Impact of temporal heterogeneity of acute hypoxia on the radiation response of experimental tumors

Abstract

Tumor hypoxia is a major factor inducing resistance to radiotherapy. Spatial limitation in oxygen (O2) diffusion usually leads to chronic hypoxia, whereas temporary shut-down of perfusion or fluctuations in red blood cell flux can cause acute hypoxia. Since the role of temporal heterogeneity of pO2 in acute hypoxia during radiotherapy remains unclear, this study focuses on analyzing the influence of temporal heterogeneity of tumor hypoxia upon radiotherapy by modeling the temporal variance of acute hypoxia. The computational simulation was conducted on digital 2D tumor phantoms. The O2 diffusion and consumption within the tumor tissues were calculated using the reaction-diffusion equation. A total of nine experimental tumor lines (FaDu, GL, C3H, RIF, SCCVII, KHT, MEF, MTG, HT29) were modeled according to known pO2 distributions. Each tumor line was first simulated 36 times with various temporal heterogeneities (dynamic hypoxia) and once again without temporal heterogeneity (static hypoxia). Temporal pO2 fluctuations were modeled according to known red blood cell (RBC) fluxes. All tumor phantoms were irradiated with 30 fractions of 2 Gy. Cell survival was calculated as a function of pO2 and radiation dose via linear quadratic model. The simulation results indicate that the temporal heterogeneity varies with different tumor types, and tumor line HT29 shows the most significant impact of temporal heterogeneity upon the treatment effect. The ratio between the surviving fractions without and with temporal variance ranges from 1.44 to 6.28. Given the same mean pO2, the fraction of killed tumor cells in dynamic hypoxia is higher than in static hypoxia. A temporal heterogeneity index (THI) denoting normalized average pO2 temporal variance is proposed. The results show that for similar mean tumor pO2, a strong inverse correlation between THI and the surviving fraction is observed for each tumor line. THI is highly proportional to the fraction of acute hypoxia and to the RBC flux. The proposed THI corresponds well to the fraction of acute hypoxia.