Breathing-motion induced interplay effects for stereotactic body radiotherapy of liver tumours using flattening-filter free volumetric modulated arc therapy.

The purpose of this study was to investigate breathing-motion induced interplay effects for stereotactic body radiotherapy (SBRT) of liver tumours treated with flattening-filter free (FFF) volumetric modulated arc therapy (VMAT). Ten patients previously treated with liver SBRT were included in this study. All patients had four-dimensional computed tomography (4DCT) scans acquired prior to treatment. The 4DCT was sorted into 8-10 phases covering an equal time interval. A FFF VMAT plan was created for one fraction in the mid-ventilation phase for each patient. To generate dose distributions including both interplay effects and dose blurring, a sub-plan was calculated for each phase. The total dose distributions were accumulated to the mid-ventilation phase using the deformed vector fields (DVF) from deformable image registration between the corresponding CT and the mid-ventilation phase CT. A blurred dose distribution, not including interplay effects, was also obtained by distributing the delivery of the whole plan uniformly on all phases, and was similarly accumulated to the mid-ventilation phase. To isolate interplay effects, this blurred dose distribution was subtracted from the total dose distribution with interplay effects. The near minimum dose (D 98%), mean dose (D mean), heterogeneity index (HI), and the near minimum dose difference (ΔD 98%) between the accumulated dose distributions with and without interplay effects were calculated within the gross tumour volume (GTV) for each patient. Comparing the accumulated dose distributions with and without interplay effects, the D 98% decreased for nine of the ten patients and the HI increased for all patients. The median and minimum differences in D 98% were -2.1% and -5.0% (p = 0.006), respectively, and the median HI significantly increased from 6.2% to 12.2% (p = 0.002). The median ΔD 98% was -4.0% (range -7% to -1.5%). In conclusion, statistically significant breathing-induced interplay effects were observed for a single fraction of FFF VMAT liver SBRT, resulting in heterogeneous dose distributions within the GTV.

Analysis of dose heterogeneity using a subvolume-DVH.

The dose-volume histogram (DVH) is universally used in radiation therapy for its highly efficient way of summarizing three-dimensional dose distributions. An apparent limitation that is inherent to standard histograms is the loss of spatial information, e.g. it is no longer possible to tell where low- and high-dose regions are, and whether they are connected or disjoint. Two methods for overcoming the spatial fragmentation of low- and high-dose regions are presented, both based on the gray-level size zone matrix, which is a two-dimensional histogram describing the frequencies of connected regions of similar intensities. The first approach is a quantitative metric which can be likened to a homogeneity index. The large cold spot metric (LCS) is here defined to emphasize large contiguous regions receiving too low a dose; emphasis is put on both size, and deviation from the prescribed dose. In contrast, the subvolume-DVH (sDVH) is an extension to the standard DVH and allows for a qualitative evaluation of the degree of dose heterogeneity. The information retained from the two-dimensional histogram is overlaid on top of the DVH and the two are presented simultaneously. Both methods gauge the underlying heterogeneity in ways that the DVH alone cannot, and both have their own merits-the sDVH being more intuitive and the LCS being quantitative.

Reference dosimetry at the neutron capture therapy facility at Studsvik.

The purpose of this publication was to present and evaluate the methods for reference dosimetry in the epithermal neutron beam at the neutron capture therapy facility at Studsvik. Measurements were performed in a PMMA phantom and in air using ionization chambers and activation probes in order to calibrate the epithermal neutron beam. Appropriate beam-dependant calibration factors were determined using Monte Carlo methods for the detectors used in the present publication. Using the presented methodology, the photon, neutron and total absorbed dose to PMMA was determined with an estimated uncertainty of +/- 5.0%, +/- 25%, and +/- 5.5% (2 SD), respectively. The uncertainty of the determination of the photon absorbed dose was comparable to the case in conventional radiotherapy, while the uncertainty of the neutron absorbed dose is much higher using the present methods. The thermal neutron group fluence, i.e., the neutron fluence in the energy interval 0-0.414 eV, was determined with an estimated uncertainty of +/- 2.8% (2 SD), which is acceptable for dosimetry in epithermal neutron beams.

