Dose-rate scaling factor estimation of THOR BNCT test beam.

In 1998, an epithermal neutron test beam was designed and constructed at the Tsing Hua Open-Pool Reactor (THOR) for the purpose of preliminary dosimetric experiments in boron neutron capture therapy (BNCT). A new epithermal neutron beam was designed at this facility, and is currently under construction, with clinical trials targeted in late 2004. Depth dose-rate distributions for the THOR BNCT test beam have been measured by means of activation foil and dual ion chamber techniques. Neutron and structure-induced gamma spectra measured at the test beam exit were configured into a source function for the Monte Carlo-based treatment planning code NCTPlan. Dose-rate scaling factors (DRSFs) were determined to normalize computationally derived dose-rate distributions with experimental measurements in corresponding mathematical and physical phantoms, and to thus enable accurate treatment planning using the NCTPlan code. A similar approach will be implemented in characterizing the new THOR epithermal beam in preparation for clinical studies. This paper reports the in-phantom calculated and experimental dosimetry comparisons and derived DRSFs obtained with the THOR test beam.

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.

Pharamacokinetic modeling for boronophenylalanine-fructose mediated neutron capture therapy: 10B concentration predictions and dosimetric consequences.

A two-compartment open model has been developed for predicting 10B concentrations in blood following intravenous infusion of the L-p-boronophenylalanine-fructose complex in humans and derived from pharmacokinetic studies of 24 patients in Phase I clinical trials of boron neutron capture therapy. The 10B concentration profile in blood exhibits a characteristic rise during the infusion to a peak of approximately 32 microg/g (for infusion of 350 mg/kg over 90 min) followed by a biexponential disposition profile with harmonic mean half-lives of 0.32 +/- 0.08 and 8.2 +/- 2.7 h, most likely due to redistribution and primarily renal elimination, respectively. The mean model rate constants k12, k21, and k10 are (mean +/- SD) 0.0227 +/- 0.0064 min(-1), 0.0099 +/- 0.0027 min(-1), 0.0052 +/- 0.0016 min(-1), respectively, and the central compartment volume of distribution V1 is 0.235 +/- 0.042 L/kg. In anticipation of the initiation of clinical trials using an intense neutron beam with concomitantly short irradiations, the ability of this model to predict, in advance, the average blood 10B concentration during brief irradiations was simulated in a retrospective analysis of the pharmacokinetic data from these patients. The prediction error for blood boron concentration and its effect on simulated dose delivered for each irradiation field are reported for three different prediction strategies. In this simulation, error in delivered dose (or, equivalently, neutron fluence) for a given single irradiation field resulting from error in predicted blood 10B concentration was limited to less than 10%. In practice, lower dose errors can be achieved by delivering each field in two fractions (on two separate days) and by adjusting the second fraction's dose to offset error in the first.

A theoretical model for the microdosimetry of discontinuous distributions of heavy particle tracks.

A novel approach to solving microdosimetry problems using conditional probabilities and geometric concepts has been developed. This approach is valid for cases where a convex site is immersed in uniform or discontinuous distributions of heavy charged particle tracks and assumes no restrictions in site geometry or the kind of randomness. These conditions are relevant to the study of microdosimetry in applications such as neutron capture therapy (NCT), irradiation experiments using heavy ion particle beams, environmental radon, or occupational exposure to radioactive materials. Expressions applicable to the case of surface-distributed sources of tracks are presented that may represent situations such as NCT, where boron compounds are bound to the membranes of cellular nuclei. Microdosimetric spectra, specific energy averages, and mean number of 10B capture reactions for cell inactivation are calculated, showing their dependence on 10B localisation.

Reference dosimetry calculations for neutron capture therapy with comparison of analytical and voxel models.

