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Boron neutron capture therapy relies on the preferential delivery of a (10)B-compound to tumor cells. The BSH-biodistribution was investigated in nu/nu mice and human patients. The boron concentration was measured with prompt gamma ray spectroscopy. BSH accumulates to a very low extent not only in brain, but also in fat tissue, bone and muscle, which makes BSH an interesting drug not only for brain lesions but also for tumors located at the extremities. The differential uptake in different organs indicates a complex mechanism.

Generally, the determination of the gamma-ray dose in a mixed neutron-gamma field is obtained by using "neutron-insensitive" detectors. For this purpose, graphite, magnesium, and aluminum ionization chambers are available. It is known that graphite chambers suffer from porosity, and magnesium chambers encounter oxidation and manufacturing problems. So far, the aluminum chamber is mostly applied in fast neutron fields. This study presents the results of an aluminum chamber, flushed with argon gas, when applied in a neutron and gamma mixed field. A computer model of the ionization chamber is developed for an accurate interpretation of the responses. Special interest is given to the charge that can be measured after the irradiation has stopped, which is due to decay of 28 Al. The Monte Carlo code MCNPX is used to simulate the neutrons, gammas, and charged particles in and around the Al-Ar chamber. The detector is modeled in detail, and all possible reactions that can occur in the materials of the chamber are incorporated. The response of the Al-Ar chamber is compared with the results of a Mg-Ar chamber in terms of collected charge. All individual components contributing to the signal of the detector are identified and calculated. Although the decay charge produced by aluminum is much higher, in comparison to magnesium, a better estimation of the gamma dose is expected when the decay charge in aluminum can be accurately determined. Another advantage is that the higher activation in Al can be used for identifying the neutron contribution. Despite the great detail in the model used, there is an ∼25% discrepancy between the experimental and simulated total charges for both the Mg-Ar and Al-Ar chambers, which evidently requires further investigation. The Al-Ar chamber can be used complementarily to the Mg-Ar chamber as gamma dosimeter in a mixed field of neutrons and gammas.

The neutron and gamma dose in boron neutron capture therapy (BNCT) can be determined by using ionization chambers of different materials. However, inexplicable results, such as negative doses, are sometimes obtained. Computer simulations using MCNPX can help one to understand the behavior of ionization chambers. This paper deals with a part of this investigation: the contribution of protons to the total measured charge in a tissue equivalent (TE) ionization chamber that is flushed with methane-based TE gas. The inherentproblem is that the Monte Carlo code MCNPX cannot track protons below 1 MeV. A custom-made program, called Proton Produced Ionization Chamber Charge (PPICC), calculates the deposited energy and thus the charge in the TE gas per proton. For this, it uses the stopping powers for protons in TE plastic and gas. MCNPX provides the total number of protons produced by all neutron interactions near the gas. To check this new procedure, measurements and simulations have been performed using a validated mixed beam of neutrons and gammas. The neutron fluence consists of 12% fast neutrons and 87% epithermal neutrons. In one setup the chamber is free-in-air (epithermal/fast neutronfield) and in the other is in a cubic polymethylmethacrylate phantom at 25 mm depth (thermal/epithermal neutron field). The total charge is the sum of the charges due to electrons, originating from primary and neutron-induced gammas, and protons from 1 H(n,n) 1 H and 14 N(n,p) 14 C reactions. The total measured and calculated charges in the two setups have acceptable uncertainties and are in good agreement. The charge collected in a TE ionization chamber can be simulated in a mixed field of neutrons and gammas. The charge resulting from proton recoil in the gas is unexpectedly large.

Boron Neutron Capture Therapy (BNCT) is based on the ability of the stable isotope 10B to capture neutrons, which leads to a nuclear reaction producing an alpha- and a 7Li-particle, both having a high biological effectiveness and a very short range in tissue, being limited to approximately one cell diameter. This opens the possibility for a highly selective cancer therapy. BNCT strongly depends on the selective uptake of 10B in tumor cells and on its distribution inside the cells. The chemical properties of boron and the need to discriminate different isotopes make the investigation of the concentration and distribution of 10B a challenging task. The most advanced techniques to measure and image boron are described, both invasive and non-invasive. The most promising approach for further investigation will be the complementary use of the different techniques to obtain the information that is mandatory for the future of this innovative treatment modality. © 2008 Elsevier Ireland Ltd. All rights reserved.

