RADIATION RESEARCH       164, 221–229 (2005)
0033-7587/05 $15.00
   2005 by Radiation Research Society.
All rights of repr...
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                 FIG. 1. Isometric view ...
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elsewhere (5). Small ( 0.1 ml) or low...
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procedures. The equipment available ranges from...
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TECHNICAL ADVANCE                                                                   229

      Therapy (M. F. Hawthorne, K...
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MIT User Center for Neutron Capture Therapy Resarch

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MIT User Center for Neutron Capture Therapy Resarch

  1. 1. RADIATION RESEARCH 164, 221–229 (2005) 0033-7587/05 $15.00 2005 by Radiation Research Society. All rights of reproduction in any form reserved. TECHNICAL ADVANCE The MIT User Center for Neutron Capture Therapy Research Otto K. Harling,a,1 Kent J. Riley,b Peter J. Binns,b Hemant Patelc,2 and Jeffrey A. Coderrea a Department of Nuclear Science and Engineering and b Nuclear Reactor Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; and c Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215 this research in the U.S. and elsewhere. The current status Harling, O. K., Riley, K. J., Binns, P. J., Patel, H. and Cod- of this modality has been reviewed in a recent special vol- erre, J. A. The MIT User Center for Neutron Capture Ther- ume of the Journal of Neuro-Oncology (2). Major progress apy Research. Radiat. Res. 164, 221–229 (2005). has been made on many fronts, including the development Neutron capture therapy (NCT) research encompasses a and construction of high-performance neutron beams (3). wide range of preclinical and clinical studies needed to devel- Although boron delivery compounds have also improved op this promising but complex cancer treatment. Many spe- (4), there is still general agreement that better compounds cialized facilities and capabilities including thermal and epi- with greater selectivity are needed. Improved compounds thermal neutron irradiation facilities, boron analysis, special- are on the critical path to the successful development of ized mixed-field dosimetry, animal care facilities and proto- BNCT, and a coordinated approach is needed to develop cols, cell culture laboratories, and, for human clinical studies, and investigate new capture compounds that can be used licenses and review board approvals are required for NCT to treat various disease sites. The necessary supporting research. Such infrastructure is essential, but much of it is not technologies such as boron analysis (5, 6) and treatment readily available within the community. This is especially true planning (7, 8) are established, and our understanding of for neutron irradiation facilities, which often require signifi- cant development and capital investment too expensive to du- the radiobiology of BNCT (9) has progressed significantly. plicate at each site performing NCT research. To meet this Clinical trials of BNCT were initiated with better-penetrat- need, the NCT group at the Massachusetts Institute of Tech- ing epithermal neutron beams in the mid-1990s (10, 11) nology (MIT) has established a User Center for NCT re- and have continued in the U.S., Japan and several European searchers that is already being accessed successfully by vari- countries. BNCT research and development in all relevant ous groups. This paper describes the facilities, capabilities and areas has become a truly international effort with new re- other resources available at MIT and how the NCT research search and clinical activities in Taiwan, Russia and Argen- community can access them. 2005 by Radiation Research Society tina as well as preliminary studies that have begun in ad- ditional European and Asian countries. Primary brain cancer, glioblastoma multiforme (GBM), INTRODUCTION has been the main target of Phase I/II BNCT clinical studies in the U.S. and Europe. The tolerance of normal brain tissue Neutron capture therapy (NCT) for cancer is an experi- to BNCT irradiations has been determined from these lim- mental tumor cell targeting therapy. This promising but ited studies, and the median survival using p-boronophe- complex radiation therapy requires the administration of tu- nylalanine (BPA) appears comparable to that for conven- mor-seeking compounds, usually containing 10B, that con- tional radiotherapy (10). BNCT has also been studied for centrate preferentially in tumor cells followed by irradiation melanoma metastases in a limited number of intracranial as with suitable neutron beams. well as peripheral subcutaneous cases where local tumor Although research in NCT with boron