Unifying dose specification between clinical BNCT centers in the Americas.

A dosimetry intercomparison between the boron neutron capture therapy groups of the Massachusetts Institute of Technology (MIT) and the Comisión Nacional de Energía Atómica (CNEA), Argentina was performed to enable combined analyses of NCT patient data between the different centers. In-air and dose versus depth measurements in a rectangular water phantom were performed at the hyperthermal neutron beam facility of the RA-6 reactor, Bariloche. Calculated dose profiles from the CNEA treatment planning system NCTPlan that were calibrated against in-house measurements required normalizations of 1.0 (thermal neutrons), 1.13 (photons), and 0.74 (fast neutrons) to match the dosimetry of MIT.

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.

Normalisation of prescribed dose in BNCT.

Normalisation of prescribed dose in boron neutron capture therapy (BNCT) is needed to facilitate combining clinical data from different centres in the world to help expedite development of the modality. The approach being pursued within the BNCT community is based upon improving precision in the measurement and specification of absorbed dose. Beam characterisations using a common method are complete as are comparative dosimetry measurements between clinical centres in Europe and the USA. Results from treatment planning systems at these centres have been compared with measurements performed by MIT, and the scale factors determined are being confirmed with independent tests using measurements in an ellipsoidal water phantom. Dose normalisations have successfully been completed and applied to retrospectively analyse treatment plans from Brookhaven National Laboratory (1994-99) so that reported doses are consistently expressed with the trials performed during 1994-2003 at Harvard-MIT. Dose response relationships for adverse events and other endpoints can now be more accurately established.

Epithermal neutron beams for clinical studies of boron neutron capture therapy: a dosimetric comparison of seven beams.

A comparison of seven epithermal neutron beams used in clinical studies of boron neutron capture therapy (BNCT) in Sweden (Studsvik), Finland (Espoo), Czech Republic (ReZ), The Netherlands (Petten) and the U.S. (Brookhaven and Cambridge) was performed to facilitate sharing of preclinical and clinical results. The physical performance of each beam was measured using a common dosimetry method under conditions pertinent to brain irradiations. Neutron fluence and absorbed dose measurements were performed with activation foils and paired ionization chambers on the central axis both in air and in an ellipsoidal water phantom. The overall quality of each beam was assessed by figures of merit determined from the total weighted dose profiles that assumed the presence of boron in tissue. The in-air specific beam contamination from both fast neutrons and gamma rays ranged between 8 and 65 x 10(-11) cGy(w) cm2 for the different beams and the epithermal neutron flux intensities available at the patient position differed by more than a factor of 20 from 0.2-4.3 x 10(9) n cm(-2) s(-1). Percentage depth dose profiles measured in-phantom for the individual photon, thermal and fast-neutron dose components differed only subtly in shape between facilities. Assuming uptake characteristics consistent with the currently used boronated phenylalanine, all the epithermal beams exhibit a useful penetration of 8 cm or greater that is sufficient to irradiate a lesion seated at the brain midline. The performance of the existing facilities will benefit from the introduction of advanced compounds through improved beam penetrability. This could increase by as much as 2 cm for the purest of beams, although the beam intensities generally need to be increased to between 2-5 x 10(9) n cm(-2) s(-1) to maintain manageable irradiation times. These data provide the first consistent measurement of beam performance at the different centers and will enable a preliminary normalization of the calculated patient dosimetry.

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.

Dosimetric measurements with a brain equivalent plastic walled ionization chamber in an epithermal neutron beam.

The tissue substitute A-181 plastic, which has an elemental composition matching both the constituent hydrogen and nitrogen of brain tissue, was assessed for dosimetry in boron neutron capture therapy (BNCT). The sensitivity of an A-181 walled ionization chamber relative to photons for all neutrons in a clinical epithermal beam was calculated to vary between 0.79 +/- 0.04 in-air and 0.95 +/- 0.01 at depths of 4 cm and greater in-phantom. Differences in the total neutron doses measured with A-150 and A-181 plastic-walled chambers were attributed, within experimental error, to the dose produced by thermal neutron capture reactions from the different concentrations of nitrogen in the two tissue substitutes. The response of the A-181 chamber was converted to total neutron dose with an uncertainty increasing with depth in-phantom from 13 to 23% the magnitude of which is determined by the subtraction of a relatively large photon dose. The use of A-181 in place of A-150 plastic will no longer require partitioning the measured neutron dose by energy and should simplify dose reporting in BNCT.

A state-of-the-art epithermal neutron irradiation facility for neutron capture therapy.

