Abstract
Simple SummaryFLASH radiotherapy is a treatment technique of interest that involves radiation delivered at ultra-high dose rates >100 times faster than traditional radiation therapy, which has been shown to spare radiation damage to normal tissue but maintain tumor control capabilities. Proton therapy uses spread-out proton Bragg peaks to reduce radiation dose to normal tissue by directing the highest dose of radiation to the tumor volume. In this study, irradiation of the whole abdomen of mice was performed with proton beams at FLASH dose rates in order to investigate the normal tissue sparing capabilities of the spread-out Bragg peak compared to the entrance region of the proton depth dose curve.Ultra-high dose rate FLASH proton radiotherapy (F-PRT) has been shown to reduce normal tissue toxicity compared to standard dose rate proton radiotherapy (S-PRT) in experiments using the entrance portion of the proton depth dose profile, while proton therapy uses a spread-out Bragg peak (SOBP) with unknown effects on FLASH toxicity sparing. To investigate, the biological effects of F-PRT using an SOBP and the entrance region were compared to S-PRT in mouse intestine. In this study, 8–10-week-old C57BL/6J mice underwent 15 Gy (absorbed dose) whole abdomen irradiation in four groups: (1) SOBP F-PRT, (2) SOBP S-PRT, (3) entrance F-PRT, and (4) entrance S-PRT. Mice were injected with EdU 3.5 days after irradiation, and jejunum segments were harvested and preserved. EdU-positive proliferating cells and regenerated intestinal crypts were quantified. The SOBP had a modulation (width) of 2.5 cm from the proximal to distal 90%. Dose rates with a SOBP for F-PRT or S-PRT were 108.2 ± 8.3 Gy/s or 0.82 ± 0.14 Gy/s, respectively. In the entrance region, dose rates were 107.1 ± 15.2 Gy/s and 0.83 ± 0.19 Gy/s, respectively. Both entrance and SOBP F-PRT preserved a significantly higher number of EdU + /crypt cells and percentage of regenerated crypts compared to S-PRT. Moreover, tumor growth studies showed no difference between SOBP and entrance for either of the treatment modalities.
Highlights
FLASH radiotherapy (RT) involves the delivery of ultra-high dose rates, above approximately 40 Gy/s [1,2], to elicit normal tissue sparing while maintaining the tumor cell killing capabilities of conventional dose rates below 1 Gy/s
To the best of our knowledge, the impact of linear energy transfer (LET) increase on the proton FLASH sparing effect has not been reported and this is the first demonstration of the toxicity sparing effects of proton FLASH on normal tissues using the spread-out Bragg peak (SOBP) region of proton dose deposition
We demonstrate the capability and film validation of SOBP proton delivery to targets at FLASH dose rates through a double-scattering system with energy modulation performed by a ridge filter
Summary
FLASH radiotherapy (RT) involves the delivery of ultra-high dose rates, above approximately 40 Gy/s [1,2], to elicit normal tissue sparing while maintaining the tumor cell killing capabilities of conventional dose rates below 1 Gy/s. Proton FLASH radiobiology studies have used a shoot-through method irradiating with the entrance region of a high-energy proton beam and delivering the Bragg peak beyond the target (typically outside of a patient/mouse). The ionization density and linear energy transfer (LET) of the proton dose is increased in the Bragg peak, leading to an enhancement of relative biological effect [14,16]. To the best of our knowledge, the impact of LET increase on the proton FLASH sparing effect has not been reported and this is the first demonstration of the toxicity sparing effects of proton FLASH on normal tissues using the spread-out Bragg peak (SOBP) region of proton dose deposition
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