compounds control was observed (12–15). Recently, liver metastases of (BNCT) has a long history of development since its origi- colo-rectal cancer in two European patients exhibited good nation in the U.S. in the 1950s [see for example Slatkin response to intraoperative BNCT (16). In Japan, brain tu- (1)], the last 15 years have seen a significant expansion of mors have been a major focus of BNCT, with an increasing number of treatments directed at melanoma and head and 1 Address for correspondence: Department of Nuclear Science and En- neck cancers. In all, a few hundred brain tumor patients gineering, Massachusetts Institute of Technology, NW13-200, 138 Al- bany Street, Cambridge, MA 02139; e-mail: oharling@mit.edu. have been treated with BNCT in Japan using either BPA, 2 Present address: Wyeth Pharmaceuticals, Clinical Research/Oncology, sodium borocaptate (BSH) or, in a few cases, a combination 35 Cambridge Park Drive, CPD 3100-2, Cambridge, MA 02140. of these two boron delivery agents. Several long-term sur- 221
  2. 2. 222 TECHNICAL ADVANCE FIG. 1. Isometric view of the MITR with the thermal neutron irradiation facility, M-011, directly beneath the core of the 5 MW research reactor and the epithermal beam facility, FCB, shown on the right-hand side of the figure. vivors with GBM have been observed in the Japanese ex- REACTOR FACILITIES AND CAPABILITIES perience with BNCT (17). Good local control was observed Thermal Neutron Irradiation Facility in a few recently treated head and neck cancers (18, 19). Further advancement in the clinical application of BNCT Low-energy (thermal) neutron beams are necessary for requires new, more selective boron delivery agents, many preclinical studies with small animals or cell cultures and of which are currently available but must undergo extensive for clinical irradiations of shallow malignancies. The re- testing in animal experiments before they can be considered cently upgraded and renovated thermal neutron irradiation for testing in clinical trials. facility located beneath the core of the MITR is shown on A wide range of research facilities and interdisciplinary the lower left portion of Fig. 1. capabilities are required for the development of BNCT as Source neutrons for the thermal neutron beam, known as a clinically useful therapy. Some facilities, in particular the the M-011 beam, originate in the D2O reflector/moderator neutron irradiation facilities, needed for preclinical and below the core of the MITR. These neutrons reach thermal clinical research require significant capital investments and equilibrium with the moderator before they enter the ver- are available at very few sites. Currently the only U.S. site tical beam line and have an energy spectrum optimal for with high-performance epithermal and thermal neutron ir- NCT irradiations of targets up to approximately 3.5 cm radiation facilities suitable for preclinical and clinical stud- deep in tissue. The thermal neutrons are collimated by the ies is located at the Massachusetts Institute of Technology reactor-grade graphite walls of the vertical beam line that Research Reactor (MITR). The 5 MW MITR operates with minimize intensity loss by elastically scattering many neu- a high capacity factor, 24 h per day, 250–300 days per year. trons back into the main beam that would otherwise be lost. These specialized neutron facilities, along with a variety of Three separate shutters, water, Boral (boron carbide in an supporting technologies and capabilities, were developed to aluminum honeycomb), and lead plus borated polyethylene, support preclinical and clinical NCT programs for MIT re- are located upstream of the beam aperture in the medical searchers and their medical collaborators. Recently it has room and are used to control the beam during irradiations. become possible, with the support of the U.S. Department Irradiations are monitored by four similar fission coun- of Energy, to make this unique suite of facilities and ca- ters located at the edge of the beam and spaced at 90 pabilities available to non-MIT researchers. In this paper intervals. Their outputs are sent to industrial-quality pro- we describe the resources available, the level of support grammable logic controllers (PLCs). The four detectors that can be provided currently, and how interested users monitor not only beam intensity but also symmetry during can access the NCT User Center. irradiation. This provides an overall system check of beam