As clinical trials of Neutron Capture Therapy (NCT) are initiated in the U.S. and other countries, new treatment planning codes are being developed to calculate detailed dose distributions in patient-specific models. The thorough evaluation and comparison of treatment planning codes is a critical step toward the eventual standardization of dosimetry, which, in turn, is an essential element for the rational comparison of clinical results from different institutions. In this paper we report development of a reference suite of computational test problems for NCT dosimetry and discuss common issues encountered in these calculations to facilitate quantitative evaluations and comparisons of NCT treatment planning codes. Specifically, detailed depth-kerma rate curves were calculated using the Monte Carlo radiation transport code MCNP4B for four different representations of the modified Snyder head phantom, an analytic, multishell, ellipsoidal model, and voxel representations of this model with cubic voxel sizes of 16, 8, and 4 mm. Monoenergetic and monodirectional beams of 0.0253 eV, 1, 2, 10, 100, and 1000 keV neutrons, and 0.2, 0.5, 1, 2, 5, and 10 MeV photons were individually simulated to calculate kerma rates to a statistical uncertainty of <1% (1 std. dev.) in the center of the head model. In addition, a "generic" epithermal neutron beam with a broad neutron spectrum, similar to epithermal beams currently used or proposed for NCT clinical trials, was computed for all models. The thermal neutron, fast neutron, and photon kerma rates calculated with the 4 and 8 mm voxel models were within 2% and 4%, respectively, of those calculated for the analytical model. The 16 mm voxel model produced unacceptably large discrepancies for all dose components. The effects from different kerma data sets and tissue compositions were evaluated. Updating the kerma data from ICRU 46 to ICRU 63 data produced less than 2% difference in kerma rate profiles. The depth-dose profile data, Monte Carlo code input, kerma factors, and model construction files are available electronically to aid in verifying new and existing NCT treatment planning codes.

A theoretical model for event statistics in microdosimetry. I: Uniform distribution of heavy ion tracks.

In this work we describe a novel approach to solving microdosimetry problems using conditional probabilities and geometric concepts. The intersection of a convex site with a field of randomly oriented straight track segments is formulated in terms of the relative overlap between the chord associated with the action line of the track and the track itself. This results in a general formulation that predicts the contribution of crossers, stoppers, starters, and insiders in terms of two separate functions: the chord length distribution (characteristic of the site geometry and the type of randomness) and an independent set of conditional probabilities. A Monte Carlo code was written in order to validate the proposed approach. The code can represent the intersection between an isotropic field of charged particle tracks and a general ellipsoid of unrestricted geometry. This code was used to calculate the event distribution for a sphere as well as the expected mean value and variance of the track length distribution and to compare these against the deterministic calculations. The observed agreement was shown to be very good, within the precision of the Monte Carlo approach. The formulation is used to calculate the event frequency, lineal energy, and frequency mean specific energy for several monoenergetic and isotropic proton fields in a spherical site, as a function of the site diameter, proton energy, and the event type.

A theoretical model for event statistics in microdosimetry. II: Nonuniform distribution of heavy ion tracks.

A microdosimetry model, described in Part I, applies to the case of a convex site immersed in a uniform distribution of heavy particle tracks, and assumes no restrictions in site geometry or the kind of randomness. In Part II, this model is extended to include nonuniform distributions of particle tracks. This situation is relevant to the study of microdosimetry, for example, in boron neutron capture, in irradiation experiments using heavy ion particle beams, where the sources of particle tracks are external to the cell, or in irradiation from internally incorporated particle-emitting radionuclides, such as environmental radon or occupational exposure to radioactive materials. The formalism developed permits the calculation of statistical properties, track length distributions, and microdosimetric spectra for convex sites where the "inner" and "outer" concentrations of sources may be different, or for tracks originating on the surface of a convex site. Expressions applicable to the case of surface-distributed sources of tracks are presented that may represent situations such as boron compounds bound to the membrane of a cellular nucleus in boron neutron capture. A series of Monte Carlo calculations and analytical solutions, illustrating the case of spherical site geometry, are presented and compared. Finally, microdosimetric spectra and specific energy averages are calculated for alpha and lithium particles originating from thermal neutron capture in 10B, showing their dependence on 10B localization (extra-site, uniform, intra-site, or surface-distributed).

A pharmacokinetic model for the concentration of 10B in blood after boronophenylalanine-fructose administration in humans.

