Tibaray, Inc.

Objective. To develop and validate a treatment planning system (TPS) for a novel x-ray ultra-high dose rate (UHDR) system and compare its performance with conventional volumetric modulated arc therapy (VMAT). Approach. A TPS was developed for a novel x-ray UHDR system featuring stationary beamlines and a Scanning Pencil-beam High-speed Intensity-modulated x-ray source (SPHINX). We studied an exemplary case using 16 beam angles, 1D scanning perpendicular to the bore axis, and a linear accelerator operating at 12 MeV electron energy with 1 mA average beam current. Treatment plans were generated using various system configurations and compared with clinical VMAT plans for lung (PTV: 239cm3), brain (PTV: 372cm3), and head-and-neck (PTV: 55cm3) cases. Configurations included different beamlet widths for lung cancer, coplanar and conical beam arrangements for brain cancer, and different beamlet spacings for head-and-neck cancer. Dose distributions in terms of target conformity and homogeneity indices, local dose rates (LDR), local irradiation time (LIT), and organ-at-risk (OAR) sparing were compared. A validation workflow combining Monte Carlo simulations with TPS-generated treatment parameters was developed and tested on a lung case to ensure TPS dose calculation accuracy. Main results. TPS-generated plans achieved comparable target coverage to VMAT while delivering significantly higher dose rates (⩾12.5 Gy/s vs. 0.03 Gy/s) and ultra-short LITs. However, UHDR plans in general showed increased OAR mean doses. Conical beam arrangements in the brain case yielded higher maximum LDRs at isocenter of up to 49 Gy/s with LITs as low as 37 ms, but increased integral dose. The head-and-neck case demonstrated high LDRs (62 Gy/s to 98% of PTV) within 20 ms, with minimal differences between beamlet spacing configurations. The lung case validation workflow demonstrated ⩾98% 3D γ-index pass rate using 3%/3 mm threshold, confirming plan accuracy. Significance. The developed UHDR-TPS enables treatment planning for a novel x-ray UHDR system. In this preliminary study, it achieved plan quality comparable to VMAT for the specific lung, brain, and head-and-neck cancer cases studied, while delivering significantly higher dose rates and shorter irradiation times. Further optimization of the UHDR delivery with x-rays is needed, however, to decrease OAR doses and validate these initial findings.

Post-lumpectomy radiotherapy (RT) reduces in-breast tumor recurrence by eradicating residual, occult breast cancer (BC) that may be in the mm size scale. The ability of FLASH-RT to eradicate BC relative to conventional dose rate (CONV) RT is unknown. ∼ 20Gy RT is currently used clinically for single-fraction breast IORT. Determine the effectiveness of FLASH compared to CONV in eradicating small tumors in an orthotopic, syngeneic model of BC using single-fraction 20 or 30Gy RT.

Radiation sensitive, mammary tumor cell line Py117 from the transgenic model of the mouse mammary tumor virus promoter driving the polyoma middle T antigen (MMTV- PyMT) efficiently forms non-metastatic, orthotopic tumors in C57BL/6 mice. 10⁶ Py117 cells were injected orthotopically into the left 4^th mammary fat pad of C57Bl/6J mice. Radiotherapy was performed with a custom jig that allows for fixed positioning of the target volume (2x2cm radiation field) with 5mm of margin into surrounding tissue. Tumors were irradiated at ∼30mm³ volume or, for comparison, at a range of greater volumes (200-800mm³) with 20 or 30Gy FLASH or CONV with 16-17 MeV electrons.

Small 30mm³ tumors regressed until ∼ day 15 after 20Gy single fraction RT then regrew for both FLASH and CONV. 30mm³ tumors were eradicated with both FLASH and CONV at 30Gy with no regrowth up to day 35 post-RT. Larger tumors irradiated with 30Gy regressed until ∼ day 12 post-RT then regrew for both FLASH and CONV. There was no significant difference in growth delay or tumor eradication between FLASH and CONV in any cohort.

FLASH was as effective as CONV in controlling growth and eradicating murine BC. Based on other preclinical studies, single-fraction doses between 20 and 30Gy, as well as hypofractioned RT schedules, may identify FLASH doses that achieve comparable tumor control with less toxicity than CONV. Such findings would encourage clinical trials of FLASH in human BC.

A growing body of pre-clinical research has demonstrated the potential of ultra-high dose-rate (UHDR) radiotherapy to reduce normal tissue toxicity while maintaining tumor control. However, owing to a wide range of technical difficulties, no existing x-ray systems are capable of highly conformal UHDR radiotherapy to humans. In this work, we designed and simulated a novel x-ray UHDR system representing a next-generation solution for rapid and highly conformal treatment delivery. This system comprises 16 stationary beamlines employing a new class of highly efficient linear accelerator to generate 12 MeV electron beams electromagnetically steered onto a bremsstrahlung target, a collimator with channels to create a divergent array of x-ray beamlets, and a translating patient couch. The system design was tuned to maximize the dose rate while minimizing beam penumbra and cross-channel leakage. A simulation framework was developed to facilitate iteration of machine parameters during optimization. A treatment plan for a case of locally advanced lung cancer was generated using an in-house optimizer to assess the capabilities of the x-ray UHDR system. Individual beamlets of 10, 15, and 20-mm in size can produce isocenter dose rates of 17.3, 18.7, and 19.7-Gy/mAs and cross-channel leakage of 2.3, 1.9, and [Formula: see text], respectively. The novel UHDR 10-Gy/fraction plan exhibited comparable or improved conformity, homogeneity, and mean dose to organs at risk compared to the clinically used plan and it was delivered in 500 ms with more than [Formula: see text] of target volume receiving local dose rates higher than 40Gy/s.