Biokinetic analysis of tissue boron (¹°B) concentrations of glioma patients treated with BNCT in Finland.

A total of 98 patients with glioma were treated with BPA-F-mediated boron neutron capture therapy (BNCT) in Finland from 1999 to 2011. Thirty-nine (40%) had undergone surgery for newly diagnosed glioblastoma and 59 (60%) had malignant glioma recurrence after surgery. In this study we applied a closed 3-compartment model based on dynamic (18)F-BPA-PET studies to estimate the BPA-F concentrations in the tumor and the normal brain with time. Altogether 22 patients with recurrent glioma, treated within the context of a clinical trial, were evaluated using their individual measured whole blood (10)B concentrations as an input to the model. The delivered radiation doses to tumor and the normal brain were recalculated based on the modeled (10)B concentrations in the tissues during neutron irradiation. The model predicts from -7% to +29% (average, +11%) change in the average tumor doses as compared with the previously estimated doses, and from 17% to 61% (average, 36%) higher average normal brain doses than previously estimated due to the non-constant tumor-to-blood concentration ratios and considerably higher estimated (10)B concentrations in the brain at the time of neutron irradiation.

The alanine detector in BNCT dosimetry: dose response in thermal and epithermal neutron fields.

PURPOSE: The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed. METHODS: Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particle spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a (60)Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes fluka and mcnp. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen & Olsen alanine response model. RESULTS: The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields. CONCLUSIONS: The alanine detector can be used without difficulty in neutron fields. The response has been understood with the model used which includes the relative effectiveness. Results and the corresponding discussion lead to the conclusion that application in neutron fields for medical purpose is limited by its sensitivity but that it is a useful tool as supplement to other detectors and verification of neutron source descriptions.

The FiR 1 photon beam model adjustment according to in-air spectrum measurements with the Mg(Ar) ionization chamber.

The mixed neutron-photon beam of FiR 1 reactor is used for boron-neutron capture therapy (BNCT) in Finland. A beam model has been defined for patient treatment planning and dosimetric calculations. The neutron beam model has been validated with an activation foil measurements. The photon beam model has not been thoroughly validated against measurements, due to the fact that the beam photon dose rate is low, at most only 2% of the total weighted patient dose at FiR 1. However, improvement of the photon dose detection accuracy is worthwhile, since the beam photon dose is of concern in the beam dosimetry. In this study, we have performed ionization chamber measurements with multiple build-up caps of different thickness to adjust the calculated photon spectrum of a FiR 1 beam model.

Epithermal neutron beam interference with cardiac pacemakers.

In this paper, a phantom study was performed to evaluate the effect of an epithermal neutron beam irradiation on the cardiac pacemaker function. Severe malfunction occurred in the pacemakers after substantially lower dose from epithermal neutron irradiation than reported in the fast neutron or photon beams at the same dose rate level. In addition the pacemakers got activated, resulting in nuclides with half-lives from 25 min to 115 d. We suggest that BNCT should be administrated only after removal of the pacemaker from the vicinity of the tumor.

Effect of the calibration in water and the build-up cap on the Mg(Ar) ionization chamber measurements.

Magnesium-walled argon gas flow ionization chamber (Mg(Ar)) is used for photon dose measurements in the epithermal neutron beam of FiR 1 reactor in Finland. In this study, the photon dose measurements were re-evaluated against calculations applying a new chamber calibration factor defined in water instead of in air. Also, effect of the build-up cap on the measurements was investigated. The new calibration factor provides improved agreement between measured and calculated photon dose. Use of the build-up cap does not affect the measured signal in water in neutron beam.

Comparative study of dose calculations with SERA and JCDS treatment planning systems.

