Synchrotron X-ray microbeam dosimetry with a 20†micrometre resolution scintillator fibre-optic dosimeter.

Cancer is one of the leading causes of death worldwide. External beam radiation therapy is one of the most important modalities for the treatment of cancers. Synchrotron microbeam radiation therapy (MRT) is a novel pre-clinical therapy that uses highly spatially fractionated X-ray beams to target tumours, allowing doses much higher than conventional radiotherapies to be delivered. A dosimeter with a high spatial resolution is required to provide the appropriate quality assurance for MRT. This work presents a plastic scintillator fibre optic dosimeter with a one-dimensional spatial resolution of 20 µm, an improvement on the dosimeter with a resolution of 50 µm that was demonstrated in previous work. The ability of this probe to resolve microbeams of width 50 µm has been demonstrated. The major limitations of this method were identified, most notably the low-light signal resulting from the small sensitive volume, which made valley dose measurements very challenging. A titanium-based reflective paint was used as a coating on the probe to improve the light collection, but a possible effect of the high-Z material on the probes water-equivalence has been identified. The effect of the reflective paint was a 28.5 ±â€…4.6% increase in the total light collected; it did not affect the shape of the depth-dose profile, nor did it explain an over-response observed when used to probe at low depths, when compared with an ionization chamber. With improvements to the data acquisition, this probe design has the potential to provide a water-equivalent, inexpensive dosimetry tool for MRT.

Quantitative characterization of the X-ray beam at the Australian Synchrotron Imaging and Medical Beamline (IMBL).

A critical early phase for any synchrotron beamline involves detailed testing, characterization and commissioning; this is especially true of a beamline as ambitious and complex as the Imaging & Medical Beamline (IMBL) at the Australian Synchrotron. IMBL staff and expert users have been performing precise experiments aimed at quantitative characterization of the primary polychromatic and monochromatic X-ray beams, with particular emphasis placed on the wiggler insertion devices (IDs), the primary-slit system and any in vacuo and ex vacuo filters. The findings from these studies will be described herein. These results will benefit IMBL and other users in the future, especially those for whom detailed knowledge of the X-ray beam spectrum (or `quality') and flux density is important. This information is critical for radiotherapy and radiobiology users, who ultimately need to know (to better than 5%) what X-ray dose or dose rate is being delivered to their samples. Various correction factors associated with ionization-chamber (IC) dosimetry have been accounted for, e.g. ion recombination, electron-loss effects. A new and innovative approach has been developed in this regard, which can provide confirmation of key parameter values such as the magnetic field in the wiggler and the effective thickness of key filters. IMBL commenced operation in December 2008 with an Advanced Photon Source (APS) wiggler as the (interim) ID. A superconducting multi-pole wiggler was installed and operational in January 2013. Results are obtained for both of these IDs and useful comparisons are made. A comprehensive model of the IMBL has been developed, embodied in a new computer program named spec.exe, which has been validated against a variety of experimental measurements. Having demonstrated the reliability and robustness of the model, it is then possible to use it in a practical and predictive manner. It is hoped that spec.exe will prove to be a useful resource for synchrotron science in general, and for hard X-ray beamlines, whether they are based on bending magnets or insertion devices, in particular. In due course, it is planned to make spec.exe freely available to other synchrotron scientists.

Preclinical radiotherapy at the Australian Synchrotron's Imaging and Medical Beamline: instrumentation, dosimetry and a small-animal feasibility study.

Therapeutic applications of synchrotron X-rays such as microbeam (MRT) and minibeam (MBRT) radiation therapy promise significant advantages over conventional clinical techniques for some diseases if successfully transferred to clinical practice. Preclinical studies show clear evidence that a number of normal tissues in animal models display a tolerance to much higher doses from MRT compared with conventional radiotherapy. However, a wide spread in the parameters studied makes it difficult to make any conclusions about the associated tumour control or normal tissue complication probabilities. To facilitate more systematic and reproducible preclinical synchrotron radiotherapy studies, a dedicated preclinical station including small-animal irradiation stage was designed and installed at the Imaging and Medical Beamline (IMBL) at the Australian Synchrotron. The stage was characterized in terms of the accuracy and reliability of the vertical scanning speed, as this is the key variable in dose delivery. The measured speed was found to be within 1% of the nominal speed for the range of speeds measured by an interferometer. Furthermore, dose measurements confirm the expected relationship between speed and dose and show that the measured dose is independent of the scan direction. Important dosimetric parameters such as peak dose, valley dose, the collimator output factor and peak-to-valley dose ratio are presented for 5 mm × 5 mm, 10 mm × 10 mm and 20 mm × 20 mm field sizes. Finally, a feasibility study on three glioma-bearing rats was performed. MRT and MBRT doses were prescribed to achieve an average dose of 65 Gy in the target, and magnetic resonance imaging follow-up was performed at various time points after irradiation to follow the tumour volume. Although it is impossible to draw conclusions on the different treatments with such a small number of animals, the feasibility of end-to-end preclinical synchrotron radiotherapy studies using the IMBL preclinical stage is demonstrated.

