Dosimetric and biologic intercomparison between electron and proton FLASH beams.

BACKGROUND AND PURPOSE: The FLASH effect has been validated in different preclinical experiments with electrons (eFLASH) and protons (pFLASH) operating at an average dose rate above 40 Gy/s. However, no systematic intercomparison of the FLASH effect produced by eFLASHvs. pFLASH has yet been performed and constitutes the aim of the present study. MATERIALS AND METHODS: The electron eRT6/Oriatron/CHUV/5.5 MeV and proton Gantry1/PSI/170 MeV were used to deliver conventional (0.1 Gy/s eCONV and pCONV) and FLASH (≥110 Gy/s eFLASH and pFLASH) dose rates. Protons were delivered in transmission. Dosimetric and biologic intercomparisons were performed using previously validated dosimetric approaches and experimental murine models. RESULTS: The difference between the average absorbed dose measured at Gantry 1 with PSI reference dosimeters and with CHUV/IRA dosimeters was -1.9 % (0.1 Gy/s) and + 2.5 % (110 Gy/s). The neurocognitive capacity of eFLASH and pFLASH irradiated mice was indistinguishable from the control, while both eCONV and pCONV irradiated cohorts showed cognitive decrements. Complete tumor response was obtained after an ablative dose of 20 Gy delivered with the two beams at CONV and FLASH dose rates. Tumor rejection upon rechallenge indicates that anti-tumor immunity was activated independently of the beam-type and the dose-rate. CONCLUSION: Despite major differences in the temporal microstructure of proton and electron beams, this study shows that dosimetric standards can be established. Normal brain protection and tumor control were produced by the two beams. More specifically, normal brain protection was achieved when a single dose of 10 Gy was delivered in 90 ms or less, suggesting that the most important physical parameter driving the FLASH sparing effect might be the mean dose rate. In addition, a systemic anti-tumor immunological memory response was observed in mice exposed to high ablative dose of electron and proton delivered at CONV and FLASH dose rate.

Dosimetric and biologic intercomparison between electron and proton FLASH beams.

Background and purpose: The FLASH effect has been validated in different preclinical experiments with electrons (eFLASH) and protons (pFLASH) operating at a mean dose rate above 40 Gy/s. However, no systematic intercomparison of the FLASH effect produced by e vs. pFLASH has yet been performed and constitutes the aim of the present study. Materials and methods: The electron eRT6/Oriatron/CHUV/5.5 MeV and proton Gantry1/PSI/170 MeV were used to deliver conventional (0.1 Gy/s eCONV and pCONV) and FLASH (≥100 Gy/s eFLASH and pFLASH) irradiation. Protons were delivered in transmission. Dosimetric and biologic intercomparisons were performed with previously validated models. Results: Doses measured at Gantry1 were in agreement (± 2.5%) with reference dosimeters calibrated at CHUV/IRA. The neurocognitive capacity of e and pFLASH irradiated mice was indistinguishable from the control while both e and pCONV irradiated cohorts showed cognitive decrements. Complete tumor response was obtained with the two beams and was similar between e and pFLASH vs. e and pCONV. Tumor rejection was similar indicating that T-cell memory response is beam-type and dose-rate independent. Conclusion: Despite major differences in the temporal microstructure, this study shows that dosimetric standards can be established. The sparing of brain function and tumor control produced by the two beams were similar, suggesting that the most important physical parameter driving the FLASH effect is the overall time of exposure which should be in the range of hundreds of milliseconds for WBI in mice. In addition, we observed that immunological memory response is similar between electron and proton beams and is independent off the dose rate.

Experimental validation of an analytical microdosimetric model based on Geant4-DNA simulations by using a silicon-based microdosimeter.

