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.

Background: Children with brain tumors undergoing radiotherapy are at particular risk of radiationinduced morbidity and are therefore routinely considered for proton therapy (PT) to reduce the dose to healthy tissues. The aim of this study was to apply pediatric constraints and normal tissue complication probability (NTCP) models when evaluating the differences between PT and contemporary photon-based radiotherapy, volumetric modulated arc therapy (VMAT). Methods: Forty patients (aged 1-17 years) referred from Norwegian institutions to cranial PT abroad during 2014-2016 were selected for VMAT re-planning using the original CT sets and target volumes. The VMAT and delivered PT plans were compared by dose/volume metrics and NTCP models related to growth hormone deficiency, auditory toxicity, visual impairment, xerostomia, neurocognitive outcome and secondary brain and parotid gland cancers. Results: The supratentorial brain, temporal lobes, hippocampi, hypothalamus, pituitary glands, cochleas, salivary glands, optic nerves and chiasm received lower mean doses from PT. Reductions in population median NTCP were significant for auditory toxicity (VMAT: 3.8%; PT: 0.3%), neurocognitive outcome (VMAT: 3.0 IQ points decline at 5 years post RT; PT: 2.5 IQ points), xerostomia (VMAT: 2.0%; PT: 0.6%), excess absolute risk of secondary cancer of the brain (VMAT: 9.2%; PT: 6.7%) and salivary glands (VMAT: 2.8%; PT:0.5%). Across all patients, 23/38 PT plans had better or comparable estimated risks for all endpoints (within ±10% of the risk relative to VMAT), whereas for 1/38 patients all estimates were better or comparable with VMAT. Conclusions: PT reduced the volumes of normal tissues exposed to radiation, particularly low-to-intermediate dose levels, and this was reflected in lower NTCP. Of the included endpoints, substantial reductions in population medians were seen from the delivered PT plans for auditory complications, xerostomia, and risk of secondary cancers of the brain and salivary glands.

Enhancing treatment of locally advanced non-small cell lung cancer (LA-NSCLC) by using pencil beam scanning proton therapy (PBS-PT) is attractive, but little knowledge exists on the effects of uncertainties occurring between the planning (Plan) and the start of treatment (Start). In this prospective simulation study, we investigated the clinical potential for PBS-PT under the influence of such uncertainties. Imaging with 4DCT at Plan and Start was carried out for 15 patients that received state-of-the-art intensity-modulated radiotherapy (IMRT). Three PBS-PT plans were created per patient: 3D robust single-field uniform dose (SFUD), 3D robust intensity-modulated proton therapy (IMPT), and 4D robust IMPT (4DIMPT). These were exposed to setup and range uncertainties and breathing motion at Plan, and changes in breathing motion and anatomy at Start. Target coverage and dose-volume parameters relevant for toxicity were compared. The organ at risk sparing at Plan was greatest with IMPT, followed by 4DIMPT, SFUD and IMRT, and persisted at Start. All plans met the preset criteria for target robustness at Plan. At Start, three patients had a lack of CTV coverage with PBS-PT. In conclusion, the clinical potential for heart and lung toxicity reduction with PBS-PT was substantial and persistent. Altered breathing patterns between Plan and Start jeopardized target coverage for all PBS-PT techniques.

IntroductionTumor hypoxia is associated with poor treatment outcome. Hypoxic regions are more radioresistant than well‐oxygenated regions, as quantified by the oxygen enhancement ratio (OER). In optimization of proton therapy, including OER in addition to the relative biological effectiveness (RBE) could therefore be used to adapt to patient‐specific radioresistance governed by intrinsic radiosensitivity and hypoxia.MethodsA combined RBE and OER weighted dose (ROWD) calculation method was implemented in a FLUKA Monte Carlo (MC) based treatment planning tool. The method is based on the linear quadratic model, with α and β parameters as a function of the OER, and therefore a function of the linear energy transfer (LET) and partial oxygen pressure (pO2). Proton therapy plans for two head and neck cancer (HNC) patients were optimized with pO2 estimated from [18F]‐EF5 positron emission tomography (PET) images. For the ROWD calculations, an RBE of 1.1 (RBE1.1,OER) and two variable RBE models, Rørvik (ROR) and McNamara (MCN), were used, alongside a reference plan without incorporation of OER (RBE1.1).ResultsFor the HNC patients, treatment plans in line with the prescription dose and with acceptable target ROWD could be generated with the established tool. The physical dose was the main factor modulated in the ROWD. The impact of incorporating OER during optimization of HNC patients was demonstrated by the substantial difference found between ROWD and physical dose in the hypoxic tumor region. The largest physical dose differences between the ROWD optimized plans and the reference plan was 12.2 Gy.ConclusionThe FLUKA MC based tool was able to optimize proton treatment plans taking the tumor pO2 distribution from hypoxia PET images into account. Independent of RBE‐model, both elevated LET and physical dose were found in the hypoxic regions, which shows the potential to increase the tumor control compared to a conventional optimization approach.

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