Image guidance protocol for synchrotron microbeam radiation therapy.

The protocol for image-guided microbeam radiotherapy (MRT) developed for the Australian Synchrotron's Imaging and Medical Beamline (IMBL) is described. The protocol has been designed for the small-animal MRT station of IMBL to enable future preclinical trials on rodents. The image guidance procedure allows for low-dose monochromatic imaging at 50 keV and subsequent semi-automated sample alignment in 3D with sub-100 µm accuracy. Following the alignment, a beamline operation mode change is performed and the relevant beamline components are automatically aligned for the treatment (pink) beam to be delivered on the sample. Here, the small-animal MRT station, the parameters and procedures for the image guidance protocol, as well as the experimental imaging results using phantoms are described. Furthermore, the experimental validation of the protocol using 3D PRESAGE(®) dosimeters is reported. It is demonstrated that the sample alignment is maintained after the mode change and the treatment can be delivered within the same spatial accuracy of 100 µm. The results indicate that the proposed approach is viable for preclinical trials of small-animal MRT.

Influence of sub-nanosecond time of flight resolution for online range verification in proton therapy using the line-cone reconstruction in Compton imaging.

Online ion range monitoring in hadron therapy can be performed via detection of secondary radiation, such as promptγ-rays, emitted during treatment. The promptγemission profile is correlated with the ion depth-dose profile and can be reconstructed via Compton imaging. The line-cone reconstruction, using the intersection between the primary beam trajectory and the cone reconstructed via a Compton camera, requires negligible computation time compared to iterative algorithms. A recent report hypothesised that time of flight (TOF) based discrimination could improve the precision of theγfall-off position (FOP) measured via line-cone reconstruction, where TOF comprises both the proton transit time from the phantom entrance untilγemission, and the flight time of theγ-ray to the detector. The aim of this study was to implement such a method and investigate the influence of temporal resolution on the precision of the FOP. Monte Carlo simulations of a 160 MeV proton beam incident on a homogeneous PMMA phantom were performed using GATE. The Compton camera consisted of a silicon-based scatterer and CeBr3scintillator absorber. The temporal resolution of the detection system (absorber + beam trigger) was varied between 0.1 and 1.3 ns rms and a TOF-based discrimination method applied to eliminate unlikely solution(s) from the line-cone reconstruction. The FOP was obtained for varying temporal resolutions and its precision obtained from its shift across 100 independentγemission profiles compared to a high statistics reference profile. The optimal temporal resolution for the given camera geometry and 108primary protons was 0.2 ns where a precision of 2.30 ± 0.15 mm (1σ) on the FOP was found. This precision is comparable to current state-of-the-art Compton imaging using iterative reconstruction methods or 1D imaging with mechanically collimated devices, and satisfies the requirement of being smaller than the clinical safety margins.

Impact of magnetic fields on dose measurement with small ion chambers illustrated in high-resolution response maps.

PURPOSE: Dosimetry of ionizing radiation in the presence of strong magnetic fields is gaining increased relevance in light of advances for MRI-guided radiation therapy. While the impact of strong magnetic fields on the overall response of ionization chambers has been simulated and measured before, this work investigates the local impact of the magnetic field on dose response in an ion chamber. High-resolution 1D and 2D response maps have been created for two small clinical thimble ionization chambers, the PinPoint chambers 31006 and 31014 (Physikalisch Technische Werkstaetten Freiburg, Germany). METHODS: Working on the Imaging and Medical Beam Line of the Australian Synchrotron an intense kilovoltage radiation beam with very low divergence, collimated to 0.1 mm was used to scan the chambers by moving them on a 2D motion platform. Measured current and beam position were correlated to create the response maps. Small neodymium magnets were used to create a field of about 0.25 T. Chamber axis, magnetic field, and beam direction were perpendicular to each other. Measurements were performed with both orientations of the magnetic field as well as without it. Chamber biases of 5 and 250 V in both polarities were used. RESULTS: The local distribution of the response of small thimble-type ionization chambers was found to be impacted by a magnetic field. Depending on the orientation of the magnetic field, the chamber response near the stem was either enhanced or reduced with the response near the tip behaving the opposite way. Local changes were in the order of up to 40% compared to measurements without the magnetic field present. Bending of the central electrode was observed for the chamber with the steel electrode. The size of the volume of reduced collection near the guard electrode was impacted by the magnetic field. As the here investigated beam and field parameters differ from those of clinical systems, quantitatively different results would be expected for the latter. However, the gyroradii encountered here were similar to those of a 6-7 MV MRI linac with a 1.5 T magnet. CONCLUSIONS: Magnetic fields impact the performance of ionization chambers also on a local level. For practical measurements this might mean a change in the effective point of measurement, in addition to any global corrections. Further knowledge about the local response will help in selecting or constructing optimized chambers for use in magnetic fields.

