R. G. Fairchild

Current status of 10B-neutron capture therapy: Enhancement of tumor dose via beam filtration and dose rate, and the effects of these parameters on minimum boron content: A theoretical evaluation

At least 8 classes of compounds are being evaluated in various laboratories around the world as possible vehicles for the transport of boron to tumor for neutron capture therapy (NCT). A parameter of major importance is the minimum concentration of boron needed in tumor in order to produce improved results in cancer therapy. Calculations are made here of the minimum boron content in tumor necessary for NCT. These estimations are obtained for various neutron beams, on the basis of therapeutic gain produced by the effective dose (absorbed dose X relative biological effect). The effects of repair are considered, in anticipation of having boronated bio-molecules with selective and long-term binding to tumor cells, thus allowing protracted irradiations. Pure epithermal neutron beams (free of significant fast neutron and gamma contamination) are found to offer major advantages, particularly when the effects of repair are included. The various boron compounds being investigated for NCT are evaluated on the basis of necessary minimum boron content in tumor.

The Relative Biological Effectiveness in V79 Chinese Hamster Cells of the Neutron Capture Reactions in Boron and Nitrogen

V79 Chinese hamster cells were irradiated in the presence of different amounts of boric acid with thermal neutrons at the Medical Research Reactor at Brookhaven National Laboratory. From the linear dose-survival curves observed, a D0 value of 66 rad for the 10B(n, alpha) 7Li neutron capture reaction was obtained. No dependence of this value on the concentration of boric acid was found. Comparing this value to the D0 value of 150 rad obtained with 250 kVp X rays between 10 and 0.01% survival, an extrapolated RBE value of 2.3 was calculated. By irradiation of the same line of cells with cold neutrons at the Institut Laue - Langevin , a D0 value for the 14N(n,p)14C reaction of 77 rad was obtained, with a corresponding RBE value of 1.9. Comparison is made with previously published RBE values for the 10B(n, alpha) 7Li reaction.

Microanalytical techniques for boron analysis using the 10B(n,α)7Li reaction

In order to predict the efficacy of boronated compounds for neutron capture therapy (NCT), it is mandatory that the boron concentration in tissues be known. Various techniques for measurement of trace amounts of boron (1–100 ppm) are available, including chemical and physical procedures. Experience has shown that, with the polyhedral boranes and carboranes in particular, the usual colorimetric and spark emission spectroscopic methods are not reliable. Although these compounds may be traced with additional radiolabels, direct physical detection of boron by nondestructive methods is clearly preferable. Boron analysis via detection of the prompt‐γ ray from the 1 0B(n,α)7Li reaction has been shown to be a reliable technique. Two prompt‐γ facilities developed at Brookhaven National Laboratory are described. One, at the 60‐MW high flux beam reactor, uses sophisticated beam extraction techniques to enhance thermal neutron intensity and reduce fast neutron and γ contamination. The other was constructed at Brookhaven’s 5‐MW medical research reactor and uses conventional shielding and electronics to provide an ‘‘on‐line’’ boron analysis facility adjacent to beams designed for NCT, thus satisfying one of the requisites for clinical application of this procedure. Technical restrictions attendant upon the synthesis and testing of boronated biomolecules often require the measurement of trace amounts of boron in extremely small (mg) samples. A track‐etching technique capable of detecting ng amounts of boron in mg liquid or cell samples is described. Thus it is possible to measure the boron content in small amounts (mg samples) of antibodies, or boron uptake in cellsgrown in tissue culture.

Development and Dosimetry of an `Epithermal' Neutron Beam for Possible Use in Neutron Capture Therapy I. `Epithermal' Neutron Beam Development

The possibility exists of destroying neoplastic cells in vivo by introducing a suitable neutron-capturing isotope such as 10B and subsequently irradiating the area with a beam of thermal neutrons (energy < 0·5eV). An advantage can be gained by using epithermal neutrons (energy 10 KeV to 0·5eV), since they provide deeper penetration in tissue than do thermal neutrons. The Brookhaven Medical Research Reactor has been used to obtain an epithermal neutron beam giving a thermal neutron flux density of 1·42×1010 n/cm2-sec at 3 cm depth in tissue; the beam used gave the highest number of epithermal neutrons per unit of contaminating radiations.

