Abstract
Solid tumours often present regions with severe oxygen deprivation (hypoxia), which are resistant to both chemotherapy and radiotherapy. Increased radiosensitivity as a function of the oxygen concentration is well described for X-rays. It has also been demonstrated that radioresistance in anoxia is reduced using high-LET radiation rather than conventional X-rays. However, the dependence of the oxygen enhancement ratio (OER) on radiation quality in the regions of intermediate oxygen concentrations, those normally found in tumours, had never been measured and biophysical models were based on extrapolations. Here we present a complete survival dataset of mammalian cells exposed to different ions in oxygen concentration ranging from normoxia (21%) to anoxia (0%). The data were used to generate a model of the dependence of the OER on oxygen concentration and particle energy. The model was implemented in the ion beam treatment planning system to prescribe uniform cell killing across volumes with heterogeneous radiosensitivity. The adaptive treatment plans have been validated in two different accelerator facilities, using a biological phantom where cells can be irradiated simultaneously at three different oxygen concentrations. We thus realized a hypoxia-adapted treatment plan, which will be used for painting by voxel of hypoxic tumours visualized by functional imaging.
Highlights
Solid tumours often present regions with severe oxygen deprivation, which are resistant to both chemotherapy and radiotherapy
It is a negative prognostic and predictive factor owing to its multiple contributions to resistance to cell death, angiogenesis, vasculogenesis, invasiveness, metastasis, altered metabolism and genomic instability[2]
The increase of radioresistance is quantified by the oxygen enhancement ratio (OER), i.e., the ratio of iso-effective doses in hypoxic and fully oxygenated conditions: OER
Summary
Solid tumours often present regions with severe oxygen deprivation (hypoxia), which are resistant to both chemotherapy and radiotherapy. Hypoxia is a feature of most tumours, albeit with variable incidence and severity within a given patient population[1] It is a negative prognostic and predictive factor owing to its multiple contributions to resistance to cell death (chemoresistance, radioresistance), angiogenesis, vasculogenesis, invasiveness, metastasis, altered metabolism and genomic instability[2]. Charged particle therapy is a cutting-edge radiotherapy technique which, among several physical and radiobiological peculiar advantages[4,5], has the potential of a reduced OER. This is due to the special features of this type of radiation, characterized by a high linear energy transfer
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