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.

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.

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.

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.

Enhanced boron uptake in RG 2 rat gliomas by electropermeabilization in vivo--a new possibility in boron neutron capture therapy.

Accumulation of boron in tumor tissue is an indispensable requirement for boron neutron capture therapy and it is important that the uptake is as high as possible. In this work we have studied the influence of electropermeabilization in vivo on the uptake of boron in normal and RG 2 glioma bearing Fischer 344 rats. Two different boron compounds, a sulfhydryl boron hydride (BSH) and a boronated porphyrin (BOPP), have been investigated. The rats were infused intravenously during 5 min with 175 micrograms BSH/g body weight or 12 micrograms BOPP/g body weight. Two electrodes were placed 5 mm apart in the brain and electropermeabilization was performed with eight square 400 V pulses at 4 and 7 min after the end of the infusion. After 6 h the animals were killed, and the boron content in the tumors and the surrounding brain was measured with neutron-activated autoradiography. In electropermeabilized healthy animals the BOPP uptake was low and limited to the electrode lesions, whereas BSH was spread extensively throughout the hemisphere. Rats with gliomas showed doubled (BOPP) to 10-fold (BSH) uptake of boron in the tumor when electropermeabilization was performed as compared with untreated animals. We conclude that electropermeabilization in the future may provide an interesting possibility to increase the uptake of certain boron compounds before neutron capture therapy.

A new brain tumour therapy combining bleomycin with in vivo electropermeabilization.

The potentials of in vivo electropermeabilization in combination with bleomycin in brain tumor treatment have been explored. In the brain of normal Fischer 344 rats, 2 electrodes were placed 5 mm apart. Electropermeabilization was performed with 8 to 12 exponential 400 V pulses with a time constant of 325 microseconds. Some animals were given bleomycin i.v., 1mg/kg b.w., 4 minutes before electric pulses delivery. No adverse effects were recorded during the observation of the animals during the following month. The effect of bleomycin and electropermeabilization upon tumour growth was studied in rats with glioma cells (RG2) implanted in the head of the right caudate nucleus. Treatment was given at different time intervals after the implantation of tumor cells and the effect upon survival was studied. Bleomycin alone did not prolong the survival of the animals. On the contrary, bleomycin plus electropermeabilization on the 10th, 11th or 12th day after inoculation increased the survival time to almost double that of untreated animals. We conclude that this treatment may be of value in brain tumour therapy.

Neutron capture imaging of 10B in tissue specimens.

Boron Neutron Capture Therapy (BNCT) is an attractive concept for radiation treatment of malignant tumours. The patients receive a 10B-carrying compound with selective uptake in tumour cells, after which they are irradiated with epithermal neutrons. Theoretically, the tumour cells are killed by the high-LET particles produces in 10B(n, alpha)7Li reactions inside or close to the cell nucleus, while healthy brain cells with no boron uptake will be spared. In practice, a successful BNCT depends on the actual boron-distribution in the tissue, and consequently a new boron-compound aimed for BNCT must undergo detailed bio-distribution studies before clinical trials. In experimental work there is accordingly a great need for methods for quantitative bio-distribution measurements in tissue samples. In this paper we present an improved technique for neutron activated autoradiography providing quantitative boron images of freeze-sectioned tissue specimens from highly malignant rat brain gliomas. Particular attention has been paid to the correlation with the morphology of the specimens and to the altered self-absorption properties due to freeze-drying. A self-absorption correction factor for tumour tissue has been experimentally determined.

Beta camera low activity tumor imaging.

A new technique, the beta camera, to complement film autoradiography, with fast quantitative imaging of beta particle-emitting radionuclides has been developed. It consists of a thin plastic scintillator and a light-sensitive microchannel plate detector. The thin tissue sample is mounted on the scintillator. Our first system had a high background and a moderate spatial resolution of 900 microns. We now report an improved system with a photomultiplier tube mounted on the scintillator of the microchannel plate detector. Only events registered by both detectors are accepted. A fast coincidence unit processes the signals, and if a time overlap exists, an event is generated in the beta camera. In the coincidence mode, images with low activity distribution of 201Tl (count rate 1 s-1) in 50 microns-thick slices of a human glioma tumor could be recorded with a spatial resolution of 500 microns.