  3. 3. TECHNICAL ADVANCE 223 TABLE 1 In-Air Measurements of Thermal Neutron Flux as well as Fast-Neutron and Photon Dose Components in the M-011 Thermal Neutron Beam at the Position Used for Small- Animal or Cell Culture Irradiations Thermal flux Fast-neutron dose Photon dose rate Specific fast-neutron Specific photon dose (109 n cm 2 s 1) rate (mGy min 1) (mGy min 1) dose (10 13 Gy cm2) (10 13 Gy cm2) 5.9 0.3 20 188 10 0.5 5.3 0.4 Notes. The absorbed doses per neutron per cm2 or specific doses are also provided. Reactor power is 5 MW. stability. The beam monitoring, control and safety systems To account for these variables, irradiations are administered use redundant monitors, signal processing, electronic cir- by programming the automated control system with beam cuits, and PLCs to permit safe continuation of irradiations monitor counts that are determined separately for each ex- should any individual component fail. The PLCs log essen- periment through prior calibration. tial data and control shutter opening and closing to ensure When patients or large animals are to be irradiated in the that neutron fluences (doses) are delivered to within 1% of thermal beam, they are positioned on a couch that is raised target. Safety interlocks to protect the staff and patients are hydraulically toward the ceiling where a collimator is also monitored continuously by the PLCs. A PC with a mounted beneath the lowest shutter. The size and shape of large-screen monitor is used for online display of the status this patient collimator aperture can be changed readily. Cur- of the irradiation and for record keeping but does not con- rently two circular collimator apertures are available with trol the irradiations. This important function is assigned ex- diameters of 8 and 12 cm. Beam intensities for patient or clusively to the redundant PLCs. All important systems large animal irradiations are lower than those for small an- have back-up power from an uninterruptible power supply imals irradiated in the shielding box. Nevertheless, with (UPS). Manual controls, located on the M-011 operator’s compounds such as BPA, therapeutic doses for superficial console, can override the automated functions of the PLCs melanoma can be delivered in less than 10 min with a sin- at any time to close shutters or, if necessary, scram the gle field. reactor. The M-011 beam has been fully characterized using the Irradiations using the M-011 beam are performed in a procedures routinely employed for mixed-field dosimetry well-shielded irradiation room (shown in Fig. 1). Experi- at MIT (20). Table 1 provides in-air measurements of the ments or patients can be viewed during an irradiation thermal neutron flux as well as photon and fast-neutron through a shielded window and with closed-circuit televi- dose rates at the position typically used for small-animal or sion. Background dose rates with all shutters closed are low cell culture irradiations. The high thermal neutron flux of enough to allow staff to enter and work in the irradiation 5.9 109 n cm 2 s 1 combined with the low photon and room even with the reactor operating at full power. A negligible fast-neutron contamination is indicative of the shielding box constructed of lithiated polyethylene is po- excellent performance of the beam for preclinical cell cul- sitioned in the neutron beam to perform small-animal or ture and animal studies as well as clinical trials of BNCT cell culture irradiations. Small animals are shielded by a for superficial melanoma. As an example, the biologically 2.5-cm-thick lithiated polyethylene lid that covers most of weighted dose [Gy(w); see ref. (9) for a discussion of the animals and contains an aperture of the desired size and BNCT weighting factors] as a function of depth with BPA shape, depending on the application. A variety of sites can is shown in Fig. 2. Measurements were performed along be irradiated with a rectangular aperture of 2 cm 14 cm the central axis of an ellipsoidal water-filled phantom (21) where, for example, two rats can be positioned side by side using the 12-cm beam aperture to approximate conditions for brain tumor irradiations or four mice can be positioned during therapy. The individual dose components are plotted for irradiation of subcutaneous tumors on the legs. Cell as points and the total tumor and tissue doses are fitted with culture irradiations do not require a shielding lid because a least-squares polynomial to help guide the eye. The fast- the largest possible beam aperture is used to irradiate the neutron and photon components were measured using cultures uniformly. Phantoms, ionization chambers, and paired ionization chambers, while the 10B(n, )7Li and gold foils can also be mounted in the irradiation box to 14 N(n,p)14C doses are determined from the measured ther- determine dose rates from thermal neutrons, rays and fast mal neutron flux using kerma coefficients of 8.66 10 8 neutrons. The box is inserted into a recess in the borated and 7.88 10 12 Gy cm , respectively. A boron concen- 2 polyethylene shutter that accurately positions the animals tration of 18 g g 1, which has been observed in preclinical or cells in the beam line when the shutter is opened. Irra- and clinical research, is used (22) together with a tissue diation times vary between approximately 5 and 25 min nitrogen concentration of 3.5% in muscle and skin. A boron depending on the dose required to achieve the desired ra- concentration of 65 g g 1 is assumed for tumor. A weight- diation response as well as experimental conditions such as ing factor of 3.8 is applied for the boron capture reaction geometry, boron concentration and reactor operating power. in tumor and normal tissues. Normal tissue dose is domi-
