Pencil beam scanning proton FLASH maintains tumor control while normal tissue damage is reduced in a mouse model.

• Local tumor control is the same with pencil beam scanning proton FLASH vs conventional dose rates. • Normal tissue effects assessed as acute skin damage and radiation induced fibrosis as endpoints. • Normal tissue sparing effect of FLASH demonstrated in the same animals as tumor control. • FLASH irradiation results in a dose modifying factor of 1.14 for fibrosis. • And a dose modifying factor of >1.30 for acute skin damage (moist desquamation). Preclinical studies indicate a normal tissue sparing effect when ultra-high dose rate (FLASH) radiation is used, while tumor response is maintained. This differential response has promising perspectives for improved clinical outcome. This study investigates tumor control and normal tissue toxicity of pencil beam scanning (PBS) proton FLASH in a mouse model. Tumor bearing hind limbs of non-anaesthetized CDF1 mice were irradiated in a single fraction with a PBS proton beam using either conventional (CONV) dose rate (0.33–0.63 Gy/s field dose rate, 244 MeV) or FLASH (71–89 Gy/s field dose rate, 250 MeV). 162 mice with a C3H mouse mammary carcinoma subcutaneously implanted in the foot were irradiated with physical doses of 40–60 Gy (8–14 mice per dose point). The endpoints were tumor control (TC) assessed as no recurrent tumor at 90 days after treatment, the level of acute moist desquamation (MD) to the skin of the foot within 25 days post irradiation, and radiation induced fibrosis (RIF) within 24 weeks post irradiation. TCD 50 (dose for 50% tumor control) was similar for CONV and FLASH with values (and 95% confidence intervals) of 49.1 (47.0–51.4) Gy for CONV and 51.3 (48.6–54.2) Gy for FLASH. RIF analysis was restricted to mice with tumor control. Both endpoints showed distinct normal tissue sparing effect of proton FLASH with MDD 50 (dose for 50% of mice displaying moist desquamation) of <40.1 Gy for CONV and 52.3 (50.0–54.6) Gy for FLASH, (dose modifying factor at least 1.3) and FD 50 (dose for 50% of mice displaying fibrosis) of 48.6 (43.2–50.8) Gy for CONV and 55.6 (52.5–60.1) Gy for FLASH (dose modifying factor of 1.14). FLASH had the same tumor control as CONV, but reduced normal tissue damage assessed as acute skin damage and radiation induced fibrosis. [ABSTRACT FROM AUTHOR]