Photon Activation of Iododeoxyuridine: Biological Efficacy of Auger Electrons

Photon activation therapy is a binary system being investigated as a potential therapeutic modality to improve the treatment of malignancies, particularly the highly lethal and malignant brain tumor, glioblastoma multiforme. Its success relies upon the incorporation of a target atom in the immediate vicinity of a tumor cells critical site, followed by the activation of this atom with photons of energies suitable for the induction of the photoelectric effect and its concomitant Auger cascades. The collective action of the Auger electrons imparts high-LET type damage at the critical site. Photon activation therapy uses iodine from stable iododeoxyuridine (IdUrd) as the target atom, and monochromatic photons above the K absorption edge of iodine (33.2 keV) as the activating agent. Although IdUrd is a cell-sensitizing agent, work described was designed to separate the biological efficacy due to sensitization from that of the Auger effect. Chinese hamster V79 cells with and without IdUrd in cellular DNA were irradiated at the X17B1 beam line in the National Synchroton Light Source of Brookhaven National Laboratory. Monochromatic photons above (33.4 keV) and below (32.9 keV) the K absorption edge were used to determine if any additional biological damage would accrue from the Auger cascades. The 33.4-keV photons were found to be a factor of 1.4 times more effective than 32.9-keV photons in damaging iodinated cells. The sensitizing effect, evaluated separately, was found to be a factor of 2.2 at 10% survival, regardless of photon energy. Thus the total therapeutic gain was 1.4 x 2.2 = 3.1. Irradiations of noniodinated control cells showed no difference in their response to energies above and below the iodine K edge.

Thermoluminescence of LiF TLD‐100: Glow‐curve kinetics

The thermoluminescence kinetics have been determined for the 13 glow peaks contained in the glow curves obtained from LiF TLD‐100 after exposure to 60Co irradiations. The glow curves were constructed from measurements made with recently developed equipment for recording emission spectra at closely spaced temperature intervals. In addition, the recorded data has been subjected to all corrections needed to make it suitable for reliable kinetic analysis. The recorded emission spectra can be described by a single Gaussian‐shaped band whose width and peak‐energy parameters vary erratically with temperature or, alternatively, by resolving the observed spectra into three Gaussian‐shaped bands whose parameters vary with temperatures in accord with theoretical expressions relating the emission‐spectra peak energy and full width at half‐maximum to the sample temperature. The kinetics and kinetic parameters were independently determined for the two most intense resolved emission bands. All peaks are described by first‐order kinetics and the independently determined parameters are in very good agreement. The glow curves for the least intense component are also described by the same kinetics and parameters. Inasmuch as the single‐band emission is a superposition of the three components, the same kinetics and parameters apply to the glow curve constructed from unresolved spectra. The identification number, nominal peak temperature in °C (for a heating rate of 10.3 °C/min), the activation energy E (eV), and preexponential factor s (sec−1) for the 13 peaks are as follows: (1) 1.62, 1.04, and 1014; (2) 94, 1.07, and 1013; (3a) 112, 0.987, and 1011; (3) 137, 1.05, and 1011; (4) 170, 1.54, and 4×1015; (5) 190, 2.20, and 1022; (5a) 210, 1.61, and 1015; (6) 235, 1.70, and 1015; (7) 260, 1.79, and 1015; (8) 285, 1.96, and 5×1015; (9) 315, 2.10, and 1016; (10) 345, 2.19, and 1016; (11) 370, 2.27, and 1016. The unusual value of s=1022 for the 190 °C peak, previously reported by other authors, was obtained during this study. However, it appears that this value can be obtained from relatively simple mechanisms and one of these is described.The thermoluminescence kinetics have been determined for the 13 glow peaks contained in the glow curves obtained from LiF TLD‐100 after exposure to 60Co irradiations. The glow curves were constructed from measurements made with recently developed equipment for recording emission spectra at closely spaced temperature intervals. In addition, the recorded data has been subjected to all corrections needed to make it suitable for reliable kinetic analysis. The recorded emission spectra can be described by a single Gaussian‐shaped band whose width and peak‐energy parameters vary erratically with temperature or, alternatively, by resolving the observed spectra into three Gaussian‐shaped bands whose parameters vary with temperatures in accord with theoretical expressions relating the emission‐spectra peak energy and full width at half‐maximum to the sample temperature. The kinetics and kinetic parameters were independently determined for the two most intense resolved emission bands. All peaks are described by fir...