Three treatment planning systems developed for clinical boron neutron capture therapy (BNCT) use are SERA developed by INL/Montana State University, NCTPlan developed by the Harvard-MIT and the CNEA group and JAEA computational dosimetry system (JCDS) developed by Japan Atomic Energy Agency (JAEA) in Japan. Previously, performance of the SERA and NCTPlan has been compared in various studies. In this preliminary study, the dose calculations performed with SERA and JCDS systems were compared in single brain cancer patient case with the FiR 1 epithermal neutron beam. A two-field brain cancer treatment plan was performed with the both codes. The dose components to normal brain, tumor and planning target volume (PTV) were calculated and compared in case of one radiation field and combined two fields. The depth dose distributions and the maximum doses in regions of interest were compared. Calculations with the treatment planning systems for the thermal neutron induced ((10)B and nitrogen) dose components and photon dose were in good agreement. Higher discrepancy in the fast neutron dose calculations was found. In case of combined two-field treatment plan, overall discrepancy of the maximum weighted dose was approximately 3% for normal brain and PTV and approximately 4% for tumor dose.

An international dosimetry exchange for BNCT part II: computational dosimetry normalizations.

The meaningful sharing and combining of clinical results from different centers in the world performing boron neutron capture therapy (BNCT) requires improved precision in dose specification between programs. To this end absorbed dose normalizations were performed for the European clinical centers at the Joint Research Centre of the European Commission, Petten (The Netherlands), Nuclear Research Institute, Rez (Czech Republic), VTT, Espoo (Finland), and Studsvik, Nyköping (Sweden). Each European group prepared a treatment plan calculation that was bench-marked against Massachusetts Institute of Technology (MIT) dosimetry performed in a large, water-filled phantom to uniformly evaluate dose specifications with an estimated precision of +/-2%-3%. These normalizations were compared with those derived from an earlier exchange between Brookhaven National Laboratory (BNL) and MIT in the USA. Neglecting the uncertainties related to biological weighting factors, large variations between calculated and measured dose are apparent that depend upon the 10B uptake in tissue. Assuming a boron concentration of 15 microg g(-1) in normal tissue, differences in the evaluated maximum dose to brain for the same nominal specification of 10 Gy(w) at the different facilities range between 7.6 and 13.2 Gy(w) in the trials using boronophenylalanine (BPA) as the boron delivery compound and between 8.9 and 11.1 Gy(w) in the two boron sulfhydryl (BSH) studies. Most notably, the value for the same specified dose of 10 Gy(w) determined at the different participating centers using BPA is significantly higher than at BNL by 32% (MIT), 43% (VTT), 49% (JRC), and 74% (Studsvik). Conversion of dose specification is now possible between all active participants and should be incorporated into future multi-center patient analyses.

An international dosimetry exchange for boron neutron capture therapy. Part I: Absorbed dose measurements.

An international collaboration was organized to undertake a dosimetry exchange to enable the future combination of clinical data from different centers conducting neutron capture therapy trials. As a first step (Part I) the dosimetry group from the Americas, represented by MIT, visited the clinical centers at Studsvik (Sweden), VTT Espoo (Finland), and the Nuclear Research Institute (NRI) at Rez (Czech Republic). A combined VTT/NRI group reciprocated with a visit to MIT. Each participant performed a series of dosimetry measurements under equivalent irradiation conditions using methods appropriate to their clinical protocols. This entailed in-air measurements and dose versus depth measurements in a large water phantom. Thermal neutron flux as well as fast neutron and photon absorbed dose rates were measured. Satisfactory agreement in determining absorbed dose within the experimental uncertainties was obtained between the different groups although the measurement uncertainties are large, ranging between 3% and 30% depending upon the dose component and the depth of measurement. To improve the precision in the specification of absorbed dose amongst the participants, the individually measured dose components were normalized to the results from a single method. Assuming a boron concentration of 15 microg g(-1) that is typical of concentrations realized clinically with the boron delivery compound boronophenylalanine-fructose, systematic discrepancies in the specification of the total biologically weighted dose of up to 10% were apparent between the different groups. The results from these measurements will be used in future to normalize treatment plan calculations between the different clinical dosimetry protocols as Part II of this study.

