TU‐G‐BRA‐03: A Mechanism‐Based Approach to Predict Relative Biological Effectiveness and the Effects of Tumor Hypoxia in Charged Particle Radiotherapy

Abstract

The potential biological advantages of charged particles, such as protons and carbon ions, have not yet been fully exploited in radiation oncology. With increasing particle stopping power, relative biological effectiveness (RBE) increases and the radioprotective effect of tumor hypoxia decreases. In this work, a mechanism‐based approach to quantify the effects of oxygen and radiation quality on double strand break (DSB) induction and cell killing is presented for clinically‐relevant proton and carbon ion beams. DSB yields are quantified as a function of stopping power and oxygen concentration using the Monte Carlo Damage Simulation (MCDS). Formulas derived from the Repair‐Misrepair‐Fixation (RMF) model are presented that link dose‐averaged linear‐quadratic (LQ) parameters to DSB induction and processing. Predicted trends in radiosensitivity parameters with stopping power and oxygen concentration are compared to published experimental data. The dependence of RBE estimates on dose, tissue radiosensitivity, and position within the spread out Bragg peak (SOBP) is shown. RBE‐weighted doses are calculated for representative SOBP and a range of oxygen concentrations. Alternate biological models are also briefly reviewed. The RMF model is shown to predict published survival data well up to an LET of ∼150–200 keV/micron for V79, HSG, and T1 cells irradiated with He‐3, C‐12, and Ne‐20 under normoxic and anoxic conditions. Clinically‐relevant RBE estimates are shown to increase as particle energy, dose, and tissue alpha/beta decrease. For normoxic chordoma tissue with (alpha/beta)x=2 Gy and a 5 cm SOBP with a nominal absorbed dose of 1 Gy, entrance RBE is ∼1.0 and ∼1.3 for proton and carbon ions, respectively. Proton RBE ranges from 1.03 to 1.34 from the proximal to distal edge. Under the same conditions, the RBE for carbon ions ranges from 1.8 to 5.4. For extreme levels of hypoxia, proton and carbon ion doses in the SOBP may need to be increased by factors as high as 2.9 and 1.6, respectively, to achieve a uniform biological effect. The proposed approach to calculate RBE for clinical beams of charged particles is advantageous because it is guided by well‐established physical and biological considerations. The use of biologically motivated models to estimate RBE and hypoxia effects for clinically relevant oxygen concentrations enhances our understanding of the potential for protons and carbon ions to overcome the radioprotective effect of tumor hypoxia. Large variations in predicted RBE across an SOBP may produce undesirable biological hot and cold spots. Biologically optimized treatment plans that correct for radiation quality and tissue oxygenation have the potential to substantially improve treatment outcomes.Learning objectives:1. To review the relationship between DSB induction and cell killing2. To understand the effects of radiation quality and oxygen concentration on cell killing in proton and carbon ion radiotherapy