Validation of a Monte Carlo simulation for Microbeam Radiation Therapy on the Imaging and Medical Beamline at the Australian Synchrotron

Microbeam Radiation Therapy (MRT) is an emerging cancer treatment modality characterised by the use of high-intensity synchrotron-generated x-rays, spatially fractionated by a multi-slit collimator (MSC), to ablate target tumours. The implementation of an accurate treatment planning system, coupled with simulation tools that allow for independent verification of calculated dose distributions are required to ensure optimal treatment outcomes via reliable dose delivery. In this article we present data from the first Geant4 Monte Carlo radiation transport model of the Imaging and Medical Beamline at the Australian Synchrotron. We have developed the model for use as an independent verification tool for experiments in one of three MRT delivery rooms and therefore compare simulation results with equivalent experimental data. The normalised x-ray spectra produced by the Geant4 model and a previously validated analytical model, SPEC, showed very good agreement using wiggler magnetic field strengths of 2 and 3 T. However, the validity of absolute photon flux at the plane of the Phase Space File (PSF) for a fixed number of simulated electrons was unable to be established. This work shows a possible limitation of the G4SynchrotronRadiation process to model synchrotron radiation when using a variable magnetic field. To account for this limitation, experimentally derived normalisation factors for each wiggler field strength determined under reference conditions were implemented. Experimentally measured broadbeam and microbeam dose distributions within a Gammex RMI457 Solid Water® phantom were compared to simulated distributions generated by the Geant4 model. Simulated and measured broadbeam dose distributions agreed within 3% for all investigated configurations and measured depths. Agreement between the simulated and measured microbeam dose distributions agreed within 5% for all investigated configurations and measured depths

Validation of Geant4-based Simulation and Characterisation of Silicon Dosimeters for Quality Assurance and Beam Monitoring in Microbeam Radiation Therapy

Despite extensive research into improvements in brain cancer treatment, the cancer re- lated mortality since 1983 has remained nearly constant. Synchrotron-based radiotherapy microbeam radiation therapy (MRT) has emerged as a promising novel treatment aimed at improving tumour control while reducing normal tissue toxicities in brain cancer pa- tients. The complex features of the synchrotron source and microbeam (MB) array re- quires careful consideration in the quest towards the progression of MRT to clinical trials. The research presented in this PhD thesis aims contributes to the international field of re- search through advances in MRT quality assurance (QA) processes relating to treatment planning, dosimetry and treatment delivery verification. Specifically, this thesis evalu- ates an independent Geant4 Treatment Planning System (TPS) verification tool, a novel p-type epitaxial silicon strip detector, and finally the transmission characteristics of two silicon–based multi-strip detectors for transmission–based real-time beam monitoring in MRT. One major outcome is the development and implementation of the first exclusive Geant4 Monte Carlo model of the Imaging and Medical Beamline (IMBL) at the Australian Syn- chrotron (AS). This model was successfully validated experimentally, with agreement between simulated and measured broadbeam (BB) and microbeam (MB) dose distribu- tions within 3% and 5% respectively for all investigated configurations and measure- ment depths. Through this development, the research identified a potential limitation in the G4SynchrotronRadiation process when modelling the synchrotron radiation pro- duction in variable magnetic fields. Correction factors are necessary to account for the synchrotron radiation production modelling limitations in key MRT beamline configura- tions. The novel p-type epitaxial silicon strip detector demonstrates desirable detector characteristics for implementation in high resolution MRT dosimetry. Notable improve- ments, over a previous generation device, include improvement in the energy dependence (relative to water) and spatial resolution. The improvements in detector design pioneer a method for developing accurate silicon-based dosimetry for application in routine MRT QA. Suitable implementation enables pre-clinical trials and future clinical trials. Further work investigates the impact of a novel back-etched silicon–based multi-strip beam mon- itor on the MRT beam quality and dose deposition characteristics. Evaluated by means of Monte Carlo simulation and experimental methods, recommendations are made for implementing and modelling silicon–based beam monitors within the context of a future TPS

X-ray microbeam measurements with a high resolution scintillator fibre-optic dosimeter

Synchrotron microbeam radiation therapy is a novel external beam therapy under investigation, that uses highly brilliant synchrotron x-rays in microbeams 50 μm width, with separation of 400 μm, as implemented here. Due to the fine spatial fractionation dosimetry of these beams is a challenging and complicated problem. In this proof-of-concept work, we present a fibre optic dosimeter that uses plastic scintillator as the radiation conversion material. We claim an ideal one-dimensional resolution of 50 μm. Using plastic scintillator and fibre optic makes this dosimeter water-equivalent, a very desirable dosimetric property. The dosimeter was tested at the Australian Synchrotron, on the Imaging and Medical Beam-Line. The individual microbeams were able to be resolved and the peak-to-valley dose ratio and the full width at half maximum of the microbeams was measured. These results are compared to a semiconductor strip detector of the same spatial resolution. A percent depth dose was measured and compared to data acquired by an ionisation chamber. The results presented demonstrate significant steps towards the development of an optical dosimeter with the potential to be applied in quality assurance of microbeam radiation therapy, which is vital if clinical trials are to be performed on human patients