At the High Flux Reactor (HFR), Petten, The Netherlands, EORTC clinical trials of Boron Neutron Capture Therapy (BNCT) have been in progress since 1997. BNCT involves the irradiation of cancer patients by a beam of neutrons, with an energy range of predominantly 1 eV to 10 keV. The patient is infused with a tumor-seeking, (10)B-loaded compound prior to irradiation. Neutron capture in the (10)B atoms results in a high local radiation dose to the tumor cells, whilst sparing the healthy tissue. Neutron capture, however, also occurs in other atoms naturally present in tissue, sometimes resulting in radionuclides that will be present after treatment. The patient is therefore, following BNCT, radioactive. The importance of this induced activity with respect to the absorbed dose in the patient as well as to the radiation exposure of the staff has been investigated.As a standard radiation protection procedure, the ambient dose equivalent rate was measured on all patients following BNCT using a dose ratemeter. Furthermore, some of the patients underwent measurements using a gamma-ray spectrometer to identify which elements and confirm which isotopes are activated.Peak levels, i.e., at contact and directly after irradiation, are of the order of 40-60 muSv/h, falling to10 muSv/h 30-50 min after treatment. The average ambient dose equivalent in the first 2 h at a distance of 2 m from the patient is in the order of 2.5 muSv. The ambient dose equivalent rate in 2 m distance from the patient's head at the earliest time of leaving the reactor center (20 min after the end of treatment) is far less than 1 muSv/h. The main radioisotopes were identified as (38)Cl, (49)Ca, and (24)Na. Furthermore, in two patients, the isotopes (198)Au and (116m)In were also present. The initial activity is predominantly due to (49)Ca, whilst the remaining activity is predominantly due to (24)Na.The absorbed dose resulting from the activated isotopes in the irradiated volume is in the order of1% of the prescribed dose and therefore does not add a significant contribution to the absorbed dose in the target volume. In other parts of the patient's body, the absorbed dose by induced activity is magnitudes smaller and can be neglected. The levels of radiation received by staff members and non-radiation workers (i.e., accompanying persons) are well below the recommended limits.

Purpose: Gamma-ray spectroscopic scans to measure boron concentrations in the irradiated volume were performed during treatment of 5 patients suffering from brain tumors with boron neutron capture therapy (BNCT). In BNCT, the dose that is meant to be targeted primarily to the tumor is the dose coming from the reaction 10 B(n,α) 7 Li, which is determined by the boron concentration in tissue and the thermal neutron fluence rate. The boron distribution throughout the head of the patient during the treatment is therefore of major interest. The detection of the boron distribution during the irradiation was until now not possible. Methods and Materials: Five patients suffering from glioblastoma multiforme and treated with BNCT in a dose escalation study were administered the boron compound, boron sulfhydryl (BSH; Na 2 B 12 H 11 SH). Boron concentrations were reconstructed from measurements performed with the gamma-ray telescope which detects locally the specific gamma rays produced by neutron capture in 10 B and 1 H. Results: For all patients, at a 10 B concentration in blood of 30 ppm, the boron concentration in nonoperated areas of the brain was very low, between 1 and 2.5 ppm. In the target volume, which included the area where the tumor had been removed and where remaining tumor cells have to be assumed, much higher boron concentrations were measured with large variations from one patient to another. Superficial tissue contained a higher concentration of 10 B than the nonoperated areas of the brain, ranging between 8 and 15 ppm. Conclusions: The measured results correspond with previous tissue uptake studies, confirming that normal brain tissue hardly absorbs the boron compound BSH. Gamma-ray telescope measurements seem to be a promising method to provide information on the biodistribution of boron during therapy. Furthermore, it also opens the possibility of in vivo dosimetry.

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.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.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.

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.

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.

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.

Each medical intervention must be performed respecting Health Protection directives, with special attention to Quality Assurance (QA) and Quality Control (QC). This is the basis of safe and reliable treatments. BNCT must apply QA programs as required for performance and safety in (conventional) radiotherapy facilities, including regular testing of performance characteristics (QC). Furthermore, the well-established Quality Management (QM) system of the nuclear reactor used has to be followed. Organization of these complex QM procedures is offered by the international standard ISO 9001:2008.

Since October 1997, a clinical trial of Boron Neutron Capture Therapy (BNCT) for glioblastoma patients has been in progress at the High Flux Reactor, Petten, the Netherlands. The trial is a European Organisation for Research and Treatment of Cancer (EORTC) protocol (#11 961) and, as such, must be conducted following the highest quality management and procedures, according to good clinical practice and also other internationally accepted codes. The complexity of BNCT involves not only strict international procedures, but also a variety of techniques to measure the different aspects of the irradiation involved when treating the patient. Applications include: free beam measurements using packets of activation foils; in-phantom measurements for beam calibration using ionisation chambers, pn-diodes and activation foils; monitoring of the irradiation beam during patient treatment using fission chambers and GM-counters; boron in blood measurements using prompt gamma ray spectroscopy; radiation protection of the patient and staff using portable radiation dosimeters and personal dosimeters; and in vivo measurements of the boron in the patient using a prompt gamma ray telescope. The procedures and applications of such techniques are presented here, with particular emphasis on the importance of the quality assurance/quality control procedures and its reporting.

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).

