Sci-Sat AM: Brachy - 01: Evaluation of dose-volume metrics for microbeam radiation therapy.

Microbeam radiation therapy (MRT) is an experimental technique delivering an array of high dose synchrotron X-ray microbeams. Development of metrics to predict the biological efficacy of MRT dose distributions is needed to guide further MRT research and for potential translation to human trials. The most commonly used metric is the peak-to-valley-dose ratio (PVDR) relating the dose at the microbeam center to that between two microbeams. We investigate three additional metrics that characterize dose distributions from a more volumetric perspective - the peak-to-mean-valley-dose ratio (PMVDR), mean dose, and percentage volume below a threshold. The metrics are evaluated for Monte Carlo simulations of dose distributions in three cubic head phantoms (2, 4 and 8 cm side lengths) for microbeam widths of 25, 50, and 75 µm and centre-to-centre spacings of 100, 200 and 400 µm. The ratio of the PMVDR to the PVDR varied from 0.24 to 0.80 for the different configurations, indicating a difference in the predicted geometric dependence of outcome for these two metrics. The mean dose was 102, 79, and 42 % of the mean skin dose for the 2, 8, and 16 cm head phantoms, respectively. The percentage volume below a 10% dose threshold was highly dependent on geometry, with ranges for the different collimation configurations of 2 - 87% and 33 - 96% for the 2 and 16 cm heads, respectively. Different dose-volume metrics exhibit different dependencies on MRT geometry parameters, suggesting that reliance on PVDR as a predictor of therapeutic outcome may be insufficient.

Effects of pulsed, spatially fractionated, microscopic synchrotron X-ray beams on normal and tumoral brain tissue.

Microbeam radiation therapy (MRT) uses highly collimated, quasi-parallel arrays of X-ray microbeams of 50-600keV, produced by third generation synchrotron sources, such as the European Synchrotron Radiation Facility (ESRF), in France. The main advantages of highly brilliant synchrotron sources are an extremely high dose rate and very small beam divergence. High dose rates are necessary to deliver therapeutic doses in microscopic volumes, to avoid spreading of the microbeams by cardiosynchronous movement of the tissues. The minimal beam divergence results in the advantage of steeper dose gradients delivered to a tumor target, thus achieving a higher dose deposition in the target volume in fractions of seconds, with a sharper penumbra than that produced in conventional radiotherapy. MRT research over the past 20 years has yielded many results from preclinical trials based on different animal models, including mice, rats, piglets and rabbits. Typically, MRT uses arrays of narrow ( approximately 25-100 microm wide) microplanar beams separated by wider (100-400 microm centre-to-centre) microplanar spaces. The height of these microbeams typically varies from 1 to 100 mm, depending on the target and the desired preselected field size to be irradiated. Peak entrance doses of several hundreds of Gy are surprisingly well tolerated by normal tissues, up to approximately 2 yr after irradiation, and at the same time show a preferential damage of malignant tumor tissues; these effects of MRT have now been extensively studied over nearly two decades. More recently, some biological in vivo effects of synchrotron X-ray beams in the millimeter range (0.68-0.95 mm, centre-to-centre distances 1.2-4 mm), which may differ to some extent from those of microscopic beams, have been followed up to approximately 7 months after irradiation. Comparisons between broad-beam irradiation and MRT indicate a higher tumor control for the same sparing of normal tissue in the latter, even if a substantial fraction of tumor cells are not receiving a radiotoxic level of radiation. The hypothesis of a selective radiovulnerability of the tumor vasculature versus normal blood vessels by MRT, and of the cellular and molecular mechanisms involved remains under investigation. The paper highlights the history of MRT including salient biological findings after microbeam irradiation with emphasis on the vascular components and the tolerance of the central nervous system. Details on experimental and theoretical dosimetry of microbeams, core issues and possible therapeutic applications of MRT are presented.

MOSFET dosimetry with high spatial resolution in intense synchrotron-generated x-ray microbeams.

Various dosimeters have been tested for assessing absorbed doses with microscopic spatial resolution in targets irradiated by high-flux, synchrotron-generated, low-energy (approximately 30-300 keV) x-ray microbeams. A MOSFET detector has been used for this study since its radio sensitive element, which is extraordinarily narrow (approximately 1 microm), suits the main applications of interest, microbeam radiation biology and microbeam radiation therapy (MRT). In MRT, micrometer-wide, centimeter-high, and vertically oriented swaths of tissue are irradiated by arrays of rectangular x-ray microbeams produced by a multislit collimator (MSC). We used MOSFETs to measure the dose distribution, produced by arrays of x-ray microbeams shaped by two different MSCs, in a tissue-equivalent phantom. Doses were measured near the center of the arrays and maximum/minimum (peak/valley) dose ratios (PVDRs) were calculated to determine how variations in heights and in widths of the microbeams influenced this for the therapy, potentially important parameter. Monte Carlo (MC) simulations of the absorbed dose distribution in the phantom were also performed. The results show that when the heights of the irradiated swaths were below those applicable to clinical therapy (< 1 mm) the MC simulations produce estimates of PVDRs that are up to a factor of 3 higher than the measured values. For arrays of higher microbeams (i.e., 25 microm x 1 cm instead of 25 x 500 microm2), this difference between measured and simulated PVDRs becomes less than 50%. Closer agreement was observed between the measured and simulated PVDRs for the Tecomet MSC (current collimator design) than for the Archer MSC. Sources of discrepancies between measured and simulated doses are discussed, of which the energy dependent response of the MOSFET was shown to be among the most important.