Photon quality correction factors for ionization chambers in an epithermal neutron beam.

Photon quality correction factors (kQy) for ionization chamber photon dosimetry in an epithermal neutron beam were determined according to a modified absorbed dose to water formalism which was extended to mixed radiation fields. We have studied two commercially available ionization chambers in the epithermal neutron beam optimized for BNCT at the facility at Studsvik, Sweden. One of the chambers is nominally neutron insensitive; a magnesium-walled detector flushed with pure argon gas (denoted by Mg/Ar). The second chamber has approximately the same sensitivity for neutrons and photons; it is considered a 'tissue equivalent' detector, with A-150 walls flushed with methane-based tissue-equivalent gas (denoted by TE/TE). The kQy-factors in epithermal neutron beams have previously been assumed to be equal to unity or estimated from measurements in clinical accelerator produced photon beams. In this work the kQy-factors have been determined from absorbed dose calculations using cavity theory together with Monte Carlo derived electron fluences obtained with the MCNP4c system for water and PMMA phantoms. The calculated quality correction factors differ substantially from unity, being in the order of 10% for the Mg/Ar detector at shallow phantom depths, and between 2 and 4% for other depths and for the TE/TE chamber.

Toward clinical application of prompt gamma spectroscopy for in vivo monitoring of boron uptake in boron neutron capture therapy.

In boron neutron capture therapy (BNCT) the absorbed dose to the tumor cells and healthy tissues depends critically on the boron uptake. Pronounced individual variations in the uptake patterns have been observed for two boron compounds currently used in clinical trials. This implies a high uncertainty in the determination of the boron dose component. In the present work a technique known as prompt gamma spectroscopy (PGS) is studied that potentially can be used for in vivo and noninvasive boron concentration determination at the time of the treatment. The technique is based upon measurement of gamma rays promptly emitted in the 10B(n,alpha)7Li and 1H(n,gamma)2D reactions. The aim of this work is to prepare the present setup for clinical application as a monitor of boron uptake in BNCT patients. Therefore, a full calibration and a set of phantom experiments were performed in a clinical setting. Specifically, a nonuniform boron distribution was studied; a skin/ dura, a larger blood vessel, and tumor within a head phantom was simulated. The results show that it is possible to determine a homogeneous boron concentration of 5 microg/g within +/-3% (1 standard deviation). In the nonuniform case, this work shows that the boron concentration can be determined through a multistep measurement procedure, however, with a somewhat higher uncertainty (approximately 10%). The present work forms the basis for a subsequent clinical application of the PGS setup aimed at in vivo monitoring of boron uptake.

Independent checking of the delivered dose for high-energy X-rays using a hand-held PC.

BACKGROUND AND PURPOSE: The requirements on the delivered dose in radical radiation therapy are extremely high. The dose should be within a few percent and also delivered with high accuracy in space. Vendors and users have successfully managed to implement radiation therapy systems, which are able to achieve these demands with high accuracy and reproducibility. These systems include computerized tomography scanners, treatment planning systems, simulators, treatment machines, and record and verify systems. More and more common are also computer networks to assure data integrity when transferring information between the systems. Even if these systems are commissioned and kept under quality assurance programs to maintain their accuracy, errors may be introduced. Especially, the human factor is an uncontrolled parameter that may introduce errors. Thus, unintentional changes or incorrect handling of data may occur during clinical use of the equipment. Having an independent dose calculation system implemented in the daily quality assurance process may assure a high quality of treatments and avoidance of severe errors. MATERIALS AND METHODS: To accomplish this, a system of equations for calculating the absorbed dose to the prescription point from the set-up information, has been compiled into a dose-calculation engine. The model is based on data completely independent of the treatment planning system (TPS). The fundamental parameter in the dose engine is the linear attenuation coefficient for the primary photons. This parameter can readily be determined experimentally. The dose calculation engine has been programmed into a hand-held PC allowing direct calculation of the dose to the prescription point when the first treatment is delivered to the patient. RESULTS AND CONCLUSION: The model is validated with measurements and is shown to be within +/-1.0% (1 SD). Comparison against a state-of-the-art TPS shows an average difference of 0.3% with a standard deviation of +/-2.1%. An action level covering 95% of the cases has been chosen, i.e. +/-4.0%. Deviations larger than this are with a high probability due to erroneous handling of the patient set-up data. This system has been implemented into the daily clinical quality control program.