MCNP study for epithermal neutron irradiation of an isolated liver at the Finnish BNCT facility.

A successful boron neutron capture treatment (BNCT) of a patient with multiple liver metastases has been first given in Italy, by placing the removed organ into the thermal neutron column of the Triga research reactor of the University of Pavia. In Finland, FiR 1 Triga reactor with an epithermal neutron beam well suited for BNCT has been extensively used to irradiate patients with brain tumors such as glioblastoma and recently also head and neck tumors. In this work we have studied by MCNP Monte Carlo simulations, whether it would be beneficial to treat an isolated liver with epithermal neutrons instead of thermal ones. The results show, that the epithermal field penetrates deeper into the liver and creates a build-up distribution of the boron dose. Our results strongly encourage further studying of irradiation arrangement of an isolated liver with epithermal neutron fields.

The TL analysis methods used to determine absorbed gamma doses in vivo for the BNCT patients treated at FiR 1.

The gamma dose determination using thermoluminescent (TL) dosimeters in mixed neutron-gamma fields, such as in boron neutron capture therapy (BNCT), is difficult due to the thermal neutron sensitivity of the detectors; especially when equipment capable of glow curve analysis is not available. The two TL analysis methods used previously in Finnish BNCT to correct the measured TL signal to obtain absorbed gamma dose in vivo were studied and compared, and an enhanced method was introduced. The three TL methods were found surprisingly consistent despite, e.g. the rough estimate made in the first method.

Design and construction of shoulder recesses into the beam aperture shields for improved patient positioning at the FiR 1 BNCT facility.

Improvements have been made at the FiR 1 BNCT facility to ease the positioning of the patient with a tumor in the head and neck region into a lateral neutron beam. Shoulder recesses were constructed horizontally on both sides of the beam aperture. When shoulder recesses are not needed, they are filled with neutron attenuating filling blocks. MCNP simulations using an anthropomorphic human model BOMAB phantom showed that the main contribution to the increase in the effective dose to the patient's body due to the shoulder recesses was from the neutron dose of the arm. In a position when one arm is inside the shoulder recess, the maximal effective dose of the patient was estimated to be 0.7Sv/h. Dose measurements using the twin ionization chamber technique showed that the neutron dose increased on the sides as predicted by the MCNP model but there was no noticeable change in the gamma doses. When making the recesses into the lithium containing neutron shield material tritium contamination was confined using an underpressurized glove box and machine tools with local exhaust. The shoulder recesses give space for more flexible patient positioning and can be considered as a significant improvement of the Finnish BNCT facility.

Enhanced blood boron concentration estimation for BPA-F mediated BNCT.

The blood boron concentration regulates directly the BNCT irradiation time in which the prescribed dose to the patient is delivered. Therefore a proper estimation of the blood boron concentration for the treatment field based on the measured blood samples before irradiation is required. The bi-exponential model fit using Levenberg-Marquardt method was implemented for this purpose to provide the blood boron concentration estimates directly to the treatment data flow during the BNCT procedure. The harmonic mean bi-exponential decay half-lives of the studied patient data (n=28) were 15+/-8 and 320+/-70 min for the faster and slower half-life. The model uncertainty (n=28) was reasonably low, 0.7+/-0.1 microg/g (about 5%). The implemented algorithm provides a robust method for temporal blood boron concentration estimation for BPA-F mediated BNCT. Utilization of the infusion data improves the reliability of the estimate. The overall data flow during the treatment fulfills the practical requirements concerning the BNCT procedure.

Dosimetric comparison at FiR 1 using microdosimetry, ionisation chambers and computer simulation.

