Modeling the Relationship between Fluorodeoxyglucose Uptake and Tumor Radioresistance as a Function of the Tumor Microenvironment

Abstract

High fluorodeoxyglucose positron emission tomography (FDG-PET) uptake in tumors has often been correlated with increasing local failure and shorter overall survival, but the radiobiological mechanisms of this uptake are unclear. We explore the relationship between FDG-PET uptake and tumor radioresistance using a mechanistic model that considers cellular status as a function of microenvironmental conditions, including proliferating cells with access to oxygen and glucose, metabolically active cells with access to glucose but not oxygen, and severely hypoxic cells that are starving. However, it is unclear what the precise uptake levels of glucose should be for cells that receive oxygen and glucose versus cells that only receive glucose. Different potential FDG uptake profiles, as a function of the microenvironment, were simulated. Predicted tumor doses for 50% control (TD50) in 2 Gy fractions were estimated for each assumed uptake profile and for various possible cell mixtures. The results support the hypothesis of an increased avidity of FDG for cells in the intermediate stress state (those receiving glucose but not oxygen) compared to well-oxygenated (and proliferating) cells.

Modeling the Cellular Response of Lung Cancer to Radiation Therapy for a Broad Range of Fractionation Schedules

“…Cell loss takes place in the highly hypoxic H -compartment, which is assumed to receive no oxygen or glucose. In the I -compartment, which recieves glucose but not oxygen, neither proliferation nor cell loss is assumed to take place (27). A fraction of cells in the P -compartment constantly proliferate.…”

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“… (a) Approximate value, compatible with the range defined in Wenzl and Wilkens 2011. (b) Clavo et al 1995; Jeong and Deasy 2014. (c) Chan et al 2008. A reduced value of the OER is expected for extremely hypoxic cells due to chronic stress and the decreasing availability of homologous recombination.…”

“…This model has been used to describe fraction size effects, reoxygenation, the relationship between FDG-avidity and tumour radioresistance, among others (Jeong et al 2013; Jeong and Deasy 2014; Robinson et al 2015). In all cases, the studies assume inter- and intra-tumour homogeneity: only one voxel with a standard hypoxia level is simulated, and the result is extrapolated in three dimensions.…”

“…In our model, FDG uptake is assumed to be proportional to the number of proliferative and intermediately hypoxic tumour cells, with the latter taking up 50% more FDG per cell. This assumption is based on the observation that (i) hypoxic tumour cells enhance glycolisis to compensate for the lack of oxygen to produce energy, (ii) FDG-avid tumours tend to correlate with increased local failure (Ghooshkhanei et al 2014; Wang et al 2013; Xie et al 2011), and (iii) for the baseline TCP model, the best correspondence between FDG uptake and TCD 50 is obtained when one assumes that cells in the I compartment have enhanced FDG-avidity (Jeong and Deasy 2014). In this paper we study the relative fractional change in maximum FDG uptake observed 30 days after the start of treatment, δ FDG = FDG 30 /FDG 1 .…”

“…Recently, a model also inspired by the LQ model introduced a further level of complexity with respect to classical models by focusing on tumour voxels or tumourlets , rather than the whole tumour (Jeong et al 2013; Jeong and Deasy 2014; Robinson et al 2015). Population equations are applied to describe key processes such as proliferation and cell loss, and within each tumourlet cells are classified according to nutrient availability in order to explain the interplay between proliferation and hypoxia.…”