Otto K. Harling

The development of a miniaturized disk bend test for the determination of postirradiation mechanical properties

Abstract A Miniaturized Disk Bend Test capable of extracting postirradiation mechanical behavior information from disk-shaped specimens no larger than those used for Transmission Electron Microscopy is currently being developed. Finite element analysis is performed to convert the experimentally measured load-deflection data into useful engineering information. Since neutron irradiation costs scale with specimen volume, successful development of miniaturized mechanical property tests could provide significant savings in irradiation testing costs for nuclear materials used in fusion and other nuclear technologies. In addition, it may be possible to provide mechanical behavior information which is not ordinarily obtainable due to space limitations in irradiation experiments.

Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer

Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high grade gliomas, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, the United States, Finland and several other European countries, Argentina and Taiwan. Accelerators producing epithermal neutron beams also could be used for BNCT and these are being developed in several countries. It is anticipated that the first Japanese accelerator will be available for therapeutic use in 2013. The major hurdle for the design and synthesis of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations in the range of 20 μg/g. This would be sufficient to deliver therapeutic doses of radiation with minimal normal tissue toxicity. Two boron drugs have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or “BPA”, and sodium borocaptate or “BSH” (Na2B12H11SH). In this report we will provide an overview of other boron delivery agents that currently are under evaluation, neutron sources in use or under development for BNCT, clinical dosimetry, treatment planning, and finally a summary of previous and on-going clinical studies for high grade gliomas and recurrent tumors of the head and neck region. Promising results have been obtained with both groups of patients but these outcomes must be more rigorously evaluated in larger, possibly randomized clinical trials. Finally, we will summarize the critical issues that must be addressed if BNCT is to become a more widely established clinical modality for the treatment of those malignancies for which there currently are no good treatment options.

A Critical Examination of the Results from the Harvard-MIT NCT Program Phase I Clinical Trial of Neutron Capture Therapy for Intracranial Disease

SummaryA phase I trial was designed to evaluate normal tissue tolerance to neutron capture therapy (NCT); tumor response was also followed as a secondary endpoint. Between July 1996 and May 1999, 24 subjects were entered into a phase 1 trial evaluating cranial NCT in subjects with primary or metastatic brain tumors. Two subjects were excluded due to a decline in their performance status and 22 subjects were irradiated at the MIT Nuclear Reactor Laboratory. The median age was 56 years (range 24–78). All subjects had a pathologically confirmed diagnosis of either glioblastoma (20) or melanoma (2) and a Karnofsky of 70 or higher. Neutron irradiation was delivered with a 15 cm diameter epithermal beam. Treatment plans varied from 1 to 3 fields depending upon the size and location of the tumor. The10B carrier,l-p-boronophenylalanine-fructose (BPA-f), was infused through a central venous catheter at doses of 250 mg kg−1 over 1 h (10 subjects), 300 mg kg−1 over 1.5 h (two subjects), or 350 mg kg−1 over 1.5–2 h (10 subjects). The pharmacokinetic profile of10B in blood was very reproducible and permitted a predictive model to be developed. Cranial NCT can be delivered at doses high enough to exhibit a clinical response with an acceptable level of toxicity. Acute toxicity was primarily associated with increased intracranial pressure; late pulmonary effects were seen in two subjects. Factors such as average brain dose, tumor volume, and skin, mucosa, and lung dose may have a greater impact on tolerance than peak dose alone. Two subjects exhibited a complete radiographic response and 13 of 17 evaluable subjects had a measurable reduction in enhanced tumor volume following NCT.

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.

