Dennis Greenberg

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.

An improved neutron collimator for brain tumor irradiations in clinical boron neutron capture therapy

To improve beam penetration into a head allowing the treatment of deeper seated tumors, two neutron collimators were built sequentially and tested for use in the clinical boron neutron capture therapy (BNCT) program at the epithermal neutron irradiation facility of the Brookhaven Medical Research Reactor. The collimators were constructed from lithium-impregnated polyethylene, which comprises Li2CO3 powder (approximately 93% enriched isotopic 6Li) uniformly dispersed in polyethylene to a total 6Li content of 7.0 wt. %. The first collimator is 7.6 cm thick with a conical cavity 16 cm in diameter on the reactor core side tapering to 8 cm facing the patients head. The second collimator is 15.2 cm thick with a conical cavity 20 cm in diameter tapering to 12 cm. A clinical trial of BNCT for patients with malignant brain tumors is underway using the first collimator. Results of phantom dosimetry and Monte Carlo computations indicate that the new 15.2 cm thick collimator will improve the neutron beam penetration. Thus, the second collimator was made and will be used in an upcoming clinical trial. In-air and in-phantom mixed-field dosimetric measurements were compared to Monte Carlo computations for both collimators. The deeper penetration is achieved but at a sacrifice in beam intensity. In this report, a performance comparison of both collimators regarding various fluence rate and absorbed dose distributions in a head model is presented and discussed.

Enhancement of the epithermal neutron beam used for boron neutron capture therapy

PURPOSE This report describes a study to enhance the epithermal neutron beam at the Brookhaven Medical Research Reactor by increasing the epithermal neutron flux and/or reducing contamination by fast neutrons. METHODS AND MATERIALS The beam was reevaluated using Monte Carlo calculations and flux and dose measurements in air and in an ellipsoidal head phantom at the patient irradiation port. Changes in its geometry and materials were considered, including rearranging the fuel elements in the reactor core and redesigning the moderator and the patient irradiation port. RESULTS Calculations of the new fluxes and doses at the patient irradiation port showed that the epithermal neutron flux can be increased by 100%, while the fast neutron dose per epithermal neutron can be reduced by 38%. In 1992, some of the proposed changes were made. In June 1992, measurements were made after one additional fuel element was added to replace a graphite spacer block on the epithermal beam side of the reactor core. The results show that the epithermal neutron flux increased by 18%, as predicted by the Monte Carlo calculations. In October 1992, the fuel elements in the reactor core were rearranged by placing four new fuel elements in the first row facing the epithermal port; the intensity of the epithermal neutron beam increased by 50% and the fast neutron and gamma doses per epithermal neutron may have decreased slightly. CONCLUSION The epithermal neutron beam at the Brookhaven Medical Research Reactor has gained a 50% increase in the epithermal neutron flux and the fast neutron and gamma doses per epithermal neutron are reduced slightly after the rearrangement of the fuel elements in the core.

A physical dosimetry intercomparison for BNCT

An intercomparison of physical dosimetry methods used at the Massachusetts Institute of Technology (MIT) and Brookhaven National Laboratory was completed to enable retrospective analysis of BNCT trials. Measurements were performed under reference conditions pertinent to clinical irradiations at the epithermal neutron beam facility of the Brookhaven Medical Research Reactor (BMRR) using procedures developed at MIT during similar trials. Thermal neutron flux was determined from gold foil activation experiments and good agreement was found between the depth profiles measured in-phantom by the two groups. At a depth of 3.5 cm where the measured flux is greatest, the ratio of the MIT/BMRR measurements is 1.01+/-0.10 if the same reporting procedures are applied. Photon and fast neutron absorbed dose rates were assessed using ionization chambers with separate graphite and A-150 plastic walls. Measurement of the in-phantom photon depth dose component agreed favorably with that previously reported by the BMRR group using thermoluminescent dosimeters. At a depth of 3.5 cm the ratio of the MIT measurements to those made by the BMRR group was 0.89+/-0.12. In-air measurements of the fast neutron and photon absorbed dose rates agreed within the limits of experimental uncertainty. Additional studies were performed in the ellipsoidal water phantom regularly used for beam characterizations at MIT. No significant differences in the thermal neutron flux measured in either a solid PMMA cube or an ellipsoidal shaped water phantom were observed on the central axis of the beam. This study confirms the reproducibility and uniformity of dosimetry measurements performed by the two independent groups undertaking BNCT trials in the USA and provides the physical data necessary to compare BMRR treatment protocols with those applied at Harvard-MIT.

