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.

Purpose: Modern facilities for actively scanned ion beam radiotherapy allow in principle the use of helium beams, which could present specific advantages, especially for pediatric tumors. In order to assess the potential use of these beams for radiotherapy, i.e., to create realistic treatment plans, the authors set up a dedicated ⁴He beam model, providing base data for their treatment planning system TRiP98, and they have reported that in this work together with its physical and biological validations.Methods: A semiempirical beam model for the physical depth dose deposition and the production of nuclear fragments was developed and introduced in TRiP98. For the biological effect calculations the last version of the local effect model was used. The model predictions were experimentally verified at the HIT facility. The primary beam attenuation and the characteristics of secondary charged particles at various depth in water were investigated using ⁴He ion beams of 200 MeV/u. The nuclear charge of secondary fragments was identified using a ΔE/E telescope. 3D absorbed dose distributions were measured with pin point ionization chambers and the biological dosimetry experiments were realized irradiating a Chinese hamster ovary cells stack arranged in an extended target.Results: The few experimental data available on basic physical processes are reproduced by their beam model. The experimental verification of absorbed dose distributions in extended target volumes yields an overall agreement, with a slight underestimation of the lateral spread. Cell survival along a 4 cm extended target is reproduced with remarkable accuracy.Conclusions: The authors presented a simple simulation model for therapeutical ⁴He beams which they introduced in TRiP98, and which is validated experimentally by means of physical and biological dosimetries. Thus, it is now possible to perform detailed treatment planning studies with ⁴He beams, either exclusively or in combination with other ion modalities.

We present a method for adapting a biologically optimized treatment planning for particle beams to a spatially inhomogeneous tumor sensitivity due to hypoxia, and detected e.g., by PET functional imaging. The TRiP98 code, established treatment planning system for particles, has been extended for including explicitly the oxygen enhancement ratio (OER) in the biological effect calculation, providing the first set up of a dedicated ion beam treatment planning approach directed to hypoxic tumors, TRiP-OER, here reported together with experimental tests. A simple semi-empirical model for calculating the OER as a function of oxygen concentration and dose averaged linear energy transfer, generating input tables for the program is introduced. The code is then extended in order to import such tables coming from the present or alternative models, accordingly and to perform forward and inverse planning, i.e., predicting the survival response of differently oxygenated areas as well as optimizing the required dose for restoring a uniform survival effect in the whole irradiated target. The multiple field optimization results show how the program selects the best beam components for treating the hypoxic regions. The calculations performed for different ions, provide indications for the possible clinical advantages of a multi-ion treatment. Finally the predictivity of the code is tested through dedicated cell culture experiments on extended targets irradiation using specially designed hypoxic chambers, providing a qualitative agreement, despite some limits in full survival calculations arising from the RBE assessment. The comparison of the predictions resulting by using different model tables are also reported.

Largely unnoticed, all life on earth is constantly exposed to low levels of ionizing radiation. Radon, an imperceptible natural occurring radioactive noble gas, contributes as the largest single fraction to radiation exposure from natural sources. For that reason, radon represents a major issue for radiation protection. Nevertheless, radon is also applied for the therapy of inflammatory and degenerative diseases in galleries and spas to many thousand patients a year. In either case, chronic environmental exposure or therapy, the effect of radon on the organism exposed is still under investigation at all levels of interaction. This includes the physical stage of diffusion and energy deposition by radioactive decay of radon and its progeny and the biological stage of initiating and propagating a physiologic response or inducing cancer after chronic exposure. The purpose of this manuscript is to comprehensively review the current knowledge of radon and its progeny on physical background, associated cancer risk and potential therapeutic effects.

The pain-relieving effects of low-dose radon therapies on patients suffering from chronic painful inflammatory diseases have been described for centuries. Even though it has been suggested that low doses of radiation may attenuate chronic inflammation, the underlying mechanisms remain elusive. Thus, the RAD-ON01 study was initiated to examine the effects of radon spa therapy and its low doses of alpha radiation on the human immune system. In addition to an evaluation of pain parameters, blood was drawn from 100 patients suffering from chronic painful degenerative musculoskeletal diseases before as well as 6, 12, 18, and 30 weeks after the start of therapy. We verified significant long-term pain reduction for the majority of patients which was accompanied by modulations of the peripheral immune cells. Detailed immune monitoring was performed using a multicolor flow cytometry-based whole blood assay. After therapy, the major immune cells were only marginally affected. Nevertheless, a small but long-lasting increase in T cells and monocytes was observed. Moreover, neutrophils, eosinophils and, in particular, dendritic cells were temporarily modulated after therapy. Regarding the immune cell subsets, cytotoxic T and NK cells, in particular, were altered. However, the most prominent effects were identified in a strong reduction of the activation marker CD69 on T, B, and NK cells. Simultaneously, the percentage of HLA-DR⁺ T cells was elevated after therapy. The RAD-ON01 study showed for the first time a modulation of the peripheral immune cells following standard radon spa therapy. These modulations are in line with attenuation of inflammation.

To measure the effect of acute oxygen depletion on cell survival for different types of radiation, experiments have been performed using Chinese hamster ovary (CHO) cells and RAT-1 rat prostate cancer cells. A special chamber has been developed to perform irradiations under different levels of oxygenation. The oxygen concentrations used were normoxia (air), hypoxia (94.5% N₂, 5% CO₂, 0.5% O₂) and anoxia (95% N₂, 5% CO₂). Cells were exposed to X-rays and to C-, N- or O-ions with linear energy transfer (LET) values ranging from 100–160 keV/µm. The oxygen enhancement ratio (OER) and relative biological effectiveness (RBE) values have been calculated from the measured clonogenic survival curves. For both cell lines, the X-ray OER depended on the survival level. For particle irradiation, OER was not dependent on the survival level but decreased with increasing LET. The RBE of CHO cells under oxic conditions reached a plateau for LET values above 100 keV/µm, while it was still increasing under anoxia. In conclusion, the results demonstrated that our chamber could be used to measure radiosensitivity under intermediate hypoxia. Measurements suggest that ions heavier than carbon could be of additional advantage in the irradiation, especially of radioresistant hypoxic tumor regions.