The first PET glimpse of a proton FLASH beam.

We demonstrate the first ever recorded positron-emission tomography (PET) imaging and dosimetry of a FLASH proton beam at the Proton Center of the MD Anderson Cancer Center. Two scintillating LYSO crystal arrays, read out by silicon photomultipliers, were configured with a partial field of view of a cylindrical poly-methyl methacrylate (PMMA) phantom irradiated by a FLASH proton beam. The proton beam had a kinetic energy of 75.8 MeV and an intensity of about 3.5 × 1010protons that were extracted over 101.5 ms-long spills. The radiation environment was characterized by cadmium-zinc-telluride and plastic scintillator counters. Preliminary results indicate that the PET technology used in our tests can efficiently record FLASH beam events. The instrument yielded informative and quantitative imaging and dosimetry of beam-activated isotopes in a PMMA phantom, as supported by Monte Carlo simulations. These studies open a new PET modality that can lead to improved imaging and monitoring of FLASH proton therapy.

3D prompt gamma imaging for proton beam range verification.

We tested the ability of a single Compton camera (CC) to produce 3-dimensional (3D) images of prompt gammas (PGs) emitted during the irradiation of a tissue-equivalent plastic phantom with proton pencil beams for clinical doses delivered at clinical dose rates. PG measurements were made with a small prototype CC placed at three different locations along the proton beam path. We evaluated the ability of the CC to produce images at each location for two clinical scenarios: (1) the delivery of a single 2 Gy pencil beam from a hypo-fractionated treatment (~9 × 108 protons), and (2) a single pencil beam from a standard treatment (~1 × 108 protons). Additionally, the data measured at each location were combined to simulate measurements with a larger scale, clinical CC and its ability to image shifts in the Bragg peak (BP) range for both clinical scenarios. With our prototype CC, the location of the distal end of the BP could be seen with the CC placed up to 4 cm proximal or distal to the BP distal falloff. Using the data from the simulated full scale clinical CC, 3D images of the PG emission were produced with the delivery of as few as 1 × 108 protons, and shifts in the proton beam range as small as 2 mm could be detected for delivery of a 2 Gy spot. From these results we conclude that 3D PG imaging for proton range verification under clinical beam delivery conditions is possible with a single CC.

Feasibility Studies of a New Event Selection Method to Improve Spatial Resolution of Compton Imaging for Medical Applications.

A Compton imaging method for medical applications that includes new energy determination and data filtering techniques has been tested using several point sources with known emission lines. Using a prototype Compton camera, a distance-of-closest approach technique has been employed to determine the initial energy of the incoming γs and to ensure the reconstructed source position is within an acceptable distance from the known γ source location. Further analysis is done by implementing a Compton line filtering technique, keeping only those interactions whose deposited energy in the first interaction matches the theoretical energy deposition predicted by the Compton equation. Using this new event filtering method, we see improvements in the full width at half maximum in the lateral profiles of γ point sources of up to 70% over standard Compton imaging methods, as well as achievable spatial resolutions in the reconstructed images of better than 2 mm. In addition, this new Compton imaging method was able to reconstruct an extended source of γ rays emitted during irradiation of a water tank with a clinical proton radiotherapy beam.

Hyperthermia sensitization and proton beam triggered liposomal drug release for targeted tumor therapy.

PURPOSE: The objectives of this study were to: 1) determine if mild hyperthermia (40-42°C) can sensitize tumor cells for more effective proton beam radiotherapy (PBRT); 2) characterize the survival fraction of cells exposed to PBRT; and 3) characterize release of the drug doxorubicin (Dox) from low temperature sensitive liposomes (LTSLs) without exposure to mild hyperthermia in combination with PBRT. METHODS: Dox was actively loaded in LTSLs. A549 monolayer cells were incubated with 100-200 nM of Dox-LTSL (±mild hyperthermia). Cell irradiation (0-6 Gy) was performed by placing the cell culture plates inside a solid water phantom and using a clinical proton treatment beam with energy of 150 MeV. End points were survival fraction, radiation-mediated Dox release, and reactive oxygen species (ROS) production. RESULTS: Hyperthermia effectively sensitized cells for PBRT and lowered the cell survival fraction (SF) by an average of 9.5%. The combination of 100 nM Dox-LTSL and PBRT (1-6 Gy) achieved additive to synergistic response at various dose combinations. At higher radiation doses (>3 Gy), the SF in the Dox and Dox-LTSL groups was similar (~20%), even in the absence of hyperthermia. In addition, 30% of the Dox was released from LTSLs and a 1.3-1.6 fold increase in ROS level occurred compared to LTSL alone therapy. CONCLUSIONS: The combination of LTSLs and PBRT achieves additive to synergistic effect at various dose combinations in vitro. Concurrent PBRT and Dox-LTSL treatment significantly improved the cytotoxic outcomes of the treatment compared to PBRT and Dox chemotherapy without LTSLs. We hypothesize that PBRT may induce drug release from LTSL in the absence of hyperthermia.