Film dosimetry studies for patient specific quality assurance in microbeam radiation therapy.

Microbeam radiation therapy (MRT) uses synchrotron arrays of X-ray microbeams to take advantage of the spatial fractionation effect for normal tissue sparing. In this study, radiochromic film dosimetry was performed for a treatment where MRT is introduced as a dose boost in a hypofractionated stereotactic radiotherapy (SRT) scheme. The isocenter dose was measured using an ionization chamber and two dimensional dose distributions were determined using radiochromic films. To compare the measured dose distribution to the MRT treatment plan, peak and valley were displayed in separate dosemaps. The measured and computed isocenter doses were compared and a two-dimensional 2%/2 mm normalized γ-index analysis with a 90% passing rate criterion was computed. For SRT, a difference of 2.6% was observed in the dose at the isocenter from the treatment plan and film measurement, with a passing rate of 96% for the γ-index analysis. For MRT, peak and valley doses differences of 25.6% and 8.2% were observed, respectively but passing rates of 96% and 90% respectively were obtained from the normalized γ-index maps. The differences in isocenter doses measured in MRT should be further investigated. We present the methodology of patient specific quality assurance (QA) for studying MRT dose distributions and discuss ideas to improve absolute dosimetry. This patient specific QA will be used for large animal trials quality assurance where MRT will be administered as a dose boost in conventional SRT. The observed remaining discrepancies should be studied against approximations in the TPS phantom materials, beams characteristics or film read-out procedures.

Locomotion and eating behavior changes in Yucatan minipigs after unilateral radio-induced ablation of the caudate nucleus.

The functional roles of the Caudate nucleus (Cd) are well known. Selective Cd lesions can be found in neurological disorders. However, little is known about the dynamics of the behavioral changes during progressive Cd ablation. Current stereotactic radiosurgery technologies allow the progressive ablation of a brain region with limited adverse effects in surrounding normal tissues. This could be of high interest for the study of the modified behavioral functions in relation with the degree of impairment of the brain structures. Using hypofractionated stereotactic radiotherapy combined with synchrotron microbeam radiation, we investigated, during one year after irradiation, the effects of unilateral radio-ablation of the right Cd on the behavior of Yucatan minipigs. The right Cd was irradiated to a minimal dose of 35.5 Gy delivered in three fractions. MRI-based morphological brain integrity and behavioral functions, i.e. locomotion, motivation/hedonism were assessed. We detected a progressive radio-necrosis leading to a quasi-total ablation one year after irradiation, with an additional alteration of surrounding areas. Transitory changes in the motivation/hedonism were firstly detected, then on locomotion, suggesting the influence of different compensatory mechanisms depending on the functions related to Cd and possibly some surrounding areas. We concluded that early behavioral changes related to eating functions are relevant markers for the early detection of ongoing lesions occurring in Cd-related neurological disorders.

Experimental optimisation of the X-ray energy in microbeam radiation therapy.

Microbeam radiation therapy has demonstrated superior normal tissue sparing properties compared to broadbeam radiation fields. The ratio of the microbeam peak dose to the valley dose (PVDR), which is dependent on the X-ray energy/spectrum and geometry, should be maximised for an optimal therapeutic ratio. Simulation studies in the literature report the optimal energy for MRT based on the PVDR. However, most of these studies have considered different microbeam geometries to that at the Imaging and Medical Beamline (50 µm beam width with a spacing of 400 µm). We present the first fully experimental investigation of the energy dependence of PVDR and microbeam penumbra. Using monochromatic X-ray energies in the range 40-120 keV the PVDR was shown to increase with increasing energy up to 100 keV before plateauing. PVDRs measured for pink beams were consistently higher than those for monochromatic energies similar or equivalent to the average energy of the spectrum. The highest PVDR was found for a pink beam average energy of 124 keV. Conversely, the microbeam penumbra decreased with increasing energy before plateauing for energies above 90 keV. The effect of bone on the PVDR was investigated at energies 60, 95 and 120 keV. At depths greater than 20 mm beyond the bone/water interface there was almost no effect on the PVDR. In conclusion, the optimal energy range for MRT at IMBL is 90-120 keV, however when considering the IMBL flux at different energies, a spectrum with 95 keV weighted average energy was found to be the best compromise.