Tissue equivalent proportional counter microdosimetry has been applied in the dosimetry of epithermal neutron beams as they can provide an independent and accurate method to determine gamma ray and neutron absorbed doses. Dosimetric comparison has been performed using a tissue equivalent proportional counter, dual ionisation chambers and DORT computer code at FiR 1 boron neutron capture therapy facility in Espoo, Finland. The three methods were applied to determine neutron and gamma ray absorbed doses at 25, 40, 60 and 120 mm depths along the beam centerline in a water-filled PMMA phantom. The determined absorbed doses were found to agree within the limits of the estimated uncertainties.

Progress with the NCT international dosimetry exchange.

The international collaboration that was organized to undertake a dosimetry exchange for purposes of combining clinical data from different facilities conducting neutron capture therapy has continued since its founding at the 9th ISNCT symposium in October 2000. The thrust towards accumulating physical dosimetry data for comparison between different participants has broadened to include facilities in Japan and the determination of spectral descriptions of different beams. Retrospective analysis of patient data from the Brookhaven Medical Research Reactor is also being considered for incorporation into this study to increase the pool of available data. Meanwhile the next essential phase of comparing measurements of visiting dosimetry groups with treatment plan calculations from the host institutes has commenced. Host centers from Petten, Finland and the Czech Republic in Europe and MIT in the USA have applied the regular calculations and clinical calibrations from their current clinical studies, to generate treatment plans in the large standard phantom used for measurements by visiting participants. These data have been exchanged between the participants and scaling factors to relate the separate dose components between the different institutes are being determined. Preliminary normalization of measured and calculated dosimetry for patients is nearing completion to enable the physical radiation doses that comprise a treatment prescription at a host institute to be directly related to the corresponding measured doses of a visiting group. This should serve as an impetus for the direct comparison of patient data although the clinical requirements for achieving this need to be clearly defined. This may necessitate more extensive comparisons of treatment planning calculations through the solution of test problems and clarification regarding the question of dose specification from treatment calculations in general.

Quality assurance procedures for the neutron beam monitors at the FiR 1 BNCT facility.

In order to assure the stability of the beam, the reliability of the beam monitoring system and the quality of the patient dose delivered, several procedures are followed at the FiR 1 epithermal beam in Finland. Routine procedures include in-phantom activation measurements before each patient treatment and a long-term follow-up of the results. The sensitivity of the beam monitors to external objects in the beam and to variations in the control rod positions in the reactor has been checked and found insignificant. The linearity of the beam monitor channels has been checked with activation measurements. It was found that due to saturation effects a correction of 11% has to be applied when extrapolating results from experiments at low power to full power using the reference monitor channel. The correction is even larger for other channels with higher count rates.

Measurement of free beam neutron spectra at eight BNCT facilities worldwide.

Eight epithermal neutron beams, constructed for clinical or preclinical studies of NCT, have been dosimetrically characterized by in-air measurements with a set of activation foils for the determination of the neutron energy spectra in free beam. Measurements have been made on the already closed epithermal BNCT facility at the BMRR of the Brookhaven National Laboratory, on the HFR at JRC in Petten, The Netherlands, on the epithermal mode beam at KURRI, Japan, on the fission converter beam at MIT, USA, on the epithermal beam of the RA-6 facility in Bariloche, Argentina, on the epithermal beam at WSU, USA, on the mixed mode beam at JRR-4 at JAERI, Japan, as well as on the epithermal beam at FiR 1 at VTT, Espoo, Finland.

Computational study of the required dimensions for standard sized phantoms in boron neutron capture therapy dosimetry.