On beam quality and stopping power ratios for high-energy x-rays.

The aim of this work is to quantitatively compare two commonly used beam quality indices, IPR(20/10) and %dd(10)x, with respect to their ability to predict stopping power ratios (water to air), s(w,air), for high-energy x-rays. In particular, effects due to a varied amount of filtration of the photon beam will be studied. A new method for characterizing beam quality is also presented, where the information we strive to obtain is the moments of the spectral distribution. We will show how the moments enter into a general description of the transmission curve and that it is possible to correlate the moments to s(w,air) with a unique and simple relationship. Comparisons with TPR(20/10) and %dd(10), show that the moments are well suited for beam quality specification in terms of choosing the correct s(w,air).

Transmission measurements in air using the ESTRO mini-phantom.

The aim of this work is to study the possibility of using the ESTRO mini-phantom for transmission measurements of primary kerma in water at a point free in air. We discuss in-air measurements in general, with special attention given to in-air equivalent measurements using a water equivalent mini-phantom. The study includes four different photon energies (4, 6, 10 and 18 MV), where scoring of dose and primary kerma inside a mini-phantom in narrow beam geometry is performed with the Monte Carlo code EGS4. The results reveal that relative measurements (i.e. with and without a water absorber present) at 10 cm depth in a mini-phantom do not represent the variation of primary kerma in water at a point free in air (deviations as large as 7% at 4 MV are observed). Minimum deviations are obtained at depths somewhat larger than the depth of dose maximum. The observed deviations are due to a considerable beam hardening in the water absorber, which changes the amount of attenuation and scatter inside the mini-phantom.

Quality control of measured x-ray beam data.

The purpose of this study was to examine whether the quality of measured x-ray beam data can be judged from how well the data agree with a semiempirical formula. Tissue-phantom ratios (TPR) and output factors for several accelerators in the energy range 4-25 MV were fitted to the formula, separating the dose contributions from primary and phantom-scattered photons. The former was described by exponential attenuation in water, with beam hardening, and the latter by the scatter-to-primary dose ratio using two parameters related to the probability and the directional distribution of the scattered photons. Electron disequilibrium was not considered. Two approaches were evaluated. In one, the attenuation and hardening coefficients were determined from measurements in a narrow-beam geometry; in the other, they were extracted by the fitting procedure. Measured and fitted data agreed within +/- 2% in both cases. The differences were randomly distributed and had a standard deviation of typically 0.7%. Singular points with errors were easily identified. Systematic errors were revealed by increased standard deviation. However, when the attenuation was derived by the fitting algorithm, the attenuation coefficient deviated significantly from the experimental value. It is concluded that the semiempirical formula can serve to evaluate and verify beam data measured in water and that the physically most accurate description requires that the attenuation and hardening coefficients be determined in a narrow-beam geometry. The attenuation coefficient is an excellent measure of both the primary and the scatter dose component, i.e., of beam quality.

Dosimetric comparison of treatment planning systems in irradiation of breast with tangential fields.

