Nowadays there is a rising interest towards exploiting new therapeutical beams beyond carbon ions and protons. In particular, 16O ions are being widely discussed due to their increased LET ...distribution. In this contribution, we report on the first experimental verification of biologically optimized treatment plans, accounting for different biological effects, generated with the TRiP98 planning system with 16O beams, performed at HIT and GSI. This implies the measurements of 3D profiles of absorbed dose as well as several biological measurements. The latter includes the measurements of relative biological effectiveness along the range of linear energy transfer values from 20 up to 750 keV μm−1, oxygen enhancement ratio values and the verification of the kill-painting approach, to overcome hypoxia, with a phantom imitating an unevenly oxygenated target. With the present implementation, our treatment planning system is able to perform a comparative analysis of different ions, according to any given condition of the target. For the particular cases of low target oxygenation, 16O ions demonstrate a higher peak-to-entrance dose ratio for the same cell killing in the target region compared to 12C ions. Based on this phenomenon, we performed a short computational analysis to reveal the potential range of treatment plans, where 16O can benefit over lighter modalities. It emerges that for more hypoxic target regions (partial oxygen pressure of 0.15% or lower) and relatively low doses ( 4 Gy or lower) the choice of 16O over 12C or 4He may be justified.
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.
Performing realistic and reliable in vitro biological dose verification with good resolution for a complex treatment plan remains a challenge in particle beam therapy. Here, a new 3D bio-phantom ...consisting of 96-well plates containing cells embedded into Matrigel matrix was investigated as an alternative tool for biological dose verification. Feasibility tests include cell growth in the Matrigel as well as film dosimetric experiments that rule out the appearance of field inhomogeneities due to the presence of the well plate irregular structure. The response of CHO-K1 cells in Matrigel to radiation was studied by obtaining survival curves following x-ray and monoenergetic 12C ion irradiation, which showed increased radioresistance of 3D cell cultures in Matrigel as compared to a monolayer. Finally, as a proof of concept, a 12C treatment plan was optimized using in-house treatment planning system TRiP98 for uniform cell survival in a rectangular volume and employed to irradiate the 3D phantom. Cell survival distribution in the Matrigel-based phantom was analyzed and compared to cell survival in a reference setup using cell monolayers. Results of both methods were in good agreement and followed the TRiP98 calculation. Therefore, we conclude that this 3D bio-phantom can be a suitable, accurate alternative tool for verifying the biological effect calculated by treatment planning systems, which could be applied to test novel treatment planning approaches involving multiple fields, multiple ion modalities, complex geometries, or unconventional optimization strategies.
To investigate the influence of chronic hypoxia and anoxia on cell survival after low- and high-LET radiation, CHO-K1 cells were kept for 24 h under chronic hypoxia (94.5% N2; 5% CO2; 0.5% O2) or ...chronic anoxia (95% N2; 5% CO2). Irradiation was performed using 250 kVp X-rays or carbon ions with a dose average LET of 100 keV/ m either directly under the chronic oxygenation states, or at different time points after reoxygenation. Moreover, the cell cycle distribution for cells irradiated under different chronic oxic states was measured over 24 h during reoxygenation. The measurements showed a fairly uniform cell cycle distribution under chronic hypoxia, similar to normoxic conditions. Chronic anoxia induced a block in G1 and a strong reduction of S-phase cells. A distribution similar to normoxic conditions was reached after 12 h of reoxygenation. CHO cells had a similar survival under both acute and chronic hypoxia. In contrast, survival after irradiation under chronic anoxia was slightly reduced compared to that under acute anoxia. We conclude that, in hamster cells, chronic anoxia is less effective than acute anoxia in inducing radioresistance for both X-rays and carbon ions, whereas in hypoxia, acute and chronic exposures have a similar impact on cell killing.
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.
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