Polo-like kinase 1 inhibitor BI6727 sensitizes 9L gliosarcoma cells to ionizing irradiation

Surgery, chemotherapy and radiotherapy remain as the major treatment strategies for cancers. Some agents such as anti-cancer drugs have capacity to enhance the radiation sensitivity of cancer cells at G2/M phase, leading to an improved radiotherapeutic efficacy. BI6727 is an ATP-competitive pololike kinase 1 (Plk 1)inhibitor and an anti-cancer drug. Using the radio-resistant 9L rat gliosarcoma cells as model, we examined the effect of BI6727 on cell growth and assessed the chemoradiotherapeutic efficiency between 150 kVp conventional irradiation (dose rate of 0.76 Gy min−1 ) and 66 keV synchrotron x-ray broad beam irradiation (dose rate of 46 Gy s−1). Our studies showed that BI6727 significantly caused cell growth arrest at G2/M phase and inhibited 9L cell proliferation with EC50 of 58.1 nM. In combinatory treatment, irradiation of BI6727-treated 9L cells with synchrotron x-rays at a dose rate of 46 Gy s−1 resulted in significant reduction of the cell survival compared to the conventional x-rays at a dose rate of 0.76 Gy min−1. These results indicated that Plk1 inhibitor BI6727 enhanced radio-sensitization of 9L cells in a dose rate dependent manner. For clinical application, irradiation with high dose rate is a promising strategy to improve chemo-radiotherapeutic efficacy for gliosarcoma cancer

Characterisation and evaluation of a PNP strip detector for synchrotron microbeam radiation therapy

The Quality Assurance requirements of detectors for Synchrotron Micro-beam Radiation Therapy are such that there are limited commercial systems available. The high intensity and spatial fractionation of synchrotron microbeams requires detectors be radiation hard and capable of measuring high dose gradients with high spatial resolution sensitivity. Silicon single strip detectors are a promising candidate for such applications. The PNP strip detector is an alternative design of an already proven technology and is assessed on its contextual viability. In this study, the electrical and charge collection efficiency properties of the device are characterised. In addition, a dedicated TCAD model is used to support ion beam induced charge measurements to determine the spatial resolution of the detector. Lastly, the detector was used to measure the full width half maximum and peak to valley dose ratio for microbeams with only a slight over response. With the exception of radiation hardness the PNP detector is a promising candidate for quality assurance in microbeam radiation therapy

New 3D Silicon detectors for dosimetry in Microbeam Radiation Therapy

Microbeam Radiation Therapy (MRT) involves the use of a spatially fractionated beam of synchrotron generated X-rays to treat tumours. MRT treatment is delivered via an array of high dose \u27peaks\u27 separated by low dose \u27valleys\u27. A good Peak to Valley Dose Ratio (PVDR) is an important indicator of successful treatment outcomes. MRT dosimetry requires a radiation hard detector with high spatial resolution, large dynamic range, which is ideally real-time and tissue equivalent. We have developed a Silicon Strip Detector (SSD) and very recently, a new 3D MESA SSD to meet the very stringent requirements of MRT dosimetry. We have compared these detectors through the characterisation of the MRT radiation field at the Australian Synchrotron Imaging and Medical Beamline. The EPI SSD was able to measure the microbeam profiles and PVDRs, however the effective spatial resolution was limited by the detector alignment options available at the time. The geometry of the new 3D MESA SSD is less sensitive to this alignment restriction was able to measure the microbeam profiles within 2 ¿m of that expected. The 3D MESA SSD measured PVDRs were possibly affected by undesired and slow charge collection outside the sensitive volume and additional scattering from the device substrate

Experimental evaluation of the dosimetric impact of intrafraction prostate rotation using film measurement with a 6DoF robotic arm

