Extension of the calibration curve for the PGRA facility in Petten.

At the boron neutron capture therapy (BNCT) facility in Petten, the Netherlands, (10)B concentrations in biological materials are measured with the prompt gamma ray analyses facility that is calibrated using certified (10)B solutions ranging from 0 to 210 ppm. For this study, newly certified (10)B solutions ranging up to 1972 ppm are added. MCNP simulations of the setup range to 5000 ppm. A second order polynomial (as already used) will fit (10)B-concentrations less than 300 ppm. Above 300 ppm a fitted third order polynomial is needed to describe the calibration curve accurately.

Validating a MCNPX model of Mg(Ar) and TE(TE) ionisation chambers exposed to 60CO gamma rays.

For an accurate determination of the absorbed doses in complex radiation fields (e.g. mixed neutron-gamma fields), a better interpretation of the response of ionisation chambers is required. This study investigates a model of the ionisation chambers using a different approach, analysing the collected charge per minute as a response of the detector instead of the dose. The MCNPX Monte Carlo code is used. In this paper, the model is validated using a well-known irradiation field only: a (60)Co source. The detailed MCNPX models of a Mg(Ar) and TE(TE) ionisation chamber is investigated comparing the measured charge per minute obtained free-in-air and in a water phantom with the simulated results. The difference between the calculations and the measurements for the TE(TE) chamber is within +/-2% whereas for the Mg(Ar) chamber is around +7%. The systematic discrepancy in the case of Mg(Ar) chamber is expected to be caused by an overestimation of the sensitive volume.

Set-up and calibration of a triple ionization chamber system for dosimetry in mixed neutron/photon fields.

The aim of this study is to introduce a triple ionization chamber system to separate dose components of mixed neutron/photon fields. Fast and thermal neutron dose components have a different biological effectiveness than gamma dose components. If boron neutron capture is used to enhance the dose in certain areas of a patient, the precise knowledge of the thermal neutron flux is essential. A tissue equivalent and two magnesium ionization chambers have been prepared for use in a triple chamber system for this purpose. One of the magnesium chambers is coated with (10)B on the inside to enhance its response to thermal neutrons. All three chambers have been calibrated at a cobalt source, medical linear accelerators and several neutron sources. The chambers have been studied in Monte Carlo simulations and the results are compared with measurements.

Gadolinium enhances the sensitivity of SW-1573 cells for thermal neutron irradiation.

Gadolinium neutron capture therapy (Gd-NCT) is an experimental cancer treatment based on the physical principal that neutron capture by gadolinium-157 ensures the release of focal high-dose radiation, such as gamma-rays and electrons. Survival and induction of chromosomal aberrations of human SW-1573 cells was studied after thermal neutron irradiation without and with gadolinium. After neutron irradiation with Gd-DTPA, an alpha-enhancement factor of 2.3 was obtained compared to thermal neutron irradiation alone. Gd-DTPA could not radioenhance the cells for gamma-ray irradiation. Induction of colour junctions and chromosome fragments by thermal neutron irradiation and Gd-NCT were studied using PCC-FISH. Correlations (r2-value) between survival and chromosome aberrations ranged from 0.81 to 0.94 for colour junctions and from 0.78 to 0.98 for chromosome fragments of chromosomes 18 and 2 respectively. Thermal neutron irradiation with or without gadolinium induced more chromosome aberrations than gamma-ray irradiation. After correction for chromosome length it appeared that both chromosomes were equally sensitive to radiation. It is concluded that Gd-NCT at a non-toxic concentration of gadolinium is effective in inducing cell death and chromosome aberrations in in vitro cell cultures.

Towards in vivo monitoring of neutron distributions for quality control of BNCT.

Dose delivery in boron neutron capture therapy (BNCT) is complex because several components contribute to the dose absorbed in tissue. This dose is largely determined by local boron concentration, thermal neutron distribution and patient positioning. In vivo measurements of these factors would considerably improve quality control and safety. During therapy, a y-ray telescope measures the y-rays emitted following neutron capture by hydrogen and boron in a small volume of the head of a patient. Scans of hydrogen y-ray emissions could be used to verify the actual distribution of thermal neutrons during neutron irradiation. The method was first tested on different phantoms. These measurements showed good agreement with calculations based on thermal neutron distributions derived from a treatment planning program and from Monte Carlo N-particle (MCNP) simulations. Next, the feasibility of telescope scans during patient irradiation therapy was demonstrated. Measurements were reproducible between irradiation fractions. In theory, this method can be used to verify the positioning of the patient in vivo and the delivery of thermal neutrons in tissue. However, differences between measurements and calculations based on a routine treatment planning program were observed. These differences could be used to refine the treatment planning. Further developments will be necessary for this method to become a standard quality control system.

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.

Comparison of quality assurance for performance and safety characteristics of the facility for Boron Neutron Capture therapy in Petten/NL with medical electron accelerators.

