Is Mini Beam Ready for Human Trials? Results of Randomized Study of Treating De-Novo Brain Tumors in Canines Using Linear Accelerator Generated Mini Beams.

The main challenge in treating malignant brain neoplasms lies in eradicating the tumor while minimizing treatment-related damage. Conventional radiation treatments are associated with considerable side effects. Synchrotron generated micro-beam radiation (SMBRT) has shown to preserve brain architecture while killing tumor cells, however physical characteristics and limited facility access restrict its use. We have created a new clinical device which produces mini beams on a linear accelerator, to provide a new type of treatment called mini-beam radiation therapy (MBRT). The objective of this study is to compare the treatment outcomes of linear accelerator based MBRT versus standard radiation treatment (SRT), to evaluate the tumor response and the treatment-related changes in the normal brain with respect to each treatment type. Pet dogs with de-novo brain tumors were accrued for treatment. Dogs were randomized between standard fractionated stereotactic (9 Gy in 3 fractions) radiation treatment vs. a single fraction of MBRT (26 Gy mean dose). Dogs were monitored after treatment for clinical assessment and imaging. When the dogs were euthanized, a veterinary pathologist assessed the radiation changes and tumor response. We accrued 16 dogs, 8 dogs in each treatment arm. In the MBRT arm, 71% dogs achieved complete pathological remission. The radiation-related changes were all confined to the target region. Structural damage was not observed in the beam path outside of the target region. In contrast, none of the dogs in control group achieved remission and the treatment related damage was more extensive. Therapeutic superiority was observed with MBRT, including both tumor control and the normal structural preservation. The MBRT findings are suggestive of an immune related mechanism which is absent in standard treatment. These findings together with the widespread availability of clinical linear accelerators make MBRT a promising research topic to explore further treatment and clinical trial opportunities.

Medical linear accelerator mounted mini-beam collimator: design, fabrication and dosimetric characterization.

The goal of this work was to design, build and experimentally characterize a linear accelerator mounted mini-beam collimator for use at a nominal 6 MV beam energy. Monte Carlo simulation was used in the design and dosimetric characterization of a compact mini-beam collimator assembly mounted to a medical linear accelerator. After fabrication, experimental mini-beam dose profiles and central axis relative output were measured and the results used to validate the simulation data. The simulation data was then used to establish traceability back to an established dosimetric code of practice. The Monte Carlo simulation work revealed that changes in collimator blade width have a greater influence on the valley-to-peak dose ratio than do changes in blade height. There was good agreement between the modeled and measured profile data, with the exception of small differences on either side of the central peak dose. These differences were found to be systematic across all depths and result from limitations associated with the collimator fabrication. Experimental mini-beam relative output and simulation data agreed to better than ± 2.0%, which is well within the level of uncertainty required for dosimetric traceability of non-standard field geometries. A mini-beam collimator has now been designed, built and experimentally characterized for use with a commercial linear accelerator operated at a nominal 6 MV beam energy.

Clinical use of diodes and micro-chambers to obtain accurate small field output factor measurements.

There have been substantial advances in small field dosimetry techniques and technologies, over the last decade, which have dramatically improved the achievable accuracy of small field dose measurements. This educational note aims to help radiation oncology medical physicists to apply some of these advances in clinical practice. The evaluation of a set of small field output factors (total scatter factors) is used to exemplify a detailed measurement and simulation procedure and as a basis for discussing the possible effects of simplifying that procedure. Field output factors were measured with an unshielded diode and a micro-ionisation chamber, at the centre of a set of square fields defined by a micro-multileaf collimator. Nominal field sizes investigated ranged from 6 × 6 to 98 × 98 mm(2). Diode measurements in fields smaller than 30 mm across were corrected using response factors calculated using Monte Carlo simulations of the diode geometry and daisy-chained to match micro-chamber measurements at intermediate field sizes. Diode measurements in fields smaller than 15 mm across were repeated twelve times over three separate measurement sessions, to evaluate the reproducibility of the radiation field size and its correspondence with the nominal field size. The five readings that contributed to each measurement on each day varied by up to 0.26  %, for the "very small" fields smaller than 15 mm, and 0.18 % for the fields larger than 15 mm. The diode response factors calculated for the unshielded diode agreed with previously published results, within uncertainties. The measured dimensions of the very small fields differed by up to 0.3 mm, across the different measurement sessions, contributing an uncertainty of up to 1.2 % to the very small field output factors. The overall uncertainties in the field output factors were 1.8 % for the very small fields and 1.1 % for the fields larger than 15 mm across. Recommended steps for acquiring small field output factor measurements for use in radiotherapy treatment planning system beam configuration data are provided.

