Ultra-high dose rate radiation has been reported to produce a more favorable toxicity and tumor control profile compared to conventional dose rates that are used for patient treatment. So far, the so-called FLASH effect has been validated for electron, photon and scattered proton beam, but not yet for proton pencil beam scanning (PBS). Because PBS is the state-of-the-art delivery modality for proton therapy and constitutes a wide and growing installation base, we determined the benefit of FLASH PBS on skin and soft tissue toxicity. Using a pencil beam scanning nozzle and the plateau region of a 250 MeV proton beam, a uniform physical dose of 35 Gy (toxicity study) or 15 Gy (tumor control study) was delivered to the right hind leg of mice at various dose rates: Sham, Conventional (Conv, 1 Gy/s), Flash60 (57 Gy/s) and Flash115 (115 Gy/s). Acute radiation effects were quantified by measurements of plasma and skin levels of TGF-β1 and skin toxicity scoring. Delayed irradiation response was defined by hind leg contracture as a surrogate of irradiation-induced skin and soft tissue toxicity and by plasma levels of 13 different cytokines (CXCL1, CXCL10, Eotaxin, IL1-beta, IL-6, MCP-1, Mip1alpha, TNF-alpha, TNF-beta, VEGF, G-CSF, GM-CSF and TGF- β1). Plasma and skin levels of TGF-β1, skin toxicity and leg contracture were all significantly decreased in FLASH compared to Conv groups of mice. FLASH and Conv PBS had similar efficacy with regards to growth control of MOC1 and MOC2 head and neck cancer cells transplanted into syngeneic, immunocompetent mice. These results demonstrate consistent delivery of FLASH PBS radiation from 1 to 115 Gy/s in a clinical gantry. Radiation response following delivery of 35 Gy indicates potential benefits of FLASH versus conventional PBS that are related to skin and soft tissue toxicity.

To provide ultrahigh dose rate (UHDR) pencil beam scanning (PBS) proton dosimetry comparison of clinically used plane-parallel ion chambers, PTW (Physikalisch-Technische Werkstaetten) Advanced Markus and IBA (Ion Beam Application) PPC05, with a proton graphite calorimeter in a support of first in-human proton FLASH clinical trial. Methods: Absolute dose measurement intercomparison of the plane-parallel plate ion chambers and the proton graphite calorimeter was performed at 5-cm water-equivalent depth using rectangular 250-MeV single-layer treatment plans designed for the first in-human FLASH clinical trial. The dose rate for each field was designed to remain above 60 Gy/s. The ion recombination effects of the plane-parallel plate ion chambers at various bias voltages were also investigated in the range of dose rates between 5 and 60 Gy/s. Two independent model-based extrapolation methods were used to calculate the ion recombination correction factors k s to compare with the two-voltage technique from most widely used clinical protocols. Results: The mean measured dose to water with the proton graphite calorimeter across all the predefined fields is 7.702 ± 0.037 Gy. The average ratio over the predefined fields of the PTW Advanced Markus chamber dose to the calorimeter reference dose is 1.002 ± 0.007, whereas the IBA PPC05 chamber shows ∼3% higher reading of 1.033 ± 0.007. The relative differences in the k s values determined from between the linear and quadratic extrapolation methods and the two-voltage technique for the PTW Advanced Markus chamber are not statistically significant, and the trends of dose rate dependence are similar. The IBA PPC05 shows a flat response in terms of ion recombination effects based on the k s values calculated using the two-voltage technique. Differences in k s values for the PPC05 between the two-voltage technique and other modelbased extrapolation methods are not statistically significant at FLASH dose rates. Some of the k s values for the PPC05 that were extrapolated from the three-voltage linear method and the semiempirical model were reported less than unity possibly due to the charge multiplication effect, which was negligible compared to the volume recombination effect in FLASH dose rates. Conclusions: The absolute dose measurements of both PTW Advanced Markus and IBA PPC05 chambers are in a good agreement with the NationalThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Pencil beam scanning proton therapy makes possible intensity modulation, resulting in improved target dose conformity and organ-at-risk (OAR) dose sparing. This benefit, however, results in increased sensitivity to certain clinical and beam delivery parameters, such as respiratory motion. These effects can cause plan degeneration, which could lead to decreased tumor dose or increased OAR dose. This study evaluated the measurements of proton pencil beam scanning delivery made with a 2D ion chamber array in solid water on a 1D motion platform, where respiratory motion was simulated using sine and cosine 4 waves representing sinusoidal symmetric and realistic asymmetric breathing motions, respectively. Motion amplitudes were 0.5 cm and 1 cm corresponding to 1 cm and 2 cm of maximum respiratory excursions, respectively, with 5 sec fixed breathing cycle. The treatment plans were created to mimic spherical targets of 3 cm or 10 cm diameter located at 5 cm or 1 cm depth in solid water phantom. A reference RBE dose of 200 cGy per fraction was delivered in 1, 5, 10, and 15 fractions for each dataset. We evaluated dose conformity and uniformity at the center plane of targets by using the Conformation Number and the Homogeneity Index, respectively. Results indicated that dose conformity as well as homogeneity was more affected by motion for smaller targets. Dose conformity was better achieved for symmetric breathing patterns than asymmetric breathing patterns regardless of the number of fractions. The presence of a range shifter with shallow targets reduced the motion effect by improving dose homogeneity. While motion effects are known to be averaged out over the course of multifractional treatments, this might not be true for proton pencil beam scanning under asymmetrical breathing pattern. K E Y W O R D S conformity index, homogeneity index, interplay effect, motion platform, proton pencil beam scanning, respiratory motion ---