PURPOSE: The objectives of this study are: (1) to investigate the dosimetric differences of the different treatment planning systems (TPS) in breast irradiation with tangential fields, and (2) to study the effect of beam characteristics on dose distributions in tangential breast irradiation with 6 MV linear accelerators from different manufacturers. METHODS AND MATERIALS: Nine commercial and two university-based TPS are evaluated in this study. The computed tomographic scan of three representative patients, labeled as "small", "medium" and "large" based on their respective chest wall separations in the central axis plane (CAX) were used. For each patient, the tangential fields were set up in each TPS. The CAX distribution was optimized separately with lung correction, for each TPS based on the same set of optimization conditions. The isodose distributions in two other off-axis planes, one 6 cm cephalic and the other 6 cm caudal to the CAX plane were also computed. To investigate the effect of beam characteristics on dose distributions, a three-dimensional TPS was used to calculate the isodose distributions for three different linear accelerators, the Varian Clinac 6/100, the Siemens MD2 and the Philips SL/7 for the three patients. In addition, dose distributions obtained with 6 MV X-rays from two different accelerators, the Varian Clinac 6/100 and the Varian 2100C, were compared. RESULTS: For all TPS, the dose distributions in all three planes agreed qualitatively to within +/- 5% for the "small" and the "medium" patients. For the "large" patient, all TPS agreed to within +/- 4% on the CAX plane. The isodose distributions in the caudal plane differed by +/- 5% among all TPS. In the cephalic plane in which the patient separation is much larger than that in the CAX plane, six TPS correctly calculated the dose distribution showing a cold spot in the center of the breast contour. The other five TPS showed that the center of the breast received adequate dose. Isodose distributions for 6 MV X-rays from three different accelerators differed by about +/- 3% for the "small" patient and more than +/- 5% for the "large" patient. For two different 6 MV machines of the same manufacturer, the isodose distribution agreed to within +/- 2% for all three planes for the "large" patient. CONCLUSION: The differences observed among the various TPS in this study were within +/- 5% for both the "small" and the "medium" patients while doses at the hot spot exhibit a larger variation. The large discrepancy observed in the off-axis plane for the "large" patient is largely due to the inability of most TPS to incorporate the collimator angles in the dose calculation. Only six systems involved agreed to within +/- 5% for all three patients in all calculation planes. The difference in dose distributions obtained with three accelerators from different manufacturers is probably due to the difference in beam profiles. On the other hand, the 6 MV X-rays from two different models of linear accelerators from the same manufacturer have similar beam characteristics and the dose distributions are within +/- 2% of each other throughout the breast volume. In general, multi-institutional breast treatment data can be compared within a +/- 5% accuracy.

Off-axis primary-dose measurements using a mini-phantom.

The characterization of the incident photon beam is usually divided into its dependence on collimator setting (head-scatter factor) and off-axis position (primary off-axis ratio). These parameters are normally measured "in air" with a build-up cap thick enough to generate full dose build-up at the depth of dose maximum. In order to prevent any influence from contaminating electrons, it has been recommended that head-scatter measurements are carried out using a mini-phantom rather than a conventional build-up cap. Due to the volume of the mini-phantom, the effects from attenuation and scatter are not negligible. In relative head-scatter measurements these effects cancel and the head scatter is thus a good representation of the variation of the incident photon beam with collimator setting. However, in off-axis measurements, attenuation and scatter conditions vary due to beam softening and do not cancel in the calculation of the primary off-axis ratio. The purpose of the present work was to estimate the effects from attenuation and phantom scatter in order to determine their influence on primary off-axis ratio measurements. We have characterized the off-axis beam-softening effect by means of narrow-beam transmission measurements to obtain the effective attenuation coefficient as a function of off-axis position. We then used a semi-analytical expression for the phantom-scatter calculation that depends solely on this attenuation coefficient. The derived formalism for relative "in air" measurements using a mini-phantom is clear and consistent, which enables the user to separately calculate the effects from scatter and attenuation. For the investigated beam qualities, 6 and 18 MV, our results indicate that the effects from attenuation and scatter in the mini-phantom nearly cancel (the combined effect is less than 1%) within 12.5 cm from the central beam axis. Thus, no correction is needed when the primary off-axis ratio is measured with a mini-phantom.

Pharmacokinetics of Na2B12H11SH (BSH) in patients with malignant brain tumours as prerequisite for a phase I clinical trial of boron neutron capture.

The disposition of Na2B12H11SH (BSH) in patients with malignant glioma has been investigated, in preparation for a Phase I clinical trial of boron neutron capture therapy. BSH was found to possess a linear disposition over the dosage interval investigated (up to 75 mg/kg). A bi-phasic blood pharmacokinetics was observed. Tumour-to-blood ratios showed variations between patients between 0.08 and 5.1. The data allow the definition of amount of BSH and timing of infusion for a Phase I clinical trial protocol.

