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, 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.

Fission reactor based epithermal neutron irradiation facilities for routine clinical application in BNCT--Hatanaka memorial lecture.

Based on experience gained in the recent clinical studies at MIT/Harvard, the desirable characteristics of epithermal neutron irradiation facilities for eventual routine clinical BNCT are suggested. A discussion of two approaches to using fission reactors for epithermal neutron BNCT is provided. This is followed by specific suggestions for the performance and features needed for high throughput clinical BNCT. An example of a current state-of-the-art, reactor based facility, suited for routine clinical use is discussed. Some comments are provided on the current status of reactor versus accelerator based epithermal neutron sources for BNCT. This paper concludes with a summary and a few personal observations on BNCT by the author.

Functional and histological changes in rat lung after boron neutron capture therapy.

The motivation for this work was an unexpected occurrence of lung side effects in two human subjects undergoing cranial boron neutron capture therapy (BNCT). The objectives were to determine experimentally the biological weighting factors in rat lung for the high-LET dose components for a retrospective assessment of the dose to human lung during cranial BNCT. Lung damage after whole-thorax irradiation was assessed by serial measurement of breathing rate and evaluation of terminal lung histology. A positive response was defined as a breathing rate 20% above the control group mean and categorized as occurring either early (<110 days) or late (>110 days). The ED(50) values derived from probit analyses of the early breathing rate dose-response data for X rays and neutrons were 11.4+/-0.4 and 9.2+/-0.6 Gy, respectively, and were similar for the other end points. The ED(50) values for irradiation with neutrons plus p-boronophenylalanine were 8.7+/-1.0 and 6.7+/-0.4 for the early and late breathing rate responses, respectively, and 7.0+/-0.5 Gy for the histological response. The RBEs for thermal neutrons ranged between 2.9+/-0.7 and 3.1+/-1.2 for all end points. The weighting factors for the boron component of the dose differed significantly between the early (1.4+/-0.3) and late (2.3+/-0.3) breathing rate end points. A reassessment of doses in patients during cranial BNCT confirmed that the maximum weighted doses were well below the threshold for the onset of pneumonitis in healthy human lung.

Improved dose targeting for a clinical epithermal neutron capture beam using optional (6)Li filtration.

PURPOSE: The aim of this study was to construct a (6)Li filter and to improve penetration of thermal neutrons produced by the fission converter-based epithermal neutron beam (FCB) for brain irradiation during boron neutron capture therapy (BNCT). METHODS AND MATERIALS: Design of the (6)Li filter was evaluated using Monte Carlo simulations of the existing beam line and radiation transport through an ellipsoidal water phantom. Changes in beam performance were determined using three figures of merit: (1) advantage depth (AD), the depth at which the total biologically weighted dose to tumor equals the maximum weighted dose to normal tissue; (2) advantage ratio (AR), the ratio of the integral tumor dose to that of normal tissue averaged from the surface to the AD; and (3) advantage depth dose rate (ADDR), the therapeutic dose rate at the AD. Dosimetry performed with the new filter installed provided calibration data for treatment planning. Past treatment plans were recalculated to illustrate the clinical potential of the filter. RESULTS: The 8-mm-thick Li filter is more effective for smaller field sizes, increasing the AD from 9.3 to 9.9 cm, leaving the AR unchanged at 5.7 but decreasing the ADDR from 114 to 55 cGy min(-1) for the 12 cm diameter aperture. Using the filter increases the minimum deliverable dose to deep seated tumors by up to 9% for the same maximum dose to normal tissue. CONCLUSIONS: Optional (6)Li filtration provides an incremental improvement in clinical beam performance of the FCB that could help to establish a therapeutic window in the future treatment of deep-seated tumors.

The MIT user center for neutron capture therapy research.

Neutron capture therapy (NCT) research encompasses a wide range of preclinical and clinical studies needed to develop this promising but complex cancer treatment. Many specialized facilities and capabilities including thermal and epithermal neutron irradiation facilities, boron analysis, specialized mixed-field dosimetry, animal care facilities and protocols, cell culture laboratories, and, for human clinical studies, licenses and review board approvals are required for NCT research. Such infrastructure is essential, but much of it is not readily available within the community. This is especially true for neutron irradiation facilities, which often require significant development and capital investment too expensive to duplicate at each site performing NCT research. To meet this need, the NCT group at the Massachusetts Institute of Technology (MIT) has established a User Center for NCT researchers that is already being accessed successfully by various groups. This paper describes the facilities, capabilities and other resources available at MIT and how the NCT research community can access them.

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 with (10)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 modalities.

Microdosimetric intercomparison of BNCT beams at BNL and MIT.

Microdosimetric measurements have been performed at the clinical beam intensities in two epithermal neutron beams, the Brookhaven Medical Research Reactor and the M67 beam at the Massachusetts Institute of Technology Research Reactor, which have been used to treat patients with Boron Neutron Capture Therapy (BNCT). These measurements offer an independent assessment of the dosimetry used at these two facilities, as well as provide information about the radiation quality not obtainable from conventional macrodosimetric techniques. Moreover, they provide a direct measurement of the absorbed dose resulting from the BNC reaction. BNC absorbed doses measured within this study are approximately 15% lower than those estimated using foil activation at both MIT and BNL. Finally, an intercomparison of the characteristics and radiation quality of these two clinical beams is presented. The techniques described here allow an accurate quantitative comparison of the physical absorbed dose as well as a measure of the biological effectiveness of the absorbed dose delivered by different epithermal beams. No statistically significant differences were observed in the predicted RBEs of these two beams. The methodology presented here can help to facilitate the effective sharing of clinical results in an effort to demonstrate the clinical utility of BNCT.

Fission reactor neutron sources for neutron capture therapy--a critical review.

The 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.

A critical examination of the results from the Harvard-MIT NCT program phase I clinical trial of neutron capture therapy for intracranial disease.

A 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 I 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. The 10B 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 of 10B 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.

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.

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.