Patient-specific margins for proton therapy of lung.

Lung cancer treatment presents a greater treatment planning and treatment delivery challenge in proton beam therapy compared to conventional photon therapy due to the proton beam's energy deposition sensitivity to the breathing-induced dynamic tissue density variations along the beam path. Four-dimensional computed tomography (4D-CT) has been defined as the explicit inclusion of temporal changes of tumor and normal organ mobility into an image series. It allows more accurate delineation of lung cancer target volumes by suppression of any breathing motion artifacts present in the CT images. It also allows analysis of the tumor's 3D spatial movement within a breathing phase cycle. The motivation for this study was to investigate dosimetric errors caused by lung tumor motion in order to find an optimal method of design for patient compensators and apertures for a passive scattering beam delivery system and treatment of the patient under free breathing conditions. In this study, the maximum intensity projection (MIP) method was compared to patient-specific internal margin designs based on a single breathing phase at the end-of inhale (EOI) or middle-of-exhale (MOE). It was found that MIP method provides superior tumor dose distribution compared to patient-specific internal margin designs derived from 4D-CT.

Morphological study of endothelial cells during freezing.

Microvascular injury is recognized as a major tissue damage mechanism of ablative cryosurgery. Endothelial cells lining the vessel wall are thought to be the initial target of freezing. However, details of this injury mechanism are not yet completely understood. In this study, ECMatrix 625 was used to mimic the tumour environment and to allow the endothelial cells cultured in vitro to form the tube-like structure of the vasculature. The influence of water dehydration on the integrity of this structure was investigated. It was found that the initial cell shape change was mainly controlled by water dehydration, dependent on the cooling rate, resulting in the shrinkage of cells in the direction normal to the free surface. As the cooling was prolonged and temperature was lowered, further cell shape change could be induced by the chilling effects on intracellular proteins, and focal adhesions to the basement membrane. Quantitative analysis showed that the freezing induced dehydration greatly enhanced the cell surface stresses, especially in the axial direction. This could be one of the major causes of the final breaking of the cell junction and cell detachment.

Imaging and dosimetric errors in 4D PET/CT-guided radiotherapy from patient-specific respiratory patterns: a dynamic motion phantom end-to-end study.

Effective positron emission tomography / computed tomography (PET/CT) guidance in radiotherapy of lung cancer requires estimation and mitigation of errors due to respiratory motion. An end-to-end workflow was developed to measure patient-specific motion-induced uncertainties in imaging, treatment planning, and radiation delivery with respiratory motion phantoms and dosimeters. A custom torso phantom with inserts mimicking normal lung tissue and lung lesion was filled with [(18)F]FDG. The lung lesion insert was driven by six different patient-specific respiratory patterns or kept stationary. PET/CT images were acquired under motionless ground truth, tidal breathing motion-averaged (3D), and respiratory phase-correlated (4D) conditions. Target volumes were estimated by standardized uptake value (SUV) thresholds that accurately defined the ground-truth lesion volume. Non-uniform dose-painting plans using volumetrically modulated arc therapy were optimized for fixed normal lung and spinal cord objectives and variable PET-based target objectives. Resulting plans were delivered to a cylindrical diode array at rest, in motion on a platform driven by the same respiratory patterns (3D), or motion-compensated by a robotic couch with an infrared camera tracking system (4D). Errors were estimated relative to the static ground truth condition for mean target-to-background (T/Bmean) ratios, target volumes, planned equivalent uniform target doses, and 2%-2 mm gamma delivery passing rates. Relative to motionless ground truth conditions, PET/CT imaging errors were on the order of 10-20%, treatment planning errors were 5-10%, and treatment delivery errors were 5-30% without motion compensation. Errors from residual motion following compensation methods were reduced to 5-10% in PET/CT imaging, <5% in treatment planning, and <2% in treatment delivery. We have demonstrated that estimation of respiratory motion uncertainty and its propagation from PET/CT imaging to RT planning, and RT delivery under a dose painting paradigm is feasible within an integrated respiratory motion phantom workflow. For a limited set of cases, the magnitude of errors was comparable during PET/CT imaging and treatment delivery without motion compensation. Errors were moderately mitigated during PET/CT imaging and significantly mitigated during RT delivery with motion compensation. This dynamic motion phantom end-to-end workflow provides a method for quality assurance of 4D PET/CT-guided radiotherapy, including evaluation of respiratory motion compensation methods during imaging and treatment delivery.