Design and experimental testing of air slab caps which convert commercial electron diodes into dual purpose, correction-free diodes for small field dosimetry.

PURPOSE: Two diodes which do not require correction factors for small field relative output measurements are designed and validated using experimental methodology. This was achieved by adding an air layer above the active volume of the diode detectors, which canceled out the increase in response of the diodes in small fields relative to standard field sizes. METHODS: Due to the increased density of silicon and other components within a diode, additional electrons are created. In very small fields, a very small air gap acts as an effective filter of electrons with a high angle of incidence. The aim was to design a diode that balanced these perturbations to give a response similar to a water-only geometry. Three thicknesses of air were placed at the proximal end of a PTW 60017 electron diode (PTWe) using an adjustable "air cap". A set of output ratios (ORDet (fclin) ) for square field sizes of side length down to 5 mm was measured using each air thickness and compared to ORDet (fclin) measured using an IBA stereotactic field diode (SFD). kQclin,Qmsr (fclin,fmsr) was transferred from the SFD to the PTWe diode and plotted as a function of air gap thickness for each field size. This enabled the optimal air gap thickness to be obtained by observing which thickness of air was required such that kQclin,Qmsr (fclin,fmsr) was equal to 1.00 at all field sizes. A similar procedure was used to find the optimal air thickness required to make a modified Sun Nuclear EDGE detector (EDGEe) which is "correction-free" in small field relative dosimetry. In addition, the feasibility of experimentally transferring kQclin,Qmsr (fclin,fmsr) values from the SFD to unknown diodes was tested by comparing the experimentally transferred kQclin,Qmsr (fclin,fmsr) values for unmodified PTWe and EDGEe diodes to Monte Carlo simulated values. RESULTS: 1.0 mm of air was required to make the PTWe diode correction-free. This modified diode (PTWeair) produced output factors equivalent to those in water at all field sizes (5-50 mm). The optimal air thickness required for the EDGEe diode was found to be 0.6 mm. The modified diode (EDGEeair) produced output factors equivalent to those in water, except at field sizes of 8 and 10 mm where it measured approximately 2% greater than the relative dose to water. The experimentally calculated kQclin,Qmsr (fclin,fmsr) for both the PTWe and the EDGEe diodes (without air) matched Monte Carlo simulated results, thus proving that it is feasible to transfer kQclin,Qmsr (fclin,fmsr) from one commercially available detector to another using experimental methods and the recommended experimental setup. CONCLUSIONS: It is possible to create a diode which does not require corrections for small field output factor measurements. This has been performed and verified experimentally. The ability of a detector to be "correction-free" depends strongly on its design and composition. A nonwater-equivalent detector can only be "correction-free" if competing perturbations of the beam cancel out at all field sizes. This should not be confused with true water equivalency of a detector.

A practical and theoretical definition of very small field size for radiotherapy output factor measurements.