An open two-compartment model has been developed for predicting (10)B concentrations in blood after intravenous infusion of the l-p-boronophenylalanine-fructose complex (BPA-F) in humans and derived from studies of pharmacokinetics in 24 patients in the Harvard-MIT Phase I clinical trials of BNCT. The (10)B concentration profile in blood exhibits a characteristic rise during the infusion to a peak of approximately 32 microg/g (for infusion of 350 mg/kg over 90 min) followed by a biphasic exponential clearance profile with half-lives of 0.34 +/- 0.12 and 9.0 +/- 2.7 h, due to redistribution and primarily renal elimination, respectively. The model rate constants k(1), k(2) and k(3) are 0.0227 +/- 0.0064, 0.0099 +/- 0.0027 and 0.0052 +/- 0.0016 min(-1), respectively, and the central compartment volume of distribution, V(1), is 0.235 +/- 0.042 kg/kg. The validity of this model was demonstrated by successfully predicting the average pharmacokinetic response for a cohort of patients who were administered BPA-F using an infusion schedule different from those used to derive the parameters of the model. Furthermore, the mean parameters of the model do not differ for cohorts of patients infused using different schedules.

Computational validation of the stereology principle applied to the microdosimetry of boron neutron capture therapy.

High resolution quantitative autoradiography (HRQAR) is a novel technique that has been developed in our laboratory and applied to the microdosimetry of boron neutron capture therapy (BNCT). High resolution quantitative autoradiography is employed to define the microdistribution of boron-10 atoms within a 1-2 microm frozen tissue section. This microdistribution is used as input to a novel two-dimensional Monte Carlo charged particle transport calculation that computes various microdosimetric parameters, such as the number of nuclear "hits," energy absorbed in the nuclei, etc., within the environment of actual tissue morphology (i.e., cell nuclei, cytoplasm, and intracellular space). Stereological transformation is then implemented to transform the two-dimensional calculations into effectively three-dimensional results. In the present study no seek to demonstrate the validity of the surrogate two-dimensional 2-D computation as being quantitatively equivalent to a hypothetical full 3-D calculation. The results show that within the limitations of the test parameters used the surrogate 2-D and 3-D results are completely equivalent within the statistical constraints of the Monte Carlo calculations. Limitations of this approach also are evaluated, including a Monte Carlo calculation of the influence of the thickness of the histological tissue section and the track detector and the influence of 4He and 7Li particle lateral and range straggling.

Proton nuclear magnetic resonance measurement of p-boronophenylalanine (BPA): a therapeutic agent for boron neutron capture therapy.

Noninvasive in vivo quantitation of boron is necessary for obtaining pharmacokinetic data on candidate boronated delivery agents developed for boron neutron capture therapy (BNCT). Such data, in turn, would facilitate the optimization of the temporal sequence of boronated drug infusion and neutron irradiation. Current approaches to obtaining such pharmacokinetic data include: positron emission tomography employing F-18 labeled boronated delivery agents (e.g., p-boronophenylalanine), ex vivo neutron activation analysis of blood (and very occasionally tissue) samples, and nuclear magnetic resonance (NMR) techniques. In general, NMR approaches have been hindered by very poor signal to noise achieved due to the large quadrupole moments of B-10 and B-11 and (in the case of B-10) very low gyromagnetic ratio, combined with low physiological concentrations of these isotopes under clinical conditions. This preliminary study examines the feasibility of proton NMR spectroscopy for such applications. We have utilized proton NMR spectroscopy to investigate the detectability of p-boronophenylalanine fructose (BPA-f) at typical physiological concentrations encountered in BNCT. BPA-f is one of the two boron delivery agents currently undergoing clinical phase-I/II trials in the U.S., Japan, and Europe. This study includes high-resolution 1H spectroscopic characterization of BPA-f to identify useful spectral features for purposes of detection and quantification. The study examines potential interferences, demonstrates a linear NMR signal response with concentration, and presents BPA NMR spectra in ex vivo blood samples and in vivo brain tissues.

Microdosimetry for boron neutron capture therapy: a review.

A review of the microdosimetry of boron neutron capture therapy is presented focusing on the progression of key scientific ideas and developments in this field rather than on a comprehensive and inclusive review of the literature. The author concludes that from a microdosimetry perspective the field is highly advanced, but what is lacking is the correlation of the proposed models and results with experimental radiobiological data.