BACKGROUND AND PURPOSE: The European Council Directive on health protection 97/43/EURATOM requires radiotherapy quality assurance programmes for performance and safety characteristics including acceptance and repeated tests. For Boron Neutron Capture therapy (BNCT) at the High Flux Reactor (HFR) in Petten/NL such a programme has been developed on the basis of IEC publications for medical electron accelerators. RESULTS: The fundamental differences of clinical dosimetry for medical electron accelerators and BNCT are presented and the order of magnitude of dose components and their stability and that of the main other influencing parameter 10B concentration for BNCT patient treatments. A comparison is given for requirements for accelerators and BNCT units indicating items which are not transferable, equal or additional. Preliminary results of in vivo measurements done with a set of 55Mn, 63Cu and 197Au activation foils for all single fields for the four fractions at all 15 treated patients show with < +/- 4% up to now a worse reproducibility than the used dose monitoring systems (+/- 1.5%) caused by influence of hair position on the foil-skull distance. CONCLUSIONS: Despite the more complex clinical dosimetry (because of four relevant dose components, partly of different linear energy transfer (LET)) BNCT can be regulated following the principles of quality assurance procedures for therapy with medical electron accelerators. The reproducibility of applied neutron fluence (proportional to absorbed doses) and the main safety aspects are equal for all teletherapy methods including BNCT.

On-line reconstruction of low boron concentrations by in vivo gamma-ray spectroscopy for BNCT.

Boron neutron capture therapy (BNCT) is a radiation therapy in which the neutron capture reaction of 10B is used for the selective destruction of tumours. At the High Flux Reactor (HFR) in Petten, a therapy facility with an epithermal neutron beam has been built. In the first instance, patients with brain tumours will be treated. The doses delivered to the tumour and to the healthy tissue depend on the thermal neutron fluence and on the boron concentrations in these regions. An accurate determination of the patient dose during therapy requires knowledge of these time-dependent concentrations. For this reason, a gamma-ray telescope system, together with a reconstruction formalism, have been developed. By using a gamma-ray detector in a telescope configuration, boron neutron capture gamma-rays of 478 keV emitted by a small specific region can be detected. The reconstruction formalism can calculate absolute boron concentrations using the measured boron gamma-ray detection rates. Besides the boron gamma-rays, a large component of 2.2 MeV gamma-rays emitted at thermal neutron capture in hydrogen is measured. Since the hydrogen distribution is almost homogeneous within the head, this component can serve as a measure of the total number of thermal neutrons in the observed volume. By using the hydrogen gamma-ray detection rate for normalization of the boron concentration, the reconstruction tool eliminates the greater part of the influence of the inhomogeneity of the thermal neutron distribution. MCNP calculations are used as a tool for the optimization of the detector configuration. Experiments on a head phantom with 5 ppm 10B in healthy tissue showed that boron detection with a standard deviation of 3% requires a minimum measuring time of 2 min live time. From two position-dependent measurements, boron concentrations in two compartments (healthy tissue and tumour) can be determined. The reconstruction of the boron concentration in healthy tissue can be done with a standard deviation of 6%. The gamma-ray telescope can also be used for in vivo dosimetry.

Microdosimetry model for boron neutron capture therapy: I. Determination of microscopic quantities of heavy particles on a cellular scale.

Due to the limitations of existing microdosimetry models, a new model called MICOR has been developed to analyze the spatial distribution of microscopic energy deposition for boron neutron capture therapy (BNCT). As in most existing models, the reactions independent of the incident neutron energy such as the boron and the nitrogen capture reactions can be considered. While other models do not include reactions that are dependent on the neutron energy such as the proton recoil reaction, the present model is designed so that the energy deposition resulting from these reactions is included. The model MICOR has been extended to enable the determination of the biological effects of BNCT, which cannot be done with the existing models. The present paper describes the determination of several microscopic quantities such as the number of hits, the energy deposition in the cell nucleus, and the distribution of lineal and specific energy deposition. The companion paper (Radiat. Res. 155, 000-000 2001) deals with the conversion of these microscopic quantities into biological effects. The model is used to analyze the results of a radiobiological experiment performed at the HB11 facility in the HFR in Petten. This analysis shows the value of the model in determining the dose depositions on a cellular scale and the importance of the extension to the energy deposition of the proton recoil.

Microdosimetry model for boron neutron capture therapy: II. Theoretical estimation of the effectiveness function and surviving fractions.

A model has been developed to obtain a better understanding of the effects of boron neutron capture therapy (BNCT) on a cellular scale. This model, the microdosimetry model MICOR, has been developed to include all reactions important for BNCT. To make the model more powerful in the translation from energy deposition to biological effect, it has been designed to be capable of calculating the effectiveness function. Based on this function, the model can calculate surviving fractions, RBE values and boron concentration distributions. MICOR has been used to analyze an extensive set of biological experiments performed at the HB11 beam in Petten. For V79 Chinese hamster cells, the effectiveness function is determined and used to generate surviving fractions. These fractions are compared with measured surviving fractions, which results in a good agreement between the measured and calculated surviving fractions (within the uncertainties of the measurements).