Measurement and calculation of characteristic prompt gamma ray spectra emitted during proton irradiation.

In this paper, we present results of initial measurements and calculations of prompt gamma ray spectra (produced by proton-nucleus interactions) emitted from tissue equivalent phantoms during irradiations with proton beams. Measurements of prompt gamma ray spectra were made using a high-purity germanium detector shielded either with lead (passive shielding), or a Compton suppression system (active shielding). Calculations of the spectra were performed using a model of both the passive and active shielding experimental setups developed using the Geant4 Monte Carlo toolkit. From the measured spectra it was shown that it is possible to distinguish the characteristic emission lines from the major elemental constituent atoms (C, O, Ca) in the irradiated phantoms during delivery of proton doses similar to those delivered during patient treatment. Also, the Monte Carlo spectra were found to be in very good agreement with the measured spectra providing an initial validation of our model for use in further studies of prompt gamma ray emission during proton therapy.

Prompt gamma-ray emission from biological tissues during proton irradiation: a preliminary study.

In this paper, we present the results of a preliminary study of secondary 'prompt' gamma-ray emission produced by proton-nuclear interactions within tissue during proton radiotherapy. Monte Carlo simulations were performed for mono-energetic proton beams, ranging from 2.5 MeV to 250 MeV, irradiating elemental and tissue targets. Calculations of the emission spectra from different biological tissues and their elemental components were made. Also, prompt gamma rays emitted during delivery of a clinical proton spread-out Bragg peak (SOBP) in a homogeneous water phantom and a water phantom containing heterogeneous tissue inserts were calculated to study the correlation between prompt gamma-ray production and proton dose delivery. The results show that the prompt gamma-ray spectra differ significantly for each type of tissue studied. The relative intensity of the characteristic gamma rays emitted from a given tissue was shown to be proportional to the concentration of each element in that tissue. A strong correlation was found between the delivered SOBP dose distribution and the characteristic prompt gamma-ray production. Based on these results, we discuss the potential use of prompt gamma-ray emission as a method to verify the accuracy and efficacy of doses delivered with proton radiotherapy.

Assessment of the accuracy of an MCNPX-based Monte Carlo simulation model for predicting three-dimensional absorbed dose distributions.

In recent years, the Monte Carlo method has been used in a large number of research studies in radiation therapy. For applications such as treatment planning, it is essential to validate the dosimetric accuracy of the Monte Carlo simulations in heterogeneous media. The AAPM Report no 105 addresses issues concerning clinical implementation of Monte Carlo based treatment planning for photon and electron beams, however for proton-therapy planning, such guidance is not yet available. Here we present the results of our validation of the Monte Carlo model of the double scattering system used at our Proton Therapy Center in Houston. In this study, we compared Monte Carlo simulated depth doses and lateral profiles to measured data for a magnitude of beam parameters. We varied simulated proton energies and widths of the spread-out Bragg peaks, and compared them to measurements obtained during the commissioning phase of the Proton Therapy Center in Houston. Of 191 simulated data sets, 189 agreed with measured data sets to within 3% of the maximum dose difference and within 3 mm of the maximum range or penumbra size difference. The two simulated data sets that did not agree with the measured data sets were in the distal falloff of the measured dose distribution, where large dose gradients potentially produce large differences on the basis of minute changes in the beam steering. Hence, the Monte Carlo models of medium- and large-size double scattering proton-therapy nozzles were valid for proton beams in the 100 MeV-250 MeV interval.

Patient neutron dose equivalent exposures outside of the proton therapy treatment field.

A large fraction of dose to healthy tissue located outside of the treatment field during proton therapy is attributable to neutrons produced in the beam-delivery apparatus. In this work, the neutron dose equivalent (H) per therapeutic proton absorbed dose (D) was estimated for typical treatment conditions as a function of range modulation width, angle with respect to the incident proton beam, and the distance from the isocentre at the Harvard Cyclotron Laboratory's (Cambridge, MA) passively spread treatment field using Monte Carlo simulations. For a beam with 16 cm penetration (depth) and a 5 x 5 cm2 lateral field size at the patient location along the incident beam direction at 100 cm from the isocentre, the predicted H/D values are 0.35 and 0.60 mSv Gy(-1) from the simulations and measurements, respectively. At all locations, the predicted H/D values are within a factor of 2 and 3 of the measured result for no modulation and 8.2 cm of modulation, respectively.

A real-time, fibre optic dosimetry system using Al2O3 fibres.

Al2O3:C optical fibres were examined for potential use as real-time luminescence dosemeters for use in radiotherapy applications. The dosimetric properties of the fibres were studied in order to determine their usefulness as luminescence dosemeters. The measurements were performed by connecting the Al2O3:C fibres to a standard fused silica optical fibre and the optically stimulated luminescence (OSL) and radioluminescence (RL) were measured through the fibre. The OSL and RL responses of the Al2O3 fibre probes were measured during irradiation to determine the potential of the Al2O3:C fibres in a real-time fibre optic dosimetry system.