Monte Carlo-based treatment planning for boron neutron capture therapy using custom designed models automatically generated from CT data

PURPOSE A Monte Carlo-based treatment planning code for boron neutron capture therapy (BNCT), called NCTPLAN, has been developed in support of the New England Medical Center-Massachusetts Institute of Technology program in BNCT. This code has been used to plan BNCT irradiations in an ongoing peripheral melanoma BNCT protocol. The concept and design of the code is described and illustrative applications are presented. METHODS AND MATERIALS NCTPLAN uses thin-slice Computed Tomography (CT) image data to automatically create a heterogeneous multimaterial model of the relevant body part, which is then used as input to a Monte Carlo simulation code, MCNP, to derive distributions within the model. Results are displayed as isocontours superimposed on precisely corresponding CT images of the body part. Currently the computational slowness of the dose calculations precludes efficient treatment planning per se, but does provide the radiation oncologist with a preview of the doses that will be delivered to tumors and to various normal tissues, and permits neutron irradiation times in Megawatt-minutes (MW-min) to be calculated for specific dose prescriptions. The validation of the NCTPLAN results by experimental mixed-field dosimetry is presented. A typical application involving a cranial parallel-opposed epithermal neutron beam irradiation of a human subject with a glioblastoma multiforme is illustrated showing relative biological effectiveness-isodose (RBE) distributions in normal CNS structures and in brain tumors. Parametric curves for the MITR-II M67 epithermal neutron beam, showing the gain factors (gain factor = minimum tumor dose/maximum normal brain dose) for various combinations of boron concentrations in tumor and in normal brain, are presented. RESULTS The NCTPLAN code provides good computational agreement with experimental measurements for all dose components along the neutron beam central axis in a head phantom. For the M67 epithermal beam the gain factor for 1, boronophenylalanine for a small midline brain tumor under typical distribution assumptions is 1.4-1.8 x . Implementation of the code under clinical conditions is demonstrated. CONCLUSION The NCTPLAN code has been shown to be well suited to treatment-planning applications in BNCT. Comparison of computationally derived dose distributions in a phantom compared with experimental measurements demonstrates good agreement. Automatic superposition of isodose contours with corresponding CT image data provides the ability to evaluate BNCT doses to tumor and to normal structures. Calculation of gain factors suggests that for the M67 epithermal neutron beam, more advantage is gained from increasing boron concentrations in tumor than from increasing the boron tumor-to-normal brain ratio.

Boron neutron capture therapy: cellular targeting of high linear energy transfer radiation.

Boron neutron capture therapy (BNCT) is based on the preferential targeting of tumor cells with10 B and subsequent activation with thermal neutrons to produce a highly localized radiation. In theory, it is possible to selectively irradiate a tumor and the associated infiltrating tumor cells with large single doses of high-LET radiation while sparing the adjacent normal tissues. The mixture of high- and low-LET dose components created in tissue during neutron irradiation complicates the radiobiology of BNCT. Much of the complexity has been unravelled through a combination of preclinical experimentation and clinical dose escalation experience. Over 350 patients have been treated in a number of different facilities worldwide. The accumulated clinical experience has demonstrated that BNCT can be delivered safely but is still defining the limits of normal brain tolerance. Several independent BNCT clinical protocols have demonstrated that BNCT can produce median survivals in patients with glioblastoma that appear to be equivalent to conventional photon therapy. This review describes the individual components and methodologies required for effect BNCT: the boron delivery agents; the analytical techniques; the neutron beams; the dosimetry and radiation biology measurements; and how these components have been integrated into a series of clinical studies. The single greatest weakness of BNCT at the present time is non-uniform delivery of boron into all tumor cells. Future improvements in BNCT effectiveness will come from improved boron delivery agents, improved boron administration protocols, or through combination of BNCT with other modalites.

The Fission Converter-Based Epithermal Neutron Irradiation Facility at the Massachusetts Institute of Technology Reactor