Phantom assessment of lung dose from proton arc therapy.

PURPOSE: To compare resultant lung dose from proton arc therapy of the chest wall to that from electron arc therapy. METHODS AND MATERIALS: A 200 MeV proton beam from the Indiana University Cyclotron was range shifted and modulated to provide a spread out Bragg peak extending from the surface to a depth of 4 cm in water. The chest wall of an Alderson Rando phantom was irradiated by this beam, collimated to a 20 x 4 cm field size, while it rotated on a platform at approximately 1 rpm. For comparison, electron arc therapy of the Rando phantom chest wall was similarly performed with 12 MeV electrons and the resultant lung dose measured in each case. RESULTS: Dose-volume histograms for the Rando phantom left lung indicate a reduced volume of irradiated lung for protons at all dose levels and an integral lung dose that is half that for electron arc therapy in the case studied. In addition, a more uniform dose coverage of the target volume was achieved with the proton therapy. CONCLUSION: This study demonstrates a potential role for proton arc therapy as an alternative to electron arc therapy when lung dose must be minimized.

A reliable method for quantitating chromatin fragments by flow cytometry to predict the effect of total body irradiation and hyperthermia on mice.

The frequencies of chromatin fragments, including micronuclei, in murine thymus cells, spleen cells and bone marrow cells have been used as a quantitative indicator of gamma-ray induced chromosome damage and could be used to screen potential radioprotective agents as well. The yield of chromatin fragments induced in mice receiving different dosage levels of total body irradiation alone and in mice also given whole body hyperthermia as a potent radioprotector were assessed by flow cytometric analysis. Our results demonstrated that chromatin fragments induced by irradiation in vivo was clearly dose-dependent and that chromatin fragments could potentially serve as a biological indicator of radiation damage. One hour of whole body hyperthermia at 40 degrees C (+/- 0.2 degree C) given 20 hours before a lethal dosage (900 cGy) of total body irradiation protects 100% of DBA/2 mice from an LD 100/16 irradiation dose (dose of irradiation that killed 100% of the mice in 16 days). This is in good agreement with the percent of chromatin fragments formed in the cells of the protected animals, which showed no significant difference from those observed in the normal mice. The results indicate that whole body hyperthermia protected the thymus and bone marrow from irradiation damage. This study provides further evidence which supports that whole body hyperthermia can act as a potent radioprotector in vivo. Measurement of the frequencies of chromatin fragments by flow cytometry is simple and reliable. The method can be applied to screen radioprotective agents.

Proton loss model for therapeutic beam dose calculations.

A transport algorithm called the proton loss (PL) model is developed for proton pencil beams of therapeutic energies. The PL model takes into account inelastic nuclear reactions, pathlength straggling, and energy-loss straggling and predicts the 3D dose distribution from a proton pencil beam. In proton beams, the multiple scattering and ionizational energy loss processes approach their diffusional limit where scattering and energy loss probability densities become Gaussian. Therefore we chose to derive the PL model from the Fermi-Eyges diffusional multiple scattering theory and the Gaussian theory of energy straggling. We first introduce a generalization of the Fermi-Eyges equation for proton pencil beams, labeled the proton loss (PL) transport equation. This new equation includes terms that model inelastic nuclear reactions as a depth-dependent absorption and pathlength straggling as a quasi-absorption. Then energy straggling is taken into account by using a weighted superposition of a discrete number of elementary pencil beams. These elementary pencil beams have different initial energies and lose energy according to the CSDA, thus they have different ranges of penetration. A final solution for the proton beam transport is obtained as a linear combination of elementary pencil beam solutions with weights defined by the Gaussian evolution of the proton energy spectrum with depth. A numerical comparison of the dose distribution predictions of the PL model with measurements and PTRAN Monte Carlo simulations indicates the model is both computational fast and accurate.