At the Massachusetts Institute of Technology (MIT) the first fission converter-based epithermal neutron beam (FCB) has proven suitable for use in clinical trials of boron neutron capture therapy (BNCT). The modern facility provides a high intensity beam together with low levels of contamination that is ideally suited for use with future, more selective boron delivery agents. Prescriptions for normal tissue tolerance doses consist of 2 or 3 fields lasting less than 10 min each with the currently available beam intensity, that are administered with an automated beam monitoring and control system to help ensure safety of the patient and staff alike. A quality assurance program ensures proper functioning of all instrumentation and safety interlocks as well as constancy of beam output relative to routine calibrations. Beam line shutters and the medical room walls provide sufficient shielding to enable access and use of the facility without affecting other experiments or normal operation of the multipurpose research reactor at MIT. Medical expertise and a large population in the greater Boston area are situated conveniently close to the university, which operates the research reactor 24 h a day for approximately 300 days per year. The operational characteristics of the facility closely match those established for conventional radiotherapy, which together with a near optimum beam performance ensure that the FCB is capable of determining whether the radiobiological promise of NCT can be realized in routine practice.

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.

T cell uptake for the use of boron neutron capture as an immunologic research tool.

An immunologic tool based on manipulation of the boron neutron capture reaction was previously proposed in the context of heart transplantation research to examine the temporal relationship between parenchymal rejection (representing immune cell infiltration) and transplantation-associated arteriosclerosis (characterized by progressive vascular occlusion). Critical to the development of this method is the uptake of boron by specific cells of the immune system, namely T cells, without adverse effects on cell function, which may be assessed by the ability of boron-loaded cells to produce IFNgamma, a protein with substantial impact on rejection. This work presents the evaluation of two carboranyl thymidine analogs. Advantages of this type of boron compound are reduced risk of leakage and effective dose delivery based on their incorporation into cellular nuclear material. Results indicate that uptake of these boronated nucleosides is high with no adverse effects on cell function, thereby warranting the continued development of this technique that has potentially wide applicability in immunological models.

Effects of boron neutron capture irradiation on the normal lung of rats.

The whole lung of rats was irradiated with X-rays, thermal neutrons, or thermal neutrons in the presence of p-boronophenylalanine (BPA). A >/= 20% increase in breathing rate, in the period 40-80 days after irradiation, was indicative of radiation-induced pneumonitis. The ED(50) (+/-SE) for a >/= 20% increase in breathing rate, relative to age-matched controls, was 11.6 +/- 0.13 Gy for X-rays and 9.6 +/- 0.08 Gy for neutrons only. This indicated a thermal neutron beam RBE of 1.2 and an RBE of 2.2 for the high-LET components of the dose, assuming a dose reduction factor of 1.0 for gamma rays. Preliminary data indicate the compound biological effectiveness factor for BPA in the lung is approximately 1.5.

Preliminary treatment planning and dosimetry for a clinical trial of neutron capture therapy using a fission converter epithermal neutron beam.

A Phase I/II clinical trial of neutron capture therapy (NCT) was conducted at Harvard-MIT using a fission converter epithermal neutron beam. This epithermal neutron beam has nearly ideal performance characteristics (high intensity and purity) and is well-suited for clinical use. Six glioblastoma multiforme (GBM) patients were treated with NCT by infusion of the tumor-selective amino acid boronophenylalanine-fructose (BPA-F) at a dose of 14.0 g/m(2) body surface area over 90 min followed by irradiation with epithermal neutrons. Treatments were planned using NCTPlan and an accelerated version of the Monte Carlo radiation transport code MCNP 4B. Treatments were delivered in two fractions with two or three fields. Field order was reversed between fractions to equalize the average blood boron concentration between fields. The initial dose in the dose escalation study was 7.0 RBEGy, prescribed as the mean dose to the whole brain volume. This prescription dose was increased by 10% to 7.7 RBEGy in the second cohort of patients. A pharmacokinetic model was used to predict the blood boron concentration for determination of the required beam monitor units with good accuracy; differences between prescribed and delivered doses were 1.5% or less. Estimates of average tumor doses ranged from 33.7 to 83.4 RBEGy (median 57.8 RBEGy), a substantial improvement over our previous trial where the median value of the average tumor dose was 25.8 RBEGy.

Tolerance of normal human brain to boron neutron capture therapy.