PURPOSE: This work introduces the concept of very small field size. Output factor (OPF) measurements at these field sizes require extremely careful experimental methodology including the measurement of dosimetric field size at the same time as each OPF measurement. Two quantifiable scientific definitions of the threshold of very small field size are presented. METHODS: A practical definition was established by quantifying the effect that a 1 mm error in field size or detector position had on OPFs and setting acceptable uncertainties on OPF at 1%. Alternatively, for a theoretical definition of very small field size, the OPFs were separated into additional factors to investigate the specific effects of lateral electronic disequilibrium, photon scatter in the phantom, and source occlusion. The dominant effect was established and formed the basis of a theoretical definition of very small fields. Each factor was obtained using Monte Carlo simulations of a Varian iX linear accelerator for various square field sizes of side length from 4 to 100 mm, using a nominal photon energy of 6 MV. RESULTS: According to the practical definition established in this project, field sizes ≤ 15 mm were considered to be very small for 6 MV beams for maximal field size uncertainties of 1 mm. If the acceptable uncertainty in the OPF was increased from 1.0% to 2.0%, or field size uncertainties are 0.5 mm, field sizes ≤ 12 mm were considered to be very small. Lateral electronic disequilibrium in the phantom was the dominant cause of change in OPF at very small field sizes. Thus the theoretical definition of very small field size coincided to the field size at which lateral electronic disequilibrium clearly caused a greater change in OPF than any other effects. This was found to occur at field sizes ≤ 12 mm. Source occlusion also caused a large change in OPF for field sizes ≤ 8 mm. Based on the results of this study, field sizes ≤ 12 mm were considered to be theoretically very small for 6 MV beams. CONCLUSIONS: Extremely careful experimental methodology including the measurement of dosimetric field size at the same time as output factor measurement for each field size setting and also very precise detector alignment is required at field sizes at least ≤ 12 mm and more conservatively ≤ 15 mm for 6 MV beams. These recommendations should be applied in addition to all the usual considerations for small field dosimetry, including careful detector selection.

Small field dosimetric characterization of a new 160-leaf MLC.

The goal of this work was to perform a 6 MV small field characterization of the new Agility 160-leaf multi-leaf collimator (MLC) from Elekta. This included profile measurement analysis and central axis relative output measurements using various diode detectors and an air-core fiber optic scintillation dosimeter (FOD). Data was acquired at a depth of 10.0 cm for field sizes of 1.0, 0.9, 0.8, 0.7, 0.6 and 0.5 cm. Three experimental data sets, comprised of five readings, were made for both the relative output and profile measurements. Average detector-specific output ratios (OR[overline](f(clin))(det))) were calculated with respect to a field size of 3.0 cm and small field replacement correction factors (k(f(clin),f(msr))(Q(clin),Q(msr))) derived for the diodes using the scintillation dosimeter readings as the baseline. The standard experimental uncertainty on OR[overline](f(clin))(det)) was calculated at a 90% confidence interval and the coefficient of variation (CV) used to characterize the detector-specific measurement precision. The positional accuracy of the collimation system was also investigated by analyzing the repeated profile measurements and field width constancy investigated as a function of collimator rotation. For comparison the output and profile measurements were repeated using the Elekta 80-leaf MLCi2 on a beam matched linac at 6 MV. The measured OR[overline](f(clin))(det)) varied as a function of detector and MLC design. At the smallest field size the standard experimental uncertainty on OR[overline](f(clin))(det)) was consistent across all detectors at approximately 0.5% and 1.0% for Agility and MLCi2 collimators respectively. The CV associated with the FOD measurements were greater than that of the diodes but did not translate into increased measurement uncertainty. At the smallest field size, the diode detector correction factors were approximately 2% greater for MLCi2 than that required for the Agility. Profile data revealed the Agility MLC to have a greater positional reproducibility than both the MLCi2 and the linac diaphragms (jaws), as also reflected in the experimental uncertainties on OR[overline](f(clin))(det)). The relative output, profile widths and associated uncertainties were all found to differ between the two MLC systems investigated, as were the field size specific diode detector replacement correction factors. The data also clearly showed that the Agility 160-leaf MLC performs to a tighter positional tolerance than the MLCi2.

Monte Carlo modelling of diode detectors for small field MV photon dosimetry: detector model simplification and the sensitivity of correction factors to source parameterization.

