Abstract
BACKGROUND: Spatially fractionated radiation therapy (SFRT) has therapeutic potential as a priming therapy which boosts tumor control. However, the optimal delivery and spatial fractionation parameters have not been deciphered and the mechanisms at play are not yet fully understood. PURPOSE: This paper highlights our preclinical setups for mini-grid SFRT with 6 MeV electrons delivered at conventional to ultrahigh dose rates, using a flexible collimator system. These setups let us explore relevant spatial fractionation parameters to observe their effect on tumor growth and normal tissue toxicity. Preclinical studies here may reveal the parameters of highest clinical relevance for SFRT and combination therapies. METHODS: For preclinical experiments with electron spatial fractionation, 6.5 mm thick brass collimators were made with 7- (or 19-) hole hexagonally packed ∅ 0.65-2 mm apertures, with 1.6-5 mm CTC distances. Irradiated EBT-XD Gafchromic film downstream of collimators were analyzed to obtain peak-to-valley dose ratios (PVDR), full width at half maxima (FWHM), and peak doses at various depths in solid water, and at surface when increasing the separations from collimators in air. Male and female C57BL/6 mice were injected subcutaneously with UPPL1541 bladder cancer cells in the right flank. After 10-13 days, a single dose treatment was delivered to the tumors with either ∅14 mm circular homogeneous field (10 Gy delivered at 3 kGy s(-1)), or using a 7-hole (∅ of 2 and 5 mm center-to-center distances) spatially fractionated field; peak doses of 30 Gy delivered at 820 Gy s(-1), 20 Gy at 860 Gy s(-1), and 20 Gy at < 0.1 Gy s(-1). Tumor growth and time to triple tumor volume (TTTV) were measured and compared between treatment regimens. RESULTS: Similar PVDRs were obtained with 7- and 19-hole inserts (35 and 31 at surface, respectively). Peak widths increased with depth, and maximal peak dose rates were > 1.8 kGy s(-1). A displacement in air from the collimator exit decreased PVDRs at the phantom surface; from 32 to 16 at ∼10 mm distance, and to 6 at ∼20 mm distance. Peak doses also reduced to ∼57 % at 10 mm distance, and to ∼33% at 20 mm distance. Film measurements at the mouse phantom surface produced peak and valley dose rates of > 850 Gy s(-1) and ∼60 Gy s(-1) respectively, with a PVDR > 14. Tumor growth delays for spatially fractionated FLASH 30 Gy (peak dose, with a 2.1 Gy valley dose, and a 10 Gy average dose) and homogeneous FLASH 10 Gy electron irradiation regimens were similar. Both regimens also demonstrated significantly longer TTTV compared to control and spatially fractionated conventional 20 Gy (peak dose, with a 1.4 Gy valley dose, and a 6.7 Gy average dose) regimens (p < 0.05). No significant differences in body weight and skin damage were observed, indicating acceptable treatment tolerability. CONCLUSIONS: Spatially fractionated electron FLASH treatments with 30 Gy peak doses and 2.1 Gy valley doses provide effective tumor growth delay and prolonged tumor control akin to 10 Gy homogeneous irradiations. Here we demonstrate that combining spatial modulation, higher peak doses, and FLASH dose rates can produce favorable tumor response.