  4. 4. 224 TECHNICAL ADVANCE cannot sustain the fission chain reaction by itself. Thermal neutrons from the MITR-II are absorbed in the FCB fuel and, in essence, are converted to higher-energy fission neu- trons. The fission neutrons originating in the converter are filtered and moderated by aluminum, polytetrafluoroethyl- ene (Teflon ) and cadmium. Undesired photons are atten- uated with a lead shield. The resulting large-area epithermal neutron beam is directed toward the patient irradiation po- sition by a lead-lined collimator. A final or patient colli- mator protrudes into the well-shielded medical irradiation room and features easily variable apertures 8 to 16 cm in diameter. Apertures of different size or shape can easily be implemented if required. The patient collimator with vari- able aperture sizes and its extension into the medical room allow easy positioning of patients for placement of the ra- FIG. 2. The weighted dose–depth distribution in the M-011 thermal diation field anywhere on the body. The right side of Fig. neutron beam measured along the central axis of a water-filled ellipsoidal 1 provides an overall view of the FCB facility including phantom for the 12-cm aperture using boron concentrations and weighting the shielded medical irradiation room. The irradiation room factors representative of BPA as an example for treating superficial tu- has sufficient space for a gurney and positioning couch. mors such as subcutaneous melanoma. Fast-neutron dose rates are neg- Patient observation during irradiations is facilitated by a ligible and therefore are not plotted. large shielded glass window and closed-circuit television monitors. Two-way audio communication is also available nated by the 10B(n, )7Li reaction due to the relatively high between the patient and clinical staff. Laser projections il- concentration of boron. Photons and thermal neutron cap- luminate the central axis of the beam from both sides of ture reactions in tissue nitrogen also produce some adven- the patient to help with positioning and optics that penetrate titious dose to normal tissue. However, the fast-neutron the wall of the collimator provide the clinical staff a beam’s dose component in this high-purity beam is so low, even eye view of field placement. at its expected maximum near the surface, that it has neg- Three shutters control the FCB. A beam monitoring and ligible influence on the total normal tissue dose. The useful control system similar to that described previously for the penetration or advantage depth (AD) and the maximum M-011 thermal beam is used to automatically open and normal tissue (skin or muscle) dose rate (or ADDR) shown close the three beam shutters: a thermal neutron absorbing in Fig. 2 are respectively 3.5 cm and 2.4 Gy(w) min 1. Skin shutter on the reactor side of the fission converter, a large tolerance doses of approximately 12 Gy(w) can be reached water shutter in the lead collimator, and a fast-acting lead in 5 min, and a therapeutic ratio greater than unity would and boronated heavy concrete shutter close to the patient be achieved at depths up to the AD. A well-benchmarked collimator. Neutron fluences are calibrated against mea- Monte Carlo model of the MITR-II core and M-011 beam surements and treatment planning calculations of the ab- line has also been developed. This model allows the ac- sorbed dose and are routinely delivered to within 1% of the curate calculation of flux and absorbed doses for any con- prescribed target using this system. ceivable experimental study including clinical trials. Table 2 provides the in-air epithermal neutron flux and The MIT thermal neutron irradiation facility with its dose rates from photon and fast-neutron radiation in the high-intensity, low-background beam and automated con- beam. The epithermal flux of 3.2 4.6 109 n cm 2 s 1, trol systems is well suited for research in BNCT. Small- depending on final collimation, is currently the highest animal and cell culture irradiations can easily be performed available of any epithermal neutron beam used for BNCT in the facility, and clinical studies for shallow tumors can (23). If desired, higher intensity can be obtained by opti- also be fully supported. mizing converter fuel loading and/or increasing reactor