The increased radioresistance of hypoxic cells compared to well-oxygenated cells is quantified by the oxygen enhancement ratio (OER). In this study we created a FLUKA Monte Carlo based tool for inclusion of both OER and relative biological effectiveness (RBE) in biologically weighted dose (ROWD) calculations in proton therapy and applied this to explore the impact of hypoxia. Methods: The RBE-weighted dose was adapted for hypoxia by making RBE model parameters dependent on the OER, in addition to the linear energy transfer (LET). The OER depends on the partial oxygen pressure (pO 2 ) and LET. To demonstrate model performance, calculations were done with spread-out Bragg peaks (SOBP) in water phantoms with pO 2 ranging from strongly hypoxic to normoxic (0.01-30 mmHg) and with a head and neck cancer proton plan optimized with an RBE of 1.1 and pO 2 estimated voxel-by-voxel using [ 18 F]-EF5 PET. An RBE of 1.1 and the Rørvik RBE model were used for the ROWD calculations. Results: The SOBP in water had decreasing ROWD with decreasing pO 2 . In the plans accounting for oxygenation, the median target doses were approximately a factor 1.1 lower than the corresponding plans which did not consider the OER. Hypoxia adapted target ROWDs were considerably more heterogeneous than the RBE 1.1weighted doses. Conclusion:We realized a Monte Carlo based tool for calculating the ROWD. Read-in of patient pO 2 and estimation of ROWD with flexibility in choice of RBE model was achieved, giving a tool that may be useful in future clinical applications of hypoxia-guided particle therapy.

PurposeHypoxia contributes to radiotherapy resistance and more aggressive behaviour of several types of cancer. This study was designed to evaluate the repeatability of intratumour uptake of the hypoxia tracer [18F]EF5 in paired PET/CT scans.MethodsTen patients with newly diagnosed head and neck cancer (HNC) received three static PET/CT scans before chemoradiotherapy: two with [18F]EF5 a median of 7 days apart and one with [18F]FDG. Metabolically active primary tumour volumes were defined in [18F]FDG images and transferred to co-registered [18F]EF5 images for repeatability analysis. A tumour-to-muscle uptake ratio (TMR) of 1.5 at 3 h from injection of [18F]EF5 was used as a threshold representing hypoxic tissue.ResultsIn 10 paired [18F]EF5 PET/CT image sets, SUVmean, SUVmax, and TMR showed a good correlation with the intraclass correlation coefficients of 0.81, 0.85, and 0.87, respectively. The relative coefficients of repeatability for these parameters were 15%, 17%, and 10%, respectively. Fractional hypoxic volumes of the tumours in the repeated scans had a high correlation using the Spearman rank correlation test (r = 0.94). In a voxel-by-voxel TMR analysis between the repeated scans, the mean of Pearson correlation coefficients of individual patients was 0.65. The mean (± SD) difference of TMR in the pooled data set was 0.03 ± 0.20.ConclusionPretreatment [18F]EF5 PET/CT within one week shows high repeatability and is feasible for the guiding of hypoxia-targeted treatment interventions in HNC.