The effects of divergence and nonuniformity on the x-ray pencil-beam dose kernel.

The scattered-photon part of pencil-beam dose kernels for high-energy x-ray beams can be derived experimentally by differentiating the broad-beam scatter-to-primary dose ratio as a function of radius. Formally, this requires a uniform and parallel beam, and the procedure is complicated by the nonideal, actual beam conditions: the primary dose profile is not uniform, the beam quality is not constant, and the distance to the source is not infinite. The experimentally determined scatter-to-primary ratios can be corrected for these effects before they are differentiated to give the pencil-beam kernels. The correction factors were calculated and shown to reach as much as 5% of the true scatter-to-primary ratio. The effect on the pencil beam was evaluated and corrected pencil beams were determined.

Tissue-phantom ratios from percentage depth doses.

When converting fractional (percentage) depth doses to tissue-phantom ratios, one must use a factor that accounts for the different source-to-point distances. Two minor correction factors are also involved. One is the ratio of total to primary dose at the two different distances from the source, for the same depth and field size. This factor is usually ignored. It was determined experimentally that this can introduce up to 1.5% error at 6 MV. The second correction factor reflects differences related to scattered photons and electrons at the depth of normalization in the two geometries. This correction is accounted for in published conversion procedures. It was found to be less than 1% provided the normalization depth is sufficient for electron equilibrium, which occurs first well beyond the depth of maximum dose. One may avoid electron-equilibrium problems by using an interim normalization depth that provides electron equilibrium with some margin, renormalizing to a shallower depth if desired. With this precaution, the accuracy when measured fractional depth doses were converted to tissue-phantom ratios was comparable to that of directly measured tissue-phantom ratios even when the correction factors were ignored.

Experimental determination of the dose kernel in high-energy x-ray beams.

A semiempirical method to characterize the pencil-beam dose kernel is presented. Results from measurements are described by mathematical models of the applicable physical processes. The measurements were made with 6 and 25 MV x-ray beams from a linear accelerator. Broad-beam notations were used consistently, and the pencil-beam quantities were obtained by differentiation. The results were compared to pencil-beam kernels calculated by Monte Carlo techniques. The analysis of the measured data included a number of approximations. It was assumed that all the constituent pencil beams in the field are parallel, i.e., the divergence is ignored. Furthermore, the lateral variations of the incident photon fluence and the energy spectrum were disregarded. Monte Carlo calculations, on the other hand, are based on an average energy spectrum over the field, and are free from divergence and variations in the incident photon fluence. Measured and Monte Carlo calculated pencil beams nevertheless agreed well, and the approximations mentioned caused at maximum 2.7% discrepancies for the largest field size at 6 MV.

A stochastic model for subcellular dosimetry in boron neutron capture therapy.

The therapeutic effectiveness of boron neutron capture therapy is highly dependent on the microscopic distribution of the administered boron compound. Two boron compounds with different uptake mechanisms in the tumour cells may thus cause effects of different degrees even if the macroscopic boron concentrations in the tumour tissue are the same. This difference is normally expressed quantitatively by the so-called relative local efficiency (RLE). In this work, a stochastic model for the subcellular dosimetry has been developed. This model can be used to calculate the probability for an energy deposition above a certain threshold level in the cell nucleus due to a single neutron capture reaction. If a threshold cell-kill function is assumed, and if the dose is low enough that multiple energy depositions are rare, the model can also be applied to calculations of the survival probability for a cell population. Subcellular boron distributions in rats carrying RG 2 rat gliomas were measured by subcellular fractionation after administration of two different boron compounds: a sulphydryl boron hydride (BSH) and a boronated porphyrin (BOPP). Based on these data, the RLE factors were then calculated for these compounds using the stochastic model.

Performance of sulfhydryl boron hydride in patients with grade III and IV astrocytoma: a basis for boron neutron capture therapy.