The first European clinical trial on BNCT (EORTC protocol 11961) started in 1997.1 Thjs is a phase I study, aimed to define the Maximum Tolerated Dose and Dose Limiting Toxicity in gliobastoma patients using BSH as boron carrier and fractionated radiation at the Epithermal Neutron Facility at Petten. Beside the evaluation of the systemic toxicity of BSH, and the early radiation toxicity in the irradiated volume, special emphasis has been placed on the late radiation morbidity. In addition survival will be observed. Up to this date 14 patients have been entered into the study, 12 males and 2 females at six Neurosurgery Centers in five European countries.

In October 1997, after a preparatory phase of 8 years, the first patient in Europe was treated by BNCT at the High Flux Reactor (HFR) of the European Commission in Petten, The Netherlands.1 The preparation for the first clinical BNCT trial in Europe included comprehensive scientific experimental and human investigations with the boron compound borocaptate sodium (BSH).2,3 A multitude of open legal and administrative questions had to be overcome. Furthermore a complex structure had to be organized and the procedures had to be defined how to perform a multi-national, multi-institutional study using a nuclear reactor distant from hospital for patient treatment performed by an international team on a multidisciplinary base.4 The international standards of clinical research as well as the accepted rules and definitions of conventional radiotherapy were applied, involving independent experts in order to assure the quality of the study and the quality of the Performance of patient treatment. The goal was to execute the project to a very high Standard as would be expected in the leading radiotherapy depart-ments in Europe.5

In EORTC trial 11961 “Glioma Treatment with BNCT”, the treatment with BNCT is given in four fractions, on four consecutive days. Prior to each fraction, BSH (Na2B12H11SH) is infused in amounts such that 30ppm boron is reached as average over the four fractions. Before the BNCT treatment, BSH is administered at the time point of surgery, in order to gain data on the pharmacokinetics of BSH in the individual patient. On this basis, and assuming that each dosage of BSH is purely additive and that the pharmacokinetics of BSH at surgery is a good prediction of the pharmacokinetics at treat-ment, an individual prescription scheme can be established beforehand.

The boron drug Na2B12H11SH (BSH) is presently being used in a clinical Phase I trial for glioma treatment with boron neutron capture therapy (BNCT). This study is carried out in The Netherlands at the High Flux Reactor of the European Commission. Patients are recruited from six neurosurgical centers in five European countries.

The therapeutic effect of boron neutron capture therapy depends on the microscopic distribution of the boron atoms. A given macroscopic boron distribution can yield completely different therapeutic effects for different distributions of the boron atoms on a microscopic scale. In this work, a stochastic model for the subcellular dosimetry has been developed to calculate the effect of BNCT in tumour cells as well as in capillaries for different capture reactions and for proton recoil. The microdosimetry model calculates the dose distribution on a cellular scale, the probability functions of energy depositions in the cell nucleus (hit size curve) and the cell survival fractions.

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.

Treatment planning aims at optimizing the radiation dose delivered over the target volume, while keeping the dose delivered to the healthy tissue at a minimum. Most efforts in treatment planning research for BNCT tend to concentrate on the second part of this aim [1, 2], as inhomogeneities in the sub-and inter-cellular boron distribution may cause considerable dose inhomogeneity. Homogeneity of the thermal and epithermal neutron fluence to the target volume should be an important goal of BNCT research.

For a successful application of BNCT knowledge of the boron pharmacokinetics is of great importance. For the future clinical trials at Petten Prompt Gamma-Ray Analysis (PGRA) will be applied to determine 10 B concentrations in patients’ blood samples. The boron concentration within the tumour volume can then be deduced from pharmacokinetic studies. With the rapidly obtained results from PGRA it will be possible to tailor the irradiation of each patient according to their individual boron pharmacokinetics.

In BNCT the total dose delivered to the tumor and to the healthy tissue depends on several factors. Knowledge of the 10B distribution, the thermal neutron fluence, the epithermal neutron fluence, the fast neutron fluence and the photon dose is necessary for the calculation of the total dose delivered to all points of interest in the patient. Calculations using either Monte Carlo or deterministic codes, both commonly applied in reactor physics for neutron and photon transport calculations, have been proposed for treatment planning of BNCT1,2. Due to the large calculation times needed for these kinds of calculations, such a procedure for external photon beam treatment planning is not yet available for daily usage in radiotherapy institutions3. Therefore, little experience has been gained with these procedures in clinical situations. External photon beam treatment planning is currently based on empirical knowledge of the dose distributions under reference conditions. Beam parameters measured in a large cubical water-phantom are corrected with deterministic algorithms to calculate dose distributions in other geometries3. Treatment planning of BNCT based on Monte Carlo calculations as well as using such a semi-empirical approach is in development in the Petten-Amsterdam BNCT group4. It is the purpose of this work to investigate wether the relatively simple semi-empirical approach can be used for the treatment planning of BNCT using an epithermal neutron beam.