power without affecting the excellent beam characteristics. Epithermal Neutron Irradiation Facility Specific beam contamination from photons and neutrons is also provided in Table 2. The contamination levels in the MIT operates a state-of-the-art high-intensity, low-back- FCB are very low and have a minimal influence on clinical ground epithermal neutron (0.5 eV En 10 keV) irra- beam performance. The performance of the FCB is illus- diation facility known as the fission converter beam (FCB). trated by the example shown in Fig. 3, where the various The FCB is the first epithermal neutron irradiation facility dose–depth distributions in a water-filled ellipsoidal head to use a subcritical fission converter as a neutron source for phantom are plotted as points and a least-squares polyno- NCT. Details concerning the design, construction and per- mial is fitted to the total tumor and tissue doses to guide formance of the FCB are provided elsewhere (23, 24). The the eye (24). Tumor and normal brain (blood) concentra- neutron source is a heavy water-cooled 235U fuel source that tions as well as the applied weighting factors are consistent
  5. 5. TECHNICAL ADVANCE 225 TABLE 2 In-Air Measurements of the Epithermal Flux as well as Fast-Neutron and Photon Dose Rates in the FCB at the Patient Position with Several Different Collimators (24) Fast-neutron Specific Aperture Epithermal flux dose rate Photon dose rate fast-neutron dose Specific photon diameter (cm) (109 n cm 2 s 1) (mGy min 1) (mGy min 1) (10 13 Gy cm2) dose (10 13 Gy cm2) 16 4.6 0.6 38 4 97 4 1.4 0.2 3.5 0.5 12 4.3 0.6 36 4 94 4 1.4 0.2 3.6 0.5 10 3.4 0.4 34 4 90 4 1.7 0.3 4.4 0.6 8 3.2 0.4 34 4 74 3 1.8 0.3 3.9 0.5 Notes. Specific doses are also provided. Reactor power is 5 MW and the converter power is 83 kW. with those observed with the BPA capture compound (9, large animal irradiations where deep penetration to the can- 22) and are the same as those used for the thermal neutron cer site is required. beam in Fig. 2 except that a nitrogen concentration of 2.2% is applied for brain and a weighting factor of 1.3 is used Boron Analysis instead of 3.8 to account for the microdistribution of boron that accumulates in normal brain (9). The useful penetration Nondestructive analysis of biological samples for the 10B (10) using the 12-cm aperture is 9.3 cm. This is adequate isotope is carried out using a prompt -ray neutron acti- for treating the deepest locations in an average-sized human vation analysis (PGNAA) system at the MIT Research Re- brain. The peak dose rate to normal tissue is 1.25 Gy(w) actor, shown schematically in Fig. 4. Typical samples con- min 1, which means that a peak normal tissue dose of 12 sist of blood or tissue with volumes of 0.1 to 10 ml. No Gy(w) can be delivered in 9.6 min with a single beam special sample preparation is required, and the high sensi- placement. Assuming a homogeneous distribution of boron, tivity of the MIT prompt -ray system, 18 counts s 1 g 1 the tumor dose in this example is expected to vary from a 10 B, allows rapid analysis, usually in several minutes for 2 peak of 77 down to 12 Gy(w) at the maximum useful depth. g or more of 10B. A holder designed for 1- or 10-ml Teflon A 6Li filter has been constructed to further increase the vials is used to position samples for analysis in the neutron useful beam penetration by approximately 6 mm with the beam and can easily be adjusted to accommodate samples BPA compound. An increase in converter power by 30– of different size or shape. A dedicated computer worksta- 50% is planned in the near future that will help compensate tion is used for acquiring, analyzing and storing data as for the intensity loss with the filter inserted for an irradia- well as for printing results. The PGNAA facility is in the tion. main experimental hall of the MITR and is convenient to The intensity of the FCB is currently the highest avail- both the thermal and epithermal neutron beams so that bo- able of any epithermal neutron source and, in conjunction ron concentrations can be measured concurrently with the with high beam purity, is well suited for clinical trials or use of these facilities. PGNAA results can be readily in- corporated into animal experiments or patient irradiations to adjust beam delivery and precisely administer the desired (or prescribed) dose from capture in boron. Detailed infor- mation concerning the prompt -ray system is available FIG. 3. The weighted depth–dose distribution in the FCB measured along the central axis of a water-filled ellipsoidal phantom for the 12- cm-diameter aperture using boron concentrations and weighting factors representative of BPA as an example for treating deep-seated brain tu- FIG. 4. Schematic plane view of the prompt -ray activation analysis mors. system located in the main reactor hall.