This study investigated the rationale of boron neutron capture therapy (BNCT) for the treatment of Grade III and IV astrocytoma. The European Community joint research program on BNCT plans to use sulfhydryl boron hydride (BSH) in clinical trials. The work presented here, examines the performance of BSH in eight patients with Grade III and IV astrocytoma using a measurement technique which precisely correlates the boron uptake with the histology of the tumor and the peritumoral brain. Astrocytomas are exceptionally heterogeneous and spread migrating tumor cells into the surrounding brain. The patients were infused with 50 mg BSH per kilogram of body weight at 12, 18, 24 or 48 hours before surgery. At the time of operation, specimens were obtained of the tumor, skin, muscle, dura, blood, urine, and, when surgically possible, the brain adjacent to tumor. In three patients the intracellular boron distribution was investigated by subcellular fractionation. The blood clearance was biphasic with half-lives of 0.6 and 8.2 hours. After 3 days, approximately 70% of the dose injected was excreted in the urine. The maximum boron concentration in the tumor was 20 ppm, 12 hours after the infusion. The tumor-to-blood ratios ranged between 0.2 and 1.4, with the highest values after 18 to 24 hours. In the brain specimens the boron concentration never exceeded 1 ppm. This work confirms a selective uptake of boron in the tumor compared to the surrounding brain and that boron, to some extent, is incorporated in the tumor cells.

A comparative study on the pharmacokinetics and biodistribution of boronated porphyrin (BOPP) and sulfhydryl boron hydride (BSH) in the RG2 rat glioma model.

Boron neutron capture therapy is a treatment modality for cancer that depends on the specific uptake of boron by the tumor cells. The infiltrative growth of malignant gliomas requires that boron reach and accumulate in migrating cells outside the margin of the tumor; thus, it is important that the biodistribution of new boron compounds is also studied in the surrounding healthy brain tissue. This study is undertaken in the present work, in which the biodistribution and pharmacokinetics of sulfhydryl boron hydride (BSH) and boronated porphyrin (BOPP) in the RG2 rat glioma model are investigated. This model mimics the characteristics of human glioma with cells migrating into the surrounding brain. The animals were infused intravenously with either BSH (25 micrograms or 175 micrograms of boron per gram of body weight) or BOPP (12 micrograms of boron per gram body weight). For the low dose of BSH, the maximum tumor-boron content was 8 ppm at approximately 9 hours after the infusion with a tumor-to-blood ratio of 0.6. At the higher dose, the corresponding figures were 15 ppm after 12 hours with a tumor-to-blood ratio of 0.5. For BOPP, a tumor-boron concentration of 81 ppm was achieved 24 hours after the infusion and sustained in that range for at least 72 hours. The tumor-to-blood ratio at 24 hours was slightly above 6, but continued to increase as the blood was cleared. These results indicate that both compounds are spread into the normal brain tissue following the same pathways as the migrating tumor cells and in this way can be taken up even in distant tumor cell foci.

Necrosis of malignant gliomas after intratumoral injection of 201Tl in vivo in the rat.

Fourteen adult Fischer 344 rats were inoculated in vivo unilaterally in the caudate nucleus in the brain with malignant RG 2 glioma cells. By 3 weeks a tumor with a diameter of 3-6 mm normally develops. Ten animals which survived the repeated periods of anesthesia and thallium (Tl) injections (intratumorally three times of 201Tl, 15-23 days after inoculation) showed a prolonged retention of radioactivity at the site of injection with no uptake in other organs except for the kidneys. Singular circumscribed necroses were found post-mortem at the site of injection, comprising malignant glioma tumor tissue, which in six animals was absent, in three animals was markedly reduced in size compared with controls and in one animal had the expected size. In four animals metastases were found in distant locations in the brain; in three of these cases there was a retention of radioactivity in the tumor. The selective necrotizing effect on the tumor cells is interpreted as mainly due to emission of Auger electrons from intracellularly accumulated 201Tl, giving rise to very high energy deposition in the vicinity of the cell nucleus. The results should also have implications for the treatment of human malignant gliomas.