The minimum size of a water phantom used for calibration of an epithermal neutron beam of the boron neutron capture therapy (BNCT) facility at the VTT FiR 1 research reactor is studied by Monte Carlo simulations. The criteria for the size of the phantom were established relative to the neutron and photon radiation fields present at the thermal neutron fluence maximum in the central beam axis (considered as the reference point). At the reference point, for the most commonly used beam aperture size at FiR 1 (14 cm diameter), less than 1% disturbance of the neutron and gamma radiation fields in a phantom were achieved with a minimum a 30 cm x 30 cm cross section of the phantom. For the largest 20 cm diameter beam aperture size, a minimum 40 cm x 40 cm cross-section of the phantom and depth of 20 cm was required to achieve undisturbed radiation field. This size can be considered as the minimum requirement for a reference phantom for dosimetry at FiR 1. The secondary objective was to determine the phantom dimensions for full characterization of the FiR 1 beam in a rectangular water phantom. In the water scanning phantom, isodoses down to the 5% level are measured for the verifications of the beam model in the dosimetric and treatment planning calculations. The dose distribution results without effects caused by the limited phantom size were achieved for the maximum aperture diameter (20 cm) with a 56 cm x 56 cm x 28 cm rectangular phantom. A similar approach to study the required minimum dimensions of the reference and water scanning phantoms can be used for epithermal neutron beams at the other BNCT facilities.

Study of the relative dose-response of BANG-3 polymer gel dosimeters in epithermal neutron irradiation.

Polymer gels have been reported as a new, potential tool for dosimetry in mixed neutron-gamma radiation fields. In this work, BANG-3 (MGS Research Inc.) gel vials from three production batches were irradiated with 6 MV photons of a Varian Clinac 2100 C linear accelerator and with the epithermal neutron beam of the Finnish boron neutron capture therapy (BNCT) facility at the FiR 1 nuclear reactor. The gel is tissue equivalent in main elemental composition and density and its T2 relaxation time is dependent on the absorbed dose. The T2 relaxation time map of the irradiated gel vials was measured with a 1.5 T magnetic resonance (MR) scanner using spin echo sequence. The absorbed doses of neutron irradiation were calculated using DORT computer code, and the accuracy of the calculational model was verified by measuring gamma ray dose rate with thermoluminescent dosimeters and 55Mn(n,gamma) activation reaction rate with activation detectors. The response of the BANG-3 gel dosimeter for total absorbed dose in the neutron irradiation was linear, and the magnitude of the response relative to the response in the photon irradiation was observed to vary between different gel batches. The results support the potential of polymer gels in BNCT dosimetry, especially for the verification of two- or three-dimensional dose distributions.

Boron neutron capture therapy (BNCT): implications of neutron beam and boron compound characteristics.

The potential efficacy of boron neutron capture therapy (BNCT) for malignant glioma is a significant function of epithermal-neutron beam biophysical characteristics as well as boron compound biodistribution characteristics. Monte Carlo analyses were performed to evaluate the relative significance of these factors on theoretical tumor control using a standard model. The existing, well-characterized epithermal-neutron sources at the Brookhaven Medical Research Reactor (BMRR), the Petten High Flux Reactor (HFR), and the Finnish Research Reactor (FiR-1) were compared. Results for a realistic accelerator design by the E. O. Lawrence Berkeley National Laboratory (LBL) are also compared. Also the characteristics of the compound p-Boronophenylaline Fructose (BPA-F) and a hypothetical next-generation compound were used in a comparison of the BMRR and a hypothetical improved reactor. All components of dose induced by an external epithermal-neutron beam fall off quite rapidly with depth in tissue. Delivery of dose to greater depths is limited by the healthy-tissue tolerance and a reduction in the hydrogen-recoil and incident gamma dose allow for longer irradiation and greater dose at a depth. Dose at depth can also be increased with a beam that has higher neutron energy (without too high a recoil dose) and a more forward peaked angular distribution. Of the existing facilities, the FiR-1 beam has the better quality (lower hydrogen-recoil and incident gamma dose) and a penetrating neutron spectrum and was found to deliver a higher value of Tumor Control Probability (TCP) than other existing beams at shallow depth. The greater forwardness and penetration of the HFR the FiR-1 at greater depths. The hypothetical reactor and accelerator beams outperform at both shallow and greater depths. In all cases, the hypothetical compound provides a significant improvement in efficacy but it is shown that the full benefit of improved compound is not realized until the neutron beam is fully optimized.