Organisation and management of the first clinical trial of BNCT in Europe (EORTC protocol 11961).EORTC BNCT study group.

Boron Neutron Capture Therapy is based on the ability of the isotope 10B to capture thermal neutrons and to disintegrate instantaneously producing high LET particles. The only neutron beam available in Europe for such a treatment is based at the European High Flux Reactor HFR at Petten (The Netherlands). The European Commission, owners of the reactor, decided that the potential benefit of the facility should be opened to all European citizens and therefore insisted on a multinational approach to perform the first clinical trial in Europe on BNCT. This precondition had to be respected as well as the national laws and regulations. Together with the Dutch authorities actions were undertaken to overcome the obvious legal problems. Furthermore, the clinical trial at Petten takes place in a nuclear research reactor, which apart from being conducted in a non-hospital environment, is per se known to be dangerous. It was therefore of the utmost importance that special attention is given to safety, beyond normal rules, and to the training of staff. In itself, the trial is an unusual Phase I study, introducing a new drug with a new irradiation modality, with really an unknown dose-effect relationship. This trial must follow optimal procedures, which underscore the quality and qualified manner of performance.

Monitoring of blood-10B concentration for boron neutron capture therapy using prompt gamma-ray analysis.

The aim of the present study was to monitor the blood-10B concentration of laboratory dogs receiving boron neutron capture therapy, in order to obtain optimal agreement between prescribed and actual dose. A prompt gamma-ray analysis system was developed for this purpose at the High Flux Reactor in Petten. The technique was compared with inductively coupled plasma-atomic emission spectrometry and showed good agreement. A substantial variation in 10B clearance pattern after administration of borocaptate sodium was found between the different dogs. Consequently, the irradiation commencement was adjusted to the individually determined boron elimination curve. Mean blood-10B concentrations during irradiation of 25.8 +/- 2.2 micrograms/g (1 SD, n = 18) and 49.3 +/- 5.3 micrograms/g (1 SD, n = 17) were obtained for intended concentrations of 25 micrograms/g and 50 micrograms/g, respectively. These variations are a factor of two smaller than irradiations performed at a uniform post-infusion irradiation starting time. Such a careful blood-10B monitoring procedure is a prerequisite for accurately obtaining such steep dose-response curves as observed during the dog study.

A scintillation spectrometer for direct comparison of neutron energy spectra at high and low rates.

The energy spectrum of the HB11 beam at HFR, Petten, has previously been measured by proton and alpha recoil in hydrogen and helium gas proportional counters at power levels of a few kW. There is some doubt whether the spectrum remains the same at the much higher power of 45 MW required for therapeutic fluxes. In order to test this point, a scintillation detector has been developed at the Paul Scherrer Institute, Villingen, Switzerland. While the device is again based on the proton recoil reaction, a combination of mm-sized plastic scintillators and fast electronics will allow it to operate at both a few kW and 45 MW, permitting direct comparison of energy spectra at these very different power levels. Results of preliminary tests at LFR, Petten, are presented.

Determination of the gamma-ray dose in an epithermal neutron beam.

Neutron beams used for Boron Neutron Capture Therapy (BNCT) are always accompanied by photons. These two irradiation components have different relative biological effectiveness. Therefore it is necessary to determine the neutron and photon absorbed dose in the mixed field separately. All gamma-ray detectors however are also sensitive for neutrons. In this work preliminary results are presented using TLD-700 chips, a Mg(Ar) ionisation chamber and a GM-counter to determine the gamma-ray component in a mixed beam of gamma-rays and neutrons. The results show a good agreement between the GM-counter and the ionisation chamber, indicating a small relative neutron sensitivity (ku) for these detectors. The sensitivity of TLD-700 for thermal neutrons however gives rise to a detector response for which a correction is necessary. The uncertainty however in the relative gamma-ray sensitivity (hu) of the detectors is at this moment too large to determine accurate values of the relative neutron sensitivities.

An investigation of the possibilities of BNCT treatment planning with the Monte Carlo method.

The neutron fluence distribution inside two types of water phantom have been calculated with the Monte Carlo programme MCNP for the epithermal neutron beam at the Petten Low Flux Reactor. Comparison between the calculated and the measured neutron fluence distributions showed a reasonable agreement. The influence of beam and phantom geometry on the neutron fluence distribution has been calculated. An increase of the field size leads to a somewhat deeper position of the maximum of the thermal neutron fluence distribution in the cylindrical phantom. The possible use of beam modifying devices like wedges and blocks has been tested with this model. Blocks have been modelled that can locally reduce the fast neutron skin dose by 70%.