FLASH (ultra-high dose rate) radiotherapy spares normal tissue while keeping tumor control. However, the mechanism of the FLASH effect remains unclear and may have consequences beyond the irradiate...

Purpose. Recent studies suggest ultra-high dose rate (FLASH) irradiation can spare normal tissues from radiotoxicity, while efficiently controlling the tumor, and this is known as the ‘FLASH effect’. This study performed theoretical analyses about the impact of radiolytic oxygen depletion (ROD) on the cellular responses after FLASH irradiation. Methods. Monte Carlo simulation was used to model the ROD process, determine the DNA damage, and calculate the amount of oxygen depleted ( L _ROD ) during FLASH exposure. A mathematical model was applied to analyze oxygen tension (pO ₂ ) distribution in human tissues and the recovery of pO ₂ after FLASH irradiation. DNA damage and cell survival fractions (SFs) after FLASH irradiation were calculated. The impact of initial cellular pO ₂ , FLASH pulse number, pulse interval, and radiation quality of the source particles on ROD and subsequent cellular responses were systematically evaluated. Results. The simulated electron L _ROD range was 0.38–0.43 μ M Gy ⁻¹ when pO ₂ ranged from 7.5 to 160 mmHg. The calculated DNA damage and SFs show that the radioprotective effect is only evident in cells with a low pO ₂ . Different irradiation setups alter the cellular responses by modifying the pO ₂ . Single pulse delivery or multi-pulse delivery with pulse intervals shorter than 10–50 ms resulted in fewer DNA damages and higher SFs. Source particles with a low linear energy transfer (LET) have a higher capacity to deplete oxygen, and thus, lead to a more conspicuous radioprotective effect. Conclusions . A systematic analysis of the cellular response following FLASH irradiation was performed to provided suggestions for future FLASH applications. The FLASH radioprotective effect due to ROD may only be observed in cells with a low pO ₂ . Single pulse delivery or multi-pulse delivery with short pulse intervals are suggested for FLASH irradiation to avoid oxygen tension recovery during pulse intervals. Source particles with low LET are preferred for their conspicuous radioprotective effects.

In the heavy ion therapy, not only the distribution of physical absorbed dose, but also the relative biological effectiveness (RBE) weighted dose needs to be taken into account. The microdosimetric kinetic model (MKM) can predict the RBE value of heavy ions with saturation-corrected dose-mean specific energy, which has been used in clinical treatment planning at the National Institute of Radiological Sciences. In the theoretical assumption of the MKM, the yield of the primary lesion is independent of the radiation quality, while the experimental data shows that DNA double strand break (DSB) yield, considered as the main primary lesion, depends on the LET of the particle. Besides, the β parameter of the MKM is constant with LET resulting from this assumption, which also differs from the experimental conclusion. In this study, a modified MKM was developed, named MMKM. Based on the experimental DSB yield of mammalian cells under the irradiation of ions with different LETs, a RBE _DSB (RBE for the induction of DSB)-LET curve was fitted as the correction factor to modify the primary lesion yield in the MKM, and the variation of the primary lesion yield with LET is considered in the MMKM. Compared with the present the MKM, not only the α parameter of the MMKM for mono-energetic ions agree with the experimental data, but also the β parameter varies with LET and the variation trend of the experimental result can be reproduced on the whole. Then a spread-out Bragg peaks (SOBP) distribution of physical dose was simulated with Geant4 Monte Carlo code, and the biological and clinical dose distributions were calculated, under the irradiation of carbon ions. The results show that the distribution of clinical dose calculated with the MMKM is closed to the distribution with the MKM in the SOBP, while the discrepancy before and after the SOBP are both within 10%. Moreover, the MKM might overestimate the clinical dose at the distal end of the SOBP more than 5% because of its constant β value, while a minimal value of β is calculated with the MMKM at this position. Besides, the discrepancy of the averaged cell survival fraction in the SOBP calculated with the two models is more than 15% at the high dose level. The MMKM may provide a reference for the accurate calculation of the RBE value in heavy ion therapy.

In vivo measurement is a main method of internal contamination evaluation, particularly for large numbers of people after a nuclear accident. Before the practical application, it is necessary to obtain the counting efficiency of the detector by calibration. The virtual calibration based on Monte Carlo simulation usually uses the reference human computational phantom, and the morphological difference between the monitored personnel with the calibrated phantom may lead to the deviation of the counting efficiency. Therefore, a phantom library containing a wide range of heights and total body masses is needed. In this study, a Chinese reference adult male polygon surface (CRAM_S) phantom was constructed based on the CRAM voxel phantom, with the organ models adjusted to match the Chinese reference data. CRAM_S phantom was then transformed to sitting posture for convenience in practical monitoring. Referring to the mass and height distribution of the Chinese adult male, a phantom library containing 84 phantoms was constructed by deforming the reference surface phantom. Phantoms in the library have 7 different heights ranging from 155 cm to 185 cm, and there are 12 phantoms with different total body masses in each height. As an example of application, organ specific and total counting efficiencies of Ba-133 were calculated using the MCNPX code, with two series of phantoms selected from the library. The influence of morphological variation on the counting efficiency was analyzed. The results show only using the reference phantom in virtual calibration may lead to an error of 68.9% for total counting efficiency. Thus the influence of morphological difference on virtual calibration can be greatly reduced using the phantom library with a wide range of masses and heights instead of a single reference phantom.

High-Z gold nanoparticles (AuNPs) conjugated to a targeting antibody can help to improve tumor control in radiotherapy while simultaneously minimizing radiotoxicity to adjacent healthy tissue. This paper summarizes the main findings of a joint research program which applied AuNP-conjugates in preclinical modeling of radiotherapy at the Klinikum rechts der Isar, Technical University of Munich and Helmholtz Zentrum München. A pharmacokinetic model of superparamagnetic iron oxide nanoparticles was developed in preparation for a model simulating the uptake and distribution of AuNPs in mice. Multi-scale Monte Carlo simulations were performed on a single AuNP and multiple AuNPs in tumor cells at cellular and molecular levels to determine enhancements in the radiation dose and generation of chemical radicals in close proximity to AuNPs. A biologically based mathematical model was developed to predict the biological response of AuNPs in radiation enhancement. Although simulations of a single AuNP demonstrated a clear dose enhancement, simulations relating to the generation of chemical radicals and the induction of DNA strand breaks induced by multiple AuNPs showed only a minor dose enhancement. The differences in the simulated enhancements at molecular and cellular levels indicate that further investigations are necessary to better understand the impact of the physical, chemical, and biological parameters in preclinical experimental settings prior to a translation of these AuNPs models into targeted cancer radiotherapy.