Spatial response of synthetic microDiamond and diode detectors measured with kilovoltage synchrotron radiation.

PURPOSE: To map the spatial response of four solid-state radiation detectors of types commonly used for radiotherapy dosimetry. METHODS: PTW model 60016 Diode P, 60017 Diode E, 60018 Diode SRS, and 60019 microDiamond detectors were radiographed using a high resolution conventional X-ray system. Their spatial response was then investigated using a 0.1 mm diameter beam of 95 keV average energy photons generated by a synchrotron. The detectors were scanned through the beam while their signal was recorded as a function of position, to map the response. These 2D response maps were created in both the end-on and side-on orientations. RESULTS: The results show the location and size of the active region. End-on, the active area was determined to be centrally located and within 0.2 mm of the manufacturer's specified diameter. The active areas of the 60016 Diode P, 60017 Diode E, 60018 Diode SRS detectors are uniform to within approximately 5%. The 60019 microDiamond showed local variations up to 30%. The extra-cameral signal in the microDiamond was calculated from the side-on scan to be approximately 8% of the signal from the active element. CONCLUSIONS: The spatial response of four solid-state detectors has been measured. The technique yielded information about the location and uniformity of the active area, and the extra-cameral signal, for the beam quality used.

Comparative toxicity of synchrotron and conventional radiation therapy based on total and partial body irradiation in a murine model.

Synchrotron radiation can facilitate novel radiation therapy modalities such as microbeam radiation therapy (MRT) and high dose-rate synchrotron broad-beam radiation therapy (SBBR). Both of these modalities have unique physical properties that could be exploited for an improved therapeutic effect. While pre-clinical studies report promising normal tissue sparing phenomena, systematic toxicity data are still required. Our objective was to characterise the toxicity of SBBR and MRT and to calculate equivalent doses of conventional radiation therapy (CRT). A dose-escalation study was performed on C57BLJ/6 mice using total body and partial body irradiations. Dose-response curves and TD50 values were subsequently calculated using PROBIT analysis. For SBBR at dose-rates of 37 to 41 Gy/s, we found no evidence of a normal tissue sparing effect relative to CRT. Our findings also show that the MRT valley dose, rather than the peak dose, best correlates with CRT doses for acute toxicity. Importantly, longer-term weight tracking of irradiated animals revealed more pronounced growth impairment following MRT compared to both SBBR and CRT. Overall, this study provides the first in vivo dose-equivalence data between MRT, SBBR and CRT and presents systematic toxicity data for a range of organs that can be used as a reference point for future pre-clinical work.

Characterization of a synthetic single crystal diamond detector for dosimetry in spatially fractionated synchrotron x-ray fields.

PURPOSE: Modern radiotherapy modalities often use small or nonstandard fields to ensure highly localized and precise dose delivery, challenging conventional clinical dosimetry protocols. The emergence of preclinical spatially fractionated synchrotron radiotherapies with high dose-rate, sub-millimetric parallel kilovoltage x-ray beams, has pushed clinical dosimetry to its limit. A commercially available synthetic single crystal diamond detector designed for small field dosimetry has been characterized to assess its potential as a dosimeter for synchrotron microbeam and minibeam radiotherapy. METHODS: Experiments were carried out using a synthetic diamond detector on the imaging and medical beamline (IMBL) at the Australian Synchrotron. The energy dependence of the detector was characterized by cross-referencing with a calibrated ionization chamber in monoenergetic beams in the energy range 30-120 keV. The dose-rate dependence was measured in the range 1-700 Gy/s. Dosimetric quantities were measured in filtered white beams, with a weighted mean energy of 95 keV, in broadbeam and spatially fractionated geometries, and compared to reference dosimeters. RESULTS: The detector exhibits an energy dependence; however, beam quality correction factors (kQ) have been measured for energies in the range 30-120 keV. The kQ factor for the weighted mean energy of the IMBL radiotherapy spectrum, 95 keV, is 1.05 ± 0.09. The detector response is independent of dose-rate in the range 1-700 Gy/s. The percentage depth dose curves measured by the diamond detector were compared to ionization chambers and agreed to within 2%. Profile measurements of microbeam and minibeam arrays were performed. The beams are well resolved and the full width at halfmaximum agrees with the nominal width of the beams. The peak to valley dose ratio (PVDR) calculated from the profiles at various depths in water agrees within experimental error with PVDR calculations from Gafchromic film data. CONCLUSIONS: The synthetic diamond detector is now well characterized and will be used to develop an experimental dosimetry protocol for spatially fractionated synchrotron radiotherapy.