Shielding for neutron scattered dose to the fetus in patients treated with 18 MV x-ray beams.

Neutrons are associated with therapeutic high energy x-ray beams as a contaminant that contributes significant unwanted dose to the patient. Measurement of both photon and neutron scattered dose at the position of a fetus from chest irradiation by a large field 18 MV x-ray beam was performed using an ionization chamber and superheated drop detector, respectively. Shielding construction to reduce this scattered dose was investigated using both lead sheet and borated polyethylene slabs. A 7.35 cm lead shield reduced the scattered photon dose by 50% and the scattered neutron dose by 40%. Adding 10 cm of 5% borated polyethylene to this lead shield reduced the scattered neutron dose by a factor of 7.5 from the unshielded value. When the 5% borated polyethylene was replaced by the same thickness of 30% borated polyethylene there was no significant change in the reduction of neutron scatter dose. The most efficient shield studied reduced the neutron scatter dose by a factor of 10. The results indicate that most of the scattered neutrons present at the position of the fetus produced by an 18 MV x-ray beam are of low energy and in the thermal to 0.57 MeV range since lead is almost transparent to neutrons with energies lower than 0.57 MeV. This article constitutes the first report of an effective shield to reduce neutron dose at the fetus when treating a pregnant woman with a high energy x-ray beam.

Application of Fermi scattering theory to a magnetically scanned electron linear accelerator.

This paper uses a solution to the Fermi electron transport equation for an isotropic point source to characterize the magnetically scanned broad electron beams from the Sagittaire Therac 40 accelerator in the air space above patients. Thick lead collimation is shown to be adequately modeled by an infinitely thin absorbing plate when used to predict penumbra shape. A relationship between broad beam penumbra width and the value of the root-mean-square spatial Gaussian spread sigma (z) of an elementary pencil beam is derived. This relationship is applicable for any rectangular field size. Measurement of the variation in broad beam penumbra width with source-surface distance (SSD) for a 7-MeV beam locates the isotropic source to be coincident with the exit window of the accelerator and indicates that the scattering effect of the monitor chamber may be considered negligibly small. Using this source location accurate predictions of beam profile shape for any clinically used beam energy, SSD, or field size are made in the presence of lead trimmer collimation. Field penumbra beyond the photon collimation system is formed in each lateral direction by two lead blocks whose faces are aligned along a diverging ray emanating from the source. The photon collimator closest to the source restricts the field size causing a variation of both fluence and the mean square angle spread of the electrons across the plane at the level of the lower collimator. This variation is accounted for by introducing an empirical perturbation factor into the mathematical formalism. An interesting feature of this perturbation factor is that it is field size dependent and its effect on penumbra width may be scaled for both beam energy and SSD to accurately predict beam profile shape.

An EGS4 Monte Carlo examination of the response of a PTW-diamond radiation detector in megavoltage electron beams.

The EGS4 Monte Carlo code has been used to investigate the response of a PTW/diamond detector irradiated in both clinical and monoenergetic megavoltage electron beams ranging in energy from 5 to 20 MeV. The sensitive volume of the PTW/diamond detector simulated has a thickness of 0.4 mm and a diameter of 4.4 mm. Irradiation was simulated at various depths in a water phantom. The results show that the PTW/diamond detector has a constant response (within 1.0%) in electron beams if irradiated at depths closed to dmax, and its response is almost independent of irradiation depth or incident electron energy (within 3%). A detailed examination of the average detector dose shows that the sensitive volume of the PTW/diamond detector acts as a Spencer-Attix cavity within 1%. The encapsulation of the bare diamond detector with low-Z epoxy and polystyrene wall material does not affect its response in electron beams. The difference in response between the unencapsulated (TLD) and the encapsulated form of the detector is less than 0.5% for all depths over electron energy range investigated.

A Monte Carlo comparison of the response of the PTW-diamond and the TL-diamond detectors in megavoltage photon beams.

