Experimental characterization of proton minibeam therapy delivery under FLASH dose-rate conditions

Proton minibeam radiation therapy (pMBRT) introduces spatial fractionation of dose distributions at submillimeter resolution, offering a promising approach to reducing normal tissue toxicity while maintaining effective tumor control. However, the high monitor unit (MU) requirements of multi-slit collimators (MSC) result in extended delivery times, posing a significant challenge. This study explores the feasibility of integrating pMBRT with ultra-high-dose-rates (UHDR) to overcome this limitation while leveraging potential biological synergies to enhance the therapeutic index and advance clinical applications. The study utilized the IBA ProteusONE compact proton therapy system equipped with two MSCs, each with center-to-center distances of 2.8 mm, slit widths of 1.0 mm, and thicknesses of 6.5 cm and 10 cm. UHDR delivery was achieved with 228 MeV protons at a current of 125 nA, while clinical beams operated at 226 MeV with 1-5 nA. Dose measurements using Gafchromic films in solid water phantoms were compared with Monte Carlo simulations. Delivery times were compared for FLASH and clinical beams. PBS dose rate was calculated based on the spot delivery log file. The study successfully demonstrated pMBRT dose distributions under UHDR, significantly reducing treatment times to 2.5 s compared to 3 min for clinical beams. The 10 cm collimator achieved higher peak-to-valley dose ratios (PVDRs) at 2 cm depth (4.36) than the 6.5 cm collimator (2.57), optimizing UHDR delivery conditions. Results highlight the potential to improve dose delivery efficiency while maintaining spatial resolution and dose modulation, supporting future clinical advancements. This study demonstrates the feasibility of integrating pMBRT with UHDR using a clinical proton therapy system. By addressing challenges associated with delivery times and leveraging the combined advantages of spatial fractionation and ultra-high-dose-rates, this work paves the way for the clinical translation of pMBRT with UHDR, offering innovative possibilities for treating challenging malignancies with high-dose precision therapy.