Abstract B149: Quantitative FMISO imaging to assess regional tumor hypoxia as a predictor of response to therapy.

Abstract

Abstract Hypoxia is associated with resistance to RT and chemotherapy in malignant tumors, where the burden of hypoxic tumor present before as well as after RT influences treatment outcome. Due to the low retention in normal oxygenated tissue, FMISO is an effective quantitative imaging agent for tumor hypoxia. Because FMISO has a partition coefficient near one, the concentrations in oxygenated tissue and blood rapidly equilibrate and are essentially identical. Normalizing the FMISO uptake data to blood activity, has permitted the generation of a threshold value, above which indicates tissue hypoxia. Through our earlier work using FMISO in tumor cells in culture, animal tumor models and human patient studies, we have determined empirically that blood-normalized tissue uptake (T/B) above a threshold can reliably be used to indicate tissue hypoxia and predict outcome [reviewed in Krohn et al. J Nucl Med 49(suppl 2):129S-148S, 2008]. Over the time course of FMISO uptake after injection, vascularized normoxic tissues tend to equilibrate with blood activity and the ratio of tissue-to-blood tends toward a mean of slightly less than 1. In the collection of FMISO regional tissue activity from normoxic tissue types (muscle, cerebellum, breast, lung; n > 400), the T/B values were consistently (> 90%) less than 1. In the examination of various hypoxic thresholds from normoxic brain tissue, a value of 1.1 results in 10% hypoxia, which is unrealistic for normal functioning brain tissue; a value of 1.2 results in ∼2.5% hypoxia and 0% for T/B=1.3. Thus a FMISO T/B ratio threshold of 1.2 adequately characterizes normoxic tissue; a FMISO T/B value >1.2 indicates hypoxia. Applying a hypoxic threshold T/B value for FMISO permits the determination of hypoxic volume (HV, mL) of a tissue region that can be determined as the volume of pixels within the tissue VOI above the hypoxic threshold. This simple static image analysis is one of the strengths of FMISO-PET; it captures both the intensity and spatial distribution of tumor hypoxia. In this imaging procedure, a static scan of 20 min duration is acquired 2 hrs after tracer injection during which three venous blood samples are acquired. The quantitative parameters from FMISO imaging that describe tissue hypoxia are the maximum value (T/Bmax) determined from the pixel within the tumor that has the highest uptake, and HV. HV depicts the extent of tumor that has crossed the threshold for hypoxia and T/Bmax depicts the severity of the hypoxia. In general HV and T/Bmax are correlated within an individual patient. Quantitative FMISO imaging can be used to select patients with hypoxic tumors and to identify regions of hypoxia that might be subjected to more intense therapy. Kaplan-Meier survival analysis and multivariate Cox regressions were used to show that T/Bmax or HV are independent predictors of TTP and survival, where progression was defined by clinical criteria. Serial FMISO studies can also be used to follow the reoxygenation response after radiation or chemotherapies such as anti-VEGF treatments. Supported by NIH Grant P01 CA042045-23. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B149. Citation Format: Mark Muzi, Janet O'Sullivan, Janet F. Eary, Kenneth A. Krohn. Quantitative FMISO imaging to assess regional tumor hypoxia as a predictor of response to therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B149.