A novel approach to the microdosimetry of neutron capture therapy. Part I. High-resolution quantitative autoradiography applied to microdosimetry in neutron capture therapy.

A novel approach to the microdosimetry of neutron capture therapy has been developed using high-resolution quantitative autoradiography (HRQAR) and two-dimensional Monte Carlo simulation. This approach has been applied using actual cell morphology (nuclear and cytoplasmic cell structures) and the measured microdistribution of boron-10 in a transplanted murine brain tumor (GL261) containing p-boronophenylalanine (BPA) as the boron compound. The 2D Monte Carlo transport code for the alpha and 7Li charged particles from the 10B(n,alpha)7Li reactions has been developed as a surrogate to a full 3D approach to calculate a variety of different microdosimetric parameters. The HRQAR method and the surrogate 2D Monte Carlo approach are described in detail and examples of their use are presented.

Dosimetry of 252Cf sources for neutron radiotherapy with and without augmentation by boron neutron capture therapy.

Interstitial and intracavity 252Cf sources have been used to treat a number of tumor types with encouraging results. In particular these tumors include a variety of cervical, head-and-neck, and oral-cavity cancers and possible malignant gliomas. As a neutron source, 252Cf offers certain theoretical advantages over photon therapy (i.e., in treating tumors with significant hypoxic or necrotic components). With the recent availability of 10B-labeled tumor-seeking compounds, the usefulness of 252Cf may be further improved by augmenting the 252Cf dose to the tumor with an additional dose due to the fission (following thermal neutron capture) of 10B located in the tumor itself. While the high mean neutron energy permits 252Cf to deliver a high-LET, low-OER dose to the tumor on a macroscopic scale, thermalization of neutrons followed by 10B capture may augment this dose at the cellular level if adequate loading of tumor cells with 10B is possible. This paper presents results of a Monte Carlo simulation study investigating the dosimetric characteristics of linear 252Cf sources both with and without the quantitative increase in tumor dose possible with the addition of 10B. Results are displayed in the form of "along and away" tables and dose profiles in a water phantom. Comparisons of Monte Carlo results with experimental and analytical dosimetry data available in the literature are also presented.

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.

Clinical considerations for neutron capture therapy of brain tumors.

The radiotherapeutic management of primary brain tumors and metastatic melanoma in brain has had disappointing clinical results for many years. Although neutron capture therapy was tried in the United States in the 1950s and 1960s, the results were not as hoped. However, with the newly developed capability to measure boron concentrations in blood and tissue both quickly and accurately, and with the advent of epithermal neutron beams obviating the need for scalp and skull reflection, it should now be possible to mount such a clinical trial of NCT again and avoid serious complications. As a prerequisite, it will be important to demonstrate the differential uptake of boron compound in brain tumor as compared with normal brain and its blood supply. If this can be done, then a trial of boron neutron capture therapy for brain tumors should be feasible. Because boronated phenylalanine has been demonstrated to be preferentially taken up by melanoma cells through the biosynthetic pathway for melanin, there is special interest in a trial of boron neutron capture therapy for metastatic melanoma in brain. Again, the use of an epithermal beam would make this a practical possibility. However, because any epithermal (or thermal) beam must contain a certain contaminating level of gamma rays, and because even a pure neutron beam causes gamma rays to be generated when it interacts with tissue, we think that it is essential to deliver treatments with an epithermal beam for boron neutron capture therapy in fractions in order to minimize the late-effects of low-LET gamma rays in the normal tissue. I look forward to the remainder of this Workshop, which will detail recent progress in the development of epithermal, as well as thermal, beams and new methods for tracking and measuring the uptake of boron in normal and tumor tissues.

Monte Carlo based dosimetry and treatment planning for neutron capture therapy of brain tumors.

