Finn Stecher-Rasmussen

Boron analysis and boron imaging in biological materials for Boron Neutron Capture Therapy (BNCT)

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.

Boron concentrations in brain during boron neutron capture therapy: in vivo measurements from the Phase I trial EORTC 11961 using a gamma-ray telescope

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 10B(n,alpha)7Li, 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 10B and 1H. RESULTS For all patients, at a 10B 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 10B 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.

Organisation and management of the first clinical trial of BNCT in Europe (EORTC Protocol 11961)

Boron Neutron Capture Therapy is based on the ability of the isotope10B 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 therfore 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.

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.

Microdosimetry Model for Boron Neutron Capture Therapy: I. Determination of Microscopic Quantities of Heavy Particles on a Cellular Scale

Abstract van Vliet-Vroegindeweij, C., Wheeler, F. J., Stecher-Rasmussen, F., Moss, R. and Huiskamp, R. 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

Abstract van Vliet-Vroegindeweij, C., Wheeler, F. J., Stecher-Rasmussen, F. and Huiskamp, R. 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).

From Filter Installation to Beam Characterization

The replacement of the vessel of the High Flux Reactor in Petten (1984) offered a unique opportunity to upgrade the neutron beam facilities. In the former thermal column, a Large Neutron Facility was installed, in which a target position views the entire surface of one side of the reactor core box. Through the increased solid angle a factor of about 10 higher neutron flux is obtained at the Large Neutron Facility as compared to the conventional beam holes of the HFR.

Sodium mercaptoundecahydro-closo-dodecaborate (BSH), a boron carrier that merits more attention

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.

Procedural and practical applications of radiation measurements for BNCT at the HFR Petten

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 Semi-Empirical Method of Treatment Planning for Boron Neutron Capture Therapy

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.