A detailed Monte Carlo study of the PTW-diamond solid state detector response in megavoltage photon beams (60Co gamma rays to 25 MV x rays) has been performed with the EGS4 Monte Carlo Code. The sensitive volume of the diamond detector is a disk of diameter 4.4 mm and thickness 0.40 mm. The phantom material was water and the irradiation depth was usually 3 cm but additional simulations were performed at six other depths for the 10 and 25 MV x rays. Results show that the PTW-diamond detector response per unit of absorbed dose is constant within 1% for photon beam energies ranging from 60Co gamma rays to 25 MV x rays. Accurate depth dose curves for 10 and 25 MV x-ray beams may be measured with the diamond detector since the response per unit of absorbed dose at different depths in a water phantom is also constant to within 1% for depths ranging from 3 to 25 cm and field sizes ranging from 2.5 cm by 2.5 cm to 10 cm by 10 cm. An examination of the difference between the PTW-diamond detector and the wall-less form of the detector (e.g., TLDs) revealed that there is no significant difference in their response in megavoltage photon beams. This implies that the encapsulation of the diamond dosimeter causes less than a 1.3% change in its response for these megavoltage photon beams. Analysis of the total dose deposited in the sensitive volume of the detector shows that the PTW-diamond detector behaves as an intermediate-sized cavity, not a simple Bragg-Gray cavity, since the dose contribution from photon interactions within the cavity (alpha(c)) to the total cavity dose is 8% for 25 MV x rays and increases to 42% for 60Co gamma rays.

Depth ionization curves for an unmodulated proton beam measured with different ionization chambers.

Differences in depth dose curves for a 78 MeV unmodulated proton beam were measured with four commercially available ionization chambers. Measurements were performed both in water and in a commercially available solid water phantom. A depth scaling factor (Cpl) was determined from the ratio of depths distal to the Bragg peak where the dose is reduced to 80% of the maximum dose in water and in the solid water phantom. This scaling factor provides good agreement between the ionization curves at all depths in water and in this solid water phantom. There is no significant difference in the value of the depth scaling factor between the ratios (R80wat/R80med) and (R50wat/R50med), or (R100wat/R100med) for 78 MeV unmodulated proton beams. The depth scaling factor for this commercially available solid water phantom is 1.023. An effective point of measurement for a cylindrical ionization chamber was found to be slightly greater than the 50% of the cavity radius proposed by the AAPM-TG25 dosimetry protocol for electron beams and amounts to 62.5% of the cavity radius of cylindrical ionization chambers. The ion collection efficiency, Pion, and the polarity correction factor, Ppol, for all the ionization chambers studied are within 1% and 0.4% of unity, respectively. Absolute doses measured with a parallel plate ionization chamber in water and in the solid water phantom show that the doses measured in the solid water phantom are 1.4% +/- 0.5% lower than in water. The dose rate dependent response of the beam line monitor chamber was also investigated. Agreement between all the chambers was within 1.5% at the dose rates studied but the results showed that all four ionization chambers are less dose rate dependent than the monitor chamber.

Comparative Ngas measurements for a parallel plate chamber in proton, electron, and 60Co beams.

The TG21 protocol introduced the Ngas calibration method for parallel plate chambers in high-energy electron beams. This calibration method was performed for a Markus parallel plate chamber in proton and electron beams of various energies as well as a 60Co beam. For an individual chamber, the Ngas value in proton beams differs from the Ngas value in cobalt and electron beams by the ratio of (W/e) for proton beams to that of a 60Co beam. While the replacement correction factor is essential for Markus chambers in low-energy electron beams, the results of our Nppgas measurements in proton beams showed that the Markus chamber does not need a replacement correction factor for therapeutic proton beams of energy 20-170 MeV. These results indicate that the 0.7-mm guard ring of the Markus chamber is adequate to prevent the in-scattering of secondary electrons produced by proton irradiation of the chamber wall or medium.

A solution to the Yang equation with electron energy loss following Harder's formula.

The Yang diffusion transport equation for charged particles was modified to allow the linear angular scattering power to vary with penetration depth in the scattering medium. Assuming charged particle energy loss to be a linear function of depth, conditional solutions to this transport equation have been found for the two cases of interest specified by Yang. The normalized excess path length distributions predicted for a 10-MeV electron beam show a shift toward larger excess path lengths compared to Yang's solutions.