Monte Carlo based dosimetry and computer-aided treatment planning for neutron capture therapy have been developed to provide the necessary link between physical dosimetric measurements performed on the MITR-II epithermal-neutron beams and the need of the radiation oncologist to synthesize large amounts of dosimetric data into a clinically meaningful treatment plan for each individual patient. Monte Carlo simulation has been employed to characterize the spatial dose distributions within a skull/brain model irradiated by an epithermal-neutron beam designed for neutron capture therapy applications. The geometry and elemental composition employed for the mathematical skull/brain model and the neutron and photon fluence-to-dose conversion formalism are presented. A treatment planning program, NCTPLAN, developed specifically for neutron capture therapy, is described. Examples are presented illustrating both one and two-dimensional dose distributions obtainable within the brain with an experimental epithermal-neutron beam, together with beam quality and treatment plan efficacy criteria which have been formulated for neutron capture therapy. The incorporation of three-dimensional computed tomographic image data into the treatment planning procedure is illustrated. The experimental epithermal-neutron beam has a maximum usable circular diameter of 20 cm, and with 30 ppm of B-10 in tumor and 3 ppm of B-10 in blood, it produces (with RBE weighting) a beam-axis advantage depth of 7.4 cm, a beam-axis advantage ratio of 1.83, a global advantage ratio of 1.70, and an advantage depth RBE-dose rate to tumor of 20.6 RBE-cGy/min (cJ/kg-min). These characteristics make this beam well suited for clinical applications, enabling an RBE-dose of 2,000 RBE-cGy/min (cJ/kg-min) to be delivered to tumor at brain midline in six fractions with a treatment time of approximately 16 minutes per fraction. With parallel-opposed lateral irradiation, the planar advantage depth contour for this beam (with the B-10 distribution defined above) encompasses nearly the whole brain. Experimental calibration techniques for the conversion of normalized to absolute treatment plans are described.

Monte Carlo methods of neutron beam design for neutron capture therapy at the MIT Research Reactor (MITR-II).

Monte Carlo methods of coupled neutron/photon transport are being used in the design of filtered beams for Neutron Capture Therapy (NCT). This method of beam analysis provides segregation of each individual dose component, and thereby facilitates beam optimization. The Monte Carlo method is discussed in some detail in relation to NCT epithermal beam design. Ideal neutron beams (i.e., plane-wave monoenergetic neutron beams with no primary gamma-ray contamination) have been modeled both for comparison and to establish target conditions for a practical NCT epithermal beam design. Detailed models of the 5 MWt Massachusetts Institute of Technology Research Reactor (MITR-II) together with a polyethylene head phantom have been used to characterize approximately 100 beam filter and moderator configurations. Using the Monte Carlo methodology of beam design and benchmarking/calibrating our computations with measurements, has resulted in an epithermal beam design which is useful for therapy of deep-seated brain tumors. This beam is predicted to be capable of delivering a dose of 2000 RBE-cGy (cJ/kg) to a therapeutic advantage depth of 5.7 cm in polyethylene assuming 30 micrograms/g 10B in tumor with a ten-to-one tumor-to-blood ratio, and a beam diameter of 18.4 cm. The advantage ratio (AR) is predicted to be 2.2 with a total irradiation time of approximately 80 minutes. Further optimization work on the MITR-II epithermal beams is expected to improve the available beams.

Neutron capture therapy beams at the MIT Research Reactor.

Several neutron beams that could be used for neutron capture therapy at MITR-II are dosimetrically characterized and their suitability for the treatment of glioblastoma multiforme and other types of tumors are described. The types of neutron beams studied are: 1) those filtered by various thicknesses of cadmium, D2O, 6Li, and bismuth; and 2) epithermal beams achieved by filtration with aluminum, sulfur, cadmium, 6Li, and bismuth. Measured dose vs. depth data are presented in polyethylene phantom with references to what can be expected in brain. The results indicate that both types of neutron beams are useful for neutron capture therapy. The first type of neutron beams have good therapeutic advantage depths (approximately 5 cm) and excellent in-phantom ratios of therapeutic dose to background dose. Such beams would be useful for treating tumors located at relatively shallow depths in the brain. On the other hand, the second type of neutron beams have superior therapeutic advantage depths (greater than 6 cm) and good in-phantom therapeutic advantage ratios. Such beams, when used along with bilateral irradiation schemes, would be able to treat tumors at any depth in the brain. Numerical examples of what could be achieved with these beams, using RBEs, fractionated-dose delivery, unilateral, and bilateral irradiation are presented in the paper. Finally, additional plans for further neutron beam development at MITR-II are discussed.