PURPOSE: To study the agreement between proton microdosimetric distributions measured with a silicon-based cylindrical microdosimeter and a previously published analytical microdosimetric model based on Geant4-DNA in-water Monte Carlo simulations for low energy proton beams. METHODS AND MATERIAL: Distributions for lineal energy (y) are measured for four proton monoenergetic beams with nominal energies from 2.0 MeV to 4.5 MeV, with a tissue equivalent proportional counter (TEPC) and a silicon-based microdosimeter. The actual energy for protons traversing the silicon-based microdosimeter is simulated with SRIM. Monoenergetic beams with these energies are simulated with Geant4-DNA code by simulating a water cylinder site of dimensions equal to those of the microdosimeter. The microdosimeter response is calibrated by using the distribution peaks obtained from the TEPC. Analytical calculations for y ¯ F and y ¯ D using our methodology based on spherical sites are also performed choosing the equivalent sphere to be checked against experimental results. RESULTS: Distributions for y at silicon are converted into tissue equivalent and compared to the Geant4-DNA simulated, yielding maximum deviations of 1.03% for y ¯ F and 1.17% for y ¯ D . Our analytical method generates maximum deviations of 1.29% and 3.33%, respectively, with respect to experimental results. CONCLUSION: Simulations in Geant4-DNA with ideal cylindrical sites in liquid water produce similar results to the measurements in an actual silicon-based cylindrical microdosimeter properly calibrated. The found agreement suggests the possibility to experimentally verify the calculated clinical y ¯ D with our analytical method.

Proton Irradiation Platforms for Preclinical Studies of High-Dose-Rate (FLASH) Effects at RARAF.

Limited availability of proton irradiators optimized for high-dose-rate studies makes the preclinical research of proton FLASH therapy challenging. We assembled two proton irradiation platforms that are capable of delivering therapeutic doses to thin biological samples at dose rates equal to and above 100 Gy/s. We optimized and tested dosimetry protocols to assure accurate dose delivery regardless of the instantaneous dose rate. The simplicity of the experimental setups and availability of custom-designed sample holders allows these irradiation platforms to be easily adjusted to accommodate different types of samples, including cell monolayers, 3D tissue models and small animals. We have also fabricated a microfluidic flow-through device for irradiations of biological samples in suspension. We present one example of a measurement with accompanying preliminary results for each of the irradiation platforms. One irradiator was used to study the role of proton dose rate on cell survival for three cancer cell lines, while the other was used to investigate the depletion of oxygen from an aqueous solution by water radiolysis using short intense proton pulses. No dose-rate-dependent variation was observed between the survival fractions of cancer cells irradiated at dose rates of 0.1, 10 and 100 Gy/s up to 10 Gy. On the other hand, irradiations of Fricke solution at 1,000 Gy/s indicated full depletion of oxygen after proton doses of 107 Gy and 56 Gy for samples equilibrated with 21% and 4% oxygen, respectively.

LET dependent response of GafChromic films investigated with MeV ion beams.

The change in optical properties of GafChromic films depends not only on the absorbed dose, but also on the linear energy transfer (LET) of the ionizing radiation. The influence of LET on the film dose-response relationship is especially important when films are applied for dosimetry of energetic charged particles. In the present study, we examined the response of the unlaminated EBT3 and MD-V3 films to proton, deuterium and helium beams with energies in the range of several megaelectronvolts (MeV). Films were exposed to doses up to 200 Gy and a model based on the bimolecular chemical reaction was chosen to fit the measured film signals. The LET in the active layers of the films and the dose correction factors were computed with Monte Carlo software TRIM. Signal quenching, observed for all ion beams in comparison to x-rays, was investigated as a function of the LET in the range of 10-100 keV µm-1. The response of the films got weaker with increasing the LET and showed no dependence on the ion species. The LET effect was quantified by introducing a modified expression for the relative effectiveness (RE) by which a unique RE value is assigned to a single LET. The RE defined in that way decreased from about 90% for LET of 10 keV µm-1 to less than 50% for LET of 100 keV µm-1. Similar behavior was observed for EBT3 and MD-V3 film models.