Purpose: Tumor motion during radiotherapy can cause a reduction in target dose coverage and an increase in healthy tissue exposure. Tumor motion is not strictly translational and often exhibits complex six degree-of-freedom (6DoF) translational and rotational motion. Although the dosimetric impact of prostate tumor translational motion is well investigated, the dosimetric impact of 6DoF motion has only been studied with simulations or dose reconstruction. This study aims to experimentally quantify the dose error caused by 6DoF motion. The experiment was designed to test the hypothesis that 6DoF motion would cause larger dose errors than translational motion alone through gamma analyses of two-dimensional film measurements. Methods: Four patient-measured intrafraction prostate motion traces and four VMAT 7.25 Gy/Fx SBRT treatment plans were selected for the experiment. The traces represented typical motion patterns, including small-angle rotations (6°). Gafchromic film was placed inside a custom-designed phantom, held by a high-precision 6DoF robotic arm for dose measurements in the coronal plane during treatment delivery. For each combination of the motion trace and treatment plan, two film measurements were made, one with 6DoF motion and the other with the three-dimensional (3D) translation components of the same trace. A gamma pass rate criteria of 2% relative dose/2 mm distance-to-agreement was used in this study and evaluated for each measurement with respect to the static reference film. Two test thresholds, 90% and 50% of the reference dose, were applied to investigate the difference in dose coverage for the PTV region and surrounding areas, respectively. The hypothesis was tested using a Wilcoxon signed-rank test. Results: For each of the 16 plan and motion trace pairs, a reduction in the gamma pass rate was observed for 6DoF motion compared with 3D translational motion. With 90% gamma-test threshold, the reduction was 5.8% ± 7.1% (P < 0.01). With 50% gamma-test threshold, the reduction was 4.1% ± 4.8% (P < 0.01). Conclusion: For the first time, the dosimetric impact of intrafraction prostate rotation during SBRT treatment was measured experimentally. The experimental results support the hypothesis that 6DoF tumor motion causes higher dose error than translation motion alone

X-Tream dosimetry of highly brilliant X-ray microbeams in the MRT hutch of the Australian Synchrotron

The X-Tream dosimetry system developed at the Centre for Medical Radiation Physics (University of Wollongong, Australia) utilises a high resolution silicon Single Strip Detector to characterise synchrotron radiation microbeams for the purpose of Quality Assurance of Microbeam Radiation Therapy. Firstly, a comparison of the Silicon Strip Detector performance with respect to a conventional PinPoint Ionisation Chamber for broad beams and microbeams is given. These results are then extended to characterise the horizontal microbeam radiation field available in the high flux experimental hutch of the Imaging and Medical BeamLine at the Australian Synchrotron. The Silicon Strip Detector measured depth dose curve of the broad beam agrees very well with the PinPoint Ionisation Chamber measurements between 10 and 50 mm depth in water. Significant deviations from the PinPoint Ionisation Chamber response are observed with increasing depth. Microbeam profiles measured by the Silicon Strip Detector are well resolved but clearly affected by misalignment of the Silicon Strip Detector with respect to the microbeams. Future beamline technical improvements will alleviate this issue

Experimental Evaluation of the Dosimetric Impact of Intrafraction Prostate Rotations Using Film Measurement with a 6 DoF Robotic Arm

Purpose Tumor motion during radiotherapy can cause a reduction in target dose coverage and an increase in healthy tissue exposure. Tumor motion is not strictly translational and often exhibits complex six degree‐of‐freedom (6DoF) translational and rotational motion. Although the dosimetric impact of prostate tumor translational motion is well investigated, the dosimetric impact of 6DoF motion has only been studied with simulations or dose reconstruction. The present study aims to experimentally quantify the dose error caused by 6DoF motion. The experiment was designed to test the hypothesis that 6DoF motion would cause larger dose errors than translational motion alone through gamma analyses of 2D film measurements. Methods Four patient‐measured intrafraction prostate motion traces and four VMAT 7.25Gy/Fx SBRT treatment plans were selected for the experiment. The traces represented typical motion patterns, including small‐angle rotations (\u3c4°), transient movement, persistent excursion and erratic rotations (\u3e6°). Gafchromic film was placed inside a custom‐designed phantom, held by a high precision 6DoF robotic arm for dose measurements in the coronal plane during treatment delivery. For each combination of the motion trace and treatment plan, two film measurements were made, one with 6DoF motion and the other with the 3D translation components of the same trace. A gamma pass rate criteria of 2% relative dose/2 mm distance‐to‐agreement was used in this study and evaluated for each measurement with respect to the static reference film. Two test thresholds, 90% and 50% of the reference dose, were applied to investigate the difference in dose coverage for the PTV region and surrounding areas, respectively. The hypothesis was tested using a Wilcoxon signed‐rank test. Results For each of the sixteen plan and motion trace pairs, a reduction of the gamma pass rate was observed for 6DoF motion compared with 3D translational motion. With 90% gamma‐test threshold, the reduction was 5.8% ± 7.1% (p\u3c0.01). With 50% gamma‐test threshold, the reduction was 4.1% ± 4.8%(p\u3c0.01). Conclusion For the first time, the dosimetric impact of intrafraction prostate rotation during SBRT treatment was measured experimentally. The experimental results support the hypothesis that 6DoF tumor motion causes higher dose error than translation motion alone