  6. 6. 226 TECHNICAL ADVANCE elsewhere (5). Small ( 0.1 ml) or low-concentration ( 0.5 g g 1) samples can be analyzed using the complementary technique of ICP-AES. This destructive analysis system is available at the laboratory but requires samples in liquid, particulate-free solution and is capable of measuring bulk boron concentrations as low as 20 ng g 1. Microscopic Imaging of 10B in Tissue MIT, in collaboration with scientists from New England Medical Center and the Beth Israel Deaconess Medical Center, developed a technique for imaging the boron mi- crodistribution superimposed on the corresponding cell morphology (25).3 High-resolution quantitative autoradi- ography (HRQAR) has a spatial resolution of nearly 2 m and a sensitivity for 10B of approximately 0.1 g g 1. HRQAR can be applied to frozen tissue sections (2–4 m thick) that have been stained to reveal cellular structures. Figure 5 is an HRQAR image of rat skin with black su- perimposed tracks indicating the location of boron atoms. Though labor-intensive, this technique can be very useful for evaluating the radiobiological effects arising from dif- ferent boron compounds at disease sites where tumor re- sponse to BNCT is mediated by parenchymal cells. Dedi- cated resources and procedures are being developed so that NCT center users can use this analytical technique in their own research. Further details concerning HRQAR can be found elsewhere.3 OTHER AVAILABLE SUPPORT Animal Experiment Facilities The User Center can assist experimenters with animal studies. Approvals and housing. All animal research must adhere to local and federal guidelines and legal mandates regarding the use, care and maintenance of laboratory animals (26– 28). These encompass both biological and radiation safety issues. The Division of Comparative Medicine (DCM) at MIT authorizes all animal experimentation protocols. Pro- tocols and procedures that are already approved within the user’s establishment can be adapted for use at MIT, or new protocols can be written specifically for the planned exper- FIG. 5. HRQAR autoradiogram showing tracks from thermal neutron iments. These procedures can be complicated when animals capture reactions with boron in tissue. From the microscopic image anal- arrive from outside institutions and require the use of quar- ysis of this sectioned rat skin, the boron concentrations in the epidermis, antine facilities. The staff within the User Center are avail- dermis and subdermal muscle were measured at 20 g g 1 while the hair able to assist all outside users in obtaining the appropriate bulb measured 60 g g 1. permissions necessary for their particular experiments as well as ensuring that their animals can be housed at the can also be made for receiving animals or transporting an- MIT facilities for the duration of the irradiations. The User imals to and from the user’s laboratory. This is a major Center will ensure that the appropriate housing and care advantage since it means that an outside user does not have staff are available for the duration of the stay and arrange to be present at MIT in advance of the animals’ arrival. for appropriate radiation safety monitoring. Arrangements Surgical facilities for animal experiments. Arrangements 3 W. S. Kiger III, Developments in micro and macro-dosimetry of neu- can also be made for the user to perform certain surgical tron capture therapy, Part I. Ph.D. Thesis, Massachusetts Institute of Tech- procedures at MIT when necessary. Specially equipped and nology, Cambridge, MA, 2000. approved laboratories are available for all aseptic surgical
  7. 7. TECHNICAL ADVANCE 227 procedures. The equipment available ranges from consum- valuable not only in meeting all regulatory, ethical and le- ables such as sterile needles and syringes to closed-circuit gal requirements for clinical studies but also in providing inhalation anesthesia. The User Center can also provide ex- advice and guidance on aspects of clinical studies to pert assistance with in vivo research. Available staff are achieve the desired results. User Center staff serve as the skilled in a broad range of procedures such as vessel can- interface between the outside users and the MIT IRBs. Due nulation, tumor induction, stereotactic CNS injections, dis- to the high level of involvement required of the User Center section and physiological experiments. This is particularly staff in any clinical studies, such studies are usually carried useful for those users who have no previous experience in out as formal collaborations between the MIT NCT staff or