FLASH Effect Is Not Always Induced by Ultra-high Dose-rate Proton Irradiation Under Hypoxic Conditions.

BACKGROUND/AIM: Pre-clinical studies have shown that irradiation with electrons at an ultra-high dose-rate (FLASH) spares normal tissue while maintaining tumor control. However, most in vitro experiments with protons have been conducted using a non-clinical irradiation system in normoxia alone. This study evaluated the biological response of non-tumor and tumor cells at different oxygen concentrations irradiated with ultra-high dose-rate protons using a clinical system and compared it with the conventional dose rate (CONV). MATERIALS AND METHODS: Non-tumor cells (V79) and tumor cells (U-251 and A549) were irradiated with 230 MeV protons at a dose rate of >50 Gy/s or 0.1 Gy/s under normoxic or hypoxic (<2%) conditions. The surviving fraction was analyzed using a clonogenic cell survival assay. RESULTS: No significant difference in the survival of non-tumor or tumor cells irradiated with FLASH was observed under normoxia or hypoxia compared to the CONV. CONCLUSION: Proton irradiation at a dose rate above 40 Gy/s, the FLASH dose rate, did not induce a sparing effect on either non-tumor or tumor cells under the conditions examined. Further studies are required on the influence of various factors on cell survival after FLASH irradiation.

Dose Rate Effects on Hydrated Electrons, Hydrogen Peroxide, and a OH Radical Molecular Probe Under Clinical Energy Protons.

We report the dose rate dependence of radiation chemical yields (G value) of water radiolysis products under clinical energy protons (230 MeV) to understand mechanisms of the FLASH radiotherapy performed at ultra-high dose rate (>40 Gy/s). The G value of 7-hydoroxy-coumarin-3-carboxylic acid (7OH-C3CA) produced by reactions of coumarin-3-carboxylic acid (C3CA) with OH radicals and oxygen is evaluated by fluorescence method. Also, those of hydrated electrons and hydrogen peroxide are derived by absorption method using Saltzman and Ghomley techniques, respectively. Both G values of 7OH-C3CA and hydrated electrons decrease with increasing dose rate. The relative evolution of 7OH-C3CA is -39 ± 2% between 0.1 and 50 Gy/s. This value is higher than that of hydrated electrons, measured at -21 ± 4%. The G value of hydrogen peroxide in ultra-pure water also decreases with increasing dose rate. In comparison to these findings, we represent the increase of the G value of hydrogen peroxide with increasing dose rate in the mixture solution of MeOH and NaNO3, which act as scavengers of OH radicals and hydrated electrons, respectively, that decompose hydrogen peroxide. This finding indicates that a complex track structure can be expected with increasing dose rate and the reduction of OH radicals by forming hydrogen peroxide would be related to the sparing effect of healthy tissues.

FLASH dose rate calculation based on log files in proton pencil beam scanning therapy.

BACKGROUND: In radiation therapy, irradiating healthy normal tissues in the beam trajectories is inevitable. This unnecessary dose means that patients undergoing treatment risk developing side effects. Recently, FLASH radiotherapy delivering ultra-high-dose-rate beams has been re-examined because of its normal-tissue-sparing effect. To confirm the mean and instantaneous dose rates of the FLASH beam, stable and accurate dosimetry is required. PURPOSE: Detailed verification of the FLASH effect requires dosimeters and a method to measure the average and instantaneous dose rate stably for 2- or 3-dimensional dose distributions. To verify the delivered FLASH beam, we utilized machine log files from the built-in monitor chamber to develop a dosimetry method to calculate the dose and average/instantaneous dose rate distributions in two or three dimensions in a phantom. METHODS: To create a spread-out Bragg peak (SOBP) and deliver a uniform dose in a target, a mini-ridge filter was created with a 3D printer. Proton pencil beam line scanning plans of 2 × 2 cm2 , 3 × 3 cm2 , 4 × 4 cm2 , and round shapes with 2.3 cm diameter patterns delivering 230 MeV energy protons were created. The absorbed dose in the solid water phantom of each plan was measured using a PPC05 ionization chamber (IBA Dosimetry, Virginia, USA) in the SOBP region, and the log files for each plan were exported from the treatment control system console. Using these log files, the delivered dose and average dose rate were calculated using two methods: a direct method and a Monte Carlo (MC) simulation method that uses log file information. The computed and average dose rates were compared with the ionization chamber measurements. Additionally, instantaneous dose rates in user-defined volumes were calculated using the MC simulation method with a temporal resolution of 5 ms. RESULTS: Compared to ionization chamber dosimetry, 10 of 12 cases using the direct calculation method and 9 of 11 cases using the MC method had a dose difference below ±3%. Nine of 12 cases using the direct calculation method and 8 of 11 cases using the MC method had dose rate differences below ±3%. The average and maximum dose differences for the direct calculation and MC method were-0.17, +0.72%, and -3.15, +3.32%, respectively. For the dose rate difference, the average and maximum for the direct calculation and MC method were +1.26, +1.12%, and +3.75, +3.15%, respectively. In the instantaneous dose rate calculation with the MC simulation, a large fluctuation with a maximum of 163 Gy/s and a minimum of 4.29 Gy/s instantaneous dose rate was observed in a specific position, whereas the mean dose rate was 62 Gy/s. CONCLUSIONS: We successfully developed methods in which machine log files are used to calculate the dose and the average and instantaneous dose rates for FLASH radiotherapy and demonstrated the feasibility of verifying the delivered FLASH beams.