Comparison of superheated drop detector with phosphorous pentoxide powder for the detection of neutrons in 18 MV x rays.

Neutron dose equivalent measurements were performed in and around an 18 MV x-ray beam using superheated drop detectors (SDD) and phosphorous pentoxide (P2O5) powder. The neutron dose equivalent profiles for various field sizes of 10 X 10 cm2, 20 X 20 cm2, and 30 X 30 cm2 were measured. The results measured with the P2O5 were checked for any gross systematic errors by comparing with the published results computed by using Monte Carlo calculations. A comparison was then made between the neutron dose equivalent profiles measured with the P2O5 and the SDD. The results of this comparison show that the neutron dose equivalents measured with the two types of detectors agree with each other for measurements about 20 cm away from the beam edges. However, in and near the beam edges the SDD measurements are upto 50% less than the neutron dose equivalents measured using P2O5 for the 18 MV x-ray beam.

A restricted angular scattering model for electron penetration in dense media.

A restricted angular scattering model for electron penetration in dense media is presented. In the model, the Fermi-Eyges transport equation is modified through the addition of an extra term which may be interpreted as representing an apparent force opposing the scattering of electrons into wider angles. The introduction of this extra term allows the modeling of the measured saturation in the mean square angular spread of electrons with depth. The restricted scattering model retains the Gaussian features of the Fermi-Eyges model and, therefore, may be readily incorporated into existing dose computation algorithms. Good agreement is obtained with measured angular electron distribution data for a point monodirectional beam over a wide range of incident electron energies (5-20 MeV) and scattering media (atomic numbers of 6 to 82). Also, a comparison of the restricted scattering model predictions with measurements of the lateral pencil beam spread shows an improvement over the predictions of Fermi-Eyges model close to the end of the electron range. Broad beam profiles were generated using both the Fermi-Eyges and restricted scattering models. A comparison of predicted and measured beam profiles shows that the restricted scattering model is a significant improvement over the Fermi-Eyges model for the prediction of beam penumbra shape in homogeneous media.

Extension of a numerical algorithm to proton dose calculations. I. Comparisons with Monte Carlo simulations.

A numerical algorithm originally developed for electron dose calculations [Med. Phys. 21, 1591 (1994)] has been modified for use with proton beams. The algorithm recursively propagates the proton distribution in energy, angle, and space from one level in an absorbing medium to another at slightly greater depth until all protons stop. Vavilov's theory is used to predict, at any point in the absorber, the broadening of the primary proton energy-spectrum. Moliere's theory is applied to describe the angular distribution, and it is shown that the Gaussian first term of Moliere's series expansion is of sufficient accuracy for dose calculations. These multiple scattering and energy loss distributions are sampled using equal probability spacing to optimize computational speed while maintaining calculational accuracy. Inelastic nuclear collisions along the proton trajectories are modeled by a simple exponential extinction. Predictions of the algorithm for absolute dose deposition by a 160 MeV initially monoenergetic proton beam are compared with the results of Monte Carlo simulations performed with the PTRAN code. The excellent level of agreement between the results of these two methods of dose calculation (< 5% dose and < 3 mm spatial deviations) demonstrate that dose deposition from proton beams may be computed to high accuracy using this algorithm without the need for extensive empirical measurement as input.

Comparison of methods to determine electron pencil beam spread in tissue-equivalent media.

This study has intercompared the predictions of Fermi-Eyges theory for the rms spatial spread (sigma) of an electron pencil beam scattering in muscle-, lung- and bone-equivalent media with those of; two range straggling modifications to the theory, Monte Carlo simulations, and an empirical method based on broad beam penumbra. Systematic differences among the results obtained by these methods for the values of sigma have been identified. Monte Carlo simulations are lower than the predictions of Fermi-Eyges theory for sigma at all depths whereas the broad beam penumbra method results are in reasonable agreement with Fermi-Eyges theory at depths less than approximately 0.7 times the range of the incident electrons. All of the methods investigated have an increasing discrepancy from the predictions of Fermi-Eyges theory with depth, especially close to the end of the electron range. The two range-straggling modifications to Fermi-Eyges theory developed for soft tissue do not agree with either measured or Monte Carlo results for sigma in homogeneous scattering media of lung and bone.