Data from the Harvard-MIT and the BNL Phase I and Phase I/II clinical trials, conducted between 1994 and 1999, have been analyzed and combined, providing the most complete data set yet available on the tolerance of the normal human brain to BPA-mediated boron neutron capture therapy. Both peak (1cm(3)) dose and average whole-brain dose show a steep dose-response relationship using somnolence syndrome as the clinical endpoint. Probit analysis indicates that the doses associated with a 50% incidence for somnolence (ED(50)+/-SE) were 6.2+/-1.0 Gy(w) for average whole-brain dose and 14.1+/-1.8 Gy(w) for peak brain dose.

The design, construction and performance of a variable collimator for epithermal neutron capture therapy beams.

A patient collimator for the fission converter based epithermal neutron beam (FCB) at the Massachusetts Institute of Technology Research Reactor (MITR-II) was built for clinical trials of boron neutron capture therapy (BNCT). A design was optimized by Monte Carlo simulations of the entire beam line and incorporates a modular construction for easy modifications in the future. The device was formed in-house by casting a mixture of lead spheres (7.6 mm diameter) in epoxy resin loaded with either 140 mg cm(-3) of boron carbide or 210 mg cm(-3) of lithium fluoride (95% enriched in 6Li). The cone shaped collimator allows easy field placement anywhere on the patient and is equipped with a laser indicator of central axis, beam's eye view optics and circular apertures of 80, 100, 120 and 160 mm diameter. Beam profiles and the collateral dose in a half-body phantom were measured for the 160 mm field using fission counters, activation foils as well as tissue equivalent (A-150) and graphite walled ionization chambers. Leakage radiation through the collimator contributes less than 10% to the total collateral dose up to 0.15 m beyond the edge of the aperture and becomes relatively more prominent with lateral displacement. The measured whole body dose equivalent of 24 +/- 2 mSv per Gy of therapeutic dose is comparable to doses received during conventional therapy and is due principally (60-80%) to thermal neutron capture reactions with boron. These findings, together with the dose distributions for the primary beam, demonstrate the suitability of this patient collimator for BNCT.

Performance characteristics of the MIT fission converter based epithermal neutron beam.

A pre-clinical characterization of the first fission converter based epithermal neutron beam (FCB) designed for boron neutron capture therapy (BNCT) has been performed. Calculated design parameters describing the physical performance of the aluminium and Teflon filtered beam were confirmed from neutron fluence and absorbed dose rate measurements performed with activation foils and paired ionization chambers. The facility currently provides an epithermal neutron flux of 4.6 x 10(9) n cm(-2) s(-1) in-air at the patient position that makes it the most intense BNCT source in the world. This epithermal neutron flux is accompanied by very low specific photon and fast neutron absorbed doses of 3.5 +/- 0.5 and 1.4 +/- 0.2 x 10(-13) Gy cm2, respectively. A therapeutic dose rate of 1.7 RBE Gy min(-1) is achievable at the advantage depth of 97 mm when boronated phenylalanine (BPA) is used as the delivery agent, giving an average therapeutic ratio of 5.7. In clinical trials of normal tissue tolerance when using the FCB, the effective prescribed dose is due principally to neutron interactions with the nonselectively absorbed BPA present in brain. If an advanced compound is considered, the dose to brain would instead be predominately from the photon kerma induced by thermal neutron capture in hydrogen and advantage parameters of 0.88 Gy min(-1), 121 mm and 10.8 would be realized for the therapeutic dose rate, advantage depth and therapeutic ratio, respectively. This study confirms the success of a new approach to producing a high intensity, high purity epithermal neutron source that attains near optimal physical performance and which is well suited to exploit the next generation of boron delivery agents.

Sensitivity studies of beam directionality, beam size, and neutron spectrum for a fission converter-based epithermal neutron beam for boron neutron capture therapy.

Sensitivity studies of epithermal neutron beam performance in boron neutron capture therapy are presented for realistic neutron beams with varying filter/moderator and collimator/delimiter designs to examine the relative importance of neutron beam spectrum, directionality, and size. Figures of merit for in-air and in-phantom beam performance are calculated via the Monte Carlo technique for different well-optimized designs of a fission converter-based epithermal neutron beam with head phantoms as the irradiation target. It is shown that increasing J/phi, a measure of beam directionality, does not always lead to corresponding monotonic improvements in beam performance. Due to the relatively low significance, for most configurations, of its effect on in-phantom performance and the large intensity losses required to produce beams with very high J/phi, beam directionality should not be considered an important figure of merit in epithermal neutron beam design except in terms of its consequences on patient positioning and collateral dose. Hardening the epithermal beam spectrum, while maintaining the specific fast neutron dose well below the inherent hydrogen capture dose, improves beam penetration and advantage depth and, as a desirable by-product, significantly increases beam intensity. Beam figures of merit are shown to be strongly dependent on beam size relative to target size. Beam designs with J/phi approximately 0.65-0.7, specific fast neutron doses of 2-2.6x10(-13) Gy cm2/n and beam sizes equal to or larger than the size of the head target produced the deepest useful penetration, highest therapeutic ratios, and highest intensities.