Boron neutron capture therapy of ocular melanoma and intracranial glioma using p-boronophenylalanine

During conventional radiotherapy, the dose that can be delivered to the tumor is limited by the tolerance of the surrounding normal tissue within the treatment volume. Boron Neutron Capture Therapy (BNCT) represents a promising modality for selective tumor irradiation. The key to effective BNCT is selective localization of {sup 10}B in the tumor. We have shown that the synthetic amino acid p-boronophenylalanine (BPA) will selectively deliver boron to melanomas and other tumors such as gliosarcomas and mammary carcinomas. Systemically delivered BPA may have general utility as a boron delivery agent for BNCT. In this paper, BNCT with BPA is used in treatment of experimentally induced gliosarcoma in rats and nonpigmented melanoma in rabbits. The tissue distribution of boron is described, as is response to the BNCT. 6 refs., 4 figs., 1 tab.

Physical and biological doses produced from neutron capture in a 235U foil

As a follow-on study to the feasibility of neutron capture therapy (NCT) with 235U brachytherapy seeds, physical doses were calculated and measured for the radiation from a 235U foil in a lucite phantom which was irradiated at the epithermal neutron irradiation port of the Brookhaven Medical Research Reactor. In addition, cell survival experiments were performed to obtain the relative biological effectiveness (RBE) for the neutron part of the radiation. The calculated absorbed doses agree with the measured ones. From cell survival experiments, it is deduced that the fission neutrons from the 235U foil have a RBE of 3.0 while the fast neutrons in the beam have a RBE of 3.8. Also observed is that, with the cells 7 mm from the foil, a significant amount of absorbed dose comes from the beta rays of 235U fission events. This absorbed dose from beta rays is a significant addition to the therapeutic dose. Due to the limited ranges of beta rays in tissue, this absorbed dose is restricted to the vicinity of the foil. This is the first demonstration of beta rays as part of NCT.

Gadolinium as an Element for Neutron Capture Therapy

Gadolinium is being studied as an alternate active element to B for Neutron Capture Therapy (NCT). The advantages of Gd-157 as compared to B-10 are that Gd-157 has a very large thermal neutron cross section (455,000 b), and Gd containing compounds that target tumors are being developed as MRI contrast agents. A disadvantage is that the products of the Gd + n reaction, gamma rays and Auger electrons, do not appear to be as well suited to NCT as the products of the B + n reaction, but these still may be effective in destroying tumors. Because of the advantages of Gd, an investigation of Gd as an element for NCT is proceeding at Brookhaven National Laboratory (BNL)1.

Radiation Risks from p-Boronophenylalanine-Mediated BNCT for Glioblastoma Multiforme

Boron neutron capture therapy (BNCT) is a binary treatment modality that requires selective delivery of a 10B-labeled compound to a tumor and slow neutron irradiation of the tumor-bearing tissues. The capture of thermalized neutrons by 10B releases high linear-energy-transfer (LET) alpha (α) and 7Li particles via the 10B(n,α)7Li reaction. These particles can kill or render non-clonogenic 10B-rich tumor cells while sparing boron-poor tissues. A phase I/II clinical trial of p-boronophenylalanine (≥95% 10B enriched)-mediated BNCT for GBM is being conducted using the Brookhaven Medical Research Reactor’s clinical epithermal neutron irradiation facility.

Therapeutic effects of S-35-thiouracil in balb/c mice carrying harding-passey melanoma

Thiouracil (TU) selectively binds to the pigment melanin during melanogenesis and is rapidly cleared from normal tissues. This compound shows little affinity for pre-formed melanin. BALB/c mice, carrying the subcutaneously transplanted Harding-Passey melanoma, were given i.p. injections of 35S-labeled thiouracil in a range of doses and administration schedules. Injected doses ranged from 1.3 to 10 mCi per mouse with resultant tumor dose rates of 10 to 30 cGy/hr, respectively. At the lower dose rates, growth delay of approximately 1 to 2 weeks was observed in all tumors. At the highest doses used, complete tumor regression (no regrowth) was observed in some cases, with extended growth delays of approximately 6 weeks in the rest. These results illustrate the possible utility of radiolabeled thiouracil as a systemically administered brachytherapy agent for melanoma.