Demonstration of the FLASH Effect Within the Spread-out Bragg Peak After Abdominal Irradiation of Mice.

Purpose: The effects of FLASH-level dose rates delivered at the spread-out Bragg peak (SOBP) on normal tissue damage in mice were investigated. Materials and Methods: Fifty nontumor-bearing mice received abdominal irradiation, 30 at FLASH dose rates (100 Gy/s) and 20 at conventional dose rates (0.1 Gy/s). Total dose values ranged from 10 to 19 Gy, delivered in a single spot by a synchrocyclotron proton therapy system. Centered on the abdomen, the collimated field delivered was an 11-mm diameter circle with a water-equivalent depth of 2.4 cm from entrance to distal 80% dose. A ridge filter was used to provide dose uniformity over the full 2.4-cm range. The spatial distribution was identical for both the FLASH and conventional deliveries. Results: Overall survival and individual mouse weights were tracked for 21 days after the exposure date, and LD50 values were compared for the FLASH and conventional dose rate groups. Mice exposed to FLASH dose rates had a higher LD50 value as compared with mice exposed to conventional dose rates, with a dose-dependent improvement in survivability of 10% to 20%. The FLASH cohort also showed greater or equal percent population survival for each day of the study. Conclusion: These results are preliminary confirmation of the potential for the combination of the advantages of the Bragg peak with the normal tissue sparing benefits of FLASH treatments. This experiment also confirms that pulsed synchrocyclotrons can be used for the purpose of FLASH research and treatment.

Spread-out Bragg peak proton FLASH irradiation using a clinical synchrocyclotron: Proof of concept and ion chamber characterization.

PURPOSE: The purpose of this work is to (a) demonstrate the feasibility of delivering a spread-out Bragg peak (SOBP) proton beam in ultra-high dose rate (FLASH) using a proton therapy synchrocyclotron as a major step toward realizing an experimental platform for preclinical studies, and (b) evaluate the response of four models of ionization chambers in such a radiation field. METHODS: A clinical Mevion HYPERSCAN® synchrocyclotron was adjusted for ultra-high dose rate proton delivery. Protons with nominal energy of 230 MeV were delivered in pulses with temporal width ranging from 12.5 µs to 24 µs spanning from conventional to FLASH dose rates. A boron carbide absorber and a range modulator block were placed in the beam path for range modulation and creating an SOBP dose profile. The radiation field was defined by a brass aperture with 11 mm diameter. Two Faraday cups were used to determine the number of protons per pulse at various dose rates. The dosimetric response of two cylindrical (IBA CC04 and CC13) and two plane-parallel (IBA PPC05 and PTW Advanced Markus® ) ionization chambers were evaluated. The dose rate was measured using the plane-parallel ionization chambers. The integral depth dose (IDD) was measured with a PTW Bragg Peak® ionization chamber. The lateral beam profile was measured with EBT-XD radiochromic film. Monte Carlo simulation was performed in TOPAS as the secondary check for the measurements and as a tool for further optimization of the range modulators' design. RESULTS: Faraday cups measurement showed that the maximum protons per pulse is 39.9 pC at 24 µs pulse width. A good agreement between the measured and simulated IDD and lateral beam profiles was observed. The cylindrical ionization chambers showed very high ion recombination and deemed not suitable for absolute dosimetry at ultra-high dose rates. The average dose rate measured using the PPC05 ionization chamber was 163 Gy/s at the pristine Bragg peak and 126 Gy/s at 1 cm depth for the SOBP beam. The SOBP beam range and modulation were measured 24.4 mm and 19 mm, respectively. The pristine Bragg peak beam had 25.6 mm range. Simulation results showed that the IDD and profile flatness can be improved by the cavity diameter of the range modulator and the number of scanned spots, respectively. CONCLUSIONS: Feasibility of delivering protons in an SOBP pattern with >100 Gy/s average dose rate using a clinical synchrocyclotron was demonstrated. The dose heterogeneity can be improved through optimization of the range modulator and number of delivered spots. Plane-parallel chambers with smaller gap between electrodes are more suitable for FLASH dosimetry compared to the other ion chambers used in this work.

Feasibility of proton FLASH irradiation using a synchrocyclotron for preclinical studies.

PURPOSE: It has been recently shown that radiotherapy at ultrahigh dose rates (>40 Gy/s, FLASH) has a potential advantage in sparing healthy organs compared to that at conventional dose rates. The purpose of this work is to show the feasibility of proton FLASH irradiation using a gantry-mounted synchrocyclotron as a first step toward implementing an experimental setup for preclinical studies. METHODS: A clinical Mevion HYPERSCAN® synchrocyclotron was modified to deliver ultrahigh dose rates. Pulse widths of protons with 230 MeV energy were manipulated from 1 to 20 µs to deliver in conventional and ultrahigh dose rate. A boron carbide absorber was placed in the beam for range modulation. A Faraday cup was used to determine the number of protons per pulse at various dose rates. Dose rate was determined by the dose measured with a plane-parallel ionization chamber with respect to the actual delivery time. The integral depth dose (IDD) was measured with a Bragg ionization chamber. Monte Carlo simulation was performed in TOPAS as the secondary check for the measurements. RESULTS: Maximum protons charge per pulse, measured with the Faraday cup, was 54.6 pC at 20 µs pulse width. The measured IDD agreed well with the Monte Carlo simulation. The average dose rate measured using the ionization chamber showed 101 Gy/s at the entrance and 216 Gy/s at the Bragg peak with a full width at half maximum field size of 1.2 cm. CONCLUSIONS: It is feasible to deliver protons at 100 and 200 Gy/s average dose rate at the plateau and the Bragg peak, respectively, in a small ~1 cm2 field using a gantry-mounted synchrocyclotron.

