Chondrosarcomas are particularly difficult to treat due to their resistance to chemotherapy and radiotherapy. However, particle therapy can enhance local control and patient survival rates. To improve our understanding of the basic cellular radiation response, as a function of dose and linear energy transfer (LET), we developed a novel water phantom-based setup for cell culture experiments and characterized it dosimetrically. In a direct comparison, human chondrosarcoma cell lines were analyzed with regard to their viability, cell proliferation, cell cycle, and DNA repair behavior after irradiation with X-ray, proton, and carbon ions. Our results clearly showed that cell viability and proliferation were inhibited according to the increasing ionization density, i.e., LET, of the irradiation modes. Furthermore, a prominent G₂/M arrest was shown. Gene expression profiling proved the upregulation of the senescence genes CDKN1A (p21), CDKN2A (p16NK4a), BMI1, and FOXO4 after particle irradiation. Both proton or C-ion irradiation caused a positive regulation of the repair genes ATM, NBN, ATXR, and XPC, and a highly significant increase in XRCC1/2/3, ERCC1, XPC, and PCNA expression, with C-ions appearing to activate DNA repair mechanisms more effectively. The link between the physical data and the cellular responses is an important contribution to the improvement of the treatment system.

Purpose: The accurate knowledge of the effective point of measurement (P_eff) is particularly important for measurements in proximity to high dose gradients such as in the distal fall‐off of particle beams. For plane‐parallel ionization chambers (ICs), P_eff is well known and located at the center of the inner surface of the entrance window. For cylindrical ICs, P_eff is shifted from the chamber's center toward the beam source. According to IAEA TRS‐398, this shift can be calculated as 0.75·r_cyl for light ions with r_cyl being the radius of the cavity. For proton beams and in absence of a dose gradient, no shift is recommended. We have experimentally determined P_eff for the 0.125 cc Semiflex IC in both proton and carbon ion beams.Methods: The first method consisted of simultaneous irradiation of a plane‐parallel IC and the Semiflex in a 4‐cm wide spread‐out Bragg peak. In the second method, a single‐energy beam was used, and both ICs were positioned successively at the same measurement depths. For both approaches, the shift of the distal edge of the depth ionization distributions recorded by the two chambers at different reference points was used to calculate P_eff of the Semiflex. Both methods were applied in carbon ion beams, and only the latter was applied in proton beams.Results: Both methods yielded a similar P_eff for carbon ions, 0.88·r_cyl, and 0.84·r_cyl, which results in a difference of only 0.1 mm. The difference to the recommended value of 0.75·r_cyl is 0.4 and 0.3 mm, respectively, which is larger than the positioning uncertainty. In the proton beam, a P_eff of 0.92·r_cyl was obtained.Conclusions: The P_eff for the 0.125 cc Semiflex IC is shifted further from the cavity center as recommended by IAEA TRS‐398 for light ions, with the shift for proton beams being even larger than for carbon ion beams.

Microdosimetry is increasingly adopted in the characterization of proton and carbon ion beams used in cancer therapy. Spectra and mean values of lineal energy calculated in frequency and dose are seen by many as the tools which, by complementing dosimetric measurements, allow for the most complete characterization of the therapeutic radiation fields. The urgency is now to consolidate the experience and converge to commonly accepted methodologies. In this context, the purpose of this work is to study the effects of the energy-loss straggling and the delta-ray escape, considering slab-sensitive volumes; these are, in fact, the typical shapes of solid-state microdosimeters, which are widely used in investigating light ion therapy beams. The method considers the energy distribution of delta rays resulting from the collision of the impinging ion and, taking into account the escape, convolutes it with itself as many times as the expected number of collisions in the sensitive volume thickness. The resulting distribution is compared to the experimental microdosimetric spectrum showing a substantially good agreement. The extension of the methodology to a wider range of ion energy and detector characteristics is instrumental for a detector-independent microdosimetric assessment of the radiation fields.

Particle therapy using pencil beam scanning (PBS) faces large uncertain- ties related to ranges and target motion. One possibility to improve existing mitigation strategies is a 2D range modulator (2DRM). A 2DRM offers faster irradiation times by reducing the number of layers and spots needed to create a spread-out Bragg peak. We have investigated the impact of 2DRM on microdosimetric spectra measured in proton and carbon ion beams. Two 2DRMs were designed and 3D printed, one for. 124.7 MeV protons and one for 238.6 MeV/u carbon ions. Their dosimetric validation was performed using Roos and PinPoint ionization chamber and EBT3 films. Monte Carlo simulations were done using GATE. A silicon-based solid-state microdosimeter was used to collect pulse-height spectra along three depths for two irradiation modalities, PBS and a single central beam. For both particle types, the original pin design had to be optimized via GATE simulations. The difference between the R80 of the simulated and measured depth dose curve was 0.1 mm. The microdosimetric spectra collected with the two irradiation modalities overlap well. Their mean lineal energy values differ over all positions by 5.2 % for the proton 2DRM and 2.1 % for the carbon ion 2DRM. Radiation quality in terms of lineal energy was independent of the irradiation method. This supports the current approach in reference dosimetry, where the residual range is chosen as a beam quality index to select stopping power ratios.

A first benchmark of the Monte Carlo (MC) code GATE was performed for microdosimetry in carbon ion beams. A validated MC model can, in turn, be used to calculate the radiation quality in lineal energy for any number of energies or treatment plans. Measurements were performed at five depths along a carbon ion pencil beam with a nominal energy of 284.7 MeV/u, with additional offside central axis (off-CAX) measurements at four depths. The silicon-on-insulator detector used was modeled with a simplified sensitive volume geometry in the Monte Carlo (MC) toolkit GATE. The source code of GATE was modified to allow the scoring of lineal energy for slab sensitive volumes. On average, the difference between the measured and simulated spectra (assuming the same keVµm^-1 cut-off value) was 15 % and 13 % for the frequency-mean and dose-mean lineal energy, respectively. By applying a shift in depth of 500µm towards the beam nozzle, the differences decreased to 10 % and 5 %, mostly affecting the positions in and the fall-off after the Bragg peak. The position in the fragmentation tail showed an edge at a different position than the expected carbon ion edge, which was determined through theoretical (stopping power tables) as well as computational (MC) means to be caused by boron ions. MC is a powerful tool for any potential future clinical application of microdosimetry, provided the beam model has been benchmarked with experimental data. The detector geometry can be approximated with its sensitive volume if the water equivalent thickness of the detector is well known.

In order to overcome the resistance to radiotherapy in human chondrosarcoma cells, the prevention from efficient DNA repair with a combined treatment with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) inhibitor AZD7648 was explored for carbon ion (C-ion) as well as reference photon (X-ray) irradiation (IR) using gene expression analysis, flow cytometry, protein phosphorylation, and telomere length shortening. Proliferation markers and cell cycle distribution changed significantly after combined treatment, revealing a prominent G₂/M arrest. The expression of the G₂/M checkpoint genes cyclin B, CDK1, and WEE1 was significantly reduced by IR alone and the combined treatment. While IR alone showed no effects, additional AZD7648 treatment resulted in a dose-dependent reduction in AKT phosphorylation and an increase in Chk2 phosphorylation. Twenty-four hours after IR, the key genes of DNA repair mechanisms were reduced by the combined treatment, which led to impaired DNA repair and increased radiosensitivity. A time-dependent shortening of telomere length was observed in both cell lines after combined treatment with AZD7648 and 8 Gy X-ray/C-ion IR. Our data suggest that the inhibition of DNA-PKcs may increase sensitivity to X-rays and C-ion IR by impairing its functional role in DNA repair mechanisms and telomere end protection.