The goal of this work was to examine the use of simplified diode detector models within a recently proposed Monte Carlo (MC) based small field dosimetry formalism and to investigate the influence of electron source parameterization has on MC calculated correction factors. BEAMnrc was used to model Varian 6 MV jaw-collimated square field sizes down to 0.5 cm. The IBA stereotactic field diode (SFD), PTW T60016 (shielded) and PTW T60017 (un-shielded) diodes were modelled in DOSRZnrc and isocentric output ratios (OR(fclin)(detMC)) calculated at depths of d = 1.5, 5.0 and 10.0 cm. Simplified detector models were then tested by evaluating the percent difference in (OR(fclin)(detMC)) between the simplified and complete detector models. The influence of active volume dimension on simulated output ratio and response factor was also investigated. The sensitivity of each MC calculated replacement correction factor (k(fclin,fmsr)(Qclin,Qmsr)), as a function of electron FWHM between 0.100 and 0.150 cm and energy between 5.5 and 6.5 MeV, was investigated for the same set of small field sizes using the simplified detector models. The SFD diode can be approximated simply as a silicon chip in water, the T60016 shielded diode can be modelled as a chip in water plus the entire shielding geometry and the T60017 unshielded diode as a chip in water plus the filter plate located upstream. The detector-specific (k(fclin,fmsr)(Qclin,Qmsr)), required to correct measured output ratios using the SFD, T60016 and T60017 diode detectors are insensitive to incident electron energy between 5.5 and 6.5 MeV and spot size variation between FWHM = 0.100 and 0.150 cm. Three general conclusions come out of this work: (1) detector models can be simplified to produce OR(fclin)(detMC) to within 1.0% of those calculated using the complete geometry, where typically not only the silicon chip, but also any high density components close to the chip, such as scattering plates or shielding material is necessary to be included in the model, (2) diode detectors of smaller active radius require less of a correction and (3) (k(fclin,fmsr)(Qclin,Qmsr)) is insensitive to the incident the electron energy and spot size variations investigated. Therefore, simplified detector models can be used with acceptable accuracy within the recently proposed small field dosimetry formalism.

Implementing a newly proposed Monte Carlo based small field dosimetry formalism for a comprehensive set of diode detectors.

PURPOSE: The goal of this work was to implement a recently proposed small field dosimetry formalism [Alfonso et al., Med. Phys. 35(12), 5179-5186 (2008)] for a comprehensive set of diode detectors and provide the required Monte Carlo generated factors to correct measurement. METHODS: Jaw collimated square small field sizes of side 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, and 3.0 cm normalized to a reference field of 5.0 cm × 5.0 cm were used throughout this study. Initial linac modeling was performed with electron source parameters at 6.0, 6.1, and 6.2 MeV with the Gaussian FWHM decreased in steps of 0.010 cm from 0.150 to 0.100 cm. DOSRZnrc was used to develop models of the IBA stereotactic field diode (SFD) as well as the PTW T60008, T60012, T60016, and T60017 field diodes. Simulations were run and isocentric, detector specific, output ratios (OR(det)) calculated at depths of 1.5, 5.0, and 10.0 cm. This was performed using the following source parameter subset: 6.1 and 6.2 MeV with a FWHM = 0.100, 0.110, and 0.120 cm. The source parameters were finalized by comparing experimental detector specific output ratios with simulation. Simulations were then run with the active volume and surrounding materials set to water and the replacement correction factors calculated according to the newly proposed formalism. RESULTS: In all cases, the experimental field size widths (at the 50% level) were found to be smaller than the nominal, and therefore, the simulated field sizes were adjusted accordingly. At a FWHM = 0.150 cm simulation produced penumbral widths that were too broad. The fit improved as the FWHM was decreased, yet for all but the smallest field size worsened again at a FWHM = 0.100 cm. The simulated OR(det) were found to be greater than, equivalent to and less than experiment for spot size FWHM = 0.100, 0.110, and 0.120 cm, respectively. This is due to the change in source occlusion as a function of FWHM and field size. The corrections required for the 0.5 cm field size were 0.95 (± 1.0%) for the SFD, T60012 and T60017 diodes and 0.90 (± 1.0%) for the T60008 and T60016 diodes-indicating measured output ratios to be 5% and 10% high, respectively. Our results also revealed the correction factors to be the same within statistical variation at all depths considered. CONCLUSIONS: A number of general conclusions are evident: (1) small field OR(det) are very sensitive to the simulated source parameters, and therefore, rigorous Monte Carlo linac model commissioning, with respect to measurement, must be pursued prior to use, (2) backscattered dose to the monitor chamber should be included in simulated OR(det) calculations, (3) the corrections required for diode detectors are design dependent and therefore detailed detector modeling is required, and (4) the reported detector specific correction factors may be applied to experimental small field OR(det) consistent with those presented here.