On the nuclear halo of a proton pencil beam stopping in water.

The dose distribution of a proton beam stopping in water has components due to basic physics and may have others from beam contamination. We propose the concise terms core for the primary beam, halo (see Pedroni et al 2005 Phys. Med. Biol. 50 541-61) for the low dose region from charged secondaries, aura for the low dose region from neutrals, and spray for beam contamination. We have measured the dose distribution in a water tank at 177 MeV under conditions where spray, therefore radial asymmetry, is negligible. We used an ADCL calibrated thimble chamber and a Faraday cup calibrated integral beam monitor so as to obtain immediately the absolute dose per proton. We took depth scans at fixed distances from the beam centroid rather than radial scans at fixed depths. That minimizes the signal range for each scan and better reveals the structure of the core and halo. Transitions from core to halo to aura are already discernible in the raw data. The halo has components attributable to coherent and incoherent nuclear reactions. Due to elastic and inelastic scattering by the nuclear force, the Bragg peak persists to radii larger than can be accounted for by Molière single scattering. The radius of the incoherent component, a dose bump around midrange, agrees with the kinematics of knockout reactions. We have fitted the data in two ways. The first is algebraic or model dependent (MD) as far as possible, and has 25 parameters. The second, using 2D cubic spline regression, is model independent. Optimal parameterization for treatment planning will probably be a hybrid of the two, and will of course require measurements at several incident energies. The MD fit to the core term resembles that of the PSI group (Pedroni et al 2005), which has been widely emulated. However, we replace their T(w), a mass stopping power which mixes electromagnetic (EM) and nuclear effects, with one that is purely EM, arguing that protons that do not undergo hard single scatters continue to lose energy according to the Beth-Bloch formula. If that is correct, it is no longer necessary to measure T(w), and the dominant role played by the 'Bragg peak chamber' vanishes. For mathematical and other details we will refer to Gottschalk et al (2014, arXiv: 1409.1938v1), a long technical report of this project.

Radiobiological intercomparison of the 160 MeV and 230 MeV proton therapy beams at the Harvard Cyclotron Laboratory and at Massachusetts General Hospital.

The purpose of this study was to determine the relative biological effectiveness (RBE) along the axis of two range-modulated proton beams (160 and 230 MeV). Both the depth and the dose dependence of RBE were investigated. Chinese hamster V79-WNRE cells, suspended in medium containing gelatin and cooled to 2 °C, were used to obtain complete survival curves at multiple positions throughout the entrance and 10 cm spread-out Bragg peak (SOBP). Simultaneous measurements of the survival response to (60)Co gamma rays served as the reference data for the proton RBE determinations. For both beams the RBE increased significantly with depth in the 10 cm SOBP, particularly in the distal half of the SOBP, then rose even more sharply at the distal edge, the most distal position measured. At a 4 Gy dose of gamma radiation (S = 0.34) the average RBE values for the entrance, proximal half, distal half and distal edge were 1.07 ± 0.01, 1.10 ± 0.01, 1.17 ± 0.01 and 1.21 ± 0.01, respectively, and essentially the same for both beams. At a 2 Gy dose of gamma radiation (S = 0.71) the average RBE values rose to 1.13 ± 0.03, 1.15 ± 0.02, 1.26 ± 0.02 and 1.30 ± 0.02, respectively, for the same four regions of the SOBP. The difference between the 4 Gy and 2 Gy RBE values reflects the dose dependence of RBE as measured in these V79-WNRE cells, which have a low α/ß value, as do other widely used cell lines that also show dose-dependent RBE values. Late-responding tissues are also characterized by low α/ß values, so it is possible that these cell lines may be predictive for the response of such tissues (e.g., spinal cord, optic nerve, kidney, liver, lung). However, in the very small number of studies of late-responding tissues performed to date there appears to be no evidence of an increased RBE for protons at low doses. Similarly, RBE measurements using early responding in vivo systems (mostly mouse jejunum, an early-responding tissue which has a large α/ß âˆ¼ 10 Gy) have generally shown little or no detectable dose dependence. It is useful to compare the RBE values reported here to the commonly used generic clinical RBE of 1.1, which assumes no dependence on depth or on dose. Our proximal RBEs obviously avoid the depth-related increase in RBE and for doses of 4 Gy or more, the low-dose increase in RBE is also minimized, as shown in this article. Thus the proximal RBE at a 4 Gy dose of 1.10 ± 0.01, quoted above, represents an interesting point of congruence with the clinical RBE for conditions where it could reasonably be expected in the measurements reported here. The depth dependence of RBE reported here is consistent with the majority of measurements, both in vitro and in vivo, by other investigators. The dose dependence of RBE, on the other hand, is tissue specific but has not yet been demonstrated for protons by RBE values in late-responding normal tissue systems. This indicates a need for additional RBE determination as function of dose, especially in late-responding tissues.