotherapy and also promotes a variety of changes in tumor biology through inducible promoters. The purpose of this study was to evaluate the use of positron emission tomography (PET) imaging with fluorine-18 fluoromisonidazole (FMISO) in soft tissue sarcomas (STS) as a measure of hypoxia and to compare the results with those obtained using [(18)F]fluorodeoxyglucose (FDG) and other known biologic correlates. FDG evaluates energy metabolism in tumors while FMISO uptake is proportional to tissue hypoxia. FMISO uptake was compared with FDG uptake. Vascular endothelial growth factor (VEGF) expression was also compared with FMISO uptake. Nineteen patients with STS underwent PET scanning with quantitative determination of FMISO and FDG uptake prior to therapy (neo-adjuvant chemotherapy or surgery alone). Ten patients receiving neo-adjuvant chemotherapy were also imaged after chemotherapy but prior to surgical resection. Standardized uptake value (SUV) was used to describe FDG uptake; regional tissue to blood ratio (>or=1.2 was considered significant) was used for FMISO uptake. Significant hypoxia was found in 76% of tumors imaged prior to therapy. No correlation was identified between pretherapy hypoxic volume (HV) and tumor grade ( r=0.15) or tumor volume ( r=0.03). The correlation of HV with VEGF expression was 0.39. Individual tumors showed marked heterogeneity in regional VEGF expression. The mean pixel-by-pixel correlation between FMISO and FDG uptake was 0.49 (range 0.09-0.79) pretreatment and 0.32 (range -0.46-0.72) after treatment. Most tumors showed evidence of reduced uptake of both FMISO and FDG following chemotherapy. FMISO PET demonstrates areas of significant and heterogeneous hypoxia in soft tissue sarcomas. The significant discrepancy between FDG and FMISO uptake seen in this study indicates that regional hypoxia and glucose metabolism do not always correlate. Similarly, we did not find any relationship between the hypoxic volume and the tumor volume or VEGF expression. Identification of hypoxia and development of a more complete biologic profile of STS will serve to guide more rational, individualized cancer treatment approaches.

Evaluation of hypoxia in an experimental rat tumour model by [18F]Fluoromisonidazole PET and immunohistochemistry

“…To compare these data with the immunohistochemical measurements, the staining-positive fractions of PIMO and CA IX were multiplied with the corresponding tumour volumes to obtain the respective hypoxic volumes. The decision to use hypoxic volumes rather than hypoxic fractions is also supported by Rajendran et al (2003), who discussed the fact that the use of hypoxic fractions is a variable with considerable uncertainty.…”

Reproducibility of Intratumor Distribution of 18F-Fluoromisonidazole in Head and Neck Cancer

“…In this study, we adopted the criterion suggested by Rajendran et al (19) of a T/B ratio of ≥1.2 to delineate tumor hypoxia. Our results included an analysis of the voxel-by-voxel FMISO voxel uptake within the entire tumor volume from repeat PET studies, with and without applying a T/B threshold criterion.…”

“…Rajendran et al (18) showed the feasibility of this approach using 18 F-FMISO PET to detect tissue hypoxia (corresponding to pO 2 values of ≤3 mm Hg) in imaging studies and showed that 18 F-FMISO uptake was directly related to tissue hypoxia (19). Different tumor/blood and tumor/muscle threshold ratios have been proposed as quantitative criteria for delineating hypoxic tumor volumes (19)(20)(21)(22)(23). To our knowledge, no standard PET criterion for defining hypoxia has yet been established.…”

Evolutionary dynamics of the Warburg effect: Glycolysis as a collective action problem among cancer cells

“…Tumors, however, consistently rely on glycolysis even in the presence of abundant oxygen (Beckner et al, 2005;Griguer et al, 2005;Kelloff et al, 2005;Rajendran et al, 2003). Since the anaerobic metabolism of glucose to lactic acid is substantially less efficient than oxidation to CO 2 and H 2 O, tumor cells must increase glucose flux in order to maintain sufficient ATP production.…”