capability for animal research within their own institu- and the outside users. tion. Thus the User Center is able to ease the burden of the regulatory aspects as well as the practical considerations Licenses for Clinical Use of MIT Neutron Beams for any outside user wanting to carry out NCT-related an- The epithermal neutron irradiation facility described in imal studies. this paper is fully licensed for use in human irradiations, and the thermal beam facility can be so licensed if desired. Cell Culture Laboratory Detailed procedures for the conduct of human BNCT have A fully equipped cell culture laboratory is located in the been developed and approved by the U.S. Nuclear Regu- building directly adjacent to the MITR and is available to latory Commission and are part of the MITR’s Technical outside users with staff and expertise in cell culture pro- Specifications. These procedures are carefully followed to cedures. Alternatively, the MIT BNCT User Center is de- ensure the safety of patients and staff. veloping the ability to screen new boron compounds sub- mitted by outside chemists. In the past, the evaluation of Present Studies new boron compounds has been largely informal, with no The NCT research community is using the facilities, ca- fixed methodology for intercomparison of results for dif- pabilities and other support outlined above with over a doz- ferent compounds. A more formal compound-screening en experiments proposed or in progress by scientists from program has been established that evaluates compounds in universities, industry and national laboratories. These stud- vitro and then, if warranted, in vivo. The objectives are to ies are evaluating new compounds, novel delivery methods, identify improved boron compounds for BNCT of glio- and radiobiology to advance NCT toward an accepted clin- blastoma or metastatic tumors in the brain and to identify ical modality. To date, 14 different experiments involving new boron compounds suitable for BNCT of other possible nine outside users have successfully used the collaborative tumor sites. Procedures have been developed to evaluate support of the in-house research staff, irradiation facilities, the in vitro toxicity of new boron compounds in the pres- and MIT university infrastructure to conduct in vivo exper- ence and absence of neutron irradiation that minimize the iments. Table 3 summarizes this research. Several in vitro amount of test compound required. experiments are planned once various cell culture tech- A Philips RT250 X-ray unit is also available for photon niques have been fully optimized to allow their efficient control irradiations of cells or small animals. The dose rate use for the evaluation of trial compounds. The satisfactory can be varied from approximately 0.1 to 2.0 Gy min 1. This completion of these experiments has demonstrated the suc- unit is located only a short distance from the cell culture cess of the MIT NCT User Center in supporting scientists laboratory. from all parts of the country and the experiences gained are enabling the center to evolve and further adapt to the IRB Oversight for Human Studies practical needs of the NCT research community. Three internal review boards, or IRBs, have oversight responsibilities for human experiments at MIT. While it is SUMMARY OF CAPABILITIES AND ACCESS MIT’s policy that clinical aspects of human studies that TO USER CENTER may be performed at MIT are the responsibility of non- The available funding currently allows the MIT NCT MIT clinicians, these IRBs must review and authorize all User Center to provide the following: such studies. The first of these review boards is the MITR Reactor Safeguards Committee (RSC), which is concerned 1. Thermal and epithermal neutron irradiations. primarily with physical safety. The other two review boards 2. Physical and computational dosimetry associated with are the Committee on Radiation Experiments with Human irradiation experiments and clinical studies. Subjects (COREHS) and the Committee on Use of Humans 3. Analyses of 10B in tissue samples. as Experimental Subjects (COUHES). These committees 4. Use of surgical facilities for small-animal surgery. approve documents such as the experimental protocol and 5. Use of a cell culture laboratory. the patient’s consent form and require regular reporting of 6. Access to the MIT animal care facilities. progress in trials, principal findings, and adverse events. 7. Assistance with the design of animal and cell culture The broad-ranging expertise in the MIT IRBs has proven experiments as well as clinical trials.