A method for the calculation of electron energy-straggling spectra.

To calculate electron beam dose distributions accurately, numerical methods of electron transport calculations must account for the statistical variation (or "straggling") in electron energy loss. This paper shows that the various energy straggling theories that are applicable to short path lengths all derive from a single statistical model, known as the compound Poisson process. This model in turn relies on three assumptions: (1) the number of energy-loss events in a given path length is Poisson distributed; (2) events are mutually independent; and (3) each event has the same probability distribution for energy loss (i.e., the same energy-loss cross section). Applying the principles of the compound Poisson process and using fast Fourier transforms, a new method for calculating energy-loss spectra is developed. The spectra calculated using this method for 10, 20, and 30 MeV electrons incident on graphite and aluminum absorbers agreed with Monte Carlo simulations (EGS4) within 1% in the spectral peak. Also, stopping powers derived from the calculated spectra agreed within 1.2%, with stopping powers tabulated by the International Commission on Radiation Units and Measurements. Several numerical transport methods "propagate" the electron distribution (in position, direction, and energy) over small discrete increments of path length. Thus the propagation of our calculated spectra over multiple path length increments is investigated. For a low atomic number absorber (graphite in this case), calculated spectra agreed with EGS4 Monte Carlo simulations over the full electron range, provided the path length increments were sufficiently small (less than 0.5 g/cm2). It is concluded from these results that numerical methods of electron transport should restrict the size of path length increments to less than 0.5 g/cm2 if energy straggling is to be modeled accurately.

Inclusion of energy straggling in a numerical method for electron dose calculation.

Energy straggling along electron trajectories has been incorporated into a numerical algorithm for electron beam dose calculations. Landau's theory is used to predict, at any point in the absorber, the broadening of the primary electron energy spectrum due to energy loss straggling. Numerical calculations have been performed for electron beams with energies of 10-30 MeV incident upon water in order to determine the variation of dose with depth and variation of energy spectra with pathlength. These calculations are compared with the results of Monte Carlo simulations performed with the EGS4 code. The inclusion of energy loss straggling in the numerical calculations leads to predictions of energy spectra and dose deposition that are in good agreement with modified Monte Carlo simulations in which bremsstrahlung is ignored and the energy given to knock-on electrons is deposited at the site of their creation. Less satisfactory agreement was achieved when these calculations were compared to full Monte Carlo simulations that included the bremsstrahlung events and transported the knock-on electrons. It is concluded that bremsstrahlung energy loss must also be included into this algorithm, if an acceptable dose computation accuracy is to be achieved for clinical applications.

A model for the time dependent three-dimensional thermal distribution within iceballs surrounding multiple cryoprobes.

A time dependent three-dimensional finite difference model of iceball formation about multiple cryoprobes has been developed and compared to experimental data. Realistic three-dimensional probe geometry is specified and the number of cryoprobes, the cryoprobe cooling rates, and the locations of the probes are arbitrary inputs by the user. The simulation accounts for observed longitudinal thermal gradients along the cryoprobe tips. Thermal histories for several points around commercially available cryoprobes have been predicted within experimental error for one, three, and five probe configurations. The simulation can be used to generate isotherms within the iceball at arbitrary times. Volumes enclosed by the iceball and any isotherms may also be computed to give the ablative ratio, a measure of the iceball's killing efficiency. This ratio was calculated as the volume enclosed by a critical isotherm divided by the total volume of the iceball for assumed critical temperatures of -20 and -40 degrees C. The ablative ratio for a single probe is a continuously decreasing function of time but when multiple probe configurations are used the ablative ratio increases to a maximum and then essentially plateaus. Maximum values of 0.44 and 0.55 were observed for three and five probe configurations, respectively, with an assumed critical temperature of -20 degrees C. Assuming a critical temperature of -40 degrees C, maximum ablative ratios of 0.21 and 0.3 for three and five probe configurations, respectively, were observed.