EUD-based radiotherapy treatment plan evaluation: incorporating physical and Monte Carlo statistical dose uncertainties.

The purpose of this work is to quantify the impact of dose uncertainty on radiobiologically based treatment plan evaluation. Dose uncertainties are divided into two categories: physical and statistical. Physical dose uncertainty is associated with the systematic and/or random errors incurred during treatment planning and/or delivery. The dose uncertainty associated with Monte Carlo calculated dose distributions is deemed statistical and noted as artificial with respect to the actual delivered dose. We will refer to all dose uncertainties that arise from either calculation or delivery as stochastic. Both physical and statistical dose uncertainties are considered at the intra- and inter-voxel levels. To account for voxel dose uncertainty, we calculate the mean survival fraction (SF) for the random dose deposition. Mathematically, the expression for the mean survival fraction is identical to that used by Niemierko (1997 Med. Phys. 24 103-10) in defining equivalent uniform dose (EUD). To distinguish between spatial and probabilistic dose variations, we define equivalent stochastic dose (ESD) as a voxel dose that gives the mean expected survival fraction for the randomly deposited dose. For a probability density function f(D), that represents the probabilistic voxel dose, SF(ESD) can be calculated by convolving SF(D) with f(D). In the case where the probability density function follows a Gaussian distribution, an analytic expression is derived for SF(ESD). The derived expression is verified using the Monte Carlo method and ESD values calculated with varied radiosensitivities for cases of 60 and 70 Gy at 2 Gy per fraction. The analytic expression is also extended to account for a multi-voxel dose distribution that incorporates a spatial dose heterogeneity. The results show that survival fraction increases with an increased dose uncertainty. This reduction depends on radiobiological parameters attributed to tissue and tumour. For tissue, ESD drops to 55% of the mean physical dose when the dose has a 10% intra- and inter-voxel dose uncertainty and inhomogeneity.

Modelling an extreme water-lung interface using a single pencil beam algorithm and the Monte Carlo method.

The goal of this study was to quantify, in a heterogeneous phantom, the difference between experimentally measured beam profiles and those calculated using both a commercial convolution algorithm and the Monte Carlo (MC) method. This was done by arranging a phantom geometry that incorporated a vertical solid water-lung material interface parallel to the beam axis. At nominal x-ray energies of 6 and 18 MV, dose distributions were modelled for field sizes of 10 x 10 cm(2) and 4 x 4 cm(2) using the CadPlan 6.0 commercial treatment planning system (TPS) and the BEAMnrc-DOSXYZnrc Monte Carlo package. Beam profiles were found experimentally at various depths using film dosimetry. The results showed that within the lung region the TPS had a substantial problem modelling the dose distribution. The (film-TPS) profile difference was found to increase, in the lung region, as the field size decreased and the beam energy increased; in the worst case the difference was more than 15%. In contrast, (film-MC) profile differences were not found to be affected by the material density difference. BEAMnrc-DOSXYZnrc successfully modelled the material interface and dose profiles to within 2%.