Clinical aspects of neutron capture therapy

This document contains 36 papers presented at a conference on the current states of boron neutron capture therapy. Topics include radiation dose rates, clinical trials, dose fractionation, therapeutic results, neoplasms, radiation tolerance, and the blood-brain barrier. Individual papers are indexed separately for the data base. (TEM)

Installation and Testing of an Optimized Epithermal Neutron Beam at the Brookhaven Medical Research Reactor (BMRR)

NCT is a binary system, in which 10B is physiologically targeted to tumor and then allowed to interact with thermal neutrons generated in the treatment volume by an externally applied neutron beam. Consequently, an unusually large number of parameters are obtained, which bear on the resultant Therapeutic Gain (TG). However, a perusal of these data, as illustrated in Figure 7, indicates that the TG would increase significantly beyond values projected in this paper if the absolute amount of 10B could be increased above 30 ppm. For example, increasing 10B concentration in tumor to 45 ppm would increase TG by approximately 33% (with a T/N of 5). A similar increase in TG would follow an increase in T/N from 5 to 10. Those associated with the development of boron compounds for NCT feel that such developments are within reach.

Biodistribution and toxicity of 2,4-divinyl-nido-o-carboranyldeuteroporphyrin IX in mice

BALB/c mice with transplanted subcutaneous KHJJ mammary carcinomas were given 2,4-divinyl-nido-o-carboranyldeuteroporphyrin IX (VCDP), a prospective boron carrier for boron neutron-capture therapy, to determine the dose schedule that results in maximal boron uptake in tumor. A total dose of 270 +/- 10 micrograms/g body weight given in a 4-day multiple intraperitoneal injection schedule (3/day) resulted in 30-50 micrograms boron/g tumor. After such a dose, thrombocytopenia, granulocytosis and altered liver enzyme levels were measured in the blood. Blood boron clearance was followed for an 18 hr to 6 day post-injection period. Toxic effects of VCDP subsided within 4-6 days after the last injection. In view of the greater than 30 micrograms/g peak accumulation of boron in tumor from VCDP and the subsequent rapid reversal of VCDP toxicity, further studies of VCDP in small mammals relevant to its distribution, toxicity and potential clinical use for neutron-capture therapy of tumors appear warranted.

Thermoluminescence of LiF TLD‐100: Emission‐spectra measurements

The thermoluminescence of LiF TLD‐100 dosimeter crystals has been studied using recently developed equipment for determining simultaneously the emission intensity and the emission spectrum as a function of sample temperature. Measurements were made on numerous samples exposed to 60Co irradiations at room temperature and at exposures varying from 500 to 3×107 R. Spectra were obtained at 1.38 and 5.5 °C intervals over the temperature range 20–350 °C. Below 105 R the thermoluminescent emission can be described by a single Gaussian‐shaped band whose peak energy and full width vary irregularly with temperature and not in accord with the well‐known expressions, given in the text, relating the emission‐spectra peak energy and full width at half‐maximum to the sample temperature. However, the emission is accurately described by three Gaussian‐shaped bands whose approximate peak energies and full widths are 3.01, 0.90; 2.90, 0.72; and 2.71, 0.96 eV. The peak energies and full widths of these three bands vary with ...