Abstract A new type of epithermal neutron irradiation facility for use in neutron capture therapy has been designed, constructed, and put into operation at the Massachusetts Institute of Technology Research Reactor (MITR). A fission converter, using plate-type fuel and driven by the MITR, is used as the source of neutrons. After partial moderation and filtration of the fission neutrons, a high-intensity forward directed beam is available with epithermal neutron flux [approximately equal to]1010 n/cm2·s, 1 eV ≤ E ≤ 10 keV, at the entrance to the medical irradiation room, and epithermal neutron flux = 3 to 5 × 109 n/cm2·s at the end of the patient collimator. This is currently the highest-intensity epithermal neutron beam. Furthermore, the system is designed and licensed to operate at three times higher power and flux should this be desired. Beam contamination from unwanted fast neutrons and gamma rays in the aluminum, polytetrafluoroethylene, cadmium and lead-filtered beam is negligible with a specific fast neutron and gamma dose, Dγ,fn/ϕepi [less than or approximately equal] 2 × 10–13 Gy cm2/nepi. With a currently approved neutron capture compound, boronophenylalanine, the therapeutically advantageous depth of penetration is >9 cm for a unilateral beam placement. Single fraction irradiations to tolerance can be completed in 5 to 10 min. An irradiation control system based on beam monitors and redundant, high-reliability programmable logic controllers is used to control the three beam shutters and to ensure that the prescribed neutron fluence is accurately delivered to the patient. A patient collimator with variable beam sizes facilitates patient irradiations in any desired orientation. A shielded medical room with a large window provides direct viewing of the patient, as well as remote viewing by television. Rapid access through a shielded and automatically operated door is provided. The D2O cooling system for the fuel has been conservatively designed with excess capacity and is fully instrumented to ensure detection and control of off-normal conditions. A wide range of possible abnormal events or accident scenarios has been analyzed to show that even in the worst cases, there should be no fission product release through fuel damage. This facility has been licensed to operate by the U.S. Nuclear Regulatory Commission, and initial operation commenced in June 2000.

Treatment planning and dosimetry for the Harvard-MIT Phase I clinical trial of cranial neutron capture therapy☆

PURPOSE A Phase I trial of cranial neutron capture therapy (NCT) was conducted at Harvard-MIT. The trial was designed to determine maximum tolerated NCT radiation dose to normal brain. METHODS AND MATERIALS Twenty-two patients with brain tumors were treated by infusion of boronophenylalanine-fructose (BPA-f) followed by exposure to epithermal neutrons. The study began with a prescribed biologically weighted dose of 8.8 RBE (relative biologic effectiveness) Gy, escalated in compounding 10% increments, and ended at 14.2 RBE Gy. BPA-f was infused at a dose 250-350 mg/kg body weight. Treatments were planned using MacNCTPlan and MCNP 4B. Irradiations were delivered as one, two, or three fields in one or two fractions. RESULTS Peak biologically weighted normal tissue dose ranged from 8.7 to 16.4 RBE Gy. The average dose to brain ranged from 2.7 to 7.4 RBE Gy. Average tumor dose was estimated to range from 14.5 to 43.9 RBE Gy, with a mean of 25.7 RBE Gy. CONCLUSIONS We have demonstrated that BPA-f-mediated NCT can be precisely planned and delivered in a carefully controlled manner. Subsequent clinical trials of boron neutron capture therapy at Harvard and MIT will be initiated with a new high-intensity, high-quality epithermal neutron beam.

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.

Fission reactor neutron sources for neutron capture therapy — a critical review

SummaryThe status of fission reactor-based neutron beams for neutron capture therapy (NCT) is reviewed critically. Epithermal neutron beams, which are favored for treatment of deep-seated tumors, have been constructed or are under construction at a number of reactors worldwide. Some of the most recently constructed epithermal neutron beams approach the theoretical optimum for beam purity. Of these higher quality beams, at least one is suitable for use in high through-put routine therapy. It is concluded that reactor-based epithermal neutron beams with near optimum characteristics are currently available and more can be constructed at existing reactors. Suitable reactors include relatively low power reactors using the core directly as a source of neutrons or a fission converter if core neutrons are difficult to access. Thermal neutron beams for NCT studies with small animals or for shallow tumor treatments, with near optimum properties have been available at reactors for many years. Additional high quality thermal beams can also be constructed at existing reactors or at new, small reactors. Furthermore, it should be possible to design and construct new low power reactors specifically for NCT, which meet all requirements for routine therapy and which are based on proven and highly safe reactor technology.