  8. 8. 228 TECHNICAL ADVANCE TABLE 3 Summary of Research Performed Using the MIT NCT User Center Facility Tumor/cell line Animal Purpose Non-MIT experiments PGNAA — — Boron concentration assay of new compounds Thermal beam F98 glioma Rats Evaluating efficacy of convection-enhanced delivery and various compounds Thermal beam L929 TK /TK — In vitro compound assay Thermal beam F98 glioma Rats Evaluating efficacy of BNCT combined with gene-medi- ated immunoprophylaxis Thermal beam EMT-6 Mice Evaluating efficacy of porphyrin-based compounds PGNAA T cells — Evaluating boron uptake in immunological cells PGNAA FaDu Mice Biodistribution study of new compound HRQAR F98 glioma Rats Analysis of boron microdistribution Epithermal beam — — International dosimetry exchange MIT experiments Thermal beam — Rats Evaluating radiosensitivity of rat lung to NCT irradia- tions Epithermal beam and PGNAA — Mice Investigating mechanisms mediating the GI syndrome HRQAR Various tissues — HRQAR development Clinical trials Epithermal beam GBM and intracranial melanoma Humans Phase I tolerance study Epithermal beam Subcutaneous melanoma Humans Phase II dose–response study 8. IRB oversight for clinical studies. REFERENCES 9. In the future, we expect to be able to perform micro- 1. D. N. Slatkin, A history of boron neutron capture therapy for brain scopic imaging of boron by HRQAR. This would in- tumors. Neurosurgery 44, 443–450 (1999). clude computer-based radiobiological analysis of the 2. R. F. Barth, Guest Ed., Boron neutron capture therapy: A critical measured boron distribution. assessment. J. Neuro-Oncol. 62, 1–219 (2003). 3. O. K. Harling and K. J. Riley, Fission reactor neutron sources for neutron capture therapy—a critical review. J. Neuro-Oncol. 62, 7– Users should be aware that funds and labor resources for 17 (2003). the MIT NCT User Center are limited and are subject to 4. M. F. Hawthorne and M. W. Lee, A critical assessment of boron target annual renewal. However, the User Center is committed to compounds for boron neutron capture therapy. J. Neuro-Oncol. 62, making every effort within these constraints to assist NCT 33–45 (2003). researchers by expediting important studies through the use 5. K. J. Riley and O. K. Harling, An improved prompt gamma neutron activation analysis facility using a focused diffracted beam. Nucl. of the facilities and capabilities described in this paper. Po- Instrum. Methods B 143, 414–421 (1998). tential users are invited to contact the responsible MIT 6. W. Bauer, P. L. Micca and B. M. White, A rapid method for the direct staff1,4 for general information and to schedule use of the analysis of boron in whole blood by atomic emission spectroscopy. NCT User Center research facilities and capabilities. In Advances in Neutron Capture Therapy (A. H. Soloway, R. F. Barth and D. E. Carpenter, Eds.), pp. 403–407. Plenum Press, New York, 1993. ACKNOWLEDGMENTS 7. R. G. Zamenhof, E. Redmond, II, G. R. Solares, D. Katz, K. J. Riley, W. S. Kiger and O. K. Harling, Monte-Carlo based treatment plan- ning for boron neutron capture therapy using custom designed mod- Support for the MIT NCT User Center has been provided by the U.S. els automatically generated from CT data. Int. J. Radiat. Oncol. Biol. Department of Energy through the new program ‘‘Innovations in Nuclear Phys. 35, 383–397 (1996). Infrastructure and Education’’, Office of Nuclear Energy, Science and 8. D. W. Nigg, Computational dosimetry and treatment planning con- Technology (contract no. DE-FG07-02ID14420) as well as the Office of siderations for neutron capture therapy. J. Neuro-Oncol. 62, 75–86 Biological and Environmental Research (contract no. DE-FG02- (2003). 02ER63358). The Massachusetts Institute of Technology provides the 9. J. A. Coderre and G. M. Morris, The radiation biology of boron bulk of the support needed to operate the MIT Reactor. The authors thank neutron capture therapy. Radiat. Res. 151, 1–18 (1999). Dr. W. S. Kiger III for providing the HRQAR image shown in Fig. 5 and 10. A. D. Chanana, J. Capala, M. Chada, J. A. Coderre, A. Z. Diaz, Jingli Kiger for assistance in designing the animal shielding box used in E. H. Elowitz, J. Iwai, D. D. Joel, H. B. Liu and L. Wielopolski, the thermal neutron beam. Boron neutron capture therapy for glioblastoma multiforme: interim results from the Phase I/II dose-escalation studies. Neurosurgery 44, Received: June 16, 2004; accepted: March 29, 2005 1182–1193 (1999). 11. P. M. Busse, R. G. Zamenhof, O. K. Harling, I. Kaplan, J. Kaplan, C. F. Chuang, J. T. Goorley, W. S. Kiger, K. J. Riley and M. R. 4 Additional contacts: P. J. Binns, binns@mit.edu, 617-253-2099; K. J. Palmer, The Harvard-MIT BNCT Program: Overview of the clinical Riley, flavor@mit.edu, 617-258-5938. trials and translational research. In Frontiers in Neutron Capture
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