The GEANT4 toolkit for microdosimetry calculations: application to microbeam radiation therapy (MRT).

Theoretical dose distributions for microbeam radiation therapy (MRT) are computed in this paper using the GEANT4 Monte Carlo (MC) simulation toolkit. MRT is an innovative experimental radiotherapy technique carried out using an array of parallel microbeams of synchrotron-wiggler-generated x rays. Although the biological mechanisms underlying the effects of microbeams are still largely unknown, the effectiveness of MRT can be traced back to the natural ability of normal tissues to rapidly repair small damages to the vasculature, and on the lack of a similar healing process in tumoral tissues. Contrary to conventional therapy, in which each beam is at least several millimeters wide, the narrowness of the microbeams allows a rapid regeneration of the blood vessels along the beams' trajectories. For this reason the calculation of the "valley" dose is of crucial importance and the correct use of MC codes for such purposes must be understood. GEANT4 offers, in addition to the standard libraries, a specialized package specifically designed to deal with electromagnetic interactions of particles with matter for energies down to 250 eV. This package implements two different approaches for electron and photon transport, one based on evaluated data libraries, the other adopting analytical models. These features are exploited to cross-check theoretical computations for MRT. The lateral and depth dose profiles are studied for the irradiation of a 20 cm diameter, 20 cm long cylindrical phantom, with cylindrical sources of different size and energy. Microbeam arrays are simulated with the aid of superposition algorithms, and the ratios of peak-to-valley doses are computed for typical cases used in preclinical assays. Dose profiles obtained using the GEANT4 evaluated data libraries and analytical models are compared with simulation results previously obtained using the PENELOPE code. The results show that dose profiles computed with GEANT4's analytical model are almost indistinguishable from those obtained with the PENELOPE code, but some noticeable differences appear when the evaluated data libraries are used.

Determination of dosimetrical quantities used in microbeam radiation therapy (MRT) with Monte Carlo simulations.

Microbeam radiation therapy (MRT) is being performed by using an array of narrow rectangular x-ray beams (typical beam sizes 25 microm X 1 cm), positioned close to each other (typically 200 microm separation), to irradiate a target tissue. The ratio of peak-to-valley doses (PVDR's) in the composite dose distribution has been found to be strongly correlated with the normal tissue tolerance and the therapeutic effect of MRT. In this work a Monte Carlo (MC) study of the depth- and lateral-dose profiles in water for single x-ray microbeams of different shapes and energies has been performed with the MC code PENELOPE. The contributions to the dose deposition from different interaction types have been determined at different distances from the center of the microbeam. The dependence of the peak dose, in a water phantom, on the microbeam field size used in the preclinical trials, has been demonstrated. Composite dose distributions for an array of microbeams were obtained using superposition algorithms and PVDR's were determined and compared with literature results obtained with other Monte Carlo codes. The dependence of the PVDR's on microbeam width, x-ray energy used, and on the separation between adjacent microbeams has been studied in detail.

Calculations of electron fluence correction factors using the Monte Carlo code PENELOPE.

In electron-beam dosimetry, plastic phantom materials may be used instead of water for the determination of absorbed dose to water. A correction factor phi(water)plastic is then needed for converting the electron fluence in the plastic phantom to the fluence at an equivalent depth in water. The recommended values for this factor given by AAPM TG-25 (1991 Med. Phys. 18 73-109) and the IAEA protocols TRS-381 (1997) and TRS-398 (2000) disagree, in particular at large depths. Calculations of the electron fluence have been done, using the Monte Carlo code PENELOPE, in semi-infinite phantoms of water and common plastic materials (PMMA, clear polystyrene, A-150, polyethylene, Plastic water and Solid water (WT1)). The simulations have been carried out for monoenergetic electron beams of 6, 10 and 20 MeV, as well as for a realistic clinical beam. The simulated fluence correction factors differ from the values in the AAPM and IAEA recommendations by up to 2%, and are in better agreement with factors obtained by Ding et al (1997 Med. Phys. 24 161-76) using EGS4. Our Monte Carlo calculations are also in good accordance with phi(water)plastic values measured by using an almost perturbation-free ion chamber. The important interdependence between depth- and fluence-scaling corrections for plastic phantoms is discussed. Discrepancies between the measured and the recommended values of phi(water)plastic may then be explained considering the different depth-scaling rules used.