FLASH radiotherapy sparing effect on the circulating lymphocytes in pencil beam scanning proton therapy: impact of hypofractionation and dose rate

Abstract Purpose . The sparing effect of ultra-high dose rate (FLASH) radiotherapy has been reported, but its potential to mitigate depletion of circulating blood and lymphocytes (CL) has not been investigated in pencil-beam scanning-based (PBS) proton therapy, which could potentially reduce the risk of radiation-induced lymphopenia. Material and methods . A time-dependent framework was used to score the dose to the CL during the course of radiotherapy. For brain patients, cerebral vasculatures were semi-automatic segmented from 3T MR-angiography data. A dynamic beam delivery system was developed capable of simulating spatially varying instantaneous dose rates of PBS treatment plans, and which is based on realistic beam delivery parameters that are available clinically. We simulated single and different hypofractionated PBS intensity modulated proton therapy (IMPT) FLASH schemes using 600 nA beam current along with conventionally fractionated IMPT treatment plan at 2 nA beam current. The dosimetric impact of treatment schemes on CL was quantified, and we also evaluated the depletion in subsets of CL based on their radiosensitivity. Results . The proton FLASH sparing effect on CL was observed. In single-fraction PBS FLASH, just 1.5% of peripheral blood was irradiated, whereas hypofractionated FLASH irradiated 7.3% of peripheral blood. In contrast, conventional fractionated IMPT exposed 42.4% of peripheral blood to radiation. PBS FLASH reduced the depletion rate of CL by 69.2% when compared to conventional fractionated IMPT. Conclusion . Our dosimetric blood flow model provides quantitative measures of the PBS FLASH sparing effect on the CL in radiotherapy for brain cancer. FLASH Single treatment fraction offers superior CL sparing when compared to hypofractionated FLASH and conventional IMPT, supporting assumptions about reducing risks of lymphopenia compared to proton therapy at conventional dose rates. The results also indicate that faster conformal FLASH delivery, such as passive patient-specific energy modulation, may further enhance the sparing of the immune system.