Head phantoms for neutron capture therapy.

A water-filled head phantom that is designed for use in boron neutron capture therapy is described. The shape of this ellipsoidal phantom, based on the Synder head model, and its composition are designed to simulate the neutron slowing down properties of the human skull and brain. Small ion chambers or activation foils can be placed in many locations within the phantom volume. This permits accurate three-dimensional mapping of all relevant dose components and use of these dose contours for beam development as well as for benchmarking of computer-based patient treatment codes.

Mixed field dosimetry of epithermal neutron beams for boron neutron capture therapy at the MITR-II research reactor.

During the past several years, there has been growing interest in Boron Neutron Capture Therapy (BNCT) using epithermal neutron beams. The dosimetry of these beams is challenging. The incident beam is comprised mostly of epithermal neutrons, but there is some contamination from photons and fast neutrons. Within the patient, the neutron spectrum changes rapidly as the incident epithermal neutrons scatter and thermalize, and a photon field is generated from neutron capture in hydrogen. In this paper, a method to determine the doses from thermal and fast neutrons, photons, and the B-10(n, alpha)Li-7 reaction is presented. The photon and fast neutron doses are measured with ionization chambers, in realistic phantoms, using the dual chamber technique. The thermal neutron flux is measured with gold foils using the cadmium difference technique, the thermal neutron and B-10 doses are determined by the kerma factor method. Representative results are presented for a unilateral irradiation of the head. Sources of error in the method as applied to BNCT dosimetry, and the uncertainties in the calculated doses are discussed.

Dosimetric effects of beam size and collimation of epithermal neutrons for boron neutron capture therapy.

A series of studies of "ideal" beams has been carried out using Monte Carlo simulation with the goal of providing guidance for the design of epithermal beams for boron neutron capture therapy (BNCT). An "ideal" beam is defined as a monoenergetic, photon-free source of neutrons with user-specified size, shape and angular dependence of neutron current. The dosimetric behavior of monoenergetic neutron beams in an elliptical phantom composed of brain-equivalent material has been assessed as a function of beam diameter and neutron emission angle (beam angle), and the results are reported here. The simulation study indicates that substantial differences exist in the dosimetric behavior of small and large neutron beams (with respect to the phantom) as a function of the extent of beam collimation. With a small beam, dose uniformity increases as the beam becomes more isotropic (less collimated); the opposite is seen with large beams. The penetration of thermal neutrons is enhanced as the neutron emission angle is increased with a small beam; again the opposite trend is seen with large beams. When beam size is small, the dose delivered per neutron is very dependent on the extent of beam collimation; this does not appear to be the case with a larger beam. These trends in dose behavior are presented graphically and discussed in terms of their effect on several figures of merit, the advantage depth, the advantage ratio, and the advantage depth-dose rate. Tables giving quick summaries of these results are provided.

Boron neutron capture therapy for murine malignant gliomas.

Boron neutron capture therapy (BNCT) involves administration of a boron compound followed by neutron irradiation of the target organ. The boron atom captures a neutron, which results in the release of densely ionizing helium and lithium ions that are highly damaging and usually lethal to cells within their combined track length of approximately 12 microns. Prior to Phase I clinical trials for patients with malignant gliomas, mice with glioma 261 intracerebral tumors were fed D,L-3-(p-boronophenyl)alanine and irradiated with total tumor doses of 1000-5000 RBE-cGy of single fraction thermal neutrons to determine the maximum tolerated dose and effect on survival. These mice were compared to mice that received D,L-3-(p-boronophenyl)alanine alone, neutron irradiation alone, photon irradiation alone, or no treatment. Additional normal mice received escalating doses of neutron irradiation to determine its toxicity to normal brain. BNCT caused a dose-dependent, statistically significant prolongation in survival at 1000-5000 RBE-cGy. At 3000 RBE-cGy, median survival rates of the BNCT and untreated control groups were 68 and 22 days, respectively, with a long-term survival rate of 33%. At 4000 RBE-cGy, median survival was 72 and 21 days, respectively, with a long-term survival rate of 43%. At lower radiation doses, the extended survival was comparable between the BNCT and photon-irradiated mice; however, at 3000 and 4000 RBE-cGy the median survival of BNCT-treated mice was significantly greater than photon-irradiated mice. The maximum tolerated single fraction dose to normal brain was approximately 2000 RBE-cGy.